WO2001015734A2 - High viscosity liquid controlled delivery system and medical or surgical device - Google Patents
High viscosity liquid controlled delivery system and medical or surgical device Download PDFInfo
- Publication number
- WO2001015734A2 WO2001015734A2 PCT/US2000/023270 US0023270W WO0115734A2 WO 2001015734 A2 WO2001015734 A2 WO 2001015734A2 US 0023270 W US0023270 W US 0023270W WO 0115734 A2 WO0115734 A2 WO 0115734A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- group
- hydroxy
- alkanoyl
- medical
- Prior art date
Links
- 0 *OCC(C(C1O*)O*)(O*)OCC1O* Chemical compound *OCC(C(C1O*)O*)(O*)OCC1O* 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N CC1CCCC1 Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
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
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/60—Sugars; Derivatives thereof
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/44—Medicaments
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0026—Sprayable compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/006—Antidandruff preparations
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2984—Microcapsule with fluid core [includes liposome]
- Y10T428/2985—Solid-walled microcapsule from synthetic polymer
Definitions
- the present invention relates to novel nonpolymeric compounds and compositions that form liquid, high viscosity materials suitable for the delivery of biologically active substances in a controlled fashion, and for use as medical or surgical devices.
- the materials can optionally be diluted with a solvent to form a material of lower viscosity, rendering the material easy to administer.
- This solvent may be water insoluble or water soluble, where the water soluble solvent rapidly diffuses or migrates away from the material in vivo, leaving a higher viscosity liquid material.
- Biodegradable matrices for drug delivery are useful because they obviate the need to remove the drug-depleted device.
- the most common matrix materials for drug delivery are polymers.
- the field of biodegradable polymers has developed rapidly since the synthesis and biodegradability of polylactic acid was reported by Kulkarni et al., in 1966 ("Poly lactic acid for surgical implants," Arch. Surg., 93:839).
- Examples of other polymers which have been reported as useful as a matrix material for delivery devices include polyanhydrides, polyesters such as polyglycolides and polylactide-co-glycolides, polyamino acids such as polylysine, polymers and copolymers of polyethylene oxide, acrylic terminated polyethylene oxide, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes.
- Degradable materials of biological origin are well known including, for example, crosslinked gelatin.
- Hyaluronic acid has been crosslinked and used as a degradable swelling polymer for biomedical applications (U.S. Patent 4,957,744 to Delia Valle et al.; (1991) "Surface modification of polymeric biomaterials for reduced thrombogenicity,” Polym. Mater. Sci . Eng, (52: 731-735]).
- Biodegradable hydrogels have also been developed for use in controlled drug delivery as carriers of biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents, and cell suspensions. Temporary preservation of functional properties of a carried species, as well as the controlled release of the species into local tissues or systemic circulation, have been achieved. See for example, U.S. Patent No. 5,149,543 to Cohen. Proper choice of hydrogel macromers can produce membranes with a range of permeability, pore sizes and degradation rates suitable for a variety of applications in surgery, medical diagnosis and treatment.
- Dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds.
- Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions.
- Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in a liquid medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.
- Emulsions are defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids.
- Emulsion formulations include water in oil and oil in water emulsions, multiple emulsions, microemulsions, microdroplets, and liposomes.
- Microdroplets are unilamellar phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, as defined in U.S. Patent Nos. 4,622,219 and 4,725,442 issued to Haynes.
- Liposomes are phospholipid vesicles prepared by mixing water-insoluble polar lipids with an aqueous solution. The unfavorable entropy caused by mixing the insoluble lipid in the water produces a highly ordered assembly of concentric closed membranes of phospholipid with entrapped aqueous solution.
- Patent No. 4,938,763 to Dinn, et al. discloses a method for forming an implant in situ by dissolving a non-reactive, water insoluble thermoplastic polymer in a biocompatible, water soluble solvent to form a liquid, placing the liquid within the body, and allowing the solvent to dissipate to produce a solid implant.
- the polymer solution can be placed in the body via syringe.
- the implant can assume the shape of its surrounding cavity.
- the implant is formed from reactive, liquid oligomeric polymers which contain no solvent and which cure in place to form solids, usually with the addition of a curing catalyst.
- the invention relates to compounds, and to compositions containing them, as well as to methods of using these compounds and compositions as delivery vehicles, for example as controlled delivery vehicles, for substances, such as bioactive substances.
- the invention also relates to these compounds, compositions, and methods of using them as medical or surgical devices, such as medical or surgical implants, films, or graft compositions.
- the compositions are generally in liquid form, and contain at least one non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37 °C, that does not crystallize neat under ambient or physiological conditions.
- compositions can be dissolved in a physiologically acceptable solvent to lower their viscosity, rendering them easier to administer.
- the solvent diffuses or otherwise dissipates away from the material, which thus increases significantly in viscosity, and thereby forms a controlled release matrix for a bioactive substance, or a medical or surgical implant, film, or graft.
- Non-water soluble solvents may also be used, but will diffuse away from the nonpolymeric ester or mixed ester much more slowly. Dissolution in solvent is particularly useful with nonpolymeric esters or mixed esters having very high viscosities, e.g., on the order of 100,000 cP at 37 °C.
- nonpolymeric esters or mixed esters suitable for use in the invention while having viscosities above 5,000 cP at 37 °C, are not as viscous, and may be administered neat, i.e., without the additicn of a solvent.
- the invention in another aspect, relates to a method of administering a biologically active substance to a plant or an animal (including humans) by administering to the plant or animal a 5 composition containing a non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37 °C, that does not crystallize neat under ambient or physiological conditions and a biologically active substance.
- the particular method of administration may vary, and may include topical, oral (e.g., as a solution, emulsion, or in a gelatin capsule), nasal, pulmonary, 10 rectal, vaginal, or injectable routes for animals, and topical or injectable routes for plants.
- oral e.g., as a solution, emulsion, or in a gelatin capsule
- nasal, pulmonary, 10 rectal, vaginal, or injectable routes for animals e.g., as a solution, emulsion, or in a gelatin capsule
- nasal, pulmonary, 10 rectal, vaginal, or injectable routes for animals e.g., as a solution, emulsion, or in a gelatin capsule
- nasal, pulmonary, 10 rectal, vaginal, or injectable routes for animals e.g., as a solution, emulsion, or in a gelatin capsule
- injectable routes for animals e.g., as a solution, emulsion, or in a
- the invention relates to a medical or surgical implant, film, or graft composition containing a non-water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37 °C, that does not crystallize neat under ambient or physiological conditions.
- the invention relates to a method for the in vivo formation of an implant, film, or graft in a patient in need thereof, including: ( 1 ) contacting a mixture containing:
- a non- water soluble, high viscosity, liquid carrier material comprising a nonpolymeric ester or mixed ester of one or more carboxylic acids, having a viscosity of at least 5,000 cP at 37 °C, that
- the mixture has as viscosity of less than approximately 4,000 cP, even more particularly, less than approximately 1,000 cP, at 37 °C.
- the invention relates to novel compounds having a structure selected from the group consisting of: 30
- R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, wherein n is between 1 and 20, and wherein at least one of R 1 , R 2 , and R 3 is other than hydrogen;
- R and R ⁇ are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R 1 and R 2 is other than hydrogen;
- R 1 , R 2 , R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than hydrogen;
- R 1 , R 2 , R , R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R 1 , R 2 , R 3 ,
- R >4 , r R>5 , and R is other than hydrogen
- R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R 1 , R 2 , R 3 , and R 4 is other than hydrogen.
- the novel compound has the structure:
- R 1 , R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein at least one of R ! , R 2 , R 3 , and R 4 is other than hydrogen.
- liquid compositions of the invention can be used in any of the utilities or applications disclosed for HVLCM or LVLCM in U.S. Serial No. 08/944,022, U.S. Serial No. 478,450, and U.S. Serial No. 08/474,337, now U.S. Patent No. 5,747,058, the entire contents of each of which are hereby incorporated by reference.
- FIG. 1 is a graph showing the cumulative release profiles for bupivacaine from decaglycerol tetraoleate and from a 1,6-hexanediol lactate ⁇ -hydroxycaproic acid according to the invention.
- FIG. 2 is a graph showing the cumulative release profile for estradiol from a glycerol lactate glycolate according to the invention.
- FIG. 3 is a graph showing the cumulative release profile for progesterone from a 1,6- hexanediol lactate glycolate according to the invention.
- FIG. 4 is a graph showing the cumulative release profile for lysozyme from hexaglycerol dioleate and a glycerol lactate glycolate according to the invention.
- the high viscosity liquid carrier material should be selected that is non-polymeric, non- water soluble, and has a viscosity of at least 5,000 cP, (and optionally at least 10,000, 15,000; 20,000; 25,000 or even 50,000 cP) at 37°C that does not crystallize neat under ambient or physiological conditions.
- non-water soluble refers to a material that is soluble in water to a degree of less than one percent by weight under ambient conditions.
- nonpolymeric refers to esters or mixed esters having essentially no repeating units in the acid moiety of the ester, as well as esters or mixed esters having acid moieties wherein functional units in the acid moiety are repeated a small number of times (i.e., oligomers). Generally, materials having more than five identical and adjacent repeating units or mers in the acid moiety of the ester are excluded by the term “nonpolymeric” as used herein, but materials containing dimers, trimers, tetramers, or pentamers are included within the scope of this term.
- the number of repeat units is calculated based upon the number of lactide or glycolide moieties, rather than upon the number of lactic acid or glycolic acid moieties, where a lactide repeat unit contains two lactic acid moieties esterified by their respective hydroxy and carboxy moieties, and where a glycolide repeat unit contains two glycolic acid moieties esterified by their respective hydroxy and carboxy moieties.
- Esters having 1 to about 20 etherified polyols in the alcohol moiety thereof, or 1 to about 10 glycerol moieties in the alcohol moiety thereof, are considered nonpolymeric as that term is used herein.
- the high viscosity liquid carrier material decreases in viscosity, in some cases significantly, when mixed with a solvent to form a low viscosity liquid carrier material (LVLCM) that can be administered as a medical or surgical implant, graft, or film, or mixed with a biologically active substance for controlled delivery, or a combination thereof.
- the LVLCM biologically active substance composition is typically easier to place in the body than a HVLCM/biologically active substance composition, because it flows more easily into and out of syringes or other implantation means. It also can easily be formulated as an emulsion.
- the LVLCM can have any desired viscosity. It has been found that a viscosity range for the LVLCM of less than approximately 6,000 cP, more particularly, less than approximately 4,000 cP, even more particularly, less than approximately 1 ,000 cP, and yet even more particularly less than 200 cP, is typically useful for in vivo applications.
- the particular HVLCM used in the invention can be one or more of a variety of materials.
- Suitable materials include nonpolymeric esters or mixed esters of one or more carboxylic acids.
- the ester is formed from carboxylic acids that are esterified with a polyol having from about 2 to about 20 hydroxy moieties, and which may include 1 to about 20 etherified polyols.
- Particularly suitable carboxylic acids for forming the acid moiety of the ester of the HVLCM include carboxylic acids having one or more hydroxy groups, e.g., those obtained by ring opening alcoholysis of lactones, or cyclic carbonates or by the alcoholysis of carboxylic acid anhydrides. Amino acids are also suitable for forming esters with the polyol.
- the ester or mixed ester contains an alcohol moiety having one or more terminal hydroxy moieties that have been esterified with one or more carboxylic acids obtained by alcoholysis of a carboxylic acid anhydride, such as a cyclic anhydride.
- Nonlimiting examples of suitable carboxylic acids that can be esterified to form the HVLCM of the invention include glycolic acid, lactic acid, ⁇ -hydroxycaproic acid, serine, and any corresponding lactones or lactams, trimethylene carbonate, and dioxanone.
- the hydroxy- containing acids may themselves be further esterified through the reaction of their hydroxy moieties with additional carboxylic acid, which may be the same as or different from other carboxylic acid moieties in the material.
- Suitable lactones include, but are not limited to, glycolide, lactide, ⁇ -caprolactone, butyrolactone, and valerolactone.
- Suitable carbonates include but are not limited to trimethylene carbonate and propylene carbonate.
- the alcohol moiety of the ester or mixed ester may be derived from a polyhydroxy alcohol having from about 2 to about 20 hydroxy groups, and as indicated above, may be formed by etherifying 1 to 20 polyol molecules.
- Suitable alcohol moieties include those derived by removing one or more hydrogen atoms from: monofunctional C]-C 2 o alcohols, difunctional Cp C 20 alcohols, trifunctional alcohols, hydroxy-containing carboxylic acids, hydroxy-containing amino acids, phosphate-containing alcohols, tetrafunctional alcohols, sugar alcohols, monosaccharides, and disaccharides, sugar acids, and polyether polyols.
- the alcohol moieties may include one or more of: dodecanol, hexanediol, more particularly, 1,6- hexanediol, glycerol, glycolic acid, lactic acid, hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid, serine, ATP, pentaerythritol, mannitol, sorbitol, glucose, fructose, sucrose, glucuronic acid, polyglycerol ethers containing from 1 to about 10 glycerol units, polyethylene glycols containing 1 to about 20 ethylene glycol units.
- At least one of the carboxylic acid moieties of the esters or mixed esters of the invention comprise at least one oxy moiety In an even more particular embodiment, each of the carboxylic acid moieties comprise at least one oxy moiety.
- At least one of the carboxylic acid moieties of the esters or mixed esters of the invention contains 2 to 4 carbon atoms. In an even more particular embodiment, each of the carboxylic acid moieties of the esters or mixed esters of the invention contain 2 to 4 carbon atoms.
- At least one of the carboxylic acid moieties of the ester or mixed ester of the invention has 2 to 4 carbon atoms and contains at least one oxy moiety.
- each of the carboxylic acid moieties of the ester or mixed ester of the invention has 2 to 4 carbon atoms and contains at least one oxy moiety.
- the invention includes compounds, compositions, and methods of use as described above, wherein the HVLCM has a structure selected from the group consisting of: I:
- R,R,R,R,R,R,R,R,R, and R are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl; wherein at least three of R , R ⁇ , R R 4 , R ⁇ R°, R', and R are other than hydrogen; and wherein when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are selected from the group consisting of acetyl and isobutyryl, at least three of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are acetyl;
- R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl and wherein n is between 1 and 20;
- n is an integer between 4 and 8
- R 1 and R 2 are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy- substituted alkanoyl;
- R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl;
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy- substituted alkanoyl; VIII:
- R , R , R , and R are independently selected from the group consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl.
- one or more of the alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl groups may comprise alkanoyl moieties having 2 to 6 carbon atoms, including the carbonyl carbon.
- each of formulae I through VIII comprise at least one hydroxy-substituted or acyloxy-substituted alkanoyl moiety.
- at least one of these hydroxy-substituted or acyloxy-substituted alkanoyl moieties comprise alkanoyl moieties having 2 to 6 carbon atoms, including the carbonyl carbon.
- the acyl groups forming the acyloxy substituents of the invention may be any moiety derived from a carboxylic acid in accordance with the commonly accepted definition of the term "acyl.” More particularly, the acyl groups of the compositions of the invention may be of the form R 9 CO-, where R 9 is optionally oxy-substituted alkyl of 2-6 carbon atoms. This oxy- substitution may take the form of hydroxy substitution, or substitution with additional acyl moieties.
- R 9 may be an oligomer of oxy-substituted carboxylic acids, linked by ester bonding between the hydroxy of one acid and the carboxy of another acid.
- R 9 may comprise 1 to 5 lactide or glycolide units, where a lactide unit contains two lactic acid moieties esterified together and a glycolide unit contains two glycolic acid moieties esterified together.
- R 9 may contain mixed lactide and glycolide units, or may contain mixed lactic acid and glycolic acid, without the presence of lactide or glycolide units.
- Particular HVLCM materials include components according to formulae II or III, wherein
- R 1 , R 2 , and R 3 are independently lactoyl, polylactoyl, ⁇ -caproyl, hydroxyacetyl, or polyhydroxyacetyl, in particular, polylactoyl and ⁇ -caproyl, or polylactoyl and polyhydroxyacetyl.
- oxy-substituted carboxylic acid moieties in the ester or mixed ester of the invention is advantageous.
- these acid moieties are present in the form of oligomeric esters (i.e., a subsequent acid moiety joined to the previous acid moiety through esterification of the subsequent carboxy with the previous oxy)
- hydrolysis of the material is considerably easier than for oligomers made with more than 6 carbon atoms because the material is more hydrophilic.
- the HVLCM be water insoluble, but somewhat hydrophilic.
- HVLCMs synthesized with more hydrophilic units will be expected to absorb water more rapidly and degrade more quickly.
- a HVLCM made by covalently linking 4 moles of glycolide to one mole of glycerol will be expected to absorb water more rapidly and degrade more quickly than a HVLCM made by covalently linking 2 moles of glycolide and 2 moles of lactide to one mole of glycerol.
- Similar increases can be expected for more flexible molecules and for more branched, spherical molecules based on free volume arguments. Use of flexible and branched molecules may also have the benefit of lowering the viscosity of the LVLCM.
- carboxylic acids and/or polyols of different chain length and using carboxylic acids having oxy-substitution allows a precise control of the degree of hydrophilicity and of the solubility of the resulting ester.
- These materials are sufficiently resistant to dissolution in vivo that they are able to provide a controlled release of bioactive substances into the body accompanied or followed by oxy bonds hydrolyzing in vivo.
- the invention excludes the acetate and isobutyrate ester of sucrose having a ratio of acetate to isobutyrate acid moieties of 2:6.
- sucrose acetate isobutyrate ester having a ratio of acetate to isobutyrate moieties of 2:6 is included within the scope of the invention for use in aerosol formulations, as well as for the delivery of lysozyme, paclitaxel, 5-fluorouracil, and antiretroviral drugs like AZT and ddC, as described and exemplified below.
- This material can be made according to the procedures described in U.S. Patent No. 2,931,802.
- the HVLCM esters of the invention can be made by reacting one or more alcohols, in particular one or more polyols, which will form the alcohol moiety of the resulting esters with one or more carboxylic acids, lactones, lactams, carbonates, or anhydrides of the carboxylic acids which will form the acid moieties of the resulting esters.
- the esterification reaction can be conducted simply by heating, although in some instances addition of a strong acid or strong base esterification catalyst may be used.
- an esterification catalyst such as stannous 2-ethylhexanoate can be used.
- Sucrose acetate isobutyrates can be made by following the procedures described in U.S. Patent No. 2,931,802.
- the polyol can be viewed as an oligomerization initiator, in the sense that it provides a substrate for esterification of carboxylic acids, in particular, of oligomers of lactide, glycolide, or other esterified hydroxy-substituted carboxylic acids.
- Solvents
- the HVLCM can be mixed with a viscosity lowering solvent to form a lower viscosity liquid carrier material (LVLCM), which can then be mixed with the biologically active substance to be delivered, prior to administration.
- LLCM lower viscosity liquid carrier material
- solvents can water soluble, non-water soluble, or water miscible, and can include, acetone, benzyl alcohol, benzyl benzoate, N-(betahydromethyl) lactamide, butylene glycol, caprolactam, caprolactone, corn oil, decylmethylsulfoxide, dimethyl ether, dimethyl sulfoxide, 1- dodecylazacycloheptan-2-one, ethanol, ethyl acetate, ethyl lactate, ethyl oleate, glycerol, glycofurol (tetraglycol), isopropyl myristate, methyl acetate, methyl ethyl ketone, N-methyl-2- pyrrolidone, MIGLYOLs (esters of caprylic and/or capric acids with glycerol or alkylene glycols, e.g., MIGLYOL 810 or 812 (caprylic/capric acid
- the solvent may be or may include one or more propellants, such as CFC propellants like trichlorofluoromethane and dichlorofluoromethane, non-CFC propellants like tetrafluoroethane (R-134a), 1,1 ,1,2,3,3,3- heptafluoropropane (R-227), dimethyl ether, propane, and butane.
- propellants such as CFC propellants like trichlorofluoromethane and dichlorofluoromethane, non-CFC propellants like tetrafluoroethane (R-134a), 1,1 ,1,2,3,3,3- heptafluoropropane (R-227), dimethyl ether, propane, and butane.
- solvents and/or propellants include benzyl benzoate, dimethyl sulfoxide, ethanol, ethyl lactate, glycerol, glycofurol (tetraglycol), N-methyl-2-pyrrolidone.
- MIGLYOL 810 polyethylene glycol, propylene carbonate, 2-pyrrolidone, and tetrafluoroethane.
- the composition When the composition is used as a LVLCM in conjunction with administration of a biologically active substance, it should contain a solvent that the HVLCM is soluble in. In certain instances, the substance to be delivered is also soluble in the solvent.
- the solvent should be non-toxic and otherwise biocompatible. Solvents that are toxic should not be used for pharmaceutical or agricultural purposes.
- the solvents used to inject the composition into animals should not cause significant tissue irritation or necrosis at the site of implantation, unless irritation or necrosis is the desired effect.
- the solvent should be at least water soluble, so that it will diffuse quickly into bodily fluids or other aqueous environment, causing the composition to coagulate or solidify.
- the solvent is not completely miscible with water or bodily fluids so that diffusion of the solvent from the composition, and the corresponding increase in viscosity of the composition, are slowed.
- esters of 1,6-hexanediol or glycerol are used as the HVLCM, some possible solvents are ethanol, N-methy/pyrrolidone, propylene carbonate, and PEG 400.
- the solvent is typically added to the compositions in an amount in the range from about 1 percent to about 95 percent by weight, more particularly from about 5 to about 90 wt%, relative to the total weight of the composition. Even more particularly, the solvent is present in the composition in an amount in the range from about 10 percent to about 55 percent by weight. Other particular ranges include from about 10 percent to 50 percent by weight, and from about 10 to about 30 percent by weight.
- a further embodiment involves the use of solvents that are not solvents for the HVLCM such that when combined with the HVLCM singularly or in combination with a solvent for the HVLCM, the resulting composition forms an emulsion.
- emulsions may contain the HVLCM in the dispersed phase such as in the case of SAIB/MIGLYOL mixtures that are emulsified in water or glycerol, or they may contain the HVLCM as a component of the continuous phase such as in the case of an aqueous solution that is emulsified in the HVLCM or a solution of the HVLCM in a water immiscible solvent.
- this substance may be any substance that exhibits a desired property.
- the substance is a biologically active substance.
- biologically active substance refers to an inorganic or organic molecule including a drug, peptide, protein, carbohydrate (including monosaccharides, oligosaccharides, and polysaccharides), nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, or a small molecule linked to a protein, glycoprotein, steroid, nucleic acid (any form of DNA, including CDNA, or RNA, or a fragment thereof), nucleotide, nucleoside, oligonucleotides (including antisense oligonucleotides), gene, lipid, hormone, vitamin, including vitamin C and vitamin E, or combination thereof, that causes a biological effect when administered in vivo to an animal, including but not limited to birds and mammals, including humans.
- Suitable proteins include, but are not limited to, human growth hormone, fibroblast growth factor (FGF), erythropoietin (EPO), platelet derived growth factor (PDGF), granulocyte colony stimulating factor (g-CSF), bovine somatotropin (BST), tumor necrosis factor (TNF), transforming growth factor-beta (TGF-Beta), interleukins, insulin, and interferon.
- FGF fibroblast growth factor
- EPO erythropoietin
- PDGF platelet derived growth factor
- g-CSF granulocyte colony stimulating factor
- BST bovine somatotropin
- TGF-Beta tumor necrosis factor
- interleukins insulin, and interferon.
- drug refers to any substance used internally or externally as a medicine for the treatment, cure, or prevention of a disease or disorder, and includes but is not limited to immunosuppressants, antioxidants, anesthetics, analgesics, chemotherapeutic agents, steroids (including retinoids), hormones, antibiotics, antivirals, antifungals, antiproliferatives, antihistamines, anticoagulants, antiphotoaging agents, melanotropic peptides, nonsteroidal and steroidal anti-inflammatory compounds, antipsychotics, and radiation absorbers, including UV- absorbers.
- biologically active substance also includes agents such as insecticides, pesticides, fungicides, rodenticides, and plant nutrients and growth promoters.
- the composition functions as a vaccine and the substance to be delivered is an antigen.
- the antigen can be derived from a cell, bacteria, or virus particle, or portion thereof.
- antigen may be a protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, or combination thereof, which elicits an immunogenic response in an animal, for example, a mammal, bird, or fish.
- the immunogenic response can be humoral or cell-mediated.
- the material to which the immunogenic response is to be directed is poorly antigenic, it may be conjugated to a carrier such as albumin or to a hapten, using standard covalent binding techniques, for example, with one of the several commercially available reagent kits.
- composition of the invention can also be used to elicit both mucosal and systemic immune responses by administration of the HVLCM of the invention, optionally with a solvent to decrease its viscosity as described above, in combination with an immunogenic material, in a vaccine that is administered to a mucosal surface, e.g., intranasally, intravaginally, or intrarectally.
- the immunogenic material may be any immunogenic agent whose delivery to mucosal tissue is desired.
- immunogenic materials include antigens to vaccinate against viral, bacterial, protozoan, or fungal diseases, such as such as respiratory syncytial, parainfluenza viruses, Hemophilus influenza, Bordetella pertussis, Neisseria gonorrhoeae, Streptococcus pneumoniae, and Plasmodium falciparum or other diseases caused by pathogenic microorganisms, antigens to vaccinate against diseases caused by macro-organisms such as helminthic pathogens, and antigens to vaccinate against allergens.
- viral, bacterial, protozoan, or fungal diseases such as such as respiratory syncytial, parainfluenza viruses, Hemophilus influenza, Bordetella pertussis, Neisseria gonorrhoeae, Streptococcus pneumoniae, and Plasmodium falciparum
- the HVLCM or LVLCM is selected from formulae II through VIII above.
- Vaccines of this type can be prepared and administered by following the procedures described for SAIB in U.S. Provisional Application Serial No. 60/132,096, filed April 30, 1999, the entire contents of which are hereby incorporated by reference.
- the composition functions as a controlled release composition for reproductive therapy, in humans or animals.
- the HVLCM or LVLCM may be combined with gonadotropin releasing hormone or its analogs or agonists.
- the HVLCM or LVLCM is not SAIB having an acetate to butyrate ratio of 2:6.
- the HVLCM or LVLCM is selected from formulae II through VIII above.
- Non-limiting examples of pharmacological materials include anti-infectives such as nitrofurazone, sodium propionate, antibiotics, including penicillin, tetracycline, oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, chloramphenicol, erythromycin, and azithromycin; sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, and anti-virals including idoxuridine; antiallergenics such as antazoline, methapyritene, chlorpheniramine, pyrilamine prophenpyridamine, hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21 -
- the active compound is included in the composition in an amount sufficient to deliver to the host animal or plant an effective amount to achieve a desired effect.
- the amount of drug or biologically active agent incorporated into the composition depends upon the desired release profile, the concentration of drug required for a biological effect, and the desired period of release of the drug.
- the concentration of active compound in the composition will also depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the composition may be administered in one dosage, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- the biologically active substance is typically present in the composition in the range from about 0.1 percent to about 20 percent by weight, more particularly from about 0.5 percent to about 20 percent by weight relative to the total weight of the composition, and more typically, between approximately 1 percent to about 15 percent by weight, and more. Another preferred range is from about 2 percent to about 10 percent by weight. For very active agents, such as growth factors, preferred ranges are less than 1 % by weight, and less than 0.0001%.
- Both soluble and insoluble substances can be distributed in the HVLCM or LVLCM for controlled delivery.
- the formulations containing biologically active substances and an HVLCM or LVLCM may be further formulated with polymeric excipients to provide a drug delivery matrix with modified properties, for example a faster or slower degradation rate.
- the resulting composition may be formed into microspheres, or into a macroscopic implant, or other geometries and sizes according to techniques known in the art.
- a pre-formed microsphere or implant with a biologically active substances incorporated therein can be combined with the HVLCM or LVLCM, for example as an injection vehicle.
- the HVLCM or LVLCM will form an secondary barrier to provide enhanced drug delivery.
- the HVLCM or LVLCM phase may or may not contain other biologically active substances, according to the specific biological requirement.
- These other biologically active substances may be any of those described above, provided that the biologically active substance must be suitable for incorporation into microspheres or implants according to techniques known in the art.
- a variety of additives can optionally be added to the HVLCM or LVLCM to modify the properties of the material as desired, and in particular to modify the release properties of the composition with respect to biologically active substances contained therein.
- the additives can be present in any amount which is sufficient to impart the desired properties to the composition.
- the amount of additive used will in general be a function of the nature of the additive and the effect to be achieved, and can be easily determined by the routineer. Suitable additives are described in U.S. Patent No. 5,747,058, the entire contents of which are hereby incorporated by reference.
- suitable additives include water, biodegradable polymers, non- biodegradable polymers, natural oils, synthetic oils, carbohydrates or carbohydrate derivatives, inorganic salts, BSA (bovine serum albumin), surfactants, organic compounds, such as sugars, and organic salts, such as sodium citrate.
- BSA bovine serum albumin
- surfactants organic compounds, such as sugars, and organic salts, such as sodium citrate.
- additives can also be used to lengthen the delivery time for the active ingredient, making the composition suitable for treatment of disorders or conditions responsive to longer term administration.
- suitable additives in this regard include those disclosed in U.S. Patent No. 5,747,058.
- suitable additives for this purpose include polymeric additives, such as cellulosic polymers and biodegradable polymers.
- suitable cellulosic polymers include cellulose acetates, cellulose ethers, and cellulose acetate butyrates.
- Suitable biodegradable polymers include polylactones, polyanhydrides, and polyorthoesters, in particular, polylactic acid, polyglycolic acid, polycaprolactone, and copolymers thereof.
- the additive When present, the additive is typically present in the compositions in an amount in the range from about 0.01 percent to about 20 percent by weight, more particularly from about 0.1 percent to about 20 percent by weight, relative to the total weight of the composition, and more typically, is present in the composition in an amount in the range from about 1, 2, or 5 percent to about 10 percent by weight. Certain additives, such as buffers, are only present in small amounts in the composition.
- biodegradable polymers and oligomers One category of additives are biodegradable polymers and oligomers.
- the polymers can be used to alter the release profile of the substance to be delivered, to add integrity to the composition, or to otherwise modify the properties of the composition.
- suitable biodegradable polymers and oligomers include: poly(lactide), poly(lactide-co- glycolide), poly(glycolide), poly(caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoesters, polycyanoacrylates, poly(phosphazines), poly(phosphoesters), polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, degradable polyurethanes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), chitin, chitosan, and copolymers, ter
- poly( ⁇ -hydroxy acid)s examples include poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid), and their copolymers.
- polylactones examples include poly( ⁇ - caprolactone), poly( ⁇ -valerolactone) and poly(gammabutyrolactone).
- Non-limiting examples of nonerodible polymers which can be used as additives include: polyacrylates, ethylene-vinyl acetate polymers, cellulose and cellulose derivatives, acyl substituted cellulose acetates and derivatives thereof, non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, polyvinyl (imidazole), chlorosulphonated polyolefms, polyethylene oxide, and polyethylene.
- Preferred non-biodegradable polymers include polyvinyl pyrrolidone, ethylene vinylacetate, polyethylene glycol, cellulose acetate butyrate (“CAB”) and cellulose acetate propionate ("CAP").
- a further class of additives which can be used in the present compositions are natural and synthetic oils and fats.
- Oils derived from animals or from plant seeds of nuts typically include glycerides of the fatty acids, chiefly oleic, palmitic, stearic, and linoleic. As a rule the more hydrogen the molecule contains the thicker the oil becomes.
- Non-limiting examples of suitable natural and synthetic oils include vegetable oil, peanut oil, medium chain triglycerides, soybean oil, almond oil, olive oil, sesame oil, peanut oil, fennel oil, camellia oil, corn oil, castor oil, cotton seed oil, and soybean oil, either crude or refined, and medium chain fatty acid triglycerides.
- Fats are typically glyceryl esters of higher fatty acids such as stearic and palmitic. Such esters and their mixtures are solids at room temperatures and exhibit crystalline structure. Lard and tallow are examples. In general oils and fats increase the hydrophobicity of the HVLCM, slowing degradation and water uptake.
- C. Carbohydrates and Carbohydrate Derivatives Another class of additives which can be used in the present compositions are carbohydrates and carbohydrate derivatives.
- Non-limiting examples of these compounds include monosaccarides (simple sugars such as fructose and its isomer glucose (dextrose); disaccharides such as sucrose, maltose, cellobiose, and lactose; and polysaccharides.
- Uses of the LVLCM and HVLCM Compositions The composition described herein can be administered to the host through a variety of methods which can vary depending on the result to be achieved.
- the composition can be administered, for example, topically, systematicdly (for example, mucosally (orally, rectally, vaginally, or nasally), parenterally (intravenously, subcutaneously, intramuscularly, or intraperitoneally), or through the pulmonary system, in an appropriate carrier, if desired.
- the composition can be applied via injection, pouring, spray dip, aerosol, or coating applicator. Aerosols or mists of the composition can be administered using an aerosol propellant, e.g., for topical administration, or using a suitable nebulizer, e.g., for pulmonary, nasal, or oral mucosal administration.
- the present compositions are administered as liquids via injection, or in an aerosol, paste or emulsion.
- a water-soluble solvent when administered via injection as a LVLCM, if a water-soluble solvent has been used in the composition, the solvent leaches into the aqueous fluid of the host, forming a highly viscous depot for the controlled delivery of substances or a coating for tissue that can prevent or minimize adhesions.
- the use of a water soluble solvent in making the LVLCM significantly decreases the leaching time.
- the small amount of solvent in the solution evaporates upon application allowing the LVLCM to set-up as an HVLCM.
- Formation of aerosols and emulsions can be accomplished using techniques known to those skilled in the art. See, for example, Ansel, H.C. et al., Pharmaceutical Dosa ⁇ Forms and Drug Delivery Systems, sixth ed., 1995.
- the compositions can be used to form protective tissue coatings, and in particular, can be used to prevent the formation of surgical adhesions.
- the HVLCM can adhere to the surrounding tissue or bone, and can thus be injected subdermally like collagen to build up tissue or to fill in defects. It can also be injected into wounds including burn wounds to prevent the formation of deep scars.
- the degradation time of the HVLCM can be modulated, for example, by using a polymer as an additive to the HVLCM.
- compositions may optionally contain biologically active substances including but not limited to, anesthetics, analgesics, antibiotics, and antinflammatories.
- the HVLCM and LVLCM materials of the invention can be used not only for the controlled release and delivery of substances, such as bioactive substances, to plants or animals, but also as medical or surgical devices, as described in U.S. Serial No. 08/944022, the entire contents of which are incorporated by reference.
- compositions of the invention include, but are not limited to blocking surgical adhesions, void filling, guided tissue regeneration, inducing hemostasis, tissue adhesive, scaffolding, and wound dressing.
- Each of these applications can optionally include release of a biologically active substance, or drug delivery.
- the nonpolymeric ester or mixed ester composition as a wound dressing readily accommodates various growth factors to accelerate healing of the wound.
- a composition can be used having the non-polymeric non- water-soluble liquid carrier material present in an amount from about 99.5 percent to about 25 percent by weight, relative to the total weight of the composition.
- compositions can be diluted with a solvent, including but not limited to one or more of ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone, N- methylpyrrolidone, propylene carbonate, glycofurol, capric/caprylic triglycerides, benzyl benzoate, ethyl oleate, isopropyl myristate, triethyl citrate, and any aerosol propellant, to a concentration of the non-polymeric non- water-soluble liquid carrier material of about 10 to about 90 % by weight, calculated based on the total weight of the composition, to obtain an implantable or sprayable composition.
- a solvent including but not limited to one or more of ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone, N-
- a sprayed-on or painted-on film to block adhesion of similar or dissimilar organs is suitable.
- the nonpolymeric ester or mixed ester composition is formulated in any of a variety of solvents, including ethanol, ethyl lactate, Nmethyl-2- pyrrolidone, or any common aerosol propellant, dimethyl ether, or any propellant, with or without an additive, and can be applied as an aerosol spray.
- the resulting film may effect adhesion, cohesion, degradation or porosity, or a combination thereto.
- the nonpolymeric ester or mixed ester composition is typically suitable like collagen for cosmetic repair.
- the nonpolymeric ester or mixed ester composition is useful for holding bone chips together in a fracture, and may optionally include an anesthetic, antibiotic, or growth factor for targeted delivery.
- Guided tissue regeneration is another application, such as periodontal repair to block epithelial migration.
- the compositions of the present invention are applied from solution.
- Typical drugs incorporated into these compositions for guided tissue regeneration include but are not limited to a variety of growth factors and cell reattachment factors.
- compositions of the present invention are biodegradable.
- Suitable additives include, but are not limited to polyvinyl alcohol, polyethylene glycol or carboxymethyl cellulose.
- Suitable solvents include ethyl lactate and propylene carbonate.
- a spray-on or paint-on formulation of the nonpolymeric ester or mixed ester composition is suitable as a tissue adhesive for wound closure, either as a primary sealant or in conjunction with sutures or staples.
- Suitable additives include but are not limited to carboxymethylcellulose or polyvinylpyrrolidone.
- Suitable solvents include but are not limited to propylene carbonate, ethyl lactate, glycofural, dimethylsulfoxide, 2-pyrrolidone, N-methyl-2-pyrrolidone, and ethanol.
- Biologically active substances incorporated into these compositions for tissue adhesion include but are not limited to antibiotics, anti-inflammatory compounds, analgesics, anesthetics and growth factors.
- Scaffolding is another device utility for the compositions of the present invention, and is particularly adaptive to new tissue growth.
- a typical formulation includes polyvinylpyrrolidone and tricalcium phosphate.
- the scaffolding provides a matrix suitable for the attachment and growth of bone or nerve cells.
- Biologically active substances incorporated into these compositions for scaffolding include but are not limited to growth factors.
- compositions of the present invention are a wound dressing, with or without appropriate drugs incorporated therein.
- the wound dressing functions to protect the wound and accelerate the healing process.
- the nonpolymeric ester or mixed ester composition is applied as an aerosol spray.
- Biologically active substances incorporated into these compositions in wound dressing include but are not limited to antibiotics, such as amikacin, anti-inflammatory compounds, analgesics, anesthetics, or growth factors such as fibroblast growth factors.
- the compositions of the invention are used as for controlled release delivery of biologically active substances, or as devices or implants, the compositions can have very high viscosities.
- the HVLCM materials have a viscosity at 37 °C of at least 5,000 cP. In a more particular embodiment, the HVLCM materials have viscosities above 10,000 cP, more particularly above 15,000 cP, even more particularly above 20,000, 25,000, or 50,000 cP at 37 °C.
- Example 1 High Viscosity Liquids of DL-Lactide / ⁇ -Caprolactone 75/25 Initial Mole Concentration, reacted with 1,6-HexanedioI.
- a clean, one liter glass reaction flask was fitted with a stainless steel mechanical stirrer rinsed with acetone, and dried for 3 hours under 0.5 mm Hg vacuum, while immersed in a 150°C oil bath.
- the reaction vessel was removed from the bath, allowed to cool, then charged with 197.5 grams (1.37 mol) of DL-Lactide, 52.5 grams (0.46 mol) of ⁇ -Caprolactone, and 40 grams (0.34 mol) of 1,6-Hexanediol.
- Example 1 The procedure detailed in Example 1 was used to prepare a material using 247.13g (1.71 mol) DL-Lactide, 62.87g (0.54mol) Glycolide, and 49.6g (0.42mol) 1,6-Hexanediol. Following initial melting, 1.84mL ( 260 ⁇ mol) of a 0.141M stannous 2-ethylhexanoate solution in toluene was added. The resulting product had an inherent viscosity of 0.058dL/g in CHC1 3 at 30°C. The material was a liquid at room temperature.
- Example 2 The procedure described in Example 1 was used to prepare a material using 198.14g (1.37mol) DL-Lactide, 54.8g (0.47mol) ⁇ -caprolactone, and 40g (0.43 mol) Glycerol. Following initial melting, 1.36mL ( 210 ⁇ mol) of a 0.154M stannous 2-ethylhexanoate solution in toluene was added. The resulting product had an inherent viscosity of 0.038dL/g in CHC1 3 at 30°C. The product was a liquid at room temperature.
- Example 2 The procedure described in Example 1 was used to prepare a compound using 247.33g (1.72mol) DL-Lactide, 62.87g (0.54mol) Glycolide, and 50.0g (0.54 mol) Glycerol. Following initial melting, 1.46mL ( 260 ⁇ mol) of a 0.179M stannous 2-ethylhexanoate solution in toluene was added. The resulting product had an inherent viscosity of 0.028dL/g in CHC1 3 at 30°C. The material was a liquid at room temperature.
- Example 5 High Viscosity Liquid of Glycolide Reacted with Glycerol
- a clean, one liter glass reaction flask was fitted with a stainless steel mechanical stirrer rinsed with acetone, and dried for 3 hours under 0.5 mm Hg vacuum, while immersed in a 150°C oil bath.
- the reaction vessel was removed from the bath, allowed to cool, then charged with 174 grams (1.5 mol) of glycolide and 92 grams (1.0 mol) of glycerol.
- the reaction flask was purged 5 times with nitrogen, and immersed in the oil bath at 150°C. The mixture was stirred slowly to facilitate phase change after a majority of the mixture appeared to have been melted.
- Example 5 The procedure described in Example 5 was used to prepare a material using 513 gms (4.5 mol) ⁇ -caprolactone and 93 g (0.5 mol) 1-dodecanol. Following addition of reagents, 1.36mL (210 ⁇ mol) of a 0.154M stannous 2-ethylhexanoate solution in toluene was added. The reaction proceeded as described in Example 5 and was purified as described therein.
- Example A CAPROL 10G4O (decaglycerol tetraoleate) was dissolved in benzyl benzoate at a weight ratio of 50:50. Bupivacaine was dissolved in this mixture at a concentration of 8.75 wt%. Drops weighing approximately 100 mg were precipitated into a test tube containing 40 mL of buffer. Samples of the buffer were removed at specified time points and replaced with fresh buffer. The samples were analyzed by UV-vis spectrophotometry at 265 nm to determine the concentration of bupivacaine in each buffer sample. At 4 hours, less than 7.5 wt% of the bupivacaine in the drop had been released to the buffer. At 48 hours, around 24.0 wt% of the bupivacaine had been released. The cumulative release profile is shown in FIG. 1.
- Example B The 1 ,6-hexanediol lactate ⁇ -hydroxycaproic acid produced in Example 1 was dissolved in N-methylpyrrolidone at a weight ratio of 70:30. 10 wt% bupivacaine base was then added to this mixture and dissolved. Drops weighing approximately 100 mg were precipitated into 40 mL buffer. Samples of buffer were removed at specified times and replaced with fresh buffer. Buffer samples were analyzed by UV-vis spectrophotometry at 265 nm to determine the concentration of bupivacaine in each buffer sample. At 4 hours, around 4.1 wt% of the bupivacaine contained in the precipitated drop had been released. At 24 hours, around 8.6 wt% of the bupivacaine had been released. The cumulative release profile is shown in FIG. 1.
- Example C The glycerol lactate glycolate prepared according to Example 4 was dissolved in ethanol at a weight ratio of 70:30. 10 wt% estradiol was then added to this mixture as a suspension. The formulation was homogenized prior to testing to ensure adequate mixing. Drops of this formulation were injected into a test tube containing buffer. The glycerol lactate glycolate precipitated, forming a depot from which the estradiol was slowly released. Samples of the buffer were removed at specified times and replaced with fresh buffer. The buffer samples removed from each test tube were analyzed by UV-vis spectrophotometry at 280 nm to determine the estradiol concentration in each sample. The assayed concentration was used to calculate the percent of estradiol released from the drop. FIG. 2 shows a cumulative release profile for estradiol.
- the 1,6-hexanediol lactate glycolate prepared according to Example 2 was dissolved in propylene carbonate at a weight ratio of 80:20. 10 wt% of progesterone was incorporated as a suspension into this mixture. The formulation was homogenized prior to testing to ensure adequate mixing. The resulting formulation was analyzed to determine its in vitro dissolution profile. Drops of the formulation were injected into a test tube containing buffer. The 1,6 hexanediol lactate glycolate precipitated, forming a depot from which the progesterone was slowly released. Samples of the buffer were removed at specified times and replaced with fresh buffer. The buffer samples were analyzed by UV-vis spectrophotometry at 244 nm to determine drug concentration in each sample. The assayed concentration was used to calculate the percentage of progesterone that had been released from the drop. The cumulative release profile is shown in FIG. 3.
- the glycerol lactate ⁇ -hydroxycaproic acid prepared according to Example 3 was dissolved in polyethylene glycol (PEG) 400 at a weight ratio of 36:64. Lysozyme was ground with a mortar and pestle and the resulting powder was incorporated into the mixture as a suspension at a concentration of 10 wt%. The formulation was mixed thoroughly with a spatula. Samples of the formulation, approximately 500 ⁇ L in volume, were injected into three test tubes each containing 10 mL of buffer. Aliquots of buffer (8 mL) were removed at specified times and replaced with fresh buffer. Each sample of buffer containing lysozyme was analyzed with a micro BCA protein assay reagent kit to determine protein content in the dissolution sample. The assayed lysozyme concentration was used to calculate the percent of lysozyme that had been released from the drop. The cumulative release profile is shown in FIG. 4.
- bupivacaine base 0.87 g was added to an aerosol container.
- 8.47 g of an SAIB/propylene carbonate solution (70:30) containing 2.5 wt% of a biodegradable polymer (65:35 DLPLG) was added to the container.
- 0.98 g of ethanol was added to help the drug dissolve.
- approximately 16 g of propellant R- 134a (1,1,1 ,2-tetrafluoroethane) was added. The mixture formed a solution that was easily sprayed with no bubbling or foaming.
- SAIB was dissolved in propellants 134a (1,1, 1,2-tetrafluoroethane) and 227 (1,1,1,2,3,3,3-heptafluoropropane) at levels of 5 and 10 wt%. Clear solutions were formed.
- Example M An additional example was conducted to evaluate a novel controlled-release system, which uses a high-viscosity compound, sucrose acetate isobutyrate (SAIB), for use in providing sustained release of lysozyme.
- SAIB sucrose acetate isobutyrate
- a small amount of solvent converts SAIB to an easily injectable liquid. Once injected, the solvent dissipates forming a high viscosity, biodegradable implant. Release profiles can be altered with different solvents and additives.
- Ground lysozyme (10 wt%) was suspended in SAIB/solvent mixtures including the solvents ethyl lactate, N-methyl-2-pyrrolidone ( ⁇ MP), MIGLYOL 810, and benzyl benzoate.
- release ranged from 1.3 wt% for the 70:30 SAIB/NMP formulation (110.3 ⁇ 5.0 % activity) to 4.5 wt% for the 40:60 SAIB/ethyl lactate formulation (107.6 ⁇ 6.1 % activity).
- the percent released at 7 days ranged from 46.7% for 40:60 SAIB/ethyl lactate (88.9 ⁇ 6.8 % activity) to 96.4% for 70:30 SAIB/MIGLYOL (107.6 ⁇ 7.0% activity).
- Addition of 0.5 wt% of each of the three polymers to an SAIB/NMP formulation did not significantly affect the release profile.
- Example N An additional example was conducted to evaluate the effects of formulation variables on release of chemotherapeutic agents — paclitaxel and 5-fluorouracil (5-FU) — from formulations based on an SAIB delivery system.
- SAIB sucrose acetate isobutyrate
- a fully-esterified, water-insoluble sucrose derivative as an excipient. It can be formulated as a low- to medium-viscosity liquid by the addition of small amounts of solvents such as ethanol, MIGLYOL, ethyl lactate, propylene carbonate, or DMSO, resulting in an easily injectable formulation.
- Solutions of SAIB in the appropriate solvent were prepared with and without the incorporation of an additive.
- the active was weighed into a test tube and the SAIB/mixture was added and mixed thoroughly to yield a solution or suspension at the desired drug loading. Single drops of the mixture were precipitated into buffer by injection with standard syringes and needles. Samples were maintained at 37 °C in a shaker, sampled periodically, and analyzed by UV-vis spectrophotometry for active release. Paclitaxel and 5-FU samples were analyzed at 232 nm and 266 nm, respectively.
- the effect of drug loading was evaluated for paclitaxel. Drug loadings of 5, 25, and 50 mg/mL were compared. After 7 days, the cumulative release for these three drug loading were 106.4%o, 85.9%o, and 33.8%, respectively.
- the effect of surfactant additives was also evaluated. A 25 mg/mL paclitaxel formulation and a 10 mg/mL 5-FU formulation, both in 85: 15 SAIB/EtOH, were made and 5 wt % Cremophor ® EL was added. The addition of this surfactant increased the rate of release for both formulations. The percent released from the paclitaxel formulation increased from 56.0% to 77.0% after two days in vitro.
- the percent released from the 5-FU formulation increased from 80.6% to 106.0%) after two days.
- a second surfactant, Pluronic ® L-101 was added to a 10 mg/mL 5-FU in 85: 15 SAIB/EtOH formulation. This surfactant also increased the amount released from 80.6% to 102.0% after two days.
- the rate of release of drugs such as paclitaxel and 5-fluorouracil from the SAIB delivery system can be modulated by formulation variables including drug loading and surfactant type. Also, the duration of release of these drugs from this system can be varied from a few hours to several days with the shorter duration seen at the lower drug loading and with the addition of a surfactant.
- Example O Another example was conducted to evaluate the potential of the SAIB delivery system to provide extended release following oral administration of antiretroviral drugs used for treating HIV infections.
- the SAIB delivery system uses sucrose acetate isobutyrate (SAIB), a fully-esterified, water-insoluble sucrose derivative, as an excipient.
- SAIB sucrose acetate isobutyrate
- Zidovudine (AZT) and dideoxycytodine (ddC) suspensions were prepared by mixing drug with SAIB/solvent solutions with and without a cellulosic coexcipient. Approximately 1 g of each formulation was filled into soft gelatin capsules, which were heat sealed. Dissolution profiles were determined using Apparatus 2, Method B (USP XXIII) at a paddle speed of 50 rpm. Individual gelcaps were placed in separate dissolution vessels, and samples of the buffer in each vessel were obtained at 0.25, 0.5, 1, 2, 3, 6, and 24 hours. The samples were analyzed at 266 and 272 nm on a Perkin Elmer Lambda 20 UV-vis spectrophotometer for AZT and ddC drug content, respectively.
- Release of AZT and ddC can be modulated simply by the use of different solvents in the SAIB delivery system.
- the cumulative percent released at 2 hours for an 11.1 wt %> AZT formulation was 104.1% and 74.2% for a 0.225 wt % ddC formulation.
- the cumulative percent released at 2 hours for an 11.1 wt %> AZT formulation was 104.1% and 74.2% for a 0.225 wt % ddC formulation.
- an 85:15 SAIB/EtOH combination was used, 71.2% of the drug in the AZT formulation had been released and 59.5% of the drug in the ddC formulation. Release can also be modified by altering drug loading.
- formulations of the SAIB delivery system can be modified to provide a range of dissolution profiles for AZT and ddC. By providing controlled release of these actives, this system can reduce the number of pills needed per day, reduce cost of manufacture, and improve patient compliance.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU73319/00A AU7331900A (en) | 1999-08-27 | 2000-08-24 | High viscosity liquid controlled delivery system and medical or surgical device |
AT00961358T ATE307611T1 (en) | 1999-08-27 | 2000-08-24 | LIQUID HIGH VISCOSITY CONTROLLED RELEASE SYSTEM AND MEDICAL OR SURGICAL DEVICE |
DE60023520T DE60023520T2 (en) | 1999-08-27 | 2000-08-24 | LIQUID HIGH VISCOSITY SYSTEM WITH CONTROLLED RELEASE AND MEDICAL OR SURGICAL DEVICE |
EP00961358A EP1212092B1 (en) | 1999-08-27 | 2000-08-24 | High viscosity liquid controlled delivery system and medical or surgical device |
CA002382540A CA2382540C (en) | 1999-08-27 | 2000-08-24 | High viscosity liquid composition for the delivery of substances |
JP2001520145A JP4276807B2 (en) | 1999-08-27 | 2000-08-24 | Delivery system and medical or surgical device controlled by high viscosity liquid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/385,107 US6413536B1 (en) | 1995-06-07 | 1999-08-27 | High viscosity liquid controlled delivery system and medical or surgical device |
US09/385,107 | 1999-08-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001015734A2 true WO2001015734A2 (en) | 2001-03-08 |
WO2001015734A3 WO2001015734A3 (en) | 2001-09-13 |
Family
ID=23520037
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/023270 WO2001015734A2 (en) | 1999-08-27 | 2000-08-24 | High viscosity liquid controlled delivery system and medical or surgical device |
Country Status (9)
Country | Link |
---|---|
US (3) | US6413536B1 (en) |
EP (1) | EP1212092B1 (en) |
JP (2) | JP4276807B2 (en) |
AT (1) | ATE307611T1 (en) |
AU (3) | AU7331900A (en) |
CA (1) | CA2382540C (en) |
DE (1) | DE60023520T2 (en) |
ES (1) | ES2254219T3 (en) |
WO (1) | WO2001015734A2 (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004082658A1 (en) * | 2003-03-20 | 2004-09-30 | Bayer Healthcare Ag | Controlled release system containing saccharose acetate isobutyrate |
JP2006512370A (en) * | 2002-12-19 | 2006-04-13 | アルザ・コーポレーション | A stable non-aqueous single phase gel and its formulation for delivery from an implantable device |
WO2006071613A2 (en) * | 2004-12-23 | 2006-07-06 | Alza Corporation | Injectable non-aqueous suspension |
WO2008092084A2 (en) * | 2007-01-26 | 2008-07-31 | Centocor, Inc. | Injectable non-aqueous suspension with high concentration of therapeutic agent |
WO2016079331A1 (en) * | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for enhancing the effect of radiotherapy |
WO2016079330A1 (en) * | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for local drug release |
US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
US9655861B2 (en) | 2007-12-06 | 2017-05-23 | Durect Corporation | Oral pharmaceutical dosage forms |
WO2017198858A1 (en) * | 2016-05-20 | 2017-11-23 | Technical University Of Denmark | Palpable marker composition |
US9855333B2 (en) | 2013-03-15 | 2018-01-02 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9918982B2 (en) | 2002-12-13 | 2018-03-20 | Durect Corporation | Oral drug delivery system |
EP2849723B1 (en) | 2012-05-18 | 2018-05-02 | Genentech, Inc. | High-concentration monoclonal antibody formulations |
US10471002B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
US11083796B2 (en) | 2005-07-26 | 2021-08-10 | Durect Corporation | Peroxide removal from drug delivery vehicle |
US11400019B2 (en) | 2020-01-13 | 2022-08-02 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
Families Citing this family (124)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7833543B2 (en) * | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
US6413536B1 (en) * | 1995-06-07 | 2002-07-02 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system and medical or surgical device |
NZ509797A (en) * | 1998-07-10 | 2003-11-28 | Univ Sydney | Prophylactic treatments of neovascularisation in macular degeneration using a steroid |
US6565874B1 (en) * | 1998-10-28 | 2003-05-20 | Atrix Laboratories | Polymeric delivery formulations of leuprolide with improved efficacy |
AUPQ496500A0 (en) * | 2000-01-06 | 2000-02-03 | University Of Sydney, The | Kit |
EP1274459B1 (en) * | 2000-04-19 | 2005-11-16 | Genentech, Inc. | Sustained release formulations comprising growth hormone |
US8470359B2 (en) | 2000-11-13 | 2013-06-25 | Qlt Usa, Inc. | Sustained release polymer |
US9080146B2 (en) | 2001-01-11 | 2015-07-14 | Celonova Biosciences, Inc. | Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface |
EP1379197A4 (en) * | 2001-03-23 | 2009-06-03 | Durect Corp | Delivery of drugs from sustained release devices implanted in myocardial tissue or in the pericardial space |
US7318931B2 (en) * | 2001-06-21 | 2008-01-15 | Genentech, Inc. | Sustained release formulation |
US20030118658A1 (en) * | 2001-12-21 | 2003-06-26 | Trogolo Jeffrey A. | High aspect ratio encapsulated inorganic antimicrobial additive for controlled release |
US7357949B2 (en) * | 2001-12-21 | 2008-04-15 | Agion Technologies Inc. | Encapsulated inorganic antimicrobial additive for controlled release |
DK1532974T3 (en) * | 2002-03-12 | 2009-05-11 | Galderma Res & Dev | Composition comprising 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthic acid, for the treatment of dermatological disorders |
US8075585B2 (en) | 2002-08-29 | 2011-12-13 | Stryker Corporation | Device and method for treatment of a vascular defect |
GB0222522D0 (en) | 2002-09-27 | 2002-11-06 | Controlled Therapeutics Sct | Water-swellable polymers |
US7344505B2 (en) * | 2002-10-15 | 2008-03-18 | Transoma Medical, Inc. | Barriers and methods for pressure measurement catheters |
US7544674B2 (en) * | 2002-10-25 | 2009-06-09 | Galderma S.A. | Topical skin care composition |
US7354574B2 (en) * | 2002-11-07 | 2008-04-08 | Advanced Ocular Systems Limited | Treatment of ocular disease |
US20040224020A1 (en) * | 2002-12-18 | 2004-11-11 | Schoenhard Grant L. | Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats |
US7776355B2 (en) * | 2003-07-03 | 2010-08-17 | Medics Pharmaceutical Corporation | Delivery system for topical medications |
US20050025817A1 (en) * | 2003-07-03 | 2005-02-03 | Bhatia Kuljit S. | Delivery system for topical medications |
CA2541373A1 (en) * | 2003-07-18 | 2005-02-03 | Hill Dermaceuticals, Inc. | Topical skin care composition containing refined peanut oil |
US20070140999A1 (en) * | 2003-07-18 | 2007-06-21 | Hill Dermaceuticals, Inc. | Topical skin care composition containing refined peanut oil |
US7083802B2 (en) * | 2003-07-31 | 2006-08-01 | Advanced Ocular Systems Limited | Treatment of ocular disease |
US7087237B2 (en) * | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
US20050181018A1 (en) * | 2003-09-19 | 2005-08-18 | Peyman Gholam A. | Ocular drug delivery |
US7083803B2 (en) * | 2003-09-19 | 2006-08-01 | Advanced Ocular Systems Limited | Ocular solutions |
US20060099173A1 (en) * | 2003-10-24 | 2006-05-11 | Nancy Puglia | Topical skin care composition |
CA2552241C (en) * | 2003-12-30 | 2013-10-01 | Durect Corporation | Co-polymeric devices for controlled release of active agents |
EP1708734A4 (en) * | 2004-01-07 | 2009-06-17 | Trimeris Inc | HIV gp41 HR2-DERIVED SYNTHETIC PEPTIDES, AND THEIR USE IN THERAPY TO INHIBIT TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS |
JP2005220333A (en) * | 2004-02-03 | 2005-08-18 | Bmg Inc | Biologically decomposable and absorbable polymer and method for producing the same |
WO2005074942A1 (en) * | 2004-02-04 | 2005-08-18 | Retmed Pty Ltd | Slow release steroid composition |
US8048086B2 (en) | 2004-02-25 | 2011-11-01 | Femasys Inc. | Methods and devices for conduit occlusion |
US9238127B2 (en) | 2004-02-25 | 2016-01-19 | Femasys Inc. | Methods and devices for delivering to conduit |
US8052669B2 (en) | 2004-02-25 | 2011-11-08 | Femasys Inc. | Methods and devices for delivery of compositions to conduits |
US8048101B2 (en) | 2004-02-25 | 2011-11-01 | Femasys Inc. | Methods and devices for conduit occlusion |
CA2557216A1 (en) * | 2004-02-26 | 2005-09-09 | Advanced Ocular Systems Limited | Heparin for the treatment of ocular pathologies |
US20050192257A1 (en) * | 2004-02-26 | 2005-09-01 | Peyman Gholam A. | Predictors for patients at risk for glaucoma from steroid therapy |
CA2562356A1 (en) * | 2004-04-08 | 2005-10-27 | Retmed Pty Ltd | Treatment of ophthalmic conditions with mineralcorticoids |
US20050232876A1 (en) * | 2004-04-19 | 2005-10-20 | Robin Lynn Minga | Skin care compositions |
WO2005102303A2 (en) * | 2004-04-21 | 2005-11-03 | Advanced Ocular Systems Limited | Antiprostaglandins for the treatment of ocular pathologies |
WO2006002067A1 (en) * | 2004-06-15 | 2006-01-05 | Milos Chvapil | Composition and method using local application of lipophilic lathyrogens in sustained release formulations |
US7479289B2 (en) * | 2004-07-02 | 2009-01-20 | Medicis Pharmaceutical Corporation | Stable cleanser compositions containing sulfur |
US7655682B2 (en) | 2004-07-02 | 2010-02-02 | Medicis Pharmaceutical Corporation | Triple anti-irritant composition |
GB0417401D0 (en) | 2004-08-05 | 2004-09-08 | Controlled Therapeutics Sct | Stabilised prostaglandin composition |
LT2767292T (en) * | 2004-09-17 | 2016-12-12 | Durect Corporation | Sustained Local Anesthetic Composition Containing SAIB |
BRPI0518383A2 (en) | 2004-10-25 | 2008-11-18 | Polyzenix Gmbh | Chargeable polymeric particles for therapeutical and / or diagnostic applications and methods for preparing and using them |
US9114162B2 (en) | 2004-10-25 | 2015-08-25 | Celonova Biosciences, Inc. | Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same |
US9107850B2 (en) | 2004-10-25 | 2015-08-18 | Celonova Biosciences, Inc. | Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same |
US20210299056A9 (en) | 2004-10-25 | 2021-09-30 | Varian Medical Systems, Inc. | Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods |
US20060122152A1 (en) * | 2004-12-03 | 2006-06-08 | Peyman Gholam A | Heparin for the treatment of ocular pathologies |
JP2008525436A (en) * | 2004-12-23 | 2008-07-17 | デュレクト コーポレーション | Controlled release composition |
US20070014760A1 (en) | 2005-07-18 | 2007-01-18 | Peyman Gholam A | Enhanced recovery following ocular surgery |
WO2007011880A2 (en) | 2005-07-18 | 2007-01-25 | Minu, L.L.C. | Enhanced ocular neuroprotection/neurostimulation |
US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
US7456251B2 (en) | 2006-02-02 | 2008-11-25 | Trimeris, Inc. | HIV fusion inhibitor peptides with improved biological properties |
ZA200807571B (en) * | 2006-03-01 | 2009-08-26 | Ethypharm Sa | Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion |
EP2374472B9 (en) | 2006-03-16 | 2019-06-12 | Dyax Corp. | Compositions and methods for treating ophthalmic disorders |
US7458953B2 (en) * | 2006-06-20 | 2008-12-02 | Gholam A. Peyman | Ocular drainage device |
EP2044142A2 (en) * | 2006-06-29 | 2009-04-08 | Medtronic, Inc. | Poly(orthoester) polymers, and methods of making and using same |
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 |
SI2046382T1 (en) * | 2006-07-10 | 2016-12-30 | ESBATech an Alcon Biomedical Research Unit LLC | scFv ANTIBODIES WHICH PASS EPITHELIAL AND/OR ENDOTHELIAL LAYERS |
US20080160065A1 (en) * | 2006-07-12 | 2008-07-03 | Janet Anne Halliday | Drug delivery polymer with hydrochloride salt of clindamycin |
GB0620685D0 (en) | 2006-10-18 | 2006-11-29 | Controlled Therapeutics Sct | Bioresorbable polymers |
US8337883B2 (en) * | 2006-11-03 | 2012-12-25 | Durect Corporation | Transdermal delivery systems |
FR2910321B1 (en) | 2006-12-21 | 2009-07-10 | Galderma Res & Dev S N C Snc | CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
FR2910320B1 (en) | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
KR20100016142A (en) * | 2007-04-03 | 2010-02-12 | 트라이머리스, 인코퍼레이티드 | Novel formulations for delivery of antiviral peptide therapeutics |
DK2167039T3 (en) * | 2007-05-18 | 2017-01-09 | Durect Corp | Improved depot formulations |
MX337286B (en) | 2007-05-25 | 2016-02-22 | Indivior Uk Ltd | Sustained delivery formulations of risperidone compounds. |
MX2010003179A (en) * | 2007-09-25 | 2010-04-30 | Trimeris Inc | Methods of synthesis for therapeuthic anti-hiv peptides. |
CA2705520C (en) * | 2007-11-13 | 2016-06-28 | Surmodics Pharmaceuticals, Inc. | Viscous terpolymers as drug delivery platform |
AU2013202707C1 (en) * | 2007-12-06 | 2015-07-30 | Durect Corporation | Oral pharmaceutical dosage forms |
US20090181068A1 (en) * | 2008-01-14 | 2009-07-16 | Dunn Richard L | Low Viscosity Liquid Polymeric Delivery System |
CA2714506C (en) * | 2008-02-08 | 2016-06-07 | Qps Llc | Composition for sustained release delivery of proteins or peptides |
US8586103B2 (en) * | 2008-02-08 | 2013-11-19 | Foresee Pharmaceuticals, Llc | Non-polymeric compositions for controlled drug delivery |
GB0804619D0 (en) * | 2008-03-12 | 2008-04-16 | Norbrook Lab Ltd | A topical ectoparasiticide composition |
US20090263456A1 (en) * | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Methods and Compositions for Reducing Preventing and Treating Adhesives |
US8475823B2 (en) * | 2008-04-18 | 2013-07-02 | Medtronic, Inc. | Baclofen formulation in a polyorthoester carrier |
US8956642B2 (en) * | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
EP2303393A4 (en) * | 2008-05-07 | 2011-10-19 | Obj Ltd | Method and apparatus for enhanced transdermal diffusion |
US10070888B2 (en) | 2008-10-03 | 2018-09-11 | Femasys, Inc. | Methods and devices for sonographic imaging |
US9554826B2 (en) | 2008-10-03 | 2017-01-31 | Femasys, Inc. | Contrast agent injection system for sonographic imaging |
US8822546B2 (en) * | 2008-12-01 | 2014-09-02 | Medtronic, Inc. | Flowable pharmaceutical depot |
US20100143437A1 (en) * | 2008-12-09 | 2010-06-10 | Morris Edward J | Implantable analgesic |
US8974808B2 (en) * | 2008-12-23 | 2015-03-10 | Surmodics, Inc. | Elastic implantable composites and implants comprising same |
US8951546B2 (en) * | 2008-12-23 | 2015-02-10 | Surmodics Pharmaceuticals, Inc. | Flexible implantable composites and implants comprising same |
US9415197B2 (en) * | 2008-12-23 | 2016-08-16 | Surmodics, Inc. | Implantable suction cup composites and implants comprising same |
US20100168807A1 (en) * | 2008-12-23 | 2010-07-01 | Burton Kevin W | Bioactive terpolymer compositions and methods of making and using same |
US9480643B2 (en) | 2008-12-23 | 2016-11-01 | Surmodics Pharmaceuticals, Inc. | Implantable composites and implants comprising same |
US20120207770A1 (en) | 2009-10-14 | 2012-08-16 | Nanyang Technological University | Antiproliferative agent |
US9452037B2 (en) | 2010-05-25 | 2016-09-27 | International Scientific Pty Ltd | Delivery of oral care products |
US9272044B2 (en) | 2010-06-08 | 2016-03-01 | Indivior Uk Limited | Injectable flowable composition buprenorphine |
GB2513060B (en) | 2010-06-08 | 2015-01-07 | Rb Pharmaceuticals Ltd | Microparticle buprenorphine suspension |
US9463330B2 (en) | 2010-06-17 | 2016-10-11 | International Scientific Pty Ltd | Delivery of skin care products |
EP2611868B1 (en) | 2010-08-30 | 2020-01-08 | Surmodics Pharmaceuticals, Inc. | Biodegradable terpolymers and terpolymer blends as pressure-sensitive adhesives |
EP2626092B1 (en) * | 2011-04-01 | 2015-08-05 | Zhuhai Ortus Biotechnology Co., Ltd. | Medical absorbable hemostatic material for bone wounds and preparation method therefor |
TW201334791A (en) * | 2011-11-23 | 2013-09-01 | Durect Corp | Radiation-sterilized biodegradable drug delivery compositions |
US10220093B2 (en) | 2013-02-28 | 2019-03-05 | Mira Pharma Corporation | Long-acting semi-solid lipid formulations |
JP6363115B2 (en) | 2013-02-28 | 2018-07-25 | ミラ ファーマ コーポレイション | Injectable local anesthetic semi-solid preparation and composition thereof |
EA033537B1 (en) | 2013-03-11 | 2019-10-31 | Durect Corp | Injectable controlled release composition comprising high viscosity liquid carrier |
US20140308352A1 (en) | 2013-03-11 | 2014-10-16 | Zogenix Inc. | Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material |
MX352907B (en) | 2013-03-15 | 2017-12-13 | Heron Therapeutics Inc | Compositions of a polyorthoester and an aprotic solvent. |
WO2014144984A1 (en) | 2013-03-15 | 2014-09-18 | Durect Corporation | Compositions with thixotropy and enhanced dissolution reproducibility and stability |
US20160303242A1 (en) | 2013-12-09 | 2016-10-20 | Durect Corporation | Pharmaceutically Active Agent Complexes, Polymer Complexes, and Compositions and Methods Involving the Same |
WO2015123734A1 (en) * | 2014-02-21 | 2015-08-27 | The University Of Sydney | Liquid carrier materials |
GB201404139D0 (en) | 2014-03-10 | 2014-04-23 | Rb Pharmaceuticals Ltd | Sustained release buprenorphine solution formulations |
EP3154552B1 (en) | 2014-06-11 | 2021-03-24 | International Scientific Pty Ltd | Device and method to treat or prevent joint degeneration |
US20200197315A1 (en) | 2016-07-06 | 2020-06-25 | Durect Corporation | Oral dosage form with drug composition, barrier layer and drug layer |
US11752099B2 (en) * | 2017-03-27 | 2023-09-12 | W. L. Gore & Associates, Inc. | Injectable and biodegradable polymer formulations for controlled release of bioactive agents |
CA3059449A1 (en) | 2017-04-24 | 2018-11-01 | Cocrystal Pharma, Inc. | Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication |
US11890395B2 (en) | 2017-06-16 | 2024-02-06 | Avery Therapeutics, Inc. | Three dimensional tissue compositions and methods of use |
US11426418B2 (en) | 2017-12-06 | 2022-08-30 | Mira Pharma Corporation | Injectable long-acting semi-solid gel formulations |
US10561606B2 (en) | 2017-12-06 | 2020-02-18 | Mira Pharma Corporation | Injectable long-acting local anesthetic semi-solid gel formulations |
EP3829719A1 (en) | 2018-07-27 | 2021-06-09 | Cocrystal Pharma, Inc. | Pyrrolo[2,3-b]pyridin derivatives as inhibitors of influenza virus replication |
EP3849978B1 (en) | 2018-09-10 | 2022-11-02 | Cocrystal Pharma, Inc. | Pyridopyrazine and pyridotriazine inhibitors of influenza virus replication |
AU2019361038A1 (en) | 2018-10-17 | 2021-05-13 | Cocrystal Pharma, Inc. | Combinations of inhibitors of influenza virus replication |
US20220048897A1 (en) | 2018-11-26 | 2022-02-17 | Cocrystal Pharma, Inc. | Inhibitors of influenza virus replication |
CA3143104A1 (en) | 2019-06-12 | 2020-12-17 | Technical University Of Denmark | Dissacharide formulations for controlled drug release |
US20230151034A1 (en) | 2020-03-17 | 2023-05-18 | Cocrystal Pharma, Inc. | Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication |
IL297069A (en) | 2020-04-10 | 2022-12-01 | Cocrystal Pharma Inc | Inhibitors of norovirus and coronavirus replication |
WO2023014758A1 (en) | 2021-08-03 | 2023-02-09 | Cocrystal Pharma, Inc. | Inhibitors for coronaviruses |
EP4282435A1 (en) | 2022-05-23 | 2023-11-29 | Danmarks Tekniske Universitet | Formulations of active pharmaceutical ingredients and excipients in icells via hydrophobic ion pairing |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0290983A2 (en) * | 1987-05-15 | 1988-11-17 | Henkel Kommanditgesellschaft auf Aktien | Resorbable bone wax |
WO1994015587A2 (en) * | 1993-01-06 | 1994-07-21 | Kinerton Limited | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
EP0635531A2 (en) * | 1993-07-20 | 1995-01-25 | Ethicon Inc. | Liquid copolymers of epsilon-caprolactone and lactide |
EP0711548A1 (en) * | 1994-10-18 | 1996-05-15 | Ethicon, Inc. | Injectable microdispersions for soft tissue repair and augmentation |
DE19714765A1 (en) * | 1997-04-10 | 1998-10-15 | Merck Patent Gmbh | Use of low molecular weight, oligomeric esters of alpha-hydroxy acids and / or aromatic o-hydroxy acids in cosmetic formulations |
WO1999013913A2 (en) * | 1997-09-15 | 1999-03-25 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system as a device |
EP1010436A1 (en) * | 1998-12-19 | 2000-06-21 | MERCK PATENT GmbH | Improved bone wax composition |
WO2000078335A1 (en) * | 1999-06-18 | 2000-12-28 | Southern Biosystems, Inc. | COMPOSITIONS FOR CONTROLLED RELEASE OF THE HORMONE GnRH AND ITS ANALOGS |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2931802A (en) | 1958-04-30 | 1960-04-05 | Eastman Kodak Co | Mixed esters of glucose and sucrose |
GB1088992A (en) | 1963-09-19 | 1967-10-25 | Squibb & Sons Inc | Protective dressings |
US4411890A (en) | 1981-04-14 | 1983-10-25 | Beckman Instruments, Inc. | Synthetic peptides having pituitary growth hormone releasing activity |
US3743398A (en) | 1971-03-22 | 1973-07-03 | Eastman Kodak Co | Motion picture projector |
NO139560C (en) | 1972-04-29 | 1979-04-04 | Takeda Chemical Industries Ltd | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE NONAPEPTIDAMIDE DERIVATIVES |
DK568274A (en) | 1973-11-01 | 1975-06-23 | Wellcome Found | |
DE2438350C3 (en) | 1974-08-09 | 1979-06-13 | Hoechst Ag, 6000 Frankfurt | Peptides with a strong LH-RH / FSH-RH action, process for their production and pharmaceutical preparations containing them |
DE2438352A1 (en) | 1974-08-09 | 1976-02-26 | Hoechst Ag | PEPTIDE CYCLOPROPYLAMIDE WITH LH-RH / FSHRH EFFECT |
GB1524747A (en) | 1976-05-11 | 1978-09-13 | Ici Ltd | Polypeptide |
JPS55154991A (en) * | 1979-05-23 | 1980-12-02 | Hisamitsu Pharmaceut Co Inc | Beta-d-fructopyranoside derivative |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
US4906474A (en) | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4622219A (en) | 1983-06-17 | 1986-11-11 | Haynes Duncan H | Method of inducing local anesthesia using microdroplets of a general anesthetic |
US4725442A (en) | 1983-06-17 | 1988-02-16 | Haynes Duncan H | Microdroplets of water-insoluble drugs and injectable formulations containing same |
US4891225A (en) | 1984-05-21 | 1990-01-02 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
IT1198449B (en) | 1986-10-13 | 1988-12-21 | F I D I Farmaceutici Italiani | ESTERS OF POLYVALENT ALCOHOLS OF HYALURONIC ACID |
US5391381A (en) | 1987-06-25 | 1995-02-21 | Alza Corporation | Dispenser capable of delivering plurality of drug units |
US5350741A (en) | 1988-07-30 | 1994-09-27 | Kanji Takada | Enteric formulations of physiologically active peptides and proteins |
JPH0296516A (en) | 1988-09-29 | 1990-04-09 | Dainippon Pharmaceut Co Ltd | Granule and production thereof |
US5702716A (en) | 1988-10-03 | 1997-12-30 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
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 |
IT1240643B (en) | 1990-05-11 | 1993-12-17 | Mediolanum Farmaceutici Spa | BIOLOGICALLY ACTIVE PEPTIDES CONTAINING IN 2-ALCHYL TRIPTOFANE CHAIN |
US5149543A (en) | 1990-10-05 | 1992-09-22 | Massachusetts Institute Of Technology | Ionically cross-linked polymeric microcapsules |
US5399363A (en) | 1991-01-25 | 1995-03-21 | Eastman Kodak Company | Surface modified anticancer nanoparticles |
EP0539559A1 (en) | 1991-04-03 | 1993-05-05 | Eastman Kodak Company | HIGH DURABILITY MASK FOR DRY ETCHING OF GaAs |
JP3313124B2 (en) | 1991-07-31 | 2002-08-12 | 森下仁丹株式会社 | SEAMLESS CAPSULES CONTAINING A HYDROPHILIC SUBSTANCE AND PROCESS FOR PRODUCING THE SAME |
US5487898A (en) | 1991-08-26 | 1996-01-30 | Abbott Laboratories | Compositions and method for the sublingual or buccal administration therapeutic agents |
YU87892A (en) | 1991-10-01 | 1995-12-04 | Eli Lilly And Company Lilly Corporate Center | INJECTIBLE LONG TERM RELEASE FORMULATIONS AND PROCEDURES FOR THEIR OBTAINING AND USE |
AU2605592A (en) | 1991-10-15 | 1993-04-22 | Atrix Laboratories, Inc. | Polymeric compositions useful as controlled release implants |
US5545408A (en) | 1991-10-21 | 1996-08-13 | Peptide Technology Limited | Biocompatible implant for the timing of ovulation in mares |
US5340572A (en) | 1993-02-08 | 1994-08-23 | Insite Vision Incorporated | Alkaline ophthalmic suspensions |
DE69413955T2 (en) | 1993-03-17 | 1999-04-01 | Minnesota Mining & Mfg | AEROSOL COMPOSITION CONTAINING A DERIVATIVE DERIVATIVE FROM ESTER, AMID OR MERCAPTOESTER |
US6042811A (en) | 1993-03-17 | 2000-03-28 | 3M Innovative Properties Company | Aerosol formulation containing a diol-diacid derived dispersing aid |
DE4322826A1 (en) * | 1993-07-08 | 1995-01-12 | Galenik Labor Freiburg Gmbh | Pharmaceutical preparation |
JPH07112940A (en) | 1993-08-26 | 1995-05-02 | Takeda Chem Ind Ltd | Sustained-release parenteral preparation and its production |
JPH07115901A (en) | 1993-10-28 | 1995-05-09 | Fuji Bibaretsuji:Kk | Emulsified composition and drink rich in docosahexaenoic acid |
EP0739210B1 (en) | 1993-12-29 | 2002-07-24 | Matrix Pharmaceutical, Inc. | Compositions for local delivery of cytostatic agents |
JP4259610B2 (en) | 1994-04-08 | 2009-04-30 | キューエルティー・ユーエスエイ・インコーポレーテッド | Liquid delivery composition |
US5747058A (en) | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
US6413536B1 (en) * | 1995-06-07 | 2002-07-02 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system and medical or surgical device |
BRPI9609033B8 (en) | 1995-06-07 | 2017-04-04 | Durect Corp | composition and emulsion for the controlled release of a substance. |
US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
JPH10115901A (en) | 1996-10-09 | 1998-05-06 | Noritsu Koki Co Ltd | Photographic developing processor |
ES2158611T3 (en) | 1996-12-20 | 2001-09-01 | Alza Corp | COMPOSITION IN INJECTABLE GEL WITH RETARD EFFECT AND PROCEDURE FOR THE PREPARATION OF SUCH COMPOSITION. |
US6126919A (en) | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
US5840329A (en) | 1997-05-15 | 1998-11-24 | Bioadvances Llc | Pulsatile drug delivery system |
US6051558A (en) | 1997-05-28 | 2000-04-18 | Southern Biosystems, Inc. | Compositions suitable for controlled release of the hormone GnRH and its analogs |
-
1999
- 1999-08-27 US US09/385,107 patent/US6413536B1/en not_active Expired - Lifetime
-
2000
- 2000-08-24 JP JP2001520145A patent/JP4276807B2/en not_active Expired - Lifetime
- 2000-08-24 ES ES00961358T patent/ES2254219T3/en not_active Expired - Lifetime
- 2000-08-24 CA CA002382540A patent/CA2382540C/en not_active Expired - Fee Related
- 2000-08-24 DE DE60023520T patent/DE60023520T2/en not_active Expired - Lifetime
- 2000-08-24 EP EP00961358A patent/EP1212092B1/en not_active Expired - Lifetime
- 2000-08-24 AT AT00961358T patent/ATE307611T1/en not_active IP Right Cessation
- 2000-08-24 AU AU73319/00A patent/AU7331900A/en not_active Abandoned
- 2000-08-24 WO PCT/US2000/023270 patent/WO2001015734A2/en active IP Right Grant
- 2000-10-26 US US09/699,002 patent/US7053209B1/en not_active Expired - Fee Related
-
2005
- 2005-09-01 AU AU2005205766A patent/AU2005205766A1/en not_active Abandoned
-
2006
- 2006-05-24 US US11/440,642 patent/US20060210599A1/en not_active Abandoned
-
2009
- 2009-01-08 JP JP2009002735A patent/JP2009143935A/en active Pending
- 2009-04-03 AU AU2009201321A patent/AU2009201321A1/en not_active Abandoned
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0290983A2 (en) * | 1987-05-15 | 1988-11-17 | Henkel Kommanditgesellschaft auf Aktien | Resorbable bone wax |
WO1994015587A2 (en) * | 1993-01-06 | 1994-07-21 | Kinerton Limited | Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides |
EP0635531A2 (en) * | 1993-07-20 | 1995-01-25 | Ethicon Inc. | Liquid copolymers of epsilon-caprolactone and lactide |
EP0711548A1 (en) * | 1994-10-18 | 1996-05-15 | Ethicon, Inc. | Injectable microdispersions for soft tissue repair and augmentation |
DE19714765A1 (en) * | 1997-04-10 | 1998-10-15 | Merck Patent Gmbh | Use of low molecular weight, oligomeric esters of alpha-hydroxy acids and / or aromatic o-hydroxy acids in cosmetic formulations |
WO1999013913A2 (en) * | 1997-09-15 | 1999-03-25 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system as a device |
EP1010436A1 (en) * | 1998-12-19 | 2000-06-21 | MERCK PATENT GmbH | Improved bone wax composition |
WO2000078335A1 (en) * | 1999-06-18 | 2000-12-28 | Southern Biosystems, Inc. | COMPOSITIONS FOR CONTROLLED RELEASE OF THE HORMONE GnRH AND ITS ANALOGS |
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11179326B2 (en) | 2002-06-25 | 2021-11-23 | Durect Corporation | Short duration depot formulations |
US10471002B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
US10471001B2 (en) | 2002-06-25 | 2019-11-12 | Durect Corporation | Short duration depot formulations |
US9918982B2 (en) | 2002-12-13 | 2018-03-20 | Durect Corporation | Oral drug delivery system |
JP2006512370A (en) * | 2002-12-19 | 2006-04-13 | アルザ・コーポレーション | A stable non-aqueous single phase gel and its formulation for delivery from an implantable device |
US8231903B2 (en) | 2003-03-20 | 2012-07-31 | Bayer Animal Health Gmbh | Controlled release system |
AU2004222646B2 (en) * | 2003-03-20 | 2010-04-29 | Bayer Intellectual Property Gmbh | Controlled release system containing saccharose acetate isobutyrate |
WO2004082658A1 (en) * | 2003-03-20 | 2004-09-30 | Bayer Healthcare Ag | Controlled release system containing saccharose acetate isobutyrate |
JP2008525457A (en) * | 2004-12-23 | 2008-07-17 | アルザ・コーポレーシヨン | Injectable non-aqueous suspension |
WO2006071613A3 (en) * | 2004-12-23 | 2007-02-15 | Alza Corp | Injectable non-aqueous suspension |
WO2006071613A2 (en) * | 2004-12-23 | 2006-07-06 | Alza Corporation | Injectable non-aqueous suspension |
US11083796B2 (en) | 2005-07-26 | 2021-08-10 | Durect Corporation | Peroxide removal from drug delivery vehicle |
WO2008092084A3 (en) * | 2007-01-26 | 2008-11-20 | Centocor Inc | Injectable non-aqueous suspension with high concentration of therapeutic agent |
US8802095B2 (en) | 2007-01-26 | 2014-08-12 | Durect Corporation | Injectable, non-aqueous suspension with high concentration of therapeutic agent |
WO2008092084A2 (en) * | 2007-01-26 | 2008-07-31 | Centocor, Inc. | Injectable non-aqueous suspension with high concentration of therapeutic agent |
US9655861B2 (en) | 2007-12-06 | 2017-05-23 | Durect Corporation | Oral pharmaceutical dosage forms |
US10206883B2 (en) | 2007-12-06 | 2019-02-19 | Durect Corporation | Oral pharamaceutical dosage forms |
US9884056B2 (en) | 2008-11-03 | 2018-02-06 | Durect Corporation | Oral pharmaceutical dosage forms |
US9616055B2 (en) | 2008-11-03 | 2017-04-11 | Durect Corporation | Oral pharmaceutical dosage forms |
US10328068B2 (en) | 2008-11-03 | 2019-06-25 | Durect Corporation | Oral pharmaceutical dosage forms |
EP2849723B1 (en) | 2012-05-18 | 2018-05-02 | Genentech, Inc. | High-concentration monoclonal antibody formulations |
US9907851B2 (en) | 2013-03-15 | 2018-03-06 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9855333B2 (en) | 2013-03-15 | 2018-01-02 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US10300142B2 (en) | 2013-03-15 | 2019-05-28 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
WO2016079331A1 (en) * | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for enhancing the effect of radiotherapy |
CN107249570A (en) * | 2014-11-21 | 2017-10-13 | 丹麦技术大学 | The gel preparation discharged for topical remedy |
WO2016079330A1 (en) * | 2014-11-21 | 2016-05-26 | Technical University Of Denmark | Gel formulations for local drug release |
US11065201B2 (en) | 2014-11-21 | 2021-07-20 | Technical University Of Denmark | Gel formulations for local drug release |
EP3220887A1 (en) * | 2014-11-21 | 2017-09-27 | Technical University of Denmark | Gel formulations for local drug release |
IL263071A (en) * | 2016-05-20 | 2018-12-31 | Univ Denmark Tech Dtu | Palpable marker composition |
US11058780B2 (en) | 2016-05-20 | 2021-07-13 | Technical University Of Denmark | Palpable marker composition |
CN109475491A (en) * | 2016-05-20 | 2019-03-15 | 丹麦技术大学 | Can palpation label compositions |
KR20190026662A (en) * | 2016-05-20 | 2019-03-13 | 테크니칼 유니버시티 오브 덴마크 | Promotable marker composition |
WO2017198858A1 (en) * | 2016-05-20 | 2017-11-23 | Technical University Of Denmark | Palpable marker composition |
US11400019B2 (en) | 2020-01-13 | 2022-08-02 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
US11771624B2 (en) | 2020-01-13 | 2023-10-03 | Durect Corporation | Sustained release drug delivery systems with reduced impurities and related methods |
Also Published As
Publication number | Publication date |
---|---|
JP4276807B2 (en) | 2009-06-10 |
AU7331900A (en) | 2001-03-26 |
CA2382540A1 (en) | 2001-03-08 |
EP1212092B1 (en) | 2005-10-26 |
US6413536B1 (en) | 2002-07-02 |
US20060210599A1 (en) | 2006-09-21 |
ATE307611T1 (en) | 2005-11-15 |
CA2382540C (en) | 2009-06-16 |
JP2009143935A (en) | 2009-07-02 |
EP1212092A2 (en) | 2002-06-12 |
DE60023520T2 (en) | 2006-07-27 |
ES2254219T3 (en) | 2006-06-16 |
JP2003508449A (en) | 2003-03-04 |
AU2005205766A1 (en) | 2005-09-29 |
US7053209B1 (en) | 2006-05-30 |
AU2009201321A1 (en) | 2009-04-23 |
WO2001015734A3 (en) | 2001-09-13 |
DE60023520D1 (en) | 2005-12-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1212092B1 (en) | High viscosity liquid controlled delivery system and medical or surgical device | |
US7833543B2 (en) | High viscosity liquid controlled delivery system and medical or surgical device | |
EP1006935B1 (en) | High viscosity liquid controlled delivery system | |
US5747058A (en) | High viscosity liquid controlled delivery system | |
US5968542A (en) | High viscosity liquid controlled delivery system as a device | |
CA2686137C (en) | Improved depot formulations | |
AU2006203112A1 (en) | High viscosity liquid controlled delivery system as a device | |
MXPA97009606A (en) | Liquid system of controlled release and viscosity elev |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2382540 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 73319/00 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000961358 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2000961358 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWG | Wipo information: grant in national office |
Ref document number: 2000961358 Country of ref document: EP |