WO1991016058A1 - Composition et procede de traitement local de tissus abimes ou malades - Google Patents

Composition et procede de traitement local de tissus abimes ou malades Download PDF

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Publication number
WO1991016058A1
WO1991016058A1 PCT/US1991/002912 US9102912W WO9116058A1 WO 1991016058 A1 WO1991016058 A1 WO 1991016058A1 US 9102912 W US9102912 W US 9102912W WO 9116058 A1 WO9116058 A1 WO 9116058A1
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composition
molecular weight
daltons
heparin
copolymer
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PCT/US1991/002912
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English (en)
Inventor
R. Martin Emanuele
Robert L. Hunter
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Cytrx Corporation
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Priority to AU78692/91A priority Critical patent/AU647484B2/en
Priority to BR919106377A priority patent/BR9106377A/pt
Priority to JP3509151A priority patent/JPH0776175B2/ja
Publication of WO1991016058A1 publication Critical patent/WO1991016058A1/fr

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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
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method and composition for the topical treatment of damaged or diseased tissue. More particularly, the present invention is a composition and method for effectively treating damaged or diseased skin and tissue and promoting the healing of the damaged or diseased skin and tissue.
  • the term “topical treatment” means the treatment of the surface of the body of an animal or human or an internal surface of the human or animal that has been externalized either during surgery or by traumatic injury.
  • damaged tissue means tissue damaged by surgery, ischemia, burns, toxins, trauma or other noxious insult.
  • diseased tissue means tissue that is infected with a microorganism such as a yeast, bacteria or virus or a combination of organisms. The infection can be independent of or as a result of damage to the tissue.
  • burns means tissue injuries caused by thermal, electrical, ionizing or solar radiation or chemical agents.
  • Tissue damage caused by either surgery, ischemia, burns, toxins, trauma or other noxious insults illicits similar physiological responses.
  • Tissue damage caused by a variety of topical insults results in similar physiological responses and requires the same care and precautions.
  • Bums are tissue injuries caused by thermal, electrical, ionizing or solar radiation, or chemical agents.
  • the common mechanism of burns is denaturation of protein, resulting in cell injury or death. The effect is in accord with the type, duration, and intensity of action of the particular agent causing the burn.
  • the first local evidence of a bum is dilation of capillaries and small vessels with increased capillary permeability.
  • the resultant plasma loss under the epidermis produces edema.
  • evidence of cellular injury can be seen histologically as swollen or pyknotic nuclei with coagulation of cytoplasm.
  • collagen fibriles lose their distinctness.
  • Dead tissue, warmth, and moisture provide ideal conditions for bacterial growth.
  • the type of pathogen depends partly on the location of the burn; nasalpharyngeal inhabitants such as streptococci and staphylococci predominate in upper body burns, while cold form bacteria and clostridia are often important in lower body burns. What is needed is a method of covering the burn and protecting the burned area from the environment Burns are usually classified into three types. In first degree burns, damage is limited to the outer layer of the epidermis with erythema, increased warmth, tenderness, and pain. Edema, but not vesiculatipn, , usually occurs.
  • Second degree bums damage extends through the epidermis and involves the dermis, but not sufficiently to interfere with rapid regeneration of the epithelium. Vesicles, blebes, or bullae form.
  • third degree or full thickness burns destruction of both the epidermis and dermis is seen. Vesiculation is often absent and severe pain is unusual after the acute initial pain, because of the destruction of the nerve endings.
  • the surface may be charred, coagulated, or white and lifeless (as from skulls), and sometimes is insensitive to pin prick. A burn may show varying degrees of damage in different areas. Frequently, it is difficult to distinguish between second and third degree bums until areas of third degree depth demarcate.
  • third degree burns which are characterized by deep destruction of the skin so that the reepithelization must take place largely or entirely from the edges of the wound
  • conventional treatment is identical with the previous outline.
  • burns of more than a few square centimeters require skin grafting. In small areas of third degree depth, this can be done within a few days of the injury by excision of the burned area. This is followed by application of split thickness grafts.
  • the fluid requirements of the patient need to be immediately addressed.
  • the surface wounds of patients with extensive third degree bums are usually treated with an 0.5% solution of silver nitrate or mafenide cream.
  • Raake Raake, W., "Comparison of the Anti- inflammatory Effect of Mucopolysaccharide Ointments with Ointments Containing Heparin in the UV Erythema Test," Arzenim.-ForschlDrug Res. 34 (I)(4), pgs. 449-451 (1984)) the anti-inflammatory effects of heparin are investigated.
  • the Raake reference did not disclose any studies wherein heparin was used to treat wounds nor did the reference disclose the use of heparin with poloxamers.
  • the treatment should inhibit inflammatory processes, provide relief from pain and accelerate the healing process without compromise of endogenous physiologic mechanisms such as blood coagulation.
  • the treatment should be easily applied and should be effective over long periods of time.
  • the present invention provides a composition and method for the topical treatment of damaged tissue.
  • the composition of the present invention comprises a solution of polyoxyethylene-polyoxypropylene block copolymer and an effective concentration of an acid mucopolysaccharide.
  • the polyoxyethylene-polyoxypropylene block copolymer has the following general formula:
  • a is an integer such that the hydrophobe represented by C3H6O has a molecular weight of at least 2250 daltons and b is an integer such that the hydrophile portion represented by C2H4O constitutes from about 10 to
  • the copolymer is and an acid mucopolysaccharide are dissolved in an aqueous solution. It is preferable that the acid mucopolysaccharide have little or no anticoagulant activity or to be of sufficient molecular size or charge so as not to be absorbed in the ciruculation to avoid the toxicity exhibited by many acid mucopolysaccharides.
  • the composition is then topically applied to damaged tissue. This allows manifestation of the therapeutic effects of the acid mucopolysaccharide at concentrations producing minimal or no compromise to the blood coagulation system. Because the preferred copolymer is a liquid at room temperature or below, and is a gel at body temperature, the aqueous gel composition forms a protective gel over the damaged tissue.
  • the solution which comprises the present invention unexpectedly accelerates healing of the damaged or diseased tissue while at the same time keeping the damaged tissue moist and protected from contamination by microorganisms. It is believed that the copolymer forms a matrix which slows the diffusion of mucopolysaccharide to the damaged or diseased tissue.
  • the gelled copolymer with the acid mucopolysaccharide admixed therein provides a continuous and constant bathing of the area with the mucopolysaccharide over a long period of time. Because the copolymer gel is an aqueous gel, there is also the added advantage of the gel keeping the diseased or damaged tissue moist without the inconvenience of having to bandage the tissue.
  • copolymer/acid mucopolysaccharide admixture can be added to the copolymer/acid mucopolysaccharide admixture as deemed necessary.
  • conventional antimicrobial agents could be added to the copolymer/glycosaminoglycan admixture to protect the damaged tissue from infection.
  • Growth factors such as human growth hormone, tissue derived growth factor, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and/or nerve growth factor may be added to the copolymer/acid mucopolysaccharide admixture to promote the regrowth of healthy tissue. This would be particularly important in treating bums.
  • composition of the present invention further comprises a pharmaceutically acceptable topical carrier admixed with an acid mucopolysaccharide.
  • the pharmaceutically acceptable topical carrier may be any suitable, commercially available ointment, cerate or salve. Other pharmaceutically active agents can be added to the carrier.
  • the composition is administered topically to damaged or diseased tissue. Accordingly, it is an object of the present invention to provide a composition and method that is effective in topically treating damaged or diseased tissue.
  • an aqueous gel composition that is effective in topically treating damaged or diseased tissue.
  • the aqueous gel composition of the present invention comprises an admixture of an acid mucopolysaccharide and a polyoxyethylene- polyoxypropylene block copolymer that has the physical property of being a liquid at room temperature or below and a gel at body temperature.
  • the polyoxyethylene-polyoxypropylene block copolymer has the following general formula:
  • the polyoxyethylene-polyoxypropylene block copolymer preferably has a hydrophobe represented by C3H6O with a molecular weight between approximately 2250 and 6000 daltons with the most preferable molecular weight of the C3H6O of approximately 4000 daltons.
  • the surface active copolymer blocks are formed by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst. There is some statistical variation in the number of monomer units which combine to form a polymer chain in each copolymer. The molecular weights given are approximations of the average weight of copolymer molecule in each preparation. It is to be understood that the blocks of propylene oxide and ethylene oxide do not have to be pure. Small amounts of other materials can be admixed so long as the overall physical chemical properties are not substantially changed. A more detailed discussion of the preparation of these products is found in U.S. Patent No. 2,674,619, which is incorporated herein by reference. Preparation of the copolymer portion of the present invention is described in U. S. Patent Nos. 3,925,241 and 3,867,533, both of which are incorporated herein by reference. Illustrative block copolymers of the following general formula:
  • Hy rop obe ase s t e ( 3 6 ) a por on o the copolymer molecule.
  • Hydrophile base is the (C2H .O)b portion of the copolymer molecule.
  • minima define a minimum weight percent concentration of the block copolymer with a specific hydrophobe having a minimum weight percent of ethylene oxide that is necessary to form a gel.
  • a minimum weight percent of ethylene oxide is required before a specific block copolymer will form a gel in an aqueous solution.
  • At least a 40 percent weight concentration of the block copolymer having a hydrophobe of at least 2,250 molecular weight with at least about 50 weight percent of ethylene oxide condensed therewith- will be necessary to form a gel in an aqueous solution.
  • the block copolymers above the minima indicated in Table I will form gels in aqueous solutions up to 90 weight percent concentration and higher. Above 90 weight percent concentration, however, the gels tend to become indistinguishable from the starting block copolymer itself. It is to be understood that the molecular weight of the hydrophobe may be other than those illustrated in Table I.
  • a gel may be formed from the block copolymer at a concentration of 40 weight percent in an aqueous solution where about 45 weight percent of ethylene oxide is present in the block copolymer.
  • HO(C H O) (C H O) (C H O) H 2 4 V 3 6 V 2 4 'b is an integer such that the average molecular weight of the hydrophobe is about 2250 daltons, then the ethylene oxide content is from 50 to 90 weight percent of the copolymer, the total average molecular weight of the copolymer is from 4600 daltons to 10,750 daltons and the gel composition comprises from 40 to 50 weight percent of the copolymer.
  • 2 4 b 3 6 a 2 4 'b is an integer such that the average molecular weight of the hydrophobe is about 2750 daltons, then the ethylene oxide content is from 45 to
  • the total average molecular weight of the copolymer is from 4910 daltons to 13500 daltons and the gel composition comprises from 40 to 50 weight percent of the copolymer.
  • HO(C H O) (C H O) (C H O) H v 2 4 V 3 6 V 2 4 'b is an integer such that the average molecular weight of the hydrophobe is about 3250 daltons, then the ethylene oxide content is from 35 to 90 weight percent of the copolymer, the total average molecular weight of the copolymer is from 4910 daltons to 15,510 daltons, and the gel composition comprises from 30 to 50 weight percent of the copolymer,
  • 2 4 b 3 6 a 2 4 b is an integer such that the average molecular weight of the hydrophobe is about 4000 daltons, then the ethylene oxide content is from 35 to 90 weight percent of the copolymer, the total average molecular weight of the copolymer is from 6150 daltons to 20,000 daltons and the gel composition comprises from 30 to 50 weight percent of the copolymer, with the further proviso that when a in the formula is an integer such that the average molecular weight of the hydrophobe is about 4000 daltons, the ethylene oxide content is from 70 to 90 weight percent, the total average molecular weight of the block polymer is from 16,000 daltons to 20,000 daltons and the gel composition comprises from 15 to 50 weight percent of the copolymer.
  • the preferred polyoxyethylene-polyoxypropylene copolymer is poloxamer 407 which has a chemical formula of ⁇ -hydro- omega- hydroxy- poly(oxyethylene) ⁇ oi- poly(oxypropylene)56 - poly(oxyethylene) ⁇ oi.
  • the poloxamer 407 can also be represented by the following formula: HO(C H O) (C H O) (C H O) H x 2 4 3 6 V 2 4 'b wherein the molecular weight of the hydrophobe (C3H6O) is approximately
  • the acid mucopolysaccharides also known as glycosaminoglycans, that are admixed or dissolved with the copolymer generally consist of recurring disaccharide units, each of which contains a derivative of an aminohexose, usually D-glucosamine or D-galactosamine. At least one of the two sugars in the recurring disaccharide unit of acid mucopolysaccharides contains an acidic group having a negative charge at pH 7, the negative group being either a carboxylate or sulfate group.
  • An example of an acidic hexose is D-glucuronate, derived from D-glucose by oxidation of the ⁇ carbon atom to a carboxylate group.
  • Acid mucopolysaccharides are thus heteropolysaccharides because they consist of at least two kinds of monosaccharides in alternating sequence which vary in such characteristics as chain length and charge density.
  • muco- refers to the fact that these polysaccharides were first isolated from mucin, the slippery, lubricating proteoglycan of mucous secretions.
  • the acid mucopolysaccharide hyaluronic acid derived from the intercellular cement of animal tissues contains many alternating units of D- glucuronic acid and N-acetyl-D-glucosamine.
  • Hyaluronic acid forms highly viscous, jellylike solutions. Hyaluronic acid is often found combined with other mucopolysaccharides.
  • Chondroitin a major polysaccharide of cartilage proteoglycans, contains alternating units of D-glucuronic acid and N-acetyl-D-galactosamine. Chondroitin may be regarded as the parent material for other widely distributed polysaccharides, such as chondroitin sulfate A and chondroitin sulfate C, which differ only in the position in which sulfate is esterified to the galactosamine moiety.
  • chondroitin sulfates Another important mucopolysaccharide, long termed chondroitin sulfates is dermatan sulfate ( ⁇ -L-iduronosyl-(l-3)- ⁇ -D-N-acytylgalactosamine
  • Dermatan consists of repeating disaccharide units of iduronosyl and acetylgalactosamine. It can be isolated from various tissues including blood vessel walls and skin. Dermatan sulfate catalyses the thrombin-heparin cofactor II interaction. Despite the antithrombotic effects of dermatan sulfate, dermatan compounds generally are weak anticoagulants.
  • the acid polysaccharide heparin is generated by certain types of cells that are especially abundant in the lining of arterial blood vessels.
  • Heparin like other mucopolysaccharides, is an anionic carbohydrate chain synthesized as part of a proteoglycan.
  • the basic building blocks of heparin are alternating units of uronic acid and N-acetylglucosamine with the predominant repeat disaccharide unit being L-iduronic acid and 2-amino-2-deoxy-D-glucose.
  • the L-iduronic acid arises from the epimerization of D-glucuronic acid at position 5 during its biosynthesis and, in general, increases in the L-iduronic acid residues parallels the increase in sulfation of the heparin.
  • Heparin exhibits strong anticoagulant activity.
  • Low molecular weight heparins have a mean molecular weight of less than approximately 6000 daltons show much stronger anticoagulant activity than higher molecular weight heparins.
  • the preferred acid mucopolysaccharides that are used in the present invention have little or no anticoagulant activity.
  • Heparans are another group of acid mucopolysaccharides. Chemically, heparans have the same carbohydrate backbone as heparin but differ in their sulfate content and distribution of charged groups. Heparans and other acid mucopolysaccharides exhibit significantly less anticoagulant properties compared to heparin.
  • strongly anionic acid mucopolysaccharides are generally preferred when practicing the present invention.
  • “Strongly anionic” means a molecule with a high negative charge density.
  • the strongly anionic acid mucopolysaccharides have a greater therapeutic effect when compared to weakly anionic acid mucopolysaccharides.
  • Strongly anionic acid mucopolysaccharides can be prepared by any method capable of distinguishing molecules with a higher negative charge density from those of lower charge density. Electrophoresis or ion exchange chromatography are two such methods and are well known by those of ordinary skill in the art. Another method would simply utilize the anionic mucopolysaccharide as the free base rather than the sodium, calcium or lithium salt as they are commonly manufactured.
  • the size of the acid mucopolysaccharide can vary greatly.
  • the molecular weight of the mucopolysaccharide that is used in the topical treatment of the present invention can be from between 3000 daltons to
  • the preferable average molecular weight of the acid mucopolysaccharides is between approximately 5000 and 50,000 daltons.
  • the most preferable molecular weight of the acid mucopolysaccharides is between approximately 10,000 and 20,000 daltons. It is to be understood that the molecular weight of the acid mucopolysaccharide is not a critical factor in the present invention, and that any one preparation of acid mucopolysaccharide will contain a population of molecules that can vary greatly in size. This variance in size of molecules does not necessarily reduce the effectiveness of the present invention.
  • the present invention utilizes acid mucopolysaccharides of higher molecular weight to minimize systemic absorption and restrict the biologic actions to the locally applied area. (See Emanuele, et al., "The Effect of
  • an acid mucopolysaccharide can be used in the present invention where the acid mucopolysaccharide is of sufficient molecular size such that it is not absorbed systemically.
  • the most preferred acid mucopolysaccharide for use in the present invention is dermatan sulfate.
  • the average molecular weight of dermatan sulfate is estimated to be approximately 30,000 daltons depending on its source and method of preparation.
  • the concentration of dermatan sulfate in the composition of the present invention is preferably between approximately 10 mg per ml and 100 mg per ml.
  • the more preferred concentration of dermatan sulfate is between 25 mg per ml and 75 mg per ml with a most preferred concentration of dermatan sulfate of approximately 50mg per ml.
  • Another preferred acid mucopolysaccharide for use in the present invention has a high molecular weight.
  • the preferred average molecular weight of the heparin is approximately 15,000 daltons.
  • the concentration of heparin in the composition of the present invention is preferably between approximately 10 mg per ml and 100 mg per ml.
  • the more preferred concentration of heparin is between 20 mg per ml and 50 mg per ml with a most preferred concentration of heparin of approximately 25 mg per ml.
  • Each mg of heparin is expected to contain approximately 100 units of activity.
  • the acid mucopolysaccharides include, but are not limited to, heparin, heparan sulfate, heparinoids, dermatan sulfate, pentosan polysulfate, chondroitin sulfate and hyaluronic acid.
  • the acid mucopolysaccharides may also be admixed with pharmaceutically acceptable topical carriers.
  • the carrier may comprise any commercially available base including but not limited to waxes, petrolatum, and glycerides. More specifically, the acid mucopolysaccharide may be admixed to commercially available salves, ointments or cerates containing a variety of pharmaceutically active agents.
  • compositions prepared in accordance with the present invention comprise at least the following ingredients: (1) a pharmaceutically effective concentration of a acid mucopolysaccharide and (2) an aqueous gel comprising, based on 100 parts by weight, (a) from 15 to 50 parts, preferably from 15 to 25 parts, of a polyoxyethylene-polyoxypropylene- block copolymer and (b) from 50 to 85 parts, preferably from about 75 to 85 parts, of water.
  • the method of the present invention comprises the steps of topically administering to a human or animal with damaged or diseased tissue a composition comprising an admixture of a polyoxyethylene-polyoxypropylene block copolymer that has the physical property of being a liquid at room temperature or below and a gel at body temperature, and an acid mucopolysaccharide.
  • the composition is described hereinabove.
  • the composition of the present invention can be administered by dabbing, dripping, pouring, spraying or painting the composition onto the damaged or diseased tissue.
  • the composition of the present invention comprising the block copolymer and acid mucopolysaccharide can be administered by inserting the damaged or diseased tissue into a solution of the composition thereby allowing the composition to gel onto the tissue.
  • the composition of the present invention should be administered so that a gel layer forms over the damaged or diseased tissue thereby allowing the damaged or diseased tissue to be protected from the environment
  • the topical administration of the composition of the present invention includes administration to the surface of the body as well as administration to tissue that is exposed through surgery or trauma.
  • the composition and method of the present invention is particularly effective in treating bums. These bums can be chemical bums, thermal bums, electrical bums or radioactive bums.
  • the present invention is also effective in treating other types of tissue damage such as traumatic damage, including but not limited to, compound fractures, cuts, abrasions or damage due to infection with bacteria, fungi or other microorganisms.
  • antimicrobial agents may be added to the composition of the present invention to retard infection.
  • the antimicrobial agent may be an antibiotic, antifungal agent or a mixture thereof.
  • Representative antimicrobial agents that can be used in practicing the present invention include, but are not limited to, penicillins, cephalosporins, bacitracins, aminoglycosides and polypeptide antibiotics and the bacteriastatic compounds including, but not limited to, chloramphenicol, tetracyclines, macrolides, sulfonamides and aminosalicylic acid.
  • Antifungal agents that can be used in practicing the present invention include, but are not limited to, nystatin, amphotericin B and griseofuvin.
  • silver ions can be used in practicing the present invention.
  • the silver salts that can be employed in the preparation of the gels of the present invention are those silver salts which will preferably dissolve in water at a minimum concentration of 0.1% by weight.
  • Representative silver salts include silver nitrate, silver acetate, silver sulfate, and silver lactate.
  • the amount of silver salt that will produce a beneficial effect is between about 0.1% and 1.0% by weight of silver salt based on the weight of the water in the gel.
  • Growth factors such as human growth hormone, tissue derived growth factor, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and/or nerve growth factor may optionally be added to the composition of the present invention, either singly or in combination, to enhance the growth and development of the damaged or diseased tissue.
  • anti-inflammatory agents may be added to reduce inflammation in the damaged or diseased tissue.
  • composition of the present invention can optionally contain anesthetics to alleviate pain when applied to the damaged or diseased tissue.
  • anesthetics that can be employed in the present invention include, but are not limited to, lidocaine and procaine.
  • the copolymer in this example has the following general formula:
  • Example I The composition of Example I is administered to a patient with a second degree bum on his arm.
  • the composition is placed in a syringe and is cooled to approximately 20°C.
  • the composition is slowly applied to the surface of the bum, allowing the liquid composition to gel on the bum. Enough of the composition is added to form a gel that is approximately 0.2 cm in depth.
  • a topically-applicable gel composition that is effective for treating damaged or diseased tissue is prepared using the following ingredients: Parts Ingredients
  • the copolymer in this example has the following general formula:
  • Example IV The composition of Example HI is administered to a patient with a first degree bum on his leg.
  • the composition is placed in a syringe and is cooled to approximately 20°C.
  • the composition is slowly applied to the surface of the bum, allowing the liquid composition to gel on the bum. Enough of the composition is added to form a gel that is approximately 0.2 cm in depth.
  • the copolymer in this example has the following general formula:
  • Example V The composition of Example V is administered to a patient with a third degree bum on his torso.
  • the composition is placed in a syringe and is cooled to approximately 20°C.
  • the composition is slowly applied by spraying the composition onto the surface of the bum, allowing the liquid composition to gel on the bum. Enough of the composition is added to form a gel that is approximately 0.2 cm in depth.
  • the copolymer in this example has the following general formula:
  • Example VII The composition of Example VII is administered to a patient with a second degree sunburn on his back.
  • the composition is placed in a syringe at room temperature.
  • the composition is slowly applied by dripping the composition onto the surface of the bum, allowing the liquid composition to gel on the bum. Enough of the composition is added to form a gel that is approximately 0.1 cm in depth.
  • Example IX A topically-applicable gel composition which is effective in treating bums is prepared from the following ingredients: Parts Ingredients
  • the copolymer (poloxamer 407, BASF Corporation, Parsippany, NJ)) in this example has the following general formula: HO(C H O) (C H O) (C H O) H 2 4 V 3 6 a 2 4 b wherein the molecular weight of the hydrophobe (C3H6O) is approximately 4000 daltons and the total molecular weight of the compound is approximately
  • topically-applicable gel composition in the treatment of thermally injured tissue were studied in a guinea pig model ' of split thickness burns. Deeply anesthetised, hairless guinea pigs were subjected to thermal tissue injury by placing a 5 cm ⁇ , 80g metal probe (heated to 80°C) on their back for exactly 5 seconds. Thirty minutes post bum, animals were either left untreated (control), treated with the 20% gel of poloxamer 407 without dermatan or treated with 20% poloxamer 407 and 5% dermatan sulfate (Scientific Protein Labs, Waunakee, WS). Treated animals received 0.5 ml applications of the appropriate test article at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 24, 28,
  • the effects of the topically-applicable gel composition on skin thickness in the bum model are shown in Table IV.
  • the poloxamer/dermatan treated animals had a less skin thickness when compared to either poloxamer only treated animals or control animals. This was especially true at one day post bum.
  • the effects of the topically-applicable gel composition on erythema in the bum model are shown in Table V. Erythema was scored as 0 for little or no erythema to 3 for maximum erythema. As can be seen in Table V, the animals that were treated with the poloxamer/dermatan combination had less erythema than did the animals that were treated with poloxamer only or were left untreated.

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Abstract

L'invention comprend un gel aqueux ou un support à usage local pharmaceutiquement acceptable contenant une dose efficace d'un mucopolysaccharide d'acide. La composition contenant le gel aqueux se présente sous forme liquide à température ambiante et sous forme de gel à la température du corps, constituant ainsi une composition pouvant être appliquée aisément aux tissus abîmés ou malades. Après application locale aux tissus, la composition de l'invention forme une couverture sur les tissus, protégeant ces derniers et accélérant la cicatrisation.
PCT/US1991/002912 1990-04-26 1991-04-25 Composition et procede de traitement local de tissus abimes ou malades WO1991016058A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU78692/91A AU647484B2 (en) 1990-04-26 1991-04-25 Composition and method for topical treatment of damaged or diseased tissue
BR919106377A BR9106377A (pt) 1990-04-26 1991-04-25 Composicao e processo para o tratamento topico de tecido lesado ou enfermo
JP3509151A JPH0776175B2 (ja) 1990-04-26 1991-04-25 損傷されたかまたは病気になった組織の局所的処置用の組成物および方法

Applications Claiming Priority (4)

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US51350990A 1990-04-26 1990-04-26
US513,509 1990-04-26
US68703491A 1991-04-22 1991-04-22
US687,034 1991-04-22

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EP (1) EP0526578A4 (fr)
JP (1) JPH0776175B2 (fr)
CN (1) CN1058341A (fr)
AU (1) AU647484B2 (fr)
BR (1) BR9106377A (fr)
CA (1) CA2081340A1 (fr)
IE (1) IE911403A1 (fr)
IL (1) IL97976A0 (fr)
PT (1) PT97504A (fr)
WO (1) WO1991016058A1 (fr)

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EP0852236A1 (fr) * 1995-09-19 1998-07-08 Seikagaku Corporation Agent anti-inflammatoire
US6093391A (en) * 1992-10-08 2000-07-25 Supratek Pharma, Inc. Peptide copolymer compositions
EP1038528A1 (fr) * 1991-05-31 2000-09-27 Gliatech, Inc. Medicament et implant contenant de l' alginate pour traiter la fibrose
US6153193A (en) * 1993-04-28 2000-11-28 Supratek Pharma Inc. Compositions for targeting biological agents
US6221959B1 (en) 1994-11-18 2001-04-24 Supratek Pharma, Inc. Polynucleotide compositions
US6277410B1 (en) * 1992-10-08 2001-08-21 Supratek Pharma Inc. Copolymer compositions for oral delivery
US6353055B1 (en) 1994-11-18 2002-03-05 Supratek Pharma Inc. Polynucleotide compositions
FR2833268A1 (fr) * 2001-12-12 2003-06-13 Fabre Pierre Dermo Cosmetique Nouvelle association contenant un poloxamer et de l'acide chondroitine sulfurique et/ou une glycoproteine et son utilisation
AU2018276567B2 (en) * 2017-05-31 2021-09-16 Oji Holdings Corporation Moisturizing topical preparation
US11274165B2 (en) 2017-02-28 2022-03-15 Oji Holdings Corporation Pentosan polysulfate, pharmaceutical composition, and anticoagulant
US11286272B2 (en) 2016-08-31 2022-03-29 Oji Holdings Corporation Production method for acidic xylooligosaccharide, and acidic xylooligosaccharide
US11312790B2 (en) 2016-08-31 2022-04-26 Oji Holdings Corporation Production method for pentosan polysulfate
US11344570B2 (en) 2017-12-20 2022-05-31 Oji Holdings Corporation Pentosan polysulfate and medicine containing pentosan polysulfate
US11390693B2 (en) 2017-09-12 2022-07-19 Oji Holdings Corporation Pentosan polysulfate and method for producing pentosan polysulfate

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JP2001187740A (ja) * 2000-01-05 2001-07-10 Seikagaku Kogyo Co Ltd 創傷治療剤
CN111228466B (zh) * 2020-02-27 2023-06-27 温州医科大学 治疗糖尿病足的含氧气微泡的水凝胶及其制备方法和用途

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1038528A1 (fr) * 1991-05-31 2000-09-27 Gliatech, Inc. Medicament et implant contenant de l' alginate pour traiter la fibrose
US6417173B1 (en) 1991-05-31 2002-07-09 Gliatech, Inc. Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers
US6756362B2 (en) 1991-05-31 2004-06-29 Dikla Roufa Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers
US6093391A (en) * 1992-10-08 2000-07-25 Supratek Pharma, Inc. Peptide copolymer compositions
US6277410B1 (en) * 1992-10-08 2001-08-21 Supratek Pharma Inc. Copolymer compositions for oral delivery
US6153193A (en) * 1993-04-28 2000-11-28 Supratek Pharma Inc. Compositions for targeting biological agents
US6221959B1 (en) 1994-11-18 2001-04-24 Supratek Pharma, Inc. Polynucleotide compositions
US6353055B1 (en) 1994-11-18 2002-03-05 Supratek Pharma Inc. Polynucleotide compositions
EP0852236A1 (fr) * 1995-09-19 1998-07-08 Seikagaku Corporation Agent anti-inflammatoire
EP0852236A4 (fr) * 1995-09-19 2005-06-01 Seikagaku Kogyo Co Ltd Agent anti-inflammatoire
WO2003050190A3 (fr) * 2001-12-12 2003-12-11 Fabre Pierre Dermo Cosmetique Nouvelle association contenant un poloxamer et de l'acide chondroitine sulfurique et/ou une glycoproteine et son utilisation
WO2003050190A2 (fr) * 2001-12-12 2003-06-19 Pierre Fabre Dermo-Cosmetique Nouvelle association contenant un poloxamer et de l'acide chondroitine sulfurique et/ou une glycoproteine et son utilisation
FR2833268A1 (fr) * 2001-12-12 2003-06-13 Fabre Pierre Dermo Cosmetique Nouvelle association contenant un poloxamer et de l'acide chondroitine sulfurique et/ou une glycoproteine et son utilisation
US11286272B2 (en) 2016-08-31 2022-03-29 Oji Holdings Corporation Production method for acidic xylooligosaccharide, and acidic xylooligosaccharide
US11312790B2 (en) 2016-08-31 2022-04-26 Oji Holdings Corporation Production method for pentosan polysulfate
US11274165B2 (en) 2017-02-28 2022-03-15 Oji Holdings Corporation Pentosan polysulfate, pharmaceutical composition, and anticoagulant
AU2018276567B2 (en) * 2017-05-31 2021-09-16 Oji Holdings Corporation Moisturizing topical preparation
US11278485B2 (en) 2017-05-31 2022-03-22 Oji Holdings Corporation Moisturizing topical preparation
US11390693B2 (en) 2017-09-12 2022-07-19 Oji Holdings Corporation Pentosan polysulfate and method for producing pentosan polysulfate
US11344570B2 (en) 2017-12-20 2022-05-31 Oji Holdings Corporation Pentosan polysulfate and medicine containing pentosan polysulfate

Also Published As

Publication number Publication date
PT97504A (pt) 1992-02-28
CN1058341A (zh) 1992-02-05
IL97976A0 (en) 1992-06-21
JPH05506861A (ja) 1993-10-07
AU7869291A (en) 1991-11-11
JPH0776175B2 (ja) 1995-08-16
BR9106377A (pt) 1993-04-27
AU647484B2 (en) 1994-03-24
IE911403A1 (en) 1991-11-06
EP0526578A4 (en) 1993-09-22
EP0526578A1 (fr) 1993-02-10
CA2081340A1 (fr) 1991-10-27

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