CN1183151C - 替利霉素的球状附聚物、其制备方法及其在制备药剂中的用途 - Google Patents
替利霉素的球状附聚物、其制备方法及其在制备药剂中的用途 Download PDFInfo
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- CN1183151C CN1183151C CNB008120943A CN00812094A CN1183151C CN 1183151 C CN1183151 C CN 1183151C CN B008120943 A CNB008120943 A CN B008120943A CN 00812094 A CN00812094 A CN 00812094A CN 1183151 C CN1183151 C CN 1183151C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- 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
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- 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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Abstract
本发明涉及球状替利霉素附聚物,并且涉及其制备方法,包括制备替利霉素晶体的悬浮液,所述晶体随后用不溶于逐渐结晶的替利霉素的相进行包衣。本发明球状替利霉素附聚物用于制备微胶囊。
Description
本发明涉及替利霉素(telithromycin)的球状附聚物、其制备方法及其在制备药剂中的用途。
替利霉素或11,12-二脱氧-3-脱((2,6-二脱氧-3-C-甲基-3-O-甲基-α-L-核吡喃己糖基)氧)-6-O-甲基-3-氧代-12,11-(氧羰基((4-(4-(3-吡啶基)-1H-咪唑-1-基)丁基)亚氨基))-红霉素是具有下述结构的有抗生素性质的产物:
其在欧洲专利680967中描述并要求保护。
对于该产物,口服途径是优选的给药形式。一些患者,特别是儿童,吞咽片剂和胶囊有困难,因此理想的是得到给药的其它有效形式,诸如例如口服悬浮剂,易于使用或在使用时临时配制。
替利霉素是有效的成分,其具有令人不愉快的味道。因此,必须制备盖仑制剂,其掩盖了产物的味道,但是提供好的生物可利用率。
替利霉素的物化特性使其可微胶囊化,即,用聚合物或聚合物的混合物包衣活性成分。
微胶囊化可通过喷涂聚合物或通过界面聚合或通过凝聚进行。为得到好的微胶囊化,必须得到活性成分的球状颗粒,颗粒不能太小,以防止其彼此附聚,也不能太大,从而溶解不致太慢,并且颗粒必须是球状的,从而用聚合物包覆活性成分是合适的,并且是为了得到良好的活性成分释放动力学。
本发明涉及替利霉素的附聚物。
如下所述,通过将晶体直接转变成球型物质得到球状附聚物。
关于通常意义的球状附聚物,可参考Frederica Guillaume和Anne-Marie Guyot-Hermann在Il Farmaco XLVIII 1993第473页以及其后各页的文章报导。
本发明的附聚物可很好地微胶囊化,本发明特别涉及其用途,其特征在于球状附聚物被一层聚合物包围以得到所需的盖仑制剂药剂形式,例如微胶囊。
本发明涉及替利霉素球状附聚物,其特征在于颗粒的尺寸在30-400微米之间。
本发明尤其涉及替利霉素球状附聚物,其特征在于颗粒的中值尺寸位于80-150微米之间,特别是替利霉素球状附聚物,其特征在于颗粒的中值尺寸位于趋近100微米处,即,其特征在于半数附聚物尺寸小于100微米。
本发明还涉及制备球状附聚物的方法,其特征在于制备替利霉素的悬浮液,这些晶体随后用不溶于逐渐结晶的替利霉素的相进行包衣。
本发明特别涉及一种制备方法,其特征在于使用替利霉素在丙酮中的溶液。
本发明更特别涉及一种制备方法,其特征在于在丙酮/异丙醚混合物中进行结晶。
在一个优选的实施方案中,结晶在-5--15℃进行。通过调节搅拌速度控制球状附聚物的尺寸。
最后,本发明涉及通过上述制备方法得到的替利霉素的球状附聚物。
下述实施例非限制性地说明本发明。
实施例:
a)丙酮溶液的制备
在氮气气氛下引入下列物质:
-替利霉素 64g
-无水纯丙酮 128ml
在轻微的氮气过压下、在19-21℃之间进行搅拌,进行检查以确保溶解完全。
如果需要,加入水以得到2.9%产物,加入:
-去离子水 0.26ml
b)结晶
在氮气气氛下将下列物质引入装配了机械搅拌器、测温探针和氮气入口的双夹套反应器中:
-异丙醚 640ml
-无水纯丙酮 12.8ml
温度稳定在19-21℃。
加入5重量%的丙酮溶液,同时以350rpm搅拌。
然后,以350rpm搅拌的同时,通过在
-异丙醚 3.2ml中用声处理悬浮0.96g微粒化的替利霉素来引发结晶。
引发后立即发生结晶。
在20±1℃进行搅拌15分钟,然后在30分钟将悬浮液冷却到-10±1℃。
加入剩余的丙酮溶液:
-替利霉素丙酮溶液 157.2g
在-10℃再搅拌1小时。
c)分离
彻底干燥并用澄清法洗涤,进行2次,每次使用
-异丙醚 64ml
在真空下40℃炉中进行干燥,然后在500μm网栅筛分。得到50.4g替利霉素球状附聚物。
颗粒测定法
用HELOS SYMPATEC型粒度计通过激光衍射测定颗粒尺寸。
得到的结果如下:
10%的颗粒直径<77微米
50%的颗粒直径<107微米
90%的颗粒直径<166微米
图1表示上述操作得到的附聚物,标度为:
1cm=150微米
用途
实施例的产品用于通过简单的凝聚或通过直接喷涂适宜聚合物制备微胶囊,微胶囊用于制备临时制备的口服悬浮液。
制备的悬浮液可被儿童接受,并且保持良好的释放动力学。
Claims (6)
1.制备替利霉素球状附聚物的方法,其特征在于制备替利霉素晶体的悬浮液,这些晶体随后用不溶于逐渐结晶的替利霉素的相进行包衣。
2.根据权利要求1的制备方法,其特征在于使用替利霉素在丙酮中的溶液。
3.根据权利要求1的制备方法,其特征在于在丙酮/异丙醚混合物中进行结晶。
4.根据权利要求2的制备方法,其特征在于在丙酮/异丙醚混合物中进行结晶。
5.根据权利要求1-4任一项的制备方法,其特征在于结晶在-5至-15℃进行。
6.替利霉素的球状附聚物用于制备微胶囊化形式的用途,其特征在于球状附聚物被一层聚合物包围以得到所需的盖仑制剂形式。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9910810A FR2797875B1 (fr) | 1999-08-26 | 1999-08-26 | Agglomerats spheriques de telithromycine, leur procede de preparation et leur application dans la preparation de formes pharmaceutiques |
FR99/10810 | 1999-08-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1371386A CN1371386A (zh) | 2002-09-25 |
CN1183151C true CN1183151C (zh) | 2005-01-05 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB008120943A Expired - Fee Related CN1183151C (zh) | 1999-08-26 | 2000-08-28 | 替利霉素的球状附聚物、其制备方法及其在制备药剂中的用途 |
Country Status (34)
Country | Link |
---|---|
US (1) | US6825218B1 (zh) |
EP (1) | EP1212336B1 (zh) |
JP (1) | JP4871467B2 (zh) |
KR (1) | KR100718222B1 (zh) |
CN (1) | CN1183151C (zh) |
AR (1) | AR025398A1 (zh) |
AT (1) | ATE255590T1 (zh) |
AU (1) | AU774385B2 (zh) |
BR (1) | BR0013569B1 (zh) |
CA (1) | CA2382497C (zh) |
CO (1) | CO5190666A1 (zh) |
CZ (1) | CZ2002594A3 (zh) |
DE (1) | DE60006976T2 (zh) |
DK (1) | DK1212336T3 (zh) |
EA (1) | EA005080B1 (zh) |
ES (1) | ES2209970T3 (zh) |
FR (1) | FR2797875B1 (zh) |
HK (1) | HK1049167B (zh) |
HR (1) | HRP20020167B1 (zh) |
HU (1) | HU229075B1 (zh) |
IL (2) | IL148128A0 (zh) |
ME (2) | ME00112B (zh) |
MX (1) | MXPA02001988A (zh) |
NO (1) | NO322622B1 (zh) |
PL (1) | PL204100B1 (zh) |
PT (1) | PT1212336E (zh) |
RS (1) | RS50433B (zh) |
SI (1) | SI1212336T1 (zh) |
SK (1) | SK287588B6 (zh) |
TR (1) | TR200200506T2 (zh) |
TW (1) | TWI272949B (zh) |
UA (1) | UA73523C2 (zh) |
WO (1) | WO2001014393A2 (zh) |
ZA (1) | ZA200201599B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9902202D0 (sv) * | 1999-06-10 | 1999-06-10 | Astra Ab | Production of aggregates |
FR2821747B1 (fr) * | 2001-03-09 | 2004-07-02 | Ethypharm Lab Prod Ethiques | Suspension de telithromycine a gout masque |
EP1524966B1 (en) * | 2002-07-19 | 2009-11-25 | Aventis Pharma S.A. | Taste masked oral composition of telithromycin |
WO2004009059A1 (en) * | 2002-07-19 | 2004-01-29 | Aventis Pharma S.A. | Taste masked oral composition of telithromycin |
US20040013737A1 (en) * | 2002-07-19 | 2004-01-22 | Philippe Becourt | Taste masked oral composition of telithromycin |
EP1610878B1 (en) * | 2003-02-21 | 2014-09-03 | University Of Bath | Process for the production of particles |
US20050014706A1 (en) * | 2003-07-14 | 2005-01-20 | Kanakeshwari Falzari | Method of treating tuberculosis |
WO2007039914A2 (en) * | 2005-10-06 | 2007-04-12 | Alembic Limited | Novel polymorphs of telithromycin |
US20090075917A1 (en) * | 2007-09-19 | 2009-03-19 | Protia, Llc | Deuterium-enriched telithromycin |
KR101324862B1 (ko) * | 2011-07-12 | 2013-11-01 | (주)에이에스텍 | 클로피도그렐 황산수소염의 구형 입자, 이를 포함하는 약학적 조성물 및 이의 제조방법 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE31635T1 (de) * | 1983-06-22 | 1988-01-15 | Univ Ohio State Res Found | Herstellung von feinen materialien. |
JPH02227130A (ja) * | 1989-02-28 | 1990-09-10 | Taisho Pharmaceut Co Ltd | 球形微小凍結粒子の製造法 |
FR2719587B1 (fr) * | 1994-05-03 | 1996-07-12 | Roussel Uclaf | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments. |
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