CN1152434A - S(+)-乙哚乙酸的口服制剂 - Google Patents
S(+)-乙哚乙酸的口服制剂 Download PDFInfo
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- CN1152434A CN1152434A CN96112008A CN96112008A CN1152434A CN 1152434 A CN1152434 A CN 1152434A CN 96112008 A CN96112008 A CN 96112008A CN 96112008 A CN96112008 A CN 96112008A CN 1152434 A CN1152434 A CN 1152434A
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- acid
- etodolac
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- 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
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
本发明公开了含有S(+)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸,也称为S(+)乙哚乙酸的传入感受器可接受的制剂,该制剂中优选含有一种酸性成分。
Description
本发明涉及乙哚乙酸的新制剂。具体地说,本发明涉及使用S(+)-乙哚乙酸的传入感受器可接受的口服制剂。为了这一目的,传入感觉器可接受的化合物、物质和制剂即它们能与受者口腔味觉感受器接触并且通常可被受者的感觉接受,特别是味觉接受。具体地说,本发明的传入感觉器可接受的制剂中的S(+)-乙哚乙酸成分没有不愉快的苦味道,这种味道一般与乙哚乙酸的外消旋混合物有关。发明背景
乙哚乙酸是一种非甾类抗炎药(NSAID),它在动物模型中表现出抗炎、镇痛和解热的活性。和其它NSAID一样,乙哚乙酸的机理尚未完全理解,但是据信它与抑制前列腺素的生物合成有关。乙哚乙酸目前由Wyeth-Ayerst Laboratories以Lodine片剂和胶囊剂的形式出售,这些片剂和胶囊剂使用乙哚乙酸的外消旋混合物。
美国专利3939178(Demerson等)讲授和要求了某些吡喃并[3,4-B]吲哚和噻喃并[3,4-B]吲哚,包括Lodine片剂和胶囊剂的(±)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-B]吲哚-1-乙酸组分。
美国专利4710511(Wooley)公开了一种使用乙哚乙酸组合物抑制关节强硬来治疗关节炎的方法。美国专利4742076讲述了一种使用该化合物降低类风湿因子血液水平的方法。美国专利4966768(Michelucci等)描述了一种乙哚乙酸的持续释放形式,它含有乙哚乙酸、羟丙基甲基纤维素、乙基纤维素和诸如磷酸二氢钠等释放速率调节剂的必需成分,羟丙基甲基纤维素中羟丙氧基的含量约为重量的7.O%至8.6%。
Demerson等在Journal of Medicinal Chemistry(1983,第26卷,第12期,1778-1780页)中公开了生化和药理实验,该实验表明乙哚乙酸几乎所有的作用都归因于S(+)对映体。
PCT申请WO93/17680中讲述了使用光学纯R(-)乙哚乙酸治疗疼痛的方法和组合物。WO93/17680表明,光学纯的R(-)乙哚乙酸实质上降低了与乙哚乙酸外消旋混合物用药相关的某些预计的不良作用。
没有进行包衣或掩蔽味道的乙哚乙酸由于它令人不快的苦味而尚未充分用于许多制剂中,这些制剂会使乙哚乙酸接触受者的味蕾。因此,本发明提供含有未包衣及未掩蔽的乙哚乙酸作为活性成分的传入感受器可接受的制剂很有意义。同时,本发明制剂的制备不需要另外的将乙哚乙酸成分包衣或将味道掩蔽成分掺入该制剂的步骤,这也是很有意义的。发明描述
乙哚乙酸是一种吡喃羧酸,化学命名为(±)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸,其具有下述结构式:它目前由Wyeth-Ayerst Laboratories,Division ofAmerican Home products Corporation,P.O.Box 8299,Phil adelphia,PA19101作为外消旋混合物以Lodine片剂和胶囊剂的形式出售。乙哚乙酸是一种非甾类抗炎药(NSAID),具有抗炎、解热镇痛活性,在本领域中有很多记载。乙哚乙酸可以通过本领域已知的方法制备,例如美国专利3939178(Demerson等)中的描述,该专利引入本文作为参考。乙哚乙酸的外消旋体也可通过本领域的已知方法拆分。例如,如美国专利4520203(Abraham等)所述,可以通过非对映体盐与(+)-辛可宁结晶而拆分,得到近100%对映体纯度的(+)-乙哚乙酸,总产率为81%(回收(+)-辛可宁)。
已发现,乙哚乙酸的右旋型或S(+)型,即S(+)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸(本文也指乙哚乙酸的eutomer或乙哚乙酸eutomer)不具有外消旋乙哚乙酸的令人不快的苦味。因此,可以理解并认为在本发明范围内乙哚乙酸S(+)立体异构体(基本不含R(-)形式,优选不含R(-)形式)的使用可开创各种乙哚乙酸制剂,这些制剂对口服用药来说是药学上及传入感受器可接受的。
这一认知不仅为本领域的技术人员提供了开创传入感受器可接受的乙哚乙酸制剂的能力,而且不需要对乙哚乙酸包衣或进行味道掩蔽的附加步骤。在许多情况下,对药物包衣的技术是不完善的,这就使得一部分化合物可能易于接触味蕾。类似地,当在可能咀嚼的制剂中,牙齿的磨碎动作可以刺穿制剂的包衣颗粒而释放出一些令人不快味道的物质。本发明制剂始于可接受的味觉基本成分,即消除了令人不快物质的不期望释放的机会。这一改善不仅提高了商业性以及降低了该制剂的生产成本,而且也改善了受者对规定剂量方案的依从性。
鉴于这一认知,本发明包括传入感受器可接受的口服制剂,该口服制剂含有(单独或与其它传入感受器及药学上可接受的成分结合)基本不含R(-)形式的乙哚乙酸的S(+)立体异构体,优选不含R(-)形式。这些口服制剂包括那些制剂中的活性成分及其它成分一般会接触受者味觉和/或嗅觉感受器的口服制剂。这种制剂包括(但并不局限于)传入感受器可接受的液体乙哚乙酸分散体、悬浮液、乳剂、糖浆剂、胶体、香囊(sachets)、片剂(包括咀嚼片、颊含片和舌下片)、粉剂或颗粒剂、泡腾剂、扁囊剂、锭剂或糖锭、糊剂、泡沫剂、洁齿剂和凝胶剂。由于NSAID可用于兽医,因此对动物特别是猫和狗等宠物的传入感受器可接受的制剂也可在本发明的范围内制得。
在最简单的形式中,本发明包括传入感受器可接受的乙哚乙酸制剂,该制剂含有乙哚乙酸eutomer本身。该化合物可以单独口服以缓解本领域中乙哚乙酸可缓解的病症。乙哚乙酸的eutomer可以与有助于药物口服给药的水、果汁、软饮料、牛奶或其它液体或饮料同服。其它简化服药方式包括将eutomer用于食品,然后以常规方式食用。任何受者,特别是儿童都可优选这些与食物或饮用有关的给药途径。
优选本发明的含有乙哚乙酸eutomer的制剂还含有足量的酸性成分以维持制剂的pH值低于7,优选在2和6之间。用于这些制剂的可药用酸包括(但并不局限于)常用的食物酸,例如柠檬酸、酒石酸、苹果酸、富马酸、乳酸、己二酸、抗坏血酸、天冬氨酸、异抗坏血酸、谷氨酸和琥珀酸。
本发明含有乙哚乙酸eutomer的组合物可用于市场上现有的Lodine片剂和和胶囊的建议用量。本领域的技术人员可以理解,和其它NSAID一样,患者个体之间对乙哚乙酸的反应可不同。因此,推荐的初始治疗剂量应是对大多数受者可能有效的剂量,然后可根据受者观察到的有利的和不良作用调整剂量。
在健康的年轻至中年成人中使用乙哚乙酸发现,在给予400毫克单次乙哚乙酸剂量后即可减轻急性疼痛症状并维持5到6小时,而给予200毫克后缓解症状可维持4到5小时。本发明的制剂包括从10毫克或更低用量至1000毫克或更高用量的乙哚乙酸eutomer。本发明制剂的建议乙哚乙酸用量是,开始200-400毫克剂量,随后每6到8小时为50毫克至400毫克,优选200毫克至400毫克。如果要减轻骨关节炎症状,则需要初始剂量为800至1200毫克/天的分次剂量。这些分次剂量可以是400毫克,一天三次或两次或者300毫克,一天四次或三次。如果与其它NSAID同用,则建议可减轻症状的最低剂量和最长的给药间隔。本文所述及要求的组合物中乙哚乙酸的建议每日总剂量为600至1200毫克/天(以分次剂量给药),例如400毫克,一天三次或两次,300毫克、一天四次或三次或者200毫克、一天四次或三次。可以理解,尽管下述实施例中列出了乙哚乙酸eutomer的含量,但是下面的配方可以用上述任何剂量的乙哚乙酸eutomer构成。
尽管本发明乙哚乙酸eutomer不会对所用制剂造成不良味道,但是本文所述的配方中可包括甜味剂或矫味剂以增加制剂的整体气味、味道和适宜性。这些甜味剂包括所有可药用的甜味剂,包括(但并不局限于)糖浆、甘氨酸、玉米浆、糖(如蔗糖、葡萄糖、果糖和蜜饯糖)、山梨醇、糖精、蔗糖、糖精钠、糖精钙、天冬酰苯丙氨酸甲酯(可以从Illinois,Deerfield的Nutrasweet公司以Nutrasweet的商品名购得)、卡哈苡苷、新橙皮苷二氢查耳酮、甘草、紫苏醛、木糖醇、右旋糖、甘露糖和乳糖。
本文的制剂也可包括可药用赋形剂、填充剂、稀释剂、润滑剂、崩解剂、悬浮剂或稳定剂以及粘合剂,包括(但并不局限于)硬脂酸镁、十二烷基硫酸钠、微晶纤维素、聚乙烯吡咯烷酮、明胶、藻酸、阿拉伯胶、柠檬酸钠、复合硅酸盐、碳酸钙、甘氨酸、糊精、蔗糖、山梨醇、磷酸氢二钙、硫酸钙、乳糖、高岭土、甘露糖醇、氯化钠、滑石、干淀粉(如玉米、马铃薯或木薯淀粉)及粉末糖。
本发明制剂的简单形式中包括含有乙哚乙酸eutomer的粉末状或颗粒剂量制剂。例如,该eutomer可单独以粉末或颗粒形式口服用药。受者希望将这种粉末或颗粒放在口腔中,然后通过饮用一种液体或食用一种固体食物而将其冲下。由于本文所述剂量中S(+)乙哚乙酸的相对小的体积,它优选包含在粉末或颗粒的剂量形式中形成一种或多种传入感受器可接受的粉末药物组分。它们可以是具有附加药物活性的化合物或者本文所述的填充物、甜味剂等。可以理解,任何剂量的乙哚乙酸eutomer都可以按这种方式给药,只是附加成分的体积应限定在受者可接受的含量内。
随着乙哚乙酸S(+)eutomer的应用,传入感受器可接受的口服液体乙哚乙酸剂量形式可以配制出并使用。用水即可以制备这种液体制剂。
这些口服液可以包括任何使用乙哚乙酸eutomer的口服液体制剂,包括将所需剂量的乙哚乙酸eutomer简单掺入常规消耗量的饮料中,包括(但并不局限于)例如碳酸水或非碳酸水、果汁、咖啡、茶、软饮料和牛奶。由于乙哚乙酸eutomer单剂量占用相对小的体积,因此优选将其掺入少量可控制的一种或多种可药用的上品及传入感受器可接受的物质中,例如本文所述的那些物质。
在本发明一种优选的口服液中,该口服液包括约0.8%至4%(重量比组合物的总体积)的乙哚乙酸eutomer、约0.1%至约2%(重量比组合物的总体积)的悬浮稳定剂、约20%至约70%(重量比组合物的总体积)的一种或多种矫味剂、约30%至约70%(重量比组合物的总体积)的水,并且该组合物含有一种可药用及传入感受器可接受的食物酸,例如柠檬酸或磷酸,含量为0.1%至约2%(重量比体积)。优选的悬浮剂包括黄原胶、微晶纤维素、羧甲基纤维素钠和多乙氧基醚80。下述实施例1和2描述了如何制备这两种制剂。实施例1
成 分 百分数(重量/体积) 每15升的克数
黄原胶 0.15 22.5微晶纤维素 0.75 112.5苯甲酸钠,NF 0.25 37.5柠檬酸,一水合,USP 0.95 142.5
蔗糖,NF 50.00 7500.0
玉米糖浆 20.00 3000.00乙哚乙酸Eutomer 2.0 300.0羧甲基纤维素钠,USP 0.10 15.0多乙氧基醚80,BF 0.30 45.0
红色FDC40色素 0.15 2.25
EDTA二钠,USP 0.05 7.5
合成柠檬调味油 0.16 24.0
磷酸 加至pH为3.0-3.5 加至pH为3.0-3.5
纯化水,USP 加至100毫升 加至15000毫升
这种口服液体制剂的第一部分是如下制备的。首先将山梨醇溶液和甘油装入配有搅拌器的套锅中。然后将羧甲基纤维素钠组分喷洒到该溶液上并混合10分钟直至其完全润湿。然后将混合物加热至约70℃并混合至胶完全水合,随后冷却混合物至45℃,加入多乙氧基醚组分。继续混合同时将混合物冷却至30℃。把乙哚乙酸eutomer缓慢喷洒到该混合物上,继续混合15分钟。
第二部分是把所需量的水装入配有桨式混合器的容器中,缓慢加入黄原胶并通过高速切力混合约25分钟而使黄原胶水合。然后将其装入一个的分离的混合容器中,该容器配有桨式混合器和相当于总批量体积(4500至6000毫升)的约30%至约40%的水。然后将微晶纤维素喷洒到水上,于中速切力混合约30分钟直至完全分散纤维素。
将上述第一部分中所需量的黄原胶加到纤维素悬浮液中,混合约15分钟或者混合至得到均匀悬浮液。然后缓慢加入蔗糖,混合约15分钟或者混合至观察不到蔗糖颗粒。可加入着色剂(例如上述的红色FDC40色素)并混合至其分散到混合物中。
然后再加入上述第一部分的浆液,缓慢混合约15分钟。接着加入苯甲酸钠、EDTA二钠和柠檬酸及矫味剂并在每次加入后混合约5分钟。混合下加入磷酸组分直至配方的pH值达到约3.0至约3.5。最后的配方应用水平衡并且混合至配方均匀。实施例2
使用S(+)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸(乙哚乙酸eutomer)的口服液制剂的另一实施例如下:
成分 百分数(重量/体积) 每15升的克
数
黄原胶 0.15 22.5微晶纤维素 0.75 112.5苯甲酸钠,NF 0.25 37.5水合柠檬酸,USP 0.95 142.5蔗糖,NF 50.00 7500.0甘油,USP 10.00 15 00.00山梨醇溶液,USP 10.00 1500.00乙哚乙酸Eutomer 2.0 300.0羧甲基纤维素钠,USP 0.10 15.0多乙氧基醚80,BF 0.30 45.0红色FDC40色素 0.15 2.25EDTA二钠,USP 0.05 7.5合成柠檬调味油 0.16 24.0
盐酸 加至pH为2.5-3.5 加至pH为2.5-3.5
纯化水,USP 加至100毫升 加至15000毫升
该制剂可以如下制备。将山梨醇溶液和甘油量入配有搅拌器的套锅中。在该溶液上喷洒羧甲基纤维素钠,混合10分钟或者混合至所有颗粒都完全润湿。然后将所得混合物加热至约70℃,混合至胶完全水合,然后冷却混合物至45℃,加入多乙氧基醚80。继续混合同时将混合物冷却至30℃。然后缓慢将乙哚乙酸eutomer加入该混合物中,继续混合15分钟而制备下述乙哚乙酸浆。
将第二种溶液(即指黄原胶溶液)先制备成1%重量的黄原胶的水溶液形式。应将黄原胶缓慢加到水中,在高速切力下混合约25分钟。在配有混合器的另一混合容器中装入相当于总批量体积(4500至6000毫升)的约30%至约40%(重量/体积)的水。然后将微晶纤维素喷洒到水上,于中速切力混合约30分钟或者混合至微晶纤维素完全悬浮。然后将所需量的黄原胶溶液加到微晶纤维素悬浮液中,混合15分钟或者混合至得到均匀悬浮液。
然后将蔗糖缓慢加到第二种溶液中,混合15分钟或者混合至观察不到蔗糖颗粒。接着可加入着色剂。然后缓慢加入所需量的乙哚乙酸浆液,混合15分钟。然后顺序加入苯甲酸钠、EDTA二钠和柠檬酸并在每次加入后混合约5分钟。混合下加入盐酸组分直至配方的pH值达到约2.5至约3.5。然后混合下加入余量水直至配方均匀。实施例3含有乙哚乙酸Eutomer的咀嚼片
含有乙哚乙酸eutomer并且包括在本发明范围内的咀嚼片应理解为包括本领域已知的可药用的及传入感受器可接受的咀嚼片剂。这些制剂包括具有a)本文所述剂量的乙哚乙酸eutomer;b)约5毫克至约4 00毫克,优选约10毫克至约200毫克的固体酸化剂成分,例如本文所述的食物酸组分;和c)约50毫克至约5克,优选约100毫克至约1克的可药用及传入感受器可接受的赋形剂,例如dexrates、麦芽糖糊精、乳糖、改性食物淀粉、硬脂酸铝、口香糖基质和致密食物级糖以及其它适用作填充物和载体的物质。可选择性地,这些咀嚼片剂可以含有最多至约100毫克的可药用助流剂或润滑剂。该咀嚼片的一个实例如下:
成分 要求/片剂 1000个药片的进料量乙哚乙酸Eutomer 200毫克 0.200千克柠檬酸,USP 0.020千克甘露糖醇,USP 0.532千克聚乙二醇,8000,NF,粉末 0.144千克留兰香油,Aromalok, 0.00480千克180235,Fritzsche硬脂酸镁,USP 0.00580千克理论片重 = 916.6毫克乙哚乙酸Eutomer咀嚼片的生产方法:注意:所有的操作都必须在不超过30%的相对湿度下并且在不超过27℃(80°F)的温度下进行。
该配方的咀嚼片如下制备。首先在混合器中混合乙哚乙酸eutomer、山梨醇、柠檬酸、聚乙二醇9000和留兰香油约10分钟。然后将这种新形成的混合物用#14筛(中速、刀向前)通过磨。然后将硬脂酸铝加到该混合物中并混合约1分钟。接着将该混合后的混合物用5/8″扁圆的斜边冲头和冲模挤压成准确重量的药片。
本发明的传入感受器可接受的乙哚乙酸eutomer制剂也包括泡腾或泡沫制剂。这些制剂包括任何在泡腾配方中使用乙哚乙酸eutomer的药物组合物,特别是含有传入感受器可接受的酸(例如食物级酸)的泡腾或泡沫结合体及碳酸盐的组合物。用于这些制剂中的可药用酸包括(但不局限于)柠檬酸、酒石酸、苹果酸、富马酸、己二酸、抗坏血酸、天冬氨酸、异抗坏血酸、谷氨酸和琥珀酸。如果需要,甘氨酸也可用作酸性组分的一部分,但是最优选的是甘氨酸不组成酸性成分的大部分。最优选的是这种泡腾制剂的酸性组分超过碳酸盐组分以使泡腾溶液的pH值低于7,更优选低于6。
碳酸盐包括任何可药用的和传入感受器可接受的泡腾或泡沫碳酸盐,包括(但并不局限于)碳酸氢钠、碳酸钾、碳酸钠、碳酸钙、碳酸铝、碳酸镁等。可以理解,这些配方中的酸性和碳酸盐成分可以含有一种或多种可接受的酸或碳酸盐。
广而言之,本发明的泡腾或泡沫制剂含有活性乙哚乙酸eutomer和任何有效量的酸和碳酸盐成分。优选地,这三种组分的部分含有a)所需量的乙哚乙酸eutomer,b)约0.1%至约50%重量的酸性成分和c)约0.1%至50%重量的碳酸盐成分。
例如,该药物的单剂量包括a)10-1000毫克的乙哚乙酸eutomer,b)0.5-8克柠檬酸或者等量的一种或多种本文所述的其它可接受的酸,和c)0.5-8克碳酸氢钠或者等量的一种或多种本文所述的其它可接受的碳酸盐。本领域的技术人员可以理解,这些制剂中的各组分可以根据所需药物剂量、所需制造的泡腾或泡沫量以及加入该制剂的液体pH值的不同而不同。
也可以理解,除了这三种组分外,本发明的泡腾或泡沫制剂可以包括另外的可药用及传入感受器可接受的成分,包括(但并不局限于)填充剂、矫味剂、着色剂、甜味剂、粘合剂、可药用气味增强剂、香料等。这些制剂也可以包括其它药物活性物,例如止痛剂、抗组胺药、抗酸药、消气体药等。本发明范围内的泡腾或泡沫制剂的实例包括如下:含有乙哚乙酸Eutomer的泡腾粉末
本发明的100剂批量的泡腾或泡沫粉可以通过混合任何下列混合物(有或没有其他成分)而制备:实施例4a)1,000至100,000毫克的乙哚乙酸eutomer
b)110克酒石酸
c)100克碳酸氢钠实施例5a)1,000至100,000毫克的乙哚乙酸eutomer
b)150克苹果酸
c)150克富马酸
d)100克碳酸钙
e)180克碳酸镁
f)100克果糖实施例6a)1,000至100,000毫克的乙哚乙酸eutomer
b)250克柠檬酸
c)125克碳酸钾
d)100克碳酸铵实施例7a)1,000至100,000毫克的乙哚乙酸eutomer
b)10克柠檬酸
c)10克碳酸氢钠
b)40克蔗糖
e)10克山梨醇
f)10克甘露糖醇
g)10克羟丙基纤维素
h)5克羧甲基纤维素实施例8含有乙哚乙酸Eutomer的泡腾片
制备500个200毫克药片:
项目 成分 含量 每片
1 乙哚乙酸eutomer,细粉 100g 200mg
2 碳酸氢钠 386g
3 酒石酸 164g
4 柠檬酸 250g
5 聚乙二醇6000 100g
理论片重 2.0克生产过程:注意:步骤#1后所有的步骤都应在不超过30%相对湿度及27℃的环境中完成。
1.在80℃至105℃将项目1、2、3和4干燥1至4小时。
2.混合项目1、2、3和4以制得均匀粉末。
3.使步骤#2的混合物通过60目筛。
4.将项目#5过60目筛。
5.将过筛后的项目#5加到步骤#3的混合物中,混合使均匀分布。
6.用扁的、斜边5/8″冲头和冲模压成2.0克片重的药片。使用说明:
将所需剂量(每片200毫克)置于一种液体中,例如约三液体盎司的水中直至完全崩解。实施例9乙哚乙酸Eutomer的泡腾颗粒:
为制备500个小包,用实施例8的成分代替项目5的成分,该成分是无水橙味的粉末(来自Virginia Dare,Brooklyn,NY11232);同时用下述两个步骤替换实施例8的步骤6:
步骤6:将步骤5的粉末置于流化床塔中,当粉末被空气悬浮后,喷洒入足量的水以制得粒度接近10目的颗粒。
步骤7:加热干燥颗粒并转移到不高于25%相对湿度的区域内包装在密封小包(每包2.0克)中。
将所需数量的颗粒小包加到水中直至所有颗粒都崩解后即可将这些泡腾颗粒口服给药。快速崩解固体剂量形式
本发明传入感受器可接受的组合物可采取的另外形式是美国专利4371516中所述的快速溶解或崩解的剂量形式,该专利引入本文作为参考。这些形式优选可溶性固体形式,该固体形式设计成与液体,例如水或受者口腔唾液接触时即可在数秒内破碎。这些形式优选在与液体接触的10秒内崩解。这种制剂对儿童或老年患者或者不能接受治疗及试图将药物吐出或将未崩解的形成隐藏在口腔而后弃去的其它患者的给药特别有用。
用于制备本发明的快速崩解剂量形式的方法详述于美国专利4371516(Gregory等)和4305502(Gregory等),下面的实施例表明了含有乙哚乙酸eutomer优选剂量范围的快速崩解剂量形式的制备。实施例10
75个单个50毫克的乙哚乙酸eutomer快速崩解剂量可以下述方式制备:
(a)将30.0克明胶(B.P.)在加热及持续搅拌下溶于1000毫升纯水中制备水解明胶溶液。然后将所得明胶溶液在121℃和15p.s.i.高压灭菌1小时。然后使明胶溶液冷却至室温。
(b)将含有75个圆柱型凹槽的铝模(每个凹槽的直径约0.5厘米,深1厘米)在不锈钢盘中于液氮中冷却至约-192℃。将100克乙哚乙酸eutomer、20克苯甲酸、0.25克F.D.C.黄色5号着色剂和0.5克Norda喷雾干燥的橙味矫味剂与明胶溶液混合,在继续搅拌下用皮下注射器将1/2毫升的混合物加到每个凹槽中。将凹槽中的内容物冷冻。然后将模子在室温于0.3mmHg的真空中放置过夜。然后将每个含有50毫克乙哚乙酸eutomer的冷冻干燥制剂从模子中移出并密封储存。当口服或加到液体中时,每个制剂会在数秒内溶解。
本领域的技术人员可以理解,上述技术可用于配制本发明的含有各种单剂量的乙哚乙酸eutomer的快速崩解剂量形式。这些溶液可包括各种矫味剂、甜味剂、着色剂等以使不同受者更欢迎该溶液。此外,其它载体物可用于替换部分水解的明胶。它们包括(但并不局限于)多糖,例如水解葡聚糖、藻酸盐(如藻酸钠)和糊精或者它们彼此的混合物或与其它载体物(包括阿拉伯胶、聚乙烯醇或聚乙烯吡咯烷酮)的混合物。
为制备这些快速崩解制剂,优选使用乙哚乙酸eutomer的细粉形式以消除在受者口腔中产生制剂崩解剂杂质感觉的可能性。更优选地,乙哚乙酸eutomer是含有50微米或更小颗粒的微粉形式。本领域的技术人员可以理解,这些制剂由于其设计的本质,如果受到潮湿或者物理操作或冲击即可崩解。因此,可以理解应小心处理这些制剂并将其包装在容器中以减少其提前崩解的危险性,例如美国专利4305502中所述的包装。
下面实施例11至14列出了乙哚乙酸eutomer和其它成分的结合物,可以按上述方式将其加到1000毫升的明胶溶液或者其它适当的载体物中。实施例1110毫克乙哚乙酸eutomer/剂量
a)20克乙哚乙酸eutomer
b)30克果糖
c)10克苯甲酸实施例12100毫克乙哚乙酸eutomer/剂量
a)200克乙哚乙酸eutomer
b)0.25克F.D.C.黄色5号着色剂
c)0.5克Norda喷雾干燥橙味矫味剂
d)25克蔗糖
e)20克苯甲酸实施例13200毫克乙哚乙酸eutomer/剂量
a)400克乙哚乙酸eutomer
b)0.25克F.D.C.黄色5号着色剂
c)10克果糖
d)15克蔗糖
e)40克苯甲酸实施例14400毫克乙哚乙酸eutomer/剂量-不含水解明胶
a)533.33克乙哚乙酸eutomer
b)17克藻酸钠
c)35克葡聚糖
d)15克天冬酰苯丙氨酸甲酯
e)蒸馏水加至1000毫升
f)50克苯甲酸
不含有前面实施例中水解明胶的实施例14的制剂可以在含有150个圆柱型凹槽的220×330毫米聚氯乙烯层的凹槽中制备,每个凹槽约0.7厘米深,直径为约1.4厘米,其已在固体二氧化碳中冷却。该制剂可通过将乙哚乙酸eutomer在超声振荡下悬浮在含有上面所列藻酸钠、葡聚糖和天冬酰苯丙氨酸甲酯的水中而制备。然后将0.75毫升悬浮液放入每个聚氯乙烯层的凹槽中,冷冻干燥即可完成快速崩解固体制剂。实施例151克乙哚乙酸eutomer/剂量-不含水解明胶
a)1,333.33克乙哚乙酸eutomer
b)20克聚乙烯醇
c)20克聚乙烯吡咯烷酮
d)30克蔗糖
e)0.2克吐温80
f)蒸馏水加至1000毫升
g)50克苯甲酸
用上面所列各成分及前一实施例所述的二氧化碳冷却的聚氯乙烯层即可以产生另一快速崩解固体制剂的实例。这可以如下完成。将聚乙烯醇加到约500毫升的热蒸馏水中,然后再冷却。接着加入聚乙烯吡咯烷酮、蔗糖和吐温80,振摇混合物以溶解所有固体。加入乙哚乙酸eutomer,用超声振荡分散。然后加入蒸馏水使该混合物的终体积达1000毫升。然后把0.75毫升该溶液加到每个凹槽中用以冷冻干燥得最终的固体制剂。颊含齐(Buccal Formulations)
含有本发明乙哚乙酸eutomer的颊含剂可以用美国专利4764378(Keith等)中的方法制备,该专利引入本文作为参考。最优选的是,在颊含剂中掺入酸性组分例如微粉化的固体食物酸中。这种食物酸可占最终颊含剂重量的约0.1-2.0%,如果需要可以加入更多的酸。实施例16糖锭或锭剂
含有本文所述的任何剂量乙哚乙酸eutomer的糖锭或锭剂可以通过本领域的已知方法制备。例如,可以通过铸模及随后通过蒸发含有乙哚乙酸eutomer的浓糖浆而干燥来制备这种糖锭,如果需要,可以加入阿拉伯胶或西黄蓍胶等增稠剂。这种类型的糖锭通常是指糖块锭剂。用下面的成分和技术,可以制备本文所述的任何剂量乙哚乙酸eutomer的糖块锭剂。下面是用于制备含有100毫克乙哚乙酸eutomer的糖锭的配方。
成分 含量
蔗糖 6000克
酒石 30.0克(选择性)
玉米糖浆 4000克
柠檬酸(过100目 100毫克/4克
筛的细粉)
乙哚乙酸eutomer 100毫克/4克
通过将上面所列的蔗糖、酒石(选择性)和玉米糖浆在搅拌下加到原料釜中,然后煮沸溶解蔗糖和酒石而制备这些糖锭。当在约290°F同时蒸发掉了约30%初始容量而形成稠厚沸泡时,应将上述成分移开热源。混合这些组分直至物料冷却至约280°F。此时应在搅拌下于物料中加入柠檬酸和乙哚乙酸eutomer以形成均匀分散体。当物料冷却至约190°F时,将物料卷成绳或柱型并分成4克的小块。然后将这些小块放在筛上,冷却至环境温度。
用9200克可压缩糖,例如Dipac牌可压缩糖(DominoSugar Co.,New York,NY)及上述含量的酒石(选择性)、柠檬酸和乙哚乙酸eutomer(或者其它优选剂量的乙哚乙酸eutomer)可制备更易于崩解的糖锭或锭剂。将这些组分均匀混合并压成所需大小(例如上述的4克大小)的糖锭。
作为可压缩糖的替代物,可以将等量的蔗糖或乳糖与适当的粘合剂(例如525克藻酸钠)和药学上合适的成粒液充分混合而制得湿润物料。使该湿润物料通过成粒机而压成所需大小的糖锭。洁齿剂组合物
本领域已知的牙粉组合物中可含有S(+)乙哚乙酸(优选含有另外的酸性成分)以用来预防或减少骨丢失和/或促进已丢失骨骼的再生长。可以理解,本文的洁齿剂包括任何用于处理及维持牙齿和口腔组织的牙用制剂。其包括(但并不局限于)糊、胶、粉、颗粒组合物、液体等。本发明范围内的一个牙膏实例可通过将下面所列各非水组分缓慢加到水中,然后用轧制机经常规混合而制备得。实施例17
成分 组成(%)
S(+)乙哚乙酸 1%
硅酸镁铝 1%
柠檬酸 1%
磷酸二钙 46%
薄荷或其它矫味剂 4%
羧甲基纤维素钠 0.5%
十二烷基硫酸钠 2%
水 44.5%
本发明范围内的传入感受器可接受的洁齿剂包括任何已知的洁齿剂制剂,优选含有或已加入了酸性组分。这种类型的膏剂可含有例如10-50%重量的磨擦系统、0.5-10%重量的增稠剂、10-80%重量的湿润剂、0.1-1%重量的甜味剂、0.05-2%重量的矫味剂、0.001-0.02%重量的着色剂、1-7.5%重量的表面活性剂、0.1-0.8%重量的抗菌防腐剂和0.01-5%重量的酸化剂。
这些制剂中的磨擦组分包括焦磷酸钙、水合二氧化硅、不溶性偏磷酸钠、有机聚合物、三水合氧化铝、二水合磷酸二钙、无水磷酸二钙和碳酸钙。增稠剂可以包括白炭黑、热解二氧化硅、沉淀二氧化硅、羧甲基纤维素、羧乙烯基聚合物、黄原胶和角叉菜胶。所用的湿润剂包括山梨醇、甘油和聚乙二醇。可用的甜味剂包括糖精、木糖醇、环己氨磺酸盐、天冬酰苯丙氨酸甲酯和thaumatin。根据味道和市场的接受性可改进矫味剂,可包括薄荷、留兰香、冬青、肉桂和茴香等香料以及香精油。这种洁齿制剂可选用任何FDA批准的着色剂。表面活性剂可包括十二烷基硫酸钠、月桂酰肌氨酸钠、pluronics、吐温类、椰子单甘油酯磺酸钠、十二烷基苯磺酸钠和磺基琥珀酸二辛钠。所用的抗菌剂和防腐剂包括对羟基苯甲酸酯、山梨酸和苯甲酸。这些形式中所用的酸性组分包括本文所述的食物酸,包括乳酸、柠檬酸、磷酸和酒石酸。
这种洁齿剂的一个实例可由下述成分形成。实施例18
成分 作用 重量百分数乙哚乙酸eutomer 活性成分 2.0%二氧化硅干凝胶 磨擦剂 14.0%白炭黑 增稠剂 7.5%羧甲基纤维素钠 增稠剂 1.0%山梨醇 湿润剂 6 0%糖精 甜味剂 0.2%单氟磷酸钠 氟化物源 0.76%十二烷基硫酸钠 表面活性剂 5%(29%溶液)Tutti Fruitti香料 矫味剂 1%(Virginia Dare,AK27)等量的羟苯甲酸乙酯、羟苯抗菌防腐剂 0.4%甲酸甲酯和羟苯甲酸丙酯FDC蓝No.1 着色剂 1%磷酸 酸化剂 加至pH值为5.0-5.2软化水 赋形剂 加至100%
为了降低牙齿结构脱矿质作用的可能性,建议该配方的pH值不低于约5.0。单氟磷酸钠是在所需pH值范围内可使用的合适的氟化物源。口香糖制剂
本发明范围内另一传入感受器可接受的制剂是口香糖类型的制剂。可以理解,这种制剂可以通过将乙哚乙酸eutomer,最优选的是与适当的酸性成分一起掺入到传入感受器可接受的口香糖基质中而制备得。本发明的口香糖制剂的一个实例可以用如下实施例19的成分制备。实施例19
成分 在配方中的作用 每3g单位的含量 每3kg批量的含量乙哚乙酸eutomer,微活性成分 0.010g 10g粉化糖胶树胶 胶基 1.000g 1000g氢化松香的甘油酯 胶基 0.200g 200g蔗糖,细粉 甜味剂 1.600g 1600g塔鲁香脂 酸化剂 0.187g 187g肉桂油 矫味剂 0.003g 3g
可以将上面所列各组分结合到口香糖制剂中,即通过将胶基加热至软化,接着分别加入酸化剂、甜味剂、乙哚乙酸eutomer和矫味剂,每次加入后都要捏合成均匀混合物。然后用浆纱机将最后的均匀口香糖制剂轧制,用细粉化蔗糖切成3克的小块以便于使用,然后是标准包装和打包。可以理解,其它口香糖制剂也可在本发明范围内使用,上述配方中的成分可以用其它等量的功能组分替代,包括本文用于其它制剂的组分。兽医用制剂
也可以理解,使用传入感受器可接受的制剂在兽医应用中很重要。尽管兽医专家可能对任何哺乳动物都推荐使用NSAID,但是特别是对于宠物,例如狗和猫,主人和管理者更欣赏可易于接受的口服剂量制剂给药,而不是必须用动物约制技术来给药。
本发明的兽医用制剂包括前述任何固体或液体的剂量形式,它们都可以用于动物。可以将这些制剂配入动物的食物或饮水中,或者单独以药物整体形式给药。如果是单独给药,建议该制剂中含有通常可诱惑动物的成分,优选有味道的成分。例如,猫和狗可使用肝脏、海味、猪肉、肝粉、大豆粉、糖、鳕鱼肝油、大豆食、鱼食、骨食、酵母、麦胚食、鱼食等调味基质成分或其它已知的食物基质或者它们的结合物。这些成分在上面所列配方中可用作矫味剂或者它们可作为填料而替代本文所述的其它物质。可以理解,本发明的动物用口服制剂中各成分的百分比大部分可以通过动物的大小及所需制剂的大小而确定。例如,一个相对小的咀嚼片可以含有下述混合及挤压物:实施例20
成分 重量百分数
乙哚乙酸eutomer 60%
调味基质成分 15-25%
微晶纤维素 10-20%
聚乙烯吡咯烷酮K29-32 2-6%
硬脂酸铝 1-2%
乳酸 0.1-2.0%
为了制备含有所需剂量乙哚乙酸eutomer的大固体制剂,各组分的含量应按需增加,例如下述配方:实施例21
成分 重量百分数
乙哚乙酸eutomer 15%
调味基质成分 35-45%
磷酸二氢钙 15-25%
微晶纤维素 15-25%
聚乙烯吡咯烷酮K29-32 2-6%
硬脂酸铝 1-2%
最优选的是这些配方中也含有酸性成分,例如固体食物酸。例如,柠檬酸或苹果酸等食物酸可以占制剂重量的1-5%,如果需要,酸性成分的含量可以增加。可用于动物给药的另一咀嚼固体配方如下:实施例22
成分 毫克/片
乙哚乙酸eutomer 5-500
乳清,干糖 2,000
脱水肝脏 210
干酵母 50
硬脂酸铝,NF 50
柠檬酸 30实施例23
宠物用的另一咀嚼片可以通过下述成分和方法制备得。本实施例为含有乙哚乙酸eutomer的200毫克片剂的制备,但是可以理解,任何所需的剂量都可以按这种配方类型配制。
成分 含量/片 含量/1000片批量乙哚乙酸eutomer 200mg 200g羟基乙酸淀粉钠,NF(SSG) 600mg 600g喷雾干燥的U.S.P.乳糖 4441mg 441g脱水肝脏 252mg 252g干酵母 62mg 62g硬脂酸铝 45mg 45g富马酸 100mg 100g
该配方的咀嚼片可以如下制备。将乙哚乙酸eutomer、羟基乙酸淀粉钠、喷雾干燥的乳糖、富马酸、脱水肝脏和干酵母在适当的混合器中混合至均匀而制备得。然后将2/3量的硬脂酸铝加到例如约10%的所述各组分的混合物中,混合均匀。然后将剩余的成分块加入,充分混合以分散含有团块的硬脂酸铝。接着将该混合物击块制粒成中度硬度并且用#10筛通过旋转制粒机分大小。然后将剩余的硬脂酸铝在混合下加到制粒混合物中。可将该配方的最后的片压成片剂形式,例如用11/16″的平面冲头在12至15SCU的硬度压片。该类型的片剂可以整个给药或者碎成小部分低剂量给药。
基于本文所公开的内容,本领域的技术人员可以在本发明的范围内利用S(+)乙哚乙酸制备各种传入感受器可接受的口服制剂。
Claims (11)
1.一种传入感受器可接受的口服药物组合物,该组合物含有基本没有R(-)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸的S(+)1,8-二乙基-1,3,4,9-四氢吡喃并[3,4-b]吲哚-1-乙酸和一种酸性成分。
2.权利要求1的传入感受器可接受的药物组合物,其中酸性成分包括柠檬酸、酒石酸、苹果酸、富马酸、乳酸、己二酸、抗坏血酸、天冬氨酸、异抗坏血酸、谷氨酸和琥珀酸,或者它们的混合物。
3.权利要求1的传入感受器可接受的药物组合物,另外含有传入感受器可接受的药物载体。
4.权利要求3的传入感受器可接受的药物组合物,该组合物包含在粉末状或颗粒状制剂中。
5.权利要求3的传入感受器可接受的药物组合物,该组合物包含在液体制剂中。
6.权利要求3的传入感受器可接受的药物组合物,该组合物包含在咀嚼片剂中。
7.权利要求3的传入感受器可接受的药物组合物,该组合物包含在泡腾制剂中。
8.权利要求3的传入感受器可接受的药物组合物,该组合物包含在锭剂中。
9.权利要求3的传入感受器可接受的药物组合物,该组合物包含在快速崩解的固体剂量制剂中。
10.权利要求3的传入感受器可接受的药物组合物,该组合物包括可咀嚼的兽医用制剂。
11.权利要求3的传入感受器可接受的药物组合物,该组合物包括口香糖制剂。
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EA199600029A2 (ru) | 1996-12-30 |
CA2178686A1 (en) | 1996-12-14 |
ZA964928B (en) | 1997-12-10 |
NO962491D0 (no) | 1996-06-12 |
NO962491L (no) | 1996-12-16 |
CZ170296A3 (en) | 1997-04-16 |
EA199600029A3 (ru) | 1997-03-31 |
MA23907A1 (fr) | 1996-12-31 |
EP0748628A2 (en) | 1996-12-18 |
TR199600499A2 (tr) | 1996-12-21 |
HUP9601635A2 (en) | 1997-04-28 |
NZ286791A (en) | 1998-01-26 |
JPH093071A (ja) | 1997-01-07 |
CO4700456A1 (es) | 1998-12-29 |
HUP9601635A3 (en) | 2000-06-28 |
EP0748628A3 (en) | 1997-04-23 |
PL314732A1 (en) | 1996-12-23 |
PE10898A1 (es) | 1998-03-20 |
HU9601635D0 (en) | 1996-08-28 |
EE9600067A (et) | 1996-12-16 |
EA000047B1 (ru) | 1998-04-30 |
SV1996000051A (es) | 1997-02-17 |
AU5588096A (en) | 1997-01-02 |
SK74396A3 (en) | 1997-04-09 |
KR970000228A (ko) | 1997-01-21 |
IL118636A (en) | 2000-02-17 |
US5958445A (en) | 1999-09-28 |
BR9602758A (pt) | 1998-04-22 |
IN182040B (zh) | 1998-12-12 |
AR003435A1 (es) | 1998-08-05 |
SG46737A1 (en) | 1998-02-20 |
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