CN111544569A - Buserelin acetate freeze-dried powder injection for animal injection and preparation method and application thereof - Google Patents
Buserelin acetate freeze-dried powder injection for animal injection and preparation method and application thereof Download PDFInfo
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- CN111544569A CN111544569A CN202010401967.6A CN202010401967A CN111544569A CN 111544569 A CN111544569 A CN 111544569A CN 202010401967 A CN202010401967 A CN 202010401967A CN 111544569 A CN111544569 A CN 111544569A
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- injection
- buserelin acetate
- dried powder
- freeze
- animal
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- 238000002347 injection Methods 0.000 title claims abstract description 91
- 239000007924 injection Substances 0.000 title claims abstract description 91
- 108010037003 Buserelin Proteins 0.000 title claims abstract description 70
- PYMDEDHDQYLBRT-DRIHCAFSSA-N Buserelin acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 PYMDEDHDQYLBRT-DRIHCAFSSA-N 0.000 title claims abstract description 65
- 229960005064 buserelin acetate Drugs 0.000 title claims abstract description 65
- 241001465754 Metazoa Species 0.000 title claims abstract description 47
- 239000000843 powder Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 27
- 229920002307 Dextran Polymers 0.000 claims abstract description 27
- 229930195725 Mannitol Natural products 0.000 claims abstract description 27
- 235000010355 mannitol Nutrition 0.000 claims abstract description 27
- 239000000594 mannitol Substances 0.000 claims abstract description 27
- 230000001850 reproductive effect Effects 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 238000000859 sublimation Methods 0.000 claims description 33
- 230000008022 sublimation Effects 0.000 claims description 33
- 239000000706 filtrate Substances 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 29
- 239000008215 water for injection Substances 0.000 claims description 29
- 238000010438 heat treatment Methods 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 19
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000008055 phosphate buffer solution Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- 238000007710 freezing Methods 0.000 claims description 13
- 230000008014 freezing Effects 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 239000000273 veterinary drug Substances 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 238000004108 freeze drying Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000011049 filling Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical group CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 8
- 229930182555 Penicillin Natural products 0.000 description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 6
- 229940049954 penicillin Drugs 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 5
- 229960002719 buserelin Drugs 0.000 description 5
- 230000016087 ovulation Effects 0.000 description 5
- 230000009027 insemination Effects 0.000 description 4
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical group [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000005262 decarbonization Methods 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 238000005057 refrigeration Methods 0.000 description 3
- 238000005096 rolling process Methods 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000012173 estrus Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides buserelin acetate freeze-dried powder injection for animal injection and a preparation method and application thereof, belonging to the technical field of veterinary drugs; the buserelin acetate freeze-dried powder injection for animal injection comprises the following raw materials in parts by mass for preparation: 0.03-0.08 part of buserelin acetate, 25-35 parts of dextran and 25-35 parts of mannitol; the pH value of the buserelin acetate freeze-dried powder injection for animal injection is 5.5-6.5. The buserelin acetate freeze-dried powder injection for animal injection is a stable preparation, can be quickly dissolved and has good solubility. The buserelin acetate freeze-dried powder injection for animal injection can be used for improving the reproductive performance of animals.
Description
Technical Field
The invention relates to the technical field of veterinary drugs, in particular to buserelin acetate freeze-dried powder injection for animal injection and a preparation method and application thereof.
Background
Buserelin acetate is a synthetic hypothalamic secreted natural gonadotropin releasing hormone (GnRH/LHRH) analogue, is a water-soluble polypeptide drug, is completely absorbed after subcutaneous injection administration, is concentrated in the liver, the kidney and the anterior pituitary, has a biological half-life of 80min, can promote the secretion of luteinizing hormone LH, follicle stimulating hormone FSH and sex hormone to be increased, has a pharmacological effect of 20-170 times of LHRH, is clinically used for the treatment of prostatic cancer, endometriosis and infertility, and needs to be injected for multiple times when in use. Buserelin acetate for injection in the prior art is less researched. Busherelin acetate-PLGA sustained-release nanoparticles for injection are researched by Hulei (see [ Busherelin, research on Busherelin acetate-PLGA sustained-release nanoparticles for injection, third military medical university, 2009 ]), and are human medicines. The national veterinary drug administration regulations are clear, and the use of human drugs for animals is prohibited. At present, buserelin acetate freeze-dried powder injection special for animals is lacked.
Disclosure of Invention
The invention aims to provide buserelin acetate freeze-dried powder injection for animal injection and a preparation method and application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides buserelin acetate freeze-dried powder injection for animal injection, which comprises the following raw materials in parts by mass for preparation: 0.03-0.08 part of buserelin acetate, 25-35 parts of dextran and 25-35 parts of mannitol; the pH value of the buserelin acetate freeze-dried powder injection for animal injection is 5.5-6.5.
Preferably, the water content of the freeze-dried powder injection is less than or equal to 3 percent.
Preferably, the raw materials for preparing the buserelin acetate freeze-dried powder injection for animal injection also comprise phosphate buffer solution and water for injection.
The invention also provides a preparation method of the buserelin acetate freeze-dried powder injection for animal injection, which comprises the following steps:
1) mixing a dextran aqueous solution, a mannitol aqueous solution, a phosphate buffer solution and water for injection to obtain a first mixed solution, adding activated carbon into the first mixed solution, stirring for 25-35 min at 75-85 ℃, removing the activated carbon, filtering, and collecting a first filtrate;
2) adjusting the pH value of the first filtrate to 5.5-6.5, mixing the first filtrate with buserelin acetate and water for injection to obtain a second mixed solution, and filtering the second mixed solution with a microporous filter membrane to obtain a second filtrate;
3) cooling the second filtrate to-40 ℃, and pre-freezing for 3-5 h at-40 ℃ to obtain a pre-frozen mixture;
4) heating the pre-frozen mixture to-18 ℃, and carrying out primary sublimation drying for 10-20 h under the conditions of-18 ℃ and 0.2-0.4 mbar vacuum degree to obtain a primary sublimation dried substance;
5) and heating the first sublimation dried substance to 28-32 ℃, and carrying out second sublimation drying for 4-6 h at the temperature of 28-32 ℃ under the vacuum degree of 0.002-0.006 mbar to obtain the buserelin acetate freeze-dried powder injection for animal injection.
Preferably, the mass concentration of the dextran in the dextran aqueous solution in the step 1) is 25-35 g/100 mL; the mass concentration of mannitol in the mannitol aqueous solution is 25-35 g/100 mL.
Preferably, the volume ratio of the dextran aqueous solution, the mannitol aqueous solution, the phosphate buffer solution and the water for injection in the step 1) is 1: 1: 1: 9.
preferably, the reagent used for adjusting the pH of the first filtrate in step 2) comprises citric acid or lactic acid.
Preferably, the ratio of the mass of octreotide to the volume of the first mixed solution in step 2) is 45-55 mg: 1000 mL.
Preferably, the cooling time in the step 3) is less than or equal to 1 h.
Preferably, the heating time in the step 4) is less than or equal to 1 h.
The invention also provides application of the buserelin acetate freeze-dried powder injection for animal injection in preparation of a medicine for improving reproductive performance of animals.
The invention has the beneficial effects that: the invention provides buserelin acetate freeze-dried powder injection for animal injection, which comprises the following raw materials in parts by mass for preparation: 0.03-0.08 part of buserelin acetate, 25-35 parts of dextran and 25-35 parts of mannitol; the pH value of the buserelin acetate freeze-dried powder injection for animal injection is 5.5-6.5. The buserelin acetate freeze-dried powder injection for animal injection is a stable preparation, can be quickly dissolved and has good solubility. The buserelin acetate freeze-dried powder injection for animal injection can be used for improving the reproductive performance of animals.
Detailed Description
The invention provides buserelin acetate freeze-dried powder injection for animal injection, which comprises the following raw materials in parts by mass for preparation: 0.03-0.08 part of buserelin acetate, 25-35 parts of dextran and 25-35 parts of mannitol; preferably, the buserelin acetate freeze-dried powder injection for animal injection comprises the following raw materials for preparation in parts by mass: 0.05 part of buserelin acetate, 30 parts of dextran and 30 parts of mannitol; the pH value of the buserelin acetate freeze-dried powder injection for animal injection is 5.5-6.5, preferably 5-6, and more preferably 5.5; the water content of the freeze-dried powder injection is preferably less than or equal to 3 percent; the raw materials for preparing the buserelin acetate freeze-dried powder injection for animal injection preferably also comprise phosphate buffer solution and water for injection; the phosphate buffer solution and the water for injection are used in the amount defined in the preparation method.
In the present invention, the phosphate buffer is preferably a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer; the pH value of the disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution is preferably 6; the concentration of the disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution is preferably 0.2 mol/L; the disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution preferably comprises the following components in 100 mL: 0.2mol/L Na2HPO4Aqueous solution 12.3mL, 0.2mol/LNaH2PO487.7mL of aqueous solution.
In the present invention, buserelin acetate, dextran and mannitol are conventionally commercially available.
The buserelin acetate freeze-dried powder injection for animal injection is suitable for pigs, cattle and sheep.
The invention also provides a preparation method of the buserelin acetate freeze-dried powder injection for animal injection, which comprises the following steps:
1) mixing a dextran aqueous solution, a mannitol aqueous solution, a phosphate buffer solution and water for injection to obtain a first mixed solution, adding activated carbon into the first mixed solution, stirring for 25-35 min at 75-85 ℃, removing the activated carbon, filtering, and collecting a first filtrate;
2) adjusting the pH value of the first filtrate to 5.5-6.5, mixing the first filtrate with buserelin acetate and water for injection to obtain a second mixed solution, and filtering the second mixed solution with a microporous filter membrane to obtain a second filtrate;
3) cooling the second filtrate to-40 ℃, and pre-freezing for 3-5 h at-40 ℃ to obtain a pre-frozen mixture;
4) heating the pre-frozen mixture to-18 ℃, and carrying out primary sublimation drying for 10-20 h under the conditions of-18 ℃ and 0.2-0.4 mbar vacuum degree to obtain a primary sublimation dried substance;
5) and heating the first sublimation dried substance to 28-32 ℃, and carrying out second sublimation drying for 4-6 h at the temperature of 28-32 ℃ under the vacuum degree of 0.002-0.006 mbar to obtain the buserelin acetate freeze-dried powder injection for animal injection.
Firstly, mixing a dextran aqueous solution, a mannitol aqueous solution, a phosphate buffer solution and water for injection to obtain a first mixed solution, adding activated carbon into the first mixed solution, stirring for 25-35 min at 75-85 ℃, removing the activated carbon, filtering, and collecting a first filtrate.
In the invention, the mass concentration of dextran in the dextran aqueous solution is preferably 25-35 g/100mL, more preferably 30g/100 mL; the solvent of the dextran aqueous solution is preferably water for injection; the mass concentration of mannitol in the mannitol aqueous solution is preferably 25-35 g/1000mL, and more preferably 30g/1000 mL; the solvent of the mannitol water solution is preferably water for injection; the volume ratio of the dextran aqueous solution, the mannitol aqueous solution, the phosphate buffer solution and the water for injection is preferably 1: 1: 1: 9.
in the present invention, the ratio of the volume of the first mixed liquid to the mass of the activated carbon is preferably 100 mL: 0.1 g; the mode of removing the active carbon and filtering is preferably titanium rod decarburizing and filtering.
In the invention, the activated carbon has the function of removing a heat source, and the titanium rod decarburizing filtration can completely remove the activated carbon.
After the first filtrate is obtained, adjusting the pH value of the first filtrate to 5.5-6.5, mixing the first filtrate with buserelin acetate and water for injection to obtain a second mixed solution, and filtering the second mixed solution by using a microporous filter membrane to obtain a second filtrate; the reagent for adjusting the pH value of the first filtrate preferably comprises citric acid or lactic acid; the pH value after adjustment is preferably 5-6, and more preferably 5.5; the mass of buserelin acetate and the volume of the first mixed solution are preferably in a ratio of 45-55 mg: 1000mL, more preferably 50 mg: 1000 mL; the pore size of the microfiltration membrane is preferably 0.22 μm.
After the second filtrate is obtained, the preferable method of the invention further comprises the step of filling the second filtrate into a penicillin bottle; the canning amount is preferably 1 mL/bottle; after the second filtrate is filled in a penicillin bottle, the second filtrate is cooled to-40 ℃, and is pre-frozen for 3-5 hours at the temperature of-40 ℃ to obtain a pre-frozen mixture; the cooling time is preferably less than or equal to 1 h; the pre-freezing means is preferably a freeze-drying chamber. In the invention, the size of the penicillin bottle is preferably 3 mL.
After the pre-frozen mixture is obtained, heating the pre-frozen mixture to-18 ℃, and carrying out first sublimation drying for 10-20 h under the conditions of-18 ℃ and 0.2-0.4 mbar vacuum degree to obtain a first sublimation dried substance; the heating time is preferably less than or equal to 1 h; the time of the first sublimation drying is preferably 15 hours.
After the first sublimation dried substance is obtained, heating the first sublimation dried substance to 28-32 ℃, and carrying out second sublimation drying for 4-6 h under the conditions of 28-32 ℃ and 0.002-0.006 mbar vacuum degree to obtain buserelin acetate freeze-dried powder injection for animal injection; the heating time is preferably less than or equal to 0.5 h.
The invention also provides the application of the buserelin acetate freeze-dried powder injection for animal injection in the preparation of the medicine for improving the reproductive performance of animals; the improvement in reproductive performance of the animal comprises increasing ovulation rate, increasing pregnancy rate, or increasing litter size; the animals preferably include pigs, cattle and sheep.
When the buserelin acetate freeze-dried powder injection for animal injection is used for improving the reproductive performance of animals, the dosage is 50-100 mug/kg of body weight; the administration mode is subcutaneous or intravenous injection.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparing buserelin acetate freeze-dried powder injection for pet injection: calculated by 1000 bottles, the composition comprises 0.1g of buserelin acetate, 30g of dextran, 30g of mannitol and proper amounts of hydrochloric acid and sodium hydroxide, wherein the water content is less than or equal to 3 percent, and the pH value is 6.0.
1. Weighing 30g of dextran, adding 100mL of water for injection, heating to 80 ℃, and stirring for dissolving; weighing 30g of mannitol, adding 100mL of water for injection, stirring for dissolving, adding 100mL of 10 times of phosphate buffer solution, mixing, adding 900mL of water for injection, and stirring for uniformly mixing; adding 0.1% (0.1mg/100mL) of activated carbon, heating to 80 deg.C, stirring for 30min, performing cyclic decarbonization with titanium rod, and cooling the filtrate to 15 deg.C;
2. adding buserelin acetate 100mg into the solution, stirring for dissolving, adjusting the pH value to 6.0 by using hydrochloric acid and sodium hydroxide solution, and adding water for injection to 1000 mL;
3. sterile filtering the solution prepared in the step 2 by a 0.22 mu microporous filter membrane, and filling the solution into a penicillin bottle in a sterile room; the filling amount is 1 mL/bottle;
4. put into the sabot with xiLin bottle, the freeze-drying case is from last sheet layer to lower sheet layer in proper order, puts into temperature probe in the filling bottle, puts near sight glass hole and closes the chamber door after observing the sample, freezes in advance, and the process of freezing in advance is: firstly, reducing the temperature in a freeze-drying box to-40 ℃ within 1h, and pre-freezing for 3-5 h at-40 ℃;
5. after the pre-freezing and the refrigeration of the condenser are finished, starting a vacuum pump to ensure that the vacuum degree in a freeze-drying box is 0.2-0.4 mbar;
6. first sublimation drying
Heating the plate layer to-18 ℃ within 1h, starting sublimation, keeping the temperature of-18 ℃ and the vacuum degree of 0.2-0.4 mbar for 10-20 h, and finishing the first sublimation when the temperature of the product is not increased any more;
7. second sublimation
After the first sublimation drying is finished, removing residual moisture, heating the plate layer to 30 ℃ within 0.5h, and keeping the temperature at 30 ℃ for 5h to enable the temperature of the product to be close to 25-30 ℃, wherein the vacuum degree is 0.002-0.006 mbar; finishing freeze drying; discharging the box;
8. and (5) rolling a cover, checking, and packaging after the product is qualified.
Example 2
The buserelin acetate freeze-dried powder injection for pet injection is prepared from buserelin acetate 0.05g, dextran 20g, mannitol 40g, and appropriate amount of hydrochloric acid and sodium hydroxide, wherein the water content is less than or equal to 3%, and the pH value is 5.5, wherein the content is 1000 bottles.
1. Weighing 20g of dextran, adding 100mL of water for injection, heating to 80 ℃, and stirring for dissolving; weighing 40g of mannitol, adding 100mL of water for injection, stirring for dissolving, adding 100mL of 10 times of phosphate buffer solution, mixing, adding 900mL of water for injection, and stirring for uniformly mixing; adding 0.1% (0.1mg/100mL) of activated carbon, heating to 80 deg.C, stirring for 30min, performing cyclic decarbonization with titanium rod, and cooling the filtrate to 15 deg.C;
2. adding buserelin acetate 100mg into the solution, stirring for dissolving, adjusting the pH value to 5.5 by using hydrochloric acid and sodium hydroxide solution, and adding water for injection to 1000 mL;
3. sterile filtering the solution prepared in the step 2 by a 0.22 mu microporous filter membrane, and filling the solution into a penicillin bottle in a sterile room; the filling amount is 1 mL/bottle;
4. put into the sabot with xiLin bottle, the freeze-drying case is from last sheet layer to lower sheet layer in proper order, puts into temperature probe in the filling bottle, puts near sight glass hole and closes the chamber door after observing the sample, freezes in advance, and the process of freezing in advance is: firstly, reducing the temperature in a freeze-drying box to-40 ℃ within 1h, and pre-freezing for 3-5 h at-40 ℃;
5. after the pre-freezing and the refrigeration of the condenser are finished, starting a vacuum pump to ensure that the vacuum degree in a freeze-drying box is 0.2-0.4 mbar;
6. first sublimation drying
Heating the plate layer to-18 ℃ within 1h, starting sublimation, keeping the temperature of-18 ℃ and the vacuum degree of 0.2-0.4 mbar for 10-20 h, and finishing the first sublimation when the temperature of the product is not increased any more;
7. second sublimation
After the first sublimation drying is finished, removing residual moisture, heating the plate layer to 30 ℃ within 0.5h, and keeping the temperature at 30 ℃ for 5h to enable the temperature of the product to be close to 25-30 ℃, wherein the vacuum degree is 0.002-0.006 mbar; finishing freeze drying; discharging the box;
8. and (5) rolling a cover, checking, and packaging after the product is qualified.
Example 3
The buserelin acetate freeze-dried powder injection for pet injection is prepared from buserelin acetate 0.1g, dextran 40g, mannitol 20g, and appropriate amount of hydrochloric acid and sodium hydroxide, wherein the water content is less than or equal to 3%, and the pH value is 6.5, wherein the content is 1000 bottles.
1. Weighing 40g of dextran, adding 100mL of water for injection, heating to 80 ℃, and stirring for dissolving; weighing 20g of mannitol, adding 100mL of water for injection, stirring for dissolving, adding 100mL of 10 times of phosphate buffer solution, mixing, adding 900mL of water for injection, and stirring for uniformly mixing; adding 0.1% (0.1mg/100mL) of activated carbon, heating to 80 deg.C, stirring for 30min, performing cyclic decarbonization with titanium rod, and cooling the filtrate to 15 deg.C;
2. adding buserelin acetate 100mg into the solution, stirring for dissolving, adjusting the pH value to 6.0 by using hydrochloric acid and sodium hydroxide solution, and adding water for injection to 1000 mL;
3. sterile filtering the solution prepared in the step 2 by a 0.22 mu microporous filter membrane, and filling the solution into a penicillin bottle in a sterile room; the filling amount is 1 mL/bottle;
4. put into the sabot with xiLin bottle, the freeze-drying case is from last sheet layer to lower sheet layer in proper order, puts into temperature probe in the filling bottle, puts near sight glass hole and closes the chamber door after observing the sample, freezes in advance, and the process of freezing in advance is: firstly, reducing the temperature in a freeze-drying box to-40 ℃ within 1h, and pre-freezing for 3-5 h at-40 ℃;
5. after the pre-freezing and the refrigeration of the condenser are finished, starting a vacuum pump to ensure that the vacuum degree in a freeze-drying box is 0.2-0.4 mbar;
6. first sublimation drying
Heating the plate layer to-18 ℃ within 1h, starting sublimation, keeping the temperature of-18 ℃ and the vacuum degree of 0.2-0.4 mbar for 10-20 h, and finishing the first sublimation when the temperature of the product is not increased any more;
7. second sublimation
After the first sublimation drying is finished, removing residual moisture, heating the plate layer to 30 ℃ within 0.5h, and keeping the temperature at 30 ℃ for 5h to enable the temperature of the product to be close to 25-30 ℃, wherein the vacuum degree is 0.002-0.006 mbar; finishing freeze drying; discharging the box;
8. and (5) rolling a cover, checking, and packaging after the product is qualified.
Example 4
Accelerated stability examination was performed on the compositions for injection prepared in examples 1, 2 and 3, and the samples were placed in a constant temperature and humidity cabinet with a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 65%. + -. 5%, and sampled at 0, 1, 2, 3 and 6 months respectively, and the results are shown in Table 1, and the appearance, clarity, color, pH value and content of the samples are all in accordance with the requirements in Table 1.
TABLE 1 accelerated test results of buserelin acetate for injection (specification: 0.05m, 0.1mg)
Example 5: example 1 Effect of buserelin acetate lyophilized powder for animal injection on sow reproductive function
Grouping experiments: the 270 postweaned sows were divided into 3 groups: 50. mu.g Buserelin group, 100. mu.g Buserelin group, and physiological saline control group. After the sow is weaned for 77h, different doses are used for treatment, namely 50 mu g of Buserelin group (50 mu g of Buserelin acetate freeze-dried powder for one injection), 100 mu g of Buserelin (100 mu g of Buserelin acetate freeze-dried powder for one injection) and physiological saline neck subcutaneous administration, and ovulation condition is detected for 32-48 h. The estrus sows with clear standing reactions are transferred to a limit fence and are subjected to first insemination, reproductive hormone is injected 3-5 min before insemination, insemination is performed for three times in each estrus, the insemination interval is 8-12 h every time, 80mL of effective sperm is obtained in each sperm, and the number of effective sperm is more than 30 hundred million. All sows are fed in the same pigsty and fed by the same feeder, and full-value granular feed is adopted. And (3) carrying out B-ultrasonic examination on the conception rate of the sows 25d after the mating of the sows of each test group and the control group, and carrying out statistical analysis on the total litter size and the alive litter size of the sows after the delivery of the sows. The results are shown in table 2:
TABLE 2 reproductive performance index statistics for different groups of sows
**P<0.01,*P<0.05。
Table 2 shows that the weaned sows are concentrated in ovulation 32-48 h after treatment; in the 50 mu g Buserelin treatment group, the ovulation rate of multiple sows reaches 96.6 percent, and the number of ovulated sows, the number of sows born with fetus, the total number of litter size and the total number of litter size alive are obviously different from those of the control group; in the 100 mu g Buserelin treatment group, the ovulation rate of the sows in multiple births reaches 100 percent, and the difference between the number of the ovulated sows, the number of the sows in birth, the total litter size and the total litter size of the sows in birth is extremely obvious compared with that of a control group; the total litter size and the live litter size of litters are significantly different from those of the control group. Both 50. mu.g of Buserelin and 100. mu.g of Buserelin were shown to improve reproductive performance in sows.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. Buserelin acetate freeze-dried powder injection for animal injection comprises the following raw materials in parts by mass for preparation: 0.03-0.08 part of buserelin acetate, 25-35 parts of dextran and 25-35 parts of mannitol; the pH value of the buserelin acetate freeze-dried powder injection for animal injection is 5.5-6.5.
2. The buserelin acetate freeze-dried powder injection for animal injection according to claim 1, wherein the water content of the freeze-dried powder injection is less than or equal to 3%.
3. The buserelin acetate freeze-dried powder injection for animal injection according to claim 1, wherein raw materials for preparing the buserelin acetate freeze-dried powder injection for animal injection further comprise phosphate buffer and water for injection.
4. The preparation method of buserelin acetate freeze-dried powder injection for animal injection as claimed in any one of claims 1-3, comprising the following steps:
1) mixing a dextran aqueous solution, a mannitol aqueous solution, a phosphate buffer solution and water for injection to obtain a first mixed solution, adding activated carbon into the first mixed solution, stirring for 25-35 min at 75-85 ℃, removing the activated carbon, filtering, and collecting a first filtrate;
2) adjusting the pH value of the first filtrate to 5.5-6.5, mixing the first filtrate with buserelin acetate and water for injection to obtain a second mixed solution, and filtering the second mixed solution with a microporous filter membrane to obtain a second filtrate;
3) cooling the second filtrate to-40 ℃, and pre-freezing for 3-5 h at-40 ℃ to obtain a pre-frozen mixture;
4) heating the pre-frozen mixture to-18 ℃, and carrying out primary sublimation drying for 10-20 h under the conditions of-18 ℃ and 0.2-0.4 mbar vacuum degree to obtain a primary sublimation dried substance;
5) and heating the first sublimation dried substance to 28-32 ℃, and carrying out second sublimation drying for 4-6 h at the temperature of 28-32 ℃ under the vacuum degree of 0.002-0.006 mbar to obtain the buserelin acetate freeze-dried powder injection for animal injection.
5. The preparation method of claim 4, wherein the mass concentration of dextran in the dextran aqueous solution in step 1) is 25-35 g/100 mL; the mass concentration of mannitol in the mannitol aqueous solution is 25-35 g/100 mL.
6. The method according to claim 5, wherein the volume ratio of the dextran aqueous solution, the mannitol aqueous solution, the phosphate buffer solution and the water for injection in step 1) is 1: 1: 1: 9.
7. the method of claim 4, wherein the reagent used to adjust the pH of the first filtrate in step 2) comprises citric acid or lactic acid.
8. The method according to claim 4, wherein the cooling time in step 3) is 1h or less.
9. The method according to claim 4, wherein the heating time in step 4) is 1h or less.
10. The use of buserelin acetate lyophilized powder for injection as claimed in any of claims 1-3 in the preparation of a medicament for improving reproductive performance of an animal.
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