EP0758246A1 - Pharmaceutical composition comprising hyaluronic acid for the clearing of arteriosclerosis - Google Patents

Pharmaceutical composition comprising hyaluronic acid for the clearing of arteriosclerosis

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Publication number
EP0758246A1
EP0758246A1 EP95916533A EP95916533A EP0758246A1 EP 0758246 A1 EP0758246 A1 EP 0758246A1 EP 95916533 A EP95916533 A EP 95916533A EP 95916533 A EP95916533 A EP 95916533A EP 0758246 A1 EP0758246 A1 EP 0758246A1
Authority
EP
European Patent Office
Prior art keywords
amount
dosage amount
pharmaceutical composition
hyaluronic acid
oxidant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95916533A
Other languages
German (de)
French (fr)
Inventor
Rudolf Edgar Falk
Samuel Simon Asculai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NORPHARMCO Inc
Original Assignee
NORPHARMCO Inc
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Filing date
Publication date
Application filed by NORPHARMCO Inc filed Critical NORPHARMCO Inc
Publication of EP0758246A1 publication Critical patent/EP0758246A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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

Definitions

  • This invention relates to the treatment of arterial disease and pharmaceutical compositions suitable for such use. Particularly the invention relates to the clearing of atherosclerosis. BACKGROUND OF THE INVENTION
  • Atherosclerosis is prevalent in the North American population believed to be caused in part by a diet rich in cholesterol. Over the years, deposits of yellowing plaques (atheromos) containing for example cholesterol, other lipoid material, lipophages and/ or other substances build up on the inner wall of the arteries (for example within the intima of large and medium-sized arteries) of a person causing the arteries to narrow inhibiting the free flow of blood. That person thus increases his/her risk of becoming a heart attack and/or stroke victim.
  • yellowing plaques containing for example cholesterol, other lipoid material, lipophages and/ or other substances
  • Balloon angioplasty is a widely accepted method of opening blockages in the coronary arteries.
  • ID inner diameter
  • 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.
  • reblockage occurs not by cholesterol build-up but by build up of endothelial cells on the inner wall of the artery reducing the inner diameter (ID) of the artery leading to an infarct.
  • This narrowing of the inner diameter (ID) of tubular walls or proliferation of cells is not however restricted or limited to the coronary arteries. It can also occur post operatively causing restenosis in for example peripheral vascular systems.
  • Applicants have provided a new method and treatment of clearing atherosclerosis in which deposits of plaques (atheromos) containing cholesterol, other lipoid material, lipophages and other substances have built up within the arterial walls of a patient for example within the intima of large and medium-sized arteries.
  • the method of treatment comprises administering for example, intravenously to a patient, at least one dosage amount of a pharmaceutical composition formulated according to embodiments of the invention.
  • dosage amounts administered over a number of weeks for example 2 - 12 weeks
  • intervals of for example two-three days from one administration to the next administration are suitable.
  • One patient was given 45 treatments over a 5-6 week period in equal intervals.
  • Another patient required only two treatments.
  • Still another patient received dosage amounts intravenously over a period of 12 weeks at two dosage amounts per week.
  • the dosage amounts comprise an effective non- toxic amount of each of a chelating agent, for example and preferably EDTA (common name for ethylenediaminetetraacetic acid), a non-steroidal anti- inflammatory drug (NSAID) (for example diclofenac, tromethamine salt of ketoralac (sold under the trade mark Toradol), indomethacin, piroxicam, ibuprofen), an anti-oxidant (for example and preferably vitamin C) and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof (for example the sodium salt), homologues, analogues, derivatives, esters, complexes, fragments and subunits.
  • the form of hyaluronic acid is preferably sodium hyaluronate having a molecular weight of less than about 750,000 daltons, for example a molecular weight of about 150,000 to 225,000 daltons.
  • Suitable dosage amounts may each comprise: (i ) about 1 -3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA);
  • an NSAID for example 30 mg of diclofenac sodium or the tromethamine salt of ketoralac
  • Treatment may also vary and in some instances may be administered one day after another, in one day intervals or in other instances, over alternate days. Of 6 patients treated, they averaged 10-15 treatments. All of the patients had subjective improvement in function, improved arterial blood flow by Doppler in affected vessels, and clearing of occlusion by angiography.
  • Suitable forms of sodium hyaluronate may include a fraction supplied by Hyal Pharmaceutical Corporation supplied in 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 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 (and preferably all characteristics) consisting of the following: i) a molecular weight within the range of 150,000- 225,000; ii) less than about 1.25% sulphated mucopoly- saccharides on a total weight basis; iii) less than about 0.6% protein on a total weight basis; iv) less than about 150 ppm iron on a total weight basis; v) less than about 15 ppm lead on a total weight basis; vi) less than 0.0025% gluco
  • the hyaluronic acid is mixed with water and the fraction of hyaluronic acid has a mean average molecular weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid may comprise at least one characteristic selected from the group (and preferably all characteristics) consisting of the following characteristics: i ) l e s s th an ab o u t 1 % s u l ph ate d 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; i v ) less than about 10 ppm lead on a total weight basis; v ) less than 0.00166% glucosamine; v i ) less than 0.0166% glucuronic acid; vii ) less than 0.0166% N-acetylglucosamine; viii) less than
  • UV/Vis Scan 190-820nm Matches reference scan
  • Hyaluronan HA-M5070 sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications:
  • hyaluronic acid and/or its salts, and analogues, homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine.
  • a kinematic viscosity of a 1 % solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
  • Canadian Letters Patent 1 ,205,031 (which refers to United States Patent 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
  • EDTA is the preferred chelating agent
  • suitable chelating agents such as Desferal (tm) which is deferoxamine methanesulfonate. Desferal comes in vials, Applicants believe, of 500 mg and 2 gm.
  • the NSAID blocks production of prostaglandin II and thromboxane.
  • the anti-oxidant Applicants believe, promotes prostacycline production.
  • any substance which promotes postacycline production may be suitable as an anti-oxidant.
  • a local anesthetic for example xylocaine (2%)
  • a bicarbonate of soda may also be added to the dosage amount.
  • the new method of treatment of clearing atherosclerosis employs new combinations of therapeutic agents in dosage amounts, the new dosage amounts each comprising a chelating agent, an NSAID, an antioxidant and a form of hyaluronic acid selected from hyaluronic acid, salts thereof (for example sodium hyaluronate), homologues, analogues, derivatives, complexes, esters, fragments and subunits in a suitable carrier, for example sterile water, for intravenous use.
  • the dosage amounts are preferably packaged in intravenous bags for single dose administration to a patient.
  • Suitable amounts of the therapeutic agents may comprise those previously indicated or others that may be understood by those skilled in the art from reading this specification.
  • the therapeutic agents may comprise : ( i ) about 1-3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA); (ii ) about 15-30 mg of an NSAID (for example 30 mg of diclofenac sodium); (iii) about 12-50 gm anti-oxidant (for example 12.5 gm of sodium ascorbate); and ( i v ) about 50 mg to in excess of 1000 mg (because of a lack of toxicity) of a form of hyaluronic acid (for example 100-
  • 120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons is provided for the treatment of atherosclerosis for clearing atheromos comprising cholesterol and other substances (plaque) from the arterial walls.
  • NSAID for example 30 mg of diclofenac sodium
  • anti-oxidant for example 12.5 gm of sodium ascorbate
  • hyaluronic acid for example 100-
  • 120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons is provided in the manufacture of a pharmaceutical composition for systemic (preferably intravenous) administration for the treatment of atherosclerosis.
  • sodium hyaluronate (molecular weight less than about 750,000 daltons usually about 225,000 daltons) in sterile water, by intravenous administration for 2-4 days.
  • the anti-oxidant is sodium ascorbate (vitamin C)
  • the vitamin C it is thought reduces (trims) the size (the length) of the form of hyaluronic acid, reducing its molecular weight.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A method of clearing atherosclerosis comprising the step of administering to a patient, at least one dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of each of a chelating agent, a non-steroidal anti-inflammatory drug (NSAID), an anti-oxidant and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits.

Description

PHARMACEUTICAL COMPOSITION COMPRISING HYALURONIC ACID FOR THE CLEARING OF ARTERIOSCLEROSIS
FIELD OF INVENTION
This invention relates to the treatment of arterial disease and pharmaceutical compositions suitable for such use. Particularly the invention relates to the clearing of atherosclerosis. BACKGROUND OF THE INVENTION
Atherosclerosis is prevalent in the North American population believed to be caused in part by a diet rich in cholesterol. Over the years, deposits of yellowing plaques (atheromos) containing for example cholesterol, other lipoid material, lipophages and/ or other substances build up on the inner wall of the arteries (for example within the intima of large and medium-sized arteries) of a person causing the arteries to narrow inhibiting the free flow of blood. That person thus increases his/her risk of becoming a heart attack and/or stroke victim.
Balloon angioplasty is a widely accepted method of opening blockages in the coronary arteries. 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 cells on the inner wall of the artery reducing the inner diameter (ID) of the artery leading to an infarct. This narrowing of the inner diameter (ID) of tubular walls or proliferation of cells is not however restricted or limited to the coronary arteries. It can also occur post operatively causing restenosis in for example peripheral vascular systems.
It is therefore an object of this invention to provide a new method of clearing atherosclerosis. It is a further object of the invention to provide a new method of clearing the arteries of atheromos containing for example cholesterol, other lipoid material, lipophages and/or other substances.
It is a further object of this invention to provide pharmaceutical compositions suitable for use in such methods of treatment. It is still a further object of this invention to provide dosage amounts of the pharmaceutical composition suitable for use in such methods of treatment.
Further and other objects of the invention will be realized by those skilled in the art from the following. In accordance with the invention, Applicants have provided a new method and treatment of clearing atherosclerosis in which deposits of plaques (atheromos) containing cholesterol, other lipoid material, lipophages and other substances have built up within the arterial walls of a patient for example within the intima of large and medium-sized arteries. The method of treatment comprises administering for example, intravenously to a patient, at least one dosage amount of a pharmaceutical composition formulated according to embodiments of the invention. While the number and timing of administration of each dosage amount varies from patient to patient, dosage amounts administered over a number of weeks (for example 2 - 12 weeks) at intervals of for example two-three days from one administration to the next administration are suitable. One patient was given 45 treatments over a 5-6 week period in equal intervals. Another patient required only two treatments. Still another patient received dosage amounts intravenously over a period of 12 weeks at two dosage amounts per week. The dosage amounts comprise an effective non- toxic amount of each of a chelating agent, for example and preferably EDTA (common name for ethylenediaminetetraacetic acid), a non-steroidal anti- inflammatory drug (NSAID) (for example diclofenac, tromethamine salt of ketoralac (sold under the trade mark Toradol), indomethacin, piroxicam, ibuprofen), an anti-oxidant (for example and preferably vitamin C) and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof (for example the sodium salt), homologues, analogues, derivatives, esters, complexes, fragments and subunits. The form of hyaluronic acid is preferably sodium hyaluronate having a molecular weight of less than about 750,000 daltons, for example a molecular weight of about 150,000 to 225,000 daltons.
Suitable dosage amounts may each comprise: (i ) about 1 -3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA);
(ii ) about 15-30 mg of an NSAID (for example 30 mg of diclofenac sodium or the tromethamine salt of ketoralac
(Toradol);
(iii) about 12-50 gm anti-oxidant (for example in one embodiment 12.5 gm of vitimin C and in another embodiment 25 gm of vitamin C); and (i v) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid (because for example of a lack of toxicity of for example sodium hyaluronate), for example in one dosage amount in excess of 200 mg per dosage amount (and in another dosage amount, 100-120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons); in sterile water (for example 200 ml of sterile water for intravenous administration).
Other suitable dosage amounts may be selected depending on the patient. Treatment may also vary and in some instances may be administered one day after another, in one day intervals or in other instances, over alternate days. Of 6 patients treated, they averaged 10-15 treatments. All of the patients had subjective improvement in function, improved arterial blood flow by Doppler in affected vessels, and clearing of occlusion by angiography.
Suitable forms of sodium hyaluronate may include a fraction supplied by Hyal Pharmaceutical Corporation supplied in 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 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 (and preferably all characteristics) consisting of the following: i) a molecular weight within the range of 150,000- 225,000; ii) less than about 1.25% sulphated mucopoly- saccharides on a total weight basis; iii) less than about 0.6% protein on a total weight basis; iv) less than about 150 ppm iron on a total weight basis; 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; x) a UV extinction coefficient at 257 nm of less than about 0.275; xi) 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 has a mean average molecular weight within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid may comprise at least one characteristic selected from the group (and preferably all characteristics) consisting of the following characteristics: i ) l e s s th an ab o u t 1 % s u l ph ate d 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; i v ) less than about 10 ppm lead on a total weight basis; v ) less than 0.00166% glucosamine; v i ) 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 Applicants also propose to use sodium hyaluronate produced and supplied by LifeCore™ Biomedical, Inc., having the following specifications: Characteri stics Specification Appearance White to cream colored particles
Odor No perceptible odor
Viscosity Average < 750,000 Daltons
Molecular Weight
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 Fe P b Hg Ni
2.0 5.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0
Microbial Bioburden None observed
Endotoxin < 0.07EU/mg NaHy
Biological Safety Testing Passes Rabbit Ocular Toxicity Test Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications:
Specifications' Test
Results
Lot No. HG1004
PH 6.12
Condroitin Sulfate not detected
Protein 0.05%
Heavy Metals Not more than 20 ppm
Arsenic Not more than 2 ppm
Loss on Drying 2.07%
Residue on Ignition 16.69%
Intrinsic Viscosity 12.75 dl/s (XW: 679,000)
Nitrogen 3.14%
Assay 104.1% Microbiological Counts 80/g
E. coli Negative
Mold and Yeast Not more than 50/g
Other forms of hyaluronic acid and/or its salts, and analogues, homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in prior art documents provided the form of hyaluronic acid chosen is suitable for transport of the medicine.
The following references teach hyaluronic acid, sources thereof, and processes for the manufacture and recovery thereof which may prove to be suitable.
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 cm-^/g., and preferably greater than about 2000 cm^/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 10^ 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 humour, 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 -anti genic . "
Canadian Letters Patent 1 ,205,031 (which refers to United States Patent 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; and 500,000 to 730,000 and discusses processes of their manufacture .
While EDTA is the preferred chelating agent, other suitable chelating agents may be used such as Desferal (tm) which is deferoxamine methanesulfonate. Desferal comes in vials, Applicants believe, of 500 mg and 2 gm.
The NSAID, Applicants believe, blocks production of prostaglandin II and thromboxane. The anti-oxidant, Applicants believe, promotes prostacycline production. Thus, any substance which promotes postacycline production may be suitable as an anti-oxidant.
To reduce/prevent pain in the patient's vein during infusion of the intravenously administered dosage amount, 5-20 cc of a local anesthetic (for example xylocaine (2%)) may be added to the dosage amount. Twenty (20) cc of 5% bicarbonate of soda may also be added to the dosage amount.
According to another aspect of the invention the new method of treatment of clearing atherosclerosis (clearing atheromos) employs new combinations of therapeutic agents in dosage amounts, the new dosage amounts each comprising a chelating agent, an NSAID, an antioxidant and a form of hyaluronic acid selected from hyaluronic acid, salts thereof (for example sodium hyaluronate), homologues, analogues, derivatives, complexes, esters, fragments and subunits in a suitable carrier, for example sterile water, for intravenous use. The dosage amounts are preferably packaged in intravenous bags for single dose administration to a patient. Suitable amounts of the therapeutic agents may comprise those previously indicated or others that may be understood by those skilled in the art from reading this specification. Thus, the therapeutic agents may comprise : ( i ) about 1-3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA); (ii ) about 15-30 mg of an NSAID (for example 30 mg of diclofenac sodium); (iii) about 12-50 gm anti-oxidant (for example 12.5 gm of sodium ascorbate); and ( i v ) about 50 mg to in excess of 1000 mg (because of a lack of toxicity) of a form of hyaluronic acid (for example 100-
120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons); in sterile water (for example, 200 ml).
According to another aspect of the invention, the use of (i ) about 1-3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA); (ii ) about 15-30 mg of an NSAID (for example 30 mg of diclofenac sodium; (iii) about 12-50 gm anti-oxidant (for example 12.5 gm of sodium ascorbate; and
(i v ) about 50 mg to in excess of 1000 mg (because of a lack of toxicity) of a form of hyaluronic acid (for example 100-
120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons); is provided for the treatment of atherosclerosis for clearing atheromos comprising cholesterol and other substances (plaque) from the arterial walls.
According to another aspect of the invention the use of (i ) about 1-3 gm of the chelating agent/70 kg person (for example 3 gm of EDTA);
(ii) about 15-30 mg of an NSAID (for example 30 mg of diclofenac sodium; (iii) about 12-50 gm anti-oxidant (for example 12.5 gm of sodium ascorbate; and (i v ) about 50 mg to in excess of 1000 mg (because of a lack of toxicity) of a form of hyaluronic acid (for example 100-
120 mg sodium hyaluronate having a molecular weight of about 150,000-225,000 daltons); is provided in the manufacture of a pharmaceutical composition for systemic (preferably intravenous) administration for the treatment of atherosclerosis.
When the dosage amounts are administered to patients with advanced arterial disease over the time periods referred to, the patients have shown significant improvement in symptoms. The patients were assessed by angiography and their blood flow by Doppler where possible. Patients for example received 15-30 treatments of the following drug combination :
3 gm EDTA
15 mg toradol or diclofenac
12.5 gm sodium ascorbate
50 mg sodium hyaluronate (molecular weight less than about 750,000 daltons usually about 225,000 daltons) in sterile water, by intravenous administration for 2-4 days.
In two patients, the occlusions cleared and the patients have returned to a normal angiogram.
In one patient, suffering angina after receiving 45 treatments over 5-6 weeks, the patient no longer suffers any symptoms of angina.
Another patient who was treated with 25 treatments, administered twice weekly, no longer suffers any pain in his legs. Another patient who almost had heart failure in response to bronchial infection, is now after treatment, assymtematic.
Where the anti-oxidant is sodium ascorbate (vitamin C), the vitamin C it is thought reduces (trims) the size (the length) of the form of hyaluronic acid, reducing its molecular weight.
As many changes can be made to the methods of treatment, pharmaceutical compositions, and dosage amounts of the pharmaceutical composition used 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

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE AS FOLLOWS:
1. A method of clearing atherosclerosis comprising the step of administering to a patient, at least one dosage amount of a pharmaceutical composition comprising an effective non-toxic amount of each of a chelating agent, a non-steroidal anti-inflammatory drug (NSAID), an anti¬ oxidant and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits.
2. The method of claim 1 wherein the form of hyaluronic acid is sodium hyaluronate having a molecular weight less than about 750,000 daltons.
3. The method of claim 2 wherein the at least one dosage amount comprising a plurality of dosage amounts administered intravenously at suitable intervals over a period of time.
4. The method of claim 3 wherein the chelating agent is EDTA.
5. The method of claim 3 wherein the NSAID is selected from diclofenac, tromethamine salt of ketoralac, indomethacin, piroxicam, and ibuprofen .
The method of claim 3 wherein the anti-oxidant is Vitamin C.
7. The method of claim 2 wherein the at least one such dosage amount comprises ( i ) about 1-3 gm of the chelating agent/70 kg person;
(ii ) about 15-30 mg of an NSAID;
(iii) about 12-50 gm anti-oxidant; and
( i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid; in sterile water.
8. The method of claim 3 wherein the at least one such dosage amount comprises
( i ) about 1-3 gm of the chelating agent/70 kg person;
(ii ) about 15-30 mg of an NSAID;
(iii ) about 12-50 gm anti-oxidant; and ( i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid; in sterile water.
9. The method of claim 7 or 8 wherein the chelating agent is EDTA.
10. The method cf claim 7 or 8 wherein the NSAID is selected from diclofenac sodium or tromethamine salt of ketoralac.
11. The method of claim 7 or 8 wherein the anti-oxidant is selected from 12.5 to 25 gm of Vitamin C.
12. The method of claim 7 or 8 wherein the amount of sodium hyaluronate exceeds 200 mg.
13. The method of claim 7 or 8 wherein the amount of sodium hyaluronate is about 100 to about 120 mg, and the sodium hyaluronate has a molecular weight of about 150,000 - 225,000 daltons.
14. The method of claim 7 or 8 wherein the dosage amount further comprises 200 ml of sterile water.
15. The method of claim 7 or 8 wherein the dosage amount further comprises an effective amount of a local anesthetic.
16. The method of claim 15 wherein the dosage amount further comprises an effective amount of bicarbonate of soda.
17. A pharmaceutical composition suitable for intravenous administration, the pharmaceutical composition comprising an effective non-toxic amount of each of a chelating agent, a non-steroidal anti- inflammatory drug (NSAID), an anti-oxidant and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits.
18. The pharmaceutical composition of claim 17 in a container suitable for use for intravenous administration.
19. The pharmaceutical composition of claim 17 or 18 wherein the form of hyaluronic acid is sodium hyaluronate having a molecular weight less than about 750,000 daltons.
20. The pharmaceutical composition of claim 19 wherein the chelating agent is EDTA.
21. The pharmaceutical composition of claim 19 wherein the NSAID is selected from diclofenac, tromethamine salt of ketoralac, indomethacin, piroxicam, and ibuprofen.
22. The pharmaceutical composition of claim 19 wherein the anti-oxidant is Vitamin C.
23. The pharmaceutical composition of claim 19 comprising (i ) about 1-3 gm of the chelating agent/70 kg person; (ii ) about 15-30 mg of an NSAID;
(iii) about 12-50 gm anti-oxidant; and (i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid; in sterile water.
24. The pharmaceutical composition of claim 23 wherein the chelating agent is EDTA.
25. The pharmaceutical composition of claim 23 wherein the NSAID is selected from diclofenac sodium or tromethamine salt of ketoralac.
26. The pharmaceutical composition of claim 23 wherein the anti-oxidant is selected from Vitamin C.
27. The pharmaceutical composition of claim 23 wherein the amount of sodium hyaluronate exceeds 200 mg.
28. The pharmaceutical composition of claim 23 wherein the amount of sodium hyaluronate is about 100 to about 120 mg, and the sodium hyaluronate has a molecular weight of about 150,000 - 225,000 daltons.
29. The pharmaceutical composition of claim 23 wherein the pharmaceutical composition further comprises sterile water.
30. The pharmaceutical composition of claim 23 wherein the dosage amount further comprises an effective amount of a local anesthetic.
31. The pharmaceutical composition of claim 30 wherein the dosage amount further comprises an effective amount of bicarbonate of soda.
32. A dosage amount of a pharmaceutical composition for administration to a patient, the dosage amount comprising an effective non-toxic amount of each of a chelating agent, a non-steroidal anti- inflammatory drug (NSAID), an anti-oxidant and a form of hyaluronic acid, selected from hyaluronic acid, salts thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits.
33. The dosage amount of claim 32 in a form suitable for intravenous administration.
34. The dosage amount of claim 33 wherein the form of hyaluronic acid is sodium hyaluronate having a molecular weight less than about 750,000 daltons.
35. The dosage amount of claim 34 wherein the chelating agent is EDTA.
36. The dosage amount of claim 34 wherein the NSAID is selected from diclofenac, tromethamine salt of ketoralac, indomethacin, piroxicam, and ibuprofen.
37. The dosage amount of claim 34 wherein the anti-oxidant is
Vitamin C.
38. The dosage amount of claim 34 wherein the dosage amount comprises
(i ) about 1-3 gm of the chelating agent/70 kg person;
(ii ) about 15-30 mg of an NSAID;
(iii ) about 12-50 gm anti-oxidant; and (i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid ; in sterile water.
39. The dosage amount of claim 38 wherein the chelating agent is EDTA.
40. The dosage amount of claim 38 wherein the NSAID is selected from diclofenac sodium or tromethamine salt of ketoralac.
41. The dosage amount of claim 38 wherein the anti-oxidant is selected from 12.5 to 25 gm of Vitamin C.
42. The dosage amount of claim 38 wherein the amount of sodium hyaluronate exceeds 200 mg.
43. The dosage amount of claim 38 wherein the amount of sodium hyaluronate is about 100 to about 120 mg, and the sodium hyaluronate has a molecular weight of about 150,000 - 225,000 daltons.
44. The dosage amount of claim 38 wherein the dosage amount further comprises sterile water.
45. The dosage amount of claim 38 wherein the dosage amount further comprises an effective amount of a local anesthetic.
46. The dosage amount of claim 45 wherein the dosage amount further comprises an effective amount of bicarbonate of soda.
47. The use of an effective non-toxic amount of each of a chelating agent, non-steroidal anti-inflammatory drug, an anti-oxidant and a form of hyaluronic acid selected from hyaluronic acid, a salt thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits in the manufacture of a pharmaceutical composition for the treatment of atherosclerosis.
48. The use of claim 47 wherein the pharmaceutical composition is a dosage amount and in a form suitable for intravenous administration.
49. The use of claim 47 or 48 wherein the form of hyaluronic acid is sodium hyaluronate having a molecular weight less than about 750,000 daltons.
50. The use of claim 49 wherein the chelating agent is EDTA.
51. The use of claim 49 wherein the NSAID is selected from diclofenac, tromethamine salt of ketoralac, indomethacin, piroxicam, and ibuprofen .
52. The use of claim 49 wherein the anti-oxidant is Vitamin C.
53. The use of claim 49 wherein the pharmaceutical composition comprises
(i ) about 1-3 gm of the chelating agent/70 kg person;
(ii ) about 15-30 mg of an NSAID;
(iii) about 12-50 gm anti-oxidant; and
(i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid ; in sterile water.
54. The use of claim 53 wherein the chelating agent is EDTA.
55. The use of claim 53 wherein the NSAID is selected from diclofenac sodium or tromethamine salt of ketoralac.
56. The use of claim 53 wherein the anti-oxidant is selected from 12.5 to 25 gm of Vitamin C.
57. The use of claim 53 wherein the amount of sodium hyaluronate exceeds 200 mg.
58. The use of claim 53 wherein the amount of sodium hyaluronate is about 100 to about 120 mg, and the sodium hyaluronate has a molecular weight of about 150,000 - 225,000 daltons.
59. The use of claim 53 wherein the dosage amount further comprises of sterile water.
60. The use of claim 53 wherein the dosage amount further comprises an effective amount of a local anesthetic.
61. The use of claim 60 wherein the dosage amount further comprises an effective amount of bicarbonate of soda.
62. The use of an effective non-toxic amount of a pharmaceutical composition comprising a chelating agent, non-steroidal anti- inflammatory drug, an anti-oxidant and a form of hyaluronic acid selected from hyaluronic acid, a salt thereof, homologues, analogues, derivatives, esters, complexes, fragments and subunits for the treatment of atherosclerosis.
63. The use of claim 62 wherein the pharmaceutical composition is a dosage amount and in a form suitable for intravenous administration.
64. The use of claim 62 or 63 wherein the form of hyaluronic acid is sodium hyaluronate having a molecular weight less than about 750,000 daltons.
65. The use of claim 64 wherein the chelating agent is EDTA.
66. The use of claim 64 wherein the NSAID is selected from diclofenac, tromethamine salt of ketoralac, indomethacin, piroxicam, and ibuprofen .
67. The use of claim 64 wherein the anti-oxidant is Vitamin C.
68. The use of claim 64 wherein at least one such dosage amount comprises
(i ) about 1 -3 gm of the chelating agent/70 kg person; (ii ) about 15-30 mg of an NSAID; (iii ) about 12-50 gm anti-oxidant; and ( i v ) between about 50 mg to well in excess of 1000 mg of the form of hyaluronic acid ; in sterile water.
69. The use of claim 68 wherein the chelating agent is EDTA.
70. The use of claim 68 wherein the NSAID is selected from diclofenac sodium or tromethamine salt of ketoralac.
71. The use of claim 68 wherein the anti-oxidant is selected from 12.5 to 25 gm of Vitamin C.
72. The use of claim 68 wherein the amount of sodium hyaluronate exceeds 200 mg.
73. The use of claim 68 wherein the amount of sodium hyaluronate is about 100 to about 120 mg, and the sodium hyaluronate has a molecular weight of about 150,000 - 225,000 daltons.
74. The use of claim 68 wherein the dosage amount further comprises of sterile water.
75. The use of claim 68 wherein the dosage amount further comprises an effective amount of a local anesthetic.
76. The use of claim 75 wherein the dosage amount further comprises an effective amount of bicarbonate of soda.
EP95916533A 1994-04-29 1995-04-27 Pharmaceutical composition comprising hyaluronic acid for the clearing of arteriosclerosis Withdrawn EP0758246A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA2122551 1994-04-29
CA002122551A CA2122551A1 (en) 1994-04-29 1994-04-29 Clearing of atherosclerosis
PCT/CA1995/000243 WO1995029683A1 (en) 1991-07-03 1995-04-27 Pharmaceutical composition comprising hyaluronic acid for the clearing of arteriosclerosis

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CA2166155C (en) * 1995-12-27 2008-02-05 Eva Anne Turley Agents binding to hyaluronic acid binding domains and the use thereof
US6294170B1 (en) 1997-08-08 2001-09-25 Amgen Inc. Composition and method for treating inflammatory diseases
PL343617A1 (en) * 2000-10-31 2002-05-06 Pabianickie Zaklad Farma Novel application of 2-(4-isobutylphenyl)propionic acid, pharmacological agent and therapeutic method
FR2994846B1 (en) 2012-08-29 2014-12-26 Vivacy Lab COMPOSITION, STERILIZED, COMPRISING AT LEAST ONE HYALURONIC ACID AND MAGNESIUM ASCORBYL PHOSPHATE
CN112972490B (en) * 2021-03-04 2022-02-18 中国人民解放军军事科学院军事医学研究院 Application of hyaluronic acid in preparing medicine for preventing or treating iron death related diseases

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US5095037B1 (en) * 1989-12-21 1995-12-19 Nissho Kk Combined anti-inflammatory agent
WO1994007505A1 (en) * 1991-07-03 1994-04-14 Norpharmco Inc. Use of hyaluronic acid and forms to prevent arterial restenosis

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