Note: Descriptions are shown in the official language in which they were submitted.
~vo 93~J9766 2 1 0 0 6 ~ 7 PCT/US92/09725
METIIOD FOR TREATMENT OF ACUTE AND CIIRONIC PAINFUL ARTHROPATHIC
CONVITIONS IN HUMAN AND OTHER MAMMALS
. _
FIELD OF T~E INVENTION
The present invention is directed toward a method for
treatment or prophylaxis of painful conditions, especially pain
associated with degenerative conditions of both hard and soft
tissues, by the administration of a pain relieving effective
dose of an angiogenesis inhibiting effective amount of sodium
chondroitin sulfates to animals of mammalian species, including
humans, in a safe and efficient manner.
~ACRGROUND OF THE INVENTION
As used herein, the term "arthritic disease" refers to any
disease state characterized by significant joint inflammation
associated with secondary pain. "SCS" as utilized herein in the
specification and claims is the acronym for sodium chondroitin
sul~ate. The product, SCS is a purified extract of shark
cartilage.
The applicant is aware of the following prior art which
pertains to the subject matter of this application.
INFLAMMATORY JQI~T DI~EA8E~
A major consequence of chronic inflammatory joint disease
(rheumatoid arthritis) and degenerative arthritis
(osteoarthritis or osteoarthrosis) is loss of function of those
effected joints. osteoarthrosis usually has an insidious onset
of pain, stiffness and reduced range of movement. It commonly
affects one or only a small number of joints. Joint laxity
develops with locking and aberration. Most often e~fected are
the joints which have been used the most or previously affected
by trauma or inflammatory processes. Such joints suffer the
greatest damage. Thus, the weight-bearing joints of the hips
and knees, the lumbar spine and first carpometacarpal joints
are common victims of the disease.
The essential features of rheumatoid arthritis are cyclic
pain and swelling of several joints with morning stiffness
continuing for sevexal weeks. It tends to affect the peripheral
small joints symmetrically.
Other common inflammatory arthropathies include alkylosing
spondylitis, psoriatic arthropathy, septic (suppurative3
arthritis, Reiter's disease and gouty arthritis. Other
21006~7
W093/09766 PCT/US9~/n9725
2-
traumatic and non-traumatic joint injuries include synovitis,
capsulitis and the like.
The loss of function is due to destruction of the major
structural components of the joint, cartilage and bone, and
subsequent loss of the proper joint anatomy. ~s a consequence
of chronic disease, joint destruction ensues and can lead to
irreversible and permanent damage to the joint and loss of
function. Destruction of architecture of the joint may be
mediated by angiogenesis.
10 ANGIOGEl~E8I~ ~ '
Angiogenesis is the development of a network of blood
vessels which typically would lead to a vascular bed capable of
sustaining viable tissue. It is characterized by the directed
growth of new capillaries toward a specific stimulus, many of
which have been proposed. Angiogenesis is a necessary step.
It has been implicated to play an important role in the
pathophysiology (the establishment and development) of certain
inflammatory conditions. In osteoarthritis, for instance, it
is involved in the reinitiation of cartilage growth and
mineralization. Also, the vascular proliferation appears to be
important in the pathogenesi5 of rheumatoid arthritis. Semble
et al., J. Rheumat. 12: 237, 1985. Thus, the inhibition o a
angi~genesis is a prerequisite objective to control/alleviate
inflammatory conditions.
~rI~-I~I;~A~ORY DRrlG8
It is apparent from the discussion above that the
inflammatory diseases o~ the joints cause an extremely high
level of discomfort and pain and in many instances the results
are crippling. The requirement for treatment is unquestioned
and the treatment is in many cases continuous as none of
commercially available drugs for treatments of these diseases
is significantly e fective in achieving true remission of the
disease in mo~t individuals affected by these diseases. Thus,
the disease is, generally speaking, incurable.
The commonly used anti-inflammatory druqs which are
sometimes administered with other analgesics, have been shown
to have significant drawbacks including exhibiting several (and
W O 93/09766 2 1 ~ 0 6 ~ 7 PC~r/US92/09725
--3--
often se~ere) side effects, for instance, faecal blood loss
(anti-prostaglandins), hypertension (glucocorticoid), bone
marrow depression (immunosuppre;sants) or intestinal ulceration
(NSAIDs - non-steroid anti-inflammatory drugs). Obviously, the
drugs that would alleviate inflammatory conditions by
inhibiting angiogenesi~ are of great interest.
~iNGIOGENE8I8 INnHI~ITOR~
Several naturally-occurring angiogenesis inhibitors have
been found. For instance, Research Resource Reporter, page 7,
lo December 1981, reports the isolation of factor from cartilage
which slows tumor growth and also reports similar factors from
other tissues. However, all these factors appear to be
proteins having molecular weights in the range between 3,500
and 25,000 Daltons. Also, J. Folkman et al., Science, 221:
719, 1983, describes the angiogenesis inhibitory effects of
heparin and heparin fragments.
Moreover, at present all of identified candidate drugs
exhibit severe host toxicity. Maione et al., Trends Pharmacol.
Sci, l1, 457, 1990.
It is apparent that a composition which would inhibit the
action of angiogenesis factor in promoting the development of
blood vessels, would have an adverse effect upon the growth of
tumors, on the development of the psoriatic lesion, on
development of retinopathy or rheumatoid arthritis.
C~ONDROI~IN ~ULFATE PREPARATION8 AB T~ER~PEU~IC AGBNTS
The use of chondroitin sulfate preparations in treatment
of and as preventive therapy for a variety of diseases has been
previously reported.
The use of these drugs in the treatment of cardiovascular
diseases including myocardial infractions, acute coronary
insufficiency and acute myocardial ischemia are described in
U.S. Pat. Nos. 3,895,106 and 3,894,107 to Morrison.
U.S. Patent No. 4,640,912 to Hausman describes the use of
chondroitin sulfate preparations in the treatment and reduction
of incidence of pathological conditions ranging from cancer,
bacterial infections, trauma, irritation or--damage to the
linings of the renal pelvis, ureter, urethra and ~ladder caused
~100~7
W093/09766 PCT/US92/09725
by placement of foreign objects, tubes or instruments into the
renal pelvis, ureter, urethra and bladder or kidney.
Among the most pertinent prior art known to applicant is
U.S. Pat. No. 4,971,955 issued November 20, 1990 to Soll et al.
The patent relates to the utilization of chondroitin sulfate as
a protective agent prior to and/or during anticipated trauma
and to promote separation of tissue planes during surgical
intrusions. Soll et alO disclose that chondroitin sulfates are
useful in alleviating aseptic joint inflammation ( i.e.
microorganism-free infectîon) of the large joints and
preventing further degeneration of the cartilage through
protection of cells in the joint cavity and through lubrication
of the joint surfaces of four-legged animals such as horses.
Chondroitin sulfate isolated from shark cartilage has been
~ound particularly useful in anterior segment surgery. The
mode of action of chondroitin sulfates in their passive and
active role has been discussed in some detail in this patent.
Patentees further disclose that chondroitin sulfates may limit
or even eliminate the activities of accidental septic
infections (i.e. caused by microbial
invasion). Since chondroitin sulfates are viscous, they
restrict the ~novement and the flow of inflammatory products
such as proteins and large molecules.
DI~ET~YL 8~FO~ID~
The use of dimethyl sulfoxide as an agent for enhanced
ti~sua penetration of other substances is known in the art. It
is, for example, described in great detail in U.S. Pat. No.
~,296, 104, No., 3,551,554, No 3.711,606 and No. 3,743,727.-
Cartilage is one of few avascular tissues in the body.
The notion that a factor (molecule(s)) endowed with
angiogenesis inhibitor activity may be present in mammalian
cartilages is not new. Several fractions having such activity
have been identi~ied in and prepared ~rom natural sources,
including calf and shark. The latter became an especially
attractive source since it has been observed that elasmobranchs
such as sharks, in contra~t to mammals and even bony fish and
~O93/09766 l~C~/US92/Og725
2100~7
--5--
amphibians, rarely exhibit neoplasm. see Guenther et al.,
Biochim. ~iophys. ~cta, 372, 321; 1974.
Leur has described the angiogenesis inhibitory ~ctivity of
shark cartilage (Federation Proceedings, September 1986) but
failed to teach or suggest analgesic properties, which are
especially useful in the treatment of inflammations ln hard and
soft tissue in mammals.
In an article published in Science, ~, 1185;1983,
Langer and co-workers have reported the presence of the
angiogenesis inhibitory activity in both calf and shark
cartilage and have described the high extraction of this
inhibitor from shark as opposed to calf cartilage. More
specifically, the authors have noted that one weight unit of
shark cartilage extract inhibits roughly one thousand times
stronger vascular growth toward solid tumors than the same
amount of extract from calf cartilage. Yet, they have failed
to identify the nature of the inhibitor molecule. Moreover,
Langer and co-workers have observed that the fractions having
increased collagenase specific activity are practically free of
significant angiogenesis inhibitory activity. The only utility
which is disclosed refers to proposed antitumor studies.
In a more recent paper from the same laboratory relating
to cartilage-derived neovascularization inhibitor (CDI) it has
been reported that chondroitin sulfate A does not inhibit
angiogenesis in vivo. See Moses et al., Science, 248:
1408,1990. CDI molecule is a 28 amino acid peptide extracted
from calf scapular cartilage. This reference apparently
suggests that there may be subtle differences in the amino acid
sequences from species to species, however the presence of the
angiogenesis inhibitor and its physiological activity are
essentially identical., i.e. prevention of neovascularization
in otherwise avascular cartilage. Bovine and other mammalian
sources yield predominantly chondroitin sulfate A (see U.S.
Patent No. 3,895,106 to Morrison; see also U.S. Patent No.
4,302,577 to Rucker). Therefore, it is apparent that CDI
molecule(s) taught by this reference are not associated with
chondroitin sulfates. In contrast to this communication, the
21~0~7
O 93/09766 PC~r/US92/09725 --6--
applicant has found that the sodium chondroitin sulfate
preparations used in the claimed method inhibit both
angiogenesis and collagenase activity. Heretofore, it has not
been recognized in the art of pharmacology and medicine that
collagenase and angiogenesis inhibitory activity-rich
preparations of sodium chondroitin sulfate derived from shark
cartilage extract may have utility in the treatment and relief
of pain, especially pain associated with the various forms of
inflammations including the inflammations of hard and soft
tissue.
Similarly, Oikawa et al., (Canc. Lett, 51, 181: 1990)
reported that their heat resistant fractions in the molecular
weight range between 103 and 104 of Japanese basking shark
cartilage have angiogenesis inhibitory activity.
~UMMARY OF ~H~ INVENTION
The present invention relates to a method useful for
ePfectively treating, relieving and preventing both acute and
chronic pain, especially such pain associated with inflammation
of both hard and soft tissues in animals of mammalian species,
20 including humans in an efficient and patient-friendly manner. -
The methods are very powerful and effectively inhibit both
angiogenesis ancl ~ollagenase activity. The method entails
administering a sterile and endotoxin free pharmacologically
effective amount of sodium chondroitin sulfate derived from
shark ~artilage extract, preferably via systemic routes of
administration such as, for axample, parenteral routes. Sodium
chondroitin sulfate is a sodium salt of chondroitin sulfate C,
sodium salt of chondroitin sulfate D (sodium salt of
chondroitin polysulfate) or mixtures thereof. Sodium
chondroitin sulfates from shark cartilage may be blended with
sodium chondroitin sulfates from a non-shark source, for
example, a mixture of at least 60 wt % of sodium chondroitin
sul~ate derived from shark cartilage and up to 40 wt % of
sodium chondroitin sulfates derived from a non-shark source.
Because of its long duration of action, the claimed method
is particularly well-suited for both systemic and local
treatment. Thus, apart from systemic routes of administration,
~VO93/~97G6 2 1 0 0 6 ~ 7 PCT/US92/09725
the method of this invention may be used for treating
individuals in need of such pain relieving treatment locally at
a disease site, for exampl~, via intra-articular injections or
transdermal applications.
Using the methods of the invention, substantial
improvement can be obtained in the efficacy of the treatment
since the utilized mixture of sodium chondroitin sulfates, in
terms of both angiogenesis inhibitory activity and collagenase
inhibitor activity, is found to be up to 1000 times more potent
lo on a milligram basis than the prior art compositions.
This invention also provides a method of transdermal
topical patch drug delivery for the treatment both locally and
systemically of painful conditions of soft and hard tissues.
This method entails administering a pharmacologically effective
amount oP sodium chondroitin sulfate derived ~rom shark
cartilage and dimethyl sulfoxide (DMSO) to enhance tissue
penetration. Sodium chondroitin sulfate (SCS) as used herein
is a sodium salt of chondroitin sulfate C, sodium salt of
chondroitin sulfate D (sodium salt of chondroitin polysulfate)
or mixtures thereof. A blend of sodium chondroitin ~ulfates
from shark cartilage and sodium chondroitin sulfates from a
non-shark source, for example, at least 60 ~ by weight of SCS
and up to 40 % by weight of non-shark SCS, preferably a mixture
of from about 65 to about 95 wt % of sodium chondroitin sulfate
C derived from shark cartilage and from about 5 to 35 wt ~ of
sodium chondroitin sulfates derived from a non-shark source may
be used to practice this invention.
The treatment of painful conditions which often occur in
conjunction with angiogenesis, such as bursitis or tendinitis,
is also comprehended by the present invention.
The SCS preparation used in the present invention is a
heterogeneous glycosaminoglycan preparation with peptide
content. The peptide is linked to the chondroitin sulfate and
to the chondroitin polysulfate in specific linkage regions. See
Seno, J.Biochem., 83, 953-6: 1978; se also Akiyama et al,
Biochem. Biophys. Acta, 674, 289-96: 1981). When derived from
natural sources, the peptide is chemically bound to the
2 1 0 0 6 ~ l
WOg3/09766 PCT/US92/()~725
--8--
chondroitin sulfate molecule. Also, it is known that even the
highly purified preparations of the chondroitin sulfate6
contain r~sidual proteins (up to 17 wt ~) which appears to be
resistant to the treatment with various types of proteasPs. In
terms of the purity, the composition of the instant invention
is sterile and free of endotoxin, and is pharmaceutically
acceptable as an administrable drug preparation via parenteral
routes.
These and other advantages and objects of the invention
will become apparent from the following more detailed
description of this invention.
DE'rl~.ILED DE5CRIPTION OF THE INVENTION :.
According to Soll et al chondroitin sulfate is effective
in their invention at all molecular weights, i.e in
order of about 50,000 to lOO,D00 Daltons, depending on the
source, if administered topically or directly to the aggrieved
cells.
It has now been found that the blend of high molecular
weight, analgesic specific fractions of the sodium salt of
chondroitin sulfate (i.e., sodium chondroitin sulfatP C, sodium
sulfate D, or mixtures thereof) which is associated with both
angiogenesis and collagenase inhibitors and derived from both
non-shark and ~hark cartilage is active pharmacologically when
administered parenterally to human and other mammals including
for example, horses and dogs. The blend contains at least 60
wt ~, preferably from about 65 to 95 wt ~, and more preferably -
about 95 wt % of shark cartilase sodium chondroitin sulfates
and up to 40 wt %, preferably from 5 to 35 wt % of sodium
chondroitin sulfates derived from a cartilage of non-6hark-
origin. When non-shark cartilage is used, it is prefarably
mammalian cartilage, and more preferably bovine cartilage.
Preferably, the non-shark source is selected from bovine
trachea and bovine nasal ~epta. A highly purified ch mical
grade blend of shark sodium chondroitin sulfate (70 wt %) and
~5 bovine sodium chondroitin sulfates (30 wt %) is now
commercially available.
~VV93/09766 ~ 0 6 ~ 7 PC~/US92/~9725
~ his blend of SCSs is most useful for treating both acute
and chronic painful conditions of both hard and soft tissues
where an inappropriate development of capillary vessels leads
to further progression of degenerative conditions ~i.e.,
degenerative joint diseases, rheumatic diseases, etc.). The
representative examples of soft tissue injury include sprains
and strains of ligaments, tendons, and muscles. Degenerative
joint disease is an example of a hard tissue injury.
It has further been found that a high molecular weight
fraction of sodium chondroitin sulfates (SCS) derived from
shark cartilage, preferably from shark fin, is superior to
lower molecular weight sodium chondroitin sulfates derived from
shark skin and vertebral column and from mammalian cartilage in
terms of both analgesic and anti-angiogenesis properties.
Shark fin derived SCS is predominantly sodium chondroitin
sulfate C (SCS-C) or sodium chondroitin sulfate D (SCS-D) (also
known as sodium chondroitin polysulfate) which is a
polysulfated form of sodium chondroitin sulfate C~ It is
sodium chondroitin sulfates C and D, which exhibit the
analgesic effect of the present method. The molecular weights
of chondroitin sulfates extracted from shark fin cartilages
which are effective in the present invention ranges from 18,000
to 104,000 Daltons. Preferably, the fractions comprising
chondroitin sulfates having a molecular weight of at least
40,000 are used to practice the invention. The fractions
having a molecular weight in the range from 40,000 to 55,000
Daltons are especially preferred. It has been found that the
higher molecular weight coincides with a higher viscosity and
a more concentrated presence o~ angiogenesis inhibitor peptide
and a greater number of SCS molecules per weight unit of raw
material. It has been further found that the preparation in
the higher molecular weight ranges demonstrates enhanced
collagenase inhibitor act~vity. SCS-C derived from shark
vertebral column and shark skin have molecular weights in the
range of 28,000 to 35,000. From the pharmacological point of
view, these differences in molecular weights make the higher
molecular weight fractions more desirable, although the lower
2 10 0 ~ 5 1
W093/09766 PCT/VS92/~972~
-10--
weight SCS preparations can also be utilized for the
therapeutic indications previously described.
The exact mechanism of action has not been established
yet. However, to explain the beneficial effects of the claimed
composition it is proposed that the composition:
a) is a potent inhibitor of collagenase and
proteolytic enzymes;
b) protects cellular membranes from enzymatic
degradation;
c) stimulates chondrocytes and synoviocytes to
produce high molecular weight sulfated and non-
sulfates glycosaminoglycans;
d) is a powerful scavenger of oxygen-derived free
radicals;
e) causes a sharp decline of proinflammatory
mediators , i.e., PGE-2~ LTB-4, LTC-4, and the
like, in inflammatory exudates;
f) is a potent angiogenesis factor inhibitor which
suppresses the hyperproliferation and migration
of capillary endothelial cells in and around
damaged cartilage and subchondral bone;
incidentally in the normal state these
structures are essentially
avascular and they become abnormally
hypervascularized as degenerative arthritic
conditions progress.
It should be noted that the process of neovascular~zation may
play a major role in the hyperproliferation and calcification
oP cellular and non-cellular components within the affected
tis~ues of individuals with painful degenerative and non-
de~enerative inflammatory conditions.
A powdered form of a highly purified chemical grade
preparation of shark cartilage is commercially available. One
of the identified manufacturers of the highly puri~ied chemical
grade preparation of shark cartilage is Calbiochem Behring
Corp., LaJolla, CaliforniaO This commercial preparation has
been used in various chemical processes such as a process for
~0~/09766 2 1 0 0 6 ~ 7 PCT/US92/097Z5
-11--
the selective extracorporeal precipitation of low-density
lipoprotein described in U.S. Patent 4,908,354 to Seidel et al.
Also, an extract containing 99.5 % of a mixture of sodium
chondroitin sulfate C and sodium chondroitin sulfate D, and a
highly purified chemical grade blend of shark sodium
chondroitin sulfates (70 wt %) and bovine sodium chondroitin
sulfates (30 wt ~) are commerci.ally available.
A stock solution of ten percent weight/volume is prepared
by dissolving the shark cartilage extract sodium chondroitin
sulfates in sterile ~ater for injection USP. The stock
solution is then sterilized initially by filtration through a
series of suitable microporous filters. Preferably, these
membranes have an absolute pore rating in the range from about
0.22 micrometer to about 0.5 micrometer. Most preferably,
0.22 micron disk filters manufactured by and commercially
available from Millipore Corporation, Bedford, MA are used.
The sterile solution is collected into a sterile evacuated
container, preferably glass.
It has been also found that it is imperative to remove all
traces of endotoxin that may be present, even in SCS products
manufactured as pharmaceutica~ grade i.e., sterile and pyrogen
free. It should be noted that even commercially available
product designated "endotoxin free" still may contain up to 0.5
~g/ml of endotoxin, as allowed by the FDA- standards upon
meeting the standards of the pyrogen-free test (endotoxin
test). Sterile solutions of sodium chondroitin sulfates that
contain pyrogens and/or endotoxins are not only worthless as
analgesic agents parenterally, but are harmful and actually
make painful conditions much worse due to the "pyrogen
reaction." Severe and local painful reactions occur at sites
of injection and generalized whole body soreness with weakness,
malaise, muscle and joint pain with joint inflammation, fever,
chills, decrease in blood pressure, nausea and vomiting are
some of the harmful effects of contaminated solutions of sodium
chondroitin sulfates that are merely "sterile." Shark
cartilage extracts contain harmful pyrogens and endotoxins as
well as other proteins which are capable of causing severe and
2 1 ~ ~ b~ c~ 7
W093/09766 PCT/~S~2/09725
-12-
even fatal allergicthypersensitivity reactions when used for
injections. Accordingly, remaining endotoxins are removed by
filtering the sterile stock solution through endotoxin removing
filters.
It has been found by the present inventor that by
utilizing a series of endotoxin removing filters, preferably
Pall Posidyne filters, one is able to ultrapurify the
commercially available product from residual endotoxin
contamination. The inventor has further found that a minimum
of five (5) filters in succession is necessary to obtain
suitable preparations. The resultant solution is both sterile
and endotoxin-~ree.
Nylon microporous filter membranes which may be used in
the endotoxin removal step are commercially available. One of
suitable filter membrane is manufactured by the cocasting
process and available ~rom Pall Corporation, Biosupport
Division, of Glen Cove, New York, under the trademark SCF or
the trademark Set SAVER, or the trademark N66 Posidyne. A
matrix of Nylon 66 is modified and functionalized with a hiqh
density of positively charged groups on its surface, typically
by the addition of quat~rnary amine groups. According to the
manufacturer, a high concentration of these cationic functional -
groups at the pore surface of the material displays a little
variation in a positive zeta potential in both acidic and basic
solutions over a wide pH range and is preferably designed to
remove a variety of substances including endotoxin, i.e.,
toxins produced as a result of bacterial growth or
decomposition. See Degen, et al., U.S. Patent 4,702,804.
The foregoing filter materials are illustrative of
suitable positively charged matrices that may ba used in
pr~paring stock solution for use in the pharmaceutical
composition of this invention. Any suitable microporous
polymeric membrane may be used. The criteria for selecting the
filter include, for example, the requisite porosity, ability to
withstand stsrilization techniques, including gamma ray
radiation, and charge capability for effectively removing
~ndotoxin.
~093/09766 2 1 0 0 6 ~ 7 PCT/US92/09725
-13-
The stock solution may be passed through one or more
filters. Preferably, a series of at least five 0.22 micron
Pall brand PosidyneTM endotox:in removing filters are used to
practice this invention.
5 FORMULATION AND ADMINI~3TRATION
Compositions containing the active analgesic fractions for
treatment of pain may be internally administered to a living
animal body in any one of various ways, for example,
parenterally in the form of sterile solutions or suspensions
and in some cases intravenously in the form of sterile
solutions. In forming the compositions, the active ingredient,
i.e. sodium chondroitin sulfate C, D or mixtures thereof is
incorporated in a suitable carrier, illustratively a
pharmaceutical carrier, i.e., water, saline, and the like.
The compositions of the invention may be produced by any
of the following general methods.
In a first embodiment, the compositions of the invention
are prepared by simply mixing the endotoxin free fractions as
described above with known pharmaceutically acceptable
carrier(s) by any art-known method.
In a second embodiment, the compositions of the present
invention are prepared by admixing DMS0 with the endotoxin-free
composition. According to the invention, pharmaceutical
compositions containing both SCS and DMSo have greater
effectiveness than could be predicted by combining (in additive
fashion) the known or theoretical effectiveness of the
individual agents. It has been found, for example, that the
addition of dimethyl sulfoxide (DMS03 in amounts of from about
50 to 99 % by weight, and preferably from about 9o to 99 weight
percent, to sodium chondroitin sulfates composition will
significantly enhance the penPtration of the SCS into the blood
stream. Additional information concerning the effectiveness of
DM50 in transporting large molecules (high-molecular weight
molecules) through the intact skin may be found, for example,
in Remington's Pharmaceutical Sciences, 15th Edition.
Advantageously, the compositions are formulated as dosage
units, each unit being adapted to supply a fixed dose of active
21 ~OIi!il
W~93/09766 PCT~US92/09725
-14-
ingredient(s). Unit ampules and prefilled syringes areexamples of preferred dosage forms, however, the composition
may be o~fered in multiple-dosa~e containers and the like.
Each unit dose will contain an amount of SCS effective to
inhibit angiogenesis. It is only necessary that the active
ingredient constitutes an effective amount, i.e., such that a
suitable dosage will be consistent with the dosage form
employed. The exact dosages, as well as daily dosages for the
subject, may vary depending on whether the subject is human or
animal and according to such factors as age, sex, extent of the
disease, and so forth, but for instance in horses, usually a
therapy is initiated by administering intramuscularly a one
time loading dose of about 1,000 mg, followed 48-96 hours later
with a maintenance dosage o~ about 500 mg (intramuscularly)
every 48-96 hours, based on the individual response. The
daily parenteral dosage for a sexually mature human subject is
from 0.5 mg to 2.0 milligrams per kg of body weight, with from
0.5 to 1 milligram per kg of body weight being preferred per
unit dose.
The SCS containin~ composition used herein is safe and
efficacious in remission of painful inflammatory conditions and
other painful conditions. Acute, subacute and chronic
administration of the composition in horses revealed no signs
or symptoms of toxicity even at dosages exceeding six times the
recommended do9e (up to 3,000 mg) administered for fourteen
(14) weeks. Peak plasma levels of the composition are achieved
within sne to two hours following a single intramuscular
injection, although there may be considerable individual
variations. Plasma half-life and analgesic activity may
reflect factors such as protein binding, organ uptake and
concentration of the active agent in analgesic exudates.
The active agents of the invention may be com~ined with
other pharmacologically active agents, or with buffers or the
like for administration as long as the antagonistic effect is
avoided. The proportions of these agents in the composition
may vary widely.
~'093/09766 ~ O b ~ 7 PCT/US92/09725
The parenteral dosage forms may be injected by the
subcutaneous, intramuscular, intravenous or intra-articular
routes. For parenteral administration, the composition is
administered in solution or s~spension and its dosage may
include any conventional injectable solutions together with
pharmaceutically acceptable preservatives and buffers. For
intramuscular injections it is preferred that the chondroitin
sulfates are present at a final concentration of about 10 %
(wt/vol) in a pharmaceutically acceptable vehicle. For intra~
lo articular injections, the preferred concentrations of the
chondroitin sulfates are in the range from about 10 to 25 %
(wt/vol). Preferred daily dose levels in mammals would be up to
1 mg/kg of mammalian body weight.
The SCS-containing composition may also be provided in
powder form which is redissolved before use in a suitable
vehicle, for instance, sterile, endotoxin free water or
saline.
Based on animal test results, it is clear that
administering an effective dose of SCS alone or in combination
with DMSO according to the present invention, is an effective
method for reducing pain associated with inflammatory and other
painful aonditions.
Applicant has found that an inflammatory or other painful
conditions may be successfully treated by applying to the skin
a mixture of sodium chondroitin sulfate and dimethyl sulfoxide
in amounts effective to ameliorate tha inflammation when
applied to an area of the skin proximate to the inflammation.
More specifically, the method which utilizes a dimethyl
sulfoxide-sodium chondroitin sulfate transdermal topical patch
drug delivery system has been found to be effective for the
treatment of painful inflammatory conditions of soft and hard
tissues, both locally and systemically. The preferred form of
the topical patch delivery system contains a mixture of sodium
chondroitin ~ulfate(s) combined with dimethyl sulfoxide in a
ratio of from about 1:1 to about 1:15 by weight. A more
preferred form of the topical patch drug delivery system
contains about 10 wt % of the mixture of sodium chondroitin
(i 5 ~
W093/09766 PCT/~S92/097~5
-16-
sulfate and about 90 wt % of DMSO. The patch is applied to a
shaved, clean and non-irritated area of skin and changed every
96 hours. The contained mixture is slowly released and
penetrates the skin to deliver both local and systemic
medication. It is hypothesized that the ingredients act
together to achieve a synergistic result more effective than
can be obtained from both agents individually, and more
effective than could be predicted from the mere addition of the
known efficacies of the individual ingredients
The method of the present invention provides effective
symptomatic relief for individuals suffering from arthritic
disease, pain associated inflammatory conditions, or other
painful conditions. It is believed that in many instances,
true remission of these diseases will be achieved.
EXAMPLE 1
~I!EBT PROCEDIJRE8 FOR A88E~8ING DEGREE OF LAMENE8~ IN
E:XP13RIMEN'rAI. A21IM~L8
Thirty three standard bred racehorses suffering from
various physical maladies, for instance, lameness due to
various traumatic and non-traumatic inflammatory conditions
including degenerative joint disease, tendinitis (bowed
tendons), suspensory li~ament desmitis, ligament strains and
sprains, periostitis and sore muscles have been subjected to
treatment with the composition of the present invention. All
horses displayed soreness and or lameness prior to initial
tr~atment with the composition of this invention. The clegree
of lameness was rated 0 to 3 with 0 being least severe and 3
being the most severe by the objective criteria.
Each of these horses was administered an initial loading
dose of 1000 mg of a blend of about 70 wt % of sodium sal~ of
chondroitin sulfate C derived from shark cartilaga and about 30
wt ~ of sodium salt of chondroitin sulfates derived from bovine
nasal septa/trachea via the intramuscular route. This
preparation was purchased from SKK - Japan and further purified
to remove endotoxin as previously described. The animals were
~093/09766 2 l PCT/US92/09725
17
examined twenty-four (24) hours later and a response was
evaluated.
A favorable response was based on a three (3) point
improvement seen after 24 hours from the drug administration.
Rating of the improve~ent was based on the degree of local
signs and symptoms of pain, including local heat, swelling,
tenderness and range of motion
Twenty-eight (28) horses were judged to have had an
excellent response from a single 1000 mg (10 ml) injection of
a blend of about 70 wt ~ of sodium salt of chondroitin sulfate
C derived from shark cartilage and about 30 wt ~ of sodium salt
of chondroitin sulfates derived from bovine nasal
septa/trachea. There was a marked reduction of symptoms so as
to allow training or racing without soreness or lameness.
Ninety-six (96) hours following the initial dose all thirty-
three (33) horses were again treated with a single 500 mg
intramuscular injection of the same preparation. 24 hours
later all 33 horses were judged to have had a beneficial
response. The degree of lameness was rated 0 to 3 with 0 being
least severe and 3 being the most severe by the same objective
criteria. Table 1 records the results of this experiment.
EXAMPLE 2
Forty lame race-horses were egually assigned to two
treatment groups, i.e., Group I and Group II. These horses
were subjectively evaluated for lameness, pain on palpation,
pain with flexion, degree of flexion, swelling and heat before
treatment.
In accordance with the invention, all horses of Group I
were injected intramuscularly with a one time dose of 500 mg
sodium chondroitin sulfate D from shark fin extracts purified
according to the invention procedure. The initial injections
were followed 96 hours later with a maintenance dosage`of 500
mg (intramuscularly). These animals were subjectively
evaluated on days 1 and 4 for lameness, pain on palpation, pain
with flexion, degree of flexion, swelling and heat after before
treatment. The results of the treatment are shown in Table I.
CO~IPARATIVE EXAHPLE 1
21~0 65~
W093/09766 PCT/US9~tO9725
-18-
To compare the results of the experiment described above,
twenty horses of Group II were injected intramuscularly on days
l and 4 with 500 mg of Adequan, a product of Luitpold
Pharmaceuticals. The5e animals were subjectively evaluated on
days l and 4 fo~ lameness, pain on palpation, pain with
flexion, degree of flexion, fiwelling and heat after before
treatment. The results of the treatment ar~ shown in Table I.
Tahle l: Chan~es in clinical variables* followinq treatment
with i,m. in~e~tions of SCPS** and PSGAG***
lO treatment number of horses
total positive response negative response
(improvement) tnot improvement)
SCPS 20 l8
PSGAG 20 3 17
~ variables: lameness, pain on palpation, pain with
flexion, degree of flexion, swelling and heat~
** SCPS: sodium chondroitin sulfate D = sodium chondroitin
polysulfate from shark extract. SCPS has a molecular
weight in the range of 18,000 to 104,000 Daltons and is
essentially free of endotoxin.
*** PSGAG: Adequan i.m.; a product of Luitpoid
Pharmaceuticals, Inc.; polysulfated glycosaminoglycan
extracted from bovine tracheal tissue and having a
molecular weight of lO,OOO - 12,000 dalton~ (see attached
literature).
The results indicate that the composition given in a
single injection produce consistent, significant analgesic
activity as evidenced by favorable response ra-te of 82 ~ when
given in the claime~ doses.
W093/09766 21~ 0 6 ~ 7 -19- PCT/US92/09725
This example is not intended to limit or restrict the
scope of the invention in any way, and should not be construed
as providing dosage forms, reglmens and methods of
administration which must be utilize~ exclusively to practice
the invention.
It has thus been shown that there are provided
compositions and methods which achieve the various objects of
the invention and which are well adapted to meet the conditions
of practical use. Various modifications and equivalents will
be apparent to one skilled in the art and may be made in the
fractions, methods, and pharmaceutical compositions of the
present invention without departing from the spirit and scope
thereof, and it is therefore to be understood that the
invention is to be limited only by the scope of the appended
claims.
