CN1154066A - 褐霉酸片的制备 - Google Patents

褐霉酸片的制备 Download PDF

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CN1154066A
CN1154066A CN95194320A CN95194320A CN1154066A CN 1154066 A CN1154066 A CN 1154066A CN 95194320 A CN95194320 A CN 95194320A CN 95194320 A CN95194320 A CN 95194320A CN 1154066 A CN1154066 A CN 1154066A
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salt
fucidin
granule
slice
packed density
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CN1070703C (zh
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E·P·拉斯穆森
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Leo Pharma AS
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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Communicable Diseases (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Formation And Processing Of Food Products (AREA)

Abstract

没有肠溶衣的褐霉酸钠盐片的制备，该制备方法是将干粉形式的活性成分在滚压机中压片，然后粉碎成可压片的颗粒。

Description

褐霉酸片的制备
褐霉酸是一种既可肠道又可非肠道使用的抗菌素。
用作固体口服形式时，常用易溶于水和乙醇的钠盐。
八十年代初，褐霉酸钠盐用作胶囊和片剂，片剂为肠溶的，由于胶囊剂的胃部付作用，片剂为优选剂型。
饭前用片剂(直径大于6-7mm)时，也许是由于‘片子随着食物’，观察到血药浓度的个体差异较大，取决于食物经过胃部的时间，这一因素对每个人来说都是不同的。在片子到达溶解肠溶片的胃肠道部分之前，活性褐霉酸钠盐未被释放出，其释放取决于与食物一起经过胃部的时间和胃肠道的PH，这导致受治疗病人血药浓度难以预计的变化。
为避免血药浓度不利的差别，有必要生产没有肠溶衣的片剂。可是，为了避免或减少胃肠道上部胃部的副作用，需要制成一种能迅速崩解的片剂，所述片剂应是薄膜衣片，用有机溶剂薄膜包衣，以避免褐霉酸钠盐的不快气味。
褐霉酸钠盐具有较大的粉末体积，流动性差，加上对模壁的磨蚀作用，因此使其不能在压片机(打锭)中压片或至少是非常困难的，唯一的可能性是在压片前制成颗粒。
湿法造粒可使问题得到部分解决：掺合，混匀，重新研磨及润滑，在制备过程中使用有机溶剂(如氯代烃)。
出于对环境和/或毒理的考虑，应避免使用这类有机溶剂。
由于褐霉酸钠盐在水或醇中的高溶解度，用水或醇将其湿润进行湿法造粒是不可能的。而是试图把所述溶剂喷到盐上，但这样得到的物质非常疏松、体积庞大，很难将其一次投到压片机中，更糟的是，这将导致片子的稳定性更差。
丙酮应该是一种更好的溶液，但由于此溶剂的高度易燃性，必须要在隔离的安全的加工厂中进行操作。
现已证明压片前所需的造粒过程可用叫作滚压机或‘Chilsonator’这一特殊加工设备用干法造粒来完成。这些机器在特高压力下将预混合的粉末在两个反向转动的滚筒中压紧。所得物质形状取决于滚筒的构形，为脆螺条，片或碎片，比上述湿法制出的颗粒的填充密度0.40g/cm3要密得多。压紧的物质被粉碎成适于压片造粒的、填充密度范围在0.45-0.9(优先为0.5-0.7)g/cm3的颗粒，并用此物质做成成品片子。
因而本发明提供了一种制备没有肠溶衣的褐霉酸钠盐片的方法，该方法是将干粉状的褐霉酸钠盐在滚压机中压紧，并将压紧的物质粉碎成填充密度范围在0.45-0.9g/cm3之间的颗粒，然后这些颗粒被压成片子。
本发明进一步提供了一种没有肠溶衣的褐霉酸钠盐片，该片剂是由被压紧褐霉酸钠盐的干燥颗粒制成的，该颗粒的填充密度为0.45-0.9g/cm3。另一方面，本发明提供了一种用于制备刚刚定义的片剂的颗粒，该颗粒含有被压紧的的褐霉酸钠盐粉末，并且填充密度为0.45-0.9g/cm3。
本发明还提供了一种制备没有肠溶衣的褐霉酸钠盐片的方法，该方法是将压紧的粉末状的、填充密度为0.45-0.9g/cm3的褐霉酸钠盐制成片子。
用压紧的物质制成的颗粒平均微粒大小还是在100μm-300μm更好。颗粒填充密度在0.5-0.7g/cm3更好。
用α-生育酚将活性物质包衣也是可能的，这会使片剂的贮存稳定性更好。
对这些新片子的试验表明，它与普通片的生物利用度数值相同，因而新片子是将以往对人类治疗的有利作用与对环境更好、更安全的生产方法结合在一起。
另外，已证明无论是有还是没有α-生育酚包衣的新片子，都比传统的(或以前的)湿法造粒制出的片子的贮存稳定性要高。
以下实施例仅作说明用：实施例1
粉末状的褐霉酸钠盐进行湿法造粒。
被压紧的物质的密度为0.46g/cm3。粉碎并筛分出颗粒大小为0.160mm的微粒。将颗粒压成每片含250mg褐霉酸钠盐的片子(批号：9106651)。用羟丙基甲基纤维素将片子薄膜包衣。
实施例2
用α-生育酚包衣的褐霉酸钠盐作起始原料重复实施例1的操作(批号：9106151)。被压紧的物质的填充密度为0.46g/cm3，粉碎后颗粒平均大小为0.25mm。实施例3
在指温度下，将实施例1和实施例2的片子及用填充密度为0.40g/cm3的粉末湿法造粒(用高速颗粒机制成)做成的片子贮存于有聚丙烯盖子的玻璃瓶中。用Ph.Eur.2nd Ed，PII798中所述反相HPLC法测得的分析结果列于下表：
                         褐霉酸片剂-贮存比较
    贮    存     降  解  产  物，以％计
温  度 时间，月   批  号14360R   批  号9106651   批号9106151
    20     0     0.3     0.9     0.5
    20     6     0.7     1.2     0.9
    20     12     1.0     2.0     0.5
    20     24     2.5     0.9     0.5
    20     36     2.8     2.1     0.4
    20     48     5.2     n.d.     0.6
    30     0     0.3     0.9     0.5
    30     6     0.9     0.9
    30     12     3.4     0.7     0.5
    30     24     11.8     1.6     0.7
    30     36     14.2     2.6     0.7
    40     0     0.3     0.9     0.5
    40     3     0.5     2.1     0.5
    40     6     1.7     1.6     0.9
    40     12     9.0     1.9     2.0
在所有的试验贮存温度下都有明显的改进但最明显的是在30℃和40℃时。

Claims (9)

1、一种制备没有肠溶衣的褐霉酸钠盐片的方法，该方法是将干粉状的褐霉酸钠盐在滚压机中压紧，将制成的压紧的物质粉碎成填充密度为0.45-0.9g/cm3g的颗粒，然后由颗粒压成片子。
2、一种权利要求1的方法，所述颗粒微粒大小为100-300μm。
3、一种权利要求1或权利要求2的方法，其中颗粒的填充密度为0.5-0.7g/cm3。
4、一种上述任意权利要求的方法，其中粉末状的褐霉酸钠盐是用α-生育酚包衣。
5、一种上述任意权利要求的方法，其中的片子被做成薄膜衣片。
6、没有肠溶衣的褐霉酸钠盐片，是由被压紧的粉末状的褐霉酸钠盐的干燥颗粒制成的，该颗粒的填充密度为0.45-0.9g/cm3。
7、一种用于制备权利要求6的片剂的颗粒，该颗粒含有被压紧的粉末状的褐霉酸钠盐，并且颗粒的填充密度为0.45-0.9g/cm3。
8、一制备没有肠溶衣的褐霉酸钠盐片剂的方法，该方法是将填充密度为0.45-0.9g/cm3的、被压紧的粉末状的褐霉酸钠盐压成片子。
9、权利要求6的片子，或权利要求7的颗粒，或权利要求8的方法，所述填充密度为0.5-0.7g/cm3。
CN95194320A 1994-07-26 1995-07-21 褐霉酸片的制备 Expired - Lifetime CN1070703C (zh)

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GB9415048A GB9415048D0 (en) 1994-07-26 1994-07-26 Tablet
GB9415048.9 1994-07-26

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CN1154066A true CN1154066A (zh) 1997-07-09
CN1070703C CN1070703C (zh) 2001-09-12

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JP (1) JP3853358B2 (zh)
KR (1) KR100358614B1 (zh)
CN (1) CN1070703C (zh)
AT (1) ATE209496T1 (zh)
AU (1) AU681980B2 (zh)
CA (1) CA2193235C (zh)
CZ (1) CZ286197B6 (zh)
DE (1) DE69524226T2 (zh)
DK (1) DK0773783T3 (zh)
ES (1) ES2163521T3 (zh)
FI (1) FI117666B (zh)
GB (1) GB9415048D0 (zh)
HU (1) HU221483B (zh)
NZ (1) NZ290806A (zh)
PL (1) PL180935B1 (zh)
PT (1) PT773783E (zh)
RO (1) RO118633B1 (zh)
RU (1) RU2140272C1 (zh)
WO (1) WO1996003128A1 (zh)

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AU9022098A (en) * 1997-08-20 1999-03-08 Fuisz Technologies Ltd. Process for improving flow and compression of tableting compositions
AU2006310873B2 (en) 2005-10-31 2012-05-24 Leo Pharma A/S Preparation of an antibiotic crystalline fusidic acid
FR2895908B1 (fr) * 2006-01-12 2008-03-28 France Etat Procede de fabrication d'une forme pharmaceutique de phosphate d'oseltamivir
JP5249568B2 (ja) * 2007-12-06 2013-07-31 旭化成ケミカルズ株式会社 成形用粉末、およびこれを用いた圧縮成形組成物、ならびに成形用粉末の製造方法
DE102008051783A1 (de) * 2008-10-17 2010-04-22 Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg Valsartan enthaltende Tablette
EP2382968A1 (en) 2010-03-26 2011-11-02 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Particle size distribution of fusidic acid granules

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NL7411402A (nl) * 1973-09-13 1975-03-17 Leo Pharm Prod Ltd Werkwijze voor het bereiden van een middel tegen arthritis.
EP0300073A1 (en) * 1987-07-22 1989-01-25 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Use of fusidic acid in the treatment of aids-related complex and full-blown aids

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NZ290806A (en) 1998-01-26
AU681980B2 (en) 1997-09-11
PL318261A1 (en) 1997-05-26
PL180935B1 (pl) 2001-05-31
HU221483B (en) 2002-10-28
CA2193235A1 (en) 1996-02-08
CN1070703C (zh) 2001-09-12
CZ22997A3 (en) 1997-04-16
KR100358614B1 (ko) 2003-01-10
HUT76836A (en) 1997-11-28
AU3164495A (en) 1996-02-22
RO118633B1 (ro) 2003-08-29
GB9415048D0 (en) 1994-09-14
FI965214A (fi) 1996-12-27
EP0773783B1 (en) 2001-11-28
HU9700217D0 (en) 1997-04-28
DE69524226T2 (de) 2002-06-27
FI965214A0 (fi) 1996-12-27
CZ286197B6 (cs) 2000-02-16
KR970704447A (ko) 1997-09-06
JPH10502937A (ja) 1998-03-17
ATE209496T1 (de) 2001-12-15
DK0773783T3 (da) 2002-04-02
ES2163521T3 (es) 2002-02-01
WO1996003128A1 (en) 1996-02-08
EP0773783A1 (en) 1997-05-21
FI117666B (fi) 2007-01-15
RU2140272C1 (ru) 1999-10-27
JP3853358B2 (ja) 2006-12-06
CA2193235C (en) 2008-03-18
PT773783E (pt) 2002-04-29
DE69524226D1 (de) 2002-01-10

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