Note: Descriptions are shown in the official language in which they were submitted.
W095/30421 ~ ~ ~ ~ ~ ~ 4 PGTI1895100288
-1-
Use of certain methanebisnhosohonic acid derivatives to prevent vrosthesis
loosening and
prosthesis ieration
Arthroplasty, especially of the hip joint, is now a common procedure for the
treatment of
patients with osteoarthritis, rheumatoid arthritis and osteoporotic fracture.
Approximately
800 000 hip replacements are performed globally each year. This number is
rising
steadily, younger patients are being treated and patients are living much
longer and they
all expect to lead a mobile, independent life. Despite the indisputable
success of this
technique, often complications arise and may eventually require costly
surgical revision (3
or 4 revisions being not uncommon for a single patient).
The most common complications are aseptic prosthesis loosening [see for
example H.
Malchau et al., Acta Orthop. Scand. 64 (1993) 497-506; R.D. Mulroy Jr. and
W.H. Harris,
J. Bone Joint Surg. (Br) 72-B (1990) 757-760; M. Winter et al., Clin. Orthop.
Rel.
Research 282 (1992) 73-80] and migration of the prosthesis through bone
without overt
loosening [see for example B.B. Wroblewski and P.D. Siney, Clin. Orthop. Rel.
Research
285 (1992) 45-47; M. Winter et al., loc. cit.]. These complications result in
considerable
morbidity, such as pain and reduced mobility. They occur with both cemented
and
uncemented, prostheses, regardless of design, material or coating.
Previous approaches to prevent these complications have concentrated on
alterations to the
design of the prosthesis and the selection of different materials for its
construction [see for
example H. Malchau et al., loc. cit.; R.D. Mulroy Jr. and W.H. Harris, loc.
cit.; M. Winter
et al., loc. cit.; B.B. Wroblewski and P.D. Siney, loc. cit.; J. Wilson-
MacDonald et al., J.
Bone Joint Surg. (Br) 72-B (1990) 423-430]. Apart from some preliminary
research with
non-steroidal anti-inflammatory drugs [A. Ohlin and U.H. Lerner, Bone and
Mineral 20
(1993) 67-78; J.H. Herman et al., J. Rheumatol. 21 (1994) 338-343], a
pharmacological
approach to prevent or treat the complications of arthroplasty, especially hip
arthroplasty,
has not been successful.
Methanebisphosphonic acid derivatives, in particular bisphosphonate compounds
(_
bisphosphonates), are used clinically to inhibit excessive bone resorption in
a variety of
diseases such as tumour-induced osteolysis, Paget's disease and osteoporosis
[H. Fleisch,
Handbook of Expl. Pharmacol. 83 (1988) 441-465j. Radiolabelled bisphosphonates
are
also used diagnostically to identify sites of high bone turnover [B.D. Collier
et al., J. Nucl.
Med. 34 (1993) 2241-2246; I. Fogelman et al., J. Nucl. Med. 34 (1993) 2247-
2252].
CA 02183764 2005-02-15
21489-9236
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In the orthopaedic field in general, there is a
strong prejudice against using bisphosphonates. Firstly,
attempts to use the commercially available bisphosphonate
etidronate in the prevention of heterotopic ossification -
which is another complication after arthroplasty but is very
different from prosthesis loosening and prosthesis migration
- proved either ineffective, or even detrimental due to a
rebound effect [see for example D.E. Garland, Clin. Orthop.
Rel. Research 263 (1991) 13-29; B.J. Thomas and
H.C. Amstutz, The Hip 1987, 59-69; B.J. Thomas, Orthop.
Clin. North America 23 (1992) 347-358].
Furthermore, there is increasing evidence that
some bisphosphonates may inhibit bone formation and
mineralization. Kanis, for example, teaches in Lancet 1984,
27-33 that bisphosphonates, as inhibitors of bone
resorption, may delay the repair of microfractures by
reducing the rate of remodelling. As another example,
Reid et al. in Lancet 1988, 143-146 found that
bisphosphonate treatment, in this particular case done with
disodium pamidronate, caused a reduction in bone formation
and a very low rate of bone turnover which raised the
possibility of impaired microfracture repair. Adamson
et al. [Lancet 342 (1993) 1459-1460) reports that
pamidronate may inhibit bone mineralization in Paget's
disease.
Surprisingly, it has now been found that certain
methanebisphosphonic acid derivatives are useful for the
cost-effective prevention or treatment of these
complications of joint replacement, especially hip
replacement, in mammals including man.
CA 02183764 2005-02-15
21489-9236
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According to ore aspect of the present invention,
there is provided use of 1-hydroxy-2-(imidazol-1-yl)ethane-
1,1-diphosphonic acid, or a pharmaceutically acceptable salt
or hydrate thereof, in manufacture of a pharmaceutical
composition for prevention or treatment of prosthesis
loosening or prosthesis migration in a mammal.
According to another aspect of the present
invention, there is provided use of 1-hydroxy-2-(imidazol-1-
yl)ethane-1,1-diphosphonic acid, or a pharmaceutically
acceptable salt or hydrate thereof, for prevention or
treatment of prosthesis loosening or prosthesis migration in
a mammal.
According to yet another aspect of the present
invention, there is provided 1-hydroxy-2-(imidazol-1-
yl)ethane-1,1-diphosphonic acid, or a pharmaceutically
acceptable salt or hydrate thereof, for prevention or
treatment of prosthesis loosening or prosthesis migration in
a mammal.
According to still another aspect of the present
invention, there is provided a pharmaceutical composition
comprising 1-hydroxy-2-(imidazol-1-yl)ethane-l,l-
diphosphonic acid, or a pharmaceutically acceptable salt or
hydrate thereof, and a pharmaceutically acceptable carrier,
diluent or excipient, for prevention or treatment of
prosthesis loosening or prosthesis migration in a mammal.
This can be demonstrated by appropriate in vitro
and in vivo tests. In particular, in vivo experiments show
that the bisphosphonates according to the invention are
effective in preventing prosthesis loosening in the treated
animals, e.g. sheep. This is demonstrated, for example, by
the following test methods: 12 adult female sheep, approx.
CA 02183764 2005-02-15
21489-9236
-2b-
50 kg body weight, are randomly divided into 2 groups
of 6 animals and all undergo a unilateral total hip
replacement operation with implantation of a titanium
prosthesis. Immediately after surgery one group of animals
receives an i.v. infusion of bisphosphonate and the other
group receives saline. This treatment may be subsequently
repeated, for example at 4 and 8 weeks. At regular monthly
intervals the hip and femoral region of each animal is
subjected to both standard and quantitative digital
radiography to assess changes in bone density around the
prosthesis as an early indicator of prosthesis loosening.
In addition the animals are walked over a Kistler force
plate to measure vertical ground reaction force
W0 95130421 PCT/IB95/00288
-3-
from both hind limbs to determine limb functionality and, indirectly, pain. At
12 months
after the operation, and 2 weeks prior to sacrifice, the animals receive a
double injection,
days apart, of the fluorescent bone label oxytetracycline to facilitate
histomorphometric
analysis. At the end of the labelling period the animals are killed and the
femurs with the
implants are removed for post-mortem analysis. Precision sections, cut and
polished from
the femurs, are subjected to microradiography to determine bone loss around
the implant.
Similar sections are also analyzed by histomorphometry to assess bone
resorption and
formation at the tissue level. Finally sections of bone containing the implant
are subjected
to a mechanical "push-out" test on a materials testing machine to measure the
strength of
bonding between the metal implant and the surrounding bone.
A comparison of the test animals treated with a bisphosphonate according to
the invention
with the controls clearly shows that bisphosphonate treatment is beneficial to
prevent and
treat prosthesis loosening.
The invention therefore relates to the use of a methanebisphosphonic acid
derivative
selected from
3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g.
pamidronate;
3-(N,N-dimethylamino}-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-
APD;
4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronic acid), e.g.
alendronate;
6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP; 3-(N-
methyl-
N-n-pentylamino)-1-hydroxypropane-l,l-diphosphonic acid, e.g. methyl-pentyl-
APD (_
BM 21.0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid; 1-
hydroxy-2-
(3-pyridyl)ethane-1,1-diphosphonic acid (risedronic acid), e.g. risedronate,
including
N-methyl pyridinium salts thereof, for example N-methyl pyridinium iodides
such as
NE-10244 or NE-10446; 1-(4-chlorophenylthio)methane-1,1-diphosphonic acid
(tiludronic
acid), e.g. tiludronate; 3-[N-(2-phenylthioethyl)-N-methylamino]-1-
hydroxypropane-
1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic
acid, e.g.
EB 1053 (Leo); I-(N-phenylaminothiocarbonyl)methane-1,1-diphosphonic acid,
e.g. FR
78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid
tetraethyl
ester, e.g. U-81581 (Upjohn); 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-
l,l-diphosphonic acid, e.g. YM 529; and 1,1-dichloromethane-1,1-diphosphonic
acid
(clodronic acid), e.g. clodronate; or a pharmaceutically acceptable salt
thereof, or any
hydrate thereof,
WO 95/30421 PCTIIB95100288
-4-
(for the manufacture of a pharmaceutical composition) for the prevention and
treatment of
prosthesis loosening and prosthesis migration in mammals including man.
As already mentioned above, prosthesis loosening and prosthesis migration
often occurs as
a complication after arthoplasty. Arthroplasty means a partial, e.g. hemi, or
total
ar2hroplasty of any joint, especially hip and knee, and in particular hip.
Pharmaceutically acceptable salts are preferably salts with bases,
conveniently metal salts
derived from groups Ia, Ib, IIa and IIb of the Periodic Table of the Elements,
including
alkali metal salts, e.g. potassium and especially sodium salts, or alkaline
earth metal salts,
preferably calcium or magnesium salts, and also ammonium salts with ammonia or
organic amines.
Especially preferred pharmaceutically acceptable salts are those where one,
two, three or
four, in particular one or two, of the acidic hydrogens of the bisphosphonic
acid are
replaced by a pharmaceutically acceptable canon, in particular sodium,
potassium or
ammonium, in first instance sodium.
A very preferred group of pharmaceutically acceptable salts is characterized
by having
one acidic hydrogen and one pharmaceutically acceptable canon, especially
sodium, in
each ofthe phosphonic acid groups.
All the methanebisphosphonic acid derivatives mentioned above are well known
from the
literature. This includes their manufacture (see e.g. EP-A-513 760, pp. 13-
48). For
example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid is prepared as
described e.g.
in US patent 3,962;432 as well as in US patents 4,639,338 and 4,711,880, and 1-
hydroxy-
2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is prepared as described e.g. in
US patent
4,939,130.
A particular embodiment of the invention is represented by the use of a
methane-
bisphosphonic acid derivative which is selected from 3-amino-1-hydroxypropane-
1,1-diphosphonic acid, 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic
acid,
4-amino-1-hydroxybutane-1,1-diphosphonic acid, 6-amino-1-hydroxyhexane-1,1-
diphos-
phonic acid,3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic
acid,
1-hydroxy-2-{imidazol-1-yl)ethane-1,1-diphosphonic acid; 1-hydroxy-2-(3-
pyridyl)ethane-1,1-diphosphonic acid, and N-methyl pyridinium salts thereof; 1-
(4-chloro-
WO 95/30421 21 ~ 3 7 6 4
-S-
phenylthio)methane-1,1-diphosphonic acid, 3-[N-(2-phenylthioethyl)-N-
methylamino]-
1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-I-yl)propane-
1,1-
diphosphonic acid,l-{N-phenylaminothiocarbonyl)methane-1,1-diphosphonic acid,
5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, 1-
hydroxy-
2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid, a pharmaceutically
acceptable salt thereof, and any hydrate thereof.
A preferred embodiment of the invention is represented by the use of a methane-
bisphosphonic acid derivative which is selected from 3-amino-1-hydroxypropane-
1,1-diphosphonic acid, 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic
acid,
4-amino-1-hydroxybutane-1,1-diphosphonic acid,6-amino-1-hydroxyhexane-1,1-
diphos-
phonic acid, 3-{N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic
acid,
1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid; I-hydroxy-2-(3-
pyridyl)ethane-1,1-diphosphonic acid, 3-[N-(2-phenylthioethyl)-N-methylamino]-
1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-I-yl)propane-
1,1-
diphosphonic acid, 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-
diphosphonic
acid, a pharmaceutically acceptable salt thereof, and any hydrate thereof.
A very preferred embodiment of the invention is represented by the use of a
methane-
bisphosphonic acid derivative which is selected from pamidronic acid,
alendronic acid,
3-(N-methyl-N-n-pentylamino)-I-hydroxypropane-1,1-diphosphonic acid, 1-hydroxy-
2-
(imidazol-1-yl)ethane-1,1-diphosphonic acid,risedronic acid and tiludronic
acid, a
pharmaceutically acceptable salt thereof, and any hydrate thereof.
An especially preferred embodiment of the invention is represented by the use
of a
methanebisphosphonic acid derivative which is selected from I-hydroxy-2-
(imidazol-1-
yl)ethane-1,1-diphosphonic acid and 3-amino-1-hydroxypropane-1,1-diphosphonic
acid,a
pharmaceutically acceptable salt thereof, and any hydrate thereof.
Further the invention relates to the use of 1-hydroxy-2-(imidazol-1-yl)ethane-
1,1-diphos-
phonic acid or a pharmaceutically acceptable salt thereof or any hydrate
thereof.
Further the invention relates to the use of 3-amino-1-hydroxypropane-l, l-
diphosphonic
acid or a pharmaceutically acceptable salt thereof or any hydrate thereof.
The pharmaceutically useful methanebisphosphonic acid derivatives may be used
in the
R'O 95130421 PGT/1895/00288
-6-
form of a possible isomer or of a mixture of isomers, typically as optical
isomers such as
enantiomers or diastereoisomers or geometric isomers, typically cis-trans
isomers. The
optical isomers are obtained in the form of the pure antipodes and/or as
racemates.
The pharmaceutically useful methanebisphosphonic acid derivatives can also be
used in
the form of their hydrates or include other solvents used for their
crystallisation.
The methanebisphosphonic acid derivative is preferably used in the form of a
pharmaceutical preparation that contains a therapeutically effective amount of
the active
ingredient optionally together with or in admixture with inorganic or organic,
solid or
liquid, pharmaceutically acceptable carriers which are suitable for
administration.
The pharmaceutical compositions may be, for example, compositions for enteral,
such as
oral, rectal, aerosol inhalation or nasal administration, compositions for
parenteral, such as
intravenous or subcutaneous administration, or compositions for transdermal
administration (e.g. passive or iontophoretic). Furthermore, direct local
administration at
the time of operation comes into consideration. What is meant by the latter
type of
administration is the coating of the exposed bone surface to which the implant
is attached,
with a bisphosphonate according to the invention, for example by washing the
bone
surface with a bisphosphonate solution. What is not meant by this type of
administration is
the coating of the prosthesis with bisphosphonates.
Preferably, the pharmaceutical compositions are adapted to oral or parenteral
(especially
intravenous or transdermal) administration before, during or after prosthesis
implantation,
or to local administration during prosthesis implantation. Intravenous and
oral, first and
foremost intravenous, adminstration is considered to be of particular
importance.
The particular mode of administration and the dosage will be selected by the
attending
physician taking into account the particulars of the patient, especially age,
weight, life
style, activity level, hormonal status (e.g. post-menopausal), bone mineral
density and
type of prosthesis to be implanted.
The dosage of the active ingredient may depend on various factors, such as
effectiveness
and duration of action of the active ingredient, mode of administration, warm-
blooded
species, andlor sex, age, weight and individual condition of the warm-blooded
animal.
WO 95130421 PCT/JB95/00288
-7_
Normally the dosage is such that a single dose of from 0.002 - 3.40 mg/kg,
especially
0.01 - 2.40 mg/kg, is administered to a warm-blooded animal weighing
approximately
75 kg. If desired, this dose may also be taken in several, optionally equal,
partial doses.
"mglkg" means mg drug per kg body weight of the mammal - including man - to be
treated.
The dose mentioned above - either administered as a single dose (which is
preferred) or in
several partial doses - may be repeated, for example once daily, once weekly,
once every
month, once every three months, once every six months or once a year. In other
words, the
pharmaceutical compositions may be administered in regimens ranging from
continuous
daily therapy to intermittent cyclical therapy.
Preferably, the methanebisphosphonic acid derivatives are administered in
doses which
are in the same order of magnitude as those used in the treatment of the
diseases
classically treated with methanebisphosphonic acid derivatives, such as
Paget's disease,
tumour-induced hypercalcaemia or osteoporosis. In other words, preferably the
methanebisphosphonic acid derivatives are administered in doses which would
likewise be
therapeutically effective in the treatment of Paget's disease, tumour-induced
hypercalcaemia or osteoporosis, i.e. preferably they are administered in doses
which
would likewise effectively inhibit bone resorption.
Formulations in single dose unit form contain preferably from about I % to
about 90 °lo,
and formulations not in single dose unit form contain preferably from about
0.1 °Jo to about
20 gb, of the active ingredient. Single dose unit forms such as capsules,
tablets or dragdes
contain e.g. from about 1 mg to about 500 mg of the active ingredient.
The invention further relates to the use of a composition for the manufacture
of a
medicament, e.g. in single dose unit form, for the prevention and treatment of
prosthesis
loosening and prosthesis migration in mammals including man, wherein the
composition
contains 0.002 - 3.40 mg/kg, especially 0.01 - 2.40 mglkg, of a
methanebisphosphonic
acid derivative as defined above per dosage form.
Moreover, the invention relates to the use of a methanebisphosphonic acid
derivative as
defined above at a dose of 0.002 - 3.40 mglkg, especially 0.01 - 2.40 mg/kg,
per dosage
form for the manufacture of a medicament for the prevention and treatment of
prosthesis
WO 9S/30421 ~' ~ ~ ~ ~ ~ PCT11895/00288
_g_
loosening and prosthesis migration in mammals including man.
Pharmaceutical preparations for enteral and parenteral administration are, for
example,
those in dosage unit forms, such as dragBes> tablets or capsules and also
ampoules. They
are prepared in a manner known per se, for example by means of conventional
mixing,
granulating, confectioning> dissolving or lyophilising processes. For example,
pharmaceutical preparations for oral administration can be obtained by
combining the
active ingredient with solid carriers, where appropriate granulating a
resulting mixture,
and processing the mixture or granulate, if desired or necessary after the
addition of
suitable adjuncts, into tablets or dragBe cores.
Suitable carriers are especially fillers, such as sugars, for example lactose,
saccharose,
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for
example
tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as
starch
pastes, using, for example, com, wheat, rice or potato starch, gelatin,
tragacanth, methyl-
cellulose and/or polyvinylpyrrolidone and, if desired, disintegrators, such as
the
above-mentioned starches, also carboxymethyl starch, crosslinked
polyvinylpyrrolidone,
agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are
especially
flow-regulating agents and lubricants, for example silicic acid, talc, stearic
acid or salts
thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
Drage cores
are provided with suitable coatings that may be resistant to gastric juices,
there being used,
inter alb-concentrated sugar solutions that optionaliy contain gum arabic,
talc,
polyvinylpyrrolidone, polyethylene glycol andlor titanium dioxide, or lacquer
solutions in
suitable organic solvents or solvent mixtures or, to produce coatings that are
resistant to
gastric juices, solutions of suitable cellulose preparations, such as
acetylcellulose
phthalate or hydroxypropylmethylcellulose phthalate. Colouring substances or
pigments
may be added to the tablets or drage coatings, for example for the purpose of
identification
or to indicate different doses of active ingredient.
Other orally administrable pharmaceutical preparations are dry-filled capsules
made of
gelatin, and also soft, sealed capsules made of gelatin and a plasticiser,
such as glycerol
or sorbitol. The dry-filled capsules may contain the active ingredient in the
form of a
granulate, for example in admixture with fillers, such as lactose, binders,
such as starches,
and/or glidants, such as talc or magnesium stearate, and, where appropriate,
stabilisers. In
soft capsules the active ingredient is preferably dissolved or suspended in
suitable liquids,
such as fatty oils, paraffin oil or liquid polyethylene glycols, it being
possible also for
w0 95130421 PCTI1895I00288
-9-
stabilisers to be added.
Parenteral formulations are especially injectable fluids that are effective in
various
manners, such as intravenously, intramuscularly, intraperitoneally,
intranasally,
intradermally or subcutaneously. Such fluids are preferably isotonic aqueous
solutions or
suspensions which can be prepared before use, for example from lyophilised
preparations
which contain the active ingredient alone or together with a pharmaceutically
acceptable
carrier. The pharmaceutical preparations may be sterilised and/or contain
adjuncts, For
example preservatives, stabilisers, wetting agents and/or emulsifiers,
solubilisers, salts for
regulating the osmotic pressure and/or buffers.
Suitable formulations for transdermal application include an effective amount
of the active
ingredient with carrier. Advantageous carriers include absorbable
pharmacologically
acceptable solvents to assist passage through the skin of the host.
Characteristically,
transdermal devices are in the form of a bandage comprising a backing member,
a
reservoir containing the compound optionally with carriers, optionally a rate
controlling
barrier to deliver the active ingredient of the skin of the host at a
controlled and
predetermined rate over a prolonged period of time, and means to secure the
device to the
skin.
The following Examples illustrate the invention described hereinbefore. The
term "active
ingredient" is to be understood as being any one of the methanebisphosphonic
acid
derivatives mentioned above as being useful according to the present
invention.
Example 1: Capsules containing coated pellets of, for example, disodium
pamidronate
pentahydrate, as active ingredient:
Core pellet:
active ingredient{ground) 197.3 mg
Microcrystalline cellulose 52.7 mg
(Avicel~ PH 105)
250.0 mg
+ Inner coating:
Cellulose HP-M 603 10.0 mg
Polyethylene glycol 2.0 mg
~~~1 ~3~~64
WO 95130421 PCTl1B95ID0188
-10-
Talc 8.0 mg
270.0 mg
+ Gastric juice-resistant outer coating:
Eudragit~ L 30 D-(solid) 90.0 mg
Triethyl citrate 21.0 mg
Antifoam~ AF 2.0 mg
Water
Talc 7.0 mg
390.0 mg
A mixture of disodium pamidronate with Avicel~ PH 105 is moistened with water
and
kneaded, extruded and formed into spheres. The dried pellets are then
successively coated
in the fluidized bed with an inner coating, consisting of cellulose HP-M 603,
polyethylene
glycol (PEG) 8000 and talc, and the aqueous gastric juice-resistant coat,
consisting of
Eudragit~ L 30 D, triethyl citrate and Antifoam~ AF. The coated pellets are
powdered
with talc and Fzlled into capsules (capsule size 0) by means of a commercial
capsule filling
machine, for example Hbfliger and Karg.
Example 2: Monolith adhesive transdermal system, containing as active
ingredient, for
example, I-hydroxy-2-(imidazol-1-yl)-ethane-I,1-diphosphonic acid:
Composition:
polyisobutylene (PIB) 300 5.0 g
(Oppanol B 1, BASF)
PIB 35000 3.0 g
(Oppanol B 10, BASF)
P1B 1200000 -- 9.0 g
(Oppanol B 100, BASF)
hydrogenated hydrocarbon resin 43.0 g
(Escorez 5320, Exxon)
I-dodecylazacycloheptan-2-one 20.0 g
(Atone, Nelson Res., Irvine/CA)
2183764
WO 95130421 PCTI1895100288
-11-
active ingredient Zp~O Q
Total 100.0 g
Preparation:
The above components are together dissolved in 150 g of special boiling point
petroleum
fraction 100-125 by rolling on a roller gear bed. The solution is applied to a
polyester film
(Hostaphan, Kalle) by means of a spreading device using a 300 ltm doctor
blade, giving a
coating of about 75 g/m2. After drying (15 minutes at 60°C), a silicone-
treated polyester
film (thickness 75 p,m, Iaufenberg) is applied as the peel-off film. The
finished systems
are punched out in sizes in the wanted form of from 5 to 30 cm2 using a
punching tool.
The complete systems are sealed individually in sachets of aluminised paper.
Example 3: Vial containing 1.0 mg dry, lyophilized 1-hydroxy-2-(imidazol-1-yl}-
ethane-1,1-diphosphonic acid (mixed sodium salts thereof). After dilution with
1 ml of
water, a solution (concentration 1 mg/ml) for i.v. infusion is obtained.
Composition:
active ingredient (free diphosphonic acid) 1.0 mg
mannitol 46.0 mg
Trisodium citrate x 2 H20 ca. 3.0 mg
water
1 ml
water for injection 1 ml .
In 1 ml of water, the active ingredient is titrated with trisodium citrate x 2
H20 to pH 6Ø
Then, the mannitol is added and the solution is lyophilized and the
lyophilisate filled into
a vial.
Example 4: Ampoule containing disodium pamidronate pentahydrate dissolved in
water.
The solution (concentration 3 mg/ml) is for i.v. infusion after dilution.
Composition:
active ingredient 18.73 mg
2.1.83:7 6.~
WO 95!30421 PCTlIB95/00288
-12-
( = 15.0 mg of anhydrous active ingredient)
mannitol 250 mg
water for injection 5 ml .
Example 5: Tablets each containing 50 mg of 3-[N-(2-phenylthioethyl)-N-
methylamino]-
1-hydroxypropane-1,1-diphosphonic acid can be prepared as follows:
Composition (10,000 tablets)
Active ingredient 500.0 g
Lactose 500.0 g
Potato starch 325.0 g
Gelatin 8.0 g
Talc 60.0 g
Magnesium stearate 10.0 g
Silicon dioxide (finely divided)20.0 g
Ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch,
and the mixture
is moistened with an ethanolic solution of the gelatin and granulated through
a sieve. After
the granules have dried, the remainder of the potato starch, the magnesium
stearate and the
silicon dioxide are admixed and the mixture compressed to give tablets each
weighing
145.0 mg and containing 50.0 mg of active ingredient, which can, if desired,
be provided
with breaking grooves to enable the dosage to be more finely adjusted.
