EP1299048A1 - Biologisch abbaubares träger-material sowie abgabesysteme für biologisch aktive substanzen - Google Patents

Biologisch abbaubares träger-material sowie abgabesysteme für biologisch aktive substanzen

Info

Publication number
EP1299048A1
EP1299048A1 EP01918249A EP01918249A EP1299048A1 EP 1299048 A1 EP1299048 A1 EP 1299048A1 EP 01918249 A EP01918249 A EP 01918249A EP 01918249 A EP01918249 A EP 01918249A EP 1299048 A1 EP1299048 A1 EP 1299048A1
Authority
EP
European Patent Office
Prior art keywords
agents
biodegradable
peg
glyceryl
poly
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.)
Withdrawn
Application number
EP01918249A
Other languages
English (en)
French (fr)
Other versions
EP1299048A4 (de
Inventor
Atul J. Shukla
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.)
Individual
Original Assignee
Individual
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
Priority claimed from US09/605,661 external-priority patent/US6432438B1/en
Priority claimed from IN694MU2000 external-priority patent/IN189074B/en
Priority claimed from CN 00120871 external-priority patent/CN1206001C/zh
Application filed by Individual filed Critical Individual
Publication of EP1299048A1 publication Critical patent/EP1299048A1/de
Publication of EP1299048A4 publication Critical patent/EP1299048A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/141—Plasticizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
    • C08K5/00—Use of organic ingredients
    • C08K5/04—Oxygen-containing compounds
    • C08K5/10—Esters; Ether-esters
    • C08K5/11—Esters; Ether-esters of acyclic polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • Biodegradable vehicles and delivery systems which can be mixed with one or more physiologically, pharmacologically and biologically active substance(s) (BAS), are provided.
  • the biodegradable vehicle (without any BAS-loading) can be used as a biodegradable filler or spacer to fill in cavities or body tissues in animals, birds and humans.
  • the biodegradable vehicle can be mixed with one or more BAS.
  • the delivery systems loaded with BAS can be used to control the release of the BAS from the delivery system for a prolonged period of time.
  • the consistency and rheology, hydrophilicity and hydrophobicity, and in vivo degradation rates of the biodegradable vehicles and BAS loaded delivery systems are controlled by modulating the types of polymers or copolymers, molecular weight of polymers and copolymers, copolymer ratios, and ratios of blends of polymers or copolymers with different molecular weights or different hydrophilicity or hydrophobicity, types of plasticizers, concentration of plasticizers, ratios of two or more plasticizers used in combination.
  • the release characteristics of the BAS from the biodegradable delivery system are also controlled by the above-mentioned factors.
  • the present invention also provides methods for preparing these biodegradable vehicles and delivery systems.
  • biodegradable polymers refer to those polymers, which are slowly converted to nontoxic degradation products in the body. Examples include homopolymers and copolymers of polylactic acid or polylactide (PLA), polyglycolic acid or polyglycolide, polycaprolactone (PCL), polyanhydrides, polyphosphoesters, polyorthoesters, polyaminoacids, pseudopolyaminoacids, polyhydroxybutyrates, polyhydroxyvalerates, polyphosphazenes, polyalkylcyanoacrylates, polydioxanone, poly( ⁇ -decaloactone), poly(glycolide-co-trimethylene carbonate), polyethylene carbonate), poly(iminocarbonate), poly(l,3-propylene malonate), poly(ethylene-l,4-phenylene-bis-oxyacetate), poly(ester- amides).
  • PLA polylactic acid or polylactide
  • PCL polycaprolactone
  • PCL polyanhydrides
  • biodegradable polymers in biodegradable delivery systems of BAS are: ready availability of polymers, polymers used are nontoxic, biocompatibile and biodegradable, facile predictability of biodegradation rates of the polymers, ease of modification of the degradation characteristics of the polymers, regulatory approval of some of the commonly used biodegradable polymers, ease of fabrication of the polymers into various types of devices and the possibility of controlling the release of BAS by polymers over the desired length of time.
  • BAS release characteristics from a polymeric delivery system depends on the physicochemical characteristics of the BAS molecule, polymer and other excipients, and the dosage form.
  • the important factors governing BAS release characteristics from the delivery- systems prepared with biodegradable polymers are polymer molecular weight, copolymer ratio, polymer hydrophilicity or lipophilicity, percentage of various polymers in a blend consisting of polymers with varying molecular weights or copolymer ratios, hydrophilicity or hydrophilicity of the platicizer, percentage of various hydrophilic and hydrophilic plasticizers in a blend of varying types of plasticizers, degree of plasticization, particle size and percentage of BAS-loading, hydrophilicity or lipophilicity of the incorporated BAS, solubility of the BAS in both the delivery system and in the biological fluids, physical form of the formulation (i.e.
  • BAS delivery systems have been prepared from biodegradable polymers. These include microparticles such as microspheres and microcapsules (Schindler A, Jeffcoat R, Kimmel GL, Pitt CG, Wall ME and Zwelinger R., in: Contemporary Topics in Polymer Science, Pearce EM and Schaefgen JR, eds., Vol. 2, Plenum Publishing Corporation, New York, pp. 251-289, 1977; Mason NS, Gupta DNS, Keller, DW, Youngquist RS, and Sparks RF. Biomedical applications of microencapsulation, (Lim F, ed.), CRC Press Inc., Florida, pp.
  • Sustained drug delivery systems II Factors affecting release rates from poly- ⁇ -caprolactone and related biodegradable polyesters., J. Pharm. Sci., 68(12):1534-1538, 1979), discs (Cowsar DR, Dunn RL., Biodegradable and non-biodegradable fibrous delivery systems, in: Long acting Contraceptive Delivery Systems, Zatuchni GI, Goldsmith A, Shelton JD and Sciarra JJ, eds., Ha ⁇ er & Row, Publishers, Philadelphia, pp.145-148, 1984), wafers (Brem et al., J. Neurosurgery, 74:441-446, 1991) and solutions (Dunn et al, U.S.
  • all the drug delivery systems described in the aforementioned section contains at least one BAS, which is inco ⁇ orated into the drug delivery system during the manufacturing of the dosage form. It is often difficult (if not impossible) to individualize BAS dosing (or change the BAS-loading) in these drug delivery systems. Also, there exists a possibility where a certain percentage of BAS often degrades because of its exposure to the solvents, chemicals or other harsh manufacturing conditions during the preparation of the drug delivery system or during storage of the finished product.
  • the present invention relates to compositions and methods of preparing biodegradable vehicles and delivery systems.
  • the present invention also provides compositions of biodegradable vehicles and BAS-loaded delivery systems, and the process of blending one or more BAS with the biodegradable vehicles.
  • the biodegradable vehicles can be used as biodegradable fillers or spacers (e.g., an artificial tissue) to fill in cavities or body tissues in animals, birds and humans.
  • One or more biologically active substances (BAS) can be loaded into the biodegradable vehicle to prepare the biodegradable delivery system, which can be used to control the release of the BAS over a desired period of time.
  • BAS biologically active substances
  • the present invention provides a biodegradable vehicle comprising at least one biodegradable polymer having at least one plasticizer.
  • the plasticizer is capable of modulating the consistency, the hydrophobicity, hydrophilicity and degradation characteristics of the biodegradable vehicle.
  • the biodegradable vehicle preferably has at least one biologically active substance mixed therewith.
  • the biodegradable polymer or blends thereof is/are capable of modulating the degradation kinetics of the biodegradable vehicle and in certain instances, the consistency, the hydrophobicity and the
  • the plasticizer or blends thereof are also capable of modulating the degradation kinetics, the consistiency, the hydrophilicity and the hydrophobicity of the biodegradable vehicle as well.
  • the present invention provides a biodegradable delivery system comprising: (a) at least one biodegradable polymer, the polymer selected from polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamides and polyanhydrides; and (b) at least two plasticizers, one of the plasticizers being hydrophilic and the other of the plasticizers being hydrophobic; and (c) at least one biologically active substance.
  • the method of manufacturing the biodegradable vehicles described in the present invention involves dissolving one or more biodegradable polymers and one or more plasticizers in a volatile solvent or mixture of volatile solvents.
  • the volatile solvent or mixture of volatile solvents is/are then removed using vacuum or evaporated at an elevated temperature, or removed using both vacuum and elevated temperature.
  • the resulting biodegradable vehicles can be free flowing or viscous liquids, gels or pastes. This method is particularly suited when polymers of high molecular weights are used to prepare the vehicles or BAS delivery system, or when a high consistency of the biodegradable vehicle or BAS delivery system, is desired.
  • one or more biodegradable polymers can be directly dissolved in one or more plasticizers by stirring the mixture with or without the use of heat. This method is particularly suited when polymers of low molecular weights are used to prepare the biodegradable vehicles or BAS delivery system, or when a low consistency or BAS delivery system is desired.
  • the BAS can be loaded into the biodegradable vehicle in any physical form (i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers) at any step during the manufacturing process of biodegradable delivery systems before the volatile solvent is completely removed.
  • the BAS-loaded delivery system can also be manufactured by loading the BAS soon after the biodegradable vehicle is prepared, or blending the BAS to the biodegradable vehicle just prior to the use of the BAS-loaded biodegradable delivery system.
  • Mixing of the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stirring device, or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing.
  • a stirring device or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing.
  • the BAS is blended with the biodegradable vehicle just prior to use, it could be stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers), or gel or paste (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers).
  • a device which resembles two syringes or syringe-like devices (e.g.
  • pumps in which materials can be mixed by depressing a trigger-like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle.
  • the BAS is loaded in one syringe or compartment and the biodegradable vehicle is loaded in the other compartment.
  • a removable partition or a valve which will allow the contents of the two compartments to be mixed uniformly, separates the two compartments.
  • the mixing process is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle.
  • the resulting BAS-loaded biodegradable delivery systems can be free flowing or viscous liquids, gels or pastes
  • the BAS and the biodegradable vehicle can be packaged in two separate containers as a kit. The vehicle and the BAS can then be blended together by the aforementioned methods.
  • the biodegradable vehicles or BAS-loaded biodegradable delivery systems could be sterilized in the final package by an appropriate technique such as irradiation sterilization technique.
  • the biodegradable vehicles or BAS-loaded biodegradable delivery systems can be prepared from pre-sterilized components in an aseptic environment. Sterilization of the solvents and plasticizers used in the manufacturing process could be accomplished by an appropriate sterilization technique such as filtration, autoclaving or irradiation.
  • the polymer and the BAS used to prepare the biodegradable vehicles and the BAS-loaded biodegradable delivery systems could also be sterilized by an appropriate sterilizing technique.
  • biodegradable vehicles described in the present invention include the ease of manufacturing, injection, implantation, and application, ease of control over the consistency or rheology and hydrophilicity or hydrophobicity of the biodegradable vehicle, flexibility of tailoring in vivo degradation kinetics of the vehicles, tailoring the dose of the BAS in the biodegradable delivery systems by blending the requisite amount of BAS with the biodegradable vehicle, and enhancing stability of the BAS, especially when it is blended with the biodegradable vehicle just prior to its use.
  • a major reason for the enhanced stability of the BAS is that the BAS is not subjected to exposure to solvents, chemicals or the harsh processing conditions especially during the manufacture of the biodegradable vehicle.
  • the BAS is stored in an appropriate separate container, it does not come in contact with the biodegradable vehicle until it is blended with the vehicle.
  • biodegradable delivery systems of the present invention include ease of manufacturing, injection, implantation, and application, ease of control over the consistency or rheology and hydrophilicity or hydrophobicity of the biodegradable delivery systems, ease of inco ⁇ oration of BAS into the delivery systems, facile tailoring of the release of BAS from the biodegradable delivery systems, and control of in vivo biodegradation rates of biodegradable delivery systems.
  • the biodegradable vehicles without blending any BAS may be used as a tissue or cavity fillers or spacers in the body, whereas the biodegradable vehicles loaded with BAS may be used for the treatment of a variety of diseases and pathological conditions.
  • the final composition with or without the BAS may be injected, implanted, smeared or applied directly in animals, birds and humans.
  • the present invention provides a kit comprising a) a biodegradable vehicle; and b) a BAS.
  • the BAS is blended with the biodegradable vehicle just prior to use.
  • the BAS is stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers), or gel or paste (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers).
  • a device which resembles two syringes or syringe-like devices (e.g. pumps in which materials can be mixed by depressing a trigger-like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle.
  • Figure 1 shows a method of preparing a biodegradable vehicle and delivery systems without the use of volatile solvents.
  • Figure 2 shows a method of preparing a biodegradable vehicle and delivery systems.
  • Figure 3 shows an alternate method of preparing biodegradable delivery systems.
  • Figure 4 describes the effect of varying polymer to plasticizer ratios on cumulative amount of levonorgestrel released from biodegradable delivery systems.
  • Figure 5 describes the effect of varying polymer inherent viscosity on cumulative amount of levonorgestrel released from biodegradable delivery systems.
  • Figure 6 describes the effect of varying copolymer ratios on cumulative amount of levonorgestrel released from biodegradable delivery systems.
  • Figure 7 describes the effect of varying drug loadings on oxytetracycline base released from biodegradable delivery systems.
  • Figure 8 describes the effect of varying plasticizer compositions on oxytetracycline base released from biodegradable delivery systems.
  • Figure 9 describes the effect of varying plasticizer to polymer ratios on oxytetracycline base released from biodegradable delivery systems.
  • Figure 10 describes the effect of varying hydrophilicity of plasticizers on oxytetracycline base released from biodegradable delivery systems.
  • Figure 11 describes the effect of varying polymer to plasticizer ratios and plasticizer compositions on oxytetracycline base released from biodegradable delivery systems.
  • Figure 12 describes the effect of varying polymer molecular weights on oxytetracycline base released from biodegradable delivery systems.
  • Figure 13 describes the effect of varying drug solubility on naltrexone released from biodegradable delivery systems.
  • Figure 14 describes the effect of varying solubility of drug on oxytetracycline released from biodegradable delivery systems.
  • Figure 15 describes the effect of varying polymer molecular weights on oxytetracycline base released from biodegradable delivery systems.
  • Figure 16 describes the effect of varying polymer molecular weights on in vivo release of oxytetracycline base from biodegradable delivery systems.
  • the present invention relates to compositions of biodegradable vehicles and BAS-loaded delivery systems comprising at least one polymer and at least one plasticizer.
  • the delivery system of the present invention may also comprise r of at least one biologically active substance (BAS). It also relates to the method of preparing biodegradable vehicles and delivery systems loaded with BAS.
  • BAS biologically active substance
  • polymer includes oligomer, homopolymer, copolymer and te ⁇ olymer.
  • Biodegradable polymers are used in this invention because they form matrices that can control the release of BAS over a desired length of time, can degrade in vivo into non-toxic degradation products, and are available in varying physicochemical properties including varying hydiOphilicity and hydrophobicity, varying molecular weights, varying crystallinity and amo ⁇ hous states, and varying copolymer ratios.
  • plasticizers are used in varying ratios to convert a polymer in a solid state to a biodegradable vehicle or delivery system of varying consistency such as a free flowing or a viscous liquid, a gel or a paste.
  • Plasticizers are chemicals added to polymers to improve their flow, and therefore their processibility (Billmeyer, F., Jr. Textbook of Polymer Science, John Wiley and Sons, New York, 1984, p. 472). This is achieved by lowering their glass transition temperature (a temperature at which a glassy polymer becomes rubbery on heating and a rubbery polymer reverts to a glassy one on cooling), thus achieving a change in properties.
  • a plasticizer can only plasticize a polymer when the molecules of the plasticizer can interact with the molecules of the polymer. Hence, the plasticizers act like lubricants between the polymer chains, facilitating slippage of chain past chain under stress and extending the temperature range for segmental rotation to lower temperatures (Martin, A., Physical Pharmacy, Lea and Febiger, Philadelphia, 1993, p. 588).
  • the degree or extent of plasticization of a polymer will depend on the type and amount of plasticizer blended with the polymer. For example, higher the concentration of the plasticizer, greater the extent of plasticization or flexibility of the polymer.
  • plasticizers are available with varying physicochemical properties, including varying hydrophilicity and lipophilicity, it is possible to blend an appropriate plasticizer at a desired concentration with a selected compatible polymer such that the resulting biodegradable vehicle or BAS-loaded biodegradable delivery system has the tailored physicochemical characteristics, including varying hydrophilicity and lipophilicity, and consistency.
  • the present invention also includes formulations wherein two or more plasticizers are used in a combination or blend of varying ratios.
  • the present invention also includes formulations wherein two or more polymers or
  • copolymers with varying copolymer ratios or molecular weights are used in a combination or blend of varying ratios.
  • Methods of preparing the biodegradable vehicles and delivery systems of the present invention involve dissolving at least one biodegradable polymer in a volatile solvent or a mixture of solvents. At least one plasticizer is added to the resulting polymer solution. The volatile solvent is evaporated using vacuum or removed at an elevated temperature, or evaporated using a combination of both vacuum and elevated temperature.
  • the resulting biodegradable vehicles and delivery systems could be in the form of either free-flowing or viscous liquids, gels or pastes. This method is particularly suited when polymers of high molecular weights are used to prepare the vehicles or BAS delivery system, or when a high consistency of the biodegradable vehicle or BAS delivery system, is desired.
  • one or more biodegradable polymers can be directly dissolved in one or more plasticizers by stirring the mixture with or without the use of heat. This method is particularly suited when polymers of low molecular weights are used to prepare the biodegradable vehicles or BAS delivery system, or when a low consistency or BAS delivery system is desired.
  • Polymers suitable for preparing the biodegradable delivery systems of the present invention include, but are not limited to, homopolymers and/or copolymers of polyesters, polyorthoesters, polyphosphoesters, polyanhydrides, polyaminoacids, pseudopolyamino acids, polyamides, polyalkylcyanoacrylates, polyphosphazenes, polydioxanone, poly( ⁇ -decaloactone), poly(glycolide-co-trimethylene carbonate), poly(ethylene carbonate), poly(iminocarbonate), poly(l,3-propylene malonate), poly(ethylene-l,4-phenylene-bis-oxyacetate), and poly(ester-amides).
  • polymers include polylactic acid or polylactide (PLA) and its copolymers, polyglycolic acid or polyglycolide and its copolymers, polycaprolactone (PCL) and its copolymers, polyhydroxybutyrates and their copolymers, and polyhydroxyvalerates and polydioxanone and their copolymers.
  • PLA polylactic acid or polylactide
  • PCL polycaprolactone
  • a mixture of polymers with different molecular weights or different types, or copolymer ratios may be used to tailor physicochemical properties, the degradation characteristics of the biodegradable vehicles and the delivery systems or the release characteristics of BAS from the biodegradable delivery systems, or both.
  • Solvents used to dissolve the polymer for the preparation of biodegradable delivery system of the present invention include, but are not limited to, ketones, ethers, alcohols, amides, and chlorinated solvents.
  • Preferred solvents are acetone, ethyl acetate, methyl acetate, methylethylketone, chloroform, methylene chloride, isopropanol, ethyl alcohol, ethyl ether, methylethyl ether, hexafluroisopropanol, tertral ydrofuran, and hexafluroacetone sesquihydrate.
  • a mixture of volatile solvents may also be used to create a suitable mixture, which can dissolve both the polymer and the plasticizer.
  • Plasticizers used for the preparation of biodegradable delivery system of the present invention include, but are not limited to, citrates such as diethyl citrate (DEC), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri-n-hexyl-citrate, acetyltri-n-hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether (Transcutol ® ), propylene glycol monotertiary butyl ether, dipropylene glycol
  • Labrafils ® and Labrasol ® such as PEG-6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG-8 glycerol linoleate, PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/caprate, polyglyceryl-3 -oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate (Gelucire 44/1 ® ), PEG-32 glyceryl palmitostearate (Gelucire 50/13 ® ), PEG-32 glyceryl stearate (Gelucire 53/10 ® ), glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate (Triacetin ®
  • the BAS can be loaded in any physical form (i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers) at any step during the manufacturing process of biodegradable delivery systems before the volatile solvent is completely removed. It can also be manufactured by loading the BAS soon after the biodegradable vehicle is prepared, or blending the BAS to the biodegradable vehicle just prior to the use of the BAS-loaded biodegradable delivery system.
  • any physical form i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers
  • Mixing the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stirring device, or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing.
  • a stirring device or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing.
  • the BAS When the BAS is blended with the biodegradable vehicle just prior to use, it could be stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers), or gel or paste (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers).
  • a device which resembles two syringes or syringe-like devices (e.g.
  • BAS pumps in which materials can be mixed by depressing a trigger-like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle.
  • the BAS is loaded in one syringe or compartment and the biodegradable vehicle is loaded in the other compartment.
  • a removable partition or a valve which will allow the contents of the two compartments to be mixed uniformly, separates the two compartments.
  • the mixing process is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle.
  • the resulting BAS-loaded biodegradable delivery systems can be free flowing or viscous liquids, gels or pastes.
  • the BAS and the biodegradable vehicle can be packaged in two separate containers as a kit. The vehicle and the BAS can then be blended together by the aforementioned methods.
  • the procedure for preparing a biodegradable vehicle first, loading the BAS soon after the biodegradable vehicle is prepared, or blending the BAS to the biodegradable vehicle just prior to the use of the BAS-loaded biodegradable delivery system is shown in Figures 1 and 2.
  • the procedure of loading BAS before removing the volatile solvent or mixture of volatile solvents to prepare biodegradable delivery systems is shown in Figure 2.
  • the method of addition of the BAS is not limited to that shown in Figure 2, since the BAS can be loaded in any physical form (i.e.
  • the resulting BAS-loaded biodegradable delivery systems can be free flowing or viscous liquids, gels or pastes, wherein the BAS can be dissolved or suspended.
  • BAS include, but are not limited to, steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS - agents), narcotic agonists and antagonists, fertility regulating agents, antibodies and antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, angiogenic and antiangiogenic agents, anti-inflammatory agents, immunomodulators, vasodilators, brochiodilators.
  • growth promoting agents such as calcium phosphates
  • the bioactive agents include anticancer agents such as taxol, ca ⁇ nustine, interleukin 2, interferon, growth hormones such as human growth hormone, somatotropin hormone, antipsychotic agents such as risperidone, antibiotics such as gentamicin, tetracycline, oxytetracycline, topical anesthetic agents such as benzocaine, chloroprocaine, cocaine, procaine, propoxycaine tetracaine, depravaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, propofol and ropivacaine, analgesic agents such as mo ⁇ hine, oxycodone, fentanyl, fentanyl, sufentanyl, buto ⁇ hanol, narcotic antagonists such as naltrexone, nal ⁇ hine, naloxone, nalmefen
  • the biologically active agents include, but are not limited to, steroids such as protaglandins, estrogens, androgens, and progestins; ophthalmics such as lubricants and anti-glaucoma; antibiotics such as quinolones; saliva subsitiutes, sedative/hypnotics such as benzodiazepines and barbituates; wound care such as growth factors (EPO, FGF, G-CSF); antiparasitics (worms, malarial); anticonvulsants, muscle relaxants, nucleoside analogs, osteoporosis preparations (supplement bone growth),
  • steroids such as protaglandins, estrogens, androgens, and progestins
  • ophthalmics such as lubricants and anti-glaucoma
  • antibiotics such as quinolones
  • saliva subsitiutes such as sedative/hypnotics
  • sedative/hypnotics such as benzodiazepines and barbituates
  • antibiotics such as cephalosporins, aminoglycosides and sulfonamides, oxytocic agents and prostaglandins.
  • the physical form i.e. liquids, gels or pastes
  • consistency or rheology i.e. hydrophilicity or hydrophobicity
  • in vivo duration of stay of the biodegradable vehicles or delivery systems in vivo biodegradation rate of biodegradable vehicles or delivery systems
  • BAS release characteristics from BAS-loaded biodegradable delivery systems depend on a number of factors.
  • polymer or copolymer examples include: type of polymer or copolymer, hydrophilicity or lipophilicity of polymer or copolymer, concentration of polymer or copolymer, molecular weight of polymer or copolymer, copolymer ratios, combination of polymers or copolymers with different molecular weights, combination of copolymer with varying copolymer ratios, combination of different types of polymer with varying crystallinity, hydrophilicity or hydrophobicity, type of plasticizer, hydrophilicity or lipophilicity of plasticizer, concentration of plasticizer (polymer or copolymer to plasticizer/plasticizers ratios), combination of plasticizers, type of BAS, loading of BAS, hydrophilicity or lipophilicity of BAS, molecular weight of BAS.
  • the physicochemical interactions between the polymer, plasticizer and BAS also affect the above-mentioned properties of biodegradable vehicles and delivery systems. For example, using the present invention, it is possible
  • BAS (with specific physicochemical properties and the desired in vivo concentration), for the desired length time. This is achieved by blending an appropriately selected polymer or polymers with an appropriately selected plasticizer or mixtures of plasticizers. Besides controlling the release characteristics of the BAS from the delivery system described in the present invention, a blend of the appropriate polymer or polymers and plasticizer also controls the consistency or rheology of the delivery system.
  • blends of polyacaprolactone and polylactic acid or polycaprolactone and poly-lactic-co-glycolic acid/polylactide-co-glycolide (PLGA)) can also result in a biodegradable vehicle or biodegradable delivery system with varying degradation kinetics where the more hydrophilic or amo ⁇ hous polymer may degrade at a much faster rate than the rest of the polymers in the blend.
  • the biodegradable vehicle without any BAS may be used as a biodegradable tissue or cavity filler or spacer in the body, whereas, BAS-loaded biodegradable delivery system may be used for the treatment of a variety of diseases and pathological conditions.
  • the final composition with or without the BAS may be injected, implanted, smeared or applied in animals, birds or humans.
  • the biodegradable delivery system loaded with an antitumor agent or antiangiogenic agent can be directly injected into or adjacent to solid tumors such as brain tumor, breast tumors, melanomas, etc. It can also be injected, implanted or smeared at a site from where a solid tumor has been surgically removed, thus affording site-specific delivery for disease states that are otherwise very difficult, (if not impossible) to treat using the conventional methods of treatment.
  • BAS- loaded biodegradable vehicle can also be used in surgeries where appropriate quantities of an antibiotic, an anti-inflammatory agent, a local anesthetic or analgesic, or combinations thereof can be loaded in the biodegradable vehicle by the surgeon in an operating room, and the resulting mixture can then be injected, implanted, smeared or applied at the site of surgery to minimize the chances of localized infections or inflammation and reduce pain respectively, due to surgery.
  • an antibiotic an anti-inflammatory agent
  • a local anesthetic or analgesic or combinations thereof
  • the resulting mixture can then be injected, implanted, smeared or applied at the site of surgery to minimize the chances of localized infections or inflammation and reduce pain respectively, due to surgery.
  • PMMA polymethylmethacrylate
  • the non-degradable polymer beads have to be eventually removed before closing the wound with a suture, and the patients are then given an intravenous dose of an antibiotic or treated with an oral antibiotic.
  • This procedure can easily be corrected with the use of an antibiotic loaded biodegradable vehicle that can be injected, implanted, smeared or applied near or at the site of surgery. High concentrations of the antibiotic at the site of surgery can prevent infections.
  • the BAS delivery system need not be removed from the site of administration because of the biodegradable nature of the system.
  • the biodegradable vehicle loaded with bone growth promoting agents such as calcium sulfate, calcium phosphate or hydroxyapatite can be injected, implanted, applied or smeared at an appropriate site, where it is needed following bone, disc or spine surgery.
  • BAS such as low molecular weight heparin can also be inco ⁇ orated into the biodegradable vehicle and the resulting mixture can be used to treat conditions such as deep venous thrombosis (DNT) in trauma or surgical patients.
  • DNT deep venous thrombosis
  • the system could be loaded with a contraceptive agent, antipsychotic agent, anticonvulsants, antimalarial, antihypertensive agent, antibiotics, antiviral agents, biologically active protein and peptides, vaccines, live or killed bacteria and viruses, genes, D ⁇ A or D ⁇ A fragments, R ⁇ A or R ⁇ A fragments, and injected, implanted, smeared or applied in the body to provide a controlled release of the agents for the desired length of time.
  • Biodegradable delivery system loaded with BAS such as antiinflammatory agents, analgesics and anesthetics could be injected directly into joints or sites in the body from where the pain is emanating, thus providing relief from the excruciating pain and making the joints more mobile.
  • Antigens may also be inco ⁇ orated into the delivery system and injected, implanted or applied in animals or humans to induce the production of specific antibodies.
  • Bones fragments or powder
  • mo ⁇ hogenic proteins such as growth promoting agents of biological tissues and organs and wound-healing factors
  • Live cells and/or whole or a part of a tissue or tissues and organs can also be blended with the biodegradable vehicle and injected, implanted or applied at the site of administration.
  • the biodegradable vehicle can be prepared with blends of varying molecular weights of polymers or copolymers, or with blends of copolymers of varying copolymer ratios (e.g. 50/50 PLGA and 85/15 PLGA or 100% PLA and 25/75 PLGA) or blends of different types of biodegradable polymers with varying hydrophobicity or lipophilicity or crystallinity (e.g. 1:1 of PLA:PCL or 1:3 of PLA:PCL or 1 : 1 of 50/50 PLGA:PCL).
  • blends of varying molecular weights of polymers or copolymers e.g. 50/50 PLGA and 85/15 PLGA or 100% PLA and 25/75 PLGA
  • blends of different types of biodegradable polymers with varying hydrophobicity or lipophilicity or crystallinity e.g. 1:1 of PLA:PCL or 1:3 of PLA:PCL or 1 : 1 of 50/50 PLGA:PCL
  • the formulation which is sterile, is suitable for various topical or parenteral routes, such as intramuscular, subcutaneous, intra-articular, by suppository (e.g. per-rectum or vaginal application), intradermal.
  • topical or parenteral routes such as intramuscular, subcutaneous, intra-articular, by suppository (e.g. per-rectum or vaginal application), intradermal.
  • the biological active agents and biodegradable delivery systems are delivered or administered topically. Additionally, the agents can be delivered parenterally. Topical administration is preferred in treatment of lesions of the skin as in psoriasis, where such direct application is practical and clinically indicated.
  • An effective quantity of the compound of interest is employed in treatment.
  • the dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. For example, the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include: the route of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • Example 1 was repeated using 10% w/w of 50/50 lactide-co-glycolide copolymer and 90% w/w TEC. The resulting formulation obtained was a matrix with a liquid-like consistency.
  • Example 1 was repeated using 20% w/w of 50/50 lactide-co-glycolide copolymer and 80% w/w TEC. The resulting formulation obtained was a matrix with a viscous liquid-like consistency.
  • EXAMPLE 4 n Example 1 was repeated, using 30% w/w of 50/50 lactide-co-glycolide copolymer and 70% w/w TEC was used. The resulting formulation obtained was a matrix with a viscous liquid-like consistency.
  • Example 1 was repeated, using 40% w/w of 50/50 lactide-co-glycolide copolymer and 60% w/w TEC was used. The resulting formulation obtained was a matrix with a viscous liquid-like consistency.
  • Example 1 was repeated, using 60% w/w of 50/50 lactide-co-glycolide copolymer and 40% w/w TEC was used. The resulting formulation obtained was a matrix with a gel-like consistency.
  • Example 1 was repeated, using 70% w/w of 50/50 lactide-co-glycolide copolymer and 30% w/w TEC was used. The resulting formulation obtained was a matrix with a gel-like consistency.
  • Example 1 was repeated, using 80% w/w of 50/50 lactide-co-glycolide copolymer and 20% w/w TEC was used. The resulting formulation obtained was a matrix with thick sticky paste.
  • Example 1 was repeated with the following polymers and plasticizers as shown in Table 1 below:
  • EXAMPLE 12 Effect of varying polymer inherent viscosities on the physical state of the formulations and drug release characteristics
  • a polymer (25% w/w of 50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone. Pure polyethylene glycol 400 (PEG 400) was added to the polymer solution. The solution was stirred to yield a uniform mixture. Acetone was evaporated from the mixture by heating at 60-75°C with constant stirring. The blank formulation was kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone. The resulting formulation obtained was a matrix with a viscous liquid like consistency. Three different concentrations of oxytetracycline base (either 10, 20 or 30% w/w) were added to the blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations.
  • PEG 400 polyethylene glycol 400
  • Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant.
  • Figure 6 shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. Increasing the percentage of drug in the formulations from 10 to 30% w/w increased the cumulative amount of drug released at the end of 360 hours. This increase occurred because, at higher drug-loadings, more drug is available on the surface of the formulations for release. Moreover, a higher 3 drug concentration gradient between the formulation and the dissolution medium is expected at 30% w/w drug-loading compared to the one at 10% w/w drug loading. EXAMPLE 15
  • plasticizer compositions on drug release A polymer (25% w/w of 50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone. Either pure triethyl citrate (TEC), or polyethylene glycol 400 (PEG 400), or blends of PEG 400 and TEC (either 50/50% or 75/25% blends of PEG 400/TEC) was added to the polymer solution. The resulting solutions were stirred to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone.
  • TEC triethyl citrate
  • PEG 400 polyethylene glycol 400
  • TEC polyethylene glycol 400
  • a polymer (25% w/w of 50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone.
  • Either pure polyethylene glycol 400, triethyl citrate (TEC) or acetyl triethyl citrate (ATEC) was added to the polymer solution.
  • the resulting solutions were stirred to yield uniform mixtures.
  • Acetone was evaporated from the mixtures by heating at 60-75 °C with constant stirring.
  • the blank fonnulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone.
  • the resulting formulations obtained were matrices with a viscous liquid like consistency.
  • Oxytetracycline base (20%> w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations.
  • Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant.
  • Figure 9 shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. It is evident from the figure that drug release was fastest from formulations prepared with PEG 400, and slowest from those prepared with ATEC. Intermediate drug release was observed from formulations prepared from TEC.
  • Blank formulations were prepared by dissolving either 16.67% w/w or 25% w/w of 50/50 polylactide-co-glycolide copolymer (inherent viscosity of 0.59) and either 50/50% or 75/25% blends of PEG 400 and TEC in a minimum quantity of acetone. The resulting solutions were sti ⁇ ed to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75 °C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone. The resulting formulations obtained were matrices with a viscous liquid like consistency.
  • Oxytetracycline base (20% w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations.
  • Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant.
  • Figure 10 shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. It is evident from the figure that faster drug release was observed from formulations prepared with a 16.61% polymer and 83.3% of plasticizer blends of varying compositions (polymer to plasticizer ratio of 1:5) compared to those prepared from formulations with polymer to plasticizer ratios of 1 :3 (25% polymer and 75% plasticizer).
  • Blank formulations were prepared by dissolving 25% of a polymer (50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.64) and pure PEG 400 or 50/50% blends of PEG 400 and TEC in a minimum quantity of acetone. The solutions were stirred to yield a uniform mixture. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone. The resulting formulations obtained were a matrix with viscous liquid-like consistency.
  • naltrexone hydrochloride The release of naltrexone hydrochloride is considerably faster from formulations prepared with both pure PEG 400 and 50/50% blends of PEG 400 and TEC than the release of the hydrated naltrexone base from similar fonnulations. This is because the solubility of the naltrexone hydrochloride in the dissolution buffer is much greater than that of the hydrated naltrexone base.
  • Biodegradable delivery systems could be prepared by the procedures shown in Examples 1-20. Instead of adding a single biologically active agent, a combination of two or more biologically active agents could be inco ⁇ orated together in the said delivery system. Examples of some of the combinations of the biologically active agents include levonorgestrel and ethinyl estradiol, trimethoprim and sulfamethoxazole, trimetrexate and leucovorin, isoniazid, rifampin and ethambutol, dapsone and rifampicin, erythromycin and rifampicin, clotrimazole and nystatin, amphotericin B and flucytosine, hydrochlorothiazide and amiloride, hydrochlorothiazide and spironolactone, hydrochlorothiazide and captopril, polythiazide and rese ⁇ ine.
  • a combination of two or more plasticizers could be added to obtain a formulation with the desired consistency and hydrophilicity or hydrophobicity.
  • An example of a combination of plasticizer is acetyl triacetyl citrate (ATEC), n-methyl pyrrolidone (NMP) and a vegetable oil such as sesame oil, olive oil, safflower oil, sunflower oil, cottonseed oil or almond oil.
  • EXAMPLE 22 Biodegradable vehicle could be prepared by the procedures shown in
  • the vehicle could be loaded with BAS in a pharmacy or in an operating room by the health practitioner (a pharmacist, surgeon, nurse), just prior to administration to the patient, with an appropriate quantity of an antitumor agent and injected directly into a solid tumor or at a site from where a solid tumor has been surgically removed.
  • biodegradable vehicle loaded with an antitumor agent can also be injected into the tumor, or injected, implanted, smeared or applied at the site from where the tumor is removed by the surgeon.
  • Example 22 A similar treatment described in Example 22 can be offered to patients with brain tumors where the biodegradable vehicle prepared by the methods shown in Examples 1- 20 and loaded with an appropriate quantity of an antitumor agent.
  • the BAS-loaded delivery system can be injected, implanted or applied directly at the site in the brain from where the tumor has been removed.
  • EXAMPLE 24
  • the biodegradable vehicle prepared as shown in examples 1-20 and loaded with a BAS such as an antibiotic an anti-inflammatory agent, a local anesthetic or analgesic, or combinations thereof can also be used in surgeries where appropriate quantities of the BAS, can be mixed with the biodegradable vehicle by the surgeon in an operating room, and the resulting mixture can then be injected, implanted, smeared or applied at the site of surgery to minimize the chances of localized infections or inflammation and reduce pain respectively, due to surgery.
  • an antibiotic loaded biodegradable vehicle can also be injected, implanted, smeared or applied at the site of surgery by the surgeon at the site of surgery.
  • a biodegradable vehicle prepared by the method shown in examples 1-20 and loaded with an antibiotic can be injected, implanted, applied or smeared near or at the site of surgery.
  • High concentrations of the antibiotic at the site of surgery can prevent infections.
  • the BAS delivery system need not be removed from the site of administration because of the biodegradable nature of the system.
  • biodegradable vehicle prepared with the methods described in examples 1-20 and loaded with bone (fragments or powdered) or bone growth promoting agents such as calcium sulfate, calcium phosphates or hydroxyapatite can be injected, implanted, applied or smeared at an appropriate site where it is needed following orthopedic surgery.
  • bone growth promoting agents such as calcium sulfate, calcium phosphates or hydroxyapatite
  • biodegradable vehicle prepared with the methods described in examples 1-20 and loaded with a low molecular weight heparin can also be used to treat conditions such as deep venous thrombosis (DNT) in trauma or surgical patients.
  • DNT deep venous thrombosis
  • the biodegradable vehicle prepared with the methods described in examples 1-20 can be prepared with blends of varying molecular weights of polymers or copolymers, or with blends of copolymers of varying copolymer ratios such as 50/50 PLGA and 85/15 PLGA or 100% polylactic acid (PLA) and 25/75 PLGA, or blends of different types of biodegradable polymers with varying hydrophobicity or lipophilicity or crystallinity such as 1:1 of PLA:PCL or 1:3 of PLA:PCL or 1:1 of 50/50 PLGA.PCL.
  • EXAMPLE 29 The polymer (50/50 lactide-co-glycolide copolymer) was dissolved directly in various plasticizers with stining with or without the use of heat. Specific examples of fonnulations prepared using this method are listed in Table 6 below. The resulting formulations obtained were a matrix with a viscous liquid or gel-like consistency.
  • Table 6 Description of formulations prepared by directly mixing the polymer with the plasticizer with or without the use heat

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP01918249A 2000-06-28 2001-02-26 Biologisch abbaubares träger-material sowie abgabesysteme für biologisch aktive substanzen Withdrawn EP1299048A4 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US605661 2000-06-28
US09/605,661 US6432438B1 (en) 1997-10-29 2000-06-28 Biodegradable vehicle and filler
IN694MU2000 IN189074B (de) 2000-07-25 2000-07-25
INMU069400 2000-07-25
CN00120871 2000-08-03
CN 00120871 CN1206001C (zh) 2000-06-28 2000-08-03 生物可降解载体和生物可降解传输系统
PCT/US2001/006138 WO2002000137A1 (en) 2000-06-28 2001-02-26 Biodegradable vehicles and delivery systems of biologically active substances

Publications (2)

Publication Number Publication Date
EP1299048A1 true EP1299048A1 (de) 2003-04-09
EP1299048A4 EP1299048A4 (de) 2005-09-28

Family

ID=27178759

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01918249A Withdrawn EP1299048A4 (de) 2000-06-28 2001-02-26 Biologisch abbaubares träger-material sowie abgabesysteme für biologisch aktive substanzen

Country Status (7)

Country Link
EP (1) EP1299048A4 (de)
JP (1) JP2004511431A (de)
CN (1) CN1283215C (de)
AU (1) AU2001245346A1 (de)
CA (1) CA2413157A1 (de)
NZ (1) NZ523385A (de)
WO (1) WO2002000137A1 (de)

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7666445B2 (en) 2000-10-20 2010-02-23 The Trustees Of The University Of Pennsylvania Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use
DK1372729T3 (da) * 2001-02-23 2009-06-22 Genentech Inc Nedbrydelige polymere til injektion
GB0116341D0 (en) * 2001-07-04 2001-08-29 Smith & Nephew Biodegradable polymer systems
US6926903B2 (en) * 2001-12-04 2005-08-09 Inion Ltd. Resorbable polymer composition, implant and method of making implant
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
TWI353854B (en) 2002-06-25 2011-12-11 Alza Corp Short duration depot formulations
DK1539101T3 (da) * 2002-07-31 2009-04-27 Alza Corp Injicerbare, multi-modale polymere depotsammens tninger og anvendelser deraf
CZ294328B6 (cs) * 2002-08-22 2004-11-10 Pliva-Lachema A. S. Biodegradabilní kompozice s prolongovaným uvolňováním biologicky aktivní látky a způsob její výroby
AU2003295409B2 (en) 2002-11-06 2010-02-11 Durect Corporation Controlled release depot formulations
DK2526996T3 (da) 2002-12-20 2019-12-02 Xeris Pharmaceuticals Inc Formulering til intrakutan injektion
JP2006526424A (ja) * 2003-06-04 2006-11-24 イニオン リミテッド 生分解性インプラントおよびその製造方法
DE602004016995D1 (de) * 2003-06-26 2008-11-20 Control Delivery Sys Inc In-situ gelierendes arzneimittelabgabesystem
CA2530113C (en) 2003-06-26 2013-08-13 Control Delivery Systems, Inc. Bioerodible sustained release drug delivery systems
CA2539568C (en) * 2003-09-23 2013-09-10 Orthotherapeutics, Llc Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects
GB0329654D0 (en) 2003-12-23 2004-01-28 Smith & Nephew Tunable segmented polyacetal
US8221778B2 (en) 2005-01-12 2012-07-17 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
WO2005070332A1 (en) * 2004-01-12 2005-08-04 The Trustees Of The University Of Pennsylvania Long-term delivery formulations and methods of use thereof
US8329203B2 (en) 2004-01-12 2012-12-11 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
GB0412866D0 (en) * 2004-06-09 2004-07-14 Novartis Ag Organic compounds
US20060257448A1 (en) * 2005-05-10 2006-11-16 The University Of Zurich Resorbable polymer composition, implant and method of making implant
CA2619552A1 (en) * 2005-08-18 2007-02-22 Smith & Nephew, Plc Multimodal high strength devices and composites
US8852638B2 (en) * 2005-09-30 2014-10-07 Durect Corporation Sustained release small molecule drug formulation
WO2007058190A1 (ja) * 2005-11-16 2007-05-24 Tokai University Educational System 薬剤放出制御組成物および薬剤放出性医療器具
WO2008129245A1 (en) 2007-04-18 2008-10-30 Smith & Nephew Plc Expansion moulding of shape memory polymers
DE602008006181D1 (de) 2007-04-19 2011-05-26 Smith & Nephew Inc Graft-fixierung
EP2142227B1 (de) 2007-04-19 2012-02-29 Smith & Nephew, Inc. Multimodale formgedächtnis-polymere
EP2167039B1 (de) 2007-05-18 2016-09-28 Durect Corporation Verbesserte depot-formulierungen
CA2687979C (en) 2007-05-25 2017-07-04 Tolmar Therapeutics, Inc. Sustained delivery formulations of risperidone compounds
US8619257B2 (en) * 2007-12-13 2013-12-31 Kimberley-Clark Worldwide, Inc. Recombinant bacteriophage for detection of nosocomial infection
ES2441550T3 (es) * 2007-12-21 2014-02-05 Ludwig-Maximilians-Universität Dispositivos extruidos con forma de varilla para la Iiberación controlada de sustancias biológicas a humanos y animales
US8557273B2 (en) * 2008-04-18 2013-10-15 Medtronic, Inc. Medical devices and methods including polymers having biologically active agents therein
JP2013522239A (ja) * 2010-03-12 2013-06-13 サーモディクス，インコーポレイテッド 注射用薬物送達システム
US9272044B2 (en) 2010-06-08 2016-03-01 Indivior Uk Limited Injectable flowable composition buprenorphine
WO2012012460A1 (en) 2010-07-19 2012-01-26 Xeris Pharmaceuticals, Inc. Stable glucagon formulations for the treatment of hypoglycemia
CN103442695B (zh) 2011-03-10 2016-05-04 Xeris药物公司 肠胃外注射用肽药物的稳定制剂
SI2717914T1 (sl) * 2011-06-10 2020-07-31 Ramscor Inc. Formulacije z zadržanim sproščanjem za dostavo proteinov v oko in postopki njihove priprave
CA2853942C (en) 2011-10-31 2020-08-25 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
CN103830767A (zh) * 2012-11-26 2014-06-04 韩冰 乙酸异丁酸蔗糖酯凝胶及其用途
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US20140308352A1 (en) 2013-03-11 2014-10-16 Zogenix Inc. Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material
US9737605B2 (en) 2013-03-11 2017-08-22 Durect Corporation Injectable controlled release composition comprising high viscosity liquid carrier
CN110339153A (zh) 2013-05-24 2019-10-18 爱康生物科技有限公司 地塞米松单位剂型、试剂盒及白内障手术后炎症中的应用
AU2015300944B2 (en) 2014-08-06 2019-07-11 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
WO2016054197A1 (en) * 2014-09-30 2016-04-07 University Of Tennessee Research Foundation In situ gelling form for long-acting drug delivery
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US20180185489A1 (en) * 2015-07-01 2018-07-05 Santen Pharmaceutical Co., Ltd. Depot preparation containing citric acid ester
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
US20170128632A1 (en) * 2015-11-10 2017-05-11 II William Charles McJames Device and method for controlling the release of bioactive and therapeutic agents from an implantable medical device
US20190000834A1 (en) * 2015-12-17 2019-01-03 Verita Research Pte Ltd Injectable composition and a method of treatment of the physical addiction
CN106823010A (zh) * 2016-12-28 2017-06-13 四川国纳科技有限公司 可生物吸收聚磷酸酯氨基酸共聚物材料的用途
US11752099B2 (en) * 2017-03-27 2023-09-12 W. L. Gore & Associates, Inc. Injectable and biodegradable polymer formulations for controlled release of bioactive agents
CN117085022A (zh) 2017-06-02 2023-11-21 Xeris药物公司 抗沉淀的小分子药物制剂
CA3167217A1 (en) 2020-01-13 2021-07-22 Durect Corporation Sustained release drug delivery systems with reduced impurities and related methods
CN115779142B (zh) * 2022-11-18 2024-01-12 江南大学 一种锌合金植入物表面用可降解载药涂层及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0537559A1 (de) * 1991-10-15 1993-04-21 Atrix Laboratories, Inc. Polymerzusammensetzungen zur Verwendung als Implantate mit verzögerter Abgabe
US5447725A (en) * 1993-06-11 1995-09-05 The Procter & Gamble Company Methods for aiding periodontal tissue regeneration
WO1998027963A2 (en) * 1996-12-20 1998-07-02 Alza Corporation Gel composition and methods
WO1998048859A1 (en) * 1997-04-30 1998-11-05 Guilford Pharmaceuticals Inc. Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same
WO1999047073A1 (en) * 1998-03-19 1999-09-23 Merck & Co., Inc. Liquid polymeric compositions for controlled release of bioactive substances
WO2000024374A1 (en) * 1998-10-28 2000-05-04 Atrix Laboratories, Inc. Controlled release liquid delivery compositions with low initial drug burst

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL188266C (nl) * 1975-07-29 1992-05-18 Merck & Co Inc Werkwijze ter bereiding van een oogheelkundig inplantaat.
US4938763B1 (en) * 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5324520A (en) * 1988-12-19 1994-06-28 Vipont Pharmaceutical, Inc. Intragingival delivery systems for treatment of periodontal disease
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5487897A (en) * 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
SE9100610D0 (sv) * 1991-03-04 1991-03-04 Procordia Ortech Ab Bioresorbable material for medical use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0537559A1 (de) * 1991-10-15 1993-04-21 Atrix Laboratories, Inc. Polymerzusammensetzungen zur Verwendung als Implantate mit verzögerter Abgabe
US5447725A (en) * 1993-06-11 1995-09-05 The Procter & Gamble Company Methods for aiding periodontal tissue regeneration
WO1998027963A2 (en) * 1996-12-20 1998-07-02 Alza Corporation Gel composition and methods
WO1998027962A2 (en) * 1996-12-20 1998-07-02 Alza Corporation Injectable depot gel composition and method of preparing the composition
WO1998048859A1 (en) * 1997-04-30 1998-11-05 Guilford Pharmaceuticals Inc. Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same
WO1999047073A1 (en) * 1998-03-19 1999-09-23 Merck & Co., Inc. Liquid polymeric compositions for controlled release of bioactive substances
WO2000024374A1 (en) * 1998-10-28 2000-05-04 Atrix Laboratories, Inc. Controlled release liquid delivery compositions with low initial drug burst

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
GRAHAM P D ET AL: "Phase inversion dynamics of PLGA solutions related to drug delivery" JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 58, no. 2, 29 March 1999 (1999-03-29), pages 233-245, XP004164095 ISSN: 0168-3659 *
JARR EM ET AL: "Sustained release of lidocaine from an injectable implant system for treatment of post-operative pain" PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM ON CONTROLLED RELEASE BIOACTIVE MATERIALS, vol. 26, July 1999 (1999-07), pages 631-632, XP002133945 ISSN: 1022-0178 *
RADOMSKY M L ET AL: "The controlled release of ganirelix from the ATRIGEL(TM) injectable implant system" PROCEEDINGS OF THE CONTROLLED RELEASE SOCIETY 1993 UNITED STATES, no. 20, 1993, pages 458-459, XP009051801 *
See also references of WO0200137A1 *
SHAH N H ET AL: "A BIODEGRADABLE INJECTABLE IMPLANT FOR DELIVERING MICRO AND MACROMOLECULES USING POLY(LACTIC-CO-GLYCOLIC) ACID (PLGA) COPOLYMERS" JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 27, no. 2, 1 November 1993 (1993-11-01), pages 139-147, XP000400402 ISSN: 0168-3659 *
SHIVELY M L ET AL: "Physico-chemical characterization of a polymeric injectable implant delivery system" JOURNAL OF CONTROLLED RELEASE, ELSEVIER SCIENCE PUBLISHERS B.V. AMSTERDAM, NL, vol. 33, no. 2, February 1995 (1995-02), pages 237-243, XP004037626 ISSN: 0168-3659 *
SINGH U V ET AL: "REDUCED TOXICITY AND ENHANCED ANTITUMOR EFFICACY OF PLUMBAGIN USING POLY (LACTIC-CO-GLYCOLIC) BIODEGRADABLE INJECTABLE IMPLANT" INDIAN JOURNAL OF PHARMACOLOGY, vol. 29, no. 3, 1997, pages 168-172, XP001070322 ISSN: 0253-7613 *

Also Published As

Publication number Publication date
JP2004511431A (ja) 2004-04-15
WO2002000137A1 (en) 2002-01-03
CA2413157A1 (en) 2002-01-03
CN1438858A (zh) 2003-08-27
EP1299048A4 (de) 2005-09-28
CN1283215C (zh) 2006-11-08
NZ523385A (en) 2005-09-30
AU2001245346A1 (en) 2002-01-08

Similar Documents

Publication Publication Date Title
US20040018238A1 (en) Biodegradable vehicles and delivery systems of biolgically active substances
US6432438B1 (en) Biodegradable vehicle and filler
WO2002000137A1 (en) Biodegradable vehicles and delivery systems of biologically active substances
DE69825040T2 (de) Bioabbaubare polymere mit phosphat-endgruppen, zusammensetzungen, gegenstände und verfahren zu ihren herstelling und verwendung
JP4276807B2 (ja) 高粘度液体により制御された送達システム及び内科又は外科用デバイス
CN103491946B (zh) 可生物降解的药物释放组合物
DK2521534T3 (en) FUNCTIONALIZED TRIBLE COPOLYMERS AND COMPOSITIONS CONTAINING SUCH POLYMERS
US4568536A (en) Controlled release of pharmacologically active agents from an absorbable biologically compatible putty-like composition
JP3220331B2 (ja) 非経口投与用の吸収性液体コポリマー類
US5681873A (en) Biodegradable polymeric composition
JP7187738B2 (ja) 医薬組成物
US20080152708A1 (en) High viscosity liquid controlled delivery system and medical or surgical device
WO1996021427A1 (en) Liquid polymer delivery system
MX2014015902A (es) Suministro de farmaco biodegradable para las composiciones hidrofobicas.
EP0537559A1 (de) Polymerzusammensetzungen zur Verwendung als Implantate mit verzögerter Abgabe
JP2010531807A5 (de)
AU2005315823B2 (en) In-situ forming implant for animals
CN1206001C (zh) 生物可降解载体和生物可降解传输系统
KR20030023887A (ko) 생물학적 활성 물질의 생분해성 비히클 및 전달 시스템
PT1484033E (pt) Composições poliméricas líquidas para libertação controlada de substâncias bioactivas
Darvari et al. Controlled Release Antibiotics for Treatment of Periodontal Disease

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030128

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

A4 Supplementary search report drawn up and despatched

Effective date: 20050811

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61L 27/00 B

Ipc: 7A 61K 38/00 B

Ipc: 7A 61K 31/00 B

Ipc: 7A 61K 47/22 B

Ipc: 7A 61K 47/14 B

Ipc: 7A 61K 47/34 B

Ipc: 7A 61K 9/06 A

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060901