CN1145496C - 用于肽释放的新型组合物 - Google Patents
用于肽释放的新型组合物 Download PDFInfo
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- CN1145496C CN1145496C CNB961948647A CN96194864A CN1145496C CN 1145496 C CN1145496 C CN 1145496C CN B961948647 A CNB961948647 A CN B961948647A CN 96194864 A CN96194864 A CN 96194864A CN 1145496 C CN1145496 C CN 1145496C
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- deslorelin
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Abstract
一种药物和兽药组合物，其包括deslorelin和赋形剂，该组合物的特征在于，其在体外于37℃下以2-80μg/天的速率向如前所述的磷酸盐缓冲盐水中释放deslorelin至少200天。所述组合物的用途包括抑制生殖功能，特别是狗和猫的生殖功能，以及治疗特别是人中的前列腺和乳腺癌和其他抑制睾酮或雌二醇水平而对其有益的疾病或病症。
Description
本发明涉及用于持续释放deslorelin的药物和兽药组合物，deslorelin是肽促性腺激素释放激素(GnRH)的激动剂。所述组合物的用途包括抑制生殖功能，特别是狗和猫的生殖功能，以及治疗特别是人中的前列腺和乳腺癌和其他抑制睾酮或雌二醇水平而对其有益的疾病或病症。
家养宠物的非受控生殖已是世界范围内的难题。在较不发达的国家中，家养猫和狗的生殖相对来说是不受控制的。目前控制这些动物生殖的方法是手术阉割。在发达国家中，控制生殖更多的是在雌性动物进行卵巢切除术，在有些情况下是在雄性动物中进行睾丸切除术，或者是强行将动物与其异性分开。
不管如何小，手术技术都有一些危险。许多宠物的主人也不愿意对他们的动物进行手术改变，而是忍受不控制生殖所产生的难题以及与此相关的行为。消除家养宠物的生殖能力，但不进行手术和不靠长期的圈养方法，多年来已成为小动物研究工业的目标。目前用于此方法的药物是以类固醇为基础的药物。这些药物产生令人不快的副作用，特别是在长期使用后，它们就不再被广泛使用。
许多年来，肽促性腺激素释放激素(GnRH)已成为众多研究的主题。它是经合成并储存在内底下丘脑之神经分泌细胞中的下丘脑十肽。该释放激素是以脉冲方式释放到垂体门循环中，然后被输送至前垂体。在此，它调节促性腺激素、促黄体生成激素(LH)和促卵泡成熟激素(FSH)向周身循环中的分泌。因此，GnRH是生殖功能之神经和内分泌物之间的体液连接(此方面的综述见Conn PM(ed)1996Gonadotropin-releasing hormone Endocrine Review 7：1)。GnRH与促性腺细胞上的单独一类受体结合。这些细胞长期与GnRH接触，由于受体的改变将导致失去对该激素的应答(综述见Hazum E和Conn PM(1988)Endocrine Review 9：379-866)。对GnRH应答的低下调节的结果是抑制了促性腺激素和性激素的循环水平。其后果是抑制生殖功能以及其他受性激素水平作用的过程。
许多年来，研究者们试图以形成GnRH的抗体为基础来研制出可市售的疫苗，以便截断上述激素轴，并因而用作避孕药。本发明的申请人已使此疫苗商品化；但是，此研制出的技术还不适合于宠物的避孕。此缺乏适用性是因为在个体宠物中对疫苗应答的生物变化，而且缺少疫苗长期作用的可预测性。
在市场上通常可接受的是，一个成功的宠物避孕药优选在所有治疗的动物中都有效，而且其应答时间也是可预测的。该应答优选应为6或12个月。避孕作用的可逆性是另外一个所希望的好处。
在1987年，Louisiana的Brian Vickery(Vickery，B.H.和Nestor，J.J.(1987)In LHRH and its Analogues，Part 2，517-543页)证实对雄狗/雌狗给药超剂量的GnRH超激动剂--nafarelin，将使它们暂时失去生殖功能不定的时间，3-18个月。该方面产品研制所面临的难题是：
(i)廉价得到GnRH或者激动剂；以及
(ii)廉价的释放系统，该系统可在6-12个月内以受控的速率释放肽，所述速率和剂量将可预测并可靠地使动物暂时失去生殖功能6-12个月。
本发明的申请人已研制出一种包含deslorelin作为活性药物的组合物，该组合物在给药动物时可抑制生殖功能较长并且是可预测的时间。该组合物在停止给药后还可恢复动物的生殖功能。虽然主要是用狗来描述该组合物，但可以确信此组合物对于其他动物包括人也是有用的。
另外，在人类中使用GnRH类似物，包括deslorelin，用于抑制激素水平已有众多的文献报道。Van Leusden H.A.I.M.(GynecolEndocrinol 8(1994)215-222)已总结了使用各种的GnRH激动剂肽用于抑制女性患者的雌二醇水平，以及用于治疗子宫内膜炎和平滑肌瘤。对大量公开文献的调查可以看出，这些作者总结出，许多GnRH类似物，包括desloreline，对抑制雌二醇水平并进而治疗这些性激素促进的病症是有效的，其条件是释放的所述肽保持一恒定的最小血浓度。对于肽来说具有活性的先决条件是搅乱内源性GnRH脉冲释放的能力。这需要恒定的最小血浆浓度(该浓度没有限定)。这些作者指出，释放模式要比不同GnRH类似物之间的微小效用差异更为重要。他们还总结出，在受抑制的垂体中，保持抑制所需要的GnRH类似物剂量随着治疗时间而逐渐减少(见Sandow J和Donnez T(1990)in Brosens I，Jacobs HS和Rennebaum B(eds)LHRH analogues in Gynaecology 17-31页，Camforth：Parthenon Publishing)。
类似地，在治疗包括乳腺癌和前列腺癌的性激素依赖性肿瘤中使用包括deslorelin的GnRH激动剂也已有描述。Redding等人在(1984)Proc Natl Acad Sci USA 81：5845-5848中描述了使用GnRH类似物(D Trp6)LH-RH用于抑制鼠中的前列腺癌，并证实肽的微胶囊剂在30天的时间内释放受控的剂量，而且对于抑制血清睾酮浓度和前列腺肿瘤重量都要比每日皮下给药等剂量或双倍剂量的游离肽更为有效。该类似物在人前列腺癌患者中抑制睾酮浓度并表明肿瘤发展的数据已为Parmar H等人(1985)所证实(The Lancet Nov 30，1201-1205)。该GnRH激动剂的一个月缓释注射剂已经被批准使用，而且在治疗乳腺癌、卵巢癌和前列腺癌、子宫内膜炎、肌瘤和过早成熟的儿童中已被广泛测试并使用，其他GnRH激动剂也是如此。(Nelson JR和Corson SL(1993)Fertil Steril 59：441-3；Paul D，Conte FA，Grumbach，MM和Kaplan SL(1995)J Clin Endocrin Metab 80：546-551)。
GnRH激动剂的3个月缓释制剂也已有描述(Okada H，Doken Y，Ogawa Y.和Toguchi H(1994)Pharm Res(US)11：1199-1203)。由注射微球中的线性药物释放产生持久的血清LH、FSH(鼠)和睾酮(鼠和狗)抑制达16周以上。用于抑制雄性和雌性之性激素浓度的GnRH类似物剂量是相同的(如Plosker，G.L.和Brogden，R.V.(1994)Drugs，48卷，930-967页)。因此，对在某一性别中抑制性激素的证实也是对在另一性别中抑制的预测。
因此，本发明的申请人研制出的上述deslorelin组合物也可用于治疗如上所述的动物(包括人)中的激素依赖性疾病和病症。该组合物通过连续地释放GnRH类似物达12个月或更长的时间，可改善对上述激素依赖性疾病和病症的治疗，并减少对频繁皮下注射或植入物插入的需要。
由此，在第一方面中，本发明提供包括约2-10(w/w)％deslorelin(以活性物质计)、约0.5-2.5(w/w)％卵磷脂和约85-97.5(w/w)％硬脂的药物和/或兽药组合物，该组合物的特征在于，其在体外于37℃下以2-80μg/天的速率向如下所述的磷酸盐缓冲盐水中释放deslorelin至少200天，更优选至少300天。
在第二方面中，本发明由抑制动物之生殖功能至少3个月的方法组成，该方法包括向动物给药本发明之第一方面中所述的组合物。
在第三方面中，本发明由治疗通过抑制性激素水平而有益于治疗的疾病或病症的方法组成，该方法包括向动物给药本发明之第一方面中所述的组合物。
在本发明的优选实施方案中，所述组合物包括约2-10(w/w)％deslorelin(以活性物质计)、约0.5-2.5(w/w)％卵磷脂和约85-97.5(w/w)％硬脂。
更优选的是，所述组合物包括约5-10(w/w)％deslorelin(以活性物质计)、约0.5-1.5(w/w)％卵磷脂和约89-94(w/w)％硬脂。
特别优选的组合物是：
(I)94(w/w)％硬脂、5(w/w)％deslorelin(以活性物质计)和1(w/w)％卵磷脂，以及
(II)93(w/w)％硬脂、5(w/w)％deslorelin(以活性物质计)和2(w/w)％卵磷脂。
在本发明进一步优选的实施方案中，所述组合物用于向人、或狗和/或猫给药。
组合物的剂型通常为挤出的棒状。然后将该棒截断成预定长度用于植入动物体内。很容易理解的是，棒的长度将决定deslorelin的速率和剂量。与植入更长的棒相反，可在每个动物体内植入多个棒。
本发明之第三方面的方法所提及的疾病或病症可是任何通过长期降低性激素(睾酮或雌二醇)浓度而对其有益的疾病或病症。其例子包括前列腺癌、卵巢和乳腺癌、良性的激素依赖性疾病如子宫内膜炎、肌瘤和经前期紧张以及儿童早熟。
Deslorelin描述于美国专利4218439中。deslorelin的化学式为：[6-D-色氨酸-9-(N-乙基-L脯氨酰胺)-10-deglycinamide]或者P谷氨酸-组氨酸-色氨酸-丝氨酸-酪氨酸-D色氨酸-亮氨酸-精氨酸-脯氨酸-乙酰胺。
硬脂是部分氢化的棕榈油。其基本的脂肪酸是C16：0(45％)和C18：0(53％)。熔点是约55℃。
卵磷脂是磷脂酰胆碱。其是连接在磷酸胆碱酯上的硬脂酸、棕榈酸和油酸的二甘油酯的混合物。硬脂和卵磷脂都是在植物和动物中发现的。
为更明确地理解本发明的本质，以下将参考非限制性的实施例和附图对优选实施方案进行描述。
附图简述
图1表示的是60mg棒状组合物I的平均每日体外释放曲线，证明在开始时快速释放药物，然后连续释放较长的时间。
图2表示的是3种60mg棒状组合物I的累积体外释放曲线，证明观察到可重复的释放，延长至至少250天。
图3表示的是在对照狗中正常的血浆睾酮浓度结果图。
图4-7表示的是：
(i)由组合物II中释放的deslorelin对向下调节垂体功能的作用，其中将睾酮浓度降至0；
(ii)作用的长度；以及
(iii)作用的可逆性。
图8表示的是两条植入deslorelin组合物棒的狗的血浆睾酮浓度结果图。血浆睾酮浓度在13天后降低表明可避孕。
图9和10表示的是两条植入deslorelin组合物的狗在植入8个月后的睾丸大小数据结果图。睾丸萎缩可以看作是对垂体向下调节的应答。
图11表示的是对照狗在植入安慰剂(相同的组合物II，但没有deslorelin)后9个月时的睾丸大小数据结果图。
图12和13表示的是植入deslorelin组合物的狗的血浆睾酮浓度结果图。在观察到组合物是有效的后，将这些狗处死，以收集组织。
实施例1：狗避孕组合物I
在狗中评价包括94％硬脂、5％deslorelin(以活性物质计)和1％卵磷脂的组合物。该组合物如下制备：
在小烧杯中用刮勺将硬脂(Vandenberg Foods提供，为自由流动的直径为1mm或更小的珠)和卵磷脂(R P Shearer提供，为深棕色的粘稠浆状物)混合。然后加入deslorelin，并在赋形剂中混合彻底。将混合物转移至柱塞式压出机的桶中，该压出机带有1mm的喷嘴，其平衡至55℃。该柱塞式压出机的压力为40psi。装配柱塞，并施加压力，直至开始挤出产品。此时补偿压力，产品达到55℃。然后挤出产品--每30秒3克。将所得的挤出物冷却，然后粉碎，并通过1mm喷嘴重新挤出。进行该步骤是确保基质中的各组份均匀。然后用2.3mm的喷嘴替换1mm的喷嘴。在挤出前进行相同的产品温度平衡步骤。然后挤出产品，在冷却后将长的棒状产品截断成所需重量的长度。
使用标准技术将如此产生的棒植入雄狗中。所得结果证实体外时棒中释放的deslorelin遵循可重复的途径，而且可持续多至250天。在狗中，至少有5个月观察到了睾丸尺寸的连续减小，血浆睾酮浓度的抑制至少4个月。
图1和2提供了60mg棒体外释放的结果。实验涉及将棒浸入在含有1ml磷酸盐缓冲盐水(如下制备)的容器内，该容器放置在37℃下的循环水浴中。每日更换盐水，抽出的盐水用于用HPLC分析deslorelin。
在此所用的磷酸盐缓冲盐水(PBS-pH7.3)是如下制备的：将8.00g氯化钠、1.00g无水磷酸氢二钠、0.40g二水合磷酸二氢钠(如果无水则为0.31g)和0.05g叠氮化钠溶解在1升去离子水中。
实施例2：狗避孕组合物II
在狗中评价包括93％硬脂、5％deslorelin(以活性物质计)和2％卵磷脂的组合物。该组合物如下制备：
在小烧杯中用刮勺将硬脂珠(ADMUL PO 58，Quest InternationalAustralasia Limited)和卵磷脂(Topcithin 300，Bronson&Jacobs，Australia)混合。然后加入deslorelin，并在赋形剂中混合彻底。将混合物转移至柱塞式压出机的桶中，该压出机带有1mm的喷嘴，其平衡至55.8℃。该柱塞式压出机的压力为40psi。装配柱塞，并施加压力，直至开始挤出产品。此时补偿压力，产品达到55.8℃。然后挤出产品--每30秒3克。将所得的挤出物冷却，然后粉碎，并通过1mm喷嘴在58.3℃下重新挤出混合成粒，并挤至注入模中，在此产生直径为2.3mm、长度约为25mm的最终棒状产品。然后用γ辐射对棒状产品进行消毒。
如此制备的棒植入雄性和雌性狗中(0.5、1或2×120mg棒包含6mg deslorelin)。所得结果见图9-19以及表1-4。该结果表明，该组合物可抑制公狗中的睾酮浓度12个月或更长，在雌狗中为至少5个月。因此，本发明的组合物可在长时间内抑制狗的生殖功能。
表1
孕酮阳性雌狗--未怀孕
| 狗 | 植入 | 观察(1个月后) |
| BA1/6 | 1996年5月 | 没有治疗后的动情期 |
| BA2/6 | 1996年5月 | 没有治疗后的动情期 |
| BA3/6 | 1996年5月 | 没有治疗后的动情期 |
| PW1/6 | 1996年5月 | 中等发情表现孕酮低下 |
| PW4/12 | 1996年5月 | 治疗后孕酮降低 |
该组5条雌狗的结果表明，在植入后的最初几周内快速抑制生殖功能和血浆性激素浓度。
表2
孕酮阳性雌狗--怀孕
| 狗 | 植入 | 观察(0.5-1个月后) |
| BA1/61 | 1996年6月 | 无发情 |
| PW1/12 | 1996年5月 | 无发情 |
表3
孕酮阳性雌狗
| 狗 | 植入 | 观察(2-5个月后) |
| BB1/6 | 1996年1月 | 有发情表现，然后无活动 |
| BB2/6 | 1996年2月 | 有发情表现，然后无活动 |
| BB3/6 | 1996年2月 | 有发情表现，然后无活动 |
| BB4/6 | 1996年3月 | 有发情表现，然后无活动 |
| BB1/31 | 1996年4月 | 有发情表现，然后无活动 |
| BB1/61 | 1996年4月 | 持续发情 |
该组5条雌狗的结果表明，在植入后可抑制生殖行为和血浆激素浓度(未示出)至少5个月。
表4
狗中的植入物安全性
| 狗编号 | 植入部位的组织学 | 恢复生殖(12个月后) |
| 狗46 | 未检测到细胞变化 | 是 |
| 狗79 | 未检测到细胞变化 | 是 |
| 狗40 | 未取组织 | 是 |
| 狗47 | 未取组织 | 是 |
这些结果表明，在植入部位没有负面的病理变化发生，而且4条植入deslorelin植入物的狗在12个月后恢复生殖能力。
Claims (7)
1、一种药物和/或兽药组合物，其以活性物质计包括2-10重量％地洛瑞林(deslorelin)、0.5-2.5重量％卵磷脂和85-97.5重量％硬脂，该组合物的特征在于，其在体外于37℃下以2-80μg/天的速率向磷酸盐缓冲盐水中释放地洛瑞林至少200天，所述磷酸盐缓冲液是通过在1升去离子水中溶解8.00克氯化钠、1.00克无水磷酸氢二钠、0.40克二水合磷酸二氢钠和0.05叠氮化钠而制得的。
2、如权利要求1的组合物，其中，所述组合物以活性物质计包括5-10重量％地洛瑞林、0.5-1.5重量％卵磷脂和89-94重量％硬脂。
3、如权利要求1的组合物，其中，所述组合物以活性物质计包括5重量％地洛瑞林、1重量％卵磷脂和94重量％硬脂。
4、如权利要求1的组合物，其中，所述组合物以活性物质计包括5重量％地洛瑞林、2重量％卵磷脂和93重量％硬脂。
5、如权利要求1的组合物在制备用于抑制动物的生殖功能的药物中的应用。
6、如权利要求1的组合物在制备用于治疗通过抑制动物中睾酮或雌二醇水平而对其有益之疾症或病症的药物中的应用。
7、如权利要求6的应用，其中，所述疾病或病症选自前列腺癌、卵巢癌和乳腺癌、子宫内膜炎、肌瘤和经前期紧张以及儿童早熟。
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| WO2000004897A1 (en) * | 1998-07-20 | 2000-02-03 | Peptech Limited | Bioimplant formulation |
| US8052982B2 (en) * | 1998-07-20 | 2011-11-08 | Peptech Animal Health Pty Limited | Bioimplant formulation comprising lecithin and stearin |
| US6211221B1 (en) * | 1999-04-05 | 2001-04-03 | Johnny W. Peterson | Dietary supplement containing histidine for alleviating dysmenorrhea, endometriosis, and pre-term labor |
| WO2002036144A1 (en) * | 2000-10-30 | 2002-05-10 | University Of Zurich | Gnrh analogues for treatment of urinary incontinence |
| GB0221539D0 (en) * | 2002-09-17 | 2002-10-23 | Medical Res Council | Methods of treatment |
| CA2552241C (en) * | 2003-12-30 | 2013-10-01 | Durect Corporation | Co-polymeric devices for controlled release of active agents |
| WO2006071208A1 (en) * | 2004-12-23 | 2006-07-06 | Durect Corporation | Polymeric implants, preferably containing a mixture of peg and plg, for controlled release of a gnrh |
| RU2010114018A (ru) * | 2007-09-11 | 2011-10-20 | Мондобайотек Лабораториз Аг (Li) | Применение пептид тимозина бета 4 индивидуально или в сочетании с цекропином а в качестве терапевтического средства |
| DE102008015104A1 (de) | 2008-03-19 | 2009-09-24 | Basf Coatings Ag | Beschichtungszusammensetzung, Verfahren zu ihrer Herstellung, ihre Verwendung und mit ihr beschichtete Substrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS563846B2 (zh) * | 1972-10-12 | 1981-01-27 | ||
| US4218439A (en) * | 1977-07-14 | 1980-08-19 | The Salk Institute For Biological Studies | Peptide which inhibits gonadal function |
| US4256737A (en) * | 1979-06-11 | 1981-03-17 | Syntex (U.S.A.) Inc. | Long acting depot injectable formulations for LH-RH analogues |
| CA1257199A (en) * | 1986-05-20 | 1989-07-11 | Paul Y. Wang | Preparation containing bioactive macromolecular substance for multi-months release in vivo |
| EP0257368B1 (en) * | 1986-08-11 | 1992-03-25 | American Cyanamid Company | Compositions for parenteral administration and their use |
| US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
| US5538739A (en) * | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
| US5211952A (en) * | 1991-04-12 | 1993-05-18 | University Of Southern California | Contraceptive methods and formulations for use therein |
| WO1993015722A1 (en) * | 1992-02-07 | 1993-08-19 | Syntex (Usa) Inc. | Controlled delivery of pharmaceuticals from preformed porous microparticles |
| AUPN366795A0 (en) * | 1995-06-20 | 1995-07-13 | Peptide Technology Limited | Formulation for preventing reproductive function |
-
1995
- 1995-06-20 AU AUPN3667A patent/AUPN366795A0/en not_active Abandoned
-
1996
- 1996-06-20 ES ES96917292T patent/ES2182983T3/es not_active Expired - Lifetime
- 1996-06-20 AU AU59927/96A patent/AU701837B2/en not_active Expired
- 1996-06-20 AT AT96917292T patent/ATE223726T1/de active
- 1996-06-20 JP JP50345797A patent/JP4016133B2/ja not_active Expired - Lifetime
- 1996-06-20 DE DE122008000004C patent/DE122008000004I2/de active Active
- 1996-06-20 SI SI9630524T patent/SI0871467T1/xx unknown
- 1996-06-20 PT PT96917292T patent/PT871467E/pt unknown
- 1996-06-20 EP EP96917292A patent/EP0871467B1/en not_active Expired - Lifetime
- 1996-06-20 CA CA2225796A patent/CA2225796C/en not_active Expired - Lifetime
- 1996-06-20 US US08/981,285 patent/US5925619A/en not_active Expired - Lifetime
- 1996-06-20 DK DK96917292T patent/DK0871467T3/da active
- 1996-06-20 CN CNB961948647A patent/CN1145496C/zh not_active Expired - Lifetime
- 1996-06-20 WO PCT/AU1996/000370 patent/WO1997000693A1/en active IP Right Grant
- 1996-06-20 NZ NZ309697A patent/NZ309697A/xx not_active IP Right Cessation
- 1996-06-20 DE DE69623652T patent/DE69623652T2/de not_active Expired - Lifetime
-
1999
- 1999-01-08 HK HK99100086A patent/HK1014874A1/xx not_active IP Right Cessation
- 1999-02-17 US US09/251,411 patent/US6211152B1/en not_active Expired - Lifetime
-
2008
- 2008-01-08 NL NL300330C patent/NL300330I2/nl unknown
- 2008-01-10 FR FR08C0001C patent/FR08C0001I2/fr active Active
Also Published As
| Publication number | Publication date |
|---|---|
| DE69623652D1 (de) | 2002-10-17 |
| AU701837B2 (en) | 1999-02-04 |
| JP2001521482A (ja) | 2001-11-06 |
| FR08C0001I1 (zh) | 2008-03-21 |
| NL300330I1 (nl) | 2008-03-03 |
| DE122008000004I2 (de) | 2009-08-06 |
| EP0871467B1 (en) | 2002-09-11 |
| ATE223726T1 (de) | 2002-09-15 |
| DE122008000004I1 (de) | 2008-04-17 |
| ES2182983T3 (es) | 2003-03-16 |
| NZ309697A (en) | 1999-11-29 |
| WO1997000693A1 (en) | 1997-01-09 |
| US5925619A (en) | 1999-07-20 |
| FR08C0001I2 (zh) | 2009-11-20 |
| EP0871467A1 (en) | 1998-10-21 |
| JP4016133B2 (ja) | 2007-12-05 |
| HK1014874A1 (en) | 1999-10-08 |
| US6211152B1 (en) | 2001-04-03 |
| DE69623652T2 (de) | 2003-05-28 |
| DK0871467T3 (da) | 2002-12-23 |
| AUPN366795A0 (en) | 1995-07-13 |
| CA2225796A1 (en) | 1997-01-09 |
| PT871467E (pt) | 2002-12-31 |
| NL300330I2 (nl) | 2008-04-01 |
| CA2225796C (en) | 2011-09-20 |
| SI0871467T1 (en) | 2003-08-31 |
| AU5992796A (en) | 1997-01-22 |
| EP0871467A4 (en) | 2000-07-05 |
| CN1188414A (zh) | 1998-07-22 |
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