WO2013058726A1 - Système de gélification in situ absorbable, son procédé de fabrication et son utilisation - Google Patents

Système de gélification in situ absorbable, son procédé de fabrication et son utilisation Download PDF

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Publication number
WO2013058726A1
WO2013058726A1 PCT/US2011/056537 US2011056537W WO2013058726A1 WO 2013058726 A1 WO2013058726 A1 WO 2013058726A1 US 2011056537 W US2011056537 W US 2011056537W WO 2013058726 A1 WO2013058726 A1 WO 2013058726A1
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Prior art keywords
forming composition
situ gel
group
composition
lactide
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PCT/US2011/056537
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English (en)
Inventor
Shalaby W. Shalaby
Joel Corbett
Jason OLBRICH
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Poly-Med, Inc.
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Application filed by Poly-Med, Inc. filed Critical Poly-Med, Inc.
Priority to CA2852386A priority Critical patent/CA2852386C/fr
Priority to CN201180075605.1A priority patent/CN103998069A/zh
Priority to JP2014537033A priority patent/JP5989126B2/ja
Priority to PCT/US2011/056537 priority patent/WO2013058726A1/fr
Priority to EP11874179.2A priority patent/EP2768544A4/fr
Priority to CN201710269176.0A priority patent/CN107252498B/zh
Publication of WO2013058726A1 publication Critical patent/WO2013058726A1/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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • This application relates generally to an absorbable gel system and, in particular, to an in situ gel-forming system for various applications, such as vascular applications.
  • vascular disease such as coronary and peripheral artery diseases, aneurysms, and peripheral venous diseases, as well as vascular conditions caused by medical procedures such as angioplasty and stenting, often require localized treatment.
  • In situ gel-forming systems provide an ideal platform for the treatment of vascular diseases and conditions.
  • Biodegradable polymers such as polyester copolymers, have been used in gel-forming systems since they present tunable chemical properties, excellent mechanical properties, and good blood compatibility. These polymer compositions, however, are often too viscose to be delivered effectively through a needle or catheter and, therefore, have limited use in vascular applications where delivery through a needle or a catheter is required. Accordingly, there exists a need for an in situ gel-forming system that can be easily delivered through small- gauge needles or catheters.
  • One aspect of the present invention relates to an in situ gel-forming composition.
  • the composition comprises one or more absorbable polymers and a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfoxide (DMSO) and mixtures thereof, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • Another aspect of the present invention relates to a method for treating a vascular disease or condition in a subject.
  • the method comprises injecting into the subject, at a treatment site, an effective amount of an in situ gel -forming composition.
  • the composition comprises one or more absorbable polymers and a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfoxide (DMSO) and mixtures thereof, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • the vascular disease is a peripheral venous disease selected from spider veins, spider telangiectasias, reticular veins, reticular varicosities, venulectasias, tributary varicose veins, bulging varicose veins, vein tributaries, varicose saphenous veins, or combinations thereof.
  • the vascular disease or condition is a disease or condition selected from the group consisting of coronary and peripheral artery diseases, aneurysms, and peripheral venous diseases, and vascular conditions caused by angioplasty or stenting.
  • Another aspect of the present invention relates to method for treating a cancer or tumor in a subject.
  • the method comprises injecting into the subject an effective amount of an in situ gel-forming composition.
  • the composition comprises one or more absorbable polymers, a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfoxide (DMSO) and mixtures thereof, and one or more chemotherapy agents, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • Another aspect of the present invention relates to method for controlling bleeding in a subject during an embolization procedure.
  • the method comprises injecting into the subject, at a treatment site, an effective amount of an in situ gel-forming composition.
  • the composition comprises one or more absorbable polymers, a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfoxide (DMSO) and mixtures thereof, and one or more bioactive agents selected from the group consisting of: collagen, thrombin, activated platelets, chitosan, antifibrinolytics, vitamin K, fibrinogen, and blood coagulation factors, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • Another aspect of the present invention relates to a method for minimizing re-stenosis following angioplasty.
  • the method comprises administering at a site of angioplasty, an effective amount of an in situ gel-forming composition.
  • the composition comprises one or more absorbable polymers, a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfoxide (DMSO) and mixtures thereof, and one or more bioactive agents that inhibits neoplastic growth, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfoxide
  • Another aspect of the present invention relates to a method for endovascular repair of aneurysms to prevent type I and type II leaks.
  • the method comprises administering at a site of aneurysm, an effective amount of an in situ gel-forming composition.
  • the composition comprises one or more absorbable polymers, a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), dimethyl sulfox-ide (DMSO) and mixtures thereof, and one or more agents suitable for endovascular repair of aneurysms, wherein the composition has a viscosity in the range of about 1 cP to about 100 cP and forms a hydrogel or semi-solid mass on contact with an aqueous environment.
  • NMP N-methyl-2-pyrrolidone
  • PEG polyethylene glycol
  • DMSO dimethyl sulfox-ide
  • kits comprising the in situ gel-forming composition of the present invention and instructions about how to use the in situ gel-forming composition.
  • the kit comprises the in situ gel-forming composition packaged in a pre-filled syringe or vial.
  • Figure 1 is a diagram showing release curves of several bioactive formulations using polyurethane compositions.
  • the term "effective amount” denotes the amount of a medicament or of a pharmaceutical active ingredient which causes a biological or medical response in a tissue, system, animal or human which is sought or desired, for example, by a researcher or physician.
  • the term “effective amount” denotes an amount which, compared with a corresponding subject who has not taken this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, condition, syndrome, disease state, complaint, disorder or prevention of side effects or also the reduction in the progress of a disease, complaint or disorder.
  • the term "effective amount” also encompasses the amounts which are effective for increasing normal physiological function.
  • One aspect of the present invention relates to an injectable gel-forming composition that comprises one or more absorbable polymers, a solvent such as NMP, polyethylene glycol, DMSO, and optionally one or more bioactive agents.
  • the composition is injectable and forms a hydrogel or semi-solid mass on contact with an aqueous
  • the composition can be used for the treatment of (1) various vascular diseases, such as coronary and peripheral artery diseases, aneurysms and peripheral venous diseases, (2) vascular conditions caused by medical procedures, such as angioplasty and stenting, and (3) other applications such as localized cancer treatment.
  • various vascular diseases such as coronary and peripheral artery diseases, aneurysms and peripheral venous diseases
  • vascular conditions caused by medical procedures such as angioplasty and stenting
  • other applications such as localized cancer treatment.
  • the one or more absorbable polymers can be any absorbable
  • polyester/polyether copolymer or mixture of polyester/polyether copolymers that is miscible with a solvent such as NMP, polyethylene glycol or DMSO and is capable of forming a hydrogel or semi-solid mass on contact with an aqueous environment.
  • a solvent such as NMP, polyethylene glycol or DMSO
  • the term "absorbable polymer” or “biodegradable polymer” refers to a polyester copolymer that can be broken down by either chemical or physical process, upon interaction with the physiological environment at the implantation site, and erodes or dissolves within a period of time, e.g., within days, weeks or months.
  • An absorbable or biodegradable polymer serves a temporary function in the body, such as closing a varicose vein, supporting or seal a lumen or delivering a drug, and is then degraded or broken into components that are metabolizable or excretable.
  • the one or more absorbable polymers can be in linear or branched form.
  • the one or more absorbable polymers comprise a molecular chain having a hydrophilic block, designated "Y” herein, and a relatively hydrophobic polyester block, designated "X” herein.
  • Hydrophobic block X and hydrophilic block Y more preferably comprises a molecular structure having the following formula: X-Y-X or (X-Y) repeat, and branched structures thereof.
  • hydrophobic block X comprises a polyester formed by grafting a glycolide, lactide, ⁇ -caprolactone, p-dioxanone, trimethylene carbonate or combinations thereof, onto the hydroxylic or amino groups of a hydrophilic polymer precursor i.e., Y; hydrophilic block Y comprises a polyoxyethylene,
  • Hydrophobic Block(s) refers to absorbable polyester chain block(s) or segment(s) of variable length which, is present in an isolated form, will produce practically amorphous (with less than 5% crystallinity) or totally amorphous material having a T g of less than 25°C, and preferably, is a viscous liquid at room temperature.
  • Hydrophobic block(s) X comprises copolymeric segments of known chemistries in the art, such as, those comprised from cyclic lactones ⁇ e.g., glycolide, 1-lactide, dl-lactide, ⁇ -caprolactone, p-dioxanone, trimethylene carbonate), polyalkylene oxalate, and the like. More preferably, hydrophobic segment(s) or block(s) X comprises lactide/glycolide copolymer (with 51 to 80% 1- or dl-lactide).
  • Hydrophilic Block(s) refers to polymeric blocks or segments which, if present in an isolated form, will be water soluble.
  • Hydrophilic block(s) or segment(s) Y comprises poly(oxyethylene), with or without a minor component of a higher homolog, such as, poly(oxypropylene)-polypeptide, polyalkylene oxamate, a polysaccharide, or derivatives thereof.
  • the length of the hydrophilic block and its weight fractions can be varied to modulate the rate of gel formation, its modulus, its water content, diffusivity of bioactive drug through it, its adhesiveness to surrounding tissue, and bioabsorbability.
  • hydrogel or “hydrogel mass” as used herein, refers to materials which have a high tendency for water absorption and/or retention, and maintain mechanical integrity through physical crosslinks which are reversible in nature.
  • solid or “semi-solid mass” as used herein, refers to a material which is similar to a solid in some respects ⁇ e.g., it can support its own weight and hold its shape), but also shares some properties of liquids, such as shape conformity to something applying pressure to it, or the ability to flow under pressure.
  • the one or more absorbable polymers optionally comprise carboxylic end-groups formed by any known technique in the art, such as, for example, end-group succinylation and end-group acetylation.
  • This facilitates ionically binding a biologically active agent or drug to the absorbable polymer such that the drug release can be modulated.
  • the biologically active agent or drug is preferably present on the absorbable polymer in an insoluble form, such as, (1) a microparticulate dispersion, (2) a surface-deposited coating onto an absorbable microporous microparticles, and/or (3) ionically bound molecules onto the surfaces of absorbable microporous microparticles.
  • the one or more absorbable polymers comprise a segmented, aliphatic polyurethane comprising polyoxyalkylene glycol chains covalently linked to polyester or polyester-carbonate chain segments, interlinked with aliphatic urethane segments.
  • the polyoxyalkylene glycol chains comprise at least one type of oxyalkylene sequences selected from the group represented by oxyethylene, oxypropylene,
  • oxytrimethylene and oxytetramethylene repeat units.
  • the oxytrimethylene and oxytetramethylene repeat units.
  • polyoxyalkylene glycol chain has an average molecular weight of 200-1200 dalton.
  • the polyoxyalkylene glycol chain is PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, and derivatives thereof.
  • the polyester or polyester-carbonate chain segments are derived from at least one cyclic monomer selected from the group represented by ⁇ -caprolactone, trimethylene carbonate, p-dioxanone, 1 ,5- dioxepan-2-one, 1-lactide, dl-lactide, glycolide, morpholinedione, and combinations thereof.
  • the aliphatic urethane segments are derived from at least one diisocyanate selected from the group consisting of hexamethylene diisocyanate, lysine-derived diisocyanate, and
  • the segmented, aliphatic polyurethane has an ether/ester mass ratios of 20-49 / 80-51 , preferably 25-40 / 75-55 and, most preferably 30-40 / 70-60. In other embodiments, the segmented, aliphatic polyurethane has a
  • the segmented, aliphatic polyurethane has a prepolymer/diisocyante mass ratio of 1 :0.66, 1 :0.8 or 1 : 1.2.
  • the one or more absorbable polymers comprise a relatively slow-absorbing, segmented polyether-carbonate-urethanes (PECU), which possesses one or more of the following features: (a) exhibits ⁇ 20 percent or no solubility in water; (b) is made to be liquids at about 50°C; (c) has a weight average molecular weight exceeding 10 kDa; (d) swells in an aqueous environment leading to an increase of volume of at least 3 percent, and (e) is miscible in solvents such as NMP, polyethylene glycol or DMSO, to facilitate their use as injectable formulations that undergo gel-formation when introduced to aqueous biological sites.
  • PECU segmented polyether-carbonate-urethanes
  • the one or more absorbable polymers comprise relatively fast-absorbing segmented aliphatic polyether-ester urethanes (PEEU) and polyether-carbonate-ester urethanes (PECEU).
  • PEEU segmented aliphatic polyether-ester urethanes
  • PECEU polyether-carbonate-ester urethanes
  • the relatively fast- absorbing segmented aliphatic PEEU and PECEU possess one or more of the following features: (a) exhibit limited ( ⁇ 20 percent) or no solubility in waiter; (b) are made to be liquids at about 50°C; (c) have a weight average molecular weight exceeding 10 kDa; (d) swell in an aqueous environment leading to an increase of volume of at least 3 percent; and (e) are miscible in a solvent such as NMP, polyethylene glycol or DMSO, to facilitate their use as injectable formulations that undergo gel-formation when introduced to aqueous biological sites.
  • the one or more absorbable polymers comprise segmented, aliphatic polyether-ester urethanes (APEEU) and polyether-ester-carbonate urethanes (APEECU).
  • APEEUs and APEECUs comprise polyoxyalkylene chains (such as those derived from polyethylene glycol and block or random copolymers of ethylene oxide and propylene oxide) covalently linked to polyester or polyester-carbonate segments (derived from at least one monomer selected from the group represented by trimethylene carbonate, c-caprolactone, lactide, glycolide, p-dioxanone, l,5-dioxepan-2-one, and a morpholinedione) and interlinked with aliphatic urethane segments derived from 1 ,6 hexamethylene-, 1-4 cyclohexane-, cyclohexane-bis-methylene-, 1,8 octamethylene- or
  • the absorbable polymers comprise absorbable polyester copolymers or mixtures thereof.
  • Suitable absorbable polyester copolymers include, but are not limited to, lactide/glycolide copolymers, caprolactone/glycolide copolymers,
  • lactide/trimethylene carbonate copolymers lactide/glycolide/caprolactone tripolymers, lactide/glycolide/trimethylene carbonate tripolymers, lactide/caprolactone/trimethylene carbonate tripolymers, glycolide/caprolactone/trimethylene carbonate tripolymers, and lactide/glycolide/caprolactone/trimethylene carbonate terpolymers.
  • the polyester copolymer comprise a lactide/glycolide copolymer with a lactide/glycolide mole ratio of 60-90/40-10.
  • the gel-forming polymer is dissolved in a solvent to form an injectable liquid formulation.
  • Suitable solvents include, but are not limited to, NMP, polyethylene glycols such as PEG 400 and PEG 200, DMSO, methyl acetate, ethyl acetate, ethanol, and caprolactone monomer.
  • the polymer-to-solvent ratio can be modulated in concert with the bioactive agent " solubility, its intended release site, and preferred gelation rate and release rate.
  • the polymer-to-solvent (w/w) ratio is in the range of about 5:95 to 55:45, preferably in the range of about 20:80 to 50:50 w/w.
  • the solvent comprises NMP and the polymer-to-solvent (w/w) ratio is in the range of 10:90 to 50:50, 10:90 to 20:80, or 15:85 to 30:70.
  • the solvent comprises PEG and the polymer-to-solvent (w/w) ratio is in the range of 50:50 to 70:30.
  • the solvent comprises methyl acetate and/or ethyl acetate, and the polymer-to-solvent (w/w) ratio is in the range of 10:90 to 50:50.
  • the solvent comprises caprolactone monomer and the polymer-to-solvent (w/w) ratio is in the range of 40:60 to 60:40.
  • the solvent comprises DMSO and the polymer-to-solvent (w/w) ratio is in the range of 70:30 to 90: 10.
  • the injectable gel-forming composition may be used as vehicles for the controlled release of one or more bioactive agents.
  • bioactive agents includes, but are not limited to, antifungal agents, antibacterial agents and antibiotics, antiinflammatory agents, immunosuppressive agents, immunostimulatory agents, antiseptics, anesthetics, nutritional agents, antioxidants, lipopolysaccharide.complexing agents, peroxides, cell/tissue growth factors, antineoplastic and anticancer agents.
  • antifungal agents include, but are not limited to, polyene antifungals, azole antifungal drugs, and Echinocandins.
  • antibacterial agents and antibiotics include, but are not limited to, erythromycin, penicillins, cephalosporins, doxycycline, gentamicin, vancomycin, tobramycin, clindamycin, and mitomycin.
  • anti-inflammatory agents include, but are not limited to, non- steriodal anti-inflammatory drugs such as ketorolac, naproxen, diclofenac sodium and fluribiprofen.
  • immunosuppressive agents include, but are not limited to, glucocorticoids, alkylating agents, antimetabolites, and drugs acting on immunophilins such as ciclosporin and tacrolimus.
  • immunostimulatory agents include, but are not limited to, antibodies, TNFa, VEGF, interleukins, interferon, cytokines, toll-like receptor (TLR) agonists, cytokine receptor agonist, CD40 agonist, Fc receptor agonist, CpG-containing immunostimulatory nucleic acid, complement receptor agonist, or an adjuvant.
  • antiseptics include, but are not limited to, chlorhexidine and tibezonium iodide.
  • anesthetic examples include, but are not limited to, lidocaine, mepivacaine, pyrrocaine, bupivacaine, prilocaine, and etidocaine.
  • antioxidants include, but are not limited to, antioxidant vitamins, carotenoids, and flavonoids.
  • lipopolysaccharide complexing agents include, but are not limited to, polymyxin.
  • peroxides examples include, but are not limited to, benzoyl peroxide and hydrogen peroxide.
  • cell growth promoting factors include, but are not limited to, epidermal growth factors, human platelet derived TGF- ⁇ , endothelial cell growth factors, thymocyte-activating factors, platelet derived growth factors, fibroblast growth factor, fibronectin or laminin.
  • antineoplastic/anti-cancer agents include, but are not limited to, paclitaxel, carboplatin, miconazole, leflunamide, and ciprofloxacin.
  • agents/drugs in the same delivery system i.e., the in situ gel-forming system of the present invention can be useful in order to obtain an optimal effect.
  • an antibacterial and an antiinflammatory agent may be combined in a single copolymer to provide combined
  • the in situ gel-forming composition further comprises a sclerosant for the treatment of varicose vein.
  • the sclerosant comprises polidocanol, sodium tetradecyl sulfate, or both.
  • the in situ gel-forming composition comprises polidocanol in the amount of from 0.2% to 5.0% (w/w), 0.2% to 1.0% (w/w), 0.5% to 1.5% (w/w), 0.5% to 2.5% (w/w), 1.0% to 2.0% (w/w), 2.0% to 3.0% (w/w), 3.0% to 4.0% (w/w) and 4.0% to 5.0% (w/w).
  • the composition further comprises a vasoconstrictor.
  • vasoconstrictor include, but are not limited to, 3-(4,5-dihydro-lH-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol (hereinafter, "oxymetazoline”), epinephrine, norepinephrine, levophed, or dopamine.
  • oxymetazoline 3-(4,5-dihydro-lH-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol
  • epinephrine epinephrine
  • norepinephrine norepinephrine
  • levophed levophed
  • dopamine dopamine.
  • the vasoconstrictor is oxymetazoline.
  • the vasoconstrictor is oxymetazoline.
  • vasoconstrictor is a long acting vasoconstrictor that is effective for at least 8 hours, 10 hours, or 12 hours after administration.
  • the composition comprises both a sclerosant and a vasoconstrictor.
  • the in situ gel-forming composition further comprises a solid absorbable carrier to carry the one or more bioactive agent.
  • the bioactive agent/drug can be deposited, wholly or in part, on the solid absorbable carrier.
  • the solid absorbable carrier is an absorbable, microporous low molecular weight polyester which is highly crystalline and practically insoluble in the absorbable polymer of the in situ gel-forming composition.
  • the in situ gel-forming composition comprises the solid carrier and the absorbable polymer at a weight ratio of 20/80, with the carrier being a low molecular, microporous polyglycolide with 0.70 to 0.95 solid fraction, average particle size of 0.5-200 micron and carboxyl-bearing chains.
  • High concentration of carboxylic groups on the chains can be achieved by preparing the solid carrier using di- or poly-carboxylic acid as initiators.
  • the deposited agent on the solid carrier can exhibit a release profile which can be multiphasic, including: (a) simple, fast diffusion of soluble free drug through the in situ hydrogel; (b) slow diffusion of soluble free drug housed in the pores of the solid carrier; and, (c) drug release at the surface (both exterior and pore) of the solid carrier or the chain ends of carboxylated A chains by ion exchange of ionically bound molecules.
  • a release profile which can be multiphasic, including: (a) simple, fast diffusion of soluble free drug through the in situ hydrogel; (b) slow diffusion of soluble free drug housed in the pores of the solid carrier; and, (c) drug release at the surface (both exterior and pore) of the solid carrier or the chain ends of carboxylated A chains by ion exchange of ionically bound molecules.
  • characteristics and release profile of the agent can be modulated.
  • the absorbable carrier Comprises microspheres or nanoparticles, such as biodegradable polylactic acid (PLA) microspheres, for controlled drug delivery.
  • biodegradable polymers include, but are not limited to, polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA), poly-s-caprolactone (PCL), lactic acid-s-caprolactone copolymer (PLCL), polydioxanone (PDO), polytrimethylene carbonate (PTMC), poly(amino acid), polyanhydride, polyorthoester and copolymers thereof.
  • the microspheres or nanoparticles can be prepared by polymerizing the monomeric mixture under polymerization conditions in the presence of one or more bioactive agents such that the bioactive agent(s) is entrapped in the polymerization product.
  • the injectable gel-forming composition may further comprise other components such as stabilizers against premature polymerization ⁇ e.g., hydroxyquinone or butylated hydroxyanisole) and buffering agents to maintain desired pH.
  • stabilizers against premature polymerization e.g., hydroxyquinone or butylated hydroxyanisole
  • buffering agents to maintain desired pH.
  • the in situ gel-forming composition of the present invention is in a liquid or semi-liquid form at 37°C, preferably, at 25°C or room temperature. In certain embodiments, the in situ gel-forming composition is in a liquid at room
  • in situ gel-forming composition is an injectable liquid at room temperature.
  • injectable liquid refers to a liquid that can be administered into a recipient through an injection device commonly used in medical art, such as needles, syringes and catheters.
  • the injectable liquid has viscosity that allows the liquid to be administered through a 10 gauge needle without excessive force.
  • the injectable liquid has a viscosity that allows the liquid to be administered through a 30 gauge needle without excessive force.
  • the injectable liquid has a viscosity in the range of about 1 cP (centiPoise) to about 1000 cP, about 1 cP to about 300 cP, about 1 cP to about 100 cP, about 1 cP to about 30 cP, about 10 cP to about 300 cP, about 10 cP to about 100 cP, about 30 cP to about 300 cP and about 30 cP to about 100 cP.
  • centiPoise centiPoise
  • the in situ gel-forming composition of the present invention is formulated for rapid gelation at the treatment site.
  • the in situ gel-forming composition is capable of forming a hydrogel or semi-solid mass at a treatment site in a period of 1-120 seconds, 1-5 minutes, 5-15 minutes, or 15-30 minutes.
  • the in situ gel-forming composition forms a hydrogel or semi-solid mass at a treatment site within 15 seconds, 30 seconds, 60 seconds or 90 seconds.
  • the gelation time is determined visually by observing the period between injection and formation of the solid mass.
  • the diluent/solvent portion of the solution precipitates leaving the hardened polymeric hydrogel or semi-solid mass that can be visually detected.
  • the rate of gelation may be adjusted by adding one or more gelation accelerators to the in situ gel-forming composition.
  • Compounds that may serve as gelation accelerators include, but are not limited to, collagen, thrombin, activated platelets, chitosan, fibrinogen and antifibrinolytics.
  • the in situ gel-forming composition of the present invention is formulated for slow degradation at the treatment site. In some embodiments, the in situ gel-forming composition of the present invention is formulated for a degradation time of 1-3 weeks, 1-3 months, 3-6 months, or 6-12 months through utilization of different polymer configurations.
  • the in situ gel-forming composition can be formulated for various vascular applications.
  • the in situ gel-forming composition comprises a sclerosant and is formulated for sclerotherapy of venous obliteration.
  • the in situ gel-forming composition comprises collagen, thrombin, activated platelets, chitosan, fibrinogen or antifibrinolytics and is formulated for use in embolization procedures to control bleeding.
  • the in situ gel-forming composition comprises a chemotherapy agent and is formulated for chemo-embolization procedures for localized cancer therapy.
  • the in situ gel-forming composition comprises paclitaxel, sirolimus zotarolimus or rapamycin.and is formulated for localized release of drug to minimize re-stenosis after angioplasty.
  • the in situ gel-forming composition comprises one or more bioactive agents suitable for endovascular repair of aneurysms to prevent type I and type II leaks, and is formulated as an adjunct to endovascular repair of aneurysms to prevent type I and type II leaks.
  • bioactive agents suitable for endovascular repair of aneurysms include, but are not limited to, collagen, thrombin, activated platelets, chitosan, fibrinogen or antifibrinolytics.
  • Another aspect of the present invention relates to methods for treating various diseases and conditions using the in situ gel-forming composition of the present invention.
  • the method comprises the steps of injecting into a subject in need of such treatment an effective amount of an in situ gel-forming composition comprising one or more absorbable polymers, a solvent such as N-methyl-2-pyrrolidone (NMP), polyethylene glycol or DMSO, and optionally one or more bioactive agents, wherein said in situ gel-forming composition forms a hydrogel or semi-solid mass on contact with an aqueous environment at a treatment site.
  • NMP N-methyl-2-pyrrolidone
  • DMSO polyethylene glycol
  • bioactive agents optionally one or more bioactive agents
  • the method relates to treatment of a vascular disease or condition.
  • vascular diseases and conditions include, but are not limited to, coronary and peripheral artery diseases, aneurysms, and peripheral venous diseases, as well as vascular conditions caused by medical procedures such as angioplasty and stenting.
  • the method relates to treatment for peripheral venous diseases such as spider veins, spider telangiectasias, reticular veins, reticular varicosities, venulectasias, tributary varicose veins, bulging varicose veins, vein tributaries, varicose saphenous veins, or combinations thereof.
  • the treatment prevents or ameliorates symptoms associated with varicose vein disease, such as edema, skin changes, ulcers, sequelae of varicose veins, bruising, staining, thrombus formation, trapped blood, blood clots, or combinations thereof.
  • symptoms are prevented or ameliorated without use of compression stockings.
  • the method relates to treatment of venous
  • malformations arteriovenous malformations, Klippel-Trenaunay Syndrome, aneurysms, endoleaks after aneurysm repair, cerebral aneurysms, tumors, acute bleeding (from trauma), cancer, or combinations thereof.
  • the method relates to treatment of cancer or tumor using an in situ gel-forming composition that comprises a chemotherapy agent.
  • cancer examples include, but are not limited to, lung cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, brain, and associated nietastases.
  • the present invention relates to a method for controlling bleeding during an embolization procedure.
  • the method comprises the step of administering at a site of embolization, an effective amount of an in situ gel-forming composition comprising one or more absorbable polymers, a solvent such as NMP, polyethylene glycol or DMSO, and one or more bioactive agents, wherein said in situ gel-forming composition forms a hydrogel or semi-solid mass on contact with an aqueous environment at a treatment site.
  • Suitable bioactive agents include, but are not limited to, collagen, thrombin, activated platelets, chitosan, antifibrinolytics, vitamin K, fibrinogen, and blood coagulation factors.
  • the present invention relates to a method for minimizing re-stenosis following angioplasty.
  • the method comprises the step of
  • an effective amount of an in situ gel-forming composition comprising one or more absorbable polymers, a solvent such as N-methyl-2- pyrrolidone (NMP), polyethylene glycol or DMSO, and one or more bioactive agents, wherein said in situ gel-forming composition forms a hydrogel or semi-solid mass on contact with an aqueous environment at a treatment site.
  • Suitable bioactive agents include, but are not limited to, paclitaxel, sirolimus zotarolimus and rapamycin.
  • the present invention relates to a method for endovascular repair of aneurysms to prevent type I and type II leaks.
  • the method comprises the step of administering at a site of aneurysm, an effective amount of an in situ gel-forming composition comprising one or more absorbable polymers, a solvent such as NMP, polyethylene glycol or DMSO, and one or more bioactive agents suitable for endovascular repair of aneurysms, wherein said in situ gel-forming composition forms a hydrogel or semisolid mass on contact with an aqueous environment at a treatment site.
  • Bioactive agents suitable for endovascular repair of aneurysms include, but are not limited to, collagen, thrombin, activated platelets, chitosan, fibrinogen or antifibrinolytics.
  • Another aspect of the present invention relates to a method for drug delivery.
  • the method comprises the step of administering into a subject, an effective amount of an in situ gel-forming composition comprising one or more absorbable polymers, a solvent such as NMP, polyethylene glycol or DMSO, and biodegradable microspheres or nanoparticles comprising one or more bioactive agents, wherein said in situ gel-forming composition forms a hydrogel or semi-solid mass on contact with an aqueous environment at a treatment site. Kits
  • kits comprising the in situ gel-forming composition of the present invention and instructions about how to use the in situ gel-forming composition.
  • the kit comprises the in situ gel- forming composition packaged in a pre-filled syringe or vial.
  • 1,6-diisocyanatohexane was added and the contents were stirred until complete mixing was achieved.
  • the contents were stirred and heated to 100°C. Conditions were maintained for 1.25 hours.
  • the polymer was allowed to cool to room temperature and then dissolved in an equal part of tetrahydrofuran.
  • the polymer solution was treated with 5 mL of 2-propanol at 55°C, then precipitated in cold water.
  • the purified polymer was dried to a constant weight at 55°C on a rotary evaporator.
  • the purified polymer was characterized for molecular weight by GPC using tetrahydrofuran as the mobile phase. Identity and composition were confirmed by FT-IR and NMR, respectively.
  • EXAMPLE 2 PREPARATION AND EVALUATION OF BIO ACTIVE FORMULATIONS USING POLYURETHANE COMPOSITION OBTAINED FROM EXAMPLE 1 :
  • Example 1 An aliquot of the product of Example 1 (4.5 g) was heated to 50°C then mixed thoroughly at that temperature with polyethylene glycol (PEG-400) having a molecular weight of 400 Da (4.4 g). The mixed polymers were allowed to reach room temperature and then thoroughly mixed with a second aliquot of PEG-400 (1.1 g) premixed with the drug W solution in ethanol. The final formulation was dried under reduced pressure to distill the ethanol prior to conducting the drug release study. The release profile of the specific drug in the respective formulation was conducted using buffered solution and HPLC. Figure 1 shows exemplary release curves of doxycycline from several test formulations.
  • PEG-400 polyethylene glycol having a molecular weight of 400 Da (4.4 g).
  • the mixed polymers were allowed to reach room temperature and then thoroughly mixed with a second aliquot of PEG-400 (1.1 g) premixed with the drug W solution in ethanol.
  • the final formulation was dried under reduced pressure to distill the ethanol prior to conducting the drug release

Abstract

L'invention concerne une composition gélifiante in situ. La composition gélifiante in situ comprend au moins un polymère absorbable, des solvants tels que la N-méthyl-2-pyrrolidone, le polyéthylène glycol ou le DMSO, et facultativement au moins un agent bioactif. La composition forme un hydrogel ou une masse semi-solide lors de sa mise en contact avec un environnement aqueux. L'invention concerne également la méthode d'utilisation de la composition gélifiante in situ dans le cadre de diverses applications.
PCT/US2011/056537 2011-10-17 2011-10-17 Système de gélification in situ absorbable, son procédé de fabrication et son utilisation WO2013058726A1 (fr)

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CA2852386A CA2852386C (fr) 2011-10-17 2011-10-17 Systeme de gelification in situ absorbable, son procede de fabrication et son utilisation
CN201180075605.1A CN103998069A (zh) 2011-10-17 2011-10-17 可吸收的原位凝胶形成系统、其制备方法及用途
JP2014537033A JP5989126B2 (ja) 2011-10-17 2011-10-17 吸収性現場ゲル形成システム、その製造方法及びその使用
PCT/US2011/056537 WO2013058726A1 (fr) 2011-10-17 2011-10-17 Système de gélification in situ absorbable, son procédé de fabrication et son utilisation
EP11874179.2A EP2768544A4 (fr) 2011-10-17 2011-10-17 Systeme de gelification in situ absorbable, son procede de fabrication et son utilisation
CN201710269176.0A CN107252498B (zh) 2011-10-17 2011-10-17 可吸收的原位凝胶形成系统、其制备方法及用途

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WO2020190606A1 (fr) * 2019-03-15 2020-09-24 Poly-Med, Inc. Systèmes d'administration, méthodes et compositions formant un gel in situ

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CA2852386A1 (fr) 2013-04-25
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JP2014532082A (ja) 2014-12-04
EP2768544A4 (fr) 2015-06-24
CN107252498B (zh) 2021-02-19
EP2768544A1 (fr) 2014-08-27
CA2852386C (fr) 2019-05-21
JP5989126B2 (ja) 2016-09-07

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