CN113908114B - Fluogesterone acetate vaginal sponge - Google Patents
Fluogesterone acetate vaginal sponge Download PDFInfo
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- CN113908114B CN113908114B CN202111270459.XA CN202111270459A CN113908114B CN 113908114 B CN113908114 B CN 113908114B CN 202111270459 A CN202111270459 A CN 202111270459A CN 113908114 B CN113908114 B CN 113908114B
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- CN
- China
- Prior art keywords
- acetate
- sponge
- fluogestrel
- filling
- vaginal sponge
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims abstract description 78
- 239000003814 drug Substances 0.000 claims abstract description 51
- 239000007788 liquid Substances 0.000 claims abstract description 38
- 238000011049 filling Methods 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 14
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims abstract description 8
- KKVPWYXKKAIBTN-FDIQSBBYSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-1-fluoro-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC(F)[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 KKVPWYXKKAIBTN-FDIQSBBYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 229960003943 hypromellose Drugs 0.000 claims description 12
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 12
- JGMOKGBVKVMRFX-HQZYFCCVSA-N dydrogesterone Chemical compound C1=CC2=CC(=O)CC[C@@]2(C)[C@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 JGMOKGBVKVMRFX-HQZYFCCVSA-N 0.000 claims description 9
- 229960004913 dydrogesterone Drugs 0.000 claims description 9
- UDEWPOVQBGFNGE-UHFFFAOYSA-N benzoic acid n-propyl ester Natural products CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 claims description 7
- 229940095102 methyl benzoate Drugs 0.000 claims description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 5
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 238000007605 air drying Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 229960003415 propylparaben Drugs 0.000 claims description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- 229960002216 methylparaben Drugs 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000000022 bacteriostatic agent Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 12
- 238000012216 screening Methods 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- 230000012173 estrus Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 241001494479 Pecora Species 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000829 suppository Substances 0.000 description 6
- 230000001360 synchronised effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 239000000273 veterinary drug Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000010923 batch production Methods 0.000 description 4
- 238000009395 breeding Methods 0.000 description 4
- 230000001488 breeding effect Effects 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920002635 polyurethane Polymers 0.000 description 4
- 239000004814 polyurethane Substances 0.000 description 4
- 238000004062 sedimentation Methods 0.000 description 4
- 210000001215 vagina Anatomy 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 239000000583 progesterone congener Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- GLFJARXFVNRHNJ-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)O.C(C)[Na] Chemical compound C(C1=CC=CC=C1)(=O)O.C(C)[Na] GLFJARXFVNRHNJ-UHFFFAOYSA-N 0.000 description 2
- FLTRUVVWCAKQKS-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)O.C(CCC)[Na] Chemical compound C(C1=CC=CC=C1)(=O)O.C(CCC)[Na] FLTRUVVWCAKQKS-UHFFFAOYSA-N 0.000 description 2
- GPOHXISATQGSOK-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)O.C[Na] Chemical compound C(C1=CC=CC=C1)(=O)O.C[Na] GPOHXISATQGSOK-UHFFFAOYSA-N 0.000 description 2
- HBPBQKDKFWPSAM-UHFFFAOYSA-N CCC[Na].OC(=O)C1=CC=CC=C1 Chemical compound CCC[Na].OC(=O)C1=CC=CC=C1 HBPBQKDKFWPSAM-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229960002798 cetrimide Drugs 0.000 description 2
- 229960002152 chlorhexidine acetate Drugs 0.000 description 2
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 2
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000000249 desinfective effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 2
- 229960000452 diethylstilbestrol Drugs 0.000 description 2
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000009027 insemination Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 235000015277 pork Nutrition 0.000 description 2
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 230000002537 thrombolytic effect Effects 0.000 description 2
- 239000006216 vaginal suppository Substances 0.000 description 2
- 229940120293 vaginal suppository Drugs 0.000 description 2
- 108700012941 GNRH1 Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- -1 etc. Polymers 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000008713 feedback mechanism Effects 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 244000144992 flock Species 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- 230000029849 luteinization Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/08—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of suppositories or sticks
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- 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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
- A61K9/025—Suppositories; Bougies; Bases therefor; Ovules characterised by shape or structure, e.g. hollow layered, coated
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/34—Gestagens
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gynecology & Obstetrics (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a fluogestrel acetate sponge, which consists of a liquid medicine and a sponge, wherein the liquid medicine raw material comprises fluogestrel acetate, suspending agent hydroxypropyl methylcellulose K100M, polyethylene glycol 6000 and a bacteriostatic agent; wherein the medicinal liquid uses water as solvent. The fluogestrel acetate sponge is suitable for full-automatic filling production, and can effectively improve the preparation efficiency and the product quality.
Description
Technical Field
The invention belongs to the technical field of veterinary medicines, and particularly provides a fluogestrel acetate sponge suitable for full-automatic filling production.
Background
The sheep raising amount exceeds 3 hundred million according to 2020 data of the national statistical bureau, but the development of the related technology of the sheep raising industry is relatively lagged outside, and the development of the sheep raising industry needs to be referred to the corresponding technology in the pig raising industry, such as batch production technology, i.e. the raising of live pigs is similar to batch and large-scale production of factory-produced foods/medicines, so that the pork quality (food safety and pork quality) is improved, the production efficiency is also improved, and the resource waste is also reduced to a certain extent. Similarly, the sheep raising industry also realizes batch production, wherein the most critical link is the sheep breeding link, and only batch breeding is presented, so that batch fattening and batch marketing of mutton sheep can be realized finally.
In the batch breeding link of the ewes, the main flow technology at home and abroad at present adopts progestogen (fluogestrel acetate vaginal sponge suppository, medroxyprogesterone acetate sponge suppository and progesterone vaginal slow release agent) to induce the ewes to realize batch synchronous estrus, so that batch timed insemination (timed insemination) is carried out for breeding, batch delivery is carried out, the goats after delivery are weaned in batches, so that the progestogen is reused to induce batch synchronous estrus, and the goats after weaning are fattened in batches, thereby realizing batch production.
Fluoroprogesterone acetate vaginal sponge is a veterinary drug, i.e., a quantity of Fluoroprogesterone acetate (an artificial progestogen analog) is loaded into a polyurethane sponge to form the final product. The product is mainly used for synchronous estrus of female animals. The sponge used in the product is generally cylindrical, and has a ground diameter of 3-4cm and a height of 3-6cm. After the female animals are treated by the product, the fluogestrel acetate in the sponge is gradually and slowly released in the vagina of the female animals, so that the drug effect is exerted, and the drug effect is generally called as follows in the field of veterinary drugs at home and abroad: controlling the drug internal release device (Controlled Internal Drug Releasing). The action process is as follows: after the vaginal sponge of the fluogestrel acetate is put into the vagina, the fluogestrel acetate is slowly released from the sponge (a large number of pores are formed on the sponge) and absorbed into the body through vaginal mucosa, so that the concentration of the fluogestrel acetate in the blood plasma is kept at normal effective concentration, and the secretion of pituitary gonadotrophin and hypothalamic gonadotrophin releasing hormone is inhibited through a feedback mechanism, thereby inhibiting oestrus and ovulation and artificially prolonging the luteal phase. Once the vaginal sponge of the fluogesterone acetate is taken out, the concentration of the fluogesterone acetate is reduced, the effect is lost, and the pituitary of the animal resumes secreting gonadotrophin, thereby promoting the growth of follicles and oestrus of the animal.
The vaginal sponge of the fluogestrel acetate used in the induction batch and same-period estrus of the ewes belongs to a veterinary drug, the currently disclosed production modes are all manual production, the efficiency is low, and the related requirements of the veterinary drug GMP cannot be met. According to the information in the patent and literature materials, the traditional fluogestrel acetate vaginal sponge prescription is simpler, and organic solvents such as ethanol, acetone and grease solvents are usually selected; then, the fluogestrel acetate is dissolved in an organic solvent or grease, then, the fluogestrel acetate-organic solvent liquid medicine is filled into the sponge, the risk of liquid medicine leakage can occur in the process (the sponge is made of polyurethane or polyether, organic matters are porous structures, a large number of pores are distributed on the surface, the organic solvent such as ethanol and acetone easily permeate through the sponge), and the liquid medicine leakage leads to unqualified key quality standards such as product content (the limit specified by the national standard is not met).
Disclosure of Invention
In order to solve the problems, the applicant designs a novel fluogestrel acetate vaginal sponge formula which can be suitable for automatic production.
In one aspect, the application provides a fluoroprogesterone acetate vaginal sponge, which is characterized by comprising a liquid medicine and a sponge, wherein the liquid medicine comprises the raw materials of the fluoroprogesterone acetate, a suspending agent and a bacteriostatic agent.
Further, the suspending agent is at least one selected from hypromellose, polyethylene glycol 4000, polyethylene glycol 6000, povidone K60, lanolin, methylcellulose and carboxymethylcellulose.
Further, the suspending agent is hypromellose K100M and polyethylene glycol 6000.
Further, the bacteriostatic agent is at least one of chlorhexidine acetate, chlorhexidine gluconate, methyl (sodium) benzoate, ethyl (sodium) benzoate, propyl (sodium) benzoate, butyl (sodium) benzoate, cetrimide and dodecyl trimethyl ammonium bromide.
Further, the bacteriostat is methyl benzoate and propyl benzoate.
Further, the liquid medicine raw materials of the dydrogesterone acetate vaginal sponge comprise dydrogesterone acetate, hypromellose K100M, polyethylene glycol 6000, methyl benzoate, propyl benzoate and water.
Further, the liquid medicine of the dydrogesterone acetate vaginal sponge comprises the raw materials of 30-50mg of dydrogesterone acetate, 20-40mg of hypromellose K100M, 6000 20-80mg of polyethylene glycol, 0.5-3mg of methyl benzoate, 0.1-2mg of propyl benzoate and 0.5-5mL of water; wherein the granularity D90 of the fluogestrel acetate is less than or equal to 100 mu m.
Further, the liquid medicine of the dydrogesterone acetate vaginal sponge comprises 40mg of dydrogesterone acetate, 100M 30mg of hypromellose K, 50mg of polyethylene glycol 6000, 1.5mg of methyl benzoate, 0.5mg of propyl benzoate and 1.95mL of water; wherein the granularity D90 of the fluogestrel acetate is 40-60 mu m.
Further, the preparation process of the fluogestrel acetate vaginal sponge comprises the steps of liquid medicine preparation and filling.
Further, the preparation steps of the liquid medicine are as follows:
adding proper amount of water at 60 ℃ into a batching tank, heating in a water bath, adding the prescribed amount of hypromellose K100m, and uniformly stirring; adding polyethylene glycol-4000 with the prescription amount, and uniformly stirring; adding the prescription amount of the fluogestrel acetate, the methyl paraben and the propyl paraben, and stirring to uniformly suspend the components; adding the rest of water at 30 ℃; continuously stirring until the liquid medicine is stable and returns to room temperature; the viscosity of the detected liquid medicine should be 350-450cps.
The filling steps are as follows:
transferring the buffer tank to a vaginal sponge pouring room, and adjusting the filling amount of the filling machine to be 1.95-2.05 ml; taking out the washed and dried sponges, placing the sponges on a filling line, filling and dosing each sponge, immediately transferring the filled sponges to a product drying room for forced air drying to constant weight, wherein the drying temperature is 80+/-5 ℃.
Advantageous effects
The traditional Chinese medicine liquid is prepared into a fluogestrel acetate suspension by taking water as a solvent and adding a suspending agent, and then is filled on a blank sponge suppository. In the filling process, the liquid medicine is in a dynamic stirring state, and can be accurately and uniformly filled on the sponge. The sponge plug, although showing many pores, does not actively absorb water, usually passively, e.g. the sponge will quickly fully absorb water to saturation after squeezing in water. When the traditional Chinese medicine liquid is filled, the filling needle is inserted into the sponge to finish filling, and the filling volume is 1.9ml-2.1ml; the liquid medicine in the invention is suspension, has certain viscosity of about 400+/-50 cps, so the liquid medicine has poor fluidity in the sponge plug, and can not leak, and after the sponge plugs filled with the liquid medicine are mutually extruded, the liquid medicine can not leak, but is fully distributed in the hole-shaped space in the sponge plug. Therefore, such prescriptions can enable automated and efficient filling production.
Drawings
Fig. 1 is a diagram of a sponge plug according to the present application.
Detailed Description
EXAMPLE 1 preparation of Fluogesterone acetate sponge suppository
Sponge shape and size: a cylindrical polyurethane sponge;
size: diameter 3.7cm, height: 3.0cm;
color: white color
The composition is as follows: polyurethane sponge, fluogestrel acetate and auxiliary materials (suspension agent and preservative)
Fluogesterone acetate: main active ingredient, particle size: d90.ltoreq.100 μm, preferably 40-60 μm (to avoid dissolution or sedimentation)
Auxiliary materials:
suspending agent: at least one selected from hypromellose, polyethylene glycol 4000, polyethylene glycol 6000, polyvinylpyrrolidone K60, lanolin, methylcellulose, carboxymethylcellulose, etc., and hypromellose K100M and polyethylene glycol 6000 are preferred in the present invention. The dosage proportion aspect is as follows: hypromellose K100m, the conventional dosage is 0.05% -10%, and the preferred dosage is 1.5%; polyethylene glycol 4000, conventionally used in amounts of 0.5% to 20%, preferably 2.5% in the present invention.
Bacteriostat: the antibacterial agent of the intravaginal preparation is at least one selected from chlorhexidine acetate, chlorhexidine gluconate, methyl (sodium) benzoate, ethyl (sodium) benzoate, propyl (sodium) benzoate, butyl (sodium) benzoate, cetrimide, dodecyl trimethyl ammonium bromide and the like, and the methyl and propyl parabens are preferred in the present invention.
Preparing a fluoroprogesterone acetate liquid medicine:
adding proper amount of water at 60 deg.C (keeping water bath heating), adding hydroxypropyl methylcellulose K100m, and stirring. Adding polyethylene glycol-4000 in the prescribed amount, and stirring uniformly. Then adding the antibacterial agent with the prescription amount, adding the fluogestrel acetate, the methyl benzoate and the propyl benzoate with the prescription amount, and stirring to uniformly suspend the components. Finally, water at 30 ℃ is added to the scale. Stirring is continued until the liquid medicine is stable and returns to room temperature. The viscosity of the detected liquid medicine should be 350-450cps.
And (3) filling:
checking according to a workshop pre-production checking management system before production to confirm that all posts are in the clearing field effective period and have clearing field qualification certificate; both the equipment and the container have been cleaned and are in the expiration date.
Transferring the buffer tank to a vaginal sponge pouring room, and adjusting the filling amount of the filling machine to be 1.95-2.05 ml. Taking out the washed and dried sponges, placing the sponges on a filling line, filling and dosing each sponge, immediately transferring the filled sponges to a product drying room for forced air drying to constant weight, wherein the drying temperature is 80+/-5 ℃.
Production efficiency: previous production methods produced about 2000 tablets per day of the fluoroprogesterone acetate sponge plug, now 35000-40000 tablets per day. The improvement is 17.5-20 times.
EXAMPLE 2 prescription screening
Prescription screening 1
Table 1 prescription screening 1-Fluogesterone acetate vaginal sponge composed of different excipients
The prescription of the vaginal sponge of the fluogestrel acetate is prepared according to different prescriptions of the vaginal sponge of the table 1, and the proper prescriptions are evaluated and screened mainly from the aspects of sedimentation of the prepared medicinal liquid, leakage from the sponge during filling, release degree, content uniformity and the like after filling and drying of the sponge suppository. Different auxiliary material compositions determine different viscosities and different suspension effects.
Table 2 comparison of vaginal sponges with different Fluogesterone acetates in prescription Screen 1
Note that: * In the suspension effect, + represents a poor suspension effect, +++ represents suspension the effect is very good and the effect is very good, -representing the absence of suspension.
The prescription D liquid medicine is changed into clear solution before being filled, the clear solution is filled on the sea surface and then dried, ethanol volatilizes, the fluogestrel acetate is recrystallized in sponge (gaps), the grain size of the recrystallized fluogestrel acetate is changed and is far larger than that of the original raw material medicine, so that the grain size is larger and is not easily interpreted by a release medium when the release degree test is carried out, and the release degree is lower and does not reach the release degree limit regulation (more than or equal to 75%).
Prescription screening 2
Table 3 prescription screening 2-Fluogesterone acetate vaginal sponge composed of different suspending agents
The vaginal sponge filling liquid medicine of the fluogestrel acetate with different suspending agent compositions is produced according to the prescription in the table 3, and the proper prescription is evaluated and screened mainly from the aspects of sedimentation of the prepared liquid medicine, leakage from the sponge during filling, release degree (according to the method for detecting the release degree in the example 5) after the sponge suppository is filled and dried, content uniformity and the like. Different suspension compositions determine different viscosities and different suspension effects.
Table 4 prescription screening 2 comparison of Fluogesterone acetate vaginal sponges of different prescriptions
In table 4, the similar release effect can be achieved after the liquid medicine of the fluogestrel acetate composed of different suspending agents is filled on the sponge, and two or more suspending agents can be combined.
Prescription screening 3
Through prescription screening 1, basic raw materials and auxiliary materials and composition proportion are screened, on the basis, the granularity of the fluoroprogesterone acetate raw material medicine is screened, the medicine liquid conditions prepared by the raw material medicines with different granularity are compared, and indexes such as uniform content, release degree (according to the release degree detection method in example 5) and the like of the fluoroprogesterone acetate in the fluoroprogesterone acetate vaginal sponge after the medicine liquid is dried are compared. ( The different particle sizes determine whether the medicine can be suspended or not, the particle size is too thin, the medicine is dissolved, and the suspension effect can not be achieved; the granularity of the medicine is too large, the medicine is not easy to suspend, and sedimentation is easy to occur. )
Table 5 prescription screening 3-Fluogesterone acetate particle size screening
Table 6 prescription screening 3-comparison of Fluogesterone acetate vaginal sponges of different prescriptions
Experimental example 3 comparison of yields per production lot for two production methods
Table 7 comparison of the production efficiency of the vaginal sponge of Fluogesterone acetate produced in different modes
Example 4 preparation of Fluogesterone acetate vaginal sponge Using sponges of different sources
The sponges with different sources and different materials are used for preparing the fluogestrel acetate sponges according to the composition of raw materials and auxiliary materials in the prescription A1. The release degree, content uniformity and the like are compared.
Table 8 preparation of vaginal sponge of fluoroprogesterone acetate from sponges of different sources
DG sponge | HT sponge | SZ sponge | |
Raw and auxiliary material composition | Prescription A1 | Prescription A1 | Prescription A1 |
Whether or not to leak | Whether or not | Whether or not | Whether or not |
Degree of release | 88% | 87% | 89% |
Content uniformity | Qualified product | Qualified product | Qualified product |
Content of | Qualified product | Qualified product | Qualified product |
Example 5 comparison of pharmaceutical index of Fluogesterone acetate vaginal sponge
Content detection
The detection method refers to octadecylsilane chemically bonded silica gel used for a system applicability test under 2017 version of Chinese veterinary drug quality standard chromatographic conditions as a filler; acetonitrile-water (48:52) as mobile phase; the detection wavelength was 240nm. The theoretical plate number is not lower than 2000 calculated according to the peak of the fluogestrel acetate, and the separation degree of the peak of the fluogestrel acetate and the peak of the internal standard substance is in accordance with the requirement.
Calibration factor measurement diethylstilbestrol is taken, dissolved and diluted by adding methanol to prepare a solution containing 0.8mg of diethylstilbestrol per 1ml, and the solution is shaken uniformly to serve as an internal standard solution. About 40mg of the norfluogestrel reference substance is precisely weighed, placed in a 50ml measuring flask, added with methanol to dissolve and dilute to scale, and shaken uniformly; precisely weighing 5ml, placing in a 25ml measuring flask, precisely adding 5ml of internal standard solution, adding methanol for dilution to scale, and shaking; accurately weighing 10 μl, injecting into liquid chromatograph, and calculating correction factor.
Taking 1 product, adding 12ml of methanol, squeezing and extracting, transferring the extracting solution into a 100ml measuring flask, squeezing and extracting for 7 times by using methanol, 10ml each time, mixing the extracting solution into the measuring flask, diluting to scale by using methanol, and shaking uniformly; filtering, precisely measuring 10ml of the continuous filtrate, placing in a 25ml measuring flask, precisely adding 5ml of internal standard solution, diluting to scale with methanol, and shaking; according to the method under the fluoroprogesterone acetate content measuring item, precisely measuring 10 μl, injecting into a liquid chromatograph, measuring correction factors according to the method, and calculating to obtain the final product.
Detection result
Table 9 results of vaginal sponge content detection of Fluogesterone acetate
Lot number | Content detection results |
180321 | 99.6% |
180323 | 100.5% |
180325 | 102.1% |
Content uniformity
Table 10 results of the content uniformity test of the Fluogesterone acetate vaginal sponge
As shown in the table above, the product content uniformity is better, the standard deviation between products is smaller, and the product quality is more stable.
Degree of release
Octadecylsilane chemically bonded silica is used as a filler under chromatographic conditions; acetonitrile-water (48:52) as mobile phase; the detection wavelength was 240nm. The theoretical plate number is not less than 2000 calculated according to the peak of the fluogestrel acetate.
Detection method
Preparation of test solution 1 vaginal sponge of Fluogesterone acetate was taken, the sponge was fixed on a stainless steel support, placed in a 250ml conical flask with stopper, and 230ml of water preheated to 60℃was added to immerse the sponge completely in water without touching the flask wall. The conical flask was placed in a thermostatted shaker preheated to 60℃and the shaking speed was adjusted to 2.5 revolutions per second. After 24 hours, the sponge was removed and placed in another 250ml Erlenmeyer flask, and 230ml of water preheated to 60℃was added for the next day release. To the solution remaining after the sponge was removed, 15ml of methanol was added, cooled to room temperature, and diluted quantitatively to 250ml with water. Shaking thoroughly, filtering, and measuring the filtrate as test solution.
The method comprises the steps of taking a proper amount of the fluoroprogesterone acetate reference substance, precisely weighing, adding acetonitrile for dissolving and quantitatively diluting to prepare a solution containing 0.4mg per 1ml, precisely weighing 2ml, placing into a 50ml measuring flask, adding acetonitrile for diluting to a scale, and shaking uniformly to obtain the reference substance solution. Precisely measuring 20 μl of each of the control solution and the sample solution, injecting into a liquid chromatograph, and recording the chromatogram. Daily release was calculated as peak area according to the external standard method. The total release was calculated by continuous measurement for 12 days. The limit is 75% of the indicated amount, which should be in compliance with the regulations.
Detection result
Table 11 comparative release test results
Example 6 stability test
Three batches of the fluoroprogesterone acetate vaginal sponges were continuously produced according to the A2 formulation and production method of example 1, and stability studies were performed. Including accelerated stability testing and long term stability testing.
Accelerated stability test (temperature 40 ℃ C.+ -2 ℃ C., humidity 75% + -5%)
Table 12 results of accelerated stability test of three batches of Fluogesterone acetate vaginal sponges
Long-term stability test (temperature 40 ℃ C.+ -. 2 ℃ C., humidity 60%.+ -. 10%)
Table 13 results of long term stability test of three batches of Fluogesterone acetate vaginal sponges
EXAMPLE 7 synchronous estrus
The healthy mature nonpregnant ewe is selected to be 60, and is divided into two groups of 30. Firstly, wiping, cleaning and disinfecting the pudendum of a ewe on test day 1, then placing a sponge plug into a disinfecting plug placing device, placing a pull wire into the rear end of the plug placing device, holding the plug placing device, coating anti-corrosion lubricating oil outside the plug placing device, slightly placing an outer sleeve into the bottom of the vagina of the ewe along the longitudinal axis of the vagina of the ewe with the tip facing the longitudinal axis of the female user, slowly placing the outer sleeve inwards, and slightly moving. The extra traction wire on the vaginal suppository is cut off by surgical scissors, and the vaginal suppository is kept for 4-5cm. The thrombus setting day is 0 days and 13 days. The sheep flocks are closely concerned every day during the bolt setting period, if the bolts are dropped, the sheep should be supplemented in time, and in addition, whether the ewes have oestrus or not during the bolt setting period needs to be concerned. PMSG333 units were intramuscular injected 48h before thrombolysis, and 0.1mg of PG was intramuscular injected after thrombolysis.
The test drug one was the product of the present invention (test drug, prescription A2), the control drug was Chronogest (MSD), PMSG (Ningbo second hormone works), PG (Ningbo second hormone works).
TABLE 14 synchronous estrus results on ewes
The effect of the test drug for synchronous estrus is tested on the ewe, and the result shows that the effect of the test drug is equivalent to or even slightly better than that of the control drug group.
Claims (4)
1. The vaginal sponge of the fluogestrel acetate is characterized by comprising 30-50mg of fluogestrel acetate, 20-40mg of hypromellose K100M, 6000 20-80mg of polyethylene glycol, 0.5-3mg of methyl hydroxybenzoate, 0.1-2mg of propyl hydroxybenzoate and 0.5-5mL of water; wherein the granularity D90 of the fluogestrel acetate is less than or equal to 100 mu m.
2. The dydrogesterone acetate vaginal sponge according to claim 1, wherein the dydrogesterone acetate vaginal sponge comprises 40mg of dydrogesterone acetate, 100M 30mg of hypromellose K, 6000 mg of polyethylene glycol, 50mg of methyl benzoate, 1.5mg of propyl benzoate, 0.5mg of propyl benzoate and 1.95mL of water; wherein the granularity D90 of the fluogestrel acetate is 40-60 mu m.
3. The fluoroprogesterone acetate vaginal sponge of claim 1 or 2, wherein the process for preparing the fluoroprogesterone acetate vaginal sponge comprises the steps of preparing and filling the liquid medicine.
4. The fluoroprogesterone acetate vaginal sponge of claim 3 wherein said drug solution is formulated as follows:
adding proper amount of water at 60 ℃ into a batching tank, heating in a water bath, adding the prescribed amount of hypromellose K100m, and uniformly stirring; adding polyethylene glycol 6000 with the prescription amount, and uniformly stirring; adding the prescription amount of the fluogestrel acetate, the methyl paraben and the propyl paraben, and stirring to uniformly suspend the components; adding the rest of water at 30 ℃; continuously stirring until the liquid medicine is stable and returns to room temperature; detecting the viscosity of the liquid medicine to be 350-450cps;
the filling steps are as follows:
transferring the buffer tank to a vaginal sponge pouring room, and adjusting the filling amount of the filling machine to be 1.95-2.05 ml; taking out the washed and dried sponges, placing the sponges on a filling line, filling and dosing each sponge, immediately transferring the filled sponges to a product drying room for forced air drying to constant weight, wherein the drying temperature is 80+/-5 ℃.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1281689A (en) * | 2000-09-04 | 2001-01-31 | 南京农业大学 | Vaginal spongy suppository for iducing ewe estrus |
CN103751094A (en) * | 2013-12-31 | 2014-04-30 | 哈尔滨欧替药业有限公司 | Ornidazole vaginal expansion suppository and preparation and detection methods thereof |
CN112336699A (en) * | 2019-08-09 | 2021-02-09 | 南京科宁检测科技有限公司 | Progesterone vaginal slow-release soft capsule and its preparation method |
-
2021
- 2021-10-29 CN CN202111270459.XA patent/CN113908114B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1281689A (en) * | 2000-09-04 | 2001-01-31 | 南京农业大学 | Vaginal spongy suppository for iducing ewe estrus |
CN103751094A (en) * | 2013-12-31 | 2014-04-30 | 哈尔滨欧替药业有限公司 | Ornidazole vaginal expansion suppository and preparation and detection methods thereof |
CN112336699A (en) * | 2019-08-09 | 2021-02-09 | 南京科宁检测科技有限公司 | Progesterone vaginal slow-release soft capsule and its preparation method |
Non-Patent Citations (2)
Title |
---|
Intravaginal controlled administration of flurogestone acetate II: Development of an in vitro system for studying the intravaginal release and permeation of flurogestone acetate;MOHAN B. KABADI等;《Journal of Pharmaceutical Sciences》;第73卷(第10期);第1464-1468页 * |
羊用氟孕酮阴道海绵栓的制作及使用效果;皮文辉等;《中国畜牧杂志》;第40卷(第1期);第41页 * |
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