WO1992004891A1 - Preparation microencapsulee a liberation prolongee et sa production - Google Patents

Preparation microencapsulee a liberation prolongee et sa production Download PDF

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Publication number
WO1992004891A1
WO1992004891A1 PCT/JP1991/001224 JP9101224W WO9204891A1 WO 1992004891 A1 WO1992004891 A1 WO 1992004891A1 JP 9101224 W JP9101224 W JP 9101224W WO 9204891 A1 WO9204891 A1 WO 9204891A1
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Prior art keywords
substance
emulsion
particle size
aqueous solution
acid
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Application number
PCT/JP1991/001224
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English (en)
Japanese (ja)
Inventor
Masayuki Arakawa
Takashi Uchio
Yasushi Sato
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication date
Application filed by Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Publication of WO1992004891A1 publication Critical patent/WO1992004891A1/fr
Priority to KR1019930700774A priority Critical patent/KR100202073B1/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a micro-powered capsule which is administered to warm-blooded mammals such as humans, horses, cattle, etc., and gradually releases encapsulated physiologically active substances in the body of these warm-blooded mammals over a long period of time.
  • the present invention relates to a release preparation and a method for producing the same.
  • bioactive substances that require long-term administration, they are encapsulated in a micro-mouth capsule, and the bioactive substance encapsulated in the microcapsules is gradually released, thereby improving the efficacy of the bioactive substance. Improvements in sustainability have been made, and various methods for microencapsulating bioactive substances in this way have been proposed.
  • Japanese Patent Publication No. 1-57,087 discloses that when a WZO .ZW type emulsion is formed and a microcapsule is produced by an underwater drying method, the water-soluble drug and the drug-retaining substance are prepared.
  • 62-201,816 discloses that the viscosity of a W / 0 emulsion is reduced by 150% when a WZO / W emulsion is formed and a ⁇ -force microphone is produced by a water drying method.
  • 2-124, 814 The gazette discloses that by adding a basic drug-retaining substance to an inner aqueous layer containing a water-soluble drug, microcapsules with a low initial burst can be obtained efficiently.
  • JP-B-63-36,290 discloses a process of dissolving or dispersing an active agent such as a biologically active agent in a shell material in a solvent, and disposing the obtained suspension or solution in the solvent.
  • Disclosed is a method for producing a microforce cell that can be obtained.
  • any of the above methods has a problem that the obtained micro force cell not only has a large particle size, but also is irregular and has a wide particle size distribution.
  • “suspension properties” are described in section (4) of “16.
  • the particles in the injection solution are usually set to 150 or less, and it is necessary to perform a sorting and sizing operation using a sieve to a particle size of 150 or less. Not only significantly lowers the yield of the product, but also is an extremely cumbersome operation in itself, and must be performed in a sterile and dust-free atmosphere because it is used as a medical injection. Cause cost up Therefore, solving this point has been a serious issue in industrial production.
  • an object of the present invention is to provide a micro-mouth capsule-type sustained-release preparation having a fine and uniform particle size that does not require a sorting and sizing operation, and a method for producing the same.
  • Another object of the present invention is to provide a microcapsule-type sustained-release preparation capable of achieving a high incorporation rate of a physiologically active substance to be included therein into a microcapsule, and a method for producing the same. .
  • Another object of the present invention is to provide a good micro-mouth regardless of the concentration of an aqueous solution of a physiologically active substance as an inclusion substance or the concentration of an organic solvent solution of a biocompatible polymer substance as an outer shell substance.
  • the present invention provides a microcell-based sustained-release preparation capable of producing a capsule-type sustained-release preparation, whereby the release rate of a physiologically active substance can be appropriately changed, and a method for producing the same. And there.
  • the present invention has an inclusion having a bioactive substance and an outer shell material formed of a biocompatible polymer substance having biodegradability and / or tissue compatibility in vivo, and has a maximum particle size. 1 5 0 or less It is a microforced sustained-release preparation having an average particle diameter of 5 to 100 and a coefficient of variation of 50% or less.
  • the present invention also provides a W0-type emulsion comprising an aqueous solution containing a physiologically active substance and an organic solvent solution containing a biocompatible polymer substance having biodegradability and / or histocompatibility in vivo. Then, the W / 0 emulsion and the aqueous solution of a water-soluble polymer substance are subjected to secondary emulsification to prepare a W0 / W emulsion, and the organic solvent is evaporated from the obtained wzo zw emulsion, The secondary emulsification step described above is used to prepare a micro-alpha capsule-type sustained-release preparation containing a bioactive substance as an inclusion substance and a biocompatible polymer substance as an outer shell substance by solidifying, further washing and drying. This is a process for producing a microcapsule-type sustained-release preparation in which a salt substance having a concentration of 0.1% or saturation is present in the outer aqueous layer.
  • the physiologically active substance to be included in the micro force cell is not particularly limited as long as it has excellent hydrophilicity and is soluble in water, and is not particularly restricted by pharmacological action or the like.
  • physiologically active substances are the microforced sustained-release preparations of the present invention, which have a fine and uniform particle size, and are particularly suitable for injection preparations without the necessity of fractionating and sizing. Is possible Therefore, they are proteins, polypeptides and their derivatives that need to be injected and need to be administered over a relatively long period of time.
  • Slovodin EP type
  • G-CSF granulocyte colony stimulating factor
  • M-CSF macrophic zico oral knee stimulating factor
  • GM-CSF granulocyte Mac phagocylonic stimulating factor
  • IFN interferon
  • IFN interleukin
  • IL-1 interleukin
  • IL-2 interleukin
  • IL-3 interleukin
  • IL-4 interleukin
  • TNF tumor death factor
  • GH or STH growth hormone
  • insulin calcitonin
  • CT calcitonin
  • These physiologically active substances may be of natural origin extracted and purified from animals such as mammals, fish, birds, and other plants, or may be obtained by means of genetic recombination, synthesis, semi-synthesis, etc. May be manufactured.
  • physiologically active substances may be used alone, or two or more of them may be used in combination, if necessary.
  • the physiologically active substance differs depending on the type and properties of the substance, or is usually contained in a ⁇ -capsule in the range of 0.01 to 50% by weight.
  • biocompatible macromolecule material used as the outer shell material of the microcapsule used in the present invention is biodegradable or biocompatible, and can be used in humans, horses, cows, and other living organisms. Any substance can be used as long as it is decomposed or taken into tissues when it enters, and any substance can be used.
  • biodegradable biocompatible high molecular substances include, for example, polylactic acid. Polyglycolic acid, polytaenoic acid, polylingic acid, polylactic acid glycolic acid copolymer, etc.
  • Polyalkylene oxalates such as methylene oxide, polyorthoesters, polycarbonates such as polyorthocarbonate and polyethylenecarbonate, and poly- ⁇ "-benzyl-L-glutamic acid And polyamino acids such as poly-L-alanine, etc.
  • biocompatible high-molecular-weight biocompatible materials that are biocompatible include, for example, polystyrene, polyacrylic acid, polymethacrylic acid, styrene, and styrene.
  • Copolymer of acrylic acid and methacrylic acid copolymer of acrylic acid and methacrylic acid, copolymer of acrylic acid and methacrylic acid, nylon, tetron, polyamino acid, silicone Copolymer, polyurethane, polybutyl acetate, polyvinyl alcohol, polyacrylamide, ethylene-vinyl acetate copolymer, maleic anhydride copolymer, dextran stearate Examples thereof include ethyl cellulose, acetyl cellulose, nitrocellulose, etc.
  • biocompatible high-molecular substances may be used alone or in combination of two or more as necessary.
  • particularly preferred biocompatible polymer substances are biodegradable biodegradable capsules of the present invention, which are particularly suitable for injection.
  • Biocompatible polymer substances especially fatty acid esters such as polylactic acid, polylactic acid, polycunic acid, polylingic acid, and polylactic glycolic acid copolymer
  • the average molecular weight of these biocompatible polymer substances is preferably about 1,000 to 200,000, and more preferably about 1,000 to 200,000. It is in the range of 2,000 to 100,000.
  • the biocompatible polymer substance is used depending on the type and the like, but is usually used in a microcapsule in an amount of 20 to 99% by weight, preferably 40 to 95% by weight.
  • a water-soluble stabilizer or excipient may be used, if necessary, for the purpose of ensuring the stability of the above-mentioned physiologically active substance, or increasing the amount of this physiologically active substance to facilitate handling.
  • shapeing agent can be encapsulated in microcapsules.
  • stabilizers used for this purpose include proteins such as albumin and gelatin; amino acids such as glycine, arginine, histidine, lysine, glutamic acid, and aspartic acid; Salts, surfactants such as sorbitan fatty acid ester, polyoxyethylene fatty acid ester, and dalyserine fatty acid ester; chelating agents such as ethylenediaminetetraacetate and citric acid; and darcose and sucrose. And sugars such as fructose, trehalose, dextrin, dextran, mannitol and sorbitol, and sugar alcohols.
  • excipients include natural water-soluble gums such as arabic gum and xanthan gum, and natural water-soluble gums such as casein, gelatin, collagen, albumin, cellulose, starch, and agar.
  • examples include a high molecular compound and a synthetic water-soluble high molecular compound such as lipoxymethylcellulose and polysaccharide. The amount of these stabilizers and excipients used is determined depending on the type and purpose thereof, but is usually about 0 to 500% based on the biocompatible polymer.
  • a WZO-type emulsion is prepared from an aqueous solution and an organic solvent solution of a biocompatible polymer, and when the W0-type emulsion is secondarily emulsified with an aqueous solution of a water-soluble polymer, the outer aqueous layer is formed.
  • a WZO-no W-type emulsion is prepared, and a physiologically active substance is included from the obtained W / OZW-type emulsion.
  • microcapsule containing a molecular substance as an outer shell substance
  • the obtained microcapsule has a maximum particle size of 150 or less, usually 75 or less, and a more preferable form is 30 or less
  • the average particle size is 5 to 100, usually 5 to 25, and more preferably in the range of 5 to 15 / m
  • the coefficient of variation is 50% or less. It can be used as it is without injection.
  • the maximum particle size is affected by the conditions of emulsification and the concentration of the solution, and may be around 150 depending on these conditions.
  • the maximum particle size is obtained by calculating the particle size of the largest particle in one lot
  • the average particle size is obtained by calculating the average value of 500 particle sizes
  • the coefficient of variation is (standard deviation) ⁇ (Average particle size) It is a value obtained by calculating from the formula of X100.
  • microcapsule-type sustained-release preparation of the present invention is produced by the following method.
  • a biocompatible polymer substance is dissolved in an organic solvent to prepare an organic solvent solution.
  • the organic solvent used for this purpose may be any solvent which has a relatively low boiling point, is immiscible with water, and dissolves a biocompatible polymer.
  • the concentration of the biocompatible polymer substance in the organic solvent solution can be appropriately changed depending on the type of the biocompatible polymer substance to be used, but is usually 0.5 to 50% by weight, preferably It is about 1 to 40% by weight.
  • the above-mentioned physiologically active substance and a water-soluble stabilizing agent or excipient added as necessary are dissolved in predetermined water to prepare an aqueous solution thereof.
  • a pH adjuster is added as necessary for the purpose of maintaining its stability and solubility.
  • PH regulators used for this purpose include, for example, acids such as sulfuric acid, citric acid, acetic acid, and carbonic acid, and sodium and calcium salts thereof, and various buffers such as a phosphate buffer. Liquids can be mentioned.
  • the amount of use of these pH adjusters is not particularly limited, but is usually about several tens of mM concentration.
  • the aqueous solution of the physiologically active substance prepared in this manner is added to the organic solvent solution of the biocompatible polymer substance under high-speed stirring to prepare a WZO type emulsion.
  • the stirring speed at this time is usually 1,000 to 30,000 rpm, preferably 5,000 to 28,000 rPm, and the emulsification temperature is about -100 to 40, preferably about -50 to 20. Is good.
  • the WZO-type emulsion thus prepared is then mixed with a prepared aqueous solution of a water-soluble polymer substance in the presence of a salt substance having a concentration of 0.1 M to a saturation concentration in the outer aqueous layer, It is secondarily emulsified into a W / 0 emulsion.
  • water-soluble polymer used in the secondary emulsification step examples include polyvinyl alcohol (PVA), polyvinylpyrrolidone carboxymethyl senorelose sodium, gelatin, chitin and its derivatives, xanthonone and Derivatives, hyaluronic acid and its sodium salts, dextran, pectin, chondroitin sulfate and its sodium salts, and the like can be mentioned. In addition to being used alone, two or more can be used as a mixture.
  • concentration of the water-soluble polymer substance in the aqueous solution is usually in the range of 0.05 to 5.0% by weight, preferably in the range of 0.1 to 2.0% by weight.
  • the salt substance to be present in the outer water layer during the secondary emulsification is an emulsion formed at the interface between the previously prepared WZO emulsion and the outer water layer.
  • Any material can be used as long as it can improve the stability and suppress the swelling of the biocompatible polymer substance, and is not particularly limited.
  • sodium acetate sodium citrate
  • various inorganic acid salts such as sodium chloride, potassium chloride, calcium chloride, sodium sulfate, sulfuric acid potassium, and the like. Examples thereof include ammonium salts such as ammonium sulfate, and quaternary amine salts such as link mouth ride and tetramethylammonium chloride.
  • These salt substances are usually present in the outer water layer in the range of 0.1 M concentration to the saturation concentration, preferably in the range of 0.5 M concentration to the saturation concentration, and more preferably in the range of 0.1 M concentration to the saturation concentration. If the concentration is low, the problem of bursting occurs, and if the concentration is higher than the saturation concentration, the problem of embedding of salt occurs. And the method of making this salt substance exist in the outer water layer For the wzo / w-type emulsion to be prepared in the secondary emulsification step, it only needs to be present in the outer water layer as a result, and it may be added to an aqueous solution of a water-soluble polymer in advance. Also, it may be added separately when the W / 0 emulsion is mixed with an aqueous solution of a water-soluble polymer substance.
  • the W / 0 / W type emulsion thus prepared is then stirred at room temperature or at 0 to 50 ° C, preferably at 0 to 25, to evaporate the organic solvent.
  • the biocompatible polymer material of the outer shell material is solidified to generate micro force cells.
  • microcapsules are separated by means such as centrifugation or filtration, washed and dried if necessary. Thereafter, if necessary, the dispersion is re-dispersed in an aqueous solution containing an appropriate excipient such as mannitol, and dried by freeze-drying or the like to remove the residual organic solvent. Produces a micronized capsule-type sustained-release preparation with excellent dispersibility.
  • microcapsules obtained as described above have a maximum particle size of 150 or less and an average particle size of 5 to 100, and a coefficient of variation of 50% or less. In particular, it can be used as an injection as it is, without performing a sorting and sizing operation.
  • the microcapsule-type sustained-release preparation of the present invention can be used for injections, powders, granules, tablets, tablets, etc., depending on the pharmacological action of a physiologically active substance contained as an inclusion in the microcapsules for therapeutic purposes.
  • a physiologically active substance contained as an inclusion in the microcapsules for therapeutic purposes can be formulated into any dosage form such as suppositories, it has a fine and uniform particle size and has needle penetration and redispersibility as it is without the need for sorting and sizing. It is suitable as an injection.
  • the microcapsule-type sustained-release preparation of the present invention has a fine and uniform particle size.
  • a salt substance having a concentration of 0.1% or more is present in the outer water layer.
  • the properties of the interface between the WZO-type emulsion and the aqueous solution of a water-soluble polymer are improved, and as a result, a microcellular sustained-release preparation having a fine and uniform particle size is obtained. It is considered to be obtained.
  • FIG. 1 is a graph showing the time-dependent change in the rEPO content of the rEPO-owned microcapsule obtained in Example 1. [Best mode for carrying out the invention]
  • rEPO Genetically modified human erythropoietin 1 rag and two high-grade gelatin type B (manufactured by Nitsubishi, Al-treated gelatin with an average molecular weight of about 7,000) 40ni of 1 ffig It was dissolved in water for injection and sterile-filtered through a membrane filter with a pore size of 0.22 (manufactured by Nippon Millipore Limited: Mylex GV) to obtain an aqueous solution of a physiologically active substance.
  • rEPO Genetically modified human erythropoietin
  • the dispersion containing the W / 0 / W type emulsion is gently stirred at room temperature to volatilize the remaining methylene chloride, and the polylactic acid-glycolic acid is removed. After solidification of the polymer, microcapsules generated by centrifugation at 3,000 rpm for 10 minutes were collected.
  • microforce obtained in this manner was dispersed again in water for injection, and the operation of centrifugation was repeated 5 times, so that polybutyl alcohol, sodium chloride and free water were released into the outer water layer.
  • the obtained rEP0, polylactic acid-glycolic acid copolymer was washed.
  • microcapsules finally collected were redispersed in 5% aqueous mannitol solution 5 and then freeze-dried. The above steps were all performed aseptically and dustlessly.
  • the maximum particle size of the rEPO0 Municipal Mikuguchi capsule obtained in this way was 15, the average particle size was 8.0, and the coefficient of variation was 40%. Also, the uptake rate of rEPO was about 95%.
  • the r EP 0 microcapsule obtained in Example 1 above was dispersed in a 50 mM monophosphate buffer (pH 7.4) containing 0.05% of Tween 20 in a rotary culture machine. (Taiyo scientific industrial ⁇ : KT - 50) using, in O thermostatic bath Te 37 and invert rotated at 25 r P ⁇ - After a predetermined time, the dispersion was subjected to centrifugation (3,000 rpm, 10 minutes) to collect microcapsules.
  • the amount of r EPO in the microcapsules was adjusted by dissolving the collected microcapsules with 1 rag of acetonitrile and then adjusting the total volume to lOfflg with 50 mM phosphate buffer. It was quantified by liquid chromatography (HPLC).
  • the solution was aseptically filtered through a 0.22 membrane filter to obtain an aqueous solution of a physiologically active substance.
  • the aqueous solution was dropped into the organic solvent solution under stirring (28,000 rpm) with a homogenizer, and further stirred and mixed at the same rotation speed for 30 seconds to obtain a WZO-type emulsion.
  • the above-mentioned WZO-type emulsion was added to 0.5% -polyvinyl alcohol aqueous solution 200, and the mixture was stirred and mixed at a speed of 10,000 rpm for 30 seconds to form a W / 0 / W-type emulsion. Thereafter, in the same manner as in Example 1 above, rEPO0 microcapsules were obtained.
  • the r EPO house-owned microcapsules obtained in this way are Had a maximum particle size of 40, an average particle size of 22%, and a coefficient of variation of 45%.
  • the uptake rate of rEP0 was about 80%.
  • the aqueous solution was dropped into the organic solvent solution under stirring (28,000 rpm) with a homogenizer, and the mixture was further stirred and mixed at the same rotation speed for 30 seconds to obtain a WZO-type emulsion.
  • the above-mentioned W0 type emulsion was added to a 0.5% aqueous solution of 0.5% polybutylpyrrolidone containing 1M sodium sulfate, which had been previously ice-cooled separately, and added at a speed of 10,000 rpm for 30 minutes.
  • the mixture was stirred and mixed for 2 seconds to produce a W / 0 ZW type emulsion.
  • rG—CSF microcapsules were obtained.
  • the obtained rG—CSF-containing microcapsule capsule had a maximum particle size of 50, an average particle size of 20, and a coefficient of variation of 40%.
  • the uptake rate of rG—CSF was about 90%.
  • the above-mentioned WZO-type emulsion was added to 200 ml of 0.5% -rubiximetyl cell ⁇ -sodium sodium water solution containing 1 M ammonium sulfate, which had been separately ice-cooled, and the speed was increased to 10,000 rpm. For 30 seconds to form a WZOZW emulsion. Thereafter, r EPO microcapsules were obtained in the same manner as in Example 1 above. The obtained r ⁇ ⁇ ⁇ ⁇ ⁇ 0 micro-capsule has the largest particle size.
  • the average particle size was 55 and the coefficient of variation was 48%.
  • the uptake rate of r r ⁇ 0 was about 95%.
  • a 1M-chlorinated reamer which has been separately ice-cooled, is set up. 0. ⁇ % —200 gelatin aqueous solution of purified gelatin in the Japanese Pharmacopoeia.
  • the above-mentioned W / 0 emulsion is added, and ⁇ , ⁇ pm
  • the mixture was stirred and mixed at the speed described above for 30 seconds to form a W / 'OZW type emulsion.
  • microcapsules containing rG—CSF were obtained.
  • the obtained rG-CSF microcapsule had a maximum particle size of 60, an average particle size of 25, and a coefficient of variation of 44%.
  • the uptake rate of rG—CSF was about 90%.
  • the obtained r E P 0 ⁇ own microcapsule has the maximum particle size.
  • a solution of a biocompatible polymer substance in an organic solvent was obtained.
  • 1 ng of rPO and 40 m of Nibbi Greater Gelatin Type B were dissolved in 1 i of water for injection in the Japanese Pharmacopoeia, and sterile-filtered through a membrane filter with a pore size of 0.22 to obtain an aqueous solution of a physiologically active substance.
  • the above aqueous solution was dropped into the above organic solvent solution under stirring (28,000 rpm) with a homogenizer, and the mixture was further stirred and mixed at the same rotation speed for 30 seconds to obtain a WZ0 type emulsion.
  • each of the WZ0 emulsions was added to 200% of a 0.5% aqueous solution of sodium borohydride containing sodium chloride of various concentrations, which had been previously ice-cooled separately, and the emulsion was added at a speed of 10,000 rpm. After stirring and mixing for 2 seconds, a WZ0ZW type emulsion was formed.
  • the dispersion containing these WZOZW-type emulsions was gently stirred at room temperature to volatilize the remaining methylene chloride and solidify the polylactic acid-glycolic acid copolymer. Thereafter, microcapsules generated by centrifugation at 3,000 rpm for 10 minutes were collected.
  • microcapsules thus obtained were dispersed again in water for injection, and the operation of centrifugation was repeated 5 times to remove the boryl alcohol, sodium chloride and the sodium chloride in the outer water layer.
  • r EPO polylactic acid glycolic acid copolymer was washed.
  • microcapsules finally collected were redispersed in 5% aqueous mannitol solution 5 and then freeze-dried.
  • the presence of a predetermined concentration of a salt substance in the outer water layer when a wzozw type emulsion is produced allows the particle size to be fine and fine without the need for viscosity adjustment and sorting and sizing. Uniform micro force can be produced, which is industrially advantageous.
  • the micro-force Busel-type sustained-release preparation comprising the physiologically active substance of the present invention and the biocompatible polymer produced by this method has excellent sustained-release properties, and can be administered by a single administration. The drug effect of the physiologically active substance can be exhibited over a long period of time.

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  • Engineering & Computer Science (AREA)
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Abstract

Préparation microencapsulée à libération prolongée comprenant une substance physiologiquement active constituant le noyeau ainsi qu'un polymère biocompatible pouvant se décomposer in vivo et/ou compatible avec les tissus in vivo et constituant l'enveloppe, ladite préparation étant produite à partir d'un émulsion W/O/W dont la confection consiste premièrement à préparer une émulsion W/O à partir d'une solution aqueuse de la substance physiologiquement active ainsi qu'une solution du polymère biocompatible dans un solvant organique, puis à procéder à une émulsification secondaire entre l'émulsion W/O et une solution aqueuse d'un polymère soluble dans l'eau en présence d'une substance contenant des sels avec une concentration de 0,1 M ou concentration de saturation dans la poche d'eau extérieure. La microcapsule a un diamètre particulaire maximum de 150 νm ou moins, un diamètre particulaire moyen compris entre 5 et 100 νm, ainsi qu'un coéfficient de variation du diamètre particulaire de 50 % ou moins, de sorte qu'on peut l'utiliser comme injection sans qu'il faille procéder à un fractionnement particulaire et un ajustement de la grosseur des particules.
PCT/JP1991/001224 1990-09-14 1991-09-13 Preparation microencapsulee a liberation prolongee et sa production WO1992004891A1 (fr)

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KR1019930700774A KR100202073B1 (ko) 1990-09-14 1993-03-13 마이크로캡슐형 서방성 제제 및 그의 제조법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP24278390A JPH04124127A (ja) 1990-09-14 1990-09-14 マイクロカプセル型徐放性製剤及びその製造法
JP2/242783 1990-09-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025221A1 (fr) * 1992-06-11 1993-12-23 Alkermes Controlled Therapeutics, Inc. Systeme d'apport de medicament sous forme d'erythropoietine
EP0582459A3 (en) * 1992-08-07 1994-06-29 Takeda Chemical Industries Ltd Production of microcapsules of water-soluble drugs
US5599583A (en) * 1994-05-27 1997-02-04 Micro Flo Company Encapsulation with water soluble polymer
GB2316316A (en) * 1996-08-23 1998-02-25 Int Centre Genetic Eng & Bio Sustained release of erythropoietin from microspheres
JP2008184468A (ja) * 1995-03-10 2008-08-14 Roche Diagnostics Gmbh 微粒子の形のポリペプチド含有投薬形

Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
JP4234803B2 (ja) * 1997-10-27 2009-03-04 久光製薬株式会社 薬物放出速度が制御された医薬組成物
DE69911110T2 (de) * 1998-04-23 2004-04-08 Dainippon Ink And Chemicals, Inc. In Wasser selbstdispergierbares Teilchen aus bioabbaubarem Polyester und Verfahren zu seiner Herstellung
CA2407472A1 (fr) * 2000-06-14 2002-10-23 Takeda Chemical Industries, Ltd. Compositions a liberation continue

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JPS4912024A (fr) * 1972-05-18 1974-02-02
JPS4933738B1 (fr) * 1969-01-16 1974-09-09
JPS5094112A (fr) * 1973-12-06 1975-07-26
JPS5793912A (en) * 1980-10-06 1982-06-11 Sutooru Research Ando Dev Corp Manufacture of microcapsule
JPS62201816A (ja) * 1985-02-07 1987-09-05 Takeda Chem Ind Ltd マイクロカプセルの製造法
JPS63233926A (ja) * 1986-08-08 1988-09-29 Takeda Chem Ind Ltd ペプチド含有マイクロカプセルおよびその製造法

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JPS4933738B1 (fr) * 1969-01-16 1974-09-09
JPS4912024A (fr) * 1972-05-18 1974-02-02
JPS5094112A (fr) * 1973-12-06 1975-07-26
JPS5793912A (en) * 1980-10-06 1982-06-11 Sutooru Research Ando Dev Corp Manufacture of microcapsule
JPS62201816A (ja) * 1985-02-07 1987-09-05 Takeda Chem Ind Ltd マイクロカプセルの製造法
JPS63233926A (ja) * 1986-08-08 1988-09-29 Takeda Chem Ind Ltd ペプチド含有マイクロカプセルおよびその製造法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025221A1 (fr) * 1992-06-11 1993-12-23 Alkermes Controlled Therapeutics, Inc. Systeme d'apport de medicament sous forme d'erythropoietine
EP0582459A3 (en) * 1992-08-07 1994-06-29 Takeda Chemical Industries Ltd Production of microcapsules of water-soluble drugs
US5611971A (en) * 1992-08-07 1997-03-18 Takeda Chemical Industries, Ltd. Production of microcapsules of water-soluble drugs
US5599583A (en) * 1994-05-27 1997-02-04 Micro Flo Company Encapsulation with water soluble polymer
JP2008184468A (ja) * 1995-03-10 2008-08-14 Roche Diagnostics Gmbh 微粒子の形のポリペプチド含有投薬形
GB2316316A (en) * 1996-08-23 1998-02-25 Int Centre Genetic Eng & Bio Sustained release of erythropoietin from microspheres

Also Published As

Publication number Publication date
JPH04124127A (ja) 1992-04-24
KR100202073B1 (ko) 1999-06-15
AU8491291A (en) 1992-04-15

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