CN1121238C - 口服施用的具有简单组成和高生物利用度的环孢菌素新制剂形式及其制造方法 - Google Patents

口服施用的具有简单组成和高生物利用度的环孢菌素新制剂形式及其制造方法 Download PDF

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CN1121238C
CN1121238C CN95196010A CN95196010A CN1121238C CN 1121238 C CN1121238 C CN 1121238C CN 95196010 A CN95196010 A CN 95196010A CN 95196010 A CN95196010 A CN 95196010A CN 1121238 C CN1121238 C CN 1121238C
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cyclosporin
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M·奥尔布里希
H·波特
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Abstract

本发明关系到简单组成和高生物利用度的环孢菌素的新型口服制剂形式，其中含0.5到2重量份(p/wt)的一种或多种无定形环孢菌素，优选是环孢菌素A和/或环孢菌素G和6到9重量份的一种或多种饱和C10-C22羟基脂肪酸聚乙二醇酯，特别是SolutolHS 15，和1-3重量份的一种或多种一元或多元醇，优选是乙醇和丙二醇。此剂型制造是先将无定形环孢菌素溶于乙醇再于搅拌下加丙二醇和Solutol至得清亮，粘稠溶液，此溶液包装为一饮服溶液或装入胶囊。

Description

口服施用的具有简单组成和高生物利用度的 环孢菌素新制剂形式及其制造方法
本发明涉及环孢菌素，特别是包含在流体制剂中作口服剂的环孢菌素A。
环孢菌素是由微生物产生的中性环肽类，其最重要的代表是环孢菌素A，它用在器官移植中抑制器官排斥和用于骨髓移植中。环孢菌素A的微生物生产方法和其分离及纯化成无定形无色粉末的方法已在德国专利2455859中公开。
环孢菌素A也被日益用于自身免疫疾病如牛皮癣，眼色素层炎，肾病综合症及其它疾病的治疗。
环孢菌素类之抗炎和抗寄生物性质亦有述及。
由于环孢菌素的疏水性，很难制备其生物活性物质具有高的生物利用度的药物组合物。特别是在药代动力学参数上已知的剂量形式表现出广泛的个体内和个体间的变动。在同样剂量时不同病人血液中环孢菌素水平变化达50％。甚至在同-病人自上吸收变化也很大。但是免疫抑制疗法却依赖于在剂量依赖的副作用和移植器官排斥之间的一个很窄的治疗窗口。
差的生物利用度特别是由于在含水剂型中环孢菌素混合物的环孢菌素低溶解度所致。
因此作了很多努力以解决这些药物学问题。
已知的商品化剂型采用于复杂的亲脂和亲水溶剂，以及增溶剂，其目的是溶解环孢菌素并使其保持于水性体系的溶液中。它们至少含有四种成分，即生物活性物质，植物油，乙醇和一种表面活性剂。
美国专利4388307揭示了用油和乙醇与共溶剂一起作药物载体。依据此项专利，商品化的可饮用环孢菌素溶液含有橄榄油、乙醇和作表面活性物的Labrafil。但是，这种配方遗留下一些问题，油和表面活性载体常有一些不愉快的气味和/或味道。另外，具有不饱和脂肪酸的油易于酸败。
其次，在含油配方中相对高的乙醇含量也是必要的。但是这样高的乙醇含量又造成对于给儿童服药的困难和产生储存问题。
当用来填充胶囊时，为了避免蒸发就有必要用包入铝泡包装增加了费用。
英国专利2222770揭示一种新剂型包括以产生微乳状液作为解决的途径。这些体系含有4到6个成分，它们形成一个生物活性物质，亲脂亲水相和表面活性剂的复杂体系。这种类型的体系又有增加交叉反应的危险，和所用的物质之一不为病人耐受的危险。
德国专利3924207揭示了一种方法，制备静脉用药的稳定的水注射液，其中，
a)1重量份环孢菌素
b)8-13重量份的一种或多种饱和羟基脂肪酸与聚乙二醇的单酯和
c)1-3重量份的一种或多种一元和/或多元醇被混合。在此项专利中，用于口服的药物剂型式并未被制出和研究过。试图用水稀释这些制剂则环孢菌素沉淀，因之这就减低其生物利用度。
所有的商品剂型均含油性亲脂成分(玉米油，橄榄油(Kemeloil)，玉米油的单、二、三甘油酯)和一种或多种分散剂及一元或多元醇。
由德国专利3843054证实，斜方晶体如CY-A/X-II和特别是CY-A/X-III尤其适于生产药剂剂型。这些配方据称含有稳定的和细微颗粒型的环孢菌素和/或具有更好的稳定性或更有利的释放特性。这些剂型最适于表皮或眼表面的用药。所述的应用超声来生产无溶剂化斜方晶体的方法在二业规模上难于实行。同样也表明无定形的环孢菌素不太适合作剂量形式。
按本发明的惊人发现，上述问题均已解决，在环孢菌素的口服剂型中具有简单组成和高生物利用度，以一种可饮用溶液或胶囊的形式，其中含有：
a)0.5到2份，优选是1重量份的一种或多种无定形环孢菌素作生物活性物质。
b)6到9份，优选是7.5重量份的一种或多种饱和C10-C22羟基脂肪酸的聚乙二醇甘油单酯，优选是聚乙二醇-660-12-(羟基)-硬脂酸，
c)1-3份，优选是2重量份的一种或多种一元或多元醇作助溶剂，优选是乙醇和丙二醇，环孢菌素的溶解性被大为增加，特别是以水稀释，且保持这些特定量的比例时。
这并非通常所假定的，因为可比的剂型使用脂肪酸的聚乙二醇酯作为疏水和亲水相之间的添加的增溶剂。
更令人惊讶的还是这样一种制剂表现出与商业品(见上述)生物等价度。
尤其是并没预见到这种没有亲脂成分的简单制剂能达到那样高的生物利用度。
进一步还发现在口服剂型中，正是由于使用无定形的环孢菌素，在环孢菌素含量＞5％得到特别好的溶解性，而且在用水稀释时它还能保持为一种稳定的清亮溶液。
因此本项发明关系到一种可饮溶液或包装胶囊口服剂型，按下述比例的量含有下列成分：
a)0.5-2重量份，优选1重量份的1种或多种环孢菌素，特别是环孢菌素A或G，它们以无定形状态使用，
b)6-9重量份，优选是7.5重量份的一种或多种聚乙二醇和饱和的C10-C22羟基脂肪酸的单酯成分结合在分子中，特别是聚乙二醇-660-12-(羟基)-硬脂酸，
c)1到3重量份，优选是2重量份的一种或多种一元或多元醇作助溶剂，优选是乙醇或丙二醇。
按照本发明在生产过程中必须小心地保持用料量的比例，环孢菌素一开始就在室温下连接搅拌使完全溶于乙醇，接着在室温和连接搅拌下加入丙二醇和聚乙二醇-660-12-(羟基)-硬脂酸。按这种方法所得的溶液含100mg/ml生物活性物质。按已知方法作成可饮用溶液或作成胶囊，例如每粒含100mg，50mg，或25mg生物活性物质的胶囊。
按照本专利这种组合物的生产详细解释在下述实例中：
实例1
100g无定形环孢菌素A于室温下搅拌溶入127ml乙醇中。接着在室温下继续搅拌加入96ml丙二醇。在得到一个环孢菌素A的清亮溶液后，进一步搅拌下加入750g聚乙二醇-660-12-(羟基)-硬脂酸。得到一个含100mg/ml环孢菌素A的清亮粘稠溶液。
实例2
如例1中制得的环孢菌素A溶液按1∶40比例用水稀释，得到的溶液保持清亮并稳定数月以上。

Claims (10)

1.一种可饮用溶液或胶囊形式的口服环孢菌素剂型，其中所述剂型含有：
a)0.5-2重量份的一种或多种无定形环孢菌素作为活性成分，
b)6-9重量份的一种或多种饱和的C10-C22羟基脂肪酸的聚乙二醇单酯，
c)1-3重量份的一种或多种一元或多元醇作为助溶剂。
2.权利要求1的剂型，其中使用无定形的环孢菌素A或环孢菌素G作为活性成分。
3.权利要求1的环孢菌素剂型，其中含有1重量份的一种或多种无定形环孢菌素。
4.权利要求1的环孢菌素剂型，其中含有7.5重量份的一种或多种饱和的C10-C22羟基脂肪酸的聚乙二醇单酯。
5.权利要求1的环孢菌素剂型，其中含有2重量份的一种或多种一元或多元醇。
6.权利要求1的环孢菌素剂型，其中所述的多种饱和的C10-C22羟基脂肪酸的聚乙二醇单酯是聚乙二醇-660-12-(羟基)-硬脂酸。
7.权利要求1的环孢菌素剂型，其中所述的一元或多元醇是乙醇和/或丙二醇。
8.权利要求1的剂型，其中所述剂型为胶囊形式。
9.一种生产权利要求1或2的可饮用溶液或胶囊形式的口服环孢菌素剂型的方法，该方法包括：一开始就在室温搅拌下，
a)将100g无定形环孢菌素溶解在127ml乙醇中，
b)仍在室温搅拌下，加入96ml丙二醇，和最后仍在室温搅拌下，
c)加入750g聚乙二醇-660-12-(羟基)-硬脂酸，得到一种清亮粘稠的环孢菌素溶液，将其按已知的方式装瓶得到可饮用的溶液或包装为胶囊形式。
10.权利要求9的方法，其中的无定形环孢菌素是环孢菌素A。
CN95196010A 1994-11-03 1995-07-19 口服施用的具有简单组成和高生物利用度的环孢菌素新制剂形式及其制造方法 Expired - Fee Related CN1121238C (zh)

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