CN1694685A - 透粘膜的药物施用形式 - Google Patents
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Abstract
公开了扁平形的透粘膜药物施用形式，其由活性物质在磷脂酰基级分或者该磷脂酰基级分与马来酸和烷基乙烯基醚的共聚物的混合物中的固溶体组成。该施用形式以在口腔中的低溶解度为特点，这导致快速和在更长的时间内恒定的活性物质释放。这种药物施用形式特别适合用于治疗成瘾性药物的滥用和依赖。
Description
本发明涉及优选为扁平形的、在含水环境中形成液体-晶体结构或相的施用形式，特别是口服施用形式，借助于该施用形式可以在口腔中可控地吸收活性物质，特别是在未角质化的区域中，该施用形式具有基于磷脂的基质作为基体物质。特别地，本发明涉及具有所述性质的施用形式，将其制成扁囊剂(Oblaten)(“薄片层剂(wafer)”)的形式。另外，本发明还包括制备这种施用形式的方法。
本发明使得能够可控地释放广谱的活性物质给口腔粘膜，例如释放在人体的ZNS(中枢神经系统)、心血管系统、肌肉和骨骼系统以及呼吸系统中起作用的活性物质，此外还有用作抗感染药、抗生素以及激素的活性物质。
可考虑作为用于本发明的施用形式的优选活性物质是这样的物质，即这些物质适合用于治疗成瘾性药物滥用或者成瘾性药物依赖，特别是用于治疗不同成因的尼古丁依赖和酒精依赖。下面提及的物质或物质类别特别适合于此适应症：7-氮杂双环(2.2.1)-庚烷和7-氮杂双环(2.2.1)-庚烯及其衍生物；Ebibatidin和衍生物；稠和的吲哚衍生物；亚苄基和亚肉桂基-Annabasiene；美加明，金丝桃素，大麻碱(Cannabinoid)受体(CB1)拮抗剂SR 141716，贝氟沙通(Befloxatone)，噁唑烷酮衍生物如匹莫林，安非他酮(Buproprion)和活性物质CP-52655，以及上面提及的物质的酸加成盐。
所述活性物质、其制备以及其药理学活性描述于下列US专利文献中：US 6,255,490；US 6,177,451；US 6,117,889；US 5,998,409和US 5,977,144。
在口腔中释放、随后通过口腔粘膜吸收的活性物质的药物施用形式，例如口腔和舌下片剂，在许多方面都是有利的。这些药物施用形式使得能够容易地将药物给予某些患者，这些患者例如由于吞咽困难而造成难以摄取其他口服药物形式。因为吸收通过口腔粘膜并避开胃肠道进行，因此保证了快速地起作用和高的活性物质利用率。除了舌下或口腔片剂之外，也可考虑扁平形的扁囊剂类型的施用形式(也称为“薄片层剂”)用作具有前述特性的口服药物形式。这些施用形式由于其小的层厚度和快速的分解能力或可溶性而特别适合用于在口腔中快速释放药物和其他活性物质。通常这样的扁囊剂类型的药物形式由成膜的水溶性聚合物如某些纤维素衍生物制成。当与水或唾液接触时，由聚合物形成的“薄片层剂”的基质结构被分解，或者该结构被溶解，从而释放出在其中的活性物质。活性物质释放的开始和时间过程在很大程度上依赖于药物形式(“薄片层剂”)的厚度和基质结构的性质。基质的结构决定了释放(特性)；聚合物的性质，或者说聚合物混合物的性质和组成决定了与粘膜的粘着。因此，这种施用形式的厚度基本上取决于其应含有和释放的活性物质的性质和数量。随着厚度增加相应延缓了“薄层片剂”的分解或溶解。特别地，较厚的“薄片层剂”，还有具有相对较小的厚度的“薄片剂”由于其扁平而光滑的形式以及延迟的分解而倾向于粘着并牢固地粘贴在腭和口腔的其他粘膜表面上。这一方面取决于在表面溶解的聚合物层。
在DE-A-100 32 456和DE-A-101 07 659中描述了这样的“薄片层剂”，其故意地具有减少的粘着或附着在口腔粘膜上的倾向，并达到加速释放活性物质的目的。
该施用形式在施用处(例如口腔)的停留时间，或者说分解时间优选地位于5秒至1分钟的范围内，更优选地位于10秒至1分钟的范围内，和最优选地位于10秒至30秒的范围内。该施用形式的基质含有水溶性聚合物或这样的聚合物的混合物作为基体物质。在此优选地使用合成的或部分合成的聚合物或者天然来源的生物聚合物，这些聚合物是成膜的和水溶性的，和/或例如还适合于形成泡沫。
作为特别合适的载体(基质)，在此描述了优选选自下列的聚合物，即纤维素衍生物、聚乙烯醇、聚丙烯酸酯和聚乙烯吡咯烷酮。在纤维素衍生物的情况下，特别优选羟丙基甲基纤维素、羧甲基纤维素、羟丙基纤维素、羟甲基纤维素和甲基纤维素，以及其他经取代的纤维素衍生物。在此，植物、微生物或合成来源的水溶性多糖同样是优选的，特别是那些不是纤维素衍生物的多糖，例如出芽短梗霉聚糖、黄原胶、藻酸盐、葡聚糖、琼脂-琼脂、果胶和角叉藻。此外还要提及蛋白质，优选明胶或者其他成凝胶的蛋白质以及蛋白质水解物。在上面提及的专利或者公开文献中合适的载体材料同样还包括酪蛋白酸盐、乳清和植物蛋白质、明胶以及(鸡)蛋白和它们的混合物。
从EP-B-0 450 141中得知一种用于施用活性物质的载体材料，其具有这样的组成，即其在口服摄取之后与唾液接触时快速地溶解。该材料是多孔的、脱水的、骨架类型的载体物质，特别是基于蛋白质、多糖和/或磷脂如卵磷脂，但是在其中没有给出该卵磷脂的规格。所描述的明胶-多糖载体还可以扁囊剂的形式进行使用。载体物质最后在与唾液接触的时候进行再水合，并由此得到带有粘性的表面，这导致该施用形式粘着在口腔中。
在所述现有技术中所描述的“薄片层剂”体系和其物理化学结构具有下列缺点：
1.该系统快速地溶解，因此不能够或者只是非常小部分地将活性物质和粘膜进行较长的时间的接触，而较长时间的接触便于在口腔范围内吸收活性物质，
2.即使在与粘膜保持较长时间的接触的情况下，该基质也只是用作不促进渗透的支架形成剂。
这些特性对于这样的活性物质的粘膜施用是不利的，即这些活性物质必须被快速吸收，也就是说要求快速地起作用，并同时必须在长的时间期间保证恒定的血液含有量。这样的活性物质特别是上述适合用于治疗成瘾性药物的滥用和依赖的物质。
因此，本发明的任务是提供扁平形的或者说“薄片层剂”类型的施用体系，
1.在口腔粘膜上，特别是在系带、舌的腹面的区域内或者在“口腔底”中，即在口腔的未角质化区域中粘着较长的时间，
2.活性物质以这样的形式提供使用，即该形式不仅能够快速地而且能够在较长的时间期间内在口腔区域中进行恒定的吸收，
3.是味道温和的，或者说介导了味道温和的感觉。
这一任务根据本发明是如此解决的，即透粘膜施用形式的基体由活性物质在下列物质中的固溶体组成，
a)磷脂酰胆碱，其脂肪酸残基至少90％是饱和的，或者
b)在a)中所述的磷脂酰胆碱与马来酸和烷基乙烯基醚的共聚物的混合物。
根据a)和b)的基体另外可以含有其他药用耐受的辅助剂或添加剂，例如中等链长的聚乙烯吡咯烷酮，其也用于改善本发明的施用形式的味道。
特别是磷脂酰胆碱级分Epikuron 180或者Epikuron 180H经证明适合用于本发明的施用形式。
将它们溶解在纯的醇中，用磷脂酰胆碱并通过干燥制备固体透明的膜，在该膜中活性物质以固溶体存在。这些膜以足够长的时间粘着在口腔粘膜上。当水渗入这些膜中时，从膜表面中出现髓磷脂类型的结构，在该结构中活性物质进一步溶解。在此，不涉及囊泡状的活性物质(“装入胶囊的”微小单元)，而是涉及薄片状的中间相，在其薄片状区域中，活性物质以分子形式存在。这些薄片状的中间相特别适合贴附在粘膜上。
依赖于剩余溶剂(乙醇)的含量或者添加少量纯的烃(例如低粘度的石蜡)或具有低的羟基数的甘油三酯，来控制髓磷脂的形成直至获得类似于机钻油乳化液的自发乳化的凝胶系统。
Claims (11)
1.以在口腔中的低溶解度和快速地且在较长的时间内恒定地释放活性物质为特色的扁平形的透粘膜药物施用形式，其特征在于，该施用形式由活性物质在下列物质中的固溶体和可选的其他药用耐受的辅助剂或添加剂组成，
a)磷脂酰胆碱级分，其中脂肪酸残基至少90％是饱和的，或者
b)在a)中详细描述的磷脂酰胆碱级分与马来酸和烷基乙烯基醚的共聚物的混合物。
2.根据权利要求1的施用形式，其特征在于，该施用形式含有至少80重量％的根据a)的磷脂酰胆碱级分。
3.根据权利要求1或2的施用形式，其特征在于，该施用形式含有聚乙烯吡咯烷酮作为添加剂。
4.根据权利要求1-3中任一项的施用形式，其特征在于，活性物质适合用于治疗成瘾性药物的滥用和对这些药物的依赖。
5.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质为稠和的吲哚衍生物和/或其酸加成盐。
6.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质选自下列化合物组成的组，7-氮杂双环(2.2.1)-庚烷、7-氮杂双环(2.2.1)-庚烯和/或所述化合物的衍生物之一。
7.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质为Ebibatidin和/或该化合物的衍生物。
8.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质为亚苄基和亚肉桂基-Annabasiene和/或该化合物的衍生物。
9.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质选自化合物美加明、金丝桃素、CP-52655和安非他酮和/或它们的衍生物。
10.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质选自噁唑烷酮衍生物和贝氟沙通。
11.根据权利要求1-4中一项或多项的施用形式，其特征在于，活性物质为大麻素受体(CB1)拮抗剂SR 141716。
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| DE10251963.3 | 2002-11-08 | ||
| DE10251963A DE10251963A1 (de) | 2002-11-08 | 2002-11-08 | Transmucosale pharmazeutische Darreichungsform |
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| US3706831A (en) * | 1971-05-14 | 1972-12-19 | Abbott Lab | Method for treatment of drug addiction |
| SE8206744D0 (sv) * | 1982-11-26 | 1982-11-26 | Fluidcarbon International Ab | Preparat for kontrollerad avgivning av substanser |
| JPS6115829A (ja) * | 1984-06-29 | 1986-01-23 | Toyobo Co Ltd | 口腔粘膜適用徐放性ニフエジピン製剤 |
| DE3910543A1 (de) * | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | Transdermales therapeutisches system mit erhoehtem wirkstofffluss und verfahren zu seiner herstellung |
| US5079018A (en) * | 1989-08-14 | 1992-01-07 | Neophore Technologies, Inc. | Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs |
| US5998409A (en) * | 1992-03-12 | 1999-12-07 | Smithkline Beecham Plc | Condensed indole derivatives as 5HT4 -receptor antagonists |
| US5977144A (en) * | 1992-08-31 | 1999-11-02 | University Of Florida | Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines |
| US5817679A (en) | 1993-04-01 | 1998-10-06 | University Of Virginia | 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands |
| US5453523A (en) * | 1993-06-16 | 1995-09-26 | Emulsion Technology, Inc. | Process for obtaining highly purified phosphatidylcholine |
| WO1995007078A1 (en) | 1993-09-10 | 1995-03-16 | Cytomed, Inc. | Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists |
| US6117889A (en) * | 1994-04-01 | 2000-09-12 | University Of Virginia | 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents |
| JPH07291854A (ja) * | 1994-04-26 | 1995-11-07 | Tanabe Seiyaku Co Ltd | 溶解性の改善された医薬品製剤 |
| AU2703795A (en) * | 1994-06-23 | 1996-01-19 | Procter & Gamble Company, The | Treatment of nicotine craving and/or smoking withdrawal symptoms with a transdermal or transmucosal composition containing nicotine and caffeine or xanthine |
| DE19701949A1 (de) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermales therapeutisches System |
| CN1155410C (zh) * | 1997-10-03 | 2004-06-30 | 卡里药品公司 | 治疗尼古丁成瘾的含有尼古丁受体拮抗剂和抗抑郁药或抗焦虑药的组合物 |
| US20040028735A1 (en) * | 1997-11-14 | 2004-02-12 | Unchalee Kositprapa | Pharmaceutical formulation |
| SE9803986D0 (sv) * | 1998-11-23 | 1998-11-23 | Pharmacia & Upjohn Ab | New compositions |
| US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| AR025609A1 (es) * | 1999-09-13 | 2002-12-04 | Hoffmann La Roche | Formulaciones lipidas solidas |
| US6264981B1 (en) * | 1999-10-27 | 2001-07-24 | Anesta Corporation | Oral transmucosal drug dosage using solid solution |
| DE10024413A1 (de) * | 2000-05-19 | 2001-12-06 | Mika Pharma Gmbh | Pharmazeutische und/oder kosmetische Zubereitung |
| DE10032456A1 (de) * | 2000-07-04 | 2002-01-31 | Lohmann Therapie Syst Lts | Schnell zerfallende Darreichungsform zur Freisetzung von Wirkstoffen im Mundraum oder in Körperhöhlen |
| DE10107659B4 (de) * | 2001-02-19 | 2008-03-13 | Lts Lohmann Therapie-Systeme Ag | Mucoadhäsive zerfallsfähige Arzneizubereitung zur Wirkstoffverabreichung in der Veterinär- und Humanmedizin |
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| CA2497848A1 (en) | 2004-05-21 |
| AU2003274030A1 (en) | 2004-06-07 |
| ZA200502443B (en) | 2005-09-26 |
| EP1558209A1 (de) | 2005-08-03 |
| MXPA05004892A (es) | 2005-07-22 |
| RU2005113169A (ru) | 2006-01-20 |
| US20060013864A1 (en) | 2006-01-19 |
| AU2003274030B2 (en) | 2008-09-04 |
| PL375142A1 (en) | 2005-11-28 |
| KR20050084938A (ko) | 2005-08-29 |
| RU2342925C2 (ru) | 2009-01-10 |
| BR0315911A (pt) | 2005-09-13 |
| WO2004041239A1 (de) | 2004-05-21 |
| DE10251963A1 (de) | 2004-05-19 |
| JP2006506406A (ja) | 2006-02-23 |
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