WO2006124021A1 - Compositions et methodes de traitement de maladies diverticulaires - Google Patents

Compositions et methodes de traitement de maladies diverticulaires Download PDF

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Publication number
WO2006124021A1
WO2006124021A1 PCT/US2005/016871 US2005016871W WO2006124021A1 WO 2006124021 A1 WO2006124021 A1 WO 2006124021A1 US 2005016871 W US2005016871 W US 2005016871W WO 2006124021 A1 WO2006124021 A1 WO 2006124021A1
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Prior art keywords
polymer
composition
poly
agent
collagen
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PCT/US2005/016871
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English (en)
Inventor
William L. Hunter
Philip M. Toleikis
David M. Gravett
Rui Avelar
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Angiotech International Ag
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Priority to PCT/US2005/016871 priority Critical patent/WO2006124021A1/fr
Priority to JP2008511094A priority patent/JP2008540521A/ja
Priority to AU2005331924A priority patent/AU2005331924A1/en
Priority to CA2610948A priority patent/CA2610948C/fr
Priority to EP05772734A priority patent/EP1890739A1/fr
Publication of WO2006124021A1 publication Critical patent/WO2006124021A1/fr

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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
    • 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L31/18—Materials at least partially X-ray or laser opaque
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/30—Compounds of undetermined constitution extracted from natural sources, e.g. Aloe Vera
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/44—Radioisotopes, radionuclides
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the present invention relates generally to pharmaceutical compositions, methods and implants, and more specifically, to compositions, implants, and methods for treating diverticular disease (e.g., diverticulitis).
  • diverticular disease e.g., diverticulitis
  • Diverticular disease is a condition whereby there is herniation of the mucosa and submucosa of a hollow organ, such as the gastrointestinal (Gl) tract, urinary tract, or repiratory tract, which produces outpouchings through the muscular wall of the body passageway.
  • Gl gastrointestinal
  • diverticula can occur in any tubular organ, diverticular disease is of greatest clinical relevance in the lower Gl tract (large bowel or colon), where it can cause life threatening inflammation and infection (diverticulitis) or bleeding (lower Gl hemorrhage).
  • this condition is treated medically or through open surgical removal of the diverticula and/or complete resection of the segment of the bowel that contains them.
  • Diverticular disease (which encompasses diseases such as diverticulosis and diverticulitis) is an important medical condition and is the most common cause of large bleeds in the colon, accounting for 30% to 50% of massive Gl hemorrhage. Diverticular disease results when a small pouch (referred to as a diverticulum) in the colon bulges outward through weak spot. About 10% of Americans over the age 40 have diverticulosis (i.e., the condition of having diverticula), and the condition becomes more common as people age (33% of the population over the age of 60 and 50% of people over 80 have diverticular disease). In many patients, diverticulosis remains asymptomatic.
  • diverticulitis can cause abdominal pain (in particular around the left side of the lower abdomen), peritonitis, abscess formation, and lower Gl bleeding.
  • lower intestinal hemorrhage blood passed via the rectum.
  • the combined mortality and significant morbidity rate associated with diverticular hemorrhage is 10% to 20%, in part due to patient age and comorbidity with other conditions such as cardiac, pulmonary, or renal dysfunction.
  • diverticular bleeds are massive, painless, and self limiting. In 5% of diverticular patients, however, the bleed is substantial enough to cause cardiovascular instablility and may require transfusion.
  • Treatment of diverticular disease generally involves resuscitation, which includes large bore intravenous access, placement of a foley catheter, placement of a nasogastric tube to rule out upper gastrointestinal bleed, and administration of intravenous fluids. Patients are most frequently treated supportively with volume resuscitation, correction of coagulation abnormatlities and blood transfusion, if required. Most active lower Gl bleeds will stop spontaneously.
  • the present invention provides agents, implants, compositions, and methods, for minimally invasive delivery of selected therapeutic, fibrosis-inducing agents, implants, and compositions directly into diverticula for the treatment of patients with diverticular disease.
  • Compositions and implants, including devices, are provided herein for delivery of selected therapeutic agents into diverticula, as well as methods for making and using these agents, compositions, and implants.
  • therapeutic agents or drug-impregnated implants are provided that induce adhesion or fibrosis in the walls of the diverticula or facilitate "filling" of the diverticula in situ; thus obliterating the lumen of the diverticula and relieving symptoms or reducing the risk that subsequent complications will develop.
  • fibrosis is induced within the diverticula by local (intraluminal) or regional release of specific pharmacological agents delivered to the site via endoscopy or catheter-based interventions.
  • the present invention provides a composition comprising (a) a fibrosing agent and (b) a polymer or a compound that forms a crosslinked polymer in situ.
  • the present invention provides a composition comprising a composition comprising a fibrosing agent and a bulking agent.
  • the present invention provides a method for treating a diverticular disease that comprises introducing into a diverticulum in a host, a therapeutically effective amount of a fibrosing agent or a composition comprising a fibrosing agent, wherein the fibrosing agent induces a fibrotic response within the diverticulum, thereby treating diverticular disease in the host.
  • the present invention provides a method for inducing fibrosis in a diverticulum of a host in need thereof that comprises introducing a composition into the diverticulum of the host, said composition comprising a fibrosing agent, wherein the agent induces fibrosis within the diverticulum.
  • the present invention provides a method for treating a diverticular disease that comprises introducing into a diverticulum in a host a composition, said composition comprising (a) fibrosing agent and (b) a polymer or a compound that forms a crosslinked polymer in situ, wherein the compostion induces a fibrotic response within the diverticulum, thereby treating diverticular disease in the host.
  • the present invention provides a method for inducing fibrosis in a diverticulum of a host, comprising inserting a composition into the host, said composition comprising (a) a fibrosing agent and (b) a polymer or a compound that forms a crosslinked polymer in situ, wherein the composition induces fibrosis in the host.
  • the present invention provides a method for making an implant comprising combining (a) a fibrosing agent; (b) a polymer, or a composition comprising a polymer; and (c) an anti-infective agent, wherein the fibrosing agent induces a fibrotic response within a diverticulum.
  • the present invention provides a kit for use in treating a diverticular disease, comprising: (a) a dry powder composition that comprises (i) a first component having a core substituted with m nucleophilic groups, where m>2; and (ii) a second component having a core substituted with n electrophilic groups, where n>2 and m+n>4; wherein the nucleophilic and electrophilic groups are non-reactive in a dry environment but are rendered reactive upon exposure to an aqueous environment such that the componenets inter-react in the aqueous environment to form a three-dimensional composition; (b) a first buffer solution having a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution having a pH within the range of about 6.0 to 11.0; and (d) a third component comprising a fibrosing agent, wherein each component is packaged separately and admixed immediately prior to use.
  • a dry powder composition that comprises (i) a
  • the fibrosing agent may be one or more of the following: a fibrosing agent that promotes cell regeneration, a fibrosing agent that promotes angiogenesis, a fibrosing agent that promotes fibroblast migration, a fibrosing agent that promotes fibroblast proliferation, a fibrosing agent that promotes deposition of extracellular matrix, a fibrosing agent that promotes tissue remodeling, a fibrosing agent that is a diverticular wall irritant, silk (such as silkworm silk, spider silk, recombinant silk, raw silk, hydrolyzed silk, acid-treated silk, and acylated silk), talc, chitosan, polylysine, fibronectin, bleomycin or an analogue or derivative thereof, a fibrosing agent that connective tissue growth factor (CTGF), metallic beryllium or an oxide thereof, copper, saracin, silica, crystalline silicates, quartz dust, tal
  • CTGF connective tissue growth factor
  • one or more of the following polymer may be used alone (as a fibrosing agent) or in combination with each of the fibrosing agents listed above or otherwise described herein: a copolymer, a block copolymer, a random copolymer, a biodegradable polymer, a non-biodegradable polymer, a hydrophilic polymer, a hydrophobic polymer, a polymer having hydrophilic domains, a polymer having hydrophobic domains, a non-conductive polymer, an elastomer, a hydrogel ' , a silicone polymer, a hydrocarbon polymer, a styrene-derived polymer, a butadiene-derived polymer, a macromer, a poly( ethylene glycol), a collagen or a derivative thereof, a methylated collagen, a combination of a collagen or a derivative thereof and a fibrinogen, a combination of a collagen or a
  • one or more of the following anti-infective agents may be used alone (if capable of functioning as a fibrosing agent), with each of the fibrosing agents listed above (or otherwise described herein), with each of the polymers listed above (or otherwise described herein), or with each of the combination of the fibrosing agents listed above (or otherwise described herein) and the polymers listed above (or otherwise described herein): an anthracycline, doxorubicin, mitoxantrone, a fluoropyrimidine, 5-fluorouracil (5-FU), a folic acid antagonist, methotrexate, a podophylotoxin, etoposide, camptothecin, a hydroxyurea, a platinum complex, cisplatin, an antibiotic, doxycycline, metronidazole, trimethoprim- sulfamethoxazole, a fourth generation penicillin (e.g., a urei
  • trimethoprim including cefixime, spectinomycin, tetracycline, nitrofurantoin, polymyxin B, and neomycin sulfate).
  • one or more of the following bulking agents may be used alone (if capable of functioning as a fibrosing agent), with each of the fibrosing agents listed above (or otherwise described herein), with each of the polymers listed above (or otherwise described herein), with each of the combination of the fibrosing agents listed above (or otherwise described herein) and the polymers listed above (or otherwise described herein), with each of the combination of the polymers listed above (or otherwise described herein) and the anti-infective agents listed above (or otherwise described herein), with each of the combination of the fibrosing agents listed above (or otherwise described herein) and the anti-infective agents listed above (or otherwise described herein): an agent or a composition that comprises microspheres, an agent or a composition that comprises a hydroxyapati
  • One aspect of the invention relates to a homogeneous dry powder composition comprised of: a first component having a core substituted with m nucleophilic groups, where m - ⁇ ; and a second component having a core substituted with n electrophilic groups, where n _ ⁇ 2 and m+n>4; wherein the nucleophilic and electrophilic groups are non-reactive in a dry environment but are rendered reactive upon exposure to an aqueous environment such that the components inter-react in the aqueous environment to form a three-dimensional matrix.
  • a pharmaceutically acceptable carrier may also be included.
  • the nucleophilic and electrophilic groups undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both.
  • the nucleophilic groups may be selected from -NH 2 , -NHR 1 , -N(R 1 ) 2> -SH, -OH, -COOH, -C 6 H 4 -OH, -H, -PH 2 , -PHR 1 , -P(R 1 ) 2 , -NH-NH 2 , -CO-NH-NH 2 , and -C 5 H 4 N, where R 1 is a hydrocarbyl group, and each R 1 may be the same or different.
  • the nucleophilic groups are amino groups and the electrophilic groups are amine-reactive groups.
  • the amine-reactive groups may contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine.
  • the amine-reactive groups may be selected from carboxylic acid esters, acid chloride groups, anhydrides, ketones, aldehydes, halo, isocyanato, thioisocyanato, epoxides, activated hydroxyl groups, olefins, carboxyl, succinimidyl ester, sulfosuccinimidyl ester, maleimido, epoxy, and ethenesulfonyl.
  • the nucleophilic groups are sulfhydryl groups and the electrophilic groups are sulfhydryl-reactive groups.
  • the sulfhydryl-reactive groups may be selected so as to form a thioester, imido-thioester, thioether, or disulfide linkage upon reaction with the sulfhydryl groups.
  • the sulfhydryl-reactive groups may have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety.
  • sulfhydryl-reactive groups form a thioether linkage
  • they may be selected from maleimido, substituted maleimido, haloalkyl, epoxy, imino, aziridino, olefins, and ⁇ , ⁇ -unsaturated aldehydes and ketones.
  • the sulfhydryl-reactive groups may be selected from mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N- hydroxyphthalimide esters, N-hydroxysuccinimide esters, N- hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; esters of 1- hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy- 3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.
  • the number of nucleophilic groups in the mixture is approximately equal to the number of electrophilic groups in the mixture.
  • the ratio of moles of nucleophilic groups to moles of electrophilic groups may be about 2:1 to 1 :2, with a ratio of 1 :1 preferred.
  • the core is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C 2- i 4 hydrocarbyls, and heteroatom-containing C-2- 1 4 hydrocarbyls.
  • the core may be a synthetic or naturally occurring hydrophilic polymer.
  • the hydrophilic polymer may be a linear, branched, dendrimeric, hyperbranched, or star polymer.
  • the hydrophilic polymer may be selected from polyalkylene oxides; polyols; poly(oxyalkylene)-substituted diols and polyols; polyoxyethylated sorbitol; polyoxyethylated glucose; poly(acrylic acids) and analogs and copolymers thereof; polymaleic acids; polyacrylamides; poly(olefinic alcohols); poly(N-vinyl lactams); polyoxazolines; polyvinylamines; and copolymers thereof.
  • the hydrophilic polymer may also be selected from proteins, carboxylated polysaccharides, aminated polysaccharides, and activated polysaccharides, such as, for example, collagen and glycosaminoglycans.
  • the hydrophilic polymer is a polyalkylene oxide or polyols
  • the hydrophilic polymer may be selected from polyethylene glycol and poly( ethylene oxide)-poly(propylene oxide) copolymers.
  • the hydrophilic polymer is a polyols
  • the hydrophilic polymer may be selected from glycerol, polyglycerol and propylene glycol.
  • the hydrophilic polymer is a poly(oxyalkylene)-substituted polyol
  • the hydrophilic polymer may be selected from mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di- polyoxyethylated trimethylene glycol.
  • the hydrophilic polymer is a poly(acrylic acid), analog or copolymer thereof
  • the hydrophilic polymer may be selected from poly(acrylic acid), poly(methacrylic acid), poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide acrylates), and poly(methylalkylsulfoxide methacrylates).
  • the hydrophilic polymer is a polyacrylamide
  • the hydrophilic polymer may be selected from polyacrylamide, poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropylacrylamide), and copolymers thereof.
  • the hydrophilic polymer is a poly(olefinic alcohol)
  • the hydrophilic polymer may be selected from polyvinyl alcohols) and copolymers thereof.
  • the hydrophilic polymer is a poly(N-vinyl lactam)
  • the hydrophilic polymer may be selected from poly( vinyl pyrrolidones), polyvinyl caprolactams), and copolymers thereof.
  • the hydrophilic polymer is a polyoxazoline
  • the hydrophilic polymer may be selected from poly(methyloxazoline) and poly(ethyloxazoline).
  • the core is a hydrophobic polymer selected
  • the core may be selected from polylactic acid and polyglycolic acid.
  • the core is a C 2- - I4 hydrocarbyl
  • the core may be selected from alkanes, diols, polyols, and polyacids.
  • the core is a heteroatom-containing C 2- - I4 hydrocarbyl
  • the core may be selected from di- and poly-electrophiles.
  • the first component has the structure of formula (I)
  • the components may inter-react to form covalent bonds, noncovalent bonds, or both. Noncovalent bonds include ionic bonds, hydrogen bonds, or the association of hydrophobic molecular segments. In one preferred embodiment, all of the molecular segments are the same.
  • the homogeneous dry powder composition may further comprise a biologically active agent with or without a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a micelle, a microsphere, or a nanosphere.
  • the pharmaceutically acceptable carrier may be a degradable polymer, such as a polyester, and the polyester may be a glycolide/lactide copolymer.
  • the degradable polymer may also be comprised of residues of one or more monomers selected from the group consisting of lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, ⁇ -decanolactone, ⁇ -decanolactone, trimethylene carbonate, 1 ,4- dioxane-2-one or 1 ,5-dioxepan-2one.).
  • the homogeneous dry powder composition may further comprise a biologically active agent.
  • the biologically active agent is a fibrosing agent or a composition comprising a fibrosis agent.
  • the fibrosing agent is in another embodiment of the invention, the homogeneous dry powder composition further comprises a biologically active agent that is a fibrosing agent.
  • the anti-fibrotic agent may be used to promote any of the following; regeneration; angiogenesis; fibroblast migration; fibroblast proliferation; deposition of extracellular matrix (ECM); and tissue remodeling.
  • the fibrosing agent may also be used as a diverticular wall irritant.
  • Fibrosing agents that may be used in the homogeneous dry powder composition may be or may be comprised of silk; silkworm silk; spider silk; recombinant silk; raw silk; hydrolyzed silk; acid-treated silk; acylated silk; mineral particles; talc; chitosan; polylysine; fibronectin; bleomycin; or CTGF.
  • the fibrosing agent may also be in the form of a particulate, which may be a biodegradable particulate or a non-biodegradable particulate.
  • Biodegradable particulates may be comprised of a material selected from the group consisting of polyester, polyanhydride, poly(anhydride ester), poly(ester-amide), poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut, alginate, starch, cellulose and cellulose ester.
  • Non-biodegradable particulates may be comprised of a material selected from the group consisting of polyester, polyurethane, silicone, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylate, and silk.
  • preferred particulates may be a particulate form of a member selected from the group consisting of silk, talc, starch, glass, silicate, silica, calcium phosphate, calcium sulfate, calcium carbonate, hydroxyapatite, synthetic mineral, polymethylmethacrylate, silver nitrate, ceramic and other inorganic particles.
  • the biologically active agent promotes bone growth.
  • the fibrosing agent may promote the bone growth.
  • Fibrosing agents that may promote bone growth may include a bone morphogenic protein and an osteogenic growth factor, the latter which may be selected from transforming growth factor, platelet-derived growth factor, and fibroblast growth factor.
  • the homogeneous dry powder composition with a fibrosing agent further comprises a pharmaceutical agent that induces sclerosis (a sclerosant), wherein the sclerosant may be a surfactant or it may be selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol.
  • a sclerosant may be a surfactant or it may be selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol.
  • the homogeneous dry powder composition with a fibrosing agent further comprises an inflammatory cytokine, which may be selected from the group consisting of TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-a, IL-1 , IL-1- ⁇ , IL-8, IL-6, and growth hormone.
  • an inflammatory cytokine which may be selected from the group consisting of TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM-CSF, IGF-a, IL-1 , IL-1- ⁇ , IL-8, IL-6, and growth hormone.
  • the homogeneous dry powder composition with a fibrosing agent further comprises an agent that stimulates cell proliferation, which may be selected from the group consisting of dexamethasone, isotretinoin (13-cis retinoic acid), 17- ⁇ -estradiol, estradiol, 1- ⁇ - 25 dihydroxyvitamin D 3 , diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid (ATRA), and analogues and derivatives thereof.
  • an agent that stimulates cell proliferation which may be selected from the group consisting of dexamethasone, isotretinoin (13-cis retinoic acid), 17- ⁇ -estradiol, estradiol, 1- ⁇ - 25 dihydroxyvitamin D 3 , diethylstibesterol, cyclosporine A, L-NAME, all-trans retinoic acid (ATRA), and analogues and derivatives thereof.
  • the biologically active agent is mixed with the first and second components to form a mixture.
  • the biologically active agent is chemically coupled to the first component or to the second component.
  • the selected amino acid residues are lysine.
  • the selected amino acid residues are cysteine.
  • Yet another aspect of the invention relates to a crosslinkable composition
  • a crosslinkable composition comprised of: (a) a first crosslinkable component having m nucleophilic groups, wherein m ⁇ ; and (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n ⁇ and m+n _-5, the first component comprises two or more amino acid residues selected from the group consisting of amino acids comprising primary amine groups and amino acids comprising thiol groups, the second component comprises a polyethylene glycol moiety, the electrophilic groups are succinimidyl moieties, and each of the first and second crosslinkable components is biocompatible, synthetic, and nonimmunogenic, and further whererin crosslinking of the composition results in a biocompatible, nonimmunogenic, crosslinked matrix.
  • the selected amino acid residues are lysine.
  • the selected amino acid residues are cysteine.
  • Still another aspect of the invention relates to a crosslinkable composition
  • a crosslinkable composition comprised of: (a) a first crosslinkable component having m nucleophilic groups, wherein m ⁇ ; and (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n __2 and m+n ⁇ >, the first component comprises two or more amino acid residues selected from the group consisting of amino acids comprising primary amine groups and amino acids comprising thiol groups, the second component comprises a multifunctionally activated polyethylene glycol, and each of the first and second crosslinkable components is biocompatible, synthetic, and nonimmunogenic, and further wherein crosslinking of the composition results in a biocompatible, nonimmunogenic, crosslinked matrix.
  • the selected amino acid residues are lysine.
  • the selected amino acid residues are cysteine.
  • Another aspect of the invention relates to a method of forming a three-dimensional matrix comprising the steps of: (a) providing a composition of the invention; and (b) rendering the nucleophilic and electrophilic groups reactive by exposing the composition to an aqueous environment to effect inter-reaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and (c) allowing a three-dimensional matrix to form.
  • a preferred composition for use in this method is the homogeneous dry powder composition.
  • the three- dimensional matrix of the invention described immediately above may be formed without input of any external energy or by polymerization.
  • the pH of the first buffer solution is selected to retard the reactivity of the nucleophilic groups on the first component by rendering the nucleophilic groups relatively non-nucleophilic.
  • the second buffer solution neutralizes the effect of the first buffer solution, so that the nucleophilic groups of the first component regain their nucleophilic character and inter-react with the electrophilic groups of the second component.
  • the composition, first buffer solution and second buffer solution are housed separately in a multiple- compartment syringe system having a multiple barrels, a mixing head, and an exit orifice; step (b)(i) comprises adding the first buffer solution to the barrel housing the composition to dissolve the composition and form a homogeneous solution, and extruding the homogeneous solution into the mixing head; step (b)(ii) comprises simultaneously extruding the second buffer solution into the mixing head; and step (c) further comprises extruding the resulting composition through the orifice onto a surface.
  • Yet another aspect of the invention relates to a method of sealing tissue of a patient comprising the steps of: (a) providing a composition of the invention; (b) rendering the nucleophilic and electrophilic groups reactive by exposing the composition to an aqueous environment to effect inter-reaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution to form a mixture; and (c) placing the mixture into contact with tissue and allowing a three-dimensional matrix to form and seal the tissue.
  • a preferred composition for use in this method is the homogeneous dry powder composition.
  • a further aspect of the invention relates to a method of forming a three-dimensional matrix on a surface of a device comprising the steps of: (a) providing a composition of the invention; and (b) rendering the nucleophilic and electrophilic groups reactive by exposing the composition to an aqueous environment to effect inter-reaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and applying the homogeneous solution to a surface of a device; and allowing the three-dimensional matrix to form.
  • a preferred composition for use in this method is the homogeneous dry powder composition.
  • Yet another aspect of the invention relates to a method of promoting scarring in the vicinity of a medical implant comprising the steps of: (a) providing a composition of the invention; (b) rendering the nucleophilic and electrophilic groups reactive by exposing the composition to an aqueous environment to effect inter-reaction; wherein said exposure comprises: (i) dissolving the composition in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution; and (c) applying the mixture to a surface of a medical implant and allowing a three-dimensional matrix to form on the surface of the medical implant; and (d) placing the medical implant into an animal host, wherein release of the fibrotic agent from the matrix inhibits scarring in the animal host.
  • the fibrotic agent is released into tissue in the vicinity of the implant after deployment of the implant.
  • a further aspect of the invention relates to a kit for use in medical applications, comprising: (a) a homogeneous dry powder composition comprised of: (i) a first component having a core substituted with m nucleophilic groups, where m . ⁇ ; and (ii) a second component having a core substituted with n electrophilic groups, where n _ ⁇ _ and m+n>4; wherein the nucleophilic and electrophilic groups are non-reactive in a dry environment but are rendered reactive upon exposure to an aqueous environment such that the components inter-react in the aqueous environment to form a three-dimensional matrix; (b) a first buffer solution having a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution having a pH within the range of about 6.0 to 11.0; wherein each component is packaged separately and admixed immediately prior to use.
  • a homogeneous dry powder composition comprised of: (i) a first component having a core
  • kits for use in medical applications comprising: (a) a composition of the invention; (b) a first buffer solution having a pH within the range of about 1.0 to 5.5; and (c) a second buffer solution having a pH within the range of about 6.0 to 11.0, wherein each component is packaged separately and admixed immediately prior to use.
  • a preferred composition of the invention for use in this kit is the homogeneous dry powder composition. It is preferred that each component of the kit is in a separate sterile package.
  • the kit may further comprise a delivery device, which in one embodiment, may be a multi-compartment device.
  • a preferred multicompartment device of the invention is a multiple-compartment syringe system having multiple barrels, a mixing head, and an exit orifice.
  • the homogeneous dry powder composition, the first buffer solution, and the second buffer solution are housed separately in the multiple-compartment syringe system.
  • the delivery device is a pressurized delivery system.
  • a preferred pressurized delivery system comprises: a plurality of fluid component inlets each adapted to communicate with a source of different fluid components; at least one carrier fluid inlet adapted to communicate with a source of a pressurized carrier fluid; a diffuser surface located downstream from the plurality of fluid component inlets and the at least one carrier fluid inlet; and an outlet extending through the diffuser surface, wherein the diffuser surface is adapted to receive fluid components thereon and has a shape effective to direct and maintain each received fluid component in a different flow path toward the outlet for mixing and dispensing therethrough by the pressurized carrier fluid from the at least one carrier fluid inlet.
  • a preferred pressurized carrier fluid is pressurized air and the preferred fluid components are the first buffer solution and the second buffer solution of the invention.
  • kits for use in medical applications further comprises a biologically active agent and the medical application involves delivering the biologically active agent.
  • the biologically active agent may be packaged with the homogeneous dry powder composition and may further comprise a pharmaceutically acceptable carrier packaged with the biologically active agent and the homogeneous dry powder composition.
  • the biologically active agent may also be packaged as a solution with the first buffer or as a solution with the second buffer.
  • the kit may further comprise a pharmaceutically acceptable carrier as a fourth component.
  • the biologically active agent is packaged with the pharmaceutically acceptable carrier.
  • Figure 1 is a graph showing the effect of cyclosporine A on proliferation of human smooth muscle cells.
  • Figure 2 is a graph showing the effect of dexamethasone on proliferation of human fibroblasts.
  • Figure 3 is a graph showing the effect of all-trans retinoic acid (ATRA) on proliferation of human smooth muscle cells.
  • ATRA all-trans retinoic acid
  • Figure 4 is a graph showing the effect of isotretinoin on proliferation of human smooth muscle cells.
  • Figure 5 is a graph showing the effect of 17- ⁇ -estradiol on proliferation of human fibroblasts.
  • Figure 6 is a graph showing the effect of 1 ⁇ ,25-dihydroxy-vitamin D 3 on proliferation of human smooth muscle cells.
  • Figure 7 is a graph showing the effect of PDGF-BB on smooth muscle cell migration.
  • Figure 8 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk coated perivascular polyurethane (PU) films relative to arteries exposed to uncoated PU films.
  • PU perivascular polyurethane
  • Figure 9 is a bar graph showing the area of granulation tissue in carotid arteries exposed to silk suture coated perivascular PU films relative to arteries exposed to uncoated PU films.
  • Figure 10 is a bar graph showing the area of granulation tissue in carotid arteries exposed to natural and purified silk powder and wrapped with perivascular PU film relative to a control group in which arteries are wrapped with perivascular PU film only.
  • Figure 11 is a bar graph showing the area of granulation tissue (at
  • Figure 12 is a bar graph showing indicating the area of perivascular granulation tissue quantified by computer-assisted morphometric analysis in rat carotid arteries treated with control uncoated PU films and with PU films treated with degummed and virgin silk strands. As shown in the figure, both types of silk markedly increased granulation tissue growth around the blood vessel to the same extent.
  • Figure 13 shows representative histology sections of rat carotid arteries treated with PU films coated with degummed and virgin silk strands. As shown in the figure, both types of silk induced a marked tissue reaction around the treated blood vessel. Movat stain, 100X.
  • Figure 14 shows representative histology sections of rat carotid arteries treated with PU films coated with degummed and virgin silk strands showing the granulation tissue that had grown around the treated vessels.
  • the silk strands had broken down into small particles surrounded by giant cells and macrophages.
  • the granulation tissue was highly vascularized and contained numerous inflammatory cells and fibroblasts. Extracellular matrix deposition was also extensive. H&E stain 200X.
  • Figure 15 shows the release profile for cyclosporine A from a polyurethane film as analyzed by HPLC.
  • the present invention provides minimally invasive, endoluminal, and endoscopic procedures that can be used to close, temporarily or permanently, diverticula through the administration of pharmacological compositions that induce scarring of the lumen of the diverticula and elimination of the diverticular sac.
  • implants, procedures, and therapeutic compositions are provided for treatment of diverticula using endoscopic and imaging-guided interventions.
  • pharmaceutical agents that promote one or more aspects of the production of fibrous (scar) tissue or tissue regeneration.
  • compositions and methods are described for administering fibrosis-inducing agents and drug- delivery compositions such that the pharmaceutical agent is delivered in therapeutic levels over a time period sufficient for fibrosis and healing to occur.
  • Numerous specific implants are described that produce superior clinical outcomes by promotion of scarring and healing of diverticula.
  • Medical implant refers to a device or object or composition that is implanted (completely or partially) or inserted into a body. Accordingly, an implant refers to any object or composition placed in the body for the purpose of restoring physiological function, reducing/alleviating symptoms associated with disease, and/or repairing/replacing damaged or diseased organs and tissues.
  • Diverticulitis refers to diseases such as diverticulosis and diverticulitis. Diverticular disease results when a small pouch (referred to as a diverticulum) in the colon bulges outward through weak spot. The condition of having diverticula is called diverticulosis. When the pouches become infected or inflamed, the condition is called diverticulitis. Diverticulitis can cause abdominal pain, in particular, around the left side of the lower abdomen, and lower Gl bleeding. Often the site of the herniations is the same site of penetration for a nutrient artery, leading to the approximation of the neck of the sack and arterial supply.
  • Fibrosis refers to the formation of fibrous tissue in response to injury or medical intervention.
  • Four general components to the process of fibrosis (or scarring) include (1 ) formation of new blood vessels (angiogenesis); (2) migration and proliferation of fibroblasts; (3) deposition of extracellular matrix (ECM); and (4) remodeling (maturation and organization of the fibrous tissue).
  • Therapeutic agents which promote also referred to interchangeably herein as induce, stimulate, cause, increase, accelerate, and the like
  • fibrosis-inducing agents are referred to interchangeably herein as "fibrosis-inducing agents," “scarring agents,” “fibrosing agents,” “adhesion-inducing agents,” and the like.
  • These agents promote fibrosis through one or more mechanisms including, for example, inducing or promoting angiogenesis, stimulating migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), inducing extracellular matrix (ECM) production, and promoting tissue remodeling.
  • connective tissue cells such as fibroblasts, smooth muscle cells, vascular smooth muscle cells
  • ECM extracellular matrix
  • numerous therapeutic agents described herein can have the additional benefit of promoting tissue regeneration (the replacement of injured cells by cells of the same type).
  • sclerosing refers to a tissue reaction in which an irritant is applied locally to a tissue that results in an inflammatory reaction and is followed by scar tissue formation at the site of irritation.
  • a pharmaceutical agent that induces or promotes sclerosis is referred to as a "sclerosant,” or a “sclerosing agent.”
  • sclerosants include ethanol, dimethyl sulfoxide, surfactants (e.g., Triton X, sorbitan monolaurate, sorbitan sesquioleate, glycerol monostearate and polyoxyethylene, polyoxyethylene cetyl ether, etc.), sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, ethanolamine, phenol, sarapin and sotradecol.
  • surfactants e.g., Trit
  • Radiographic guidance refers to the placement of a drug delivery cathether, medical device, implant, biomaterial, therapeutic agent, access port or device and the like using medical imaging for guidance and to confirm accurate placement. Imaging technology is used to allow manipulation and intervention in a minimally invasive fashion (i.e., so as not to require open surgery). Any imaging technology can be used depending on the tissue being treated, but includes, for example, x-ray, angiography, MRI, CT scanning, ultrasound, PET scanning, and nuclear medicine scanning.
  • Endoscopic guidance refers to the placement of a drug delivery cathether, medical device, implant, biomaterial, therapeutic agent, access port or device and the like using endoscopy for direct visualization of the target tissue for guidance and to confirm accurate placement.
  • Endoscopes are used to allow direct visualization in a minimally invasive fashion (i.e., so as not to require open surgery) by inserting a small camera into the body via an orifice (mouth, anus) or a small incision. Any endoscopic technology can be used depending on the tissue being treated, but includes, for example, flexible endoscopes, rigid endoscopes, gastroscopes, ERCP, bronchoscopes, proctoscopes, angioscopes, and colonoscopes.
  • inter-react and “inter-reaction” as used herein refer to the formation of covalent bonds, noncovalent bonds, or both.
  • the term thus includes crosslinking, which involves both intermolecular crosslinks and optionally intramolecular crosslinks as well, arising from the formation of covalent bonds. Entanglement is another example of non-covalent bonding that may result after inter-reaction between two or more reactive groups.
  • Covalent bonding between two reactive groups may be direct in which case an atom in reactive group is directly bound to an atom in the other reactive group or it may be indirect through a linking group.
  • Noncovalent bonds include ionic (electrostatic) bonds, hydrogen bonds, or the association of hydrophobic molecular segments, which may be the same or different.
  • a crosslinked matrix may, in addition to covalent bonds, also include such intermolecular and/or intramolecular noncovalent bonds.
  • hydrophilic and hydrophobic are generally defined in terms of an HLB value, i.e., a hydrophilic lipophilic balance.
  • a high HLB value indicates a hydrophilic compound, while a low HLB value characterizes a hydrophobic compound.
  • HLB values are well known in the art, and generally range from 1 to 18.
  • Preferred multifunctional compound cores are hydrophilic, although as long as the multifunctional compound as a whole contains at least one hydrophilic component, crosslinkable hydrophobic components may also be present.
  • aqueous medium includes solutions, suspensions, dispersions, colloids, and the like containing water.
  • aqueous environment means an environment containing an aqueous medium.
  • dry environment means an environment that does not contain an aqueous medium.
  • active agent biologically active agent
  • therapeutic agent pharmaceutically active agent
  • drug drug
  • the terms include agents that are therapeutically effective as well as prophylactically effective. Also included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired effect.
  • compositions, implants, and methods for treating diverticular disease Described in more detail below are therapeutic agents; compositions and implants for delivering the therapeutic agents; and methods for treating diverticulitis using the agents and compositions discussed herein.
  • therapeutic agents also referred to herein as 'therapeutic agents' or 'drugs'
  • the agent may be formulated with one or more other materials, e.g., a polymeric carrier, which formulations are discussed below.
  • a polymeric carrier which formulations are discussed below.
  • therapeutic agents are specifically identified herein, and others may be readily determined based upon in vitro and in vivo (animal) models such as those provided in the Examples.
  • Therapeutic agents that promote fibrosis can be identified through in vivo models such as the rat carotid artery model.
  • One or more therapeutic agents may be introduced into a host for treatment of diverticular disease.
  • a host may be a mammal, which may be a human (such as a patient or subject in need of treatment or a non-human mammal.
  • exemplary non-human mammals include, but are not limited to, a non-human primate, a rodent (e.g., rat, mouse, rabbit, hamster), a cat, dog, horse, pig, bovine, sheep, or goat.
  • a host in need of treatment is a host who has developed or is at risk for developing a diverticular disease.
  • a fibrosis-inducing pharmacologic agent or an implant adapted to include or to release an agent that induces fibrosis is administered onto or into diverticula.
  • a medical implants is provided that comprises at least one of (i) a fibrosis-inducing agent (fibrosing agent) and (ii) a composition that comprises a fibrosis-inducing agent.
  • the fibrosing agent When placed within diverticula, the fibrosing agent is capable of inducing fibrosis formation that would otherwise not occur.
  • methods for inducing a fibrosis in a diverticulum and for treating a diverticular disease, wherein a fibrosis-inducing agent and/or an implant/composition that comprises a fibrosis-inducing agent, are placed into a host (e.g., a mammal) having diverticula.
  • a host e.g., a mammal
  • a therapeutic agent includes a fibrosis-inducing agent that is a diverticular wall irritant, for example, talcum powder, metallic beryllium and oxides thereof, copper, silk, coated silk sutures, uncoated silk sutures, virgin silk, degummed silk, saracin, silica, crystalline silicates, talc, quartz dust, and ethanol; a component of extracellular matrix; fibronectin, collagen, fibrin, or fibrinogen.
  • a fibrosis-inducing agent that is a diverticular wall irritant, for example, talcum powder, metallic beryllium and oxides thereof, copper, silk, coated silk sutures, uncoated silk sutures, virgin silk, degummed silk, saracin, silica, crystalline silicates, talc, quartz dust, and ethanol; a component of extracellular matrix; fibronectin, collagen, fibrin, or fibrinogen.
  • a fibrosis-inducing agent may also be poly(ethylene terephthalate (Dacron), polylysine, poly(ethylene-co-vinylacetate), chitosan, N-carboxybutylchitosan, an RGD protein, or a polymer of vinyl chloride.
  • Therapeutic agents include adhesives, such as cyanoacrylates and crosslinked poly( ethylene glycol) - methylated collagen and may also include an inflammatory cytokine (e.g., TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM- CSF, IGF-a, IL-1 , IL-8, IL-6, and growth hormone); connective tissue growth factor (CTGF); a bone morphogenic protein (BMP) (e.g., BMP-2, BMP-3, BMP- 4, BMP-5, BMP-6, or BMP-7); and bleomycin or an analogue or derivative thereof.
  • an inflammatory cytokine e.g., TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF, GM- CSF, IGF-a, IL-1 , IL-8, IL-6, and growth hormone
  • CTGF connective tissue growth factor
  • BMP bone morphogenic protein
  • BMP-7 e
  • a fibrosis-inducing agent also includes a proliferative agent that stimulates cellular proliferation, for example, dexamethasone, isotretinoin, 17- ⁇ - estradiol, estradiol, diethylstibesterol, cyclosporine A, a//-trans retinoic acid (ATRA), and analogues and derivatives thereof.
  • a proliferative agent that stimulates cellular proliferation for example, dexamethasone, isotretinoin, 17- ⁇ - estradiol, estradiol, diethylstibesterol, cyclosporine A, a//-trans retinoic acid (ATRA), and analogues and derivatives thereof.
  • the fibrosis or adhesion-inducing agent suitable for use in the treatment of diverticula is silk.
  • Silk refers to a fibrous protein, and may be obtained from a number of sources, typically spiders and silkworms. Typical silks contain about 75% of actual fiber, referred to as fibroin, and about 35% sericin, which is a gummy protein that holds the filaments together.
  • Silk filaments are generally very fine and long - as much as 300-900 meters long.
  • Bombyx mori is the most common, and most silk comes from this source.
  • silkworms include Philosamia cynthia ricini, Antheraea yamamai, Antheraea pernyi, and Antheraea mylitta.
  • Spider silk is relatively more difficult to obtain, however, recombinant techniques hold promise as a means to obtain spider silk at economical prices (see, e.g., U.S. Patent Nos. 6,268,169; 5,994,099; 5,989,894; and 5,728,810, which are exemplary only).
  • Biotechnology has allowed researchers to develop other sources for silk production, including animals ⁇ e.g., goats) and vegetables (e.g., potatoes). Silk from any of these sources may be used in the present invention.
  • a commercially available silk protein is available from Croda, Inc., of Parsippany, N.J., and is sold under the trade names CROSILK LIQUID (silk amino acids), CROSILK 10,000 (hydrolyzed silk), CROSILK POWDER (powdered silk), and CROSILKQUAT (cocodiammonium hydroxypropyl silk amino acid).
  • CROSILK LIQUID sik amino acids
  • CROSILK 10,000 hydrolyzed silk
  • CROSILK POWDER powdered silk
  • CROSILKQUAT cocodiammonium hydroxypropyl silk amino acid
  • SERICIN available from Pentapharm, LTD, a division of Kordia, BV, of the Netherlands. Further details of such silk protein mixtures can be found in U.S. Patent. No. 4,906,460, to Kim, et al., assigned to Sorenco.
  • Silk useful in the present invention includes natural (raw) silk, hydrolyzed silk, and modified silk, i.e., silk that has undergone a chemical, mechanical, or vapor treatment, e.g., acid treatment or acylation (see, e.g., U.S. Patent No. 5,747,015).
  • a chemical, mechanical, or vapor treatment e.g., acid treatment or acylation
  • Raw silk is typically twisted into a strand sufficiently strong for weaving or knitting.
  • Four different types of silk thread may be produced by this procedure: organzine, crepe, tram and thrown singles.
  • Organzine is a thread made by giving the raw silk a preliminary twist in one direction and then twisting two of these threads together in the opposite direction.
  • Crepe is similar to organzine but is twisted to a much greater extent. Twisting in only one direction two or more raw silk threads makes tram. Thrown singles are individual raw silk threads that are twisted in only one direction. Any of these types of silk threads may be used in the present invention.
  • the silk used in the present invention may be in any suitable form that allows the silk to be joined with the medical implant applied to the diverticula, for example, the silk may be in thread or powder-based forms.
  • the silk can be prepared in the powdered form by several different methods. For example the silk can be milled (e.g., cryomill) into a powdered form. Alternatively the silk can be dissolved in a suitable solvent (e.g., HFIP or 9M LiBr) and then sprayed (electrospray, spray dry) or added to a non-solvent to produce a powder.
  • a suitable solvent e.g., HFIP or 9M LiBr
  • the silk may have any molecular weight, where various molecular weights are typically obtained by the hydrolysis of natural silk, where the extent and harshness of the hydrolysis conditions determines the product molecular weight.
  • the silk may have an average (number or weight) molecular weight of about 200 to 5,000. See, e.g., JP-B-59-29199 (examined Japanese patent publication) for a description of conditions that may be used to hydrolyze silk.
  • the silk may be virgin silk, partially degummed, or degummed silk.
  • the silk can also further comprise a coating.
  • the coating may be a silicone-based coating, a wax based coating, or a degradable polymer based coating.
  • the fibrosis-inducing agent is a fibroin protein, or a fragment or fragments thereof.
  • the fibroin protein may be a synthetic analogue that is made and that has one or more of the known repeat sequences of the fibroin protein.
  • the fibrosing agent is sarecin.
  • Sarecin is a component of virgin silk that can be used to assist in the induction of a fibrotic response.
  • fibrosing agents include CTGF (connective tissue growth factor); inflammatory microcrystals (e.g., crystalline minerals such as crystalline silicates); bromocriptine, methylsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol, bleomycin, naturally occurring or synthetic peptides containing the Arg-Gly-Asp (RGD) sequence, generally at one or both termini (see, e.g., U.S. Patent No.
  • CTGF connective tissue growth factor
  • inflammatory microcrystals e.g., crystalline minerals such as crystalline silicates
  • bromocriptine methylsergide, methotrexate, chitosan, N-carboxybutyl chitosan, carbon tetrachloride, thioacetamide, fibrosin, ethanol,
  • fibrosis-inducing agents include bone morphogenic proteins ⁇ e.g., BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VgM ), BMP-7 (OP-1 ), BMP-8, BMP-9, BMP-10, BMP-11 , BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.
  • BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of particular utility.
  • Bone morphogenic proteins are described, for example, in U.S. Patent Nos.
  • one fibrosis-inducing agent is a wool.
  • the term “wool” refers to an entangled mass of fibers without any ordered arrangement, while the term “fiber” refers to a particle with a length to diameter ratio (“aspect ratio”) of at least about 3:1 and roughly parallel edges.
  • Wool that may be used in the compositions and methods described herein induces an enhanced fibrotic response between the medical implant and the tissue adjacent to the in vivo medical implant.
  • the medical implant would generate a "normal" adhesion between the adjacent tissue and the medical implant, while in the presence of the wool, the same medical implant is capable of generating an enhanced adhesion (e.g., via an enhanced matrix deposition response to the presence of the wool).
  • Wool useful as a fibrosis inducing agent may be obtained or prepared from natural sources (e.g., animal wool and wood wool). Alternatively, it may be artificially synthesized (e.g., polymeric wool and mineral wool).
  • Animal wool refers to animal hair fibers, typically derived from the fleece of sheep or lamb, goat (e.g., Angora and Cashmere), camel, alpaca, llama, vicuna, or the like. Animal wool is a dead tissue that has a complex morphological and chemical structure, which make it unique among textile fibers. Morphologically, wool fibers are biological composites, with each component having a different physical and chemical composition. Wool fibers are generally composed of three different types of spindle-shaped cortical cells surrounded by a sheath of overlapping, rectangular cell known as the cuticle, which forms the external layer of the fiber. Approximately 90% of the cortical cell type is made up of longitudinally arrayed intermediate filaments with accompanying matrix.
  • Animal wool fibers exhibit a range of diameters, lengths, and crimp (i.e., a measure of fiber curvature), which allows the wool fibers to entrap air.
  • Animal wool is also hygroscopic and is able to absorb and desorb large amounts of water as the relative humidity surrounding the fiber changes. Furthermore, animal wool liberates heat if it absorbs water. These properties contribute to animal wool's extraordinary insulating quality.
  • Animal wool belongs to a family of proteins called a-keratins, which also include materials such as hooves, horns, nails, claws, and beak.
  • a characteristic feature of a-keratins (also referred to as "hard” keratins) is a higher concentration of sulfur than "soft” keratins, such as those in the skin.
  • Clean animal wool contains about 82% keratinous proteins that are high in sulfur content, and about 17% of the fiber is protein with a relatively low sulfur content ( ⁇ 3%).
  • the sulfur in wool occurs in the form of the amino acid cysteine. Due to the high cysteine content, animal wool is highly cross-linked by disulfide bonds that render it essentially insoluble.
  • animal wool contains about 170 different types of polypeptides varying in relative molecular mass from below 10,000 to greater than 50,000.
  • the groups of proteins that constitute animal wool are not uniformly distributed throughout the fiber but are aggregated within various regions.
  • Animal wool also contains about 1% non- proteinaceous material that consists mainly of free and structural lipids and polysaccharide materials, trace elements, and pigments (e.g., melanin).
  • Animal wool is usually harvested from animals by annual shearing.
  • the fiber length is determined largely by the rate of growth, which in turn depends on both genetic and environmental factors. For instance, typical merino fibers are 50-125 mm long and have irregular crimp (curvature).
  • Animal wool fibers exhibit a range of diameters, which also depend on both genetics and environment. For example, coarse wool fibers generally have a diameter of 25-70 mm, while fine merino fibers typically have a diameter of 10- 25 mm.
  • wood wool is a specially prepared, non-compressed wood fiber frequently used in surgical dressings and packaging materials. Wood wool fibers also can be obtained from pine needles.
  • Synthetic wool includes, for example, mineral wools, such as glass wool, stone wool, and slag wool, and wool made from polymeric materials.
  • Mineral wool may be formed, for example, from a molten, inorganic material such as glass, stone, or slag that is spun into a fiber-like structure. Inorganic rock or slag is the main component (typically 98%) of stone wool. The remaining 2% organic content is generally a thermosetting resin binder (an adhesive) and a small amount of oil. Glass wool products usually contain about 95% inorganic material.
  • Glass wool is made from sand or recycled glass, limestone, and soda ash,which are the same ingredients used for familiar glass objects such as window panes or glass bottles. Glass fiber may, additionally, include a small amount of boron. Stone wool can be made from volcanic rock, typically basalt or dolomite. Slag wool is made from blast furnace slag (waste).
  • wool fibers have an average length of about, or at least about, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 mm or longer. In certain embodiments, the lengths of wool fibers are in a range of about 1-5 mm, 5-10 mm, 10-50 mm, 50-100 mm, 1-10 mm, 1-50 mm, or 1-
  • wool fibers have an average diameter of about, or at least about, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or
  • the diameters of wool fibers are in a range of about 1-3 mm, 3-5 mm, 5-10 mm, 10-50 mm, 1-10 mm, or 1-50 mm. In certain embodiments, the average length to diameter ratio of wool fibers is 3:1 , 4:1,
  • wool may be further processed into other forms or shapes, for example, sheet, powder, thread, braid, filament, fiber, film, foam, and the like. In certain embodiments, the wool is further processed into threads or powder. In certain other embodiments, the wool is further processed into the form of a spiral or coil.
  • Wool may be used alone or may be used in combination with a medical implant, such as described herein.
  • wool may be used in combination with one or more of other fibrosis inducing agents described herein.
  • Wool may be secured to a medical implant by any of a number of methods. Suitable methods include, without limitation, interweaving the wool into the implant, interweaving the wool into the implant structure; attaching the wool to the implant via knotting or suturing it around the implant structure; attaching the wool to the medical implant by means of an adhesive; and using one or more sutures to "sew" the wool onto the medical implant.
  • a plurality of separated wool braids or threads is attached to the medical implant.
  • the wool is secured only to the outside of the medical implant. In another embodiment, the wool is secured to distal regions of the medical implant.
  • the wool may be attached to the implant portion of the medical implant, or it may be attached to the implant portion of the medical implant, or it may be attached to both the implant and implant portions of the medical implant.
  • the wool threads can be located on the implant in various configurations that may result in either partial or complete coverage of the exterior of the implant. The threads could be attached around the ends of the implant. The wool threads can be attached in bands along the medical implant. The attachment could be in a vertical, horizontal, or diagonal manner.
  • the polymeric thread(s) can be attached to either the implant component or the implant component of the medical implant.
  • the wool thread may be allowed to extend some distance from the medical implant.
  • only one end of the wool threads may be secured to the medical implant, thereby allowing the other end of the thread to extend away from the implant.
  • both ends of the thread may be secured to a medical implant, however, the mid-portion of the thread is not secured to the medical implant, and the ends of the thread are secured at a sufficiently short distance from one another that the mid-portion is free to extend away from the medical implant.
  • the ends of the wool threads can be attached to the medical implant, and/or one or more points along the wool thread can be attached to the medical implant.
  • the ends of the wool thread are not attached to the medical implant. Rather, one or more points along the wool thread are attached to the medical implant.
  • the wool thread(s) can be made into a preformed structure (e.g., mesh, looped bundle, and the like) that is then attached to the medical implant.
  • fibrosis-inducing agents suitable for the induction of fibrosis within a diverticulum include crosslinked compositions that comprise amino-functional groups.
  • amino- functionalized polyethylene glycol e.g., 4-armed tetra-amino PEG [1Ok]
  • 4-armed NHS functionalized PEG e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate
  • a 4-armed thiol functionalized PEG e.g., pentaerythritol poly( ethylene glycol)ether tetra-thiol
  • the 4-arm amino-functionalized PEG such that the amount of amino functional groups in the final composition can be varied.
  • These reagents can be mixed at the time of application to provide an in situ forming crosslinked hydrogel.
  • These reagents could be premixed to produce the crosslinked material.
  • the material can be made in various forms such as rods, tubes, films, meshes, screens, threads, fibers, slabs, or spheres.
  • the crosslinked material could also be milled to produce a particulate material.
  • These materials can be dried (e.g., air, vacuum, freeze-dried) and used as a dry powdered material. Alternatively the materials can be hydrated just prior to application. These materials can further comprise one of the fibrosis-inducing agents described herein.
  • fibrosis-inducing agents of use in the management of diverticular disease include components of extracellular matrix (e.g., fibronectin, fibrin, fibrinogen, collagen (e.g., bovine collagen), fibrillar and non-fibrillar collagen, adhesive glycoproteins, proteoglycans (e.g., heparin sulfate, chondroitin sulfate, dermatan sulfate), hyaluronan, secreted protein acidic and rich in cysteine (SPARC), thrombospondins, tenacin, and cell adhesion molecules (including integrins, vitronectin, fibronectin, laminin, hyaluronic acid, elastin, bitronectin), proteins found in basement membranes, and fibrosin) and inhibitors of matrix metalloproteinases, such as TIMPs (tissue inhibitors of matrix metalloproteinases) and synthetic TIMPs, e.g.
  • the agent is a diverticular vessel wall irritant; the fibrosing agent is or comprises silk; the fibrosing agent is or comprises silkworm silk; the fibrosing agent is or comprises spider silk; the fibrosing agent is or comprises recombinant silk; the fibrosing agent is or comprises raw silk; the fibrosing agent is or comprises hydrolyzed silk; the fibrosing agent is or comprises acid-treated silk; the fibrosing agent is or comprises acylated silk; the fibrosing agent is in the form of strands; the fibrosing agent is in the form of tufts; the fibrosing agent is in the form of microparticulates; the fibrosing agent is or comprises mineral particles; the fibrosing agent is or comprises talc; the fibrosing agent is or comprises chitosan; the fibrosing agent is or comprises polylysine; the fibrosing agent is or comprises fibronectin; the fibrosing agent is or comprises bleomycin;
  • the thread is biodegradable (e.g., it comprises a material selected from the group consisting of polyester, polyanhydride, poly(anhydride ester), poly(ester-amide), poly(ester-urea), polyorthoester, polyphosphoester, polyphosphazine, polycyanoacrylate, collagen, chitosan, hyaluronic acid, chromic cat gut, alginate, starch, cellulose and cellulose ester); or the thread is non-biodegradable (e.g., it comprises a material selected from the group consisting of polyester, polyurethane, silicone, polyethylene, polypropylene, polystyrene, polyacrylate, polymethacrylate, polyacrylics, polymethacrylics, and silk); the thread is coated with a polymer, the thread is coated with a pharmaceutical agent that induces a fibrotic response in the patient, the thread is coated with a pharmaceutical agent that induces an osteogenic response in the patient; the composition further comprises an agent
  • the agent that promotes bone growth is a bone morphogenic protein or the agent that promotes bone growth is an osteogenic growth factor (e.g., transforming growth factor, platelet-derived growth factor, and fibroblast growth factor);
  • the composition further comprises a pharmaceutical agent that induces sclerosis (a sclerosant, e.g., a sclerosant is selected from the group consisting of ethanol, dimethyl sulfoxide, sucrose, sodium chloride, dextrose, glycerin, minocycline, tetracycline, doxycycline, polidocanol, sodium tetradecyl sulfate, sodium morrhuate, and sotradecol, or the sclerosant may be a surfactant);
  • the composition further comprises an inflammatory cytokine (e.g., an inflammatory cytokine selected from the group consisting of TGF ⁇ , PDGF, VEGF, bFGF, TNF ⁇ , NGF 1 GM-
  • an implant or composition may include an agent that promotes fibrosis and a second composition or compound which acts to have an inhibitory effect on pathological processes in or around the treatment site.
  • agents which can inhibit pathological processes include, but not limited to, the following classes of compounds: anti-inflammatory agents
  • MMP matrix metalloproteinase
  • Patent No. 6,258,823 and everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772).
  • Further representative examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos.
  • tyrosine kinase inhibitors such as imantinib, ZK-222584, CGP-52411 , CGP-53716, NVP-AAK980-NX, CP- 127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI- 606.
  • drugs that may be included in the compositions and implants of the invention include MMP inhibitors such as nimesulide, PKF-241- 466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU- 171829, AG-3433, PNU-142769, SU-5402, and dexlipotam.
  • MMP inhibitors such as nimesulide, PKF-241- 466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU- 171829, AG-3433, PNU-142769, SU-5402, and dexlipotam.
  • Other examples of drugs that may be included in the compositions and implants of the invention include p38 MAP kinase inhibitors such as CGH-2466 and PD-98-59.
  • cytokine inhibitors include TNF-484A, PD- 172084, CP-293121 , CP-353164, and PD-168787.
  • drugs that may be included in the compositions and implants of the invention include include NFKB inhibitors, such as, AVE-0547, AVE-0545, and IPL-576092.
  • HMGCoA reductase inhibitors such as, pravestatin, atorvastatin, fluvastatin, dalvastatin, glenvastatin, pitavastatin, CP- 83101
  • a diverticular implant or composition incorporates or is coated with a composition that promotes fibrosis, as well as a composition or compound that acts to stimulate cellular proliferation.
  • agents that stimulate cellular proliferation include, pyruvic acid, naltrexone, leptin, D-glucose, insulin, amlodipine, alginate oligosaccharides, minoxidil, dexamethasone, isotretinoin (13-cis retinoic acid), 17- ⁇ -estradiol, estradiol, 1- ⁇ -25 dihydroxyvitamin D 3i diethylstibesterol, cyclosporine A, L-NAME (L-NG-nitroarginine methyl ester (hydrochloride)), all- trans retinoic acid (ATRA), and analogues and derivatives thereof.
  • agents that stimulate cellular proliferation include sphingosine 1- phosphate receptor agonist (e.g., FTY-720 (1 ,3-propanediol, 2-amino-2-(2-(4- octylphenyl)ethyl)-,hydrochloride; immunostimulants, such as lmupedone (methanone, [5-amino-2-(4-methyl-1 -piperidinyl)phenyl](4-chlorophenyl)-, DIAPEP227 synthetic peptide (Peptor Ltd., Israel)); and nerve growth factor agonist, e.g., NG-012 (5H,9H,13H,21H,25H,-dibenzo[k,u][1 ,5,9,15,19] pentaoxacyclotetracosin-5,9,13,21 ,25-pentone, 7,8,11 ,12,15,16,23,24,27,28- deca
  • the diverticular implant or composition may include a fibrosing agent and a haemostatic agent (a thrombotic or clotting agent) that promotes clotting and hemostatis upon implantation of a medical implant (or composition).
  • a haemostat or haemostatic agent is any agent that arrests chemically or mechanically the flow of blood from an open vessel.
  • a haemostatic agent can be applied directly to a bleeding site, and the agent functions in the presence of actively flowing blood.
  • a haemostatic agent may chemically or biologically arrest the flow of blood by interfering with one or more steps in the clotting cascade, such as by accelerating the clotting mechanism (e.g., COSTASIS). The increased clotting then serves as a physical barrier to the flow of blood.
  • a haemostatic agent may in a more direct manner mechanically or physically block the flow of blood (e.g., COSEAL) and thus may be referred to as a sealant (an agent used to prevent leakage of liquids gases or solids).
  • a haemostatic agent may be applied or claped to a tissue surface to provide a barrier to the flow of blood.
  • a diverticular implant contains a haemostatic agent or composition comprising a haemostatic agent and/or an agent or composition that promotes fibrosis.
  • an implant is coated on one aspect with a composition that promotes fibrosis, as well as being coated with a composition or agent that is hemostatic on another aspect of the implant.
  • hemostatic agents include fibrin; aminocaproic acid; tranexamic acid; aprotinin; desmopressin; vitamin K; Tisseel® and FloSeal® (which are fibrinogen- containing formulations) (Baxter Healthcare Corp., Glendale, CA); CrossSeal® (American Red Cross); CoSeal® (PEG-containing formulation) and CoStasis® (collagen-containing formulation) (Angiotech BioMaterials Corp., Palo Alto, CA); and CryoSeal® AHS (Thermogenesis, Sacramento, CA).
  • a composition and medical implant includes a fibrosing agent and an anti-infective agent, which reduces the likelihood of infections in medical implants.
  • Infection is a common complication that results from the implantation of foreign bodies such as medical devices and implants into a host or patient.
  • Foreign materials provide an ideal site for microorganisms to attach and colonize.
  • the risk that a host will develop an infection may be increased as a consequence of an impairment of host defenses against infection in the microenvironment surrounding a foreign material. These factors make medical implants particularly susceptible to infection.
  • a composition for treating and/or managing diverticular infection may include an anti-infective agent, antibiotic, or other agent that inhibits (impairs or decreases) the growth or division rate or kills a microorganism (for example, bacteria and yeast).
  • a microorganism for example, bacteria and yeast.
  • Diverticulitis can occur when inspissated stool, a fecalith trapped within a diverticulum, results in local infection (or abscess formation) within the diverticulum. When severe, this can lead to perforation and the formation of generalized peritonitis.
  • diverticula lumen may be sterilized such that bacteria are not contained within the developing scar tissue. This will lessen the possibility that an infection or abscess will develop at a later point in time.
  • anti-infective agent refers to an agent that reduces the likelihood of an infection.
  • An agent is demonstrated to be an active anti- infective agent toward a microorganism by assays routinely practiced by persons skilled in the art, for example, an in vitro assay determining inhibition of bacterial growth as indicated by the M. I. C. (minimimum inhibitory concentration).
  • anti-infective agents are chemotherapeutic agents that have antimicrobial activity at low doses (e.g., anthracyclines, fluoropyrimidines, folic acid antagonists, podophylotoxins, camptothecins, hydroxyureas, and platinum complexes.
  • An anti-septic agent refers to an agent or substance that is capable of effective antisepsis, that is, prevention of infection by inhibiting the growth of an infectious organism without necessarily killing the organism.
  • Representative examples of anti-septic agents include chlorhexadine, triclosan, and chloroxylenol.
  • Antibiotic refers to an agent that kills or inhibits the growth of microorganisms. Antibiotics may have a narrow or wide range of activity against either one or both of Gram-positive and Gram-negative organisms. Antibiotic agents can be identified through in vitro inhibition of bacterial growth as shown in the M. I. C. assay described herein.
  • antibiotics include gentamicin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, neomycin sulfate, cephazolin sodium, metronidazole, Ciprofloxacin, piperacillin, Cefoxitin, Cefepime,Azithromycin, andTrimethoprom- sulfamethoxazole.
  • a composition comprises, or an implant is loaded or coated with a composition that promotes fibrosis, as well as being loaded or coated with an an anti-infective agent ⁇ e.g., antibiotic, chemotherapeutic agent, and/or antiseptic agent) or a composition that includes an antibiotic (or antiseptic agent).
  • an anti-infective agent e.g., antibiotic, chemotherapeutic agent, and/or antiseptic agent
  • Representative examples are provided herein of agents such as chemotherapeutic agents that can be released from a composition, and which have potent antimicrobial activity at extremely low doses.
  • a wide variety of anti-infective agents can be used in combination with the present compositions. Suitable anti-infective agents may be readily determined by methods practiced in the art and as exemplified in the assays provided in Example 41.
  • anati-infective agents (A) anthracyclines (e.g., doxorubicin and mitoxantrone); (B) fluoropyrimidines (e.g., 5-FU); (C) folic acid antagonists (e.g., methotrexate); (D) podophylotoxins (e.g., etoposide); (E) camptothecins; (F) hydroxyureas; and (G) platinum complexes (e.g., cisplatin).
  • anthracyclines e.g., doxorubicin and mitoxantrone
  • fluoropyrimidines e.g., 5-FU
  • C folic acid antagonists (e.g., methotrexate)
  • D podophylotoxins
  • E camptothecins
  • F hydroxyureas
  • platinum complexes e.g., cisplatin
  • Anti-infective agents have the capability to prevent infection, reduce the incidence of abscess formation, treat diverticulitis, and/or contribute to sterilization of the lumen of the diverticula during the scarring process.
  • Such anti-infective agents include, but are not limited to antibiotics and anticancer agents.
  • implants may be coated with antimicrobial drugs. Representative examples of implants and coating of implants with antimicrobial drugs are provided in U.S. Patent No. 5,520,664, U.S. Patent No. 5,709,672, U.S. Patent No. 6,361 ,526, U.S. Patent No. 6,261,271 , U.S. Patent No. 5,902,283, U.S. Patent No. 5,624,704, and U.S. Patent No. 5,709,672.
  • Antibiotics and combinations of antibiotics that are used by those skilled in the medical art include the following exemplary antibiotics: fourth generation penicillins such as mezlocillin and piperacillin (ureidopenicillins), carbenicillin and ticarcillin (carboxypenicillins), and analogues and derivatives thereof; first generation cephalosporins such as cephazolin, Cephazolin Sodium, Cephalexin (Keflex), Cefazolin (Ancef), Cephapirin (Cefadyl), and Cephalothin (Keflin), and analogues and derivatives thereof; Ticarcillin; second generation cephalosporins such as Cefuroxime (Ceftin (oral) andZinocef), Cefotetan (Cefotan), and Cefoxitin (Mefoxin), and analogues and derivatives thereof; third generation cephalosporin such as Naxcel (Ceftiofur Sodium), Cefdinir
  • inhibitors of protein synthesis such as aminoglycosides including streptomycin, gentamicin, gentamicin sulfate, tobramycin, and amikacin, amikacin sulfate, and analogues and derivatives thereof; inhibitors of protein synthesis such as the MSL group including macrolides (Erythromycin), long acting macrolides (Azithromycin) and lincosamides (Clindamycin) and streptogramins (Syneroid), clarithromycin, kanamycin, kanamycin sulfate, and analogues and derivatives thereof.
  • MSL group including macrolides (Erythromycin), long acting macrolides (Azithromycin) and lincosamides (Clindamycin) and streptogramins (Syneroid), clarithromycin, kanamycin, kanamycin sulfate, and analogues and derivatives thereof.
  • antibiotics include inhibitors of DNA snthesis such as the quinolones including ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin, levofloxacin, trovafloxacin, and analogues and derivatives thereof, as well as other inhibitors of DNA synthesis such as metronidazole and analogues and derivatives thereof.
  • Other antibiotics include inhibitors of folate metabolism such as sulfonamides and trimethoprim, and analogues and derivatives thereof.
  • Additional agents include but are not limited to cefixime, spectinomycin, tetracycline, nitrofurantoin, doxycycline, polymyxin B, neomycin, neomycin sulfate, and analogues and derivatives thereof.
  • the anti-infective agent is gentamicin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin B, neomycin sulfate, cephazolin sodium, metronidazole, ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromycin, or trimethoprim-sulfamethoxazole.
  • additional therapeutic agents may be delivered in combinations.
  • Such combinations include, by way of example, but are not limited to amoxicillin and clavulanate, ampicillin and sulbactam, trimethoprom- sulfamethoxazole, ampicillin and probenecid, amoxicillin and probenecid, penicillin G and probenecid, and penicillin and a penicillinase inhibitor.
  • Antibiotics described herein and used by those skilled in the medical art may be administered orally (1-2 grams per day depending upon factors such as age and/or weight and/or mass of the patient). As described herein, one or more antibiotics may also be administered parenterally or an antibiotic may be administered in a composition that includes the fibrosis agent, or may be administered in combination with an implant.
  • agents e.g., chemotherapeutic agents
  • agents that can be incorporated onto or into, or released from, an implant or a composition implanted within a diverticulum, and which have potent antimicrobial activity at extremely low doses.
  • a wide variety of anti-infective agents can be used in combination with a fibrosing agent.
  • chemotehrapeutic/anti- infective agents (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).
  • anthracyclines e.g., doxorubicin and mitoxantrone
  • fluoropyrimidines e.g., 5-FU
  • C folic acid antagonists (e.g., methotrexate)
  • D podophylotoxins
  • E camptothecins
  • F hydroxyureas
  • platinum complexes e.g., cisplatin
  • Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:
  • R groups are as follows: Ri is CH 3 or CH 2 OH; R 2 is daunosamine or H; R 3 and R 4 are independently one of OH, NO 2 , NH 2 , F, Cl, Br, I, CN, H or groups derived from these; R 5 is hydrogen, hydroxyl, or methoxy; and R ⁇ - ⁇ are all hydrogen. Alternatively, R 5 and R 6 are hydrogen and R 7 and Rs are alkyl or halogen, or vice versa.
  • Ri may be a conjugated peptide.
  • R 5 may be an ether linked alkyl group.
  • R 5 may be OH or an ether linked alkyl group.
  • Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2 CH(CH 2 -X)C(O)-R 1 , wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062).
  • R 3 may have the following structure:
  • Rg is OH either in or out of the plane of the ring, or is a second sugar moiety such as R 3 .
  • R 1O may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
  • Ri 0 may be derived from an amino acid, having the structure - C(O)CH(NHRii)(Ri 2 ), in which Rn is H, or forms a C 3-4 membered alkylene with R- I2 .
  • R- I2 may be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
  • exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:
  • Doxorubicin OCH 3 C(O)CH 2 OH plane
  • Daunorubicin OCH 3 C(O)CH 3 plane
  • Idarubicin OH out of ring
  • Pirarubicin OCH 3 C(O)CH 2 OH
  • anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A 3 , and plicamycin having the structures:
  • anthracyclines include, FCE 23762, a doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. ScL 82(11 ):1151-1154, 1993), ruboxyl (Rapoport ef a/., J. Controlled Release 5 ⁇ (2):153-162, 1999), anthracycline disaccharid ⁇ doxorubicin analogue (Pratesi et al., Clin. Cancer Res.
  • the therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • fluoropyrimidine analog such as 5-fluorouracil
  • an analogue or derivative thereof including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • 5-FudR 5- fluoro-deoxyuridine
  • an analogue or derivative thereof including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc, Perkin Trans. 7(19):3145-3146, 1998), 5-fluorouracil derivatives with 1 ,4- oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, Anticancer Res.
  • the therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin.
  • Methotrexate analogues have the following general structure:
  • R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.
  • Ri may be N
  • R 2 may be N or C(CH 3 )
  • R 3 and R 3 1 may H or alkyl, e.g., CH 3
  • R 4 may be a single bond or NR, where R is H or alkyl group.
  • R 5, Re, and/or Rs may be H, OCH 3 , or alternately they can be halogens or hydro groups.
  • R 7 is a side chain of the general structure:
  • the carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2+ salt.
  • Rg and Ri 0 can be NH 2 or may be alkyl substituted.
  • Exemplary folic acid antagonist compounds have the structures:
  • N-( ⁇ -aminoacyl) methotrexate derivatives Cheung et al., Pteridines 3(1-2):101-2, 1992
  • biotin methotrexate derivatives Fean et al., Pteridines 3(1-2):131-2, 1992
  • D-glutamic acid or D-erythrou threo-4-fluoroglutamic acid methotrexate analogues
  • the therapeutic agent is a Podophyllotoxin, or a derivative or an analogue thereof.
  • exemplary compounds of this type are etoposide or teniposide, which have the following structures:
  • podophyllotoxins include Cu(II)- VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7): 1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4 ⁇ -amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), ⁇ -lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem.
  • the therapeutic agent is camptothecin, or an analogue or derivative thereof.
  • Camptothecins have the following general structure.
  • X is typically O, but can be other groups, e.g., NH in the case of 21 -lactam derivatives.
  • R 1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated Ci -3 alkane.
  • R 2 is typically H or an amino containing group such as (CHs) 2 NHCH 2 , but may be other groups e.g., NO 2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups.
  • R 3 is typically H or a short alkyl such as C 2 H 5 .
  • R 4 is typically H but may be other groups, e.g., a methylenedioxy group with R 1 .
  • camptothecin compounds include topotecan, irinotecan (CPT-11 ), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11 -methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin.
  • Exemplary compounds have the structures:
  • Camptothecins have the five rings shown here.
  • the ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
  • Camptothecins are believed to function as topoisomerase I inhibitors and/or DNA cleavage agents.
  • the therapeutic agent of the present invention may be a hydroxyurea.
  • Hydroxyureas have the following general structure:
  • Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R 1 is:
  • R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • R 1 is a cycloalkenyl group, for example N-[3-[5-(4- fluorophenylthio)-furyl]-2-cyclopen'ten-1-yl]N-hydroxyurea
  • R 2 is H or an alkyl group having 1 to 4 carbons and R 3 is H
  • X is H or a cation.
  • Suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein R 1 is a phenyl group substituted with one or more fluorine atoms; R 2 is a cyclopropyl group; and R 3 and X is H.
  • n is 0-2 and Y is an alkyl group.
  • the hydroxyurea has the structure:
  • the therapeutic agent is a platinum compound.
  • suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:
  • X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; Ri and R 2 are alkyl, amine, amino alkyl may be further substituted, and are basically inert or bridging groups.
  • Ri and R 2 are alkyl, amine, amino alkyl may be further substituted, and are basically inert or bridging groups.
  • Pt(II) complexes Zi and Z 2 are non-existent.
  • Z-i and Z 2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
  • Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897.
  • platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:
  • platinum compounds include (CPA) 2 Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-[PtCI 2 (4,7-H-5-methyl-7- oxo]1 ,2,4[triazolo[1 ,5-a]pyrimidine) 2 ] (Navarro et al., J. Med. Chem. 41(3):332- 338, 1998), [Pt(cis-1 ,4-DACH)(trans-CI 2 )(CBDCA)] . V 2 MeOH cisplatin (Shamsuddin et al., Inorg. Chem.
  • compositions and implants may be used for treating a diverticular disease. Because medical implants and compositions are made in a variety of configurations, forms, and sizes, the exact dose of a therapeutic agent administered will vary with the implant size, surface area, design, and portions of the implant coated. In addition, the number and size of diverticula present may be considered when determining the total amount of drug and material administered to a host. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (for example, the portion of the implant being coated), total drug dose administered can be measured, and appropriate surface concentrations of active drug can be determined. Regardless of the method of application of the drug, whether in a composition or applied to the medical implant, the anticancer/anti-infective agents described herein, used alone or in combination, may be administered under the following dosing guidelines.
  • the total dose of doxorubicin applied to the implant preferably does not exceed 25 mg (range of 0.1 ⁇ g to 25 mg).
  • the total amount of drug applied is in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area ⁇ i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) falls within the range of 0.01 ⁇ g - 100 ⁇ g per mm 2 of surface area.
  • doxorubicin is applied to the diverticular surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters are preferably used in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "7 - 10 "4 M of doxorubicin is maintained on the surface.
  • surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 "4 M) although for some embodiments lower concentrations are sufficient.
  • doxorubicin is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • Analogues and derivatives of doxorubicin (as described previously) with similar functional activity can also be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).
  • the total dose of mitoxantrone applied preferably does not exceed 5 mg (range of 0.01 ⁇ g to 5 mg).
  • the total amount of drug applied is in the range of 0.1 ⁇ g to 1 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated falls within the range of 0.01 ⁇ g - 20 ⁇ g per mm 2 of surface area.
  • mitoxantrone is applied to the diverticular surface at a dose of 0.05 ⁇ g/mm 2 - 3 ⁇ g/mm 2 .
  • the above dosing parameters are preferably utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "5 - 10 6 M of mitoxantrone is maintained.
  • drug concentrations on the implant surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10 ⁇ 5 M) although for some embodiments lower drug levels will be sufficient.
  • mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be used for the methods and compositions described herein; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).
  • the total dose of 5-fluorouracil applied preferably does not exceed 250 mg (range of 1.0 ⁇ g to 250 mg).
  • the total amount of drug applied is in the range of 10 ⁇ g to 25 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated falls within the range of 0.1 ⁇ g - 1 mg per mm 2 of surface area.
  • 5- fluorouracil is applied to the diverticular or implnt surface at a dose of 1.0 ⁇ g/mm 2 - 50 ⁇ g/mm 2 .
  • the above dosing parameters can be used in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10 "4 - 10 ⁇ 7 M of 5-fluorouracil is maintained.
  • surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10 "4 M) although for some embodiments lower drug levels will be sufficient.
  • 5-fluorouracil is released from the implant surface such that anti- infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • Analogues and derivatives of 5-fluorouracii (as described previously) with similar functional activity can be used. The above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (i.e., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5- fluorouracil is administered at twice the above parameters, etc.).
  • the total dose of etoposide applied preferably does not exceed 25 mg (range of 0.1 ⁇ g to 25 mg).
  • the total amount of drug applied is in the range of 1 ⁇ g to 5 mg.
  • the dose per unit area i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated falls within the range of 0.01 ⁇ g - 100 ⁇ g per mm 2 of surface area.
  • etoposide is applied to the diverticular surface at a dose of 0.1 ⁇ g/mm 2 - 10 ⁇ g/mm 2 .
  • the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a concentration of 10 "5 - 10 ⁇ 6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10 "5 M; although for some embodiments lower drug levels will be sufficient).
  • etoposide is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months.
  • the drug is released in effective concentrations for a period ranging from 1 week - 6 months.
  • analogues and derivatives of etoposide (as described previously) with similar functional activity can be used in the compositions and methods described herein.
  • the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (i.e., a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).
  • Haemostatic Agents are adjusted according to the relative potency of the analogue or derivative as compared to the parent compound.
  • CoStasis® as an exemplary hemostatic agent, whether it is applied as a polymer coating, incorporated into the polymers which make up an implant, applied as an implant, or applied to tissue
  • the total volume of CoStasis® delivered as an implant or from an implant or composition, or coated onto the surface of an implant or tissue preferably does not exceed 25 mL (range of 0.2 mL to 25 mL).
  • the total amount of CoStasis® in the composition or implant is in the range of 0.5 mL to 15 mL.
  • the amount per unit area of the implant or tissue i.e., the amount of CoStasis® as a function of the surface area of the portion of the implant or tissue to which it is applied and/or incorporated
  • the amount per unit area of the implant or tissue falls within the range of 0.01 mL - 5.0 mL per cm 2 of surface area coated.
  • CoStasis® is applied on an implant or tissue surface at a dose of 0.1 mL/cm 2 -0.5 mL/cm 2 of surface area coated.
  • CoStasis® may release such pharmacologically active agent(s) at differing rates, as such, the above dosing parameters are preferably used in combination with the release rate of the drug from the composition or implant such that a minimum concentration of 0.01 nM - 1000 ⁇ M of pharmacologically active agent is delivered to the tissue.
  • an agent is released from the surface of an implant such that fibrosis in the diverticulum is promoted for a period ranging from several hours to several months.
  • an agent is released from the surface of an implant such that bacterial growth is inhibited for a period ranging from several hours to several months.
  • an agent may be released in effective concentrations for a period ranging from 1 hour- 30 days.
  • the above dosing parameters of CoStasis® may be adjusted for an analogue or derivative of CoStasis® or of a component of the composition according to the relative potency of the analogue or derivative of the pharmacologically active agent as compared to the parent pharmacologically active agent (e.g., a compound twice as potent is administered at half the above parameters, a compound half as potent may be administered administered at twice the above parameters, etc.).
  • Tisseel® as an exemplary hemostatic agent, whether it is applied as a polymer coating, incorporated into the polymers which make up an implant, applied as an implant, or applied to tissue, the total volume of Tisseel® delivered as an implant or from an implant or composition, or coated onto the surface of an implant or tissue, preferably does not exceed 25 mL (range of 0.2 ml_ to 25 mL). In one embodiment, the total amount of Tisseel® in the composition or implant is in the range of 0.5 mL to 15 mL.
  • the amount per unit area of the implant or tissue i.e., the amount of Tisseel® as a function of the surface area of the portion of the implant or tissue to which it is applied and/or incorporated
  • the amount per unit area of the implant or tissue falls within the range of 0.01 mL - 5.0 mL per cm 2 of surface area coated.
  • Tisseel® is applied on an implant or tissue surface at a dose of 0.1 mL/cm 2 -0.5 mL/cm 2 of surface area coated.
  • Tisseel® may release such pharmacologically active agent(s) at differing rates, as such, the above dosing parameters are preferably used in combination with the release rate of the drug from the composition or implant such that a minimum concentration of 0.01 nM - 1000 ⁇ M of pharmacologically active agent is delivered to the tissue.
  • an agent is released from the surface of an implant such that fibrosis in the diverticulum is promoted for a period ranging from several hours to several months.
  • an agent is released from the surface of an implant such that bacterial growth is inhibited for a period ranging from several hours to several months.
  • an agent may be released in effective concentrations for a period ranging from 1 hour - 30 days.
  • the above dosing parameters of Tisseel® may be adjusted for an analogue or derivative of Tisseel® or of a component of Tisseel® according to the relative potency of the analogue or derivative of the pharmacologically active agent as compared to the parent pharmacologically active agent (e.g., a compound twice as potent is administered at half the above parameters, a compound half as potent may be administered administered at twice the above parameters, etc.).
  • the total volume of FloSeal® delivered as an implant or from an implant or composition, or coated onto the surface of an implant or tissue preferably does not exceed 25 mL (range of 0.2 mL to 25 mL).
  • the total amount of FloSeal® in the composition or implant is in the range of 0.5 mL to 15 mL.
  • the amount per unit area of the implant or tissue i.e., the amount of FloSeal® as a function of the surface area of the portion of the implant or tissue to which it is applied and/or incorporated
  • the amount per unit area of the implant or tissue falls within the range of 0.01 mL - 5.0 mL per cm 2 of surface area coated.
  • FloSeal® is applied on an implant or tissue surface at a dose of 0.1 mL/cm 2 -0.5 mL/cm 2 of surface area coated.
  • FloSeal® may release such pharmacologically active agent(s) at differing rates, as such, the above dosing parameters are preferably used in combination with the release rate of the drug from the composition or implant such that a minimum concentration of 0.01 nM - 1000 ⁇ M of pharmacologically active agent is delivered to the tissue.
  • an agent is released from the surface of an implant such that fibrosis in the diverticulum is promoted for a period ranging from several hours to several months.
  • an agent is released from the surface of an implant such that bacterial growth is inhibited for a period ranging from several hours to several months.
  • an agent may be released in effective concentrations for a period ranging from 1 hour - 30 days.
  • the above dosing parameters of FloSeal® may be adjusted for an analogue or derivative thereof according to the relative potency of the analogue or derivative of the pharmacologically active agent when compared to the parent pharmacologically active agent (e.g., a compound twice as potent is administered at half the above parameters, a compound half as potent may be administered administered at twice the above parameters, etc.).
  • CoSeal® as an exemplary hemostatic agent, whether it is applied as a polymer coating, incorporated into the polymers which make up an implant, applied as an implant, or applied to tissue
  • the total volume of CoSeal® delivered as an implant or from an implant or composition, or coated onto the surface of an implant or tissue preferably does not exceed 30 ml_ (range of 0.2 mL to 30 ml_).
  • the total amount of CoSeal® in the composition or implant is in the range of 0.5 mL to 15 mL.
  • the amount per unit area of the implant or tissue i.e., the amount of CoSeal® as a function of the surface area of the portion of the implant or tissue to which it is applied and/or incorporated
  • the amount per unit area of the implant or tissue falls within the range of 0.01 mL - 5.0 mL per cm 2 of surface area coated.
  • CoSeal® is applied on an implant or tissue surface at a dose of 0.1 mL/cm 2 -0.5 mL/cm 2 of surface area coated.
  • CoSeal® may release such pharmacologically active agent(s) at differing rates, as such, the above dosing parameters are preferably used in combination with the release rate of the drug from the composition or implant such that a minimum concentration of 0.01 nM - 1000 ⁇ M of pharmacologically active agent is delivered to the tissue.
  • an agent is released from the surface of an implant such that fibrosis in the diverticulum is promoted for a period ranging from several hours to several months.
  • an agent is released from the surface of an implant such that bacterial growth is inhibited for a period ranging from several hours to several months.
  • an agent may be released in effective concentrations for a period ranging from 1 hour - 30 days.
  • the above dosing parameters of CoSeal® may be adjusted for a derivative or analogue of a physiologically active agent of CoSeal® according to the relative potency of the analogue or derivative of the pharmacologically active agent as compared to the parent pharmacologically active agent (e.g., a compound twice as potent is administered at half the above parameters, a compound half as potent may be administered administered at twice the above parameters, etc.).
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5- fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide)
  • podophylotoxins e.g., etoposide
  • anthracyclines e.g., doxorubicin or mitoxantrone
  • fluoropyrimidines e.g., 5-fluorouracil
  • folic acid antagonists e.g., methotrexate and/or podophylotoxins (e.g., etoposide
  • the anti-infective agent may be further combined with a fibrosing agent and/or hemostatic agent for the comprehensive management of acute diverticulitis.
  • Drug-coated, drug-impregnated, or drug containing implants are provided herein that induce adhesion or fibrosis in the diverticular, or facilitate "filling" of the diverticular sac with scar tissue or fibrotic tissue in situ.
  • fibrosis is induced by local or regional release of specific pharmacological agents that become localized within the diverticular. Nmerous methods are available for optimizing delivery of the fibrosis-inducing agent to the diverticula, and several of these are described below.
  • Medical implants as described herein contain and/or are adapted to release an agent which induces fibrosis or adhesion to the surrounding tissue.
  • Medical implants may be adapted to have incorporated into their structure a fibrosis-inducing agent, adapted to have a surface coating of a fibrosis-inducing agent and/or adapted to release a fibrosis-inducing agent by (a) directly affixing to the implant a desired fibrosis-inducing agent or composition containing the fibrosis-inducing agent (e.g., by either spraying the medical implant with a drug and/or carrier (polymeric or non-polymeric)-drug composition to create a film or coating on all, or parts of the internal or external surface of the implant; by dipping the implant into a drug and/or carrier (polymeric or non-polymeric)-drug solution to coat all or parts of the implant; or by other covalent or non-covalent (e.g., mechanically attached via knotting or
  • an implant is or comprises a bulking agent.
  • a bulking agent refers to a liquid, solid or semi-solid ingredient used either alone or in combination with another material (e.g., a polymer) to partially or fully seal or fill a void (e.g., a diverticulum) or lumen within a host.
  • a bulking agent may be applied directly into the treatment site or may be injected into the tissue immediately surrounding the treatment area.
  • Bulking agent also refers to compound and mixtures that undergo a chemical reaction, precipitation, or crystallization in situ, which can partially or fully seal or fill a void or lumen within a host. Bulking agents can be used to increase the volume, extend, or dilute other solids.
  • a bulking agent may have a fixed volume or may increase in volume as it comes into contact with body fluids in the host and begins to swell.
  • a bulking agent may be in an injectable form (e.g., solution, gel, paste, and the like) or in the form of an implant.
  • the bulking agent may be in the form of a three dimensional object, such as, a film, mesh, microsphere, bead, or another shape).
  • the bulking agent may be combined with a polymeric composition (e.g., a gel or hydrogel) to facilitate delivery of the agent into the host.
  • bulking agents include inorganic materials such as minerals, glasses, ceramics (e.g., ground and powdered ceramics and glasses), clays, calcium carbonate, magnesium carbonate, pumice, talc, zinc oxide, hydroxyapatite, cornstarch, cellulose, wood (e.g., saw dust), naturally occurring materials such as bone, leather, horn, hair, various proteinaceous materials, such as collagen and collagen containing materials (e.g., collagen based injectable products, including those derived from non- bovine, human, or recombinant sources), polysaccharides ⁇ e.g., hyaluronic acid), and synthetic polymers (e.g., ethylene vinyl alcohol polymer implant, acrylates, methacrylates, acrylics, polydimethylsiloxane, silicone, and the like).
  • inorganic materials such as minerals, glasses, ceramics (e.g., ground and powdered ceramics and glasses), clays, calcium carbonate, magnesium carbonate, pumice, talc,
  • Bulking agents for use in treating diverticulitis may be combined with one or more fibrosis-inducing agents as described herein.
  • Bulking agents include but are not limited to commercially available products such as collagen- based injectable products, including those derived from non-bovine, human, or recombinant sources; injectable microspheres from Artes Medical, Inc.
  • urethral bulking agents containing silk and elastin proteins Protein Polymer Technologies, San Diego, CA); cross-linked silicon microballoon filled with biocompatible polymer (UROVIVE from American Medical Systems, Minnetonka, MN); and URYX bulking agent and Embolyx from Microtherapeutics, Inc., San Clemente, CA and Genyx Medical, Inc., Aliso Viejo, CA.
  • Other manufacturers of carriers suitable for use in bulking compositions include CR. Bard, Inc. (Murray Hill, NJ), Collagenesis, Inc. (Acton, MA), American Medical Systems, Mentor, Uromed Corporation (Norwood, MA), Boston Scientific Corporation, Johnson & Johnson (Ethicon, Inc.), Cook Group, Inc. (Bloomington, IN), W. L. Gore & Associates, and SURx, Inc. (Pleasonton, CA).
  • TISSUMEND Il Veterinary Products Laboratories; Phoenix, AZ
  • VETBOND 3M Company; St. Paul, MN
  • TISSUEMEND TEI Biosciences, Inc.; Boston, MA
  • HISTOACRYL or HISTOACRYL BLUE Davis & Geek; St.
  • This hydrogel may further contain collagen, methylated collagen and/or gelatin.
  • Other hydrogels can include crosslinked polysaccharides (e.g,. carboxymethyl cellulose, dextran, hyaluronic acid, chitosan, alignate etc), vinyl based crosslinked hydrogels (e.g., polyacrylates, polyacrylic acids, polymethacrylic acids, poly(hydroxyethylmethacrylate)).
  • These hydrogels can further comprise a fibrosis-inducing agent and/or an anti-infective agent and/or a hemostatic agent, and can be applied to the diverticula.
  • a mesh or film or other similar material may be inserted or applied to a diverticulum.
  • This mesh, film, or similar material is capable, at least in part, to fill the diverticulum.
  • An in-situ sealant, glue, or embolic agent may be used to maintain the position of the mesh or film in the diverticulum.
  • a fibrosis-inducing agent, an anti-infective agent, and/or a hemostatic agent may also be used in combination with the mesh or film.
  • the one or more agents may be applied directly to the diverticular tissue or to the mesh or film according to any of the methods described herein.
  • the fibrosis-inducing agent may be delivered to the diverticula as a solution via a catheter inserted into the diverticula under endoscopic or radiographic guidance.
  • the fibrosis-inducing agent can be incorporated directly into the solution to provide a homogeneous solution or dispersion.
  • the solution is an aqueous solution.
  • the aqueous solution may further include buffer salts, as well as viscosity modifying agents (e.g., hyaluronic acid, alginates, CMC, and the like).
  • the solution can include a biocompatible solvent, such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP.
  • the fibrosis- inducing agent can be incorporated into a carrier so that therapeutic levels can be delivered locally into the diverticula for periods long enough for complete healing and fibrosis to occur (weeks to months).
  • a desired fibrosis-inducing agent may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymeric composition (which may be either biodegradable or non-biodegradable) or non-polymeric composition in order to release the fibrosis-inducing agent over a period of time.
  • biodegradable and non-biodegradable polymers, polymer conjugates as well as non-polymeric materials can be used to accomplish the local delivery of the fibrosis-inducing agent, hemostatic agent and/or anti- infective agent into the diverticula.
  • biodegradable polymers suitable for the delivery of fibrosis-inducing agents, hemostatic agents and/or anti-infective agents into diverticula include albumin, collagen, gelatin, hyaluronic acid, aliphatic, heteroatomic and aromatic esters of hyaluronic acid, thiol containing hyaluronic acid derivatives, starch, cellulose and cellulose derivatives (e.g., methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextrans, carboxymethyl dextran, amino-dextran, polysaccharides, fibrinogen, poly(ether ester) multiblock copolymers, based on poly( ethylene glycol) and poly(butylene terephthalate), tyrosine-derived polycarbonates (e.g., U.S.
  • Patent No. 6,120,491 poly(hydroxyl acids), poly(D,L-lactide), poly(D,L-lactide-co- glycolide), poly(glycolide), poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate) and poly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), poly(acrylamides), polyanhydrides, poly(ester-amides), poly(ester-imides), poly(ester-ureas), poly(ester-urethane-ureas), poly(anhydride-esters), poly(anhydride-imides), polyphosphazenes, poly(amino acids), poly(alkylene oxide)-poly(ester) block copolymers (e.g., X-Y, X-Y-X or Y- X-Y, where X is a poly
  • non-degradable polymers suitable for the delivery of fibrosis-inducing agents, hemostatic agents and/or anti-infective agents into diverticula include poly(ethylene-co-vinyl acetate) ("EVA") copolymers, silicone rubber, acrylic polymers (e.g., polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, poly(butyl methacrylate)), poly(alkylcyanoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(hexylcyanoacrylate), and poly(octylcyanoacrylate)), polyethylene, polypropylene, polyamides (nylon 6,6), polyurethanes (including hydrophilic polyurethanes), poly(ester-urethanes), poly(ether-urethanes), poly(ester-urea), polycarbonate urethane)s, polyethers (poly(ethylene oxide), poly(propylene oxide),
  • Polymers may also be developed which are either anionic (e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid) and copolymers thereof, and poly(acrylic acid) and copolymers thereof, as well as blends thereof) or cationic (e.g., chitosan, poly- L-lysine, polyethylenimine, and poly(allyl amine) and blends thereof (see generally, Dunn et al., J. Applied Polymer ScL 50:353-365, 1993; Cascone et al., J.
  • anionic e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid) and copolymers thereof, and poly(acrylic acid) and copolymers thereof,
  • Particularly preferred polymeric carriers for sustained delivery of the afformentioned therapeutic agents into diverticula include poly(ethylene-co- vinyl acetate), cellulose esters (nitrocellulose), poly(hydroxymethacrylate), poly(methylmethacrylate), poly(ethylene-co-acrylic acid), poly(vinylpyrrolidone) polyurethanes (e.g., CHRONOFLEX AL and CHRONOFLEX AR (both from CardioTech International, Inc., Woburn, MA) and BIONATE (Polymer Technology Group, Inc., Emeryville, CA), poly (D,L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (valerolactone), polyanhyd rides, poly(anhydride esters), poly(ester-amides), poly(ester-ureas), copolymers of poly (caprolactone
  • polysaccharides such as hyaluronic acid, chitosan and fucans, and copolymers of polysaccharides with degradable polymers, as well as crosslinked compositions of the above.
  • Other representative polymers capable of sustained localized delivery of fibrosis-inducing agents, hemostatic agents and/or anti-infective agents into diverticula include carboxylic polymers, polyacetates, polyacrylamides, polycarbonates, polyethers, substituted polyethylenes, polyvinylbutyrals, polysilanes, polyureas, polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylhalides, pyrrolidones, isoprene rubbers, thermal-setting polymers, cross-linkable acrylic and methacrylic polymers, ethylene acrylic acid copolymers, styrene acrylic copolymers, vinyl acetate polymers and copolymers, vinyl acetal polymers and copolymers, epoxies, melamines, other amino resins, phenolic polymers, and copolymers thereof, water-insoluble cellulose ester polymers (including cellulose a
  • the polymers as described herein can also be blended or copolymerized in various compositions appropriately to deliver therapeutic doses of fibrosis-inducing agents, hemostatic agents, and/or anti-infective agents to diverticula.
  • Polymeric carriers for fibrosis-inducing agents, hemostatic agents, and/or anti-infective agents can be fashioned in a variety of forms, with desired release characteristics and/or with specific properties.
  • polymeric carriers may be fashioned to release a therapeutic agent upon exposure to a specific triggering event such as pH (see, e.g., Heller et al., "Chemically Self- Regulated Drug Delivery Systems," in Polymers in Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer Sci. 45:343-354, 1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J.
  • pH-sensitive polymers include poly(acrylic acid) and its derivatives (including for example, homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid), copolymers of such homopolymers, and copolymers of poly(acrylic acid) and acrylmonomers such as those discussed above.
  • Other pH sensitive polymers include polysaccharides such as cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan.
  • Yet other pH sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.
  • fibrosis-inducing agents, hemostatic agents, and/or anti- infective agents can be delivered to diverticula via polymeric carriers which are temperature sensitive (see, e.g., Chen et al., "Novel Hydrogels of a Temperature-Sensitive Pluronic Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug Delivery," in Proceed. Intern. Symp. Control. ReI. Bioact Mater, 22:167-168, Controlled Release Society, Inc., 1995; Okano, "Molecular Design of Stimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery," in Proceed. Intern. Symp, Control. ReI. Bioact. Mater.
  • thermogelling polymers and their gelatin temperature [LCST ( 0 C)] include homopolymers such as poly(N-methyl-N-n-propylacrylamide), 19.8; poly(N-n-propylacrylamide), 21.5; poly(N-methyl-N-isopropylacrylamide), 22.3; poly(N-n-propylmethacrylamide), 28.0; poly(N-isopropylacrylamide), 30.9; poly(N, n-diethylacrylamide), 32.0; poly(N-isopropylmethacrylamide), 44.0; poly(N-cyclopropylacrylamide), 45.5; poly(N-ethylmethyacrylamide), 50.0; poly(N-methyl-N-ethylacrylamide), 56.0; poly(N-cyclopropylmethacrylamide), 59.0; and poly(N-ethylacrylamide), 72.0.
  • homopolymers such as poly(N-methyl-N-n-propylacrylamide), 19.
  • thermogelling polymers may be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water-soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate and derivatives thereof, such as butyl methacrylate, acrylamide, and N-n-butyl acrylamide).
  • acrylmonomers e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate and derivatives thereof, such as butyl methacrylate, acrylamide, and N-n-butyl acrylamide.
  • thermogelling polymers include cellulose ether derivatives such as hydroxypropyl cellulose, 41 0 C; methyl cellulose, 55°C; hydroxypropylmethyl cellulose, 66°C; and ethylhydroxyethyl cellulose, polyalkylene oxide-polyester block copolymers of the structure X-Y, Y-X-Y and X-Y-X where X is a polyalkylene oxide and Y is a biodegradable polyester (e.g., PLG-PEG-PLG) and PLURONICS such as F-127, 10 - 15 °C; L-122, 19°C; L-92, 26°C; L-81 , 20°C; and L-61 , 24°C.
  • PLG-PEG-PLG biodegradable polyester
  • PLURONICS such as F-127, 10 - 15 °C; L-122, 19°C; L-92, 26°C; L-81 , 20°C; and L-61
  • gel composition is a gel formed by the combination of a chitosan solution with glycerol phosphate.
  • Fibrosis-inducing agents, hemostatic agents, and/or anti-infective agents may be linked by occlusion in the matrices of the polymer, bound by covalent linkages, or encapsulated in microcapsules.
  • therapeutic compositions are provided in non- capsular formulations such as microspheres (ranging from nanometers to micrometers in size), pastes, and threads of various size, films and sprays.
  • therapeutic compositions may be fashioned in any size ranging from 50 nm to 500 ⁇ m, depending upon the particular use (diverticula can occur in a variety of anatomical sites and sizes to be described below). These compositions can be in the form of microspheres
  • compositions can be formed, for example, by spray-drying methods, milling methods, coacervation methods, W/O (water-oil) emulsion methods, W/O/W emulsion methods, and solvent evaporation methods.
  • these compositions can include microemulsions, emulsions, liposomes and micelles. Alternatively, such compositions may also be readily applied as a
  • spray which solidifies into a film or tissue surface coating at the implantation site.
  • Such sprays may be prepared from microspheres of a wide array of sizes, including for example, from 0.1 ⁇ m to 3 ⁇ m, from 10 ⁇ m to 30 ⁇ m, and from 30 ⁇ m to 100 ⁇ m, and are ideal for delivery via the delivery port of an endoscope.
  • Therapeutic compositions of the present invention may also be prepared in a variety of paste or gel forms.
  • therapeutic compositions are provided which are liquid at one temperature (e.g., temperature greater than 37°C, such as 40 0 C, 45°C, 50 0 C, 55 0 C or 6O 0 C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37°C).
  • temperature e.g., temperature greater than 37°C, such as 40 0 C, 45°C, 50 0 C, 55 0 C or 6O 0 C
  • solid or semi-solid at another temperature e.g., ambient body temperature, or any temperature lower than 37°C.
  • Such "thermopastes” may be readily made utilizing a variety of techniques (see, e.g., PCT Publication WO 98/24427).
  • Other pastes may be applied as a liquid, which solidify in vivo due to dissolution of a water-soluble component of the paste and precipitation of encapsulated drug into the aqueous body environment.
  • polymeric carriers are provided which are adapted to contain and release a hydrophobic fibrosis- inducing, hemostatic and/or anti-infective compound, and/or the carrier containing the hydrophobic compound(s), in combination with a carbohydrate, protein or polypeptide.
  • the polymeric carrier provides sustained release for a therapeutic agent (e.g., a fibrosis-inducing agent, anti- infective agent, an antibiotic, or another type of agent) from a composition comprising the carrier and an agent.
  • the polymeric carrier contains or comprises regions, pockets, or granules of one or more hydrophobic compounds.
  • hydrophobic compounds may be incorporated within a matrix which contains the hydrophobic therapeutic compound, followed by incorporation of the matrix within the polymeric carrier.
  • matrices can be utilized in this regard, including for example, carbohydrates and polysaccharides such as starch, cellulose, dextran, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid and proteins or polypeptides such as albumin, collagen, fibrin, and/or gelatin.
  • hydrophobic compounds may be contained within a hydrophobic core, and this core contained within a hydrophilic shell.
  • the polymeric carriers used to deliver therapeutic agents into the diverticula can be materials that are formed in situ.
  • the precursors can be monomers or macromers that contain unsaturated groups which can be polymerized or crosslinked.
  • the monomers or macromers can then, for example, be injected into the diverticular sac or onto the surface of the diverticula and polymerized or crosslinked in situ using a radiation source (e.g., visible or UV light) or a free radical system (e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide).
  • a radiation source e.g., visible or UV light
  • a free radical system e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide.
  • the polymerization or crosslinking step can be performed immediately prior to, simultaneously to, or post injection of the reagents into the diverticula.
  • compositions that undergo free radical polymerization or crosslinking reactions are described in WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, and WO 00/64977, U.S. Patent Nos. 5,900,245; 6,051 ,248; 6,083,524; 6,177,095; 6,201 ,065; 6,217,894; 6,639,014; 6,352,710; 6,410,645; 6,531 ,147; 5,567,435; 5,986,043; and 6,602,975, and U.S. Patent Application Publication Nos. 2002/012796, 2002/0127266, 2002/0151650, 2003/0104032, 2002/0091229, and 2003/0059906.
  • the reagents can undergo an electrophilic-nucleophilic reaction to produce a crosslinked matrix.
  • Polymers terminated with nucleophilic groups such as amine, sulfhydryl, hydroxyl, -PH 2 or CO-NH-NH 2 can be used as the nucleophilic reagents and polymers terminated with electrophilic groups such as succinimidyl, carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(CsH 4 N) or activated esters, such as are used in peptide synthesis can be used as the electrophilic reagents.
  • a 4-armed thiol derivatized poly(ethylene glycol) e.g., pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl
  • a 4 armed NHS-derivatized polyethylene glycol e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate
  • basic conditions pH > about 8
  • the electrophilic- or nucleophilic- terminated polymers can further comprise a polymer that can enhance the mechanical and/or adhesive properties of the in situ forming compositions.
  • This polymer can be a degradable or non-degradable polymer.
  • the polymer may be collagen or a collagen derivative, for example methylated collagen.
  • An example of an in situ forming composition uses pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagen as the reactive reagents.
  • the in situ forming material polymer can be a polyester. Polyesters that can be used in in situ forming compositions include poly(hydroxyesters).
  • the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, ⁇ -decanolactone, ⁇ -decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2-one.
  • Representative examples of these types of compositions are described in U.S. Patent. Nos. 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT Publication Nos. WO 2004/028547.
  • the electrophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises an electrophilic group (e.g., disuccinimidyl glutarate).
  • a small molecule or oligomer that comprises an electrophilic group (e.g., disuccinimidyl glutarate).
  • the nucleophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises a nucleophilic group (e.g., dicysteine, dilysine, trilysine, etc.).
  • a nucleophilic group e.g., dicysteine, dilysine, trilysine, etc.
  • in situ forming materials include those based on the crosslinking of proteins (described in, for example, U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,310,036; 6,458,147; 6,371 ,975; US Patent Application Publication Nos. 2004/0063613A1 , 2002/0161399A1 , and 2001 /0018598A1 , and PCT Publication Nos.
  • crosslinked polymer compositions are prepared by reacting a first synthetic polymer containing two or more nucleophilic groups with a second synthetic polymer containing two or more electrophilic groups, where the electrophilic groups are capable of covalently binding with the nucleophilic groups.
  • the first and second polymers are each non-immunogenic.
  • the matrices are not susceptible to enzymatic cleavage by, e.g., a matrix metalloproteinase (e.g., collagenase) and are therefore expected to have greater long-term persistence in vivo than collagen-based compositions.
  • polymer refers inter alia to polyalkyls, polyamino acids, polyalkyleneoxides and polysaccharides. Additionally, for external or oral use, the polymer may be polyacrylic acid or carbopol.
  • synthetic polymer refers to polymers that are not naturally occurring and that are produced via chemical synthesis. As such, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Synthetic collagen, and synthetic hyaluronic acid, and their derivatives, are included. Synthetic polymers containing either nucleophilic or electrophilic groups are also referred to herein as "multifunctionally activated synthetic polymers.” The term
  • multifunctionally activated refers to synthetic polymers which have, or have been chemically modified to have, two or more nucleophilic or electrophilic groups which are capable of reacting with one another (i.e., the nucleophilic groups react with the electrophilic groups) to form covalent bonds.
  • Types of multifunctionally activated synthetic polymers include difunctionally activated, tetrafunctionally activated, and star-branched polymers.
  • Multifunctionally activated synthetic polymers for use in the present invention must contain at least two, more preferably, at least three, functional groups in order to form a three-dimensional crosslinked network with synthetic polymers containing multiple nucleophilic groups (i.e., "multi- nucleophilic polymers"). In other words, they must be at least difunctionally activated, and are more preferably trifunctionally or tetrafunctionally activated. If the first synthetic polymer is a difunctionally activated synthetic polymer, the second synthetic polymer must contain three or more functional groups in order to obtain a three-dimensional crosslinked network. Most preferably, both the first and the second synthetic polymer contain at least three functional groups.
  • Multi-nucleophilic polymers Synthetic polymers containing multiple nucleophilic groups are also referred to generically herein as "multi-nucleophilic polymers.”
  • multi-nucleophilic polymers must contain at least two, more preferably, at least three, nucleophilic groups. If a synthetic polymer containing only two nucleophilic groups is used, a synthetic polymer containing three or more electrophilic groups must be used in order to obtain a three- dimensional crosslinked network.
  • Preferred multi-nucleophilic polymers for use in the compositions and methods of the present invention include synthetic polymers that contain, or have been modified to contain, multiple nucleophilic groups such as primary amino groups and thiol groups.
  • Preferred multi-nucleophilic polymers include: (i) synthetic polypeptides that have been synthesized to contain two or more primary amino groups or thiol groups; and (ii) polyethylene glycols that have been modified to contain two or more primary amino groups or thiol groups.
  • reaction of a thiol group with an electrophilic group tends to proceed more slowly than reaction of a primary amino group with an electrophilic group.
  • the multi-nucleophilic polypeptide is a synthetic polypeptide that has been synthesized to incorporate amino acid residues containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
  • Poly(lysine) a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred.
  • Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
  • Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000; more preferably, within the range of about 5,000 to about 100,000; most preferably, within the range of about 8,000 to about 15,000.
  • Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.) and Aldrich Chemical (Milwaukee, Wl).
  • Polyethylene glycol can be chemically modified to contain multiple primary amino or thiol groups according to methods set forth, for example, in Chapter 22 of Poly( ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, N.Y. (1992). Polyethylene glycols which have been modified to contain two or more primary amino groups are referred to herein as "multi-amino PEGs.” Polyethylene glycols which have been modified to contain two or more thiol groups are referred to herein as "multi-thiol PEGs.” As used herein, the term "polyethylene glycol(s)" includes modified and or derivatized polyethylene glycol(s).
  • Multi-amino PEGs useful in the present invention include Huntsman's Jeffamine diamines ("D” series) and triamines ("T” series), which contain two and three primary amino groups per molecule, respectively.
  • Polyamines such as ethylenediamine (H 2 N-CH 2 -CH 2 -NH 2 ), tetramethylenediamine (H 2 N-(CH 2 ) 4 -NH 2 ), pentamethylenediamine (cadaverine) (H 2 N-(CH 2 )S-NH 2 ), hexamethylenediamine (H 2 N-(CHs) 6 -NH 2 ), di(2- aminoethyl)amine (HN-(CH 2 -CH 2 -NH 2 ) 2 ), and tris(2-aminoethyl)amine (N-(CH 2 - CH 2 -NH 2 ) 3 ) may also be used as the synthetic polymer containing multiple nucleophilic groups.
  • ethylenediamine H 2 N-CH 2 -CH 2 -NH 2
  • tetramethylenediamine H 2 N-(CH 2 ) 4 -NH 2
  • pentamethylenediamine cadaverine
  • Multi-electrophilic polymers Synthetic polymers containing multiple electrophilic groups are also referred to herein as "multi-electrophilic polymers.”
  • the multifunctionally activated synthetic polymers must contain at least two, more preferably, at least three, electrophilic groups in order to form a three-dimensional crosslinked network with multi-nucleophilic polymers.
  • Preferred multi-electrophilic polymers for use in the compositions of the invention are polymers which contain two or more succinimidyl groups capable of forming covalent bonds with nucleophilic groups on other molecules.
  • Succinimidyl groups are highly reactive with materials containing primary amino (NH 2 ) groups, such as multi-amino PEG, poly(lysine), or collagen. Succinimidyl groups are slightly less reactive with materials containing thiol (SH) groups, such as multi-thiol PEG or synthetic polypeptides containing multiple cysteine residues. As used herein, the term "containing two or more succinimidyl groups" is meant to encompass polymers which are preferably commercially available containing two or more succinimidyl groups, as well as those that must be chemically derivatized to contain two or more succinimidyl groups.
  • succinimidyl group is intended to encompass sulfosuccinimidyl groups and other such variations of the "generic" succinimidyl group.
  • the presence of the sodium sulfite moiety on the sulfosuccinimidyl group serves to increase the solubility of the polymer.
  • Hydrophilic polymers and, in particular, various derivatized polyethylene glycols are preferred for use in the compositions of the present invention.
  • PEG refers to polymers having the repeating structure (OCH 2 -CH 2 )n- Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 4 to 13 of U.S. Patent 5,874,500, incorporated herein by reference.
  • suitable PEGS include PEG succinimidyl propionate (SE-PEG), PEG succinimidyl succinamide (SSA-PEG), and PEG succinimidyl carbonate (SC-PEG).
  • the crosslinked matrix is formed in situ by reacting pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG) and pentaerythritol poly( ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) as reactive reagents. Structures for these reactants are shown in U.S. Patent 5,874,500.
  • Each of these materials has a core with a structure that may be seen by adding ethylene oxide-derived residues to each of the hydroxyl groups in pentaerythritol, and then derivatizing the terminal hydroxyl groups (derived from the ethylene oxide) to contain either thiol groups (so as to form 4-armed thiol PEG) or N-hydroxysuccinimydyl groups (so as to form 4-armed NHS
  • PEG polyethylene glycol
  • a linker group present between the ethylene oxide derived backbone and the reactive functional group, where this product is commercially available as COSEAL from Angiotech Pharmaceuticals Inc.
  • a group "D” may be present in one or both of these molecules, as discussed in more detail below.
  • preferred activated polyethylene glycol derivatives for use in the invention contain succinimidyl groups as the reactive group. However, different activating groups can be attached at sites along the length of the PEG molecule.
  • PEG can be derivatized to form functionally activated PEG propionaldehyde (A-PEG), or functionally activated PEG glycidyl ether (E-PEG), or functionally activated PEG-isocyanate (I-PEG), or functionally activated PEG-vinylsulfone (V-PEG).
  • A-PEG functionally activated PEG propionaldehyde
  • E-PEG functionally activated PEG glycidyl ether
  • I-PEG functionally activated PEG-isocyanate
  • V-PEG functionally activated PEG-vinylsulfone
  • Hydrophobic polymers can also be used to prepare the compositions of the present invention.
  • Hydrophobic polymers for use in the present invention preferably contain, or can be derivatized to contain, two or more electrophilic groups, such as succinimidyl groups, most preferably, two, three, or four electrophilic groups.
  • electrophilic groups such as succinimidyl groups, most preferably, two, three, or four electrophilic groups.
  • hydrophobic polymer refers to polymers which contain a relatively small proportion of oxygen or nitrogen atoms.
  • Hydrophobic polymers which already contain two or more succinimidyl groups include, without limitation, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-- dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
  • DSS disuccinimidyl suberate
  • BS3 bis(sulfosuccinimidyl) suberate
  • DSP dithiobis(succinimidylpropionate)
  • BSOCOES bis(2-succinimidooxycarbonyloxy) ethyl sulfone
  • DTSPP 3,3'-- dithiobis(sulfosucc
  • Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons.
  • Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups.
  • polyacids can be derivatized to contain two or more functional groups, such as succinimidyl groups.
  • Polyacids for use in the present invention include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid). Many of these polyacids are commercially available from DuPont Chemical Company (Wilmington, DE).
  • polyacids can be chemically derivatized to contain two or more succinimidyl groups by reaction with an appropriate molar amount of N-hydroxysuccinimide (NHS) in the presence of N.N'-dicyclohexylcarbodiimide (DCC).
  • NHS N-hydroxysuccinimide
  • DCC N.N'-dicyclohexylcarbodiimide
  • Polyalcohols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various methods, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers, respectively, as described in U.S. application Ser. No. 08/403,358.
  • Polyacids such as heptanedioic acid (HOOC-(CH 2 ) 5 -COOH), octanedioic acid (HOOC-(CH 2 ) 6 - COOH), and hexadecanedioic acid (HOOC-(CH 2 )i 4 -COOH) are derivatized by the addition of succinimidyl groups to produce difunctionally activated polymers.
  • heptanedioic acid HOOC-(CH 2 ) 5 -COOH
  • octanedioic acid HOOC-(CH 2 ) 6 - COOH
  • hexadecanedioic acid HOOC-(CH 2 )i 4 -COOH
  • Polyamines such as ethylenediamine, tetramethylenediamine, pentamethylenediamine (cadaverine), hexamethylenediamine, bis (2- aminoethyl)amine, and tris(2-aminoethyl)amine can be chemically derivatized to polyacids, which can then be derivatized to contain two or more succinimidyl groups by reacting with the appropriate molar amounts of N- hydroxysuccinimide in the presence of DCC, as described in U.S. application Ser. No. 08/403,358. Many of these polyamines are commercially available from DuPont Chemical Company.
  • X and Y may be the same or different, i.e., a synthetic polymer may have two different electrophilic groups, or two different nucleophilic groups, such as with glutathione.
  • the backbone of at least one of the synthetic polymers comprises alkylene oxide residues, e.g., residues from ethylene oxide, propylene oxide, and mixtures thereof.
  • alkylene oxide residues e.g., residues from ethylene oxide, propylene oxide, and mixtures thereof.
  • 'backbone' refers to a significant portion of the polymer.
  • the synthetic polymer containing alkylene oxide residues may be described by the formula X-polymer-X or Y-polymer-Y, wherein X and Y are as defined above, and the term "polymer” represents - (CH 2 CH 2 O) n - or -(CH(CH 3 )CH 2 O) n - or -(CH 2 -CH 2 -O) n -(CH(CH 3 )CH 2 -O) n -. In these cases the synthetic polymer would be difunctional.
  • the required functional group X or Y is commonly coupled to the polymer backbone by a linking group (represented below as "Q"), many of which are known or possible.
  • Q a linking group
  • Exemplary Q groups include -O-(CH 2 ) n -; -S-(CH 2 ) n -; -NH-(CH 2 V; -O 2 C-NH-(CH 2 ) n -; -O 2 C-(CHz) n -; -O 2 C-(CR 1 H) n -; and -0-R 2 -CO-NH-, which provide synthetic polymers of the partial structures: polymer-O-(CH 2 ) n -(X or Y); polymer-S-(CH 2 )n-(X or Y); polymer-NH-(CH 2 ) n -(X or Y); polymer-O 2 C-NH- (CH 2 )n-(X or Y); polymer-O 2 C-(CH 2 ) n -(X or Y); polymer-O 2 C-(CR 1 H) n -(X or Y); and polymer-O-R 2 -CO-NH-(X
  • n 1-10
  • R 1 H or alkyl (i.e., CH 3 , C 2 H 5 , etc.);
  • R 2 CH 2 , or CO-NH-CH 2 CH 2 ; and Q 1 and Q 2 may be the same or different.
  • D Polymer-O-COCH 2 CH 2 -O-Polymer.
  • An additional group, represented below as "D" can be inserted between the polymer and the linking group, if present.
  • D group One purpose of such a D group is to affect the degradation rate of the crosslinked polymer composition in vivo, for example, to increase the degradation rate, or to decrease the degradation rate. This may be useful in many instances, for example, when drug has been incorporated into the matrix, and it is desired to increase or decrease polymer degradation rate so as to influence a drug delivery profile in the desired direction.
  • An illustration of a crosslinking reaction involving first and second synthetic polymers each having D and Q groups is shown below.
  • Some useful biodegradable groups "D" include polymers formed from one or more ⁇ -hydroxy acids, e.g., lactic acid, glycolic acid, and the cyclization products thereof (e.g., lactide, glycolide), ⁇ -caprolactone, and amino acids.
  • the polymers may be referred to as polylactide, polyglycolide, poly(co- lactide-glycolide); poly- ⁇ -caprolactone, polypeptide (also known as poly amino acid, for example, various di- or tri-peptides) and poly(anhydride)s.
  • a first synthetic polymer containing multiple nucleophilic groups is mixed with a second synthetic polymer containing multiple electrophilic groups. Formation of a three-dimensional crosslinked network occurs as a result of the reaction between the nucleophilic groups on the first synthetic polymer and the electrophilic groups on the second synthetic polymer.
  • concentrations of the first synthetic polymer and the second synthetic polymer used to prepare the compositions of the present invention will vary depending upon a number of factors, including the types and molecular weights of the particular synthetic polymers used and the desired end use application. In general, when using multi-amino PEG as the first synthetic polymer, it is preferably used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition, while the second synthetic polymer is used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition.
  • a final composition having a total weight of 1 gram would contain between about 5 to about 200 milligrams of multi-amino PEG, and between about 5 to about 200 milligrams of the second synthetic polymer.
  • Use of higher concentrations of both first and second synthetic polymers will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel.
  • Compositions intended for use in tissue augmentation will generally employ concentrations of first and second synthetic polymer that fall toward the higher end of the preferred concentration range.
  • Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower polymer concentrations.
  • the second synthetic polymer is generally stored and used in sterile, dry form to prevent the loss of crosslinking ability due to hydrolysis which typically occurs upon exposure of such electrophilic groups to aqueous media.
  • Processes for preparing synthetic hydrophilic polymers containing multiple electrophylic groups in sterile, dry form are set forth in U.S. Patent 5,643,464.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • polymers containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored in aqueous solution.
  • one or both of the electrophilic- or nucleophilic-terminated polymers described above can be combined with a synthetic or naturally occurring polymer.
  • the presence of the synthetic or naturally occurring polymer may enhance the mechanical and/or adhesive properties of the in situ forming compositions.
  • Naturally occurring polymers, and polymers derived from naturally occurring polymer that may be included in in situ forming materials include naturally occurring proteins, such as collagen, collagen derivatives (such as methylated collagen), fibrinogen, thrombin, albumin, fibrin, and derivatives of and naturally occurring polysaccharides, such as glycosaminoglycans, including deacetylated and desulfated glycosaminoglycan derivatives.
  • a composition comprising naturally-occurring protein and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising albumin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally-occurring protein and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising albumin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally-occurring protein and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising methylated collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrinogen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising thrombin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising albumin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising fibrin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising naturally occurring polysaccharide and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising deacetylated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • a composition comprising desulfated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
  • the presence of protein or polysaccharide components which contain functional groups that can react with the functional groups on multiple activated synthetic polymers can result in formation of a crosslinked synthetic polymer-naturally occurring polymer matrix upon mixing and/or crosslinking of the synthetic polymer(s).
  • the electrophilic groups on the second synthetic polymer will react with the primary amino groups on these components, as well as the nucleophilic groups on the first synthetic polymer, to cause these other components to become part of the polymer matrix.
  • lysine-rich proteins such as collagen may be especially reactive with electrophilic groups on synthetic polymers.
  • the naturally occurring protein is polymer may be collagen.
  • collagen or “collagen material” refers to all forms of collagen, including those which have been processed or otherwise modified and is intended to encompass collagen of any type, from any source, including, but not limited to, collagen extracted from tissue or produced recombinantly, collagen analogues, collagen derivatives, modified collagens, and denatured collagens, such as gelatin.
  • collagen from any source may be included in the compositions of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
  • human or other mammalian source such as bovine or porcine corium and human placenta
  • the preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art.
  • U.S. Patent No. 5,428,022 discloses methods of extracting and purifying collagen from the human placenta.
  • U.S. Patent No. 5,667,839 discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows.
  • Collagen of any type including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred.
  • Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a xenogeneic source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
  • Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used.
  • Non-crosslinked atelopeptide fibrillar collagen is commercially available from I named Aesthetics (Santa Barbara, CA) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM I Collagen and ZYDERM Il Collagen, respectively.
  • Glutaraldehyde crosslinked atelopeptide fibrillar collagen is commercially available from lnamed Corporation (Santa Barbara, CA) at a collagen concentration of 35 mg/ml under the trademark ZYPLAST Collagen.
  • Collagens for use in the present invention are generally in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml; preferably, between about 30 mg/ml to about 90 mg/ml.
  • nonfibrillar collagen may be preferred for use in compositions that are intended for use as bioadhesives.
  • nonfibrillar collagen refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.
  • Collagen that is already in nonfibrillar form may be used in the compositions of the invention.
  • nonfibrillar collagen is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH.
  • Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.
  • Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, issued Aug.
  • methylated collagen is particularly preferred for use in bioadhesive compositions, as disclosed in U.S. application Ser. No. 08/476,825.
  • Collagens for use in the crosslinked polymer compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agent.
  • the fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above.
  • Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids (e.g., arginine), inorganic salts (e.g., sodium chloride and potassium chloride), and carbohydrates (e.g., various sugars including sucrose).
  • the polymer may be collagen or a collagen derivative, for example methylated collagen.
  • An example of an in situ forming composition uses pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4- armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagen as the reactive reagents.
  • This composition when mixed with the appropriate buffers can produce a crosslinked hydrogel.
  • the naturally occurring polymer may be a glycosaminoglycan.
  • Glycosaminoglycans e.g., hyaluronic acid
  • glycosaminoglycan may be derivatized.
  • glycosaminoglycans can be chemically derivatized by, e.g., deacetylation, desulfation, or both in order to contain primary amino groups available for reaction with electrophilic groups on synthetic polymer molecules.
  • Glycosaminoglycans that can be derivatized according to either or both of the aforementioned methods include the following: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate, and heparin.
  • Derivatization of glycosaminoglycans by deacetylation and/or desulfation and covalent binding of the resulting glycosaminoglycan derivatives with synthetic hydrophilic polymers is described in further detail in commonly assigned, allowed U.S. patent application Ser. No..08/146,843, filed Nov. 3, 1993.
  • the collagen is added to the first synthetic polymer, then the collagen and first synthetic polymer are mixed thoroughly to achieve a homogeneous composition.
  • the second synthetic polymer is then added and mixed into the collagen/first synthetic polymer mixture, where it will covalently bind to primary amino groups or thiol groups on the first synthetic polymer and primary amino groups on the collagen, resulting in the formation of a homogeneous crosslinked network.
  • Various deacetylated and/or desulfated glycosaminoglycan derivatives can be incorporated into the composition in a similar manner as that described above for collagen.
  • hydrocolloids such as carboxymethylceilulose may promote tissue adhesion and/or swellability.
  • compositions of the present invention having two synthetic polymers may be administered before, during or after crosslinking of the first and second synthetic polymer.
  • Certain uses, which are discussed in greater detail below, such as tissue augmentation, may require the compositions to be crosslinked before administration, whereas other applications, such as tissue adhesion, require the compositions to be administered before crosslinking has reached "equilibrium.”
  • the point at which crosslinking has reached equilibrium is defined herein as the point at which the composition no longer feels tacky or sticky to the touch.
  • the first synthetic polymer and second synthetic polymer may be contained within separate barrels of a dual-compartment syringe.
  • the two synthetic polymers do not actually mix until the point at which the two polymers are extruded from the tip of the syringe needle into the patient's tissue. This allows the vast majority of the crosslinking reaction to occur in situ, avoiding the problem of needle blockage which commonly occurs if the two synthetic polymers are mixed too early and crosslinking between the two components is already too advanced prior to delivery from the syringe needle.
  • first synthetic polymer and second synthetic polymer may be mixed according to the methods described above prior to delivery to the tissue site, then injected to the desired tissue site immediately (preferably, within about 60 seconds) following mixing.
  • first synthetic polymer and second synthetic polymer are mixed, then extruded and allowed to crosslink into a sheet or other solid form. The crosslinked solid is then dehydrated to remove substantially all unbound water.
  • the resulting dried solid may be ground or comminuted into particulates, then suspended in a nonaqueous fluid carrier, including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid.
  • a nonaqueous fluid carrier including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid.
  • the suspension of particulates can be injected through a small- gauge needle to a tissue site
  • the first and/or second synthetic polymers may be combined with a hydrophilic polymer, e.g., collagen or methylated collagen, to form a composition useful in the present invention.
  • a hydrophilic polymer e.g., collagen or methylated collagen
  • the compositions useful in the present invention include a hydrophilic polymer in combination with two or more crosslinkable components. This embodiment is described in further detail in this section.
  • the hydrophilic polymer component may be a synthetic or naturally occurring hydrophilic polymer.
  • Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen and derivatives thereof, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and poiygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
  • Collagen [e.g., methylated collagen) and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.
  • collagen from any source may be used in the composition of the method; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
  • human or other mammalian source such as bovine or porcine corium and human placenta
  • the preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. See, e.g., U.S. Pat. No. 5,428,022, to Palefsky et al., which discloses methods of extracting and purifying collagen from the human placenta. See also U.S. Patent No. 5,667,839, to Berg, which discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows.
  • collagen refers to all forms of collagen, including those that have been processed or otherwise modified.
  • Collagen of any type including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred.
  • Either atelopeptide or telopeptide- containing collagen may be used; however, when collagen from a source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
  • Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used.
  • Non-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation (Santa Barbara, Calif.) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM ® I Collagen and ZYDERM ® Il Collagen, respectively.
  • Glutaraldehyde-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation at a collagen concentration of 35 mg/ml under the trademark ZYPLAST ® .
  • Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml.
  • nonfibrillar collagen refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen. Collagen that is already in nonfibrillar form may be used in the compositions of the invention.
  • nonfibrillar collagen is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH.
  • Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.
  • Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen, propylated collagen, ethylated collagen, methylated collagen, and the like, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, to Miyata et al., which is hereby incorporated by reference in its entirety. Due to its inherent tackiness, methylated collagen is particularly preferred, as disclosed in U.S. Patent No. 5,614,587 to Rhee et al.
  • Collagens for use in the crosslinkable compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agents.
  • the fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above.
  • Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred.
  • Preferred biocompatible alcohols include glycerol and propylene glycol.
  • Non-biocompatible alcohols such as ethanol, methanol, and isopropanol
  • Preferred amino acids include arginine
  • Preferred inorganic salts include sodium chloride and potassium chloride.
  • carbohydrates such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.
  • fibrillar collagen has less surface area and a lower concentration of reactive groups than nonfibrillar, fibrillar collagen is less preferred.
  • fibrillar collagen or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compositions intended for long-term persistence in vivo, if optical clarity is not a requirement.
  • Synthetic hydrophilic polymers may also be used in the present invention.
  • Useful synthetic hydrophilic polymers include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly( ethylene oxide)- poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di- polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalky
  • compositions of the invention also comprise a plurality of crosslinkable components.
  • Each of the crosslinkable components participates in a reaction that results in a crosslinked matrix.
  • the crosslinkable components Prior to completion of the crosslinking reaction, the crosslinkable components provide the necessary adhesive qualities that enable the methods of the invention.
  • the crosslinkable components are selected so that crosslinking gives rise to a biocompatible, nonimmunogenic matrix useful in a variety of contexts including adhesion prevention, biologically active agent delivery, tissue augmentation, and other applications.
  • the crosslinkable components of the invention comprise: a component A, which has m nucleophilic groups, wherein m > 2 and a component B, which has n electrophilic groups capable of reaction with the m nucleophilic groups, wherein n > 2 and m + n > 4.
  • An optional third component, optional component C which has at least one functional group that is either electrophilic and capable of reaction with the nucleophilic groups of component A, or nucleophilic and capable of reaction with the electrophilic groups of component B may also be present.
  • the total number of functional groups present on components A, B and C, when present, in combination is > 5; that is, the total functional groups given by m + n + p must be > 5, where p is the number of functional groups on component C and, as indicated, is > 1.
  • Each of the components is biocompatible and nonimmunogenic, and at least one component is comprised of a hydrophilic polymer.
  • the composition may contain additional crosslinkable components D 1 E, F, etc., having one or more reactive nucleophilic or electrophilic groups and thereby participate in formation of the crosslinked biomaterial via covalent bonding to other components.
  • the m nucleophilic groups on component A may all be the same, or, alternatively, A may contain two or more different nucleophilic groups.
  • the n electrophilic groups on component B may all be the same, or two or more different electrophilic groups may be present.
  • the functional group(s) on optional component C if nucleophilic, may or may not be the same as the nucleophilic groups on component A, and, conversely, if electrophilic, the functional group(s) on optional component C may or may not be the same as the electrophilic groups on component B.
  • R 1 , R 2 and R 3 are independently selected from the group consisting of C 2 to C14 hydrocarbyl, heteroatom-containing C 2 to C 14 hydrocarbyl, hydrophilic polymers, and hydrophobic polymers, providing that at least one of R 1 , R 2 and R 3 is a hydrophiiic polymer, preferably a synthetic hydrophilic polymer;
  • X represents one of the m nucleophilic groups of component A, and the various X moieties on A may be the same or different;
  • Y represents one of the n electrophilic groups of component B, and the various Y moieties on A may be the same or different;
  • Fn represents a functional group on optional component C
  • Q 1 , Q 2 and Q 3 are linking groups; m >2, n >2, m + n is ⁇ 4, q, and r are independently zero or 1 , and when optional component C is present, p >1 , and s is independently zero or 1.
  • X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y.
  • Y may be virtually any electrophilic group, so long as reaction can take place with X.
  • the only limitation is a practical one, in that reaction between X and Y should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation.
  • the reactions between X and Y should be complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.
  • nucleophilic groups suitable as X include, but are not limited to, -NH 2 , -NHR 4 , -N(R 4 ) 2 , -SH 1 -OH, -COOH, -C 6 H 4 -OH, -PH 2 , -PHR 5 , - P(R 5 ) 2 , -NH-NH 2 , -CO-NH-NH 2 , -C 5 H 4 N, etc.
  • R 4 and R 5 are hydrocarbyl, typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl.
  • Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors.
  • Organometallic nucleophiles are not, however, preferred.
  • organometallic moieties include: Grignard functionalities -R 6 MgHaI wherein R 6 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities.
  • nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophile.
  • the composition when there are nucleophilic sulfhydryl and hydroxyl groups in the crosslinkable composition, the composition must be admixed with an aqueous base in order to remove a proton and provide an -S " or -O " species to enable reaction with an electrophile.
  • a nonnucleophilic base is preferred.
  • the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described infra in Section E.
  • electrophilic groups provided within the crosslinkable composition i.e., on component B, must be made so that reaction is possible with the specific nucleophilic groups.
  • the Y groups are selected so as to react with amino groups.
  • the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
  • a carboxylic acid group perse is not susceptible to reaction with a nucleophilic amine
  • components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • a carboxylic acid can be reacted with an alkoxy-substituted N- hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N- hydroxysulfosuccinimide ester, respectively.
  • Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group.
  • a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction.
  • thionyl chloride or an acyl chloride capable of an exchange reaction Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.
  • the electrophilic groups present on Y are groups that react with a sulfhydryl moiety.
  • Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in PCT Publication No. WO 00/62827 to Wallace et al.
  • such "sulfhydryl reactive" groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N- hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N- hydroxyglutarimide esters; esters of 1-hydroxybenzotriazole; 3-hydroxy-3,4- dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.
  • auxiliary reagents can also be used to facilitate bond formation, e.g., i-ethyl-S- ⁇ -dimethylaminopropyllcarbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
  • sulfhydryl reactive groups that form thioester linkages
  • various other sulfhydryl reactive functionalities can be utilized that form other types of linkages.
  • compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
  • sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron- withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o- nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc.
  • auxiliary reagents i.e., mild oxidizing agents such as hydrogen peroxide, can be used to facilitate disulfide bond formation.
  • sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups.
  • groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and ⁇ , ⁇ -unsatu rated aldehydes and ketones.
  • This class of sulfhydryl reactive groups are particularly preferred as the thioether bonds may provide faster crosslinking and longer in vivo stability.
  • the electrophilic functional groups on the remaining component(s) must react with hydroxyl groups.
  • the hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophile such as an epoxide group, an aziridine group, an acyl halide, or an anhydride.
  • suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.
  • a carboxylic acid group can act as a nucleophile in the presence of a fairly strong base, but generally acts as an electrophile allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophile.
  • covalent linkages in the crosslinked structure that result upon covalent binding of specific nucleophilic components to specific electrophilic components in the crosslinkable composition include, solely by way of example, the following (the optional linking groups Q 1 and Q 2 are omitted for clarity):
  • the functional groups X and Y and FN on optional component C may be directly attached to the compound core (R 1 , R 2 or R 3 on optional component C 1 respectively), or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders.”
  • chain extenders In structural formulae (I), (II) and (III), the optional linking groups are represented by Q 1 , Q 2 and Q 3 , wherein the linking groups are present when q, r and s are equal to 1 (with R, X, Y, Fn, m n and p as defined previously).
  • linking groups are well known in the art. See, for example, International Patent Publication No. WO 97/22371. Linking groups are useful to avoid steric hindrance problems that are sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several multifunctionally activated compounds together to make larger molecules. In a preferred embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be incorporated into components A, B, or optional component C to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
  • linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride linkages, such as obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; ⁇ -hydroxy acid linkages, such as may be obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as may be obtained by incorporation of caprolactone, valerolactone, ⁇ -butyrolactone and p- dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment.
  • non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, PCT WO 99/07417.
  • enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
  • Linking groups can also enhance or suppress the reactivity of the various nucleophilic and electrophilic groups.
  • electron- withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect.
  • electron-withdrawing groups adjacent to a carbonyl group e.g., the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl
  • sterically bulky groups in the vicinity of a functional group can be used to diminish reactivity and thus coupling rate as a result of steric hindrance.
  • n is generally in the range of 1 to about 10
  • R 7 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower aikyl
  • R 8 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • lower alkylene e.g., methylene, ethylene, n-propylene, n-butylene, etc.
  • phenylene or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • linking groups are as follows: If higher molecular weight components are to be used, they preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
  • the Component Core The "core" of each crosslinkable component is comprised of the molecular structure to which the nucleophilic or electrophilic groups are bound. Using the formulae (I) R 1 -[Q 1 ] q -X) m , for component A, (II) R 2 (-[Q 2 ] r Y) n for component B, and (111)
  • each molecular core of the reactive components of the crosslinkable composition is generally selected from synthetic and naturally occurring hydrophilic polymers, hydrophobic polymers, and C 2 -C 14 hydrocarbyl groups zero to 2 heteroatoms selected from N, O and S 1 with the proviso that at least one of the crosslinkable components A, B, and optionally C, comprises a molecular core of a synthetic hydrophilic polymer.
  • at least one of A and B comprises a molecular core of a synthetic hydrophilic polymer.
  • the crosslinkable component(s) is (are) hydrophilic polymers.
  • hydrophilic polymer refers to a synthetic polymer having an average molecular weight and composition effective to render the polymer "hydrophilic" as defined above.
  • synthetic crosslinkable hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly( ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di- polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethyl)
  • the synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
  • the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
  • the polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer.
  • Biodegradable segments are those that degrade so as to break covalent bonds.
  • biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ.
  • Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc.
  • Larger biodegradable "blocks” will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer.
  • Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
  • Suitable synthetic crosslinkable hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
  • Poly(lysine) a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred.
  • Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
  • Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000.
  • Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).
  • the synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
  • the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
  • the polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ.
  • Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc.
  • Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer.
  • Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
  • preferred synthetic crosslinkable hydrophilic polymers are polyethylene glycol (PEG) and polyglycerol (PG), particularly highly branched polyglycerol.
  • PEG polyethylene glycol
  • PG polyglycerol
  • Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and do not typically interfere with the enzymatic activities and/or conformations of peptides.
  • a particularly preferred synthetic crosslinkable hydrophilic polymer for certain applications is a polyethylene glycol (PEG) having a molecular weight within the range of about 100 to about 100,000 mol. wt., although for highly branched PEG, far higher molecular weight polymers can be employed - up to 1 ,000,000 or more - providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000.
  • the preferred molecular weight is about 1 ,000 to about 20,000 mol. wt., more preferably within the range of about 7,500 to about 20,000 mol. wt.
  • the polyethylene glycol has a molecular weight of approximately 10,000 mol. wt.
  • Naturally occurring crosslinkable hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
  • Collagen and glycosaminoglycans are examples of naturally occurring hydrophilic polymers for use herein, with methylated collagen being a preferred hydrophilic polymer.
  • hydrophilic polymers herein must contain, or be activated to contain, functional groups, i.e., nucleophilic or electrophilic groups, which enable crosslinking. Activation of PEG is discussed below; it is to be understood, however, that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.
  • Activated forms of PEG are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly( ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992); and Shearwater Polymers, Inc. Catalog, Polyethylene Glycol Derivatives, Huntsville, Alabama (1997-1998).
  • FIGS. 1 to 10 of U.S. Patent 5,874,500 Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 1 to 10 of U.S. Patent 5,874,500, as are generalized reaction products obtained by reacting the activated PEGs with multi-amino PEGs, i.e., a PEG with two or more primary amino groups.
  • the activated PEGs illustrated have a pentaerythritol (2,2-bis(hydroxymethyl)-1 ,3-propanediol) core.
  • Such activated PEGs are readily prepared by conversion of the exposed hydroxyl groups in the PEGylated polyol (i.e., the terminal hydroxyl groups on the PEG chains) to carboxylic acid groups (typically by reaction with an anhydride in the presence of a nitrogenous base), followed by esterification with N-hydroxysuccinimide, N- hydroxysulfosuccinimide, or the like, to give the polyfunctionally activated PEG.
  • the crosslinkable compositions of the invention can also include hydrophobic polymers, although for most uses hydrophilic polymers are preferred.
  • Polylactic acid and polyglycolic acid are examples of two hydrophobic polymers that can be used. With other hydrophobic polymers, only short-chain oligomers should be used, containing at most about 14 carbon atoms, to avoid solubility-related problems during reaction.
  • Low Molecular Weight Components :
  • the molecular core of one or more of the crosslinkable components can also be a low molecular weight compound, i.e., a C 2 -Ci 4 hydrocarbyl group containing zero to 2 heteroatoms selected from N, O, S and combinations thereof.
  • a molecular core can be substituted with nucleophilic groups or with electrophilic groups.
  • the component may be, for example, ethylenediamine (H 2 N-CH 2 CH 2 -NH 2 ), tetramethylenediamine (H 2 N-(CH 4 )-NH 2 ), pentamethylenediamine (cadaverine) (H 2 N-(CHs)-NH 2 ), hexamethylenediamine (H 2 N-(CHe)-NH 2 ), bis(2-aminoethyl)amine (HN-[CH 2 CH 2 -NH 2 ] 2 ), or tris(2- aminoethyl)amine (N-[CH 2 CH 2 -NH 2 ] 3 ).
  • ethylenediamine H 2 N-CH 2 CH 2 -NH 2
  • tetramethylenediamine H 2 N-(CH 4 )-NH 2
  • pentamethylenediamine cadaverine
  • H 2 N-(CHs)-NH 2 hexamethylenediamine
  • bis(2-aminoethyl)amine HN-[CH 2 CH
  • Low molecular weight diols and polyols include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol, all of which require activation with a base in order to facilitate their reaction as nucleophiles.
  • Such diols and polyols may also be functionalized to provide di- and poly-carboxylic acids, functional groups that are, as noted earlier herein, also useful as nucleophiles under certain conditions.
  • Polyacids for use in the present compositions include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid), all of which are commercially available and/or readily synthesized using known techniques.
  • Low molecular weight di- and poly-electrophiles include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS 3 ), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
  • DSS disuccinimidyl suberate
  • BS 3 bis(sulfosuccinimidyl) suberate
  • DSP dithiobis(succinimidylpropionate)
  • BSOCOES bis(2-succinimidooxycarbonyloxy) ethyl sulfone
  • DTSPP 3,3'-dithiobis(sulfosuccin
  • di- and poly- electrophiles can also be synthesized from di- and polyacids, for example by reaction with an appropriate molar amount of N-hydroxysuccinimide in the presence of DCC.
  • Polyols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various known techniques, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers.
  • Suitable delivery systems for the homogeneous dry powder composition (containing at least two crosslinkable polymers) and the two buffer solutions may involve a multi-compartment spray device, where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment.
  • a multi-compartment spray device where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment.
  • Many devices that are adapted for delivery of multi-component tissue sealants/hemostatic agents are well known in the art and can also be used in the practice of the present invention.
  • the composition can be delivered using any type of controllable extrusion system, or it can be delivered manually in the form of a dry powder, and exposed to the aqueous environment at the site of administration.
  • the homogeneous dry powder composition and the two buffer solutions may be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acidic buffer solution and basic buffer solution) into separate syringe barrels.
  • the composition, first buffer solution and second buffer solution can be housed separately in a multiple-compartment syringe system having a multiple barrels, a mixing head, and an exit orifice.
  • the first buffer solution can be added to the barrel housing the composition to dissolve the composition and form a homogeneous solution, which is then extruded into the mixing head.
  • the second buffer solution can be simultaneously extruded into the mixing head.
  • the resulting composition can then be extruded through the orifice onto a surface.
  • the syringe barrels holding the dry powder and the basic buffer may be part of a dual-syringe system, e.g., a double barrel syringe as described in U.S. Patent 4,359,049 to Redl et al.
  • the acid buffer can be added to the syringe barrel that also holds the dry powder, so as to produce the homogeneous solution.
  • the acid buffer may be added (e.g., injected) into the syringe barrel holding the dry powder to thereby produce a homogeneous solution of the first and second components. This homogeneous solution can then be extruded into a mixing head, while the basic buffer is simultaneously extruded into the mixing head.
  • the homogeneous solution and the basic buffer are mixed together to thereby form a reactive mixture.
  • the reactive mixture is extruded through an orifice and onto a surface (e.g., tissue), where a film is formed, which can function as a sealant or a barrier, or the like.
  • the reactive mixture begins forming a three-dimensional matrix immediately upon being formed by the mixing of the homogeneous solution and the basic buffer in the mixing head. Accordingly, the reactive mixture is preferably extruded from the mixing head onto the tissue very quickly after it is formed so that the three-dimensional matrix forms on, and is able to adhere to, the tissue.
  • the electrophilic component or components are generally stored and used in sterile, dry form to prevent hydrolysis.
  • Processes for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in sterile, dry form are set forth in commonly assigned U.S. Patent No. 5,643,464 to Rhee et al.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • Components containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored either dry or in aqueous solution. If stored as a dry, particulate, solid, the various components of the crosslinkable composition may be blended and stored in a single container. Admixture of all components with water, saline, or other aqueous media should not occur until immediately prior to use.
  • the crosslinking components can be mixed together in a single aqueous medium in which they are both unreactive, i.e., such as in a low pH buffer. Thereafter, they can be sprayed onto the targeted tissue site along with a high pH buffer, after which they will rapidly react and form a gel.
  • Suitable liquid media for storage of crosslinkable compositions include aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM.
  • a sulfhydryl-reactive component such as PEG substituted with maleimido groups or succinimidyl esters is prepared in water or a dilute buffer, with a pH of between around 5 to 6.
  • Buffers with pKs between about 8 and 10.5 for preparing a polysulfhydryl component such as sulfhydryl-PEG are useful to achieve fast gelation time of compositions containing mixtures of sulfhydryl-PEG and SG-PEG.
  • These include carbonate, borate and AMPSO (3-[(1 ,1-dimethyl-2 ⁇ hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid).
  • a pH of around 5 to 9 is preferred for the liquid medium used to prepare the sulfhydryl PEG.
  • Collagen + Fibrinogen and/or Thrombin e.g., Costasis
  • the polymer composition may include collagen in combination with fibrinogen and/or thrombin.
  • an aqueous composition may include a fibrinogen and FXIII, particularly plasma, collagen in an amount sufficient to thicken the composition, thrombin in an amount sufficient to catalyze polymerization of fibrinogen present in the composition, and Ca 2+ and, optionally, an antifibrinolytic agent in amount sufficient to retard degradation of the resulting adhesive clot.
  • the composition may be formulated as a two-part composition that may be mixed together just prior to use, in which fibrinogen/FXIII and collagen constitute the first component, and thrombin together with an antifibrinolytic agent, and Ca 2+ constitute the second component.
  • Plasma which provides a source of fibrinogen
  • the plasma may be obtained from the patient for which the composition is to be delivered.
  • the plasma can be used "as is" after standard preparation which includes centrifuging out cellular components of blood.
  • the plasma can be further processed to concentrate the fibrinogen to prepare a plasma cryoprecipitate.
  • the plasma cryoprecipitate can be prepared by freezing the plasma for at least about an hour at about -20 °C, and then storing the frozen plasma overnight at about 4 °C to slowly thaw.
  • the thawed plasma is centrifuged and the plasma cryoprecipitate is harvested by removing approximately four-fifths of the plasma to provide a cryoprecipitate comprising the remaining one-fifth of the plasma.
  • fibrinogen/FXIII preparations may be used, such as cryoprecipitate, patient autologous fibrin sealant, fibrinogen analogs or other single donor or commercial fibrin sealant materials.
  • Approximately 0.5 ml to about 1.0 ml of either the plasma or the plasma-cryoprecipitate provides about 1 to 2 ml of adhesive composition which is sufficient for use in middle ear surgery.
  • Other plasma proteins e.g., albumin, plasminogen, von Willebrands factor, Factor VIII, etc.
  • Collagen preferably hypoallergenic collagen
  • the collagen may be atelopeptide collagen or telopeptide collagen, e.g., native collagen.
  • the collagen augments the fibrin by acting as a macromolecular lattice work or scaffold to which the fibrin network adsorbs. This gives more strength and durability to the resulting glue clot with a relatively low concentration of fibrinogen in comparison to the various concentrated autogenous fibrinogen glue formulations (i.e., AFGs).
  • the form of collagen which is employed may be described as at least "near native" in its structural characteristics. It may be further characterized as resulting in insoluble fibers at a pH above 5; unless crosslinked or as part of a complex composition, e.g., bone, it will generally consist of a minor amount by weight of fibers with diameters greater than 50 nm, usually from about 1 to 25 volume % and there will be substantially little, if any, change in the helical structure of the fibrils.
  • the collagen composition must be able to enhance gelation in the surgical adhesion composition.
  • ZYDERM Collagen Implant has a fibrillar diameter distribution consisting of 5 to 10 nm diameter fibers at 90% volume content and the remaining 10% with greater than about 50 nm diameter fibers.
  • ZCI is available as a fibrillar slurry and solution in phosphate buffered isotonic saline, pH 7.2, and is injectable with fine gauge needles.
  • cross-linked collagen available as ZYPLAST may be employed.
  • ZYPLAST is essentially an exogenously crosslinked (glutaraldehyde) version of ZCl. The material has a somewhat higher content of greater than about 50 nm diameter fibrils and remains insoluble over a wide pH range. Crosslinking has the effect of mimicking in vivo endogenous crosslinking found in many tissues.
  • Thrombin acts as a catalyst for fibrinogen to provide fibrin, an insoluble polymer and is present in the composition in an amount sufficient to catalyze polymerization of fibrinogen present in the patient plasma. Thrombin also activates FXIII, a plasma protein that catalyzes covalent crosslinks in fibrin, rendering the resultant clot insoluble.
  • FXIII a plasma protein that catalyzes covalent crosslinks in fibrin, rendering the resultant clot insoluble.
  • the thrombin is present in the adhesive composition in concentration of from about 0.01 to about 1000 or greater NIH units (NIHu) of activity, usually about i to about 500 NlHu, most usually about 200 to about 500 NIHu.
  • the thrombin can be from a variety of host animal sources, conveniently bovine.
  • Thrombin is commercially available from a variety of sources including Parke-Davis, usually lyophilized with buffer salts and stabilizers in vials which provide thrombin activity ranging from about 1000 NIHu to 10,000 NIHu.
  • the thrombin is usually prepared by reconstituting the powder by the addition of either sterile distilled water or isotonic saline. Alternately, thrombin analogs or reptile-sourced coagulants may be used.
  • the composition may additionally comprise an effective amount of an antifibrinolytic agent to enhance the integrity of the glue clot as the healing processes occur.
  • antifibrinolytic agents include aprotinin, C1 -esterase inhibitor and ⁇ -amino-n-caproic acid (EACA).
  • ⁇ - amino-n-caproic acid the only antifibrinolytic agent approved by the FDA, is effective at a concentration of from about 5 mg/ml to about 40 mg/ml of the final adhesive composition, more usually from about 20 to about 30 mg/ml.
  • EACA is commercially available as a solution having a concentration of about 250 mg/ml. Conveniently, the commercial solution is diluted with distilled water to provide a solution of the desired concentration. That solution is desirably used to reconstitute lyophilized thrombin to the desired thrombin concentration.
  • in situ forming materials based on the crosslinking of proteins are described, e.g., in U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,458,147; 6,371 ,975; 5,290,552; 6,096,309; U.S. Patent Application Publication Nos. 2002/0161399; 2001/0018598 and PCT Publication Nos. WO 03/090683; WO 01/45761 ; WO 99/66964 and WO 96/03159).
  • the therapeutic agent is released from a crosslinked matrix formed, at least in part, from a self-reactive compound.
  • a self-reactive compound comprises a core substituted with a minimum of three reactive groups.
  • the reactive groups may be directed attached to the core of the compound, or the reactive groups may be indirectly attached to the compound's core, e.g., the reactive groups are joined to the core through one or more linking groups.
  • Each of the three reactive groups that are necessarily present in a self-reactive compound can undergo a bond-forming reaction with at least one of the remaining two reactive groups.
  • the term "self-reactive” is not intended to mean that each self-reactive compound necessarily reacts with itself, but rather that when a plurality of identical self-reactive compounds are in combination and undergo a crosslinking reaction, then these compounds will react with one another to form the matrix.
  • the compounds are "self-reactive" in the sense that they can react with other compounds having the identical chemical structure as themselves.
  • the self-reactive compound comprises at least four components: a core and three reactive groups.
  • the self-reactive compound can be characterized by the formula (I), where R is the core, the reactive groups are represented by X 1 , X 2 and X 3 , and a linker (L) is optionally present between the core and a functional group.
  • the core R is a polyvalent moiety having attachment to at least three groups (i.e., it is at least trivalent) and may be, or may contain, for example, a hydrophilic polymer, a hydrophobic polymer, an amphiphilic polymer, a C 2-I4 hydrocarbyl, or a C 2 - 14 hydrocarbyl which is heteroatom- containing.
  • the linking groups L 1 , L 2 , and L 3 may be the same or different.
  • the designators p, q and r are either 0 (when no linker is present) or 1 (when a linker is present).
  • the reactive groups X 1 , X 2 and X 3 may be the same or different.
  • each of these reactive groups reacts with at least one other reactive group to form a three-dimensional matrix. Therefore X 1 can react with X 2 and/or X 3 , X 2 can react with X 1 and/or X 3 , X 3 can react with X 1 and/or X 2 and so forth.
  • a trivalent core will be directly or indirectly bonded to three functional groups, a tetravalent core will be directly or indirectly bonded to four functional groups, etc.
  • Each side chain typically has one reactive group.
  • the invention also encompasses self-reactive compounds where the side chains contain more than one reactive group.
  • the self-reactive compound has the formula (II):
  • X' - O-V Y' - O ⁇ J C R' where: a and b are integers from 0-1 ; c is an integer from 3-12; R' is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C 2- i 4 hydrocarbyls, and heteroatom-containing C 2 - 14 hydrocarbyls; X' and Y' are reactive groups and can be the same or different; and L 4 and L 5 are linking groups. Each reactive group inter-reacts with the other reactive group to form a three-dimensional matrix.
  • the compound is essentially non-reactive in an initial environment but is rendered reactive upon exposure to a modification in the initial environment that provides a modified environment such that a plurality of the self-reactive compounds inter-react in the modified environment to form a three-dimensional matrix.
  • R is a hydrophilic polymer.
  • X 1 is a nucleophilic group and Y' is an electrophilic group.
  • the following self-reactive compound is one example of a compound of formula (II):
  • R 4 has the formula:
  • the reactive groups are selected so that the compound is essentially non-reactive in an initial environment.
  • the compound Upon exposure to a specific modification in the initial environment, providing a modified environment, the compound is rendered reactive and a plurality of self-reactive compounds are then able to inter-react in the modified environment to form a three-dimensional matrix.
  • modification in the initial environment include the addition of an aqueous medium, a change in pH, exposure to ultraviolet radiation, a change in temperature, or contact with a redox initiator.
  • the core and reactive groups can also be selected so as to provide a compound that has one of more of the following features: are biocompatible, are non-immunogenic, and do not leave any toxic, inflammatory or immunogenic reaction products at the site of administration.
  • the core and reactive groups can also be selected so as to provide a resulting matrix that has one or more of these features.
  • the self-reactive compounds inter-react form a three-dimensional matrix.
  • the term "substantially immediately” is intended to mean within less than five minutes, preferably within less than two minutes, and the term “immediately” is intended to mean within less than one minute, preferably within less than 30 seconds.
  • the self-reactive compound and resulting matrix are not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and are therefore not readily degradable in vivo.
  • the self-reactive compound may be readily tailored, in terms of the selection and quantity of each component, to enhance certain properties, e.g., compression strength, swellability, tack, hydrophilicity, optical clarity, and the like.
  • R is a hydrophilic polymer.
  • X is a nucleophilic group
  • Y is an electrophilic group
  • Z is either an electrophilic or a nucleophilic group. Additional embodiments are detailed below.
  • a higher degree of inter-reaction e.g., crosslinking
  • n be an integer from 2-12.
  • the compounds may be the same or different.
  • the self-reactive compound Prior to use, the self-reactive compound is stored in an initial environment that insures that the compound remain essentially non-reactive until use. Upon modification of this environment, the compound is rendered reactive and a plurality of compounds will then inter-react to form the desired matrix.
  • the initial environment, as well as the modified environment, is thus determined by the nature of the reactive groups involved.
  • the number of reactive groups can be the same or different. However, in one embodiment of the invention, the number of reactive groups are approximately equal. As used in this context, the term “approximately” refers to a 2:1 to 1 :2 ratio of moles of one reactive group to moles of a different reactive groups. A 1 :1 :1 molar ratio of reactive groups is generally preferred.
  • the concentration of the self-reactive compounds in the modified environment when liquid in nature, will be in the range of about 1 to 50 wt%, generally about 2 to 40 wt%.
  • the preferred concentration of the compound in the liquid will depend on a number of factors, including the type of compound (i.e., type of molecular core and reactive groups), its molecular weight, and the end use of the resulting three-dimensional matrix. For example, use of higher concentrations of the compounds, or using highly functionalized compounds, will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel.
  • compositions intended for use in tissue augmentation will generally employ concentrations of self-reactive compounds that fall toward the higher end of the preferred concentration range.
  • Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower concentrations of the self-reactive compounds.
  • the reactive groups are electrophilic and nucleophilic groups, which undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both.
  • electrophilic refers to a reactive group that is susceptible to nucleophilic attack, i.e., susceptible to reaction with an incoming nucleophilic group.
  • Electrophilic groups herein are positively charged or electron-deficient, typically electron- deficient.
  • nucleophilic refers to a reactive group that is electron rich, has an unshared pair of electrons acting as a reactive site, and reacts with a positively charged or electron-deficient site.
  • the modification in the initial environment comprises the addition of an aqueous medium and/or a change in pH.
  • X1 also referred to herein as
  • X can be a nucleophilic group and X2 (also referred to herein as Y) can be an electrophilic group or vice versa, and X3 (also referred to herein as Z) can be either an electrophilic or a nucleophilic group.
  • X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y and also with Z, when Z is electrophilic (ZEL)-
  • Y may be virtually any electrophilic group, so long as reaction can take place with X and also with Z when Z is nucleophilic (ZNU)-
  • the only limitation is a practical one, in that reaction between X and Y, and X and ZEL, or Y and ZNU should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation.
  • the reactions between X and Y, and between either X and Z E L or Y and ZNU are complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.
  • nucleophilic groups suitable as X or F ⁇ NU include, but are not limited to: -NH 2 , -NHR 1 , -N(R 1 ) 2> -SH, -OH, -COOH, -C 6 H 4 -OH, -H, -PH 2 , -PHR 1 , -P(R 1 ) 2 , -NH-NH 2 , -CO-NH-NH 2 , -C 5 H 4 N, etc.
  • R 1 is a hydrocarbyl group and each R1 may be the same or different.
  • R 1 is typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl.
  • Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors.
  • organometallic moieties include: Grignard functionalities -R 2 MgHaI wherein R 2 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities.
  • nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophilic group.
  • the compound when there are nucleophilic sulfhydryl and hydroxyl groups in the self-reactive compound, the compound must be admixed with an aqueous base in order to remove a proton and provide an -S ' or -O " species to enable reaction with the electrophilic group.
  • a non- nucleophilic base is preferred.
  • the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described herein.
  • electrophilic groups provided on the self-reactive compound must be made so that reaction is possible with the specific nucleophilic groups.
  • the Y and any ZEL groups are selected so as to react with amino groups.
  • the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
  • the amine-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine, for example the carboxylic acid esters and aldehydes noted above, as well as carboxyl groups (-COOH). Since a carboxylic acid group per se is not susceptible to reaction with a nucieophilic amine, components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
  • DCC dicyclohexylcarbodiimide
  • DHU dicyclohexylurea
  • a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy- succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N- hydroxysulfosuccinimide ester, respectively.
  • Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group.
  • a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction. Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.
  • the amine-reactive groups are selected from succinimidyl ester (-0(CO)-N(COCH 2 ⁇ ), sulfosuccinimidyl ester (-O(CO)-N(COCH 2 ) 2 -S(O) 2 OH), maleimido (-N(COCH) 2 ), epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.
  • the electrophilic groups present on Y and ZEL are groups that react with a sulfhydryl moiety.
  • Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in WO 00/62827 to Wallace et al.
  • sulfhydryl reactive groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N- hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; esters of 1- hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy- 3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates.
  • auxiliary reagents can also be used to facilitate bond formation, e.g., 1 -ethyl-3-[3- dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
  • sulfhydryl reactive groups that form thioester linkages
  • various other sulfhydryl reactive functionalities can be utilized that form other types of linkages.
  • compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
  • sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron- withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o- nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc.
  • auxiliary reagents i.e., mild oxidizing agents such as hydrogen peroxide
  • sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups.
  • groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and ⁇ , ⁇ -unsaturated aldehydes and ketones.
  • the electrophilic functional groups on the remaining component(s) must react with hydroxyl groups.
  • the hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophilic group such as an epoxide group, an aziridine group, an acyl halide, an anhydride, and so forth.
  • suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes. It will also be appreciated that certain functional groups can react as nucleophilic or as electrophilic groups, depending on the selected reaction partner and/or the reaction conditions.
  • a carboxylic acid group can act as a nucleophilic group in the presence of a fairly strong base, but generally acts as an electrophilic group allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophilic group.
  • the initial environment typically can be dry and sterile. Since electrophilic groups react with water, storage in sterile, dry form will prevent hydrolysis.
  • the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or e- beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
  • the modification of a dry initial environment will typically comprise the addition of an aqueous medium.
  • the initial environment can be an aqueous medium such as in a low pH buffer, i.e., having a pH less than about 6.0, in which both electrophilic and nucleophilic groups are non-reactive.
  • aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM.
  • Modification of an initial low pH aqueous environment will typically comprise increasing the pH to at least pH 7.0, more preferably increasing the pH to at least pH 9.5.
  • the modification of a dry initial environment comprises dissolving the self-reactive compound in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution.
  • the buffer solutions are aqueous and can be any pharmaceutically acceptable basic or acid composition.
  • the term "buffer" is used in a general sense to refer to an acidic or basic aqueous solution, where the solution may or may not be functioning to provide a buffering effect (i.e., resistance to change in pH upon addition of acid or base) in the compositions of the present invention.
  • the self-reactive compound can be in the form of a homogeneous dry powder.
  • This powder is then combined with a buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous acidic aqueous solution, and this solution is then combined with a buffer solution having a pH within the range of about 6.0 to 11.0 to form a reactive solution.
  • 0.375 grams of the dry powder can be combined with 0.75 grams of the acid buffer to provide, after mixing, a homogeneous solution, where this solution is combined with 1.1 grams of the basic buffer to provide a reactive mixture that substantially immediately forms a three-dimensional matrix.
  • Acidic buffer solutions having a pH within the range of about 1.0 to 5.5 include by way of illustration and not limitation, solutions of: citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3-[(1 ,1-dimethyl-2- hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid), acetic acid, lactic acid, and combinations thereof.
  • the acidic buffer solution is a solution of citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof.
  • the acidic buffer preferably has a pH such that it retards the reactivity of the nucleophilic groups on the core.
  • the acidic buffer is an acidic solution that, when contacted with nucleophilic groups, renders those nucleophilic groups relatively non-nucleophilic.
  • An exemplary acidic buffer is a solution of hydrochloric acid, having a concentration of about 6.3 mM and a pH in the range of 2.1 to 2.3. This buffer may be prepared by combining concentrated hydrochloric acid with water, i.e., by diluting concentrated hydrochloric acid with water.
  • this buffer A may also be conveniently prepared by diluting 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or diluting 1.84 grams of concentrated hydrochloric acid to a volume to 3 liters, or diluting 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters, or diluting 3.07 grams concentrated hydrochloric acid to a volume of 5 liters, or diluting 3.68 grams of concentrated hydrochloric acid to a volume to 6 liters.
  • the concentrated acid is preferably added to water.
  • Basic buffer solutions having a pH within the range of about 6.0 to 11.0 include by way of illustration and not limitation, solutions of: glutamate, acetate, carbonate and carbonate salts (e.g., sodium carbonate, sodium carbonate monohydrate and sodium bicarbonate), borate, phosphate and phosphate salts (e.g., monobasic sodium phosphate monohydrate and dibasic sodium phosphate), and combinations thereof.
  • the basic buffer solution is a solution of carbonate salts, phosphate salts, and combinations thereof.
  • the basic buffer is an aqueous solution that neutralizes the effect of the acidic buffer, when it is added to the homogeneous solution of the compound and first buffer, so that the nucleophilic groups on the core regain their nucleophilic character (that has been masked by the action of the acidic buffer), thus allowing the nucleophilic groups to inter-react with the electrophilic groups on the core.
  • An exemplary basic buffer is an aqueous solution of carbonate and phosphate salts.
  • This buffer may be prepared by combining a base solution with a salt solution.
  • the salt solution may be prepared by combining 34.7 g of monobasic sodium phosphate monohydrate, 49.3 g of sodium carbonate monohydrate, and sufficient water to provide a solution volume of 2 liter.
  • a 6 liter solution may be prepared by combining 104.0 g of monobasic sodium phosphate monohydrate, 147.94 g of sodium carbonate monohydrate, and sufficient water to provide 6 liter of the salt solution.
  • the basic buffer may be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water.
  • the basic buffer is typically prepared by adding the base solution as needed to the salt solution, ultimately to provide a mixture having the desired pH, e.g., a pH of 9.65 to 9.75.
  • the basic species present in the basic buffer should be sufficiently basic to neutralize the acidity provided by the acidic buffer, but should not be so nucleophilic itself that it will react substantially with the electrophilic groups on the core. For this reason, relatively "soft" bases such as carbonate and phosphate are preferred in this embodiment of the invention.
  • a three-dimensional matrix of the present invention may combine an admixture of the self-reactive compound with a first, acidic, buffer (e.g., an acid solution, e.g., a dilute hydrochloric acid solution) to form a homogeneous solution.
  • a first, acidic, buffer e.g., an acid solution, e.g., a dilute hydrochloric acid solution
  • This homogeneous solution is mixed with a second, basic, buffer (e.g., a basic solution, e.g., an aqueous solution containing phosphate and carbonate salts) whereupon the reactive groups on the core of the self-reactive compound substantially immediately inter-react with one another to form a three- dimensional matrix.
  • a basic, buffer e.g., a basic solution, e.g., an aqueous solution containing phosphate and carbonate salts
  • the reactive groups are vinyl groups such as styrene derivatives, which undergo a radical polymerization upon initiation with a redox initiator.
  • redox refers to a reactive group that is susceptible to oxidation-reduction activation.
  • vinyl refers to a reactive group that is activated by a redox initiator, and forms a radical upon reaction.
  • X, Y and Z can be the same or different vinyl groups, for example, methacrylic groups.
  • the initial environment typically will be an aqueous environment. The modification of the initial environment involves the addition of a redox initiator.
  • the reactive groups undergo an oxidative coupling reaction.
  • X, Y and Z can be a halo group such as chloro, with an adjacent electron-withdrawing group on the halogen- bearing carbon (e.g., on the "L" linking group).
  • exemplary electron-withdrawing groups include nitro, aryl, and so forth.
  • the modification in the initial environment comprises a change in pH.
  • a base such as KOH
  • the self-reactive compounds then undergo a de-hydro, chloro coupling reaction, forming a double bond between the carbon atoms, as illustrated below:
  • the initial environment typically can be can be dry and sterile, or a non-basic medium.
  • the modification of the initial environment will typically comprise the addition of a base.
  • the reactive groups are photoinitiated groups.
  • the modification in the initial environment comprises exposure to ultraviolet radiation.
  • X can be an azide (-N 3 ) group and Y can be an aikyl group such as -CH(CH 3 ) 2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage: -NH-C(CH3)2-CH2-.
  • X can be a benzophenone (-(C 6 HU)-C(O)-(CeHs)) group and Y can be an aikyl group such as -CH(CH 3 ⁇ or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage:
  • the initial environment typically will be in an ultraviolet radiation- shielded environment. This can be for example, storage within a container that is impermeable to ultraviolet radiation.
  • the modification of the initial environment will typically comprise exposure to ultraviolet radiation.
  • the reactive groups are temperature-sensitive groups, which undergo a thermochemical reaction.
  • the modification in the initial environment thus comprises a change in temperature.
  • temperature-sensitive refers to a reactive group that is chemically inert at one temperature or temperature range and reactive at a different temperature or temperature range.
  • X, Y, and Z are the same or different vinyl groups.
  • the initial environment typically will be within the range of about 10 to 3O 0 C.
  • the modification of the initial environment will typically comprise changing the temperature to within the range of about 20 to 4O 0 C.
  • the reactive groups may be directly attached to the core, or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders.”
  • chain extenders In the formula (I) shown above, the optional linker groups are represented by L 1 , L 2 , and L 3 , wherein the linking groups are present when p, q and r are equal to 1.
  • linking groups are well known in the art. See, for example, WO 97/22371 to Rhee et al. Linking groups are useful to avoid steric hindrance problems that can sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several self-reactive compounds together to make larger molecules. In one embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be used to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
  • linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride linkages, such as those obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; ⁇ -hydroxy acid linkages, such as those obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as those obtained by incorporation of caprolactone, valerolactone, ⁇ -butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment.
  • non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, WO 99/07417 to Coury et al.
  • enzymatically degradable linkages include Leu- Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
  • Linking groups can also be included to enhance or suppress the reactivity of the various reactive groups. For example, electron-withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity.
  • Carbon-carbon double bonds and carbonyl groups will also have such an effect.
  • electron-withdrawing groups adjacent to a carbonyl group e.g., the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl
  • a carbonyl group e.g., the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl
  • sterically bulky groups in the vicinity of a reactive group can be used to diminish reactivity and thus reduce the coupling rate as a result of steric hindrance.
  • x is generally in the range of 1 to about 10;
  • R 2 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl; and
  • R 3 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • lower alkylene e.g., methylene, ethylene, n-propylene, n-butylene, etc.
  • phenylene or amidoalkylene (e.g., -(CO)-NH-CH 2 ).
  • linking groups are as follows. If a higher molecular weight self-reactive compound is to be used, it will preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
  • each self-reactive compound is comprised of the molecular structure to which the reactive groups are bound.
  • the molecular core can a polymer, which includes synthetic polymers and naturally occurring polymers.
  • the core is a polymer containing repeating monomer units.
  • the polymers can be hydrophilic, hydrophobic, or amphiphilic.
  • the molecular core can also be a low molecular weight components such as a C- 2 -14 hydrocarbyl or a heteroatom-containing C 2 _i4 hydrocarbyl.
  • the heteroatom-containing C 2 - M hydrocarbyl can have 1 or 2 heteroatoms selected from N, O and S.
  • the self-reactive compound comprises a molecular core of a synthetic hydrophilic polymer.
  • hydrophilic polymer refers to a polymer having an average molecular weight and composition that naturally renders, or is selected to render the polymer as a whole "hydrophilic.” Preferred polymers are highly pure or are purified to a highly pure state such that the polymer is or is treated to become pharmaceutically pure. Most hydrophilic polymers can be rendered water soluble by incorporating a sufficient number of oxygen (or less frequently nitrogen) atoms available for forming hydrogen bonds in aqueous solutions. Synthetic hydrophilic polymers may be homopolymers, block copolymers including di-block and tri-block copolymers, random copolymers, or graft copolymers.
  • the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
  • the polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments preferably degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ.
  • Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc.
  • Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer.
  • Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
  • biodegradable segments that may form part of the hydrophilic polymer core include polyesters such as polylactide, polyethers such as polyalkylene oxide, polyamides such as a protein, and polyurethanes.
  • the core of the self-reactive compound can be a diblock copolymer of tetrafunctionally activated polyethylene glycol and polylactide.
  • Synthetic hydrophilic polymers that are useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol (PEG) and poly( ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (PG) and particularly highly branched polyglycerol, propylene glycol; poly(oxyalkylene)-substituted diols, and poly(oxyalkylene)-substituted polyols such as mono-, di- and tri- polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; poly(acrylic acids) and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid
  • molecular weight refers to the weight average molecular weight of a number of molecules in any given sample, as commonly used in the art.
  • a sample of PEG 2,000 might contain a statistical mixture of polymer molecules ranging in weight from, for example, 1 ,500 to 2,500 daltons with one molecule differing slightly from the next over a range.
  • Specification of a range of molecular weights indicates that the average molecular weight may be any value between the limits specified, and may include molecules outside those limits.
  • a molecular weight range of about 800 to about 20,000 indicates an average molecular weight of at least about 800, ranging up to about 20 kDa.
  • suitable synthetic hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
  • Poly(lysine) a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred.
  • Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
  • Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000.
  • Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).
  • preferred synthetic hydrophilic polymers are PEG and PG, particularly highly branched PG.
  • PEG polyethylene glycol
  • PG polypropylene glycol
  • Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and does not typically interfere with the enzymatic activities and/or conformations of peptides.
  • a particularly preferred synthetic hydrophilic polymer for certain applications is a PEG having a molecular weight within the range of about 100 to about 100,000, although for highly branched PEG, far higher molecular weight polymers can be employed, up to 1 ,000,000 or more, providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000.
  • the preferred molecular weight is about 1 ,000 to about 20,000, more preferably within the range of about 7,500 to about 20,000.
  • the polyethylene glycol has a molecular weight of approximately 10,000.
  • Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, fibrin and thrombin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
  • Collagen and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.
  • collagen refers to all forms of collagen, including those, which have been processed or otherwise modified.
  • collagen from any source may be used in the compounds of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
  • the preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art.
  • U.S. Patent No. 5,428,022 to Palefsky et al. discloses methods of extracting and purifying collagen from the human placenta
  • Collagen of any type including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compounds of the invention, although type I is generally preferred.
  • Either atelopeptide or telopeptide- containing collagen may be used; however, when collagen from a natural source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide- containing collagen.
  • Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the invention, although previously crosslinked collagen may be used.
  • Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml.
  • intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used.
  • Gelatin may have the added benefit of being degradable faster than collagen.
  • Nonfibrillar collagen is generally preferred for use in compounds of the invention, although fibrillar collagens may also be used.
  • nonfibrillar collagen refers to any modified or unmodified collagen material that is in substantially nonfibrillar form, i.e., molecular collagen that is not tightly associated with other collagen molecules so as to form fibers.
  • a solution of nonfibrillar collagen is more transparent than is a solution of fibrillar collagen.
  • Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.
  • Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Patent No. 4,164,559 to Miyata et al.
  • Methylated collagen which contains reactive amine groups, is a preferred nucleophile-containing component in the compositions of the present invention.
  • methylated collagen is a component that is present in addition to first and second components in the matrix-forming reaction of the present invention. Methylated collagen is described in, for example, in U.S. Patent No. 5,614,587 to Rhee et al.
  • Collagens for use in the compositions of the present invention may start out in fibrillar form, then can be rendered nonfibrillar by the addition of one or more fiber disassembly agent.
  • the fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above.
  • Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred.
  • Preferred biocompatible alcohols include glycerol and propylene glycol.
  • Non-biocompatible alcohols such as ethanol, methanol, and isopropanol
  • Preferred amino acids include arginine
  • Preferred inorganic salts include sodium chloride and potassium chloride.
  • carbohydrates such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.
  • Fibrillar collagen is less preferred for use in the compounds of the invention. However, as disclosed in U.S. Patent No. 5,614,587 to Rhee et al., fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compounds intended for long-term persistence in vivo.
  • the core of the self-reactive compound may also comprise a hydrophobic polymer, including low molecular weight polyfunctional species, although for most uses hydrophilic polymers are preferred.
  • hydrophobic polymers herein contain a relatively small proportion of oxygen and/or nitrogen atoms.
  • Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons.
  • Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing, for example, multiple nucleophilic groups. Thus, use of short-chain oligomers can avoid solubility-related problems during reaction.
  • Polylactic acid and polyglycolic acid are examples of two particularly suitable hydrophobic polymers.
  • amphiphilic polymers have a hydrophilic portion and a hydrophobic (or lipophilic) portion.
  • the hydrophilic portion can be at one end of the core and the hydrophobic portion at the opposite end, or the hydrophilic and hydrophobic portions may be distributed randomly (random copolymer) or in the form of sequences or grafts (block copolymer) to form the amphiphilic polymer core of the self-reactive compound.
  • the hydrophilic and hydrophobic portions may include any of the aforementioned hydrophilic and hydrophobic polymers.
  • amphiphilic polymer core can be a hydrophilic polymer that has been modified with hydrophobic moieties (e.g., alkylated PEG or a hydrophilic polymer modified with one or more fatty chains ), or a hydrophobic polymer that has been modified with hydrophilic moieties (e.g., "PEGylated” phospholipids such as polyethylene glycolated phospholipids).
  • hydrophobic moieties e.g., alkylated PEG or a hydrophilic polymer modified with one or more fatty chains
  • hydrophobic polymer that has been modified with hydrophilic moieties e.g., "PEGylated” phospholipids such as polyethylene glycolated phospholipids.
  • the molecular core of the self-reactive compound can also be a low molecular weight compound, defined herein as being a C 2- - I4 hydrocarbyl or a heteroatom-containing C 2 - I4 hydrocarbyl, which contains 1 to 2 heteroatoms selected from N, O, S and combinations thereof.
  • Such a molecular core can be substituted with any of the reactive groups described herein.
  • Alkanes are suitable C 2 - 14 hydrocarbyl molecular cores.
  • Exemplary alkanes, for substituted with a nucleophilic primary amino group and a Y electrophilic group include, ethyleneamine (H 2 N-CH 2 CH 2 -Y), tetramethyleneamine (H 2 N-(CH 4 )-Y), pentamethyleneamine (H 2 N-(CH 5 )-Y), and hexamethyleneamine (H 2 N-(CH 6 )-Y).
  • Low molecular weight diols and polyols are also suitable C 2 - 14 hydrocarbyls and include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol.
  • Polyacids are also suitable C 2 - 14 hydrocarbyls, and include trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)- based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid).
  • Low molecular weight di- and poly-electrophiles are suitable heteroatom-containing C 2- i 4 hydrocarbyl molecular cores. These include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS 3 ), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
  • DSS disuccinimidyl suberate
  • BS 3 bis(sulfosuccinimidyl) suberate
  • DSP dithiobis(succinimidylpropionate)
  • BSOCOES bis(2-succinimidooxycarbonyloxy) ethyl sulfone
  • the self-reactive compound of the invention comprises a low-molecular weight material core, with a plurality of acrylate moieties and a plurality of thiol groups.
  • the self-reactive compounds are readily synthesized to contain a hydrophilic, hydrophobic or amphiphilic polymer core or a low molecular weight core, functionalized with the desired functional groups, i.e., nucleophilic and electrophilic groups, which enable crosslinking.
  • a self-reactive compound having a polyethylene glycol (PEG) core is discussed below.
  • PEG polyethylene glycol
  • Multi-functionalized forms of PEG are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly( ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992).
  • Multi-functionalized forms of PEG are of particular interest and include, PEG succinimidyl glutarate, PEG succinimidyl propionate, succinimidyl butylate, PEG succinimidyl acetate, PEG succinimidyl succinamide, PEG succinimidyl carbonate, PEG propionaldehyde, PEG glycidyl ether, PEG- isocyanate, and PEG-vinylsulfone.
  • Multi-amino PEGs useful in the present invention include the Jeffamine diamines ("D” series) and triamines ("T” series), which contain two and three primary amino groups per molecule.
  • Analogous poly(sulfhydryl) PEGs are also available from Nektar Therapeutics, e.g., in the form of pentaerythritol poly(ethylene glycol) ether tetra-sulfhydryl (molecular weight 10,000). These multi-functionalized forms of PEG can then be modified to include the other desired reactive groups.
  • Reaction with succinimidyl groups to convert terminal hydroxyl groups to reactive esters is one technique for preparing a core with electrophilic groups.
  • This core can then be modified include nucleophilic groups such as primary amines, thiols, and hydroxyl groups.
  • Other agents to convert hydroxyl groups include carbonyldiimidazole and sulfonyl chloride.
  • electrophilic groups may be advantageously employed for reaction with corresponding nucleophilic groups.
  • the in situ forming material may be a biocompatible crosslinked polymer that is formed from water soluble precursors having electrophilic and nucleophilic groups capable of reacting and crosslinking in situ (see, e.g., U.S. Patent No. 6,566,406).
  • the in situ forming material may be hydrogel that may be formed through a combination of physical and chemical crosslinking processes, where physical crosslinking is mediated by one or more natural or synthetic components that stabilize the hydrogel-forming precursor solution at a deposition site for a period of time sufficient for more resilient chemical crosslinks to form (see, e.g., U.S. Patent No.
  • the in situ forming material may be formed upon exposure to an aqueous fluid from a physiological environment from dry hydrogel precursors (see, e.g., U.S. Patent No. 6,703,047).
  • the in situ forming material may be a hydrogel matrix that provides controlled release of relatively low molecular weight therapeutic species by first ' dispersing or dissolving the therapeutic species within relatively hydrophobic rate modifying agents to form a mixture; the mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion (see, e.g., 6,632,457).
  • the in situ forming material may be a multi-component hydrogel system (see, e.g., U.S. Patent No. 6,379, 373).
  • the in situ forming material may be a multi-arm block copolymer that includes a central core molecule, such as a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region (see, e.g., 6,730,334).
  • the in situ forming material may include a gel-forming macromer that includes at least four polymeric blocks, at least two of which are hydrophobic and at least one of which is hydrophilic, and including a crosslinkable group (see, e.g., 6,639,014).
  • the in situ forming material may be a water-soluble macromer that includes at least one hydrolysable linkage formed from carbonate or dioxanone groups, at least one water-soluble polymeric block, and at least one polymerizable group (see, e.g., U.S. Patent No. 6,177,095).
  • the in situ forming material may comprise polyoxyalkylene block copolymers that form weak physical crosslinks to provide gels having a paste-like consistency at physiological temperatures.
  • the in situ forming material may be a thermo-irreversible gel made from polyoxyalkylene polymers and ionic polysaccharides (see, e.g., U.S. Patent No. 5,126,141 ).
  • the in situ forming material may be a gel forming composition that includes chitin derivatives (see, e.g., U.S. Patent No. 5,093,319), chitosan-coagulum (see, e.g., U.S. Patent No. 4,532,134), or hyaluronic acid (see, e.g., U.S. Patent No. 4,141 ,973).
  • the in situ forming material may be an in situ modification of alginate (see, e.g., U.S. Patent No. 5,266,326 ).
  • the in situ forming material may be formed from ethylenically unsaturated water soluble macromers that can be crosslinked in contact with tissues, cells, and bioactive molecules to form gels (see, e.g., U.S. Patent No. 5,573,934).
  • the in situ forming material may include urethane prepolymers used in combination with an unsaturated cyano compound containing a cyano group attached to a carbon atom, such as cyano(meth)acrylic acids and esters thereof (see, e.g., U.S. Patent No. 4,740,534).
  • the in situ forming material may be a biodegradable hydrogel that polymerizes by a photoinitiated free radical polymerization from water soluble macromers (see, e.g., U.S. Patent No. 5,410,016).
  • the in situ forming material may be formed from a two component mixture including a first part comprising a serum albumin protein in an aqueous buffer having a pH in a range of about 8.0-11.0, and a second part comprising a water-compatible or water-soluble bifunctional crosslinking agent, (see, e.g., U.S. Patent No. 5,583,114).
  • in situ forming materials that can be used include those based on the crosslinking of proteins.
  • the in situ forming material may be a biodegradable hydrogel composed of a recombinant or natural human serum albumin and poly( ethylene) glycol polymer solution whereby upon mixing the solution cross-links to form a mechanical non-liquid covering structure which acts as a sealant. See e.g., U.S. Patent No. 6,458,147 and 6,371 ,975.
  • the in situ forming material may be composed of two separate mixtures based on fibrinogen and thrombin that are dispensed together to form a biological adhesive when intermixed either prior to or on the application site to form a fibrin sealant.
  • the in situ forming material may be composed of ultrasonically treated collagen and albumin which form a viscous material that develops adhesive properties when crosslinked chemically with glutaraldehyde and amino acids or peptides. See e.g., U.S. Patent No. 6,310,036.
  • the in situ forming material may be a hydrated adhesive gel composed of an aqueous solution consisting essentially of a protein having amino groups at the side chains (e.g., gelatin, albumin) which is crosslinked with an N-hydroxyimidoester compound. See e.g., U.S. Patent No. 4,839,345.
  • the in situ forming material may be a hydrogel prepared from a protein or polysaccharide backbone (e.g., albumin or polymannuronic acid) bonded to a cross-linking agent (e.g., polyvalent derivatives of polyethylene or polyalkylene glycol). See e.g., U.S. Patent No. 5,514,379.
  • the in situ forming material may be composed of a polymerizable collagen composition that is applied to the tissue and then exposed to an initiator to polymerize the collagen to form a seal over a wound opening in the tissue. See e.g., U.S. Patent No. 5,874,537.
  • the in situ forming material may be a two component mixture composed of a protein (e.g., serum albumin) in an aqueous buffer having a pH in the range of about 8.0-11.0 and a water-soluble bifunctional polyethylene oxide type crosslinking agent, which transforms from a liquid to a strong, flexible bonding composition to seal tissue in situ.
  • a protein e.g., serum albumin
  • a water-soluble bifunctional polyethylene oxide type crosslinking agent which transforms from a liquid to a strong, flexible bonding composition to seal tissue in situ.
  • the in situ forming material may be composed of a protein, a surfactant, and a lipid in a liquid carrier, which is crosslinked by adding a crosslinker and used as a sealant or bonding agent in situ. See e.g., U.S.
  • the in situ forming material may be composed of two enzyme-free liquid components that are mixed by dispensing the components into a catheter tube deployed at the vascular puncture site, wherein, upon mixing, the two liquid components chemically cross-link to form a mechanical non-liquid matrix that seals a vascular puncture site. See e.g., U.S. Patent Application Nos. 2002/0161399A1 and 2001/0018598A1.
  • the in situ forming material may be a cross-linked albumin composition composed of an albumin preparation and a carbodiimide preparation which are mixed under conditions that permit crosslinking of the albumin for use as a bioadhesive or sealant. See e.g., PCT Publication No. WO 99/66964.
  • the in situ forming material may be composed of collagen and a peroxidase and hydrogen peroxide, such that the collagen is crosslinked to from a semi-solid gel that seals a wound. See e.g., PCT Publication No. WO 01/35882.
  • in situ forming materials that can be used include those based on isocyanate or isothiocyanate capped polymers.
  • the in situ forming material may be composed of isocyanate-capped polymers that are liquid compositions which form into a solid adhesive coating by in situ polymerization and crosslinking upon contact with body fluid or tissue.
  • the in situ forming material may be a moisture-curing sealant composition composed of an active isocyanato-terminated isocyanate prepolymer containing a polyol component with a molecular weight of 2,000 to 20,000 and an isocyanurating catalyst agent. See e.g., U.S. Patent No. 5,206,331.
  • the reagents can undergo an electrophilic-nucleophilic reaction to produce a crosslinked matrix.
  • Polymers containing and/or terminated with nucleophilic groups such as amine, sulfhydryl, hydroxyl, -PH 2 or CO-NH-NH 2 can be used as the nucleophilic reagents and polymers containing and/or terminated with electrophilic groups such as succinimidyl, carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C 5 H 4 N) or activated esters, such as are used in peptide synthesis can be used as the electrophilic reagents.
  • nucleophilic groups such as amine, sulfhydryl, hydroxyl, -PH 2 or CO-NH-NH 2
  • electrophilic groups such as succinimidyl, carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C 5 H 4 N) or
  • a 4- armed thiol derivatized poly( ethylene glycol) e.g., pentaerythritol poly( ethylene glycol)ether tetra-sulfhydryl
  • a 4 armed NHS-derivatized polyethylene glycol e.g., pentaerythritol poly(ethylene glycol)ether tetra- succinimidyl glutarate
  • pH > about 8 Representative examples of compositions that undergo such electrophilic-nucleophilic crosslinking reactions are described, for example, in U.S. Patent. Nos.
  • the electrophilic- or nucleophilic- terminated polymers can further comprise a polymer that can enhance the mechanical and/or adhesive properties of the in situ forming compositions.
  • This polymer can be a degradable or non-degradable polymer.
  • the polymer may be collagen or a collagen derivative, for example methylated collagen.
  • An example of an in situ forming composition uses pentaerythritol poly( ethylene glycol)ether tetra-sulfhydryl) (4-armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) (4-armed NHS PEG) and methylated collagen as the reactive reagents.
  • This composition when mixed with the appropriate buffers can produce a crosslinked hydrogel.
  • This composition when mixed with the appropriate buffers can produce a crosslinked hydrogel.
  • the reagents that can form a covalent bond with the tissue to which it is applied may be used.
  • Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C 5 H 4 N) or activated esters, such as are used in peptide synthesis may be used as the reagents.
  • a 4 armed NHS-derivatized polyethylene glycol e.g., pentaerythritol poly( ethylene glycol)ether tetra-succinimidyl glutarate
  • the 4 armed NHS-derivatized polyethylene glycol is applied to the tissue under basic conditions (pH > about 8).
  • basic conditions pH > about 8
  • compositions of this nature that may be used are disclosed in PCT Application Publication No. WO 04/060405 and WO 04/060346, and U.S. Patent Application No. 10/749,123.
  • the in situ forming material polymer can be a polyester.
  • Polyesters that can be used in in situ forming compositions include poly(hydroxyesters).
  • the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, ⁇ -decanolactone, ⁇ -decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one.
  • Representative examples of these types of compositions are described in U.S. Patent. Nos. 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT Publication Nos. WO 2004/028547.
  • the electrophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises an electrophilic group (e.g., disuccinimidyl glutarate).
  • the nucleophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises a nucleophilic group (e.g., dicysteine, dilysine, trilysine, etc.).
  • in situ forming materials include those based on the crosslinking of proteins (described in, for example, U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,310,036; 6,458,147; 6,371 ,975; US Patent Application Publication Nos. 2004/0063613A1 , 2002/0161399A1 , and 2001 /0018598A1 , and PCT Publication Nos.
  • in situ forming materials that are of particular interest in the treatment of diverticula, both alone and in combination with the therapeutic agents described previously, can include reagents that comprise one or more cyanoacrylate groups. These reagents can be used to prepare a poly(alkylcyanoacrylate) or poly(carboxyalkylcyanoacrylate) (e.g., poly(methylcyanoacrylate) poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(hexylcyanoacrylate), poly(methoxypropylcyanoacrylate), and poly(octylcyanoacrylate)) as well as copolymers and mixtures of these.
  • poly(alkylcyanoacrylate) or poly(carboxyalkylcyanoacrylate) e.g., poly(methylcyanoacrylate) poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacryl
  • blends include blends of ethyl cyanoacrylate and methoxypropyl acrylate, methoxyproypl cyanoacrylate and octyl cyanoacrylate and methoxybutyl cyanoacrylate and butyl cyanoacrylate.
  • examples of commercially available cyanoacrylates that can be used include DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUEMEND, TISSUMEND II, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT.
  • the cyanoacrylate compositions can further comprise additives to stabilize the reagents or alter the rate of reaction of the cyanoacrylate, alter the flexibility of the finally cured polymer, or alter the viscosity of the product.
  • a trimethylene carbonate based polymer or an oxalate polymer of poly(ethylene glycol) or a ⁇ -caprolactone based copolymer can be mixed with a 2- alkoxyalkylcyanoacrylate (e.g., 2-methoxypropylcyanoacrylate).
  • stabilizers include sulfur dioxide (SO 2 ) or polyphosphoric acid. Representative examples of these compositions are described in U.S. Patent Nos. 5,350,798 and 6,299,631.
  • the cyanoacrylate composition can be prepared by capping heterochain polymers with a cyanoacrylate group.
  • the cyanoacrylate-capped heterochain polymer preferably has at least two cyanoacrylate ester groups per chain.
  • the heterochain polymer can comprise an absorbable poly(ester), poly(ester-carbonate), poly(ether-carbonate) and poly(ether-ester).
  • the poly(ether-ester)s described in U.S. Patent Nos. 5,653,992 and 5,714,159 can also be used as the heterochain polymers.
  • a triaxial poly( ⁇ -caprolactone-co-trimethylene carbonate) is an example of a poly(ester-carbonate) that can be used.
  • the heterochain polymer may be a polyether.
  • polyethers examples include poly(ethylene glycol), poly(propylene glycol) and block copolymers of poly(ethylene glycol) and polypropylene glycol) (e.g., PLURONICS group of polymers including but not limited to PLURONIC F127 or F68). Representative examples of these compositions are described in U.S. Patent No. 6,699,940.
  • the biologically active fibrosis-inducing agent, anti-infective, and/or hemostatic agent can be delivered with a non-polymeric compound (e.g., a carrier).
  • a non-polymeric carrier can include sucrose derivatives (e.g., sucrose acetate isobutyrate, sucrose oleate), sterols such as cholesterol, stigmasterol, ⁇ -sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; Ci 2 -C 24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C-is -C 36 mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, gly
  • the therapeutic compositions include (i) a fibrosis-inducing agent and/or (ii) an anti-infective agent.
  • the therapeutic compositions may include one or more additional therapeutic agents (such as described above), for example, a hemostatic agent.
  • additional therapeutic agents such as described above
  • Other agents that may be combined with the therapeutic compositions include, e.g., anti-inflammation agents, matrix metalloproteinase inhibitors, cytokine inhibitors, IMPDH inhibitors, immunomodulatory agents, tyrosine inhibitors, p38 MAP kinase inhibitors, NFK ⁇ inhibitors, HMGCoA reductase inhibitors, apoptosis antagonist, caspase inhibitors, and JNK inhibitors.
  • the present invention provides compositions comprising i) a fibrosing agent and ii) a polymer or a compound that forms a crosslinked polymer in situ.
  • a fibrosing agent ii) a polymer or a compound that forms a crosslinked polymer in situ.
  • 1a A fibrosing agent that promotes cell regeneration.
  • 2a A fibrosing agent that promotes angiogenesis.
  • a fibrosing agent that promotes fibroblast migration A fibrosing agent that promotes fibroblast migration.
  • a fibrosing agent that promotes fibroblast proliferation A fibrosing agent that promotes fibroblast proliferation.
  • 5a A fibrosing agent that promotes deposition of extracellular matrix.
  • 6a A fibrosing agent that promotes tissue remodeling.
  • a fibrosing agent that is a diverticular wall irritant that is a diverticular wall irritant.
  • a fibrosing agent that is silk (such as silkworm silk, spider silk, recombinant silk, raw silk, hydrolyzed silk, acid-treated silk, and acylated silk) 9a.
  • a fibrosing agent that is talc is silk (such as silkworm silk, spider silk, recombinant silk, raw silk, hydrolyzed silk, acid-treated silk, and acylated silk) 9a.
  • a fibrosing agent that is chitosan that is chitosan.
  • a fibrosing agent that is fibronectin that is fibronectin.
  • a fibrosing agent that is bleomycin or an analogue or derivative thereof.
  • a fibrosing agent that is connective tissue growth factor (CTGF).
  • CTGF connective tissue growth factor
  • a fibrosing agent that is silica that is silica.
  • a fibrosing agent that is crystalline silicates that is crystalline silicates.
  • a fibrosing agent that is ethanol is ethanol.
  • a fibrosing agent that is a component of extracellular matrix is a component of extracellular matrix.
  • a fibrosing agent that is collagen 24a.
  • a fibrosing agent that is fibrin 24a.
  • a fibrosing agent that is fibrinogen that is fibrinogen.
  • a fibrosing agent that is poly( ethylene terephthalate).
  • a fibrosing agent that is poly(ethylene-co-vinylacetate).
  • 29a A fibrosing agent that is N-carboxybutylchitosan.
  • 30a A fibrosing agent that is an RGD protein.
  • a fibrosing agent that is a polymer of vinyl chloride.
  • a fibrosing agent that is cyanoacrylate that is cyanoacrylate.
  • a fibrosing agent that is crosslinked poly(ethylene glycol)- methylated collagen 34a.
  • a fibrosing agent that is an inflammatory cytokine 34a.
  • a fibrosing agent that is TGF ⁇ is TGF ⁇ .
  • a fibrosing agent that is PDGF is PDGF.
  • a fibrosing agent that is VEGF that is VEGF.
  • a fibrosing agent that is GM-CSF is GM-CSF.
  • a fibrosing agent that is IGF-a is IGF-a.
  • a fibrosing agent is IL-8.
  • a fibrosing agent is IL-6.
  • a fibrosing agent that is a growth hormone that is a growth hormone.
  • a fibrosing agent that is a bone morphogenic protein that is a bone morphogenic protein.
  • a fibrosing agent that is isotretinoin that is isotretinoin.
  • a fibrosing agent that is estradiol that is estradiol.
  • a fibrosing agent that is a//-trans retinoic acid or an analogue or derivative thereof.
  • a fibrosing agent that is wool including animal wool, wood wool, and mineral wool.
  • a fibrosing agent that is bFGF that is bFGF.
  • a fibrosing agent that is polyurethane that is polyurethane.
  • a fibrosing agent that is polytetrafluoroethylene.
  • IGF insulin-like growth factor
  • HGF hepatocyte growth factor
  • CSF colony-stimulating factor
  • a fibrosing agent that is an interferon that is an interferon.
  • a fibrosing agent that is endothelin-1 is endothelin-1.
  • 69a A fibrosing agent that is angiotensin II.
  • 70a A fibrosing agent that is bromocriptine.
  • a fibrosing agent that is methylsergide that is methylsergide.
  • a fibrosing agent that is fibrosin that is fibrosin.
  • a fibrosing agent that is an adhesive glycoprotein 75a.
  • a fibrosing agent that is a proteoglycan 75a.
  • a fibrosing agent that is hyaluronan that is hyaluronan.
  • a fibrosing agent that is secreted protein acidic and rich in cysteine SPARC.
  • a fibrosing agent that is a thrombospondin 78a.
  • a fibrosing agent that is tenacin 78a.
  • a fibrosing agent that is a cell adhesion molecule that is a cell adhesion molecule.
  • a fibrosing agent that is an inhibitor of matrix metalloproteinase 82a.
  • a fibrosing agent that is a tissue inhibitor of matrix metalloproteinase 82a.
  • a fibrosing agent that is methotrexate is methotrexate.
  • compositions comprising each of the foregoing 86 (i.e., 1a through 85a) listed fibrosing agents or classes of fibrosing agents, with each of the following 98 (i.e., 1 b through 97b) polymers and compounds:
  • 29b A synthetic isocyanate-containing compound.
  • 30b A polymer formed from reactants comprising a synthetic thiol-containing compound.
  • 35b A synthetic compound containing at least three thiol groups.
  • 36b A polymer formed from reactants comprising a synthetic compound containing at least four thiol groups.
  • 37b A synthetic compound containing at least four thiol groups.
  • 38b A polymer formed from reactants comprising a synthetic amino-containing compound.
  • 47b A synthetic compound comprising a carbonyl-oxygen- succinimidyl group.
  • 48b A polymer formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.
  • a synthetic compound comprising at least two carbonyl- oxygen-succinimidyl groups.
  • a synthetic compound comprising at least three carbonyl- oxygen-succinimidyl groups.
  • a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.
  • a polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.
  • 59b A synthetic polyalkylene oxide-containing compound having reactive amino groups.
  • 60b A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.
  • a synthetic polyalkylene oxide-containing compound having reactive thiol groups is provided.
  • a polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen- succinimidyl groups.
  • a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups having reactive carbonyl-oxygen-succinimidyl groups.
  • a synthetic compound comprising a biodegradable polyester block.
  • a polymer formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.
  • 67b A synthetic polymer formed in whole or part from lactic acid or lactide.
  • a polymer formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.
  • 69b A synthetic polymer formed in whole or part from glycolic acid or glycolide.
  • 70b A polymer formed from reactants comprising polylysine.
  • 71 b Polylysine.
  • a polymer formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
  • a polymer formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon- caprolactone.
  • a polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.
  • a polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.
  • a polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen- succinimide groups.
  • Pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.
  • a polymer formed from reactants comprising pentaerythritol poly( ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.
  • Pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.
  • a polymer formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.
  • compositions comprising each of the foregoing 86 (1a through 85a) listed fibrosing agents or classes of fibrosing agents, with each of the foregoing 98 (1 b through 97b) polymers and compounds:
  • each of the following is a distinct aspect of the present invention: 1a+1b; 1a + 2b; 1a + 3b; 1a+4b; 1a+5b; 1a+6b; 1a+7b; 1a+8b; 1a+9b; 1a+10b;

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Abstract

L'invention concerne des agents, des compositions et des implants qui sont utilisés dans le traitement de maladies diverticulaires (telles que la diverticulose et la diverticulite. En particulier, des agents induisant la fibrose, des agents hémostatiques et/ou des agents anti-infectieux, ou des compositions contenant un ou plusieurs de ces agents, sont destinés à être utilisés dans des méthodes de traitement des maladies diverticulaires.
PCT/US2005/016871 2005-05-12 2005-05-12 Compositions et methodes de traitement de maladies diverticulaires WO2006124021A1 (fr)

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PCT/US2005/016871 WO2006124021A1 (fr) 2005-05-12 2005-05-12 Compositions et methodes de traitement de maladies diverticulaires
JP2008511094A JP2008540521A (ja) 2005-05-12 2005-05-12 憩室疾患の治療のための組成物と方法
AU2005331924A AU2005331924A1 (en) 2005-05-12 2005-05-12 Compositions and methods for treating diverticular disease
CA2610948A CA2610948C (fr) 2005-05-12 2005-05-12 Compositions et methodes de traitement de maladies diverticulaires
EP05772734A EP1890739A1 (fr) 2005-05-12 2005-05-12 Compositions et methodes de traitement de maladies diverticulaires

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Cited By (26)

* Cited by examiner, † Cited by third party
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WO2009157558A1 (fr) * 2008-06-26 2009-12-30 科研製薬株式会社 Agent de régénération de la membrane du tympan ou du canal auditif externe
WO2010075298A3 (fr) * 2008-12-23 2011-01-13 Surmodics Pharmaceuticals, Inc. Composites implantables et compositions comprenant des agents biologiquement actifs libérables
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CA2610948A1 (fr) 2006-11-23

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