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WO2000040259A1 - Microsphere a liberation prolongee utilisee pour encapsuler des analogues de la luteoliberine, et son procede de production - Google Patents

Microsphere a liberation prolongee utilisee pour encapsuler des analogues de la luteoliberine, et son procede de production Download PDF

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Publication number
WO2000040259A1
WO2000040259A1 PCT/KR1999/000071 KR9900071W WO0040259A1 WO 2000040259 A1 WO2000040259 A1 WO 2000040259A1 KR 9900071 W KR9900071 W KR 9900071W WO 0040259 A1 WO0040259 A1 WO 0040259A1
Authority
WO
WIPO (PCT)
Prior art keywords
microsphere
release
releasing hormone
luteinizing hormone
set forth
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.)
Ceased
Application number
PCT/KR1999/000071
Other languages
English (en)
Inventor
Myoung Ki Baek
Jin Kyu Park
Mork Soon Park
Tae Kwan Park
Seung Ho Choi
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.)
Dong Kook Pharmaceutical Co Ltd
Original Assignee
Dong Kook Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dong Kook Pharmaceutical Co Ltd filed Critical Dong Kook Pharmaceutical Co Ltd
Priority to MXPA01005540A priority Critical patent/MXPA01005540A/es
Priority to BR9916945-2A priority patent/BR9916945A/pt
Priority to CA002358495A priority patent/CA2358495A1/fr
Priority to JP2000592014A priority patent/JP2002534392A/ja
Publication of WO2000040259A1 publication Critical patent/WO2000040259A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • the present invention relates to a microsphere encapsulating luteinizing hormone-releasing hormone (hereinafter referred to as "LHRH”) analogues, which is able to constantly release them for a long period of time. Also, the present invention is concerned with a method for preparing such a prolonged release microsphere.
  • LHRH luteinizing hormone-releasing hormone
  • GnRH gonadotropin-releasing hormone
  • LHRH analogues act on the pituitary gland to inhibit the secretion of LH, thus resulting in the antagonizing of the liberation of testosterone and estrogen into the bloodstream.
  • the diseases caused by testosterone and estrogen such as prostatic cancer, breast cancer, endometriosis and the like, have recently been therapeutically treated.
  • LHRH is, however, very instable within the gastro-intestinal tract and shows a low uptake efficiency therein. Therefore, the administration of LHRH has been usually performed via injection.
  • the administration via injection also has a significant disadvantage of being very poor in bioavailibility so that LHRH is required to be injected daily.
  • Such injection administration also requires a long cure period, which causes a problem in a patient's adaptation to the drug, therapeutic efficiency, and treatment.
  • PLGA poly(lactide-co- glycolide)
  • PLGA poly(lactide-co- glycolide)
  • the released form and structural stability of proteins with high molecular weights are the most difficult barriers in commercializing them into medicinal drugs.
  • research efforts have been and continue to be directed to the development of various additives and new preparation processes by which the proteins can be commercialized while maintaining their activity.
  • microspheres made of PLGA are decomposed into lactic acid and glycolic acid by hydrolysis in the body and metabolized.
  • PLGA is not harmful to the human body nor shows side effects from the decomposed products.
  • the microspheres made of PLGA can release their contents, e.g. therapeutically effective ingredients, at a constant rate for a desired period of time.
  • U.S. Pat. No. 4,711,782 introduces a technique for producing microporous microcapsules from similar polymers by W/OAV (water in oil in water) double emulsification.
  • This technique is usually used to capsulate water-soluble drugs.
  • gelatin is used together to retain the drug, and this aqueous layer is dispersed in an organic layer containing the polymer with the aid of a homogenizer, so as to give a primary emulsion.
  • this primary emulsion is dispersed in water containing polyvinyl alcohol as a surfactant, to give a secondary emulsion.
  • the organic solvent is diffused into the aqueous layer and evaporated, so that the polymer is solidified to form the microcapsules. They are then freeze- dried.
  • the negative charge of the carboxyl group attached to the end of the biodegradable polymer form an ion bond with the positive charges that the peptide drugs possess, increasing the drug content in the microsphere and preventing the drugs from being released excessively at an initial time due to diffusion.
  • the dodecyl group plays an important role in controlling the degradation rate of the microsphere. Consequently, the microspheres in the body release LHRH analogues continuously to maintain the concentration of testosterone and estrogen in blood for an extended period of time, so as to improve the therapeutic efficiency of and the patient's adaptation to the drugs. Therefore, it is an object of the present invention to provide a prolonged release microsphere which can control the release of drugs for a sustained period of time.
  • a prolonged released microsphere which is composed of a poly(lactide-co-glycolide) copolymer and encapsulate a luteinizing hormone-releasing hormone analogue.
  • a method for preparing a prolonged release microsphere comprising the steps of: dissolving a copolymer of lactide and glycolide in methylene chloride; dissolving a luteinizing hormone-releasing hormone analogue and a release-controlling material in a subsidiary solvent; combining the above two solutions with each other to produce an emulsion phase; dispersing the emulsion phase in a solution of polyvinyl alcohol in distilled water to give a single emulsion system; removing the combined solvent of the emulsion phase to generate a polymeric microsphere; and freeze-drying the polymeric microsphere.
  • a microsphere which retains therapeutically effective drugs and continuously releases them for a sustained period of time is prepared from a mixture of biodegradable polymers.
  • therapeutically effective drugs LHRH analogues are of particular interest. Therefore, if the microspheres retaining LHRH analogues are administered, they release the drugs for a long period of time, whereby testosterone or estrogen can be maintained at a low level in the blood and an improvement in therapeutic effect and patient's adaptation to the drugs can be brought about.
  • the prolonged release microsphere which encapsulates LHRH analogues has an aporous, fine and uniform inner structure, so that its drug content rate is enhanced.
  • the microsphere can be prepared in a single emulsion process.
  • LHRH analogues including goserelin acetate, nafarelin acetate, buserelin acetate and leuprorelin acetate, are dissolved in a subsidiary solvent and added to an organic solvent containing a polymer to give an oil phase which is then dispersed in an aqueous phase.
  • a preferred example of the organic solvent useful in the invention is methylene chloride.
  • the aqueous phase is obtainable by dissolving polyvinyl alcohol.
  • the subsidiary solvent which dissolves LHRH should be miscible with the organic solvent (methylene chloride) and water, both.
  • the subsidiary solvent include N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), acetone, ethanol, ethyl acetate, and methyl ethyl ketone (MEK) with the most preference to NMP.
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • MEK methyl ethyl ketone
  • This subsidiary solvent plays an important role in providing the microsphere with an aporous fine structure.
  • the release of LHRH analogues is controlled in a double manner by the actions of the functional groups, i.e. carboxyl group and dodecyl group, attached to the ends of the two polymers which compose the microsphere.
  • the carboxyl group forms a hydrophobic ion pair with LHRH analogues, so the release rate thereof is retarded.
  • the dodecyl group inhibits the enzymatic action to degrade the microsphere, so the integrity of the biodegradable microsphere is sustained. Therefore, the drug contained in the microsphere is bot released in a sudden burst.
  • the compound suitable to retard the release rate of LHRH analogues must form the hydrophobic ion pair with LHRH analogues as well as can be dissolved in the organic solvent.
  • Preferable examples to meet these standards include sodium oleate, deoxycholic acid, cholic acid, fatty acids and phosphatidic acids.
  • the biodegradable microsphere of the present invention is aporous with an ultrafine inner structure, as shown in Figs. 1 and 2.
  • the data obtained from an in vitro release test demonstrate that LHRH is released at relatively constant rates from the microspheres of the invention, as shown in Fig. 3.
  • the microspheres were measured for their weight loss in order to obtain the information about their biodegradation rates, which finally told that the microspheres are completely decomposed on around the 45th day after testing, as shown in Fig. 4.
  • the data obtained from an in vivo release test, shown in Fig. 5, are well correlated with those of Fig. 4.
  • a microsphere was made from biodegradable PLGA in an O/W (oil in water) mono-emulsif ⁇ cation method.
  • PLGA which has a dodecyl group at its end and a molecular weight of
  • the biodegradable microspheres prepared in Examples were tested for in vitro release as follows. 5 mg of the freeze-dried microsphere were dispersed in a vial containing a solution of 0.05% Tween 80 in 10 ml of a 0.333 M phosphate buffer and stored at 37 °C for 28 days. A test sample was taken every third day from the first day to the thirtieth day. The ten samples thus taken were centrifuged. After the removal of the supernatant, the microspheres were quantified for the drugs through an HPLC with a mobile phase of 3 : 1 ammonium acetate:methanol at a flow rate of 1.0 ml/min at 280 nm. The results were shown in Fig. 3.
  • the biodegradable microspheres prepared in Examples were tested for in vitro release as follows.
  • the microspheres were introduced into the femoral regions of rats via intramuscular injection and the remaining microspheres were taken from the femoral regions by incising the regions every fifth day.
  • the microspheres taken were homogenized in 10 ml of a solution of 0.02 wt% Tween 80 (polyoxyethylene 20 oleate, Junsei Chemical Co.) in a 0.333 M phosphate buffer (pH 7.0). After further addition of 10 ml of the buffer and 10 ml of methylene chloride, the drugs were extracted in an aqueous layer. These extracts were quantified by HPLC under the same condition as that of the in vitro release test and the results are shown in Fig. 5.
  • Fig. 1 is an SEM photograph showing the microsphere of the present invention
  • Fig. 2 is an SEM photograph showing a cross section of the microsphere of the present invention.
  • Fig. 3 is a plot showing the in vitro release rates of the microspheres against time.
  • Fig. 4 is a plot showing the weight loss rates of the microspheres against time.
  • Fig. 5 is a plot showing the in vivo release rates of the microspheres against time.
  • the microspheres prepared according to the present invention have much finer inner structures than do conventional microspheres, by virtue of which the microspheres are secure in a constant release rate.
  • the single emulsion system of the present invention simplifies the preparation process of the microsphere, enabling it to maintain a drug content of 10% or more.
  • the charged groups of the release-controlling materials associated with the polymers minimize the excess release of the oppositely charged drugs at -loan initial stage, playing an important role in keeping the release rate constant.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Reproductive Health (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

L'invention concerne une microsphère à libération prolongée, qui peut libérer constamment des substances médicinales, telles que des analogues de la lutéolibérine et qui peut en encapsuler des quantités importantes. On produit ladite microsphère en dissolvant un copolymère de lactide et de glycolide dans du chlorure de méthylène, en dissolvant un analogue de lutéolibérine et une matière de retenue dans un solvant auxiliaire, en combinant les deux solutions sus-mentionnées, de sorte qu'une phase d'émulsion soit produite, en dispersant la phase d'émulsion dans une solution de poly(alcool de vinyle) dans de l'eau distillée, afin de produire un seul système d'émulsion, en enlevant le solvant combiné de la phase d'émulsion, de manière à générer une microsphère polymère; en lyophylisant la microsphère polymère. La microsphère de l'invention présente une structure interne beaucoup plus fine et est donc sûre en ce sa vitesse de libération est constante. Le système d'émulsion unique qui simplifie la préparation, permet le maintien d'une teneur en médicament de 10 % ou plus. Les groupes chargés des matières de retenue associées aux polymères minimisent la libération excessive de médicaments à charge opposée dans une étape initiale, ce qui est important dans le maintien d'une vitesse de libération constante.
PCT/KR1999/000071 1998-12-30 1999-02-11 Microsphere a liberation prolongee utilisee pour encapsuler des analogues de la luteoliberine, et son procede de production Ceased WO2000040259A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
MXPA01005540A MXPA01005540A (es) 1998-12-30 1999-02-11 Microesferas de liberacion prolongada para encapsular analogos de la hormona liberadora de la hormona luteinizante y metodo para prepararlas.
BR9916945-2A BR9916945A (pt) 1998-12-30 1999-02-11 Microesferas de liberação prolongada encapsulando análagos de hormÈnio liberador de hormÈnio luteinizante e método para preparar microesferas de liberação prolongada
CA002358495A CA2358495A1 (fr) 1998-12-30 1999-02-11 Microsphere a liberation prolongee utilisee pour encapsuler des analogues de la luteoliberine, et son procede de production
JP2000592014A JP2002534392A (ja) 1998-12-30 1999-02-11 黄体化ホルモン放出ホルモン類似体をカプセル化する持続放出性のマイクロスフェアおよびその調製方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1019980062142A KR100321854B1 (ko) 1998-12-30 1998-12-30 루테이나이징 호르몬 릴리싱 호르몬 동족체를 함유하는 장기 서방출성 미립구 및 그의 제조방법
KR1998/62142 1998-12-30

Publications (1)

Publication Number Publication Date
WO2000040259A1 true WO2000040259A1 (fr) 2000-07-13

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PCT/KR1999/000071 Ceased WO2000040259A1 (fr) 1998-12-30 1999-02-11 Microsphere a liberation prolongee utilisee pour encapsuler des analogues de la luteoliberine, et son procede de production

Country Status (10)

Country Link
JP (1) JP2002534392A (fr)
KR (1) KR100321854B1 (fr)
CN (1) CN1348383A (fr)
AR (1) AR017480A1 (fr)
BR (1) BR9916945A (fr)
CA (1) CA2358495A1 (fr)
MX (1) MXPA01005540A (fr)
TR (1) TR200101913T2 (fr)
WO (1) WO2000040259A1 (fr)
ZA (1) ZA992059B (fr)

Cited By (23)

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WO2004000363A1 (fr) * 2002-06-25 2003-12-31 Takeda Pharmaceutical Company Limited Procédé de production d'une composition à libération prolongée
EP1529784A1 (fr) * 2003-11-06 2005-05-11 Iseu da Silva Nunes Anhydrides polymères de magnésium et ammonium-phospholinoléat-palmitoléat protéique
US7053134B2 (en) 2002-04-04 2006-05-30 Scimed Life Systems, Inc. Forming a chemically cross-linked particle of a desired shape and diameter
US7094369B2 (en) 2002-03-29 2006-08-22 Scimed Life Systems, Inc. Processes for manufacturing polymeric microspheres
US7131997B2 (en) 2002-03-29 2006-11-07 Scimed Life Systems, Inc. Tissue treatment
US7311861B2 (en) 2004-06-01 2007-12-25 Boston Scientific Scimed, Inc. Embolization
US7449236B2 (en) 2002-08-09 2008-11-11 Boston Scientific Scimed, Inc. Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient
US7462366B2 (en) 2002-03-29 2008-12-09 Boston Scientific Scimed, Inc. Drug delivery particle
US7501179B2 (en) 2005-12-21 2009-03-10 Boston Scientific Scimed, Inc. Block copolymer particles
EP1488807A4 (fr) * 2002-03-11 2009-07-08 Takeda Pharmaceutical Medicaments permettant de traiter une maladie dependant d'une hormone sexuelle
US7588825B2 (en) 2002-10-23 2009-09-15 Boston Scientific Scimed, Inc. Embolic compositions
WO2009150136A1 (fr) * 2008-06-09 2009-12-17 Boehringer Ingelheim International Gmbh Nouvelles particules à principe actif incorporé pour inhalation
US7662408B2 (en) 2004-02-10 2010-02-16 Takeda Pharmaceutical Company Limited Sustained-release preparations
US20100234305A1 (en) * 1998-10-28 2010-09-16 Qlt Usa, Inc. Polymeric delivery formulations of leuprolide with improved efficacy
WO2013050169A1 (fr) 2011-10-05 2013-04-11 Acino Ag Procédé de production d'un mélange pulvérulent homogène, procédé de production d'un implant et implant
WO2013090634A1 (fr) * 2011-12-14 2013-06-20 Abraxis Bioscience, Llc Utilisation d'excipients polymères pour la lyophilisation ou la congélation de particules
US8470359B2 (en) 2000-11-13 2013-06-25 Qlt Usa, Inc. Sustained release polymer
US8951973B2 (en) 2008-08-29 2015-02-10 Kevin Burton Controlled-released peptide formulations
US9283035B2 (en) 2005-04-28 2016-03-15 Boston Scientific Scimed, Inc. Tissue-treatment methods
US9463426B2 (en) 2005-06-24 2016-10-11 Boston Scientific Scimed, Inc. Methods and systems for coating particles
US10398724B2 (en) 2002-06-12 2019-09-03 Boston Scientific Scimed, Inc. Bulking agents
US11285109B2 (en) 2020-05-08 2022-03-29 M. Technique Co., Ltd. Microsphere comprising PLGA or PLA in which a biologically active substance is uniformly dispersed and a sustained release formulation comprising the same
US11617720B2 (en) 2020-05-08 2023-04-04 M. Technique Co., Ltd. Main agent uniformly dispersed microsphere and a sustained release formulation comprising the same

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EP1660039B1 (fr) * 2003-07-18 2016-09-28 Oakwood Laboratories L.L.C. Prevention de reduction de poids moleculaire du polymere, de formation d'impuretes et de gelification dans des compositions polymeres
KR100622996B1 (ko) * 2005-03-03 2006-09-14 한국과학기술원 약물이 봉입된 비다공성 고분자 미립 담체 및 이의 제조방법
KR101663560B1 (ko) * 2009-02-13 2016-10-10 동국제약 주식회사 균일한 서방출성 미립구의 제조방법
JP2016527308A (ja) * 2013-08-06 2016-09-08 ドン クック ファーマシューティカル カンパニー リミテッド エンテカビル微小球及びこれを含む非経口投与用医薬組成物
US20160106804A1 (en) * 2014-10-15 2016-04-21 Yuhua Li Pharmaceutical composition with improved stability
CN109394705B (zh) * 2018-12-04 2021-11-19 沈阳药科大学 一种戈舍瑞林缓释微球冻干粉及其制备方法
US20210346296A1 (en) * 2020-05-08 2021-11-11 M. Technique Co., Ltd. A biologically active substance uniformly dispersed microsphere and a sustained release formulation comprising the same
KR20240079177A (ko) * 2022-11-28 2024-06-04 동국제약 주식회사 인-시튜 임플란트를 형성할 수 있는 서방형 약학 조성물 및 이의 제조방법

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US5192741A (en) * 1987-09-21 1993-03-09 Debiopharm S.A. Sustained and controlled release of water insoluble polypeptides
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US4675189A (en) * 1980-11-18 1987-06-23 Syntex (U.S.A.) Inc. Microencapsulation of water soluble active polypeptides
US4835139A (en) * 1983-09-23 1989-05-30 Debiopharm S.A. Process for increasing the antagonistic effect of peptidic compounds on hormone-dependent diseases
GB2165517A (en) * 1984-10-17 1986-04-16 Debiopharm Sa Micro-encapsulation of medicaments
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CA2358495A1 (fr) 2000-07-13
MXPA01005540A (es) 2004-06-22
KR20000045577A (ko) 2000-07-25
KR100321854B1 (ko) 2002-08-28
JP2002534392A (ja) 2002-10-15
AR017480A1 (es) 2001-09-05
BR9916945A (pt) 2001-11-06
CN1348383A (zh) 2002-05-08
ZA992059B (en) 1999-09-27

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