WO2002015913A1 - Treatment of trauma, and other indications - Google Patents
Treatment of trauma, and other indications Download PDFInfo
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- WO2002015913A1 WO2002015913A1 PCT/US2000/023072 US0023072W WO0215913A1 WO 2002015913 A1 WO2002015913 A1 WO 2002015913A1 US 0023072 W US0023072 W US 0023072W WO 0215913 A1 WO0215913 A1 WO 0215913A1
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- polymer
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- 0 CC(C(**)*C1)C1C=CC Chemical compound CC(C(**)*C1)C1C=CC 0.000 description 7
- DSBZQTNEAMXXGL-UHFFFAOYSA-N C=CC(OCCNC(OCCOC(C=C)=O)=O)=O Chemical compound C=CC(OCCNC(OCCOC(C=C)=O)=O)=O DSBZQTNEAMXXGL-UHFFFAOYSA-N 0.000 description 1
- XZSSCSWXDJSMAM-UHFFFAOYSA-N C=CC(OCCOC(C(N)OC(C=C)=O)=O)=O Chemical compound C=CC(OCCOC(C(N)OC(C=C)=O)=O)=O XZSSCSWXDJSMAM-UHFFFAOYSA-N 0.000 description 1
- HOESOQUZLLBLSV-UHFFFAOYSA-N COCC(NOC(C1NCC1)=O)=O Chemical compound COCC(NOC(C1NCC1)=O)=O HOESOQUZLLBLSV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
-
- 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
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
Definitions
- the invention relates to the use of a polyanionic polymer that can be a microgel, with or without certain enzymes, for treating wounds, such as corneal ulcerations, internal trauma, such as that caused by surgery; as well as for treating inflammatory diseases and their sequelae, and to reducing adhesions or inhibiting adhesion formation.
- a polyanionic polymer that can be a microgel, with or without certain enzymes, for treating wounds, such as corneal ulcerations, internal trauma, such as that caused by surgery; as well as for treating inflammatory diseases and their sequelae, and to reducing adhesions or inhibiting adhesion formation.
- the invention further relates to the use of an enzyme in any pharmaceutically acceptable carrier for the treatment of inflammatory diseases, corneal wounds and inhibiting adhesion formation.
- the invention relates, among other things, to a method of treating an area affected by a trauma, including trauma from corneal wounds and internal trauma that includes administering to the affected area a trauma treating effective amount of a composition comprising a polyanionic polymer or an enzyme such as a protease or both.
- a non-addition polyanionic polymer as defined in the specification below, or a microgel, is used.
- a pre-formed polymer is preferred.
- a polyanionic polymer having hydrolytically susceptible bonds can be used.
- a corneal wound treated by a method ofthe invention can include a corneal ulcer, a corneal abrasion, or a chemical or physical insult to the cornea susceptible to giving rise to a corneal ulcer.
- Infected corneal ulcer are usefully treated with the methods ofthe invention.
- Internal trauma such as surgical wounds or trauma to a membrane that covers either an internal organ or tissue or the cavity in which one or more internal organs or tissues reside can be treated by a method ofthe invention.
- a membrane can be a serous membrane such as the peritoneum, the pericardium, the epicardium, and the pleura.
- a membrane can also be an epithelium, including the endothelium or a meninges.
- the treated internal trauma can include trauma to a tendon or a tendon sheath or to a nerve or a nerve sheath, or an internal surgical wound.
- the internal trauma can be one susceptible of giving rise to adhesions and the amount of polyanionic polymer administered is an amount effective to inhibit or reduce formation or reformation of adhesions.
- the invention can relate to a method for reducing or inhibiting the formation or reformation of adhesions comprising the step of administering to an area affected by a trauma susceptible to giving rise to adhesions an effective amount of a composition comprising a polyanionic polymer, such as a non-addition polyanionic polymer or a polymer forming a microgel, and more preferably a preformed non-addition polyanionic polymer.
- a polyanionic polymer such as a non-addition polyanionic polymer or a polymer forming a microgel, and more preferably a preformed non-addition polyanionic polymer.
- the invention can also relate to a method of inhibiting or reducing the formation of adhesions following implantation of an implantable device.
- a method of treating an inflammatory disease which can include administering to an area affected by the disease, an inflammatory disease treating effective amount of a composition comprising one or more ofthe following: a polyanionic polymer or a protease that has an activity comprising at least two of a chymotrypsin, trypsin, collagenase, and elastase activity.
- the invention provides a method of treating a corneal wound that can include administering to an affected area an effective amount of a composition comprising a protease that has an activity comprising at least two of a chymotrypsin, trypsin, collagenase, and elastase activity.
- Examples of an inflammatory disease can include osteoarthritus, rheumatoid arthritis, cervical spondylosis, cumulative trauma disorder (harmful and painful condition caused by overuse or overexertion of some part ofthe musculoskeletal system, often resulting from work-related physical activities; it is characterized by inflammation, pain, or dysfunction ofthe involved joints, bones, ligaments, and nerves), endometriosis, pelvic inflammatory disease, adhesive peritonitis, appendicitis, peridentitis, pericarditis or pleuritis.
- Examples of cumulative trauma disorder can include tendonitis, tenosynovitis or carpal tunnel syndrome.
- the inflammatory disease is susceptible of giving rise to adhesions and the inflammatory disease treating effective amount is effective to inhibit or reduce the formation of such adhesions.
- Methods ofthe invention can include the administration of one or more ofthe following: a steroid, a nonsteroidal anti-inflammatory agent; a streptokinase, a fibrinolytic agent, a multifunctional hydrolase having an activity comprising at least two of a chymotrypsin, trypsin, collagenase or elastase activity, an antagonist of an inflammatory cytokine or a surfactant.
- the invention provides compositions that can include a protease or a hydrolase.
- the protease or hydrolase can have an activity comprising at least two of a chymotrypsin, trypsin, collagenase, and elastase activity.
- the protease or hydrolase can be a multifunctional enzyme that is (a) a first enzyme and has at least about 60% sequence similarity with a reference sequence which is AA64-300 of SEQ ID NO:2 or AA1-300 of SEQ ID NO:2 or a sequence differing from these by at least one ofthe residue differences found in SEQ ID NO:4, 6, 8, 10, or 12 or (b) a second enzyme which is Panaeus vanameii 1, Panaeus vanameii 2, Panaeus monodon chymotryptic-1, Panaeus monodon tryptic, Panaeus monodon chymotryptic-2, Uc pugilator enzyme
- the invention provides polyanionic polymers and methods which can include administering such polyanionic polymers.
- methods of administering an effective amount of a composition comprising a non-addition polyanionic polymer are provided.
- a microgel made from one or more ethylenically unsaturated compounds (where strands of such polymer can optionally be linked by at least one linking moiety comprising a hydrolytically susceptible bond), one or more of which can have: i) one or more functional groups that can be titrated with base to form negatively charged functional groups, or ii) one or more precursor groups that are precursors ofthe functional groups that can be titrated with base; which precursor groups are converted to the functional groups;
- the polymer functional groups can include -C(0)OR 4 ; -0-S(0 2 )OR 4 ,
- R 4 is a cleavage permitting group, preferably independently C ⁇ - Cg normal or branched alkyl, phenyl, or benzyl.
- R 4 is a cleavage permitting group, preferably independently C ⁇ - Cg normal or branched alkyl, phenyl, or benzyl.
- the mole fraction of total ethylenic double bonds in the combination from which the crosslinked polyanionic polymer can be made that is contributed by the ethylenically unsaturated crosslinking agent is 0.02 or less, or preferably 0.01 or less in some embodiments.
- the polyanionic polymer is a microgel (meaning, typically, that it is appropriately crosslinked). In some embodiments, iv) the ratio of macroviscosity of the polyanionic polymer composition to the microviscosity ofthe polyanionic polymer composition is 10,000 or less. In some embodiments, the polymer is pre-formed. In some embodiments, the polymer can be a non-addition polymer, as defined in the specification below.
- polymers ofthe invention can be made from one or more ethylenically unsaturated compounds can be represented by the structure:
- Y is -C(0)OR 4 ; -0-S(0 2 )OR 4 ; -S(0 2 )OR 4 ; or -S(0)OR 4 ; wherein R 4 is hydrogen or a cleavage permitting group, preferably, to C 6 normal or branched alkyl, phenyl, or benzyl;
- R 1 , R 2 , and R 3 are independently selected from, hydrogen, Ci-C ⁇ alkyl (or C 1 -C 4 or C ⁇ -C 3 alkyl), carboxy, halogen, cyano, isocyanato, C ⁇ -C 6 hydroxyalkyl (or -C 4 hydroxyalkyl), alkoxyalkyl having 2 to 12 (or 2 to 6) carbon atoms, Cj-C ⁇ haloalkyl (or C 1 -C 4 ), Ci-C ⁇ Cyanoalkyl (or C 1 -C 4 ), C 3 - C 6 cycloalkyl, C ⁇ -C 6 carboxyalkyl (or C 1 -C 4 carboxyalkyl), aryl, hydroxyaryl, haloaryl, cyanoaryl, - C 6 alkoxyaryl (or -C 4 alkoxyaryl), carboxyaryl, nitroaryl, or a group -X-Y; wherein alkyl or alkoxy groups are
- R 1 , R 2 and R 3 can be independently hydrogen or C ⁇ -C 3 alkyl and X is a direct bond or Ci-C 3 alkylene.
- the cleavage permitting group can include, in some embodiments, one or more to C ⁇ normal or branched alkyl, phenyl or benzyl groups.
- aryl means phenyl or a 5 or 6-membered heteroaryl group having up to Q - 2 heteroatoms independently selected from O, S, and N; wherein Q is the total number of atoms in the ring.
- the polyanionic polymer is a crosslinked polyanionic polymer.
- the polymers are characterized by a mole fraction of ethylenic double bonds in the combination from which the polyanionic polymer is made that is contributed by the ethylenically unsaturated crosslinking agent is 0.02 or less, preferably 0.01 or less.
- the ethylenically unsaturated crosslinking agent is an allylether of sucrose or an allyl ether of pentaerythritol.
- the ethylenically unsaturated crosslinking agent can be, for example, an allyl ether of pentaerythritol or pentaerythritol triacrylate.
- the unsaturated crosslinking agent is an acrylate of pentaerythritol.
- the unsaturated crosslinking agent can be an acrylate-ester-acrylate pentaerythritol.
- the polyanionic polymer is crosslinked by reaction of a crosslinking agent with polyanionic polymer optionally having (or derivatized to have) one or more pendant functional groups on the polyanionic polymer capable of reacting with a functional group ofthe crosslinking agent.
- the methods ofthe invention can be practiced with a polyanionic polymer which has (or is functionalized to have) one or more pendant first functional groups selected from hydroxy, acyl halide, chloroformate, and mercapto; and wherein the crosslinking ofthe polyanionic polymer can be by reaction of a crosslinking agent having second functional groups reactive with the first functional groups.
- the pendant first functional groups can be mercapto groups and the second functional groups can be vinylic double bonds.
- the crosslinking agent can be the diacrylate of an ⁇ , ⁇ -diol, such as ethylene glycol or polyethylene glycol, or the diacrylate of a chain extended ⁇ , ⁇ -diol, wherein the chain extensions comprise residues of a hydroxy carboxylic acid selected for example from glycolic acid, lactic acid, 3-hydroxypropionic acid, hydroxylated 3-methylbutyric acid, hydroxyvaleric acid and hydroxy proline (hydroxylated C 2 - C 5 carboxylic acids and hydroxy proline).
- an ⁇ , ⁇ -diol such as ethylene glycol or polyethylene glycol
- chain extensions comprise residues of a hydroxy carboxylic acid selected for example from glycolic acid, lactic acid, 3-hydroxypropionic acid, hydroxylated 3-methylbutyric acid, hydroxyvaleric acid and hydroxy proline (hydroxylated C 2 - C 5 carboxylic acids and hydroxy proline).
- the pendant first functional groups can be hydroxyl groups
- the second functional groups can be carboxylic acid chloride or chloroformate groups
- the crosslinking agent comprising a residue of either an ⁇ , ⁇ -diol or a chain extended , ⁇ -diol.
- the crosslinking agent can include, for example, a chain extended ⁇ , ⁇ - diol (for example, ethylene glycol or polyethylene glycol) wherein the chain extensions can include residues of a hydroxy carboxylic acid such as glycolic acid, lactic acid, 3-hydroxypropionic acid, 3- methylbutyric acid, hydroxyvaleric acid, and hydroxy proline, or residues of an amino acid such as glycine, alanine, glutamic acid, and aspartic acid.
- the functionalized polyanionic polymer is polyacrylic acid having at least one N-(2-mercapto)ethyl carboxamide group optionally also having at least one pendant first functional group that is a mercapto group.
- the ethylenically unsaturated linking agent (which can be a crosslinking agent) comprises an ethylenically unsaturated derivative of a multidentate compound, comprising two or more two or more ethylenically unsaturated moieties, each such moiety being linked to the multidentate compound through a hydrolytically susceptible bond.
- the which multidentate compound can comprise two or more functional groups that can be, independently, hydroxy, amino, or mercapto groups; wherein the derivative can include two or more ethylenically unsaturated moieties linked to a different oxy, amino, or thio group ofthe residue ofthe multidentate compound through an ester, thioester, or amide bond.
- the multidentate compound can be an ⁇ , ⁇ -diol, or ethylene glycol, diethylene glycol, or polyethylene glycol.
- the , ⁇ -diol can be polyethylene glycol.
- the multidentate compound can be an ⁇ , ⁇ -diamine, such as ethylene diamine.
- the multidentate compound can be, for example, an amino aliphatic alcohol, an amino aliphatic diol, an amino aliphatic triol, a hydroxyl aliphatic diamine, and a hydroxyl aliphatic triamine an amino aliphatic thiol, an amino aliphatic dithiol, an amino aliphatic trithiol, a mercapto aliphatic diamine, or a mercapto aliphatic triamine.
- the hydrolytically susceptible bond can, in some embodiments, be formed of or more residues of a hydroxy carboxylic acid such as glycolic acid, lactic acid, 3-hydroxypropionic acid, 3-methylbutyric acid, hydroxyvaleric acid, or hydroxy proline.
- the hydrolytically susceptible bond-forming group can include, in some embodiments, at least one residue of an amino acid.
- the invention provides a method of isolating a multifunctional proteolytic enzyme from a biological specimen comprising extracting the multifunctional proteolytic enzyme using fresh water.
- the biological specimen is not mechanically disrupted.
- Some embodiments provide for applying the fresh water extract to an affinity column having a ligand, wherein the ligand is aminophenylboronate.
- Some embodiments ofthe invention provide a method of isolating a multifunctional proteolytic enzyme from a biological extract that includes applying the biological extract to an affinity column having a ligand, wherein the ligand can be aminophenylboronate.
- a method includes a composition comprising a polymer, wherein the polymer comprises a polypeptide comprising residues of one or more polycarboxylic amino acids.
- the polymer can be a dicarboxylic amino acid with the formula:
- D is a straight or branched alkylene having substituent E that is a straight or branched alkylene wherein D and E taken together have up to 10 carbon atoms.
- the dicarboxylic amino acid can be, for example, glutamic acid, aspartic acid, poly(glutamic acid) or poly(aspartic acid).
- a polyanionic polymer has a main chain comprising one or more hydrolytically susceptible selected from the group consisting of ester, carbonate, thiocarbonate, urethane, carbamate and urea.
- one or more hydrolytically susceptible links can include a residue of a hydroxy acid.
- the ⁇ -hydroxy acid can be, for example, lactic acid.
- the main chain of the polyanionic polymer can include a residue of an ⁇ , ⁇ -diol, diamine or dithiol.
- Some embodiments involve use of a polyanionic polymer formed by the reaction ofthe bis- acrylate of ethylene glycol, the bis-acrylamide of ethanediamine, or N-(2-acryloyloxy) ethyl acrylamide with a bis-mercapto end-capped polyanionic oligomer and made by polymerization of one or more ethylenically unsaturated compounds.
- AM is an anionic monomer consistent with the monomers described in the Summary. Note that consistent with the Summary and the further description below, not all ofthe monomer contributing to a PAP is itself anionic.
- MW is molecular weight.
- PAA is a Poly(acrylic acid) based polymer.
- PAO is polyalkylene oxide, of which PEG is an example.
- PAOs are typically have C2 to C4 repeating units, with C3 and C4 repeating units typically blended with C2 (ethyleneoxide) to increase water solubility.
- the size ofthe PAO segments is preferably such the molecular weights for 90% or more ofthe segments is 50 kd or 40 kd or less.
- the average molecular weight ofthe segments is from 20 kd to 40 kd, or 25 kd to 35 kd.
- PAO segments have molecular weight averages of at least 500, more preferably at least 1,000.
- PAP is a polyanionic polymer in accordance with the polymer described in the Summary.
- PEG is polyethylene glycol.
- acid number refers to the amount of potassium hydroxide in milligrams needed to neutralize a gram of a dry material.
- a material is dry if it contains not more that 2% by weight of water, an organic solvent, or organic monomer.
- aliphatic includes both aliphatic and cycloaliphatic, unless otherwise indicated.
- alkyl means a linear or branched alkyl group having 1-6 carbon atoms and including halogen substitution of one or more ofthe hydrogens ofthe alkyl group.
- antagonist of an inflammatory cytokine shall include any substance that tends to nullify the action of an inflammatory cytokine, for example as a drug that binds to a cell receptor without eliciting a biological response.
- Inflammatory cytokines shall include any cytokine protein or biological factor capable of stimulating an inflammatory response in living tissue.
- cleavage-permitting group means a moiety containing OR 4 in which the OR 4 group can be chemically altered, substituted or exchanged so that the residue is -OH or -O ⁇ .
- cumulative trauma disorder means a trauma caused by repetitive motion, repetitive stress or repetitive injury to a portion ofthe body.
- Examples of cumulative trauma disorder include, but are not limited to, tendonitis, tensynovitis or carpal tunnel syndrome.
- effective amount The meaning of "effective amount” will be recognized by clinicians but includes an amount effective to reduce, ameliorate or eliminate one or more symptoms ofthe disease sought to be treated or the condition sought to be avoided or treated, or to otherwise produce a clinically recognizable change in the pathology ofthe disease or condition.
- enzymatically active segment means a segment of a multifunctional protein having activity comprising at least one of a chymotrypsin, trypsin, collagenase, elastase or exo peptidase activity.
- fibrinolytic agent Fibrinolysin or agents that convert plasminogen to f ⁇ brinolysin. They may be endogenous or exogenous like the bacterial enzymes used in thromboembolism.
- hydrogel is a combination with water of a hydrophilic polymer, which may be linear, branched, covalently crosslinked, ionically crosslinked, physically crosslinked, or crosslinked by hydrogen bonding. A hydrogel has 50% or more water by weight. Examples of hydrophilic polymers that form hydrogels are carboxymethylcellulose, carboxypolymethylene, and poly(hydroxyethyl methacrylate).
- hydrolase means an enzyme that degrades bonds formed by dehydration reactions such as amide, ester, or ether bonds.
- the term encompasses, but is not limited to, proteases such as trypsin and chymotrypsin.
- isoform means a naturally occurring sequence variant of a substantially homologous protein within the same organism.
- the isoform shares at least about 80% identity, and more preferably, at least about 85% identity with a reference sequence.
- krill-derived multifunctional protein means a multifunctional protein having the same sequence as a protein isolated from krill having the properties ofthe protein described in the section entitled
- This protein is also referred to as the "krill- derived multifunctional hydrolase” and includes all isoforms ofthe protein.
- the amino acid sequence included in SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 or SEQ ID NO:6 or other isoforms thereof or chimeric polypeptides thereof are examples of krill-derived multifunctional proteins.
- labile spacer group shall include a chemical functional group which is susceptible to enzymatic or non-enzymatic hydrolysis or oxidation.
- the labile spacer group can, in some embodiments, have one or more residues of a hydroxy carboxylic acid such as glycolic acid, lactic acid, 3-hydroxypropionic acid, 3-methylbutyric acid, hydroxyvaleric acid, or hydroxy proline.
- the labile spacer group can include, in some embodiments, at least one residue of an amino acid.
- the hydrolytically susceptible bonds are substituted with labile spacer groups.
- linking moiety comprising a hydrolytically susceptible bond refers to a chemical moiety including at least one hydrolytically susceptible bond that links one segment of polymer to another. Such a linking moiety can join two ends of linear polymer, thereby lengthening the polymer, or provide a crosslinker. Linking moieties can be formed with linking agents or by reaction of functional groups on respective segments of polymer.
- microgel means a viscoelastic mass of discrete particles, each discrete particle comprising crosslinked polyanionic polymer and each particle having a size in its aqueous swollen state at neutral pH of between 0.1 and 1000 ⁇ m.
- the particles of aqueous swollen polyanionic polymer have 70% or more water and the crosslinking is ionic, covalent, or through hydrogen bonding.
- microviscosity is measured, for example, by any method set forth in R.Y. Lochhead et al., "Poly(acrylic acid) Thickeners: The Importance of Gel Microrheology and Evaluation of Hydrophobically Modified Derivatives as Emulsifiers," in Polymers in Aqueous Media, pp. 113-147, 1989, which document is incorporated by reference herein in its entirety.
- One such method measures microdiffusion with bimodal gold sols, for example allowing for microdiffusion to be measured for a microstructure centered around 10 nm and lOOnm.
- mono or disaccharide means such a saccharide or disaccharide (such as sucrose), which can be reduced to the nonreducing form or oxidized to contain up to one carboxylic acid.
- multidentate compound is a compound having two or more functional groups selected from hydroxy, amino, or mercapto (thiol). Examples of multidentate compounds include ethylene glycol, amino ethanol, polyethylene glycol, glycerol, and pentaerythritol.
- multifunctional protein means a protein having activity comprising at least one of a chymotrypsin, trypsin, collagenase, elastase or exo peptidase activity or asialo GM j ceramide binding activity, and substantial homology to at least a segment of a krill-derived multifunctional protein.
- neutral functional group means a functional group that is not titrated by acid or base.
- Non-addition polymer is a polymer wherein the polyanionic polymer segments are not formed by the addition reaction of a strong nucleophile (excluding radicals) with an ethylenic unsaturation in a second molecule.
- a non-addition polymer for the purposes of this application, can include any polymer where such polyanionic segments are produced by any means including free-radical polymerization, cationic polymerization, or anionic polymerization, as well as polymers formed by condensation reactions.
- the linking moieties or linking agents used in, or used to form, the polymers can be formed by any appropriate chemistry — even though such moieties or agents can have polymeric components.
- nonsteroidal anti-inflammatory agent Any anti-inflammatory agent that inhibits the production of prostaglandins.
- physiological pH means a pH between 6.5 and 7.5.
- polyanionic polymer means a polymer having an acyclic backbone and having ionizable functional groups, for example carboxy groups, that become negatively charged functional groups, for example carboxy late anions, at physiological pH.
- a gram of polyanionic polymer has 0.001 moles or more of functional groups that can be titrated with KOH.
- the ionizable functional groups can be directly chemically bonded to the polymer backbone or they can be chemically bonded to a side group or side chain that is in turn chemically bonded to the main chain.
- Carboxypolymethylene is an example of a polyanionic polymer in which the ionizable functional group is directly bonded to the main chain
- ⁇ - Poly(glutamic acid) is an example of a polyanionic polymer in which the ionizable functional group is bonded to a side group that is an ethylene group.
- pre-formed polymer is a polymer that is chemically formed ex situ, prior to administration to a subject.
- reference protein or sequence means a reference protein sequence which is AA64-300 of SEQ ID NO: 1 or AA1-300 of SEQ ID NO: 1 or a sequence differing from these by at least one ofthe residue differences tabulated below:
- surfactant any surface active agent that changes the nature of a surface, including lowering the surface tension of a liquid.
- unit of multifunctional hydrolase is defined as the amount of enzyme that catalyzes the hydrolysis of 1 ⁇ mol of substrate per minute at 25°C, wherein succinyl-ala-ala-pro-phe-p-nitroanilide (Sigma Chemical Co., St. Louis, MO) is the substrate, and hydrolysis is monitored via the absorbance change at 410 nm.
- the extinction coefficient ⁇ of -nitroanilide is 8800 M "! cm _1 , thus the multiplication factor to convert dA/minute into U/minute of sample is 5.68, when 20 ⁇ l of sample is used.
- the invention provides a method for treating wounds and other trauma to anatomical membranes of a metazoan, including but not limited to mammals, humans, food animals, such as cows, pigs, sheep, goats, and the like, companion animals, such as dogs, domestic cats, horses, and the like, and exotic animals, such as elephants, apes, large cats, whales, and the like.
- membrane is used broadly and includes tissue boundaries and tissue surfaces, such as the dura mater and the surfaces of tendons; the anterior limiting area of the cornea; membranes covering internal organs or lining the cavities in which the organs reside, which include tendons within their sheaths; and internal and external epithelia and mesothelia.
- epithelium is herein used in its broadest sense and will be understood to refer to simple, stratified, and transitional epithelia, as well as the endothelium of serous membranes.
- the epidermis and the conjunctival epithelium on the suhstantia basement ofthe cornea are external epithelia.
- Internal epithelium includes surfaces, which are sometimes denoted endothelia, such as the peritoneum, pleura, and pericardium and like membranes that cover internal structures and organs, such as the viscera, the body cavity wall, and the like.
- Trauma that is treated by the method ofthe invention may or may not result in breach ofthe membrane or tissue boundary. Wounds can result from a disease condition, for example vascular insufficiency or infection associated with a pathogen, burns (thermal or chemical), or from application of external force to a membrane or tissue surface by accident or surgery.
- Noxious stimuli includes the action of heat or corrosive chemicals, for example acids and caustics, as well as manipulation of an organ during surgery.
- corneal wounds is intended to encompass any injury to the cornea, for example, infection by a pathogen, a corneal abrasion, a corneal ulcer, or an insult capable of giving rise to a corneal ulcer in a mammal, including but not limited to humans, food animals, such as cows, pigs, sheep, goats, and the like, companion animals, such as dogs, domestic cats, horses, and the like, and exotic animals, such as elephants, apes, large cats, whales, and the like.
- An insult capable of giving rise to a corneal ulcer can be chemical, for example exposure to a corrosive chemical, or it can be physical, for example impact by a foreign object or a surgical incision as in keratoplasty (e.g., corneal grafting) or keratotomy (e.g., radial keratotomy).
- keratoplasty e.g., corneal grafting
- keratotomy e.g., radial keratotomy
- the method ofthe invention is particularly useful in the treatment of, for example, ulcerations and other injuries of corneal tissue as well as cutaneous wounds such as decubitus ulcers, venous ulcers, burns, or pressure sores.
- Treatment of corneal ulcers according to the method ofthe invention retards or arrests growth ofthe ulcer, which, if left unchecked, can lead to perforation.
- Treatment of corneal ulcers according to the method ofthe invention also improves the rate of healing, that is the rate of return ofthe cornea or skin to its pre-trauma condition, reducing the risk of opportunistic infection, and inhibits or reduces formation of scar tissue.
- a preferred target ofthe present inventive method of treatment is a corneal ulcer that is associated with an infection, such as viral infection caused by a Herpes virus (HSV), or a bacterial infection, such as one of a pseudomonad or a Moraxella species (as in Moraxella hovis that causes corneal ulcerations in cattle).
- the present method comprises administering to an affected area ofthe cornea an effective amount of a composition containing a polyanionic polymer, for example a microgel from a crosslinked carboxypolymethylene.
- Treatment of cutaneous wounds by the present method preferably includes application to an area affected by a cutaneous wound of a polyanionic composition for which the ratio of macroviscosity to microviscosity is 10,000 or less and that, in some embodiments contains a multifunctional krill-derived hydrolase .
- area affected by a cutaneous wound varies with the size, location, and severity ofthe wound but includes the wound itself and an area around the wound (such as within 3 cm).
- the method ofthe invention is likewise particularly useful in the inhibition or reduction ofthe incidence or severity of adhesions, for example those that frequently form between the peritoneum and viscera, or between non-adjacent areas ofthe peritoneum, following surgical procedures that inflict internal trauma, including internal surgical wounds.
- Adhesions are scar tissue that first develops as fibrous bands between two tissue surfaces that, despite being in apposition, normally have free movement relative to each other.
- the adhesions arise as a result of repair processes after an insult or a noxious stimulus has damaged the integrity of one or both opposing surfaces. Noxious stimuli include trauma (both surgical and accidental), infection, and any physical or chemical agent that can cause inflammation leading to a repair response.
- Adhesions prevent the normal movement between the affected surfaces, dysfunction ofthe underlying organ or pain may result.
- Adhesions start as thin and filmy strands, largely composed of fibrin, which are easily disrupted at this stage. With time they become organized, laying down collagen and becoming vascularized. At this stage, only surgical division will separate the adhering structures. This becomes necessary when the function ofthe tethered organ is impaired or viability is at risk.
- the method as it relates to inhibition of post-operative formation of adhesions, is applicable to other types of adhesions apart from those ofthe peritoneum.
- the present method comprises treating the affected area of, in, or around a trauma; for example a surgical incision, or corneal ulcer or injury by applying to the affected area a trauma- treating effective amount of a composition that includes either a polyanionic polymer, a multifunctional hydrolase or both.
- the hydrolase can be a protease, particularly a multifunctional krill-derived serine protease.
- the present method comprises treating the area affected by a corneal wound or surgical wound with a composition that includes a polyanionic polymer that can contain a protease, preferably a multi-functional krill-derived protease.
- the affected area will depend on the nature, size, and location ofthe trauma.
- the affected area can be the entire exposed surface ofthe eye.
- the trauma is an internal surgical wound involving a body cavity
- the affected area includes surfaces of organs or tissues in the body cavity into which the surgical incision (wound) is made.
- the affected area is the entire peritoneal cavity and the organs residing within the peritoneal cavity;
- the affected area is the entire thoracic cavity and the organs residing within the thoracic cavity.
- the affected area includes the area ofthe incision and extends from 1 or 2 to as many as 15 cm from the incision ofthe tendon sheath and includes the surfaces of tissues surrounding the tendon and its sheath.
- the present method comprises treating the area affected by an internal trauma to reduce post trauma formation of adhesions by applying to the affected area an effective amount of a polyanionic polymer.
- the polyanionic polymer can crosslinked.
- the amount of polyanionic polymer in the composition is between 0.5 and 2.5 weight percent.
- the composition has 1% crosslinked polyanionic polymer.
- the present method comprises treating the affected area of a cutaneous wound, such as a decubitus ulcer, venous ulcer, burn, or pressure sore, by applying to the affected area an effective amount of a composition comprising a polyanionic polymer that can contain a hydrolase, preferably a protease, most preferably a multifunctional krill-derived serine protease.
- a composition comprising a polyanionic polymer that can contain a hydrolase, preferably a protease, most preferably a multifunctional krill-derived serine protease.
- An effective amount of a composition of this embodiment of the invention is an amount sufficient to promote debridement and to prevent odor and unwanted seepage and infection in the cutaneous wound, and preferably to cause it to heal faster that it would if it were merely cleansed and dressed.
- the present method comprises treating the affected area ofthe peritoneum, the epicardium, pericardium, or the pleura traumatized by an internal trauma by applying an effective amount of a composition comprising a polyanionic polymer that can contain a krill- derived protease, preferably a protease, more preferably a multifunctional krill-derived protease.
- the present method comprises treating the area ofthe spine, the meninges, for example dura mater (protective membrane for neural tissue), or nerves and nerve sheaths traumatized by surgery or injury to reduce or inhibit fonnation of adhesions by applying an effective amount of a composition comprising a polyanionic polymer described above that can contain a protease, preferably a krill-derived protease.
- a composition comprising a polyanionic polymer described above that can contain a protease, preferably a krill-derived protease.
- such affected area can be treated with a hydrolase, in any pharmaceutically acceptable vehicle carrier as is known in the art.
- the present method comprises treating the area of a tendon and its sheath affected by internal trauma, for example a surgical wound as in tenoplasty.
- Areas subject to cumulative trauma or other trauma can be treated by administering to an area affected by the trauma, a trauma treating effective amount of a composition comprising one or more ofthe following: a polyanionic polymer or a protease that has an activity comprising at least two of a chymotrypsin, trypsin, collagenase, and elastase activity.
- a trauma treating effective amount of a composition comprising one or more ofthe following: a polyanionic polymer or a protease that has an activity comprising at least two of a chymotrypsin, trypsin, collagenase, and elastase activity.
- Non-limiting examples of cumulative trauma disorder which can be treated by methods ofthe invention include tendonitis, tenosynovitis and carpal tunnel syndrome.
- the present method comprises treating the area affected by internal trauma to reduce formation of adhesions by applying to the affected area an effective amount of a krill-derived multifunctional protease.
- the krill-derived multifunctional protease can be applied to the affected area in any pharmaceutically acceptable vehicle ofthe known art.
- Pharmaceutically acceptable vehicles serve as carriers for administration of pharmacologically active material such as the multifunctional protease ofthe invention but do not interfere with the action ofthe active material or the bodily functions ofthe animal to which it is administered.
- Isotonic saline solution is an example of a pharmaceutically acceptable vehicle.
- Pharmaceutically acceptable vehicles can have excipients known in the art such as dextran, calcium chloride, glycine, citric acid, and sorbitol, to mention a few.
- compositions ofthe invention containing crosslinked polyanionic polymers can also be applied to the area affected by bowel, thoracic, cranial, tendon, and gynecological surgery to inhibit or reduce the formation or reformation of adhesions.
- the invention provides a method for treating a surgical implant with a composition comprising a polyanionic polymer, which can be a microgel, to reduce adhesion formation between the implant and areas of tissue surrounding the implant or between different areas ofthe tissue surrounding the implant by applying to the surface ofthe surgical implant a coating including the composition having a thickness from between about 0J mm to about 5mm.
- Surgical implants with which the method can be used include joint and bone prostheses, including prosthetics ofthe inner ear, cranial plates, and cardiac pacemakers, drug delivery implants and in-dwelling catheters, among others.
- the present method comprises treating or managing inflammatory diseases or conditions with an associated inflammatory component, such as rheumatoid arthritis or other autoimmune disorders, by administering a composition comprising a polyanionic polymer, an enzyme, preferably a hydrolase, or both.
- the composition can be administered, for example, to an area affected by the condition or disease with an inflammatory component or sequelae thereof.
- conditions that are included in the method of this embodiment include localized chronic inflammation, such as that which occurs in chronic osteoarthritis.
- the crosslinked polyanionic polymers used in the method ofthe invention can be made by any method that provides a crosslinked polymer having an acyclic backbone and functional groups capable of ionizing to an anionic form under physiological conditions.
- the polyanionic polymers used in the method ofthe invention can be obtained by polymerization of a mixture that includes an ethylenically unsaturated crosslinking agent and at least one monomer that has an ionizable functional group capable of becoming negatively charged.
- the ionizable functional group is a base-titratable functional group.
- the carboxy group is an example of a base titratable functional group.
- the polyanionic polymer can also be obtained from a precursor polymer having precursor functional groups that can be hydrolyzed to the ionizable functional groups that, in turn, can become negatively charged.
- a carboxylate ester is a precursor for a carboxy group which, when treated with base, becomes a negatively charged carboxylate anion.
- the precursor polymer can be obtained by polymerization of a mixture that includes one or more monomers at least one of which has a precursor for a functional group that is capable of becoming negatively charged.
- the precursor group can be converted to the functional group capable of becoming negatively charged by, for example, hydrolysis, or any other means as will be obvious to one skilled in the art from inspection ofthe chemical structure ofthe precursor group. Conversion ofthe precursor group can be made to occur prior to, at the time of, or after administration of a composition.
- the backbone, or main chain, of polyanionic polymers useful in the practice ofthe invention includes repeat units that can be derived from polymerization of one or more monomers of structure I, wherein the double bond shown is disposed to polymerization at least by free radical polymerization.
- R 1 , R 2 , and R 3 ; X; and Y are defined as set forth above.
- Suitable monomers include acrylic acid, methacrylic acid, allyl sulfonic acid, itaconic acid, maleic acid or its anhydride, itaconic acid, citraconic acid, to mention a few.
- Many other monomers that can be used to make polyanionic polymers that form microgels with water are described by Huang et al., United States Patent 4,509,949, incorporated herein by reference.
- crosslinked polyanionic polymers that can form microgels the term backbone and main chain are used interchangeably and will be understood to refer to that portion ofthe polymer chains not derived from crosslinking agents.
- the microgel has a particle size between 1 and 500 ⁇ m in its aqueous swollen state at a pH between 6 and 8. In other embodiments, the microgel has a particle size between 10 and 500 ⁇ m in its aqueous swollen state at a pH between 6 and 8.
- the polyanionic polymers used in the method ofthe invention can be homopolymers, having repeat units derived from only one monomer described by structure I, or they can be multipolymers derived from polymerization of a mixture of any number of monomers of structure I.
- Co-, ter-, quatra-, and other multipolymers can include repeat units from monomers that do not bear ionizable groups or precursors therefor, for example styrene, that are capable of copolymerizing with the monomers of structure I, with the proviso that the final polymer has 0.001 or more moles, preferably 0.0014 or more moles, more preferably 0.01 mole or more, of base titratable functional groups per gram of polymer (on a commercially acceptable dry basis).
- a base titratable functional group is a functional group, for example a carboxy group, that can be titrated with KOH.
- polyanionic polymer is crosslinked and forms a microgel when combined with water.
- Preferred crosslinked polyanionic polymers are chemically crosslinked. Chemical crosslinking can be by ionic or covalent bonds, preferably it is by covalent bonds. The crosslinking can be introduced at the time the polyanionic polymer is made, or it can be introduced after the polyanionic polymer is made.
- the chemical crosslinks can be durable under physiological conditions or they can be hydrolytically susceptible (labile) under physiological conditions. With respect to crosslinks, labile means susceptible to enzymatic or non-enzymatic hydrolysis or oxidation.
- crosslinking by covalent bonds is introduced at the time the polyanionic polymer is made by using one or more chemical crosslinking agents that have at least two ethyleneically unsaturated carbon-carbon double bonds disposed to polymerize by the same mechanism as the monomers represented by structure I, preferably a free radical mechanism.
- Chemical crosslinking agents introduced at the time the polyanionic polymer is made can be selected to result in covalent crosslinks that will be durable under physiological conditions after application of a composition containing a polyanionic polymer. That is, the crosslinks introduced by the crosslinking agent resist break-down or scission under physiological conditions.
- crosslinking agents that can be introduced at the time the polyanionic polymer is made and that result in durable crosslinks include divinyl benzene and alkenyl ethers of polyhydric alcohols, for example the triallyl ether of pentaerythritol available from Aldrich Chemical (catalog 25-172-0), among others.
- Commercially available ethylenically unsaturated ethers or esters of those polyhydric alcohols having 3 or more hydroxyl groups typically are provided as a mixture in which some ofthe hydroxyl groups may be underivatized.
- Reference herein to a particular degree of etherification or esterification for example tri- or terra-, will be understood to also refer to commercially important mixtures of etherified or esterified polyhydric alcohols as are known in the art to include minor amounts of etherified or esterified polyhydric alcohols having a lower or higher than indicated degree of etherification or esterification.
- reference to a particular mole fraction of double bonds will be understood to encompass the variation expected because of this known variation in the degree of derivatization.
- the crosslinks between chains of polyanionic polymer are capable of breaking- down under physiological conditions.
- break-down ofthe crosslinks can facilitate eventual elimination ofthe polyanionic polymer from the animal being treated because fragments of reduced molecular size (molecular weight) are formed when the crosslinks break down and the smaller fragments are more easily eliminated (Yamaoka et al., J. Pharm. Sci, 84, 349(1995). Break-down ofthe crosslinks is facilitated if the two or more ethylenic double bonds ofthe crosslinking agent are separated by functional groups, for example esters or amides, that are disposed to hydrolysis.
- crosslinking agents having ester linkages include acrylates and methacrylates of dihydric and polyhydric alcohols such as ethylene glycol, diethylene glycol, pentaerythritol, glycerol, and sorbitol.
- Such crosslinking agents are either commercially available (e.g., pentaerythritol triacrylate, Aldrich Chemical catalog 2 t, ⁇ !9), or can be readily prepared from the polyhydric alcohol and acryloyl or methacryloyl chloride.
- Acrylates and methacrylates of polyethylene glycols having molecular weights between 200 and 40,000 can also be used as crosslinking agents.
- Ethylenically unsaturated derivatives of oligosaccharides, or their reduction products can be used as crosslinkers.
- a particularly preferred crosslinking agent of this type is allyl sucrose.
- Crosslinking agents in which there is at least one carbonate or carbamate group between each ethylenic double bond and any other ethylenic double bond ofthe crosslinking agent can also be used.
- Bis-(2'-acryloxyethyl) carbonate, pentaerythritol tri(2'-acryloxyethyl)formate, and N-(2- acryloxy)ethyl-(2-acryloxy)ethyl carbamate are examples of carbonate-linked and carbamate-linked crosslinking agents.
- Crosslinked polyanionic polymers having hydrolytically susceptible crosslinks can also be prepared with crosslinking agents in which the ethylenic double bonds are linked by urea groups.
- N,N'-di(2'-acryloxyethyl)urea is an example of a urea- linked crosslinking agent.
- Crosslinking agents based on lactic acid can also be used.
- l-(2-acryloxypropanoyl)-2-acryloxy ethane is an example of such a crosslinking agent.
- Crosslinking by non-durable covalent bonds can be introduced after the polyanionic polymer is made by functionalizing the polyanionic polymer and reacting it with a suitable crosslinking agent.
- Y of structure I is a carboxyl group
- from 0.1 % to 10% ofthe carboxyl groups in the polymer can be functionalized to the acid chloride by, for example, the action of thionyl chloride.
- the acid chloride groups so formed can be reacted with, for example, an ⁇ , ⁇ -diamine or ⁇ , ⁇ -diol, for example a polyethylene glycol, to form covalent crosslinks through amide or ester groups on different polymer chains.
- Crosslinking can also be introduced after the polyanionic polymer is formed by providing pendant hydroxyl groups on the polyanionic polymer and reacting these with a bischloroformate, for example the bischloroformate of an ⁇ , ⁇ -diol.
- the polyanionic polymer can be provided with pendant hydroxyl groups by polymerizing one or more monomers of structure I with vinyl acetate, followed by hydrolysis ofthe acetate groups, or by copolymerizing one or more monomers of structure I with, for example, hydroxyethylmethacrylate (HEMA).
- HEMA hydroxyethylmethacrylate
- the amount of vinyl acetate or HEMA copolymerized will be sufficient to provide 0.1 to 10 hydroxyl groups per 1000 repeat units on a moles basis.
- crosslinker Preferably the amount of crosslinker is kept low.
- Preferred crosslinked polyanionic polymers form microgels with water and are made by polymerization of a mixture of one or more monomers of structure I and one or more ethylenically unsaturated crosslinking agents ofthe type discussed above.
- the amount of crosslinking agent or agents used is effective to produce a crosslinked polyanionic polymer that forms a microgel when combined with water.
- the ethylenic double bonds ofthe one or more ethylenically unsaturated crosslinking agents preferably account for less than 0.02 mole fraction and preferably less that 0.01 mole fraction of all ethylenically unsaturated double bonds in the combination of one or more monomers and one or more crosslinking agents.
- the ethylenically unsaturated crosslinking agent account for 0.001 mole fraction or more of all ethylenically unsaturated double bonds in the combination of one or more monomers and one or more crosslinking agents.
- mole fractions are calculated on the basis ofthe nominal number of ethylenic double bonds in the ethylenically unsaturated crosslinking agent and are adjusted for the known variation in the average number of double bonds per molecule of commercially available ethylenically unsaturated crosslinking agents as discussed above.
- the polyanionic polymer employed in the practice ofthe method of the invention has an acid number of at least about 100, more preferably at least about 200, yet more preferably at least about 400, still yet more preferably at least about 600, still more preferably at least about 700, when the polymer is in a commercially acceptable "dry" preparation such as a preparation containing the polymer and for example up to 2% moisture, residual solvent, or residual monomer.
- the polyanionic polymer has 0.001 moles or more, preferably 0.0014 moles or more, more preferably 0.014 moles or more, of base titratable functional groups per gram of polymer in a commercially acceptable dry formulation.
- the polyanionic polymers preferably have, in a 0.5% w/v neutralized aqueous solution (e.g. pH between 6 to 8), a Brookfield RVF or RVT viscosity, which is a measure of macroviscosity, of at least about 2,000 cP, more preferably at least about 4,000 cP (20 rpm at 25°C). These viscosity parameters are with respect to the acid form ofthe polymers. See, R.Y. Lochhead et al., Polymers in Aqueous Media, pp. 113-147, 1989 on macroviscosity (Brookfield viscosity) and microviscosity of polymer solutions. However, in certain preferred embodiments, the macroviscosity is no more than about 100,000 times greater than the microviscosity, preferably no more than about 10,000 times greater.
- a Brookfield RVF or RVT viscosity which is a measure of macroviscosity, of at least about 2,000 cP, more preferably at least about 4,000
- the crosslinked polyanionic polymer is a crosslinked homopolymer or copolymer of acrylic acid, such as the polymers sold by the BFGoodrich Company, Specialty Polymers and Chemicals Division (Brecksville, OH) under the tradename Carbopol, such as carbopol 971P, Carbopol 934P and Carbopol 974P, which are preferred in the order: 971P more than 934P; and 934P more than 974P.
- Carbopol such as carbopol 971P, Carbopol 934P and Carbopol 974P, which are preferred in the order: 971P more than 934P; and 934P more than 974P.
- carboxypolymethylenes or carbomers which can be composed of any suitable number of monomers, and in a particular treatment, can be of a uniform number of such monomers or of a variable number of monomers per preparation applied to an area affected by a wound.
- carboxypolymethylene can have a variable number of carboxyl groups attached to the polymethylene backbones.
- crosslinker the triallyl ether of pentaeiythritol (at 0.1% to 2.5 % ,w/w, based on other monomers) is suitable.
- Suitable salts can be, where a microgel is employed, combined with a microgel, the suitability of which is determined by the requirement that the microgel itself not cause harm to the injured cornea, peritoneum, or any other tissue with which the microgel comes in contact.
- Suitable salts include, but are not limited to, potassium or sodium chloride, particularly when provided at physiological concentrations, as are known in the art.
- a composition used in the practice ofthe method ofthe invention can include glycerol, the carboxypolymethylene, and distilled water, and is adjusted as to pH using a base such as sodium hydroxide potassium hydroxide, alkyl amines such as diisopropanolamine (DIP A), and the like.
- a stock solution of a suitable concentration of glycerol can be prepared with distilled water, and is preferably an 87% (w/w) glycerol solution, the remainder of which is distilled water.
- a stock solution of a suitable solution of base such as sodium hydroxide can also be prepared with distilled water, for example, a 10% (w/w) sodium hydroxide solution, the remainder of which is water.
- the polymer composition useful in the practice ofthe present method preferably has the following ranges of end concentrations ofthe ingredients: (1) glycerol, from about 0 to about 60% (w/w); (2) carboxypolymethylene, from about 0.1% to about 10% (w/w), more preferably from about 0.4% to about 7%, yet more preferably, from about 1% to about 5%; the remainder ofthe formulation being distilled water.
- glycerol from about 0 to about 60% (w/w);
- carboxypolymethylene from about 0.1% to about 10% (w/w), more preferably from about 0.4% to about 7%, yet more preferably, from about 1% to about 5%; the remainder ofthe formulation being distilled water.
- Sodium hydroxide, 10% stock is used for pH adjustment, resulting in an essentially neutral prepared pH, more preferably a pH from about 7 to about 7.8, yet more preferably a pH from about 7.2 to about 7.6.
- the polyanionic polymer composition can also be prepared with excipients intended to protect the multifunctional hydrolase upon freeze drying or upon the reconstitution thereof with distilled water, or both.
- excipients include, for example, calcium chloride, glycine, citric acid, sorbitol, and dextran.
- a vial that contains, for example, 50 units ofthe multifunctional hydrolase (which units are defined above) when freezedrying is contemplated preferably includes the following excipients in the range of concentration given: (1) calcium chloride, from about 0.6 mM to about 1 mM, (2) glycine, from none up to about 12 mM, preferably from about 6 mM to about 10 mM, most preferably about 8 mM; (3) citric acid, from none up to about 12 mM, preferably from about 6 mM to about 10 mM, most preferably about 8 mM; (4) sorbitol, from about 100 mM to about 200 mM, preferably between about 150 mM and 170 mM, most preferably about 160 mM; and (5) dextran, from about 1% to about 10% by weight, preferably between about 7% to about 8% by weight, most preferably 6% by weight.
- a preferred embodiment ofthe invention provides for treatment of wounds, especially cutaneous wounds, with an above described polyanionic polymer composition, optionally combined with a suitable multifunctional hydrolase.
- the multifunctional hydrolase preferably has proteolytic activity corresponding to that of at least one from the group comprising a chymotrypsin, trypsin, collagenase, elastase and exo peptidase activity. More preferably, the multifunctional hydrolase has at least two of said proteolytic activities; yet more preferably, at least three of said proteolytic activities; even more preferably, at least four of said proteolytic activities; and most preferably, all of said proteolytic activities.
- compositions used in the context ofthe method ofthe invention can be applied to the area to be so treated, for example topically.
- Polyanionic polymer compositions can be applied as paste, jelly, or in sheets that can be prehydrated or hydrated in situ by bodily fluids.
- polyanionic polymer compositions can be administered as a paste, jelly, or pourable liquid formulation.
- multifunctional krill-derived protein can be administered in a pharmaceutically acceptable vehicle, for example isotonic saline solution.
- the multifunctional protein can also be administered to an area affected by an internal surgical wound in a composition that includes a polyanionic polymer.
- the multifunctional protein is administered to the area affected by a surgical wound in a composition that contains a microgel.
- a particularly preferred microgel contains a crosslinked polyanionic polymer.
- Crosslinked carboxypolymethylene is a useful crosslinked polyanionic polymer.
- Treatment of corneal wounds can be effected using hydrolase in any pharmaceutically acceptable vehicle according to standard pharmaceutical practice.
- vehicle can be a microgel.
- compositions for treatment of corneal wounds can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or pofyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchronium chloride, and the usual quantities of diluents and/or carriers.
- the composition containing multifunction protein to be administered to the eye includes a polyanionic polymer composition.
- the method of treating a corneal ulcer preferably comprises administering to an affected eye a composition comprising the multifunctional hydrolase, wherein a corneal ulcer treating effective amount ofthe multifunctional hydrolase is administered, and wherein the multifunctional hydrolase preferably has at least two of a chymotrypsin, trypsin, collagenase, elastase or exo peptidase activity, and at least about 60% sequence similarity with a reference sequence. More preferably, the hydrolase has at least three of said proteolytic activities and at least about 80% sequence identity with the reference sequence.
- the hydrolase has at least three of said proteolytic activities and at least about 90% sequence similarity with the reference sequence. Even more preferably, the hydrolase has at least three of said proteolytic activities and at least about 90% sequence identity with the reference sequence. Yet even more preferably, the hydrolase has at least three of said proteolytic activities and at least about 95% sequence similarity with the reference sequence.
- the method can include pretreatment or simultaneous treatment, or both, ofthe traumatized membrane with corticosteroids, such as cortisone, alone or in combination with an antihistamine.
- the multifunctional hydrolase used in the context ofthe invention preferably is a krill-derived hydrolase, such as a proteinase. More preferably, the multifunctional hydrolase is part of a multifunctional protein, which may have non-enzymatic functions as well as enzymatic functions. Crustaceans, including antarctic krill, are useful sources for the multifunctional protein of the invention.
- a protein having "multifunctional activity,” is defined herein as including at least one of a chymotrypsin, trypsin, collagenase, elastase or exo peptidase activity, or asialo GM j ceramide binding activity.
- a preferred suitable dose of multifunctional krill-derived protein per application ranges from about 0.01 U/ml to about 10 U/ml, where typically a layer of from 0.5 to 5 mm of carrier such as cream, ointment, polyanionic polymer or the like is applied, more preferably about 0.01 U/ml to about 1.0 U/ml, still more preferably about 0.2 U/ml.
- This dosage range applies to vehicles such as gels, ointments, creams, liquids, sprays, aerosols, and the like. In some embodiments, such as wound debridement, larger dosages may be used initially.
- Lozenges preferably are designed to deliver about 0.01 U to about 10 U, more preferably about 0.01 U to about 1.0 U, still more preferably about 0.2 U.
- the protein composition will generally be applied from about 1 to about 10 times per day, preferably from about 2 to about 5 times per day. These values, of course, will vary with a number of factors including the type and severity ofthe disease, and the age, weight and medical condition ofthe patient, as will be recognized by those of ordinary skill in the medical arts. It is believed that substantially higher doses can be used without substantial adverse effect.
- the multifunctional protein will be administered in an effective amount.
- the invention provides a method for treating trauma susceptible to giving rise to the formation of adhesions by administering to the area affected by such trauma with an effective amount of a composition that includes a polyanionic polymer (e.g., microgel).
- a composition that includes a polyanionic polymer e.g., microgel.
- polyanionic polymer e.g., microgel
- the composition to be administered is preferably buffered to a physiologically suitable pH, such as pH 6.5 to pH 7.5.
- a physiologically suitable pH such as pH 6.5 to pH 7.5.
- salts and stabilizing agents can be added in amounts effective to increase activity or stabilize the enzyme.
- the multifunctional hydrolase used in the context ofthe invention preferably has the above-described proteolytic activity and at least about 60% sequence identity or similarity with a reference sequence. More preferably, the multifunctional hydrolase has at least about 70% identity or similarity with the reference sequence; yet more preferably, at least about 80% or 85% identity or similarity with the reference sequence; even more preferably, at least about 90% or 95%o identity or similarity with the reference sequence; and most preferably, at least about 97% identity or similarity with the reference sequence. While the percentage similarity noted above is preferred, the percentage identity is more preferred.
- administration vehicles including, without limitation, slow release formulations, liposomal formulations and polymeric matrices.
- the method of treatment of trauma by administering the polyanionic polymer composition, with or without the multifunctional hydrolase or other agents, such as antibiotics, is preferably conducted for a suitable time, the suitability of which will be known to the skilled practitioner for example from inspection ofthe affected tissue and the kind and severity ofthe condition being treated.
- the treatment is preferably administered at least until healing ofthe affected wound is complete, more preferably for at least an additional five days thereafter.
- Corneal wounds can be, for example, treated for 2 to 35 days. In other cases, the treatment is conducted for at least about 10 days, more preferably for at least about 20 days, yet more preferably for at least about 28 or 35 days.
- Treatment of cutaneous wounds with a composition containing a polyanionic polymer composition and a multifunctional hydrolase can be from 7 to 42 days. Treatments are preferably accomplished via application at least once per day, more preferably twice a day up to about six times a day, using methods of topical application to the eye as are known in the art.
- the multifunctional hydrolase has a preferred molecular weight of from about 20 kd to about 40 kd; more preferably, the molecular weight is from about 26 kd to about 32 kd.
- Preferred multifunctional hydrolases include, but are not limited to Panaeus vanameii 1, Panaeus vanameii 2, Panaeus monodon chymotryptic-1, Panaeus monodon tryptic, Panaeus monodon chymotryptic-2, Ucapugilator enzyme I, Ucapugilator enzyme II, Kamchatka crab IA, Kamchatka crab IIA, Kamchatka crab IIB, Kamchatka crab IIC, Crayfish protease 1, Salmon enzyme 1, Atlantic cod I Atlantic cod II or third Atlantic cod trypsin (described in European J. Biochem., 180: 85-94 (1989) and Protein Resource Accession No. S03570.
- these specific enzymes comprise the following respective peptide sequences: Panaeus vanameii 1, I-V-G-G-V-E-A-T-P-H-S-W-P-H-Q-A-A-L-F-I-D-D-M-Y-F(SEQ ID NO:2); Panaeus vanameii 2, I-V-G-G-V-E-A-T-P-H-S-X-P-H-Q-A-A-L-F-I (SEQ ID NO:3); Panaeus monodon tryptic I-V-G-G-T-A-V-T-P-G-E-F-P-Y-Q-L-S-F-Q-D-S-I-E-G-V (SEQ ID NO:4); Panaeus monodon chymotryptic-1; I-V-G-G-V-E-A-V-P-G-V-W-P- Y-Q-A-A-A-S
- PHM- 101 is a purified preparation of a krill multifunctional hydrolase. Methods of purifying the enzyme, as well as preferred characteristics, are described in PCT/US99/14751.
- the inventive method can include pretreatment or simultaneous treatment, or both, ofthe affected tissue with a suitable antibiotic.
- a suitable antibiotic is one that retains its potency when placed in physiological conditions. Some antibiotics are preferred for topical use on tissue, such as, but not limited to ciprofloxacin.
- the antibiotic can be included in the treatment using the polyanionic polymer with or without the multifunctional hydrolase. 6. Hydrolytically susceptible polymers
- polyanionic polymer comprising hydrolytically susceptible bonds comprising: two or more polyanionic polymer segments; linking moieties coupling the polyanionic polymer segments, wherein the linking moieties comprise (I) or (II) below or both: (I) a segment joining joined via amide, ester or thioester bonds incorporating an acyl or acyl analog moiety ofthe polyanionic polymer, wherein the segment comprises: (a) a C t to C
- a linear polyanionic polymer comprising: two or more polyanionic polymer segments each terminating at one or both ends with a linker that is an oxygen or sulfur residue from a hydroxide or thiol moiety; and linker moieties cleavable at internal amide, ester or thioester bonds linking the linkers to form the linear polyanionic polymer.
- the polymer can comprise a monomer moiety which consists of atoms selected from carbon, hydrogen, oxygen and sulfur and comprises carbon and hydrogen.
- a core which is a Cj to C ⁇ 2 (preferably to C ⁇ 0 or to C 5 ) alkylene with three or more (e.g., up to 5 or 6) linking hydroxyls or thiols or a mono or disaccharide with three or more linking hydroxyls is reacted with (b) three or more (e.g., eight) equivalents of a cyclic diester ofthe following formula:
- R 1 and R 2 are independently methylene or ethylene which can be substituted with up to two Ci to C 4 alkyls.
- the resulting multivalent core has a structure with substituents at the former hydroxyls or thiols which are -R 3 n , where n is zero or more (such as zero to eight) with the total sum ofthe n values being at least three to eight (such as three to eight), and R 3 is independently:
- R 1 and R 2 are methylene, which can be substituted.
- the substitution is to C 2 alkyl.
- the terminal hydroxyls from the opened cyclic diester are reacted to substitute the hydroxyl with an ester or ether- linked unsaturated moiety adapted to be reactive in a subsequent free-radical polymerization (which in turn in adapted to yield polyanionic polymer segments).
- this moiety is a ester-linked acryloyl radical, as can be formed for example with acryloylchloride.
- the average of n is preferably 1 or 2.
- the subsequent free radical polymerization is preferably adapted to limit (e.g., with a chain terminator) the polyanionic polymer segments to molecular weights for 90% or more ofthe segments of 50 kd or 40 kd or less. In one embodiment, 95% or 98% or more ofthe segments fall within these size limits.
- the average molecular weight- is from 20 kd to 40 kd, or 25 kd to 35 kd. Appropriate chain terminators are known in the art.
- the polyanionic polymer has polyanionic segments of these sizes crosslinked with multivalent crosslinkers containing hydrolytically susceptible bonds.
- Core moieties can be reacted with compounds of formula (52) at an elevated temperature effective to melt such compounds of formula (52), such as 120°C for lactide, and the reaction conducted over, for example, an 20 or more hours.
- An example of forming the linked moieties adapted to be reactive in a subsequent free-radical polymerization is reacting with acryloylchloride in dichloromethane in the presence of triethylamine at ambient temperature.
- polyanionic polymers include any in which comprise two or more linearly linked polyanionic segments, where the linkages are through hydrolytically susceptible linking moieties connecting to terminal oxo or thio moieties ofthe polyanionic segments, such as those described below under Approach IV.
- the segments fall within one or more ofthe size restraints described here.
- These linear multimers of polyanionic segments can be further crosslinked with hydrolytically susceptible linking moieties.
- polyanionic polymers containing carboxylates, for which a sampling ofthe carboxylate-providing monomers (e.g., 1 of 20) are derivatized to attach -X-R 4 -Y-H via an amide, ester or thioester bond, where X and Y are independently S, O or NH and R 4 is a straight chain CrCio (preferably C
- X and Y are different to provide differential reactivities that facilitate selective addition of one end to the polyanionic polymer.
- linking moiety has the structure:
- R 5 can be or include a segment of PAP (such as PEG), which preferably has molecular weight within the above-described preferred ranges. Aside from PAP, which may not be present, R 5 preferably has molecular weight of less than 5,000, more preferably less than 1,000. A large number of examples of R 5 are described herein.
- the polymers crosslinked with the linking moieties described in the preceding text of this Section 6 or with hydrolytically susceptible bonds and the polyanionic polymer segments sizes described in the preceding text of this Section 6 are " polymers.”
- the linking agents or linking moieties ofthe invention can be obtained via a variety of approaches, such as those detailed below. Generally, most ofthe linking agents or linking moieties are used to create polymers according to the following: Approach I: Formation of degradable cross-linked PAP during free-radical polymerization. Carbomers are formed presently by polymerization of acrylic acid in the presence of a degradable crosslinking agent. The contributions of this Approach I come by design of linking moieties to yield hydrolytically degradable hydrogels.
- One or more hydrolytically susceptible links are placed within the crosslinking agent, e.g. between the sites of polymerizable unsaturation. This is contrasted with the crosslinking agent that is used in commercial Carbomers, (1), which is designed to be hydrolytically stable:
- the anionic monomers it may be advantageous to polymerize the anionic monomers under conditions that the PAP MW is relatively low, approximately 50,000 and less, for example, using chain transfer agents or with high concentrations of initiator.
- bonds that are known to be hydrolytically susceptible within the linking moiety such as esters, amides, carbonates, ureas, and the like.
- bonds that are known to be hydrolytically susceptible within the linking moiety such as esters, amides, carbonates, ureas, and the like.
- bonds that are known to be hydrolytically susceptible within the linking moiety such as esters, amides, carbonates, ureas, and the like.
- bonds that are known to be hydrolytically susceptible within the linking moiety such as esters, amides, carbonates, ureas, and the like.
- a linking agent that contains both a carbonate and an ester, which can be expected to degrade faster than (2), can be prepared from pentaerythritol and hydroxyethylacrylate linked with phosgene:
- LB Degradable linking moieties based on two or more unsaturated sites of polymerization, for example, materials from hydroxyethylacrylate (4) and/or aminoethylacrylate (5):
- dimerization of (4) and (5) with phosgene will yield at least one ofthe following, depending on the dimerized pair:
- anhydride crosslinking agent which can be expected to degrade faster than (10):
- I.D. Degradable linking moieties based on lactic acid or other hydroxy acids: I.D.I.: One can react lactic acid (14)
- I.D.2. One can also use lactyl esters, i.e. dimers of lactic acid, or dimers of other hydroxy acids.
- lactyl esters i.e. dimers of lactic acid, or dimers of other hydroxy acids.
- Like structures can be formed with more than two unsaturated sites of polymerization and with other hydroxy acids.
- ester-containing group can be obtained by reacting PAO with acryloylchloride to obtain (21)
- lactic acid esters such as be reacting PAO diol with lactic acid and phosgene to fo ⁇ n (22):
- n is preferably 10 or less, more preferably 5 or less.
- (26) can be acrylated to yield (27);
- Analogous amide and urea structures can be obtained from PAO diamine. In general, these structures will degrade more slowly than their ester and carbonate analogues.
- the hydroxyl side groups can be cross-linked by reaction with PAO diol activated with phosgene to yield (29):
- PAP derivatize some of side-chain carboxyl groups (or analogous groups) with aminoethane thiolgroups, and cross-links these with a degradable diacrylate linking agent, for example, (21) to yield (30):
- (31) can also be formed from the copolymer with hydroxyethylacrylate and then coupling with PAO after activation ofthe PAO with phosgene.
- ⁇ .D. One can incorporate lactic acid, or other hydroxy acids, in the linkers from the hydroxy 1- containing copolymer (shown here from the hydrolysis product of a copolymer with vinyl acetate) after ring opening of lactide under non-polymerizing conditions to obtain (32):
- (32) can then be coupled with phosgene-activated PAO diol to obtain (33):
- Approach UI Cross-linking of PAP: As in Approach II, one can cross-link or link PAP after polymer-forming reaction.
- HI. A. For example, one can start with PAP, form a small fraction ofthe acid chloride, and cross-link with 1,2-ethanediol, or a similar diol, to obtain (35): O
- the anhydride linked material may be obtained directly (37)
- (38) can be used to cross-link a phosgene-activated homopolymer to obtain (39) or with an acid- chloride activated homopolymer PAP to obtain (40):
- Coupling of short PAP chains via degradable moieties can be used to obtain a linear PAP with a high molecular weight.
- the size ofthe degradable block can be increased by reaction of hydroxyl terminated PAP with, for example, a PAO diol, activated by phosgene to yield (43):
- hydroxyl groups of 2 such polymer segments can be reacted with 1,1'- carbonyldiimidazole (GDI) (or phosgene can be used) to obtain a high molecular weight PAP composed of PAP blocks separated by lactyl moieties, for example, (45):
- GDI 1,1'- carbonyldiimidazole
- (44) can be coupled to (41) in this way, yielding (46):
- IV.B. Degradable linear PAP from PAP segments.
- Example. This example sets forth methods for preparing hydrogel and microgel used in the context of the present invention.
- the microgel is used by itself or in combination with other agents, such as the krill-derived multifunctional hydrolases also set forth herein.
- Carbopol® polyanionic polymers (BFGoodrich Company, Specialty Polymers and Chemicals, Brecksville, OH), diisopropanol amine (Aldrich), distilled water, and 10% sodium hydroxide.
- the final concentrations ofthe component chemicals were: 23.5% w/v Glycerol stock (which is 87% w/w); 0.8% w/v ofthe desired polyanionic polymer; and distilled water and the sodium hydroxide
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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EP00957680A EP1318819A4 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
PCT/US2000/023072 WO2002015913A1 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
CA002425206A CA2425206A1 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
JP2002520834A JP2004506688A (en) | 2000-08-23 | 2000-08-23 | Treatment of injuries and other indications |
BR0017340-1A BR0017340A (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma and other indications |
AU2000269264A AU2000269264A1 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
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PCT/US2000/023072 WO2002015913A1 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
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PCT/US2000/023072 WO2002015913A1 (en) | 2000-08-23 | 2000-08-23 | Treatment of trauma, and other indications |
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EP (1) | EP1318819A4 (en) |
JP (1) | JP2004506688A (en) |
AU (1) | AU2000269264A1 (en) |
BR (1) | BR0017340A (en) |
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Cited By (9)
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JP2005538160A (en) * | 2002-09-04 | 2005-12-15 | ポリヒール リミテッド | Anti-inflammatory microsphere-containing composition for healing ocular tissue |
US7241736B2 (en) | 2003-11-10 | 2007-07-10 | Angiotech International Ag | Compositions and methods for treating diverticular disease |
EP1913948A1 (en) * | 2002-04-30 | 2008-04-23 | Sifi S.p.A | Re-epithelializing pharmaceutical compositions containing xanthan gum |
EP2045321A3 (en) * | 2005-05-27 | 2009-06-17 | Direvo Biotech AG | Serine proteases with altered sensitivity to activity-modulating substances |
CN105555847A (en) * | 2013-09-19 | 2016-05-04 | 微温森公司 | Polymer films |
US9907880B2 (en) | 2015-03-26 | 2018-03-06 | Microvention, Inc. | Particles |
US9938367B2 (en) | 2013-09-19 | 2018-04-10 | Terumo Corporation | Polymer particles |
US10118980B1 (en) | 2013-11-08 | 2018-11-06 | Terumo Corporation | Polymer particles |
US10201632B2 (en) | 2016-09-28 | 2019-02-12 | Terumo Corporation | Polymer particles |
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- 2000-08-23 BR BR0017340-1A patent/BR0017340A/en not_active IP Right Cessation
- 2000-08-23 CA CA002425206A patent/CA2425206A1/en not_active Abandoned
- 2000-08-23 AU AU2000269264A patent/AU2000269264A1/en not_active Abandoned
- 2000-08-23 EP EP00957680A patent/EP1318819A4/en not_active Withdrawn
- 2000-08-23 WO PCT/US2000/023072 patent/WO2002015913A1/en not_active Application Discontinuation
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BR0017340A (en) | 2003-12-09 |
CA2425206A1 (en) | 2002-02-28 |
JP2004506688A (en) | 2004-03-04 |
EP1318819A1 (en) | 2003-06-18 |
AU2000269264A1 (en) | 2002-03-04 |
EP1318819A4 (en) | 2006-03-15 |
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