CN106138052A - A kind of Thalidomide preparation and preparation method thereof - Google Patents
A kind of Thalidomide preparation and preparation method thereof Download PDFInfo
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- CN106138052A CN106138052A CN201510181604.5A CN201510181604A CN106138052A CN 106138052 A CN106138052 A CN 106138052A CN 201510181604 A CN201510181604 A CN 201510181604A CN 106138052 A CN106138052 A CN 106138052A
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- preparation
- thalidomide
- aluminum
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- dissolution
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- 229960003433 thalidomide Drugs 0.000 title claims abstract description 64
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 26
- 229940079593 drug Drugs 0.000 claims abstract description 20
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002245 particle Substances 0.000 claims description 25
- 229920002472 Starch Polymers 0.000 claims description 16
- 239000008107 starch Substances 0.000 claims description 16
- 235000019698 starch Nutrition 0.000 claims description 16
- 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 claims description 10
- 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 10
- 239000008101 lactose Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 229960000502 poloxamer Drugs 0.000 claims description 6
- 229920001983 poloxamer Polymers 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000003292 glue Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 239000000080 wetting agent Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 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 2
- 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 2
- 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 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 2
- 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 2
- VRAIHTAYLFXSJJ-UHFFFAOYSA-N alumane Chemical compound [AlH3].[AlH3] VRAIHTAYLFXSJJ-UHFFFAOYSA-N 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 229920001903 high density polyethylene Polymers 0.000 claims description 2
- 239000004700 high-density polyethylene Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000001814 pectin Substances 0.000 claims description 2
- 235000010987 pectin Nutrition 0.000 claims description 2
- 229920001277 pectin Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 235000001630 Pyrus pyrifolia var culta Nutrition 0.000 claims 1
- 240000002609 Pyrus pyrifolia var. culta Species 0.000 claims 1
- -1 Thalidomide compound Chemical class 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 235000013539 calcium stearate Nutrition 0.000 claims 1
- 239000008116 calcium stearate Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 235000001055 magnesium Nutrition 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 37
- 238000012360 testing method Methods 0.000 abstract description 10
- 238000004806 packaging method and process Methods 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 40
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000000034 method Methods 0.000 description 6
- 102220042174 rs141655687 Human genes 0.000 description 6
- 229910000989 Alclad Inorganic materials 0.000 description 5
- 238000010298 pulverizing process Methods 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 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 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- UEJJHQNACJXSKW-SECBINFHSA-N (R)-thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@@H]1CCC(=O)NC1=O UEJJHQNACJXSKW-SECBINFHSA-N 0.000 description 1
- UEJJHQNACJXSKW-VIFPVBQESA-N (S)-thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1[C@H]1CCC(=O)NC1=O UEJJHQNACJXSKW-VIFPVBQESA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- OPCRGEVPIBLWAY-QNRZBPGKSA-N ethyl (2E,4Z)-deca-2,4-dienoate Chemical class CCCCC\C=C/C=C/C(=O)OCC OPCRGEVPIBLWAY-QNRZBPGKSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical compound NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of stability-enhanced Thalidomide preparation.Test proves, and uses plastic-aluminum to add the form of aluminum bag packaging between 5-40 μm the size controlling that feeds intake of Thalidomide crude drug, can reach the preparation of more high-dissolution and stability in preparation process.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular it relates to a kind of stability-enhanced Thalidomide preparation and
Preparation method.
Background technology
Thalidomide (thalidomide) is a kind of glutamate derivatives, chemical entitled phthalimide group glutaramide,
Its chemical structural formula is as follows:
Thalidomide is that white is to off-white color crystalline powder, odorless, tasteless.Two
Methylformamide or pyridine are dissolved, soluble,very slightly in water, methanol or ethanol, in ether, chloroform or benzene not
Molten.Fusing point is 269 DEG C～274 DEG C.
Thalidomide is racemic compound, has two kinds of isomerss of R and S.It is used for initially as downern
Treatment vomiting during pregnancy, but because there being obvious teratogenesis, after be stopped application.Along with going deep into of pharmacological mechanism research,
At present, it has been found that its have sedation, antiinflammatory action, inhibitory action to TNF-α, immunoregulation effect,
Suppression angiogenesis etc.；The clinical indication of Thalidomide also obtain to be re-recognized, in inflammation, pernicious swollen
Tumor and the multiple disease relevant to autoimmune are used widely.
Research is thought, R-Thalidomide is relevant with sedation, and S-Thalidomide has with immunomodulating and antiinflammatory
Close, both mutual phase transformations of internal energy, and current medicine is both mixture.
Owing to Thalidomide is insoluble drug, and the particle diameter of the dissolution of preparation and stability and crude drug has very
Big association；Additionally, pharmaceutical packing form also can affect dissolution and the stability of preparation, it is therefore desirable to research
Exploitation have suitable diameter of aspirin particle and suitable manner of packing, have preferable dissolution and the medicine of stability and
Preparation.
Summary of the invention
It is an object of the invention to provide a kind of stability-enhanced Thalidomide preparation.
The invention provides a kind of Thalidomide preparation, described preparation includes the Thalidomide of dose therapeutically effective
Compound and pharmaceutically acceptable carrier or adjuvant, and the particle diameter model that feeds intake of described Thalidomide crude drug
Enclose for 5-40 μm.
In another preference, the described Thalidomide crude drug particle size range that feeds intake is 5-30 μm.
In another preference, the described Thalidomide crude drug particle size range that feeds intake is 7-20 μm.
In another preference, described preparation manner of packing includes plastic-aluminum, plastic-aluminum additional aluminum bag, aluminum aluminum or HDPE
Bottle mode.
In another preference, described preparation manner of packing is plastic-aluminum additional aluminum bag.
In another preference, described preparation type is tablet and/or capsule.
In another preference, described preparation type is tablet.
In another preference, described preparation type is capsule.
In another preference, described pharmaceutically acceptable carrier or adjuvant include: filler, binding agent,
Wetting agent, disintegrating agent, surfactant, lubricant or a combination thereof thing.
In another preference, in described capsule, component includes consisting of (in parts by weight calculate):
Thalidomide 25, lactose 85, poloxamer 2.5, carboxymethyl starch sodium 5,10% starch slurry 20 and
Pulvis Talci 2.5.
In another preference, the component in described tablet includes consisting of (in parts by weight calculate):
Thalidomide 25, microcrystalline Cellulose 15, lactose 70, sodium lauryl sulphate 2.5, carboxymethyl form sediment
Powder sodium 5,5% polyvidone 35 and magnesium stearate 2.5.
In another preference, described filler include lactose, starch, microcrystalline Cellulose, sucrose, dextrin,
Pregelatinized Starch, mannitol, xylitol, sorbitol or a combination thereof thing.
In another preference, described binding agent and/or wetting agent include: hypromellose, hydroxypropyl
Cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvidone, gelatin, arabic gum, starch,
Polyethylene Glycol, pectin, water, ethanol or a combination thereof thing.
In another preference, described disintegrating agent includes starch, carboxymethylstach sodium, polyvinylpolypyrrolidone, low takes
Receive or a combination thereof thing for hydroxypropyl cellulose, cross-linked carboxymethyl cellulose.
In another preference, described surfactant includes poloxamer, Tweens, spans, poly-mountain
Pear ester class or a combination thereof thing.
In another preference, described lubricant includes stearic acid, magnesium stearate, silicon dioxide, stearic acid
Calcium, Pulvis Talci, sodium lauryl sulphate or a combination thereof thing.
Accompanying drawing explanation
Fig. 1-4 shows the different-grain diameter of crude drug in Thalidomide preparation.
Detailed description of the invention
The present inventor is through long-term extensively in-depth study, by a large amount of screenings and test, finds by controlling sand
Profit degree amine particle diameter has remarkable result to the dissolution improving preparation；Pass through the preferred of packaging material simultaneously, it is possible to increase
The dissolution stability of preparation long term storage.
Experiment shows, particle size range is that the crude drug of 5-40 μm can effectively improve dissolving out capability.Preferably grain
Footpath scope is 5-30 μm, and preferred particle size range is 7-20 μm.
Experiment it is also shown that compared with numerous conventional packaged forms, the packaged form of plastic-aluminum additional aluminum bag, can not only
Preferably keep the activity (main by every wet/lucifuge) of medicine, and can significantly improve long-term unexpectedly
The dissolving out capability of the Thalidomide medicine (such as capsule) deposited.
Term
As used herein, term " dissolution " refers to that medicine is from the dissolution regulation solvent of the solid preparations such as tablet
Speed and degree.Dissolution is an important indicator of the quality control of solid dosage forms such as tablet, typically requires this type of
Preparation all should make the inspection of dissolution.
Main advantages of the present invention have:
The invention provides a kind of stability-enhanced Thalidomide preparation, including the conventional solid such as capsule and tablet
Preparation.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are only used for
The bright present invention rather than restriction the scope of the present invention.The experiment side of unreceipted actual conditions in the following example
Method, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise
Percentage ratio and number are percentage by weight and parts by weight.
The preparation of embodiment 1 Thalidomide Capsule
Supplementary material prescription: Thalidomide 25g, lactose 85g, poloxamer 2.5g, carboxymethyl starch sodium 5g, 10%
Starch slurry 20g and Pulvis Talci 2.5g.
Its preparation process is Thalidomide to be ground into particle diameter 1 at D90=7.69 μm, lactose, carboxymethyl starch
It is standby that sodium, poloxamer cross 80 mesh sieves after pulverizing.Thalidomide and adjuvant thereof is weighed according to recipe quantity.By sand profit
Degree amine is mixed homogeneously with lactose, carboxymethyl starch sodium, poloxamer.Add 10% starch slurry 20g, stir and cut
Cutting several minutes soft material, cross 16 mesh sieves and pelletize, wet granular is dried below 60 DEG C, with 16 mesh sieve granulate, adds
Enter Pulvis Talci, mix homogeneously, detect intermediate particle content, calculate every loading amount, use full-automatic filling machine to fill
Granule is in No. 3 capsules, and interior alclad is moulded, outer alclad bag, obtains 1000 Thalidomide Capsules.
The preparation of embodiment 2 Thalidomide Capsule
The supplementary material prescription of the present embodiment, with embodiment 1, measures the particle diameter 2 of crude drug Thalidomide after pulverizing
D90=16.86 μm, uses preparation method and the packaged form of embodiment 1, prepares 1000 Thalidomide Capsules.
The preparation of embodiment 3 Thalidomide Capsule
The supplementary material prescription of the present embodiment, with embodiment 1, measures the particle diameter 3 of crude drug Thalidomide after pulverizing
D90=26.69 μm, uses preparation method and the packaged form of embodiment 1, prepares 1000 Thalidomide Capsules.
The preparation of embodiment 4 Thalidomide Capsule
The crude drug Thalidomide do not pulverized, with embodiment 1, is directly fed intake by the supplementary material prescription of the present embodiment, its
The D90=41.43 μm of particle diameter 4, uses preparation method and the packaged form of embodiment 1, prepares 1000 husky profits
Degree amine capsule.
Embodiment 5 capsule dissolubility is tested
Each 6 of the capsule of Example 1,2,3,4 preparation, respectively according to dissolution method, with 1000mL
Water is dissolution medium, basket method, and rotating speed 100rpm operates in accordance with the law, takes appropriate dissolution fluid after 45min, uses ultraviolet
-visible spectrophotometry, measures absorbance at 293nm wavelength；Separately take Thalidomide reference substance appropriate, add
State after dissolution medium dissolved dilution becomes finite concentration, be measured in the same method, calculate the dissolution of each embodiment capsule.Result
As shown in table 1 below:
0 day dissolution results of table 1 Thalidomide Capsule
| Detection object | Crude drug particle diameter (D90, μm) | 0 day dissolution (%) |
| The capsule of embodiment 1 preparation | 7.69 | 98.1 |
| The capsule of embodiment 2 preparation | 16.86 | 95.7 |
| The capsule of embodiment 3 preparation | 26.69 | 86.4 |
| The capsule of embodiment 4 preparation | 41.43 | 63.5 |
From the above it is apparent that along with in Thalidomide Capsule crude drug feed intake the increase of particle diameter, capsule
The dissolution of 0 day reduces the most successively, even occurs less than 70% underproof phenomenon.This result of the test confirms control
The Thalidomide particle diameter processed meaning to 0 day dissolution of capsule.
Additionally, the present invention uses jet mill that Thalidomide crude drug has carried out minimum pulverizing, particle diameter D90
In 3-4 μm.Use this crude drug to carry out in preparation process research process to find, this particle diameter crude drug easily electrostatic
Adsorbing agglomerating, preparations shaping technology difficulty is bigger.
In conjunction with above-mentioned result of the test, the preferred Thalidomide of the present invention particle diameter D90 that feeds intake is in 7-20 μm, to ensure system
The dissolution that agent is higher.
Embodiment 6 capsule accelerated stability test
Within capsule embodiment 1,2,3,4 prepared, alclad is moulded, the form of additional aluminum bag is placed in 60 DEG C, 75%RH
Under carry out the accelerated stability test of 6 months, evaluate the stability of each embodiment capsule；Simultaneously by each embodiment glue
Capsule is directly placed under equal acceleration environment with the form of plastic-aluminum, compares evaluation, the capsule dissolubility knot of the 6th month
The most as shown in table 2 below.
Table 2 Thalidomide Capsule accelerates 6 months dissolution test result
It is accelerated it can be seen from the results above that each embodiment prepares capsule with the packaged form of plastic-aluminum additional aluminum bag
After test, the capsule dissolution stability of 6 months using different-grain diameter crude drug to prepare all does not shows notable fall
Low, preparation stability is good；But, after aluminum-plastic packaged form accelerated test, each capsule dissolubility is remarkably decreased.
Above-mentioned dissolution result shows, after using the particular envelope form of plastic-aluminum overcoat aluminum bag, each Thalidomide Capsule is adding
The stable experiment of speed shows unexpected quality improve, i.e. significantly carried by the packaged form of plastic-aluminum overcoat aluminum bag
The dissolving out capability of Thalidomide Capsule after high long-term storage.
Embodiment 7
For investigating humidity or the illumination impact on the dissolution stability of capsule, glue embodiment 1-4 prepared further
Capsule is randomly divided into two groups, and one group of exposed lucifuge placement 6 month under the conditions of room temperature 92.5%RH, one group at light at room temperature
It is loaded in water white transparency closed glass medicine bottle according to (4500lux) under case and places 6 months every wet illumination, investigate dissolution
The situation of change of degree.
Result is as shown in table 3:
6 months dissolution results are accelerated in table 3 Thalidomide Capsule high humidity or illumination
It can be seen from the results above that respectively significantly reducing, at illumination condition all occurs in group dissolution
There is not significant change in lower dissolution.Visible, humidity is the most notable to the stability influence of Thalidomide Capsule.So,
The present invention preferably packs every the packaged form of the preferable plastic-aluminum of wet performance additional aluminum bag.
The preparation of embodiment 8 Thalidomide tablet
Supplementary material prescription: Thalidomide 25g, microcrystalline Cellulose 15g, lactose 70g, sodium lauryl sulphate 2.5g,
Carboxymethyl starch sodium 5g, 5% polyvidone 35g and magnesium stearate 2.5g.
Its preparation process is Thalidomide to be ground into particle diameter 1 in D90=7.69 μm, microcrystalline Cellulose, lactose,
It is standby that carboxymethyl starch sodium, sodium lauryl sulphate cross 80 mesh sieves after pulverizing.Thalidomide is weighed according to recipe quantity
And adjuvant.Thalidomide is mixed with microcrystalline Cellulose, lactose, carboxymethyl starch sodium, sodium lauryl sulphate
Uniformly.Adding 5% polyvidone 35g, stir and shear several minutes soft material, cross 16 mesh sieves and pelletize, wet granular exists
Less than 60 DEG C are dried, and with 16 mesh sieve granulate, add the magnesium stearate of recipe quantity, mix homogeneously, middle of detection
Grain content, calculates every blade amount, punch diameter Φ=6mm, tabletting, and interior alclad is moulded, additional aluminum bag, obtains 1000
Sheet Thalidomide tablet.
The preparation of embodiment 9 Thalidomide tablet
Supplementary material prescription prepared by the present embodiment is with embodiment 8, the crude drug Thalidomide directly will do not pulverized
Feed intake, the D90=41.43 μm of its particle diameter 4, use preparation method and the packaged form of embodiment 8, prepare
1000 tablets of Thalidomide tablets.
Embodiment 10 Dissolution of Tablet is tested
Each 6 of the tablet of Example 8,9 preparation, respectively according to dissolution method, with 1000mL water be
Dissolution medium, slurry processes, rotating speed 50rpm, operate in accordance with the law, when 45min, take appropriate dissolution fluid, use
Ultraviolet visible spectrophotometry, measures absorbance at 293nm wavelength；Separately take Thalidomide reference substance to fit
Amount, adds after above-mentioned dissolution medium dissolved dilution becomes finite concentration, is measured in the same method, calculates each embodiment tablet
Dissolution.Result is as shown in table 4 below:
0 day dissolution results of table 4 Thalidomide sheet
| Detection object | 0 day dissolution (%) |
| The tablet of embodiment 8 preparation | 95.1 |
| The tablet of embodiment 9 preparation | 58.5 |
Equally, from the above it is apparent that in Thalidomide sheet the crude drug particle diameter that feeds intake the biggest, sheet
The agent dissolution of 0 day is relatively low.This result of the test further demonstrate that control Thalidomide particle diameter is to compositions
The meaning of 0 day dissolution of preparation.In conjunction with the dissolution test result of above-described embodiment 1-4, the present invention is preferred
Thalidomide feeds intake particle diameter D90 at 7-20 μm, the dissolution higher to ensure preparation.
Embodiment 11 tablet accelerated stability test
Within tablet embodiment 8,9 prepared, alclad is moulded, the form of additional aluminum bag is placed in 60 DEG C, 75%RH
Under carry out the accelerated stability test of 6 months, evaluate the stability of each embodiment tablet；Simultaneously by each enforcement
Example tablet is directly placed under equal acceleration environment with aluminum-plastic packaged form, compares evaluation, the 6th month
Dissolution of Tablet result is as shown in table 5 below.
Table 5 Thalidomide sheet accelerates 6 months dissolution results
It can be seen from the results above that each embodiment tablet is accelerated examination with plastic-aluminum additional aluminum bag packaged form
After testing, each embodiment dissolution stability preparation stability of 6 months is good；But, only with aluminum-plastic packaged shape
After formula is accelerated test, dissolution is remarkably decreased.So, test result indicate that, by the additional aluminum of plastic-aluminum
The packaged form of bag can be good at improving the dissolution stability of tablet.
The all documents mentioned in the present invention are incorporated as reference the most in this application, just as each document coverlet
Solely it is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, this area
The present invention can be made various changes or modifications by technical staff, and these equivalent form of values fall within right appended by the application equally
Claim limited range.
Claims (9)
1. a Thalidomide preparation, described preparation include dose therapeutically effective Thalidomide compound and
Pharmaceutically acceptable carrier or adjuvant, it is characterised in that the particle diameter model that feeds intake of described Thalidomide crude drug
Enclose for 5-40 μm.
2. preparation as claimed in claim 1, it is characterised in that described preparation manner of packing include plastic-aluminum,
Plastic-aluminum additional aluminum bag, aluminum aluminum or HDPE bottle mode.
3. preparation as claimed in claim 1, it is characterised in that described preparation type is tablet and/or glue
Wafer.
4. preparation as claimed in claim 1, it is characterised in that described pharmaceutically acceptable carrier or auxiliary
Material includes: filler, binding agent, wetting agent, disintegrating agent, surfactant, lubricant or a combination thereof thing.
5. preparation as claimed in claim 1, it is characterised in that described filler include lactose, starch,
Microcrystalline Cellulose, sucrose, dextrin, pregelatinized Starch, mannitol, xylitol, sorbitol or a combination thereof thing.
6. preparation as claimed in claim 1, it is characterised in that described binding agent and/or wetting agent include:
Hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvidone, bright
Glue, arabic gum, starch, Polyethylene Glycol, pectin, water, ethanol or a combination thereof thing.
7. preparation as claimed in claim 1, it is characterised in that described disintegrating agent includes that starch, carboxylic first are formed sediment
Powder sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose are received or a combination thereof thing.
8. preparation as claimed in claim 1, it is characterised in that described surfactant include poloxamer,
Tweens, spans, poly yamanashi esters or a combination thereof thing.
9. preparation as claimed in claim 1, it is characterised in that described lubricant includes stearic acid, tristearin
Acid magnesium, silicon dioxide, calcium stearate, Pulvis Talci, sodium lauryl sulphate or a combination thereof thing.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995004533A2 (en) * | 1993-08-04 | 1995-02-16 | Andrulis Pharmaceuticals Corporation | Treatment of rheumatoid arthritis with thalidomide alone or in combination with other anti-inflammatory agents |
| CN1738607A (en) * | 2002-11-14 | 2006-02-22 | 细胞基因公司 | Pharmaceutical compositions and dosage forms of thalidomide |
| CN101612138A (en) * | 2009-07-16 | 2009-12-30 | 浙江亚太药业股份有限公司 | Cefetamet pivoxil hydrochloride capsule and preparation method thereof |
-
2015
- 2015-04-16 CN CN201510181604.5A patent/CN106138052B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995004533A2 (en) * | 1993-08-04 | 1995-02-16 | Andrulis Pharmaceuticals Corporation | Treatment of rheumatoid arthritis with thalidomide alone or in combination with other anti-inflammatory agents |
| CN1738607A (en) * | 2002-11-14 | 2006-02-22 | 细胞基因公司 | Pharmaceutical compositions and dosage forms of thalidomide |
| CN101612138A (en) * | 2009-07-16 | 2009-12-30 | 浙江亚太药业股份有限公司 | Cefetamet pivoxil hydrochloride capsule and preparation method thereof |
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