CN115105476B - Orlistat freeze-dried oral preparation and preparation process thereof - Google Patents
Orlistat freeze-dried oral preparation and preparation process thereof Download PDFInfo
- Publication number
- CN115105476B CN115105476B CN202210250785.2A CN202210250785A CN115105476B CN 115105476 B CN115105476 B CN 115105476B CN 202210250785 A CN202210250785 A CN 202210250785A CN 115105476 B CN115105476 B CN 115105476B
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- China
- Prior art keywords
- polyoxyethylene
- freeze
- orlistat
- drying
- dried
- Prior art date
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- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 title claims abstract description 84
- 229960001243 orlistat Drugs 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 238000004108 freeze drying Methods 0.000 claims abstract description 34
- 239000004094 surface-active agent Substances 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- 239000000375 suspending agent Substances 0.000 claims abstract description 11
- -1 polyoxyethylene monooleate Polymers 0.000 claims description 84
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 51
- 238000003756 stirring Methods 0.000 claims description 37
- 238000007872 degassing Methods 0.000 claims description 32
- 238000001035 drying Methods 0.000 claims description 25
- 125000005456 glyceride group Chemical group 0.000 claims description 22
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 229960001855 mannitol Drugs 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 12
- 238000007710 freezing Methods 0.000 claims description 12
- 238000003760 magnetic stirring Methods 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 229920002307 Dextran Polymers 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 11
- 229960002086 dextran Drugs 0.000 claims description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 11
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 7
- 229930006000 Sucrose Natural products 0.000 claims description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 229940100242 glycol stearate Drugs 0.000 claims description 7
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000005720 sucrose Substances 0.000 claims description 7
- 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 6
- 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 6
- 239000004166 Lanolin Substances 0.000 claims description 6
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- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 5
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 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 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
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- 235000019322 gelatine Nutrition 0.000 claims description 5
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- 229960003943 hypromellose Drugs 0.000 claims description 5
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 claims description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 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 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 229960002920 sorbitol Drugs 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
- HOVAGTYPODGVJG-UVSYOFPXSA-N (3s,5r)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol Chemical compound COC1OC(CO)[C@@H](O)C(O)[C@H]1O HOVAGTYPODGVJG-UVSYOFPXSA-N 0.000 claims description 2
- RUHCWQAFCGVQJX-RVWHZBQESA-N (3s,8s,9s,10r,13r,14s,17r)-3-hydroxy-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-1-one Chemical compound C1C=C2C[C@H](O)CC(=O)[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 RUHCWQAFCGVQJX-RVWHZBQESA-N 0.000 claims description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims description 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- BXCRLBBIZJSWNS-UHFFFAOYSA-N 2-hydroxyethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCCO BXCRLBBIZJSWNS-UHFFFAOYSA-N 0.000 claims description 2
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- 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
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229940086609 Lipase inhibitor Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960002900 methylcellulose Drugs 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012778 molding material Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- 238000012418 validation experiment Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention belongs to the technical field of medicines, and particularly provides an orlistat oral freeze-dried tablet and a preparation method thereof. The oral freeze-dried tablet contains orlistat, a surfactant, a freeze-drying excipient and a suspending agent; the components are prepared into mixed liquid, and freeze-dried tablets can be obtained through freeze drying. The freeze-dried tablet provided by the invention has good disintegration property and greatly improved stability; the better medicine dispersion uniformity and the excellent dissolution characteristic of the medicine obviously improve the bioavailability of the medicine, thereby improving the oil discharge effect of the medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a medicinal preparation, and particularly provides an orlistat freeze-dried oral preparation and a preparation method thereof.
Background
Orlistat is a long-acting, specific and strong-acting specific gastrointestinal lipase inhibitor, and can deactivate the two enzymes by forming covalent bonds with lipase active serine positions in the stomach and small intestinal cavities, so that the deactivated enzymes can not decompose fat in food into free fatty acid and glycerol which can be absorbed by human bodies, thereby reducing fat intake and playing a role in reducing weight.
Orlistat has the chemical name: (S) -2-carboxamide-4-methyl-pentanoic acid (S) -1- [ [ (2S, 3S) -3-hexyl-4-oxo-cyclobutyl ] methyl ] -dodecyl ester having the structural formula:
orlistat is white crystalline powder, is almost insoluble in water, is easily soluble in chloroform, is extremely easily soluble in methanol and ethanol, is easily pyrolyzed, and has very low solubility in water in a physiological pH range; the melting point is 40-42 ℃, and the material is degraded by hydrolysis or heat. The conventional oral solid preparation capsules and tablets are unfavorable for the release of the orlistat because the orlistat is insoluble in water, have lower bioavailability, and are easy to generate sticking in the process of tabletting or capsule filling because the melting point of the orlistat is lower.
US6004996 discloses a preparation method of orlistat preparation, which is to prepare a drug into pellets and then fill the pellets into hard capsules, but the capsules are unstable to high temperature and high humidity, the capsules can absorb moisture, soften and be sticky when the ambient temperature is 22-24 ℃ and the relative humidity is more than 60%, the capsules change more quickly when the capsules are stored under high temperature and high humidity conditions, and the capsules can adhere in the storage process, the disintegration time limit is obviously prolonged and are difficult to disintegrate. Meanwhile, in order to solve the problem of sticking a punch rod in the capsule production process, a process for preparing the micropill is adopted, and the molding material is microcrystalline cellulose, but the microcrystalline cellulose, sodium carboxymethyl starch and the like have poor compatibility with orlistat, so that the stability of the preparation is poor, and the impurity content is high.
Patent CN103006601A discloses an orlistat tablet and a preparation method thereof, wherein the tablet is formed by directly tabletting an orlistat phospholipid composition containing silicon dioxide and a pharmaceutical excipient, and solves the problems of poor stability in storage and sticking of the orlistat in a conventional tabletting process, but has the problems of poor dissolution rate, complex preparation process and low bioavailability.
Patent CN108785272A discloses an orlistat soft capsule preparation and a preparation method thereof, and the orlistat soft capsule prepared by the method has less impurity content and improved dissolution; however, the soft capsule has a larger influence on the disintegration time of the soft capsule due to external environmental factors during the storage period, and the gelatin crosslinking reaction is more likely to occur under the conditions of high temperature and illumination, so that the disintegration or dissolution delay occurs. Meanwhile, orlistat is a weight-losing medicament and is taken with oily auxiliary materials, so that the weight-losing effect of the orlistat is definitely reduced.
Patent CN1514725B discloses a pharmaceutical combination comprising a lipase inhibitor and a sucrose fatty acid ester, which combination produces a drug which shows about 1.7 times higher efficacy than orlistat, but no good solution is proposed for the stability of orlistat formulations.
In view of the above disclosed adjuvants and formulation techniques for preparing orlistat formulations, how to further improve the stability, safety and bioavailability of orlistat is a technical problem to be solved in the art. In addition, in the prior art, when the capsule is not taken by a swallowed patient, the capsule content may be poured out for taking, and the tablet may be ground for taking, so that the taste is not improved.
Disclosure of Invention
Aiming at the technical problems that the existing orlistat preparation still has stability, safety, dissolution and bioavailability to be solved, the invention provides an orlistat oral freeze-dried tablet. The freeze-dried tablet has the characteristics of good taste, rapid disintegration, less impurity content, high stability, good medicine dispersibility and the like; the oral freeze-dried tablet can obviously improve the bioavailability of orlistat.
The invention comprises the following specific contents:
in one aspect, the invention provides an orlistat oral lyophilized tablet comprising orlistat, a surfactant, a lyophilization excipient and a suspending agent; the components are prepared into mixed liquid, and freeze-dried tablets can be obtained through freeze drying.
Preferably, the orlistat oral freeze-dried tablet contains 1 mg-200 mg of orlistat; preferably from 10mg to 100mg of orlistat; further preferably, the orlistat is contained in an amount of 15 to 60 mg.
Preferably, the oral freeze-dried tablet comprises 1 part by weight of orlistat and 0.05-1 part by weight of surfactant; further preferably, the orlistat comprises 1 part and the surfactant comprises 0.06-0.8 part; still more preferably, the orlistat comprises 1 part and the surfactant comprises 0.1 to 0.6 part.
Preferably, the oral freeze-dried tablet comprises 1 part of orlistat and 0.1-10 parts of freeze-dried excipient by weight; further preferably, the orlistat comprises 1 part and the freeze-drying excipient comprises 0.1 to 6 parts; still more preferably, the orlistat comprises 1 part and the lyophilized excipient comprises 0.1 to 4 parts.
Preferably, the oral freeze-dried tablet comprises 1 part of orlistat and 0.02-0.8 part of suspending agent by weight; further preferably, the suspending agent is 0.05 to 0.4 part by 1 part by weight of orlistat.
Preferably, the surfactant is selected from ionic or nonionic surfactants having an HLB of from 8 to 18.
Preferably, the surfactant is selected from polyoxyethylene monooleate, polyoxyethylene monostearate, polyoxyethylene stearate, polyoxyethylene monopalmitate, alkylaryl sulfonate, triethanolamine oleate, polyoxyethylene oleyl ether, polyoxyethylene alkylphenol, polyoxyethylene acetylated lanolin derivative, polyoxyethylene alkyl aromatic ether, polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan lanolin derivative, polyoxyethylene esters of mixed fatty acids and resin acids, polyoxyethylene cholesterol ether, polyoxypropylene lanolin ether, polyoxyethylene methyl glucoside sesquioleate, polyoxyethylene monooleate, polyoxyethylene oleyl ether, polyoxyethylene stearyl alcohol, polyoxyethylene cetyl alcohol, polyoxyethylene oxypolystearyl stearate, polyoxyethylene lauryl ether, polyoxyethylene oleyl alcohol, polyoxyethylene fatty alcohol, polyethylene glycol monopalmitate, polyoxyethylene monolaurate, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, polyethylene glycol stearate, polyethylene glycol caprate, sucrose stearate, sucrose palmitate, tween, polyoxyethylene 20/40/60/80/21/85/65/81, AEO-glyceryl monostearate, AEO-9 or a plurality of fatty esters.
Further preferred is one or a combination of lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, sucrose stearate, sucrose palmitate, sucrose glycerate, polyoxyethylene monostearate, polyoxyethylene monooleate, polyoxyethylene monopalmitate, polyethylene glycol stearate, caprylic/capric polyethylene glycol glyceride.
Still more preferably, it is one or a combination of lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, and linoleoyl polyoxyethylene glyceride.
Preferably, the lyophilization excipient is selected from one or more of glycine, lysine, alanine, proline, sodium glutamate, mannitol, sorbitol, maltitol, xylitol, lactitol, dextran, cyclodextrin, maltodextrin, trehalose, sucrose, lactose, glucose, phosphate, calcium carbonate or sodium acetate; even more preferred is mannitol or dextran or a mixture thereof.
Preferably, the suspending agent is hydroxypropyl cellulose, hypromellose, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, sodium alginate, acacia, tragacanth, pectin, agar, carrageenan, deacetylated chitin or dextran, xanthan gum, gelatin; further preferred are hydroxypropyl cellulose, hypromellose, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose; still more preferred is hydroxypropyl cellulose.
In another aspect, the invention provides a preparation process of orlistat oral freeze-dried tablets, which specifically comprises the following steps:
(1) Placing the solvent with the prescription amount into a degassing bottle, sequentially adding the excipient and the suspending agent under magnetic stirring, and stirring until the excipient and the suspending agent are completely dissolved;
(2) Adding surfactant under stirring, and stirring while degassing until it is dissolved or dispersed; then adding orlistat, dispersing uniformly, and stirring while degassing until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze-drying was performed.
Preferably, the solvent in the step 1 is water or ethanol water solution; preferably purified water.
Preferably, the weight ratio of orlistat to the solvent is 1:4-20.
Preferably, the magnetic stirring speed in the step 1 is 100-2000r/min.
Preferably, the stirring speed after adding the surfactant in the step 2 is 200-800r/min.
Preferably, the stirring speed after the orlistat is added in the step 2 is 200-800r/min.
Preferably, the freeze-drying process described in step 3 comprises:
quick-freezing: placing the filled sample at the temperature of minus 170 ℃ to minus 40 ℃ for 0.5 to 3 hours;
prefreezing: the temperature of the freeze dryer plate layer is between minus 50 ℃ and minus 30 ℃ and the heat preservation is carried out for 0.5 to 3 hours;
and (3) a drying procedure: setting the temperature at-40-35 deg.c, vacuum degree at 10-50pa and drying time at 2-72 hr.
Further preferably, the freeze-drying process described in step 3 comprises:
quick-freezing: placing the filled sample at the temperature of minus 80 ℃ to minus 40 ℃ for 0.5 to 3 hours;
prefreezing: the temperature of the freeze dryer plate layer is between minus 50 ℃ and minus 30 ℃ and the heat preservation is carried out for 0.5 to 3 hours;
and (3) a drying procedure: setting the temperature at minus 30 ℃ to 30 ℃, the vacuum degree at 10 pa to 50pa and the drying time at 6h to 24h.
Compared with the prior art, the invention has the following advantages:
1. the preparation method adopts the freeze-drying method to prepare the orlistat freeze-dried oral tablet, and the proper auxiliary material ingredients are optimized, so that the disintegration speed of the preparation is improved, the dispersion uniformity of the medicine is improved, the dissolution rate is improved compared with that of the orlistat capsule sold in the market, and the freeze-dried tablet also has better taste.
2. Compared with other tablets, the orlistat freeze-dried tablet provided by the invention contains fewer auxiliary materials, and even if the orlistat freeze-dried tablet does not contain a disintegrating agent, the orlistat freeze-dried tablet still has good disintegrating property, and the stability is greatly improved; the better medicine dispersion uniformity and the excellent dissolution characteristic of the medicine obviously improve the bioavailability of the medicine, thereby improving the oil discharge curative effect of the medicine and achieving the same effect as the existing preparation by using relatively smaller dosage.
3. The freeze drying method provided by the invention can effectively avoid the sticking phenomenon caused by low melting point of orlistat in the conventional preparation method, and can not cause the problem of drug degradation caused by high temperature in the conventional preparation method, thereby ensuring the impurity content and stability of the drug.
Detailed Description
The technical solutions of the present invention are further illustrated and described below by means of specific embodiments, it being understood that the following examples are given for illustrative purposes only and are not intended to limit the present invention, and that some alternatives apparent in the art are within the scope of protection of the present invention.
Example 1
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding mannitol and hydroxypropyl cellulose under magnetic stirring (rotating speed 1000 r/min) until the mannitol and the hydroxypropyl cellulose are completely dissolved;
(2) Adding lauroyl polyoxyethylene glyceride under stirring, and stirring at 500r/min under degassing to disperse uniformly; then adding orlistat, dispersing uniformly, and stirring until no bubbles exist while degassing (rotating speed 500 r/min) to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Example 2
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding dextran and hydroxypropyl cellulose under magnetic stirring (rotating speed 1000 r/min) until the dextran and the hydroxypropyl cellulose are completely dissolved;
(2) Adding stearoyl polyoxyethylene glyceride and sucrose stearate under stirring, and stirring (rotating speed 500 r/min) while degassing until the mixture is uniformly dispersed; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Example 3
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding mannitol and hypromellose under magnetic stirring (rotating speed 1000 r/min) until the mannitol and hypromellose are completely dissolved;
(2) Adding the linoleoyl polyoxyethylene glyceride and the sucrose palmitate under stirring, and stirring (rotating speed 500 r/min) while degassing until the materials are uniformly dispersed; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Example 4
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding mannitol, dextran and hydroxyethyl cellulose under magnetic stirring (rotating speed 1000 r/min) until the mannitol, the dextran and the hydroxyethyl cellulose are completely dissolved;
(2) Adding polyoxyethylene monostearate under stirring, and stirring (rotation speed 500 r/min) while degassing until dispersion is uniform; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 80 ℃ and preserving heat for 0.5h;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 50 ℃, and preserving heat for 0.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 6 hr.
Example 5
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding maltodextrin, dextran and methylcellulose under magnetic stirring (rotating speed 1000 r/min) until the maltodextrin, dextran and methylcellulose are completely dissolved;
(2) Adding caprylic/capric polyethylene glycol glyceride under stirring, and stirring at 500r/min while degassing until the mixture is uniformly dispersed; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 40 ℃ and preserving heat for 3 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to minus 30 ℃, and preserving heat for 3 hours;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 13 hr.
Example 6
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding maltodextrin and hydroxypropyl cellulose under magnetic stirring (rotating speed 2000 r/min) until the maltodextrin and the hydroxypropyl cellulose are completely dissolved;
(2) Adding polyoxyethylene monopalmitate under stirring, and stirring while degassing (rotating speed 500 r/min) until the polyoxyethylene monopalmitate is uniformly dispersed; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 50 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Example 7
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding glycine and sodium carboxymethylcellulose under magnetic stirring (rotating speed 2000 r/min) until the glycine and sodium carboxymethylcellulose are completely dissolved;
(2) Adding Tween 80 under stirring, and stirring at 800r/min under degassing to dissolve completely; then adding orlistat, dispersing uniformly, and stirring while degassing (the rotating speed is 800 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Example 8
Prescription (I)
(II) preparation method
(1) Placing the prescribed amount of purified water into a degassing bottle, and adding lactose and xanthan gum under magnetic stirring (rotating speed of 800 r/min) until the lactose and xanthan gum are completely dissolved;
(2) Adding polyethylene glycol stearate under stirring, and stirring (rotation speed 200 r/min) while degassing until the mixture is dispersed uniformly; then adding orlistat, dispersing uniformly, and stirring while degassing (rotating speed 500 r/min) until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Comparative example 1
Prescription (I)
(II) preparation method:
(1) Placing the purified water with the prescription amount into a degassing bottle, adding gelatin with the prescription amount, soaking for 10 minutes, heating and stirring for dissolution (the temperature is not more than 70 ℃) with a hot water bath method, and cooling to room temperature after the gelatin is dissolved. Mannitol was added sequentially under magnetic stirring (rotation speed 1000 r/min) until complete dissolution.
(2) Orlistat is added under stirring, and the mixture is obtained after dispersion by stirring (the rotating speed is 500 r/min) and degassing.
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze drying is carried out, and the freeze drying process is specifically as follows:
quick-freezing: placing the filled sample in a refrigerator at the temperature of minus 60 ℃ and preserving heat for 2 hours;
prefreezing: setting the temperature of a plate layer of the freeze dryer to be minus 40 ℃, and preserving heat for 1.5h;
and (3) a drying procedure: -30 deg.c, vacuum degree of 10-50pa and drying time of 8 hr.
Comparative example 2
Prescription (I)
(II) preparation method
Weighing lauroyl polyoxyethylene glyceride with a prescription amount, adding the lauroyl polyoxyethylene glyceride into purified water with the prescription amount, and stirring to uniformly disperse; weighing orlistat, mannitol, hydroxypropyl cellulose and sodium carboxymethyl starch according to the prescription amount, uniformly mixing, and granulating by using the aqueous solution; sieving wet granules with 20 mesh sieve, drying in fluidized bed at 35deg.C, sieving dry granules with 18 mesh sieve, and grading; then adding magnesium stearate, mixing uniformly, tabletting.
Comparative example 3
Prescription (I)
(II) preparation method:
weighing orlistat, sucrose palmitate, sodium starch glycolate, polyethylene glycol-6000, xylitol, mannitol, polyethylene glycol stearate and povidone with the prescription amount, adding a proper amount of water, uniformly mixing, and granulating by using the aqueous solution; the wet particles are filtered by a sieve with the aperture of 5mm, dried by a fluidized bed at 35 ℃, and the dry particles are sieved by a 12-mesh sieve for finishing; then adding magnesium stearate and talcum, mixing uniformly, tabletting.
Comparative example 4
Prescription (I)
(II) preparation method:
weighing orlistat, sucrose palmitate, sodium starch glycolate, microcrystalline cellulose, lactose, xylitol, mannitol, polyethylene glycol stearate and povidone with a prescription amount, adding a proper amount of water, uniformly mixing, and granulating with the water solution; the wet particles are filtered by a sieve with the aperture of 5mm, dried by a fluidized bed at 35 ℃, and the dry particles are sieved by a 12-mesh sieve for finishing; then adding sodium stearyl fumarate and glyceryl behenate, mixing, and tabletting.
Comparative example 5
Prescription (I)
(II) preparation method:
weighing orlistat, sucrose palmitate, sodium starch glycolate, lactose, xylitol, mannitol, polyethylene glycol stearate and povidone with the prescription amount, adding a proper amount of water, uniformly mixing, and granulating by using the aqueous solution; the wet particles are filtered by a sieve with the aperture of 5mm, dried by a fluidized bed at 35 ℃, and the dry particles are sieved by a 12-mesh sieve for finishing; then adding sodium stearyl fumarate and glyceryl behenate, mixing, and tabletting.
Verification embodiment
1. Appearance, mouthfeel, and disintegration Property measurement
Test samples of the validation experiments were prepared according to the prescriptions and the processes of the examples and the comparative examples, with the specification that a single tablet contained 23mg of orlistat.
Appearance: visual inspection
Mouthfeel: volunteer clothes
The tablets prepared in examples and comparative examples of the present invention were tested according to the method of examination of disintegration time of orally disintegrating tablets (chinese pharmacopoeia 2020 edition general rule 0921), and taste detection was performed while considering orally disintegrating tablets.
Disintegration time limit examination method
The instrument device mainly comprises a lifting bracket and a stainless steel pipe with a screen mesh embedded at the lower end, wherein the lifting bracket moves up and down by 10 mm+/-1 mm, and the round trip frequency is 30 times per minute.
The disintegrating basket is a stainless steel tube, the tube length is 30mm, the inner diameter is 13.0mm, and the inner diameter of a stainless steel screen (inlaid at the bottom of the stainless steel tube) is 710 mu m.
The inspection method is to fix the stainless steel tube on the bracket, immerse the stainless steel tube in a 1000ml cup, and the cup is filled with about 900ml of water with the temperature of 37 plus or minus 1 ℃ and adjust the water level height to make the screen mesh 15mm plus or minus 1mm below the water surface when the stainless steel tube is at the lowest position. The instrument is started. Taking 1 tablet of the product, placing the tablet into the stainless steel tube for inspection, and completely disintegrating and passing through a screen within 60 seconds, wherein if a small amount of the tablet is light and floats upwards or adheres to the inner wall of the stainless steel tube or the screen, the tablet can be subjected to the rule-conforming condition. The measurement was repeated for 6 pieces, and the test was allowed to be satisfied. If 1 tablet is not in accordance with the rule, 6 tablets should be taken for retesting, and all the tablets should be in accordance with the rule.
Table 1 disintegration time and mouthfeel test results
The samples tested in examples 1-8 disintegrated faster, had better mouthfeel, had better tablet appearance, and the tablets disintegrated into fine powder and dispersed evenly. In the sample trial preparation process of comparative example 1, the tablet is subjected to detection of disintegration after freeze-drying, and the tablet is agglomerated after wetting, so that the tablet is slower in disintegration and difficult to disperse. Comparative example 2 samples that were conventionally tabletted and tested were more than 2 minutes after adding a larger amount of sodium carboxymethyl starch, the disintegration time was greater than 2 minutes, and the dispersion effect of the disintegrated and disintegrated material was poorer than that of the lyophilized tablet. Comparative examples 3, 4, and 5 test samples, which generally had a general appearance, were relatively slow although they were disintegrated, and disintegrated into larger granules, and required a certain time for the raw material to be released from the granules.
2. Stability study
EXAMPLES and COMPARATIVE EXAMPLES A trial of orlistat (23 mg) was run in accelerated experiments with commercially available orlistat capsules (ALLI, 60 mg) in the form of aluminum plastic packs, commercially available orlistat capsules, placed at 30℃, 65% and sampled and assayed at 3 months.
TABLE 2 sample acceleration for 3 months related substance detection results
The accelerated experiment shows that the sample prepared by the freeze-drying process has smaller content of related substances, and the sample shows better stability after stability investigation, and the ring-opening epimer and the total impurity content are less in change compared with the preparation of the original ground 60mg capsule and the chewing tablet or the conventional tabletting.
3. Equivalent study
Orlistat lyophilized tablets (23 mg gauge), orlistat capsules (ALLI, 60mg gauge) were purchased from commercial products according to the procedure prescribed in example 1.
The method comprises the following steps: the pharmacodynamics of dogs was studied by using orlistat oral freeze-dried tablet samples (23 mg) and orlistat capsules (ALLI, 60 mg) to examine the pharmacodynamics difference after multiple administrations. The experiment is divided into orlistat capsule group and orlistat freeze-dried tablet group (specification: 23 mg). The test orlistat formulation product was orally administered to 4 Beagle dogs per group, once daily, 1 tablet or 1 granule each time, with meals. Ten days of continuous administration, 24 hours of feces per day after administration was collected, and the fecal fat excretion rate was examined. After 24h of excrement is collected, the excrement is dried, the dried excrement is taken out, and the excrement is ground into powder and then weighed. Placing the mixture into a weighed empty bottle, adding a corresponding amount of extract, evaporating the extract to dryness after extraction is completed, and weighing again to obtain the weight of fat. The fat content in the feces was expressed as a percentage (%) of the weight of fat in the feces to the dry weight of the feces, and the results are shown in Table 3.
Excel statistical software, the measurement data are represented by mean ± standard deviation, the differences between groups are compared by means of ttest analysis, and the difference represented by P <0.05 is statistically significant.
Table 3 detection of fat content in canine feces
According to the animal efficacy results, after the orlistat is orally taken, the fat content in the canine feces is higher than that before the administration for 1-10 days, and the fat content in the orlistat freeze-dried tablet group (with the specification of 23 mg) and the orlistat capsule group (with the specification of 60 mg) in the canine feces is not obviously different (P is more than 0.05).
Claims (3)
1. The orlistat oral freeze-dried tablet is characterized by comprising orlistat, a surfactant, a freeze-dried excipient and a suspending agent; preparing the components into a mixed solution, and freeze-drying to obtain a freeze-dried tablet; the oral freeze-dried tablet comprises, by weight, 1 part of orlistat, 0.05-1 part of a surfactant, 0.1-10 parts of a freeze-dried excipient and 0.02-0.8 part of a suspending agent; the surfactant is selected from ionic or nonionic surfactants with HLB of 8-18; the freeze-drying excipient is one or more of glycine, mannitol, sorbitol, maltitol, xylitol, lactitol, dextran, cyclodextrin, maltodextrin, trehalose, sucrose, lactose and glucose; the suspending agent is hydroxypropyl cellulose, hypromellose, methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, sodium alginate, acacia, tragacanth, pectin, agar, carrageenan, deacetylated chitin or dextran, xanthan gum, and gelatin; the preparation process specifically comprises the following steps:
(1) Placing the prescribed amount of solvent into a degassing bottle, and adding excipient and suspending agent under magnetic stirring until the solvent is completely dissolved;
(2) Adding surfactant under stirring, and stirring while degassing until completely dissolved; then adding orlistat, dispersing uniformly, and stirring while degassing until no bubbles exist to obtain a mixed solution;
(3) Filling the mixed liquid obtained in the step 2 into a die; freeze-drying was performed.
2. The lyophilized tablet of claim 1, wherein the surfactant is selected from polyoxyethylene monooleate, polyoxyethylene monostearate, polyoxyethylene monopalmitate, alkylaryl sulfonate, triethanolamine oleate, polyoxyethylene oleyl ether, polyoxyethylene alkylphenol, polyoxyethylene acetylated lanolin derivative, polyoxyethylene alkyl aromatic ether, polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene esters of mixed fatty acids and resin acids, polyoxyethylene cholesterol ether, polyoxypropylene lanolin alcohol ether, polyoxyethylene methyl glucoside sesquioleate, polyoxyethylene monooleate, polyoxyethylene ether, polyoxyethylene stearyl alcohol, polyoxyethylene cetyl alcohol, polyoxyethylene oxypolyethylene stearate, polyoxyethylene lauryl ether, polyoxyethylene oleyl alcohol, polyoxyethylene fatty alcohol, polyethylene glycol monopalmitate, polyoxyethylene monolaurate, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, polyethylene glycol stearate, caprylic acid glyceride, polyoxyethylene glyceryl stearate, sucrose fatty acid, aeeto, sucrose fatty acid, AEO-3, sucrose fatty acid, AEO-3, or a plurality of fatty acid esters.
3. The lyophilized tablet of claim 1, wherein the lyophilization process in step 3 comprises:
quick-freezing: placing the filled sample at the temperature of-170 to-40 ℃ for 0.5 to 3 hours;
prefreezing: the temperature of the freeze dryer plate layer is between minus 50 ℃ and minus 30 ℃ and the heat preservation is carried out for 0.5 to 3 hours;
and (3) a drying procedure: setting the temperature at-40-35 deg.c, vacuum degree at 10-50pa and drying time at 2-72 hr.
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