CN1066186A - 含地红霉素的药用制剂 - Google Patents
含地红霉素的药用制剂 Download PDFInfo
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- CN1066186A CN1066186A CN92103161A CN92103161A CN1066186A CN 1066186 A CN1066186 A CN 1066186A CN 92103161 A CN92103161 A CN 92103161A CN 92103161 A CN92103161 A CN 92103161A CN 1066186 A CN1066186 A CN 1066186A
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Abstract
本发明公开了一种改进的片剂，它含有地红霉素
的一种新的多晶型物。
Description
本发明涉及药用制剂，具体地讲，涉及含大环内酯抗菌素新的多晶型物的片剂。
地红霉素（dirithromycin）是由红霉素衍生而来的大环内酯抗菌素。该抗菌素在美国专利第4，048，306号中有详述，其化学名称为红霉素9-脱氧-11-脱氧-9，11-[亚氨基[2-（2-甲氧基乙氧基）亚乙基]氧基]-[9S，16R]。按美国专利第4，048，306号所述方法制得的地红霉素为多晶型物形式，下文称为“形式Ⅰ”。它具有如下的X射线衍射谱，其中D代表晶面间距;Ⅰ/Ⅰ0代表相对强度
D（ 
） Ⅰ/Ⅰ0
11.28 1.00
9.81 0.35
8.53 0.76
7.67 0.23
7.12 0.02
6.94 0.02
6.66 0.10
6.39 0.09
5.97 0.21
5.65 0.69
5.42 0.67
5.18 0.23
4.98 0.08
4.83 0.31
4.64 0.07
D（ 
） Ⅰ/Ⅰ0
4.43 0.40
4.26 0.17
4.14 0.05
4.06 0.15
3.86 0.15
3.76 0.17
3.62 0.10
3.50 0.08
3.43 0.03
3.35 0.07
3.04 0.07
2.95 0.02
2.88 0.02
2.84 0.02
2.71 0.03
2.66 0.02
2.58 0.03
本申请人现在发现形式Ⅰ是亚稳态的，因此不适合于药用制剂（如：片剂）
然而，根据本发明，我们惊奇地发现第二种地红霉素的多晶形物（下文称为“形式Ⅱ”）是稳定的，因此非常适合于药用制剂，例如片剂。
从而，在本发明的一个实施例中，提供了一种含地红霉素形式Ⅱ作为活性成分的片剂。当然，该片剂也将包含一种或多种药学上可接受的赋形剂，例如：粘合剂、润滑剂、崩解剂、填料等。
新的多晶型物主要具有以下X射线粉末衍射谱，其中，D代表晶面间距;Ⅰ/Ⅰ0代表相对强度。
D（ 
） Ⅰ/Ⅰ0
14.17 0.02
11.96 0.27
10.43 0.11
9.65 1.00
8.86 0.84
8.18 0.54
7.07 0.33
6.99 0.10
6.84 0.21
6.59 0.03
6.24 0.05
6.07 0.29
5.97 0.19
5.77 0.06
5.54 0.36
5.50 0.47
5.45 0.26
5.13 0.22
5.11 0.29
4.84 0.29
4.75 0.47
4.72 0.42
4.50 0.62
4.44 0.31
4.24 0.20
4.20 0.05
4.11 0.17
4.09 0.18
3.92 0.14
3.87 0.12
3.83 0.12
3.73 0.06
3.55 0.08
3.49 0.15
D（ ） Ⅰ/Ⅰ0
3.46 0.07
3.42 0.11
3.33 0.05
3.17 0.04
3.11 0.02
2.96 0.04
2.83 0.02
2.74 0.04
2.57 0.03
上述X射线粉末衍射谱是用装有石墨单色仪的Nicolet 12V粉末衍射仪测定的;铜辐射为1＝1.5418/埃。本领域技术人员知道，强度值受诸如样品制备和仪器参数的改变等因素影响，因此，衍射谱主要由D-间距构成。
由于片剂的活性成分（形式Ⅱ）将用作药物，所以它应达到药用纯度。鉴于稳定的目的，形式Ⅱ不应含大量形式Ⅰ。形式Ⅱ最好应当含不到10%形式Ⅰ，不到5%更好。
地红霉素是很有效的抗菌素。有许多较其它大环内酯抗菌素优越的地方，因为日给药总量仅需不到500mg便可。但由于该化合物对酸性介质（如胃中存在的酸性介质）很敏感，在设计口服制剂时需加以注意。在本说明书上下文中，引用美国专利第4，755，385为参考文献，本发明片剂最好用抗胃液膜包衣;即“肠溶衣”。包衣的性质对于本领域技术人员来说是公知的。往往用涂漆法包衣。
下面用实施例1-4说明形式Ⅱ的制备
实施例1
由丙酮溶剂化合物中分离地红霉素
将20g非溶剂化地红霉素加到由81ml丙酮和9ml水组成的混合溶剂中。加热至约60℃，保持60℃直至反应体积为35ml。用1小时再缓慢加100ml水，让混合物冷却至室温，将冷却的混合物置于冰浴中，搅拌1小时。过滤分离固体，用25ml冷的含67%水和33%丙酮的溶剂洗涤。室温下用40ml水洗涤固体。将地红霉素丙酮溶剂化物湿饼于室温静置过夜。
向丙酮溶剂化物湿饼中加180ml水，将混合物加热至70℃，通氮气并在70℃下搅拌4小时。立即过滤分离固体，并用30ml已温热至70℃的水洗涤。分离的固体于40℃真空干燥过夜。经X射线粉末衍射法鉴定知该固体为形式Ⅱ地红霉素。
总产率90.8%
实施例2
形式Ⅱ地红霉素的分离
将10.0g地红霉素的丙酮溶剂化物在搅拌和通氮气下加到100ml水中。将反应混合物加热至74℃，在约72-75℃下搅拌4小时。真空过滤温热的混合物，用35ml 60℃水洗，固体在50℃真空干燥过夜。经X射线粉末衍射法鉴定知该固体为形式Ⅱ地红霉素，反应总产量为8.74g（87.4%）。
实施例3
形式Ⅱ地红霉素的分离
将15g形式Ⅰ地红霉素加到150ml水中。将反应混合物加热至74℃，74℃下搅拌4小时。过滤分离固体用70℃水洗（40ml×2）。试样于25℃真空烘箱中干燥68小时，经X射线粉末衍射鉴定知固体为形式Ⅱ地红霉素。
产率：97.5%
实施例4
形式Ⅱ地红霉素的分离
将3.01g形式Ⅰ地红霉素加到15ml乙酸乙酯中，将反应混合物加热至约76℃，保持沸腾直至反应体积为约10ml。加20ml正辛烷。让混合物冷却至室温。过滤分离固体，试样于室温下干燥。经X射线粉末衍射法鉴定知产物为形式Ⅱ地红霉素。
总产率：95%
含地红霉素的药用制剂的一般制备方法已在美国专利第4，755，385号公开。制备方法大体上包括将形式Ⅱ与必要的药学上可接受载体混合，随后压成片剂，也可以涂上抗胃液包衣。然而，下面的具体实施例叙述本发明的色衣片剂的制备方法。
实施例5
下列数值对应于含250mg地红霉素形式Ⅱ作为活性成分的片剂。
片心 MG/片
地红霉素形式Ⅱ 250.0mg
碳酸镁 250.0mg
微晶纤维素 199.6mg
淀粉甘醇酸钠 10.0mg
羟丙基纤维素 15.0mg
Croscarmellose Sodium 10.0mg
硬酯酸镁 12.0mg
底涂层
羟丙基甲基纤维素2910（E-5） 16.21mg
聚乙二醇（3350） 4.63mg
丙二醇 6.95mg
苯甲醇 2.31mg
肠溶包衣
甲基丙烯酸共聚物
水分散体（L30D）（固体） 48.65mg
颜色混合白（Color Mixture
White）T3166-WE（固体） 20.31mg
柠檬酸三乙酯 1.65mg
滑石 痕量
片心
大量制造片心时可以制成单一体或其碎块，压制之前，将全部成分混合成干燥的混合物。将地红霉素（形式Ⅱ）、碳酸镁、微晶纤维素、淀粉甘醇酸钠、羟丙基纤维素和硬酯酸镁在螺带式混合机或其它类型的适当混合机（如：V型混合物、锥形混合机等）中充分混合。用滚压机或其它相当的干燥制粒设备将所得粉末混合物压制。必要时，用振荡制粒机、Fitz研磨机或其它适当的研磨设备制粒。将制好的粒与微晶纤维素、Croscarmellose sodium和硬酯酸镁在螺带式混合机或其它类型适当混合机（如V型混合机、锥型混合机等）中混合。混合后，将重量与理论值比较，粒剂在常规型压制机械（如Manesty Betapress等）中压制。在压制的全部过程中都进行片心的重量检测，将试样汇集待测。
底涂层：
将羟丙基甲基纤维素2910（E-5）、聚乙二醇、丙二醇和苯甲醇溶于蒸馏水制得底涂料。用Groen釜、贮罐或相当的设备和搅拌如Lightening混合机或相当的设备可制得该涂层溶液。
在accela Cota涂覆盘或相当的膜涂覆设备中将涂层溶液应用于上面得到的片心上。使用适当的喷洒系统，例如Accela-Spray Ⅱ，Nordson喷洒装置、Graco喷洒装置或相当的喷洒设备。必要时可改变喷洒和干燥周期直至涂上所需量的涂层溶液。
肠溶涂层
将甲基丙烯酸水分散体（L30D）、颜色混合白（T3166-WE）和柠檬酸三乙酯与蒸馏水混合制得肠溶涂层混悬液，用Groen釜、贮罐或相当的设备以及提供搅拌的设备（如Lightening混合机）或相当的设备可制得所述涂层混悬液。
在Accela Cota涂覆盘或相当的膜涂覆设备中将涂层混悬液应用于涂有底涂层的片剂上。使用适当的喷洒系统，例如Accela-Spray Ⅱ，Nordson喷洒装置、Graco喷洒装置或相当的喷洒设备。必要时可改变喷洒和干燥周期直至涂上所需量的涂层混悬液，轻轻撒些滑石粉便制成了片剂（撒滑石粉是为了增加包衣片剂的光泽）。只有痕量的光亮剂粘附在制成的片剂上。
Claims (2)
1、一种含有如说明书中定义的地红霉素形式Ⅱ作为活性成分及一种或多种药学上可接受赋形剂的片剂。
2、权利要求1的片剂，它具有一层或多层抗胃液包衣。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69284291A | 1991-04-29 | 1991-04-29 | |
| US692,842 | 1991-04-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1066186A true CN1066186A (zh) | 1992-11-18 |
| CN1069197C CN1069197C (zh) | 2001-08-08 |
Family
ID=24782254
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92103160A Expired - Fee Related CN1030611C (zh) | 1991-04-29 | 1992-04-27 | 形式ii地红霉素的制备方法 |
| CN92103161A Expired - Fee Related CN1069197C (zh) | 1991-04-29 | 1992-04-27 | 含地红霉素的药用制剂 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92103160A Expired - Fee Related CN1030611C (zh) | 1991-04-29 | 1992-04-27 | 形式ii地红霉素的制备方法 |
Country Status (27)
| Country | Link |
|---|---|
| EP (2) | EP0511800B1 (zh) |
| JP (2) | JP3135672B2 (zh) |
| KR (2) | KR100193742B1 (zh) |
| CN (2) | CN1030611C (zh) |
| AT (2) | ATE138924T1 (zh) |
| AU (2) | AU655978B2 (zh) |
| BR (2) | BR9201540A (zh) |
| CA (2) | CA2067275C (zh) |
| CY (2) | CY1946A (zh) |
| CZ (2) | CZ282021B6 (zh) |
| DE (2) | DE69214710T2 (zh) |
| DK (2) | DK0511800T3 (zh) |
| ES (2) | ES2093779T3 (zh) |
| FI (2) | FI921876A (zh) |
| GR (2) | GR3020439T3 (zh) |
| HK (2) | HK153696A (zh) |
| HU (2) | HU213613B (zh) |
| IE (2) | IE74885B1 (zh) |
| IL (2) | IL101705A (zh) |
| MX (2) | MX9201946A (zh) |
| MY (2) | MY109498A (zh) |
| NO (2) | NO179504C (zh) |
| NZ (2) | NZ242505A (zh) |
| RU (2) | RU2070203C1 (zh) |
| TW (2) | TW216399B (zh) |
| YU (2) | YU44492A (zh) |
| ZA (2) | ZA922776B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102145008A (zh) * | 2010-12-29 | 2011-08-10 | 山东鲁抗辰欣药业有限公司 | 一种地红霉素药物组合物及其制备方法 |
| CN107151261A (zh) * | 2017-06-09 | 2017-09-12 | 广州大光制药有限公司 | 一种地红霉素化合物的晶型及其结晶制备方法 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW271400B (zh) * | 1992-07-30 | 1996-03-01 | Pfizer | |
| CR5278A (es) * | 1995-03-24 | 1996-07-04 | Lilly Co Eli | Formulacion oral de 2-metil-tieno-benzodiacepina |
| ES2173057T3 (es) * | 1996-07-29 | 2004-11-16 | Abbott Laboratories | Preparacion de la forma ii cristalina de claritromicina. |
| HUP9904065A3 (en) * | 1996-09-24 | 2001-10-29 | Lilly Co Eli | Coated particle formulations containing olanzapine |
| US6390690B1 (en) | 2000-05-17 | 2002-05-21 | 3M Innovative Properties Company | Fiber optic connector for coupling devices on intersecting planes |
| CA2670482C (en) * | 2006-12-05 | 2011-10-11 | Pfizer Inc. | Motilide polymorphs |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT342770B (de) * | 1975-04-07 | 1978-04-25 | Thomae Gmbh Dr K | Verfahren zur herstellung neuer erythromycinderivate |
| DE2515075C2 (de) * | 1975-04-07 | 1985-10-24 | Dr. Karl Thomae Gmbh, 7950 Biberach | Erythromycinderivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| EP0184921A3 (en) * | 1984-12-08 | 1986-10-29 | Beecham Group Plc | Erythromycin derivatives |
| DE3524572A1 (de) * | 1985-07-10 | 1987-01-15 | Thomae Gmbh Dr K | Feste arzneimittelformen zur peroralen anwendung enthaltend 9-deoxo-11-deoxy-9,11-(imino(2-(2-methoxyethoxy)ethyliden)-oxy)-(9s)-erythromycin und verfahren zu ihrer herstellung |
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1992
- 1992-04-15 ZA ZA922776A patent/ZA922776B/xx unknown
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- 1992-04-24 IL IL10170592A patent/IL101705A/en active IP Right Grant
- 1992-04-24 YU YU44492A patent/YU44492A/sh unknown
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- 1992-04-27 NZ NZ242505A patent/NZ242505A/xx not_active IP Right Cessation
- 1992-04-27 MY MYPI92000719A patent/MY109498A/en unknown
- 1992-04-27 DE DE69214710T patent/DE69214710T2/de not_active Expired - Fee Related
- 1992-04-27 EP EP92303753A patent/EP0511800B1/en not_active Expired - Lifetime
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- 1992-04-27 MX MX9201946A patent/MX9201946A/es not_active IP Right Cessation
- 1992-04-27 FI FI921876A patent/FI921876A/fi not_active Application Discontinuation
- 1992-04-27 RU SU925011639A patent/RU2070203C1/ru not_active IP Right Cessation
- 1992-04-27 IE IE921345A patent/IE74885B1/en not_active IP Right Cessation
- 1992-04-27 AT AT92303752T patent/ATE138924T1/de not_active IP Right Cessation
- 1992-04-27 NO NO921617A patent/NO179504C/no unknown
- 1992-04-27 IE IE921346A patent/IE76296B1/en not_active IP Right Cessation
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102145008A (zh) * | 2010-12-29 | 2011-08-10 | 山东鲁抗辰欣药业有限公司 | 一种地红霉素药物组合物及其制备方法 |
| CN102145008B (zh) * | 2010-12-29 | 2013-06-05 | 辰欣药业股份有限公司 | 一种地红霉素药物组合物及其制备方法 |
| CN107151261A (zh) * | 2017-06-09 | 2017-09-12 | 广州大光制药有限公司 | 一种地红霉素化合物的晶型及其结晶制备方法 |
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