CN1029935C - 制备新药物制剂的方法 - Google Patents
制备新药物制剂的方法 Download PDFInfo
- Publication number
- CN1029935C CN1029935C CN88109129A CN88109129A CN1029935C CN 1029935 C CN1029935 C CN 1029935C CN 88109129 A CN88109129 A CN 88109129A CN 88109129 A CN88109129 A CN 88109129A CN 1029935 C CN1029935 C CN 1029935C
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- CN
- China
- Prior art keywords
- metoprolol
- accordance
- milligrams
- calcium channel
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
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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
- A61K9/20—Pills, tablets, discs, rods
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
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Abstract
控制和延迟释放难溶于水的二氢吡啶型的钙通道阻滞剂(如非洛地平)和β-肾上腺素能受体拮抗剂(如美多心安)制剂的制备方法。
Description
本发明涉及两种药物的延迟释放药物制剂以及该制剂的制备方法，所说的两种药物之一是难溶于水的化合物，即一种二氢吡啶型的钙通道阻滞剂;另一药物是一种β-肾上腺素能受体拮抗剂美多心安（metoprolol）盐。
本发明的目的在于获得一种固体制剂，该制剂具有上述两种药物的高度的生物利用度，并且与胃肠道的持续吸收性能相结合，从而达到每日服用一次后在24小时内的均匀效果。
二氢吡啶类型钙拮抗剂药物和β-肾上腺素能受体拮抗剂已广泛应用于治疗心血管疾病。
所说的二氢吡啶类型钙拮抗剂，诸如非洛地平（felodipine）、硝苯啶（nifedipine）、尼群地平（nitrendipine），已普遍应用于治疗心血管疾病，如高动脉压和缺血性心脏病。二氢吡啶类型钙拮抗剂能通过血管平滑肌的直接作用降低血管阻力和心脏负荷。二氢吡啶类型钙拮抗剂的特征在于：它在水中的溶解度极低，并且对这样的药物来说，由于它们在体内的溶解速度可能较低，所以经常可以观察到一种低而可变程度的吸收。
在现有文献中曾描述了若干增进药物吸收的方法，在DE-A-3024858中描述了一种方法，在该方法中使用了非晶态的、微溶的取代的二氢吡啶、尼卡地平，以便增进活性化合物从肠中的吸收。在EP-A-47899中描述了另一种方法，在该方法中使用了实际上不溶的二氢吡啶及硝苯啶的极小的结晶，以便增进生物利用度。这些方法和其它方法也在由S.H.Yakowsky编辑的《药物和药物科学》12卷中（Drugs and the Pharmaceutical Sciences，Vol.12）的“药物加溶技术”（“Techniques of Solubilization of drugs”）一文中描述过了。其中与本发明特别有关的是：可以使用表面活性增溶剂，来增进溶解度极低的药物的生物利用度。它阐明了吸收性质的改进可归于三个工艺：1）增进润湿、2）增进膜的渗透性和3）增溶性。
当服用二氢吡啶常规药片后，在体内血浆浓度随时间变化曲线的特征在于呈现出高峰值浓度和峰谷处的较低水平。血压反应反映血浆浓度曲线，即在峰值时有一显著效果而在24小时后效果大为减少。相应地，常规药片对于每日一次用药并不最相
宜，而由一种高质量的控制释放的制剂所产生的更均匀的血浆浓度将是可取的。
通常，控制和延迟释放是通过不同的剂型控制药物的溶解和/或扩散来达到的。若干物质已经用于此目的，诸如蜡、脂肪物质、聚合物、天然树胶、合成树胶和半合成树胶。因为羟丙基甲基纤维素（HPMC）的PH独立性能以及它的半合成来源，所以在树胶中，它构成重要的一类。Alderman.D.A.在Int.J.Pharm.Tech.&Prod.Mfr1984年5卷3期1-9页中对供口服控释剂型的亲水性基质中的纤维素醚作了叙述。在US3087790，US4226849，US4357469和US4369172中公开了为产生所需结构的HPMC的化学处理方法以及这些性质的用途。SE-A-8008646-5描述了HPMC与羟丙基纤维素的混合物，用它来控制一种药物活性化合物的释放速度。
当使用亲水性基质时，在药片与胃肠液或唾液接触后，可溶聚合物形成一种包围在药片四周的明胶层。药物的释放受限于水渗入的速度、药物扩散的速度和形成凝胶的速度（Bamba等人，Int.J.Pharm 1979年，2，307页）。凝胶结构的磨蚀也是药物从系统中释放的重要机制。所用聚合物必须迅速水化，以便保护药片不致迅速分解（Alderman1984）。
在水中具有很低溶解度的药物由于溶解不完全或溶解慢可能难于从胃肠道中加以吸收。结果，难于在不降低生物利用度的情况下通过控制这些药物的缓慢分解来增进有效作用的持续时间。（Bogentoft C和Sjogren J，《为了药物和药物产品更加安全》（Towards Better Safety of Drugs and Pharmaceutical Procucts）D.D Breimer编辑，1980年，Elsevier/North Holland Biomedical Press）。
β-肾上腺素能受体拮抗剂对于心脏的肾上腺素能的兴奋性有阻断作用，从而降低心脏组织对氧的需要。显然，这可解释它们对心绞痛的有益作用和在心肌梗塞中的心脏保护作用。此外，β-肾上腺素能受体拮抗剂能使患高动脉压的大多数病人血压正常化，这可能是由于对血液周围阻力控制的附加作用所致。对于用β-肾上腺素能受体拮抗剂处理的患心血管病的病人来说，在血液中具有所给药物的恒定浓度是有利的。为了每日一次剂量给药，β-肾上腺素能受体拮抗剂美多心安被掺入不溶基质型的控制释放药片中，诸如Durules
。然而，因给药后大约50%剂量在几小时内被释放，所以从基质药片中释放药物是不能令人满意的。对于像具有较短半衰期的美多心安那样的药物来说需要较慢的释放速度，以便获得在24小时内的均匀血浆浓度。在20-24小时期间内多美多心安的恒定释放将是可取的。具有这样性质的美多心安的制备方法在EP-A-220143中已描述过了。
业已表明β-肾上腺素能受体拮抗剂和舒张血管的二氢吡啶的结合对许多高血压病人是有利的，因为这两种药物具有协同作用（Hasson BG等人，Drugs1985年29卷（增刊2）;131-135页;Eggerston R和Hansson L Eur.J.Clin.Pharmacol 1982年21卷389-390页）。除协同作用外，共同给药的优点是可以降低二种药物中任一种单独给药时所引起的反作用（Dean S和Kendall MJ Eur.J.Clin.Pharmacol1983年24卷1-5页）。
在EP-A-163984中叙述了具有改善生物利用度的二氢吡啶衍生物和β-肾上腺素能受体拮抗剂固定结合的即时释放固态剂型。
然而，迄今还没有得到含有上述两种药物固定结合的制剂，它在每日一次剂量给药的期间内产生两种药物可再现的均匀的血浆浓度。上述两种药物之间理化性质的巨大差异，使得很难在常用控释系统基础上获得适宜的制剂。通过少次给药和改进病人的应变性，上述两种药物的控释制剂可以改善治疗（参看Hayes R.B.等人，Clin.Pharm.Ther.1977年22卷125-130页），上述制剂可用控释剂型获得。虽然对于每日一次给药的上述两种药物的控释制剂早有需求（早在1977年时就已提出），但是直到本发明人所开发的下文所描述的制剂以前，这种制剂迄今未得到。
本发明目的在于提供一种制剂，该制剂在每日一次二氢吡啶型的难溶于水的钙通道阻滞剂（诸如非洛地平或硝苯啶）和一种β-肾上腺素能受体拮抗剂（即一种美多心安盐）的两种药物给药后，在24小时期间内显出可再现的高吸收度以及均匀的血浆浓度。由于常规控释制剂能使两种药物同时显出所需释放性能，因而有必要开发一种新型的控释制剂，该制剂利用多种控制有效组分释放的机制。
由于两种药物掺进一种产品中，因而存在两个不同的机制来控制两种有效组分的释放，即一种机制是控制二氢吡啶类型钙拮抗剂部分，而另一机制是控制β-肾上腺素能受体拮抗剂部分。
按照本发明适用于控制剂的二氢吡啶类型的化合物是难溶的。本发明特别适于采用在水中溶解度小于0.1（重量）%，并且可在选择的增溶剂中或增溶剂和水的混合物中增溶的化合物。按照本发明适宜药物的例子有某些取代的二氢吡啶类，诸如硝苯啶和非洛地平。非洛地平是4-（2，3-二氯苯基）-1，4-二氢-2，6-二甲基-3，5-吡啶二羧酸乙基甲基酯;硝苯啶是1，4-二氢-2，6-二甲基-4-（2-硝基苯）-3，5-吡啶羧酸二甲酯。其它例子有尼莫地平、尼索地平和尼群地平。
将二氢吡啶类型化合物混以亲水性的溶胀剂，如羟丙基甲基纤维素（HPMC）。从这个混合物可制备固态剂型，诸如片剂或胶囊。当这样的制剂与水接触时，形成一种溶胀凝胶基质，药物从该基质被缓慢释放出来。
在各种所试验的不同亲水性的物质中，HPMC是一种适宜的凝胶剂，其它适宜的亲水性物质是瓜耳胶、黄原胶、羧亚甲基的和各种不同的纤维素性的物质，诸如：羧甲基纤维素钠和羧丙基纤维素钠。
最好主要使用羧丙基含量为4-12%（重量），特别是约8.5%（重量）、粘度低于100cps的HPMC，可加入较高粘度的HPMC以便获得药物释放的最适宜速度。粘度用标准方法测定，例如在美国药典（United States Pharmacopoeia）XXI1985年672页上所描述的。
在掺入基质中以前，二氢吡啶型的钙通道阻滞剂最好分散于非离子增溶剂中。该增溶剂允许用水或肠液稀释，而不至将二氢吡啶型的钙通道阻滞剂转变为难以吸收的形式。增溶剂的选择是很关键的。用一些常用的增溶剂或共溶剂稀释可导致药物的沉淀。把二氢吡啶型的钙通道阻滞剂与增溶剂的混合物掺入亲水性凝胶基质中，可使药物具有延长和可控的释放性。
按照本发明适于控制释放二氢吡啶型的钙通道阻滞剂的增溶剂是非离子表面活性剂，特别是像含有聚乙二醇类这样一类的酯类或醚类。它们最好从聚乙氧基化的脂肪酸类，羧基化的脂肪酸类和脂肪醇类中选择，特别是从聚乙氧基化的蓖麻油、聚乙氧基化的氢化蓖麻油、由蓖麻油所制聚乙氧基化的脂肪酸或由氢化蓖麻油所制聚乙氧基化的脂肪酸中选择。最好的增溶剂是氧乙烯化甘油的氢化蓖麻油脂肪酸酯类，诸如聚烃氧基（Polyoxyl）40氢化蓖麻油。已知市售的可用增溶剂以商品名称标示的有：Cremophor.Myrj，Polyoxyl 40 Stearate，Emerest2675和Lipa1395。
按照本发明，在制剂中增溶剂和二氢吡啶型的钙通道阻滞剂之间的比例将是10∶1或较低，最好是6∶1或较低。
β-肾上腺素能受体阻滞剂以活性组分包衣珠的形式被掺入上述凝胶系统中，至少在15小时期间内能控制释放β-肾上腺素能受体阻滞剂美多心安。这是由制备大量小的、最好是密实的颗粒而达到的，该颗粒包含美多心安盐作为主要可溶性组分并且用水不溶的聚合物膜包衣。最好的包衣含纤维素类的非质子迁移衍生物作主成分。含有美多心安的小颗粒、小珠的粒度为0.25～2毫米，最好0.35～1.0毫米。小珠可以仅含有美多心安盐或含该盐与不溶性赋形剂混合物或含美多心安盐作包衣的不溶性芯。
在制剂中的美多心安的形式是外消旋物或者是对映体之一，最好是S-异构体。美多心安适宜的可溶性盐于25℃水中溶解度小于600毫克/毫升，最好为30～600毫克/毫升。适宜的盐类例子是由有机羧酸类形成的盐，可取的是低分子量的。尤其好的是外消旋美多心安的琥珀酸盐、富马酸盐或苯甲酸盐以及美多心安的S-对映体的苯甲酸盐或山梨酸盐。
供小珠包衣的适宜聚合物材料的例子是单独的或混合在一起的、不含质子迁移基团或丙烯酸树脂（如Eudragit RL
、Eudragit RS
）的可溶或不溶性纤维素衍生物。特别好的是乙基纤维素与羧丙基甲基纤维素或羧丙基纤维素的混合物。
如上所述含美多心安的包衣小珠（按照本发明该小珠被掺入含有二氢吡啶型的钙通道阻滞剂的凝胶系统中）已在EP-A-220143中描述过了。在EP-A-220143中也描述了所说的小珠是一种制备长效美多心安制剂的适宜方法。
最终的制剂最好是片剂形式，它在凝胶基质内既含有二氢吡啶型的钙通道阻滞剂又有美多心安小
珠。美多心安珠占制剂的10～60%（重量），而凝胶剂占制剂的20-80%（重量）。所描述的控释系统的工艺性能优越，从而使它很宜于大量生产，药片可任意包膜以改善外观和稳定性。
在体内，药物吸收程度既高又能再现。在某一时期内药物在血浆中的浓度和作用由系统中药物释放速度控制。二氢吡啶型的钙通道阻滞剂的释放是由凝胶剂的性质所决定，并能在直到24小时的期间内持续。通过使用不同性质（例如粘度和凝胶强度）不同类型和数量的凝胶剂，易于改变释放速度以适应某些二氢吡啶型的钙通道阻滞剂的需要。主要通过聚合物膜的成分和厚度来改变美多心安从美多心安珠释放的速度。美多心安的释放一般可持续16～24小时。
通过精心选择填充剂和粘合剂以及凝胶剂，制剂可被加工成可接受的商品形式，诸如片剂，它显示出乎意料优越的对上述两种活性化合物的吸收性及作用的长期持续性。
在以下实施例中，按照本发明的制剂含有10～20毫克的二氢吡啶类型化合物和95毫克的美多心安琥珀酸盐。然而，依照所用二氢吡啶类型的化合物和待处理的具体情况，二氢吡啶类型的化合物的量一般在2.5毫克到80毫克之间，作为琥珀酸盐的美多心安外消旋物量一般在40到200毫克之间。当包含作为山梨酸盐的美多心安S-对映体时，其对应量为25到120毫克之间。用其它美多心安盐时，其量因该盐的分子量不同而有差异。
实施例1
克
非洛地平（Felodipine） 10
聚烃氧基40氢化蓖麻油 25
Polyvidon K 90 24
羟丙基甲基纤维素 230
硅酸铝 94
乳糖 56
纤维素（微晶） 6
美多心安琥珀酸盐 95
SiO224
乙基纤维素 32
羟丙基甲基纤维素 8
按照本发明实施例1的组合物作成每片含10毫克非洛地平及95毫克美多心安琥珀酸盐的片剂，该片剂制备方法如下：
Ⅰ.将非洛地平溶解在聚烃氧基40氢化蓖麻油中，将所得的溶液与载体材料、HPMC、Polyvidon K 90、硅酸铝、乳糖和微晶纤维素小心地混合，此混合物和乙醇一起制成颗粒并干燥。
Ⅱ.将美多心安喷射到二氧化硅芯上形成0.5毫米直径的珠，该珠通过在一流化床内向珠上喷射一种溶液来包上聚合物膜。该溶液由在二氯甲烷与异丙醇中的乙基纤维素和HPMC组成。
将Ⅰ和Ⅱ产物混合，加入润滑剂并在制片机中通过压缩制成片剂。
非洛地平和美多心安从片剂中溶解的情况见表1：
表1
在含有1%的十二烷基硫酸钠pH为6.5的磷酸盐缓冲剂中非洛地平和美多心安在体外的累积溶解量。
方法：USP溶解设备NO、2，每分钟50转。
在一定时间（小时）内释放百分数：
0 2 4 8 12 16 20
非洛地平 0 14 32 64 88 96 98
美多心安 0 5 16 39 65 86 95
实施例2
克
硝苯啶 20
Myrj51 50
羟丙基甲基纤维素 200
黄原胶 15
瓜耳胶 15
羧基聚亚甲基 4
（Carboxypolymethylene）
硅酸铝 100
美多心安琥珀酸盐 95
SiO224
乙基纤维素 23
按照实施例2的组合物作成片剂，该片剂含有20毫克硝苯啶和95毫克美多心安琥珀酸盐，片剂制备方法如下：
Ⅰ.将硝苯啶溶解在Myrj51中，并将所得溶液与载体物质、HPMC、黄原胶、瓜耳胶、羧基聚
亚甲基和硅酸铝小心混合，所得混合物和乙醇一起作成颗粒并干燥。
Ⅱ.将美多心安喷射在二氧化硅芯上，以形成0.5毫米直径的珠，并用实施例1所述的乙基纤维素的聚合物膜包衣。
将Ⅰ和Ⅱ的产品混合，加入润滑剂在制片机中压缩成片剂。
在体外，硝苯啶和美多心安二者从药片中的溶解时间被延长，见表2：
表2
硝苯啶和美多心安在含有1%十二烷基硫酸盐的pH为6.5的磷酸盐缓冲剂中的体外积累溶解量。
方法：USP溶解设备NO.2，每分钟100转。
在时间（小时）内的释放百分数：
0 2 4 8 12 16 20
硝苯啶 0 12 26 44 72 90 98
美多心安 0 6 16 34 50 62 75
现在认为实施例1和实施例2二者同样是实施本发明的最佳方式。
下列参考例描述在生物药物学研究中所用的不同制剂。参考例A阐明了常规药片。参考例B阐明一种制剂，其中将美多心安掺入特别适合于二氢吡啶类型的化合物的配方中。参考例C阐明一种制剂，其中将非洛地平掺入一种控释丸的制剂中。
参考例A
非洛地平10毫克常规片剂和
美多心安100毫克常规片剂（100毫克美多心安酒石酸盐相当于95毫克美多心安琥珀酸盐）
参考例B
克
美多心安琥珀酸盐 95
聚烃氧基40氢化蓖麻油 25
羟丙基甲基纤维素 230
硅酸铝 94
按照参考例B的组合物作成每片含95毫克美多心安琥珀酸盐的亲水基质片剂，片剂以下法制备：
将美多心安与聚烃氧基40氢化蓖麻油混合，然后小心地混以载体物质，HPMC和硅酸铝，此混合物与乙醇一起制成颗粒并干燥。加入润滑剂，通过制片机压缩成片。
此片剂在体外的溶解速度示于表3：
表3
在pH6.8的磷酸盐缓冲剂中，美多心安在体外的累积溶解量。
方法：USP溶解设备NO.2，每分钟50转。
一定时间（小时）内的释放百分数：
0 1 4 8 12 20
0 23 59 86 99 100
参考例C
克
非洛地平 66
甲基纤维素 13
甘露醇 870
聚乙烯吡咯烷酮 30
微晶纤维素 40
乙基纤维素 34
聚乙二醇 41.8
按照参考例C的组合物制成控释胶囊，每个胶囊含有10毫克非洛地平，该胶囊以下法制备：
将非洛地平微粉化，小心混以载体、甘露醇、甲基纤维素、聚乙烯吡咯烷酮和纤维素。用水湿润该混合物并球化，将所得颗粒干燥并过筛，用级分为0.71-1.12的颗粒，将该级分的颗粒用溶解于二氯甲烷和异丙醇的混合物中的乙基纤维素和聚乙二醇包衣。将此包衣颗粒填入硬明胶胶囊中，在体外从颗粒向外释放非洛地平的情况与实施例1中的片剂相似。
将按照实施例1的延迟释放制剂（ER）给12个健康者作为单剂量服用，在图1和图2示出由作为固定组合物片（ER）的非洛地平和美多心安所产生的血浆平均曲线。所得到的二种药物在血浆中的浓度将导致在24小时内连续治疗期间的均匀效果。
在图1或图2中，服用单剂量常规药片后非洛地平和美多心安在血浆中的平均浓度（参考例A）与服用实施例1制剂后的情况作了比较，美多心安常规片给10位志愿者服用：而非洛地平常规片给12位志愿者服用。
参考例C的药丸以单剂量给6位健康者服
用，经0.5、1、2、3、4、6、8和10小时后采集血浆样品，没有一个血浆样品能测出非洛地平。
按照本发明的制剂在体外实验中显示非洛地平和美多心安的实际上恒定和延迟的释放性（见表1）。体内实验的相应数据表明该产品也显示两种药物在血浆中具有可控的和均匀的浓度，见图1和图2。把上述的体内实验数据和服用常规药片后的情况相比，按照本发明的处方优点是明显的（见图1和图2）。服用常规药片后24小时，药物在血浆中的浓度极低，结果可预期其效果极差或没有效果，按照本发明硝苯啶和美多心安的固定混合物也显示出两种药物的所需延迟释放性（参照表2）。
正如从参考例B（见表3）的美多心安剂型在体外迅速释放所表明那样，在用于本发明二氢吡啶型的钙通道阻滞剂部分的亲水性溶胀基质内仅仅掺入一种美多心安盐是不可能达到所需的释放曲线的。与此类似，从一种不含增溶剂而掺入包衣珠内的药物产品不可能得到合意的二氢吡啶型的钙通道阻滞剂血浆水平。在参考例C中的健康人所做的体内研究结果表明在血浆中没有可检测得到的非洛地平。
为了减少血浆水平的波动，并为了允许二氢吡啶衍生物和美多心安每日一次剂量给药，需要延迟释放两种药物。使用一种按现有技术的单一种类的控释系统不能达到这一目的。本发明利用两种不同类型的控释系统，并将其掺入在一种独特和新的剂型中，从而提供了两种药物的最佳吸收和长效持续性。
Claims (11)
1、含有美多心安和在水中溶解度为小于0.1%(重量)的二氢吡啶型难溶于水的钙通道阻滞剂的混合物的控制释放制剂的制备方法，其特征在于使美多心安包含在含有作为主要溶解组分的美多心安盐的小珠内，所说小珠用水不溶性聚合物膜包衣，并在二氢吡啶型的钙通阻滞剂被分散于非离子增溶剂中之后，将小珠和二氢吡啶型的钙通道阻滞剂二者都掺入与水接触时能形成溶胀凝胶的基质中。
2、按照权利要求1所述的方法，其特征在于，所述的非离子增溶剂选自下列一组物质：聚乙氧基化的蓖麻油、聚乙氧基化的氢化蓖麻油、从蓖麻油所制的聚乙氧基化的脂肪酸或从氢化蓖麻油所制的聚乙氧基化的脂肪酸。
3、按照权利要求1所述的方法，其特征在于，所述的非离子增溶剂是氧乙烯化甘油的氢化蓖麻油脂肪酸酯类。
4、按照权利要求1所述的方法，其特征在于，所述的二氢吡啶型的钙通道阻滞剂是非洛地平。
5、按照权利要求1所述的方法，其特征在于，所述的二氢吡啶型的钙通道阻滞剂是硝苯啶。
6、按照权利要求1所述的方法，其特征在于，所述的凝胶基质含有羟丙基甲基纤维素。
7、按照权利要求1所述的方法，其特征在于，所述的美多心安是以它的琥珀酸盐形式加入的。
8、按照权利要求1所述的方法，其特征在于，在每单位剂量中所述的二氢吡啶型的钙通道阻滞剂的量在2.5毫克到80毫克之间，美多心安琥珀酸盐外消旋物的量在40毫克到200毫克之间。
9、按照权利要求1所述的方法，其特征在于，在每单位剂量中所述的美多心安是以S-对映体山梨酸盐的形式加入，其量在25毫克到120毫克之间。
10、按照权利要求1所述的方法，其特征在于，所述的美多心安是以其S-对映体的苯甲酸盐或山梨酸盐的形式加入的。
11、按照权利要求1所述的方法，其特征在于，水不溶性聚合物膜是不带质子迁移基团的纤维素的衍生物。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114712319A (zh) * | 2022-03-25 | 2022-07-08 | 北京诺康达医药科技股份有限公司 | 一种非洛地平盐酸普萘洛尔复方制剂及其制备方法 |
Families Citing this family (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5268182A (en) * | 1988-06-24 | 1993-12-07 | Abbott Laboratories | Sustained-release drug dosage units of terazosin |
| GB9025251D0 (en) * | 1990-11-20 | 1991-01-02 | Solomon Montague C | Nifedipine dosage forms |
| CA2106494A1 (en) * | 1991-03-18 | 1992-09-19 | James W. Young | Composition and method containing optically pure (s) metoprolol |
| US5834496A (en) * | 1991-12-02 | 1998-11-10 | Sepracor, Inc. | Methods for treating hypertension using optically pure S(-) felodipine |
| IL104192A (en) * | 1992-02-17 | 1998-01-04 | Siegfried Ag Pharma | Pharmaceutical dosage forms having prolonged release rate of zero order of the active ingredient |
| US5773025A (en) | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5662933A (en) * | 1993-09-09 | 1997-09-02 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
| US6726930B1 (en) * | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US6080428A (en) | 1993-09-20 | 2000-06-27 | Bova; David J. | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
| US6129930A (en) | 1993-09-20 | 2000-10-10 | Bova; David J. | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| US6818229B1 (en) | 1993-09-20 | 2004-11-16 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia |
| US6746691B2 (en) | 1993-09-20 | 2004-06-08 | Kos Pharmaceuticals, Inc. | Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics |
| US6676967B1 (en) | 1993-09-20 | 2004-01-13 | Kos Pharmaceuticals, Inc. | Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia |
| US5399358A (en) * | 1993-11-12 | 1995-03-21 | Edward Mendell Co., Inc. | Sustained release formulations for 24 hour release of metroprolol |
| US5399359A (en) * | 1994-03-04 | 1995-03-21 | Edward Mendell Co., Inc. | Controlled release oxybutynin formulations |
| JP3279318B2 (ja) * | 1994-04-25 | 2002-04-30 | ペンウェスト ファーマシューティカルズ カンパニー | 持続放出性賦形剤 |
| US5399362A (en) * | 1994-04-25 | 1995-03-21 | Edward Mendell Co., Inc. | Once-a-day metoprolol oral dosage form |
| US5478572A (en) * | 1994-09-06 | 1995-12-26 | Bristol-Myers Squibb Co. | Gepirone dosage form |
| US5945125A (en) * | 1995-02-28 | 1999-08-31 | Temple University | Controlled release tablet |
| WO1997026865A1 (en) * | 1996-01-29 | 1997-07-31 | Edward Mendell Co., Inc. | Sustained release excipient |
| US5783212A (en) * | 1996-02-02 | 1998-07-21 | Temple University--of the Commonwealth System of Higher Education | Controlled release drug delivery system |
| JP3148256B2 (ja) | 1996-07-08 | 2001-03-19 | エドワード メンデル カンパニー．，インコーポレーテッド | 高用量難溶性薬物用持続放出マトリックス |
| US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| EP1137403B1 (en) * | 1998-12-11 | 2009-03-11 | Nostrum Pharmaceuticals, Inc. | Sustained release tablet containing hydrocolloid and cellulose ether |
| US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
| CA2352211C (en) * | 1999-09-30 | 2009-03-24 | Edward Mendell Co., Inc. | Sustained release matrix systems for highly soluble drugs |
| ATE526950T1 (de) | 1999-10-29 | 2011-10-15 | Euro Celtique Sa | Hydrocodon-formulierungen mit gesteuerter freisetzung |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| DE60128683T2 (de) * | 2000-04-11 | 2008-01-24 | Sankyo Co., Ltd. | Stabilisierte pharmazeutische zusammenstellungen die den calziumkanalblocker azelnidipine enthalten |
| US6375972B1 (en) | 2000-04-26 | 2002-04-23 | Control Delivery Systems, Inc. | Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof |
| EP2263658A1 (en) | 2000-10-30 | 2010-12-22 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
| DE60219478T2 (de) * | 2001-07-06 | 2008-01-03 | Endo Pharmaceuticals Inc. | Orale gabe von 6-hydroxy-oxymorphon als analgetikum |
| EP1424997B1 (en) * | 2001-09-14 | 2007-11-21 | SCOLR, Inc. | Amino acid modulated extended release dosage form |
| US20040009220A1 (en) * | 2001-12-31 | 2004-01-15 | Vinay Sharma | Rate-controlled beta blockers and process for forming same |
| MXPA04009701A (es) * | 2002-04-05 | 2005-05-27 | Penwest Pharmaceuticals Co | Formulaciones de metoprolol de liberacion sostenida. |
| US8871241B2 (en) | 2002-05-07 | 2014-10-28 | Psivida Us, Inc. | Injectable sustained release delivery devices |
| US20050267143A1 (en) * | 2002-05-15 | 2005-12-01 | Davis Paul J | Pyrroloquinoline quinone drugs for treatment of cardiac injury and methods of use thereof |
| US7276514B2 (en) * | 2002-05-15 | 2007-10-02 | Charitable Leadership Foundation - Medical Technology Acceleration Program | Pyrroloquinoline quinone drugs for treatment of cardiac injury and methods of use thereof |
| US20080051428A1 (en) * | 2002-05-15 | 2008-02-28 | Davis Paul J | Pyrroloquinoline quinone drugs and methods of use thereof |
| KR20030095600A (ko) * | 2002-06-12 | 2003-12-24 | 환인제약 주식회사 | 펠로디핀을 포함하는 제어방출형 조성물 및 그 제조방법 |
| US7314640B2 (en) * | 2003-07-11 | 2008-01-01 | Mongkol Sriwongjanya | Formulation and process for drug loaded cores |
| US20070092573A1 (en) * | 2005-10-24 | 2007-04-26 | Laxminarayan Joshi | Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist |
| TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
| TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
| US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
| EP2255791B1 (en) * | 2009-04-03 | 2011-11-16 | Zaklady Farmaceutyczne Polpharma SA | Extended release pharmaceutical composition comprising metoprolol succinate |
| US8927025B2 (en) | 2010-05-11 | 2015-01-06 | Cima Labs Inc. | Alcohol-resistant metoprolol-containing extended-release oral dosage forms |
| CA2798700C (en) * | 2010-05-11 | 2018-08-21 | Cima Labs Inc. | Alcohol-resistant formulations |
| AU2012303683B2 (en) * | 2011-08-26 | 2016-09-08 | Wockhardt Limited | Methods for treating cardiovascular disorders |
| GB2512059B (en) * | 2013-03-18 | 2016-08-31 | Rolls Royce Plc | An independently moveable machine tool |
| CN113143877A (zh) * | 2021-05-07 | 2021-07-23 | 苏州康恒研新药物技术有限公司 | 一种琥珀酸美托洛尔微丸缓释片的制备方法 |
Family Cites Families (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
| CH532038A (de) * | 1970-05-25 | 1972-12-31 | Ciba Geigy Ag | Verfahren zur Herstellung von neuen Cycloheptenderivaten |
| US3951821A (en) * | 1972-07-14 | 1976-04-20 | The Dow Chemical Company | Disintegrating agent for tablets |
| US4123382A (en) * | 1973-05-25 | 1978-10-31 | Merck & Co., Inc. | Method of microencapsulation |
| DE2336218C3 (de) * | 1973-07-17 | 1985-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Orale Arzneiform |
| SE418247B (sv) * | 1975-11-17 | 1981-05-18 | Haessle Ab | Sett att framstella kroppar med reglerad frigoring av en aktiv komponent |
| US4016880A (en) * | 1976-03-04 | 1977-04-12 | Alza Corporation | Osmotically driven active agent dispenser |
| US4291016A (en) * | 1976-07-27 | 1981-09-22 | Sandoz Ltd. | Enteric coated mixture of 4-(2-hydroxy-3-isopropylamino-propoxy) indole and sodium lauryl sulphate |
| GB1542414A (en) * | 1976-08-19 | 1979-03-21 | Standard Telephones Cables Ltd | Arrangements for the controlled release of biologically active materials |
| DE2642032C2 (de) * | 1976-09-18 | 1987-04-30 | Rupprecht, Herbert, Prof. Dr., 8400 Regensburg | Verfahren zur Inkorporierung von Wirkstoffen in siliciumdioxidhaltige Trägermaterialien und eine siliciumdioxidhaltige Zubereitung |
| GB1576376A (en) * | 1977-03-30 | 1980-10-08 | Benzon As Alfred | Multiple-unit drug dose |
| US4256108A (en) * | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
| SE426548B (sv) * | 1978-12-05 | 1983-01-31 | Haessle Ab | Fast farmaceutisk beredning innehallande en terapeutiskt effektiv hjertglykosid och en polymer |
| US4357469A (en) * | 1979-06-14 | 1982-11-02 | Forest Laboratories, Inc. | Carrier base material for prolonged release therapeutic compositions |
| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| US4309406A (en) * | 1979-07-10 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4309404A (en) * | 1979-08-09 | 1982-01-05 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
| DE3033919A1 (de) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Feste arzneizubereitungen enthaltend nifedipin und verfahren zu ihrer herstellung |
| CH655658B (zh) * | 1980-09-18 | 1986-05-15 | ||
| US4326525A (en) * | 1980-10-14 | 1982-04-27 | Alza Corporation | Osmotic device that improves delivery properties of agent in situ |
| US4439195A (en) * | 1980-10-14 | 1984-03-27 | Alza Corporation | Theophylline therapy |
| US4428883A (en) * | 1981-03-06 | 1984-01-31 | The University Of Kentucky Research Foundation | Novel method of administering β-blockers and novel dosage forms containing same |
| IT1144911B (it) * | 1981-03-19 | 1986-10-29 | Pharmatec Spa | Composizione farmaceutica a rilascio controllato contenente ibuprofen |
| GB2098867B (en) * | 1981-05-21 | 1984-10-24 | Wyeth John & Brother Ltd | Sustained release pharmaceutical composition |
| JPS57209223A (en) * | 1981-06-19 | 1982-12-22 | Tanabe Seiyaku Co Ltd | Microcapsule for intracranial anti hypotension and its production |
| US4369272A (en) * | 1981-07-07 | 1983-01-18 | E. I. Du Pont De Nemours And Company | Process for preparing polyolefin resin extended pigments comprising salt milling crude pigment with the resin |
| US4484921A (en) * | 1982-02-01 | 1984-11-27 | Alza Corporation | Theophylline therapy utilizing osmotic delivery |
| US4642233A (en) * | 1982-03-22 | 1987-02-10 | Alza Corporation | Gastrointestinal drug delivery system comprising a hydrogel reservoir containing a plurality of tiny pills |
| US4434153A (en) * | 1982-03-22 | 1984-02-28 | Alza Corporation | Drug delivery system comprising a reservoir containing a plurality of tiny pills |
| US4649043A (en) * | 1982-03-22 | 1987-03-10 | Alza Corporation | Drug delivery system for delivering a plurality of tiny pills in the gastrointestinal tract |
| US4449983A (en) * | 1982-03-22 | 1984-05-22 | Alza Corporation | Simultaneous delivery of two drugs from unit delivery device |
| JPS58170712A (ja) * | 1982-03-31 | 1983-10-07 | Chiyoda Yakuhin Kk | インドメタシン徐放錠 |
| US4415547A (en) * | 1982-06-14 | 1983-11-15 | Sterling Drug Inc. | Sustained-release pharmaceutical tablet and process for preparation thereof |
| US4681583A (en) * | 1982-12-20 | 1987-07-21 | Alza Corporation | System for dispersing drug in biological environment |
| DE3247118A1 (de) * | 1982-12-20 | 1984-06-20 | Cassella Ag, 6000 Frankfurt | Neue substituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| US4578075A (en) * | 1982-12-20 | 1986-03-25 | Alza Corporation | Delivery system housing a plurality of delivery devices |
| DE3307422A1 (de) * | 1983-03-03 | 1984-09-06 | Bayer Ag, 5090 Leverkusen | Fluessigzubereitungen von dihydropyridinen, ein verfahren zu ihrer herstellung, sowie ihre verwendung bei der bekaempfung von erkrankungen |
| PH18946A (en) * | 1983-04-21 | 1985-11-14 | Elan Corp Plc | Controlled absorption pharmaceutical composition |
| GB2146531B (en) * | 1983-09-15 | 1987-04-29 | Stc Plc | Controlled release system |
| SE457505B (sv) * | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | Laminatbelagd oral farmaceutisk komposition och foerfarande foer dess framstaellning |
| IE59287B1 (en) * | 1984-02-10 | 1994-02-09 | Benzon Pharma As | Diffusion coated multiple-units dosage form |
| GB2154874B (en) * | 1984-02-29 | 1987-11-04 | Sandoz Ltd | Bromoscriptine compositions |
| IT1206166B (it) * | 1984-07-26 | 1989-04-14 | Sigma Tau Ind Farmaceuti | Dispositivo per rilasciare una sostanza in un fluido di dissoluzione con cinetica di ordine zero e procedimento per la sua preparazione |
| US4794111A (en) * | 1984-05-23 | 1988-12-27 | Bayer Aktiengesellschaft | Dihydropyridine preparations containing β-blockers |
| DE3419131A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Dihydropyridinkombinationspraeparate und verfahren zu ihrer herstellung |
| GB2159715B (en) * | 1984-06-04 | 1988-05-05 | Sterwin Ag | Pharmaceutical composition in sustained release unit dose form and process for its preparation |
| SE455836B (sv) * | 1985-10-11 | 1988-08-15 | Haessle Ab | Beredning med kontrollerad frisettning innehallande ett salt av metoprolol samt metod for framstellning av denna beredning |
| US4808413A (en) * | 1987-04-28 | 1989-02-28 | E. R. Squibb & Sons, Inc. | Pharmaceutical compositions in the form of beadlets and method |
-
1987
- 1987-10-08 SE SE8703881A patent/SE8703881D0/xx unknown
-
1988
- 1988-09-16 AU AU22374/88A patent/AU615211B2/en not_active Expired
- 1988-09-20 NZ NZ226245A patent/NZ226245A/xx unknown
- 1988-09-22 ES ES88850319T patent/ES2053815T3/es not_active Expired - Lifetime
- 1988-09-22 DE DE8888850319T patent/DE3877492T2/de not_active Expired - Lifetime
- 1988-09-22 AT AT88850319T patent/ATE84412T1/de not_active IP Right Cessation
- 1988-09-22 EP EP88850319A patent/EP0311582B1/en not_active Expired - Lifetime
- 1988-09-27 IE IE292188A patent/IE63084B1/en not_active IP Right Cessation
- 1988-09-27 NO NO884269A patent/NO177375C/no not_active IP Right Cessation
- 1988-09-29 PH PH37615A patent/PH25568A/en unknown
- 1988-09-29 US US07/250,945 patent/US4942040A/en not_active Expired - Lifetime
- 1988-10-05 IL IL87922A patent/IL87922A/xx active Protection Beyond IP Right Term
- 1988-10-06 IS IS3398A patent/IS1584B/is unknown
- 1988-10-06 DK DK198805586A patent/DK175085B1/da active
- 1988-10-06 MX MX013316A patent/MX169243B/es unknown
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- 1988-10-07 JP JP63252209A patent/JP2619936B2/ja not_active Expired - Lifetime
- 1988-10-07 KR KR88013076A patent/KR960009411B1/ko not_active IP Right Cessation
- 1988-10-07 FI FI884636A patent/FI92903C/fi not_active IP Right Cessation
- 1988-10-07 PT PT88711A patent/PT88711B/pt not_active IP Right Cessation
- 1988-10-07 CA CA000579566A patent/CA1312286C/en not_active Expired - Lifetime
- 1988-10-08 CN CN88109129A patent/CN1029935C/zh not_active Expired - Lifetime
-
1993
- 1993-01-14 GR GR930400002T patent/GR3006788T3/el unknown
-
1994
- 1994-12-15 HU HU94P/P00056P patent/HU210461A9/hu unknown
-
1996
- 1996-01-11 HK HK6296A patent/HK6296A/xx not_active IP Right Cessation
- 1996-09-27 CY CY189696A patent/CY1896A/xx unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114712319A (zh) * | 2022-03-25 | 2022-07-08 | 北京诺康达医药科技股份有限公司 | 一种非洛地平盐酸普萘洛尔复方制剂及其制备方法 |
| CN114712319B (zh) * | 2022-03-25 | 2024-01-09 | 北京诺康达医药科技股份有限公司 | 一种非洛地平盐酸普萘洛尔复方制剂及其制备方法 |
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