Note: Descriptions are shown in the official language in which they were submitted.
WO 2015/184003
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OSTEOCLAST INHIBITORS FOR PAIN
SUMMARY
[0001]
Bisphosphonate compounds are potent inhibitors of osteoclast
activity, and are used clinically to treat bone-related conditions such as
osteoporosis
and Paget's disease of bone; and cancer-related conditions including multiple
myeloma, and bone metastases from solid tumors. They generally have low oral
bioavailability.
[0002] Patchy osteoporosis and bone marrow edema may result from
osteoclast hyperactivity. Zoledronic acid is a potent inhibitor of bone
resorption and
osteoclast activity. Nitrogen containing bisphosphonates, such as zoledronic
acid,
also inhibit the mevalonate pathway in the osteoclast thereby interrupting
normal
osteoclast function.
[0003] It has
been discovered that oral dosage forms of bisphosphonate
compounds, such as zoledronic acid, can be used to treat or alleviate pain or
related
conditions.
[0004] Some embodiments include a method of enhancing the oral
bioavailability of zoledronic acid comprising orally administering a dosage
form
containing zoledronic acid in the disodium salt form.
[0005] Some
embodiments include a dosage form comprising zoledronic
acid in the disodium salt form, wherein the bioavailability, in a mammal, of
zoledronic
acid in the disodium salt form is greater than the bioavailability of
zoledronic acid in
the diacid form would be in the same dosage form.
[0006] Some
embodiments include a dosage form comprising zoledronic
acid, wherein the dosage form contains an amount of zoledronic acid in the
disodium
salt form that provides an area under the plasma concentration curve of
zoledronic
acid of about 4 ng=h/mL to about 2000 ng=h/mL to a human being to which the
dosage form is administered.
[0007] Some
embodiments include a dosage form comprising zoledronic
acid in the disodium salt form, wherein the disodium salt form is present in a
lower
molar amount than would be present if the zoledronic acid were in the diacid
form;
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and wherein the zoledronic acid in the disodium salt form has an improved
bioavailability as compared to the zoledronic acid in the diacid form to the
extent that
the lower molar amount of the disodium salt in the dosage form does not reduce
the
amount of zoledronic acid delivered to the plasma of a mammal.
[0008] Although
an oral dosage form with enhanced bioavailability with
respect to the bisphosphonate compound can be used, the treatment can also be
effective using an oral dosage form that includes a bisphosphonate compound,
such
as zoledronic acid, wherein the bioavailability of the bisphosphonate is
unenhanced,
or is substantially unenhanced.
[0009] Some
embodiments include a method of relieving inflammatory pain
comprising administering an oral dosage form containing zoledronic acid to a
mammal in need thereof, wherein the mammal experiences significant pain relief
more than 3 hours after administration of the dosage form.
[0010] Some
embodiments include a method of relieving pain associated
with an arthritis comprising administering an oral dosage form containing
zoledronic
acid to a human being in need thereof.
[0011] Some
embodiments include a method of treating complex regional
pain syndrome comprising administering an oral dosage form containing
zoledronic
acid to a mammal in need thereof.
[0012] Some
embodiments include an oral dosage form comprising
zoledronic acid, wherein the oral bioavailability of zoledronic acid is
substantially
unenhanced. For example, in some embodiments, the oral bioavailability in the
dosage form is about 0.01% to about 4%.
[0013] Some
embodiments include a pharmaceutical product comprising
more than one unit of an oral dosage form described herein. In some
embodiments,
each unit of the oral dosage form contains about 1 mg to about 50 mg of
zoledronic
acid.
[0014] Some
embodiments include a method of relieving inflammatory pain
comprising administering an oral dosage form containing zoledronic acid to a
mammal in need thereof.
[0015] In some
embodiments, the mammal receives a total monthly dose
of zoledronic acid that is about 800 mg/m2 or less.
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[0016] In some
embodiments, the dosage form contains about 10 mg/m2 to
about 20 mg/m2 based upon the body surface area of the mammal.
[0017] Some
embodiments include a method of relieving inflammatory pain
comprising orally administering zoledronic acid to a mammal in need thereof.
[0018] In some
embodiments, about 300 mg/m2 to about 600 mg/m2 of
zoledronic acid is administered per month, based upon the body surface area of
the
mammal.
[0019] In some
embodiments, about 50 mg/m2 to about 600 mg/m2 of
zoledronic acid is administered per month, based upon the body surface area of
the
mammal.
BRIEF DESCRIPTION OF DRAWINGS
[0020] FIG. us a
plot of pain compression thresholds in a rat model of
inflammatory pain using three different doses of zoledronic acid. Measurements
were taken at baseline (BL) and at various time points after dosing on the
days
indicated.
[0021] FIG. 2A is
a graph depicting reversal of arthritis pain for two
different doses of zoledronic acid in a rat model of arthritis pain.
[0022] FIG. 2B is
a graph depicting pain thresholds for two different doses
of zoledronic acid in a rat model of arthritis pain.
[0023] FIG. 3 is
a graph summarizing the results for vehicle and zoledronic
acid treated rats in a rat model of complex regional pain syndrome.
[0024] FIG. 4
depicts hindpaw pain thresholds for vehicle and zoledronic
acid treated rats in a rat model of complex regional pain syndrome.
[0025] FIG. 5
depicts weight bearing for vehicle and zoledronic acid
treated rats in a rat model of complex regional pain syndrome.
[0026] FIG. 6
depicts paw thickness change for vehicle and zoledronic acid
treated rats in a rat model of complex regional pain syndrome.
[0027] FIG. 7
depicts the aqueous solubility of disodium zoledronate
tetrahydrate as compared to the diacid form of zoledronic acid.
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[0028] FIG. 8
depicts the plasma concentration of zoledronic acid in dogs
over time after administration of 150 mg of the disodium salt form of
zoledronic acid
and the diacid form of zoledronic acid.
[0029] FIG. 9
depicts the compressibility of dosage forms containing
zoledronic acid in the disodium salt form as compared to the diacid form.
[0030] FIG. 10
depicts the change in VAS pain score compared to placebo
at three months with zoledronic acid treatment in patients with osteoarthritis
of the
knee, bone marrow lesions, and different degrees of joint space narrowing.
[0031] FIG. 11
depicts the change in VAS pain score compared to baseline
at three months with zoledronic acid treatment in patients with osteoarthritis
of the
knee, bone marrow lesions, and different degrees of joint space narrowing.
[0032] FIG. 12
depicts the change in VAS pain score compared to placebo
at three months with zoledronic acid treatment in different subgroups of
patients with
osteoarthritis of the knee and bone marrow lesions.
[0033] FIG. 13
depicts the change in BML lesion size compared to placebo
at six months with zoledronic acid treatment in patients with osteoarthritis
of the
knee, bone marrow lesions, and different degrees of joint space narrowing.
DETAILED DESCRIPTION
[0034] Inhibitors
of osteoclast activity include bisphosphonate compounds
such as pamidronate or pamidronic acid, neridronate or neridronic acid,
olpadronate
or olpadronic acid, alendronate or alendronic acid, incadronate or incadronic
acid,
ibandronate or ibandronic acid, risedronate or risedronic acid, cimadronate or
cimadronic acid, zoledronate or zoledronic acid, etidronate or etidronic acid,
clodronate or clodronic acid, tiludronate or tiludronic acid, etc.
[0035] RANK/RANKL
antagonists may be inhibitors of osteoclast activity.
RANK/RANKL antagonists include but are not limited to OPG (osteoprotegerin) or
a
variant thereof, an anti-RANKL antibody such as denosumab, a monoclonal anti-
RANKL antibody, a small interfering RNA, a microRNA, a precursor molecule, a
ribozyme, an antisense nucleic acid, or an aptamer targeting RANKL. Antibodies
such as AB-25E9, small molecules, small interfering RNAs, microRNAs, precursor
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molecules, ribozymes, antisense nucleic acids, or aptamers that target the
cell-
surface protein Siglec-15 may be osteoclast inhibitors.
[0036] Some
Bruton's tyrosine kinase (BTK) inhibitors may be inhibitors of
osteoclast activity. BTK
inhibitors can include ONO-4059; ibrutinib; Benzo[b]
thiophene-2-carboxamide, N4346-[[4-[(2R)-1,4-dimethyl-3-oxo-2-
piperazinyl]phenyl]
amino]-4,5-dihydro-4-methy1-5-oxo-2-pyraziny1]-2-methylpheny1]-4,5,6,7-
tetrahydro-
(GDC-0834); RN-486; Benzamide, 4-(1,1-dimethylethyl)-N4348-(phenylamino)
imidazo[1,2-a]pyrazin-6-yl]phenylF (CG 1-560); Benzamide, N-[344,5-dihydro-4-
methy1-61[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxo-2-pyraziny1]-2-
methylpheny1]-4-(1,1-dimethylethyl)- (CGI-1746CAS Registry No. 910232-84-7);
HM-
71224; 2-Propenamide, N-[31[5-fluoro-21[4-(2-methoxyethoxy)phenynamino]-4-
pyrimidinyl]aminolpheny1]- (CC-292, CAS Registry No. 1202757-89-8); 2-
Pyridinecarboxamide, 4444[5-fluoro-44[3-[(1-oxo-2-propen-1-
yl)amino]phenyl]amino]
-2-pyrimidinyllamino]phenoxy]-N-methyl- (CNX-774, CAS Registry No. 1202759-32-
7), AVL-101 (CAS Registry No. 1552307-34-2), AVL-291 (CAS Registry No.
1552307-35-3), and AVL-292 (CAS Registry No. 1552307-36-4), [N-(2-chloro-6-
methylpheny1)-2-(6-(4-(2-hydroxyethyl) pi perazi
n-1-y1)-2-methyl pyri midi n-4-
ylamino)thiazole-5-carboxamide] (dasatinib), alpha-cyano-beta-hydroxy-beta-
methyl-
N-(2,5-bromophenyl) propenamide (LFM-A13), and ONO-WG-307.
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0 Br
O
0 OH
Br N
H
N
1
\ N
,N
/ LFM-A13
NH2
0
lbrutinib
/\
N N
0
1 \
S HN 40
= 0
/ N
/ NH
7 _____________________________________ \
\O
GDC-0834
N 0
H
N1,,. 1N,,, zS.,,,r,,,,N 0110
NNN / H
N _________________________________________________________ CI
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Dasatinib
41111
HN
N-)
0
CG1-560
0
0
CG1-1746
0 0
N.%**N
CC-292
0
0
CNX-774
[0037] Inhibitors
of osteoclast activity may be used for a number of medical
purposes, such as treatment of undesirable conditions or diseases, including
pain
relief. This may be accomplished in many instances by administration of oral
dosage
forms. Generally, an oral dosage form comprising a bisphosphonate such as
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zoledronic acid is administered orally to a mammal, such as a human being, at
least
once, to treat a disease or condition, or to relieve pain.
[0038] The following compounds may also be osteoclast inhibitors:
_ _+
0 _ PO3H2
HO
3õ........s...,õ /\
N NP03H2
OH
¨ Compound 1 _
_ ¨+
PO3H2
P03H2 /...._\ .....,.....ek.
H203P...õ
4,,, N .õ,N/... PO3H2
OH
HO
_ _
Compound 2
[0039] The term "treating" or "treatment" broadly includes any kind of
treatment activity, including the diagnosis, cure, mitigation, or prevention
of disease
in man or other animals, or any activity that otherwise affects the structure
or any
function of the body of man or other animals.
[0040] An oral dosage form of a bisphosphonate such as zoledronic acid
may be used to treat, or provide relief of, any type of pain including, but
not limited
to, inflammatory pain, arthritis pain, complex regional pain syndrome,
lumbosacral
pain, musculoskeletal pain, neuropathic pain, chronic pain, cancer-related
pain,
acute pain, postoperative pain, etc. In some instances, pain relief may be
palliative,
or pain relief may be provided independent of improvement of the disease or
condition or the underlying cause of the disease or condition. For example,
although
the underlying disease may not improve, or may continue to progress, an
individual
suffering from the disease may experience pain relief. In some embodiments,
enhanced bioavailability of the zoledronic acid may be achieved in treating
one of
these conditions by administering a dosage form comprising zoledronic acid in
the
form of a disodium salt. This may allow a reduced molar amount of the disodium
salt
to be used as compared to what would be used with the diacid form.
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[0041] In some
embodiments, the mammal being treated is not suffering
from bone metastasis. In some embodiments, the mammal being treated is not
suffering from cancer. In some embodiments, the mammal being treated is not
suffering from osteoporosis.
[0042] For
example, zoledronic acid or another bisphosphonate may be
administered orally to relieve musculoskeletal pain including low back pain,
and pain
associated with rheumatoid arthritis, juvenile rheumatoid arthritis,
osteoarthritis,
erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies, non-
articular
rheumatism, peri-articular disorders, axial spondyloarthritis including
ankylosing
spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient
osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc. In
some
embodiments, enhanced bioavailability of the zoledronic acid may be achieved
in
treating one of these conditions by administering a dosage form comprising
zoledronic acid in the form of a disodium salt. This may allow a reduced molar
amount of the disodium salt to be used as compared to what would be used with
the
diacid form.
[0043] An
osteoclast inhibitor, such as a bisphosphonate, e.g. zoledronic
acid, may also be used to treat bone fractures or to enhance the healing of
bone
fractures.
[0044] In some
embodiments, zoledronic acid or another bisphosphonate
may also be administered orally to relieve neuropathic pain, including
diabetic
peripheral neuropathy, post-herpetic neuralgia, trigeminal
neuralgia,
monoradiculopathies, phantom limb pain, and central pain. Other causes of
neuropathic pain include cancer-related pain, lumbar nerve root compression,
spinal
cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated
neuropathy, and radio-therapy or chemo-therapy associated neuropathy. In some
embodiments, enhanced bioavailability of the zoledronic acid may be achieved
in
treating one of these conditions by administering a dosage form comprising
zoledronic acid in the form of a disodium salt. This may allow a reduced molar
amount of the disodium salt to be used as compared to what would be used with
the
diacid form.
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[0045] In some
embodiments, zoledronic acid or another bisphosphonate
may be administered orally to relieve inflammatory pain including
musculoskeletal
pain, arthritis pain, and complex regional pain syndrome. In some embodiments,
enhanced bioavailability of the zoledronic acid may be achieved in treating
one of
these conditions by administering a dosage form comprising zoledronic acid in
the
form of a disodium salt. This may allow a reduced molar amount of the disodium
salt
to be used as compared to what would be used with the diacid form.
[0046] Examples
of musculoskeletal pain include low back pain; and pain
associated with vertebral crush fractures, fibrous dysplasia, osteogenesis
imperfecta,
Paget's disease of bone, transient osteoporosis, and transient osteoporosis of
the
hip.
[0047] Arthritis
refers to inflammatory joint diseases that can be associated
with pain. Examples of arthritis pain include pain associated with
osteoarthritis,
erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis,
sero-
negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-
articular
disorders, neuropathic arthropathies including Charcot's foot, axial
spondyloarthritis
including ankylosing spondylitis, and SAPHO syndrome.
[0048] In some
embodiments, a human being that is treated for a disease
or condition, such as an inflammatory condition, e.g. arthritis, by an
osteoclast
inhibitor, such as a bisphosphonate, e.g. an oral dosage form of zoledronic
acid, has
an age of about 10 years to about 90 years, about 20 years to about 80 years,
about
30 years to about 75 years old, about 40 years to about 70 years, about 1 year
to
about 16 years, or about 80 years to about 95 years.
[0049] n some
embodiments, a human being that is treated for a disease
or condition, such as an inflammatory condition, e.g. arthritis, by an
osteoclast
inhibitor, such as a bisphosphonate, e.g. an oral dosage form of zoledronic
acid, has
suffered from the arthritis for at least 1 month, at least 2 months, at least
6 months,
or at least 1 year.
[0050] In some
embodiments, the arthritis affects a knee, an elbow, a
finger, a wrist, a shoulder, an ankle, the spine, or a hip.
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[0051] For
treatment of arthritis or joint pain, such as knee pain, in some
embodiments the person being treated has OARS! Grade 0, or Kellgren and
Lawrence Grades 0 or 1, joint space narrowing.
[0052] In some
embodiments, the person has lesions, such as bone
marrow lesions. In some embodiments the person being treated for bone marrow
lesions has normal joint space knee pain, OARSI Grade 0, or Kellgren and
Lawrence
Grades 0 or 1, joint space narrowing.
[0053] In some
embodiments, the person has baseline pain intensity of 5
or greater measured using the 0-10 numerical rating scale (NRS), or 50 mm or
greater using the 100 mm visual analog scale (VAS). In some embodiments the
person being treated for pain has normal joint space knee pain, OARSI Grade 0,
or
Kellgren and Lawrence Grades 0 or 1, joint space narrowing.
[0054] Bone
marrow lesions (BMLs) include regional bone marrow signal
intensity alterations on magnetic resonance imaging (MRI). BMLs can be present
in
the knee and can be an important feature of osteoarthritis of the knee. BMLs
have
also been described in other rheumatic conditions such as rheumatoid
arthritis,
osteonecrosis, ankylosing spondylitis, and transient osteoporosis of the hip
and are
often referred to as bone marrow edema (BME).
[0055] In some
embodiments, a person being treated for arthritis, such as
with zoledronic acid, has osteoarthritis of the knee associated with bone
marrow
lesions.
[0056] In some
embodiments, an inhibitor of osteoclast activity can be
used to treat bone marrow lesions.
[0057] In some
embodiments, an inhibitor of osteoclast activity can be
used to treat bone marrow lesions of the knee, shoulder, ankle, wrist, hand,
fingers,
spine, or hip.
[0058] Commonly
used measures of pain intensity include the visual
analog scale (VAS) and the numerical rating scale (NRS). With the VAS
approach,
patients rate the severity of their pain by marking a point on a 10-cm (or 100
mm)
VAS (0=no pain and 10=worst possible pain). With the NRS approach, patients
rate
the severity of their pain by verbally responding to a 10-point NRS (0=no pain
and
10=worst possible pain). VAS and NRS scores have been shown to be strongly
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correlated (slope of regression line, 1.01), indicating that a score on the 10-
cm VAS
is equivalent to the same score on 10-point NRS (Bijur PE et al. Acad Emerg
Med
2003; 10:390-392). For example, a VAS score of 5 cm (or 50 mm) is equivalent
to an
NRS score of 5. Knee pain in a person with a VAS score of 5 cm or 50 mm or
higher, or an NRS score of 5 or higher, may be referred to herein as moderate
to
severe knee pain.
[0059] In some embodiments, the patient suffering from pain,
inflammation, a similar condition, or any of the conditions described herein,
has an
NRS of 5 or greater, or a VAS of 5 cm or greater. In some embodiments, the
patient
has an NRS of 4 or greater, or a VAS of 4 cm or greater. In some embodiments,
the
patient has an NRS of 6 or greater, or a VAS of 6 cm or greater. In some
embodiments, the patient has an NRS of 7 or greater, or a VAS of 7 cm or
greater. In
some embodiments, the patient has an NRS of about 1, about 2, about 3, about
4,
about 5, about 6, about 7, about 8, about 9, or about 10. In some embodiments,
the
patient has a VAS of about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5
cm,
about 6 cm, about 7 cm, about 8 cm, about 9 cm, or about 10 cm.
[0060] For knee
pain or pain associated with bone marrow lesions, in
some embodiments, treatment with a nitrogen-containing bisphosphonate such as
zoledronic acid may decrease the visual analog (VAS) pain score measured using
a
100 mm scale, by at least about 5 mm, at least about 8 mm, at least about 10
mm, at
least about 15 mm, up to about 50 mm, or up to about 100 mm. In some
embodiments, the VAS score, may be decreased by at least about 5 mm, at least
about 8 mm, at least about 10 mm, at least about 15 mm, up to about 50 mm, or
up
to about 100 mm, as compared to a placebo.
[0061] Treatment
with a nitrogen-containing bisphosphonate such as
zoledronic acid may decrease the numerical rating scale (NRS) pain score
measured
using a 0-10 scale, by at least about 0.1, at least about 0.5, at least about
0.8, at
least about 1, at least about 1.5, up to about 5, or up to about 10. In some
embodiments, the NRS score may be decreased by at least about 0.1, at least
about
0.5, at least about 0.8, at least about 1, at least about 1.5, up to about 5,
or up to
about 10, as compared to a placebo.
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[0062] In some
embodiments, an inhibitor of osteoclast activity can be
used to reduce the size of bone marrow lesions. The area of the lesions may be
measured as the total area of all lesions or as the area of any one lesion. In
some
embodiments, the total area includes the medial tibial area, the medial
femoral area,
the lateral tibial area, and the lateral femoral area. In some embodiments the
bone
marrow lesion in located in the patella.
[0063] In some
embodiments, the use of an inhibitor of osteoclast activity
achieves a reduction in the total area of the bone marrow lesions of at least
about
240 mm2. In some embodiments, the reduction in total area is at least about
220
mm2, at least about 200 mm2, at least about 150 mm2, at least about 100 mm2,
or at
least about 50 mm2. In some embodiments, the reduction in size of bone marrow
lesions represents a reduction relative to baseline of at least about 10%, at
least
about 20%, at least about 30%, at least about 40%, at least about 50%, at
least
about 60%, at least about 70% at least about 80%, at least about 90%, or about
100%. In some embodiments, the reduction in area of bone marrow lesions
represents an improvement relative to placebo of at least about 10%, at least
about
20%, at least about 30%, at least about 40%, at least about 50%, at least
about
60%, at least about 70%, at least about 80%, at least about 90%, at least
about
100%, at least about 120%, at least about 150%, at least about 170%, at least
about
200%, at least about 250%, at least about 300%, at least about 350%, at least
about
400%, or at least about 450%. In some embodiments, the use of an inhibitor of
osteoclast activity inhibits an increase in the size of the bone marrow
lesions over
time.
[0064] Joint space narrowing (JSN) is typically graded using the
Osteoarthritis Research Society International (OARS!) atlas criteria, or the
Kellgren
and Lawrence (K/L) system. The OARSI atlas criteria grades JSN using a 0-3
scale
with Grade 0 indicating an absence of JSN, and Grades 1, 2 and 3 indicating
mild,
moderate, and severe JSN, respectively (Altman and Gold, Osteoarthritis
Cartilage
2007;15(Suppl A):A1-A56). The K/L system grades JSN using a 0-4 scale with
Grade 0 indicating an absence of JSN, Grade 1 indicating doubtful JSN, and
grades
2, 3 and 4 indicating minimal, moderate, and severe JSN, respectively
(Kellgren and
Lawrence , Ann Rheum Dis 1957;16:494-502). Based on these criteria, OARSI
Grade 0 (absence of JSN), approximates K/L Grades 0-1 (absence of, or doubtful
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presence of JSN). Knee pain in a person having OARS! Grade 0 or K/L Grade or 1
JSN in the knee where the pain occurs may be referred to herein as a "normal
joint
space knee pain."
[0065] In some
embodiments for patients having OARSI Grade 0 or K/L
Grades 0-1 JSN, the use of an inhibitor of osteoclast activity achieves a
reduction in
the total area of the bone marrow lesions of at least about 240 mm2. In some
embodiments, the reduction in total area is at least about 220 mm2, at least
about
200 mm2, at least about 150 mm2, at least about 100 mm2, or at least about 50
mm2.
In some embodiments, the reduction in size of bone marrow lesions represents a
reduction relative to baseline of at least about 10%, at least about 15%, at
least
about 20%, at least about 25%, at least about 30%, at least about 35%, at
least
about 40%, at least about 45%, at least about 50%, at least about 60%, at
least
about 70% at least about 80%, at least about 90%, or about 100%. In some
embodiments, the reduction in area of bone marrow lesions represents an
improvement relative to placebo of at least about 10%, at least about 20%, at
least
about 30%, at least about 40%, at least about 50%, at least about 60%, at
least
about 70%, at least about 80%, at least about 90%, at least about 100%, at
least
about 120%, at least about 150%, at least about 170%, at least about 200%, at
least
about 250%, at least about 300%, at least about 350%, at least about 400%, or
at
least about 450%. In some embodiments, the use of an inhibitor of osteoclast
activity
inhibits an increase in the size of bone marrow lesions over time.
[0066] In some
embodiments for patients having OARSI Grades 1-2 or K/L
Grades 2-4 JSN, the use of an inhibitor of osteoclast activity achieves a
reduction in
the total area of the bone marrow lesions of at least about 100 mm2. In some
embodiments, the reduction in total area is at least about 50 mm2, at least
about 60
mm2, at least about 80 mm2, at least about 85 mm2, at least about 90 mm2, at
least
about 100 mm2, at least about 105 mm2, at least about 110 mm2, or at least
about
115 mm2. In some embodiments, the reduction in size of bone marrow lesions
represents a reduction relative to baseline of at least about 10%, at least
about 20%,
at least about 30%, at least about 40%, at least about 50%, at least about
60%, at
least about 70% at least about 80%, at least about 90%, or about 100%. In some
embodiments, the reduction in area of bone marrow lesions represents an
improvement relative to placebo of at least about 10%, at least about 20%, at
least
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about 30%, at least about 40%, at least about 50%, at least about 60%, at
least
about 70%, at least about 80%, at least about 90%, at least about 100%, at
least
about 115%, at least about 125%, at least about 135%, at least about 150%, at
least
about 170%, at least about 200%, at least about 250%, at least about 300%, at
least
about 350%, at least about 400%, or at least about 450%. In some embodiments,
the use of an inhibitor of osteoclast activity inhibits an increase in the
size of bone
marrow lesions over time.
[0067] In some
embodiments, an inhibitor of osteoclast activity, such as a
nitrogen-containing bisphosphonate, including e.g. zoledronic acid, minodronic
acid,
etc., is used to treat fibromyalgia.
[0068] According
to some embodiments, administration of an inhibitor of
osteoclast activity achieves a reduction in pain that lasts at least about one
month,
two months, three months, four months, six months, or even at least about 12
months. According some embodiments, administration of an inhibitor of
osteoclast
activity achieves a reduction in pain that is observed at greater than three
hours, at
about one day, at about two to about five days, at about one week, at about
two
weeks, at about three weeks, at about one month, at about five weeks, at about
six
weeks, at about seven weeks, at about two months, at about nine weeks, at
about
ten weeks, at about eleven weeks, at about three months, at about four months,
at
about six months, or at about 12 months after administration of the inhibitor
of
osteoclast activity.
[0069] According
some embodiments, administration of an inhibitor of
osteoclast activity achieves a reduction in pain that is observed at greater
than three
hours, but at or before one week, two weeks, three weeks, four weeks, five
weeks,
six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks,
four months, five months, or six months.
[0070] According
some embodiments, administration of an inhibitor of
osteoclast activity achieves a reduction in pain that is observed at greater
than three
hours with a duration of no more than about three months, no more than about
four
months, no more than about five months, or no more than about six months.
[0071] According
to some embodiments, after the administration of an
inhibitor of osteoclast activity, the area of bone marrow lesions relative to
the size
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prior to administration remains reduced for up to three months, four months,
five
months, six months, or even up to 12 months or more. According to some
embodiments, after the administration of an inhibitor of osteoclast activity,
the area of
bone marrow lesions relative to the size prior to administration is reduced at
about
three months, at about four months, at about five months, at about six months,
or at
about 12 months.
[0072] According
to some embodiments, after administration of an inhibitor
of osteoclast activity, the size of Modic changes or VESCs relative to the
size prior to
administration remains reduced for up to three months, four months, five
months, six
months, or even up to 12 months or more. According to some embodiments, after
the administration of an inhibitor of osteoclast activity, the size of Modic
changes or
VESCs relative to the size prior to administration is reduced at about three
months,
at about four months, at about five months, at about six months, or at about
12
months.
[0073] In some
embodiments, an osteoclast inhibitor, such as a nitrogen-
containing bisphosphonate, e.g. zoledronic acid, ibandronic acid or minodronic
acid,
may be administered to relieve complex regional pain syndrome, such as complex
regional pain syndrome type 1 (CRPS-I), complex regional pain syndrome type II
(CRPS-II), CRPS-NOS, or another type of CRPS.
[0074] In some
embodiments, zoledronic acid or another bisphosphonate
may be administered orally to relieve complex regional pain syndrome, such as
complex regional pain syndrome type 1 (CRPS-I), complex regional pain syndrome
type 11 (CRPS-11), CRPS-NOS, or another type of CRPS. CRPS is a type of
inflammatory pain. CRPS can also have a neuropathic component.
[0075] Complex
regional pain syndrome is a debilitating pain syndrome. It
is characterized by severe pain in a limb that can be accompanied by edema,
and
autonomic, motor and sensory changes.
[0076] In some
embodiments, an osteoclast inhibitor, such as a nitrogen-
containing bisphosphonate, e.g. zoledronic acid or minodronic acid, may be
used to
reduce the use of non-steroidal anti-inflammatory drug (NSAIDs), opioids, or
other
pain medications, for a patient suffering from pain, inflammation, a similar
condition,
or any condition described herein. For example, use of NSAIDs, opioids, or
other
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pain medications may be reduced by at least about 5%, at least about 10%, at
least
about 15%, at least about 20%, at least about 25%, at least about 30%, at
least
about 35%, at least about 40%, at least about 45%, at least about 50%, at
least
about 60%, at least about 70%, at least about 80%, or at least about 90%, up
to
about 100%, as compared to the use of NSAIDs, opioids or other pain
medications
without administration of the osteoclast inhibitor. Use of the opioids,
NSAIDs, or
other pain medications may be reduced by at least about 5%, at least about
10%, at
least about 15%, at least about 20%, at least about 25%, at least about 30%,
at least
about 35%, at least about 40%, at least about 45%, at least about 50%, at
least
about 60%, at least about 70%, at least about 80%, or at least about 90%, up
to
about 100%, as compared to the use of NSAIDS, opioids, or other pain
medications
at baseline.
[0077] The
reduction in the use of NSAIDs, opioids, or other pain
medications may be observed at about one week, about two weeks, about three
weeks, about one month, about two months, about three months, about four
months,
about five months, about six months, about seven months, about eight months,
about nine months, about 10 months, about 11 months, or about one year or
more,
after the administration of osteoclast inhibitor.
[0078] With
respect to use of oral zoledronic acid for relieving pain
associated with an inflammatory condition, relief of pain can be short-term,
e.g. for a
period of hours after administration of the dosage form, and/or relief of pain
can be
long-term, e.g. lasting for days, weeks, or even months after oral
administration of
zoledronic acid. In some embodiments, a mammal, such as a human being,
experiences significant pain relief at least about 3 hours, at least about 6
hours, at
least about 12 hours, at least about 24 hours, at least about 48 hours, at
least about
one week, at least about 2 weeks, or at least about 3 weeks after
administration of
an oral dosage form comprising zoledronic acid. In some embodiments, a mammal,
such as a human being, experiences significant pain relief during at least
part of the
time from about 3 hours to about 2 weeks, about 3 hours to about 3 weeks,
about 3
hours to about 24 hours, about 6 hours to about 2 weeks, or about 6 hours to
about
24 hours, about 3 days to about 2 weeks, about 6 days to about 2 weeks, after
administration of an oral dosage form comprising zoledronic acid. In some
embodiments, a human being treated has significant pain relief at three
months, six
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months, nine months, or one year after administration of the most recent dose
of an
osteoclast inhibitor such as zoledronic acid.
[0079] With
respect to the treatment of any condition recited herein, in
some embodiments a first oral dosage form comprising zoledronic acid is
administered and a second oral dosage form comprising oral zoledronic acid is
administered. The timing of the administration of the two dosage forms may be
such
that, with respect to the first oral dosage form, the second oral dosage with
respect
to the first oral dosage form, the second oral dosage form is administered at
5 x Tmax
or greater (e.g., if Tmax is 1 hour, at 5 hours or later), at least 10 x T. or
greater, at
least about 15 x T. or greater, at least about 20 x T. or greater, at least
about 50
X Tmax or greater, or at least about 200 x Tmax or greater, wherein T. is the
time of
maximum plasma concentration for the first oral dosage
[0080] Some
embodiments include treatment of a condition recited herein,
such as inflammatory pain, arthritis, or complex regional pain syndrome,
wherein the
treatment comprises either: administering only one dosage form to a mammal to
treat the condition, or administering a first dosage form to the mammal,
followed by
administering a second dosage form to the mammal. If two or more dosage forms
are administered, the second oral dosage form is administered before the
maximum
pain relieving effect of the first oral dosage form is achieved, or before a
peak in the
pain relieving effect of the first oral dosage form is experienced by a
mammal,
receiving the dosage form. In some embodiments, the second oral dosage form is
administered before an observable pain relieving effect is achieved. In some
embodiments, the second dosage form is administered about 12 hours to about 60
days, about 24 hours to about 28 days, about 24 hours to about 7 days, about
24
hours to about 14 days, or about 24 hours to about 21 days, after the first
dosage
form is administered.
[0081] Some
embodiments include treatment of a condition recited herein,
such as inflammatory pain, arthritis, or complex regional pain syndrome,
wherein the
treatment comprises administering a first dosage form to the mammal, followed
by
administering a second dosage form to the mammal, wherein the second dosage
form is administered after the maximum pain relieving effect of the first oral
dosage
form is achieved, and the second oral dosage form is administered while the
mammal is still experiencing pain relief from the first oral dosage form, or
while the
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pain relieving effect from the first oral dosage form is observable. In some
embodiments, the second dosage form is administered about 12 hours to about 60
days, about 24 hours to about 28 days, about 24 hours to about 7 days, about
24
hours to about 14 days, or about 24 hours to about 21 days, after the first
dosage
form is administered.
[0082] Zoledronic acid or another bisphosphonate may also be
administered orally to relieve cancer-related pain, including pain associated
with
multiple myeloma and bone metastases from solid tumors. In some embodiments,
zoledronic acid is used to treat pain that is not cancer-related pain. For
example,
zoledronic acid may be used to treat pain that is not associated with multiple
myeloma, bone metastasis from solid tumors, hypercalcemia of malignancy, giant
cell tumor of bone, blood cancers or leukemias, or solid tumors or cancers. In
some
embodiments, enhanced bioavailability of the zoledronic acid may be achieved
in
treating one of these conditions by administering a dosage form comprising
zoledronic acid in the form of a disodium salt. This may allow a reduced molar
amount of the disodium salt to be used as compared to what would be used with
the
diacid form.
[0083] In
addition to relieving pain, oral administration of zoledronic acid or
another bisphosphonate may also be useful to treat diseases or conditions that
may
or may not include a pain component. For example, zoledronic acid or another
bisphosphonate may be useful to treat any of the pain conditions or types of
conditions listed above, including treatment that does not simply relieve the
pain of
those conditions, and treatment that is carried out in such a way that the
condition is
treated without pain relief occurring. In addition to any pain relief
zoledronic acid or
another bisphosphonate may or may not provide, zoledronic acid or another
bisphosphonate may be used to treat a disease or condition such as a metabolic
disease or condition; an inflammatory disease or condition, including an
inflammatory disease or condition that is not associated with pain; a cancer
disease
or condition; a neurological disease or condition; etc. In some embodiments,
enhanced bioavailability of the zoledronic acid may be achieved in treating
one of
these conditions by administering a dosage form comprising zoledronic acid in
the
form of a disodium salt. This may allow a reduced molar amount of the disodium
salt
to be used as compared to what would be used with the diacid form.
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[0084] In some
embodiments, oral administration of zoledronic acid or
another bisphosphonate may also be useful to treat complex regional pain
syndrome, rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, axial
spondyloarthritis including ankylosing spondylitis, acute vertebral crush
fracture,
fibrous dysplasia, SAPHO syndrome, osteoporosis, transient osteoporosis, or
transient osteoporosis of the hip. In some embodiments, enhanced
bioavailability of
the zoledronic acid may be achieved in treating one of these conditions by
administering a dosage form comprising zoledronic acid in the form of a
disodium
salt. This may allow a reduced molar amount of the disodium salt to be used as
compared to what would be used with the diacid form.
[0085] In some
embodiments, oral administration of zoledronic acid or
another bisphosphonate may also be useful to treat hypercalcemia of
malignancy,
multiple myeloma, bone metastases from solid tumors, Paget's disease of bone,
giant cell tumor of bone, blood cancers or leukemias, or solid tumors or
cancers. In
some embodiments, enhanced bioavailability of the zoledronic acid may be
achieved
in treating one of these conditions by administering a dosage form comprising
zoledronic acid in the form of a disodium salt. This may allow a reduced molar
amount of the disodium salt to be used as compared to what would be used with
the
diacid form.
[0086] Some
nitrogen-containing bisphosphonates may be represented by
Formula A:
R1 R2
P
HO'/*- \OH HO/POH
Formula A
[0087] With
respect to Formula A, Ral is F, Cl, Br, H, or OH. In some
embodiments, R1 is OH.
[0088] With
respect to Formula A, R2 is aminoalkyl, such as aminoethyl,
aminopropyl, aminopentyl, dimethylaminoethyl, methylpentylaminoethyl, etc; or
optionally substituted heterocyclyl alkyl, such as optionally substituted
imidazolylmethyl, optionally substituted pyridinymethyl, etc. In some
embodiments
R2 is optionally substituted imidazolylalkyl.
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[0089] Unless
otherwise indicated, when a compound or chemical
structural feature such as heterocyclyl alkyl is referred to as being
"optionally
substituted," it includes a feature that has no substituents (i.e.
unsubstituted), or a
feature that is substituted, meaning that the feature has one or more
substituents.
The term "substituent" has the broadest meaning known to one of ordinary skill
in the
art, and includes a moiety that replaces one or more hydrogen atoms in a
parent
compound or structural feature. The term "replaces" is merely used herein for
convenience, and does not require that the compound be formed by replacing one
atom with another. In some embodiments, a substituent may be any ordinary
organic moiety known in the art, which may have a molecular weight (e.g. the
sum of
the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15
g/mol
to 100 g/mol, 15 g/mol to 150 g/mo1,15 g/mol to 200 g/mol, 15 g/mol to 300
g/mol, or
15 g/mol to 500 g/mol. In some embodiments, a substituent comprises, or
consists
of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5
heteroatoms,
wherein each heteroatom may independently be: N, 0, P, S, Si, F, Cl, Br, or I;
provided that the substituent includes one C, N, 0, P, S, Si, F, Cl, Br, or I
atom. In
some embodiments, substituents can independently have a molecular weight of
about 15 Da to about 600 Da and can consist of 2 to 5 chemical elements,
wherein
the chemical elements are independently C, H, 0, N, P, 5, Si, F, Cl, or Br. In
some
embodiments, a substituent is optionally substituted alkyl, ¨0-alkyl (e.g.
¨OCH3, -
0C2H5, -0C3H7, -0C4H9, etc.), -S-alkyl (e.g. ¨SCH3, -SC2H5, -SC3H7, -SC4H9,
etc.), -
NR'R", ¨OH, -SH, -CN, -CF3, -NO2, perfluoroalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted amine or a halogen,
wherein
R' and R" are independently H or optionally substituted alkyl. Wherever a
substituent is described as "optionally substituted," that substituent can be
substituted with the above substituents.
[0090] For
convenience, the term "molecular weight" is used with respect
to a moiety or part of a molecule to indicate the sum of the atomic masses of
the
atoms in the moiety or part of a molecule, even though it may not be a
complete
molecule.
[0091] Examples
of nitrogen-containing bisphosphonates include but are
not limited to pamidronic acid, incadronic acid, ibandronic acid, risedronic
acid,
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minodronic acid, cimadronic acid, neridronic acid, alendronic acid, olpadronic
acid,
zoledronic acid, etc.
N¨
O
HO INH2 HO\ ,/OH
aNH Ci'l
_____________________________________ P OH P OH
8
HO\ ..OH 0
.1, 0 HO¨P=--0
HO
,µ ,"'%. Oi H HO/
0 "
HO/ OH
pamidronic acid incadronic acid ibandronic
acid
0 0
II II
HO'./ l'. 1 OH /.. % /OH
0 OH OH
/Pf--õOH
OH II HN0
N''''"¨/.'.-7- 1 -OH
1 HO' OH HO P=0
HCY 0 HO/ "'OH
risedronic acid cimadronic acid minodronic
acid
[0092] Zoledronic acid has
the structure shown below, and is also referred
to as zoledronate.
OH
0,,z,,,,s. /
.
'OH'
C(7 OH
F*71>
po.**
N------
OH
Zoledronic acid
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[0093] Unless otherwise indicated, any reference to a compound herein,
such as zoledronic acid, by structure, name, or any other means, includes
pharmaceutically acceptable salts, such as the disodium salt; alternate solid
forms,
such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical
species that may rapidly convert to a compound described herein under
conditions in
which the compounds are used as described herein.
[0094] In some embodiments, zoledronic acid is administered in a
dosage
form comprising a salt form, such as a salt of a dianion of zoledronic acid.
In some
embodiments, zoledronic acid is administered in a dosage form comprising a
disodium salt form of zoledronic acid. In some embodiments, zoledronic acid is
administered in a sodium salt form, such as a monosodium salt, a disodium
salt, a
trisodium salt, etc. In some circumstances, use of the disodium salt may be
desirable. For example, the disodium salt is much more soluble in water than
the
diacid form. As a result, in some processes, the disodium salt can be easier
to work
with than the diacid form. Additionally, the sodium salt may be more
bioavailable
and/or more rapidly absorbed when taken orally as compared to the diacid form.
[0095] Examples of salts of Compound 1 are shown below:
x-
Po3H2 P0 ft
+ 3P0 H2
HO Nt..k.7*
OH HO OH
M+ - 2M+
0 P03H- 0 P03H-
-
HO -7' -N PO3H
+
OH
OH
- 4M+
7032-
0
+
Nkr7
OH
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wherein X- is any suitable anion, e.g. F, BC, Cl-, r, OK, acetate, etc.; and
M4 is any
suitable cation, e.g. Na+, KF, NH44., etc. Many other salt forms are also
possible.
[0096] In some embodiments, Compound 1 may be further represented by
a formula,
0 /...._\ PO3 Na
2
N
-0 OH
=
[0097] In some embodiments, Compound 1 may be in a hydrate form.
[0098] In some embodiments, Compound 1 is administered in a dosage
form comprising a salt form, such as a zwitterionic form, or a salt of a
cation, a
monoanion, a dianion, a trianion, etc., of Compound 1.
[0099] Compound 1 can be present in any amount, such as less than
about 100% w/w, less than about 50% w/w, less than about 20% w/w, less than
about 10% w/w, less than about 1% w/w, less than 0.1% w/w, less than about
0.07%
w/w, less than about 0.05% w/w, less than about 0.04% w/w, less than about
0.03%
w/w, less than about 0.02% w/w; and/or greater than 0% w/w, at least about
0.00000001% w/w, at least about 0.000001% w/w, or at least about 0.00001% w/w,
based upon the total amount of zoledronic acid, Compound 1, and Compound 2
present in the composition.
[0100] Examples of salts of Compound 2 are shown below:
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X-
PO3H2 PO3H-
PO3H2 PO3H2 __
HON
+ = N PO3H2 +,,N PO3H2
PO3H2 OH
PO3H2
Mf
¨ 2M+
PO3H" PO3H"
PO3H- /_\ PO3H"
PO3H2
HO
õõ OH
P03H2 ru3H2 OH
¨ 4M+ ¨ 4Na+
PO3H" PO3H- -OH
PO3H- /_\ PO3H-
N, + = N PO3H"
HO H
PO3H- OH Pop- OH
wherein X" is any suitable anion, e.g. F, BC, Cr, r, OF-f, acetate, etc.; and
M+ is any
suitable cation, e.g. Na, K+, NH4, etc. Many other salt forms are also
possible.
[0101] In some embodiments, a salt of compound 2 may be further
represented by a formula,
PO3HNa _________________ PO3HNa
NN PO3H Na
HO OH
PO3HNa ()OH
[0102] In some embodiments, compound 2 may be in a hydrate form.
[0103] In some embodiments, Compound 2 is administered in a dosage
form comprising a salt form, such as a zwitterionic form, or a salt of a
cation, a
monoanion, a dianion, a trianion, etc., of Compound 2.
[0104] Compound 2 can be present in any amount, such as less than
about 100% w/w, less than about 50% w/w, less than about 20% w/w, less than
about 10% w/w, less than about 1% w/w, less than about 0.3%, less than about
0.2%, less than 0.1% w/w, less than about 0.08% w/w, less than about 0.07%
w/w,
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less than about 0.05% w/w, less than about 0.04% w/w, less than about 0.03%
w/w,
less than about 0.02% w/w; and/or greater than 0% w/w, at least about
0.00000001% w/w, at least about 0.000001% w/w, or at least about 0.00001% w/w,
based upon the total amount of zoledronic acid, Compound 1, and Compound 2
present in the composition.
[0105] In some embodiments, Compound 1 and Compound 2 are present
in an amount that is less than 0.1% w/w.
[0106] In some
embodiments, the administration of an osteoclast inhibitor,
such as a nitrogen-containing bisphosphonate, including, e.g. zoledronic acid,
minodronic acid, etc., to a patient or mammal in need thereof affects Modic
changes
(MCs). For example, any of the above compounds could be used to treat Modic
changes, or vertebral endplate signal changes (VESC) and bone marrow changes
visible using magnetic resonance imaging (MRI), or neck pain or back pain
associated with Modic changes.
[0107] Modic
changes, as used herein, includes its ordinary meaning in the
art and refers to pathological vertebral endplate and bone marrow changes
visible
using magnetic resonance imaging (MRI). Modic changes may also be referred to
as vertebral endplate signal changes (VESC). Modic changes, can be classified
into
various types including type 1 (M1), type 2 (M2), and type 3 (M3) lesions or
changes,
any of which may be treated using an osteoclast inhibitor, such as a nitrogen-
bisphosphonate, including, e.g. zoledronic acid, minodronic acid, etc.
Different types
of Modic changes may occur in the same patient, for example type 1 and type 2
Modic changes (M1/2). In some cases, M1 changes are related to lower back pain
than other types of Modic change.
[0108] VESCs may
be found in patients with different types of low back
pain including but not limited to spondylitis, trauma, spondyloarthropathies
including
ankylosing spondylitis, Schmorl's nodes, fracture, tumor, and spinal cord
infarction.
Lesions in ankylosing spondylitis include osteitis and spondylodiscitis, which
can be
detected using MRI or another medical imaging instrument.
[0109] Modic
changes may be found in the cervical, thoracic, lumbar, and
sacral spine. Modic changes may be found at various spinal levels such as at
C1/2,
C2/3, C3/4, C4/5, C5/6, C6/7, C7/T1, 11/2, T2/3, T3/4, 14/5, 15/6, 16/7, T7/8,
18/9,
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T9/10, 110/11, 111/12, 112/L1, L1/2, L2/3, L3/4, L4/5, L5/S1, etc., any of
which may
be treated using an osteoclast inhibitor, such as a nitrogen-bisphosphonate,
including, e.g. zoledronic acid, minodronic acid, etc.
[0110] In some
embodiments, the Modic change being treated is located at
L2/3. In some embodiments, the Modic change being treated is located at L3/4.
In
some embodiments, the Modic change being treated is located at L4/5. In some
embodiments, the Modic change being treated is located at L5/S1.
[0111] In some
embodiments, the Modic change being treated is located at
C3/4. In some embodiments, the Modic change being treated is located in at
C4/5. In
some embodiments, the Modic change being treated is located in at C5/6. In
some
embodiments, the Modic change being treated is located in at C6/7.
[0112] In some
embodiments, the Modic change being treated is located at
T5/6. In some embodiments, the Modic change being treated is located in at
16/7. In
some embodiments, the Modic change being treated is located in at T7/8. In
some
embodiments, the Modic change being treated is located in at 18/9. In some
embodiments, the Modic change being treated is located at T9/10.
[0113] In some
embodiments, the patient being treated has predominantly
M1. In some
embodiments, the patient being treated has predominantly M1 /M2. In
some embodiments, the patient being treated has predominantly M2. In some
embodiments, the patient being treated has predominantly M3.
[0114] In some
embodiments, the worst type of lesion that the patient
being treated has is Ml. In some embodiments, the worst type of lesion that
the
patient being treated has is M1/2. In some embodiments, the worst type of
lesion
that the patient being treated has is M2.
[0115] In some
embodiments, the patient being treated has Modic changes
at more two or more levels. In some embodiments the patient being treated has
Modic changes at three or more levels. In some embodiments greater pain relief
is
obtained when treating a patient with Modic changes at two levels, or three or
more
levels, than is obtained when treating a patient with Modic changes at a
single level
or at two levels.
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[0116] In some
embodiments greater pain relief is obtained when treating
a patient with Modic changes at two levels than is obtained when treating a
patient
with Modic changes at a single level.
[0117] In some
embodiments greater pain relief is obtained when treating
a patient with Modic changes at three or more levels than is obtained when
treating a
patient with Modic changes at a single level.
[0118] In some
embodiments greater pain relief is obtained when treating
a patient with Modic changes three or more levels than is obtained when
treating a
patient with Modic changes at two levels.
[0119] In some
embodiments, the inhibitor of osteoclast activity may be
used to effect a reduction in the levels of pro-inflammatory cytokines in the
patient
with low back pain or any other type of pain or condition recited herein. In
some
embodiments greater pain relief may be obtained in patients with greater
baseline
levels of pro-inflammatory cytokines when treated with an inhibitor of
osteoclast
activity, such as a nitrogen-containing bisphosphonate, including e.g.
zoledronic
acid, minodronic acid, etc. In some embodiments, greater pain relief may be
obtained in patients who experience a reduction or a greater reduction in the
levels
of pro-inflammatory cytokines when treated with an inhibitor of osteoclast
activity,
such as a nitrogen-containing bisphosphonate, including e.g. zoledronic acid,
minodronic acid, etc. Pro-inflammatory cytokines include but are not limited
to IL-1,
IL-2, IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis alpha (TNF-alpha),
interferon
gamma, etc.
[0120] In some
embodiments, the use of an inhibitor of osteoclast activity,
such as a nitrogen-containing bisphosphonate, including e.g. zoledronic acid,
minodronic acid, etc., to a patient or mammal in need thereof, achieves a
reduction
relative to baseline in the size of Modic changes or VESCs of at least about
5%, at
least about 10%, at least about 15%, at least about 20%, at least about 25%,
at least
about 30%, at least about 40%, at least about 50%, at least about 60%, at
least
about 70% at least about 80%, at least about 90%, or about 100%. In some
embodiments, the reduction the size of Modic changes or VESCs represents an
improvement relative to placebo of at least about 10%, at least about 15%, at
least
about 20%, at least about 25%, at least about 30%, at least about 40%, at
least
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about 50%, at least about 60%, at least about 70%, at least about 80%, at
least
about 90%, at least about 100%, at least about 120%, at least about 150%, at
least
about 170%, at least about 200%, at least about 250%, at least about 300%, at
least
about 350%, at least about 400%, or at least about 450%. In some embodiments,
the use of an inhibitor of osteoclast activity inhibits an increase in the
size of Modic
changes or VESCs over time.
[0121] The oral
bioavailability of zoledronic acid may be enhanced by
orally administering the zoledronic acid in the disodium salt form. For
example, the
bioavailability of zoledronic acid may be improved by at least about 10%, at
least
about 20%, at least about 30%, at least about 50%, and/or up to about 100%, or
up
to about 200%, as compared to administration of zoledronic acid in the diacid
form.
[0122] Because of
the improved bioavailability of the disodium salt a
dosage form may contain, or a mammal, such as a human being, may receive, on a
molar basis, less of the disodium salt form of zoledronic acid than would
otherwise
be administered of the diacid form of zoledronic acid. For example, a dosage
form
may contain, or a mammal may receive, at least about 10 mole% less, at least
about
20 mole% less, at least about 40 mole% less, at least about 50 mole% less,
and/or
up to about 90 mole% less or 95 mole% less, of the disodium salt form as
compared
the amount of the diacid form of zoledronic acid that would otherwise be
administered, such as a molar amount that would be administered of zoledronic
acid
in the diacid form in order to achieve the same plasma levels of zoledronic
acid.
[0123] In some
embodiments, a dosage form contains, or a mammal (such
as a human being) is administered, an amount of the disodium salt form, on a
molar
basis, that has a value of about 0.8nd to about 1.2nd or about 0.9nd to about
1.1nd,
wherein:
nd = (ba/bd)(na)
wherein ba is the bioavailability of the diacid form, bd is the
bioavailability of the
disodium salt form, and na is the number of moles of the diacid that would be
administered in a dosage form containing the diacid form of zoledronic acid.
For
example, if the diacid form has a bioavailability (ba) of 0.01 and the
disodium salt
form has a bioavailabity (bd) of 0.015, and a dosage form would normally
contain
0.001 moles of the diacid, nd would be (0.01/0.015)(0.001 moles), or about
0.00067
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moles. In some embodiments, the disodium salt is administered in an amount
that
has a value of about nd.
[0124] With
respect to oral dosage forms comprising a reduced molar
amount of the disodium salt of zoledronic acid as compared to the diacid form
of
zoledronic acid, in some embodiments, the bioavailability of the zoledronic
acid in
the disodium salt form is sufficiently high that, if the drug is administered
to a
mammal, at least as much zoledronic acid is present in the blood of the mammal
as
would be present if zoledronic acid were administered in the diacid form.
[0125] With
respect to oral dosage forms comprising the disodium salt
form of zoledronic acid, in some embodiments, the disodium salt form is
present in a
lower molar amount than would be present if the zoledronic acid were in the
diacid
form; and the zoledronic acid in the disodium salt form has an improved
bioavailability as compared to the zoledronic acid in the diacid form to the
extent that
the lower molar amount of the disodium salt in the dosage form does not reduce
the
amount of zoledronic acid delivered to the plasma of a mammal.
[0126] Some oral
dosage forms comprising zoledronic acid have a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal, e.g.
dog, rat, human, etc. Such a dosage form may have zoledronic acid present in
an
amount that results in a desired range for an area under the plasma
concentration
curve (AUC) of zoledronic acid in that particular species of mammal. For
example
the dose of zoledronic acid and a configuration of the oral dosage form may
result in
an AUC of zoledronic acid of about 1 ng=hr/mL to about 700 ng=hr/mL, about 3
ng=hr/mL to about 30 ng=hr/mL, about 3 ng=hr/mL to about 10 ng=hr/mL, about 50
ng=hr/mL to about 700 ng=hr/mL, about 130 ng=hr/mL to about 180 ng=hr/mL,
about
300 ng=hr/mL to about 450 ng=hr/mL, about 300 ng=hr/mL to about 350 ng=hr/mL,
about 300 ng=hr/mL to about 310 ng=hr/mL, about 340 ng=hr/mL to about 350
ng=hr/mL, about 370 ng=hr/mL to about 420 ng=hr/mL, about 380 ng=hr/mL to
about
390 ng=hr/mL, about 405 ng=hr/mL to about 415 ng=hr/mL, about 140 ng=hr/mL to
about 160 ng=hr/mL, about 140 ng=hr/mL to about 150 ng=hr/mL, about 150
ng=hr/mL
to about 160 ng=hr/mL, about 140 ng=hr/mL, 142 ng=hr/mL, about 155 ng=hr/mL,
about 305 ng.hr/mL, 304 ng.hr/mL, about 345 ng=hr/mL, 343 ng=hr/mL, about 385
ng=hr/mL, 384 ng=hr/mL, about 410 ng=hr/mL, or any AUC in a range bounded by,
or
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between, any of these values, upon administration of the oral dosage form to a
mammal.
[0127] Unless
otherwise indicated, the AUG refers to the AUG calculated
to the last measured concentration (AUC(0_0)and extrapolated to infinity
(AUC(0-inf)).
[0128] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
have zoledronic acid present in an amount that results in a Cõx of zoledronic
acid of
about 0.2 ng/mL to about 300 ng/mL, about 0.5 ng/mL to about 5 ng/mL, about 5
ng/mL to about 300 ng/mL, about 5 ng/mL to about 50 ng/mL, about 20 ng/mL to
about 50 ng/mL, about 30 ng/mL to about 50 ng/mL, about 50 ng/mL to about 200
ng/mL, about 50 ng/mL to about 150 ng/mL, about 80 ng/mL to about 120 ng/mL,
about 90 ng/mL to about 100 ng/mL, about 50 ng/mL to about 200 ng/mL, about 40
ng/mL, about 95 ng/mL, about 97 ng/mL, or any Cmõ in a range bounded by, or
between, any of these values, upon administration of the oral dosage form to a
mammal.
[0129] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that administration of the oral dosage form to the particular
species
of mammal results in a Tmõ of zoledronic acid of about 0.4 hr to about 1 hr,
about
0.5 hr, or about 0.75 hr, or any imax in a range bounded by, or between, any
of these
values.
[0130] In some
embodiments, the zoledronic acid in the disodium salt form
is present in an amount such that the oral dosage form provides an area under
the
plasma concentration curve of zoledronic acid of about 4 ng=h/mL to about 2000
ng=h/mL to the mammal each time the zoledronic acid in the disodium salt is
administered.
[0131] In some
embodiments, the zoledronic acid is present in an amount
such that the oral dosage form provides an area under the plasma concentration
curve of zoledronic acid of about 100 ng=h/mL to about 2000 ng=h/mL, about 100
ng=h/mL to about 1000 ng=h/mL, about 500 ng=h/mL to about 1000 ng=h/mL, or
about
500 ng=h/mL to about 700 ng=h/mL in the mammal to which the dosage form is
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administered. This amount may be suitable for administration of the oral
dosage
form about every 3 to 4 weeks.
[0132] In some
embodiments, the zoledronic acid is present in an amount
such that the oral dosage form provides an area under the plasma concentration
curve of zoledronic acid of about 20 ng=himl. to about 700 ng=h/mL, about 50
ng=h/mL to about 500 ng=h/mL, about 50 ng=h/mL to about 400 ng=h/mL, about 50
ng=h/mL to about 300 ng=h/mL, about 50 ng=h/mL to about 200 ng=h/mL, about 100
ng=h/mL to about 500 ng=h/mL, about 100 ng=h/mL to about 400 ng=h/mL, about
100
ng=h/mL to about 300 ng=h/mL, about 100 ng=h/mL to about 200 ng=h/mL, about
125
ng=h/mL to about 500 ng=h/mL, about 125 ng=h/mL to about 400 ng=h/mL, about
125
ng=h/mL to about 300 ng=h/mL, about 125 ng=h/mL to about 200 ng=h/mL, or about
200 ng=h/mL to about 300 ng=h/mL, in the mammal to which the dosage form is
administered. This amount may be suitable for weekly administration of the
oral
dosage, or for administration of 3 to 5 individual dosages during a month. The
individual dosages could be given at regular intervals, given during the first
week, or
at any other schedule that provides 3 to 5 dosages during the month.
[0133] In some
embodiments, the zoledronic acid is present in an amount
such that the oral dosage form provides an area under the plasma concentration
curve of zoledronic acid of about 4 ng=h/mL to about 100 ng=h/mL, about 10
ng.h/mL
to about 50 ng=h/mL, about 10 ng=h/mL to about 30 ng=h/mL, 20 ng=h/mL to about
700 ng=h/mL, about 50 ng=h/mL to about 500 ng=h/mL, about 50 ng=h/mL to about
400 ng=h/mL, about 50 ng=h/mL to about 300 ng=h/mL, about 50 ng=h/mL to about
200 ng=h/mL, about 100 ng=h/mL to about 500 ng=h/mL, about 100 ng=h/mL to
about
400 ng=h/mL, about 100 ng=h/mL to about 300 ng=h/mL, about 100 ng=h/mL to
about
200 ng=h/mL, about 125 ng=h/mL to about 500 ng=h/mL, about 125 ng=h/mL to
about
400 ng=h/mL, about 125 ng=h/mL to about 300 ng=h/mL, about 125 ng=h/mL to
about
200 ng=h/mL, or about 200 ng=h/mL to about 300 ng=h/mL in the mammal to which
the dosage form is administered. This
amount may be suitable for daily
administration of the oral dosage form. In some embodiments, the dosage form
may be administered for 2, 3, 4, 5, 6, 7, 8, 9, or 10, 5 to 10, or 6 to 10
consecutive
days.
[0134] Oral administration of zoledronic acid, particularly oral
administration of the disodium salt form of zoledronic acid, can result in
more
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sustained plasma levels of the drug as compared to parenteral modes of
administration, such intravenous or subcutaneous. For example, the amount of
zoledronic acid in the plasma can be significantly higher for oral
administration of the
disodium salt about 24 hours or 48 hours, or longer, after administration. In
some
embodiments, oral zoledronic acid has a 24 hour sustained plasma level factor
of
about 1 or higher, such as about 1 to about 10, about 1 to about 5, about 3 to
about
5, or about 3 to about 4. In some embodiments, an orally administered dosage
form
of zoledronic acid has a 24 hour sustained plasma level factor or a 48 hour
sustained
plasma level factor that is higher, such as at least 1.2 times, at least about
2 times,
at least about 5 times, about 1.2 times to about 20 times, about 2 times to
about 15
times, about 5 times to about 10 times, or about 8 to about 15 times that of
intravenously administered zoledronic acid. A "sustained plasma level factor,"
pf, is
determined by the equation:
pf = 1000 (Ct/Cmax)
wherein Crnax is the maximum plasma concentration of zoledronic acid after it
is
administered and Ct is the plasma concentration of zoledronic acid at the time
of
interest, such as 24 hours. For parenteral administration, the Cmax can be
about the
Co, or the concentration right after injection of the entire amount of the
drug into the
body. Sustained plasma level factors can also be obtained for other times,
such as
48 hours, by using the plasma concentration of zoledronic acid for Ct in the
equation
above. For example, if the maximum plasma level of zoledronic acid after
administration is 1000 ng/mL and the plasma level of zoledronic acid at 24
hours is 1
ng/mL, the 24 hour sustained plasma level factor is 1.
[0135] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the zoledronic acid has a 12 hour sustained plasma level
factor
of about 12 to about 50, about 20 to about 40, about 25 to about 30, about 30
to
about 35, about 35 to about 40, about 33, about 30, about 35, or any 12 hour
sustained plasma level factor in a range bounded by, or between, any of these
values, for the particular species of mammal.
[0136] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
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be configured so that the zoledronic acid has a 24 hour sustained plasma level
factor
of about 10 to about 30, about 10 to about 20, about 10 to about 15, about 12
to
about 15 or 16, about 15 to about 20, about 14, about 12, about 15, or any 24
hour
sustained plasma level factor in a range bounded by, or between, any of these
values, for the particular species of mammal.
[0137] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the zoledronic acid has a 36 hour sustained plasma level
factor
of about 6 to about 20, about 8 to about 15, about 9 to about 12 or 13, about
8 to
about 10, about 11 to about 13, about 9, about 13, or any 24 hour sustained
plasma
level factor in a range bounded by, or between, any of these values, for the
particular
species of mammal.
[0138] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the zoledronic acid has a 48 hour sustained plasma level
factor
of about 5 to about 20, about 6 to about 15, about 7 or 8 to about 12 or 13,
about 8
to about 10, about 11 to about 13, about 8, about 12, or any 48 hour sustained
plasma level factor in a range bounded by, or between, any of these values,
for the
particular species of mammal.
[0139] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the zoledronic acid has a 72 hour sustained plasma level
factor
of about 4 to about 20, about 5 to about 10, about 5 or 6 to about 10 or 11,
about 5
to about 6, about 9 to about 10, about 6, about 10, or any 72 hour sustained
plasma
level factor in a range bounded by, or between, any of these values, for the
particular
species of mammal.
[0140] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the particular species of mammal has a plasma
concentration
of zoledronic acid at 12 hours that is about 0.5 ng/mL to about 5 ng/mL, about
1
ng/mL to about 3 ng/mL, about 1 ng/mL to about 2 ng/mL, about 2 ng/mL to about
3
ng/mL, about 3 ng/mL to about 4 ng/mL, about 1.2 ng/mL, about 2.6 ng/mL, about
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3.2 ng/mL, or any plasma concentration in a range bounded by, or between, any
of
these values.
[0141] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the particular species of mammal has a plasma
concentration
of zoledronic acid at 24 hours that is about 0.2 ng/mL to about 2 ng/mL, about
0.5
ng/mL to about 1.5 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 1 ng/mL to
about 1.5 ng/mL, about 0.5 ng/mL, about 1.0 ng/mL, about 1.4 ng/mL, or any
plasma
concentration in a range bounded by, or between, any of these values.
[0142] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the particular species of mammal has a plasma
concentration
of zoledronic acid at 36 hours that is about 0.1 ng/mL to about 2 ng/mL, about
0.2
ng/mL to about 1.5 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL
to
about 1 ng/mL, about 1 ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about 0.8
ng/mL, about 1.1 ng/mL, or any plasma concentration in a range bounded by, or
between, any of these values.
[0143] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the particular species of mammal has a plasma
concentration
of zoledronic acid at 48 hours that is about 0.1 ng/mL to about 2 ng/mL, about
0.2
ng/mL to about 1.5 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL
to
about 0.9 ng/mL, about 0.9 ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, about
0.7
ng/mL, about 1.1 ng/mL, or any plasma concentration in a range bounded by, or
between, any of these values.
[0144] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the particular species of mammal has a plasma
concentration
of zoledronic acid at 72 hours that is about 0.2 ng/mL to about 1 ng/mL, about
0.2
ng/mL to about 1.5 ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.3 ng/mL
to
about 0.6 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.2 ng/mL, about 0.5
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ng/mL, about 0.9 ng/mL, or any plasma concentration in a range bounded by, or
between, any of these values.
[0145] An oral
dosage form comprising zoledronic acid having a dose of
zoledronic acid and a configuration suitable for a particular species of
mammal may
be configured so that the elimination half-life of zoledronic acid in the
particular
species of mammal is about 30 hours to about 100 hours, about 40 hours to
about
60 hours, about 40 hours to about 50 hours, about 50 hours to about 60 hours,
about
42 hours, about 51 hours, about 59 hours, or any half-life in a range bounded
by, or
between, any of these values.
[0146] As used
herein, the "elimination half-life" refers to the apparent first-
order terminal plasma elimination half-life, obtained by non-compartmental
analysis
using Win-Nonlin. A terminal plasma elimination half-life is the time required
to
reduce the plasma concentration to half after reaching pseudo-equilibrium, and
not
the time required to eliminate half the administered dose. For orally
administered
drugs, terminal plasma elimination half-life can be affected by absorption of
the drug,
as well as plasma clearance and extent of distribution.
[0147] In some
embodiments, the disodium salt form of zoledronic acid
provides an enhancement to bioavailability, as compared to the diacid form of
zoledronic acid, which adds to any enhancement to bioavailability provided by
any
bioavailability-enhancing agents in the dosage form. In some embodiments, the
disodium salt form of zoledronic acid provides an enhancement to
bioavailability, as
compared to the diacid form of zoledronic acid, which is greater than any
enhancement to bioavailability provided by any bioavailability-enhancing
agents in
the dosage form. In some embodiments, the disodium salt form of zoledronic
acid
may be administered in a dosage form that is substantially free of
bioavailability-
enhancing agents.
[0148] In some
embodiments, a dosage form comprising a disodium salt of
zoledronic acid is a solid.
[0149] In some
embodiments, a dosage form comprising a disodium salt of
zoledronic acid is used to treat an inflammatory condition.
[0150] In some
embodiments, a dosage form comprising a disodium salt of
zoledronic acid is used to treat arthritis.
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[0151] In some
embodiments, a dosage form comprising a disodium salt of
zoledronic acid is used to treat complex regional pain syndrome.
[0152] In some
embodiments, zoledronic acid is in a form that has an
aqueous solubility, meaning the solubility in water, greater than 1% (w/v),
about 5%
(w/v) to about 50% (w/v), about 5% (w/v) to about 20% (w/v), about 10% (w/v)
to
about 15% (w/v), or about 12% (w/v) to about 13% (w/v).
[0153] The disodium salt form of zoledronic acid can be more
compressible than the diacid form of zoledronic acid. This can make it easier
for a
dosage form to have a desired hardness. It can also make it easier to increase
the
drug load, so that a smaller tablet can be given for a given dosage strength.
In some
embodiments, a solid dosage form of zoledronic acid, such as the diacid form
of
zoledronic acid or the disodium salt form of zoledronic acid, can have a
hardness of
about 5 kPa to about 20 kPa or about 5 kPa to about 14 kPa.
[0154] Zoledronic
acid or another bisphosphonate may be combined with a
pharmaceutical carrier selected on the basis of the chosen route of
administration
and standard pharmaceutical practice as described, for example, in Remington's
Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated
herein by reference, in its entirety. The relative proportions of active
ingredient and
carrier may be determined, for example, by the solubility and chemical nature
of the
compounds, chosen route of administration and standard pharmaceutical
practice.
[0155] Zoledronic
acid or another bisphosphonate may be administered by
any means that may result in the contact of the active agent(s) with the
desired site
or site(s) of action in the body of a patient. The compounds may be
administered by
any conventional means available for use in conjunction with pharmaceuticals,
either
as individual therapeutic agents or in a combination of therapeutic agents.
For
example, they may be administered as the sole active agents in a
pharmaceutical
composition, or they can be used in combination with other therapeutically
active
ingredients.
[0156] In some
embodiments, an osteoclast inhibitor is co-administered
with a steroid. Suitable steroids include, for example, hydrocortisone,
hydrocortisone
acetate, cortisone acetate, tixocortol pivalate, prednisolone,
methylprednisolone,
prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone,
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amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide,
halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone,
dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate,
acleometasone dipropionate, betamethasone valerate, betamethasone
dippropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-
propionate,
fluocortilone caproate, fluocortolone pivalate, and fluprednidene acetate,
hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, and prednicarbate.
[0157] Any
effective dose of steroid can be administered to a person. In
some embodiment, the dose of steroids may be about 1 to about 500 mg of the
steroid. In some embodiments, the dose of steroids does not exceed the 25 mg
of
the steroid, and is not less than 5 mg of the steroid.
[0158] The
steroid can be given orally (for example, 7.5 mg of prednisone),
by a separate infusion (for example, 7.5 mg of methyl prednisolone), mixed in
with
zoledronic acid in the same infusion, or be administered intramuscularly,
subcutaneously, by rectal suppository, by inhalation, or injected directly
into a joint.
[0159] Zoledronic
acid or another bisphosphonate may be administered to
a human patient in a variety of forms adapted to the chosen route of
administration,
e.g., orally, rectally, or parenterally. Parenteral
administration in this respect
includes, but is not limited to, administration by the following routes:
pulmonary,
intrathecal, intravenous, intramuscular, subcutaneous, intraocular,
intrasynovial,
transepithelial including transdermal, sublingual and buccal; topically; nasal
inhalation via insufflation; and rectal systemic.
[0160] The
effective amount of zoledronic acid or another bisphosphonate
will vary depending on various factors known to the treating physicians, such
as the
severity of the condition to be treated, route of administration, formulation
and
dosage forms, physical characteristics of the bisphosphonate compound used,
and
age, weight and response of the individual patients.
[0161] The amount
of zoledronic acid or another bisphosphonate in a
therapeutic composition may vary. For example, some liquid compositions may
comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about
20%
(w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1% (w/v),
about
0.1% (w/v) to about 0.5% (w/v), about 1 /0 (w/v) to about 3% (w/v), about 3%
(w/v) to
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about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10%
(w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v),
about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or
about
40% (w/v) to about 50% (w/v) of zoledronic acid.
[0162] Some solid
compositions may comprise at least about 5% (w/w), at
least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at
least
about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about
10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30%
(w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w)
to
about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about
60% (w/w), about 70% (w/w) to about 75% (w/w), about 70% (w/w) to about 80%
(w/w), or about 80% (w/w) to about 90% (w/w) of zoledronic acid.
[0163] Any suitable amount of an osteoclast inhibitor, including a
bisphosphonate, such as a nitrogen-containing bisphosphonate, e.g. zoledronic
acid,
minodronic acid, or ibandronic acid, may be used. Some solid or liquid oral
dosage
forms, or units of oral dosage forms (referred to collectively herein as "oral
dosage
form(s)") may contain about 0.005 mg to about 20 mg, about 0.1 mg to about 10
mg,
about 0.5 mg to about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about
500
mg, about 1 mg to about 50 mg, about 10 mg to about 250 mg, about 100 mg to
about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 150 mg, about
30 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about 50
mg,
about 40 mg to about 60 mg, about 50 mg to about 60 mg, about 55 mg, about 10
mg to about 300 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg,
about 40 mg to about 150 mg, about 10 mg to about 600 mg, about 40 mg to about
600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg, about 25 mg
to about 800 mg, about 30 mg to about 800 mg, about 10 mg to about 500 mg,
about
50 mg to about 150 mg, about 50 mg, about 100 mg, about 50 mg to about 500 mg,
about 100 mg to about 2000 mg, about 300 mg to about 1500 mg, about 200 mg to
about 1000 mg, about 100 mg to about 500 mg, or about 150 mg of zoledronic
acid,
or any amount of osteoclast inhibitor in a range bounded by, or between, any
of
these values. In some embodiments, the oral osteoclast inhibitor is
administered
daily, weekly, monthly, every two or three months, once a year, or twice a
year.
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[0164] Some oral dosage forms may contain about 0.005 mg to about 20
mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to
about 5 mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg, about 10 mg
to about 250 mg, about 100 mg to about 300 mg, about 20 mg to about 200 mg,
about 20 mg to about 150 mg, about 30 mg to about 100 mg, about 1 mg to about
1,000 mg, about 10 mg to about 50 mg, about 40 mg to about 60 mg, about 50 mg
to
about 60 mg, about 55 mg, about 10 mg to about 300 mg, about 10 mg to about
150
mg, about 10 mg to about 100 mg, about 40 mg to about 150 mg, about 10 mg to
about 600 mg, about 40 mg to about 600 mg, about 40 mg to about 2000 mg, about
40 mg to about 800 mg, about 25 mg to about 800 mg, about 30 mg to about 800
mg, about 10 mg to about 500 mg, about 50 mg to about 150 mg, about 50 mg,
about 100 mg, about 50 mg to about 500 mg, about 100 mg to about 2000 mg,
about
300 mg to about 1500 mg, about 200 mg to about 1000 mg, about 100 mg to about
500 mg, or about 150 mg of osteoclast inhibitor, or any amount of osteoclast
inhibitor
in a range bounded by, or between, any of these values. In some embodiments,
the
oral osteoclast inhibitor is administered daily, weekly, monthly, every two or
three
months, once a year, or twice a year.
[0165] In some
embodiments, an oral dosage form may contain about 10
mg/m2 to about 20 mg/m2, about 15 mg/m2 to about 20 mg/m2, about 18 mg/m2,
about 80 mg/m2 to about 150 mg/m2, about 90 mg/m2 to about 150 mg/m2, about
100 mg/m2 to about 150 mg/m2 of zoledronic acid, or any amount of zoledronic
in a
range bounded by, or between, any of these values. All dosage ranges or
amounts
expressed in mg/m2 are based upon the body surface area of the mammal.
[0166] In some
embodiments, the daily oral dose of an osteoclast inhibitor,
including a bisphosphonate, such as a nitrogen-containing bisphosphonate, e.g.
zoledronic acid, minodronic acid, or ibandronic acid, is about 0.005 mg to
about 20
mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 fig, about 0.2 mg to
about 5 mg, or any amount in a range bounded by, or between, any of these
values.
In some embodiments, the daily oral dose of osteoclast inhibitor is less than
about
35 mg/m2, less than about 30 mg/m2, less than about 25 mg/m2, about 1 mg/m2 to
about 35 mg/m2, about 1 mg/m2 to about 30 mg/m2, about 1.5 mg/m2 to about 25
mg/m2, about 1.8 mg/m2 to about 20 mg/m2, about 10 mg/m2 to about 20 mg/m2,
about 10 mg/m2 to about 30 mg/m2, about 15 mg/m2 to about 20 mg/m2, about 18
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mg/m2, or any amount of zoledronic acid in a range bounded by, or between, any
of
these values.
[0167] In some
embodiments, the daily oral dose of an osteoclast inhibitor,
including a bisphosphonate, such as a nitrogen-containing bisphosphonate, e.g.
zoledronic acid, minodronic acid, or ibandronic acid, is about 0.005 mg to
about 20
mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg to
about 5 mg, or any amount of osteoclast inhibitor in a range bounded by, or
between, any of these values. In some embodiments, the daily oral dose of
osteoclast inhibitor is less than about 35 mg/m2, less than about 30 mg/m2,
less than
about 25 mg/m2, about 1 mg/m2 to about 35 mg/m2, about 1 mg/m2 to about 30
mg/m2, about 1.5 mg/m2 to about 25 mg/m2, about 1.8 mg/m2 to about 20 mg/m2,
about 10 mg/m2 to about 20 mg/m2, about 10 mg/m2 to about 30 mg/m2, about 15
mg/m2 to about 20 mg/m2, about 18 mg/m2, or any amount of osteoclast inhibitor
in a
range bounded by, or between, any of these values.
[0168] In some
embodiments the daily oral dose of zoledronic acid is about
0.005 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 10
mg, about 0.2 mg to about 5 mg, or any amount of zoledronic acid in a range
bounded by, or between, any of these values. In some embodiments, the daily
oral
dose of zoledronic acid is less than about 35 mg/m2, less than about 30 mg/m2,
less
than about 25 mg/m2, about 1 mg/m2 to about 35 mg/m2, about 1 mg/m2 to about
30
mg/m2, about 1.5 mg/m2 to about 25 mg/m2, about 1.8 mg/m2 to about 20 mg/m2,
about 10 mg/m2 to about 20 mg/m2. about 10 mg/m2 to about 30 mg/m2, about 15
mg/m2 to about 20 mg/m2, about 18 mg/m2, or any amount of zoledronic acid in a
range bounded by, or between, any of these values.
[0169] In some
embodiments, the weekly oral dose of the osteoclast
inhibitor, including a bisphosphonate, such as a nitrogen-containing
bisphosphonate,
e.g. zoledronic acid, minodronic acid, or ibandronic acid, is about 1 mg to
about 1000
mg, about 1 mg to about 500 mg, about 10 mg to about 250 mg, about 100 mg to
about 300 mg, about 10 mg to about 100 mg, about 10 mg to about 150 mg, about
mg to about 100 mg, about 10 mg to about 300 mg, about 20 mg to about 150
mg, about 20 mg to about 60 mg, about 30 mg to about 70 mg, about 40 mg to
about
60 mg, about 50 mg to about 70 mg, about 50 mg, about 55 mg, about 100 mg to
about 150 mg, or about 30 mg to about 100 mg. In some embodiments, the weeky
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oral dose of the osteoclast inhibitor is less than about 250 mg/m2, less than
about
200 mg/m2, less than about 175 mg/m2, about 6 mg/m2 to about 250 mg/m2, about
mg/m2 to about 210 mg/m2, about 10 mg/m2 to about 170 mg/m2, about 4 mg/m2
to about 140 mg/m2, about 100 mg/m2 to about 140 mg/m2, about 126 mg/m2, or
any
amount in a range bounded by, or between, any of these values. The weekly oral
dose may be given as a single dose, given once during the week, or may be
given in
2, 3, 4, 5, 6, or 7 individual doses during the week.
[0170] In some
embodiments the weekly oral dose of zoledronic acid is
about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 10 mg to about
250 mg, about 100 mg to about 300 mg, about 10 mg to about 100 mg, about 10 mg
to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 300 mg,
about
rng to about 150 mg, about 20 mg to about 60 mg, about 30 mg to about 70 mg,
about 40 mg to about 60 mg, about 50 mg to about 70 mg, about 50 mg, about 55
mg, about 100 mg to about 150 mg, or about 30 mg to about 100 mg. In some
embodiments, the wacky oral dose of zoledronic acid is less than about 250
mg/m2,
less than about 200 mg/m2, less than about 175 mg/m2, about 6 mg/m2 to about
250
mg/m2, about 10 mg/m2 to about 210 mg/m2, about 10 mg/m2 to about 170 mg/m2,
about 4 mg/m2 to about 140 mg/m2, about 100 mg/m2 to about 140 mg/m2, about
126 mg/m2, or any amount of zoledronic acid in a range bounded by, or between,
any of these values.
The weekly oral dose may be given as a single dose, given once during the
week, or
may be given in 2, 3, 4, 5, 6, or 7 individual doses during the week.
[0171] In some
embodiments, the monthly dose of the osteoclast inhibitor,
including a bisphosphonate, such as a nitrogen-containing bisphosphonate, e.g.
zoledronic acid, rninodronic acid, or ibandronic acid, or the amount of the
osteoclast
inhibitor that is administered over a period of a month, is about 5000 mg or
less,
about 4000 mg or less, about 3000 mg or less, about 2000 mg or less, about
1000
mg or less, about 700 mg or less, about 600 mg or less, about 1 mg to about
4,000
mg, about 1 mg to about 1,000 mg. about 10 mg to about 1000 mg, about 50 mg to
about 1000 mg, about 10 mg to about 600 mg, about 40 mg to about 600 mg, about
50 mg to about 600 mg, about 40 mg to about 400 mg, about 50 mg to about 200
mg, about 200 mg to about 300 mg. about 250 mg to about 350 mg, or about 100
mg
to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to about 800 mg,
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about 50 mg to about 800 mg, or about 100 mg to about 800 mg, about 40 mg to
about 1000 mg, about 50 mg to about 1000 mg, or about 100 mg to about 1000 mg,
or any monthly dose in a range bounded by, or between, any of these values. In
some embodiments, the monthly oral dose of the osteoclast inhibitor is less
than
about 1000 ring/m2, less than about 800 mg/m2, less than about 600 mg/m2,
about 10
mg/m2 to about 1000 mg/m2, about 50 mg/m2 to about 800 mg/m2, about 70 mg/m2
to about 700 mg/m2, about 100 mg/m2 to about 700 mg/m2, about 100 mg/m2 to
about 600 mg/m2, about 50 mg/m2 to about 200 mg/m2, about 300 mg/m2 to about
600 mg/m2, about 450 mg/m2 to about 600 mg/m2, about 300 mg/m2 to about 1000
mg/m2, about 400 mg/m2 to about 1000 mg/m2, about 500 mg/m2 to about 1000
mg/m2, about 400 mg/m2 to about 700 mg/m2, about 500 mg/m2 to about 600 mg/m2,
about 540 mg/m2, or any amount in a range bounded by, or between, any of these
values. A monthly dose may be given as a single dose, or as two or more
individual
doses administered during the month. In some embodiments, the monthly dose is
administered in 2 or 3 weekly doses. In some embodiments, the monthly dose is
administered in 4 or 5 weekly doses. In some embodiments, the monthly dose is
administered in 28 to 31 daily doses. In some embodiments, the monthly dose is
administered in 5 to 10 individual doses during the month. The monthly dose
may
be administered for only 1 month, or may be repeatedly administered for 2 or
more
months.
[0172] In some
embodiments, the monthly dose of zoledronic acid, or the
amount of zoledronic acid that is administered over a period of a month, is
about
5000 mg or less, about 4000 mg or less, about 3000 mg or less, about 2000 mg
or
less, about 1000 mg or less, about 700 mg or less, about 600 mg or less, about
1 mg
to about 4,000 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1000 mg,
about 50 mg to about 1000 mg, about 10 mg to about 600 mg, about 40 mg to
about
600 mg, about 50 mg to about 600 mg, about 40 mg to about 400 mg, about 50 mg
to about 200 mg, about 200 mg to about 300 mg, about 250 mg to about 350 mg,
or
about 100 mg to about 600 mg, about 40 mg to about 2000 mg, about 40 mg to
about 800 mg, about 50 mg to about 800 mg, or about 100 mg to about 800 mg,
about 40 mg to about 1000 mg, about 50 mg to about 1000 mg, or about 100 mg to
about 1000 mg, or any monthly dose in a range bounded by, or between, any of
these values. In some embodiments, the monthly oral dose of zoledronic acid is
less
than about 1000 mg/m2, less than about 800 mg/m2, less than about 600 mg/m2,
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about 10 mg/m2 to about 1000 mg/m2, about 50 mg/m2 to about 800 mg/m2, about
70 mg/m2 to about 700 mg/m2, about 100 mg/m2 to about 700 mg/m2, about 100
mg/m2 to about 600 mg/m2, about 50 mg/m2 to about 200 mg/m2, about 300 mg/m2
to about 600 mg/m2, about 450 mg/m2 to about 600 mg/m2, about 300 mg/m2 to
about 1000 mg/m2, about 400 mg/m2 to about 1000 mg/m2, about 500 mg/m2 to
about 1000 mg/m2, about 400 mg/m2 to about 700 mg/m2, about 500 mg/m2 to about
600 mg/m2, about 540 mg/m2, or any amount of zoledronic acid in a range
bounded
by, or between, any of these values. A monthly dose may be given as a single
dose,
or as two or more individual doses administered during the month. In some
embodiments, the monthly dose is administered in 2 or 3 weekly doses. In some
embodiments, the monthly dose is administered in 4 or 5 weekly doses. In some
embodiments, the monthly dose is administered in 28 to 31 daily doses. In some
embodiments, the monthly dose is administered in 5 to 10 individual doses
during
the month. The monthly dose may be administered for only 1 month, or may be
repeatedly administered for 2 or more months.
[0173] With
respect to orally administering zoledronic acid to a mammal,
such as a dog, a rat, a rabbit, a monkey, an ape, or a human being, doses of
about
0.03 mg/kg to about 10 mg/kg, or any smaller range within this range, such as
about
0.4 mg/kg to about 3 mg/kg, about 0.4 mg/kg to about 1.5 mg/kg, mg/kg, about
0.4
mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg
to
about 0.7 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about
0.9
mg/kg, about 0.9 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.1 mg/kg,
about
1.1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.3 mg/kg, about 1.3
mg/kg
to about 1.4 mg/kg, about 1.4 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to
about
1.6 mg/kg, about 1.6 mg/kg to about 1.7 mg/kg, about 1.7 mg/kg to about 1.8
mg/kg,
about 1.8 mg/kg to about 1.9 mg/kg, about 1.9 mg/kg to about 2 mg/kg, about 2
mg/kg to about 2.1 mg/kg, about 2.1 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg
to
about 2.3 mg/kg, about 2.3 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg to about
2.5
mg/kg, about 2.5 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.7 mg/kg,
about 2.7 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 2.9 mg/kg, about
2.9
mg/kg to about 3 mg/kg, about 3 mg/kg to about 3.1 mg/kg, about 3.1 mg/kg to
about
3.2 mg/kg, about 3.2 mg/kg to about 3.3 mg/kg, about 3.3 mg/kg to about 3.4
mg/kg,
about 3.4 mg/kg to about 3.5 mg/kg, about 3.5 mg/kg to about 3.6 mg/kg, about
3.6
mg/kg to about 3.7 mg/kg, about 3.7 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg
to
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about 3.9 mg/kg, about 3.9 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about
0.6
mg/kg, about 0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg,
about
1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4
mg/kg to
about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about
2
mg/kg, about 2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg,
about
2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8
mg/kg
to about 3 mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about
3.4
mg/kg, about 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg,
about 3.8 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 0.7 mg/kg, about
0.7
mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.3 mg/kg, about 1.3 mg/kg to
about
1.6 mg/kg, about 1.6 mg/kg to about 1.9 mg/kg, about 1.9 mg/kg to about 2.2
mg/kg,
about 2.2 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to about 2.8 mg/kg, about
2.8
mg/kg to about 3 mg/kg, about 3.3 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to
about 4 mg/kg, about 0.4 mg/kg to about 1 mg/kg, or about 0.5 mg/kg to about 1
mg/kg, may be a safe dose for repeated oral administration, such as once daily
dosing to once yearly dosing, once daily dosing to twice yearly dosing, once
daily
dosing to thrice yearly dosing, once daily dosing to dosing every three
months, once
daily dosing to dosing every two months, once daily dosing to dosing every two
months, once daily dosing to dosing every month, once daily dosing to dosing
every
2-4 weeks, once daily dosing to once weekly dosing, etc.
[0174] The doses
referred to in the paragraph above for administration of
zoledronic acid to a mammal may be safely administered 2, 3, 4, 5, 6, 7, 8, 9,
10, 11,
12, 13, 14, or 15 times, or about 3 to about 10 times, once a day, or less
frequently,
such as once week, once every two weeks, once a month, etc.
[0175] For once
daily to once weekly oral administration of zoledronic acid
to a mammal such as a mouse, rat, dog, primate, or a human being, in some
embodiments, a safely repeated dose may be about 0.03 mg/kg to about 4 mg/kg,
or
any smaller range within this range, such as about 0.01 mg/kg to about 0.02
mg/kg,
about 0.02 mg/kg to about 0.03 mg/kg, about 0.03 mg/kg to about 0.04 mg/kg,
about
0.04 mg/kg to about 0.05 mg/kg, about 0.05 mg/kg to about 0.06 mg/kg, about
0.06
mg/kg to about 0.07 mg/kg, about 0.07 mg/kg to about 0.08 mg/kg, about 0.08
mg/kg
to about 0.09 mg/kg, about 0.09 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to
about
0.11 mg/kg, about 0.11 mg/kg to about 0.12 mg/kg, about 0.12 mg/kg to about
0.13
mg/kg, about 0.13 mg/kg to about 0.14 mg/kg, about 0.14 mg/kg to about 0.15
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mg/kg, about 0.15 mg/kg to about 0.16 mg/kg, about 0.16 mg/kg to about 0.17
mg/kg, about 0.17 mg/kg to about 0.18 mg/kg, about 0.18 mg/kg to about 0.19
mg/kg, about 0.19 mg/kg to about 0.2 mg/kg, about 0.2 mg/kg to about 0.21
mg/kg,
about 0.21 mg/kg to about 0.22 mg/kg, about 0.22 mg/kg to about 0.23 mg/kg,
about
0.23 mg/kg to about 0.24 mg/kg, about 0.24 mg/kg to about 0.25 mg/kg, about
0.25
mg/kg to about 0.26 mg/kg, about 0.26 mg/kg to about 0.27 mg/kg, about 0.27
mg/kg
to about 0.28 mg/kg, about 0.28 mg/kg to about 0.29 mg/kg, about 0.29 mg/kg to
about 0.3 mg/kg, about 0.3 mg/kg to about 0.31 mg/kg, about 0.31 mg/kg to
about
0.32 mg/kg, about 0.32 mg/kg to about 0.33 mg/kg, about 0.33 mg/kg to about
0.34
mg/kg, about 0.34 mg/kg to about 0.35 mg/kg, about 0.35 mg/kg to about 0.36
mg/kg, about 0.36 mg/kg to about 0.37 mg/kg, about 0.37 mg/kg to about 0.38
mg/kg, about 0.38 mg/kg to about 0.39 mg/kg, about 0.39 mg/kg to about 0.4
mg/kg,
about 0.05 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg,
about
0.06 mg/kg to about 0.15 mg/kg, about 0.07 mg/kg to about 0.15 mg/kg, about
0.08
mg/kg to about 0.15 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg, about 0.1
mg/kg
to about 0.15 mg/kg, about 0.03 mg/kg to about 0.5 mg/kg, about 0.06 mg/kg to
about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to
about
0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.1 mg/kg to about 0.2
mg/kg, about 0.4 mg to about 4 mg, about 0.4 mg/kg to about 0.6 mg/kg, about
0.6
mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to
about
1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about 1.6
mg/kg,
about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2
mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about 2.4 mg/kg
to
about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about
3
mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg,
about
3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8
mg/kg
to about 4 mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.6 mg/kg to about 2
mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to about 2 mg/kg,
about
0.5 mg/kg to about 1.5 mg/kg, about 0.6 mg/kg to about 1.5 mg/kg, about 0.7
mg/kg
to about 1.5 mg/kg, about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg to
about
0.9 mg/kg, about 0.6 mg/kg to about 0.9 mg/kg, about 0.7 mg/kg to about 0.9
mg/kg,
about 0.5 mg/kg to about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7
mg/kg to about 1 mg/kg, about 0.8 mg/kg to about 1 mg/kg, or about 0.8 mg/kg
to
about 0.9 mg/kg.
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[0176] For once
weekly or less frequent oral administration of zoledronic
acid to a mammal such as a mouse, rat, dog, primate, or a human being, in some
embodiments, a safely repeated dose may be about 0.4 mg to about 10 mg, or any
smaller range within this range, such as about 0.4 mg/kg to about 0.6 mg/kg,
about
0.6 mg/kg to about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg
to
about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg to about
1.6
mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg,
about
2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about 2.4
mg/kg to
about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about
3
mg/kg, about 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg,
about
3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 3.8
mg/kg
to about 4 mg/kg, about 4 mg/kg to about 4.2 mg/kg, about 4.2 mg/kg to about
4.4
mg/kg, about 4.4 mg/kg to about 4.6 mg/kg, about 4.6 mg/kg to about 4.8 mg/kg,
about 4.8 mg/kg to about 5 mg/kg, about 5 mg/kg to about 5.2 mg/kg, about 5.2
mg/kg to about 5.4 mg/kg, about 5.4 mg/kg to about 5.6 mg/kg, about 5.6 mg/kg
to
about 5.8 mg/kg, about 5.8 mg/kg to about 6 mg/kg, about 6 mg/kg to about 6.2
mg/kg, about 6.2 mg/kg to about 6.4 mg/kg, about 6.4 mg/kg to about 6.6 mg/kg,
about 6.6 mg/kg to about 6.8 mg/kg, about 6.8 mg/kg to about 7 mg/kg, about 7
mg/kg to about 7.2 mg/kg, about 7.2 mg/kg to about 7.4 mg/kg, about 7.4 mg/kg
to
about 7.6 mg/kg, about 7.6 mg/kg to about 7.8 mg/kg, about 7.8 mg/kg to about
8
mg/kg, about 8 mg/kg to about 8.2 mg/kg, about 8.2 mg/kg to about 8.4 mg/kg,
about
8.4 mg/kg to about 8.6 mg/kg, about 8.6 mg/kg to about 8.8 mg/kg, about 8.8
mg/kg
to about 9 mg/kg, about 9 mg/kg to about 9.2 mg/kg, about 9.2 mg/kg to about
9.4
mg/kg, about 9.4 mg/kg to about 9.6 mg/kg, about 9.6 mg/kg to about 9.8 mg/kg,
about 9.8 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 2 mg/kg, about 0.6
mg/kg to about 2 mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to
about
2 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 0.6 mg/kg to about 1.5
mg/kg,
about 0.7 mg/kg to about 1.5 mg/kg, about 0.8 mg/kg to about 1.5 mg/kg, about
0.5
mg/kg to about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 mg/kg to
about
1 mg/kg, about 0.8 mg/kg to about 1 mg/kg, or about 0.8 mg/kg to about 0.9
mg/kg,
[0177] In some
embodiments, the osteoclast inhibitor comprises zoledronic
acid, and the oral zoledronic acid, or disodium salt thereof, may be
administered in
combination with about 0.1 mg to about 10 mg of zoledronic acid, or a salt
thereof,
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administered parenterally, such as intravenously. In some embodiments, about
50
mg, about 100 mg, or about 150 mg of the disodium salt of zoledronic acid is
administered orally in combination with 1 mg parenteral, such as intravenous,
zoledronic acid. In some embodiments the parenteral dose of zoledronic acid is
about 0.25 mg to about 25 mg, about 0,25 mg to about 10 mg, or about 0,5 mg to
about 7.5 mg.
[0178] With
respect to oral administration of an osteoclast inhibitor, such
as zoledronic acid, minodronic acid, ibandronic acid, or another
bisphosphonate, for
the treatment of pain associated with inflammation, arthritis, CRPS, or any
other
condition recited herein, it may helpful if the mammal or human being to which
the
osteoclast inhibitor is administered does not eat food or drink beverage,
(other than
any water required to swallow the oral dosage form) for at least about 1 hour,
at least
about 2 hours, at least about 4 hours, at least about 6 hours, at least about
8 hours,
at least about 10 hours, or at least about 12 hours before the osteoclast
inhibitor is
administered. It may also be helpful if the mammal or human being to which the
osteoclast inhibitor is administered does not eat food or drink beverage for
at least
about 30 minutes, at least about 1 hour, at least about 2 hours, at least
about 3
hours, or at least about 4 hours after the osteoclast inhibitor is
administered. In
some embodiments, a human being to which the zoledronic acid is administered
avoids lying down, or remains upright or sits upright, for at least about 30
minutes or
about 1 hour after receiving a dosage form containing the osteoclast
inhibitor.
Avoiding food or beverage before or after oral administration of the
osteoclast
inhibitor can improve the bioavailability of the osteoclast inhibitor.
[0179] The oral
bioavailability of osteoclast inhibitor in a dosage form can
vary. Some
dosage forms may have ingredients added to enhance the
bioavailability. However, bioavailability enhancement is not necessary for an
oral
dosage form to be effective. In some embodiments, the dosage form is
substantially
free of bioavailability-enhancing agents. In some embodiments, an oral dosage
form
may have an oral bioavailability of the osteoclast inhibitor¨such as
zoledronic acid,
minodronic acid, ibandronic acid¨of about 0.01% to about 10%, about 0.1% to
about 7%, about 0.1% to about 5%, etc. Without ingredients or other methods to
enhance bioavailability, bisphosphonates such as zoledronic acid typically
have a
low bioavailability in an oral dosage form. In some
embodiments, the oral
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bioavailability of zoledronic acid is unenhanced or substantially unenhanced.
For
example, the oral bioavailability of zoledronic acid can be about 0.01% to
about 5%,
about 0.01% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about
0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5%, about
0.3% to about 1%, about 1% to about 3%, about 1.2% to about 3.5%, about 1.2%
to
about 3%, about 1% to about 4%, about 1.5% to about 4.5%, about 0.1% to about
0.5%, about 0.3% to about 0.5%, about 0.5% to about 1%, about 0.6% to about
0.7%, about 0.7% to about 0.8%, about 0.8% to about 0.9%, about 0.9%, about 1%
to about 1.1%, about 1.1% to about 1.2%, about 1.2% to about 1.3%, about 1.3%
to
about 1.4%, about 1.4% to about 1.5%, about 1.5% to about 1.6%, about 1.6% to
about 1.8%, about 1.8% to about 2%, or about 2% to 2.5%.
[0180] One
embodiment is a pharmaceutical composition comprising an
osteociast inhibitor such as zoledronic acid, minodronic acid, or ibandronic
acid
wherein the oral bioavailability of zoledronic acid in the dosage form is from
about
0.01% to about 10%.
[0181] In some
embodiments, the oral bioavailability of the osteociast
inhibitor in the dosage form is about 0.01% to about 5%, about 0.1% to about
7%,
about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% to about 2%, about
0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to about 1.5%, or about
0.3% to about 1.0%.
[0182] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.01% to about 5%.
[0183] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.1% to about 7%.
[0184] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.1% to about 5%.
[0185] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.1% to about 3%.
[0186] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.1% to about 2%.
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[0187] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.2% to about 2%.
[0188] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.2% to about 1.5%.
[0189] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.3% to about 1.5%.
[0190] In some
embodiments, the oral bioavailability of zoledronic acid in
the dosage form is about 0.3% to about 1.0%.
[0191] In some
embodiments, an oral dosage form comprises about 10 mg
to about 300 mg of zoledronic acid, minodronic acid, or ibandronic acid and is
administered daily for about 2 to about 15 consecutive days. This regimen may
be
repeated once monthly, once every two months, once every three months, once
every four months, once every five months, once every six months, once yearly,
or
once every two years.
[0192] In some
embodiments, an oral dosage form comprises about 10 mg
to about 150 mg or about 10 mg to about 100 mg of zoledronic acid, minodronic
acid, or ibandronic acid and is administered daily for about 2 to about 15
consecutive
days. This regimen may be repeated once monthly, once every two months, once
every three months, once every four months, once every five months, once every
six
months, once yearly, or once every two years.
[0193] In some
embodiments, an oral dosage form comprises about 10 mg
to about 150 mg or about 10 mg to about 100 mg of zoledronic acid, minodronic
acid, or ibandronic acid and is administered daily for about 5 to about 10
consecutive
days. This regimen may be repeated once monthly, once every two months, once
every three months, once every four months, once every five months, once every
six
months, once yearly, or once every two years.
[0194] In some
embodiments, an oral dosage form comprises about 40 mg
to about 150 mg of zoledronic acid, minodronic acid, or ibandronic acid and is
administered daily for about 5 to about 10 consecutive days. This regimen may
be
repeated once monthly, once every two months, once every three months, once
every four months, once every five months, once every six months, once yearly,
or
once every two years.
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[0195] In some
embodiments, the oral zoledronic acid, minodronic acid, or
ibandronic acid may be administered as one dose of about 100 mg to about 2000
mg, In some embodiments, the oral zoledronic acid, minodronic acid, or
ibandronic
acid may be administered as one dose of about 300 mg to about 1500 mg. In some
embodiments, the oral zoledronic acid, minodronic acid, or ibandronic acid may
be
administered as one dose of about 200 mg to about 1000 mg, The dose of
zoledronic acid, minodronic acid, or ibandronic acid may be administered in a
single
or divided dose.
[0196] An
osteoclast inhibitor, such as zoledronic acid, minodronic acid, or
ibandronic acid, may be formulated for oral administration, for example, with
an inert
diluent or with an edible carrier, or it may be enclosed in hard or soft shell
gelatin
capsules, compressed into tablets, or incorporated directly with the food of
the diet.
For oral therapeutic administration, the active compound may be incorporated
with
an excipient and used in the form of ingestible tablets, buccal tablets,
coated tablets,
troches, capsules, elixirs, dispersions, suspensions, solutions, syrups,
wafers,
patches, and the like.
[0197] Tablets,
troches, pills, capsules and the like may also contain one
or more of the following: a binder such as gum tragacanth, acacia, corn starch
or
gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent
such as
corn starch, potato starch, alginic acid and the like; a lubricant such as
magnesium
stearate; a sweetening agent such as sucrose, lactose or saccharin; or a
flavoring
agent such as peppermint, oil of wintergreen or cherry flavoring. When the
unit
dosage form is a capsule, it may contain, in addition to materials of the
above type, a
liquid carrier. Various other materials may be present as coating, for
instance,
tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup
or elixir
may contain the active compound, sucrose as a sweetening agent, methyl and
propylparabens as preservatives, a dye and flavoring, such as cherry or orange
flavor. It may be desirable for material in a dosage form or pharmaceutical
composition to be pharmaceutically pure and substantially non toxic in the
amounts
employed.
[0198] Some
compositions or dosage forms may be a liquid, or may
comprise a solid phase dispersed in a liquid.
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[0199] An
osteoclast inhibitor, such as zoledronic acid, minodronic acid, or
ibandronic acid may be formulated for parental or intraperitoneal
administration.
Solutions of the active compounds as free acids or pharmacologically
acceptable
salts can be prepared in water suitably mixed with a surfactant, such as
hydroxypropylcellulose. A dispersion can also have an oil dispersed within, or
dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof.
Under
ordinary conditions of storage and use, these preparations may contain a
preservative to prevent the growth of microorganisms.
[0200] In some
embodiments, an oral dosage form may comprise a
silicified microcrystalline cellulose such as Prosolv. For example, about 20%
(wt/wt)
to about 70% (wt/wt), about 10% (wt/wt) to about 20% (wt/wt), about 20%
(wtiwt) to
about 40% (wt/wt), about 25% (wt/wt) to about 30% (wt/wt), about 40% (wt/wt)
to
about 50% (wt/wt), or about 45% (wt/wt) to about 50% (wt/wt) silicified
microcrystalline cellulose may be present in an oral dosage form or a unit of
an oral
dosage form.
[0201] In some
embodiments, an oral dosage form may comprise a
crosslinked polyvinylpyrrolidone such as crospovidone. For example, about 1%
(wt/wt) to about 10% (wt/wt), about 1% (wt/wt) to about 5% (wt/wt), or about
1%
(wt/wt) to about 3% (wt/wt) crosslinked polyvinylpyrrolidone may be present in
an
oral dosage form or a unit of an oral dosage form.
[0202] In some
embodiments, an oral dosage form may comprise a fumed
silica such as Aerosil. For example, about 0.1% (wt/wt) to about 10% (wt/wt),
about
0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about 0.6% (wt/wt)
fumed
silica may be present in an oral dosage form or a unit of an oral dosage form.
[0203] In some
embodiments, an oral dosage form may comprise
magnesium stearate. For example, about 0.1% (wt/wt) to about 10% (wt/wt),
about
0.1% (wt/wt) to about 1% (wt/wt), or about 0.4% (wt/wt) to about 0.6% (wt/wt)
magnesium stearate may be present in an oral dosage form or a unit of an oral
dosage form.
[0204] An oral
dosage form comprising zoledronic acid or another
bisphosphonate or osteoclast inhibitor may be included in a pharmaceutical
product
comprising more than one unit of the oral dosage form.
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[0205] A
pharmaceutical product containing oral dosage forms for daily
use can contain 28, 29, 30, or 31 units of the oral dosage form for a monthly
supply.
An approximately 6 week daily supply can contain 40 to 45 units of the oral
dosage
form. An approximately 3 month daily supply can contain 85 to 95 units of the
oral
dosage form. An approximately six-month daily supply can contain 170 to 200
units
of the oral dosage form. An approximately one year daily supply can contain
350 to
380 units of the oral dosage form,
[0206] A
pharmaceutical product containing oral dosage forms for weekly
use can contain 4 or 5 units of the oral dosage form for a monthly supply. An
approximately 2 month weekly supply can contain 8 or 9 units of the oral
dosage
form. An approximately 6 week weekly supply can contain about 6 units of the
oral
dosage form. An approximately 3 month weekly supply can contain 12, 13 or 14
units of the oral dosage form. An approximately six-month weekly supply can
contain 22 to 30 units of the oral dosage form. An approximately one year
weekly
supply can contain 45 to 60 units of the oral dosage form.
[0207] A pharmaceutical product may accommodate other dosing regimes.
For example, a pharmaceutical product may comprise 5 to 10 units of the oral
dosage form, wherein each unit of the oral dosage form contains about 40 mg to
about 150 mg of zoledronic acid, minodronic acid, or ibandronic acid. Some
pharmaceutical products may comprise 1 to 10 units of the oral dosage form,
wherein the product contains about 200 mg to about 2000 mg of zoledronic acid,
minodronic acid, or ibandronic acid. For such a product, each unit of the oral
dosage
form may be taken daily for Ito 10 days or 5 to 10 days during a month, such
as at
the beginning of a month.
[0208] Some oral
dosage forms comprising an osteoclast inhibitor¨such
as suitable bisphosphonates like zoledronic acid, minodronic acid, or
ibandronic acid
or salts thereof¨may have enteric coatings or film coatings. In some
embodiments,
an oral dosage form of an osteoclast inhibitor comprises a tablet having an
enteric
coating. In some embodiments, an oral dosage form of an osteoclast inhibitor
comprises a capsule having an enteric coating. In some embodiments, an oral
dosage form of an osteoclast inhibitor comprises a tablet having a film
coating. In
some embodiments, an oral dosage form of an osteoclast inhibitor comprises a
capsule having a film coating.
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[0209] Useful
doses for an antibody against RANK or RANKL, such as
denosumab, may range from about 0.1 mg/kg to about 20 mg/kg, about 0.75 mg/kg
to about 7.5 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 2
mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 to about 17 mg/kg, about 15
mg/kg to about 20 mg/kg, about 1 mg/kg, about 1 mg/kg to about 10 mg/kg, or
any
value bounded by or in between these ranges based on the body weight of the
mammal. The chosen dose may be administered repeatedly, particularly for
chronic
conditions, or the amount per dose may be increased or decreased as treatment
progresses. The chosen dose may be administered one or more times per week,
monthly, every two months, every three months, every six months, or every
year.
[0210] In some
embodiments, 60 mg of denosumab is administered
subcutaneously to patient in need of treatment. In some embodiments, the
administration is repeated every six months.
[0211] There are a number of ways that some part of Compound 1 and/or
Compound 2 may be removed from a zoledronic acid product. For example, HPLC,
preparative TLC, crystallization, sublimation, or zone purification may be
employed.
Solvents that may be useful in HPLC, TLC, or crystallization, may include, but
are
not limited to, water or organic solvents, such as hexanes, diethyl ether,
ethyl
acetate, methyl acetate, acetone, acetic acid, acetonitrile, tetrahydrofuran,
ethanol,
methanol, isopropyl alcohol, chloroform, diethyl ether, toluene,
dimethylformamide,
benzene, etc. Gradients, or two solvent systems may be employed as well. For
example, an HPLC separation may begin by elution with water, after some time
eluting with water, an organic solvent, such as acetonitrile, methanol,
ethanol, ethyl
acetate, acetone, acetic acid, methyl acetate, or another solvent could
gradually be
added to the water, or may replace the water entirely. Similarly,
crystallization or
recrystallization may employ a single solvent, or a combination of solvents.
For
example, zoledronic acid or a salt thereof, such as a disodium salt, might be
recrystallized from water, ethanol, methanol, diethyl ether, methyl acetate,
acetic
acid, etc., or a combination of these solvents or others. In some embodiments,
zoledronic acid or a salt thereof, such as a disodium salt, may be dissolved
in one
solvent, such as water or acetic acid, and crystallized by a second solvent or
solvent
system, such as hexane, diethyl ether, chloroform, dichloromethane, ethyl
acetate,
methyl acetate, acetic acid, ethanol, methanol, or a combination thereof. In
some
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embodiments, a disodium salt of zoledronic acid is dissolved in water, and
then
crystallized by adding hexane. In some embodiments, a disodium salt of
zoledronic
acid is dissolved in water, and then crystallized by adding diethyl ether. In
some
embodiments, a disodium salt of zoledronic acid is dissolved in water, and
then
crystallized by adding chloroform. In some embodiments, a disodium salt of
zoledronic acid is dissolved in water, and then crystallized by adding
dichloromethane. In some embodiments, a disodium salt of zoledronic acid is
dissolved in water, and then crystallized by adding ethyl acetate. In some
embodiments, a disodium salt of zoledronic acid is dissolved in water, and
then
crystallized by adding methyl acetate. In some embodiments, a disodium salt of
zoledronic acid is dissolved in water, and then crystallized by adding acetic
acid. In
some embodiments, a disodium salt of zoledronic acid is dissolved in water,
and
then crystallized by adding ethanol. In some embodiments, a disodium salt of
zoledronic acid is dissolved in water, and then crystallized by adding
methanol. For
embodiments employing water and a second solvent, the ratio of water to the
second
solvent (water:second solvent) may be about 1:100 to about 100:1, about 1:10
to
about 1:5, about 1:5 to about 1:4, about 1:4 to about 1:3, about 1:3 to about
1:2,
about 1:2 to about 1:1, about 1:1 to about 2:1, about 2:1 to about 3:1, about
3:1 to
about 4:1, about 4:1 to about 5:1, or about 1:1 to about 10:1.
[0212] In some
embodiments, a combination of two methods recited in the
paragraph above may be employed, such as HPLC or TLC and crystallization. In
some embodiments, a method may be repeated, such as HPLC, preparative TLC,
crystallization, sublimation, or zone purification. In some embodiments, a
purification
method recited in the paragraph above may be performed twice. In some
embodiments, a purification method recited in the paragraph above may be
performed three or four times.
[0213] In the
examples below, zoledronic acid was administered in the
disodium salt form as disodium zoledronate tetrahydrate. No
bioavailability
enhancing agents were used in the test compositions.
Example 1
Effect of Orally Administered Zoledronic Acid in Rat Model of Inflammatory
Pain
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Method:
[0214] The effect of orally administered zoledronic acid on
inflammatory
pain was examined using the rat complete Freund's adjuvant (CFA) model.
Inflammatory pain was induced by injection of 100% CFA in a 75 pL volume into
the
left hind paws of Sprague-Dawley rats on day 0, followed by assessments on
days 1-
3. Animals were orally administered vehicle (control), zoledronic acid 18
mg/m2 (or 3
mg/kg), zoledronic acid 120 mg/m2 (or 20 mg/kg), or zoledronic acid 900 mg/m2
(or
150 mg/kg) daily on days 1-3. Drug was dissolved in distilled water and
prepared
fresh daily. Animals were fasted prior to dosing. Under current FDA guidelines
for
extrapolating starting dosages from animals to humans, dosages expressed in
mg/m2 are considered equivalent between mammalian species. Thus, for example,
18 mg/m2 in a rat is considered equivalent to 18 mg/m2 in a human being, while
3
mg/kg in a rat may not be equivalent to 3 mg/kg in a human being.
[0215] Values for inflammatory pain (mechanical hyperalgesia) in the
vehicle and drug-treated animals were obtained on day 0 prior to CFA
injection, and
at baseline and post-treatment on days 1-3. Pain was assessed using a digital
Randall-Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). Animals
were
placed in a restraint sling that suspended the animal, leaving the hind limbs
available
for testing. Paw compression threshold was measured by applying increasing
pressure to the plantar surface of the hind paw with a dome-shaped tip placed
between the 3rd and 4th metatarsus. Pressure was applied gradually over
approximately 10 seconds. Measurements were taken from the first observed
nocifensive behavior of vocalization, struggle or withdrawal. A cut-off value
of 300 g
was used to prevent injury to the animal.
[0216] Reversal of inflammatory pain was calculated according to the
formula:
% reversal = ( Post-treatment ¨ Post-CFA baseline)/(Pre-CFA baseline ¨ Post-
CFA baseline) x 100.
[0217] The experiment was carried out using 9-10 animals per group.
Results:
[0218] Oral administration of zoledronic acid significantly improved
inflammatory pain thresholds compared to vehicle. Pain threshold measurements
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taken at various times are shown in FIG. I. Paw compression thresholds in the
18
mg/m2 group were higher than for vehicle during the entire measurement period
after
30 minutes from the start of treatment. On day three, paw compression
thresholds
for both the 18 mg/m2 and 900 mg/m2 groups were greater than for vehicle. An
improvement in pain threshold of 49% and 83% from baseline was observed for
the
18 mg/m2 and the 900 mg/m2 groups respectively.
[0219] Orally
administered zoledronic acid produced a 29% reversal of
inflammatory pain at the 18 mg/m2, and a 48% reversal at the 900 mg/m2 dose.
This
magnitude of effect is comparable to that obtained with clinical doses of
commercially available NSAIDs when tested in a similar model of inflammatory
pain.
Under current FDA guidelines, the reference body surface area of a human adult
is
1.62 m2. Thus, a daily dose of 18 mg/m2 corresponds to a monthly dose of about
500-560 mg/m2 or a human dose of about 800-900 mg.
[0220]
Surprisingly, the two higher doses resulted in thresholds that were
lower than vehicle on the first two days of dosing. The 120 mg/m2 group was
approximately equal or inferior to vehicle at all time points during the
assessment
period. While the 900 mg/m2 group showed effectiveness on day 3, this result
was
accompanied by significant toxicity necessitating euthanization of all the
animals in
this group two days after cessation of dosing.
Example 2
Effect of Orally Administered Zoledronic Acid in Rat Model of Arthritis Pain
Method:
[0221] The effect
of orally administered zoledronic acid on arthritis pain
was examined in the rat complete Freund's adjuvant (CFA) model of arthritis
pain. In
this model, injection of 100% complete Freund's adjuvant (CFA) in a 75 pL
volume
into the left hind paws is followed by a 10-14 day period to allow for the
development
of arthritis pain. Animals were orally administered vehicle (control),
zoledronic acid
54 mg/m2 (or 9 mg/kg), or zoledronic acid 360 mg/m2 (or 60 mg/kg), divided in
three
equal daily doses on the first three days post CFA injection. Drug was
dissolved in
distilled water and prepared fresh daily. Animals were fasted prior to dosing.
[0222] Arthritis
pain (mechanical hyperalgesia) in the vehicle and drug-
treated animals was evaluated on day 14 post CFA injection using a digital
Randall-
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Selitto device (dRS; IITC Life Sciences, Woodland Hills, CA). Animals were
placed in
a restraint sling that suspended the animal, leaving the hind limbs available
for
testing. Paw compression threshold was measured by applying increasing
pressure
to the plantar surface of the hind paw with a dome-shaped tip placed between
the
3rd and 4th metatarsus. Pressure was applied gradually over approximately 10
seconds. Measurements were taken from the first observed nocifensive behavior
of
vocalization, struggle or withdrawal. A cut-off value of 300 g was used to
prevent
injury to the animal.
[0223] Reversal of arthritis pain in the ipsilateral (CFA-injected)
paw was
calculated according to the formula:
% reversal = (ipsilateral drug threshold ¨ ipsilateral vehicle
threshold)/(contralateral vehicle threshold ¨ ipsilateral vehicle threshold) x
100.
[0224] The experiment was carried out using 7-10 animals per group.
Results:
[0225] Oral administration of zoledronic acid significantly improved
arthritis
pain thresholds compared to vehicle. As shown in FIGS. 2A and 2B, orally
administered zoledronic acid produced a dose-dependent reversal of arthritis
pain. A
reversal of 33% was observed in the 54 mg/m2 group, and reversal of 54% was
observed in the 360 mg/m2 group. Under current FDA guidelines, the reference
body surface area of a human adult is 1.62 m2. Thus, 54 mg/m2 in a rat is
equivalent
to an implied human dose of about 87 mg, and 360 mg/m2 in a rat is equivalent
to an
implied human dose of about 583 mg.
Example 3. Treatment of Complex Regional Pain Syndrome with Orally
Administered Zoledronic Acid.
[0226] The effect of orally administered zoledronic acid was examined
in
the rat tibia fracture model of complex regional pain syndrome (CRPS). CRPS
was
induced in the rats by fracturing the right distal tibias of the animals and
casting the
fractured hindpaws for 4 weeks, as described in Guo TZ et al. (Pain.
2004;108:95-
107). This animal model has been shown to replicate the inciting trauma,
natural
history, signs, symptoms, and pathologic changes observed in human CRPS
patients (Kingery WS et al., Pain. 2003;104:75-84).
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[0227] Animals were orally administered either vehicle (control) or
zoledronic acid, in a dosage of 18 mg/m2/day (3 mg/kg/day) for 28 days,
starting on
the day of fracture and casting. Drug was dissolved in distilled water and
administered by gavage. Animals were fasted for 4 hours before and 2 hours
after
dosing. At the end of the 28-day period, casts were removed, and on the
following
day, the rats were tested for hindpaw pain, edema, and warmth.
Pain assessments
[0228] Pain was
assessed by measuring hyperalgesia, and weight bearing.
[0229] To measure hyperalgesia, an up-down von Frey testing paradigm
was used. Rats were placed in a clear plastic cylinder (20 cm in diameter)
with a wire
mesh bottom and allowed to acclimate for 15 minutes. The paw was tested with
one
of a series of eight von Frey hairs ranging in stiffness from 0.41 g to 15.14
g. The
von Frey hair was applied against the hindpaw plantar skin at approximately
midsole,
taking care to avoid the tori pads. The fiber was pushed until it slightly
bowed and
then it was jiggled in that position for 6 seconds. Stimuli were presented at
an
interval of several seconds. Hindpaw withdrawal from the fiber was considered
a
positive response. The initial fiber presentation was 2.1 g and the fibers
were
presented according to the up-down method of Dixon to generate six responses
in
the immediate vicinity of the 50% threshold. Stimuli were presented at an
interval of
several seconds.
[0230] An
incapacitance device (IITC Inc. Life Science, Woodland, CA,
USA) was used to measure hindpaw weight bearing, a postural effect of pain.
The
rats were manually held in a vertical position over the apparatus with the
hindpaws
resting on separate metal scale plates and the entire weight of the rat was
supported
on the hindpaws. The duration of each measurement was 6 seconds and 10
consecutive measurements were taken at 60-second intervals. Eight readings
(excluding the highest and lowest ones) were averaged to calculate the
bilateral
hindpaw weight-bearing values. Weight bearing data were analyzed as the ratio
between right (fracture) and left hindpaw weight bearing values ((2R/(R-FL))
x100%).
Edema assessment
[0231] A laser
sensor technique was used to determine the dorsal-ventral
thickness of the hindpaw. Before baseline testing the bilateral hindpaws were
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tattooed with a 2 to 3 mm spot on the dorsal skin over the midpoint of the
third
metatarsal. For laser measurements each rat was briefly anesthetized with
isoflurane
and then held vertically so the hindpaw rested on a table top below the laser.
The
paw was gently held flat on the table with a small metal rod applied to the
top of the
ankle joint. Using optical triangulation, a laser with a distance measuring
sensor was
used to determine the distance to the table top and to the top of the hindpaw
at the
tattoo site and the difference was used to calculate the dorsal-ventral paw
thickness.
The measurement sensor device used in these experiments (4381 Precicura,
Limab,
Goteborg, Sweden) has a measurement range of 200 mm with a 0.01 mm resolution.
Hindpaw temperature measurement
[0232] The temperature of the hindpaw was measured using a fine wire
thermocouple (Omega, Stanford, CT, USA) applied to the paw skin. Six sites
were
tested per hindpaw. The six measurements for each hindpaw were averaged for
the
mean temperature.
Results
[0233] As illustrated in FIG. 3, treatment with orally administered
zoledronic acid reversed pain, restored weight bearing, and prevented edema as
compared to vehicle treated animals.
[0234] As
illustrated in FIG. 4, von Frey pain thresholds for the right
(fracture) hindpaw were reduced by 72% versus the contralateral (normal)
hindpaw
in vehicle treated animals. Zoledronate treatment reversed fracture induced
pain by
77% as compared to vehicle treatment.
[0235] As
illustrated in FIG. 5, reduction in weight bearing, a postural effect
of pain, was significantly higher in the vehicle treated group as compared to
the
zoledronic acid treated group. Weight bearing on the fracture hindlimb was
reduced
to 55% of normal in the vehicle treated group. Zoledronate treatment
significantly
restored hindlimb weight bearing as compared to vehicle treatment (86% of
normal).
[0236] As
illustrated in FIG. 6, the expected increase in hindpaw thickness
was greater in the vehicle treated group as compared to the zoledronic acid
treated
group, reflecting the development of edema. Zoledronate treatment reduced
hindpaw
edema by 60% versus vehicle treatment.
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[0237] Zoledronic acid reduced hindpaw warmth by 5% versus vehicle
treatment.
[0238] The daily dose in the above experiment was 18 mg/m2/day. Under
current FDA guidelines, the reference body surface area of a human adult is
1.62
m2. Thus, a daily dose of 18 mg/m2 corresponds to a monthly dose of about 500-
560
mg/m2 or a human dose of about 800-900 mg.
Example 6. Solubility of Disodium Salt of Zoledronic Acid
[0239] The
aqueous solubility of zoledronic acid and disodium zoledronate
tetrahydrate was determined. One gram of the test compound was measured in to
a
beaker. Demineralized water (pH 5.5) was then added in small increments to the
test
compound, and sonification was applied to the mixture. The procedure was
continued until complete dissolution was achieved. Full dissolution was
determined
to have been reached when a clear solution was present with no visible
material.
The volume of water required to reach full dissolution was used to calculate a
solubility value expressed in grams per 100 mL. The procedure was performed
for
each compound.
Results
[0240] As shown
in FIG. 7, the aqueous solubility of disodium zoledronate
tetrahydrate is approximately 50 times that of zoledronic acid. Disodium
zoledronate
tetrahydrate has a solubility of 12.5 g/100 mL compared to only 0.25 g/100 mL
for
zoledronic acid.
Example 7. Bioayailability of Orally Administered Zoledronic Acid and
Disodium Zoledronate
[0241] Tablets
were manufactured containing either pure zoledronic acid
or the disodium salt of zoledronic acid (disodium zoledronate tetrahydrate).
Both
types of tablets contained 50 mg of zoledronic acid equivalent per tablet.
Identical
excipients were used in both types of tablets, with amounts adjusted to
account for
the difference in molecular weights between the acid and the disodium salt.
[0242] Beagle
dogs were orally administered tablets containing 150 mg
zoledronic acid equivalent either in the form of disodium zoledronate (Group
1) or
pure zoledronic acid (Group 2). Each animal was given three 50 mg equivalent
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tablets (150 mg total), which were administered together. The animal's oral
cavity
was wetted with water before placing the tablets on the back of the animal's
tongue.
Animals were fasted before and after dosing. Animals were 6 to 9 months of age
and
weighed 6 to 10 kg on the day of dosing. There were three dogs per group.
[0243] Serial blood samples were collected from each animal by
venipuncture of the jugular vein at various points after dosing for
measurement of
plasma concentrations of zoledronic acid. Blood samples were collected into
chilled
tubes containing K2EDTA as the anticoagulant. Samples were then centrifuged at
approximately 3000 rpm at +4 C for 10 minutes for plasma derivation. Plasma
concentrations of zoledronic acid were measured using an LC/MS/MS method.
Results
[0244] The average plasma concentrations of zoledronic acid for each
group of dogs is summarized in Table 1 and illustrated in FIG. 8. Detectable
plasma
levels of zoledronic acid were observed for the entire 48 hours that they were
measured.
Table 1
Zoledronic Acid plasma concentrations in beagle
dogs
Plasma
Time concentration
(hour) (ng/mL)
Group 1 Disodium Zoledronate
(N=3) Tablets 0 0.00
(150 mg acid equivalent) 0.25 1193.97
0.5 1852.12
0.75 1776.51
1 1626.56
2 640.57
4 136.93
6 53.11
8 26.97
12 13.74
24 6.78
48 5.39
Group 2
(N=3) Zoledronic Acid Tablets 0 0.00
(150 mg acid equivalent) 0.25 390.92
0.5 846.19
0.75 819.15
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Table 1
Zoledronic Acid plasma concentrations in beagle
dogs
Plasma
Time concentration
(hour) (ng/mL)
1 831.77
2 477.76
4 90.11
6 28.22
8 15.10
12 6.13
24 3.18
48 1.84
[0245] Disodium
zoledronate produced significantly higher plasma levels of
zoledronic acid than pure zoledronic acid, indicating improved oral absorption
with
the salt form. Measured using peak plasma concentrations (Cmax), the disodium
salt
resulted in a 119% actual and 74% weight-adjusted increase in bioavailability
as
compared to pure zoledronic acid. Measured using area under the plasma
concentration curve (AUC0¨), bioavailability was 84% and 46% greater with the
disodium salt than with pure zoledronic acid, on an actual and weight-adjusted
basis
respectively. The average AUC0¨ for the disodium salt was 4073 ng=hr/mL and
the
average AUC0¨ for the diacid was 2217 ng=hr/mL. The AUC0¨ was found to be
dose proportional. Thus, for beagle dogs similar to those tested, about 3 mg
to
about 4 mg of the disodium salt would be expected to result in an AUC0¨ of
about
100 ng=hr/mL, and about 7 mg to about 8 mg of the disodium salt would be
expected
to result in an AUCo¨ of about 200 ng=hr/mL.
Example 8
[0246] Tablets were prepared by blending
zoledronic acid, either in the
form of the free acid or the disodium salt, with identical excipients. For
dosage forms
with a greater amount of active, the amount of the excipients was reduced
proportionally to keep the weight of the tablet at about 100 mg. After
blending, the
ingredients were compressed at varying pressures, followed by a film coating.
The
resulting tablets were then tested for hardness using a Dr. Schleuniger
Pharmatron
8M Tablet Hardness Tester. The results are shown in Table 2 and FIG. 9.
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Table 2
Compression
Force Hardness (kPa)
Disodium Disodium
Diacid Salt Salt
(psi) 50 mg 50 mg 71 mg
800 4.0 8.7 4.8
1100 6.1 11.2 6.8
1500 7.7 13.7 7.4
2000 8.7 16.3 10.7
2400 8.7 11.3
3000 11.4 14.1
4400 12.5 14.9
5500 12.8 18.2
6100 13.0
Example 9
[0247] Some embodiments
related to joint pain, bone marrow lesions, and
osteoarthritis were conceived as a result of analyzing data from a clinical
study.
Some of the results of this study were reported by Laslett et. al. in Ann
Rheum Dis
2012;71:1322-1328. Some of the description and data reported below was not
published prior to filing the present application. Fifty-two (52) patients
with clinical
knee osteoarthritis and knee bone marrow lesions (BML) were randomized to
receive either intravenous zoledronic acid (5 mg) or placebo in a double blind
fashion. All patients had to have at least one bone marrow lesion (BML) in the
affected knee on magnetic resonance imaging (MRI). All patients had x-ray of
the
knee for determination of joint space narrowing (JSN), which was graded
according
to the Osteoarthritis Research Society International (OARSI) atlas. Patients
had
either no joint space narrowing (OARSI Grade 0), or greater degrees of joint
space
narrowing (OARSI Grade 1 and Grade 2). Twenty six patients were treated with
zoledronic acid (8, 6, and 12 with OARSI Grades 0, 1, and 2, respectively).
Twenty
six patients received placebo (8, 8, and 10 with OARS! Grades 0, 1 and 2,
respectively).
[0248] Pain intensity was
assessed, at baseline and at three months, using
a 100 mm visual analog scale (VAS), with zero representing no pain and 100
representing extreme pain. The change in pain intensity from baseline to 3
months
was calculated.
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[0249] With
zoledronic acid treatment, pain was reduced significantly as
compared to placebo in patients with no joint space narrowing (OARS! Grade 0),
but
not in patients with joint space narrowing (OARS! Grades 1-2). As shown in
Table 3
and FIG. 10, average VAS scores were reduced by 15 mm as compared to placebo
in the OARSI Grade 0 group, but only by 0.28 as compared to placebo in
patients
with OARSI Grades 1-2.
[0250] In the
zoledronic acid group, average VAS scores at 3 months
decreased from baseline by approximately 25 mm and 21 mm in patients with
OARS! Grades 0 and 1, respectively, but only by 9 mm in the OARSI Grade 2
patients (FIG. 11).
Table 3. Change in VAS Pain Scores at Three Months by OARSI Grade (mm)
OARSI Grade 0 OARSI Grades
1-2
Zoledronic Acid -24.6 -13.2
Placebo -9.6 -12.9
Difference from
-15.0 -0.28
Placebo
[0251] With
zoledronic acid treatment, pain was reduced significantly as
compared to placebo in patients with baseline VAS pain intensity scores of 50
mm or
greater, but not in patients with baseline VAS scores less than 50 mm. As
shown in
Table 4, average VAS scores were reduced by 9 mm as compared to placebo in the
patients with baseline VAS 50 mm, but only by 0.6 as compared to placebo in
patients with baseline VAS < 50 mm.
Table 4. Change in VAS Pain Scores at Three Months by Baseline VAS (mm)
Baseline VAS? 50 Baseline VAS <50
mm mm
Zoledronic Acid -26.2 -7.3
Placebo -17.2 -6.7
Difference from
-9.0 -0.6
Placebo
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[0252] As
summarized in Table 5 and illustrated in FIG. 12, pain
reduction was greater in patients with baseline VAS 50 mm, greater still in
patients
with OARS! Grade 0 joint space narrowing, and greatest in patients with both
baseline VAS 50 mm and OARS! Grade 0 joint space narrowing.
Table 5. Pain Reduction Compared to Placebo at Three Months (mm)
VAS Change
All patients -4.8
Baseline VAS 50 mm -9.0
OARS! Grade 0 -15.0
Baseline VAS 50 mm + OARSI -19.4
Grade 0
[0253] BMLs were
evaluated using proton density-weighted fat saturation
MR images. BMLs were scored using Osiris software (University of Geneva,
Geneva, Switzerland). The maximum size was measured in mm2 using software
cursors applied to the greatest area of each lesion. The lesion with the
highest score
was used if more than one was present at the same site. Each patient was given
a
BML score (mm2) at each of the four sites (medial tibial, medial femoral,
lateral tibial,
and lateral femoral sites) and these were summed to create a total BML score
(mm2). The change in the total area of BMLs from baseline to 6 months was
calculated.
[0254] The size of BMLs was reduced with zoledronic acid treatment. As
shown in FIG. 13 and Table 6, average BML area decreased by approximately 190
mm2 as compared to placebo in the OARS! Grade 0 group, but only by
approximately 33 mm2 as compared to placebo in patients with OARSI Grades 1-2.
Table 6. Change in BML Size (mm2)
OARSI Grade 0 OARSI Grades
1-2
Zoledronic Acid -244 -117
Placebo -55 -84
Difference from
-190 -33
Placebo
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Example 10
Methods
[0255] A study
was performed to evaluate the efficacy of a single
intravenous infusion of 5 mg ZA in comparison with intravenous placebo
infusion
among patients with chronic low back pain (LBP) and Modic changes on MRI. This
study was a double-blinded, randomized, placebo-controlled clinical trial in
patients
with low back pain (LBP). Patients were included in the study if they had low
back
symptoms for at least three months, a LBP of at least six (6) on a 10-cm
Visual
Analog Scale (VAS) or an Oswestry Disability Index (ODD of at least 30%, and
an
Ml, mixed M1/2 or M2 type change on MRI performed within six months at most
prior to enrolment.
[0256] Patients
were excluded from the study if they had renal impairment
with reduced creatinine clearance defined as an estimated glomerular
filtration rate
(eGFR) below 40 ml/min, hypocalcemia, known hypersensitivity to zoledronic
acid or
other bisphosphonates or ingredients of the infusion product, the presence of
red
flags, nerve root entrapment or willingness for early retirement.
Premenopausal
women of childbearing potential were also excluded. Blood samples were taken
prior
to the infusion to assess the serum concentration of calcium and creatinine.
The
clinical examination included medical history and clinical assessment of
lumbar
flexibility, tendon signs, and motor and sensory testing.
[0257] After
confirmation of eligibility patients were randomized to receive
a single intravenous infusion of 5 mg zoledronic acid (n = 20) or 100 ml
saline as
placebo (n = 20) over a 15-minute period. Information on use of the
concomitant
medication and hospital admissions were recorded. Blood samples were taken for
the assessment of safety, inflammatory mediators and markers of bone turnover
at
baseline, one month and one year.
[0258] Clinical
assessments were performed 14 days before enrolment
(screening visit), and follow-up visits at one month and one year after the
infusion.
The primary outcome was the change in the intensity of LBP on VAS. Secondary
outcomes included leg pain intensity, ODI, health-related quality of life
assessed with
RAND-36, patient-reported sick leaves and lumbar flexibility. These outcome
measures were assessed at baseline and at each follow-up. Lumbar flexibility
was
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evaluated using the fingers-to-floor and trunk side bending measures (in cm).
The
percentage of patients undergoing a 20% relative improvement, the proportion
of
patients reaching a VAS score of 40 or less in the primary outcome, and
patient
acceptable symptom state (PASS) were also assessed. Pain medication use was
inquired about during the follow-up visits.
Results
[0259] Zoledronic
acid treatment resulted in a greater improvement in LBP
intensity at one month as compared to placebo treatment. Furthermore, the
patients
receiving zoledronic acid reported NSAID use at one year significantly less
often
than those in the placebo group. Overall, the improvements in most of the
evaluated
parameters were greater in the zoledronic acid group throughout the follow-up
period.
[0260] The
clinical characteristics of study participants at baseline are
displayed in Table 6. The mean LBP duration was 293 days, initial LBP
intensity on
VAS 6.7, leg pain on VAS 2.9 and the ODI score was 32%. Altogether 19 patients
in
the ZA group and 18 in the placebo group had a M1/2 lesion. Modic changes were
most commonly (70%) situated at L4/5 or L5/S1. The zoledronic acid and placebo
groups were similar as regards the demographic and background characteristics
of
all patients at baseline (Table 6).
[0261] The mean
difference (MD) between the treatment groups in the
primary outcome, intensity of LBP, significantly favored zoledronic acid at
one month
(MD 1.4; 95% Cl 0.01 to 2.9) while at one year no significant difference was
observed (MD 0.7; 95% Cl -1.0 to 2.4; Table 7). The proportion of patients
with at
least 20% improvement in intensity of LBP and PASS both favored the zoledronic
acid treatment at one month: zoledronic acid 55% vs. placebo 25% (p = 0.105)
and
zoledronic acid 50% vs. placebo 20% (p = 0.096), respectively.
[0262] For the
patients who were treated with zoledronic acid, the
reduction in pain intensity was greater in those with greater baseline pain
intensity as
shown in Table 9. The mean reduction in pain from baseline was 3.4 for
patients with
baseline pain intensity ?. 7, as compared to a reduction of only 0.1 for
patients with a
baseline pain intensity < 6.
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[0263] Of the
secondary outcomes, the improvement in ODI, favored
zoledronic acid at 1 month, the adjusted between-group difference being 6.0%
(95%
CI -0.6 to 13), but not at one year (Table 7). Similarly, side bending (to
right and left)
favored the zoledronic acid treatment at one month but not at one year (Table
7).
Changes in total RAND-36, and in the physical and mental components of RAND-36
are shown in Table 8.
[0264] At baseline, there were no differences in self-reported use of non-
steroidal anti-inflammatory drugs (NSAIDs) between the treatment groups,
whereas
at one year, only 20% of patients in the ZA group used NSAIDs versus 60% in
the
placebo group.
Table 6: Baseline characteristics of study population according to treatment
group
Zoledronic Pacebo
Characteristics Acid
n=20 n=20
Sex, n (%) men 15(75) 11(55)
Age, mean (SD) years 49 (9.3) 51(7.3)
Smoking, n (c1/0) regular smokers* 5 (25) 6 (30)
BMI, mean (SD) kg/m 26 (3.3) 27 (3.2)
Workload, n (c1/0)
-Sedentary work with limited walking 4 (20) 4 (22)
-Fairly light work with considerable walking 4 (20) 3 (17)
but no
lifting or carrying heavy objects
-Fairly strenuous work with walking and 8 (40) 6 (33)
lifting
heaving objects or climbing stairs or uphill
-Very strenuous work with lifting or carrying 4 (20) 5 (28)
heaving
objects such as shoveling, digging, or
hammering
Type of worst MC-lesion**, n
- Type I I 1
-Type I/II 19 18
- Type II 0
MC at two or more levels, n ( ./0) 7 (3.5) 4 (20)
Levels of MC, n
-L2/3 4 0
-L314 3 5
-L4/5 6 5
-L5/S1 7 10
Duration of LBP, median (IQ range) days 330 (200, 365) 315 (270, 365)
Intensity of LBP, mean (SD)*** 6.6 (1.4) 6.8 (1.6) _
Duration of leg pain, median (IQ range) days 50 (0, 100) 36 (0,
160)
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Zoledronic Pacebo
Characteristics Acid
n=20
n=20
Intensity of leg pain, mean (SD)*** 3.0 (3.1) 2.9 (2.3)
Oswestry Disability Index, %, Mean (SD) 30(11) 35(10)
Duration of sick leave during the past year, 14 (0, 48) 18(1,
181)
median (IQ range) days
RAND-36, mean (SD) 50 (8) ____________________________ 50 (7)
RAND-36 physical component, mean (SD) 51(8) 49 (8)
RAND-36 mental component, mean (SD) 51(8) 49 (9)
BMI = Body Mass Index, MC = Modic Change, LBP = low back pain, SD = standard
deviation, IQ = inter-quartile.
*Smoking at least one cigarette per day.
**If different types of MC at two or more levels, classification is based on
the
assumed severity of the type, i.e., Type I > mixed Type I/II > Type II.
***Assessed using a 10 cm Visual Analogue Scale (VAS).
Table 7. Low back symptoms and lumbar flexibility at baseline, one month and
12
months according to treatment group and between group comparisons of
difference
from baseline to one month and 12 months
Mean (SD) Mean (SD) Unadjusted Adjusted
original values change analyses analyses
ZA Placeb ZA
Placeb Differenc P Differen P*
n=20 o o e ce
n=20 (95% Cl) (95% Cl)
Intensity of LBP
6.6 6.8
Baseline (1.4) (1.6)
1.3 1.4
0.09 0.
- 1 mo. (-0.2 to 7 (0.01 to 9
04
(2.3) (2.2) (2.7) (2.1)
0.6 0.7
- 12 3.8 4.6 -2.8 -2.2 (-1.0 to
0.47 0.38
4
mos. (2.5) (2.9) (2.9) (2.5) 7
2.4) 2.4)
Intensity of leg pain'
3.0 2.9
Baseline (3.1) (2.3)
0.8 0.8
- 1 mo. (2 0.36 0.23
(-0.9 to 7 (-0.6 to 7
.3) (2.4) (2.4) (2.6)
0.6 0.5
- 12 2.1 2.7 -0.9 -0.3 0.57 (-t 0.57
o mos. (2.8) (2.6) (3.4) (3.0) 3 3
2.7) 2.2) o
Oswestry disability index, %
Baseline 30 (11) 35 (10)
5.9 -1.7 0 6.0 4.3
-.21 0.07
- 1 mo. 24 (10) 33 (13) (-2.5 to 2 (-0.6 to
(11) (9.7) 11) 13)
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Mean (SD) Mean (SD) Unadjusted Adjusted
original values change analyses analyses
ZA Placeb ZA Placeb Differenc P Differen P*
n=20 o o e ce
n=20 _ (95% Cl) (95% Cl)
3.1 5.1
- 12 -5.0 -1.9 0.47 0.23
25 (13) 33 (15) (-5.6 to (-3.4 to
mos. (15) (12) 5 1
12) 14)
Fingers-to-floor, cm
-
Baseline 23 (19) 19(18)
0 3.6
-5.1 -0.1 5. 0.30 0.40
- 1 mo. 17 (17) 19 (17) (-4.8 to (-5.0
to
6 3
15) 12)
7.1 5.3
- 12 -6.3 0.9 0.21 0.27
16(16) 20(19) (11) (-4.3 to (-4.5 to
mos. (23) 5 7
18) 15)
Sidebending to right, cm
- 14.1 13.8
Baseline (4.9) (7.2)
15.7 13.3 1.5 -0.5 0.08
- 1 mo. (-4.3 to 0:110 (-4.4 to
7
(5.9) (6.9) (4.7) (2.2)
- 12 15.7 13.8 1.6 -0.1 0
-1 4.2.6 .7
.22 0.18
(-4.3 (--1 to
mos. (5.6) (6.5) (4.8) (3.5) to 7 0
1.1) 0.8)
Sidebending to left, cm
- 15.0 13.3
Baseline (5.4) (5.5)
16.1 12.8 1.1 -0.5 - 1 mo. (5 0.07 0.05
(-3.2 to 2 (-3.4 to 1
.3) (5.9) (3.0) (2.2)
-0.7
- 12 16.2 13.7 1.2 0.5 0.60 0.45
1. 2.1)
mos. (6.7) (5.7) (5.3) (3.2) (-3.5 to 1 (-3.8) 8 -
1.0 to 8
SD = standard deviation, Cl = confidence interval, ZA = zoledronic acid, LBP =
low
back pain.
*ANCOVA: Difference between follow-up and baseline, treatment effect adjusted
for
baseline value.
aOne subject missing at baseline in placebo group and in ZA group, and one
subject
at 1 month in ZA group.
Table 8: Health-related quality of life assessed using RAND-36 at baseline,
one
month, and 12 months according to treatment group and between group
comparisons of difference from baseline to one month and 12 months
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Mean (SD) Mean (SD) Unadjusted Adjusted
original values change analyses analyses
ZA Placeb ZA Placeb Differenc P Differenc P*
n=20 o o e e
n=20 (95% Cl) (95% Cl)
Total RAND-36
50 (8) 50 (7)
Baseline
- 1 mo. 51(8) 49 (8) 0.6 -0.6 1.2 (-3 to 0.53 1.3
(-3 to 0.47
(6.4) (5.0) 5) 0 5) 7
- 12 51(8) 49 (9) 1.0 -1.0 2.1 (-3 to 0.37 2.2 (-2 to
0.31
mos. (8.7) (5.9) 7) 8 7) 4
Physical component
52 (8) 48 (8)
Baseline
- 1 mo. 52 (9) 48 (8) 0.1 -0.1 0.3 (-4 to 0.89 1.3
(-3 to 0.55
(8.6) (5.5) 5) 7 6) 4
- 12 52 (8) 48 (2) 0.3 -0.3 0.7 (-5 to 0.80 2.1 (-3 to
0.40
mos. (10) (6.5) 6) 8 7) 5
Mental component
49 (9) 51(8)
Baseline
- 1 mo. 50 (9) 50 (9) 1,0 -1.0 2.0 (-2 to 0.28
1.6 (-2 to 0.39
(6.1) (5.6) 6) 6 5) 6
- 12 51(9) 49(9) 1,8 -1.8 3.5 (-2 to 0.16 2.7 (-2 to
0.26
mos. (9.0) (6.7) 9) 7 7) 1
SD = standard deviation, Cl = confidence interval, ZA = zoledronic acid.
*ANCOVA: Difference between follow-up and baseline, treatment effect adjusted
for
baseline value.
Table 9. Pain Reduction in Patients Treated Zoledronic Acid (cm)
VAS Change from
Baseline
Baseline VAS <6 -0.1
Baseline VAS 6 and <7 -2.3
Baseline VAS 7 -3.4
Example 11
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2
0 CI CI
.)t,
/ HCI, water
0
0 0 0 Ci¨OH
N N."
99.7%
87.7% H1/4_,
8 9 10
0 PO3H2
- + P03H2 _____________ _ +
PO3H2
H .11_\
. -3 2
HON \N=ZN
or H203P PO3H2
OH OH
HO
Compound 1 Compound 2
[0265] 1,3-Bis(2-
nnethoxy-2-oxoethyl)-1H-imidazol-3-iunn chloride (9).
Methyl chloroacetate (2; 29.8 mL, 338.6 mmol, 2.0 eq) was added drop-wise to 1-
(trimethylsily1)-1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was heated
at
60 C for 24 hours. The mixture was cooled to room temperature, washed with
Et20
(3x500 mL) and dried in vacua yielding 9 (41.97 g, 168.8 mmol, 99.7%) as a
white
solid.
[0266] 1,3-
Bis(carboxymethy1)1H-innidazol-3-ium chloride (10). To 1,3-
bis(2-methoxy-2-oxoethyl)-1H-imidazol-3-iunn chloride (9; 41.00 g, 164.88
mmol, 1
eq.) was added 37% aq. HC1 (30.03 mL, 362.74 mmol, 2.2 eq.). The mixture was
stirred under reflux for 0.5 hour. The mixture was concentrated and the
remaining
solid was washed with acetone (2x200 mL) and Et20 (3x200 mL). Drying in in
vacua
gave 10 (31.89 g, 144.55 mmol, 87.7%) as a white solid.
[0267] Compound 1: Compound 10 is reacted with an equimolar amount
of phosphorous acid, followed by an equimolar amount of phosphorous
trichloride,
and an excess of water to form Compound 1, which is precipitated from ethanol.
[0268] Compound
2: 1,3-Bis(carboxymethyl)-1H-imidazol-3-ium chloride
(10, 2.00 g, 9 mmol, 1.0 eq) and H3P03 (7.37 g, 90 mmol, 10 eq) were dissolved
in
toluene (10 mL) and heated to 70 C. The reaction mixture was stirred at this
temperature for 20 min before PC13 (16 mL, 180 mmol, 20 eq) was added within
30
min. The reaction mixture was then heated to 95 C and stirred at this
temperature for
2 h. Then, aq. HC1 (30 mL, 37% HCl and 5 mL H20) was added. The reaction
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mixture was heated to 100 C and stirred at this temperature for 7 h, for 2 d
stirred at
room temperature and then filtered. The filtrate was cooled in an ice bath and
added
within 45 min to absolute Et0H (90 mL). The resulting turbid solution was
stirred for
1 h at room temperature before the solid was filtered off. The filter cake (46-
1) was
isolated and analyzed by 2D-NMR spectroscopy and mass spectrometry (m/z= 477).
The filtrate was concentrated in vacuo to give residue 46-2. Five hundred mg
of this
residue were treated with aq. NaOH (150 mg in 3.5 mL H20) and to this was
added
Et0H (7 mL). After standing overnight the liquid was decanted and the
resulting solid
(46-M4) was analyzed NMR and mass spectrometry (m/z= 477).
[0269] The following embodiments are specifically contemplated:
Embodiment I. A method
of relieving inflammatory pain comprising
administering an oral dosage form containing zoledronic acid to a mammal in
need
thereof, wherein the mammal receives a total monthly dose of zoledronic acid
that is
about 800 mg/m2 or less based upon the body surface area of the mammal.
Embodiment 2. The method
of embodiment 1, wherein the mammal is a
human being that receives a total monthly dose of zoledronic acid that is
about 30
mg/m2 to about 700 mg/m2.
Embodiment 3. The method
of embodiment 2, wherein the total monthly
dose is administered in 4 or 5 weekly doses.
Embodiment 4. The method
of embodiment 2, wherein the total monthly
dose is administered in 28 to 31 daily doses.
Embodiment 5. The method
of embodiment 2, wherein the total monthly
dose is administered in 5 to 10 individual doses during the month.
Embodiment 6. The method
of embodiment 1, wherein the mammal is a
human being that receives a total weekly dose of zoledronic acid that is about
10 mg
to about 300 mg.
Embodiment 7. The method
of embodiment 6, wherein the total weekly
dose is a single dose, administered once a week.
Embodiment 8. The method
of embodiment 6, wherein the total weekly
dose is administered in 2 to 7 individual doses during the week.
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Embodiment 9. The method
of embodiment 1, wherein the mammal is a
human being that receives a total weekly dose of zoledronic acid that is about
10 mg
to about 150 mg.
Embodiment 10. The method of any preceding embodiment, wherein the
mammal experiences significant pain relief more than 3 hours after
administration of
the dosage form.
Embodiment 11. The method of embodiment 10, wherein the mammal
experiences significant pain relief during at least a part of a time from
about 3 hours
to about 24 hours after administration of the dosage form.
Embodiment 12. The method of embodiment 10, wherein the mammal
experiences significant pain relief during at least a part of a time from
about 3 hours
to about 3 weeks after administration of the dosage form.
Embodiment 13. A method of relieving inflammatory pain comprising
administering an oral dosage form containing zoledronic acid to a mammal in
need
thereof, wherein the oral dosage form contains about 10 mg/m2 to about 20
mg/m2 of
zoledronic acid based upon the body surface area of the mammal.
Embodiment 14. The method of embodiment 13, wherein the oral dosage
form contains about 15 mg/m2 to about 20 mg/m2 of zoledronic acid based upon
the
body surface area of the mammal.
Embodiment 15. A method of relieving inflammatory pain comprising orally
administering to a mammal in need thereof, about 300 mg/m2 to about 600 mg/m2
of
zoledronic acid per month to the mammal, based upon the body surface area of
the
mammal.
Embodiment 16. The method of embodiment 15, comprising orally
administering about 450 mg/m2 to about 600 mg/m2 of zoledronic acid per month
to
the mammal, based upon the body surface area of the mammal.
Embodiment 17. The method of any preceding embodiment, wherein the
mammal is not suffering from bone metastasis.
Embodiment 18. The method of any preceding embodiment, wherein the
mammal is not suffering from cancer.
Embodiment 19. The method of any preceding embodiment, wherein the
zoledronic acid is administered as a salt of a dianion of zoledronic acid.
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Embodiment 20. A method of relieving pain associated with an arthritis
comprising administering an oral dosage form containing zoledronic acid to a
human
being in need thereof.
Embodiment 21. The method of embodiment 20, wherein the human being
receives a total monthly dose of zoledronic acid that is about 40 mg to about
2000
mg.
Embodiment 22. The method of embodiment 21, wherein the total monthly
dose is administered in 4 or 5 weekly doses.
Embodiment 23. The method of embodiment 21, wherein the total monthly
dose is administered in 28 to 31 daily doses.
Embodiment 24. The method of embodiment 21, wherein the total monthly
dose is administered in 5 to 10 individual doses during the month.
Embodiment 25. The method of embodiment 20, wherein the human being
receives a total weekly dose of zoledronic acid that is about 100 mg to about
300
mg.
Embodiment 26. The method of embodiment 25, wherein the total weekly
dose is a single dose, administered once a week.
Embodiment 27. The method of embodiment 25, wherein the total weekly
dose is administered in 2 to 7 individual doses during the week.
Embodiment 28. The method of embodiment 20, wherein the human being
receives a total weekly dose of zoledronic acid that is about 10 mg to about
100 mg.
Embodiment 29. The method of any of embodiments 20-28, wherein the
human being experiences significant pain relief more than 3 hours after
administration of the dosage form.
Embodiment 30. The method of embodiment 29, wherein the human being
experiences significant pain relief during at least a part of a time from
about 3 hours
to about 24 hours after administration of the dosage form.
Embodiment 31. The method of embodiment 29, wherein the human being
experiences significant pain relief during at least a part of a time from
about 3 hours
to about 3 weeks after administration of the dosage form.
Embodiment 32. The method of any of embodiments 20-31, wherein the
dosage form contains about 10 mg/m2 to about 20 mg/m2 of zoledronic acid based
upon the body surface area of the human being.
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Embodiment 33. The method of embodiment 32, wherein the dosage form
contains about 15 mg/m2 to about 20 mg/m2 of zoledronic acid based upon the
body
surface area of the human being.
Embodiment 34. The method of any of embodiments 20-33, wherein about
50 mg/m2 to about 200 mg/m2 of zoledronic acid is orally administered per
month,
based upon the body surface area of the human being.
Embodiment 35. The method of any of embodiments 20-31, wherein the
dosage form contains about 80 mg/m2 to about 150 mg/m2 of zoledronic acid
based
upon the body surface area of the human being.
Embodiment 36. The method of embodiment 35, wherein about 300 mg/m2
to about 1000 mg/m2 of zoledronic acid is orally administered per month, based
upon
the body surface area of the human being.
Embodiment 37. The method of any of embodiments 20-36, wherein the
human being is not suffering from bone metastasis.
Embodiment 38. The method of any of embodiments 20-37, wherein the
human being is not suffering from cancer.
Embodiment 39. The method of any preceding embodiment, wherein the
zoledronic acid is in the disodium salt form.
Embodiment 40. An oral dosage form comprising zoledronic acid, wherein
the oral bioavailability of zoledronic acid in the dosage form is about 0.01%
to about
4%.
Embodiment 41. The oral dosage form of embodiment 40, wherein the oral
dosage form contains about 10 mg to about 300 mg of zoledronic acid.
Embodiment 42. The oral dosage form of embodiment 40, wherein the oral
dosage form contains about 10 mg to about 50 mg of zoledronic acid.
Embodiment 43. The oral dosage form of any of embodiments 40-42,
wherein the oral bioavailability of zoledronic acid in the dosage form is
about 0.1% to
about 2%.
Embodiment 44. A pharmaceutical product comprising more than one unit
of an oral dosage form of embodiment 40.
Embodiment 45. The pharmaceutical product of embodiment 44, wherein
each unit of the oral dosage form contains about 1 mg to about 50 mg of
zoledronic
acid.
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Embodiment 46. The pharmaceutical product of embodiment 45,
comprising 28, 29, 30, or 31 units of the oral dosage form, for a total of
about 28 mg
to about 1600 mg of zoledronic acid to be administered in about 1 month.
Embodiment 47. The pharmaceutical product of embodiment 45,
comprising 85 to 95 units of the oral dosage form, for a total of about 85 mg
to about
4800 mg of zoledronic acid to be administered in about 3 months.
Embodiment 48. The pharmaceutical product of embodiment 45,
comprising 170 to 200 units of the oral dosage form, for a total of about 170
mg to
about 10,000 mg of zoledronic acid to be administered in about 6 months.
Embodiment 49. The pharmaceutical product of embodiment 45,
comprising 350 to 380 units of the oral dosage form, for a total of about 350
mg to
about 19,000 mg of zoledronic acid to be administered in about 1 year.
Embodiment 50. The pharmaceutical product of embodiment 44, wherein
each unit of the oral dosage form contains about 10 mg to about 300 mg.
Embodiment 51. The pharmaceutical product of embodiment 50,
comprising 4 or 5 units of the oral dosage form, for a total of about 40 mg to
about
1500 mg of zoledronic acid to be administered within a period of about 1
month.
Embodiment 52. The pharmaceutical product of embodiment 50.
comprising 8 or 9 units of the oral dosage form, for a total of about 80 mg to
about
2700 mg of zoledronic acid to be administered in about 2 months.
Embodiment 53. The pharmaceutical product of embodiment 50,
comprising 12, 13 or 14 units of the oral dosage form, for a total of about
120 mg to
about 4200 mg of zoledronic acid to be administered in about 3 months.
Embodiment 54. The pharmaceutical product of embodiment 50,
comprising 22 to 30 units of the oral dosage form, for a total of about 220 mg
to
about 9000 mg of zoledronic acid to be administered in about 6 months.
Embodiment 55. The pharmaceutical product of embodiment 50,
comprising 45 to 60 units of the oral dosage form, for a total of about 450 mg
to
about 18000 mg of zoledronic acid to be administered in about 1 year.
Embodiment 56. The pharmaceutical product of embodiment 44,
comprising 1 to 10 units of the oral dosage form, wherein the product contains
about
200 mg to about 2000 mg of zoledronic acid.
Embodiment 57. The oral dosage form of any preceding embodiment,
wherein the zoledronic acid is in the form of a sodium salt.
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Embodiment 58. The oral dosage form of any preceding embodiment,
wherein the zoledronic acid is in a form that has an aqueous solubility
greater than
1% (w/v).
Embodiment 59. The oral dosage form of any preceding embodiment,
wherein the zoledronic acid is in a form that has an aqueous solubility of
about 5%
(w/v) to about 50% (w/v).
Embodiment 60. An oral dosage form comprising zoledronic acid and an
excipient, wherein the zoledronic acid is in a form that has an aqueous
solubility
greater than 1% (w/v).
Embodiment 61. The oral dosage form of embodiment 60, wherein the
zoledronic acid is in a form that has an aqueus solubility of about 5% (w/v)
to about
50% (wily).
Embodiment 62. A method of treating complex regional pain syndrome
comprising administering an oral dosage form containing zoledronic acid to a
mammal in need thereof.
Embodiment 63. The method of embodiment 62, wherein the mammal is a
human being that receives an amount of zoledronic acid that is about 30 mg/m2
to
about 700 mg/m2 in a period of one month or less.
Embodiment 64. The method of embodiment 63, wherein 4 or 5 weekly
doses are administered in a period of one month or less.
Embodiment 65. The method of embodiment 63, wherein 28 to 31 daily
doses are administered in a period of one month or less.
Embodiment 66. The method of embodiment 63, wherein 5 to 10 individual
doses are administered during a period of one month or less.
Embodiment 67. The method of embodiment 63, wherein about 30 ring/rre
to about 700 mg/m2 of zoledronic acid is administered during only one month.
Embodiment 68. The method of embodiment 63, wherein about 30 mg/m2
to about 700 mg/m2 of zoledronic acid is administered in a period of one month
or
less for 2 or more consecutive months.
Embodiment 69. The method of embodiment 62, wherein the mammal
receives about 10 mg/m2 to about 30 mg/m2 of zoledronic acid daily.
Embodiment 70. The method of embodiment 62, wherein the mammal is a
human being that receives a total weekly dose of zoledronic acid that is about
10 mg
to about 300 mg.
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Embodiment 71. The method of embodiment 70, wherein the total weekly
dose is a single dose, administered once a week.
Embodiment 72. The method of embodiment 70, wherein the total weekly
dose is administered in 2 to 7 individual doses during the week.
Embodiment 73. The method of any of embodiments 62-72, wherein the
complex regional pain syndrome is complex regional pain syndrome type I.
Embodiment 74. The method of any of embodiments 62-72, wherein the
complex regional pain syndrome is complex regional pain syndrome type II.
Embodiment 75. The method of any preceding embodiment, wherein the
zoledronic acid is in a salt form.
Embodiment 76. The method of any of embodiments 62-75, wherein the
dosage form contains about 10 mg/m2 to about 20 mg/m2 of zoledronic acid based
upon the body surface area of the mammal.
Embodiment 77. The method of embodiment 76, wherein the dosage form
contains about 15 mg/m2 to about 20 mg/m2 of zoledronic acid based upon the
body
surface area of the mammal.
Embodiment 78. A method of treating complex regional pain syndrome,
comprising administering pamidronic acid to a human being in need thereof.
Embodiment 79. A method of treating complex regional pain syndrome,
comprising administering neridronic acid to a human being in need thereof.
Embodiment 80. A method of treating complex regional pain syndrome,
comprising administering olpadronic acid to a human being in need thereof.
Embodiment 81. A method of treating complex regional pain syndrome,
comprising administering alendronic acid to a human being in need thereof.
Embodiment 82. A method of treating complex regional pain syndrome,
comprising administering incadronic acid to a human being in need thereof.
Embodiment 83. A method of treating complex regional pain syndrome,
comprising administering ibandronic acid to a human being in need thereof.
Embodiment 84. A method of treating complex regional pain syndrome,
comprising administering risedronic acid to a human being in need thereof.
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Embodiment 85. A method of treating pain, comprising administering
pamidronic acid to a human being in need thereof.
Embodiment 86. A method of treating pain, comprising administering
neridronic acid to a human being in need thereof.
Embodiment 87. A method of treating pain, comprising administering
olpadronic acid to a human being in need thereof.
Embodiment 88. A method of treating pain, comprising administering
alendronic acid to a human being in need thereof.
Embodiment 89. A method of treating pain, comprising administering
incadronic acid to a human being in need thereof.
Embodiment 90. A method of treating pain, comprising administering
ibandronic acid to a human being in need thereof.
Embodiment 91. A method of treating pain, comprising administering
risedronic acid to a human being in need thereof.
Embodiment 92. A method of treating arthritis pain, comprising
administering pamidronic acid to a human being in need thereof.
Embodiment 93. A method of treating arthritis pain, comprising
administering neridronic acid to a human being in need thereof.
Embodiment 94. A method of treating arthritis pain, comprising
administering olpadronic acid to a human being in need thereof.
Embodiment 95. A method of treating arthritis pain, comprising
administering alendronic acid to a human being in need thereof.
Embodiment 96. A method of treating arthritis pain, comprising
administering incadronic acid to a human being in need thereof.
Embodiment 97. A method of treating arthritis pain, comprising
administering ibandronic acid to a human being in need thereof.
Embodiment 98. A method of treating arthritis pain, comprising
administering risedronic acid to a human being in need thereof.
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Embodiment 99. A method of treating inflammatory pain, comprising
administering pamidronic acid to a human being in need thereof.
Embodiment 100. A method of treating inflammatory pain, comprising
administering neridronic acid to a human being in need thereof.
Embodiment 101. A method of treating inflammatory pain, comprising
administering olpadronic acid to a human being in need thereof.
Embodiment 102. A method of treating inflammatory pain, comprising
administering alendronic acid to a human being in need thereof.
Embodiment 103. A method of treating inflammatory pain, comprising
administering incadronic acid to a human being in need thereof.
Embodiment 104. A method of treating inflammatory pain, comprising
administering ibandronic acid to a human being in need thereof.
Embodiment 105. A method of treating inflammatory pain, comprising
administering risedronic acid to a human being in need thereof.
Embodiment 106. A method of treating complex regional pain syndrome,
comprising administering etidronic acid to a human being in need thereof.
Embodiment 107. A method of treating pain, comprising administering
etidronic acid to a human being in need thereof.
Embodiment 108. A method of treating arthritis pain, comprising
administering etidronic acid to a human being in need thereof.
Embodiment 109. A method of treating inflammatory pain, comprising
administering etidronic acid to a human being in need thereof.
Embodiment 110. A method of treating complex regional pain syndrome,
comprising administering clodronic acid to a human being in need thereof.
Embodiment 111. A method of treating pain, comprising administering
clodronic acid to a human being in need thereof.
Embodiment 112. A method of treating arthritis pain, comprising
administering clodronic acid to a human being in need thereof.
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Embodiment 113. A method of treating inflammatory pain, comprising
administering clodronic acid to a human being in need thereof.
Embodiment 114. A method of treating complex regional pain syndrome,
comprising administering tiludronic acid to a human being in need thereof.
Embodiment 115. A method of treating pain, comprising administering
tiludronic acid to a human being in need thereof.
Embodiment 116. A method of treating arthritis pain, comprising
administering tiludronic acid to a human being in need thereof.
Embodiment 117. A method of treating inflammatory pain, comprising
administering tiludronic acid to a human being in need thereof.
Embodiment 118. The method of any of embodiments 78-117, wherein the
active compound is orally administered.
Embodiment 119. The method of any of embodiments 78-117, wherein the
active compound is parenterally administered.
Embodiment 120. A method of enhancing the oral bioavailability of
zoledronic acid comprising orally administering a dosage form containing
zoledronic
acid in the disodium salt form.
Embodiment 121. The method of embodiment 120, wherein the zoledronic
acid in the disodium salt form provides an enhancement to bioavailability, as
compared to zoledronic acid in the diacid form, which adds to any enhancement
to
bioavailability provided by any bioavailability-enhancing agents in the dosage
form.
Embodiment 122. The method of embodiment 120, wherein the dosage
form is substantially free of bioavailability-enhancing agents.
Embodiment 123. The method of embodiment 120, wherein the zoledronic
acid in the disodium salt form is administered to a mammal in an amount that
provides an area under the plasma concentration curve of zoledronic acid of
about 4
ng=h/mL to about 2000 ng=h/mL to the mammal each time the zoledronic acid in
the
disodium salt is administered.
Embodiment 124. The method of embodiment 123, wherein the zoledronic
acid in the disodium salt form is administered at an interval of about 3 to
about 4
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weeks in an amount that provides an area under the plasma concentration curve
of
zoledronic acid of about 100 ng=h/mL to about 2000 ng=h/mL to the mammal each
time the zoledronic acid in the disodium salt form is administered.
Embodiment 125. The method of embodiment 123, wherein the zoledronic
acid in the disodium salt form is administered weekly, or 3 to 5 times in a
month, in
an amount that provides an area under the plasma concentration curve of
zoledronic
acid of about 20 ng=h/mL to about 700 ng=h/mL to the mammal each time the
zoledronic acid in the disodium salt form is administered.
Embodiment 126. The method of embodiment 123, wherein the zoledronic
acid in the disodium salt form is administered daily in an amount that
provides an
area under the plasma concentration curve of zoledronic acid of about 4
ng=h/mL to
about 100 ng=h/mL to the mammal each time the zoledronic acid in the disodium
salt
form is administered.
Embodiment 127. The method of embodiment 120, wherein the dosage
form is a solid.
Embodiment 128. The method of embodiment 120, 121, 122, 123, 124, 125,
126, or 127, wherein the bioavailability of zoledronic acid is improved by at
least
about 20% as compared to administration of zoledronic acid in the diacid form.
Embodiment 129. The method of embodiment 120, 121, 122, 123, 124, 125,
126, 127, or 128, further comprising administering, on a molar basis, less of
the
zoledronic acid in the disodium salt form than would be administered of
zoledronic
acid in the diacid form in order to achieve the same plasma levels of
zoledronic acid.
Embodiment 130. The method of embodiment 129, wherein at least about
mole% less of the disodium salt form is administered as compared the amount of
zoledronic acid in the diacid form that would be administered in order to
achieve the
same plasma levels of zoledronic acid.
Embodiment 131. The method of embodiment 129, wherein the disodium
salt form is administered in an amount, on a molar basis, that has a value of
about
0.8n to about 1.2nd, wherein:
nd = (batd)(na)
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wherein ba is the bioavailability of the diacid form, bd is the
bioavailability of the
disodium salt form, and na is the number of moles of zoledronic acid in the
diacid
form that would be administered in order to achieve the same plasma levels of
zoledronic acid.
Embodiment 132. The method of embodiment 131, wherein the disodium
salt is administered in an amount that has a value of about nd.
Embodiment 133. The method of any of embodiments 120-132, wherein the
zoledronic acid is used to treat an inflammatory condition.
Embodiment 134. The method of embodiment 133, wherein the zoledronic
acid is used to treat arthritis.
Embodiment 135. The method of embodiment 133, wherein the zoledronic
acid is used to treat complex regional pain syndrome.
Embodiment 136. The method of any of embodiments 1-39, 62-77, and
120-135, wherein:
a first oral dosage form is administered; and
a second oral dosage form is administered;
wherein, with respect to the first oral dosage form, the second oral dosage
form is administered at 10 x Tmax or greater, wherein Tmax is the time of
maximum
plasma concentration for the first oral dosage form.
Embodiment 137. A dosage form comprising zoledronic acid in the disodium
salt form, wherein the bioavailability, in a mammal, of zoledronic acid in the
disodium
salt form is greater than the bioavailability of zoledronic acid in the diacid
form would
be in the same dosage form.
Embodiment 138. A dosage form comprising zoledronic acid in the disodium
salt form, wherein the dosage form contains an amount of zoledronic acid in
the
disodium salt form that provides an area under the plasma concentration curve
of
zoledronic acid of about 4 ng=h/mL to about 2000 ng=h/mL to a human being to
which the dosage form is administered.
Embodiment 139. The dosage form of embodiment 138, wherein the
dosage form contains an amount of zoledronic acid in the disodium salt form
that
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provides an area under the plasma concentration curve of zoledronic acid of
about
100 ng=h/mL to about 2000 ng=h/mL to a human being to which the dosage form is
administered.
Embodiment 140. The dosage form of embodiment 138, wherein the
dosage form contains an amount of zoledronic acid in the disodium salt form
that
provides an area under the plasma concentration curve of zoledronic acid of
about
20 ng=h/mL to about 700 ng=h/mL to a human being to which the dosage form is
administered.
Embodiment 141. The dosage form of embodiment 138, wherein the
dosage form contains an amount of zoledronic acid in the disodium salt form
that
provides an area under the plasma concentration curve of zoledronic acid of
about 4
ng=h/mL to about 100 ng=h/mL to a human being to which the dosage form is
administered.
Embodiment 142. A dosage form comprising zoledronic acid in the disodium
salt form,
wherein the disodium salt form is present in a lower molar amount than would
be present if the zoledronic acid were in the diacid form; and
wherein the zoledronic acid in the disodium salt form has an improved
bioavailability as compared to the zoledronic acid in the diacid form to the
extent that
the lower molar amount of the disodium salt in the dosage form does not reduce
the
amount of zoledronic acid delivered to the plasma of a mammal.
Embodiment 143. The dosage form of embodiment 137, 138, 139, 140, 141,
or 142, wherein the dosage form is a solid.
Embodiment 144. The dosage form of embodiment 142 or 143, wherein the
bioavailability of zoledronic acid in the disodium salt form is improved by at
least
about 10% as compared to an otherwise identical dosage form containing
zoledronic
acid in the diacid form.
Embodiment 145. The dosage form of embodiment 142, 143, or 144,
containing at least about 20 mole% less of the disodium salt form as compared
to
the amount of the zoledronic acid in the diacid form that would be present if
the
zoledronic acid were in the diacid form.
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Embodiment 146. The dosage form of embodiment 142, wherein the
disodium salt form is present in an amount, on a molar basis, that has a value
of
about 0.9nd to about 1.1nd, wherein:
nd = (ba/bd)(na)
wherein ba is the bioavailability of the diacid form, bd is the
bioavailability of
the disodium salt form, and na is the number of moles of the diacid form that
would
be present if the zoledronic acid were in the diacid form.
Embodiment 147. The dosage form of embodiment 146, wherein the
disodium salt is administered in an amount that has a value of about ncl-
Embodiment 148. The method of any of embodiments 1-39, 62-77, and
120-136, wherein:
only a single oral dosage form is administered; or
a first oral dosage form is administered, and a second oral dosage form is
administered after the first oral dosage form, wherein the second oral dosage
form is
administered before the maximum pain relieving effect of the first oral dosage
form is
achieved, or the second oral dosage form is administered before an observable
pain
relieving effect is achieved.
Embodiment 149. The method of embodiment 148, wherein the second oral
dosage form is administered before an observable pain relieving effect is
achieved.
Embodiment 150. The method of any of embodiments 1-39, 62-77, and
120-132, wherein a first dosage form is administered, followed by
administration of a
second dosage form, wherein the second dosage form is administered after the
maximum pain relieving effect of the first oral dosage form is achieved, and
the
second oral dosage form is administered while a pain relieving effect from the
first
oral dosage form is observable.
Embodiment 151. The method of embodiment 148, 149, or 150, wherein the
second oral dosage form is administered about 24 hours to about 28 days after
the
first oral dosage form is administered.
Embodiment 152. The method of any of embodiments 20-39, wherein the
human being is about 30 years old to about 75 years old.
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Embodiment 153. The method of any of embodiments 20-39, wherein the
human being is about 1 year old to about 16 years old.
Embodiment 154. The method of any of embodiments 20-39, wherein the
human being is about 80 years old to about 95 years old.
Embodiment 155. The method of any of embodiments 20-39, wherein the
human being has suffered from the arthritis for at least 2 months.
Embodiment 156. The method of any of embodiments 20-39, wherein the
arthritis affects, a knee, an elbow, a wrist, a shoulder, or a hip.
Embodiment 157. The method of any of embodiments 1-44, 62-133, and
144-156, wherein the mammal or human being to which the zoledronic acid is
administered does not eat food or drink beverage for at least 1 hour before
the
zoledronic acid is administered.
Embodiment 158. The method of embodiment 157, wherein the mammal or
human being to which the zoledronic acid is administered does not eat food or
drink
beverage for at least 2 hours before the zoledronic acid is administered.
Embodiment 159. The method of embodiment 158, wherein the mammal or
human being to which the zoledronic acid is administered does not eat food or
drink
beverage for at least 4 hours before the zoledronic acid is administered.
Embodiment 160. The method of embodiment 159, wherein the mammal or
human being to which the zoledronic acid is administered does not eat food or
drink
beverage for at least 6 hours before the zoledronic acid is administered.
Embodiment 161. The method of any of embodiments 157-160, wherein the
mammal or human being to which the zoledronic acid is administered does not
eat
food or drink beverage for at least 30 minutes after the zoledronic acid is
administered.
Embodiment 162. The method of embodiment 161, wherein the mammal or
human being to which the zoledronic acid is administered does not eat food or
drink
beverage for at least 1 hour after the zoledronic acid is administered.
Embodiment 163. The method of embodiment 161, where in the mammal or
human being to which the zoledronic acid is administered does not eat food or
drink
beverage for at least 2 hours after the zoledronic acid is administered.
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Embodiment 164. The method, dosage form, or product, of any preceding
embodiment, wherein the zoledronic acid in the oral dosage form has a 24 hour
sustained plasma level factor of about 1 or higher.
Embodiment 165. The method, dosage form, or product, of any preceding
embodiment, wherein the zoledronic acid in the oral dosage form has a 24 hour
sustained plasma level factor that is higher than that of intravenously
administered
zoledronic acid.
Embodiment 166. The method, dosage form, or product, of any preceding
embodiment, wherein the oral dosage form is a solid that has a hardness of
about 5
kPa to about 20 kPa.
Embodiment 167. A method of treating bone marrow lesions comprising:
selecting a patient having a bone marrow lesion and OARSI grade 0 of joint
space
narrowing, and administering an inhibitor of osteoclast activity to the
patient for the
treatment of the bone marrow lesion.
Embodiment 168. The method of embodiment 167, wherein the inhibitor of
osteoclast activity is administered at least twice.
Embodiment 169. The method of embodiment 167, wherein the inhibitor of
osteoclast activity is administered about every three months, or more
frequently.
Embodiment 170. The method of embodiment 167, wherein the inhibitor of
osteoclast activity comprises a nitrogen-containing bisphosphonate.
Embodiment 171. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises zoledronic acid.
Embodiment 172. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises pamidronic acid.
Embodiment 173. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises neridronic acid.
Embodiment 174. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises olpadronic acid.
Embodiment 175. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises alendronic acid.
Embodiment 176. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises incadronic acid.
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Embodiment 177. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises ibandronic acid.
Embodiment 178. The method of any one of embodiments 167-170,
wherein the inhibitor of osteoclast activity is or comprises risedronic acid.
Embodiment 179. The method of any one of embodiments 167-178,
wherein the inhibitor of osteoclast activity is administered orally.
Embodiment 180. The method of any one of embodiments 167-178,
wherein the inhibitor of osteoclast activity is administered intravenously.
Embodiment 181. The method of any one of embodiments 167-180,
wherein the patient experiences a reduction in bone marrow lesion size that is
at
least about 100% greater than a reduction in bone marrow lesion size achieved
with
a placebo.
Embodiment 182. The method of any one of embodiments 167-180,
wherein the patient experiences a reduction in bone marrow lesion size that is
at
least about 150% greater than a reduction in bone marrow lesion size achieved
with
a placebo.
Embodiment 183. The method of any one of embodiments 167-182,
wherein the inhibitor of osteoclast activity is administered at least twice
over a period
of at least four weeks.
Embodiment 184. The method of any one of embodiments 167-183,
wherein the inhibitor of osteoclast activity is administered once weekly for a
period of
six weeks.
Embodiment 185. The method of any one of embodiments 167-184,
wherein the inhibitor of osteoclast activity comprises zoledronic acid, and
the weekly
dose is between about 25 mg and about 75 mg.
Embodiment 186. A method of treating knee pain comprising: selecting a
patient having knee pain and OARSI grade 0 of joint space narrowing, and
administering an inhibitor of osteoclast activity to the patient for the
treatment of the
knee pain.
Embodiment 187. The method of embodiment 186, wherein the inhibitor of
osteoclast activity is administered at least twice.
Embodiment 188. The method of any one of embodiments 186-187,
wherein the inhibitor of osteoclast activity is administered about every three
months,
or more frequently.
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Embodiment 189. The method of any one of embodiments 186-188,
wherein the inhibitor of osteoclast activity comprises a nitrogen-containing
bisphosphonate.
Embodiment 190. The method of any one of embodiments 186-189,
wherein the patient experiences pain relief three months after administration
of the
inhibitor of osteoclast activity.
Embodiment 191. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises zoledronic acid.
Embodiment 192. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises pamidronic acid.
Embodiment 193. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises neridronic acid.
Embodiment 194. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises olpadronic acid.
Embodiment 195. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises alendronic acid.
Embodiment 196. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises incadronic acid.
Embodiment 197. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises ibandronic acid.
Embodiment 198. The method of any one of embodiments 186-190,
wherein the inhibitor of osteoclast activity is or comprises risedronic acid.
Embodiment 199. The method of any one of embodiments 186-198,
wherein the patient experiences a reduction in pain intensity¨when using a 100
mm
visual analog scale¨of at least about 20.
Embodiment 200. A method of treating a bone marrow lesion of the knee
comprising: selecting a patient having a bone marrow lesion of the knee and
OARSI
Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1 of joint space narrowing,
and
administering an inhibitor of osteoclast activity to the patient for the
treatment of the
bone marrow lesion.
Embodiment 201. The method of embodiment 200, wherein the inhibitor of
osteoclast activity is administered at least twice.
Embodiment 202. The method of embodiment 201, wherein the inhibitor of
osteoclast activity is administered about every three months, or more
frequently.
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Embodiment 203. The method of embodiment 200, wherein the inhibitor of
osteoclast activity comprises a nitrogen-containing bisphosphonate.
Embodiment 204. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is zoledronic acid.
Embodiment 205. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is pamidronic acid.
Embodiment 206. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is neridronic acid.
Embodiment 207. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is olpadronic acid.
Embodiment 208. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is minodronic acid.
Embodiment 209. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is incadronic acid.
Embodiment 210. The method
of embodiment 203, wherein the
inhibitor of osteoclast activity is ibandronic acid.
Embodiment 211. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is risedronic acid.
Embodiment 212. The method of embodiment 203, wherein the inhibitor of
osteoclast activity is alendronic acid.
Embodiment 213. The method of embodiment 200, wherein the inhibitor of
osteoclast activity is administered orally.
Embodiment 214. The method of embodiment 200, wherein the inhibitor of
osteoclast activity is administered intravenously.
Embodiment 215. The method of embodiment 200, wherein the patient
experiences a reduction in bone marrow lesion size that is at least about 15%
within
about 6 months after the inhibitor of osteoclast activity is administered to
the patient.
Embodiment 216. The method of embodiment 200, wherein the patient
experiences a reduction in bone marrow lesion size that is at least about 25%
within
about 6 months after the inhibitor of osteoclast activity is administered to
the patient.
Embodiment 217. The method of embodiment 201, wherein the inhibitor of
osteoclast activity is administered at least twice over a period of at least
four weeks.
Embodiment 218. The method of embodiment 201, wherein the inhibitor of
osteoclast activity is administered once weekly for a period of six weeks.
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Embodiment 219. The method of embodiment 218, wherein the inhibitor of
osteoclast activity comprises zoledronic acid, and the weekly dose is between
about
25 mg and about 75 mg.
Embodiment 220. A method of treating knee pain comprising:
a. selecting a patient having knee pain, and:
i. OARSI Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1 of joint
space narrowing, or
ii. pain intensity of 5 or greater measured using the 0-10 NRS or 5 cm or
greater using the 10 cm VAS; and
b. administering an inhibitor of osteoclast activity to the patient.
Embodiment 221. The method of embodiment 220, comprising selecting a
patient having OARSI Grade 0 or Kellgren and Lawrence Grade 0 or Grade 1 of
joint
space narrowing.
Embodiment 222. The method of embodiment 220 or 221, comprising
selecting a patient having pain intensity of 5 or greater measured using the 0-
10
NRS or 5 cm or greater using the 10 cm VAS.
Embodiment 223. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is administered at least twice.
Embodiment 224. The method of embodiment 223, wherein the inhibitor of
osteoclast activity is administered about every three months, or more
frequently.
Embodiment 225. The method of embodiment 220, wherein the inhibitor of
osteoclast activity comprises a nitrogen-containing bisphosphonate.
Embodiment 226. The method of embodiment 220, wherein the patient
experiences pain relief within about three months after the inhibitor of
osteoclast
activity is administered to the patient.
Embodiment 227. The method of embodiment 226, wherein the patient
experiences pain relief at least 24 hours after the inhibitor of osteoclast
activity is
administered to the patient.
Embodiment 228. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is zoledronic acid.
Embodiment 229. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is minodronic acid.
Embodiment 230. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is neridronic acid.
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Embodiment 231. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is olpadronic acid.
Embodiment 232. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is alendronic acid.
Embodiment 233. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is incadronic acid.
Embodiment 234. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is ibandronic acid.
Embodiment 235. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is risedronic acid.
Embodiment 236. The method of embodiment 220, wherein the patient
experiences a reduction in pain intensity¨when using a 100 mm visual analog
scale¨of at least about 5.
Embodiment 237. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is administered at least twice over a period of at least
four weeks.
Embodiment 238. The method of embodiment 220, wherein the inhibitor of
osteoclast activity is administered once weekly for a period of six weeks.
Embodiment 239. The method of embodiment 238, wherein the inhibitor of
osteoclast activity comprises zoledronic acid, and the weekly dose is between
about
25 mg and about 75 mg.
Embodiment 240. A method of treating moderate to severe knee pain
comprising administering an inhibitor of osteoclast activity to a person
suffering from
moderate to severe knee pain.
Embodiment 241. The method of embodiment 240, wherein the person
suffering from moderate to severe knee pain has a normal joint space in the
knee.
Embodiment 242. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is administered at least twice.
Embodiment 243. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is administered about every three months, or more
frequently.
Embodiment 244. The method of embodiment 240, wherein the inhibitor of
osteoclast activity comprises a nitrogen-containing bisphosphonate.
Embodiment 245. The method of embodiment 240, wherein the patient
experiences pain relief within about three months after the inhibitor of
osteoclast
activity is administered to the patient.
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Embodiment 246. The method of embodiment 245, wherein the patient
experiences pain relief at least 24 hours after the inhibitor of osteoclast
activity is
administered to the patient.
Embodiment 247. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is zoledronic acid.
Embodiment 248. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is minodronic acid.
Embodiment 249. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is neridronic acid.
Embodiment 250. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is olpadronic acid.
Embodiment 251. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is alendronic acid.
Embodiment 252. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is incadronic acid.
Embodiment 253. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is ibandronic acid.
Embodiment 254. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is risedronic acid.
Embodiment 255. The method of embodiment 240, wherein the patient
experiences a reduction in pain intensity¨when using a 100 mm visual analog
scale¨of at least about 5.
Embodiment 256. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is administered at least twice over a period of at least
four weeks.
Embodiment 257. The method of embodiment 240, wherein the inhibitor of
osteoclast activity is administered once weekly for a period of six weeks.
Embodiment 258. The method of embodiment 257, wherein the inhibitor of
osteoclast activity comprises zoledronic acid, and the weekly dose is between
about
25 mg and about 75 mg.
Embodiment 259. A method of safely delivering zoledronic acid to the blood
of a mammal through repeated oral administration comprising:
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orally administering about 0.4 mg/kg to about 4 mg/kg of zoledronic
acid to the mammal no more frequently than once a day and more frequently
than once a week; or
orally administering about 0.4 mg/kg to about 10 mg/kg to the mammal
once a week, or less frequently.
Embodiment 260. The method of any preceding embodiment, such as
embodiment 259, wherein about 0.5 mg/kg to about 2 mg/kg is orally
administered to
the mammal daily.
Embodiment 261. The method of any preceding embodiment, such as
embodiment 260, wherein about 0.6 mg/kg to about 0.9 mg/kg is orally
administered
to the mammal daily.
Embodiment 262. The method of any preceding embodiment, such as
embodiment 259, wherein about 0.5 mg/kg to about 2 mg/kg is orally
administered to
the mammal weekly.
Embodiment 263. The method of any preceding embodiment, such as
embodiment 263, wherein about 0.6 mg/kg to about 0.9 mg/kg is orally
administered
to the mammal weekly.
Embodiment 264. The method of any preceding embodiment, such as
embodiment 259, 260, 261, 262, or 263, wherein zoledronic acid is orally
administered about 3 to about 10 times.
Embodiment 265. The method of any preceding embodiment, such as
embodiment 259, 260, 261, 262, 263, or 264, wherein zoledronic acid is orally
administered in a dosage form comprising more than about 10% zoledronic acid
by
weight.
Embodiment 266. The method of any preceding embodiment, such as
embodiment 259, 260, 261, 262, 263, 264, or 265, wherein zoledronic acid is
administered in a manner and amount that results in the mammal having an AUC0-
24
of zoledronic acid that is about 50 ng=h/mL to about 500 ng=h/mL with each
administration of zoledronic acid.
Embodiment 267. The method of any preceding embodiment, such as
embodiment 266, wherein zoledronic acid is administered in a manner and amount
that results in the mammal having an AUC0_24 of zoledronic acid that is about
100
ng=h/mL to about 500 ng=h/mL with each administration of zoledronic acid.
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Embodiment 268. A method of preparing an oral dosage form that is safe
for repeated administration to a mammal comprising combining zoledronic acid
with
an excipient that is pharmaceutically acceptable to the mammal, wherein the
amount
of zoledronic acid that is combined with the excipient is such that zoledronic
acid is
present in the oral dosage form in an amount that is 0.4 mg/kg to about 10
mg/kg
based upon the weight of the mammal.
Embodiment 269. The method of any preceding embodiment, such as
embodiment 268, wherein the amount of zoledronic acid that is combined with
the
excipient is such that the oral dosage form comprises more than about 10%
zoledronic acid by weight.
Embodiment 270. The method of any preceding embodiment, such as
embodiment 268 or 269, wherein the amount of zoledronic acid that is combined
with
the excipient is such that zoledronic acid is present in the oral dosage form
in an
amount that is 0.4 mg/kg to about 3 mg/kg based upon the weight of the mammal.
Embodiment 271. The method of any preceding embodiment, such as
embodiment 270, wherein the amount of zoledronic acid that is combined with
the
excipient is such that zoledronic acid is present in the oral dosage form in
an amount
that is 0.4 mg/kg to about 1.5 mg/kg based upon the weight of the mammal.
Embodiment 272. The method of any preceding embodiment, such as
embodiment 270, wherein the amount of zoledronic acid that is combined with
the
excipient is such that zoledronic acid is present in the oral dosage form in
an amount
that is 0.6 mg/kg to about 0.9 mg/kg based upon the weight of the mammal.
Embodiment 273. The method of any preceding embodiment, such as
embodiment 268, 269, 270, 271, or 272, wherein the oral dosage form is safe
for
once daily administration of the oral dosage form for about 3 to about 10
days.
Embodiment 274. The method of any preceding embodiment, such as
embodiment 268, 269, 270, 271, or 272, wherein the oral dosage form is safe
for
once weekly administration of the oral dosage form for about 3 to about 10
weeks.
Embodiment 275. A method of safely delivering zoledronic acid to the blood
of a mammal through repeated oral administration comprising:
orally administering about 0.05 mg/kg to about 4 mg/kg of zoledronic
acid to the mammal no more frequently than once a day and more frequently
than once a week; or
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orally administering about 0.1 mg/kg to about 10 mg/kg to the mammal
once a week, or less frequently
wherein zoledronic acid is orally administered at least 5 times.
Embodiment 276. The method of any preceding embodiment, such as
embodiment 275, wherein zoledronic acid is orally administered about 5 to
about 10
times.
Embodiment 277. The method of any preceding embodiment, such as
embodiment 275 or 276, wherein zoledronic acid is orally administered in a
dosage
form comprising more than about 10% zoledronic acid by weight.
Embodiment 278. The method of any preceding embodiment, such as
embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271,
272,
273, 274, 275, 276, or 277, wherein the mammal is a human being.
Embodiment 279. The method of any preceding embodiment, such as
embodiment 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271,
272,
273, 274, 275, 276, 277, or 278, wherein about 50 mg to about 350 mg of oral
zoledronic acid is administered to the mammal per month.
Embodiment 280. An oral dosage form prepared by the method of any
preceding embodiment, such as embodiment 259, 260, 261, 262, 263, 264, 265,
266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279.
[0270] Unless
otherwise indicated, all numbers expressing quantities of
ingredients, properties such as molecular weight, reaction conditions, and so
forth
used in the specification and claims are to be understood in all instances as
indicating both the exact values as shown and as being modified by the term
"about."
Accordingly, unless indicated to the contrary, the numerical parameters set
forth in
the specification and attached claims are approximations that may vary
depending
upon the desired properties sought to be obtained. At the very least, and not
as an
attempt to limit the application of the doctrine of equivalents to the scope
of the
claims, each numerical parameter should at least be construed in light of the
number
of reported significant digits and by applying ordinary rounding techniques.
[0271] The terms
"a," "an," "the" and similar referents used in the context of
describing the invention (especially in the context of the following claims)
are to be
construed to cover both the singular and the plural, unless otherwise
indicated herein
or clearly contradicted by context. All methods described herein can be
performed in
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any suitable order unless otherwise indicated herein or otherwise clearly
contradicted by context. The use of any and all examples, or exemplary
language
(e.g., "such as") provided herein is intended merely to better illuminate the
invention
and does not pose a limitation on the scope of any claim. No language in the
specification should be construed as indicating any non-claimed element
essential to
the practice of the invention.
[0272] Groupings
of alternative elements or embodiments disclosed herein
are not to be construed as limitations. Each group member may be referred to
and
claimed individually or in any combination with other members of the group or
other
elements found herein. It is anticipated that one or more members of a group
may
be included in, or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the specification
is
deemed to contain the group as modified thus fulfilling the written
description of all
Markush groups used in the appended claims.
[0273] Certain
embodiments are described herein, including the best mode
known to the inventors for carrying out the invention. Of course, variations
on these
described embodiments will become apparent to those of ordinary skill in the
art
upon reading the foregoing description. The inventor expects skilled artisans
to
employ such variations as appropriate, and the inventors intend for the
invention to
be practiced otherwise than specifically described herein. Accordingly, the
claims
include all modifications and equivalents of the subject matter recited in the
claims
as permitted by applicable law. Moreover, any combination of the above-
described
elements in all possible variations thereof is contemplated unless otherwise
indicated
herein or otherwise clearly contradicted by context.
[0274] In
closing, it is to be understood that the embodiments disclosed
herein are illustrative of the principles of the claims. Other modifications
that may be
employed are within the scope of the claims. Thus, by way of example, but not
of
limitation, alternative embodiments may be utilized in accordance with the
teachings
herein. Accordingly, the claims are not limited to embodiments precisely as
shown
and described.
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