CN1061905A - 硬胶囊制剂 - Google Patents
硬胶囊制剂 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000007902 hard capsule Substances 0.000 title claims abstract description 29
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 23
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 23
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 22
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960001597 nifedipine Drugs 0.000 claims abstract description 20
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 239000012530 fluid Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- 229960003511 macrogol Drugs 0.000 claims description 8
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 2
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 20
- 239000012488 sample solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000007901 soft capsule Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
本发明是关于用下述液体组合物灌装硬胶囊制
得的硬胶囊制剂,液体组合物包括1份重量的心痛
定、5~25份重量在环境温度下为液体的聚乙二醇和
0.4~10份重量的聚乙烯吡咯烷酮,心痛定广泛地用
作心绞痛的治疗药物。
Description
本发明是关于用作为心绞痛治疗药物心痛定〔1,4-二氢-2,6-二甲基-4-(2′-硝基苯基)-3,5-二甲氧羰基吡啶〕的硬胶囊制剂。
由于心痛定仅略微溶于水,因此以结晶态或细的粉末状经口服给药时,其吸收性是不好的。因此,为了改进心痛定的吸收,进行了种种研究。作为改进其吸收的方法,有一已知的方法,该方法包括将心痛定溶解在聚(亚烷基)二醇或其他同类的溶剂中,并将该溶液制成软胶囊制剂(美国专利3,784,684)。
心痛定的软胶囊制剂的缺点在于,含在内部液体中的心痛定当进入水中时会作为结晶析出。为了防止心痛定结晶析出,需将聚乙烯吡咯烷酮加到内部液体中(日本专利申请公开号60-105611)。
但是,软胶囊制剂有以下的缺点:在某些保存条件下它往往会变软,并且胶囊本身容易变形和粘着。此外,另一问题是水从富水的胶囊胶皮转移到内部液体,结果导致析出心痛定结晶,为了防止心痛定结晶析出,必须应用大量的溶解溶剂,这样使胶囊的体积增大并且大胶囊给服用造成困难。另一方面,作为促进心痛定吸收的一个方法是使心痛定形成粉末状物,从心痛定和聚乙烯吡咯烷酮(PVP)制得的无定形固体溶液的粉状或颗粒制剂已经公开(欧洲专利-A-0001247和美国专利4,412,986)。但是据文献报道该类型制剂存在由于吸收水份而产生结晶转变的问题(IYAKUHIN KENKYU,12(4),1981),以及由于它们是用有机溶剂制备的,因此存在残留溶剂的问题。
除了以上所述之外,已知还有心痛定的硬胶囊制剂,它们是按下法制备的:将包括溶液形式的聚乙二醇和非溶液形式的聚乙二醇组合物装到硬胶囊中(美国专利4,894,235)。在该类型的胶囊制剂中,装进胶囊中的组合物在该胶囊内固化,结果出现一个问题,即与软胶囊相比,进入水中的心痛定较少,并且在体内它的吸收是不充分的。如以上所述,在先有技术的胶囊制剂中,内容物是液体物质的胶囊制剂是软胶囊,而在环境温度下内容物不是液体的胶囊制剂是硬胶囊。用在环境温度下为液体的物质灌装的硬胶囊是未知的。
图1表示在本发明的胶囊剂加到水中时,经过的时间与吸收率之间的关系,其中“……”表示心痛定饱和水溶液的吸收率。
本发明是关于用液体组合物灌装的硬胶囊制剂,该液体组合物包括1份重量的心痛定(以下称为NP)、5~25份重量在环境温度下为液体的聚乙二醇和0.4~10份重量的聚乙烯吡咯烷酮(以下称为PVP)。
下面将详细叙述本发明。用于本发明溶解NP的溶剂包括在环境温度下为液体的聚乙二醇,例如聚乙二醇300、聚乙二醇400和聚乙二醇600等,其中聚乙二醇600是特别好的。可以应用单一的聚乙二醇,或者它们二种或二种以上的结合,二种情况均没有遇到任何的麻烦。每1份重量的NP,通常应用5~25份重量的聚乙二醇,最好为7~18份重量的聚乙二醇。
用于本发明的PVP的分子量没有特别的限制。但是具有分子量10,000~1,000,000的PVP是较好的,分子量为20,000~100,000的PVP是更好的,分子量约为20,000~约50,000的PVP是最好的。每1份重量的NP,应用约0.4~约10份重量的PVP,应用约1~约8份重量的PVP是较好的,应用约1.5~约6份重量的PVP是更好的。
灌装到本发明硬胶囊中的内部溶液各成份的比例如下。应用NP的量为4~20%W/W,以4.5~10%W/W较好;应用PVP的量为5~45%W/W,以8~30%W/W较好;应用聚乙二醇的量为50~90%W/W,以约62~约82%W/W较好。
内部溶液在25℃的粘度为1,000~100,000CPS,以2,000~40,000CPS较好,约2,500~约25,000CPS更好。为了增加粘度,可以加入增稠剂,例如羟丙基甲基纤维素乙酸酯琥珀酸酯等,其量为每份NP加入约0.3~约0.8份。
在制备本发明的胶囊制剂中,在20~100℃,最好在40~80℃将PVP溶于聚乙二醇中,然后加入NP,制得液体制剂。然后在0~80℃,最好在20~65℃将该液体装入硬明胶胶囊中,制得胶囊制剂。然后,如果需要,可以将矫味剂、香料等加到该溶液中,加入的量以NP为基础各为约1~约5%。为此目的应用的硬胶囊通常是白色透明的,或是有色的。
除了聚乙二醇之外,完全不需要加水,并且也不需要加其他溶剂到本发明胶囊制剂的内部溶液中。
实施例1
在25℃粘度为约11,000CPS的本发明样品溶液按下法制备:在70℃将1g NP和4g PVP溶解到15g聚乙二醇600中。然后在60℃将制得的200mg样品溶液装到4号硬胶囊中,并将该胶囊用封带封口(band-sealed),得到本发明的硬胶囊制剂。
实施例2
在25℃粘度为约4,000CPS的样品溶液按下法制备:在70℃将10g NP和25g PVP溶解到115g聚乙二醇600中。然后在50℃将制得的150mg样品溶液装到4号硬胶囊中,并将该胶囊用封带封口,得到本发明的硬胶囊制剂。
对30粒如此制得的硬胶囊制剂,测定各粒胶囊制剂的重量。结果,平均重202.40mg,标准误差为0.85mg。
实施例3
在25℃粘度为约3,000CPS的样品溶液按下法制备:在50℃将10g NP和20g PVP溶解到100g聚乙二醇400中。然后在40℃将制得130mg样品溶液装到5号硬胶囊中,并将该胶囊用封带封口,得到本发明的硬胶囊剂。
实施例4
本发明的样品溶液按下法制备:在80℃将10g NP、5g羟丙基甲基纤维素乙酸酯琥珀酸酯和25g PVP K-25溶解到150g聚乙二醇600中。然后在65℃将制得的200mg样品溶液装到4号硬胶囊中,并将该胶囊用封带封口,得到本发明的硬胶囊制剂。
试验实例
对实施例1的样品,按照日本药典第11版(搅槽法,转数100,37℃,蒸馏水)的方法进行溶出试验。如图1所示,呈现出良好的溶出性质。
从以上所述可以看出,与先前的软胶囊制剂相比,本发明的硬胶囊制剂含有较高浓度的NP,因此它们的体积可以减小,并且它可以用更容易和更简单的、化费较少的方法进行生产。此外,尽管本发明的硬胶囊中有高浓度的NP,但是即使将其投入水中也没有明显的结晶析出,也没有因高浓度的NP而引起特殊的麻烦。另外,按照本发明,装入硬胶囊的样品溶液其精密度是高的,因此本发明的胶囊制剂几乎没有重量不均匀的问题。
此外,本发明的硬胶囊制剂可以容易地制得,而内部液体组合物不会由该胶囊渗漏出来。
另外,在本发明的硬胶囊制剂中,NP在水中的溶出性质是良好的,因此至少与先前的软胶囊制剂相比,可认为本发明的硬胶囊制剂在体内会具有良好的吸收性。
Claims (7)
1、制备硬胶囊制剂的方法,该方法包括将由1份重量的心痛定、5~25份重量的在环境温度下为液体的聚乙二醇和0.4~10份重量的聚乙烯吡咯烷酮组成的液体组合物装到硬胶囊中。
2、按照权利要求1的方法,其中所述液体组合物在25℃的粘度为1,000~100,000CPS。
3、按照权利要求1的方法,其中所述的聚乙二醇是聚乙二醇300、聚乙二醇400或聚乙二醇600。
4、按照权利要求1的方法,其中所述的聚乙烯吡咯烷酮的分子量为20,000~50,000。
5、按照权利要求1的方法,其中每份重量的心痛定用7~18份重量所述的聚乙二醇,1.5~6份重量所述的聚乙烯吡咯烷酮。
6、按照权利要求1的方法,其中在液体组合物中各成份的比例如下:心痛定4.5~10%W/W,聚乙二醇62~82%W/W,聚乙烯吡咯烷酮8~30%W/W。
7、按照权利要求1的方法,其中装入时的温度为0~80℃。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP32544390 | 1990-11-29 | ||
JP325443/90 | 1990-11-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1061905A true CN1061905A (zh) | 1992-06-17 |
Family
ID=18176920
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN91111215A Pending CN1061905A (zh) | 1990-11-29 | 1991-11-29 | 硬胶囊制剂 |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0488181A1 (zh) |
JP (1) | JPH0517356A (zh) |
KR (1) | KR920009395A (zh) |
CN (1) | CN1061905A (zh) |
AU (1) | AU8823391A (zh) |
CA (1) | CA2056032A1 (zh) |
CS (1) | CS363291A3 (zh) |
HU (1) | HU206622B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100578669B1 (ko) * | 1997-05-29 | 2006-12-07 | 동아제약주식회사 | 우르소데옥시콜린산을함유하는투명연질캅셀 |
WO2001060353A1 (fr) * | 2000-02-21 | 2001-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Preparation liquide a absorbabilite amelioree |
US20030003144A1 (en) * | 2001-05-01 | 2003-01-02 | Keller Brian C. | Sustained release formulations for nifedipine, dextromethorphan, and danazol |
DE102008059201A1 (de) * | 2008-11-27 | 2010-06-02 | GÖPFERICH, Achim, Prof. Dr. | In situ präzipitierende Arzneistofflösungen |
DE102021003906B4 (de) | 2021-07-30 | 2023-03-30 | Mirco Bienhaus | Verfahren und Vorrichtungen zur Herstellung fester oder halbfester Arzneiformen mit einem mehrschichtigen Aufbau |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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SU432703A3 (zh) * | 1971-08-24 | 1974-06-15 | Фридрих Боссерт, Вульф Фатер, Курт Бауер | |
GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
DE3124983A1 (de) * | 1981-06-25 | 1983-01-20 | Meditest Inst Fuer Medizinisch | Arzneiformen zur oralen verabreichung |
DE3438830A1 (de) * | 1984-10-23 | 1986-04-30 | Rentschler Arzneimittel | Nifedipin enthaltende darreichungsform und verfahren zu ihrer herstellung |
US4689233A (en) * | 1986-01-06 | 1987-08-25 | Siegfried Aktiengesellschaft | Coronary therapeutic agent in the form of soft gelatin capsules |
US5071643A (en) * | 1986-10-17 | 1991-12-10 | R. P. Scherer Corporation | Solvent system enhancing the solubility of pharmaceuticals for encapsulation |
DE3636123A1 (de) * | 1986-10-23 | 1988-05-05 | Rentschler Arzneimittel | Arzneizubereitungen zur oralen verabreichung, die als einzeldosis 10 bis 240 mg dihydropyridin enthalten |
GB8629761D0 (en) * | 1986-12-12 | 1987-01-21 | Harris Pharma Ltd | Capsules |
-
1991
- 1991-11-22 CA CA002056032A patent/CA2056032A1/en not_active Abandoned
- 1991-11-25 KR KR1019910021094A patent/KR920009395A/ko not_active Application Discontinuation
- 1991-11-26 EP EP91120201A patent/EP0488181A1/en not_active Withdrawn
- 1991-11-26 JP JP3335563A patent/JPH0517356A/ja active Pending
- 1991-11-27 AU AU88233/91A patent/AU8823391A/en not_active Abandoned
- 1991-11-28 HU HU913711A patent/HU206622B/hu not_active IP Right Cessation
- 1991-11-29 CN CN91111215A patent/CN1061905A/zh active Pending
- 1991-11-29 CS CS913632A patent/CS363291A3/cs unknown
Also Published As
Publication number | Publication date |
---|---|
KR920009395A (ko) | 1992-06-25 |
HU913711D0 (en) | 1992-02-28 |
AU8823391A (en) | 1992-06-04 |
HUT59601A (en) | 1992-06-29 |
CA2056032A1 (en) | 1992-05-30 |
JPH0517356A (ja) | 1993-01-26 |
HU206622B (en) | 1992-12-28 |
EP0488181A1 (en) | 1992-06-03 |
CS363291A3 (en) | 1992-06-17 |
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