CN1310623A - 生物植入物配方 - Google Patents
生物植入物配方 Download PDFInfo
- Publication number
- CN1310623A CN1310623A CN99808961A CN99808961A CN1310623A CN 1310623 A CN1310623 A CN 1310623A CN 99808961 A CN99808961 A CN 99808961A CN 99808961 A CN99808961 A CN 99808961A CN 1310623 A CN1310623 A CN 1310623A
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- Prior art keywords
- prescription
- activating agent
- phe
- pore former
- antagonist
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Abstract
一种药物和/或兽医配方,包括约2－30%(w/w)(以活性剂干重计)的至少一种活性剂,约0.5－20%(w/w)的成孔剂,以及余量的硬脂酸甘油酯。该配方提供该至少一种活性剂在7天至两年的时间内在人或其它动物体内的缓释。
Description
发明领域
本发明涉及药物和/或兽医的至少一种活性剂的缓释配方。优选的活性剂包括促性腺激素释放激素(GnRH)激动剂(如deslorelin)、GnRH拮抗剂(如西曲瑞克)、促生长素抑制素类似物(如促生长素抑制素-14和奥曲肽)、降脂药(如辛伐他汀)、环孢菌素(如环孢菌素A)、血管紧张素转化酶抑制剂(如卡托普利)、降钙素、P物质拮抗剂、止痛药(如吗啡)、类阿片拮抗剂(如纳曲酮)、抗抑郁药(如文拉法辛)和非甾体抗炎药(如奈普生钠)。
发明背景
由于增强作用功效及减低给药频率的原因，开发能够在一段持续时间(如达到6个月或更长时间)内对活性剂控制释放的药物和兽医配方引起了广泛的兴趣。该种配方的开发特别有利于那些通常长期由患者自己给药的药物类型(如治疗糖尿病的胰岛素、用于生殖控制和治疗性激素依赖性的疾病和症状的促性腺激素释放激素(GnRH)激动剂)和需要患者高度依从的药物类型。在兽医方面，缓释配方会降低动物和兽医/主人因需反复给予活性剂而导致的紧张。
本申请人已发现在7天至两年的时间内在人和其它动物体内活性剂的缓释可以通过使用一种固体配方而实现。该配方包括硬脂酸甘油酯作为赋形剂，它与一种物质结合，尽管不愿被理论所限制，该物质似乎在赋形剂中形成细孔和/或裂缝，从而使活性剂得以释放。
发明综述
因而，第一方面，本发明提供了一种药物和/或兽医配方，包括约2-30％(w/w)(以活性剂干重计)的至少一种活性剂，约0.5-20.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯。
在一优选的实施方案中，该配方包括约5-10％(w/w)(以活性剂干重计)的至少一种活性剂，约1.0-10.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯。
在一更为优选的实施方案中，该配方包括约5-10％(w/w)(以活性剂干重计)的至少一种活性剂，约2.0-5.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯。
第二方面，本发明提供了一种治疗人或其它动物的疾病和症状的方法，该方法包括给予人或其它动物本发明第一方面的配方。发明详细公开
本发明的配方中使用的至少一种活性剂可以选自具有药学或兽医意义的物质，并且可以是肽类(如激素和抗原)、多肽和蛋白质、核酸化合物及其衍生物如DNA和RNA中的任何一种或多种的组合。
优选的活性剂包括：(1)GnRH激动剂
特别优选的GnRH肽激动剂为deslorelin(如US4218439所述)、氟他胺(如FR7923545、WO86/01105和PT100899所述)、戈舍瑞林(如US4100274、US4128638、GB9112859和GB9112825所述)、亮丙瑞林(如US4490291、US3972859、US4008209、US4005063、DE2509783和US4992421所述)、dioxalan衍生物例如EP413209所述、曲普瑞林(如US4010125、US4018726、US4024121、EP364819和US5258492所述)、meterelin(如EP23904所述)、布舍瑞林(如US4003884、US4118483和US4275001所述)、组氨瑞林(如EP217659所述)、那法瑞林(如US4234571、WO93/15722和EP52510所述)、黄体瑞林(如US4089946所述)、亮丙瑞林(如Plosker etal.Drugs 48 930-967,1994所述)和LHRH类似物例如EP181236、US4608251、US4656247、US4642332、US4010149、US3992365和US4010149中所述。以上专利说明书和文章引入本文作参考。
最为优选的GnRH激动剂为戈舍瑞林、deslorelin、亮丙瑞林、曲普瑞林、meterelin、布舍瑞林、组氨瑞林、那法瑞林和其组合。这些化合物的分子式如下：
戈舍瑞林 C59H84N18O14C2H4O2
D-Ser(but)6Azgly10-LHRH醋酸盐
3-[5-氧-L-脯氨酰-L-色氨酰-L-丝氨酰-L-酪氨
酰-(3-O-叔丁基)-D-丝氨酰-L-亮氨酰-L-精
氨酰-L-脯氨酰]cabazamide醋酸盐
Deslorelin 6-D-色氨酸-9-(N-乙基-L-脯氨酰胺)-10-
Deglycinanide
P谷氨酰胺-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-乙基酰胺
亮丙瑞林 C59H84N16O12,C2H4O2
Leuprorelin醋酸盐
5-氧-L-脯氨酰-L-组氨酰-L-色氨酰-L-丝氨酰-
L-酪氨酰-D-亮氨酰-L-精氨酰-N-乙基-L-脯氨
酰胺醋酸盐
曲普瑞林 C59H84N16O12,C2H4O2
D-Trp6-LHRH
5-氧-L-脯氨酰-L-组氨酰-L-色氨酰-L-丝氨酰-
L-酪氨酰-D-色氨酰-L-亮氨酰-L-精氨酰-L-脯
氨酰甘氨酰胺
Meterelin Des Gly10-2-甲基-D-Trp6-Pro-乙基-酰胺9LHRH
布舍瑞林 C60H86N16O13,C2H4O2
D-Ser(But)6-Pro9-NEt LHRH醋酸盐
氧-L-脯氨酰-L-组氨酰-L-色氨酰-L-丝氨酰-L-
酪氨酰-O-叔丁基-D-丝氨酰-L-亮氨酰-L-精氨
酰-N-乙基-L-脯氨酰胺醋酸盐
组氨瑞林 Pro-His-Trp-Ser-Tyr-Leu-D(N-苄基)His-Arg-
Pro-N-乙基酰胺
那法瑞林 C66H83N17O13,xC2H4O2yH2O氧-L-脯氨酰-L-组
氨酰-L-色氨酰-L-丝氨酰-L-酪氨酰-3-(2-萘
基)-D-丙氨酰-L-亮氨酰-L-精氨酰-N-乙基-L-
脯氨酰甘氨酰胺醋酸盐水合物
根据本发明的含有GnRH激动剂作为至少一种活性剂的配方可以用于控制生殖功能，或用于治疗那些长期降低性激素水平对其有益的疾病或症状。例如prostrate癌、卵巢癌和乳腺癌、良性的激素依赖性的疾病例如子宫内膜异位、肌瘤和经前紧张、子宫纤维瘤、手术前子宫萎缩的诱导、化疗中的细菌细胞活性的抑制、多毛症、循环听觉功能障碍、儿童的卟啉症和青春期早熟、狗的良性前列腺过度紧张，以及用于其它阉割具有有益的临床效果的症状，包括T-细胞介导免疫的恢复。(2)GnRH拮抗剂
特别优选的GnRH拮抗剂为雷莫瑞克(L-prolone,1-(N2-(N-(N-(N-(N-(N-(N-(N-乙酰基-3-(2-萘基)-D-丙氨酰)-4-氯-D-苯丙氨酰-D-色氨酰)-L-丝氨酰)-L-酪氨酰-O-(6-去氧-α-L-吡喃甘露糖基)-D-丝氨酰)-L-亮氨酰)-L-精氨酰)-2-(氨基羰基)hyrazide、teverelix(D-丙氨酰胺，N-乙酰基-3-(2-萘基)-D-alayl-4-氯-D-苯丙氨酰-3-(3-吡啶基)-D-丙氨酰-L-丝氨酰-L-酪氨酰-N6-(氨基羰基)-D-赖氨酰-L-亮氨酰-N6-(1-甲基乙基)-L-赖氨酰-L-脯氨酰、西曲瑞克(D-丙氨酰胺，N-乙酰基-3-(2-萘基)-D-丙氨酰-4-氯-D-苯丙氨酰-3-(3-吡啶基)-D-丙氨酰-L-丝氨酰-L-酪氨酰-N5-(氨基羰基)-D-ol-L-亮氨酰-L-精氨酰-L-脯氨酰、加尼瑞克(N-Ac-D-Nal,D-pCl-Phe,D-Pal,DhArg(Et)2,hArg(Et)2,D-Ala)GnRH、alanex、abarelix(D-丙氨酰胺，N-乙酰基-3-(2-萘基)-D-丙氨酰-4-氯-D-苯丙氨酰-3-(3-吡啶基)-D-丙氨酰-L-丝氨酰-N-甲基-L-酪氨酰-D-天冬氨酰-L-亮氨酰-N6-(1-甲基乙基)-L-赖氨酰-L-脯氨酰；N-(S)-四氢呋喃基-Gly-D2Nal-D4Ciphe-D3Pal-Ser-NmeTyr-D-lys(Nic)Leu-Lys(Isp)-Pro-D-Ala-NH2；异丙基-13-(N-苄基-N-甲氨甲基)-7-(2,6-二氟苄基)-4,7-二氢-2-(4-异丁基氨基苯基)-4-氧噻吩并(2,3-b)吡啶-5-羧酸酯盐酸盐)。其它优选的GnRH拮抗剂如US5110904、US5300492、US5807983、US5169932、US5296468和US5502035所述。(3)促生长素抑制素类似物
特别优选的促生长素抑制素类似物包括促生长素抑制素-14、奥曲肽、兰瑞肽和angiopeptin环肽(US5569647)。
根据本发明的含有促生长素抑制素类似物作为至少一种活性剂的配方可以用于治疗例如高胰岛素血症和消化性溃疡。(4)降脂药
特别优选的降脂药包括抑制HMG CoA还原酶的化合物，例如cerevastatin、美伐他汀、辛伐他汀、普伐他汀和洛伐他汀。
根据本发明的含有这些试剂的配方可以用于治疗例如高脂蛋白血症。(5)环孢菌素
优选的环孢菌素包括天然存在的环孢菌素(例如Dreyfuss et al.,(1976)Europ.J.Appl.Microbiol.Vol.3:125-133中所述)及类似物(例如Wanger R.M.(1982)在《环孢菌素A》White D.G.G.ed.Amsterdam；Elsevier中的环孢菌素的化学中所述)。
根据本发明的含有环孢菌素或环孢菌素类似物作为至少一种活性剂的配方可以用作例如预防和治疗异体移植中的器官排异的免疫抑制。(6)血管紧张素转化酶抑制剂
优选的ACE抑制剂包括卡托普利、依那普利、群多普利特、哌道普利特、喹那普利特、fasidotril、omapatrilate和赖诺普利。
根据本发明的含有这些试剂的配方可以用作例如抗高血压药。(7)降钙素
优选的降钙素包括人、鲑鱼和猪降钙素。这些多肽的类似物也同样适用。
根据本发明的含有降钙素或降钙素类似物的配方可以用于治疗例如高钙血症、用于降低甲状旁腺功能亢进、维生素D中毒和溶骨性骨转移患者体内的磷酸盐浓度。(8)P物质拮抗剂
优选的P物质拮抗剂包括片段4-11(即Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2和变体形式)、片段5-11(即Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2和变体形式)、片段6-11(即Gln-Phe-Phe-Gly-Leu-Met-NH2和变体形式)、片段7-11(即Phe-Phe-Gly-Leu-Met-NH2和变体形式)、片段8-11(即Pte-Gly-Leu-Met-NH2和变体形式)和片段9-11(即Gly-Leu-Met-NH2和变体形式)。其它适当的P物质拮抗剂包括如本申请人在同时申请的澳大利亚临时专利申请No.PP9008中所述的那些。
根据本发明的含有P物质拮抗剂的配方可以用于治疗癌症，包括化疗引起的恶心和呕吐、疼痛、过敏、气喘、炎症(包括炎性肠疾病)及抑郁。(9)止痛药
优选的止痛药包括类阿片例如吗啡、羟甲左吗喃和度冷丁(哌替啶)，酰胺局部麻醉剂例如布比卡因、利多卡因、衣铁卡因和甲哌卡因。
根据本发明的含有这些止痛药的配方可以用于治疗急性疼痛(例如髋关节置换患者所经历的)和慢性的局部疼痛。(10)类阿片拮抗剂
优选的类阿片拮抗剂包括纳曲酮、纳洛酮和美沙酮。
根据本发明的含有类阿片拮抗剂的配方可以用于治疗对类阿片的依赖性。(11)抗抑郁药
优选的抗抑郁药包括文拉法辛、三氟丙嗪、甲氧异丁嗪、异丙嗪、丁螺环酮、吉吡隆和氟西汀(氟苯氧丙胺)。(12)非甾体抗炎药
优选的非甾体抗炎药包括奈普生钠吲哚美辛、舒林酸、托尔米丁、醋炎痛、苯酰吡酸钠、甲灭酸、非诺洛芬、氟灭酸、保泰松、氟联苯丙酸、酮洛酸和辣椒碱。
根据本发明的含有非甾体抗炎药的配方可以用于治疗手术后发炎以及与例如风湿性关节炎有关的炎症。(13)其它
其它适当的活性剂包括用于治疗社会焦虑症/社会恐惧症的帕罗西丁、用于治疗肥胖症、饮食疾病、抑郁症和疼痛的galanin拮抗剂如galanin片段1-13-Pro-Pro-Ala-Leu-Ala-Leu—Ala酰胺和galanin(1-13)-spantide 1；用于人口控制的激活素和抑制素片段如α-亚单位片段1-32和β-片段67-94；用于治疗西方综合症和婴儿痉挛的促肾上腺皮质激素(ACTH)及其变体和片段；用于生长激素缺乏儿童的替代疗法中的生长激素及其类似物；用于治疗贫血的促红细胞生成素(EPO)及类似物；用预防充血性心力衰竭，预防急性肾衰竭和蛛网膜下出血，预防和治疗动脉硬化症，治疗高血压，预防脑溢血和治疗慢性阻塞性肺部疾病的内皮素血管肽拮抗剂；用于治疗肥胖症和饮食疾病例如神经性厌食症和用于减肥的leptin及其类似物以及激动剂和拮抗剂；用于治疗如癫痫的促甲状腺素释放激素(TRH)及其类似物(如pGlu-His-Pro-Gly)；和用于治疗哮喘、系统性毛细管渗漏综合症和帕金森氏症的茶碱及其类似物。疫苗抗原，包括DNA编码疫苗抗原也可用根据本发明的配方释放。
根据本发明的配方可以包括活性剂的组合。优选的组合(包括“剂1”和“剂2”)的例子如表1所示。
表1：
| 剂1 | 剂2 |
| HMG Co A还原酶抑制剂 | Gemfibrozil |
| 非甾体抗炎药 | 米克费那特mofelil |
| GnRH激动剂 | Trk酪氨酸抑制剂 |
| GnRH激动剂 | 睾丸激素 |
| 降钙素 | 雌激素 |
| 降钙素 | Etridonate |
| 降钙素 | Pamridonate |
| 奥曲肽 | α-干扰素 |
| 奥曲肽 | IGF-1 |
| 奥曲肽 | Miclodrine |
| GrRH激动剂 | 氟利坦 |
| 羟乙茶碱 | 茶碱 |
优选地，该至少一种活性剂具有低至中等的亲脂性。更为优选地，该活性剂的log辛醇/水分配系数(log P)(Ruelle and Kesselring(1998),J Pharm Sci.Vol.87:1115-24)在5.0至-3.0的范围。最优选的是log P值在3.0至-3.0的范围内的活性剂，特别是log P在1.0至-3.0的范围内的那些。
上述活性剂种类的代表的log P值如表2所示。
表2：
| 剂 | log辛醇/水分配系数(log P) |
| 奥曲肽 | 1.40 |
| 环孢菌素A | 2.90 |
| 卡托普利 | -1.86 |
| 群多普利特 | 1.02 |
| 哌道普利特 | -0.36 |
| 喹那普利特 | 0.69 |
| 吗啡 | 0.76 |
| 利多卡因 | 2.26 |
| 美沙酮 | 3.93 |
| 异丙嗪 | 4.75 |
| 吲哚美辛 | 4.27 |
| 氟灭酸 | 1.14 |
| 保泰松 | 3.16 |
| 茶碱 | -0.02 |
| 羟乙茶碱 | 0.35 |
| TRH | -2.40 |
成孔剂可以是使该至少一种活性剂从硬脂酸甘油酯赋形剂中缓释的任何试剂或这些试剂的组合，条件是当该至少一种活性剂是GnRH激动剂时，成孔剂不能是卵磷脂。
优选地，成孔剂选自水溶性的物质，如无机盐(如盐酸盐、磷酸盐和硫酸盐)、有机盐(如醋酸盐、甲酸盐、丙酸盐、谷氨酸盐和天冬氨酸盐)、糖(如葡萄糖、海藻糖、甘露糖、半乳糖、蔗糖和低分子量的碳水化合物如羟丙基甲基纤维素(HPMC)和羧甲基纤维素(CMC))、氨基糖(如氨基葡萄糖和氨基半乳糖)、氨基酸/肽(如赖氨酸、精氨酸、谷氨酸、天冬氨酸、肌肽和阿司帕坦)、水溶性蛋白质和水溶性维生素(如维生素B)。
目前，最优选的成孔剂是卵磷脂(除了该至少一种活性剂是GnRH激动剂的情况)和氨基酸赖氨酸。卵磷脂是硬脂酸、棕榈酸和油酸的甘油二酯连接于磷酸胆碱酯的混合物。卵磷脂在包括deslorelin和硬脂酸甘油酯的缓释配方中作为成孔剂的效果如国际专利申请No.PCT/AU96/00370(WO 97/00693)中所述，该文献引入本文作参考。
从本文的实施例明显看出，所使用的成孔剂的特性和数量的变化使为了适应特定治疗用途而控制活性剂的释放情况成为可能。
硬脂酸甘油酯优选地是非晶形态。硬脂酸甘油酯为部分氢化的棕榈油，作为主要的脂肪酸，它含有C16∶0(45％)和C18∶0(53％)。硬脂酸甘油酯的熔点约为60℃。令人惊奇地，硬脂酸甘油酯似乎在接受者体内只引起轻微至中等的炎症反应，因此据信使用硬脂酸甘油脂作为赋形剂对根据本发明的配方的成功是有贡献的，从而导致该配方包囊在成纤维细胞的薄层内。本领域技术人员应认识到，包括与本发明第一方面的配方所包括的相似的赋形剂的其它配方可以类似地引起轻微至中等的炎症反应从而有助于活性剂的释放。这些其它配方被视为在本发明的范围内。
根据本发明的配方可以给予人和选自狗、猫、其它家畜和被俘获的野生动物的其它动物。
这些配方通常在体外向磷酸盐缓冲液(PBS:pH 7.3，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(若无水则为0.31g)和0.05g叠氮化钠溶解于1升去离子水中而制备)中，在37℃下在至少7天至约两年的时间内以约2-350μg/天的速率释放活性剂。
另外，该配方通常以自由流动珠或可以经过压出的杆状物的形式作为储存配方存在。
压出的杆状物可以被切成预定长度以标准的技术用于人或其它动物的植入。显而易见，杆状物的长度决定活性剂的剂量和释放速率。与植入较长的杆状物相反，可以在每个人或其它动物体内植入多于一个的杆状物。注射配制的微粒物质例如自由流动珠的悬浮液，也可以按所需的剂量和速率释放活性剂。
以自由流动珠和/或植入物给药的配方，特别是对狗使用的配方，可以用以下方法制备：
混合硬脂酸甘油酯(直径等于或小于1mm的自由流动珠，由Vandenberg Food生产)与成孔剂。然后加入活性剂并与赋形剂和成孔剂混合物彻底混合。然后该物料可以用于注射。或者，该混合物可以被转移至柱塞式压出机的桶内，该柱塞式压出机连有一个1mm喷嘴，并平衡至55℃(或其它足够软化硬脂酸甘油酯的温度)。装上压锤，施加压力(40 psi)直至开始压出产品。此时压力可下降，使产品达到55℃(或其它足够软化硬脂酸甘油酯的温度)。产品可以以例如30秒内3g的速率压出。将得到的压出物冷却、破碎，用1mm喷嘴再压出，以保证整个混合物的成分的均一性。然后可以用2.3mm直径的喷嘴代替1mm的喷嘴压出产品(使用与压出前相同的温度平衡过程)。得到的长的杆状物冷却后切成所需重量的长度，切好后用伽玛射线消毒杀菌。
另外，以生物植入物给药的配方，特别是对狗使用的配方，可以用以下方法制造：
混合硬脂酸甘油酯与成孔剂。然后加入活性剂，并彻底混入赋形剂和成孔剂中。然后混合物可被转移至柱塞式压出机的桶内，该柱塞式压出机连有一个2.3mm喷嘴，并平衡至足够软化硬脂酸甘油酯的温度。启动压出机，开始压出产品，压出物切成所需长度。切好的产品最终经消毒杀菌。
另外，在制备本发明的配方中，特别是该至少一种活性剂为肽、多肽和蛋白质时，优选对该至少一种活性剂先进行包括两步冷冻干燥过程的预处理。该冷冻干燥步骤可以按任何蛋白质物质的常用冷冻干燥方法进行。然而，优选是将活性剂在适当的溶剂例如30％(w/w)乙醇水溶液中的浓度为5-50％(更优选为5-15％)(w/w)的溶液进行冷冻干燥。冷冻干燥的活性剂可以再溶解或均化在适当的溶剂(如25-75％(w/w)的稀弱酸溶液例如1-5％(w/w)的乙酸水溶液)中并接着冷冻干燥。因此，活性剂的冷冻干燥过程可以包括如下步骤：
(ⅰ)制备活性剂浓度为5-50％(w/w)的溶液，
(ⅱ)冷冻干燥步骤(ⅰ)的溶液，
(ⅲ)用所述冷冻干燥的活性剂制备浓度为25-75％的溶液或均一物，和
(ⅳ)冷冻干燥所述步骤(ⅲ)的溶液或均一物。
术语“以活性剂干重计”为本领域一般意义。即，它用于表示配方中肽激动剂或类似物的百分含量(w/w)是以肽激动剂或类似物的干重为基础的。
说明书中使用的术语“包括”是指包括所述的步骤、成分或特征，同时包括或不包括其它步骤、成分或特征。
本发明将在本文下面通过非限制性实施例和附图进行进一步的描述。
附图简要说明：
图1给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(Ⅰ)6％deslorelin、2％赖氨酸和余量的硬脂酸甘油酯；和(Ⅱ)6％deslorelin、5％赖氨酸和余量的硬脂酸甘油酯。该图显示了活性剂的初始快速释放及其后在一长的时期(110天)的持续释放情况。
图2给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(Ⅲ)6％deslorelin、2％硫酸钠和余量的硬脂酸甘油酯；和(Ⅳ)6％deslorelin、5％硫酸钠和余量的硬脂酸甘油酯。该图显示当使用5％硫酸钠作为成孔剂时，deslorelin的初始快速释放速率更大(534μg比438μg)。初始快速释放之后(约10天结束)，在以后的95天中两种配方的释放速率均为约10-2μg/天。
图3给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(Ⅴ)6％deslorelin、2％羟丙基甲基纤维素(HPMC)和余量的硬脂酸甘油酯；和(Ⅵ)6％deslorelin、5％羟丙基甲基纤维素(HPMC)和余量的硬脂酸甘油酯。该图显示当使用5％HPMC作为成孔剂时，deslorelin的初始快速释放速率更大(685μg比403μg)。初始快速释放之后(约10天结束)，在以后的95天中两种配方的释放速率均为约10-2μg/天。
图4给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(Ⅶ)6％deslorelin、2％葡萄糖和余量的硬脂酸甘油酯；和(Ⅷ)6％deslorelin、5％葡萄糖和余量的硬脂酸甘油酯。该图显示当使用5％葡萄糖作为成孔剂时，deslorelin的初始释快速放速率更大(790μg比403μg)。初始快速释放之后(约10天结束)，在以后的95天中两种配方的释放速率均为约50-2μg/天。
图5给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(Ⅸ)6％促生长素抑制素、0％醋酸盐和余量的硬脂酸甘油酯；(Ⅹ)6％促生长素抑制素、3％醋酸盐和余量的硬脂酸甘油酯；(Ⅺ)6％促生长素抑制素、5％赖氨酸和余量的硬脂酸甘油酯；和(Ⅻ)6％促生长素抑制素、10％赖氨酸和余量的硬脂酸甘油酯。该图显示与使用醋酸钠相比，当使用赖氨酸作为成孔剂时，促生长素抑制素的初始快速释放速率较大。初始快速释放之后(约2天结束)，所有情况中的释放速率减慢并在第7天稳定下来。
图6给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(ⅩⅢ)6％纳曲酮(NX)、0％成孔剂和余量的硬脂酸甘油酯；(ⅪⅤ)6％纳曲酮(NX)、3％醋酸盐和余量的硬脂酸甘油酯；(ⅩⅤ)6％纳曲酮(NX)、5％赖氨酸和余量的硬脂酸甘油酯；和(ⅩⅥ)6％纳曲酮(NX)、10％赖氨酸和余量的硬脂酸甘油酯。该图显示所有配方在实验的23天时间内均实现了纳曲酮的缓慢逐步释放，尽管当没有成孔剂时，平均日释放量较低。
图7给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(ⅩⅦ)6％赖诺普利、0％醋酸钠和余量的硬脂酸甘油酯；(ⅩⅧ)6％赖诺普利、3％醋酸钠和余量的硬脂酸甘油酯；(ⅪⅩ)6％赖诺普利、5％赖氨酸和余量的硬脂酸甘油酯；和(ⅩⅩ)6％赖诺普利、10％赖氨酸和余量的硬脂酸甘油酯。该图显示所有配方在初始快速释放之后(约1天结束)，在实验的25天时间内均实现了赖诺普利的缓慢逐步释放，尽管在配方ⅩⅦ的情况下(即0％成孔剂)，在该时间内的平均日释放量较低。
图8给出了显示以下每种配方的三个100mg杆状物平均日体外释放情况的图：(ⅩⅪ)6％促甲状腺素释放激素(TRH)、0％醋酸盐和余量的硬脂酸甘油酯；(ⅩⅩⅫ)6％促甲状腺素释放激素(TRH)、3％醋酸盐和余量的硬脂酸甘油酯；(ⅩⅪⅡ)6％促甲状腺素释放激素(TRH)、5％赖氨酸和余量的硬脂酸甘油酯；和(ⅩⅩⅣ)6％促甲状腺素释放激素(TRH)、10％赖氨酸和余量的硬脂酸甘油酯。该图显示配方ⅩⅩⅡ、ⅩⅩⅢ、ⅩⅪⅤ在非常快的初始释放之后，在实验的28天时间内实现了TRH的缓慢逐步释放。而不含成孔剂时，在第1天以后，未观察到TRH的进一步释放。
图9给出了显示以下配方的三个100mg杆状物的平均日体外释放情况的图：(ⅩⅩⅤ)6％deslorelin、3％醋酸钠和余量的硬脂酸甘油酯。该图显示在实验的110天内实现了deslorelin的缓释。
实施例含有deslorelin和赖氨酸的配方
配方Ⅰ和Ⅱ(细节如上所述)的制备方法如下：
硬脂酸甘油酯(直径等于或小于1mm的自由流动珠，由QuestInterntional Pty Ltd(荷兰)提供)和卵磷脂(深棕色粘性糖浆，由Lucas Myer(德国)提供)用刮铲在小烧杯中手工混合。Deslorelin(Bachem，瑞士)用上述冷冻干燥过程预处理，然后加入赋形剂中并完全混合。将混合好的物料转移至柱塞式压出机的桶内，该柱塞式压出机连有一个1mm喷嘴，并平衡至55℃。柱塞式压出压力为40psi。装上压锤，施加压力，直至开始压出产品。此时压力下降，让产品达到55℃。产品以30秒内3g的速率压出。所得压出物冷却后破碎并用1mm喷嘴再压出。该步骤用以保证整个基质中成分的均一性。然后用2.3mm直径的喷嘴代替1mm的喷嘴。压出前进行同样的产品温度平衡过程。然后压出产品，冷却后，将得到的长的杆状物切成所需重量的长度。
图1给出了含有6mg deslorelin的100 mg杆状物的体外deslorelin释放结果。该分析包括将每个杆状物浸入含有1ml磷酸盐缓冲液(PBS；如本文前面所述)的独立容器内，该容器置于37℃循环水浴中。PBS每天更换，抽取出的PBS用HPLC对deslorelin进行分析。该图显示在deslorelin初始快速释放后，实现了在以后的较长时期(110天)中的缓释。在缓释期内，deslorelin的平均日释放速率为50-2μg/天。含有deslorelin和硫酸钠的配方
配方Ⅲ和Ⅳ使用硫酸钠(Ajax Chernicals，美国)作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。
图2给出了含有6mg deslorelin的100mg杆状物的体外deslorelin释放结果。该图显示与2％浓度的硫酸钠相比，当使用5％浓度的硫酸钠作为成孔剂时，deslorelin的初始快速释放速率更大(534μg比438μg)。初始快速释放之后(约10天结束)，在以后的95天中两种配方的释放速率均为约10-2μg/天。含有deslorelin和HPMC的配方
配方Ⅴ和Ⅵ使用羟丙基甲基纤维素(HPMC)作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。
图3给出了含有6mg deslorelin的100 mg杆状物的体外deslorelin释放结果。该图显示与2％浓度的HPMC相比，当使用5％浓度的HPMC作为成孔剂时，deslorelin的初始快速释放速率更大(685μg比403μg)。初始快速释放之后(约10天结束)，在以后的95天中二者的释放速率均为约10-2μg/天。含有deslorelin和葡萄糖的配方
配方Ⅶ和Ⅷ使用葡萄糖(Ajax Chernicals，美国)作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。
图4给出了含有6mg deslorelin的100mg杆状物的体外deslorelin释放结果。该图显示与2％浓度的葡萄糖相比，当使用5％浓度的葡萄糖作为成孔剂时，deslorelin的初始快速释放速率更大(790μg比403μg)。初始快速释放之后(约10天结束)，在以后的95天中两种配方的释放速率均为约50-2μg/天。含有促生长素抑制素和醋酸钠或赖氨酸的配方
配方Ⅸ至Ⅻ使用醋酸钠或赖氨酸作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。促生长素抑制素从Bachem(瑞士)得到。
图5给处了含有6mg促生长素抑制素的100mg杆状物的体外促生长素抑制素释放结果。该图显示与醋酸钠相比，当使用赖氨酸作为成孔剂时，促生长素抑制素的初始快速释放速率较大。含有纳曲酮和醋酸钠或赖氨酸的配方
配方ⅩⅢ至ⅩⅥ使用醋酸钠或赖氨酸作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。
图6给出了含有6mg纳曲酮的100mg杆状物的体外纳曲酮释放结果。该图显示所有配方在实验的23天时间内均实现了纳曲酮的缓慢逐步释放，尽管当没有成孔剂时，平均日释放量较低。含有赖诺普利和醋酸钠或赖氨酸的配方
配方ⅩⅦ至ⅩⅩ使用醋酸钠或赖氨酸作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。赖诺普利由Sigma ChemicalCo.(美国)得到。
图7给处了含有6mg赖诺普利的100mg杆状物的体外赖诺普利释放结果。该图显示所有配方在初始快速释放之后(约1天结束)，在实验的25天时间内均实现了赖诺普利的缓慢逐步释放，尽管在不含成孔剂的配方ⅩⅦ的情况下，在该时间内的平均日释放量较低。含有TRH和醋酸钠或赖氨酸的配方
配方ⅩⅪ至ⅩⅩⅣⅤ使用醋酸钠或赖氨酸作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。TRH从Sigma Chernical Co.(美国)得到。
图8给出了含有6mg TRH的100mg杆状物的体外TRH释放结果。该图显示配方ⅩⅩⅡ、ⅩⅩⅢ、ⅩⅩⅣ在非常快的初始释放之后，在实验的28天时间内均实现了TRH的缓慢逐步释放。而不含成孔剂时，在第1天以后，未观察到TRH的进一步释放。含有deslorelin和醋酸钠的配方
配方ⅩⅩⅤ使用醋酸钠作为成孔剂，采用与上述deslorelin/赖氨酸配方相同的方法制备。
图9给出了6mg杆状物的体外deslorelin释放结果。该图显示实现了110天内的deslorelin的缓释。
本领域技术人员应认识到，在不偏离本发明广泛描述的构思和范围的前提下，可以对具体实施方案展示的本发明进行很多的变动和修改。因而，这些具体实施方案在任何方面而言都被认为是说明性的，而非限制性的。
Claims (40)
1．一种药物和/或兽医配方，包括约2-30％(w/w)(以活性剂干重计)的至少一种活性剂，约0.5-20.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯，条件是该至少一种活性剂是促性腺激素释放激素(GnRH)激动剂时，成孔剂不是卵磷脂。
2．根据权利要求1的配方，其中的配方包括约5-10％(w/w)(以活性剂干重计)的至少一种活性剂，约1.0-10.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯。
3．根据权利要求1的配方，其中的配方包括约5-10％(w/w)(以活性剂干重计)的至少一种活性剂，约2.0-5.0％(w/w)的成孔剂，以及余量的硬脂酸甘油酯。
4．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自肽、多肽、蛋白质和核酸化合物及衍生物。
5．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂为GnRH激动剂。
6．根据权利要求5的配方，其中的GnRH激动剂选自deslorelin、氟他胺、戈舍瑞林、亮丙瑞林(leuprolide)、dioxalan衍生物、曲普瑞林、meterelin、布舍瑞林、组氨瑞林、那法瑞林、黄体瑞林、亮丙瑞林和LHRH类似物。
7．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自GnRH拮抗剂。
8．根据权利要求7的配方，其中的GnRH拮抗剂选自雷莫瑞克、teverelix、西曲瑞克、加尼瑞克、alanex和abarelix。
9．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自促生长素抑制素类似物。
10．根据权利要求9的配方，其中的促生长素抑制素类似物选自促生长素抑制素-14、奥曲肽、兰瑞肽和angiopeptin环肽。
11．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂为降脂药。
12．根据权利要求11的配方，其中的降脂药选自cerevastatin、美伐他汀、辛伐他汀、普伐他汀和洛伐他汀。
13．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自环孢菌素和环孢菌素类似物。
14．根据权利要求13的配方，其中的环孢菌素或环孢菌素类似物是环孢菌素A。
15．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自血管紧张素转化酶抑制剂。
16．根据权利要求15的配方，其中的血管紧张素转化酶抑制剂选自卡托普利、依那普利、群多普利特、哌道普利特、喹那普利特、fasidotril、omapatrilate和赖诺普利。
17．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自降钙素和降钙素类似物。
18．根据权利要求17的配方，其中的降钙素选自人降钙素、鲑鱼降钙素和猪降钙素。
19．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自P物质拮抗剂。
20．根据权利要求19的配方，其中的P物质拮抗剂选自Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2、Gln-Phe-Phe-Gly-Leu-Met-NH2、Phe-Phe-Gly-Leu-Met-NH2、Phe-Gly-Leu-Met-NH2和Gly-Leu-Met-NH2。
21．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自止痛药。
22．根据权利要求21的配方，其中的止痛药选自吗啡、羟甲左吗喃、度冷丁、布比卡因、利多卡因、衣铁卡因和甲哌卡因。
23．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自类阿片拮抗剂。
24．根据权利要求23的配方，其中的类阿片拮抗剂选自纳曲酮、纳洛酮和美沙酮。
25．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自抗抑郁药。
26．根据权利要求25的配方，其中的抗抑郁药选自文拉法辛、三氟丙嗪、甲氧异丁嗪、异丙嗪、丁螺环酮、吉吡隆和氟西汀。
27．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自非甾体抗炎药。
28．根据权利要求27的配方，其中的非甾体抗炎药选自奈普生钠吲哚美辛、舒林酸、托尔米丁、醋炎痛、苯酰吡酸钠、甲灭酸、非诺洛芬、氟灭酸、保泰松、氟联苯丙酸、酮洛酸和辣椒碱。
29．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自帕罗西丁、galanin拮抗剂、活化素、抑制素片段、促肾上腺皮质激素(ACTH)及其变体和片段、生长激素和生长激素类似物、促红细胞生成素(EPO)和促红细胞类似物、内皮素血管肽拮抗剂、leptin和leptin类似物、促甲状腺素释放激素(TRH)和TRH类似物、茶碱和茶碱类似物。
30．根据权利要求1-3中任一项权利要求的配方，其中的至少一种活性剂选自疫苗抗原和DNA编码疫苗抗原。
31．根据上述权利要求中任一项权利要求的配方，其中的至少一种活性剂的log辛醇/水分配系数(logP)在5.0至-3.0的范围内。
32．根据权利要求31的配方，其中的至少一种活性剂的log辛醇/水分配系数(log P)在3.0至-3.0的范围内。
33．根据权利要求31的配方，其中的至少一种活性剂的log辛醇/水分配系数(log P)在1.0至-3.0的范围内。
34．根据上述权利要求中任一项权利要求的配方，其中的成孔剂选自无机盐、有机盐、糖、氨基糖、氨基酸、肽、水溶性蛋白质、水溶性维生素以及它们的结合物。
35．根据权利要求34的配方，其中的成孔剂选自卵磷脂、赖氨酸、硫酸钠、醋酸钠、葡萄糖和羟丙基甲基纤维素(HPMC)。
36．根据上述权利要求中任一项权利要求的配方，其中的至少一种活性剂如说明书中所述，在磷酸盐缓冲液中在37℃下以约2μg-1.5mg/天的速率在体外释放，释放时间为至少7天。
37．根据上述权利要求中任一项权利要求的配方，其中的配方是自由流动珠或杆状物的形式。
38．根据上述权利要求中任一项权利要求的配方，其中的至少一种活性剂进行包括两个冷冻干燥步骤的预处理过程。
39．根据权利要求38的配方，其中的预处理过程包括如下步骤：
(ⅰ)制备活性剂的5-50％的溶液，
(ⅱ)冷冻干燥步骤(ⅰ)所述的溶液，
(ⅲ)用所述冷冻干燥的活性剂制备25-75％的溶液或匀浆，和
(ⅳ)冷冻干燥步骤(ⅲ)的溶液或匀浆。
40．一种治疗人或其它动物的疾病或症状的方法，该方法包括给予人或其它动物根据上述权利要求中任一项权利要求的配方。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AUPP4730 | 1998-07-20 | ||
| AUPP4731A AUPP473198A0 (en) | 1998-07-20 | 1998-07-20 | Bioimplant formulation II |
| AUPP4730A AUPP473098A0 (en) | 1998-07-20 | 1998-07-20 | Bioimplant formulation I |
| AUPP4731 | 1998-07-20 | ||
| AUPQ0324A AUPQ032499A0 (en) | 1999-05-13 | 1999-05-13 | Bioimplant formulation iii |
| AUPQ0324 | 1999-05-13 |
Related Child Applications (1)
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| CN 200510097821 Division CN1736487A (zh) | 1998-07-20 | 1999-07-20 | 生物植入物配方 |
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| CN1310623A true CN1310623A (zh) | 2001-08-29 |
| CN1243543C CN1243543C (zh) | 2006-03-01 |
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| CNB998089613A Expired - Lifetime CN1243543C (zh) | 1998-07-20 | 1999-07-20 | 生物植入物配方 |
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| US (2) | US6913761B1 (zh) |
| EP (1) | EP1104296B1 (zh) |
| JP (1) | JP2002521331A (zh) |
| CN (1) | CN1243543C (zh) |
| BR (1) | BR9912275A (zh) |
| CA (1) | CA2336879C (zh) |
| ES (1) | ES2389627T3 (zh) |
| MX (1) | MXPA01000674A (zh) |
| WO (1) | WO2000004897A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100509053C (zh) * | 2002-09-27 | 2009-07-08 | 赞塔里斯有限公司 | 持续释放的药物活性肽施用形式及其制备方法 |
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| US8052982B2 (en) * | 1998-07-20 | 2011-11-08 | Peptech Animal Health Pty Limited | Bioimplant formulation comprising lecithin and stearin |
| BR9912275A (pt) * | 1998-07-20 | 2001-04-17 | Peptech Ltd | Formulação de bioimplante |
| JP2003523330A (ja) | 2000-02-04 | 2003-08-05 | チルドレンズ・ホスピタル・リサーチ・ファウンデイション | アテローム性動脈硬化症および関連疾患のための脂質加水分解治療 |
| US7109171B2 (en) * | 2000-02-28 | 2006-09-19 | Praecis Pharmaceuticals Inc. | Methods for treating FSH related conditions with GnRH antagonists |
| WO2002067895A2 (en) * | 2000-11-16 | 2002-09-06 | Durect Corporation | Implant dosage form and use thereof for the delivery of a cholesterol lowering agent |
| WO2005067889A1 (en) | 2003-12-30 | 2005-07-28 | Durect Corporation | Polymeric implants, preferably containing a mixture of peg and plg, for controlled release of active agents, preferably a gnrh |
| WO2005117934A1 (en) * | 2004-05-31 | 2005-12-15 | Smart Drug Systems Inc | Sustained release composition |
| US20080254086A1 (en) * | 2004-12-23 | 2008-10-16 | Brown James E | Controlled Release Compositions |
| US20090297496A1 (en) * | 2005-09-08 | 2009-12-03 | Childrens Hospital Medical Center | Lysosomal Acid Lipase Therapy for NAFLD and Related Diseases |
| US20080261933A1 (en) * | 2007-04-23 | 2008-10-23 | Jens Hoffmann | Combination of progesterone-receptor antagonist together with a lutein-hormone-releasing hormone agonist and antagonist for use in brca mediated diseases |
| JOP20090061B1 (ar) | 2008-02-11 | 2021-08-17 | Ferring Int Center Sa | طريقة معالجة سرطان البروستاتا بمضادات الهرمونات التناسلية GnRH |
| US20110092493A1 (en) * | 2008-09-24 | 2011-04-21 | Clark Levi | Dose-controlled transdermal promethazine compositions and methods of use |
| AR092840A1 (es) | 2012-06-01 | 2015-05-06 | Ferring Bv | Elaboracion de degarelix |
| EP2832361A1 (en) * | 2013-07-29 | 2015-02-04 | Ipsen Pharma S.A.S. | Aqueous sustained release compositions of LHRH analogs |
| US9393177B2 (en) | 2013-08-20 | 2016-07-19 | Anutra Medical, Inc. | Cassette assembly for syringe fill system |
| USD774182S1 (en) | 2014-06-06 | 2016-12-13 | Anutra Medical, Inc. | Anesthetic delivery device |
| USD750768S1 (en) | 2014-06-06 | 2016-03-01 | Anutra Medical, Inc. | Fluid administration syringe |
| USD763433S1 (en) | 2014-06-06 | 2016-08-09 | Anutra Medical, Inc. | Delivery system cassette |
| US20180177777A1 (en) * | 2016-12-28 | 2018-06-28 | Michael Ballek | Formulations for mitigating opioid overdose and methods of making and using the same |
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| US4578391A (en) | 1982-01-20 | 1986-03-25 | Yamanouchi Pharmaceutical Co., Ltd. | Oily compositions of antitumor drugs |
| FR2573307B1 (fr) * | 1984-11-22 | 1988-06-10 | Virbac Ctre Rech Biolog | Implants anabolisants a liberation prolongee |
| US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
| CA1332918C (en) * | 1988-07-26 | 1994-11-08 | Colin G. Scanes | Devices and methods for growth promotion in poultry roasters |
| US4981681A (en) * | 1988-08-26 | 1991-01-01 | Vittorio Tosti | Lotion mixture and method of treating psoriasis |
| AU6430190A (en) * | 1989-10-10 | 1991-05-16 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
| CA2068216C (en) * | 1989-11-13 | 1999-04-13 | Abraham J. Domb | Lipospheres for controlled delivery of substances |
| EP0523330B1 (en) * | 1991-06-24 | 1996-03-20 | American Cyanamid Company | Implant compositions containing a biologically active protein, peptide or polypeptide |
| SI9300468A (en) | 1992-10-14 | 1994-06-30 | Hoffmann La Roche | Injectable composition for the sustained release of biologically active compounds |
| AUPN366795A0 (en) * | 1995-06-20 | 1995-07-13 | Peptide Technology Limited | Formulation for preventing reproductive function |
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| EP1007080B1 (en) * | 1996-08-30 | 2007-04-18 | Peptech Limited | Formulation for the sustained release of peptide agonists and analogues of GnRH |
| EP0945133A1 (en) * | 1998-03-26 | 1999-09-29 | Lipha | Combination for the treatment of alcohol and drug dependence containing an opioid antagonist and a NMDA receptor complex modulator |
| BR9912275A (pt) * | 1998-07-20 | 2001-04-17 | Peptech Ltd | Formulação de bioimplante |
-
1999
- 1999-07-20 BR BR9912275-8A patent/BR9912275A/pt not_active Application Discontinuation
- 1999-07-20 US US09/743,059 patent/US6913761B1/en not_active Expired - Lifetime
- 1999-07-20 CN CNB998089613A patent/CN1243543C/zh not_active Expired - Lifetime
- 1999-07-20 EP EP99932545A patent/EP1104296B1/en not_active Expired - Lifetime
- 1999-07-20 WO PCT/AU1999/000585 patent/WO2000004897A1/en active IP Right Grant
- 1999-07-20 JP JP2000560890A patent/JP2002521331A/ja active Pending
- 1999-07-20 MX MXPA01000674A patent/MXPA01000674A/es active IP Right Grant
- 1999-07-20 ES ES99932545T patent/ES2389627T3/es not_active Expired - Lifetime
- 1999-07-20 CA CA2336879A patent/CA2336879C/en not_active Expired - Lifetime
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2005
- 2005-01-25 US US11/041,270 patent/US20050276854A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100509053C (zh) * | 2002-09-27 | 2009-07-08 | 赞塔里斯有限公司 | 持续释放的药物活性肽施用形式及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1104296A4 (en) | 2004-11-10 |
| WO2000004897A1 (en) | 2000-02-03 |
| CA2336879A1 (en) | 2000-02-03 |
| MXPA01000674A (es) | 2002-04-08 |
| JP2002521331A (ja) | 2002-07-16 |
| CN1243543C (zh) | 2006-03-01 |
| BR9912275A (pt) | 2001-04-17 |
| EP1104296A1 (en) | 2001-06-06 |
| US20050276854A1 (en) | 2005-12-15 |
| EP1104296B1 (en) | 2012-06-13 |
| ES2389627T3 (es) | 2012-10-29 |
| US6913761B1 (en) | 2005-07-05 |
| CA2336879C (en) | 2010-06-01 |
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