CN117045605A - 一种高稳定性盐酸金霉素可溶性粉及其制备方法 - Google Patents
一种高稳定性盐酸金霉素可溶性粉及其制备方法 Download PDFInfo
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- CN117045605A CN117045605A CN202310965722.XA CN202310965722A CN117045605A CN 117045605 A CN117045605 A CN 117045605A CN 202310965722 A CN202310965722 A CN 202310965722A CN 117045605 A CN117045605 A CN 117045605A
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- Prior art keywords
- chlortetracycline hydrochloride
- soluble powder
- stability
- hydrochloride soluble
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OGQYJDHTHFAPRN-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)benzonitrile Chemical compound FC1=CC=CC(C(F)(F)F)=C1C#N OGQYJDHTHFAPRN-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960003185 chlortetracycline hydrochloride Drugs 0.000 title claims abstract description 61
- 239000000843 powder Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000006184 cosolvent Substances 0.000 claims abstract description 25
- 239000000375 suspending agent Substances 0.000 claims abstract description 25
- 239000003085 diluting agent Substances 0.000 claims abstract description 20
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 13
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 13
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 11
- 229960001631 carbomer Drugs 0.000 claims abstract description 11
- 239000000230 xanthan gum Substances 0.000 claims abstract description 11
- 229920001285 xanthan gum Polymers 0.000 claims abstract description 11
- 235000010493 xanthan gum Nutrition 0.000 claims abstract description 11
- 229940082509 xanthan gum Drugs 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 13
- 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 13
- 239000004472 Lysine Substances 0.000 claims description 12
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 12
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 12
- 229930091371 Fructose Natural products 0.000 claims description 9
- 239000005715 Fructose Substances 0.000 claims description 9
- 235000010489 acacia gum Nutrition 0.000 claims description 9
- 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
- QYAPHLRPFNSDNH-MRFRVZCGSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-MRFRVZCGSA-N 0.000 claims description 8
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 8
- 229920000084 Gum arabic Polymers 0.000 claims description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 8
- 239000000205 acacia gum Substances 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 8
- 235000011083 sodium citrates Nutrition 0.000 claims description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000000174 gluconic acid Substances 0.000 claims description 3
- 235000012208 gluconic acid Nutrition 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 2
- PRWXGRGLHYDWPS-UHFFFAOYSA-L sodium malonate Chemical compound [Na+].[Na+].[O-]C(=O)CC([O-])=O PRWXGRGLHYDWPS-UHFFFAOYSA-L 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims 1
- 238000000576 coating method Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000013329 compounding Methods 0.000 abstract description 7
- 241000220479 Acacia Species 0.000 abstract description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 abstract description 2
- 238000005286 illumination Methods 0.000 abstract description 2
- 235000018977 lysine Nutrition 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 125000000185 sucrose group Chemical group 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- KIPLYOUQVMMOHB-MXWBXKMOSA-L [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O Chemical compound [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O KIPLYOUQVMMOHB-MXWBXKMOSA-L 0.000 description 2
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- 238000009483 freeze granulation Methods 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N fructose group Chemical group OCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
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- 230000036211 photosensitivity Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229940063650 terramycin Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
- 229940043234 carbomer-940 Drugs 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 230000005808 skin problem Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/65—Tetracyclines
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供了一种高稳定性盐酸金霉素可溶性粉及其制备方法,按质量百分数计,包括以下组分:盐酸金霉素20~25%、pH调节剂8%~15%、抗氧剂0.1%~0.4%、助溶剂10~17%、助悬剂4%~10%和余量为稀释剂。本发明通过多种组分复配,得到的盐酸金霉素可溶性粉在溶液中的稳定性高,为了提升盐酸金霉素可溶性粉在光照下放置的稳定性,本发明所述助悬剂为重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配,本发明通过将三聚磷酸钠、柠檬酸钠和赖氨酸复配作为助溶剂,赋予盐酸金霉素可溶性粉的良好的溶解性。本发明的制备方法步骤简单,易于操作。
Description
技术领域
本发明属于药学技术领域,具体涉及一种高稳定性盐酸金霉素可溶性粉及其制备方法。
背景技术
盐酸金霉素为金霉素的盐酸盐,为金黄色或黄色结晶,无臭,味苦,遇光色渐变暗,在水或乙醇中微溶,在丙酮、乙醚或三氯甲烷中几乎不溶。抗菌谱与土霉素相似,但抗菌作用较四环素、土霉素强,可以治疗疱疮等化脓性皮肤病,轻度小面积烧伤及溃疡面的感染。目前市面上的盐酸金霉素药物,存在与辅料相容性差、使用时在药物溶解度低、稳定性差的问题,治疗效果不佳。因此急需一种新型的盐酸金霉素药物,解决现有盐酸金霉素药物存在的问题。
发明内容
本发明的目的是提供一种高稳定性盐酸金霉素可溶性粉及其制备方法,制备的盐酸金霉素可溶性粉稳定性高、溶解度好、药效好。
为了实现上述目的,本发明提供了以下技术方案:
一种高稳定性盐酸金霉素可溶性粉,按质量百分数计,包括以下组分:盐酸金霉素20~25%、pH调节剂8%~15%、抗氧剂0.1%~0.4%、助溶剂10~17%、助悬剂4%~10%和余量为稀释剂。
在一种优选的实施方式中,所述pH调节剂选自水杨酸、苹果酸、柠檬酸、琥珀酸中的至少一种。
在一种优选的实施方式中,所述稀释剂选自葡萄糖、木糖醇、果糖、蔗糖、水溶性淀粉、海藻糖、乳糖、麦芽糖中的至少一种。
优选的,所述稀释剂为重量比为1:4:0.5的蔗糖、水溶性淀粉、果糖。
本发明通过多种组分复配,得到的盐酸金霉素可溶性粉在溶液中的稳定性高,在本发明的体系中,当稀释剂为重量比为1:4:0.5的蔗糖、水溶性淀粉、果糖时,进一步提高了本发明产品的稳定性。猜测是该配比的稀释剂与助溶剂混合时不易发生反应,同时蔗糖、水溶性淀粉、果糖通过复配组合形成的立体结构,可以为其余组分充当更加牢固的载体。
在一种优选的实施方式中,所述抗氧剂选自亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠中的一种。
在一种优选的实施方式中,所述助悬剂选自黄原胶、阿拉伯胶、卡波姆中的一种或多种。
优选的,所述助悬剂为重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配。
为了提升盐酸金霉素可溶性粉在光照下放置的稳定性,优选的,所述助悬剂为重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配。猜测是通过重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配,助悬剂包裹在盐酸金霉素可溶性粉表面,降低了光敏感性。
在一种优选的实施方式中,所述助溶剂选自葡萄糖酸、柠檬酸钠、三聚磷酸钠、丙二酸钠、赖氨酸中的一种或多种。
在一种优选的实施方式中,所述助溶剂为重量比为1:(3~6):(0.7~1.5)的三聚磷酸钠、柠檬酸钠和赖氨酸复配。
本发明通过将三聚磷酸钠、柠檬酸钠和赖氨酸复配作为助溶剂,赋予盐酸金霉素可溶性粉的良好的溶解性,发明人猜测是三聚磷酸钠、柠檬酸钠和赖氨酸的螯合基团可以与盐酸金霉素可溶性粉螯合,形成溶解度更高的螯合物,同时赖氨酸可以影响三聚磷酸钠、柠檬酸钠的电荷排布,提高了三聚磷酸钠、柠檬酸钠的配位能力,进一步提升了螯合效果。但是在研发过程中,申请人发现盐酸金霉素可溶性粉的溶解时间较长,通过多次制备工艺的改良,添加三聚磷酸钠、柠檬酸钠和赖氨酸的重量比为1:(3~6):(0.7~1.5)时,可以提升溶解速度。猜测是在该比例下,三种组分的螯合基团可以和盐酸金霉素充分接触,加快了螯合的速度。
在一种优选的实施方式中,所述盐酸金霉素、pH调节剂、助溶剂、助悬剂的重量比为(3~4):(1~2):2:1。
发明人通过将盐酸金霉素、pH调节剂、助溶剂、助悬剂的重量比为(3~4):(1~2):2:1复配使用,药效高。猜测是在该比例下进行复配,可以赋予盐酸金霉素可溶性粉各种组分较高的流动性和吸附性,盐酸金霉素在肠道中的吸收效果好。
本发明第二方面提供了所述的高稳定性盐酸金霉素可溶性粉的制备方法,所述制备方法包括以下步骤:
(1)将各原料粉碎,按原料配比取各原料;
(2)将盐酸金霉素与稀释剂混合均匀,得预混料;
(3)将pH调节剂、抗氧剂、助溶剂、助悬剂添加到所述预混料中,充分混匀,真空冷冻干燥和制粒,即得高稳定性盐酸金霉素可溶性粉。
为了提高盐酸金霉素可溶性粉低温下的溶解性,在一种优选的实施方式中,将各原料粉碎至粒径≤130μm。
与现有技术相比,本发明的优点和有益效果为:
1.本发明通过多种组分复配,得到的盐酸金霉素可溶性粉在溶液中的稳定性高,通过选用所述稀释剂为蔗糖、水溶性淀粉、果糖的重量比为1:4:0.5做辅料,进一步提高了本发明产品的稳定性。
2.为了提升盐酸金霉素可溶性粉在光照下放置的稳定性,本发明所述助悬剂为重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配,通过助悬剂包裹在盐酸金霉素可溶性粉表面,降低了光敏感性。
3.本发明通过将三聚磷酸钠、柠檬酸钠和赖氨酸复配作为助溶剂,赋予盐酸金霉素可溶性粉的良好的溶解性。
4.发明人通过将盐酸金霉素、pH调节剂、助溶剂、助悬剂的重量比为(3~4):(1~2):2:1复配使用,对于皮肤问题外用药效好。
5.本发明的制备方法步骤简单,易于操作,便于推广和使用。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
本发明的原料购自以下厂家:
蔗糖麦克林,CAS:57-50-1
水溶性淀粉阿拉丁,CAS:9005-84-9
果糖麦克林,CAS:7660-25-5
黄原胶阿拉丁,CAS:11138-66-2
阿拉伯胶阿拉丁,CAS:9000-01-5
卡波姆上海皓鸿生物医药科技有限公司,卡波姆940
赖氨酸深圳乐芙生物科技有限公司,L-赖氨酸
柠檬酸钠天津锦耀翔承科技有限公司
实施例1
本实施例提供了一种高稳定性盐酸金霉素可溶性粉,按质量百分数计,包括以下组分:盐酸金霉素23%、pH调节剂11%、抗氧剂0.3%、助溶剂14%、助悬剂7%,余量为稀释剂。
所述pH调节剂为柠檬酸。
所述稀释剂为重量比为1:4:0.5的蔗糖、水溶性淀粉、果糖。
所述抗氧剂为亚硫酸氢钠。
所述助悬剂为重量比为1:1:2的黄原胶、阿拉伯胶、卡波姆复配。
所述助溶剂为重量比为1:4:0.9的三聚磷酸钠、柠檬酸钠和赖氨酸复配。
本实施例提供了所述的高稳定性盐酸金霉素可溶性粉的制备方法,所述制备方法包括以下步骤:
(1)将各原料粉碎至粒径≤130μm,按原料配比取各原料;
(2)将盐酸金霉素与稀释剂混合均匀,得预混料;
(3)将pH调节剂、抗氧剂、助溶剂、助悬剂添加到所述预混料中,充分混匀,真空冷冻干燥和制粒,即得高稳定性盐酸金霉素可溶性粉。
实施例2
本实施例提供了一种高稳定性盐酸金霉素可溶性粉,按质量百分数计,包括以下组分:盐酸金霉素22%、pH调节剂9%、抗氧剂0.1%、助溶剂16%、助悬剂8%和余量为稀释剂。
所述pH调节剂为水杨酸。
所述稀释剂为果糖。
所述抗氧剂为焦亚硫酸钠。
所述助悬剂为重量比为2:1:1的黄原胶、阿拉伯胶、卡波姆。
所述助溶剂为重量比为1:4:0.9的三聚磷酸钠、柠檬酸钠和赖氨酸复配。
实施例3
本实施例与实施例1的区别为:所述助悬剂为重量比为2:1:2的黄原胶、阿拉伯胶、卡波姆复配。
实施例4
本实施例与实施例1的区别为:所述助溶剂为重量比为4:0.5:1三聚磷酸钠、柠檬酸钠和赖氨酸复配。
实施例5
本实施例与实施例1的区别为:所述稀释剂为重量比为1:3:2的葡萄糖、木糖醇、果糖。
对比例1
本对比例与实施例1的区别为:一种高稳定性盐酸金霉素可溶性粉,按质量百分数计,包括以下组分:盐酸金霉素35%、pH调节剂3%、抗氧剂0.7%、助溶剂5%、助悬剂20%和余量为稀释剂。
对比例2
本对比例与实施例1的区别为:一种高稳定性盐酸金霉素可溶性粉,按质量百分数计,包括以下组分:盐酸金霉素35%、助溶剂10%、助悬剂3%和余量为稀释剂。
性能测试
1、将实施例和对比例的实施例和对比例的各取0.2g,溶解于100ml的0.9%生理盐水中,分别振摇5min和10min,观察其溶解情况。结果见表1。
2、将实施例和对比例的盐酸金霉素可溶性粉在高温(60℃)条件下放置,测定第10天的干燥失重;将盐酸金霉素可溶性粉在温度40±2℃、湿度75%±5%条件下放置6个月,进行加速稳定性测试,测定6个月后的干燥失重情况;结果见表1。
3、试验选取70只白鼠,随机分为7组,每组10只。将实施例和对比例的样品用0.9%生理盐水溶解,灌服剂量均为15mg/(kg·BW)(以金霉素计)。分别于给药后2.0h采集血样,测定平均血药浓度。结果见表1。
表1性能测试结果
通过结果可知,改变盐酸金霉素可溶性粉的组成,盐酸金霉素可溶性粉的可溶性和稳定性均降低。通过小鼠实验可知,本发明通过提升盐酸金霉素的溶解性,改善了小鼠对盐酸金霉素的吸收,将本发明的原料药用于制剂时能够达到更好的抗炎抗感染效果。将本发明的原料药用于治疗人体各种皮肤感染和炎症具有非常好的治疗效果,优于市面上现存的盐酸金霉素药物。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种高稳定性盐酸金霉素可溶性粉,其特征在于:按质量百分数计,包括以下组分:盐酸金霉素20~25%、pH调节剂8%~15%、抗氧剂0.1%~0.4%、助溶剂10~17%、助悬剂4%~10%和余量为稀释剂。
2.根据权利要求1所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述pH调节剂选自水杨酸、苹果酸、柠檬酸、琥珀酸中的至少一种。
3.根据权利要求2所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述稀释剂选自葡萄糖、木糖醇、果糖、蔗糖、水溶性淀粉、海藻糖、乳糖、麦芽糖中的至少一种。
4.根据权利要求3所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述助溶剂选自葡萄糖酸、柠檬酸钠、三聚磷酸钠、丙二酸钠、赖氨酸中的一种或多种。
5.根据权利要求4所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述助悬剂选自黄原胶、阿拉伯胶、卡波姆中的一种或多种。
6.根据权利要求5所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述盐酸金霉素、pH调节剂、助溶剂、助悬剂的重量比为(3~4):(1~2):2:1。
7.根据权利要求1所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述抗氧剂选自亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠中的一种。
8.根据权利要求4所述的高稳定性盐酸金霉素可溶性粉,其特征在于:所述助溶剂为重量比为1:(3~6):(0.7~1.5)葡萄糖酸、柠檬酸钠和赖氨酸复配。
9.权利要求1~8任一项所述的高稳定性盐酸金霉素可溶性粉的制备方法,其特征在于:所述制备方法包括以下步骤:
(1)将各原料粉碎,按原料配比取各原料;
(2)将盐酸金霉素与稀释剂混合均匀,得预混料;
(3)将pH调节剂、抗氧剂、助溶剂、助悬剂添加到所述预混料中,充分混匀,真空冷冻干燥,即得高稳定性盐酸金霉素可溶性粉。
10.根据权利要求9所述的制备方法,其特征在于:将各原料粉碎至粒径≤130μm。
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