US20160184493A1 - Partially absorbable fiber-reinforced composites for controlled drug delivery - Google Patents

Partially absorbable fiber-reinforced composites for controlled drug delivery Download PDF

Info

Publication number
US20160184493A1
US20160184493A1 US15064674 US201615064674A US2016184493A1 US 20160184493 A1 US20160184493 A1 US 20160184493A1 US 15064674 US15064674 US 15064674 US 201615064674 A US201615064674 A US 201615064674A US 2016184493 A1 US2016184493 A1 US 2016184493A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
absorbable
bioactive agent
fiber
ring
time
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15064674
Inventor
Shalaby W. Shalaby
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Poly-Med Inc
Original Assignee
Poly-Med Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/12Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/129Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing macromolecular fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/375Ascorbic acid, i.e. vitamin C; Salts thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135Compounds containing heavy metals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0034Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/44Medicaments
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42Use of materials characterised by their function or physical properties
    • A61L15/64Use of materials characterised by their function or physical properties specially adapted to be resorbable inside the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0014Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
    • A61F2250/003Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in adsorbability or resorbability, i.e. in adsorption or resorption time
    • A61F2250/0031Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis differing in adsorbability or resorbability, i.e. in adsorption or resorption time made from both resorbable and non-resorbable prosthetic parts, e.g. adjacent parts
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0034Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0046Ear
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222Steroids, e.g. corticosteroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/256Antibodies, e.g. immunoglobulins, vaccines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/408Virucides, spermicides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43Hormones, e.g. dexamethasone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602Type of release, e.g. controlled, sustained, slow

Abstract

This invention describes a partially absorbable, fiber-reinforced composite in the form of a ring, or a suture-like thread, with modified terminals for use as a controlled delivery system of at least one bioactive agent, wherein said composite comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric matrix containing an absorbable microparticulate ion-exchanger to modulate the release of the bioactive agent(s) for a desired period(s) of time at a specific biological site; this can be a vaginal canal, peritoneal cavity, scrotum, prostate gland, an ear loop or subcutaneous tissue. Such drug delivery systems can be used for the local administration of at least one bioactive agent, including those used as contraceptive, antimicrobial, anti-inflammatory and/or antiviral agents as well as for cancer treatment.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. Ser. No. 10/935,808, filed on Sep. 8, 2004, which is hereby incorporated by reference in its entirety.
  • FIELD OF THE INVENTION
  • This invention deals with fiber-reinforced composite systems comprising an absorbable fiber and a partially or essentially non-absorbable matrix for use in the controlled release of one or more bioactive agent(s) at the desired biological site, which may entail intravaginal, transcutaneous, intraperitoneal, and subcutaneous implantation of such systems. For the latter two routes of administration, the controlled release system is designed to be retrievable by withdrawing the non-migrating end placed subcutaneously. The composite systems can be linear or circular and are so designed as to modulate the bioactive agent(s) release profile as well as the mechanical properties, in part, through the controlled degradation of the absorbable reinforcing fiber and any other absorbable component that may be present in the matrix.
  • BACKGROUND OF THE INVENTION
  • Prior application of the same inventor have dealt with a fiber-reinforced composite ring for the controlled release of at least one bioactive agent incorporated in a biocompatible matrix reinforced with absorbable/biodegradable fibers capable of providing the mechanical properties needed for inserting and maintaining the ring in a body cavity for a desired period of time. Such ring system can be used for the intravaginal, intraperitoneal, and subcutaneous delivery of at least one bioactive agent, including those used as contraceptives.
  • U.S. application Ser. No. 60/482,898 discloses a controlled drug release device comprising a partially or fully absorbable, fiber-reinforced composite ring system comprising an absorbable or non-absorbable matrix, an absorbable, reinforcing fibrous construct and an absorbable coating to provide three modes of controlling the release of bioactive agents and one mode for modulating the mechanical property of the ring in a body cavity during device functional use. For partially absorbable ring systems, the drug release is dependent initially on the diffusion rate of the drug through the matrix and the absorbable coating. As the latter degrades with time, the diffusion through the matrix prevails. Meanwhile, as the absorbable fibrous reinforcing construct undergoes degradation with time, the mechanical strength of the composite ring decreases to provide the desired mechanical strength retention profile. For a fully absorbable composite ring system, the degradation of the matrix offers an additional mode of controlling the release profile as compared with the partially absorbable counterpart. In effect, the invention of U.S. application Ser. No. 60/482,898 deals with a fiber-reinforced composite ring system for the controlled release of at least one bioactive agent comprising a biocompatible matrix reinforced with an absorbable/biodegradable fibrous construct capable of providing the mechanical properties needed for inserting and maintaining said ring in a body cavity for the desired period of time, and wherein the absorbable/biodegradable reinforcing fibers are made primarily from one or more cyclic monomer(s) including glycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, and trimethylene carbonate.
  • For the partially absorbable/biodegradable composite ring controlled drug delivery system of U.S. application Ser. No. 60/482,898, the fiber-reinforced composite ring deals with the controlled release of at least one bioactive agent and comprises a biocompatible matrix reinforced with absorbable/biodegradable fibers capable of providing the mechanical properties needed for inserting and maintaining said ring in a body cavity for the desired period of time, wherein the reinforcing fibers are absorbable/biodegradable and the matrix is non-absorbable/non-biodegradable, wherein the non-absorbable matrix comprising a methacrylate polymer derived from at least one alkyl methacrylate monomer, and wherein the methacrylate polymer is derived from one or more alkyl methacrylate monomer(s) and N-vinyl pyrrolidone. Alternatively, the matrix may comprise a cyclodextrin or cyclodextrin derivative.
  • Obviously, the partially absorbable/biodegradable composite ring controlled drug delivery system of U.S. application Ser. No. 60/482,898 did not fully address the use of safe matrices such as silicones and polyether urethanes, which are cited in the prior art as carriers of many bioactive agents. Accordingly, this invention addresses the use of non-absorbable/biostable polyether urethane or polysiloxanes as the primary matrix component of the partially absorbable/biodegradable fiber-reinforced composite ring system comprising a drug solubility modifier for the controlled delivery of many bioactive agents including those cited in U.S. application Ser. No. 60/482,898.
  • SUMMARY OF THE INVENTION
  • The present invention deals, in general, with fiber-reinforced composite systems comprising an absorbable fiber and a partially or essentially non-absorbable matrix for use in the controlled release of one or more bioactive agent(s) at the desired biological site, which may entail intravaginal, transcutaneous, intraperitoneal, and subcutaneous implantation of such systems. For the latter two routes of administration, the controlled release system is designed to be retrievable by withdrawing the non-migrating end placed subcutaneously. The composite systems can be linear or circular and are so designed as to modulate the bioactive agent(s) release profile as well as the mechanical properties, in part, through the controlled degradation of the absorbable reinforcing fiber and any other absorbable component that may be present in the matrix.
  • This invention addresses a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein (1) the absorbable reinforcing fibers are formed from at least one cyclic monomer selected from the group consisting of glycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate, and a morpholine-2,5-dione; and (2) the biostable matrix is made of a polyether urethane elastomer or a silicone elastomer, such as copolymer polysiloxane, comprising dimethyl siloxane sequences, which can be made of at least one of the Silastic® family of silicone elastomers. It is preferred that the silicone elastomers contain evenly dispersed microparticulate silica to modulate its modulus.
  • A key aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein the absorbable microparticulate ion-exchanger is a carboxyl-bearing polyester based on at least one of the cyclic monomer selected from the group consisting of glycolide, 1-lactide, and a morpholine-2,5-dione and said partially absorbable, fiber-reinforced composite in the form of an intravaginal ring and the biological site is the vagina, wherein the reinforcing fibers are in the form of a circularly configured construct, with protruding side loops, of multifilament or monofilament yarn and wherein the matrix comprises an absorbable/biodegradable polymer comprising ester linkages, and the parent polymer is formed from at least one cyclic monomer selected from the group consisting of glycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate, and a morpholine-2,5-dione.
  • A specific aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site where (1) the biostable matrix is a silicone elastomer, such as a copolymeric polysiloxane, comprising dimethyl siloxane sequences; and (2) the absorbable microparticulate ion-exchanger is carboxyl-bearing polyester based on at least one of the cyclic monomer from the group consisting of glycolide, 1-lactide, and a morpholine-2,5-dione. It is preferred that the fiber-reinforced composite ring comprises an absorbable polymeric outer coating to modulate the release of at least one bioactive agent.
  • It is also preferred that the composite ring comprises (1) at least one bioactive agent comprises a contraceptive agent selected from the group consisting of spermiostatic agents, spermicidal agents, hormonal agents, non-steroidal agents, viscosity modifiers capable of increasing the viscosity of vaginal mucus; (2) at least one bioactive agent having contraceptive properties, which can be a combination of ascorbic acid and iron gluconate or a non-steroidal compound, such as tanapraget, that is being evaluated clinically as an oral contraceptive with fewer side effects as compared with orally administered hormones (Chemical & Engineering News, Aug. 30, 2004, p. 8); (3) at least one bioactive agent having labor induction properties; (4) least one bioactive agent that is for intravaginal and transvaginal prevention or treatment of an infection selected from bacterial infections, fungal infections, viral infections and parasitic infections; (5) at least one bioactive agent that is for the treatment of cervical or ovarian cancer; (6) at least one bioactive agent that is selected from the group consisting of antifertility drugs, testosterone, testosterone precursors, spermicidal agents, sperm immobilizers, and bisphosphonate; (7) one bioactive agent that is selected from the group consisting of antiprogestinic agents, anesthetic agents, analgesic agents, anti-inflammatory agents, antimicrobial agents, antiviral agents, and antipsychotic agents; and/or (8) at least one bioactive agent that is selected from the group consisting of monoclonal antibodies, recombinant immuno-modulator vaccines, and hematopoietic growth factors.
  • A preferred aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein the fiber-reinforced composite is an intravaginal ring comprising a bioadhesive coating, and the matrix can be microporous or capable of being microporous during end-use.
  • Another specific aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site wherein said composite is in the form of a filament having a practically spherical head for outward retrieval from the biological site, wherein the biological site is (1) a human peritoneal cavity with the head being placed subcutaneously; (2) a human scrotum or prostate gland with the head being placed subcutaneously; or (3) the ear loop of an animal or human, with the head remaining ex vivo.
  • This invention also deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site wherein said composite is in the form of a suture-like strand for threading through a biological site, wherein the biological site is (1) an animal skin or muscle with the terminals of the suture-like filament knotted at the entrance and exit points of the skin for ease of removal after the required period of time, or (2) a human skin or muscle with the terminals of the suture-like filament knotted at the entrance and exit points of the skin for ease of removal after the required period of time.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • This invention deals with a controlled drug delivery device comprising a partially absorbable, fiber-reinforced system comprising a non-absorbable elastomeric matrix, an absorbable fibrous construct to modulate the device resilience and modulus with time during end-use, an absorbable microparticulate polymeric ion-exchanger to modulate the solubility of the drug through ionic interaction and/or creation of microporosity in the matrix, and preferably a non-absorbable microparticulate, inorganic filler evenly dispersed in the elastomeric matrix to increase its modulus, and preferably, an absorbable surface coating to modulate the release of drug diffusion outward from the matrix. In effect, the device is so designed to allow for modulating the initial and in-use modulus and resilience of the device by incorporating (1) an inert microparticulate inorganic filler to control the modulus; (2) an absorbable microparticulate ion-exchanger to control the initial modulus, and in-use modulus wherein the ion-exchanger absorbs/dissolves with or without ionic conjugation with active bioagent(s); and (3) an absorbable fibrous construct to control the initial resilience and modulus and modulate both properties as it absorbs during end use. Furthermore, the partially absorbable controlled drug delivery device is so designed to (1) allow the incorporation of a safe coloring additive, such as a dispersed dye, to render said device more recognizable; (2) an absorbable microparticulate ion-exchanger that is capable of interacting with the bioactive agent(s) to increase or decrease its solubility that will, in turn, affect its release profile; and (3) allow the incorporation of at least one bioactive agent that can be a contraceptive, antimicrobial, antifungal, antiviral, antibacterial, antineoplastic, and/or anti-inflammatory.
  • The present invention deals, in general, with fiber-reinforced composite systems comprising an absorbable fiber and a partially or essentially non-absorbable matrix for use in the controlled release of one or more bioactive agent(s) at the desired biological site, which may entail intravaginal, transcutaneous, intraperitoneal, and subcutaneous implantation of such systems. For the latter two routes of administration, the controlled release system is designed to be retrievable by withdrawing the non-migrating end placed subcutaneously. The composite systems can be linear or circular and are so designed as to modulate the bioactive agent(s) release profile as well as the mechanical properties, in part, through the controlled degradation of the absorbable reinforcing fiber and any other absorbable component that may be present in the matrix.
  • This invention addresses a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein (1) the absorbable reinforcing fibers are formed from at least one cyclic monomer selected from the group consisting of glycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate, and a morpholine-2,5-dione; and (2) the biostable matrix is made of a polyether urethane elastomer or a silicone elastomer, such as copolymer polysiloxane, comprising dimethyl siloxane sequences, which can be made of at least one of the Silastic® family of silicone elastomers. It is preferred that the silicone elastomers contain evenly dispersed microparticulate silica to modulate its modulus.
  • A key aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein the absorbable microparticulate ion-exchanger is a carboxyl-bearing polyester based on at least one of the cyclic monomer selected from the group consisting of glycolide, 1-lactide, and a morpholine-2,5-dione and said partially absorbable, fiber-reinforced composite in the form of an intravaginal ring and the biological site is the vagina, wherein the reinforcing fibers are in the form of a circularly configured construct, with protruding side loops, of multifilament or monofilament yarn and wherein the matrix comprises an absorbable/biodegradable polymer comprising ester linkages, and the parent polymer is formed from at least one cyclic monomer selected from the group consisting of glycolide, 1-lactide, .epsilon.-caprolactone, p-dioxanone, trimethylene carbonate, and a morpholine-2,5-dione.
  • A specific aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site where (1) the biostable matrix is a silicone elastomer, such as a copolymeric polysiloxane, comprising dimethyl siloxane sequences; and (2) the absorbable microparticulate ion-exchanger is carboxyl-bearing polyester based on at least one of the cyclic monomer from the group consisting of glycolide, 1-lactide, and a morpholine-2,5-dione. It is preferred that the fiber-reinforced composite ring comprises an absorbable polymeric outer coating to modulate the release of at least one bioactive agent.
  • It is also preferred that the composite ring comprises (1) at least one bioactive agent comprises a contraceptive agent selected from the group consisting of spermiostatic agents, spermicidal agents, hormonal agents, non-steroidal agents, viscosity modifiers capable of increasing the viscosity of vaginal mucus; (2) at least one bioactive agent having contraceptive properties, which can be a combination of ascorbic acid and iron gluconate or a non-steroidal compound, such as tanapraget, that is being evaluated clinically as an oral contraceptive with fewer side effects as compared with orally administered hormones (Chemical & Engineering News, Aug. 30, 2004, p. 8); (3) at least one bioactive agent having labor induction properties; (4) least one bioactive agent that is for intravaginal and transvaginal prevention or treatment of an infection selected from bacterial infections, fungal infections, viral infections and parasitic infections; (5) at least one bioactive agent is for the treatment of cervical or ovarian cancer; (6) at least one bioactive agent that is selected from the group consisting of antifertility drugs, testosterone, testosterone precursors, spermicidal agents, sperm immobilizers, and bisphosphonate; (7) one bioactive agent that is selected from the group consisting of antiprogestinic agents, anesthetic agents, analgesic agents, anti-inflammatory agents, antimicrobial agents, antiviral agents, and antipsychotic agents; and/or (8) at least one bioactive agent that is selected from the group consisting of monoclonal antibodies, recombinant immunomodulator vaccines, and hematopoietic growth factors.
  • A preferred aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site, wherein the fiber-reinforced composite is an intravaginal ring comprising a bioadhesive coating, and the matrix can be microporous or capable of being microporous during end-use.
  • Another specific aspect of this invention deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site wherein said composite is in the form of a filament having a practically spherical head for outward retrieval from the biological site, wherein the biological site is (1) a human peritoneal cavity with the head being placed subcutaneously; (2) a human scrotum or prostrate gland with the head being placed subcutaneously; or (3) the ear loop of an animal or human, with the head remaining ex vivo.
  • This invention also deals with a partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct capable of providing time-dependent mechanical properties of a biostable elastomeric copolymeric matrix containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for the desired period of time at a specific biological site wherein said composite is in the form of a suture-like strand for threading through a biological site, wherein the biological site is (1) an animal skin or muscle with the terminals of the suture-like filament knotted at the entrance and exit points of the skin for ease of removal after the required period of time, or (2) a human skin or muscle with the terminals of the suture-like filament knotted at the entrance and exit points of the skin for ease of removal after the required period of time.
  • Additional illustrative examples associated with this invention are outlined below.
  • EXAMPLE 1
  • Preparation of Acid-terminated Polyglycolide Cation-exchanging Microparticulate (PG-61)
  • Glycolide was polymerized in the presence of glycolic acid and stannous octanoate to produce low molecular weight, hydrolytically degradable polyester PG-61, as described in U.S. Pat. No. 6,413,539. Purification and reduction in size of PG-61 was also conducted as per U.S. Pat. No. 6,413,539 teaching.
  • EXAMPLE 2
  • Preparation of 95/5 .epsilon.-Caprolactone/Glycolide Copolymer Coating (CT-1)
  • The CT-1 copolymer was prepared by the copolymerization of .epsilon.-caprolactone (0.625 mole) with glycolide (32.3 mmole) in the presence of glycolic acid (3.756 mmole) as the initiator and stannous octanoate (0.1247 mmole as 0.2M solution in toluene) as the catalyst. The polymerization was conducted in a mechanically stirred reactor under a dry nitrogen atmosphere at 150.degree. C. for 6.25 hours. At the conclusion of the polymerization, as determined by GPC, traces of unreacted monomer were removed by distillation under reduced pressure. The composition of the purified polymer was verified by IR and NMR. The polymer was shown to melt at 55.degree. C. as determined by DSC.
  • EXAMPLE 3
  • Preparation of Partially Absorbable, Fiber-reinforced Composite Silicone Elastomers as an Intravaginal Ring-General Method
  • Listed below are the components of an active matrix that are mixed and introduced into a closed, 2-part Teflon mold having a ring-type cavity (ID=4.3 cm, OD=5.5 cm), an inlet for introducing the reactants, and an outlet to exit displaced dry nitrogen used in pre-purging the dry mole. A circular construct (outside diameter=4.9 cm) was made as a braided multifilament yarn (with an average single filament diameter of 15 micron) having side loops was placed centrally (by virtue of the side loops) into the cavity of the lower component of the mold to allow for equidistant placement between the OD and ID of the curved ring system. A fraction of the components listed below, which have been mixed under nitrogen, was charged into the lower half of the open mold under a nitrogen atmosphere. The top part was then placed on the lower part, and the mold was closed and mechanically secured. The remaining fraction of the mixed components was then injected into the mold through the feed port.
  • List of Mixed Matrix Components and Filler
  • Two-component Silastic®
  • Fibrous Construct
  • Microparticulate Cation-exchanger (from Example 1)
  • Bioactive agent(s)
  • The charged mold is heated at 80.degree. C. for the required period of time. At the conclusion of the heating cycle, the ring was removed and coated, if so needed, with 95/5 poly(caprolactone-co-glycolide)(from Example 2) by dipping in a 5 percent solution of methylene chloride followed by drying. The ring is then used for testing in a phosphate buffered solution at 37.degree. C. as a function of time for: (1) the drug release profile at pH 4.5; and (2) compressibility retention profile, as measured in terms of the radial deformation force (RDF) that is required to attain a predetermined degree of deformation, using an MTS Universal Tester (858 MiniBionix) in the compression mode.
  • EXAMPLES 4 TO 6
  • Preparation of Partially Absorbable Fiber-reinforced Composite of Silicone Elastomers as Contraceptive Intravaginal rings: Specific Examples
  • Uncoated ring systems Ito III were prepared following the same general procedure described in Example 3 and using a mixture of ascorbic acid, iron gluconate, and PG-61 (from Example 1). The components used in preparing these rings and the curing conditions are summarized in Table I.
  • TABLE I
    Composition Data and Curing Conditions for Intravaginal Rings I to III
    Example Number
    4 5 6
    Ring Number I II III
    Silastic ® matrix:
    Type Q7-6830 Q7-6830 Q7-6840
    Weight of Component A, g 2.1 2.0 1.85
    Weight of Component B, g, 2.1 2.0 1.85
    Fiber-reinforcing Constructa, mg 150 300 300
    Cation-exchangerb, mg 171 165 152
    Active ingredients:
    Ascorbic acid, mg 343 330 304
    Fe gluconate, mg 320 330 304
    Dye (D&C Violet #2), mg 5 5 3.8
    Curing Cycle
    Temperature/Time, ° C./hour 80/15.5 80/4 80/4
    aBraided copolymeric l-lactide braided suture made of segmented 88/12 l-lactide/trimethylene carbonate as described in U.S. Pat. No. 6,342,065.
    bPG-61 from Example 1
  • EXAMPLE 7
  • Preparation of Partially Absorbable Fiber-reinforced Composite of Silicone Elastomers as Antimicrobial Intravaginal Ring IV
  • Uncoated Ring IV, was prepared following the same general procedure described in Example 3 and using Metronidazole as the bioactive agent. The components used in preparing this ring and curing conditions are summarized in Table II.
  • Ring
    Number
    IV
    Ring Composition
    Silastic ® matrix:
    Type Q7-4840
    Weight of Component A, g 2.3
    Weight of Component B, g, 2.3
    Fiber-reinforcing Constructa, mg 300
    Cation-exchangerb, mg 7
    Active ingredient, Metronidazole, mg. 137
    Dye (D&C Violet #2), mg 3.8
    Curing Cycle
    Temperature/Time, ° C./hour 80/4
    aBraided copolymeric l-lactide braided suture made of segmented 88/12 l-lactide/trimethylene carbonate as described in U.S. Pat. No. 6,342,065.
    bPG-61 from Example 1
  • EXAMPLE 8
  • Radial Deformation Force (RDF) Measurement for Evaluating Ring Compressibility: General Method
  • The initial compressibility of the ring and percent retention, during incubation in a phosphate buffered solution to simulate the biological environment, was measured in terms of the force (in Newtons) required to deform the ring, radially, by 2.54 cm. The initial compressibility was conducted by placing the ring in the lower component of the sample holder of an MTS Universal Tester (MiniBionix, Model 858) and measuring the force required to deform the upper part of the ring, radially, for a distance of 2.54 cm through the downward movement at a rate of 1 mm/sec, of the free, flat upper component of the sample holder.
  • To determine the percent retention of ring incubated in a buffered solution at pH 4.5 and 37.degree. C., the test ring was removed at the desired period, wiped with tissue paper to remove excess moisture, and the force of deformation at time “t” (Ft) was measured as noted above for the initial deformation force (Fo) testing. The percent strength retention, in terms of decrease of the RDF, was calculated as follows:

  • % RDF retention=(Fo−Ft÷Fo)×100.
  • TABLE III
    Typical Radial Deformation Force (RDF) Values and In Vitro
    Retention Data of Partially Absorbable Intravaginal Rings
    In vitroa Retention of
    Ring From Example RDF, N RDF (% @day)
    II 5 1.66 82/2 
    III 6 2.26 79/14
    IV 7 1.52 89/10
    aUsing a phosphate buffer at pH 4.5 and 37° C.
  • EXAMPLE 9
  • Determination of Daily and Cumulative In Vitro Release Rates of Ascorbic Acid and Ferrous Gluconate from Eluates of a Typical Contraceptive Ring System
  • I. Outline of the Experimental Procedure
  • The procedure consists of: (1) cutting pieces of a typical ring system (as in Examples 10, 12, 19, 20, and 21) and recording the weight (pieces are placed in separate, labelled Petri dishes); (2) placing the pieces of the ring containing ferrous gluconate into a shaker containing 5 mL of phosphate buffered saline or water to Petri dishes, sealing with parafilm, and incubating at 37.degree. C. overnight; (3) collecting the eluate and measuring the volume each day, then transferring the ring pieces to a new Petri plate in 5 mL of fresh phosphate buffered saline and following Step (2) above; (4) continuing the above procedure daily for 2-days, then drying the residual matrix and recording the final weight; and (5) determining the amount of ascorbic acid and ferrous gluconate in each daily collection of the eluate.
  • II. Determination of Ascorbic Acid
  • A. Principle: In this procedure, ascorbic acid is oxidized to dehydroascorbic acid and the latter is coupled with 2,4-dinitrophenylhydrazine. The coupling reaction forms the 2,4-dinitrophnylosazone of dehydroascorbic acid, a light brown crystalline compound. When treated with 85% H.sub.2SO.sub.4, the osazone is rearranged to form a reddish colored compound, which absorbs maximally at 500 to 550 m.mu.. It is a highly stable product under the conditions used and is well suited for calorimetric measurement.
  • B. Preparation of Reagents:
  • Reagents used included (1) trichloroacetic acid solutions, 4%; (2) 2,4-dinitrophenylhydrazine reagent (2.0 g of 2,4-dinitrophenylhydrazine were dissolved in 100 mL 9N H.sub.2SO.sub.4 [1 part of concentrated H.sub.2SO.sub.4 plus 3 parts water], 4 g of reagent thiourea were added, shaken occasionally, dissolved, filtered and then refrigerated; and (3) ascorbic acid solutions.
  • Stock Solution: Ascorbic acid of the highest purity (12.5 mg) is dissolved in 50 mL of 0.5% oxalic acid. This solution is oxidized by adding one teaspoon (or 1 g) of acid-washed Norite (activated carbon) per 50 mL, shaking thoroughly, and filtering through Whatman No. 42 filter paper. One mL of this solution contains 10 .mu.g of dehydroascorbic acid. Keep refrigerated.
  • Standard Solution of Dehydroascorbic Acid: To prepare the Standard Curve Solutions, dilute the dehydroascorbic stock solution with 4.0% trichloroacetic acid. The dilutions will serve for a range of 20 to 200 mg of ascorbic acid per liter of solution.
  • C. Procedure:
  • Two mL of Norite filtrate of unknowns, 2 mL of the dehydroascrobic acid standard solution, and 2 mL of 4% TCA (control tube) are added to glass tubes. Then 0.5 mL of 2,4-dinitrophenylhydrazine reagent is added to each tube. The tubes are placed in a constant temperature water bath at 37.degree. C. The tubes are kept immersed in the bath for approximately 1.5 hours, removed, and subsequently placed in a beaker of ice water containing generous quantities of ice. To each of the tubes in the ice water bath is added slowly 2.5 mL of 85% H.sub.2SO.sub.4. The tubes are shaken under the ice water to obtain complete mixing and are then removed to a rack. After 30 minutes, the tubes are wiped and cleaned to record the absorbance in a colorimeter, using 540 m.mu. filter. To take the reading, the control tube is used to set the colorimeter at 100% transmittance or zero absorbance.
  • III. Determination of Ferrous Gluconate
  • A. Materials and Methods:
  • The samples assayed for ferrous gluconate were taken from the solutions, which contained the Ovaprene ring over various periods of time. Reagents used for the assay were phosphate buffered saline, pH 7.4 (PBS), 1,10-Phenanthroline, sodium acetate (anhydrous), and bromophenol blue dye (pH 3.0-4.6) (Sigma), hydroquinone and acetic acid (Aldrich), and ferrous gluconate (Alfa Aesar). Spectronic 20 Genesys™ Spectrophotometer was used to read the solution absorbance.
  • The reagents for the assay were prepared as follows:
  • 1. Phosphate buffered saline (PBS)-add one packet to 1000 ml of distilled water.
  • 2. 1% solution of hydroquinone is prepared with distilled water.
  • 3. 0.5% solution of 1,10-Phenanthroline is prepared with distilled water and sodium acetate-acetic acid solution added to 4% final volume (Keep in dark and discard if any color develops).
  • 4. Sodium acetate-acetic acid buffer solution (pH 4.0)-dissolve 27 g of anhydrous sodium acetate in 50 ml of distilled water. Then add 24 ml of acetic acid and bring to a final volume of 100 ml with distilled water.
  • 5. 1 mM solution of ferrous gluconate standard is prepared with PBS.
  • 6. A 1 mg/ml solution of bromophenol blue dye is prepared with distilled water.
  • B. Procedure:
  • For the ferrous gluconate standard curve, 1 mM ferrous gluconate standard solution was diluted with PBS to produce the following final concentrations: 0.75 mM, 0.5 mM, and 0.25 mM.
  • The assay was performed by adding 600 .mu.l of the standard curve solutions and 600 .mu.l of each ring buffer to be assayed to 5-ml glass tubes. The control tube was 600 .mu.l of PBS. Using a Pasteur pipette one drop f bromophenol blue and one drop of sodium acetate solution was added to each tube, followed by the addition of 1 ml of 1% hydroquinone and 1 ml of 0.5% 1,10-Phenanthroline. The tubes were gently vortexed and incubated at 50.degree. C. for 2 hr. Using a spectrophotometer, the transmittance for each tube was read at 408 nm.
  • EXAMPLE 10
  • Determination of the Initial Release Profile of Metronidazole from Antimicrobial Ring IV
  • Specimens of Ring IV made as described in Example 7 were placed in a phosphate buffer at 37.degree. C. and pH 4.5. The concentration of released Metronidazole was determined over an eight-day period. Analysis of Metronidazole was conducted on day 2, 3, 6, and 8 and the buffer was replaced with fresh aliquots at each of these periods. The cumulative percent release data are summarized below:
  • Study Period, day
    2 3 6 8
    Cumulative % Release 4.3 5.2 7.4 8.8
  • Preferred embodiments of the invention have been described using specific terms and devices. The words and terms used are for illustrative purposes only. The words and terms are words and terms of description, rather than of limitation. It is to be understood that changes and variations may be made by those of ordinary skill art without departing from the spirit or scope of the invention, which is set forth in the following claims. In addition it should be understood that aspects of the various embodiments may be interchanged in whole or in part. Therefore, the spirit and scope of the appended claims should not be limited to descriptions and examples herein.

Claims (1)

    What is claimed is:
  1. 1. A partially absorbable, fiber-reinforced composite for the controlled delivery of at least one bioactive agent comprising an absorbable fiber construct within a biostable elastomeric, copolymeric matrix, the matrix further containing an absorbable microparticulate ion-exchanging polymer to modulate the release of said bioactive agent for a desired period of time at a specific biological site, the fiber construct capable of providing time-dependent mechanical properties.
US15064674 2003-06-26 2016-03-09 Partially absorbable fiber-reinforced composites for controlled drug delivery Abandoned US20160184493A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US48289803 true 2003-06-26 2003-06-26
US10860677 US8404272B2 (en) 2003-06-26 2004-06-03 Fiber-reinforced composite rings for intravaginal controlled drug delivery
US10935808 US8399013B2 (en) 2003-06-26 2004-09-08 Partially absorbable fiber-reinforced composites for controlled drug delivery
US13766907 US9084717B2 (en) 2003-06-26 2013-02-14 Partially absorbable fiber-reinforced composites for controlled drug delivery
US14707453 US9308168B2 (en) 2003-06-26 2015-05-08 Partially absorbable fiber-reinforced composites for controlled drug delivery
US15064674 US20160184493A1 (en) 2003-06-26 2016-03-09 Partially absorbable fiber-reinforced composites for controlled drug delivery

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US15064674 US20160184493A1 (en) 2003-06-26 2016-03-09 Partially absorbable fiber-reinforced composites for controlled drug delivery

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US14707453 Continuation US9308168B2 (en) 2003-06-26 2015-05-08 Partially absorbable fiber-reinforced composites for controlled drug delivery

Publications (1)

Publication Number Publication Date
US20160184493A1 true true US20160184493A1 (en) 2016-06-30

Family

ID=36036666

Family Applications (4)

Application Number Title Priority Date Filing Date
US10935808 Active 2027-07-24 US8399013B2 (en) 2003-06-26 2004-09-08 Partially absorbable fiber-reinforced composites for controlled drug delivery
US13766907 Active US9084717B2 (en) 2003-06-26 2013-02-14 Partially absorbable fiber-reinforced composites for controlled drug delivery
US14707453 Active US9308168B2 (en) 2003-06-26 2015-05-08 Partially absorbable fiber-reinforced composites for controlled drug delivery
US15064674 Abandoned US20160184493A1 (en) 2003-06-26 2016-03-09 Partially absorbable fiber-reinforced composites for controlled drug delivery

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US10935808 Active 2027-07-24 US8399013B2 (en) 2003-06-26 2004-09-08 Partially absorbable fiber-reinforced composites for controlled drug delivery
US13766907 Active US9084717B2 (en) 2003-06-26 2013-02-14 Partially absorbable fiber-reinforced composites for controlled drug delivery
US14707453 Active US9308168B2 (en) 2003-06-26 2015-05-08 Partially absorbable fiber-reinforced composites for controlled drug delivery

Country Status (4)

Country Link
US (4) US8399013B2 (en)
EP (1) EP1786356B1 (en)
ES (1) ES2434391T3 (en)
WO (1) WO2006028475A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9566267B2 (en) 2008-05-20 2017-02-14 Poly-Med, Inc. Biostable, multipurpose, microbicidal intravaginal devices

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0222522D0 (en) 2002-09-27 2002-11-06 Controlled Therapeutics Sct Water-swellable polymers
US8399013B2 (en) 2003-06-26 2013-03-19 Poly-Med, Inc. Partially absorbable fiber-reinforced composites for controlled drug delivery
US8404272B2 (en) 2003-06-26 2013-03-26 Poly-Med, Inc. Fiber-reinforced composite rings for intravaginal controlled drug delivery
GB0417401D0 (en) 2004-08-05 2004-09-08 Controlled Therapeutics Sct Stabilised prostaglandin composition
ES2371554T3 (en) * 2004-12-14 2012-01-05 Poly-Med, Inc. intravaginal device shaped mesh ring.
US8062658B2 (en) * 2004-12-14 2011-11-22 Poly-Med, Inc. Multicomponent bioactive intravaginal ring
GB0613333D0 (en) * 2006-07-05 2006-08-16 Controlled Therapeutics Sct Hydrophilic polyurethane compositions
GB0613638D0 (en) * 2006-07-08 2006-08-16 Controlled Therapeutics Sct Polyurethane elastomers
EP2037938A2 (en) * 2006-07-12 2009-03-25 Controlled Therapeutics (Scotland) Ltd. Drug delivery polymer with hydrochloride salt of clindamycin
GB0620685D0 (en) * 2006-10-18 2006-11-29 Controlled Therapeutics Sct Bioresorbable polymers
WO2011112976A3 (en) * 2010-03-11 2012-01-19 Worcester Polytechnic Institute Methods for regenerating skeletal muscle
KR101828619B1 (en) * 2010-03-28 2018-02-12 이브스트라, 인코포레이티드 Intravaginal drug delivery device
EP2755615A4 (en) 2011-09-14 2015-10-14 Forsight Vision5 Inc Ocular insert apparatus and methods
CA2851516C (en) 2011-10-10 2016-08-02 Nanovir, Llc Guanidinyl-substituted polyamides useful for treating human papilloma virus
US9750636B2 (en) 2012-10-26 2017-09-05 Forsight Vision5, Inc. Ophthalmic system for sustained release of drug to eye
WO2015153817A1 (en) * 2014-04-01 2015-10-08 Poly-Med, Inc. Contraceptive and related device
WO2016022664A1 (en) 2014-08-05 2016-02-11 Nanovir Llc Antiviral compounds and methods for treating infections caused by double-stranded dna viruses

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3545439A (en) 1968-01-04 1970-12-08 Upjohn Co Medicated devices and methods
US3920805A (en) * 1971-12-09 1975-11-18 Upjohn Co Pharmaceutical devices and method
US4629449A (en) 1982-07-29 1986-12-16 Alza Corporation Vaginal dispenser for dispensing beneficial hormone
US4553972A (en) * 1983-05-20 1985-11-19 Syntex (U.S.A.) Inc. Disposable intravaginal contraceptive devices releasing 1-substituted imidazoles
US6309669B1 (en) 1984-03-16 2001-10-30 The United States Of America As Represented By The Secretary Of The Army Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix
DE3765145D1 (en) 1986-03-12 1990-10-31 Euro Celtique Sa Contraceptive composition.
US5192330A (en) * 1987-01-20 1993-03-09 Smith & Nephew Richards, Inc. Orthopedic device of biocompatible polymer with oriented fiber reinforcement
US4983393A (en) 1987-07-21 1991-01-08 Maximed Corporation Intra-vaginal device and method for sustained drug release
US5211952A (en) * 1991-04-12 1993-05-18 University Of Southern California Contraceptive methods and formulations for use therein
US5176907A (en) 1991-08-13 1993-01-05 The Johns Hopkins University School Of Medicine Biocompatible and biodegradable poly (phosphoester-urethanes)
US5853886A (en) * 1996-06-17 1998-12-29 Claytec, Inc. Hybrid nanocomposites comprising layered inorganic material and methods of preparation
EP0849282A3 (en) 1996-12-19 1998-09-23 Ciba Specialty Chemicals Holding Inc. Multifunctional polymeric lubricant additives
JPH10279499A (en) 1997-04-04 1998-10-20 Takeda Chem Ind Ltd Preparation applicable to uterine mucosa
CN1184957C (en) 1997-05-07 2005-01-19 盖伦(化学制品)有限公司 Intravaginal drug delivery devices for adminsitration of testosterone and testosterone precursors
US6572874B1 (en) 1998-05-15 2003-06-03 Umd, Inc. Vaginal delivery of bisphosphonates
US6416779B1 (en) 1997-06-11 2002-07-09 Umd, Inc. Device and method for intravaginal or transvaginal treatment of fungal, bacterial, viral or parasitic infections
US6197327B1 (en) 1997-06-11 2001-03-06 Umd, Inc. Device and method for treatment of dysmenorrhea
US6039968A (en) 1997-06-24 2000-03-21 Hoechst Marion Roussel Intravaginal drug delivery device
EP0891783B1 (en) 1997-07-16 2002-06-12 IsoTis N.V. Device for tissue engineering bone comprising biodegradable thermoplastic copolyester and cultured cells
US6159240A (en) 1998-08-31 2000-12-12 Medtronic, Inc. Rigid annuloplasty device that becomes compliant after implantation
US20030206928A1 (en) 1999-04-07 2003-11-06 Pertti Tormala Bioactive, bioabsorbable surgical polyethylene glycol and polybutylene terephtalate copolymer composites and devices
US6503528B1 (en) 1999-11-19 2003-01-07 Abbott Laboratories Polymeric compositions and a method of making the same
US7416559B2 (en) 2000-10-27 2008-08-26 Poly-Med, Inc. Micromantled drug-eluting stent
US6299894B1 (en) * 2000-05-10 2001-10-09 Leiras Oy Drug delivery device, especially for the delivery of gestodene
US6552622B1 (en) * 2000-08-14 2003-04-22 William Brandes Shearon Oscillator having reduced sensitivity to supply voltage changes
CA2420348C (en) 2000-08-24 2009-08-04 Cornell Research Foundation, Inc. Non-hormonal vaginal contraceptive
US20060240071A1 (en) 2003-07-31 2006-10-26 Sidney Lerner Non-hormonal vaginal contraceptive
US20040260386A1 (en) 2003-01-31 2004-12-23 Shalaby Shalaby W. Absorbable / biodegradable tubular stent and methods of making the same
US8404272B2 (en) * 2003-06-26 2013-03-26 Poly-Med, Inc. Fiber-reinforced composite rings for intravaginal controlled drug delivery
US8399013B2 (en) 2003-06-26 2013-03-19 Poly-Med, Inc. Partially absorbable fiber-reinforced composites for controlled drug delivery
US20050208095A1 (en) 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
CN101080205B (en) 2004-07-09 2011-10-12 Hra药物实验室 Sustained release compositions containing progesterone receptor modulators
US8062658B2 (en) 2004-12-14 2011-11-22 Poly-Med, Inc. Multicomponent bioactive intravaginal ring
ES2371554T3 (en) 2004-12-14 2012-01-05 Poly-Med, Inc. intravaginal device shaped mesh ring.
US8952075B2 (en) 2008-05-22 2015-02-10 Poly-Med, Inc. Bioactive polymeric liquid formulations of absorbable, segmented aliphatic polyurethane compositions

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9566267B2 (en) 2008-05-20 2017-02-14 Poly-Med, Inc. Biostable, multipurpose, microbicidal intravaginal devices

Also Published As

Publication number Publication date Type
US9084717B2 (en) 2015-07-21 grant
US20130197099A1 (en) 2013-08-01 application
EP1786356A1 (en) 2007-05-23 application
EP1786356A4 (en) 2011-11-30 application
US8399013B2 (en) 2013-03-19 grant
ES2434391T3 (en) 2013-12-16 grant
EP1786356B1 (en) 2013-07-03 grant
WO2006028475A1 (en) 2006-03-16 application
US9308168B2 (en) 2016-04-12 grant
US20050053639A1 (en) 2005-03-10 application
US20150238419A1 (en) 2015-08-27 application

Similar Documents

Publication Publication Date Title
Mi et al. In vitro evaluation of a chitosan membrane cross-linked with genipin
Li et al. Chitosan–alginate hybrid scaffolds for bone tissue engineering
Brown et al. Controlled release of insulin from polymer matrices: control of diabetes in rats
US6147168A (en) Copolymers of absorbable polyoxaesters
US5578662A (en) Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom
US5700583A (en) Hydrogels of absorbable polyoxaesters containing amines or amido groups
US5902874A (en) Polyesteramides from cyclic monomers and surgical articles made thereof
US5958444A (en) Method for treating urinary reflux
Stevens et al. An articulated antibiotic spacer used for infected total knee arthroplasty: a comparative in vitro elution study of Simplex® and Palacos® bone cements
Schmedlen et al. Photocrosslinkable polyvinyl alcohol hydrogels that can be modified with cell adhesion peptides for use in tissue engineering
US5530074A (en) Coating for tissue drag reduction
Belt et al. Gentamicin release from polymethylmethacrylate bone cements and Staphylococcus aureus biofilm formation
Edlich et al. Physical and chemical configuration of sutures in the development of surgical infection.
US5859150A (en) Prepolymers of absorbable polyoxaesters
US5618552A (en) Absorbable polyoxaesters
Bayston et al. Prevention of hydrocephalus shunt catheter colonisation in vitro by impregnation with antimicrobials.
US3987797A (en) Antimicrobial sutures
US20040096476A1 (en) Therapeutic devices for patterned cell growth
US20040086479A1 (en) Novel dendritic polymers, crosslinked gels, and their biomedical uses
US6998134B2 (en) Biologically active implants
US5854383A (en) Aliphatic polyesters of trimethylene carbonate epsilon-caprolactone and glycolide
US5639851A (en) High strength, melt processable, lactide-rich, poly(lactide-CO-P-dioxanone) copolymers
Vert Degradable and bioresorbable polymers in surgery and in pharmacology: beliefs and facts
Wei et al. A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier
US4581028A (en) Infection-resistant materials and method of making same through use of sulfonamides