CN115429751B - Human recombinant follicle-stimulating hormone injection and preparation method thereof - Google Patents
Human recombinant follicle-stimulating hormone injection and preparation method thereof Download PDFInfo
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- CN115429751B CN115429751B CN202211152386.9A CN202211152386A CN115429751B CN 115429751 B CN115429751 B CN 115429751B CN 202211152386 A CN202211152386 A CN 202211152386A CN 115429751 B CN115429751 B CN 115429751B
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- 102000012673 Follicle Stimulating Hormone Human genes 0.000 title claims abstract description 39
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 title claims abstract description 39
- 229940028334 follicle stimulating hormone Drugs 0.000 title claims abstract description 39
- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000003381 stabilizer Substances 0.000 claims abstract description 42
- 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 35
- 239000008101 lactose Substances 0.000 claims abstract description 35
- 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 34
- 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 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 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 21
- 229910001868 water Inorganic materials 0.000 claims abstract description 14
- 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 13
- 239000000203 mixture Substances 0.000 claims description 35
- 238000009472 formulation Methods 0.000 claims description 34
- 239000003755 preservative agent Substances 0.000 claims description 22
- 239000003963 antioxidant agent Substances 0.000 claims description 20
- 235000006708 antioxidants Nutrition 0.000 claims description 20
- 239000002736 nonionic surfactant Substances 0.000 claims description 20
- 230000002335 preservative effect Effects 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- 230000003078 antioxidant effect Effects 0.000 claims description 17
- 239000000872 buffer Substances 0.000 claims description 17
- 239000008215 water for injection Substances 0.000 claims description 16
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 15
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 14
- 229930182817 methionine Natural products 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- 239000006172 buffering agent Substances 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 239000013011 aqueous formulation Substances 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229960002242 chlorocresol Drugs 0.000 claims description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 229930003836 cresol Natural products 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 235000006109 methionine Nutrition 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940013361 cresol Drugs 0.000 claims 1
- 229960003742 phenol Drugs 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 30
- 239000007788 liquid Substances 0.000 abstract description 26
- 238000010257 thawing Methods 0.000 abstract description 24
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 102000003864 Human Follicle Stimulating Hormone Human genes 0.000 abstract description 5
- 108010082302 Human Follicle Stimulating Hormone Proteins 0.000 abstract description 5
- 238000001647 drug administration Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 239000012669 liquid formulation Substances 0.000 description 19
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 13
- 229920001993 poloxamer 188 Polymers 0.000 description 8
- 229940044519 poloxamer 188 Drugs 0.000 description 8
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 2
- 102000006771 Gonadotropins Human genes 0.000 description 2
- 108010086677 Gonadotropins Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002622 gonadotropin Substances 0.000 description 2
- 229940094892 gonadotropins Drugs 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water 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
- A61K9/08—Solutions
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Gynecology & Obstetrics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Zoology (AREA)
- Pregnancy & Childbirth (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a human recombinant follicle-stimulating hormone injection water preparation and a preparation method thereof, wherein the human recombinant follicle-stimulating hormone injection consists of the following raw materials in percentage by mass and volume: 2-10% of a stabilizer of a therapeutically effective amount of human recombinant follicle-stimulating hormone, wherein the stabilizer is prepared from the following components in percentage by mass: 1 and maltose. The invention uses lactose and maltose with specific proportion as stabilizing agent in FSH liquid agent, which has excellent freeze thawing stability, can keep high stability parameter meeting application requirement after 5 freeze thawing cycles, and has stability level obviously superior to human FSH liquid agent added with other stabilizing agent under the same test condition, including the present market
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a human recombinant follicle stimulating hormone injection and a preparation method thereof.
Background
Follicle stimulating hormone (Follicle Stimulating Hormone, FSH), a heterodimeric glycoprotein, consists of non-covalently bound alpha and beta subunits, neither of which are individually biologically active, and which, when combined, cause structural changes to be biologically active, the physiological function of which is to promote ovarian (or testis) development, and to promote follicular (or sperm) formation and release.
FSH is a technical problem which is difficult to overcome in the process of preparing a pharmaceutical preparation as a protein substance. FSH is usually formulated as a lyophilized powder for injection to solve the problem of poor stability in aqueous solution. For example, EP0448146B1 discloses a lyophilized formulation comprising stabilizing gonadotropins, including FSH, with a polycarboxylic acid or a salt thereof, preferably citric acid and sucrose. As another example, EP0618808B1 discloses a lyophilized formulation which uses a combination of sucrose and glycine to stabilize gonadotropins, including FSH. However, the freeze-dried product has the following inconveniences: 1) The steps of freezing and drying are added after the preparation of the product is finished, so that the cost and the control difficulty of the process are increased, and the loss risk of protein is increased; 2) The need to add a reconstitution step prior to use increases the difficulty of administration to patients who need to administer the drug alone and increases the risk of inaccurate administration. Ease of handling and administration of FSH formulations is critical for patients in need of regular administration of FSH (e.g. patients receiving daily doses of recombinant human FSH for the purpose of inducing ovulation), especially for patients selected for autonomous administration. Based on the real needs of the patient, the ready-to-use injectable formulations are of greater concern than lyophilized formulations.
FSH has been formulated in single and multiple dose liquid form into dedicated syringes to form ready-to-inject products, e.gWhile it facilitates the daily injection needs of patients who need regular injections of FSH, there is a higher demand for stability of the medicament, in particular for storage stability, since the injection needs of the patient are continuous, and the patient will have to carry the FSH injection product (in particular the multi-dose product) at any time to transfer the storage site according to his work or living needs in order to ensure the integrity of the self-administered procedure. Intact and normative cold chain transport is sought as a protein drug, butSolving the problem that normal cold chain is strictly and inappropriately provided by common patients in daily transfer is expected that FSH instant injection products are inevitably subjected to multiple taking and storage of the patients in the application process, and further subjected to repeated heating and cooling processes, so that the freeze-thawing stability of the products is a key property that the products can meet the autonomous regular application of the patients.
Liquid formulations of hFSH containing glycine and methionine as stabilizers are disclosed in patent CN101272764B, which are capable of exhibiting good stability for 6 months storage time at room temperature, and liquid formulations of rhFSH with benzyl alcohol and benzalkonium chloride as preservatives, which have good preservative properties and which are capable of keeping FSH stable after storage for 9 weeks at 37 ℃, are disclosed in patent application CN110433136 a. FSH formulations with chlorocresol as preservative are disclosed in patent application CN113198005a, which are capable of improving the stability of rFSH with mammalian glycosylation pattern at high temperatures. However, the inventor found during the development that the existing FSH liquid preparation is not enough to resist multiple freeze-thawing cycles, the number of dissociated subunits is increased, the protein content is obviously reduced and the purity is also reduced after 5 freeze-thawing cycles, and the above results indicate that the existing FSH liquid preparation may be unstable during the repeated carrying and storage of a patient, so that the development of the FSH liquid preparation with good freeze-thawing stability is a realistic requirement for helping the patient to realize the administration freedom.
Disclosure of Invention
In order to solve the problems related to freeze-thawing stability of the injection water preparation, the invention provides a human recombinant follicle-stimulating hormone injection water preparation, which comprises the following components:
a therapeutically effective amount of human recombinant follicle stimulating hormone, stabilizer 2-10% w/v;
the mass ratio of the stabilizer is 3-4: 1 lactose and maltose;
the pH of the injection water preparation is 6.5-7.5.
Further, the stabilizer is prepared from the following components in percentage by mass: 1 and maltose.
Further, the water preparation also comprises 0.01-0.2% (w/v) of antioxidant, 0.3-2% (w/v) of preservative and 0.01-0.2% (w/v) of nonionic surfactant.
Still further, the antioxidant is selected from any one or more of methionine, ascorbic acid, sodium bisulphite, sodium metabisulfite, sodium thiosulfate, preferably methionine or ascorbic acid;
the preservative is selected from any one or more of m-cresol, benzyl alcohol, chlorocresol, chlorobutanol, phenol and cresol, preferably m-cresol or benzyl alcohol;
the nonionic surfactant is selected from poloxamer or polysorbate, preferably poloxamer 188 or polysorbate 20.
Further, the aqueous injection formulation is pH adjusted with a buffer of 6.5-7.5; the buffer is selected from phosphate, succinate, acetate and/or citrate.
Still further, the buffer is a phosphate; the phosphate is selected from sodium dihydrogen phosphate and/or disodium hydrogen phosphate.
Further, the injectable aqueous formulation comprises the following components:
300-900IU/mL of human recombinant follicle-stimulating hormone, 5-8% (w/v) of stabilizing agent, 0.01-0.1% (w/v) of antioxidant, 0.3-1% (w/v) of preservative, 0.01-0.1% (w/v) of nonionic surfactant, and buffering agent, wherein the buffering agent adjusts the pH value of the injection water preparation to 6.5-7.5.
Still further, the aqueous formulation comprises the following ingredients:
600IU/mL of human recombinant follicle-stimulating hormone, 6% (w/v) of a stabilizing agent, 0.01% (w/v) of an antioxidant, 0.3% (w/v) of a preservative, 0.01% (w/v) of a nonionic surfactant, and a buffer which adjusts the pH of the injectable aqueous formulation to 6.7-7.3.
Still further, the aqueous formulation comprises the following ingredients:
human recombinant follicle-stimulating hormone 600IU/mL, mass ratio 3:1 (w/v), methionine 0.01% (w/v), m-cresol 0.3% (w/v), poloxamer 1880.01% (w/v), and sodium dihydrogen phosphate and disodium hydrogen phosphate as buffers, which adjust the pH of the aqueous formulation to 6.7-7.3.
In another aspect, the present invention also provides a method of preparing a human recombinant follicle stimulating hormone injection, comprising the steps of:
1) Taking water for injection with the formula amount of 60-80%, and sequentially adding a buffer, lactose, maltose, an antioxidant, a nonionic surfactant and a preservative for dissolution to obtain a solution A;
2) Adding the recombinant follicle-stimulating hormone with the required effective amount for treatment into the solution A, supplementing the rest water for injection, and stirring for more than 20min to obtain a solution B;
3) Detecting the pH of the solution B, adding a buffering agent according to the requirement to control the pH to be within the range of 6.7-7.3, sub-packaging in a card bottle sterilized by an external package after filtering and sterilizing, plugging and packaging a rubber plug sterilized by damp and heat, and transferring to a cold storage at the temperature of 2-8 ℃ for storage.
Advantageous effects
The invention uses lactose and maltose with specific proportion as stabilizing agent in FSH liquid agent, which has excellent freeze thawing stability, can keep high stability parameter meeting application requirement after 5 freeze thawing cycles, and has stability level obviously superior to human FSH liquid agent added with other stabilizing agent under the same test condition, including the present marketProvides a guarantee for patients to realize the drug administration freedom, and has market popularization and application values.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
EXAMPLE 1 recombinant follicle stimulating hormone injection of the present inventors
The unit dose formula comprises:
human recombinant follicle stimulating hormone rhFSH 33 μg (corresponding to 450 IU)
Mass ratio 3:1 lactose and maltose (stabilizer) 60mg
Methionine (antioxidant) 0.1mg
M-cresol (preservative) 3.0mg
Poloxamer 188 (nonionic surfactant) 0.1mg
Na 2 HPO 4 ·2H 2 O (buffer) 1.1mg
NaH 2 PO 4 ·H 2 O (buffer) 0.45mg
Sufficient water for injection to 1mL
The preparation process comprises the following steps:
1) Taking water for injection with the formula amount of 60-80%, and sequentially adding a buffer, lactose, maltose, an antioxidant, a nonionic surfactant and a preservative according to the formula amount to dissolve to obtain a solution A;
2) Obtaining rhFSH by referring to the method of the embodiment of the applicant in the prior patent CN110305903B, adding the rhFSH into the solution A, supplementing the rest water for injection, and stirring for more than 20 minutes to obtain a solution B;
3) Detecting the pH of the solution B, using a buffering agent to control the pH to be within the range of 6.7-7.3 according to the requirement, sub-packaging in a card bottle sterilized by an external package after filtering and sterilizing, plugging and packaging a rubber plug sterilized by damp and heat, and transferring to a cold storage at the temperature of 2-8 ℃ for storage.
EXAMPLE 2 recombinant follicle stimulating hormone injection of the present invention
Single dose formulation:
44. Mu.g (corresponding to 600 IU) of human recombinant follicle stimulating hormone,
mass ratio 3:1 lactose and maltose (stabilizer) 50mg
Methionine (antioxidant) 0.1mg
M-cresol (preservative) 3.0mg
Poloxamer 188 (nonionic surfactant) 0.1mg
Na 2 HPO 4 ·2H 2 O (buffer) 1.1mg
NaH 2 PO 4 ·H 2 O (buffer) 0.45mg
Sufficient water for injection to 1mL
The preparation process comprises the following steps:
the same formulation procedure as in example 1 was used
EXAMPLE 3 recombinant follicle stimulating hormone injection of the present invention
The unit dose formula comprises:
55. Mu.g (corresponding to 750 IU) of human recombinant follicle stimulating hormone,
mass ratio 4:1 lactose and maltose (stabilizer) 80mg
Methionine (antioxidant) 0.1mg
Benzyl alcohol (preservative) 10mg
Poloxamer 188 (nonionic surfactant) 0.1mg
Na 2 HPO 4 ·2H 2 O 1.1mg
NaH 2 PO 4 ·H 2 O 0.45mg
Sufficient water for injection to 1mL
The preparation process comprises the following steps:
the same formulation procedure as in example 1 was used
EXAMPLE 4 recombinant follicle stimulating hormone injection of the present inventors
The unit dose formula comprises:
human recombinant follicle-stimulating hormone 44 μg (corresponding to 600 IU)
Mass ratio 4:1 lactose and maltose (stabilizer) 80mg
Methionine (antioxidant) 0.1mg
Benzyl alcohol (preservative) 10mg
Polysorbate 20 (non-ionic surfactant) 0.2mg
Na 2 HPO 4 ·2H 2 O 1.1mg
NaH 2 PO 4 ·H 2 O 0.45mg
Sufficient water for injection to 1mL
The preparation process comprises the following steps:
the same formulation procedure as in example 1 was used
The advantageous effects of the present invention are described below by way of test examples.
Test example 1 freeze thawing stability of human recombinant follicle-stimulating hormone injection water formulation
Test group 1 single dose liquid formulations were prepared based on lactose/maltose (3:1) as stabilizer
1. Preparation of the formulation
After lactose/maltose mass ratio 3:1 is used as a stabilizer to be compounded with different antioxidants, different nonionic surfactants or different preservatives, stability parameters of the lactose/maltose mass ratio after 5 freeze thawing cycles are tested, and specific prescriptions are shown in tables 1-2:
TABLE 1 prescription information for FSH Single dose formulations
| Component/ml | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| rhFSH | 600IU | 600IU | 600IU | 600IU |
| Na 2 HPO 4 ·2H 2 O | 1.1mg | 1.1mg | 1.1mg | 1.1mg |
| NaH 2 PO 4 ·H 2 O | 0.45mg | 0.45mg | 0.45mg | 0.45mg |
| Methionine | 0.1mg | 0.1mg | 0.1mg | 0.1mg |
| Ascorbic acid | — | — | — | — |
| Poloxamer 188 | 0.1mg | — | 0.1mg | — |
| Tween 20 | — | 0.2mg | — | 0.2mg |
| M-cresol | 3.0mg | 3.0mg | — | — |
| Benzyl alcohol | — | — | 10mg | 10mg |
| Lactose and lactose | 45mg | 45mg | 45mg | 45mg |
| Maltose | 15mg | 15mg | 15mg | 15mg |
| Water for injection | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml |
TABLE 2 prescription information for FSH Single dose formulations
Test group 2 single dose liquid formulations were prepared based on lactose/maltose (4:1) as stabilizer
After lactose/maltose mass ratio of 4:1 is used as a stabilizer to be compounded with different antioxidants, different nonionic surfactants or different preservatives, stability parameters after 5 freeze thawing cycles are tested, and specific prescriptions are shown in tables 3-4:
TABLE 3 prescription information for FSH Single dose formulations
| Component/ml | Prescription 9 | Prescription 10 | Prescription 11 | Prescription 12 |
| rhFSH | 600IU | 600IU | 600IU | 600IU |
| Na 2 HPO 4 ·2H 2 O | 1.1mg | 1.1mg | 1.1mg | 1.1mg |
| NaH 2 PO 4 ·H 2 O | 0.45mg | 0.45mg | 0.45mg | 0.45mg |
| Methionine | 0.1mg | 0.1mg | 0.1mg | 0.1mg |
| Ascorbic acid | — | — | — | — |
| Poloxamer 188 | 0.1mg | — | 0.1mg | — |
| Tween 20 | — | 0.2mg | — | 0.2mg |
| M-cresol | 3.0mg | 3.0mg | — | — |
| Benzyl alcohol | — | — | 10mg | 10mg |
| Lactose and lactose | 48mg | 48mg | 48mg | 48mg |
| Maltose | 12mg | 12mg | 12mg | 12mg |
| Water for injection | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml |
TABLE 4 prescription information for FSH Single dose formulations
| Component/ml | Prescription 13 | Prescription 14 | Prescription 15 | Prescription 16 |
| rhFSH | 600IU | 600IU | 600IU | 600IU |
| Na2HPO4·2H2O | 1.1mg | 1.1mg | 1.1mg | 1.1mg |
| NaH2PO4·H2O | 0.45mg | 0.45mg | 0.45mg | 0.45mg |
| Methionine | — | — | — | — |
| Ascorbic acid | 0.1mg | 0.1mg | 0.1mg | 0.1mg |
| Poloxamer 188 | 0.1mg | — | — | 0.1mg |
| Tween 20 | — | 0.2mg | 0.2mg | — |
| M-cresol | 3.0mg | 3.0mg | — | — |
| Benzyl alcohol | — | — | 10mg | 10mg |
| Lactose and lactose | 48mg | 48mg | 48mg | 48mg |
| Maltose | 12mg | 12mg | 12mg | 12mg |
| Water for injection | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 1ml |
Comparative group 1 Single dose liquid formulation based on different proportions of lactose/maltose as stabilizer
After the lactose/maltose other mass ratio is used as a stabilizer to be compounded with a preferable antioxidant, a nonionic surfactant and a preservative, stability parameters after 5 freeze thawing cycles are tested, and a specific prescription is shown in table 5:
TABLE 5 formulation of comparative FSH Single dose liquid formulations
| Component/ml | Comparative prescription 1 | Comparative prescription 2 | Comparative prescription 3 | Comparative prescription 4 | Comparative prescription 5 |
| rhFSH | 600IU | 600IU | 600IU | 600IU | 600IU |
| Na 2 HPO 4 ·2H 2 O | 1.1mg | 1.1mg | 1.1mg | 1.1mg | 1.1mg |
| NaH 2 PO 4 ·H 2 O | 0.45mg | 0.45mg | 0.45mg | 0.45mg | 0.45mg |
| Methionine | 0.1mg | 0.1mg | 0.1mg | 0.1mg | 0.1mg |
| Poloxamer 188 | 0.1mg | 0.1mg | 0.1mg | 0.1mg | 0.1mg |
| M-cresol | 3.0mg | 3.0mg | 3.0mg | 3.0mg | 3.0mg |
| Lactose and lactose | 50mg | 30mg | 10mg | 60mg | — |
| Maltose | 10mg | 30mg | 50mg | — | 60mg |
| Water for injection | Sufficient to 1ml | Sufficient to 1ml | Sufficient to 2ml | Sufficient to 1ml | Sufficient to 1ml |
Comparative group 2 Single dose liquid formulations based on stabilizers of different saccharides or classes
After different saccharides or amino acids are used as stabilizers to be compounded with preferred antioxidants, nonionic surfactants and preservatives, stability parameters after 5 freeze thawing cycles are tested, and specific prescriptions are shown in table 6:
TABLE 6 formula for single dose liquid FSH formulations of comparative examples
FSH liquid preparation and its preparing method
Preparation example
The liquid preparation for FSH injection of each prescription in the test group and the comparison group is prepared according to the general rule of the injection water needle process, and is specifically as follows:
1) According to the prescription information in tables 1-6, buffer, stabilizer, antioxidant, nonionic surfactant and preservative dosed according to specific batch requirements were added to 4L of water for injection to dissolve to obtain solution A, and the temperature was maintained at 2-10℃during the formulation of solution A.
2) FSH stock solution prepared according to the prior patent CN110305903B of the applicant is added into the solution A prepared in the step 1), and the volume is fixed to 5L by using water for injection to obtain solution B. The pH of the solution B was measured, the dilution was adjusted to pH7.0 using a 1mol/LNaOH solution or 1mol/LHCl, mixed well, stirred for 20min, and then filtered sterilized with a 0.22 μm cellulose acetate membrane (Sartobran 150 from Sartor IUs Co.).
Before 0.22 mu m cellulose acetate membrane filtration, the integrity test of the sterilizing filter is carried out by adopting a bubble point test method, and the integrity test is carried out before and after the filtration sample. The testing method comprises the following steps: the filter is fully soaked by ultrapure water (room temperature), the exhaust hole is closed, the liquid inlet end is connected with the pressure gauge and sterile compressed air by a high-strength pipeline, the air inlet valve is gradually opened to introduce air, the change of the number of the pressure gauge is observed, and after bubbles at the outlet of the rear part of the filter are uniform, the value of the pressure gauge is read, namely the bubble point. Filter integrity is satisfactory when the bubble point of the filter is not below the minimum bubble point specified in the product specification. If the filter is not qualified, the newly assembled filter is replaced and the integrity check is carried out, and the filtering can be started after the integrity check of the filter is qualified. After filtration, the filtration system should be qualified for integrity checking under the bubble point test method. And if the failure is treated according to the deviation treatment management system. The ingredients are made of stainless steel or disposable sterile liquid storage bags as much as possible. The time from preparation to filtration is controlled within 10 hours.
3) Subpackaging the solution B prepared in the step 2) into card-type bottles with sterilized outer packages in a sterile environment, and plugging and packaging the rubber plugs subjected to damp-heat sterilization, and transferring to a cold storage with the temperature of 2-8 ℃ for storage.
2. Detection and results
Test mode and standard:
in examining the freeze-thawing stability, the accelerated test stability and the long-term stability of the formulation, the preset standards used in the invention for representing the stability of the formulation are: the pH value is in the range of 6.7-7.3, jie Liya base is less than or equal to 5.0%, alpha subunit oxide is less than or equal to 8.0%, total oxide is less than or equal to 10.0%, protein content is 90.0-110.0%, polymer is less than or equal to 2.0%, and monomer SEC purity is more than or equal to 97.0%.
The following table sets forth various test conditions for formulation stability:
2.1 examination of the Freeze thawing stability of the liquid FSH formulations
As shown in tables 7-10, each of the prescribed FSH liquid formulations in test group 1 still had good freeze-thaw stability after undergoing 5 freeze-thaw cycles, each of the prescribed FSH liquid formulations in test group 2 was within the preset standard range of stability after undergoing 5 freeze-thaw cycles, although some of the prescriptions detected polymers, and the other indicators exhibited excellent performance, specifically as follows:
TABLE 7 Freeze-thaw stability data for liquid formulations of formulations 1-4 of test group 1
TABLE 8 Freeze-thaw stability data for liquid formulations of formulations 5-8 of test group 1
TABLE 9 Freeze-thaw stability data for liquid formulations of formulations 9-12 of trial group 2
TABLE 10 Freeze-thaw stability data for liquid formulations of formulations 13-16 of test group 2
As shown in table 11, varying the ratio of lactose/maltose interactions, e.g., 5:1, 1:1 or 1:5, or lactose or maltose alone, based on the use of the two interactions as a stabilizer, the resulting liquid formulations had significantly altered stability levels after 5 freeze-thaw cycles, as follows:
TABLE 11 Freeze-thaw stability data for liquid formulations of comparative formulas 1-5 in comparative group 1
As shown in table 12, in the case that the FSH liquid preparation is a preferred component for other components, the stabilizer is changed to other saccharides or amino acid stabilizer, and the stability level of the obtained liquid preparation is significantly changed after 5 freeze thawing cycles, specifically as follows:
TABLE 12 Freeze-thaw stability data for comparative formulas 6-11 in comparative group 2
Conclusion of freeze-thaw stability test:
1. based on tables 7-10, when lactose/maltose is compounded as a stabilizer in a mass ratio of 3:1 or 4:1, the resulting FSH liquid formulation is able to maintain satisfactory stability parameters after 5 freeze-thaw cycles, indicating that it has ideal freeze-thaw stability, even if other additive components change the compounding. The lactose/maltose 3:1 formulation, when used as a stabilizer, showed extremely excellent freeze-thaw stability results, with all prescriptions still no polymer detected after five freeze-thaw cycles. When lactose/maltose 4:1 is compounded to be used as a stabilizer, polymers are detected in most groups, but the detected amount is obviously lower than the standard amount and still belongs to a prescription with ideal freeze thawing stability which accords with the preset standard.
2. Based on table 11, when the mass ratio of lactose/maltose is further changed or when either is added alone, the resulting liquid cannot maintain good stability parameters after five freeze-thawing cycles, which are manifested to various degrees by an increase in dissociated subunit content, an increase in oxide, a decrease in protein content, an increase in polymer and a decrease in purity, making it impossible to meet preset criteria for stability.
3. Based on Table 12, it is understood that when other saccharide stabilizers or amino acid stabilizers are used, the resulting liquid preparation also fails to maintain good stability parameters after 5 freeze-thawing cycles, even if it is freshly groundNor can the prescription of (c) maintain the stability parameters after 5 freeze-thaw cycles all meet the preset criteria.
The above experimental data indicate that selecting lactose/maltose interactions as stabilizers and controlling their mass ratio in the range of 3:1-4:1 is a key technical means to achieve excellent freeze-thaw stability of FSH liquid formulations.
2.2 investigation of test group 1-2 accelerated test stability and Long term stability
As shown in the above freeze-thaw stability data, each of the prescribed FSH liquid formulations in test groups 1-2 has excellent freeze-thaw stability, and in order to verify whether it has overall stability performance, the accelerated test stability and long-term stability of each of the prescribed FSH liquid formulations in test groups 1-2 are continuously tested, and specific results are shown in tables 13-16:
TABLE 13 stability data for each prescription acceleration test in example 1
TABLE 14 Long term stability data for each formulation in example 1
TABLE 15 stability data for each prescription acceleration test in example 2
TABLE 16 Long term stability data for each prescription in example 2
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Conclusion of accelerated test stability and long term stability test
Based on tables 13-16, each prescription FSH liquid preparation of test group 1-2 has excellent freeze thawing stability, and also has good stability in acceleration test and long-term test, and the FSH liquid preparation adopting lactose/maltose to be compounded at a ratio of 3:1 or 4:1 as a stabilizer is indicated to be capable of meeting the stability requirements of storage, transportation and environmental change of the required FSH liquid preparation in daily use, so that the quality risk caused by poor freeze thawing stability of the FSH instant injection liquid preparation in the prior art is solved.
In conclusion, the invention uses lactose and maltose with specific proportions as the stabilizer in the FSH liquid agent, so that the FSH liquid agent has excellent freeze thawing stability, can still keep high stability parameters meeting application requirements after 5 freeze thawing cycles, has stability level obviously superior to that of the human FSH liquid agent added with other stabilizers under the same test condition, and comprises the liquid agent which is currently sold in the marketHas market popularization and application value. />
Claims (10)
1. A human recombinant follicle-stimulating hormone injection water formulation, characterized in that: it comprises the following components:
a therapeutically effective amount of a human recombinant follicle stimulating hormone;
6% w/v stabilizer; the mass ratio of the stabilizer is 3-4: 1 lactose and maltose;
the pH of the injection water preparation is 6.5-7.5.
2. The aqueous human recombinant follicle-stimulating hormone injection formulation of claim 1, wherein: the stabilizer is prepared from the following components in percentage by mass: 1 and maltose.
3. The aqueous human recombinant follicle-stimulating hormone injection formulation of claim 1, wherein: it also comprises 0.01 to 0.2 percent of antioxidant, 0.3 to 2 percent of preservative and 0.01 to 0.2 percent of nonionic surfactant.
4. The aqueous preparation for injection of human recombinant follicle stimulating hormone according to claim 3, wherein: the antioxidant is selected from any one or more of methionine, ascorbic acid, sodium bisulphite, sodium metabisulfite and sodium thiosulfate;
the preservative is selected from one or more of m-cresol, benzyl alcohol, chlorocresol, chlorobutanol, phenol and cresol;
the nonionic surfactant is selected from poloxamer or polysorbate.
5. The aqueous human recombinant follicle-stimulating hormone injection formulation of claim 1, wherein: the pH of the injection water preparation is regulated to 6.5-7.5 by a buffering agent;
the buffer is selected from any one or more of phosphate, succinate, acetate and citrate.
6. The aqueous human recombinant follicle-stimulating hormone injection formulation of claim 5, wherein: the buffer is phosphate; the phosphate is selected from sodium dihydrogen phosphate and/or disodium hydrogen phosphate.
7. The aqueous human recombinant follicle-stimulating hormone injection formulation of claim 3, wherein: it comprises the following components:
300-900IU/mL of human recombinant follicle-stimulating hormone, 6% w/v of stabilizing agent, 0.01-0.1% w/v of antioxidant, 0.3-1% w/v of preservative, 0.01-0.1% w/v of nonionic surfactant and buffering agent, wherein the buffering agent adjusts the pH of the injection water preparation to 6.5-7.5.
8. The aqueous preparation for injection of human recombinant follicle stimulating hormone according to claim 7, wherein: it comprises the following components:
600IU/mL of human recombinant follicle stimulating hormone, 6% w/v of stabilizer, 0.01% w/v of antioxidant, 0.3% w/v of preservative, 0.01% w/v of nonionic surfactant, and phosphate as buffer, which adjusts the pH of the injectable aqueous formulation to 6.7-7.3.
9. The aqueous preparation for injection of human recombinant follicle stimulating hormone according to claim 7, wherein: the composition comprises the following components:
human recombinant follicle-stimulating hormone 600IU/mL, mass ratio 3:1, methionine 0.01% w/v, m-cresol 0.3% w/v, poloxamer 1880.01% w/v, and sodium dihydrogen phosphate and disodium hydrogen phosphate as buffers, which adjust the pH of the aqueous formulation to 6.7-7.3.
10. A method for preparing the human recombinant follicle-stimulating hormone injection water formulation of any one of claims 3 to 8, characterized in that: it comprises the following steps:
1) Taking water for injection with the formula amount of 60-80%, and sequentially adding a buffer, lactose, maltose, an antioxidant, a nonionic surfactant and a preservative for dissolution to obtain a solution A;
2) Adding the recombinant follicle-stimulating hormone with the required effective amount for treatment into the solution A, supplementing the rest water for injection, and stirring for more than 20min to obtain a solution B;
3) Detecting the pH of the solution B, adding a buffering agent according to the requirement to control the pH to be between 6.7 and 7.3, and sterilizing to obtain the product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1795012A (en) * | 2003-04-02 | 2006-06-28 | 阿雷斯贸易股份有限公司 | Liquid pharmaceutical formulations of fsh and lh together with a non-ionic surfactant |
| CN101272764A (en) * | 2005-09-27 | 2008-09-24 | 株式会社Lg生命科学 | hFSH aqueous formulation |
| CN104524553A (en) * | 2014-12-12 | 2015-04-22 | 薛传校 | Long-acting ovulation promoting injection |
| CN108785670A (en) * | 2014-05-23 | 2018-11-13 | 费森尤斯卡比德国有限公司 | Composition of liquid medicine |
| CN113198005A (en) * | 2015-09-17 | 2021-08-03 | 葛莱高托普有限公司 | Mammalian follicle stimulating hormone compositions with improved stability |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1795012A (en) * | 2003-04-02 | 2006-06-28 | 阿雷斯贸易股份有限公司 | Liquid pharmaceutical formulations of fsh and lh together with a non-ionic surfactant |
| CN101272764A (en) * | 2005-09-27 | 2008-09-24 | 株式会社Lg生命科学 | hFSH aqueous formulation |
| CN108785670A (en) * | 2014-05-23 | 2018-11-13 | 费森尤斯卡比德国有限公司 | Composition of liquid medicine |
| CN104524553A (en) * | 2014-12-12 | 2015-04-22 | 薛传校 | Long-acting ovulation promoting injection |
| CN113198005A (en) * | 2015-09-17 | 2021-08-03 | 葛莱高托普有限公司 | Mammalian follicle stimulating hormone compositions with improved stability |
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