CN1259343A - 使用聚氧乙烯丙三基油酸酯类的压气包装 - Google Patents
使用聚氧乙烯丙三基油酸酯类的压气包装 Download PDFInfo
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- CN1259343A CN1259343A CN99124842A CN99124842A CN1259343A CN 1259343 A CN1259343 A CN 1259343A CN 99124842 A CN99124842 A CN 99124842A CN 99124842 A CN99124842 A CN 99124842A CN 1259343 A CN1259343 A CN 1259343A
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- Prior art keywords
- aerosol
- polyoxyethylene
- structural formula
- anger
- micronized
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 title claims description 3
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- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 title 1
- 239000000443 aerosol Substances 0.000 claims abstract description 33
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- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 3
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Abstract
本发明描述了带有新的悬浮稳定剂的气雾压气包装。
Description
气雾压气包装用于各种各样的目的已经很多年了。气雾压气包装可以理解为抗压的容器，通过操作一个阀而把液化推进气和有疗效的物质的混合物在压力下释放出。压气包装在例如Sucker、Fucks、和Speiser发表的Pharmazeutische Technologie一书中有描述(Thieme，斯图加特，1991年P673-688)。气雾剂和压气包装在List的Arzuneiformenlehre一文中(Wissenschaftliche Verlagsgesell-schaft，斯图加特，1985，P8-18)和Voigt的Lehrebuch der pha-rmazeutischen Technologie，(VCH，Weinheim，1987，P427-436)一书中也有描述。由Thoma所著的Aerosole(由作者出版，法兰克福，1979.5)也极详细地阐明了这种常用剂量形式。对于医药部门，把它们用于将有效物质须要直接输送到肺部并在那儿沉淀是非常有利的。气雾压气包装的优点在于使用它们可生成均匀弥散颗粒的雾团，使病人能快速吸入。结果是使其在作用部位迅速生效一例如在肺部，而这在支气管气喘疗法中是至关重要的。另一方面，直接向肺部局部施药的这种性质，使预防性的作用物质在预防气喘的侵袭中保持低剂量。这样，与通过胃肠系统施药相比，可最大限度地减小不希望的副作用的出现。
因此气雾压气包装在治疗呼吸系统的病症方面找到了广阔的用途。其简单、安全且价格便宜。伴同病人的吸收可能的问题和气雾突然喷射可能引起的问题，既可以通过在气雾包装与病人口腔之间插入膨胀室的方法避免，也可以用吸入器的特殊结构来避免，后者由病人的吸收作用引发气雾的喷射。
除了对支气管气喘预防和治疗急性气喘侵袭的吸入式应用之外，本发明的配方也可用于鼻腔喷雾或咀用喷雾(舌部和口腔部施药)。
CFC类(氟氯代烃)迄今一直用作配药的气雾推进剂。例如，下列的氟氯代烃类和烃类可以用作气雾推进剂：戊烷，正丁烷，异丁烷，TG11、TG12、TG21、TG22、TG23、TG113、TG114、TG115、TG142b和TG C 318。
氟氯代烃类的类型的命名由下列代码系统导出：
在个位的数码 ＝氟原子数
在十位的数码-1 ＝氢原子数
在百位的数码+1 ＝碳原子数
仍然空余的化合价数 ＝氯原子数
基于臭氧理论的基本原理(由于氟氯烃类和其他含氯的有机化合物破坏同温层中的臭氧)，已经找到了可用作气雾剂的液化气体，既不可燃烧，又不破坏臭氧，并且对健康也无害。
利用非氯代的氟烃类已经有一段时间了，例如，1，1，1，2-四氟乙烷(TG134a)或2H-七氟丙烷(TG227)。
除了TG134a和TG227外，还可以提到：TG152a(二氟乙烷，CH3CHF2)，TG143a(三氟乙烷，CH3CF3)和TG161(氟乙烷，CH3CH2F)。
但是，这类气雾剂的一个缺点是，它们须要使用的悬浮稳定剂和阀润滑剂在其内不能有效地溶解。因此，使用TG134a要求用大约25％的乙醇，以便溶解目前用于气雾悬浮液中的脱水山梨醇三油酸酯(SpanR85)达到充分的程度(见EP372 777A2)。也可以使用例如下列化合物：多价的醇类如甘油，酯类如乙酸乙酯，酮类如丙酮和烃类例如己烷和庚烷、戊烷，还有异丙醇。这么高的浓度的一个缺点是存在于悬浮液中的有效物质会显示出不溶解的迹象，产生粒子增大的危险。一方面，如果这种类型的悬浮液在贮存期间有效物质的颗粒尺寸增加超过了10微米会堵塞气雾阀，另一方面，由于有效物质的颗粒因为其尺寸而不再能到达肺的更深部位，效力会减小下去，直到气雾团丢去疗效。
因此急需具有下列性质的一些物质：
—从生理上看可以被接受
—从技术上看适于稳定TG134a和TG227的气雾悬浮液并适于改进其剂量阀的性能
—在TG134a或TG227中可溶的、不使用或仅少量使用生理可接受的其他加溶剂
—具有可以接受的味道
已经今人惊喜地发现，聚氧乙烯-25-丙三基油酸酯构成具有上述要求性质的物质(商品名称为“TagatR TO”，生产厂家：Goldschmidt，Essen)。聚氧乙烯-25-丙三基三油酸酯具有如下的结构式：结构式I：这里X+y+z约为20至30
HLB值为11.3，羟基数在18与33之间；酸值达到最高值2；皂化值在75与90之间而碘值在34与40之间。
羟基数的确定依据DGF-C-V 17a，酸值依据DGF-C-V 2，皂化值依据DGF-C-V 3，碘值依据DGF-C-V 11。聚氧乙烯-25-丙三基三油酸酯是一种呈琥珀色的液体。聚氧乙烯丙三基三油酸酯具有如下性质：
—生理可接受性(与脱水三梨醇三油酸酯(SpanR85)比较)
—从技术上看适于稳定TG134a和/或TG227的气雾悬浮液，并适于改进其剂量阀的性能
—可溶于TG134a或TG227内，同时存在的乙醇或类似的醇类少于1-2％
—有可以接受的味道
其他适于作为悬浮稳定剂且表现出上述性质的化合物有：——TagatRO
用化学术语说，TagatRO是一种聚氧乙烯-30-丙三基单油酸酯。
聚氧乙烯-30-丙三基单油酸酯具有如下的结构式：结构式II：
这里n：约30HLB值是16.4；羟基数在50和65之间；酸值最高为2；皂化值在30与45之间而碘值在15和19之间。——TagatRO2用化学术语，TagatRO2是一种聚氧乙烯-20-丙三基单油酸酯。聚氧乙烯-20-丙三基单油酸酯具有如下的结构式：结构式III
这里m：约20
HLB值是15.0；羟基数在70和85之间；酸值最大为2；皂化值在40和55之间而碘值在21和27之间。
带有1-2％乙醇的TG134a或TG227对传统的有效物质的溶解力是如此之低，以致对有效物质可能的结晶增大不能起任何作用。迄今商用制剂的悬浮稳定剂的HLB值小于5(例如Span85：HLB＝1.8)，并且在油包水乳化剂的范围内。(见Voigt著Lehrbuch der pharmazeutisc-hen Technologie一书中P332，Weinheim，1987)。因此，诸如聚氧乙烯-25-丙三基三油酸酯、聚氧乙烯-30-丙三基单油酸酯和聚氧乙烯-20-丙三基单酸油酯，具有11.3到16.4的HLB值，适于此目的，令人惊喜。
相对于一单位的有效物质用量，聚氧乙烯-25-丙三基三油酸酯、聚氧乙烯-30-丙三基单油酸酯和聚氧乙烯-20-丙三基单油酸酯的用量在0.3与8000之间，特别是在5与4000之间，尤其优选在15与2500之间(重量％)。
下面所列可用作有效物质：
止痛药、抗过敏药、抗菌素、抗胆碱药、抗组织胺药、抗发炎药类物质、镇咳剂、支气管扩张剂、利尿剂、酶，心血管作用物质、激素类、蛋白和肽类。止痛药的例子有可待因、二乙酰吗啡、二氢吗啡、麦角胺、芬太尼构橼酸盐、吗啡；抗过敏药的例子有色甘酸、萘多罗米；抗菌素的例子为先锋霉素、镰孢真菌素、新霉素、青霉素类、戊双脒、链霉素、磺胺类、四环素类；抗胆碱药的例子为阿托品、甲基硝酸阿托品、溴化镇痉药、溴乙东莨菪碱、氯化托螺吡咯；抗组织胺药的例子为苄酞嗪，氟斯汀、麦沙吡立伦；抗发炎的物质有二丙酸氯地米松、丁地去炎松、地塞米松、9-去氟肤轻松、氟替卡松、替泼尼旦、去炎松；镇咳剂的例子有那可丁、诺斯卡品；支气管扩张药的例子有班布特罗，双甲苯喘定，脲丁氨酚、双氯醇胺、麻黄素、肾上腺素、福莫特罗，芬忒醇、己双肾上腺素、三丁喘宁、喘息定、异丙肾上腺素、异丙喘宁、间羟喘息定、去氧肾上腺素、N-去甲麻黄碱、吡丁醇、异丙喹喘宁、茶丙喘宁、派喘宁、舒喘宁、平喘宁、磺丁喘宁、叔丁喘宁、tolobuterol；利尿剂的例子有氨氯吡脒、速尿灵；酶的一个例子为胰蛋白酶；心血管作用的物质的例子为硫氮酮和硝化甘油；激素类的例子为可的松、氢化可的松、强的松龙；蛋白和肽类的例子为环孢菌素、西曲瑞克，高血糖素、胰岛素。其他可以使用的有效物质有肾上腺色素、秋水仙碱、肝素、东莨菪碱。
也可以将上文所述物质组合使用。
用实例的方式列出的有效物质可如游离碱或酸或用作医药上可接受的盐的形式使用。例如，可以使用生理可接受的碱土金属或碱金属类或胺类、再例如乙酸盐、苯磺酸盐、苯甲酸盐、酸式碳酸盐、酸式酒石酸盐、溴化物、氯化物、碘化物、碳酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、葡萄糖酸盐、乳酸盐、pamonate羟基萘甲酸盐和硫酸盐作为抗衡离子。也可以使用酯类、例如乙酸酯、丙酮化合物、丙酸酯、二丙酸酯、戊酸酯。
TagatRTO，TagatRO或TagatRO2的用量，相对有效物质、气雾剂气体或气雾气体混合物、和可有可无的辅助物质所组成的混合物总量为例如0.01-5％(重量)，特别是0.2％到2.5％，尤其优选0.75％-1.5％(重量)。
可以加入助溶剂，例如带有2至6个碳原子的脂族醇类或其酯类或酮类或多元醇类。例子有乙醇、异丙醇、丙二醇、丙酮、乙酸乙酯、正丙醇，优选乙醇和异丙醇。
乙醇或异丙醇的用量，相对混合物的总重量为0％至10％，特别是0.1到2％，尤其优选0.2％至1％(重量)。
当然，也可以加入其他界面活性物质，例如在EP0372777中所列举的。
有效物质的悬浮，既可以在常压下进行(这种情形悬浮介质必须冷却至低温例如-35℃至-55℃)，也可以在一个压力容器中于常温下进行室温(15℃至25℃)。
悬浮液均化之后充入压力罐中，这种罐是用一个剂量阀封闭的，或者是随后封闭的。
实例1
将1000克2H-七氟丙烷(＝气雾剂227)冷却至约-55℃的温度，与在11.7克无水酒精中溶有11.7克聚氧乙烯-25-丙三基三油酸酯(商品名称：TagatRTO、Goldschmidt公司)的溶液搅拌反应。然后将16.8克微粒化了的色甘酸二钠盐和8.4克微粒化了的盐酸苯丙宁以及0.9克微粒化了的糖精钠和6.75克薄荷油加进去，生成的悬浮液进行强烈的搅拌。随着进一步的搅拌冷却，制成1170.0克带有冷却的气雾剂227的悬浮液，然后充入金属罐中，该罐是用剂量阀封闭的，每次喷射放出50微升的悬浮液。每次喷射放出1毫克的色甘酸二钠盐和0.5毫克盐酸苯丙喘宁。
实例2
将1000克2H-七氟丙烷(＝气雾剂227)冷却至约-55℃的温度，与11.7克无水酒精中溶有11.7克聚氧乙烯-30-丙三基单油酸酯(商品名称：TagatRO，Goldschmidt公司)的溶液搅拌反应。然后将16.8克微粒化了的色甘酸二钠盐和8.4克微粒化了的盐酸苯丙喘宁以及0.9克微粒化了的糖精钠和6.75克薄荷油加进去，生成的悬浮液进行强烈的搅拌。随着进一步的搅拌和冷却制成1170.0克带有冷却了的气雾剂227的悬浮液，然后充入金属罐中，该罐是用剂量阀封闭的，每次喷射放出50微升的悬浮液。每次喷射放出1毫克的色甘酸二钠盐和0.5毫克盐酸苯丙喘宁。
实例3
将1000克2H-七氟丙烷(＝气雾剂227)冷却至约-55℃的温度，与11.7克无水酒精中溶有11.7克聚氧乙烯-20-丙三基单油酸酯(商品名称：TagatRO2，Goldschmidt公司)的溶液搅拌反应。然后将16.8克微粒化了的色甘酸二钠盐和8.4克微粒化了的盐酸苯丙喘宁以及0.9克微粒化了的糖精钠和6.75克薄荷油加进去，生成的悬浮液进行强烈的搅拌。随着进一步的搅拌和冷却制成1170.0克带有冷却了的气雾剂227的悬浮液，然后充入金属罐中，该罐是用剂量阀封闭的，每次喷射放出50微升的悬浮液。每次喷射放出1毫克的色甘酸二钠盐和0.5毫克盐酸苯丙喘宁。
实例4
与实例1操作相同，只是用16.8克微粒化了的D-18024代替16.8克微粒化了的色甘酸二钠盐和8.4克微粒化了的盐酸苯丙喘宁。
每次喷射放出1毫克的D-18024。D-18024具有如下的结构式：D-18024的INN名称为flezelastine hydrochloride.
实例5
操作与例1相同，只是使用4.2克微粒化了的丁地去炎松代替16.8克微粒化的色甘酸二钠盐，8.4克微粒化的盐酸苯丙喘宁，0.9克微粒化的糖精钠和6.75克薄荷油。
每次喷射包含0.25毫克丁地去炎松。
实例6
1000克2H-七氟丙烷(＝气雾剂227)冷却至约-55℃的温度，与11.7克聚氧乙烯-25-丙三基三油酸酯(商品名称：TagatRTO，Goldschmidt公司)和6.75克Dentomint PH799959(生产厂家：Haarmann un-d Reimer，Holzminden)的混合物搅拌反应。随着进一步的搅拌和冷却，把16.8克微粒化的色甘酸二钠盐和8.4克微粒化的盐酸苯丙喘宁以及0.9克微粒化的糖精钠加入进去，生成的悬浮液强烈搅拌。随着进一步的搅拌和冷却制成1170.0克带有冷却了的气雾剂227的悬浮液，然后充入金属罐中，该罐是用剂量阀封闭的，每次喷射放出50微升悬浮液。每次喷射放出1毫克色甘酸二钠盐和0.5毫克盐酸苯丙喘宁。
Claims (5)
1.用于通过口腔吸入喷施生物有效物质的气雾压气包装，其特征在于，使用依据结构式III的聚氧乙烯-20-丙三基单油酸酯作为悬浮稳定剂和/或阀润滑剂，并且使用2H-七氟丙烷和/或1，1，1，2-四氟乙烷作为气雾剂，
结构式III
式中m为20。
2.依据权利要求1的气雾压气包装，其特征在于，依据结构式III的聚氧乙烯-20-丙三基单油酸酯相对于混合物总重量的比例在0.01％与5％之间。
3.依据权利要求1的气雾压气包装，其特征在于，依据结构式III的聚氧乙烯20-丙三基单油酸酯相对混合物总重量的比例在0.2与2.5％之间。
4.依据权利要求1的气雾压气包装，其特征在于，依据结构式III的聚氧乙烯-20-丙三基单油酸酯相对混合物总重量的比例在0.75％与1.5之间。
5.制备权利要求1至4中任一项的气雾压气包装的方法，其特征在于，使用2H-七氟丙烷和/或1，1，1，2-四氟乙烷作为气雾剂。
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| CN99124842A Expired - Fee Related CN1085526C (zh) | 1992-03-17 | 1999-11-19 | 使用聚氧乙烯丙三基油酸酯类的压气包装 |
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| DE4322703A1 (de) * | 1993-07-08 | 1995-01-12 | Asta Medica Ag | Druckgaspackungen unter Verwendung von Polyoxyethylen-glyceryl-fettsäureestern als Suspensionsstabilisatoren und Ventilschmiermittel |
| DE4340781C3 (de) * | 1993-11-30 | 2000-01-27 | Novartis Ag | Cyclosporin enthaltende flüssige Zubereitungen und Verfahren zu ihrer Herstellung |
| AU709783B2 (en) * | 1994-03-14 | 1999-09-09 | Abbott Laboratories | Aerosol drug formulations containing vitamin E |
| US5635159A (en) * | 1994-08-26 | 1997-06-03 | Abbott Laboratories | Aerosol drug formulations containing polyglycolyzed glycerides |
| GB9425160D0 (en) * | 1994-12-10 | 1995-02-08 | Glaxo Group Ltd | Medicaments |
| US5840213A (en) * | 1995-04-28 | 1998-11-24 | Great Lakes Chemical Corporation | Uses of heptafluoropropane |
| GB9526392D0 (en) | 1995-12-22 | 1996-02-21 | Glaxo Group Ltd | Medicaments |
| US5955098A (en) * | 1996-04-12 | 1999-09-21 | Flemington Pharmaceutical Corp. | Buccal non polar spray or capsule |
| GB9620187D0 (en) † | 1996-09-27 | 1996-11-13 | Minnesota Mining & Mfg | Medicinal aerosol formulations |
| US6039932A (en) * | 1996-09-27 | 2000-03-21 | 3M Innovative Properties Company | Medicinal inhalation aerosol formulations containing budesonide |
| US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
| DE19753108A1 (de) * | 1997-11-29 | 1999-08-05 | Wella Ag | Mittel zur Erhöhung der Formbarkeit und des Glanzes von Haaren |
| DZ2947A1 (fr) | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Inhalateur à compteur de dose sous pression. |
| US6315985B1 (en) * | 1999-06-18 | 2001-11-13 | 3M Innovative Properties Company | C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability |
| IT1313553B1 (it) | 1999-07-23 | 2002-09-09 | Chiesi Farma Spa | Formulazioni ottimizzate costituite da soluzioni di steroidi dasomministrare per inalazione. |
| IT1317720B1 (it) * | 2000-01-07 | 2003-07-15 | Chiesi Farma Spa | Dispositivo per la somministrazione di aerosol dosati pressurizzati inpropellenti idrofluoroalcani. |
| IT1317846B1 (it) | 2000-02-22 | 2003-07-15 | Chiesi Farma Spa | Formulazioni contenenti un farmaco anticolinergico per il trattamentodella broncopneumopatia cronica ostruttiva. |
| IT1318514B1 (it) * | 2000-05-12 | 2003-08-27 | Chiesi Farma Spa | Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari. |
| ME00220B (me) | 2000-05-22 | 2010-10-10 | Chiesi Farm Spa | Stabilne farmaceutske formulacije rastvora za inhalatore odmjerene doze pod pritiskom |
| SI1273292T1 (en) | 2001-07-02 | 2004-12-31 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
| ES2779273T3 (es) * | 2002-03-01 | 2020-08-14 | Chiesi Farm Spa | Formulación superfina de formoterol |
| EP1595531A1 (en) | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
| GB2437488A (en) * | 2006-04-25 | 2007-10-31 | Optinose As | Pharmaceutical oily formulation for nasal or buccal administration |
| US20070286814A1 (en) * | 2006-06-12 | 2007-12-13 | Medispray Laboratories Pvt. Ltd. | Stable aerosol pharmaceutical formulations |
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| US4010252A (en) * | 1974-12-19 | 1977-03-01 | Colgate-Palmolive Company | Antimicrobial compositions |
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| US4963720A (en) * | 1989-12-05 | 1990-10-16 | Jong Jiunn Neng | Apparatus for counting lump foodstuffs |
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1992
- 1992-09-16 DE DE4230876A patent/DE4230876A1/de not_active Withdrawn
- 1992-12-23 SK SK3858-92A patent/SK279953B6/sk not_active IP Right Cessation
- 1992-12-23 CZ CS923858A patent/CZ285135B6/cs not_active IP Right Cessation
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1993
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- 1993-03-04 GE GEAP19932335A patent/GEP19991518B/en unknown
- 1993-03-04 AU AU37459/93A patent/AU664080B2/en not_active Ceased
- 1993-03-04 ES ES93906483T patent/ES2105233T3/es not_active Expired - Lifetime
- 1993-03-04 HU HU9402671A patent/HU214914B/hu not_active IP Right Cessation
- 1993-03-04 JP JP51620193A patent/JP3380242B2/ja not_active Expired - Fee Related
- 1993-03-04 AT AT93906483T patent/ATE155680T1/de not_active IP Right Cessation
- 1993-03-04 RU RU94041703A patent/RU2106862C1/ru not_active IP Right Cessation
- 1993-03-04 EP EP93906483A patent/EP0630229B1/de not_active Expired - Lifetime
- 1993-03-04 DK DK93906483.8T patent/DK0630229T3/da active
- 1993-03-04 BR BR9306089A patent/BR9306089A/pt not_active Application Discontinuation
- 1993-03-04 DE DE59306978T patent/DE59306978D1/de not_active Expired - Lifetime
- 1993-03-04 KR KR1019940703219A patent/KR100255261B1/ko not_active Expired - Fee Related
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- 1993-03-16 CN CN93104061A patent/CN1069191C/zh not_active Expired - Fee Related
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1994
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1997
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1999
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