CN113633611A - Hydroxyprogesterone caproate suspension injection and preparation method thereof - Google Patents
Hydroxyprogesterone caproate suspension injection and preparation method thereof Download PDFInfo
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- CN113633611A CN113633611A CN202010393635.8A CN202010393635A CN113633611A CN 113633611 A CN113633611 A CN 113633611A CN 202010393635 A CN202010393635 A CN 202010393635A CN 113633611 A CN113633611 A CN 113633611A
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- Prior art keywords
- hydroxyprogesterone caproate
- injection
- suspension
- suspension injection
- hydroxyprogesterone
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- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 title claims abstract description 96
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 title claims abstract description 96
- 239000000725 suspension Substances 0.000 title claims abstract description 80
- 238000002347 injection Methods 0.000 title claims abstract description 67
- 239000007924 injection Substances 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 239000002245 particle Substances 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000008215 water for injection Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 22
- 238000005303 weighing Methods 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 12
- 239000003381 stabilizer Substances 0.000 claims description 11
- 230000001954 sterilising effect Effects 0.000 claims description 10
- 239000000337 buffer salt Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 7
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 7
- 229940050929 polyethylene glycol 3350 Drugs 0.000 claims description 7
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 7
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 5
- 229940068977 polysorbate 20 Drugs 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 abstract description 3
- 208000003455 anaphylaxis Diseases 0.000 abstract description 3
- 235000019438 castor oil Nutrition 0.000 abstract description 3
- 239000004359 castor oil Substances 0.000 abstract description 3
- 238000009826 distribution Methods 0.000 abstract description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 abstract 1
- -1 polyoxyethylene Polymers 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000000227 grinding Methods 0.000 description 12
- 238000001238 wet grinding Methods 0.000 description 9
- 229930182555 Penicillin Natural products 0.000 description 8
- 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 8
- 239000012528 membrane Substances 0.000 description 8
- 229940049954 penicillin Drugs 0.000 description 8
- 239000011324 bead Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000265 homogenisation Methods 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 210000002969 egg yolk Anatomy 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 239000002960 lipid emulsion Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- TWJRLUXIHIAGBB-DADHALBJSA-N (8S,9S,10R,13S,14S,17R)-17-acetyl-16-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one decanoic acid Chemical compound CCCCCCCCCC(O)=O.C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(O)[C@H](C(=O)C)[C@@]1(C)CC2 TWJRLUXIHIAGBB-DADHALBJSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000008899 Habitual abortion Diseases 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- 206010027339 Menstruation irregular Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000010495 camellia oil Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 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
- 239000000843 powder Substances 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000013112 stability test Methods 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/06—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
-
- 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
- A61P15/06—Antiabortive agents; Labour repressants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
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Abstract
The invention relates to a hydroxyprogesterone caproate suspension injection and a preparation method thereof, belonging to the technical field of medicines. The suspension injection contains hydroxyprogesterone caproate with the average particle size of 100-1000 nm. The hydroxyprogesterone caproate suspension injection prepared by the invention has controllable particle size distribution, narrow distribution, good reproducibility and good stability; oily media such as polyoxyethylene castor oil and the like are not used in the prescription, and organic solvents are not used, so that the problems of anaphylactic reaction, solvent residue and the like are avoided, and the compliance of patients is improved.
Description
Technical Field
The invention relates to a hydroxyprogesterone caproate suspension injection and a preparation method thereof, belonging to the technical field of medicines.
Background
Hydroxyprogesterone Caproate (Hydroxyprogesterone caprate), chemical structure as follows:
alias: caproic acid progesterone, long-acting progesterone, chemical name 17 alpha-hydroxypregna-4-ene-3, 20-dione caproate, belongs to progestational hormone medicines, and is white or almost white crystalline powder which is easily soluble in ethanol, acetone or ether, slightly soluble in tea oil or castor oil and insoluble in water. The current commercially available preparation only contains hydroxyprogesterone caproate injection, and the solvent is castor oil, so the injection is very painful, aseptic abscess and anaphylactic reaction are occasionally caused, patients cannot accept the injection, and the clinical use is unsafe.
The hormone medicine is easy to be damaged when passing through the liver and the gastrointestinal tract, and is rapidly metabolized and loses efficacy when being orally taken, so that the hormone medicine is ineffective when being orally taken, and is suitable for being developed into injection.
CN201610165631 patent discloses a hydroxyprogesterone caproate fat emulsion injection, soybean oil for injection, phosphatidylglycerol, lecithin, etc. are used in the prescription, because individual difference still has risk of anaphylaxis, and the fat emulsion injection is administered by intravenous injection, the drug effect maintenance time is short, the administration frequency is frequent, thereby reducing patient compliance, and clinical use has limitation.
The hydroxyprogesterone caproate is mainly used for preventing habitual abortion and irregular menstruation; the medicine needs to be taken for a long time, is insoluble in water, is suitable for being developed into a nanocrystalline suspension injection, reduces the administration times, improves the compliance of patients, and has obvious clinical application value. Therefore, the development of a safe and effective new dosage form of hydroxyprogesterone caproate has important clinical value.
Disclosure of Invention
The invention provides a hydroxyprogesterone caproate suspension injection taking water for injection as a medium and a preparation method of the hydroxyprogesterone caproate suspension injection, which is safe, stable, controllable in quality and easy for industrial mass production.
Specifically, the invention is realized by the following modes:
the invention provides a hydroxyprogesterone caproate suspension injection, which contains hydroxyprogesterone caproate with the average particle size of 100-1000 nm.
Preferably, the suspension injection also contains water for injection, a stabilizer, a buffer salt and a pH regulator.
Preferably, the pH value of the hydroxyprogesterone caproate suspension injection is 6.0-8.0.
More preferably, the average particle size of the hydroxyprogesterone caproate is 300-400 nm.
More preferably, the content of the hydroxyprogesterone caproate in the hydroxyprogesterone caproate suspension injection is 10-20%, and still more preferably 12-15%.
Further preferably, the weight ratio of the hydroxyprogesterone caproate to the stabilizer is 10-1: 1.
Further preferably, the weight ratio of the buffer salt to the stabilizer is 1: 5-50.
Further preferably, the stabilizer is selected from one or more of polysorbate 20, sodium carboxymethylcellulose, polyethylene glycol 3350 and polyethylene glycol 6000, and still further preferably, the stabilizer is polysorbate 20 and/or polyethylene glycol 3350.
Further preferably, the buffer salt is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium citrate; still more preferably sodium dihydrogen phosphate.
The invention also provides a method for preparing the hydroxyprogesterone caproate suspension injection, which comprises the following steps: (1) weighing a formula amount of stabilizer and buffer salt, dissolving in water for injection, filtering and sterilizing to prepare a solution A; (2) then weighing hydroxyprogesterone caproate in a prescription amount under an aseptic condition, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH value, and adding water for injection until the content of the hydroxyprogesterone caproate suspension injection is 10% -20%, so as to prepare a crude suspension B;
(3) and mechanically crushing the crude mixed suspension B under the aseptic condition to obtain the hydroxyprogesterone caproate suspension injection.
Preferably, the pH value in the step (2) is adjusted to 6.0-8.0.
Preferably, the mechanical pulverization in step (3) is selected from a wet grinding method, a high-pressure homogenization method or a high-shear emulsification method, and the wet grinding method is further preferred.
Preferably, the step (3) of mechanically crushing the coarse mixed suspension B is to crush the hydroxyprogesterone caproate to an average particle size of 100-1000 nm.
Compared with the prior art, the invention has the following beneficial effects:
(1) in the prior art, the hydroxyprogesterone caproate injection adopts oil as a solvent, the surface tension of oil molecules is high, the tissue absorption is slow, the liquid medicine is easy to accumulate in the tissue, the skin of an injection part is easy to be red and swollen, painful and induration after long-time large-dose injection administration, and the compliance of a patient is poor; therefore, the invention provides the injection taking water for injection as a dispersion medium, reduces adverse reactions caused to injection parts after administration, improves the medication safety and improves the tolerance of patients;
(2) the nanometer suspension prepared by wet grinding has the advantages of large drug-loading rate, narrow particle size distribution, good reproducibility and good stability;
(3) the preparation method has the advantages of simple operation, no organic solvent in the preparation process, continuous operation, good reproducibility and the like, and the preparation method has simple preparation process, no residual solvent and convenient operation and is suitable for industrial mass production.
Detailed Description
The following examples further illustrate the beneficial effects of the present invention, and the specific examples are for illustrative purposes only and do not limit the scope of the present invention. And variations and modifications obvious to those skilled in the art in light of the present disclosure are intended to be included within the scope of the present invention. The auxiliary materials or instruments used in the examples are not indicated by manufacturers, and are all conventional products commercially available.
Example 1
Prescription:
the preparation process comprises the following steps:
(1) weighing and dissolving polysorbate 20, polyethylene glycol 3350 and sodium dihydrogen phosphate in a part of water for injection according to a prescription amount, and filtering and sterilizing by using a 0.22 mu m filter membrane to prepare a solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 7.0 by using 0.1mol/L sodium hydroxide, and adding water for injection until the total amount is 100g to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 8.5m/s and a feeding speed of 50rpm, grinding the beads at a diameter of 0.3mm for 30min to obtain a hydroxyprogesterone caproate suspension injection, and subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles to obtain an average particle size of 331.6 nm.
Example 2
Prescription:
the preparation process comprises the following steps:
(1) weighing polysorbate 20 and disodium hydrogen phosphate according to the prescription amount, dissolving in part of water for injection, and filtering and sterilizing with a 0.22 mu m filter membrane to obtain a solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 7.4 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: reducing the particle size of the particles in the suspension B by a high-pressure homogenization method, reducing the pressure to 1000bar, circulating for 15 times to obtain the hydroxyprogesterone caproate suspension injection, subpackaging in penicillin bottles, and measuring the average particle size to be 317.8 nm.
Example 3
Prescription:
the preparation process comprises the following steps:
(1) weighing polyethylene glycol 3350 and citric acid according to the prescription amount, dissolving in part of water for injection, and filtering with a 0.22 μm filter membrane for sterilization to obtain solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 6.5 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 10.0m/s and a feeding speed of 70rpm, grinding the beads at a diameter of 0.3mm for 30min to obtain hydroxyprogesterone caproate suspension injection, subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles, and measuring the average particle size to be 320.1 nm.
Example 4
Prescription:
the preparation process comprises the following steps:
(1) weighing sodium carboxymethylcellulose and sodium citrate according to the prescription amount, dissolving in part of water for injection, and filtering and sterilizing with a 0.22-micron filter membrane to obtain a solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 8.0 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 10.0m/s and a feeding speed of 70rpm, grinding the beads at a diameter of 0.3mm for 15min to obtain a hydroxyprogesterone caproate suspension injection, and subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles to obtain the hydroxyprogesterone caproate suspension injection with an average particle size of 321.0 nm.
Example 5
Prescription:
the preparation process comprises the following steps:
(1) weighing polyethylene glycol 3350, polyethylene glycol 6000 and sodium dihydrogen phosphate according to the prescription amount, dissolving in part of water for injection, and filtering and sterilizing with a 0.22 μm filter membrane to obtain solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH value to 6.0 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: and reducing the particle size of the particles in the suspension B by adopting a high-shear emulsification method, wherein the rotating speed is 3000rpm, shearing is carried out for 30min, so as to obtain the hydroxyprogesterone caproate suspension injection, subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles, and measuring the average particle size to be 349.6 nm.
Example 6
Prescription:
the preparation process comprises the following steps:
(1) weighing polyethylene glycol 3350 and sodium dihydrogen phosphate according to the prescription amount, dissolving in part of water for injection, and filtering with 0.22 μm filter membrane for sterilization to obtain solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 7.0 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 10.0m/s and a feeding speed of 60rpm, grinding the beads at a diameter of 0.3mm for 15min to obtain hydroxyprogesterone caproate suspension injection, and subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles to obtain the hydroxyprogesterone caproate suspension injection with the average particle size of 301.4 nm.
Example 7
Prescription:
the preparation process comprises the following steps:
(1) weighing the sodium hydroxypropyl cellulose and the sodium citrate with the prescription dose, dissolving the sodium hydroxypropyl cellulose and the sodium citrate in part of water for injection, and filtering and sterilizing the solution by using a filter membrane with the diameter of 0.22 mu m to prepare a solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 8.0 by using 0.1mol/L sodium hydroxide, and adding water for injection to the total amount to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 10.0m/s and a feeding speed of 50rpm, grinding the beads at a diameter of 0.3mm for 3 hours to obtain hydroxyprogesterone caproate suspension injection, and subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles to obtain the hydroxyprogesterone caproate suspension injection with the average particle size of 180.5 nm.
Example 8
Prescription:
the preparation process comprises the following steps:
(1) weighing povidone and sodium dihydrogen phosphate with the prescription amount, dissolving in part of water for injection, and filtering and sterilizing with a 0.22 μm filter membrane to obtain solution A;
(2) under aseptic conditions: weighing hydroxyprogesterone caproate in a prescription amount, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH to 7.0 by using 0.1mol/L sodium hydroxide, and adding water for injection until the total amount is 100g to prepare a crude suspension B;
(3) under aseptic conditions: and (3) wet grinding the crude mixed suspension B at a grinding speed of 8.5m/s and a feeding speed of 50rpm, grinding the beads at a diameter of 0.3mm for 15min to obtain hydroxyprogesterone caproate suspension injection, and subpackaging the hydroxyprogesterone caproate suspension injection in penicillin bottles to obtain the hydroxyprogesterone caproate suspension injection with an average particle size of 1000.1 nm.
Comparative example 1
Prescription:
the preparation process comprises the following steps: (1) preparation of an aqueous phase: uniformly mixing 10% of water for injection, glycerol and a sodium hydroxide solution, and keeping the temperature to 25 ℃ for later use; (2) preparing an oil phase: weighing hydroxyprogesterone caproate, soybean oil for injection, yolk phosphatidyl glycerol and appropriate amount of anhydrous ethanol in an oil phase tank, stirring uniformly, heating to 35 deg.C, volatilizing ethanol, slowly adding yolk lecithin, and stirring at high speed until the yolk lecithin is uniformly dispersed; (3) preparing a primary emulsion: mixing the oil phase and the water phase at a certain ratio (1:15) by an emulsification pump, adding water for injection to full volume, controlling the temperature at 35 ℃, and adjusting the pH value of the primary emulsion to 8.2 by using sodium hydroxide; (4) high-pressure homogenization: homogenizing the primary emulsion between two tanks by a homogenizer under the pressure of 150bar at the primary valve and 500bar at the secondary valve, repeatedly homogenizing (3 times) until the pH of the liquid medicine is 8.0, the temperature is 35 deg.C, and the emulsion granules are qualified; (5) low-pressure homogenization: unloading the primary pressure, adjusting the secondary pressure to 20bar, and cooling to 28 ℃ through a heat exchanger; (6) filling nitrogen and filling: filtering the uniform emulsion through a filter, filling the uniform emulsion under the protection of nitrogen flow, and cleaning an infusion bottle, rolling a stopper and sealing the bottle by a conventional method to ensure that the residual oxygen content in the bottle is less than 3 percent; the filtration was carried out through a 5 μm microporous membrane and the average particle size was found to be 286.3 nm.
And (3) stability investigation:
the hydroxyprogesterone caproate injection prepared in the above examples 1-8 and comparative example 1 is respectively placed under the conditions of 40 + -2 ℃ and RH 75% + -5% for 3 months, and the average particle size and related substances are detected, and the detection results are shown in the following table 1.
The particle size detection method comprises the following steps: taking 1ml of suspension, adding 100ml of purified water to dilute the suspension by adopting a particle size tester based on a dynamic light scattering principle, stirring the suspension to uniformly disperse a sample, taking a proper amount of the suspension, slowly adding the suspension into a sample tube along the wall of the sample tube to ensure that no bubbles exist, placing the sample tube into a sample cell, and starting to measure the suspension when the temperature reaches a set temperature value; the measurement conditions were as follows: the temperature was 25 ℃ and the scattering angle was 90 ℃.
The related substance detection method comprises the following steps: using a C18 chromatography column, eluting with methanol: water (85:15) as mobile phase, detection wavelength of 225nm, flow rate of 0.8ml/min, column stability of 35 deg.C, and running time of 50 min.
TABLE 1 stability test results
According to the stability examination results, the average particle size of the hydroxyprogesterone caproate nanoparticles in examples 1-8 is slightly increased after being placed for 3 months under the conditions of 40 +/-2 ℃ and RH 75% +/-5%, but the average particle size is still within the required range, and other related substances have no obvious change. The average particle size of the fat emulsion in comparative example 1 also changed significantly, and the related substances were significantly increased. Therefore, the hydroxyprogesterone caproate suspension injection prepared in the embodiments 1-8 of the invention has better stability and is remarkably improved compared with the injection prepared in the comparative example 1.
Claims (10)
1. The hydroxyprogesterone caproate suspension injection is characterized in that: the suspension injection contains hydroxyprogesterone caproate with the average particle size of 100-1000 nm.
2. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the suspension injection also contains water for injection, a stabilizing agent, a buffer salt and a pH regulator.
3. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the average particle size of the hydroxyprogesterone caproate is 300-400 nm.
4. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the content of the hydroxyprogesterone caproate in the hydroxyprogesterone caproate suspension injection is 10-20%.
5. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the weight ratio of the hydroxyprogesterone caproate to the stabilizer is 10-1: 1.
6. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the weight ratio of the buffer salt to the stabilizer is 1: 5-50.
7. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the pH value of the hydroxyprogesterone caproate suspension injection is 6.0-8.0.
8. The hydroxyprogesterone caproate suspension injection of claim 1, wherein: the stabilizer is one or more selected from polysorbate 20, sodium carboxymethylcellulose, polyethylene glycol 3350, and polyethylene glycol 6000.
9. The hydroxyprogesterone caproate suspension injection of claim 1, wherein the buffer salt is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium citrate.
10. A method for preparing the hydroxyprogesterone caproate suspension injection as claimed in any one of claims 1 to 9, comprising the following steps:
(1) weighing a formula amount of stabilizer and buffer salt, dissolving in water for injection, filtering and sterilizing to prepare a solution A;
(2) then weighing hydroxyprogesterone caproate in a prescription amount under an aseptic condition, slowly adding the hydroxyprogesterone caproate into the solution A while stirring, stirring until the hydroxyprogesterone caproate is uniformly dispersed, adjusting the pH value, and adding water for injection until the content of the hydroxyprogesterone caproate suspension injection is 10% -20%, so as to prepare a crude suspension B;
(3) and mechanically crushing the crude mixed suspension B under the aseptic condition to obtain the hydroxyprogesterone caproate suspension injection.
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