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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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• 1994
  • 1994-04-29 CA CA002122551A patent/CA2122551A1/en not_active Abandoned
• 1995
  • 1995-04-27 AU AU23008/95A patent/AU2300895A/en not_active Abandoned
  • 1995-04-27 WO PCT/CA1995/000243 patent/WO1995029683A1/en not_active Ceased
  • 1995-04-27 JP JP52790095A patent/JP3811500B2/ja not_active Expired - Lifetime
  • 1995-04-27 EP EP95916533A patent/EP0758246A1/de not_active Withdrawn

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