JP2009275045A - Glycoprotein hormone composition - Google Patents
Glycoprotein hormone composition Download PDFInfo
- Publication number
- JP2009275045A JP2009275045A JP2009117421A JP2009117421A JP2009275045A JP 2009275045 A JP2009275045 A JP 2009275045A JP 2009117421 A JP2009117421 A JP 2009117421A JP 2009117421 A JP2009117421 A JP 2009117421A JP 2009275045 A JP2009275045 A JP 2009275045A
- Authority
- JP
- Japan
- Prior art keywords
- variant
- composition
- hormone
- fsh
- glycoprotein
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 64
- 102000003886 Glycoproteins Human genes 0.000 title claims abstract description 50
- 108090000288 Glycoproteins Proteins 0.000 title claims abstract description 50
- 229940088597 hormone Drugs 0.000 title claims abstract description 45
- 239000005556 hormone Substances 0.000 title claims abstract description 45
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 claims abstract description 50
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 claims abstract description 50
- 229940028334 follicle stimulating hormone Drugs 0.000 claims abstract description 50
- 108010073521 Luteinizing Hormone Proteins 0.000 claims abstract description 41
- 102000009151 Luteinizing Hormone Human genes 0.000 claims abstract description 41
- 229940040129 luteinizing hormone Drugs 0.000 claims abstract description 41
- 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 claims abstract description 21
- 239000008101 lactose Substances 0.000 claims abstract description 21
- 150000002016 disaccharides Chemical class 0.000 claims abstract description 11
- 239000008247 solid mixture Substances 0.000 claims abstract description 8
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims abstract description 6
- 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 claims abstract description 5
- 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 claims abstract description 5
- 229930006000 Sucrose Natural products 0.000 claims abstract description 5
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims abstract description 5
- 239000005720 sucrose Substances 0.000 claims abstract description 5
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 102000003864 Human Follicle Stimulating Hormone Human genes 0.000 claims description 6
- 108010082302 Human Follicle Stimulating Hormone Proteins 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 5
- 210000002700 urine Anatomy 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000000509 infertility Diseases 0.000 claims description 3
- 230000036512 infertility Effects 0.000 claims description 3
- 231100000535 infertility Toxicity 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000000034 method Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 229960000074 biopharmaceutical Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000012792 lyophilization process Methods 0.000 description 4
- 239000008176 lyophilized powder Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000006771 Gonadotropins Human genes 0.000 description 3
- 108010086677 Gonadotropins Proteins 0.000 description 3
- 206010036049 Polycystic ovaries Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002622 gonadotropin Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 2
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 2
- 238000012425 Freezing-thawing process Methods 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- ZDRRIRUAESZNIH-BZGUUIOASA-N (2s)-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2s)-butan-2-yl]-10-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-n-[(2s)-1-[(2-amino-2-oxoethyl)amino]- Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)[C@@H](C)O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZDRRIRUAESZNIH-BZGUUIOASA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 201000005670 Anovulation Diseases 0.000 description 1
- 206010002659 Anovulatory cycle Diseases 0.000 description 1
- 238000012270 DNA recombination Methods 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 108010057021 Menotropins Proteins 0.000 description 1
- 108010047196 Urofollitropin Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 231100000552 anovulation Toxicity 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940015047 chorionic gonadotropin Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000021121 meiosis Effects 0.000 description 1
- 230000003821 menstrual periods Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000011421 subcutaneous treatment Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- 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
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は蛋白質精製とバイオ医薬の分野に関する。具体的には、優れた安定性を持つ糖タンパク質ホルモン及びその安定剤の組成物に関する。 The present invention relates to the fields of protein purification and biopharmaceuticals. Specifically, the present invention relates to a glycoprotein hormone having excellent stability and a composition of the stabilizer.
卵胞刺激ホルモン(Follicle-stimulating hormone、略称FSH)は下垂体から分泌される糖タンパク質ホルモンであり、α鎖とβ鎖の２つのサブユニットで構成される。FSHのαサブユニットは、黄体形成ホルモン(leuteinizing hormone、略称LH)及び絨毛性ゴナドトロピン(chorionic gonadotropin、略称CG)のαサブユニットと全く同様で、92のアミノ酸を含み、分子量は約14500 Dで、52と78番目のアミノ酸のアスパラギンはN-グリコシル化のアミノ酸である。FSHのβサブユニットは、111のアミノ酸で構成され、分子量は約18000 Dで、7と24番目のアミノ酸のアスパラギンはN-グリコシル化のアミノ酸である。LHのβサブユニットは121のアミノ酸で構成され、分子量は約14800 Dであり、CGのβサブユニットは145のアミノ酸を含み、分子量は22000-39000 Dである。 Follicle-stimulating hormone (abbreviated as FSH) is a glycoprotein hormone secreted from the pituitary gland and is composed of two subunits, α chain and β chain. The α subunit of FSH is exactly the same as the α subunit of luteinizing hormone (abbreviated as LH) and chorionic gonadotropin (abbreviated as CG), contains 92 amino acids, has a molecular weight of about 14500 D, Asparagine at amino acids 52 and 78 is an N-glycosylated amino acid. The β subunit of FSH is composed of 111 amino acids, has a molecular weight of about 18000 D, and the 7th and 24th amino acids asparagine are N-glycosylated amino acids. The β subunit of LH is composed of 121 amino acids, the molecular weight is about 14800 D, the β subunit of CG contains 145 amino acids, and the molecular weight is 22000-39000 D.
FSHは臨床で主に不妊治療及び体外からの生殖補助に用いられる。FSHは下垂体や閉経後女性の尿から採取でき、DNA組換え技術によっても製造できる。 FSH is mainly used in fertility treatment and assisted reproduction from outside the body. FSH can be collected from the pituitary gland and postmenopausal women's urine and can also be produced by DNA recombination technology.
第一世代のFSH含有製品は、例えばセロノ(Serono)社のパーゴナル(Pergonal)などのヒト尿性腺刺激ホルモン(HMG)であり、FSHとLHが約１：１の比率で配合された混合物である。しかし、体内に多量のLHがあって外因性LHの追加投与の必要がない患者に対しては、LHレベルが高すぎると、卵胞の正常発生に影響を与えてしまい、減数***抑制因子がタイミング悪く抑制されると、卵子の老化が招かれ、受精と着床の機会が低下してしまう。したがって、これらの患者にとって、純FSH製剤の投与はより適宜である。一方、多すぎるLHは多嚢胞性卵巣症候群(Polycystic Ovarian Syndrome、POOS)を招きやすく、研究によれば、多すぎるLHは生殖機能に不利な作用を及ぼし、例えば、希発月経、無***、不妊及び流産を起こす。そのため、POOSの患者に対しては、純FSHによる治療はHMGより安全で、卵巣過剰刺激症候群(Ovarian Hyperstimulation Syndrome、OHSS)のリスクを低下させることができる。 The first generation FSH-containing product is a human urinary gonadotropin (HMG) such as, for example, Serono's Pergonal, which is a mixture of FSH and LH in a ratio of about 1: 1. . However, for patients who have a large amount of LH in the body and do not need additional administration of exogenous LH, if the LH level is too high, it will affect the normal development of the follicle, and the meiosis inhibitor may be timed If suppressed, the aging of the egg will be invited, and the opportunity for fertilization and implantation will decrease. Therefore, administration of pure FSH formulation is more appropriate for these patients. On the other hand, too much LH tends to cause polycystic Ovarian Syndrome (POOS), and research has shown that too much LH has adverse effects on reproductive functions, such as rare menstrual periods, anovulation, infertility. Cause miscarriage. Therefore, for patients with POOS, treatment with pure FSH is safer than HMG and can reduce the risk of Ovarian Hyperstimulation Syndrome (OHSS).
セロノ社の発売しているメトロジン(Metrodin)は極めて少量のLHを含有するFSH製剤であり、その次のメトロジン-HPは高純度のFSH製剤である。 Metrodin, marketed by Serono, is an FSH formulation containing a very small amount of LH, followed by Metrozin-HP is a high-purity FSH formulation.
なお、近年、例えばフェリング(Ferring)社のメノパー(Menopur)などの高純度のヒト尿性腺刺激ホルモン(pHMG)は市販されており、精製した高純度FSHと高純度LH或いは高純度hCG(ヒト絨毛性ゴナドトロピン、human chorionic gonadotropin)とが１：１の比率で配合された製品であって、主には一般のHMG製品の代わりとして用いられ、一般のHMG製品にある多量の不純物タンパク質による人体の過敏反応という問題も克服された。 In recent years, high-purity human urinary gonadotropin (pHMG) such as Menorpur from Ferring has been commercially available, and purified high-purity FSH and high-purity LH or high-purity hCG (human villus) This product is formulated with a 1: 1 ratio of human gonadotropin (human chorionic gonadotropin), and is mainly used as a substitute for general HMG products. Human hypersensitivity due to a large amount of impurity proteins in general HMG products The problem of reaction was also overcome.
これによって、現在の市場においては、高純度糖タンパク質ホルモンの開発と使用が注目されている。しかしながら、各種の精製手段で得られる高純度糖タンパク質ホルモンは、まず保存と検査のために一つの原料薬の様態とされ、それから製剤化される。この原料薬の様態は重要であり、通常はなるべく液体の様態ではなく、固体の様態を採取するべきである。これは、液体は保存・輸送しにくいためである。また糖タンパク質ホルモンにとっては、固体の様態を得る主要な手段は凍結乾燥であるが、高純度糖タンパク質ホルモンは凍結乾燥の過程で変性・失活しやすいため、従来技術では、液体の様態で高純度糖タンパク質ホルモンの原料薬を保存しなければならない。しかし、液体の様態では-20℃以下で保存する必要があり、そうでなければ失活しやすいという問題；液体の様態で保存されると、凍結―溶解の過程だけでなく、凍結―溶解の過程の繰り返しさえあるため、糖タンパク質ホルモンの失活がより起こされやすいという問題；液体の様態では、包装容器は低温で脆化点に近く、割れが生じやすいという問題などがある。 As a result, the development and use of high-purity glycoprotein hormones are attracting attention in the current market. However, high-purity glycoprotein hormones obtained by various purification means are first made into one raw material form for storage and inspection, and then formulated. The mode of this raw material drug is important, and it should normally be collected in a solid mode rather than a liquid mode. This is because the liquid is difficult to store and transport. For glycoprotein hormones, the main means of obtaining a solid state is lyophilization, but high-purity glycoprotein hormones are easily denatured and inactivated during the lyophilization process. Purity glycoprotein hormone raw material must be preserved. However, in the liquid state, it must be stored at -20 ° C or lower, otherwise it is easily deactivated; if stored in the liquid state, not only the freezing-thawing process but also the freezing-thawing process The problem is that the inactivation of glycoprotein hormones is more likely to occur due to the repetition of the process; in the liquid state, the packaging container is close to the embrittlement point at low temperatures and is prone to cracking.
したがって、本分野では、優れた安定性を持つ糖タンパク質ホルモンの原料薬の様態が切望されている。 Therefore, in this field, a state of a raw material drug of glycoprotein hormone having excellent stability is eagerly desired.
本発明の目的は原料薬として使用可能な、高純度の糖タンパク質ホルモンを含有する固形組成物を提供することにある。 An object of the present invention is to provide a solid composition containing a high-purity glycoprotein hormone that can be used as a raw material drug.
本発明の第一は、二糖と、糖タンパク質ホルモン又はその変異体とを含有する固形組成物を提供する。 The first of the present invention provides a solid composition containing a disaccharide and a glycoprotein hormone or a variant thereof.
他の好ましい例において、前述の糖タンパク質ホルモン又はその変異体の含有量は10μg/mg組成物以上、或いは100国際単位/mg組成物以上である。 In other preferred examples, the content of the aforementioned glycoprotein hormone or variant thereof is 10 μg / mg composition or more, or 100 international units / mg composition or more.
他の好ましい例において、前述の糖タンパク質ホルモン又はその変異体の含有量は20μg/mg組成物以上、或いは200国際単位/mg組成物以上である。 In other preferred examples, the content of the aforementioned glycoprotein hormone or variant thereof is 20 μg / mg composition or more, or 200 international units / mg composition or more.
他の好ましい例において、前述の糖タンパク質ホルモン又はその変異体は、卵胞刺激ホルモン(FSH)又はその変異体、黄体形成ホルモン(LH)又はその変異体、又はその混合物からなる群れから選ばれる。 In another preferred example, the aforementioned glycoprotein hormone or variant thereof is selected from the group consisting of follicle stimulating hormone (FSH) or variant thereof, luteinizing hormone (LH) or variant thereof, or a mixture thereof.
他の好ましい例において、前述の二糖は、ラクトース、スクロース、マルトース、トレハロース又はこれらの2種又は2種以上の混合物からなる群れから選ばれ、ラクトースであることが好ましい。 In another preferred example, the aforementioned disaccharide is selected from the group consisting of lactose, sucrose, maltose, trehalose or a mixture of two or more thereof, and is preferably lactose.
他の好ましい例において、前述の卵胞刺激ホルモン又はその変異体はヒト卵胞刺激ホルモン又はその変異体である。 In another preferred example, the aforementioned follicle stimulating hormone or variant thereof is human follicle stimulating hormone or variant thereof.
他の好ましい例において、前述のヒト卵胞刺激ホルモン又はその変異体は、組換えヒト卵胞刺激ホルモン又はその変異体、或いはヒト尿由来の卵胞刺激ホルモン又はその変異体からなる群れから選ばれる。 In another preferred example, the aforementioned human follicle stimulating hormone or variant thereof is selected from the group consisting of recombinant human follicle stimulating hormone or variant thereof, or human urine-derived follicle stimulating hormone or variant thereof.
他の好ましい例において、前述の黄体形成ホルモン又はその変異体はヒト黄体形成ホルモン又はその変異体である。 In another preferred example, said luteinizing hormone or variant thereof is human luteinizing hormone or variant thereof.
他の好ましい例において、前述のヒト黄体形成ホルモン又はその変異体は、組換えヒト黄体形成ホルモン又はその変異体、或いはヒト尿由来の黄体形成ホルモン又はその変異体からなる群れから選ばれる。 In another preferred example, the aforementioned human luteinizing hormone or variant thereof is selected from the group consisting of recombinant human luteinizing hormone or variant thereof, or luteinizing hormone derived from human urine or variant thereof.
他の好ましい例において、前述の固形組成物は冷凍乾燥粉である。 In another preferred example, the aforementioned solid composition is a freeze-dried powder.
他の好ましい例において、前述の組成物は固体であって、二糖と、含有量が10μg/mg組成物以上或いは100国際単位/mg組成物以上である糖タンパク質ホルモン又はその変異体と、からなる。 In another preferred example, the composition is a solid, comprising a disaccharide and a glycoprotein hormone or variant thereof having a content of 10 μg / mg composition or more or 100 international units / mg composition or more. Become.
本発明の第二は、前述の固形組成物を含有する医薬組成物を提供する。 The second of the present invention provides a pharmaceutical composition containing the above-described solid composition.
本発明の第三は、不妊症候群治療用の薬物の製造のための前述の固形組成物の使用を提供する。 The third aspect of the present invention provides the use of the aforementioned solid composition for the manufacture of a medicament for the treatment of infertility syndrome.
これによって、本発明は優れた安定性を持つ糖タンパク質ホルモンの原料薬の様態を提供した。 As a result, the present invention provides an aspect of a glycoprotein hormone raw material having excellent stability.
本発明者らは幅広く深く検討した結果、驚くことに、高純度の糖タンパク質ホルモンと適宜の安定剤を組み合わせて凍結乾燥することにより、安定した組成物が得られることを見出した。なかでも、安定剤は二糖であることが好ましく、ラクト−スであることが特に好ましい。 As a result of extensive and extensive studies, the present inventors have surprisingly found that a stable composition can be obtained by combining a high-purity glycoprotein hormone with an appropriate stabilizer and freeze-drying. Among these, the stabilizer is preferably a disaccharide, and particularly preferably lactose.
本発明者らは、そのとき二糖は希釈剤及び賦形剤として作用するだけでなく、より重要なのは保護剤として作用し、糖タンパク質分子を凍結乾燥の過程で発生する可能性のある立体配座変化による変性・失活から保護する一方、製品の安定性も大きく高めることを見出し、この知見に基づき本発明を完成した。 The inventors then did not only act as a diluent and excipient, but more importantly as a protective agent, the conformation that could generate glycoprotein molecules during the lyophilization process. While protecting from denaturation / deactivation due to locus change, the inventors have found that the stability of the product is greatly enhanced, and based on this finding, the present invention has been completed.
具体的には、背景技術部分で説明したように、従来技術では、高純度糖タンパク質ホルモンの中間品又は原料薬様態は液体の様態で保存されるため、保存と輸送が不便で、わずかな不注意では製品に大きな影響を与えることになる。また固体様態では、凍結乾燥の過程が糖タンパク質を失活させやすいという結果になる。 Specifically, as explained in the background section, in the conventional technology, the intermediate or raw material drug state of high-purity glycoprotein hormone is stored in a liquid state, so that it is inconvenient to store and transport, and has a slight inconvenience. Caution will have a major impact on the product. Also, in the solid state, the freeze-drying process tends to inactivate the glycoprotein.
従来技術の改良方法を探索している間に、本発明者らは、高純度糖タンパク質とラクトースが適宜に配合され、特に高純度糖タンパク質とラクトースの濃度が適宜の範囲にあると、その時ラクトースは保護剤として作用し、凍結乾燥の過程で発生する可能性のある立体配座変化による糖タンパク質分子の変性・失活を防止することを気付いた。 While searching for an improved method of the prior art, the present inventors appropriately blended high-purity glycoprotein and lactose, particularly when the concentration of the high-purity glycoprotein and lactose is within a suitable range, then lactose Noticed that it acts as a protective agent and prevents denaturation and deactivation of glycoprotein molecules due to conformational changes that may occur during the lyophilization process.
本発明において、前述の二糖(disaccharide)は単糖２分子からグリコシド結合により形成され、例えば、マルトース、ラクトース、スクロース、トレハロースなどがあり、マルトース、ラクトース、スクロースからなる群れから選ばれる１種又は多種であることが好ましく、ラクトースであることがより好ましい。 In the present invention, the above-mentioned disaccharide is formed by glycosidic bond from two monosaccharide molecules, for example, maltose, lactose, sucrose, trehalose, etc., and one kind selected from the group consisting of maltose, lactose, sucrose or It is preferable to use various types, and more preferably lactose.
本発明において、前述の糖タンパク質ホルモンの変異体とは、アミノ酸が欠失した或いは組換え技術で修飾された糖タンパク質ホルモンであるが、その基本薬効はそのまま存在する又は増強された。 In the present invention, the aforementioned glycoprotein hormone mutant is a glycoprotein hormone in which an amino acid is deleted or modified by a recombinant technique, but its basic medicinal properties are present or enhanced as they are.
本発明により提供される組成物において、二糖と糖タンパク質ホルモン又はその変異体との重量の合計は組成物の合計重量の60−100％であり、好ましくは80−99％であり、より好ましくは90−95％である。 In the composition provided by the present invention, the total weight of the disaccharide and the glycoprotein hormone or variant thereof is 60-100%, preferably 80-99%, more preferably the total weight of the composition. Is 90-95%.
本発明に係る組成物において、前述の糖タンパク質ホルモン又はその変異体の生物的力価は500−30000国際単位/mgタンパク質であり、好ましくは3500−12000国際単位/mgタンパク質である。その中の糖タンパク質ホルモンはFSH又はその変異体だけであれば、FSH又はその変異体の生物的力価は500−15000国際単位/mgタンパク質であり、好ましくは7000−12000国際単位/mgタンパク質である。その中の糖タンパク質ホルモンはLH又はその変異体だけであれば、LH又はその変異体の生物的力価は500−8000国際単位/mgタンパク質であり、好ましくは2000−6000国際単位/mgタンパク質である。 In the composition according to the present invention, the biological titer of the aforementioned glycoprotein hormone or variant thereof is 500-30000 international units / mg protein, preferably 3500-12000 international units / mg protein. If the only glycoprotein hormone is FSH or its variant, the biological titer of FSH or its variant is 500-15000 international units / mg protein, preferably 7000-12000 international units / mg protein. is there. If the glycoprotein hormone in it is only LH or its variant, the biological titer of LH or its variant is 500-8000 international units / mg protein, preferably 2000-6000 international units / mg protein. is there.
本発明に係る組成物において、前述の糖タンパク質ホルモン又はその変異体の純度は50％以上であり、好ましくは90％以上である。 In the composition according to the present invention, the purity of the aforementioned glycoprotein hormone or variant thereof is 50% or more, preferably 90% or more.
本発明により提供される組成物1mgあたりにおいて、糖タンパク質ホルモン又はその変異体の含有量は100国際単位以上であり、好ましくは200国際単位以上である。 In 1 mg of the composition provided by the present invention, the content of glycoprotein hormone or a variant thereof is 100 international units or more, preferably 200 international units or more.
本発明により提供される組成物1mgあたりにおいて、糖タンパク質ホルモン又はその変異体の含有量は10μg以上である。その中の糖タンパク質ホルモンはFSH又はその変異体だけであれば、FSH又はその変異体の含有量は10μg/mg組成物以上であり、好ましくは20μg/mg組成物以上である。その中の糖タンパク質ホルモンはLH又はその変異体だけであれば、LH又はその変異体の含有量は10μg/mg組成物以上であり、好ましくは35μg/mg組成物以上である。 The content of glycoprotein hormone or a variant thereof is 10 μg or more per 1 mg of the composition provided by the present invention. If the only glycoprotein hormone is FSH or a mutant thereof, the content of FSH or the mutant is not less than 10 μg / mg composition, preferably not less than 20 μg / mg composition. If the only glycoprotein hormone is LH or a mutant thereof, the content of LH or the mutant is 10 μg / mg composition or more, preferably 35 μg / mg composition or more.
本発明により提供される組成物において、二糖と糖タンパク質ホルモン又はその変異体との重量比は8−99:1であり、好ましくは12−60:1である。 In the composition provided by the present invention, the weight ratio of disaccharide to glycoprotein hormone or variant thereof is 8-99: 1, preferably 12-60: 1.
本発明により提供される組成物において、ラクトースと糖タンパク質ホルモン又はその変異体との重量比は8−99:1であり、好ましくは12−60:1である。その中の糖タンパク質ホルモンはFSH又はその変異体だけであれば、ラクトースとFSH又はその変異体との重量比は20−99:1であり、好ましくは30−50:1である。その中の糖タンパク質ホルモンはLH又はその変異体だけであれば、ラクトースとLH又はその変異体との重量比は8−99:1であり、好ましくは12−20:1である。 In the composition provided by the present invention, the weight ratio of lactose to glycoprotein hormone or variant thereof is 8-99: 1, preferably 12-60: 1. If the only glycoprotein hormone is FSH or its variant, the weight ratio of lactose to FSH or its variant is 20-99: 1, preferably 30-50: 1. If the only glycoprotein hormone is LH or a variant thereof, the weight ratio of lactose to LH or a variant thereof is 8-99: 1, preferably 12-20: 1.
本発明により提供される組成物は、凍結乾燥の過程で糖タンパク質ホルモンが変性・失活せず、かつ優れた安定性を持つ。 The composition provided by the present invention does not denature / inactivate glycoprotein hormones during the freeze-drying process and has excellent stability.
本発明は、(a)糖タンパク質ホルモン又はその変異体と、(b)二糖と、(c)薬学的に許容される担体と、を含有する医薬組成物を提供する。 The present invention provides a pharmaceutical composition comprising (a) a glycoprotein hormone or variant thereof, (b) a disaccharide, and (c) a pharmaceutically acceptable carrier.
本文で用いられるように、用語の「薬学的に許容される担体」とは、治療剤の投与のための担体であって、各種の賦形剤と希釈剤を含む。該当用語は、これら自身が必要な活性成分ではなく、かつ施用後あまり毒性がないような薬剤担体を示す。適宜な担体は本分野の当業者に良く知られている。Remington's Pharmaceutical Sciences (Mack Pub. Co.，N.J. 1991)には、薬学的に許容される賦形剤に関する十分な検討が見つけられる。組成物において、薬学的に許容される担体は、水、食塩水、グリセリンやエタノールのような液体を含んでもよい。なお、このような担体には、さらに崩壊剤、湿潤剤、乳化剤、pH緩衝物質などの補助性の物質が存在してもよい。 As used herein, the term “pharmaceutically acceptable carrier” is a carrier for administration of a therapeutic agent and includes various excipients and diluents. The term refers to drug carriers that are not themselves necessary active ingredients and are less toxic after application. Suitable carriers are well known to those skilled in the art. Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991) finds a thorough review of pharmaceutically acceptable excipients. In the composition, the pharmaceutically acceptable carrier may include water, saline, liquids such as glycerin and ethanol. Such carriers may further contain auxiliary substances such as disintegrants, wetting agents, emulsifiers and pH buffer substances.
前述の医薬組成物は投与経路によって各種の剤型に製造されてもよい。これらの剤型は、経口投与、スプレー投与、経直腸投与、鼻腔内投与、頬側投与、局所投与、非腸内投与、皮下、静脈内、筋肉、腹膜内、鞘内、心室内、胸骨内、頭蓋内などへの注射又は輸注、或いは一種の外植式存儲器による投与などの手段の一つで施用される。なかでも、治療に際しては、皮下投与の手段が好ましい。 The aforementioned pharmaceutical composition may be produced in various dosage forms depending on the administration route. These dosage forms include oral administration, spray administration, rectal administration, intranasal administration, buccal administration, topical administration, parenteral administration, subcutaneous, intravenous, muscle, intraperitoneal, intrathecal, intraventricular, intrasternal It is applied by one of means such as injection or infusion into the skull or the like, or administration by a kind of explanted indwelling device. Of these, subcutaneous treatment is preferred for treatment.
なお、本発明に係る医薬組成物における有効成分の投与量と投与手段は、患者の年齢、体重、性別、自然健康状況、栄養状況、有効成分の活性強度、服用、代謝速度、病症の重篤度及び診療医師の主観的判断など多くの要因によって決められる。薦めの安全有効量は通常少なくとも約10μg/kg体重で、多くの場合は約10mg/kg体重以下であり、好ましい投与量は約10μg/kg体重―約1mg/kg体重である。もちろん、具体的な投与量の決定には、投与経路、患者の健康状況などの要因を考えるべきだ。これらは全て、熟練医師の技術の範囲に含まれる。 The dose and means of administration of the active ingredient in the pharmaceutical composition according to the present invention include the patient's age, weight, sex, natural health status, nutritional status, active ingredient activity intensity, dosage, metabolic rate, serious disease It depends on many factors such as the degree and the subjective judgment of the clinician. Recommended safe effective doses are usually at least about 10 μg / kg body weight, often below about 10 mg / kg body weight, with a preferred dosage of about 10 μg / kg body weight to about 1 mg / kg body weight. Of course, in determining the specific dose, factors such as the route of administration and patient health should be considered. All of these are within the skill of a skilled physician.
本発明で述べられた上述の特徴、或は実施例で述べられる特徴は、任意に組み合わせてもよい。本明細書で開示された全ての特徴は任意の組成物の様態と併用してもよく、明細書で開示された各特徴はいずれも、同様、同等或いは類似の目的を果たす代わりの特徴により置換されてもよい。特に説明しない限り、開示された特徴は、同等または類似の特徴の一般的なシリーズの一例に過ぎない。 The features described in the present invention or the features described in the embodiments may be arbitrarily combined. All features disclosed herein may be used in conjunction with any composition aspect, and each feature disclosed in the specification is similarly replaced by an alternative feature serving an equivalent or similar purpose. May be. Unless otherwise stated, the disclosed features are only examples of a general series of equivalent or similar features.
本発明の主な利点は、以下の通りである。 The main advantages of the present invention are as follows.
(1)保存・輸送しやすい固体の様態の糖タンパク質ホルモンの組成物を提供した、
(2)本発明の方法により得られる糖タンパク質ホルモンの組成物は優れた安定性を持ち、原料薬として相応の製剤の製造に好適に用いられる。
(1) Provided a glycoprotein hormone composition in a solid state that is easy to store and transport;
(2) The composition of glycoprotein hormone obtained by the method of the present invention has excellent stability, and is suitably used for the production of a corresponding preparation as a raw material drug.
以下、具体的な実施例によって、さらに本発明を説明する。これらの実施例は本発明を説明するために用いるもので、本発明の範囲の制限にはならないと理解されるものである。以下の実施例に特に具体的な条件を説明しない実験方法は通常の条件、或いはメーカーの薦めの条件で行われる。特に説明しない限り、すべての百分率と部は重量基準である。 Hereinafter, the present invention will be further described with reference to specific examples. These examples are used to illustrate the present invention and are understood not to limit the scope of the invention. Experimental methods that do not describe specific conditions in the following examples are performed under normal conditions or conditions recommended by the manufacturer. Unless stated otherwise, all percentages and parts are by weight.
別途に定義しない限り、文中に使用されるすべての専門・科学用語は、本分野の熟練者によく知られる意味と同じである。また、記載される内容に類似或は同等の方法及び材料はいずれも本発明に使用することができる。文中に記載の好ましい実施形態及び材料は例示だけのためである。 Unless otherwise defined, all technical and scientific terms used in the sentence have the same meanings as are well known to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the present invention. The preferred embodiments and materials described in the text are for illustration only.
FSH含有組成物
本実施例において、高純度FSH(上海天偉生物製薬株式会社より購入)がFSH医薬組成物の原料として用いられ、それにおけるFSHの生物的力価は9521国際単位/mgであった。
FSH-containing composition In this example, high-purity FSH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.) was used as the raw material for the FSH pharmaceutical composition, in which the biological titer of FSH was 9521 international units / mg. It was.
0.01Mのリン酸二水素ナトリウム溶液(NaOHでpHを約6.5に調節)を50mL調整し、ラクトースを2g加え、攪拌し溶解させた後、0.22μmフィルターでろ過した。ろ過液を10mL取り、前述の高純度FSH(上海天偉生物製薬株式会社より購入)を10.0mg加え、完全に溶解させた後、皿に置き凍結乾燥機に入れ、以下のプロセスで凍結乾燥を行った。 50 mL of 0.01 M sodium dihydrogen phosphate solution (pH adjusted to about 6.5 with NaOH) was adjusted, 2 g of lactose was added, stirred and dissolved, and then filtered through a 0.22 μm filter. Take 10 mL of the filtrate, add 10.0 mg of the above-mentioned high-purity FSH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.), dissolve it completely, place it on a plate, put it in a freeze dryer, and freeze-dry it by the following process. went.
１.トレーを予め−40℃で３時間冷凍し、
２.コールドトラップで−45℃にし、
３.真空ポンプを起動させ、
４.トレーを−10℃で15時間維持し、
５.トレーを＋20℃で5時間維持し、
６.チャンバーから取り出し、凍結乾燥粉末を392mg得た。
1. Freeze the tray in advance at -40 ° C for 3 hours,
2. Set to -45 ° C with a cold trap,
3. Start the vacuum pump,
4. Keep the tray at -10 ° C for 15 hours,
5. Keep the tray at + 20 ° C for 5 hours,
6. Removed from the chamber to obtain 392 mg of lyophilized powder.
該当製品のFSHの生物的力価を測定した結果は以下の通りであった。
本対照例において、高純度FSHとラクトースを、FSH含有量が50国際単位/mg組成物合計量を下回るように配合し、さらにその凍結乾燥過程及び安定性を調べた。 In this control example, high purity FSH and lactose were blended so that the FSH content was less than 50 international units / mg total composition, and the freeze-drying process and stability were further examined.
本対照例において、高純度FSH(上海天偉生物製薬株式会社より購入)がFSH医薬組成物の原料として用いられ、それにおけるFSHの生物的力価は9521国際単位/mgであった。 In this control example, high-purity FSH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.) was used as the raw material of the FSH pharmaceutical composition, in which the biological titer of FSH was 9521 international units / mg.
0.01Mのリン酸二水素ナトリウム溶液(NaOHでpHを約6.5に調節)を500mL調整し、ラクトースを20g加え、攪拌し溶解させた後、0.22μmフィルターでろ過した。ろ過液を100mL取り、前述の高純度FSH(上海天偉生物製薬株式会社より購入)を5.0mg加え、完全に溶解させた後、皿に置き凍結乾燥機に入れ、実施例1のプロセスで凍結乾燥を行い、凍結乾燥粉末を3.89g得た。
以上の二つの例の結果より明らかなように、本発明により得られたFSH組成物は凍結乾燥の過程でほとんど変性・失活しなかったのに対して、対照例では著しい失活現象があった。
安定性対比
As is clear from the results of the above two examples, the FSH composition obtained by the present invention was hardly denatured or inactivated during the lyophilization process, whereas the control example had a significant inactivation phenomenon. It was.
Stability contrast
実施例１と対照例のサンプルの30℃における安定性を調べた結果は以下の通りであった。
これにより、本発明により得られたFSH組成物は対照例に比べて、優れた安定性を持つことがわかった。 Thereby, it was found that the FSH composition obtained according to the present invention has excellent stability as compared with the control example.
LH含有組成物
本実施例において、高純度LH(上海天偉生物製薬株式会社より購入)がLH医薬組成物の原料として用いられ、それにおけるLHの生物的力価は4307国際単位/mgであった。
LH-containing composition In this example, high-purity LH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.) was used as a raw material for LH pharmaceutical composition, in which the biological titer of LH was 4307 international units / mg. It was.
0.01Mのリン酸二水素ナトリウム溶液(NaOHでpHを約6.5に調節)を50mL調整し、ラクトースを2g加え、攪拌し溶解させた後、0.22μmフィルターでろ過した。ろ過液を10mL取り、前述の高純度LH(上海天偉生物製薬株式会社より購入)を25mg加え、完全に溶解させた後、皿に置き凍結乾燥機に入れ、実施例1のプロセスで凍結乾燥を行い、凍結乾燥粉末を402mg得た。 50 mL of 0.01 M sodium dihydrogen phosphate solution (pH adjusted to about 6.5 with NaOH) was adjusted, 2 g of lactose was added, stirred and dissolved, and then filtered through a 0.22 μm filter. Take 10 mL of the filtrate, add 25 mg of the above-mentioned high purity LH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd.), dissolve it completely, place it on a plate, put it in a freeze dryer, and freeze-dry it using the process of Example 1. And 402 mg of lyophilized powder was obtained.
該当製品のLHの生物的力価及び30℃における安定性を調べた結果は以下の通りであった。
これにより、本発明により得られたLH組成物はほとんど変性・失活せず、かつ優れた安定性を持つことがわかった。 As a result, it was found that the LH composition obtained by the present invention hardly denatured or deactivated and had excellent stability.
FSHとLHの混合物含有組成物
0.9％の塩化ナトリウム溶液(NaOH或いはHClでpHを約7.0に調節)を100mL調整し、マルトースを4g加え、攪拌し溶解させた後、0.22μmフィルターでろ過した。ろ過液を10mL取り、前述の高純度FSH(上海天偉生物製薬株式会社より購入、生物的力価は9521国際単位/mg)を10.0mg加え、さらに前述の高純度LH(上海天偉生物製薬株式会社より購入、生物的力価は4307国際単位/mg)を25mg加え、完全に溶解させた後、皿に置き凍結乾燥機に入れ、実施例1のプロセスで凍結乾燥を行い、凍結乾燥粉末を405mg得た。測定されたFSHの生物的力価は223IU/mgで、LHの生物的力価は242IU/mgであった。
Composition containing a mixture of FSH and LH
100 mL of 0.9% sodium chloride solution (pH adjusted to about 7.0 with NaOH or HCl) was adjusted, 4 g of maltose was added, and the mixture was stirred and dissolved, and then filtered through a 0.22 μm filter. Take 10 mL of the filtrate, add 10.0 mg of the above-mentioned high-purity FSH (purchased from Shanghai Tianwei Biopharmaceutical Co., Ltd., biological titer is 9521 international units / mg), and then add the above-mentioned high-purity LH (Shanghai Tianwei Biopharmaceutical) Buy from Co., Ltd., and add 25mg of biological titer (4307 international units / mg), dissolve it completely, place it on a plate, put it in a freeze dryer and freeze-dry it using the process of Example 1 405 mg was obtained. The measured biological titer of FSH was 223 IU / mg and that of LH was 242 IU / mg.
該当製品の30℃における安定性を調べた結果は以下の通りであった。
FSH凍結乾燥粉注射剤の製造
１瓶につきFSHを75IU含有するようにFSH凍結乾燥粉注射剤を100瓶製造する例は以下の通りであった。
Production of FSH lyophilized powder injections 100 bottles of FSH lyophilized powder injections were prepared as follows so as to contain 75 IU of FSH per bottle.
実施例１で製造したFSH凍結乾燥組成物35mgを注射用パイロジェンフリー水10mLに溶解させ、0.22μmフィルターで無菌ろ過し、さらに注射用パイロジェンフリー水でフィルターを洗浄した。 35 mg of the FSH lyophilized composition produced in Example 1 was dissolved in 10 mL of pyrogen-free water for injection, sterile filtered with a 0.22 μm filter, and the filter was washed with pyrogen-free water for injection.
ラクトース1gを注射用パイロジェンフリー水30mLに溶解させ、必要とすればHCl或いはNaOHでpHを6.5±0.2に調節し、0.22μmフィルターで無菌ろ過した。次に、前述のFSH溶液に加え、注射用パイロジェンフリー水で75mLに定容し、均一に混合した。 1 g of lactose was dissolved in 30 mL of pyrogen-free water for injection. If necessary, the pH was adjusted to 6.5 ± 0.2 with HCl or NaOH, and sterile filtered through a 0.22 μm filter. Next, in addition to the FSH solution described above, the volume was adjusted to 75 mL with pyrogen-free water for injection and mixed uniformly.
前述の溶液を１瓶につき0.75mLの量でアンプルに分注し、凍結乾燥した。 The above solution was dispensed into ampoules in an amount of 0.75 mL per bottle and lyophilized.
得られたアンプルにおいては、１瓶あたりにFSHが約75IU、ラクトースが約10mg含まれた。 The resulting ampoule contained about 75 IU FSH and about 10 mg lactose per bottle.
以上で記述されたのは本発明の好適な実施例に過ぎないものであり、本発明に係る実質的な技術内容の範囲はこれによって限定されるものではない。本発明の実質的な技術内容は、広汎に特許請求の範囲内に定義される。他人に完成された如何なる技術実体や方法は、特許請求の範囲に定義されたものとまったく同一であり、又は同等効果の変更であれば、特許請求の範囲に含まれるものとする。 What has been described above is only a preferred embodiment of the present invention, and the scope of the substantial technical contents according to the present invention is not limited thereto. The substantial technical content of the present invention is broadly defined in the claims. Any technical entities and methods completed by others are exactly the same as those defined in the claims, or are included in the claims if they are equivalent changes.
Claims (12)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100374254A CN101269215B (en) | 2008-05-15 | 2008-05-15 | Glucoprotein incretion composition |
| CN200810037425.4 | 2008-05-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2009275045A true JP2009275045A (en) | 2009-11-26 |
| JP5143784B2 JP5143784B2 (en) | 2013-02-13 |
Family
ID=40003607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009117421A Active JP5143784B2 (en) | 2008-05-15 | 2009-05-14 | Glycoprotein hormone composition |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP5143784B2 (en) |
| KR (1) | KR101095647B1 (en) |
| CN (1) | CN101269215B (en) |
| WO (1) | WO2009138042A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038649B (en) * | 2009-10-20 | 2015-10-14 | 丽珠医药集团股份有限公司 | Urine-promoted follicle stimulating hormone freeze and preparation method thereof |
| KR101483165B1 (en) * | 2009-12-22 | 2015-01-15 | 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 | Compositions of menopausal gonadotrophins |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02500840A (en) * | 1987-06-26 | 1990-03-22 | イスティテュト ディ リチェルカ チェサレ セローノ ソチエタ ペル アツィオニ | follicle stimulating hormone |
| JPH04217630A (en) * | 1990-03-20 | 1992-08-07 | Akzo Nv | Preparation article containing stabilized gonadotropin |
| JPH08509483A (en) * | 1993-04-28 | 1996-10-08 | アクゾ・ノベル・エヌ・ベー | Rio Spheres Containing Gonadotropin |
| JP2002542260A (en) * | 1999-04-16 | 2002-12-10 | インスチチュート マッソーネ エス．エイ． | Highly purified gonadotropin compositions and methods for their production |
| JP2005517012A (en) * | 2002-02-08 | 2005-06-09 | アルカーメス コントロールド セラピューティクス，インコーポレイテッド | Polymer-based composition for sustained release |
| JP2006522072A (en) * | 2003-04-02 | 2006-09-28 | アレス トレーディング ソシエテ アノニム | Liquid pharmaceutical composition of FSH and LH with non-ionic surfactant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1250075B (en) * | 1991-12-18 | 1995-03-30 | Serono Cesare Ist Ricerca | PHARMACEUTICAL COMPOSITIONS CONTAINING GONADOTROPINE. |
-
2008
- 2008-05-15 CN CN2008100374254A patent/CN101269215B/en active Active
-
2009
- 2009-05-14 JP JP2009117421A patent/JP5143784B2/en active Active
- 2009-05-15 WO PCT/CN2009/071806 patent/WO2009138042A1/en active Application Filing
- 2009-05-15 KR KR1020090042756A patent/KR101095647B1/en active IP Right Grant
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02500840A (en) * | 1987-06-26 | 1990-03-22 | イスティテュト ディ リチェルカ チェサレ セローノ ソチエタ ペル アツィオニ | follicle stimulating hormone |
| JPH04217630A (en) * | 1990-03-20 | 1992-08-07 | Akzo Nv | Preparation article containing stabilized gonadotropin |
| JPH08509483A (en) * | 1993-04-28 | 1996-10-08 | アクゾ・ノベル・エヌ・ベー | Rio Spheres Containing Gonadotropin |
| JP2002542260A (en) * | 1999-04-16 | 2002-12-10 | インスチチュート マッソーネ エス．エイ． | Highly purified gonadotropin compositions and methods for their production |
| JP2005517012A (en) * | 2002-02-08 | 2005-06-09 | アルカーメス コントロールド セラピューティクス，インコーポレイテッド | Polymer-based composition for sustained release |
| JP2006522072A (en) * | 2003-04-02 | 2006-09-28 | アレス トレーディング ソシエテ アノニム | Liquid pharmaceutical composition of FSH and LH with non-ionic surfactant |
Non-Patent Citations (1)
| Title |
|---|
| JPN6011062387; 低温生物工学会誌 第４９巻，第１号, 2003, ｐ．４７-５３ * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101269215A (en) | 2008-09-24 |
| KR101095647B1 (en) | 2011-12-19 |
| KR20090119741A (en) | 2009-11-19 |
| JP5143784B2 (en) | 2013-02-13 |
| WO2009138042A1 (en) | 2009-11-19 |
| CN101269215B (en) | 2011-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1165341C (en) | Liquid gonadotropin containing formulations | |
| EP3412310B1 (en) | Pharmaceutical formulations of tnf-alpha antibodies | |
| JP5620824B2 (en) | FSH liquid formulation | |
| CN107249622B (en) | Pharmaceutical composition comprising plasminogen and uses thereof | |
| US11260102B2 (en) | Manufacture of Degarelix | |
| JP6078129B2 (en) | Stable MIA / CD-RAP formulation | |
| JP2002524514A (en) | Protein preparation | |
| KR100589878B1 (en) | Human growth hormone-containing aqueous pharmaceutical composition | |
| JP4255515B2 (en) | Stabilized growth hormone formulation and method for producing the same | |
| JPH04217630A (en) | Preparation article containing stabilized gonadotropin | |
| JP3702313B2 (en) | Gonadotropin-containing pharmaceutical composition | |
| KR20080106636A (en) | Injectable ready to use solutions comprising human chorionic gonadotropin | |
| JP2003504346A (en) | Growth hormone preparations | |
| JP5143784B2 (en) | Glycoprotein hormone composition | |
| AU2017225236B2 (en) | A lyophilised pharmaceutical formulation and its use | |
| EP1034007A1 (en) | A ONE DOSE SYRINGE, COMPRISING A FREEZE-DRIED PROTEIN COMPOSITION, FOR ADMINISTERING OF A VOLUME LESS THAN 0.5 ml | |
| JP2007161702A (en) | Pharmaceutical composition for aqueous inhalation | |
| KR101483165B1 (en) | Compositions of menopausal gonadotrophins | |
| MXPA03008545A (en) | Pharmaceutical compositions containing human growth hormone. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20111129 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120224 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120703 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121002 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20121106 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121121 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151130 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5143784 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |