EP1024790A1 - Copolymeres blocs en gels injectables et biodegradables servant a administrer un medicament - Google Patents

Copolymeres blocs en gels injectables et biodegradables servant a administrer un medicament

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Publication number
EP1024790A1
EP1024790A1 EP98940801A EP98940801A EP1024790A1 EP 1024790 A1 EP1024790 A1 EP 1024790A1 EP 98940801 A EP98940801 A EP 98940801A EP 98940801 A EP98940801 A EP 98940801A EP 1024790 A1 EP1024790 A1 EP 1024790A1
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EP
European Patent Office
Prior art keywords
poly
block
block copolymer
copolymer
polymer block
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98940801A
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German (de)
English (en)
Other versions
EP1024790A4 (fr
Inventor
Byeongmoon Jeong
You Han Bae
Doo Sung Lee
Sung Wan Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Utah Research Foundation UURF
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University of Utah Research Foundation UURF
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Publication of EP1024790A1 publication Critical patent/EP1024790A1/fr
Publication of EP1024790A4 publication Critical patent/EP1024790A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K47/30—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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides

Definitions

  • the present invention relates to the preparation of thermosensitive biodegradable block copolymers and their use for parenteral or subcutaneous administration of bioactive molecules such as peptide and protein drugs. More particularly, this invention relates to thermosensitive biodegradable polymers containing bioactive molecules having a gel/sol transition temperature that is dependent upon the block length and concentration of the block copolymers .
  • thermosensitive biodegradable polymers based on poly(ether-ester) block copolymers which are described in detail hereinafter.
  • the system is based the discovery that poly (ether-ester) block copolymers having certain molecular weight and composition ranges exist as aqueous solutions at elevated temperatures, e.g. above the gel/sol transition temperature but, when the temperature is lowered below the transition temperature, e.g. to about body temperature, interact to form a semi-solid gel.
  • Thermosensitive polymers have widely been investigated as drug carriers. Homopolymers or copolymers of N-isopropylacrylamide (NIPAAm) as disclosed by Bae et al., Makromol. Chem. Rapid Commun. , 8, 481-485 (1987) and Chen, et al., Nature, 373, 49-52 (1995) are one type. Another type is triblock copolymers consisting of hydrophobic poly ropylene oxide) as the center block and hydrophilic poly(ethylene oxide) as the side blocks, e.g.
  • NIPAAm N-isopropylacrylamide
  • Another type is triblock copolymers consisting of hydrophobic poly ropylene oxide) as the center block and hydrophilic poly(ethylene oxide) as the side blocks, e.g.
  • Poloxamer brand as disclosed by Malston, et al., Macromolecules, 25, 5440-5445 (1992). These polymers are generally nonbiodegradable and their toxicities are of concern. For example, following intraperitoneal injections, Poloxamer type copolymers have been shown to enhance plasma cholesterol and triglycerol in rats. Wout et al., J.
  • thermoplastic solution requires the use of an organic solvent such as N-methyl-2-pyrrolidone, methyl ethyl ketone, dimethylformamide, propylene glycol, THF, DMSO, dodecylazacycloheptan-2-one (Azone) and the like.
  • the thermosetting system comprises the synthesis of crosslinkable polymers which can be formed and cured in-situ through the use of a curing agent.
  • thermoplastic formulations are the use of organic solvents which can be toxic or irritating to the body tissues.
  • the thermosetting system requires that the drug be admixed with the prepolymer solution prior to additions of the catalysts because the curing reaction is quite rapid and injection must take place almost immediately following the addition of the curing agent.
  • the gels degrade upon hydrolysis of the oligo( ⁇ -hydroxy acid) regions into poly(ethylene glycol), the ⁇ -hydroxy acid, and oligo(acrylic acid) and their degradation rates can be tailored by appropriate choice of the oligo( ⁇ -hydroxy acid) from less than 1 day to up to 4 months.
  • a photoinitiator an additional component, is employed as well as an additional process such as photocrosslinking. This concept is further exemplified in U.S. Patent 5,567,435.
  • An optimum material for use as an injectable or implantable polymeric drug delivery device should be biodegradable, be compatible with hydrophilic or hydrophobic drugs, and allow fabrication with simple, safe solvents, such as water, and not require additional polymerization or reaction following administration.
  • a still further object of this invention is to provide a drug delivery system for the parenteral administration of bioactive agents where there is no requirement for any surgical procedure for implantation.
  • Yet another object of this invention is to provide a method for the parenteral administration of drugs in a biodegradable polymeric matrix resulting in the formation of a gel depot within the body from which the drugs are released at a controlled rate with the corresponding biodegradation of the polymeric matrix.
  • hydrogel drug delivery system utilizing a poly(ethylene oxide) B block and biodegradable poly( ⁇ - hydroxide) A block copolymer having both thermosensitivity and biodegradabilty properties.
  • the hydrogel contains an appropriate balance of hydrophilicity (B block) and hydrophobicity (A block) enabling the hydrogel to have thermoreversibility.
  • organic solvents are not used to load such polymer systems with bioactive agents. Therefore, the need to remove any organic solvent is eliminated.
  • Parenter shall mean any route of administration other than the alimentary canal and shall specifically include intramuscular, intraperitoneal, intra- abdominal, subcutaneous, and, to the extent feasible, intravenous.
  • “Solution,” “aqueous solution” and the like when used in reference to a combination of drug and biodegradable block copolymer contained in such solution, shall mean a water based solution having such drug/polymer combination dissolved or uniformly suspended therein at a functional concentration and maintained at a temperature above the gel/sol transition temperature of the block copolymer.
  • Drug delivery liquid or “drug delivery liquid having thermal gelation properties” shall means a “solution” suitable for injection into a warm-blooded animal which forms a depot upon having the temperature lowered to the body temperature of the subject into which it is administered.
  • Depot means a drug delivery liquid following injection into a warmblooded animal which has formed a gel upon the temperature being lowered to body temperature.
  • Gel when used, shall mean a semi-solid hydrogel combination of biodegradable block copolymer and water at a temperature below the gel/sol transition temperature which is preferably at or below body temperature.
  • Gel/sol transition temperature means the temperature at which an aqueous combination of the block copolymer undergoes a phase transition between a gel and a solution. Above the gel/sol transition temperature the aqueous combination is a solution and below the gel/sol transition temperature the aqueous combination is a semi-solid hydrogel. The drug will be homogeneously contained in the solution or gel. While it is possible to formulate the block copolymers to have a wide range of gel/sol transition temperatures, it is desirable to have a gel/sol transition temperature that is just above the body temperature of the subject to which an aqueous solution of the block copolymer and drug is to be administered.
  • Biodegradable meaning that the block polymer can break down or degrade within the body to non-toxic components after all drug has been released.
  • Drug shall mean any organic compound or substance having bioactivity and adapted or used for a therapeutic purpose.
  • Poly( «-hydroxy acid) shall mean a poly( «-hydroxy acid) polymer er se or a poly( ° c -hydroxy acid) polymer or copolymer derived from the ring opening polymerization of an «-hydroxy acid precursor, such as a corresponding lactide, glycol ide or lactone.
  • Polyethylene oxide) or “PEO” and “polyethylene glycol)” or “PEG” or “polyoxyethylene” may be used interchangeably and shall mean a polymer of ethylene glycol or hydrated ethylene oxide.
  • Basic to the present invention is the utilization of a block copolymer having hydrophobic or "A” block segments and hydrophilic or "B” block segments.
  • the block copolymer will be a triblock BAB type block copolymer.
  • the block copolymer could also be a diblock BA type copolymer.
  • the biodegradable hydrophobic, or A block, segment is preferably a poly ( ⁇ -hydroxy acid) member derived or selected from the group consisting of poly(d,l-lactide), poly(l-lactide), poly(d,l-lactide-co-glycolide), poly(l-lactide-co-glycolide), poly(e-caprolactone), poly( ⁇ -butyrolactone), poly( ⁇ - valerolactone), poly(e-caprolactone-co-lactic acid), poly(e-caprolactone-co-glycolic acid-co-lactic acid), hydroxybutyric acid, malic acid and bi- or terpolymers thereof.
  • any water insoluble biodegradable copolymers can be utilized as the hydrophobic A block including semicrystalline polymers and amorphous polymers.
  • the average molecular weight of such ⁇ - hydroxy acid polymeric blocks is between about 500 and 20,000.
  • the average molecular weight of the A block is between about 500 and 15,000 and is more preferably between about 700 and 10,000.
  • the average molecular weight of the A block is between about 500 and 20,000 and is more preferably between about 700 and 15,000.
  • the hydrophilic B block segment is poly(ethylene oxide) (PEO) which is also referred to as (polyoxyethylene) or poly(ethylene glycol) (PEG) having an average molecular weight of between about 500 to 25,000 and is more preferably between about 1,000 and 10,000.
  • PEO poly(ethylene oxide)
  • PEG poly(ethylene glycol)
  • copolymers of this invention are amphiphilic diblock or triblock copolymers of the structure BA or BAB where B is a hydrophilic block and A is a hydrophobic bidodgradable block.
  • the diblock copolymers are synthesized by various methods.
  • the diblock copolymers may be synthesized by the ring opening polymerization of a cyclic monomer for the biodegradable hydrophobic A block, e.g. L-lactide from one end of a PEO block with or without the use of a catalyst.
  • the PEO is preferably a mono functional PEO of the formula:
  • X-(CH 2 CH 2 O)-Y-Z where X is a lower alkoxy group such as methoxy, ethoxy, etc. ; Y is a lower alkylene group such as methylene, ethylene, propylene, etc.; and Z is a functional group selected from the group consisting of hydroxyl (OH), amino (NIL), carboxyl (COOH), thiol (SH) and the like.
  • the cyclic monomer can be D,L-lactide, L-lactide), glycolide, D,L-lactide-co-glycolide), L-lactide-co-glycolide, e-caprolactone, ⁇ - butyrolactone, ⁇ -valerolactone, e-caprolactone-co-lactic acid, e-caprolactone-co-glycolic acid-co-lactic acid and the like.
  • stannous octoate When catalyzed, typical catalysts include stannous octoate, antimony oxide, tin chloride, aluminum isopropoxide, yttrium isopropoxide, sodium, potassium, potassium t-butoxide, sodium t-butoxide and the like. Typically stannous octoate will be used as the catalyst. Condensation Polymerization:
  • the diblock copolymers can also be synthesized by condensation polymerization of an ⁇ -hydroxy acid monomer at one end of a PEO block.
  • a monomer such as L-lactic acid, D,L-lactic acid, glycolic acid and the like is used.
  • Direct coupling of monofunctional PEO with monofunctional biodegradable hydrophobic blocks in the presence of coupling agents is another method in which the coupling agent may be present as a linkage in the copolymer.
  • Coupling agents such as a diisocyanate, e.g. hexamethylene diisocyanate (HMDI); 2,6-toluene diisocyanate; 1,6-toluene diisocyanate; 2,4-toluene diisocyanate; diphenyl methane- 4,4' diisocyanate; 3,3'-dimethyl diphenyl methane 4,4'-diisocyanate; (ortho, meta, para)phenylene diisocyanate and the like.
  • HMDI hexamethylene diisocyanate
  • 2,6-toluene diisocyanate 1,6-toluene diisocyanate
  • 2,4-toluene diisocyanate diphenyl me
  • activating agents such as carbonyl diimidazole, succinic anhydride, N-hydroxy succinimide, and p-nitrophenyl chloro formate may be utilized.
  • the triblock copolymers may be prepared by various means. Coupling of ⁇ -hydroxy acid A block with PEO blocks:
  • a difunctional biodegradable hydrophobic A block may be coupled with monofunctional PEO to form a BAB copolymer utilizing the coupling techniques mentioned above for the coupling of B and A blocks to form a diblock, e.g. by the use of diisocyanate (DIICN) coupling agents.
  • diblock copolymers can be coupled using the end functional group of biodegradable hydrophobic B (i.e. poly ( ⁇ -hydroxy acid), blocks according to the following schematic:
  • Triblock copolymers can also be prepared by ring opening polymerization of ethylene oxide at both ends of a biodegradable hydrophobic A block, e.g. poly ( ⁇ -hydroxy acid), or by sequential ring opening polymerization of cyclic monomers for the biodegradable hydrophobic block, e.g. L-lactide, followed by ethylene oxide (another cyclic monomer for PEO).
  • a biodegradable hydrophobic A block e.g. poly ( ⁇ -hydroxy acid)
  • cyclic monomers for the biodegradable hydrophobic block e.g. L-lactide
  • ethylene oxide another cyclic monomer for PEO
  • the B block is formed from appropriate molecular weights of hydrophilic poly(ethylene oxide) (PEO).
  • PEO was chosen as the hydrophilic water-soluble block domain because of its unique biocompatibility, nontoxicity, micelle forming properties, and rapid clearance from the body.
  • hydrophobic A blocks are synthesized and utilized because of their biodegradable and biocompatible properties.
  • the in vitro and in vivo degradation of these hydrophobic polymer blocks is well understood and the degradation products are natural metabolites that are readily eliminated by the body.
  • the molecular weight of the hydrophobic poly ( ⁇ -hydroxy acid) A blocks is regulated to retain desirable water-solubility and gelling properties. Also, the proportionate weight ratios of hydrophilic B block to the hydrophobic A block must also be sufficient to enable the block copolymer to possess good water solubility at the required concentrations at temperatures above body temperature. Generally, biodegradable block copolymers possessing desired thermal gelation properties are prepared wherein the hydrophilic B block makes up about 20 to 90% by weight of the copolymer and the hydrophobic A blocks makes up about 10 to 80% by weight of the copolymer.
  • the hydrophilic B block will make up between about 25 to 75 % by weight of the copolymer, and the hydrophobic biodegradable A block will also make up between about 25 to 75% by weight.
  • All resulting diblock and triblock copolymers should be soluble in aqueous solutions at functional concentrations. There is a minimum concentration for each copolymer for gelation, i.e. the gel/sol transition temperature, by lowering the temperature. Also, if concentrations are too high, aqueous solutions will be too viscous to inject parenterally. The only concentration parameter that is critical is that under which the polymer is functional. Therefore, the concentration at which the block copolymers are soluble at temperatures to be utilized for parenteral administration may be considered as the functional concentration. Generally speaking, block copolymer concentrations in the range of about 5 to 60% are in the functional range and concentrations in the range of between about 10 to 50% by weight are preferred. In order to obtain a viable phase transition of the polymer, a certain minimum concentration is required.
  • the mixture of the biodegradable polymer and bioactive agents or drugs may be prepared as an aqueous solution at a higher temperature than the gelation temperature of the polymeric material.
  • This system will cause minimal toxicity and mechanical irritation to the surrounding tissue due to the biocompatibility of the materials and will be completely biodegradable within a specific predetermined time interval.
  • the drug release from the polymeric matrix can be controlled by proper formulation of the various copolymer blocks.
  • the drug can make up between about 1 to 60 % by weight of the drug polymer combination with ranges of between about 5 to 30 % being preferred.
  • This invention is applicable to the delivery of any drug that is stable in the solution as prepared and that will release from the hydrogel matrix following administration. It would serve no useful purpose to attempt to catalog drugs as it will be readily apparent to those skilled in the art the type of drugs that can be used and minimal experimentation will be required to prove the viability of the invention as to any particular drug or class of drugs.
  • the invention may be particularly useful in the delivery of peptide or protein based drugs.
  • the invention may be useful in the delivery of a broad category of bioactive agents or drugs such as therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antidiarrheal, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness agents, antinauseants, antineoplastic, antiparkinsonism drugs, antipruritic, antipsychotic, antipyretics, antispasmodics including gastrointestinal and urinary, anticholinergic, sympathomimetic, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta- blockers, antiarrythmics, antihypertensives, diuretics, vasodilator including general coronary, peripheral and cerebral, central nervous system stimulants including cough and cold preparations, decongestants, diagnostic
  • the diblock BA copolymers consisting of PEO/PLLA were synthesized by ring opening polymerization of L-lactide (LLA) on monomethoxy poly(ethylene oxide) (PEO) according to the reaction scheme shown in Formula I:
  • the triblock BAB copolymers were synthesized by coupling the diblock BA copolymer of Formula I using hexamethylene diisocyanate (HMDI) as a coupling agent according to the reaction scheme shown in Formula II:
  • HMDI hexamethylene diisocyanate
  • hydrophilic B block can be prepared using various molecular weights of poly(L-lactic acid)
  • PLLA poly (ethylene oxide)
  • PEO poly (ethylene oxide)
  • BA copolymers were prepared wherein the A block had molecular weights of 720,
  • diblock copolymers including poly(ethylene oxide-DL-lactic acid)(PEO-PDLLA; poly(ethylene oxide-(DL-lactic acid-co-glycolic acid)), (PEO-PDLLA; poly(ethylene oxide-(DL-lactic acid-co-glycolic acid)), (PEO-PDLLA)
  • a BA Di-block ((PEO-PLLA-OH), MW: 5000-2560) was added to 200 ml of dried toluene. Residual water was removed by azeotropic distillation to a final volume of 70 ml. HMDI (55.59 mg) and stannous octoate (5.356 mg) were added to the solution, stirred at 60°C for 12 hours and then gently refluxed for 6 hours under a dry nitrogen atmosphere. The resulting triblock copolymers were purified by fractional precipitation of the copolymers out of methylene chloride using diethyl ether. The coupling reaction was monitored by GPC. The yield of triblock copolymer after fractional precipitation was 50% . The copolymers were stored in a refrigerator under nitrogen gas. Other triblock copolymers were synthesized by the same method.
  • the resulting triblock copolymers consisted of two B (PEO) blocks having a molecular weight of 5000 each and a central A (PLLA) block having molecular weights of 2040, 3000 and 5000 respectively.
  • All block copolymers shown in Table 1 were soluble in water at the stated concentrations above the gel/sol transition temperature shown. Initially, the polymers were dissolved in distilled water at an elevated temperature at the stated concentrations and placed in a tightly sealed 4 ml vial. The vials were cooled below the gelation temperature and stored at 4°C for 12 hours. The gel/sol transition temperature was defined by the gel melting temperature. The gels were equilibrated for 20 minutes at a given temperature in a water bath. Gel melting was measured by increasing the temperature 2° C/step. A gel was defined as having no flow in one minute after rotating 90° in the bath. All gels showed thermosensitivity and the gel/sol phase transition occurred within a narrow temperature range.
  • Transition temperatures and concentrations shown in Table 1 are approximations extrapolated from graphs showing gel/sol transition curves plotting temperature vs. concentration but are sufficient to demonstrate the influence of molecular weight of A and B blocks, relative amount of A vs. B block content and concentration of copolymers on the gel/sol transition temperature.
  • PEO A PLAA Aqueous solutions of diblock BA (PEO-PLAA) and triblock (PEO-PLLA-
  • PEO copolymers formed micelles at low concentrations and became gels above a certain concentration.
  • the micelle packing is thought to be the mechanism of gelation for these block copolymers.
  • the above described copolymers form a gel at lower temperatures and become a sol at higher temperatures. In other words, they do not exhibit reverse thermal gelation but follow a more traditional route in that they form solutions at higher temperature and solidify or gel as the temperature is lowered.
  • the sol/gel transition temperature can be easily manipulated as shown in Table 1.
  • the gel/sol transition can be shifted toward higher concentrations.
  • Selected block copolymers i.e.
  • a solvent-free (i.e. no organic solvent) injectable system can be designed as a controlled drug carrier.
  • This system has numerous advantages over common drug delivery systems.
  • the formulation is simple and requires no organic solvent.
  • the designed matrix if desired, can be stored at or below room temperature as a dry, solid dosage form before administration. Also, there is no requirement for a surgical procedure for implantation.
  • the system is biodegradable and possesses the typical advantages of hydrogels, e.g., little or no tissue irritation and improved biocompatability.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
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Abstract

Système et procédé servant à administrer par voie parentérale un médicament contenu dans une matrice polymère biodégradable à un animal à sang chaud, sous forme de liquide aqueux provoquant un dépôt d'hydrogel permettant d'effectuer la libération contrôlée du médicament. Ce système est composé d'un copolymère bloc sous forme liquide biodégradable et injectable servant à administrer le médicament. Ce copolymère possède une température de transition de gel à sol, de façon à constituer une solution, au-dessus de la température du corps de l'animal auquel on l'administre, et à constituer un hydrogel quand on l'administre et qu'on le refroidit à la température du corps. Ce copolymère est constitué par (i) un polymère bloc A hydrophobe de poly(α-hydroxy acide) et par (ii) un polymère bloc B hydrophile contenant un oxyde de polyéthylène. Le médicament est libéré à une vitesse contrôlé depuis le copolymère qui se dégrade biologiquement en produits non toxiques. On peut régler la température de transition de gel à sol et la vitesse de dégradation par sélection adéquate du poids moléculaire et de la concentration des constituants du polymère bloc de poly(α-hydroxy acide) et d'oxyde de polyéthylène.
EP98940801A 1997-08-08 1998-08-08 Copolymeres blocs en gels injectables et biodegradables servant a administrer un medicament Withdrawn EP1024790A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US5517497P 1997-08-08 1997-08-08
US55174P 1997-08-08
US13096798A 1998-08-07 1998-08-07
US130967 1998-08-07
PCT/US1998/016418 WO1999007343A1 (fr) 1997-08-08 1998-08-08 Copolymeres blocs en gels injectables et biodegradables servant a administrer un medicament

Publications (2)

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EP1024790A1 true EP1024790A1 (fr) 2000-08-09
EP1024790A4 EP1024790A4 (fr) 2000-10-25

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EP (1) EP1024790A4 (fr)
JP (1) JP2001517603A (fr)
KR (1) KR20010022708A (fr)
CA (1) CA2299393A1 (fr)
WO (1) WO1999007343A1 (fr)

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KR20010022708A (ko) 2001-03-26
EP1024790A4 (fr) 2000-10-25

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