CN1069214C - 非肠道给药的稳定的生长激素 - Google Patents
非肠道给药的稳定的生长激素 Download PDFInfo
- Publication number
- CN1069214C CN1069214C CN93108908A CN93108908A CN1069214C CN 1069214 C CN1069214 C CN 1069214C CN 93108908 A CN93108908 A CN 93108908A CN 93108908 A CN93108908 A CN 93108908A CN 1069214 C CN1069214 C CN 1069214C
- Authority
- CN
- China
- Prior art keywords
- complex
- growth hormone
- weight
- pst
- pig
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 102000018997 Growth Hormone Human genes 0.000 title claims abstract description 22
- 108010051696 Growth Hormone Proteins 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000000122 growth hormone Substances 0.000 claims abstract description 19
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 18
- 241001465754 Metazoa Species 0.000 claims abstract description 14
- 239000007943 implant Substances 0.000 claims description 15
- 101000868144 Sus scrofa Somatotropin Proteins 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- TUBUGIPAUYMXPQ-UHFFFAOYSA-N formaldehyde;2-methoxyphenol Chemical group O=C.COC1=CC=CC=C1O TUBUGIPAUYMXPQ-UHFFFAOYSA-N 0.000 claims description 6
- -1 methoxyl group Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 3
- 150000001299 aldehydes Chemical class 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 241000283073 Equus caballus Species 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000000384 rearing effect Effects 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 101000664736 Equus caballus Somatotropin Proteins 0.000 claims 1
- 101000868138 Ovis aries Somatotropin Proteins 0.000 claims 1
- 150000003935 benzaldehydes Chemical class 0.000 abstract 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 abstract 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 241000282898 Sus scrofa Species 0.000 description 16
- 230000003203 everyday effect Effects 0.000 description 12
- 241000282887 Suidae Species 0.000 description 9
- 210000002381 plasma Anatomy 0.000 description 7
- 230000036528 appetite Effects 0.000 description 5
- 235000019789 appetite Nutrition 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 210000003128 head Anatomy 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 2
- 108010052968 leupeptin Proteins 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 235000019753 Finisher Diet Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000006056 finisher diet Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical group COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/61—Growth hormone [GH], i.e. somatotropin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Toxicology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Fodder In General (AREA)
- Feed For Specific Animals (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Cultivation Of Plants (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
一种含有生长激素和芳香醛的稳定的复合物。特别是,该复合物含有猪生长激素和一种取代的苯甲醛并提供一种持续释放该生长激素且改善动物饲养率的方法。
Description
本发明涉及一种含有生长激素(也称为促生长素)和芳香醛的复合物。更具体地说,本发明涉及一种猪生长激素(PST)-芳香醛复合物以及生产一种可改善猪的饲养率(feed efficiency)并使PST持续释放的稳定的PST组合物的方法。
当每天以显著提高饲养率(即饮料与增量比)的基量(basis)给猪使用猪生长激素(PST)时,与对照动物相比,服药动物进食较少而体重增加却相同或较高。然而,由于给一大批动物中的每只提供该药物需要很高的代阶和大量的时间,每天以基量给猪服药是很麻烦的。因此,使用单剂量并在一个较长时期内释放PST会更为方便。服用PST最容易的方法似乎是放入饲料中。然而,象大多蛋白质和大分子药物一样,PST口服不被生物吸收。一般地,文献中没有描述过经口服途径提供蛋白质类和肽类的重要性。在欧州申请0177342中公开了使用水杨性酸盐和矿物油类来提高这些药物的口腔释放。美国专利4,548,922,还公开了使用甾类化合物增强剂如梭链孢酸。
非肠道给药,例如植入剂已用于其它大分子药物而得到了如美国专利4,666,704号中所公开的持续性释放效果。PST是一种不稳定的蛋白,易被酶解和水解。它自身能够反应并容易被蛋白酶裂解。的确,PST植入剂的不稳定性被认为是因在植入部位发生炎性反应而生成蛋白酶的缘故(美国专利5,015,627)。因为这种不稳定性,给猪使用PST,至今为止,即使真正成功,也仅是勉强地(如见美国专利4,837,381;4,857,505;5,045,312,和欧州申请0193917和0458064)。
商业上需要改进具有生长激素活性的大分子药物非肠道给药的持续释放植入剂。
所以,本发明一个目的就是提供一种在动物体内长时期稳定并释放生物活性的生长激素的组合物及制备方法。
本发明的另一个目的是提供一种PST的稳定形式,它能在猪体内长时期释放并使生物利用度和饲养率得到改善。
按照本发明,已发现当PST与一种芳香醛反应而形成一种复合物时,可提高动物的饲养率(即,增重以及饲料与增重比)。这种新的复合物不仅具有与PST相同的生物活性,也在一个持续时期内提供了类似于每天注射PST的效力。
如上所述,已进行了许多尝试来制备一种PST产品,使它能克服上述所提到的不足并能成功地给猪使用。例如,美国专利5,015,627公开了PST和亮肽素(一种三肽醛)以干粉形式混合,制粒并由该颗粒形成植入剂。这些植入剂是无效的。
意外地发现,当将PST和一种本发明的芳香醛溶于水中并从该溶液中分离复合物,所得到的结晶产物能使该生长激素持续释放。该复合物可以从水溶液中采用现有技术公知的任何方法来分离,例如,浓缩、蒸发、或冷冻干燥。由该复合物制备植入剂并给予猪,可使血浆PST水平持续长达7天。
其中X是CHO或CH2CHO,而R1和R2各自是氢、羟基、甲氧基、乙氧基、甲基或乙基。
体现在复合物和本发明方法中优选的芳香醛是式I的化合物,其中X是CHO而R1和R2各自为羟基或甲氧基。体现在复合物和本发明方法中最佳的芳香醛是2-羟基-3-甲氧基苯甲醛。该醛也常称为邻一香草醛。
制备本发明稳定的PST复合物所采用的芳香醛及其制备方法是
现有技术中公知的。
在本发明优选体现的复合物中也含有一种动物生长激素,例如,人、牛、鸟、猪、马或羊的生长激素。有利地,该复合物和方法适用于猪的生长激素。
最有利地,本发明的复合物含有2-羟基-3-甲氧基苯甲醛和猪生长激素。
式I的芳香醛可以约0.5%到约10%(按重量计)的含量存在于该复合物中。优选地,该芳香醛以约0.5%到约5.0%(按重量计)存在。
本发明的式I芳香醛和PST复合物是如下制备的:
实施例1
猪生长激素 99.0%w/w
式I的芳香醛 1.0%w/w
将该PST和醛溶于水中,并在39℃下反应6到24小时,慢慢将水分离并把所得到的产物悬浮于乙醇中。过滤该悬浮液并在一个真空箱中过夜干燥该沉淀,得到干燥的晶体。
把该晶体复合物用一台3/16英寸冲压机和冲模制成35mg小丸(植入剂)并压制约500个PST:
实施例2
猪生长激素 99.0w/w
2-羟基-3-甲氧基苯甲醛 1.0%w/w
按实施例1中的方法制备该复合物和植入剂。
实施例3
猪生长激素 99.0w/w
4-羟基-3-甲氧基苯甲醛 1.0%w/w
实施例4
猪生长激素 99.0w/w
4-甲氧基苯甲醛 1.0%w/w
按照实施例1的方法制备上述复合物。
小丸或植物剂的形状并不重要,任何适于植入的形状都可使用。除该生长激素和该芳香醛外,本发明组合物中包括其它药物赋形剂也是有益的。例如,该植入剂可以包含润滑剂,如,硬脂酸镁或硬脂酸;填充剂,如,蔗糖或乳糖以及粘合剂,如阿拉伯胶、聚乙烯吡咯烷酮或明胶。
本发明组合物可以采用任何已知植入的方法非肠道给予动物,如皮下、肌肉内、腹膜内。优选地,使用任一公知技术给动物皮下植入该植入剂组合物。
用此方法处理的动物可以包括(并不局限于此)哺乳动物如牛、羊、山羊、猪等,和鸟如家禽。
以下方法是用来测定血浆PST水平,耗食量,平均每日增量以及饲料与增量比。
把猪圈在谷仓中并于每圈有7-8头猪的圈中适应3-4周。在各圈中,猪都有进入热棚和随意进食和饮水的机会。
当这些大多数猪达到约75Kg重时,统计比较其体重并分为4个不同的处理组,每组9头猪。起始日计为0天,记录这天的体重,取对照血样并引入植入剂。在21天结束时,停止这些猪的实验。
使用一种商业上出售的家畜植入注射器给这些猪的耳后皮下注入1个小丸(取决于治疗组)并用70%EtoH擦净给药部位。在颈部用11/2英寸16g针头以5mg/头/天给猪每天注射。如下处理;
1.对照-假植入剂。
2.PST-每天注射-(5mg/头/天)
3.PST-邻-香草醛植入剂-1小丸(35mg PST)
4.PST-亮肽素植入剂-1小丸(35mg PST)。
用一只有11/2英寸针头的Vacutainer从捕获的猪颈脉抽取血样。把该血液凝固,离心并分出血浆。冷冻该血浆试样为日后测定PST所用。耗食量(feed Consumption)
在整个实验过程中所有的猪得到Enhanced Finisher diet#634。在0天,给喂料器中加入两袋饲料并称得起始重量。每天检查该喂料器并按需(不允许喂料器空着)加入一袋预先称重的饲料。记下从圈中除去所有猪当天的喂料器的最终重量。用初始重量减去最终重量并与所加的总饲料相加得每圈的总耗食量。
喂料器的初始重量
- 喂料器的最终重量
总量
每圈的总耗食量
在0天和整个实验中的七天间隔时分别给这些猪称重(用千克表示)。每天增量总平均值是从这些猪的最终重量减去在0天的初始重量并除以实验的天数得到的。
在实验过程中每圈的饲料与增量比是由每圈所有耗食量相加并除以每圈的总的体重增加量得到的。下表显示了平均每天的增量(ADG)和饲料与增量比的结果:
表1
平均每天 与对照相比 饲料与增量 对照PST处理组 增量(Kg) 增长的百分率 的比 的百分率对照(无PST) 0.71 ~ 4.4 ~5mg/头/天 0.86 21 2.7 39邻-香草醛/PST(1小丸) 0.79 11.9 3.52 21
(35mg)亮肽素/PST(1小丸) 0.70 -1.4 4.12 0
(35mg)
血浆中PST水平结果:每天注射PST 24小时后(如果有的话)血浆PST水平是非常小的。相对应的,本发明小丸植入后,表现出一个持续的血浆PST水平。
以上结果清楚表明当用植入法给予猪邻-香草醛/PST复合物时,在这些猪中所观察的平均每日增量和饲料与增量比较对照组都有所增加。
而且,该结果表明在此PST中不需加入蛋白酶抑制剂。我们现在看到一种非蛋白酶抑制剂(邻-香草醛)以一种积极的方式与PST相互作用而能够在21天期间内维持功效。
按照本发明的方法包括以一个足以延长PST血液水平并提高饲养率的量的上述PST-芳香醛复合物非肠道给予动物体。该剂量取决于好几种因素,例如,动物的大小和所需的效果。至于给予猪,该复合物优选为10mg到约500mg的用量,更好地为约30mg到约75mg,以约7到约42天的间隔给予相同剂量。
Claims (11)
2.权利要求1的复合物,其中复合物中芳香醛的含量为1重量%,生长激素的含量为99重量%。
3.权利要求1的复合物,其中X是CHO而R1和R2各自是羟基或甲氧基且生长激素选自猪、牛、鸟、马和羊生长激素。
4.权利要求3的复合物,其中醛是2-羟基-3-甲氧基苯甲醛而生长激素是猪生长激素。
5.一种提高动物饲养率的方法,它包括给予动物体内足以产生所述功效的量的权利要求1的复合物。
6.权利要求5的方法,其中复合物是猪生长激素和2-羟基-3-甲氧基苯甲醛。
7.权利要求5的方法,其中复合物的使用量是从约10mg到约500mg。
8.权利要求5的方法,其中复合物是以一种植入剂皮下约药。
9.权利要求7的方法,其中以约7到42天的间隔进行给药。
10.权利要求5的方法,其中复合物中芳香醛的含量为0.5-10重量%,生长激素的含量为90-99.5重量%。
11.权利要求10的方法,其中复合物中芳香醛的含量为1重量%,生长激素为99重量%。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/896,958 US5198422A (en) | 1992-06-11 | 1992-06-11 | Stabilized somatotropin for parenteral administration |
US896,958 | 1992-06-11 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1085804A CN1085804A (zh) | 1994-04-27 |
CN1069214C true CN1069214C (zh) | 2001-08-08 |
Family
ID=25407118
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN93108908A Expired - Fee Related CN1069214C (zh) | 1992-06-11 | 1993-06-11 | 非肠道给药的稳定的生长激素 |
Country Status (20)
Country | Link |
---|---|
US (1) | US5198422A (zh) |
EP (1) | EP0644770B1 (zh) |
JP (1) | JP3247380B2 (zh) |
KR (1) | KR100269896B1 (zh) |
CN (1) | CN1069214C (zh) |
AT (1) | ATE175355T1 (zh) |
AU (1) | AU670805B2 (zh) |
CA (1) | CA2137677C (zh) |
DE (1) | DE69322958T2 (zh) |
DK (1) | DK0644770T3 (zh) |
ES (1) | ES2125990T3 (zh) |
GR (1) | GR3029291T3 (zh) |
HU (1) | HU223944B1 (zh) |
IL (1) | IL105958A (zh) |
NO (1) | NO314784B1 (zh) |
NZ (1) | NZ253914A (zh) |
PL (1) | PL175971B1 (zh) |
TW (1) | TW341513B (zh) |
WO (1) | WO1993025222A1 (zh) |
ZA (1) | ZA934100B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA949350B (en) | 1994-01-25 | 1996-05-24 | Upjohn Co | Aqueous prolonged release formulation |
KR19990071255A (ko) | 1998-02-28 | 1999-09-15 | 성재갑 | 소마토트로핀과 비타민의 합제 조성물 |
IL139585A0 (en) * | 1998-06-26 | 2002-02-10 | Pfizer Prod Inc | Improved process for preparing schiff base adducts of amines with 0-hydroxy aldehydes and compositions of matter based thereon |
US20080113025A1 (en) * | 1998-11-02 | 2008-05-15 | Elan Pharma International Limited | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
JP2001316294A (ja) * | 2000-03-14 | 2001-11-13 | Pfizer Prod Inc | o−バニリンおよびo−バニリン/テトラメチルクロマニルカルボン酸化合物の組み合わせの使用法 |
CN100369953C (zh) * | 2002-09-09 | 2008-02-20 | 尼克塔治疗亚拉巴马公司 | 水溶性聚合物链烷醛 |
SG176314A1 (en) | 2002-12-31 | 2011-12-29 | Altus Pharmaceuticals Inc | Human growth hormone crystals and methods for preparing them |
CA2512001A1 (en) * | 2002-12-31 | 2004-07-22 | Altus Pharmaceuticals Inc. | Complexes of protein crystals and ionic polymers |
TWI429436B (zh) * | 2007-04-10 | 2014-03-11 | Helsinn Therapeutics Us Inc | 使用生長激素促泌素治療或預防嘔吐之方法 |
CN102015606B (zh) | 2007-06-08 | 2015-02-04 | 满康德股份有限公司 | IRE-1α抑制剂 |
ITMI20130341A1 (it) | 2013-03-07 | 2014-09-08 | Gm Morando S R L | Sistema schermante modulare |
CN108883066A (zh) * | 2016-01-29 | 2018-11-23 | 日产化学株式会社 | 控制了水溶性有效成分的释放的经皮吸收组合物 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1043631A (zh) * | 1988-12-13 | 1990-07-11 | 孟山都公司 | 用于控制释放多肽的组合物 |
US5015627A (en) * | 1990-07-20 | 1991-05-14 | Smithkline Beecham Corporation | Stabilized somatotropin for parenteral administration |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1296253C (en) * | 1986-10-20 | 1992-02-25 | Praveen Tyle | Stabilized growth hormone compositions |
-
1992
- 1992-06-11 US US07/896,958 patent/US5198422A/en not_active Expired - Lifetime
-
1993
- 1993-06-08 IL IL105958A patent/IL105958A/xx not_active IP Right Cessation
- 1993-06-10 ZA ZA934100A patent/ZA934100B/xx unknown
- 1993-06-11 JP JP50176894A patent/JP3247380B2/ja not_active Expired - Fee Related
- 1993-06-11 EP EP93915333A patent/EP0644770B1/en not_active Expired - Lifetime
- 1993-06-11 CN CN93108908A patent/CN1069214C/zh not_active Expired - Fee Related
- 1993-06-11 HU HU9403548A patent/HU223944B1/hu not_active IP Right Cessation
- 1993-06-11 DK DK93915333T patent/DK0644770T3/da active
- 1993-06-11 NZ NZ253914A patent/NZ253914A/en not_active IP Right Cessation
- 1993-06-11 CA CA002137677A patent/CA2137677C/en not_active Expired - Fee Related
- 1993-06-11 AU AU45354/93A patent/AU670805B2/en not_active Ceased
- 1993-06-11 ES ES93915333T patent/ES2125990T3/es not_active Expired - Lifetime
- 1993-06-11 DE DE69322958T patent/DE69322958T2/de not_active Expired - Fee Related
- 1993-06-11 AT AT93915333T patent/ATE175355T1/de not_active IP Right Cessation
- 1993-06-11 PL PL93306726A patent/PL175971B1/pl not_active IP Right Cessation
- 1993-06-11 WO PCT/US1993/005659 patent/WO1993025222A1/en active IP Right Grant
- 1993-06-11 KR KR1019940704517A patent/KR100269896B1/ko not_active IP Right Cessation
- 1993-08-17 TW TW082106587A patent/TW341513B/zh active
-
1994
- 1994-12-09 NO NO19944782A patent/NO314784B1/no not_active IP Right Cessation
-
1999
- 1999-02-03 GR GR990400371T patent/GR3029291T3/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1043631A (zh) * | 1988-12-13 | 1990-07-11 | 孟山都公司 | 用于控制释放多肽的组合物 |
US5015627A (en) * | 1990-07-20 | 1991-05-14 | Smithkline Beecham Corporation | Stabilized somatotropin for parenteral administration |
Also Published As
Publication number | Publication date |
---|---|
NO314784B1 (no) | 2003-05-26 |
DE69322958T2 (de) | 1999-05-27 |
ZA934100B (en) | 1994-06-10 |
JP3247380B2 (ja) | 2002-01-15 |
JPH07508003A (ja) | 1995-09-07 |
AU670805B2 (en) | 1996-08-01 |
IL105958A0 (en) | 1993-10-20 |
HUT68917A (en) | 1995-08-28 |
DE69322958D1 (de) | 1999-02-18 |
DK0644770T3 (da) | 1999-08-30 |
EP0644770B1 (en) | 1999-01-07 |
EP0644770A4 (en) | 1995-10-25 |
WO1993025222A1 (en) | 1993-12-23 |
NZ253914A (en) | 1997-12-19 |
CN1085804A (zh) | 1994-04-27 |
NO944782D0 (no) | 1994-12-09 |
HU9403548D0 (en) | 1995-02-28 |
EP0644770A1 (en) | 1995-03-29 |
ES2125990T3 (es) | 1999-03-16 |
IL105958A (en) | 1997-11-20 |
ATE175355T1 (de) | 1999-01-15 |
NO944782L (no) | 1994-12-09 |
GR3029291T3 (en) | 1999-05-28 |
KR100269896B1 (ko) | 2000-10-16 |
PL175971B1 (pl) | 1999-03-31 |
HU223944B1 (hu) | 2005-03-29 |
CA2137677C (en) | 1998-08-25 |
US5198422A (en) | 1993-03-30 |
AU4535493A (en) | 1994-01-04 |
CA2137677A1 (en) | 1993-12-23 |
TW341513B (en) | 1998-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1051716C (zh) | 生长激素延缓释放 | |
CN1069214C (zh) | 非肠道给药的稳定的生长激素 | |
EP0462959A1 (en) | Coated veterinary implants. | |
US4333919A (en) | Growth promotant controlled release formulations and method of treatment | |
US5015627A (en) | Stabilized somatotropin for parenteral administration | |
CN86105023A (zh) | 延长生长促进激素的释放 | |
EP0289186A2 (en) | Process for increasing the growth rate and enhancing the feed efficiency of meat producing livestock | |
CN1279981C (zh) | 作为甲状旁腺激素片段的口服递送剂的5-cnac | |
JP4616556B2 (ja) | ポリ酒石酸エステル組成物 | |
JP2952280B2 (ja) | ブタ成長促進 | |
JPH03500243A (ja) | 2‐デオキシ‐d‐ヘキソースの経口投与による産肉性動物の飼料要求率の改良方法 | |
DE69305091T2 (de) | Methode zur behandlung oder verhütung von fettleibigkeit | |
WO2003013495A1 (en) | Formulation and method for reduction of stress in meat-producing animals | |
JPS6368033A (ja) | 鳥類に換羽を誘発する方法 | |
HU204696B (en) | Process for producing ractopamin growth hormone combination | |
JP4195865B2 (ja) | 水生生物の成長促進および病気に対する抵抗力の向上のための方法 | |
RU2073461C1 (ru) | Способ повышения продуктивности молодняка овец | |
AU603187B2 (en) | Estriol growth promotant | |
Teskeredžić et al. | Intact protein absorption by the fish gut. 2. Application potential and limitations | |
HU204703B (en) | Process for producing composition having synergetic effect and usable in animal husbandry | |
NL8103855A (nl) | Bij het kweken van dieren te gebruiken preparaten en werkwijze voor het vetmesten van varkens. | |
JPH0672096B2 (ja) | 骨改善剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Applicant after: Pfizer Inc. Applicant before: Smithkline Beechan Corp. |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: SMITHKLINE BEECHAM CORP. TO: PFIZER INC. |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20010808 Termination date: 20100611 |