AP448A - Use of hyaluronic acid and forms to prevent arterial restenosis. - Google Patents
Use of hyaluronic acid and forms to prevent arterial restenosis. Download PDFInfo
- Publication number
- AP448A AP448A APAP/P/1993/000568A AP9300568A AP448A AP 448 A AP448 A AP 448A AP 9300568 A AP9300568 A AP 9300568A AP 448 A AP448 A AP 448A
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- AP
- ARIPO
- Prior art keywords
- hyaluronic acid
- amount
- person
- salts
- administered
- Prior art date
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
For the prevention of the narrowing of the tubular walls of an
Description
TITLE OF INVENTION
USE OF HYALURONIC ACID AND FORMS TO PREVENT ARTERIAL RESTENOSIS.
FIELD OF INVENTION
This invention relates to the prevention of the narrowing (stenosis) of tubular walls of an animal after the tubular walls have been traumatized. In one embodiment, this invention relates to the prevention of arterial restenosis after balloon angioplasty.
BACKGROUND OF THE INVENTION
Balloon angioplasty is a widely accepted method of opening blockages in the coronary arteries. The balloon catheter was introduced experimentally in the early 1960’s and was first applied clinically in the late 1970's. It has since assumed a major therapeutic role in the treatment of single and multiple vessel coronary artery disease (Baumgartner, H.R., 1963, Z. Ges. Exp.
Med., 137:227). However in some patients after successful treatment by balloon angioplasty, arterial restenosis occurs. This time however the narrowing of the inner diameter (ID) of the artery is caused by growth (proliferation) of endothelial cells in the areas of irritation caused by the balloon angioplasty. Thus reblockage occurs not by cholesterol build-up but by build up of endothelial ”*0 cells on the inner wall of the artery reducing the inner diameter (ID) of the artery leading to an infarct. In man, the restenotic lesion consists almost entirely, though not exclusively of vascular smooth muscle cells (Glazier, J.J., Williams,
M.G., Madden, S. and Rickards, A.F., 1990, J. Roy. Coll. Phys. Lond., 24:292). Their accumulation within the artery lumen is a result of cell migration and proliferation. These two events are almost certainly due to the coordinated interaction of a number of different cytokines likely released by early accumulation of macrophages at the site of original tissue injury. This narrowing of the inner diameter (ID) of tubular walls or proliferation of cells is not how'ever restricted or limited to the coronary arteries. It can also occur post operatively causing restenosis in for example peripheral vascular systems.
BAD ORIGINAL ft restenosis.
_ . _ · r·^, λ a Λ / ι
AH UUU -2A number of proposals have been made in the prior art to prevent
U.S. Patent 5,087,244 (Wolinsky et al.) purports to teach the use of a catheter having an inelastic balloon at one end thereof, where the balloon has minute perforations and contains a concentrated heparin solution which will be released through the perforations contacting an area of the artery after angioplasty to prevent restenosis.
U.S. Patent 5,116,864 (Hathaway et al.) purports to teach the prevention of restenosis in peripheral or cardiac vascular systems after vascular recanalisation by systemic administration of photo activatable psoralen to give serum psoralen le\’els which inhibit smooth muscle cell growth.
U.S. Patent 5,092,841 (Spears, J.R.) purports to teach the treatment of an arterial wall injured during angioplasty by delivering bio-protective material between the wall and the angioplasty catheter so that the bio-protective material is entrapped and permeates into the tissues and vessels of the arterial wall during opposition of the angioplasty catheter.
EP 356275-A (Petitou et al.) purports to teach the use of new oacylated glycosamino-glycan derivatives in the inhibition of post-operative restenosis.
Berk., B.C. et al in the J. Am. Coll. Cardiol, dated 1991 Vol. 17 #6 Supplement B, pp 111B-117B purports to discuss the pharmacologic roles of heparin and glucocorticoids to prevent restenosis after coronary angioplasty.
WO 9209561 (Itoh et al.) purports to teach the use of new AC AT inhibiting amide derivatives in treatment of restenosis after percutaneous transluminal coronary angioplasty.
WO 9208472 (Scarborough et al.) purports to teach the use of platelet antiadhesive peptide(s) obtained from snake venom for the prevention of restenosis following angioplasty.
WO 9207852 (Bovy et al.) purports to teach the use of certain biphenylalkyl xanthine derivatives to prevent post-angioplasty restenosis.
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-3WO 9205782 (Pill, J.) purports to teach the use of thromboxane-A2receptor antagonists (I) in the preparation of medicaments for inhibition of proliferative developments in obstructive vascular disorders ie. arterial restenosis.
WO 9118639 (GAj et al.) purports to teach the inhibition of stenosis after balloon angioplasty, by the administration of fibronectin by continuous or bolus infusion, or by direct infusion into the stenotic region via the angioplasty catheter.
CA 2,042,159 laid open application (Ondetti, et al.) purports to teach 10 the use of ACE inhibitor (via the oral or parenteral route) for preventing or
C; reducing the risk of restenosis following angioplasty.
U.S. 4,929,602 (Harker, et al.) purports to teach a method of inhibiting arterial restenosis by administration of D-phenyl alanyl-prolyl-arginylbalomethyl ketone peptide derivative or a hydrolalin acid addition thereof.
U.S. 4,820,732 (Shell, et al.) purports to teach a composition containing a prostaglandin compound for the reduction of restenosis and abrupt stenosis.
Applicant is also aware of a company Glycomed developing a fragment of Heparin that prevents arterial restenosis after balloon angioplasty.
In the basic research efforts in the latter 70s and the early 80’s, there existed considerable confusion as to what role immunotherapy should take in cancer. Activation or hyping of macrophages was thought to be important. However, in an examination by Romans and Falk of peritoneal macrophages obtained from patients with neoplastic disease, there was definite evidence that these macrophages were already activated yet were co-existing with cancer cells and not causing their destruction.
It has been shown by several independent investigators that the malfunction of macrophages or the putitive block is due to excessive prostaglandin and that this can be altered in tissue culture by corticosteroids, ASA, and the non-steroidal anti-inflammatory drugs, i.e. indomethacin, and
BAD ORIGINAL a r\ λ a i in
AT υ υ u *♦ o
-4naproxen (Naprosyn™). Again, in animal tumors it was repeatedly demonstrated that these substances could alter the response to neoplastic cells and that various combinations of these substances employed with immune enhancing agents could produce very credible success in eliminating experimental tumors. Lala and co-workers combined Indomethacin therapy with Interleukin 2 and showed that this could effect a cure with experiment neoplasm.
There were continued problems with the use of any of these agents in the actual human in vivo experience. All of the non-steroidal anti10 inflammatory agents (NSAID) produced major toxicity in terms of gastrointestinal, neurological, and other areas. Thus, the basis of the present approach is that under general circumstances the use of these agents in human disease, in sufficient amounts, the drug will penetrate to any pathological tissue to alter therapeutically local prostaglandin production. While intravenous preparations exist of Indomethacin and now of other agents, the data is overwhelming, that using these drugs alone produces prohibitive side effects in human subjects. Therefore only insufficient amounts can be brought into the body to effect more than occasional responses in neoplasm.
However the majority of the evidence is present to indicate and
-^0 therefore it can be postulated that the basis for neoplastic development and how the initial cell sneaks by the immune surveillance mechanism relates to its production of prostaglandin. One need postulate only one mutation to alter the amount of prostaglandin synthesis produced by cells when they become malignant to establish a mechanism of blocking out the initial cell in any immune reaction, i.e. the macrophage. It therefore became essential to develop a combination of NSAIDS for clinical use to produce a major improvement in response in neoplastic disease and other conditions where excessive prostaglandin synthesis represents the basis of the pathogenesis of this disease state, i.e. arthritis, and various others of the so-called connective tissue inflammatory disorders and/or auto-aggressive diseases.
BAD ORIGINAL ft
AP000448
-5See also:
1. Modulation of Immunity in Cancer Patients by Prostaglandin Antagonists, Immunity to Cancer H, Alan R. Liss, Inc.; and
2. Goodwin, J.S. (1981) Prostaglandin E and Cancer Growth
Potential for Immunotherapy with Prostaglandin Synthesis Inhibitors,
Augmentive Agents in Cancer Therapy. Raven Press, New York.
It is therefore an object of this invention to provide a method of treatment and formulations and pharmaceutical compositions for preventing arterial restenosis after for example balloon angioplasty when endothelial cell proliferation occurs on the inner arterial wall caused by irritation to the cells by balloon angioplasty.
It is a further object of the invention to provide such treatment using hyaluronic acid which is safe and essentially non-toxic.
It is a further object of the invention to provide methods of treatment and formulations and pharmaceutical compositions generally for preventing restenosis and inhibiting restenosis for example post operatively in peripheral vascular systems.
Further and other objects of the invention will be realized by persons skilled in the art from the following summary of the invention and discussion with respect thereto.
SUMMARY OF THE INVENTION
Applicants believe that forms of hyaluronan or hyaluronic acid (especially hyaluronic acid and salts thereof) will prevent stenosis of the inner diameter (ID) of irritated tubular walls and particularly prevent restenosis of the arterial walls by for example the proliferation of endothelial cells as a result of irritation arising from balloon angioplasty or other treatment. The forms of hyaluronic acid (for example hyaluronic acid and salts of hyaluronic acid) can be administered intravenously or by injection (in the case of direct injection of small amounts) in effective amounts of about 10mg/70kg person to in excess of
3000mg/70kg person prior to, during and/or after injury.
BAD ORIGINAL ft
ΑΡ Ο Ο ϋ 4 4 δ
-6Hyaluronan or hyaluronic acid is a glycosaminoglycan that is evolutionarily conserved and composed of repeating dissacharide units of Nacetyl-glucosamine and glucuronic acid (Laurent and Fraser, 1991, Faseb J., 6:2397). Hyaluronan exerts effects on cell adhesion, motility, growth and differentiation and many of these effects are mediated by the expression of hyaluronan receptors by responding tissues. Thus, hyaluronan was shown to be able to aggregate white cells as a result of its interaction with receptors present on these cells (review, Turley, E.A., 1992, Can, Met. Rev., 11:21). Hyaluronan accumulates almost exclusively at sites of increased receptor expression or in the presence of extracellular hyaluronan binding proteins. Two cell surface associated receptors have been molecularly characterized and include CD44 and RHAMM [Receptor for (Hyaluronan) HA - Mediate Motility). RHAMM is present in elevated amounts on cells, particularly macrophages and smooth muscle cells responding to injury.
Therefore according to one aspect of the invention, there is provided a process for the prevention of the narrowing of the tubular walls of an animal after the tubular walls have been traumatized (for example wherein the tubular walls are arteries which have been subjected to balloon angioplasty) the process comprising the administration of a therapeutically effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and subunits of hyaluronic acid to the animal to prevent narrowing of the tubular walls. (The hyaluronic acid may be administered before, during and/or after the injury). Preferably the form of hyaluronic acid is hyaluronic acid and salts thereof. The amount of the form of hyaluronic acid administered is preferably between about 10mg/70kg person and about 3000mg/70kg person.
Thus according to another aspect of the invention, a process is provided for the prevention of arterial restenosis after balloon angioplasty in a human, the process comprising the administration of a therapeutically effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues,
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-7analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid to the human to prevent arterial restenosis. Once again preferably the form of hyaluronan or hyaluronic acid is hyaluronic acid and salts thereof and preferably the amount of the form of hyaluronic acid administered is between about 10mg/70kg person and about 3000mg/70kg person. The hyaluronic acid can be administered before the procedure, for example, balloon angioplasty or during or after the procedure (immediately following).
The compositions are preferably administered intravenously in a liquid form and include suitable diluents or other adjuvants as required for administration. With respect to the amounts to be administered, they may also be administered by injection preferably at or proximate the site to be treated.
A therapeutically effective amount of stenosis inhibiting drug may be combined with the form of hyaluronic acid for administration. Such drugs may comprise any of those previously mentioned, and those understood by persons skilled in the art. One such drug is heparin. Another is a fragment of heparin.
A therapeutically effective amount of a non-steroidal antiinflammatory drug (NSAID) for enhancing the effect of the form of hyaluronic ι acid administered in the prevention of the narrowing of the tubular walls may n0 be administered with the form of the hyaluronic acid. The addition of the nonsteroidal anti-inflammatory agent will enhance the activity of the hyaluronic acid in preventing the narrowing of the tubular walls for example enhancing the arterial restenosis prevention effect of the administered hyaluronic acid and/or salts thereof for example by reducing inflammation. The NSAID may be an
NSAID suitable for the purposes and may comprise Diclofenac, Indomethacin (solubilized in for example N-Methyl Glucamine), Piroxicam, the (+.) tromethamine salt of Ketorolac, acetylsalicylic acid, Naproxen and the like. The amounts of NSAID may be appropriate accepted doses preferably administered to patients. In some cases dose amounts up to lOmg of the NSAID/kg of body weight (for example l-2mg of NSAID/kg of body weight) are suitable. With
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-8Diclofenac much larger amounts are appropriate. Where greater than normal amounts of NSAID5 are used, in order to reduce side effects caused by excess NSAID administration, greater than about 200mg of the form of Hyaluronan or Hyaluronic Acid (HA) per 70kg person may be administered to reduce and eliminate the side effects such as gastro-intestinal distress, neurological abnormalities, depression, etc., of administration of the NSAID.
A therapeutically effective amount of a free radical scavenger and anti-oxidant such as Vitamin C may also be added to the composition to enhance the effect of the Hyaluronic Acid and Hyaluronan administered. Such amount may be up to 50 grams - 100 grams in a dosage as Vitamin C is soluble and is excreted by the kidneys although much lower amounts are normally used. Other anti-oxidants and free radical scavengers may also be used. In one embodiment the composition comprises a form of hyaluronic acid, specifically preferred hyaluronic acid and/or salts thereof, an NSAID, a stenosis inhibiting drug 15 and/or Vitamin C for administration for the prevention of the narrowing of the tubular walls (for example the prevention of arterial restenosis after balloon angioplasty). The composition may comprise a pluality of dosage amounts from which one dosage amount may be withdrawn and used, each dosage amount f containing an effective amount of each of the constituents.
r Thus according to another aspect of the invention, the use of a pharmaceutical composition for the prevention of the narrowing of the tubular walls of an animal or human after the tubular walls have been traumatized is provided, the use being of a pharmaceutical composition comprising a therapeutically effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid in association with a suitable diluent or pharmaceutically acceptable carrier or other adjuvants to prevent narrowing of the tubular walls - in one embodiment being administered just before the trauma and in another, immediately after the trauma. Preferably the form of hyaluronic acid or hyaluronan is hyaluronic acid and salts thereof, for example
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-9sodium hyaluronate.
According to another aspect of the invention, the use of a pharmaceutical composition for the prevention of arterial restenosis after balloon angioplasty in a human is provided, the use being of a pharmaceutical composition comprising a therapeutically effective non-toxic amount of hyaluronic acid and/or salts and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid in association with a suitable diluent, pharmaceutically acceptable carrier or other adjuvants to prevent arterial restenosis preferably the form of hyaluronic acid is selected from hyaluronic acid and salts thereof and the amount of the form of hyaluronic acid is between about l0mg/70kg person and about 3000mg/70kg person.
In one embodiment the form of the pharmaceutical composition is for intravenous administration and is administered immediately before the trauma (for example before balloon angioplasty). In another, the composition is administered immediately after the trauma.
According to still another aspect of the invention, the pharmaceutical composition comprises a therapeutically effective amount of non-steroidal anti-inflammatory drug (NSAID) for example Diclofenac, Indomethacin (solubilized in N-Methyl Glucamine), Piroxicam, the (±)
-20 tromethamine salt of Ketorolac, acetylsalicylic acid and the like for enhancing the effect of the form of hyaluronic acid in the prevention of the narrowing of the tubular walls.
Thus according to another aspect of the invention, the use of a pharmaceutical composition for the prevention of arterial restenosis after balloon angioplasty is provided, the use being of a pharmaceutical composition comprising a therapeutically effective non-toxic amount of hyaluronic acid and/or salts thereof in association with a suitable diluent or pharmaceutically acceptable carrier or other adjuvants to prevent arterial restenosis (by administration for example intravenously of the composition). In some embodiments the amount of the hyaluronic acid and/or salts thereof is between
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-1010
Ο d° about 10mg/70kg person and about 3000mg /70kg person. The composition may further comprise a therapeutically effective amount of a non-steroidal antiinflammatory drug (NSAID) for enhancing the arterial restenosis prevention effect of the administered hyaluronic 2cid and/or salts thereof administered. The NSAID may be at accepted appropriate doses depending on the NSAID for example up to about 10mg/70kg of body weight (for example l-2mg of NSAID/kg of body weight). The appropriate dose for Diclofenac is much greater. Where it is desired to use a dose excess of NSAID, the amount of hyaluronic acid and salts thereof preferably exceeds about 200mg/70kg person.
The composition may further comprise a therapeutically effective amount of Vitamin C or other free radical scavenger or anit-oxidant for enhancing the effects of the form of hyaluronic acid to prevent narrowing of the tubular walls. The Vitamin C may be used in large amounts (for example even 50 - 100 grams) although much smaller amounts are suitable.
The composition may also comprise an effective amount of a stenosis inhibiting drug.
The composition may comprise hyaluronan or hyaluronic acid and at least of one of an NSAID, Vitamin C, free radical scavenger, anti-oxidant and stenosis inhibiting drug.
According to another aspect of the invention the use of: an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition is provided for preventing the narrowing of the tubular walls of an animal after the tubular walls have been traumatized, the use being characterized by a therapeutically effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid being incorporated into the pharmaceutical composition and being sufficient and effective to prevent the narrowing of the tubular walls
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-11which were traumatized as for example the arteries being damaged after balloon angioplasty. Preferably the form of hyaluronic acid is hyaluronic acid and/or salts thereof and the composition is in a liquid form. Preferably, the form of hyaluronic acid is utilized at a dose between about lOmg to about 3000mg/70kg person and more preferably the form of hyaluronic acid is utilized at a dose greater than 200mg/70kg person. The composition may comprise a plurality of dosage amounts.
In one embodiment the pharmaceutical composition is for prevention of arterial restenosis after balloon angioplasty in humans. In embodiments the pharmaceutical composition is given before the balloon angioplasty and immediately after the trauma.
According to another aspect of the invention, the use of;
(1) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, and (2) an agent selected from a non-steroidal anti-inflammatory drug (NSAID), a stenosis inhibiting drug, and Vitamin C, free radical scavenger and anti-oxidant and combinations thereof is provided in the manufacture of a pharmaceutical composition (including ζ Ό diluents, adjuvants and other carriers) for preventing the narrowing of the tubular walls of an animal after the tubular walls have been traumatized wherein a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid is administered to humans together writh a therapeutically effective amount of the agent (2), the use being characterized in that the amount of component (1) is an effective amount to prevent the narrowing of the tubular walls of the animal and component (2) enhances the effect of component (1) in the prevention of the narrowing of the tubular walls. Once again the pharmaceutical composition may comprise a plurality of dosage forms from which one dosage amount may be taken.
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-12Preferably component (1) is hyaluronic acid and/or salts thereof and the composition is in a liquid form (for example for intravenous use or injection). Preferably component (1) is utilized at a dose between about lOmg to about 3000mg/70kg person. In one use, component (1) is utilized at a dose greater than 200mg/70kg person.
Component 2 is utilized at amounts effective to enhance the effect of Component 1. Vitamin C may be utilized in amounts up to 50 - 100 grams per dose although much smaller amounts are more desirable. The NSAID can be administered in normally acceptable dose amounts depending on the NSAID.
With some NSAIDS the amounts are l-2mg of NSAID per Kg of body weight, in others up to about lOmg per kg bodyweight and in others such as Diclofenac, much larger amounts. Where the NSAID is used in dose excesses (greater amounts than the normally acceptable dose amounts, the amount of the form of hyaluronic acid preferably exceeds about 200mg per 70kg person. Suitable
NSAIDS include Diclofenac, Piroxicam, Indomethacin (solubilized in N-methyl glucamine), acetylsalicylic acid, ± tromethamine salt of Ketorolac, naproxen and the like.
According to another aspect of the invention a pharmaceutical composition is provided comprising (together with diluents as required) an
-20 effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, for preventing the narrowing of the tubular walls of a human after the tubular walls have been traumatized, the composition being characterized by an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid being incorporated into the pharmaceutical composition to prevent the narrowing of the tubular walls. Preferably the form of hyaluronic acid is hyaluronic acid and/or salts thereof and preferably the composition is in a liquid form (such as an intraveneous (I.V.) form in an I.V. bag with diluents and pharmaceutically acceptable carriers and
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AP 0 0 0 A A 8--------13adjuvants). The form of hyaluronic acid may be utilized at doses between about lOmg to about 3000mg/70kg person or more and in one embodiment the form of hyaluronic acid is utilized at a dose greater than 200mg/70kg person (especially where dosage excesses of NSAIDS are employed). In one embodiment the pharmaceutical composition is for prevention of arterial restenosis after balloon angioplasty in humans. The composition may be administered before the balloon angioplasty and/or after. The pharmaceutical composition may comprise a plurality of dosage amounts from which each dosage amount may be taken.
According to another aspect of the invention, a pharmaceutical composition is provided comprising (together with diluents, adjuvants and other pharmaceutically acceptable carriers as and if desired);
(1) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, and (2) an agent selected from a non-steroidal anti-inflammatory drug, a stenosis inhibiting drug, Vitamin C, an anti-oxidant and free radical scavenger and combinations thereof for preventing the narrowing of the tubular walls of an animal after the tubular walls have been traumatized, the composition being characterized by an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid being incorporated into the composition together with a therapeutically effective amount of the agent (2), to prevent the tubular walls from narrowing, the composition being characterized that the amount of component (1) is an effective amount to prevent the narrowing of the tubular walls of the animal and the amount of component (2) enhances the effect of component (1) in the prevention of the narrowing of the tubular walls. Preferably component (1) is hyaluronic acid and/or salts thereof most preferably sodium hyaluronate and preferably in a liquid dosage form such as an
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Intravenous form (I.V. Bag). The composition may be made in bulk and subsequently put into individual dosage amounts. The composition may be packaged such that a plurality of dosage amounts are carried in a container (storage container or reservoir) from which each dosage amount may be withdrawn when needed for use. In some embodiments component (1) may be utilized at a dose between about lOmg to about 1000mg/70kg person. In others the dose amounts may be up to 3000mg/70kg person or more. Preferably component (1) is utilized at a dose greater than 200mg/70kg person where dose excesses of the NSAID of component (2) are utilized. In one embodiment the pharmaceutical composition is for prevention of arterial restenosis after balloon G angioplasty in humans and may be administered before, during and/or after the treatment.
Component 2 is utilized at amounts effective to enhance the effect of Component 1. Vitamin C may be utilized in amounts up to 50 - 100 grams per dose. The NSAID can be administered in appropriate dose amounts depending on the NSAID and if given in excess amounts the amount of the form of hyaluronic acid preferably exceeds about 200mg per 70kg person. Suitable NSAIDS are Diclofenac, Piroxicam, Indomethacin (solubilized in N-methyl glucamine), acetylsalicylic acid, + tromethamine salt of Ketorolac, naproxen and „20 the like.
o
When the composition comprises an agent selected from NSAID, stenosis inhibiting drug, Vitamin C, free radical scavenger and anti-oxidant and combinations thereof, Applicants postulate that the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid also facilitates the transport of the agent to the site of irritation to enable the agent to penetrate the cells (in the artery, endothelial cells) which together will help prevent for example arterial restenosis.
By way of example and to illustrate the facilitation of the delivery or transport of a chemical to a site in a mammal, when ethyl alcohol is injected
APOOO 44 8
-15directly into a cancer tumor, and sonographic (ultrasound) assessment is made, it is not dispersed throughout the tumor. When the ethyl alcohol to be administered into a tumor is carried by hyaluronic acid and/or salts thereof, sonographic assessment of the tumor, demonstrates the dispersion of the ethyl alcohol throughout the tumor.
While Applicants postulate that the hyaluronic acid facilitates the transport and delivery, Applicants' invention may be used as described irrespective of the actual method of operation of the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid with the NSAID, stenosis inhibiting drug, Vitamin C, free radical scavenger, and/or anti-oxidant.
The combination of hyaluronic acid and salts thereof and other forms with different chemicals and drugs (for example Vitamin C, NSAIDS, stenosis inhibiting drug, etc.) alters their distribution and performance in the human body and produces an unusual targeting for underperfused tissue and/or pathological tissue. In this regard the use of ascorbic acid (Vitamin C) as a free radical scavenger (50 gm daily - 1000 times the daily dose in therapeutic purposes as a Vitamin) administered intravenously with 300 - 500mg of hyaluronic acid (sodium hyaluronate) reduces inflammation. The hyaluronic acid enhances the effect of the ascorbic acid. It is thought that this enhanced activity eliminates the free radicals by acting as a free radical scavenger.
A similar situation occurs with the NSAIDS. As a major amount of soluble indomethacin is required, the chemical product was solubilized using n-methyl glucamine at a dilution of 5mg/ml of n-methyl glucamine (NMG).
This substance is then passed through a 22 micron Milipore filter to produce sterility. This material is non-toxic at 16 fold the therapeutic dose in animals and for this reason was considered appropriate to be used in human conditions. Thus, Indocid™ solubilized in NMG is administered to human patients intravenously or intravascularly at a varying dose up to 10 mg/kg where each dose of indomethacin is combined with for example 200 - lOOOmg of hyaluronic
BAD ORIGINAL ft ad Ο 00 4 4 8 ** -16't acid (for example LifeCore™ hyaluronic acid [sodium hyaluronate]) diluted in the original solution of indomethacin and NMG with for example the LifeCore™ hyaluronic acid. This produces an appropriate mixture and can be administered safely by any of the routes. [Similar clinical studies have been done with hyaluronic acid prepared by other methods, i.e. extraction. The extracted material is satisfactory to use for intravenous.]
Thus when an NSAID for example indomethacin (dissolved in nmethyl glucamine) or other NSAID is administered with greater than 200mg hyaluronic acid for 1-2 mg/kg body weight of the NSAID (in one instance indomethacin and NMG), no major toxic side effects occur such as gastrointestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary). If the amount of hyaluronic acid is decreased below about that amount, the usual side effects may begin to reoccur. In addition, the responses that have been observed are superior when the
NSAID (for example Indocid™) is combined with hyaluronic acid demonstrating clearly that the combination is now targeting to the tissue when administered by the systemic intravenous route. Thus, it has been observed that patients when receiving in addition to other chemicals (for example ascorbic acid [Vitamin C], 50 - 200 mg NSAID - hyaluronic acid (sodium hyaluronate) (for example indomethacin and hyaluronic acid) experience dramatic relief of pain immediately. Thus Applicants believe that the addition of the NSAID for example with hyaluronic acid (sodium hyaluronate) prevents enzymatic production of prostaglandin synthetase which blocks macrophage functioning. Thus the hyaluronic acid (and salt and other forms) not only enhance the activity of the NSAID but also reduce any side effects and toxicity that is associated with the use of the prostaglandin synthesis inhibitors.
The hyaluronic acid and salts thereof may be utilized at varying doses - 10 to 1000 mg/70 kg person. As there is no toxidty, the hyaluronic acid can obviously be administered in a dose excess (for example 3000 mg/70 kg
APO00448
-17One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts and thereof suitable for use with Applicant’s invention is a fraction supplied by
Hyal Pharmaceutical Corporation. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000. The fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from (' the group consisting of the following:
| .. 20 ( | i) | a molecular weight within the range of 150,000-225,000; |
| ii) total weight basis; | less than about 1.25% sulphated mucopoly-saccharides on a | |
| iii) | less than about 0.6% protein on a total weight basis; | |
| iv) | less than about 150 ppm iron on a total weight basis; | |
| 25 | v) | less than about 15 ppm lead on a total weight basis; |
| vi) | less than 0.0025% glucosamine; | |
| vii) | less than 0.025% glucuronic acid; | |
| viii) | less than 0.025% N-acetylglucosamine; | |
| ix) | less than 0.0025% amino acids; | |
| 30 | x) | a UV extinction coefficient at 257 nm of less than about 0.275; |
BAD ORIGINAL A
AP 0 0 0 4 4 6
-18xi) a UV extinction coefficient at 280 nm of less than about 0.25;
and xii) a pH within the range of 7.3-7.9. Preferably the hyaluronic acid is mixed with water and the fraction of hyaluronic acid fraction has a mean average molecular weight within the range of 150,000-225,000. More preferably the fraction of hyaluronic acid comprises at least one characteristic selected from the group consisting of the following characteristics:
i) less than about 1% sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
iv) less than about 10 ppm lead on a total weight basis;
v) less than 0.00166% glucosamine;
vi) less than 0.0166% glucuronic acid;
vii) less than 0.0166% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
x) a UV extinction coefficient at 257 nm of less than about 0.23;
xi) a UV extinction coefficient at 280 nm of less than 0.19; and xii) a pH within the range of 7.5-7.7
Other forms of hyaluronic acid and/or its salts, and homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers. Applicants propose the use of sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc. having the following specifications
BAD ORIGINAL ft
ΑΡ 0 0 0 4 4 8
| Characteristics Appearance | Specification White to cream colored particles | ||
| Odor | No perceptible odor | ||
| Viscosity Average Molecular Weight | < 750,000 Daltons | ||
| UV/Vis Scan, 190-820nm | Matches reference scan | ||
| OD, 260nm | < 0.25 OD units | ||
| Hyaluronidase Sensitivity | Positive response | ||
| IR Scan | Matches reference | ||
| pH, lOmg/g solution | 6.2 - 7.8 | ||
| Water | 8% maximum | ||
| Protein | < 0.3 mcg/mg NaHy | ||
| Acetate | < 10.0 mcg/mg NaHy | ||
| Heavy Metals, maximum ppm As Cd Cr Co Cu 2.0 5.0 5.0 10.0 10.0 | Fe 25.0 | Fb Hg Ni 10.0 10.0 5.0 | |
| Microbial Bioburden | None observed | ||
| Endotoxin | < 0.07EU/mg NaHy | ||
| Biological Safety Testing | Passes Rabbit Ocular Toxicity Test | ||
| Applicants also propose | the use | of forms of hyaluronic acid |
described in the prior art.
The following references teach hyaluronic add, sources thereof and
BAD ORIGINAL ft _ __ __ ____ _ _ __ M Λ Λ J / ί\ . .......
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-20processes of the manufacture and recovery thereof.
United States Patent 4,141,973 teaches hyaluronic acid fractions (including sodium salts) having:
(a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,000 - that is, a limiting viscosity number greater than about 1400 cm3/g., and preferably greater than about 2000 cm3/g.;
(b) a protein content of less than 0.5% by weight;
(c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength;
(d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
(e) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological buffer of less than -11 X 103 degree - cm-/mole (of disaccharide) measured at 220 nanometers;
(f) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humor, no haze or flare in the vitreous and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1% solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being (g) sterile and pyrogen free and (h) non-antigenic.
Canadian Letters Patent 1,205,031 (which refers to United States
BAD ORIGINAL ft
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-21Patent 4,141,973 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; arid 500,000 to 730,000 and discusses processes of their manufacture.
Where high molecular weight hyaluronic acid (or salts or other 5 forms thereof) is used, it must be diluted to permit administration and ensure no coagulation or interference with body function.
One formulation of Ascorbic Acid (Vitamin C) injection USP is manufactured by Steris Laboratories, Inc., Phoenix, Arizona, 85013 U.S.A. and comprises 22 mg/ml (equivalent to sodium ascorbate 250 mg/ml) in 30ml, 50ml, or 100ml individual containers, 30ml size being preferred.
BRIEF DESCRIPTION OF THE DR-AWINGS
Surgical procedures were undertaken to illustrate an embodiment of the invention and analysis of results are illustrated in the enclosed Figures in which;
Figure 1 contains photographs of injured and sham operated arteries.
Figure 2 illustrates in graph form RHAMM (Receptor for H A (Hyaluronan) Mediated Motility) expression by the carotid arteries.
Figure 3 contains photographs of RHAMM and hyaluronan 20 expression in smooth muscle cells of the carotid artery 4 days after their injury.
Figure 4 illustrates in a bar graph the effect of RHAMM, HA binding [Hyaluronan-(Hyaluronic Acid)- binding] peptides (401-411) and anti-Rhamm antibody on the Chemotaxis of Macrophage cell lines to complement (C5a).
Figure 5 illustrates in bar graph form the effect of RHAMM HA 25 Binding peptides (401-411) of the chemotaxis of the neutrophiles to IL-8.
Figure 6 illustrates in bar graph form the effect of RHAMM HA binding peptide 401-411 on smooth muscle cell migration 5 hours after wounding.
BAD ORIGINAL
AJP Ο Ο Ο 4 4 8
-22BRJEF PESCRIPTiON..Q£JHE.EMBODIMENT
The following experiments were conducted.
rabbits were anesthetized and balloon angioplasty was performed on them. The rabbits were perfused with hyaluronan (5 mg/ml) or buffer alone and allowed their recover. Rabbits were sacrificed at 2, 24, 48 hours after injury and carotid arteries were processed for histology and serial 5-10 pm sections were taken for processing. Sections were stained with hematoxylin or with anti RHAMM antibodies. 10 sections of each treatment were analyzed.
The results of the analysis is described below with respect to the
Figures.
Figure 1: Injured carotid arteries show denudating of the endothelia cell layer and adherence of white cells (Figure IA). White cells stained positively for RHAMM relative to IgG control background (Figure IB). Carotid arteries that were exposed to hyaluronan (Figure 1C) or sham operated arteries (Figure ID) show intact endothelial cell layer and do not exhibit accumulations of white cells.
Figure 2: Western transblot analysis of RHAMM expression by carotid arteries. Carotid arteries were homogenized, the released proteins were electrophoresed on SDS-PAGE and the presence of RHAMM was detected with a
-20 mono-specific antibody. The presence of the antibody was visualized with chemiluminescence and the relative amounts of bound antibody were quantified with optical densitometry. Operated animals displayed an acute, large rapid increase in the presence of RHAMM. Levels of RHAMM had dropped by 5-6 days after tissue injury. Sham operated animals showed no increase in RHAMM expression.
Figure 3: RHAMM (Figure 3A) and hyaluronan (Figure 3B) expression in smooth muscle cells of the carotid artery 4 days after their injury. RHAMM expression on white cells elevated immediately (Fig. 1) while RHAMM expression on smooth muscle cells was increased later and concommittent with the initiation of their locomotion. Smooth muscle cells of sham operated
BAD ORIGINAL ft
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-23animals did not show a similar increase in the expression of RHAMM (Figure 3C).
Figure 4: The effect of RHAMM peptides on chemotaxis of neutrophiles in response to IL-8. RHAMM peptides that mimic the hyaluronan binding domain of RHAMM inhibit the chemotaxis of neutrophiles in a Boyden chamber assay.
Figure 5: RHAMM peptides and antibodies inhibit chemotaxis of macrophage cells lines (SI, WEHI-3) in response to complement. Complement but not heat-inactivated complement (56°C) stimulated chemotaxis of macrophage cell lines. RHAMM peptides that mimic hyaluronan binding ( domain of RHAMM and anti-RHAMM antibodies inhibit chemotaxis.
Figure 6: RHAMM peptides inhibit the locomotion of smooth muscle cells responding to injury. The RHAMM peptide that mimics the hyaluronan binding domain of RHAMM inhibits the locomotion of injury smooth muscle cells. The scrambled peptide had no effect indicating the specificity to the sense peptide.
RHAMM expression (determined by a method of detection named Western transblot analysis using mono-specific antibodies to RHAMM (Turley, e.A., Austin, L., Vandeligt, K. and Clan’, C., 1991, J. Cell Biol., 112:1041), revealed an acute increase in expression of this receptor that was detectable by two hours (Fig. 2), a time frame during which white cells were observed in control animals to adhere to the endothelium (Fig. 2). [For a further discussion of RHAMM see the article Identification of Two Hyaluronan-binding Domains in the Hyaluronan Receptor RHAMM, Baihua Yang, Liying Zhang, and Eva Ann
Turley, The Journal of Biological Chemistry, Vol. 268, No. 12, Issue of April 25, pp. 8617-8623, 1993.] RHAMM was also increased in the contralateral artery suggesting the release of a soluble factor that regulates RHAMM expression from the injured tissue. However, sham operated animals showed little increase in the expression of RHAMM (Fig. 2). In experimental animals, expression of
RHAMM was maintained for several days, then levels dropped. Examination of
BAD ORIGINAL ft ~ AP 0 0 0 4 4 8
-24fixed tissue revealed that the major cells expressing RHAMM were activated white cells and smooth muscle cells (Fig. 1, 3). The involvement of RHAMM in white cell and smooth muscle cell locomotion was assessed in vitro using image analysis to measure random locomotion and Boyden chambers to measure chemotaxis. Peptides (100 ng/plate) that mimic regions (in particular the hyaluronan binding domains) of RHAMM, inhibit macrophage (Fig. 4) neutrophiles (Fig. 5) and smooth muscle cell (Fig. 6) migration to a highly significant degree (p > 0.0001, Student’s T test). Collectively, these results indicate that RHAMM, and in particular its Hyaluronan binding capability, is essential for locomotion of white cells and smooth muscle cells and that its expression is elevated at the site of tissue injury following experimental ballon catherization in rabbits.
Hyaluronan treatment of rabbits just prior to their injury abolished adherence of white cells to endothelium resulting in tissue that appeared intact as detected by histological criteria (Fig. 1). Several days after injury, carotid arteries of hyaluronan treated rabbits appeared similar to controls displaying an intact endothelium.
The rationale for these results is that hyaluronan bound to cells expressing high levels of its receptor, RHAMM and prevented subsequent interactions of these cells with the endothelium. It is expected, that expression of the other hyaluronan receptor, CD44, is also elevated.
For a discussion and illustration of terms and expressions in this application, reference should be had to the enclosed unpublished article attached as Schedule A entitled Neointimal Formation after Balloon Catheter Injury: A Role of Hyaluronan and the Hyaluronan Receptor RHAMM, the portions thereof which discuss and illustrate terms and expressions referred to herein are incorporated herein by reference.
As many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims (41)
- THE EMBCDiMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY CR PRIVILEGE IS CLAIMED APE AS FOLLOWS:5 1. A method of preventing the na·rowing ol the tubular wal's cf an animal i^er the tubular walls have been traumatized, the method composing the acminisVation of a therapeutical'y elective non-toxic amount a term of hyaluronic add selected from hyaluronic acid, pharmaceutically acceptable salts thereof, k.-.gments thereof, and subunits of hyaluronic acid, to the an'mal to prevent10 rarrewing of the tubular walls.
- 2. The method of Claim 1, wherein the form of hyaluronic acid is | selected from hyaluronic acid and phimraceutically acceptable salts thereof whose molecular weight is less than 750,0*30 daftons.
- 3. The method of Cla'm 2, wherein the tubular walls are arteries which have been subjected to balloon angioplasty and the administration takes places before, during and/or after the balloon angioplasty.20
- 4. The method cl Claim 2, wherein the amount of the form of hya’uronic acid administered is between l0mg/7Ckg person and 3000mg /70kg person.
- 5. A method of preventing arterial restenosis a^ter balloon angcplasty in a human, the method comprising the administration of a therapeutically effective25 non-toxic amount of hyaluronic acid sails thereof, fragments thereof and subunits C ' of hyaluronic acid, to the human to prevent arterial restenosis.u
- 6. The method of C!a!m 5, wherein the form of hyaluronic acid is ejected from hyaluronic acid and pharmaceutically acceptable salts thereof whose-0 molecular weight is less than 750,000 daltons.
- 7. The method of Claim 6, wherein the amount of the form of hyaluronic acid administered :s between 10mg/70kg person and 3000mg/70kg person. _BAD ORIGINALAP Ο Ο Ο 4 4
- 8268. The method of Claim 1, 2 or 4 --.herein 4he form of hyaluronic acid is admmistered pr.or to, during and/or after the balloon angioplasty.5
- 9. The method of Claim 1, 2, 3, 4, 5, 6, or 7 whe rein the form of hyaluronic acid is sodium hyaluror.ate a dm mistered intravenously.
- 10. The method of Claim 1, 2, 3, 4, 5, 6, or 7 further comprising a therapeutically effective amount of a non-steroidal anti-inflammatory10 drug (N5AID) for enhancing the effect of the form of hyaluronic acid administered in the prevention of the narrowing of the tubular walls.
- 11. The method of Claim 10 further comprising an effective amount of at least one of Vitamin C, an anti-oxidant, a free radical15 scavenger and a stenosis inhibiting drug for enhancing the effect of the form of hyaluronic acid administered in the prevention of the arterial restenosis.
- 12. A method of preventing of arterial res'enosis after balloon20 angioplasty, the method comprising the administration of a therapeutically effective non-toxic amount of hyaluronic acid and/or pharmaceutically acceptable salts thereof whose molecular weight is less than 750,000 daltons to prevent arterial restenosis.
- 13. - The method of Claim 12, wherein the amount of the hyaluronic acid and/or salts thereof administered is between ZCmg/70kg person ar.d 3000mg /70kg person.
- 14. The method of Claim 12 or 13 further comprising a 30 therapeutically effective amount of an agent selected from a non-steroidal anti-inflammatory drug (NSATD), stenosis inhibiting drug. Vitamin C an anti-oxidant and free radical scavenger and combinations thereof for enhancing the arterial stenosis prevention effect of the administered hyaluronic acid and/or salts thereof.
- 15. The method of Claim 12 or 13 further comprising an agentAP Ο 00 4 4 8-27inhititing drug, Vitamin C, an anti-oxidant, and a free radical scavenger and combinations thereof for enhancing the arterial restenosis prevention effect of the hyaluronic acid ard/or salts thereof administered, the agent being selected in such amount to be effective in enhancing the arterial5 restenosis prevention effect of the administered hyaluronic acid and/or salts thereof.
- 16. The method of Claim 13, 14 or 15 wherein if an NSAID is selected, the amount of the NSAID is an effective dosage amount or a doseIf) excess of the NSAID and the amount ci hyaluronic acid and salts thereof exceeds 230mg/7(?kg person.C
- 17. The use of a pharmaceutical composition for the prevention of the narrowing of the tubular walls of an animal after the tubular walls15 have been traumatized, the use being of a pharmaceutical composition comprising a therapeutically effective non-toxic amount of a form of hyaluronic acid selected from hyaluronic acid, pharmaceutically acceptable salts thereof, fragments thereof, ard subunits of hyaluronic acid in association with a suitable diluent or pharmaceutically acceptable carrier20 to prevent narrowing of the tubular walls.
- 18. The use cf Claim 17, wherein the form of hyaluronic acid is selected from hyaluronic acid and pharmaceutically acceptable salts thereof whose molecular weight is less than 750,GOO daltons.t ζ-'
- 19. The use of Claim 18* wherein the tubular walls are arteries » which have been subjected to balloon angioplasty and the use has been administered before, during and/or after the balloon angioplasty.30 20. The use of Claim 17, 18 or 19, wherein the amount of the form of hyaluronic acid administered is between 10mg/7Ckg person and 3000mg /70kg person.21. The use of a pharmaceutical composition for the prevention35 of arterial restenosis after balloon angioplasty in a human, the use being of a pharmaceutical composition comprising a therapeutically effective non-AP Ο Ο Ο 4 4 8-28frsgm.erts thereof, vd subunits of hyaluronic acid in association with a suitable diluent or pharmaceutically acceptable carrier to prevent arterial restenosis.5 22. The use of Claim 21, wherein the form of hyaluronic acid is selected from hya’-ronic acid and pharmaceutically acceptable salts thereof whuse molecular weight is less than 750,000 daltons.23. The use of Claim 21 or 22, wherein the amount of the form10 of hyaluronic acid is between 10mg/7Ckg person and 3000mg.' 70 kg person.24. The use cf Claim 17, 18, 20, 21 or 22, wherein the form of the pharmaceutical composition is for intravenous administration.15 25. The use of Claim 17, 18, 20, 21 or 22, further comprising a therapeutically effective amount of an agent selected from a non-steroidal anti-inflammatory crug (NSAID), stenosis inhibiting drug. Vitamin C, anti-oxidant and free radical scavenger for enhancing the effect of the form of hyaluronic acid in the prevention of the narrowing of the tubular
- 20 walls.26. The use Qf a pharmaceutical composition for the prevention of arterial restenosis after balloon angioplasty, the use being of a pharmaceutical composition before, during and/or after balloon
- 25 angioplasty comprising a therapeutically effective non-toxic amount of hyaluronic acid and/or pharmaceutically acceptable salts thereof whose molecular weight is less than 750,000 daltons, in association with a suitable diluent or pharmaceutically acceptable carrier to prevent arterial restenosis.
- 27. The use of Claim 26, wherein the amount of the hyaluronic acid and/or salts thereof is between lCmg/70kg person and JOOOrng /70kg person.35
- 28. The use of Claim 26 or 27 further comprising an agent selected from a therapeutically effective amount of an agent selected from a non-steroidal anti-inflammatory drug (NSAID), stenosis inhibiting drug.AP Ο Ο Ο 448-29V?:min C, anti-cx’dant and free radical scavenger and combinations thereof for enhancing the arterial restenosis prevention effect of the a±r mistered hvaluroric acid and/or salts thereof administered.
- 29. The use of Claim 26 or 27 further comprising an agent se'e'ted from a therapeutically effective amount of a non-steroidal antiinfirnmatory drug (NSAID), stenosis Inhibiting drug and Vitamin C and combinations thereof for enhancing the arterial restenosis prevention effect of the hyaluronic acid and/or salts thereof administered, the nonsteroidal anti-inflcnmotory drug, stenosis Inhibiting drug and Vitamin C being selected in such amounts to be effective in enhancing the arterial res*enosis prevention effect of the administered hyaluronic acid and/or «alts thereof.
- 30. The use of Claim 28 or 29 wherein if an NSAID is selected, the amount of the NSAID is in an effective dose or a dose excess of the NSAID and the amount of hyaluronic acid and salts thereof exceeds 2GC-g/70hg pe-son.
- 31. The use of:an effective non-toxic amount of a form of hyaluronic acid selected from hyaluronic acid pharmaceutically acceptable salts thereof, fragments thereof ard subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition for presenting the narrowing of the tubular walls of an animal after the tub Jar w’alls have been traumatized, the use being characterized by an effective non-toxic amount of the form of hyaluronic acid being incorporated in,to the pharmaceutical composition.
- 32. The use of Claim 31 wherein the form of hyaluronic acid is hyal ironic add and/or salts thereof whose molecular weight is less than 75C.-C0 daltons.The use according to Claim 31 or Claim 32 in intravenous- BAD ORIGINAL 03AP Ο Ο Ο 4 4 8Rf'-3034. The use of Claim 31 or 32 wherein the form of hyaluronic acid is utilized at a dose between lOmg to 3CO0rr.g/70kg person.
- 35. The use of Claim 31 or 32 wherein the form of hyaluronic add is utilized at a dose greater than 200mg/70kg person.
- 36. The use of Claim 31 or 32 wherein the pharmaceutical composition is for prevention of arterial restenosis af:er balloon angioplasty in humans.
- 37. The use of;(1) a therapeutically effective non-toxic amount of a form of hjaluronic acid, selected from hyaluronic acid pharmaceutically acceptable salts thereof, fragments thereof, and subunits of hyaluronic acid, and (2) an agent selected from a non-steroidal antiinflammatory drug, stenosis inhibiting drug, Vitamin C, ar.d-oxidant and free radical scavenger and combinations thereof in the manufacture of a pharmaceutical composition for preventing the narrowing of the tubular walls of an animal after the tubular walls have been traumatized wherein a therapeutically effective amount of the forms of hyaluronic acid is administered to humans together with a therapeutically effective amount of the agent (2), the use being characterized in that the amount of component (1) is an effective amount to prevent the narrowing of the tubular walls of the animal and component (2) enhances the effect of component (1) in the prevention of the narrowing of the tubular walls.
- 38. The use of Claim 37 wherein component (2) is hyaluronic 30 acid and/or salts thereof whose molecular weight is less than 750,000 daltons.
- 39. The use according to Claim 37 or Claim 38 in intravenous form.
- 40. The use of Claim 37 or 38, wherein component (1) is utilized at a dose between 10mg/70kg person to 3COOmg/7Ckg person. BAD ORIGINALAP Ο Ο Ο 4 4 β-3141. The use of C'aim 37 or 38, wherein component (1) is ufi’zed at a dose greater than 200rrg<70kg person.
- 42. The use of Claim 37 or 38, wherein !h.e pharmaceutical 5 composition is for prevention of arterial restenosis after ba'Ioon angioplasty in humans.
- 43. A pharmaceutical corr.pos'tion comprising together w'th diluents, adjuvants and other pharnnaceuticai carriers as desired;10 (1) a form of hyaluronic acid selected from hyaluronic acid, pharmaceutically acceptable sails thereof, fragments thereof and subunits of hyaluronic acid, and (2) a stenosis-inhibiting drug, and at least one agent selected 'rom a non-steroidal anti-inflammatory drugs (NSA'D), Vitamin C, a ” 15 free radical scavenger, and an‘i-ox:dant and combinat'cns thereof, for preventing the narrowing of 1he tubular walls of an animal after the tubular walls have been traumatized, the composition being characterized by an effective non-toxic amount of the form of hyaluronic acid being incorporated into the composition together with a therapeuticaiiy effective amount of agent20 (2), to prevent tubular wall narrowing, the composition being characterized that the amount of component (1) is an elective amount to prevent the narrowing of the tubular walls of the animal and component (2) also enhances the effect of component (1) in the prevention of the nanowing of the tubu'ar walls.
- 44. The composition of Claim 43 or 44 wherein component (1) is hyaluronic acid and/or a pharmaceutically acceptable salt thereof whose molecular weight is less than 750,000 daltons.30
- 45. The composition of Claim 43 or 44 wherein component (1) comprises a stencsis-inhibit'ng dnug and an NSAID.
- 46. The composition according to Claim 43, 44 or 45 in injectable or intravenous form and component 1 is sodium hyalutonate.
- 47. The composition of Claim 43, 44, 45, or 46, wherein component (1) is utilized at a dose between 10mg to 3000mg/70kg person. __BAD ORIGINALAP000448-3248. The composition of Cam 43, 44, 45, cr 45, wherein ccr-por.ent (1) is uti'ized at a dose greater than 200mg/7Ckg person.
- 49. The compos Ton of C'a.m 43, 44 45, 46, 47 cr 48 wherein the 5 pharmaceutical composition is for prevention of arterial restenosis after bal'oon angioplasty in humans.
- 50. A pharrraceutcal composition comp-rsing a plurality of dcsace amounts as claimed in Claims 43, 44, 45, 46,47, 48, cr 49.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002079205A CA2079205C (en) | 1992-09-25 | 1992-09-25 | Use of hyaluronic acid and forms to prevent arterial restenosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9300568A0 AP9300568A0 (en) | 1993-10-31 |
| AP448A true AP448A (en) | 1996-01-18 |
Family
ID=4150463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1993/000568A AP448A (en) | 1992-09-25 | 1993-09-22 | Use of hyaluronic acid and forms to prevent arterial restenosis. |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0661981B1 (en) |
| JP (1) | JP3742955B2 (en) |
| CN (1) | CN1057908C (en) |
| AP (1) | AP448A (en) |
| AT (1) | ATE141054T1 (en) |
| AU (1) | AU670117B2 (en) |
| BR (1) | BR9307221A (en) |
| CA (1) | CA2079205C (en) |
| CZ (1) | CZ288986B6 (en) |
| DE (1) | DE69303931T2 (en) |
| DK (1) | DK0661981T3 (en) |
| ES (1) | ES2091031T3 (en) |
| GR (1) | GR3021171T3 (en) |
| HK (1) | HK35397A (en) |
| HU (2) | HU227067B1 (en) |
| IL (1) | IL107087A0 (en) |
| IN (1) | IN181289B (en) |
| MD (1) | MD960294A (en) |
| MX (1) | MX9305887A (en) |
| NO (1) | NO309457B1 (en) |
| NZ (1) | NZ255978A (en) |
| PL (1) | PL308201A1 (en) |
| SG (1) | SG48845A1 (en) |
| SK (1) | SK36895A3 (en) |
| TW (1) | TW271401B (en) |
| ZA (1) | ZA937068B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6663881B2 (en) | 1993-01-28 | 2003-12-16 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| KR100374666B1 (en) * | 1997-08-22 | 2003-03-04 | 덴끼 가가꾸 고교 가부시키가이샤 | Hyaluronic acid gel, process for producing the same and medical material containing the same |
| FR2813791B1 (en) | 2000-09-14 | 2004-03-12 | Lafon Labor | USE OF 2- AND 4-QUINOLONES TO INHIBIT INTIMAL NEO-PROLIFERATION |
| US6613083B2 (en) | 2001-05-02 | 2003-09-02 | Eckhard Alt | Stent device and method |
| FR2994846B1 (en) | 2012-08-29 | 2014-12-26 | Vivacy Lab | COMPOSITION, STERILIZED, COMPRISING AT LEAST ONE HYALURONIC ACID AND MAGNESIUM ASCORBYL PHOSPHATE |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
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1992
- 1992-09-25 CA CA002079205A patent/CA2079205C/en not_active Expired - Lifetime
-
1993
- 1993-09-22 PL PL93308201A patent/PL308201A1/en unknown
- 1993-09-22 AU AU48126/93A patent/AU670117B2/en not_active Expired
- 1993-09-22 ES ES93920624T patent/ES2091031T3/en not_active Expired - Lifetime
- 1993-09-22 HU HU9500857A patent/HU227067B1/en unknown
- 1993-09-22 TW TW082107796A patent/TW271401B/zh active
- 1993-09-22 DE DE69303931T patent/DE69303931T2/en not_active Expired - Lifetime
- 1993-09-22 CZ CZ1995662A patent/CZ288986B6/en not_active IP Right Cessation
- 1993-09-22 DK DK93920624.9T patent/DK0661981T3/en active
- 1993-09-22 NZ NZ255978A patent/NZ255978A/en not_active IP Right Cessation
- 1993-09-22 AP APAP/P/1993/000568A patent/AP448A/en active
- 1993-09-22 BR BR9307221A patent/BR9307221A/en not_active Application Discontinuation
- 1993-09-22 JP JP50854394A patent/JP3742955B2/en not_active Expired - Lifetime
- 1993-09-22 AT AT93920624T patent/ATE141054T1/en active
- 1993-09-22 MD MD96-0294A patent/MD960294A/en not_active Application Discontinuation
- 1993-09-22 EP EP93920624A patent/EP0661981B1/en not_active Expired - Lifetime
- 1993-09-22 SG SG1996002824A patent/SG48845A1/en unknown
- 1993-09-22 SK SK368-95A patent/SK36895A3/en unknown
- 1993-09-23 IL IL107087A patent/IL107087A0/en not_active IP Right Cessation
- 1993-09-24 CN CN93119844A patent/CN1057908C/en not_active Expired - Fee Related
- 1993-09-24 ZA ZA937068A patent/ZA937068B/en unknown
- 1993-09-24 MX MX9305887A patent/MX9305887A/en unknown
-
1995
- 1995-03-23 NO NO951122A patent/NO309457B1/en not_active IP Right Cessation
- 1995-06-13 IN IN670CA1995 patent/IN181289B/en unknown
- 1995-06-30 HU HU95P/P00651P patent/HU211698A9/en unknown
-
1996
- 1996-09-26 GR GR960402522T patent/GR3021171T3/en unknown
-
1997
- 1997-03-20 HK HK35397A patent/HK35397A/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| NONE * |
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