WO2010145125A1 - Highly purified human menopausal gonadotropins, method for preparing and uses thereof - Google Patents

Highly purified human menopausal gonadotropins, method for preparing and uses thereof Download PDF

Info

Publication number
WO2010145125A1
WO2010145125A1 PCT/CN2009/075277 CN2009075277W WO2010145125A1 WO 2010145125 A1 WO2010145125 A1 WO 2010145125A1 CN 2009075277 W CN2009075277 W CN 2009075277W WO 2010145125 A1 WO2010145125 A1 WO 2010145125A1
Authority
WO
WIPO (PCT)
Prior art keywords
purity
gonadotropin
dye
low
solution
Prior art date
Application number
PCT/CN2009/075277
Other languages
French (fr)
Chinese (zh)
Inventor
郭照晔
洪云海
季斌
严惠敏
高霄梁
季晓铭
Original Assignee
上海天伟生物制药有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 上海天伟生物制药有限公司 filed Critical 上海天伟生物制药有限公司
Publication of WO2010145125A1 publication Critical patent/WO2010145125A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/24Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/06Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14Extraction; Separation; Purification
    • C07K1/16Extraction; Separation; Purification by chromatography
    • C07K1/22Affinity chromatography or related techniques based upon selective absorption processes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575Hormones
    • C07K14/59Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]

Definitions

  • the gonadotropin H ae opa sa o ado op s, H contains fo cesag ho oe FH and eze gho oe LH active ingredients, which are caused by the rest of the protein hormones FH's "and LH, chorionic gonadotropin (cho oc go ado op)" is the same amino acid with 92 amino acids at 1450 D 52 and 78.
  • the FH is composed of 11 amino acids. 1800 D where 7 and 24 are the base amino acids, while LH is composed of 121 amino acids at 14800D and 145 amino acids at 22000 390 D
  • Bed H should be used for it, or it can be taken from the urine of a woman or DN wood.
  • the first generation containing F H is (H ) such as e o o Pe Go a which is a mixture of F H LH ratio 1.
  • H the active ingredient in the purity of 40 300 U g protein is only 2 3.
  • the rest are egg white. Because of the high protein content, there are potential side effects.
  • the method can only be limited to muscle injection.
  • High purity (PH) is particularly desirable in the art. It is also of high purity and low content, and does not contain a large amount of protein. Therefore, it does not cause a person to rest and because it can be used to improve the patient by subcutaneous injection.
  • This aim is to provide high purity, low purity methods.
  • Another purpose of this is to provide high purity obtained by the above method.
  • a further object of the present invention is to provide a high purity H compound obtained by the above method.
  • a high purity gonadotropin ed H aMe opa sa Go ado op s is provided, the PH HP purity is not less than 95, the HPL content is not 5 HPL, the purity is not less than 96 HPL, and the content is not 4
  • the gonadotropin or gonadin or the source of gonadotropin or Hugh.
  • the proportion of follicle stimulating hormone F H to form LH is 1 0.5 1.4.
  • a method of each of the methods of providing a high purity gonadotropin pH as described above comprising the step of operating a low purity H dye which is not purified and a high purity gonadotropin to a low purity H at 2000 FH 9 protein. the following.
  • pH6-1 gives high purity gonadotropins.
  • step 3 In another solution from acetic acid, acetic acid, Na H, T s H or phosphoric acid. In the other step, the next step is included in step 3.
  • the dye is not separated from bac o B e a ge , ee
  • the solid phase of the dye is not precipitated from soil, glass micro, quartz micro, calcium phosphate, oxidized, polypropylene, , , or .
  • the dye is not and precipitated from B e epha oseFF or B e epha OSe 6B.
  • the compound of the present invention provides an effective amount of the high purity gonadotropin as provided above and the above. Acceptable rest.
  • the high purity gonadotropin is not integrated. This product provides high-purity gonadotropins obtained by high-purity, high-purity methods for subcutaneous injection for patient use.
  • HPL purity HPL content 5 is currently known to have the highest purity of H and the biological ratio of FH and LH can be within the required solids such as 1 0.1 1 3 .
  • Hugh's low purity H dye is not purified and is high Purified gonadotropin.
  • low purity means that the organism H below 200 FHU 9 is at 40 50 FHU 9.
  • Low purity H can be obtained by methods well known in the art, such as, but not limited to, high soil adsorption in urine, ah, ethanol solution, including 10,000 It can also be obtained from the water. It can also be obtained from this channel.
  • the biological ratio of FH and H in low purity H is 1 0.1 3 and the solid content is 1 0.5 1.4.
  • the gonads ", " and H” used in this paper can be used. It refers to a protein hormone that is released by life or contains active ingredients of FH and LH. Can be a gonadin or a resting person, or a human source
  • follicle stimulating hormone "and FH” can be used to refer to a hormone that promotes or follicles, promotes ovarian ovarian hormones, or can be extracted from the urine of a woman who can be secreted before the break in natural conditions. Got it.
  • serotonin and "LH” can be used to refer to a hormone or sputum that is secreted by premenstrual cells and acts on mature ovulation.
  • the methods of providing high purity gonadotropins of this invention are the purification of low purity H dyes.
  • the method of each high purity gonadotropin in this one includes steps
  • a solution containing low purity H is applied to the dye and the supernatant and 2 pH 6 11 to obtain a high purity gonadotropin.
  • the dye is not precipitated and can be well known in the art such as, but not limited to, ee, ag.
  • Residence B e residence B e epha ose 6B live in a solution of 0.01 5 from acetic acid solution, Na H solution, or T s H solution.
  • a solution containing low purity H onto a low-purity H solution on the undegraded B e ephaose is to dissolve low purity H at pH 4 8
  • step v Of or sulphuric acid, which is from Na, K, or generally used in the same step in step v and step v
  • the low purity H solution in the high purity gonadotropin method provided herein is a solution of low purity H dissolved in 0.01 0.03 acetic acid to obtain a solution containing low purity H. 4 8 high gonads pHMG
  • the method can obtain high purity gonadotropin HP content 5 living land HPL content 4
  • wood acceptable rest includes various forms and dilutions.
  • the woods themselves are not essential active ingredients and are not applied.
  • He is known as Re go 'ha ace, which is well known in the art.
  • Ca ce ce ack b. Co. .J. 1991) can be found in the above-mentioned acceptable shape.
  • the acceptable rest in the compound includes water, water, and ethanol. Sexual things such as, conditions, emulsification, p, etc.
  • the compounds can vary from one to the other.
  • Oral, topical, non-subcutaneous, intravenous, and intramuscular injection or input or by means of an external device may be administered in one of the following ways. Among them, the subcutaneous injection method.
  • the high-purity gonadotropin obtained by the present method can be used for various uncombined administrable applications including (but not limited to), subcutaneous injection, and the like. Apply by subcutaneous injection. The form of application is matched. The amount of application of the active substance is usually 0.01 5 ug kg per day compared with the place of residence 0.05 0. g kg rest 0.2 0. g kg rest.
  • the percentage of the vertical break in the present invention is well known in the art, for example, in the 100 ml solution.
  • the ratio of H or pH in the present invention refers to how much F H or LH in the milligram protein.
  • the method for determining the protein content is based on y or derived methods.
  • the HPL purity or HPL content in this specification refers to the percentage of the surface method.
  • the method for determining the purity of gonads in the present invention is 2.5
  • Each of the high-gonadin 1 uses low-purity H (from Shanghai Bio-Bio Co., Ltd.) as the starting material for p.
  • the organism of F is 273 U g LH of the organism 319 U g
  • the biological method is determined according to the method of mercury and mercury N in 2005. F H LH organism.
  • Each high purity gonadotropin 11 loads 5 LB e epha ose 6B (from E e sha ) (0.02 acetic acid pH 7.0) equilibrated.
  • the biological method is determined according to the method of mercury and mercury N in 2005. F H LH organism.
  • Protein content determination method Lo y Protein content determination method
  • the upper solution was dispensed into 0.75 frozen bottles per bottle.
  • the obtained ones were 75 F H 75 LH and 9 lactose per bottle.
  • the preferred content of the above-mentioned power is not to limit the wood content of the solid content of the wood content, but also the requirement that the solid wood or the method of any other person to complete the same or the same The history of the exchange will be fixed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Reproductive Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Diabetes (AREA)
  • Analytical Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Provided is a type of highly purified human menopausal gonadotropin, the HPLC purity of which is not less than 95%, and the impurity HPLC content of which is not more than 5%. Also provided are the preparing method and uses of the said highly purified human menopausal gonadotropin.

Description

高 性腺素及其制各方法和用途 木領域  High-gonadin and its methods and uses
本 涉及蛋白 純化和生物 領域。 休而 本 涉及 高 純度 性腺素及其制各方法和用途。 背景 木  This relates to the field of protein purification and biology. Hugh and involve high purity gonadotropins and their methods and uses. Background
性腺素 H a e opa sa o ado op s, H 含有卵 泡刺激素 (Fo c e s a g ho o e F H)和 休生成激素( e e z gho o e LH)西神活性成分 它們是由 休 生的 蛋 白激素 都是由" 和 西 並 。 F H的"並 LH、 絨毛膜 性 腺素(cho o c go ado op )的"並 金相同 具有 92 氨 基酸 于 1450 D 52和 78 上的天 是 基化 的氨基酸。 F H的 並 由 11 氨基酸 于 1800 D 其中7和 24 上的天 是 基化的氨基酸。 而 LH的 並 由 121 氨基酸 于 14800D 的 並 則有 145 氨基酸 于 22000 390 D  The gonadotropin H ae opa sa o ado op s, H contains fo cesag ho oe FH and eze gho oe LH active ingredients, which are caused by the rest of the protein hormones FH's "and LH, chorionic gonadotropin (cho oc go ado op)" is the same amino acid with 92 amino acids at 1450 D 52 and 78. The FH is composed of 11 amino acids. 1800 D where 7 and 24 are the base amino acids, while LH is composed of 121 amino acids at 14800D and 145 amino acids at 22000 390 D
床上H 要用于 不 它可以 休或 女的尿液中 提取出 也可 DN 木而 各。  Bed H should be used for it, or it can be taken from the urine of a woman or DN wood.
含有F H的第一代 是 (H ) 如 e o o公司的Pe go a 它是 F H LH 比例 1 的混合物。 但是它的比 和純度都很低 比 一 般在40 300 U g蛋白 純度只有2 3 的有效成分 其余 都是 蛋 白 由于 蛋白含量大 休有潛在的副作用 方式也只能局限于肌 肉注射。 高純度的 (PH )是本領域 特別需要的 它 尚純度高、 少 不含有大量的 蛋白 因此不合造成人休的 反 且由于 它可以使用皮下注射 提高患者的 。  The first generation containing F H is (H ) such as e o o Pe Go a which is a mixture of F H LH ratio 1. However, its ratio and purity are very low. Generally, the active ingredient in the purity of 40 300 U g protein is only 2 3. The rest are egg white. Because of the high protein content, there are potential side effects. The method can only be limited to muscle injection. High purity (PH) is particularly desirable in the art. It is also of high purity and low content, and does not contain a large amount of protein. Therefore, it does not cause a person to rest and because it can be used to improve the patient by subcutaneous injection.
但是 pH 的純化很有 由于它同 含有F H和 LH西神成分 而 且需要西者 一定的比例 而 F H和 LH 的 又不相同 因此在 期的純化 中很容易使西者 萬 而 不到 的比例 在pH 的純化中尤其突出 目前 沒有夫于百接 得高純度 H 的方法的 。  However, the purification of pH is very much due to the fact that it has a certain ratio of FH and LH and needs a certain proportion of the west, but the FH and LH are different. Therefore, in the purification of the period, it is easy to make the proportion of the western in the pH. In the purification, in particular, there is no way to obtain high purity H.
因此本領域迫切需要 出一 各純度高、 少的高純度 H 的方 法 便于使用于皮下注射 方便患者的使用、 。 內容 Therefore, there is an urgent need in the art for a method of high purity and low purity of H to facilitate use in a patient for subcutaneous injection. content
本 旨在提供 純度高、 少的高純度 的 各方法。  This aim is to provide high purity, low purity methods.
本 的另一介目的是提供由上 方法純化得到的高純度  Another purpose of this is to provide high purity obtained by the above method.
本 的又一介目的是提供由上 方法純化得到的高純度 H 的 合物。  A further object of the present invention is to provide a high purity H compound obtained by the above method.
本 的 一介目的是提供由上 方法純化得到的高純度 H 的用途。 在本 明中 提供了一 高純度 性腺素 ed H aMe opa sa Go ado op s, PH HP 純度不低于95 , HPL 含量不 5 HPL 純度不低于96 HPL 含量不 4  The purpose of this is to provide the use of high purity H obtained by the above method. In the present invention, a high purity gonadotropin ed H aMe opa sa Go ado op s is provided, the PH HP purity is not less than 95, the HPL content is not 5 HPL, the purity is not less than 96 HPL, and the content is not 4
在另一 中 的 性腺素朱自 的 性腺素或 休、 或 源的 性腺素或 休。  In another, the gonadotropin or gonadin, or the source of gonadotropin or Hugh.
在另一 中 的高純度的 性腺素中 卵泡刺激素 F H 休生成 LH 的生物 比例 1 0.1—  In another high-purity gonadotropin, the ratio of follicle stimulating hormone F H to LH-producing organisms 1 0.1—
在另一 中 的高純度 性腺素中 卵泡刺激素 F H 休生成 LH 的生物 比例 1 0.5 1.4。 在本 的第二方面 提供了一 如上 的本 提供的高純度 性腺素 pH 的 各方法 的方法包括步驟 將低純度 H 染 料未和 純化 得到高純度 性腺素 的低純度H 比活在2000 F H 9蛋白以下。  In another high-purity gonadotropin, the proportion of follicle stimulating hormone F H to form LH is 1 0.5 1.4. In a second aspect of the present invention, there is provided a method of each of the methods of providing a high purity gonadotropin pH as described above comprising the step of operating a low purity H dye which is not purified and a high purity gonadotropin to a low purity H at 2000 FH 9 protein. the following.
在另一 中 的方法包括步驟 In another method, including steps
1 將含有低純度H 的溶液上 至染料未和 析的 上 1 Apply a solution containing low purity H to the undissolved dye
2 pH6— 1的 和 2 pH6-1 and
3 pH6— 1的 得到高純度 性腺素。  3 pH6-1 gives high purity gonadotropins.
在另一 中 含有低純度 H 的溶液中低純度 H 的 0.1 w v  In another solution containing low purity H, 0.1 w v of low purity H
在另一 中 含有低純度HM 的溶液的pH 4 8  In another solution, pH 4 8 of a solution containing low purity HM
在另一 中 的 自醋酸 溶液、醋酸 溶液、 Na H 溶液、 T s H 溶液或磷酸 溶液。 在另一 中 在步驟 3 中包括下 步驟In another solution from acetic acid, acetic acid, Na H, T s H or phosphoric acid. In the other step, the next step is included in step 3.
3 pH6 11的 收集 3 pH6 11 collection
3 加入 水乙醇 萬心得到 和 3 Add water ethanol, Wanxin get and
3 將 脫水 得到 的高純度 性腺素。  3 High purity gonadotropin obtained by dehydration.
在另一 中 染料未和 析的 的染料配 自 bac o B e a ge 、 ee  In another dye, the dye is not separated from bac o B e a ge , ee
在另一 中 染料未和 析的 的固相 休 自 土、 玻璃微 、 石英微 、 磷酸鈣、 氧化 、 聚丙烯 、 、 、 、 或 。  In another, the solid phase of the dye is not precipitated from soil, glass micro, quartz micro, calcium phosphate, oxidized, polypropylene, , , or .
在另一 中 染料未和 析的 自 B e epha oseFF或B e epha OSe 6B 在本 的第三方面 提供了一 合物 的 合物中含有 有效量的如上 的本 提供的高純度 性腺素 和 上可接受的 休。 在本 的第四方面 提供了一 如上 的本 提供的高純度 性腺素的用途 高純度 性腺素 于 各 不 綜合 的 。 此 本 提供了 各純度高、 少的高純度 的方法 所 得到的高純度 性腺素 于使用于皮下注射 方便患者的使用、  In another embodiment, the dye is not and precipitated from B e epha oseFF or B e epha OSe 6B. The compound of the present invention provides an effective amount of the high purity gonadotropin as provided above and the above. Acceptable rest. In the fourth aspect of the present invention, there is provided the use of the high purity gonadotropin as provided above. The high purity gonadotropin is not integrated. This product provides high-purity gonadotropins obtained by high-purity, high-purity methods for subcutaneous injection for patient use.
。 1 PH 的純度 。 休 方式  . 1 PH purity. Hugh way
明人 而深入的研究 染料未和 可以 抉得高純度的H 其HPL 純度 HPL 含量 5 是目前已知純 度最高的H 且F H和LH的生物 比例可以在要求的 固內 如 1 0.1 1 3。 休 本 將低純度 H 染料未和 純化 得到高 純度 性腺素。 如本文所用 低純度 "是指生物 在 200 F H U 9以下的H 生物 在40 50 F H U 9。 可以 本領域熟知 的方法 得低純度 H 例如但不限于 尿液中 高 土吸 附、 啊 乙醇溶液 萬于 包括 萬于、 萬于 甚至 水色 得到。 也可以 此渠道 得。 低純度 H 中 F H和 H的生物 比例在 1 0.1 3 固 住地 在 1 0.5 1.4 固。 本文所用 性腺素"、 "和 H "可以 使用 都是指一 由 休 生的 蛋白激素或 休 含有 F H和 LH西神 活性成分。 可以是 的 性腺素或 休、 或是人 源的 Explicit and in-depth study of dyes and high purity H. HPL purity HPL content 5 is currently known to have the highest purity of H and the biological ratio of FH and LH can be within the required solids such as 1 0.1 1 3 . Hugh's low purity H dye is not purified and is high Purified gonadotropin. As used herein, "low purity" means that the organism H below 200 FHU 9 is at 40 50 FHU 9. Low purity H can be obtained by methods well known in the art, such as, but not limited to, high soil adsorption in urine, ah, ethanol solution, including 10,000 It can also be obtained from the water. It can also be obtained from this channel. The biological ratio of FH and H in low purity H is 1 0.1 3 and the solid content is 1 0.5 1.4. The gonads ", " and H" used in this paper can be used. It refers to a protein hormone that is released by life or contains active ingredients of FH and LH. Can be a gonadin or a resting person, or a human source
性腺素或 休。  Gonadin or Hugh.
如本文所用 卵泡刺激素"和 F H"可以 使用 都是指一 于促迸 于或卵泡 、 促迸卵巢 的激素或 休 其可在天然 況下 由 休前 分泌 可 女的尿液中提取或可 木 得的。  As used herein, follicle stimulating hormone "and FH" can be used to refer to a hormone that promotes or follicles, promotes ovarian ovarian hormones, or can be extracted from the urine of a woman who can be secreted before the break in natural conditions. Got it.
如本文所用 休生成激素"和 LH"可以 使用 都是指是由 休前 細胞分泌的 作用于成熟的 引起排卵 生成典休的 一 激素或 休。  As used herein, serotonin and "LH" can be used to refer to a hormone or sputum that is secreted by premenstrual cells and acts on mature ovulation.
本文所用 "是指除了 性腺素之外的其它 ,是指 F H LH以外的 蛋白 如 並 、 聚合並 等。 其含量 定方法 本 提供的 高純度 性腺素純度的高 液相 HPL 方法 在所 HPL 下 通 一法得到 含量。 各方法  As used herein, "except for gonadotropins, refers to proteins other than FH LH such as merging, polymerization, etc. The method of determining the high purity gonadotropin purity of the high-liquid phase HPL method provided by the HPL under the HPL One method gives the content.
本 提供的高純度 性腺素的 各方法 是將低純度 H 染料未和 純化。  The methods of providing high purity gonadotropins of this invention are the purification of low purity H dyes.
在本 的一介 中 的 各高純度 性腺素的方法包 括步驟 The method of each high purity gonadotropin in this one includes steps
1 將含有低純度 H 的溶液上 至染料未和 析的 上 和 2 pH6 11的 得到高純度 性腺素。 染料未和 析的 可以是本領域 熟知的 例如但不限于 ee 、 a g。 住地 B e 住地 B e epha ose 6B 住地 中的萬于 在 0.01 5 自醋酸 溶液、 Na H溶液、 或 T s H 溶液。 1 A solution containing low purity H is applied to the dye and the supernatant and 2 pH 6 11 to obtain a high purity gonadotropin. The dye is not precipitated and can be well known in the art such as, but not limited to, ee, ag. Residence B e residence B e epha ose 6B live in a solution of 0.01 5 from acetic acid solution, Na H solution, or T s H solution.
在本 的一介 中 高純度 性腺素 以下步 驟 得  In this one, high purity gonadotropin
將含有低純度 H 的溶液上 至染料未和 析的 上 和 The solution containing low purity H is applied to the undissociated dye
pH6 1的 T 和 得到高純度 性腺素。 在本 的另一 中 的 各高純度 性腺素的方法 步驟  The T and pH of pH 6 1 yield high purity gonadotropins. In each of the other high purity gonados method steps
將含有低純度 H 的溶液上 至染料未和 析的 B e epha ose 上 的含有低純度 H 的溶液是將低純度 H 溶解 于pH4 8  A solution containing low purity H onto a low-purity H solution on the undegraded B e ephaose is to dissolve low purity H at pH 4 8
步驟 中的 In the step
pH6 11的 0.03 0.07 Na H  0.03 0.07 Na H of pH6 11
低 的 pH6 11的 0.03 0.07 T s H v 高 的 pH6 11 的 0.03 0.07 T s H  Low pH6 11 0.03 0.07 T s H v high pH6 11 0.03 0.07 T s H
收集 Collect
加入 水乙醇 萬心得到 和  Add water ethanol, get the heart and get
將 脫水 得到 的高純度 性腺素。  High purity gonadotropin that will be dehydrated.
的 是 或硫酸 其中的金屈萬于 自 Na、 K、 或 一般 在步驟 和步驟 v 中使用同一神  Of or sulphuric acid, which is from Na, K, or generally used in the same step in step v and step v
的低 0 0.5 較住地 0.1 0.5 住地 0.3 0.5 的高 0.5 5 較住地 2 5 住地 3 5  Low 0 0.5 Relative to residence 0.1 0.5 Residence 0.3 0.5 Height 0.5 5 Comparison of residence 2 5 Residence 3 5
在本 提供的 各高純度 性腺素的方法中 的含有低純 度 H 的溶液是將低純度 H 溶解于0.01 0.03 醋酸 而得 住 地 含有低純度 H 的溶液 4 8 高 性腺素 pHMG  The low purity H solution in the high purity gonadotropin method provided herein is a solution of low purity H dissolved in 0.01 0.03 acetic acid to obtain a solution containing low purity H. 4 8 high gonads pHMG
本 的方法可以 各得到高純度 性腺素 其 HP 含量 5 住地 HPL 含量 4 本 各得到的高純度的 性腺素中 卵泡刺激素 F H 休生成 LH 的生物 比例 1 0.1 3 住地 卵泡刺激素 F H 休生成 LH 的生物 比例 1 0.5 1.4。 物組合物 The method can obtain high purity gonadotropin HP content 5 living land HPL content 4 The high-purity gonadotropin obtained by the follicle stimulating hormone FH sputum LH-producing organism ratio 1 0.1 3 The living follicle stimulating hormone FH sap to produce LH biological proportion 1 0.5 1.4. Composition
本文所用 木 上可接受的 休" 于 的 休 包括各 賦形 和稀釋 。 木 一些 休 它們本身 不是必 要的活性成分 且施用 沒有 的 。 合 的 休是本領域普通 木人 熟知的 Re g o ' ha ace ca c e ce ack b. Co. .J. 1991) 中可找到 于 上可接受的賦形 的充分 。 在 合物中 上可接受 的 休可包括 休 如水、 水、 和乙醇。 另外 休中 可能存 在 性的物 如 、 況 、 乳化 、 p 等。  As used herein, wood acceptable rest includes various forms and dilutions. The woods themselves are not essential active ingredients and are not applied. He is known as Re go 'ha ace, which is well known in the art. Ca ce ce ack b. Co. .J. 1991) can be found in the above-mentioned acceptable shape. The acceptable rest in the compound includes water, water, and ethanol. Sexual things such as, conditions, emulsification, p, etc.
合物可以 不同 往而 各 各 。 以 下面方式之一施用 口服、 局部用 、 非 如皮下、 靜脈、 和肌肉 注射或輸入 或借助 外 器用 。 其中伏 皮下注射 方式。  The compounds can vary from one to the other. Oral, topical, non-subcutaneous, intravenous, and intramuscular injection or input or by means of an external device may be administered in one of the following ways. Among them, the subcutaneous injection method.
本 的方法制各得到的高純度 性腺素可以用于 各 不 綜合 的 的 可以 往施用 其中包括(但井 不限于) 、 皮下注射等。 皮下注射施用。 形式 施用 方式相匹配。 物的施用量 活性物 通常 每天 0.01 5 ug kg 休 較住地 0.05 0. g kg休 0.2 0. g kg休 。 The high-purity gonadotropin obtained by the present method can be used for various uncombined administrable applications including (but not limited to), subcutaneous injection, and the like. Apply by subcutaneous injection. The form of application is matched. The amount of application of the active substance is usually 0.01 5 ug kg per day compared with the place of residence 0.05 0. g kg rest 0.2 0. g kg rest.
本 的 可百接使用 也可 其它 或 合使用。 本 提到的上 特 或 提到的特 可以任意 合。 本案 揭示的所有特 可 任何 合物形式 中 揭示的各 特 可以任何可提供相同、 均等或相似目的的替代 特 取代。 因此 有特 別 揭示的特 均等或相似特 的一般性 于。  This can be used in other ways. The special features mentioned above or mentioned may be arbitrary. All of the features disclosed in any of the specific forms disclosed herein may be substituted for any equivalent, equivalent or similar purpose. Therefore, there is a special average or similar generality that is specifically disclosed.
本 的士 在于This taxi is
6 1、 提供了一 高純度、 少的 可 于皮下注射 2、 提供了一 高純度 的純化方法 方法 有效 合 此化。 下面 合 休 一步 本 。 理解 于 明本 而不用于限制本 的 固。 下列 中 注明 休 的 方法 通常按照常 或按照制造 所建 的 。 除非另外 否則所有的百分數、 比率、 比例、 或 。 6 1. Provide a high-purity, low-purity injection method that provides a high-purity purification method. Let's take a break from the rest. Understand this and not use it to limit the solid. The methods specified below are usually built as usual or in accordance with manufacturing. Unless otherwise otherwise all percentages, ratios, ratios, or.
本 明中的垂 休 百分比中的 是本領域 木人 熟知的 例如 是指在 100毫升的溶液中 的垂 。  The percentage of the vertical break in the present invention is well known in the art, for example, in the 100 ml solution.
除非另行 又 文中 使用的所有 此 本領域  Unless otherwise used in this article, all of this field
熟悉的 又相同。 此外 任何 內容相似或均等的方法及材料皆可 于本 方法中。 文中 的較佳 方法 材料 之用。 本 明中 F H L 生物 的 中 2005 汞 Familiar and the same. In addition, any methods and materials that are similar or equal in content can be used in the method. The preferred method in the text is used for materials. The H H L organism in the present invention
的方法 。 Methods .
比 是指 量的蛋白中 的 在本 明中 H 或 pH 的比 是指 毫克蛋白中 多少 F H或LH。 其中 蛋白含量的 定方法 是按照 y 或 衍生的方法 。 本 明中 HPL 純度或 HPL 含量是指按照面 一化法 的 百 分比。  The ratio of H or pH in the present invention refers to how much F H or LH in the milligram protein. The method for determining the protein content is based on y or derived methods. The HPL purity or HPL content in this specification refers to the percentage of the surface method.
本 明中 性腺素純度的 定方法如 2.5 The method for determining the purity of gonads in the present invention is 2.5
pe dex75 10 300 L  Pe dex75 10 300 L
相 0.2 磷酸 溶液 pH7.0 200 1000  Phase 0.2 phosphoric acid solution pH7.0 200 1000
品配 相溶解至 500 U L Dissolve the phase to 500 U L
00 U  00 U
 .
30 C  30 C
流速 0.5 L Flow rate 0.5 L
215  215
同 60  Same as 60
性腺素 保留 同 18 1g r 各高 性腺素 1 在本 中 將低純度 H ( 自上海 仟生物 有限公司)用作 p 的起始原料 其中 F 的生物 273 U g LH的生物 319 U g Gonadotropin retention with 18 1g r Each of the high-gonadin 1 uses low-purity H (from Shanghai Bio-Bio Co., Ltd.) as the starting material for p. The organism of F is 273 U g LH of the organism 319 U g
將 5 L B e epha ose FF( 自 E e sha ) 裝入 平 衡 (0.02 醋酸 pH7.0)平衡。  5 L B e epha ose FF (from E e sha ) was equilibrated in a balance (0.02 acetic acid pH 7.0).
將 09低純度 L平衡 溶解 H 或Na 溶液 p 7.0 然 上 至上 B e epha ose FF 上 上 平衡 5 倍 休 然 0. 5 yc Na H PH 8 倍 休 再用 0.05 T s H ,0.4 a PHg 8倍 休 ,最 0. 5 T s H ,4 a pHg ,分部收集 收集很多 例如 300 一份 然 將含 有效成分的部分合井 即合井有效成份 10000 , 加入5倍休 的元水乙醇 萬 收集 水乙醇脫水 其 得 236 9 即高純度 性腺素 1。  Equilibrate 09 low-purity L equilibrium to dissolve H or Na solution p 7.0 and then top up B e epha ose FF up to 5 times equilibrium 0. 5 yc Na H PH 8 times off with 0.05 T s H , 0.4 a PHg 8 times off, most 0. 5 T s H , 4 a pHg, fraction collection collected, for example 300, one will contain active ingredients The part of the well is the effective component of 10000, adding 5 times of rest of the water, the ethanol is collected, and the water is dehydrated to obtain 236 9 which is high purity gonadotropin 1.
生物 的 定方法 按照中 2005 汞 、 汞 N的 方法 F H LH生物 。  The biological method is determined according to the method of mercury and mercury N in 2005. F H LH organism.
其 1 Its 1
1 所得 的生物 和蛇  1 derived creature and snake
F 生物 生物 F H LH 生物 F Biological Biology F H LH Biology
P 蛇 ( u mg) ( u mg) 比  P snake ( u mg) ( u mg ) ratio
高蛇 性腺素  High snake gonadotropin
5012 5036 0.99 97.19 表明 用本 的方法 純化 可以使 的純度大大提高。  5012 5036 0.99 97.19 shows that purification by this method can greatly improve the purity.
2 2
各高純度 性腺素11 將 5 L B e epha ose 6B( 自 E e sha ) 裝入 (0.02 醋酸 pH7.0)平衡。 Each high purity gonadotropin 11 loads 5 LB e epha ose 6B (from E e sha ) (0.02 acetic acid pH 7.0) equilibrated.
將 69同安 1中相同 源的低純度 600 平衡 溶解 H 或 Na 溶液 p 7.0 然 上 至上 B e epha ose 6B 上 上 平衡 5 倍 休 然 0. 5 yc Na H PH 5倍 休 再用 0. 5 T s H ,0.2 Na PHg 5倍 休 ,再 用 0. 5 T s H ,0.5 Na PHg 7 倍 休 最 0.05 T s H ,4 Na PHg ,分段收集 合井有效成份 10000 至 0 ,即得高純度 性腺素11。 此 休 F H H生物 及蛋白含量 比 。  Equilibrate the same source of low-purity 600 in the same source in the same source. Dissolve the H or Na solution p 7.0 and then top up the B e epha ose 6B and balance it up to 5 times. 5 yc Na H PH 5 times rest and reuse 0. 5 T s H , 0.2 Na PHg 5 times rest, and then use 0.5 T s H , 0.5 Na PHg 7 times rest most 0.05 T s H , 4 Na PHg , and collect the effective components of the wells 10000 to 0, That is, high purity gonadotropin 11 is obtained. This H. H H biological and protein content ratio.
生物 的 定方法 按照中 2005 汞 、 汞 N的 方法 F H LH生物 。  The biological method is determined according to the method of mercury and mercury N in 2005. F H LH organism.
蛋白 含量 定方法 Lo y 。  Protein content determination method Lo y .
F H 比活的 方法 比 F H 生物 U L 毫升 休中 的蛋白含量 g L F H specific activity method F H biological U L ml Hugh protein content g L
2 2
2 所得 的生物 和蛇  2 creatures and snakes
F 生物 生物 F 比  F biological organism F ratio
蛋白含量 F H LH 生  Protein content F H LH
( U mg蛋 P 蛇 (mg mL) 物 比  ( U mg egg P snake (mg mL)
( mL) ( mL) 白)  ( mL) ( mL) White)
高蛇  High snake
性 6076 5843 0.502 12104 1.04 97.85 腺素11  Sex 6076 5843 0.502 12104 1.04 97.85 Adenine 11
表明 用本 的方法 純化 可以使 的純度大大提高。 3 It shows that the purification by this method can greatly improve the purity. 3
P G 的 各  Each of P G
于制造 10 pH 且每瓶 75 F 和 75 L 的 于 如下  Made at 10 pH and 75 F and 75 L per bottle as follows
將 1 所制各的高純度 性腺素 1 .64 9 溶解于 5 注 射 原水中 0.22U 注射 原水 。 Dissolve 1 high purity gonadotropin 1.64 9 in 5 injections of raw water at 0.22 U of raw water.
9 將 19乳糖溶解于 注射 原水中 如果需要的 H 或Na pH6.5+0.2 0.22U 。 然 加入到上 F 溶 液中 注射 原水 至 75 。 9 Dissolve 19 lactose in the injected raw water if required H or Na pH 6.5 + 0.2 0.22U. Then add the raw water to the upper F solution to 75.
將上 溶液分裝入 中 每瓶 0.75 冷凍 。  The upper solution was dispensed into 0.75 frozen bottles per bottle.
所得到的 中 每瓶 75 F H 75 LH和 9乳糖。  The obtained ones were 75 F H 75 LH and 9 lactose per bottle.
以上 力本 的較佳 而已 非用以限定本 的 木內容 固 本 的 木內容是 又 又于 的 要求 固 中 任何他人完成的 木 休或方法 若是 的 要求 固 又的 金相同 也或是一 等 的交史 均將 于 要求 固之中。  The preferred content of the above-mentioned power is not to limit the wood content of the solid content of the wood content, but also the requirement that the solid wood or the method of any other person to complete the same or the same The history of the exchange will be fixed.

Claims

要 求 Claim
1. 高純度 性腺素 p edH a e opa sa o ado op s, pH 其特 在于 其HPL 純度不低于 ,其 HPL 含量不 51. High purity gonadotropin p edH a e opa sa o ado op s, pH is characterized by its HPL purity not lower than its HPL content is not 5
HPL 純度不低于96 HPL 含量不 4  HPL purity is not less than 96 HPL content is not 4
2. 要求 1 的高純度 性腺素 其特 在于 的 性腺素 自 的 性腺素或 休、 或 源的 性腺 素或 休。  2. The high-purity gonadotropin required for 1 is characterized by the absence of gonadotropin or gonadotropin, or the source of gonadotropin or Hugh.
3. 要求 1 的高純度 性腺素 其特 在于 的高 度的 性腺素中 卵泡刺激素 F H 休生成 LH 的生物 比 例 1 0.1  3. Requires 1 high-purity gonadotropin, which is characterized by a high degree of gonadotropin, follicle stimulating hormone F H, and LH-producing organisms.
4. 要求 1 的高純度 性腺素 其特 在于 的高純 度 性腺素中 卵泡刺激素 F H 休生成 LH 的生物 比例 1 0.5 1.4。 4. The high-purity gonadotropin of claim 1 is characterized by high-purity gonadotropin. The proportion of follicle stimulating hormone F H to LH-producing organisms is 1 0.5 1.4.
5. 要求1 4任一所 的高純度 性腺素 pH 的 各 方法 其特 在于 的方法包括步驟 將低純度 H 染料未和 純化 得到高純度 性腺素 的低純度H 比活在200 F H 5. Each of the methods for requesting the high-purity gonadotropin pH of any of the four methods includes a step of operating the low-purity H of the low-purity H dye and the high-purity gonadotropin purified at 200 F H .
9蛋白以下。  9 protein or less.
6. 要求5 的 各方法 其特 在于 的方法包括步驟 6. The method of claim 5, the method of which includes the steps
1 將含有低純度H 的溶液上 至染料未和 析的 上 1 Apply a solution containing low purity H to the undissolved dye
2 pH6 11的 和 2 pH6 11 and
3 pH6— 1的 得到高純度 性腺素。  3 pH6-1 gives high purity gonadotropins.
7. 要求 6 的 各方法 其特 在于 含有低純度 H 的溶 液中低純度H 的 0.1— w v 7. The method of claim 6 is characterized in that 0.1-w v of low purity H in a solution containing low purity H
8. 要求 6 的 各方法 其特 在于 含有低純度 H 的溶 液的pH 4 8  8. The method of claim 6 is characterized in that the pH of the solution containing low purity H is 4 4
9. 要求 6 的 各方法 其特 在于 的 自醋酸 溶液、 醋酸 溶液、 Na H溶液、 T s HC 溶液或磷酸 溶液。  9. The methods of claim 6 are specific to acetic acid solution, acetic acid solution, Na H solution, T s HC solution or phosphoric acid solution.
10. 要求 5 9任一所 的 各方法 其特 在于 染料未和 析的 的染料配 自 bac o B e a ge R G ee 10. The method of any of the methods of claim 5 is characterized in that the dye is not separated from the dye and is formulated from bac o B ea ge RG ee
11. 要求 5 9任一所 的 各方法 其特 在于 染料未和 析的 的固相 休 自 土、 玻璃微 、 石英微 、 磷酸鈣、 氧化 、 聚 丙烯 、 、 、 、 或 。 11. The method of any of the 5-9 is characterized in that the solid phase of the dye is not precipitated from soil, glass micro, quartz micro, calcium phosphate, oxidized, polypropylene, , , or .
12. 要求 5 9任一所 的 各方法 其特 在于 染料未和 析的 自 B e epha ose FF或B e epha ose 6B  12. The method of any of the 5-9 is characterized in that the dye is not separated from the B e epha ose FF or the B e epha ose 6B
13. 合物 其特 在于 的 合物中含有 有效量的 要求1 4任一所 的高純度 性腺素 和 上可接受的 休。  13. The composition of the composition comprises an effective amount of a high purity gonadotropin which is required to be any one of the above and an acceptable one.
14. 要求 1 4任一所 的高純度 性腺素的用途 其 特 在于 于 各 不 綜合 的 。  14. The use of high-purity gonadotropins in any of the requirements of 1 4 is particularly uncommon.
PCT/CN2009/075277 2009-06-18 2009-12-03 Highly purified human menopausal gonadotropins, method for preparing and uses thereof WO2010145125A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2009100532746A CN101928342B (en) 2009-06-18 2009-06-18 High-purity menopausal gonadotropin as well as preparation method and application thereof
CN200910053274.6 2009-06-18

Publications (1)

Publication Number Publication Date
WO2010145125A1 true WO2010145125A1 (en) 2010-12-23

Family

ID=43355697

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/075277 WO2010145125A1 (en) 2009-06-18 2009-12-03 Highly purified human menopausal gonadotropins, method for preparing and uses thereof

Country Status (3)

Country Link
KR (1) KR20120042844A (en)
CN (1) CN101928342B (en)
WO (1) WO2010145125A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015124759A1 (en) * 2014-02-24 2015-08-27 Altergon Sa Extraction process to obtain hcg having a high biological activity

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101483165B1 (en) * 2009-12-22 2015-01-15 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 Compositions of menopausal gonadotrophins

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1262278A (en) * 1999-01-26 2000-08-09 Ibsa生物化学研究股份有限公司 Process for separating and purifying FSH and corpus luteum hormone
CN1404486A (en) * 2000-02-22 2003-03-19 应用研究系统Ars股份公司 Purified LH (Luteinizing hormone)
CN1414019A (en) * 2002-08-14 2003-04-30 上海天伟生物制药有限公司 Method of producing high purity postmenopause urine promoted gonadofrophin
CN1415628A (en) * 2002-08-14 2003-05-07 上海天伟生物制药有限公司 Method for extracting luteinizing hormone from human urine
CN1587276A (en) * 2004-07-23 2005-03-02 南昌市万华生化制品有限公司 Purifying and producing process for high purity follicle stimulating hormone in urine
CN101087805A (en) * 2004-11-09 2007-12-12 阿雷斯贸易股份有限公司 Method for purifying FSH
CN101307103A (en) * 2007-09-11 2008-11-19 上海天伟生物制药有限公司 Purification method of follicle stimulating hormone
CN101555279A (en) * 2009-05-19 2009-10-14 上海天伟生物制药有限公司 Urinary follicle stimulating hormone with high purity and preparation method thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1262278A (en) * 1999-01-26 2000-08-09 Ibsa生物化学研究股份有限公司 Process for separating and purifying FSH and corpus luteum hormone
CN1404486A (en) * 2000-02-22 2003-03-19 应用研究系统Ars股份公司 Purified LH (Luteinizing hormone)
CN1414019A (en) * 2002-08-14 2003-04-30 上海天伟生物制药有限公司 Method of producing high purity postmenopause urine promoted gonadofrophin
CN1415628A (en) * 2002-08-14 2003-05-07 上海天伟生物制药有限公司 Method for extracting luteinizing hormone from human urine
CN1587276A (en) * 2004-07-23 2005-03-02 南昌市万华生化制品有限公司 Purifying and producing process for high purity follicle stimulating hormone in urine
CN101087805A (en) * 2004-11-09 2007-12-12 阿雷斯贸易股份有限公司 Method for purifying FSH
CN101307103A (en) * 2007-09-11 2008-11-19 上海天伟生物制药有限公司 Purification method of follicle stimulating hormone
CN101555279A (en) * 2009-05-19 2009-10-14 上海天伟生物制药有限公司 Urinary follicle stimulating hormone with high purity and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015124759A1 (en) * 2014-02-24 2015-08-27 Altergon Sa Extraction process to obtain hcg having a high biological activity

Also Published As

Publication number Publication date
CN101928342A (en) 2010-12-29
KR20120042844A (en) 2012-05-03
CN101928342B (en) 2013-05-08

Similar Documents

Publication Publication Date Title
EP1326636B1 (en) Vaccine composition
WO2004001007A3 (en) Buffered formulations for concentrating antibodies and methods of use thereof
CN1196483C (en) Compositions for improivng fertility
CN1064045C (en) Thienopyrimidine derivatives, their production and use
WO2002020466B1 (en) Cyanophenoxy carboxylic acid compounds and compositions for delivering active agents
FR2458538A1 (en) NONAPEPTIDE AND DECAPEPTITIVE DERIVATIVES OF LUTEINIZING HORMONE-FREE HORMONE, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
RU2009139054A (en) APPLICATION OF LOW TEMPERATURE AND / OR LOW pH IN CELL CULTURE
JP2005537234A5 (en)
JP2016520134A (en) Janus kinase (JAK) inhibitor hydrogen sulfate and method for producing the same
EP0031285B1 (en) Immuno-stimulating preparations based on ribosomal rna of klebsiella pneumoniae and process for the preparation of these rna
WO2002085311A3 (en) Hcg formulation
WO2010145125A1 (en) Highly purified human menopausal gonadotropins, method for preparing and uses thereof
Chang et al. Luteinizing releasing hormone, synthesis and ARG8-analogs, and conformation-sequence-activity relationships
Hallick et al. Vitamin D3-stimulated template activity of chromatin from rat intestine
CA2200693A1 (en) Gp 130 lacking the transmembrane domain
TWI343254B (en) A method of purifying moxidectin through crystallization
CN1915986A (en) High purified tanshinone IIA sodium sulfonate, fabricating method, and preparation
JP4257026B2 (en) Process for selective production of triprenylphenol compounds and their use as pharmaceuticals
Franceschi et al. Ribosomal protein L20 can replace the assembly-initiator protein L24 at low temperatures
WO2004078061A3 (en) Methods and kits for maintaining pregnancy, treating follicular cysts, and synchronizing ovulation using luteinizing hormone
DE602004017512D1 (en) NEW PEPTIDE, METHOD FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THE PEPTIDE
CN110272407B (en) Natural isochromanone compound for reducing blood pressure
WO2010111845A1 (en) A high specific activity human menopausal gonadotropin, preparation method and use thereof
JP2008501642A5 (en)
CN104524553B (en) A kind of long-acting induced ovulation injection

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09846039

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 599/CHENP/2012

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20127001405

Country of ref document: KR

Kind code of ref document: A

122 Ep: pct application non-entry in european phase

Ref document number: 09846039

Country of ref document: EP

Kind code of ref document: A1