CN1903181A - Enteric quick-dissolving tablets contg. aconitine, and its prepn. method - Google Patents
Enteric quick-dissolving tablets contg. aconitine, and its prepn. method Download PDFInfo
- Publication number
- CN1903181A CN1903181A CNA2006100486072A CN200610048607A CN1903181A CN 1903181 A CN1903181 A CN 1903181A CN A2006100486072 A CNA2006100486072 A CN A2006100486072A CN 200610048607 A CN200610048607 A CN 200610048607A CN 1903181 A CN1903181 A CN 1903181A
- Authority
- CN
- China
- Prior art keywords
- enteric
- aconitine
- quick releasing
- coated quick
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 title claims abstract description 25
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229940039750 aconitine Drugs 0.000 title claims abstract description 25
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 6
- 239000003814 drug Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims abstract description 5
- 239000004014 plasticizer Substances 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000002671 adjuvant Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- -1 polyethylene phthalate Polymers 0.000 claims description 8
- 239000004925 Acrylic resin Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 4
- 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 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- 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 3
- 229920002472 Starch Polymers 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- 108010036781 Fumarate Hydratase Proteins 0.000 claims description 2
- 102100036160 Fumarate hydratase, mitochondrial Human genes 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical compound CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 239000008103 glucose Substances 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
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 238000000576 coating method Methods 0.000 abstract description 8
- 239000011248 coating agent Substances 0.000 abstract description 5
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 238000010298 pulverizing process Methods 0.000 abstract 1
- YRECILNLFWZVRM-XTNYDWJGSA-N bulleyaconitine a Chemical compound O=C([C@H]1[C@]2(O)C[C@H]3[C@]45[C@H](OC)CC[C@@]6(COC)CN([C@@H]5[C@H]([C@H](OC)[C@H]64)[C@](C[C@@H]2OC)(OC(C)=O)[C@H]31)CC)C1=CC=C(OC)C=C1 YRECILNLFWZVRM-XTNYDWJGSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 12
- 239000007941 film coated tablet Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000009505 enteric coating Methods 0.000 description 6
- 239000002702 enteric coating Substances 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RIPYIJVYDYCPKW-UHFFFAOYSA-N 3-Acetylaconitine Natural products CCN1CC(C(CC2OC)OC(C)=O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 RIPYIJVYDYCPKW-UHFFFAOYSA-N 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- RIPYIJVYDYCPKW-UOGIXDCTSA-N x1071 Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)OC(C)=O)(COC)CN6CC)C(=O)C1=CC=CC=C1 RIPYIJVYDYCPKW-UOGIXDCTSA-N 0.000 description 5
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 4
- QUSPUZQKMRMVFL-UHFFFAOYSA-N 2-(benzenesulfonamido)-4-methylsulfanylbutanoic acid Chemical compound CSCCC(C(O)=O)NS(=O)(=O)C1=CC=CC=C1 QUSPUZQKMRMVFL-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- 230000036407 pain Effects 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
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- 230000003110 anti-inflammatory effect Effects 0.000 description 3
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- 230000037396 body weight Effects 0.000 description 3
- 230000003467 diminishing effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000002085 irritant Substances 0.000 description 3
- 231100000021 irritant Toxicity 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 241000227129 Aconitum Species 0.000 description 2
- 241000701413 Aconitum kusnezoffii Species 0.000 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 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 2
- 102000011759 adducin Human genes 0.000 description 2
- 108010076723 adducin Proteins 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 229920002545 silicone oil Polymers 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- NWBWCXBPKTTZNQ-UHFFFAOYSA-N (16S)-4-(N-Acetyl-anthraniloyloxy)-20-aethyl-1alpha,14alpha,16-trimethoxy-aconitan-8,9-diol Natural products C1CC(OC)C2(C3C4)C5CC(C(C6)OC)C(OC)C5(O)C6(O)C4C2N(CC)CC31OC(=O)C1=CC=CC=C1NC(C)=O NWBWCXBPKTTZNQ-UHFFFAOYSA-N 0.000 description 1
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000173529 Aconitum napellus Species 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
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- 241000581650 Ivesia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229940023019 aconite Drugs 0.000 description 1
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- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
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- 239000002662 enteric coated tablet Substances 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
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- 230000007661 gastrointestinal function Effects 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 239000001384 succinic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- NWBWCXBPKTTZNQ-QOQRDJBUSA-N y4m5974f7z Chemical compound O([C@]12CN([C@@H]3[C@H]4[C@]5(O)[C@@]6(O)[C@@H](OC)[C@@H]([C@H](C5)OC)C[C@H]6[C@@]3([C@@H]1C4)[C@@H](OC)CC2)CC)C(=O)C1=CC=CC=C1N=C(C)O NWBWCXBPKTTZNQ-QOQRDJBUSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
A fast-release enteric tablet containing aconitine is proportionally prepared from aconitine-type medicine, fast-releasing additive, enteric polymer, plasticizer and solvent through superfine pulverizing, mixing, tabletting and coating.
Description
Affiliated technical field
The present invention relates to contain the medicine of organic compound, particularly contain the preparation method of the oral formulations and the said preparation thereof of aconitine.
Background technology
Medicine aconitine with easing pain and diminishing inflammation effect is an isolating aconite alkaloids from Ranunculaceae aconitum plant (Aconitum), be mainly used in diseases such as treatment rheumatism, rheumatoid and osteoarthritis, the history in existing more than 20 year of this compounds of clinical practice, its preparation comprises injection, tablet, oral liquid, soft capsule.Often with having an intense pain and the injection site redness, patient dependence is bad in use for injection; Common peroral dosage form take the back oral cavity numb, digestive tract is had stronger stimulation.Studies have shown that, aconitine disperses not open, the too high meeting of local concentration irritates nucous membrane and its hetero-organization consumingly, produces untoward reaction such as calcination, even damages partial biological tissue, for this reason, medicine is the major reason that causes adverse effect in gastral degree of scatter and speed.The Chinese patent file ' radix aconiti kunsezoffii nail element soft capsule and production method thereof ' of the Chinese patent file of publication number CN1107697A ' aconitum kusnezoffii oral tablets, capsule ' and patent No. ZL 98106595.3 all is to be the common oral drugs that primary raw material is made with the bulleyaconitine A, by upper digestive tract disintegrate, absorption.But, bulleyaconitine A under intensive gastric acid condition, facile hydrolysis and the effective ingredient of degrading; In addition, bulleyaconitine A is a kind of alkaloid, generates alkaloidal salt with hydrochloric acid reaction in gastric acid the bioavailability of product is reduced, and the comprehensive function meeting of these two factors reduces the effectiveness of aconitum kusnezoffii oral preparation.Still there is untoward reaction such as taking deutostoma fiber crops, stimulating gastrointestinal road in the former; And the latter is poor because of medicine extended release and patient's compliance, can not give full play to the effect of bulleyaconitine A.And use the patient of medicine mostly to be chronic disease, and being subjected to the influence of these slight illness, a little less than most patient's body constitution, gastrointestinal function is poor.Therefore, need to eliminate aconitine strong impulse, unstability, absorbency issue.
Propose before the present invention, the untoward reaction that during we use at the aconitine clinical drug gastrointestinal intense stimulus is occurred, studied the dynamic process of such drug absorption, such medicine is made enteric coatel tablets, attempt is exempted medicine to the stimulation of stomach and avoid the medicine inactivation that all or part of decomposition causes in gastric juice, but description of test, common enteric coated tablet can not be exempted the stimulation to intestinal.
Summary of the invention
The object of the present invention is to provide a kind of not stimulating gastrointestinal road, easily absorb, can give full play to the aconitine enteric-coated quick releasing sheet oral formulations of medicinal property.
The enteric coatel tablets of the present invention by being formed in rapid release in the intestinal, eliminate such medicine whole gastral stimulation is realized above-mentioned purpose.Concrete scheme is as follows:
The weight ratio of enteric-coated quick releasing slice prescription component and content is: aconitine medicine 0.14%～20%, disintegrating agent 1.3%～50%, label adjuvant 1.0%～35%; Enteric polymer 5%～25%, plasticizer 0.2%～5%; And volume ratio is the solvent of above component 70%～93%.
Described enteric-coated quick releasing sheet contains aconitine medicine 0.2～10mg.
Described label disintegrating agent is one or more in cross-linked carboxymethyl cellulose sodium, crosslinked carboxymethylstach sodium, cyclodextrin, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, the soluble starch.
Described enteric polymer is one or more of cellulose acetate phthalate ester, acid polyethylene phthalate ester, polyacrylic resin II or III number, Lac, methacrylic acid copolymer, cellulose acetate benzenetricarboxylic acid ester, hypromellose phthalate ester.
Contain in citric acid, L MALIC ACID, succinic acid, maleic acid, fumarase, glucose, Fructus Citri tangerinae essence, strawberry essence, the apple essence one or more in the described label adjuvant, to improve sense organ olfactory sensation or fragrance.
Preparation method at the enteric-coated quick releasing sheet that contains aconitine of above scheme has following steps:
(1) weighing aconitine medicine carries out super-refinement and crosses 1000 orders,
(2) prescription that proposes according to above claim, disintegrating agent is crossed 60 orders through refinement, adjuvant is crossed 100 orders through refinement, and with step (1) refinement after behind the medicine mixing, direct compression or make instant label with the solvent wet method,
(3) prescription that proposes according to above claim carries out film coating with enteric material to label.
The enteric-coated quick releasing formulation product of the present invention preparation shows through experiment: it is a kind of patient's gastrointestinal tract to be stimulated bulleyaconitine A class aconitine pharmaceutical preparation---the enteric rapid release oral agents little, that bioavailability is high; Stripping in gastric juice＜10%, enteric solubility is good; The rapid release experiment shows that sample can rapid disintegrate become microgranule in intestinal juice; Bioavailability can improve more than 5%; The easing pain and diminishing inflammation of aconitine is active to be improved more than 5%; And placed at normal temperatures 2 years, the every index of product all meets the requirements.
The specific embodiment
(1) prescription of the present invention and preparation technology
1, bulleyaconitine A enteric-coated quick releasing sheet
Press the component and the content of table 1 embodiment regulation, with super-refinement, cross 1000 purpose bulleyaconitine As and other auxiliary materials and mixing after, pulverize mixing, cross 100 orders, conventional granulation, tabletting promptly gets label.The cellulose acetate phthalate ester is dissolved in acetone, in addition Lac is dissolved in 95% ethanol, face times spent two liquid and share, add the phthalic acid diethylester again, mix homogeneously can use.Press the coating method coating, get finished product, every contains bulleyaconitine A (specification) and is respectively 0.2mg and 0.4mg.
Table 1 bulleyaconitine A enteric-coated quick releasing slice prescription (1000)
| Disintegrating agent, label adjuvant | Enteric-coating material, solvent | ||||||||||
| Embodiment | Bulleyaconitine A | Cross-linked carboxymethyl cellulose sodium | Magnesium stearate | Microcrystalline cellulose | Lactose | Mannitol | The cellulose acetate phthalate ester | Lac | Acetone | Ethanol | The phthalic acid diethylester |
| 1 | 0.2g | 5g | 4g | 100g | 12g | 20g | 4g | 3g | 15ml | 17ml | 0.6g |
| 2 | 0.4g | 4g | 4g | 40g | 12g | 20g | 3g | 2g | 12ml | 12ml | 0.5g |
2,3-acetylaconitine enteric-coated quick releasing sheet
Press the component and the content of table 2 embodiment regulation, 3-acetylaconitine is carried out super-refinement, cross 1000 orders, behind other various raw material blendings of doing label, the conventional granulation, tabletting promptly gets label.Take by weighing polyacrylic resin II, III number by the enteric coating recipe quantity and place the 50ml container, add 95% ethanol, resin is soaked fully, add a cover and placed 12～24 hours, make it to dissolve fully, adding tween 80, phthalic acid diethylester, Oleum Ricini successively, the back that stirs is standby.Press the coating method coating, get finished product, every contains 3-acetylaconitine (specification) and is respectively 0.3mg and 1.0mg.
Table 2 3-acetylaconitine enteric-coated quick releasing slice prescription (1000)
| Disintegrating agent, label adjuvant | Enteric-coating material, solvent | |||||||||||
| Embodiment | 3-acetylaconitine | Cyclodextrin/crosslinked carboxymethylstach sodium | Carmethose | Microcrystalline cellulose | Polyethylene Glycol-6000 | Mannitol | Flavoring orange essence | Polyacrylic resin III number | Tween 80 | 95% ethanol | The phthalic acid diethylester | Oleum Ricini |
| 3 | 0.3g | 6g | 9g | 40g | 2g | 40g | 0.1g | 1.3g | 0.3ml | 18ml | 0.2g | 0.2ml |
| 4 | 1g | 3g | 9g | 48g | 2g | 55g | 0.1g | 1.8g | 0.3ml | 21ml | 0.2g | 0.2ml |
3, lappaconitine hydrobromide enteric-coated quick releasing sheet
Press the component and the content of table 3 embodiment regulation, the raw material of various film-making cores such as lappaconitine hydrobromide is crossed 1000 order super-refinement mixings, direct compression promptly gets label, take by weighing polyacrylic resin II number and phthalic acid diethylester by the enteric coating recipe quantity and place the 60ml container, add 95% ethanol, resin is soaked fully, add a cover and placed 12～24 hours, make it to dissolve fully, stand-by.Tween 80, silicone oil, Oleum Ricini add above-mentioned stand-by liquid before coating, the back that stirs is standby.Press the coating method coating, get finished product, every contains hydrobromic acid lappaconitine (specification) and is respectively 6mg and 10mg.
Table 3 lappaconitine hydrobromide enteric-coated quick releasing slice prescription (1000)
| Disintegrating agent, label adjuvant | Enteric-coating material, solvent | |||||||||||||
| Embodiment | Lappaconitine hydrobromide (crossing 1000 orders) | Soluble starch | Microcrystalline cellulose (100 order) | Lactose (120 order) | Low-substituted hydroxypropyl cellulose (80 order) | Beta-schardinger dextrin-(80 order) | Polyethylene Glycol-6000 | Citric acid/succinic acid | Polyacrylic resin II number | Tween 80 | 95% ethanol | The phthalic acid diethylester | Oleum Ricini | Silicone oil |
| 5 | 6g | 10g | 16g | 5g | 4g | 2g | 0.8g | 0.25g | 1.6g | 0.2ml | 20ml | 0.1g | 0.1ml | 0.15ml |
| 6 | 10g | 18g | 21g | 5g | 4g | 0.9g | 0.2g | 1.9g | 0.2ml | 20ml | 0.1g | 0.1ml | 0.16ml | |
(2) rapid release of each enteric-coated quick releasing Film coated tablets label of the present invention and enteric solubility test
Test shows that the prepared label sample disintegration time of the present invention within 5～20 seconds, reaches prescription in intestinal juice.
With 0.1mol/L HCl test 2 hours, tablet was kept perfectly in this stage, stripping in gastric juice＜10% in the disintegration of tablet instrument.In the phosphate buffer of pH6.8, handled 45 minutes, disintegration of tablet, it is dispersed into small particle very soon.
(3) bulleyaconitine A enteric-coated quick releasing Film coated tablets pharmacodynamics animal contrast experiment and untoward reaction are observed
(1) analgesic activity of bulleyaconitine A enteric-coated quick releasing Film coated tablets
Use mouse writhing method: get 30 of mices, be divided into 3 groups at random, 10 every group, 120min behind the oral administration, mouse peritoneal inject 0.7% acetic acid 0.1ml/10g, and record 5～15min mouse writhing reaction times is calculated and comparable group differences significance,
Table 4: the analgesic activity of bulleyaconitine A enteric-coated quick releasing Film coated tablets
| Group | Body weight | Dosage (mg/Kg) | Turn round the body number of times | Suppression ratio |
| Blank group | 20±1.0 | Equal-volume | 30.7±7.88 | |
| The morphine group | 20±1.3 | 10 | 2.4±1.50 | 92.5％ |
| The bulleyaconitine A sheet | 20±1.1 | 0.2 | 10.5±3.42 | 76.04％ |
| The enteric-coated quick releasing sheet | 20±1.2 | 0.2 | 7.5±3.00 | 87.2％ |
(2) antiinflammatory action of bulleyaconitine A enteric-coated quick releasing Film coated tablets
Use the Whitle method, get 30 of mices, be divided into 3 groups at random, 10 every group, 120min behind the oral administration, the blue 0.2ml/ of mouse tail vein injection 0.5% ivens is the timely lumbar injection 0.7% acetic acid 0.2ml/10g in back only, puts to death mice behind the 15min, and intraperitoneal injection of saline 5ml gently rubs the back and extracts peritoneal fluid, centrifugal, supernatant is measured optical density value in the 620nm place, calculate and comparable group differences significance
Table 5: the antiinflammatory action of bulleyaconitine A enteric-coated quick releasing Film coated tablets
| Group | Body weight | Dosage (mg/Kg) | Optical density value | Suppression ratio |
| Blank group | 20±1.12 | Equal-volume | 0.28±0.05 | |
| Aspirin | 20±1.13 | 200 | 0.13±0.03 | 62.5％ |
| The bulleyaconitine A sheet | 20±1.12 | 0.2 | 0.10±0.02 | 71.4％ |
| The enteric-coated quick releasing sheet | 20±1.1 | 0.2 | 0.09±0.002 | 79.5％ |
Because product does not discharge under one's belt, thereby eliminated gastric acid the hydrolysis of bulleyaconitine A is decomposed, and rapid release and absorption in intestinal juice increased bioavailability accordingly, and then shown better analgesia, anti-inflammatory efficacy.
In this experiment, bioavailability of the present invention improves more than 5%, and easing pain and diminishing inflammation is active to be improved more than 5%.
(4) zest of aconitine enteric coating fast-release tablet of the present invention
The volunteer oral test:
The oral direct reaction that does not have stimulation oral cavities such as mouthful fiber crops; 45 experimenter's statistics show that the untoward reaction of general also is better than common oral preparation.
The digestive tract irritation test of bulleyaconitine A enteric-coated quick releasing Film coated tablets:
Get 10 of healthy rabbits, body weight: 2.0～2.2kg, male and female half and half are divided into two groups, and 5 every group, oral bulleyaconitine A sheet of difference and molten rapid release Film coated tablets, 48h puts to death rabbit behind the medicine, cuts open digestive tract such as inspection gastrointestinal, observes irritant reaction according to table 6.
Table 6 digestive tract irritant reaction level table
| Order of reaction | Irritant reaction |
| 0 | No change |
| 1 | No significant change |
| 2 | The mild hyperaemia point is arranged |
| 3 | The congested point of moderate is arranged |
| 4 | The congested point of severe is arranged, change with the small size position |
The result: the zest of the molten rapid release Film coated tablets of bulleyaconitine A is 0～1 grade; And the bulleyaconitine A sheet is 3～4 grades.The zest that shows the molten rapid release Film coated tablets of bulleyaconitine A is little.
(5) stability of each enteric-coated quick releasing Film coated tablets of embodiment
The lucifuge keeping at room temperature of the sample of embodiment was placed 1,2,3,6,12,24 month, and with reference to the inspection of Chinese Pharmacopoeia project and the general rule requirement of thin membrane coated tablet, assay shows: all samples outward appearance is constant substantially, and effective ingredient does not change yet.Therefore, think that tentatively product that the prepared various prescriptions of enteric-coated quick releasing Film coated tablets of the present invention make all can reach the shelf-life more than 2 years.
The stability test result: assay and discriminating etc. are with reference to the quality standard of current race in the quality standard.The result is as follows:
| Sample | January | February | March | June | December | 24 months |
| Example 1 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Example 2 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Example 3 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Example 4 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Example 5 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Example 6 | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
The result shows the sample of this invention preparation, and through measuring, product quality is basicly stable more than 2 years.
Above embodiment is only for the present invention is described further, and scope of the present invention is not subjected to the limitation of illustrated embodiment.
Claims (6)
1, a kind of enteric-coated quick releasing sheet that contains aconitine is characterized in that the weight ratio of enteric-coated quick releasing slice prescription component and content is: aconitine medicine 0.14%～20%, disintegrating agent 1.3%～50%, label adjuvant 1.0%～35%; Enteric polymer 5%～25%, plasticizer 0.2%～5%; And be the solvent of above component volume ratio 70%～93%.
2, a kind of enteric-coated quick releasing sheet that contains aconitine according to claim 1 is characterized in that the enteric-coated quick releasing sheet contains aconitine medicine 0.2～10mg.
3, a kind of enteric-coated quick releasing sheet that contains aconitine according to claim 1 is characterized in that disintegrating agent is one or more in cross-linked carboxymethyl cellulose sodium, crosslinked carboxymethylstach sodium, cyclodextrin, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, the soluble starch.
4, a kind of enteric-coated quick releasing sheet that contains aconitine according to claim 1 is characterized in that enteric polymer is one or more of cellulose acetate phthalate ester, acid polyethylene phthalate ester, polyacrylic resin II or III number, Lac, methacrylic acid copolymer, cellulose acetate benzenetricarboxylic acid ester, hypromellose phthalate ester.
5, a kind of enteric-coated quick releasing sheet that contains aconitine according to claim 1 is characterized in that containing in the label adjuvant in citric acid, L MALIC ACID, succinic acid, maleic acid, fumarase, glucose, Fructus Citri tangerinae essence, strawberry essence, the apple essence one or more.
6, a kind of preparation method that contains the enteric-coated quick releasing sheet of aconitine is characterized in that having following steps:
(1) weighing aconitine medicine carries out super-refinement and crosses 1000 orders,
(2) prescription that proposes according to above claim, disintegrating agent is crossed 60 orders through refinement, adjuvant is crossed 100 orders through refinement, and with step (1) refinement after behind the medicine mixing, direct compression or make instant label with the solvent wet method,
(3) prescription that proposes according to above claim carries out film coating with enteric material to label.
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| CNB2006100486072A CN100518721C (en) | 2006-08-08 | 2006-08-08 | Enteric quick-dissolving tablets containing aconitine, and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178658A (en) * | 2011-05-03 | 2011-09-14 | 中国人民解放军第三军医大学第二附属医院 | Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof |
| CN102406640A (en) * | 2010-09-26 | 2012-04-11 | 上海泰因生物技术有限公司 | Analgesic and antiphlogistic medicines and micro-needle transdermal administration method for same |
| CN102526233A (en) * | 2010-12-24 | 2012-07-04 | 无锡济民可信山禾药业股份有限公司 | Multi-unit enteric-coated preparation containing aconitine and preparation method thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1038473C (en) * | 1993-10-23 | 1998-05-27 | 云南省弥勒县制药厂 | Bulleyaconitine A oral preparation |
| CN1069519C (en) * | 1998-03-17 | 2001-08-15 | 昆明制药股份有限公司 | Bulleyaconitine A soft capsule and its production method |
| CN1535684A (en) * | 2003-04-09 | 2004-10-13 | 王 锦 | Aconitum kusnezoffii methylsine powder injection preparation and its preparation method |
| CN1287790C (en) * | 2003-09-20 | 2006-12-06 | 昆明紫健生物技术有限公司 | Kusnezoff monkshood root methyl element microcapsule and its production method |
| CN1297271C (en) * | 2003-09-30 | 2007-01-31 | 昆明紫健生物技术有限公司 | Fat emulsion injection of bulleyaconitine A and its manufacturing method |
| CN1778299A (en) * | 2004-11-19 | 2006-05-31 | 昆明五和堂药物研制有限公司 | Cavitas nasisal cavity medicine-supply preparation with radix aconiti agrestis methyl |
| CN100406012C (en) * | 2005-04-19 | 2008-07-30 | 北京正大绿洲医药科技有限公司 | Hydrobromic acid high tortoiseshell component drip pill and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102406640A (en) * | 2010-09-26 | 2012-04-11 | 上海泰因生物技术有限公司 | Analgesic and antiphlogistic medicines and micro-needle transdermal administration method for same |
| CN102526233A (en) * | 2010-12-24 | 2012-07-04 | 无锡济民可信山禾药业股份有限公司 | Multi-unit enteric-coated preparation containing aconitine and preparation method thereof |
| CN102526233B (en) * | 2010-12-24 | 2016-01-27 | 无锡济民可信山禾药业股份有限公司 | A kind of multiple-unit enteric coated preparation containing aconitine and preparation method thereof |
| CN102178658A (en) * | 2011-05-03 | 2011-09-14 | 中国人民解放军第三军医大学第二附属医院 | Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof |
| CN102178658B (en) * | 2011-05-03 | 2013-04-10 | 中国人民解放军第三军医大学第二附属医院 | Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof |
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| CN100518721C (en) | 2009-07-29 |
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