CN1068965A - 含有生物活性蛋白肽或多肽的植入组合物 - Google Patents
含有生物活性蛋白肽或多肽的植入组合物 Download PDFInfo
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- CN1068965A CN1068965A CN92105065A CN92105065A CN1068965A CN 1068965 A CN1068965 A CN 1068965A CN 92105065 A CN92105065 A CN 92105065A CN 92105065 A CN92105065 A CN 92105065A CN 1068965 A CN1068965 A CN 1068965A
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- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
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Abstract
本发明涉及一种植入组合物,它可在较长时间内
以基本上均匀而持续的数量通过肠胃道外给药施加
生物活性蛋白、肽或多肽。本发明还涉及一种提高并
保持动物血液中生物活性蛋白、肽和多肽含量的方
法。
Description
人们需要能在较长时间内均匀地持续释出药用制剂的方法及其所用的组合物,开发这类方法和组合物时所遇到的困难也是众所周知的。
本发明涉及一种可植入的组合物,它可通过肠胃道外给药后较长的时间内以基本上均匀而持续的数量施给生物活性蛋白,肽或多肽,它系由压紧的、有凹痕、并被部分包覆的组合物所构成,组合物包含一至三层,每层按重量计含有约20-80%生物活性的蛋白、肽、或多肽,约10-75%脂肪、蜡、或其混合物,约0-20%缓冲剂、盐、或其混合物,以及约0-25%糖。
令人惊奇的是,我们发现,在动物体内植入本发明的压紧、有凹痕、并被部分包覆的组合物后,可以在较长时间内提高并保持其血液中生物活性蛋白、肽或多肽的含量。
本发明的可植入的组合物,较好的是一种压紧的、有凹痕并被部分包覆的组合物,它包含一至三层,每层按重量计含有约20-80%生物活性蛋白、肽或多肽,约10-75%脂肪、蜡、或其混合物,约1-20%缓冲剂、盐、或其混合物,以及约1-25%糖。
本发明的更好的可植入的组合物,是一种压紧的、有凹痕并被部分包覆的组合物,它包含一至三层,每层按重量计含有约35-70%生物活性的蛋白、肽、或多肽,约15-50%脂肪、蜡、或其混合物,约1-10%缓冲剂、盐、或其混合物,以及5-15%糖。
适合于用在本发明的组合物中所施加的生物活性蛋白、肽和多肽,包括生长激素,促生长因子,生长因素,以及它们的其它具有生物活性的碎片和衍生物。较好的蛋白包括猪的、羊的、马的、牛的、禽类的、与人的生长激素;而且其含意包括天然的、合成的、重组的、或生物合成来源的。更好的蛋白是在α-螺旋3区(α-helix 3region)或α-螺旋2区有变异(alteration)的、这二种情况相结合的,以及它们与其它突变体相结合的各种生长激素;而以E34rpST,I122L+E34rpST,和A6TSIIR+E34rpST为最好。
适用于本发明组合物中的蜡和脂肪一般熔点高于40℃。本发明中,蜡可定义为一种低熔点的高分子量有机混合物或化合物,在室温下为固体,并且除了不包含甘油酯以外,其成份一般与脂肪和油相似。其中有一些是烃类;其它的是脂肪酸的酯和醇。这些化合物包括饱和或不饱和的长链C10-C24脂肪酸,醇,酯,盐,醚,或其混合物。它们都归属于脂类(lipids)。蜡是热塑性的,但因为它们不是高聚物,所以认为不属于塑料一类。共同的性质是:有憎水性;光滑的纹理;无毒性;没有不受欢迎的气味和颜色。它们是可燃的,并具有良好的介电性质。它们可溶于大部分有机溶剂但不溶于水。
主要的类型为:
Ⅰ.天然的
1.动物(蜂蜡,羊毛脂,紫胶蜡,中国白蜡);
2.植物(巴西蜡棕,小烛树蜡,杨梅属植物,甘蔗);
3.矿物
(a)化石或地蜡(地蜡,纯地蜡,褐煤蜡),
(b)石油蜡(石蜡,微晶疏松石蜡或鳞状蜡);
Ⅱ.合成的
1.烯类聚合物和多元醇醚酯(“聚乙二醇”)(CarboWAX);
2.氯化萘(“卤蜡”)(HaloWAX);
3.由Fischer-Tropsch合成法制得的烃类。
本发明中,脂肪可定义为高级脂肪酸(如肉豆寇酸,硬脂酸,棕榈酸)的甘油酯。这些酯及其混合物在室温下为固体,并呈现晶体结构。猪脂和牛脂就是例子。脂肪与油之间在化学方面并无差别,唯一的区别是室温下脂肪是固体而油是液体。“脂肪”通常都是具体指三酸甘油酯,而“脂类”(lipid)则是统称包括一切脂类。
较佳的脂肪是长链C10-C24脂肪酸的一甘油酯、二甘油酯和三甘油酯。这些一、二、三甘油酯主要是肉豆蔻酸酯,硬脂酸酯,棕榈酸酯,月桂酸酯,亚油酸酯,亚麻酸酯,油酸酯,及它们的残基或混合物,最好是熔点高于50℃的。而以三肉豆蔻酸甘油酯为最好。
适用于本发明组合物中的糖类包括单糖、双糖和三糖,如葡萄糖,甘露糖,山梨糖醇,甘露糖醇,乳糖,蔗糖,麦芽糖,纤维素二糖,蜜三糖。较好的糖类是非还原性的单糖,双糖和三糖,而以蔗糖,蜜三糖,山梨糖醇和甘露糖醇为最好。
在本发明的植入组合物中可加入缓冲剂,以将组合物的pH调节到约6.0-8.5,使得生长激素可溶解并随后从植入的组合物中释出。适用于本发明组合物中的缓冲剂包括钠和钾的磷酸盐、硼酸盐、碳酸盐、甘氨酸盐等或它们的混合物,而以可将组合物的pH调节到6.5-8.0的磷酸二氢钠与磷酸氢二钠的混合物为较好。
适用于本发明组合物中的盐包括氯化钠、氯化钾等。
在本发明组合物中可加入稳定剂、防腐剂、表面活性剂等添加剂或者它们的混合物。较好的稳定剂为脱氢乙酸,N-水杨酰苯胺,山梨酸、硼酸,苯甲酸,以及它们的盐;羟丙基纤维素,羟丙基甲基纤维素,亚硝酸钠,和硝酸钠。在本发明中添加剂的合适用量为0.1-20%(重量)。
令人惊奇的是,我们发现,在动物体内植入本发明的组合物,可以在较长时间内提高并保持其血液中生长激素的含量水平。一般也可观察到血液中生物活性蛋白,肽和多肽含量的提高,而且伴随着有益的和/或治疗的效果。这些效果包括在动物体内体重增加,生长率增加,饲料效率提高,体内脂肪减少,瘦肉与脂肪之比增大,肌肉体积的改善,以及授乳动物的产乳量增加。血中含量保持在较高数值,表明活性组份在缓慢释放。当活性组份在血中的含量保持在提高了的数值时,一般可观察到生长率增加,饲料效率提高,瘦肉增多,产奶量增加等性质。本发明包括使用这里所说的组合物来提高生长率,提高饲料效率,增加动物的瘦肉,增加产奶量,以及提高并保持动物血流中生长激素的含量。
本发明中用来施给生物活性蛋白,肽或多肽的可植入组合物可用以下方法制备:将活性组分、缓冲剂或盐或其混合物、和糖掺入熔融的脂肪、蜡、或其混合物中以得到一种粗粉料。然后在压制常规5/32和1/8英寸植入片的压片机上用专用冲头制得压紧并有凹痕的组合物。冲头在其中心线上有一锥形的突出部分,在压片时可在组合物上形成一锥形凹痕。然后在冲模内放入一至三层粗粉料,用专用冲头制得压紧并有凹痕的组合物。在本发明的一个较佳实施例中,各层的生物活性蛋白,肽或多肽的数量随着离开凹痕的距离而增加。然后再用一层或二层半渗透性材料包覆压紧并有凹痕的组合物,制得本发明的可植入组合物。凹痕部分基本上未被包覆,并成为活性组分在较长时间内从本发明组合物中释出的通道。
适合用来包覆本发明的压紧并有凹痕的组合物的半渗透性材料包括异丁烯酸酯共聚物,乙基纤维素聚合物等半渗透性聚合物。在半渗透聚合物中可加入1-20%(重量)的增塑剂和填充剂之类的添加剂,较好的增塑剂和填充剂分别是柠檬酸三乙酯和滑石。包围压紧并有凹痕的组合物的包覆层的厚度为约0.5-25密尔。
为了帮助进一步理解本发明,用下列实施例来更详细具体地予以说明。但本发明不应局限于这些实施例,而只由权利要求书所确定。
实施例1
用于非肠胃道给药以施加生长激素的植入组合物的制备
1.用喷雾干燥法制备生长激素,糖,缓冲剂和附加剂,使其粒度适合于掺入脂肪,蜡,或其混合物中。具体做法是:将生长激素和糖溶解于水中,然后加入所需的缓冲溶液(例如磷酸二氢钠和磷酸氢二钠的1∶2混合物)。还可加入羟丙基纤维素等添加剂并让它溶解。然后把溶液放在Buchi 190型微型喷雾干燥器中进行喷雾干燥。
颗粒状粉料的制备。将喷雾干燥粉料掺合于熔融脂肪,蜡或其混合物中,制得均匀的混合物,然后让所得的混合物冷却而得到一种粉料。将该粉料用装有5/8英寸冲头和冲模的Stokes 512型压片机压片。然后用轻型桌上锤磨机(Glen Mills Microhammer Mill)锤磨这些压片,制得一种粗颗粒粉料。
3.制备压紧而有凹痕的组合物。分层,压紧而有凹痕的组合物,是用装有5/32英寸冲模和专用冲头的Stokes 512型单片压片机制得的。冲头在其中心线上有一3mm的锥形突出部分。突出部分的底部尺寸约为1mm。要制取分层,压紧而有凹痕的组合物,首先将内端的粒状粉料放入冲模内并轻轻捣实,然后将凹痕端的粒状粉料放入冲模。压片机用手工操作,使它每次只压出一片植入片。为了制得均匀的植入片,使用一个1/8英寸的冲模和专用冲头。冲头在其中心线上有一3mm的锥状突出部分,突出部分的底部尺寸约为1mm。在冲模内放入所需数量的颗粒状粉料,用手工操作压片机就可制得均匀,压紧而有凹痕的组合物。
4.被部分包覆的植入组合物的制备。压紧并有凹痕的组合物可用一MINI HI-COATERR(Vector Laboratories的注册商标)包覆一层或二层半渗透性聚合物材料。凹痕内的表面基本上未被包覆,它成为活性组分在较长时间内从本发明组合物中释出的通道。
利用上述方法,以下面表Ⅰ所列的材料制得表Ⅱ所列的植入组合物。
表 Ⅰ
生长激素
a.I122L+E34rpST
b.E34rpST
c.A6TS11R+E34rpST
d.CAM-rpST
e.牛生长激素
脂肪或蜡
f.三肉豆寇酸甘油酯
g.三硬脂酸甘油酯
糖
h.蔗糖
i.乳糖
缓冲剂
j.磷酸二氢钠与磷酸氢二钠的1:2混合物,
k.磷酸二氢钠
l.硼酸钠
添加剂
m.羟丙基纤维素
包覆层
n.含有8%(重量)滑石的聚(丙烯酸乙酯,甲基丙烯酸甲酯)(EUDRAGITRNE30D).
o.含有15%(重量)滑石的聚(丙烯酸乙酯,甲基丙烯酸甲酯)(EUDRAGITRNE30D).
p.含有15%(重量)柠檬酸三乙酯的聚(丙烯酸乙酯,甲基丙烯酸甲酯)甲基丙烯酸乙酯三甲铵氯化物poly(ethylacrylate,methylmethacrylate)trimethylammonioethylmethacrylate chloride(EUDRAGITRRL30D)
q.含有15%(重量)柠檬酸三乙酯的聚(丙烯酸乙酯,甲基丙烯酸甲酯)甲基丙烯酸乙酯三甲铵氯化物(EUDRAGITRRS30D)。
*EUDRAGITR是Rohm pharma Gm6H的商标。
表 Ⅱ
植入组合物
实施例2
本发明的组合物在猪体内的持续释出
将猪分为每四头一组。在整个试验过程中,全部的猪都喂以含20%粗蛋白的食料。头三天不作处理,每天测得每一组猪血液中猪生长激素的含量。然后在每头猪的耳部植入两片表Ⅱ所列的植入片。每天用标准放射免疫分析(RIA)技术测定猪的血液中生长激素的含量。实验的结果综合列于下表Ⅲ中,这些结果表明本发明的组合物能有效地在较长时间内将血液中的生长激素含量提高并保持在较高的水平。
表Ⅲ
猪试验中的平均血浆rpST浓度(ng/mL,根据放射免疫分析测定)
时间 组合物编号(参见表Ⅱ)
(天) 2 7 10 11 12 13
-3 1.9 1.4 1.5 2.1 3.8 2.5
-2 0.9 2.2 2.6 4.9 2.4 3.8
-1 1.2 2.3 1.7 2.4 3.3 4.2
1 6.6 5.5 4.9 1.7 3.0 1.4
2 8.2 3.5 35.2 1.5 3.5 1.6
3 9.8 13.9 97.1 2.6 3.8 3.2
4 6.3 11.3 60.9 1.9 3.2 2.4
5 3.4 17.6 56.4 1.5 18.9 8.6
6 20.1 16.2 474.8 11.2 61.2 17.6
7 26.4 20.6 242.6 3.3 40.3 22.9
表 Ⅲ
(续)
时间 组合物编号(参见表Ⅱ)
(天) 2 7 10 11 12 13
8 26.1 20.0 110.6 118.1 35.4 41.3
9 50.0 19.4 70.7 87.0 19.7 43.0
10 42.9 25.9 45.4 56.6 30.0 55.0
11 26.1 35.7 82.4 44.3 15.7 32.5
12 16.0 34.2 47.1 34.8 22.7 35.3
13 26.2 29.8 52.1 40.1 6.7 25.0
14 19.9 31.4 28.8 54.4 8.0 39.8
15 10.2 25.3 21.3 25.9 4.8 20.0
16 8.8 20.7 19.7 31.3 4.7 12.5
17 13.4 10.5 6.8 29.2 4.9 10.2
18 8.0 15.4 7.8 18.5 4.0 10.0
19 32.1 34.4 10.0 16.1 3.8 5.3
20 5.8 9.4 8.2 14.9 2.8 6.8
21 9.6 13.6 9.9 8.7 2.7 3.1
22 15.1 11.2 5.7 7.4 35.6 7.1
23 60.8 7.1 6.0 15.9 12.8 4.3
24 4.9 7.6 12.6 11.2 4.0 4.4
25 8.4 7.0 5.4 5.4 2.3 3.4
26 8.9 6.6 4.0 5.3 2.7 6.8
27 6.7 7.3 4.8 8.6 5.0 6.5
实施例3
植入片的体外溶解性评价
在放有10mL磷酸盐缓冲溶液的塑料试管中放入两片植入片(缓冲溶液pH7.4,100mM NaCl,50mM Na2HPO4/NaH2PO4,0.2%叠氮化钠),并将该管放入一水温保持为39℃的水浴内。管子在水浴内保持两天,然后将溶液从管中取出,用高效液相色谱法(HPLC)分析相应的生长激素的含量,最后将溶液弃掉。再在管内放入新的磷酸盐缓冲溶液,管子在水浴内再放三天,然后按上面所说进行分析。这一过程以不同的时间间隔重复若干次,直至试验结束。表Ⅱ所列的几种组合物的对应的生长激素释放率综合列于表Ⅳ。
表 Ⅳ
释放率(毫克/日)
组合物
起止日 2 7 10
0-2 0.6 0.6 1.0
2-5 3.8 7.6 11.4
5-9 7.2 7.0 6.9
9-12 5.3 3.4 4.2
12-16 2.7 1.7 2.1
16-19 1.6 1.3 1.8
19-23 1.3 0.9 1.4
23-28 0.9 0.6 1.0
按照上述方法,但在与上面不同的时间间隔内分析溶液中对应的生长激素的含量,可得到表Ⅴ,表Ⅵ和表Ⅶ所示的释放率。
表 Ⅴ
释放率(毫克/日)
组合物
起止日 11 13
0-1 0.1 0.0
1-2 2.5 1.4
2-5 7.0 3.9
5-9 5.9 6.4
9-12 3.9 4.3
12-16 2.5 2.5
16-19 1.7 1.3
19-22 1.4 1.1
22-26 1.0 1.1
26-28 0.8 0.6
表 Ⅵ
释放率(毫克/日)
组合物
起止日 12
0-1 0.5
1-3 2.0
3-7 5.1
7-10 7.1
10-14 3.9
14-17 1.9
17-21 1.3
21-24 0.9
24-28 0.7
表 Ⅶ
释放率(毫克/日)
组合物
起止日 15 16 17
0-1 0.0 0.0 0.0
1-2 2.2 0.7 0.7
2-5 1.5 3.0 3.3
5-9 3.9 4.4 4.5
9-12 4.6 4.1 2.6
12-16 2.4 2.3 1.1
16-20 1.5 1.6 0.7
20-23 0.9 1.2 0.4
23-26 0.9 1.1 0.3
此外,按照上面的方法,但用三片植入片作试验,则得到表Ⅷ所示的释放率。
表 Ⅷ
释放率(毫克/日)
组合物
起止日 14
0-1 0.0
1-4 1.4
4-7 3.9
7-11 4.7
11-14 3.3
14-18 1.9
18-21 1.5
21-34 0.8
Claims (12)
1、一种可通过在肠胃道外给药后在较长时间内以基本上均匀而持续的数量释出生物活性蛋白,肽或多肽的可植入的组合物,其特征在于它由压紧并有凹痕,且被部分包覆的组合物所构成,组合物包含一至三层,每层按重量计含有约20-80%生物活性蛋白,肽或多肽,约10-75%脂肪,或蜡,或其混合物,约0-20%缓冲剂,或盐,或其混合物,以及约0-25%糖。
2、如权利要求1所述的组合物,其特征在于其中的生物活性蛋白,肽或多肽是选自生长激素,促生长因子,与生长因素,包括猪的、羊的、马的、牛的、禽类的、和人的生长激素;而脂肪是选自三肉豆蔻酸甘油酸,三棕榈酸甘油酯,与三硬脂酸甘油酯;缓冲剂是选自硼酸钠,碳酸钠,磷酸二氢钠,磷酸氢二钠,与它们的混合物;糖是选自葡萄糖,甘露糖,蔗糖,蜜三糖,山梨糖醇,甘露糖醇,和乳糖;包覆物由一至二层半渗透性材料构成;而且所说的组合物也可含有稳定剂,表面活性剂,或其混合物。
3、如权利要求2所述的组合物,其特征在于其中的猪生长激素是选自E34rpST,I122L+E34rpST,和A6TSIIR+E34rpST。
4、如权利要求2所述的组合物,其特征在于其中的缓冲剂是一种磷酸二氢钠与磷酸氢二钠的混合物。
5、如权利要求2所述的组合物,其特征在于其中的半渗透性材料是一种含有约1-20%(重量)柠檬酸乙酯或滑石的甲基丙烯酸酯共聚物,而包覆层的厚度为约0.5-25密尔。
6、如权利要求1所述的组合物,其特征在于各层的生物活性蛋白、肽或多肽的含量随着离开凹痕的距离而增加。
7、一种提高并能保持动物血液中生物活性蛋白、肽或多肽含量,提高生长率,提高饲料效率,改善瘦肉与脂肪之比,和提高授孔动物产乳量的方法,其特征在于通过肠胃道外给药以施加权利要求1所述的可植入组合物。
8、如权利要求7所述的方法,其特征在于所施加的是权利要求2所述的可植入组合物。
9、一种制备可植入组合物的方法,该组合物可在较长时间内以基本上均匀而持续的数量在肠胃道外给药以施加生物活性蛋白、肽或多肽,所述方法的特征为:
(a)将生物活性蛋白、肽或多肽与熔融的脂肪、蜡、或其混合物混合在一起(其中也可混有缓冲剂、盐、或糖),以制得一种粗粉料;
(b)将一至三层上述粗粉料压紧,以制得压紧的物体;
(c)用锥形突出部分的冲头冲压上述压紧的物体,以在该压紧的物体上形成一锥形凹痕;
(d)用半渗透性材料包覆上述压紧并有凹痕的物体,使所述凹痕成为由该压紧物体穿过包覆层的通道。
10、如权利要求9所述的方法,其特征在于步骤(b)和步骤(c)是同时进行的。
11、如权利要求9所述的方法,其特征在于其中压紧的物体是权利要求1所述的组合物。
12、如权利要求9所述的方法,其特征在于其中步骤(a)还包括以下特征:
(a)将生物活性蛋白、肽或多肽与缓冲剂、盐、或其混合物溶解于水制成溶液;
(b)将上述溶液进行喷雾干燥,以制得喷雾干燥的粉料;
(c)将上述喷雾干燥的粉料溶解于熔融的脂肪、蜡、或其混合物中,制得均匀的混合物;
(d)将上述均匀的混合物冷却以制成粉料;
(e)将上述粉料压紧,制得压紧的物体;
(f)碾磨上述压紧物体,以制得粗颗粒粉料。
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US71989891A | 1991-06-24 | 1991-06-24 | |
US719,898 | 1991-06-24 |
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EP (1) | EP0523330B1 (zh) |
JP (1) | JP3597205B2 (zh) |
KR (1) | KR100221031B1 (zh) |
CN (1) | CN1050301C (zh) |
AT (1) | ATE135565T1 (zh) |
AU (1) | AU656200B2 (zh) |
BR (1) | BR9202374A (zh) |
CA (1) | CA2071757C (zh) |
DE (1) | DE69209173T2 (zh) |
DK (1) | DK0523330T3 (zh) |
ES (1) | ES2087337T3 (zh) |
GE (1) | GEP19970992B (zh) |
GR (1) | GR3019457T3 (zh) |
HU (1) | HU217547B (zh) |
IE (1) | IE74398B1 (zh) |
IL (1) | IL102287A (zh) |
LV (1) | LV11816B (zh) |
MD (1) | MD1394G2 (zh) |
MX (1) | MX9203175A (zh) |
RU (1) | RU2080119C1 (zh) |
SG (1) | SG47955A1 (zh) |
TW (1) | TW215058B (zh) |
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ZA (1) | ZA924613B (zh) |
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US5736152A (en) * | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
US8052982B2 (en) | 1998-07-20 | 2011-11-08 | Peptech Animal Health Pty Limited | Bioimplant formulation comprising lecithin and stearin |
WO2000004897A1 (en) * | 1998-07-20 | 2000-02-03 | Peptech Limited | Bioimplant formulation |
JP2001058955A (ja) * | 1999-06-17 | 2001-03-06 | Inst Of Physical & Chemical Res | 生理活性ペプチド徐放性製剤 |
KR100890125B1 (ko) | 2000-02-24 | 2009-03-24 | 일라이 릴리 앤드 캄파니 | 소마토트로핀의 지속적인 방출을 위한 비수성 주사제제들 |
AU2001271491A1 (en) | 2000-06-26 | 2002-01-08 | Monsanto Technology Llc | Non-aqueous surfactant-containing formulations for extended release of somatotropin |
US6664234B1 (en) | 2000-06-30 | 2003-12-16 | Monsanto Technology Llc | Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin |
JP4931282B2 (ja) * | 2000-10-02 | 2012-05-16 | 日本ケミカルリサーチ株式会社 | 生理活性ペプチド含有粉末 |
DE10161078A1 (de) * | 2001-12-12 | 2003-08-28 | Achim Goepferich | Matrizes zur Stabilisierung und kontrollierten Freisetzung von Problemarzneistoffen |
JP2005145821A (ja) * | 2003-11-11 | 2005-06-09 | Kao Corp | 打錠製剤 |
SG181769A1 (en) | 2009-12-21 | 2012-07-30 | Ambrx Inc | Modified porcine somatotropin polypeptides and their uses |
US20120283171A1 (en) | 2009-12-21 | 2012-11-08 | Ambrx, Inc. | Modified bovine somatotropin polypeptides and their uses |
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US4271113A (en) * | 1978-04-17 | 1981-06-02 | Alza Corporation | Process for forming a passageway in an osmotic device |
CA1257199A (en) * | 1986-05-20 | 1989-07-11 | Paul Y. Wang | Preparation containing bioactive macromolecular substance for multi-months release in vivo |
US4863736A (en) * | 1987-03-16 | 1989-09-05 | Monsanto Company | Somatotropin prolonged release |
US4795644A (en) * | 1987-08-03 | 1989-01-03 | Merck & Co., Inc. | Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins |
HUT69680A (en) * | 1990-08-09 | 1995-09-28 | Endocon Inc | Implant and apparatus for delivering multiple drug and process for production of theese |
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