CN1006197B - 可以注射的能持久释放的配合料 - Google Patents
可以注射的能持久释放的配合料 Download PDFInfo
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- CN1006197B CN1006197B CN86105087.8A CN86105087A CN1006197B CN 1006197 B CN1006197 B CN 1006197B CN 86105087 A CN86105087 A CN 86105087A CN 1006197 B CN1006197 B CN 1006197B
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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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Fodder In General (AREA)
- Feed For Specific Animals (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
一种可以注射的、能持久释放牛生长激素的、含有一种蜡和一种油的混合物的配合料。
Description
三十五年前就已经知道给奶牛服用牛生长激素会增加牛奶的产量,而不会对牛奶成分产生不良的影响〔Cotes,et al.,Nature,164,992(1949)〕。在科茨和他的小组的工作之后,进行了许多实验以进一步探究生长激素和使奶牛增加奶产量之间的关系。最近,研究的焦点又转移到用遗传改性的微生物来生产生长激素的实验。例如,可参阅Eppard等Proc.Cornell.Nutr.Conf.,1984,p.5。有些研究者报告称,用微生物合成的牛生长激素在增加奶产量方面甚至比天然激素更为有效(DeGoeter等,第0085036号欧洲公开专利)。
本发明提供的技术是一种可以注射的能持久释放牛生长激素的配合料,此配合料由有效浓度的牛生长激素构成,牛生长激素悬浮在载体中,载体约含有1%到20%的一种蜡和80%到99%的一种油。
除非另有说明,本文中所提及的全部百分数、比例等均以重量为单位。
本发明还提出一种使奶牛增加奶产量的方法,该方法包括给牛注射有效量的上述可以注射的能持久释放生长激素的配合料。
本配合料中的蜡最好选自植物性蜡和动物性蜡。例如,可用的蜡包括西班牙草蜡、日本蜡、西蒙得木蜡、羊毛蜡、鲸蜡、中国白蜡、特别是巴西棕榈蜡和蜂蜡。各种纯度等级的蜂蜡都可使用,无论是高纯度的白色蜂蜡,还是一般的商品黄色蜂蜡,都已经成功地应用于本配合料中。此外,也可以用石蜡、地蜡和硅酮蜡。
选用的油应是易于得到适当纯品的和在生理上可被接受的。当然这些油必须是经过充分精炼的,因而贮存性能稳定。它们放置时不产生沉淀,不会产生可观察到的化学反应,以及给动物注射后不会产生可以观察到的生理反应。这些油最好是植物油,例如豆油、花生油、芝麻油、棉籽油、玉米油、橄榄油、蓖麻油、棕榈油、杏仁油等,特别是花生油和芝麻油。也可以用其它油,包括石油、矿物油和硅酮油。
制备载体时,油和蜡的一般比例范围约为1%到20%的蜡。较好是用约5%到15%的蜡,最好是用约5%到10%的蜡。一般说来,蜡的浓度愈大,配合料的持久作用时间也愈长。蜡浓度的上限是按配合料通过粗皮下注射用针头的要求来确定的。按以上所述,蜡浓度的近似上限约为20%,而配合料的粘度和可注射性是受许多因素影响的,特别是生长激素的颗粒大小和浓度以及配合料的贮存温度。因此,蜡浓度的上限不是精确的值,而是近似值,它可随配合料的其他情况而有所变化。
配合料的载体含有油和蜡。现在已经制备出没有任何其他成分的完全令人满意的配合料。然而,配合料化学家了解在某些情况下可能需要加入相当小浓度的其他成分,这不会影响本发明的实质。这些微量成分可能包括例如染料、防腐剂、防止注射处感染的抗生素、粘度调节剂或稳定剂以及抗氧化剂等,以延长配合料的贮存期限。这些微量成分的含量可能是最终配合料的万分之几到百分之几。
例如,有用的染料包括FD和C染料以及D和C染料。防腐剂包括苯甲酸、氯代丁醇、山梨酸钾、山梨酸、二氧化硫、棓酸丙酯、对羟苯甲酸酯(the parabens)、乙基香草醛、甘油、苯酚、对氯苯酚等。粘度调节剂包括肉豆蔻酸异丙酯、烘制二氧化硅、藻酸钠、甲基纤维素、单硬脂酸铝、六甘油二硬脂酸酯、甘油单硬脂酸酯等。可用的稳定剂包括象乙二胺和琼脂那类物质。抗氧化剂选自抗坏血酸棕榈酸酯、亚硫酸氢钠、焦亚硫酸钠、二氧化硫、顺丁烯二酸、棓酸丙酯、甲醛合次硫酸氢钠、丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)、叔丁基对苯二酚等类化合物。所有上述这些化合物对配合料化学家来说都是熟悉的。
本配合料中使用的牛生长激素的来源和类型并不重要。可以使用从动物得到的天然生长激素,也可以使用任何类型的从微生物得到的生长激素,这随方便和经济性而定。天然的和从微生物得到的这二种牛生长激素的物理性质都是合乎本配合料要求的。因此,任何牛生长激素都可用作本配合料中的合适的活性成分。
出版物已经介绍了许多应用微生物制备牛生长激素的方法。应当指明,某些改性的微生物能产生改性的生长激素,典型的改性是在多肽链的一端带有一个或少数几个额外的氨基酸。按照文献所述,这些改性的激素具有和天然牛生长激素相同的性质和活性。因此,在本文中,“牛生长激素”一词均包括改性的牛生长激素,它是通过遗传改性的微生物合成的,它具有天然牛生长激素的性质和活性。
下列公开专利文件和出版物阐述了改性的微生物,和使用这些微生物来合成牛生长激素的方法。
梅恩等,0095361号欧洲公开专利
乔治等,0111814号欧洲公开专利
罗特曼等,0067026号欧洲公开专利
米勒等,0047600号欧洲公开专利
弗雷泽等,0068646号欧洲公开专利
阿维夫等,2073245号英国公开专利
德博尔等,0075444号欧洲公开专利
肖纳等,Biotechnology,1985年2月,151-154
肖纳等,Proc.Nat.Acad.Sci.USA81,5403-07(1984)
用有效浓度的牛生长激素同载体结合制备配合料。浓度随持久释放作用时间的要求而定,也和注射的剂量有关。当然,需要考虑可用的生长激素的纯度或效力。
已经发现,对每头奶牛注射2-10克的配合料就可以在适当长的时间持久地释放。这样的量对注射者来说不会引起不方便,对牛来说也不会造成不舒服。供注射的配合料中生长激素的浓度约在5%到35%之间,最好约在10%到25%之间。
本配合料中载体的制备方法是将蜡溶解在油中,需要时可以加热。任何可能需要应用的微量成分,也可方便地在混合物热的时候加入。当混合物冷却时,粘度明显增加,蜡(至少一部分)会从溶液中析出。最好在已经冷却到接近环境温度时均化载体,以缩小蜡的颗粒大小,从而降低混合物的粘度。通常使用的设备都是有效的。例如,可以用一种机器在高压下迫使混合物通过细孔,或用一种高强度的混合机,混合机中有一个高速搅拌器,搅拌器由带挡板的定子紧密包围,以产生强大的剪切力。可以买到不同商标名称的许多不同型式的设备,这些设备可以提供足够的高剪切混合作用。
牛生长激素最好呈细粉状,并在比较和缓的情况下同均质化的载体混合。由于此产品是供注射的,因此生长激素的颗粒必须小到能够方便地通过皮下注射用针头。生长激素可以通过轻微搅拌同载体相混合,例如用螺旋浆式搅拌器等,但也可以在已经加入生长激素之后用高能混合,但必须注意防止局部发热和混合物通过混合机的高能区时受到过量的剪切力。
以下实例表明注射牛生长激素的优良持久释放期可达约28天。正如本发明的思想中可能显示的,可以认为两次注射之间的间隔28天,或甚至更长的间隔是方便的和经济的。因此,本配合料提供了注射牛生长激素的非常优良的方法。
根据本发明提供的能持久释放的配合料的下述一些特定实例,可以保证读者完全了解本发明和如何配制配合料。
实例1
将1800克芝麻油加热到约100℃,加入200克精炼的白蜂蜡。在恒温下搅拌此混合物直到蜡溶解于油中,然后冷却此混合物,同时不断进行轻微搅拌至约22℃。用一个Ultra-Turrax均化器均化此油-蜡混合物,直到混合物的稠度变得光滑和乳状为止,使其粘度下降。
在13.16克上述油-蜡混合物中,一边轻微搅动,一边于22℃加入2.83克的牛生长激素。该牛生长激素系根据0095361号欧洲公开专利中叙述的方法,由改性的大肠埃希尔氏杆菌培养物所合成。生长激素制备物是很纯的,对溶解物料进行光密度测定表明含有约75%的总蛋白质,对溶解物料用筛析色谱法测定表明其中约含95%的单体牛生长激素和有关物质。此配合料含有约12.6%的牛生长激素和有关物质。
实例2-7
以下实例系用实例1中叙述的方法完成的,为方便起见,兹将其成分列表如下。
载体 生长激素%
2.95%芝麻油和5%白蜂蜡 12.4
3.90%花生油和10%黄蜂蜡 12.6
4.99%花生油和1%黄蜂蜡 12.6
5.99%花生油和1%黄蜂蜡 12.6
6.99%花生油和1%黄蜂蜡 10.9
7.90%花生油和10%黄蜂蜡 12.6
8.90%硅酮(聚二甲基硅氧烷)
油,医药级350CS和
10%硅酮蜡(硬脂酸
氧三甲基硅烷-硬脂酰
醇) 12.6
9.90%硅酮油和10%硅酮蜡
(同实例8,但硅酮油系
食品级) 12.6
10.90%硅酮(聚苯基甲基硅氧
烷共聚物22.5CS)油
和10%硅酮蜡(硬脂
酸氧三甲基硅烷-硬脂
酰醇) 12.6
实例8-26
以下一组实例也是用实例1中叙述的相同步骤完成的,它说明了本发明的另一些实施例。
载体 生长激素%
11.90%花生油和10%黄蜂蜡 15
12.95%花生油和5%白蜂蜡 6
13.95%花生油和5%巴西棕榈蜡 35
14.87%豆油和13%巴西棕榈蜡 27
15.85%芝麻油和15%黄蜂蜡 9
16.97%棉籽油和3%白蜂蜡 5
17.92%棉籽油和8%巴西棕榈蜡 18
18.85%豆油和15%黄蜂蜡 22
19.80%西蒙得木油和20%硅酮蜡 30
20.82%棕榈油和18%石蜡 25
21.95%硅酮油和5%巴西棕榈蜡 20
22.93%橄榄油和7%蜂蜡 17
23.98%玉米油和2%西蒙得木蜡 32
24.89%杏仁油和11%西班牙草蜡 24
25.86%蓖麻油和14%日本蜡 14
26.83%矿物油和17%羊毛蜡 16
实例27
载体
89.80%芝麻油
9.98%白蜂蜡
0.02%棓酸丙酯
0.18%对羟苯甲酸甲酯
0.02%对羟苯甲酸丙酯
将成分混合,加热到约125℃,然后冷却到室温。按实例1中叙述的方法均化此冷却的混合物,再冷却到室温。在82份(重量计)的载体中。边轻微搅动边加入18份(重量计)按实例1的方法制备的牛生长激素制剂,这样便产生一种含12.8%牛生长激素和有关物质的配合料。
试验1
用荷斯坦奶牛试验本发明的配合料。试验开始时,这些母牛平均每天产奶56磅。试验组和对照组各7头牛。一头对照用牛因有创伤性胃炎而被排除,二头试验用牛则分别因创伤性胃炎和乳腺炎而被排除。牛是关在拴系厩舍中的,每天给二小时的室外活动,此时给厩舍打扫和更换垫草。
牛是不加限制随意采食的,饲料中含有60%的饲草(3份玉米青贮料和一份斩碎的苜蓿草)和40%精饲料,全部按干物料计。饲料中的精料部份有以下成分
成份 百分比(%)
干甜菜废丝 10.00
粗碎玉米 48.50
大豆油饼粉 33.10
石灰石 1.65
甘蔗糖蜜 3.50
磷酸二氢钠 1.05
维生素A、D3和E预混合料 0.35
硒预混合料 0.05
碳酸氢钠 0.75
微量元素的盐类 1.05
牛每天挤二次奶,分别间隔约11和13小时。记录产奶量,奶样用传统方法进行分析。
在经过14天的适应期之后,对试验组的牛进行皮下注射7.3克体内贮存注射用的实例6中的配合料,注射是使用14号针头进行的。第一次注射后第29天,这些牛再注射7.3克实例7中的配合料,在第一次注射后的第57天注射7.3克实例7中的配合料。
这样,此试验含有三个28天的持久释放期。
在从贮存注射释放生长激素后,接着测定试验牛的血浆中的牛生长激素的浓度。每周星期一和星期五用针刺从颈静脉或尾椎处取血试样,用双抗体放射免疫测定法分析这些试样。
对三个28天周期所得结果,各取平均值列入下表,其中平均分析值系以每毫升中牛生长激素的毫微克数表示的。对照组的值没有列入表中,因为在任何时候这些结果都在2.9-3.3毫微克/毫升的非常小的范围内。
天 生长激素浓度(毫微克/毫升)
2 128
5 171
9 109
12 86
16 54
19 43
23 27
26 20
正像从生长激素的非常好的释放所已经预期的那样,试验母牛的奶产量显著增加,它们的奶的成分正常。
试验2
在本试验中,试验组和对照组各用三头母牛。牛的管理和饲喂与试验1中叙述的方法相同,测定了结果并用试验1中相同的方法分析血浆中生长激素的含量。在对每头牛作贮存注射7.3克实例5中的配合料之后,试验继续29天。得到了以下这些结果。在此试验中,对照组牛的生长激素含量差异相当大,因此对照组的数据也列在表中。
天 生长激素浓度(毫微克/毫升)
对照组 试验组
0 5 6
2 9 225
4 7 106
6 10 81
8 20 50
10 17 49
12 14 47
14 15 38
16 13 34
18 8 25
20 18 31
22 10 17
24 6 21
29 7 17
试验3
本试验除去每一组只用三头牛之外,其它均按试验1中叙述的方法进行。不设对照组,但取预处理试样进行分析作为实验的对照。应用前面实例1、2和3中的配合料。每头牛在实验的第0天注射4.9克合适的配合料作为贮存注射。
在整个实验的不同日期取牛血样品,分析牛生长激素,结果如下。
生长激素浓度
天
实例1 实例2 实例3
(毫微克/毫升) (毫微克/毫升) (毫微克/毫升)
-5 2.9 3.6 3.3
-2 2.3 1.2 1.6
1 43 56 42
2 42 82 53
3 64 106 81
4 74 109 76
5 104 156 93
9 182 181 172
12 141 112 124
16 89 65 82
19 71 49 64
23 47 30 42
26 40 22 30
Claims (10)
1、可以注射的能持久释放牛生长激素的配合料,此配合料由悬浮在一种载体中的浓度为10-25%的牛生长激素组成,载体约含有1%到20%的一种蜡和80%到99%的一种油。
2、根据权利要求1的配合料,其中的油是一种植物油。
3、根据权利要求1的配合料,其中的蜡是植物蜡或动物蜡。
4、根据权利要求1的配合料,其中的载体是均质化的,约含有5%到15%的蜡。
5、根据权利要求4的配合料,其中的蜡是蜂蜡或巴西棕榈蜡。
6、根据权利要求1的配合料,其中的油是花生油或芝麻油。
7、根据权利要求5的配合料,其中的油是花生油或芝麻油。
8、根据权利要求7的配合料,其中的载体是均质化的,约含有5%到10%的蜡。
9、根据权利要求1的配合料,其中的生长激素是由遗传改性的微生物所合成的。
10、权利要求1的配合料的应用,其中对奶牛注射一次所述配合料可持续28天增加牛奶的日产量。
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US2493202A (en) * | 1946-06-07 | 1950-01-03 | Merck & Co Inc | Process of making a fluid oil-beeswax vehicle for the parenteral administration of drugs |
BE795516A (fr) * | 1972-02-17 | 1973-08-16 | Ciba Geigy | Preparations de peptides huileuses et injectables et procede pour leur preparation |
EP0085036A1 (en) * | 1982-01-18 | 1983-08-03 | Monsanto Company | Method for improved bovine milk production |
US4521409A (en) * | 1983-10-03 | 1985-06-04 | Cornell Research Foundation, Inc. | Use of growth hormone to enhance ruminant mammary development |
ES8702440A1 (es) * | 1984-10-04 | 1986-12-16 | Monsanto Co | Un procedimiento para la preparacion de una composicion de polipeptido inyectable sustancialmente no acuosa. |
IL79681A (en) * | 1985-08-12 | 1991-06-10 | Int Minerals & Chem Corp | Transition metal complexes of growth hormones and their prolonged release compositions |
US4775659A (en) * | 1985-08-19 | 1988-10-04 | Eli Lilly And Company | Injectable semi-solid formulations |
-
1986
- 1986-08-18 IL IL79765A patent/IL79765A/xx not_active IP Right Cessation
- 1986-08-18 ZA ZA866218A patent/ZA866218B/xx unknown
- 1986-08-18 CA CA000516146A patent/CA1285874C/en not_active Expired - Lifetime
- 1986-08-19 SU SU4028010A patent/SU1683493A3/ru active
- 1986-08-19 NZ NZ217267A patent/NZ217267A/xx unknown
- 1986-08-20 PH PH34167A patent/PH25861A/en unknown
- 1986-08-20 EP EP86306454A patent/EP0211691A3/en not_active Withdrawn
- 1986-08-20 EG EG530/86A patent/EG17979A/xx active
- 1986-08-20 CN CN86105087.8A patent/CN1006197B/zh not_active Expired
- 1986-08-20 DK DK396286A patent/DK396286A/da unknown
- 1986-08-21 AU AU61700/86A patent/AU591516B2/en not_active Ceased
- 1986-08-21 JP JP61197004A patent/JPS6251624A/ja active Pending
- 1986-08-22 HU HU863652A patent/HU195425B/hu not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
AU6170086A (en) | 1987-02-26 |
PH25861A (en) | 1991-12-02 |
EG17979A (en) | 1992-06-30 |
DK396286D0 (da) | 1986-08-20 |
CN86105087A (zh) | 1987-03-04 |
HUT41637A (en) | 1987-05-28 |
EP0211691A3 (en) | 1987-06-03 |
JPS6251624A (ja) | 1987-03-06 |
SU1683493A3 (ru) | 1991-10-07 |
HU195425B (en) | 1988-05-30 |
NZ217267A (en) | 1989-02-24 |
IL79765A (en) | 1992-02-16 |
ZA866218B (en) | 1988-03-30 |
DK396286A (da) | 1987-02-24 |
AU591516B2 (en) | 1989-12-07 |
CA1285874C (en) | 1991-07-09 |
EP0211691A2 (en) | 1987-02-25 |
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