KR100250572B1 - Method for the preparation of sustained release microsphere containing water soluble antibiotics - Google Patents

Method for the preparation of sustained release microsphere containing water soluble antibiotics Download PDF

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KR100250572B1
KR100250572B1 KR1019950010671A KR19950010671A KR100250572B1 KR 100250572 B1 KR100250572 B1 KR 100250572B1 KR 1019950010671 A KR1019950010671 A KR 1019950010671A KR 19950010671 A KR19950010671 A KR 19950010671A KR 100250572 B1 KR100250572 B1 KR 100250572B1
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drug
weight
microspheres
microsphere
suspension
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KR960040341A (en
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이재용
서민효
배철민
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김윤
주식회사삼양사
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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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • 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

Abstract

PURPOSE: A sustained release microsphere is provided, which contains more than 20wt.% of water soluble antibiotic drug, and releases the antibiotic drug regularly for 1-3weeks. A manufacturing process is also provided. CONSTITUTION: The manufacturing process for sustained release microsphere containing water soluble antibiotics is comprised of: adding poly D,L-lactic acid(M.W 8,000) and pulverized tetracycline hydrochloride(diameter of the particle=5μm) to dichloromethane, and mixing well to get a suspension; adding the suspension to a solution containing polyvinyl alcohol(degree of polymerization=1,500) 5wt.%, and shaking for 10minutes at 600rpm to get an emulsion; adding the emulsion to distilled water slowly while shaking for 1hour at 200rpm, separating microsphere by centrifuging, and washing with distilled water to get the microsphere.

Description

수용성 항생제를 함유하는 서방성 미크로스피어의 제조방법Method for producing sustained-release microspheres containing water-soluble antibiotics

본 발명은 수용성 항생제를 함유하는 서방성 미크로스피어의 제조방법에 관한 것이다.The present invention relates to a method for producing a sustained release microsphere containing a water-soluble antibiotic.

약물학적 활성 성분을 함유하는 서방성 제제는 약제를 짧은 간격으로 반복해서 투약할 필요가 없이 환자에게 장기간에 걸쳐 투약할 경우에 사용된다. 서방성 제제는 보통 생분해성 고분자 물질에 생리활성 성분을 함유시켜 외과수술로 체내에 이식되거나 주사기 등을 이용하여 체내에 투여되어, 고분자가 생분해됨에 따라 내부의 약물이 서서히 방출되어 환자의 체내에서 약효를 나타내게 되는 서방성 약물 전달체가 많이 제안되고 있다.Sustained-release preparations containing pharmacologically active ingredients are used for long term administration to a patient without the need for repeated doses of the medicament. Sustained release preparations usually contain biodegradable polymers that contain bioactive components and are implanted into the body by surgery, or administered in the body using syringes. Many sustained-release drug carriers have been proposed.

이러한 서방성 약물 전달체로는 체내에서 대사과정에 의해 무해한 물과 이산화탄소로 분해되는 폴리락트산, 폴리글리콜산 및 이들의 공중합체에 약물을 함유시켜 필름, 분말, 화이버 또는 펠렛 등의 형태로 체내에 주입하는 방법이 널리 공지되어 있다. 그러나 이들은 외과수술로 체내에 주입하여야 하기 때문에 일반적으로 사용하기에는 어려움이 있다.Such sustained-release drug carriers contain drugs in polylactic acid, polyglycolic acid, and copolymers thereof, which are decomposed into harmless water and carbon dioxide by metabolic processes in the body, and injected into the body in the form of films, powders, fibers, or pellets. Methods of doing this are well known. However, they are difficult to use in general because they have to be injected into the body by surgery.

한편 상기와 같은 서방성 약물 전달체의 단점을 보완하기 위하여, 일반 주사기로 피하지방질 또는 근육에 간단히 투여할 수 있으며 약물 방출 후 서서히 체내에 흡수되는 직경 0.01 내지 300㎛인 구형의 고분자 입자인 미크로스피어에 항암제 또는 호르몬제 등의 여러가지 약물을 함유시킨 투약형태가 개발되어 있다. 그러나 입자의 직경이 0.01 내지 300㎛인 미크로스피어내에 생리 활성 물질을 효과적으로 함유시키는데에는 많은 어려움이 있기 때문에, 효과적으로 미크로스피어를 제조하기 위한 여러가지 방법들이 제안되고 있다.On the other hand, in order to make up for the disadvantages of the sustained-release drug delivery system as described above, microspheres, which are spherical polymer particles having a diameter of 0.01 to 300 μm, which can be simply administered to subcutaneous fat or muscle by a general syringe and are gradually absorbed into the body after drug release. Dosage forms containing various drugs such as anticancer drugs or hormones have been developed. However, since there are many difficulties in effectively containing a bioactive substance in microspheres having a particle diameter of 0.01 to 300 µm, various methods for effectively preparing microspheres have been proposed.

그 대표적인 예로는 지용성 약물과 폴리락트산을 유기용매에 용해시킨 후, 상분리제를 포함하는 수용액에 가하여 유화시킨 다음, 유기 용매를 증발시켜 미크로스피어를 제조하는 방법(일본 특허 제334,141호(1980)); 수용성 약물을 용해시킨 수용액을 폴리락트산이 용해되어 있는 유기용매에 유화시켜 생성된 에멀젼(W/O)을 유화제를 함유하는 수용액에 다시 유화시켜 이중 에멀전(W/O/W)을 만든 후, 유기용매를 증발시켜 미크로스피어를 제조하는 방법(일본 특허 제100,516호(1985)); 또는 물과 혼합되는 아세토니트릴, 아세트산 등의 유기용매에 수용성 약물과 폴리락트산을 용해시킨 후 광유 또는 식물성 오일 등에 유화시켜 생성된 에멀젼(O/O 또는 W/O)으로부터 유기용매를 증발시켜 미크로스피어를 제조하는 방법(미국 특허 제5,100,669호) 등이 공지되어 있다.As a representative example thereof, a method of preparing a microsphere by dissolving a fat-soluble drug and a polylactic acid in an organic solvent, adding the same to an aqueous solution containing a phase separation agent, and then evaporating the organic solvent (Japanese Patent No. 334,141 (1980)). ; The aqueous solution in which the water-soluble drug is dissolved is emulsified in an organic solvent in which polylactic acid is dissolved, and the resulting emulsion (W / O) is again emulsified in an aqueous solution containing an emulsifier to form a double emulsion (W / O / W), and then A method of preparing microspheres by evaporating a solvent (Japanese Patent No. 100,516 (1985)); Or microspheres by dissolving a water-soluble drug and polylactic acid in an organic solvent such as acetonitrile or acetic acid mixed with water, and then emulsifying the organic solvent from an emulsion (O / O or W / O) produced by emulsifying mineral oil or vegetable oil. (US Pat. No. 5,100,669) and the like are known.

그러나, 상기와 같은 방법에 의해서 제조된 미크로스피어는 약물 함유량이 20중량% 이하로 약물이 방출되는데 2주일 이상이 소요되며 고분자가 체내에 완전히 흡수되는데 1개월 이상의 장기간이 소요된다. 특히 수용성 약물을 함유시키는데 유용한 방법인 이중유화법(일본 특허 제100,516호(1985))으로는 10중량% 이상의 약물을 함유시키기 어렵고, 또 미국 특허 제5,100,669호의 방법에서는 초산 등을 사용하기 때문에 산성조건에서 분해되는 약물의 활성이 소실되는 등의 단점이 있다. 그러므로 상기와 같은 방법으로 제조된 미크로스피어는 펩티드 약물, 단백질 의약품, 항암제 등 1개월 이상의 장기간에 걸쳐 매일 극미량의 투약이 필요한 경우에 적합하다.However, the microspheres prepared by the above method have a drug content of 20% by weight or less, it takes more than two weeks for the drug to be released, and it takes a long time more than one month for the polymer to be completely absorbed into the body. In particular, the double emulsification method (Japanese Patent No. 100,516 (1985)), which is a useful method for containing a water-soluble drug, is difficult to contain more than 10% by weight of the drug, and the method of US Pat. There are disadvantages such as the loss of the activity of the drug is degraded in. Therefore, the microspheres prepared by the above method are suitable for the case where a very small amount of daily dose is required for a long period of one month or more, such as peptide drugs, protein drugs, and anticancer drugs.

한편, 항생제 등의 약물은 질병치료를 위하여 1 내지 2주일의 비교적 짧은 기간내에 집중적으로 투약하는 것이 효과적인데, 대부분의 항생물질은 체내 반감기가 24시간 이하이므로 종래의 방법으로는 매일 투약하거나 하루에 3번이상 투여하여야 하는 불편함이 있다. 따라서, 이와 같은 불편을 해소하고 치료효과를 높이기 위해서는, 매일 치료 농도 이상의 약물이 방출되며 1 내지 2주일 내에 모든 약물이 방출되는 미크로스피어를 제조할 필요성이 있다.On the other hand, drugs such as antibiotics are effective to intensively administered within a relatively short period of 1 to 2 weeks for the treatment of the disease, most antibiotics have a half-life of less than 24 hours, so conventional methods are administered daily or daily There is discomfort to be administered more than three times. Therefore, in order to alleviate such inconvenience and increase the therapeutic effect, there is a need to prepare a microsphere in which drugs of a therapeutic concentration or more are released every day and all drugs are released within one to two weeks.

이에, 본 발명에서는 상기와 같은 문제점을 해결하여 수용성 약물을 10중량% 이상 함유하며 약물 방출이 1 내지 3주일 내에 종결되는 생 분해성 미크로스피어 및 이의 제조방법을 제공함을 목적으로 한다.Accordingly, an object of the present invention to solve the above problems is to provide a biodegradable microsphere and a method for preparing the same containing a water-soluble drug more than 10% by weight and drug release is terminated within 1 to 3 weeks.

상기 목적을 달성하기 위하여 본 발명에서는 생분해성 고분자 물질과 수용성 항생제 약물을 유기용매에 현탁시키고, 상기 현탁액을 비이온성 계면활성제 수용액에 유화시키고, 상기 유액을 증류수로 희석하고, 상기 희석액으로부터 생성된 미크로스피어를 분리하는 단계를 포함하는 서방성 미크로스피어의 제조방법을 제공한다.In order to achieve the above object, in the present invention, a biodegradable polymer material and a water-soluble antibiotic drug are suspended in an organic solvent, the suspension is emulsified in an aqueous solution of a nonionic surfactant, the emulsion is diluted with distilled water, and the micro-generated from the diluent. It provides a method for producing a sustained-release microspheres comprising the step of separating the spheres.

상기 다른 목적을 달성하기 위하여 본 발명에서는 수용성 항생제 약물을 20중량% 이상 함유하며, 상기 약물이 1 내지 3주 동안 일정하게 방출되는 것을 특징으로 하는 생분해성 고분자 물질로 된 서방성 미크로스피어를 제공한다.In order to achieve the above another object, the present invention provides a sustained-release microsphere made of a biodegradable polymer material containing 20% by weight or more of a water-soluble antibiotic drug, wherein the drug is constantly released for 1 to 3 weeks. .

이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

생분해성 고분자 물질을 유기용매에 녹인 용액에, 직경 5㎛ 이하로 분쇄한 항생제 분말을 가하고 잘 혼합하여 현탁액을 제조한 후 20℃ 이하로 냉각시킨다. 필요한 경우에는 첨가제를 첨가할 수 있으며, 탐침형 초음파기와 같은 통상적인 방법을 사용하여 약물입자를 잘게 분쇄할 수도 있다. 이 현탁액을 미리 제조한 1 내지 15중량%이 비이온성 계면 활성제 수용액에 가하고 잘 저어 유화시킨다. 유화된 액의 입자 크기가 균일하여지면 이를 20℃ 이하로 냉각시킨 과량의 증류수에 가하여 희석시킨다. 이어서, 미크로스피어가 생성된 현탁 수용액을 천천히 교반하여 유기 용매를 증발시킨 후, 원심 분리하거나 여과하고 이를 동결 건조하여 본 발명의 미크로스피어를 얻는다.To a solution in which the biodegradable polymer material is dissolved in an organic solvent, antibiotic powder pulverized to a diameter of 5 μm or less is added and mixed well to prepare a suspension, and then cooled to 20 ° C. or less. If necessary, additives may be added, and the drug particles may be finely pulverized using conventional methods such as probe type ultrasonicators. 1 to 15% by weight of this suspension is added to an aqueous solution of nonionic surfactant and stirred well to emulsify. Once the particle size of the emulsified liquid is uniform, it is diluted with excess distilled water cooled to 20 ° C or below. Subsequently, the suspension solution in which the microspheres are produced is slowly stirred to evaporate the organic solvent, and then centrifuged or filtered and lyophilized to obtain the microspheres of the present invention.

본 발명의 생분해성 고분자 물질로는 수불용성이며 동시에 생체 적합성과 생분해성을 갖는 지방족 고분자 물질이 적합하며, 특히 폴리락트산, 또는 락트산과 글리콜산의 공중합체가 바람직하다. 폴리락트산으로는 분자량이 10,000 이하이며, 광학활성을 갖는 L형(L-PLA) 또는 광학활성이 없는 D, L 혼합형의 호모폴리머(D,L-PLA) 모두가 사용될 수 있다. 락트산과 글리콜산의 공중합체는 락트산과 글리콜산의 혼합비가 50/50~99/1중량%인 것이 바람직하다.As the biodegradable polymer material of the present invention, an aliphatic polymer material which is water insoluble and at the same time biocompatible and biodegradable is suitable, and polylactic acid or a copolymer of lactic acid and glycolic acid is particularly preferable. As the polylactic acid, a molecular weight of 10,000 or less, and optically active L-type (L-PLA) or optically active D, L mixed homopolymer (D, L-PLA) both can be used. The copolymer of lactic acid and glycolic acid preferably has a mixing ratio of lactic acid and glycolic acid of 50/50 to 99/1% by weight.

본 발명의 미크로스피어 내에 함유될 수 있는 항생제는 특정되어 있지 않으나 치주염, 중이염, 축농증, 피부감염증 등 1 내지 3주일 동안 지속적인 투여가 요구되는 질환의 치료에 사용되는 수용성 항생제는 모두 적용된다. 예를 들어 겐타마이신, 겐타마이신 설페이트, 네오마이신, 독시싸이클린 히드로클로라이드, 목살락탐, 미노싸이클린 히드로클로라이드, 반코마이신, 세팔로틴, 세파클로, 세포탁심, 세팔로리딘, 세포티암, 세프메톡심, 세프메타졸, 세파졸린, 아목시실린, 암피실린, 에리스로마이신, 옥시테트라싸이클린 히드로클로라이드, 세포페라존, 세프티족심, 카베니실린, 클린다마이신, 콜리스틴, 티에나마이신, 피페라실린, 페니실린 또는 테트라싸이클린 히드로클로라이드 등의 항생물질, 메트로니다졸 또는 클로로헥시딘 등을 사용할 수 있다.Although antibiotics that may be contained in the microspheres of the present invention are not specified, all water-soluble antibiotics used for the treatment of diseases requiring continuous administration for 1 to 3 weeks, such as periodontitis, otitis media, sinusitis, and skin infections, are all applicable. For example, Gentamicin, Gentamicin Sulfate, Neomycin, Doxycycline Hydrochloride, Moxalactam, Minocycline Hydrochloride, Vancomycin, Cephalotin, Sephaclo, Cytoxim, Cephaloridine, Cythiam, Cemethoxime, Cef Metazole, cefazoline, amoxicillin, ampicillin, erythromycin, oxytetracycline hydrochloride, ceferrazone, ceftizone, carbenicillin, clindamycin, colistin, thienamycin, piperacillin, penicillin or tetracycline hydrochloride Antibiotics, metronidazole or chlorohexidine may be used.

상기 약물은 현탁액 제조시 직경 5㎛ 이하로 분쇄한 것이 바람직하며, 직경 1㎛ 이하의 것이 더욱 바람직하다. 이러한 미분말은 약물의 수용액을 분무 또는 동결 건조하거나, 또는 막자사발로 분쇄한 후 메쉬로 체별하여 얻을 수 있다.The drug is preferably ground to a diameter of 5 μm or less, and more preferably 1 μm or less in diameter when preparing the suspension. Such fine powder may be obtained by spraying or freeze drying an aqueous solution of the drug, or by pulverizing with a mortar and then sieving with a mesh.

상기 고분자 물질과 약물의 현탁액을 제조할 때 사용되는 유기용매로는 물과 혼합되지 않으며 휘발성이 좋은 디클로로메탄, 클로로포름 또는 아세트산에틸 등을 사용할 수 있는데, 비교적 독성이 적고 비점이 낮아서 실온에서 증발되는 디클로로메탄이 바람직하다.As the organic solvent used when preparing the suspension of the polymer and the drug, dichloromethane, chloroform, or ethyl acetate, which are not mixed with water, may be used, and dichloromethane, which is relatively toxic and has a low boiling point, is evaporated at room temperature. Methane is preferred.

본 발명에 있어서 생분해성 고분자 물질을 유기 용매에 용해시, 유기 용매와 생분해성 고분자 물질의 상대적인 비율은 미크로스피어의 입자 크기와 미크로스피어내의 약물 함량에 매우 큰 영향을 미친다. 미크로스피어의 입자크기를 5 내지 100㎛로 하고 약물 함량을 20 내지 30중량%로 할 경우 생분해성 고분자 물질 대 유기 용매의 비는 75/25 내지 10/90중량%인 것이 바람직하고, 더욱 바람직하게는 50/50 내지 25/75중량%이다. 이 조성 비율을 변화시킴으로서 미크로스피어의 입자크기를 변화시킬 수 있다.In the present invention, when the biodegradable polymer material is dissolved in an organic solvent, the relative ratio of the organic solvent and the biodegradable polymer material has a great influence on the particle size of the microspheres and the drug content in the microspheres. When the particle size of the microsphere is 5 to 100 μm and the drug content is 20 to 30 wt%, the ratio of the biodegradable polymer material to the organic solvent is preferably 75/25 to 10/90 wt%, more preferably. Is 50/50 to 25/75% by weight. By changing this composition ratio, the particle size of the microspheres can be changed.

본 발명에 있어서 상기 현탁액에는 고분자와 약물이외에도, 약물의 약리학적 성질에는 영향을 미치지 않으나 미크로스피어로부터 약물의 방출 속도, 미크로스피어의 분해 속도 등을 변화시키는 첨가제들을 함께 사용할 수 있다. 이와 같은 첨가제로는 천연 또는 합성 고분자들을 들 수 있으며, 천연 고분자로는 카제인, 젤라틴, 콜라겐, 알부민, 글로불린 또는 피브린과 같은 단백질류, 셀룰로오스, 덱스트린, 덱스트란, 펙틴, 전분, 한천 또는 만난과 같은 탄수화물을 들 수 있다. 합성 고분자 물질로는 폴리비닐피롤리돈, 폴리비닐알코올, 폴리비닐메틸에테르 또는 폴리비닐에테르와 같은 폴리비닐 화합물, 폴리아크릴산, 폴리메타크릴산 또는 카르보폴과 같은 폴리카르복시산, 폴리에틸렌글리콜과 같은 폴리에틸렌 화합물, 폴리슈크로스, 폴리글루코스 또는 폴리락토스와 같은 다당류 또는 이들의 염이 포함될 수 있다.In the present invention, in addition to the polymer and the drug, the suspension may be used with additives which do not affect the pharmacological properties of the drug but change the release rate of the drug from the microsphere, the decomposition rate of the microsphere, and the like. Such additives include natural or synthetic polymers, and natural polymers may be proteins such as casein, gelatin, collagen, albumin, globulin or fibrin, cellulose, dextrin, dextran, pectin, starch, agar or mannan. Carbohydrates. Synthetic polymer materials include polyvinyl compounds such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl methyl ether or polyvinyl ether, polycarboxylic acids such as polyacrylic acid, polymethacrylic acid or carbopol, polyethylene compounds such as polyethylene glycol Polysaccharides such as polysucrose, polyglucose or polylactose or salts thereof.

이어서 상기에서 제조한 고분자 및 약물을 함유하는 현탁액을 비이온성 계면활성제 수용액에 가하여 유화시켜 유탁액을 생성시킨다. 비이온성 계면 활성제로는 폴리비닐알코올, 폴리비닐피롤리돈 또는 폴리에틸렌옥시드 등을 사용할 수 있으며 가장 바람직한 것은 폴리비닐알코올이다. 비이온성 계면활성제 수용액의 농도는 미크로스피어의 입자크기와 미크로스피어내 약물함량에 매우 중요한 영향을 미친다. 본 발명에 바람직한 비이온성 계면활성제 수용액의 농도는 1~15중량%이며, 더욱 바람직하게는 5~10중량%이다.The suspension containing the polymer and drug prepared above is then added to an aqueous solution of nonionic surfactant to emulsify to produce an emulsion. As the nonionic surfactant, polyvinyl alcohol, polyvinylpyrrolidone or polyethylene oxide and the like can be used, and most preferably, polyvinyl alcohol. The concentration of the nonionic surfactant solution has a very important effect on the particle size of the microspheres and the drug content in the microspheres. The density | concentration of the nonionic surfactant aqueous solution preferable for this invention is 1-15 weight%, More preferably, it is 5-10 weight%.

고분자와 약물을 함유하는 현탁액과 비이온성 계면활성제를 함유하는 수용액의 온도로 역시 미크로스피어의 크기 및 약물 함량에 중요한 영향을 미치는데, 혼합시 양쪽 모두 30℃ 이하로 유지하는 것이 바람직하며, 5~20℃로 유지하는 것이 더욱 바람직하다. 온도가 30℃ 이상일 경우에는 생분해성 고분자의 유리전이온도가 낮기 때문에 고분자가 미크로스피어의 형태로 굳어지기 어렵다. 따라서, 혼합 후에도 현탁 희석액의 온도를 20 내지 30℃를 유지하는 것이 바람직하다.The temperature of suspensions containing polymers and drugs and aqueous solutions containing nonionic surfactants also have a significant effect on the size and drug content of the microspheres. It is more preferable to keep it at 20 degreeC. If the temperature is more than 30 ℃ because the glass transition temperature of the biodegradable polymer is low, the polymer is difficult to harden in the form of microspheres. Therefore, it is preferable to maintain the temperature of suspension dilution 20-30 degreeC after mixing.

계속해서 상기 유탁액을 증류수에 가하여 희석시키는데, 이때 전체 수용액 중 비이온성 계면활성제의 농도를 0.1 내지 1중량%로 하는 것이 바람직하다. 비이온성 계면활성제의 농도가 0.1중량% 보다 낮으면 미크로스피어 내부에 함유된 약물이 밖으로 빠져나갈 수 있으며, 1중량% 보다 높으면 미크로스피어가 잘 형성되지 않으므로 바람직하지 않다.Subsequently, the emulsion is added to distilled water and diluted. At this time, the concentration of the nonionic surfactant in the total aqueous solution is preferably 0.1 to 1% by weight. If the concentration of the nonionic surfactant is lower than 0.1% by weight, the drug contained in the microspheres may be taken out. If the concentration is higher than 1% by weight, the microspheres are not well formed, which is not preferable.

상기와 같이 실시하여 생성된 미크로스피어를 함유하는 현탁 수용액을 실온에서 교반에 의해 유기 용매를 증발시켜 이 수용액을 원심분리하거나 여과하여 미크로스피어를 분리한다.The suspension aqueous solution containing the microspheres produced as described above is evaporated at room temperature by evaporation of the organic solvent, and the aqueous solution is centrifuged or filtered to separate the microspheres.

본 발명에서는 분자량이 작은 생분해성 고분자 물질로 구성되며 평균 입경이 5 내지 100㎛인 미크로스피어 내에 수용성 항생제 약물을 20중량% 이상 함유시킴으로써, 체내에서 1 내지 2주 동안 지속적으로 약물을 방출한 후 상기 미크로스피어는 분해되어 없어지도록 한 것이다.In the present invention, by containing a biodegradable polymer material having a small molecular weight and containing 20% by weight or more of a water-soluble antibiotic drug in a microsphere having an average particle diameter of 5 to 100㎛, after the drug is continuously released for 1 to 2 weeks in the body Microspheres are intended to disintegrate and disappear.

본 발명에 있어서 미크로스피어내 약물의 함유량은 약물의 종류, 목적하는 약물의 약리학적 효과, 약효의 지속시간 및 1회 투여량을 고려하여 적절히 변화될 수 있는데, 10 내지 50중량% 범위로 하는 것이 가능하고, 바람직하게는 20 내지 50중량%, 가장 바람직하게는 20 내지 30중량%로 하는 것이다.In the present invention, the content of the drug in the microsphere may be appropriately changed in consideration of the type of drug, the pharmacological effect of the desired drug, the duration of the drug and the dosage of the drug, which is in the range of 10 to 50% by weight. Preferably it is 20 to 50 weight%, Most preferably, it is 20 to 30 weight%.

본 발명에 따른 미크로스피어는 피하주사, 근육주사 등의 주사제로는 물론 외용제 및 국소투여제로서 사용될 수 있다. 특히 치주염, 중이염, 축농증 등 항생제 국소투여가 필요한 곳에는 일회 투여로 일주일 이상 장기간에 걸쳐 약물을 지속적으로 투여하는 제형으로 사용될 수 있으므로, 약물의 투여 효율 및 치료 효과를 극대화시킴은 물론 간단하고 용이하게 사용될 수 있다.The microspheres according to the present invention can be used as injections such as subcutaneous injections and intramuscular injections as well as external preparations and topical administrations. Particularly, where antibiotics such as periodontitis, otitis media and sinusitis are needed, it can be used as a dosage form that continuously administers the drug for a long period of time or more in a single dose, so as to maximize the administration efficiency and therapeutic effect of the drug, as well as simple and easy. Can be used.

이하 본 발명을 하기 실시예를 통하여 좀 더 상세히 설명한다. 그러나 본 발명이 하기 실시예에 의하여 제한되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by the following examples.

[실시예 1]Example 1

평균 분자량이 8,000인 폴리 D, L-락트산 1.4g과 평균 입경 약 5㎛로 잘게 분쇄한 테트라싸이클린 염산염 0.6g을 디클로로메탄 5ml에 가하고 잘 혼합하여 현탁액을 제조하였다. 이 현탁액을 폴리비닐알코올(중합도(DP : Degree of Polymerization)=1,500) 5중량%를 포함하는 수용액 50ml에 가하고 600rpm에서 10분동안 기계 교반기로 교반하여 유탁액을 제조하였다. 상기 유탁액을 증류수 200ml에 천천히 가하면서 실온에서 200rpm으로 1시간동안 저어준 후 원심분리하여 미크로스피어를 분리하고 증류수로 세척하였다. 생성된 미크로스피어의 평균 입경은 25㎛이며 테트라싸이클린 염산염의 함유량은 22중량%이었다.1.4 g of poly D and L-lactic acid having an average molecular weight of 8,000 and 0.6 g of tetracycline hydrochloride finely pulverized to an average particle diameter of about 5 μm were added to 5 ml of dichloromethane and mixed well to prepare a suspension. The suspension was added to 50 ml of an aqueous solution containing 5% by weight of polyvinyl alcohol (Degree of Polymerization (DP) = 1500) and stirred at 600 rpm for 10 minutes with a mechanical stirrer to prepare an emulsion. The emulsion was slowly added to 200 ml of distilled water, stirred at 200 rpm for 1 hour at room temperature, followed by centrifugation to separate the microspheres and washing with distilled water. The average particle diameter of the produced microspheres was 25 micrometers, and content of tetracycline hydrochloride was 22 weight%.

상기 미크로스피어 25mg을 인산염 완충용액 10ml를 함유하는 플라스크에 넣고 37℃±0.5℃의 항온 수조에서 50rpm으로 교반하고 24시간 간격으로 완충용액을 완전히 교체하면서 자외선 흡광도를 측정(280nm)하여 방출된 약물의 양을 분석한 결과를 하기 표 1에 나타내었다.The 25 mg of microspheres were placed in a flask containing 10 ml of phosphate buffer solution, stirred at 50 rpm in a constant temperature water bath at 37 ° C. ± 0.5 ° C., and the absorbance of the released drug was measured (280 nm) while completely replacing the buffer solution every 24 hours. The results of analyzing the amounts are shown in Table 1 below.

[표 1]TABLE 1

상기와 같이 24시간 간격으로 교체한 완충 용액 중 30㎕를 취하여 항생물질 조사용 종이 디스크(지름 6.4mm)에 적셔 바실러스 세레우스(Bacillus cereus)가 미리 접종되어 있는 아가판에 얹은 후, 이 아가판을 통상의 방법으로 배양하여 균의 생장이 억제된 영역의 지름을 측정하는 방법으로 미크로스피어로부터 방출된 약물의 생리활성을 조사한 결과는 하기 표 2와 같다.Take 30 µl of the buffer solution replaced at 24 hour intervals as described above, soak in a paper disk (6.4 mm in diameter) for antibiotic irradiation, and place it on agar plate in which Bacillus cereus is inoculated in advance. To examine the physiological activity of the drug released from the microspheres by the method of culturing in a conventional manner to measure the diameter of the region in which the growth of bacteria is inhibited is shown in Table 2 below.

[표 2]TABLE 2

[실시예 2]Example 2

평균 분자량이 8,000인 폴리 D, L-락트산 2.1g과 평균 입경 약 5㎛로 잘게 분쇄한 미노싸이클린 염산염 0.9g을 디클로로메탄 7.5ml에 가하고 잘 혼합하여 현탁액을 제조하였다. 이 현탁액을 폴리비닐알코올(DP=1,500) 8중량%를 포함하는 수용액 50ml에 가하고 600rpm에서 10분동안 기계 교반기로 교반하여 유탁액을 제조하였다. 상기 유탁액을 증류수 450ml에 천천히 가하면서 실온에서 200rpm으로 1시간동안 저어준 후 원심분리하여 미크로스피어를 분리하고 증류수로 세척하였다. 생성된 미크로스피어의 평균 입자 크기는 20㎛이며 미노싸이클린 염산염의 함유량은 27중량%이었다.2.1 g of poly D and L-lactic acid having an average molecular weight of 8,000 and 0.9 g of minocycline hydrochloride finely pulverized to an average particle diameter of about 5 µm were added to 7.5 ml of dichloromethane, and mixed well to prepare a suspension. This suspension was added to 50 ml of an aqueous solution containing 8% by weight of polyvinyl alcohol (DP = 1,500) and stirred at 600 rpm for 10 minutes with a mechanical stirrer to prepare an emulsion. The emulsion was slowly added to 450 ml of distilled water, stirred at 200 rpm for 1 hour at room temperature, followed by centrifugation to separate the microspheres and washing with distilled water. The resulting microspheres had an average particle size of 20 μm and a content of minocycline hydrochloride was 27% by weight.

상기 미크로스피어 20mg과 인산염 완충용액 20ml를 사용하여 실시예 1과 동일하게 하여 약물 방출 특성(자외선 흡광도 : 280nm) 및 방출되는 약물의 생리활성을 측정하였으며, 그 결과는 하기 표 3 및 4와 같다.Using 20 mg of microspheres and 20 ml of phosphate buffer solution, the drug release characteristics (ultraviolet absorbance: 280 nm) and the physiological activity of the released drug were measured in the same manner as in Example 1, and the results are shown in Tables 3 and 4 below.

[표 3]TABLE 3

[표 4]TABLE 4

[실시예 3]Example 3

평균 분자량이 7,500인 폴리 D, L-락트산-글리콜산 공중합체(락트산/글리콜산=7/3 w/w) 1.5g과 평균 입경 약 5㎛로 잘게 부순 메트로니다졸 0.5g을 디클로로메탄 5ml에 가하고 잘 혼합하여 현탁액을 제조하였다. 이 현탁액을 폴리비닐알코올(DP=1,500) 5중량%를 포함하는 수용액 50ml에 가하고 600rpm에서 10분동안 기계 교반기로 교반하여 유탁액을 제조하였다. 상기 유탁액을 증류수 250ml에 천천히 가하면서 실온에서 200rpm으로 1시간동안 저어준 후 원심분리하여 미크로스피어를 분리하고 증류수로 세척하였다. 생성된 미크로스피어의 평균 입자 크기는 20㎛이며 메트로니다졸의 함유량은 28중량%이었다.1.5 g of poly D, L-lactic acid-glycolic acid copolymer (lactic acid / glycolic acid = 7/3 w / w) having an average molecular weight of 7,500 and 0.5 g of metronidazole crushed to an average particle diameter of about 5 μm were added to 5 ml of dichloromethane. Mixing gave a suspension. This suspension was added to 50 ml of an aqueous solution containing 5% by weight of polyvinyl alcohol (DP = 1,500) and stirred at 600 rpm for 10 minutes with a mechanical stirrer to prepare an emulsion. The emulsion was slowly added to 250 ml of distilled water, stirred at 200 rpm at room temperature for 1 hour, and then centrifuged to separate the microspheres and washed with distilled water. The resulting microspheres had an average particle size of 20 μm and a metronidazole content of 28 wt%.

상기 미크로스피어 25mg과 인산염 완충용액 10ml를 사용하여 실시예 1과 동일하게 하여 약물 방출 특성(자외선 흡광도 : 254nm) 및 방출되는 약물의 생리활성을 측정하였으며, 그 결과는 하기 표 5 및 6과 같다.The drug release characteristics (ultraviolet absorbance: 254 nm) and the physiological activity of the released drug were measured in the same manner as in Example 1 using 25 mg of microspheres and 10 ml of phosphate buffer solution, and the results are shown in Tables 5 and 6 below.

[표 5]TABLE 5

[표 6]TABLE 6

[실시예 4]Example 4

평균 분자량이 7,500인 폴리 D, L-락트산-글리콜산 공중합체(락트산/글리콜산=7/3 w/w) 2.1g과 평균 입경 약 5㎛로 잘게 부순 암피실린 0.9g을 디클로로메탄 7.5ml에 가하고 잘 혼합하여 현탁액을 제조하였다. 이 현탁액을 폴리비닐알코올(DP=1,500) 8중량%를 포함하는 수용액 50ml에 가하고 600rpm에서 10분동안 기계 교반기로 교반하여 유탁액을 제조하였다. 상기 유탁액을 증류수 350ml에 천천히 가하면서 실온에서 200rpm으로 1시간동안 저어준 후 원심분리하여 미크로스피어를 분리하고 증류수로 세척하였다. 생성된 미크로스피어의 평균 입자 크기는 23㎛이며 메트로니다졸의 함유량은 24중량%이었다.2.1 g of poly D, L-lactic acid-glycolic acid copolymer (lactic acid / glycolic acid = 7/3 w / w) having an average molecular weight of 7,500 and 0.9 g of ampicillin finely ground to an average particle diameter of about 5 μm were added to 7.5 ml of dichloromethane. Mix well to prepare a suspension. This suspension was added to 50 ml of an aqueous solution containing 8% by weight of polyvinyl alcohol (DP = 1,500) and stirred at 600 rpm for 10 minutes with a mechanical stirrer to prepare an emulsion. The emulsion was slowly added to 350 ml of distilled water, stirred at 200 rpm at room temperature for 1 hour, followed by centrifugation to separate the microspheres and washing with distilled water. The resulting microspheres had an average particle size of 23 μm and a metronidazole content of 24% by weight.

상기 미크로스피어 30mg과 인산염 완충용액 10ml를 사용하여 실시예 1과 동일하게 하여 약물 방출 특성(자외선 흡광도 : 254nm)을 측정하였으며, 그 결과는 하기 표 7과 같다.The drug release characteristics (ultraviolet absorbance: 254 nm) were measured in the same manner as in Example 1 using 30 mg of the microspheres and 10 ml of the phosphate buffer solution, and the results are shown in Table 7 below.

[표 7]TABLE 7

[실시예 5 내지 11][Examples 5 to 11]

폴리 D, L-락트산 또는 폴리 D, L-락트산-글리콜산 공중합체 및 디클로로메탄을 사용하고 약물 및 비이온성 계면활성제의 종류 및 양과 기타조건을 하기 표 8과 같이 한 것을 제외하고는 실시예 1과 동일하게 실시하였으며, 입자의 평균 입경, 약물함유량 및 총 약물 방출기간은 하기 표 8과 같다.Example 1 except that poly D, L-lactic acid or poly D, L-lactic acid-glycolic acid copolymer and dichloromethane were used, and the kind and amount and other conditions of the drug and nonionic surfactant were as shown in Table 8 below. It carried out in the same manner as, the average particle diameter, drug content and total drug release period of the particles are shown in Table 8.

[표 8]TABLE 8

Claims (7)

생분해성 고분자 물질과 평균입경이 0㎛보다 크고 5㎛이하인 수용성 항생제 약물을, 디클로로메탄, 클로로포름 및 아세트산에틸로 이루어진 군으로부터 선택된 유기용매에 현탁시키고, 상기 현탁액을 1 내지 15중량%의 비이온성 계면활성제 수용액에 유화시키고, 상기 유액을 증류수로 희석하고, 상기 희석액으로부터 생성된 미크로스피어를 분리하는 단계를 포함하는 서방성 미크로스피어의 제조방법.A biodegradable polymeric material and a water-soluble antibiotic drug having an average particle diameter of greater than 0 µm and less than 5 µm are suspended in an organic solvent selected from the group consisting of dichloromethane, chloroform and ethyl acetate, and the suspension is subjected to 1 to 15% by weight of a nonionic interface. Emulsifying in an aqueous activator solution, diluting the emulsion with distilled water, the method for producing a sustained-release microspheres comprising the step of separating the microspheres produced from the diluent. 제1항에 있어서, 상기 생분해성 고분자 물질이 분자량 2,000 내지 10,000 범위의 폴리락트산 또는 락트산과 글리콜산 공중합체의 올리고머인 것을 특징으로 하는 방법.The method of claim 1 wherein the biodegradable polymeric material is an oligomer of polylactic acid or a lactic acid and glycolic acid copolymer having a molecular weight ranging from 2,000 to 10,000. 제1항에 있어서, 상기 생분해성 고분자 물질과 유기 용매의 비가 75/25 내지 10/90중량%인 것을 특징으로 하는 방법.The method of claim 1, wherein the ratio of the biodegradable polymeric material and the organic solvent is 75/25 to 10/90% by weight. 제1항에 있어서, 상기 비이온성 계면활성제가 폴리비닐알코올, 폴리비닐피롤리돈 또는 폴리에틸렌옥시드인 것을 특징으로 하는 방법.The method of claim 1 wherein the nonionic surfactant is polyvinyl alcohol, polyvinylpyrrolidone or polyethylene oxide. 제1항에 있어서, 상기 희석액 중 비이온성 계면활성제가 0.1 내지 1중량%인 것을 특징으로 하는 방법.The method of claim 1, wherein the nonionic surfactant in the diluent is 0.1 to 1% by weight. 제1항의 방법에 따라 제조된, 수용성 항생제 약물을 20 내지 50중량% 범위로 함유하며, 상기 약물이 1 내지 3주 동안 일정하게 방출되는 것을 특징으로 하는 생분해성 고분자 물질로 된 서방성 미크로스피어.A sustained-release microsphere made of a biodegradable polymeric material, comprising the water-soluble antibiotic drug prepared in the method of claim 1 in a range of 20 to 50% by weight, wherein the drug is constantly released for 1 to 3 weeks. 제6항에 있어서, 상기 약물이 테트라싸이클린 히드로클로라이드, 미노싸이클린 히드로클로라이드, 암피실린, 겐타마이신 설페이트인 것을 특징으로 하는 미크로스피어.The microsphere of claim 6, wherein the drug is tetracycline hydrochloride, minocycline hydrochloride, ampicillin, gentamicin sulfate.
KR1019950010671A 1995-05-01 1995-05-01 Method for the preparation of sustained release microsphere containing water soluble antibiotics KR100250572B1 (en)

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KR100845009B1 (en) 2007-08-07 2008-07-08 한국생명공학연구원 Porous polymer particles immobilized charged molecules and method thereof
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