CN100500151C - Water-soluble medicine sublingual-medicating formulation - Google Patents
Water-soluble medicine sublingual-medicating formulation Download PDFInfo
- Publication number
- CN100500151C CN100500151C CNB2004100307482A CN200410030748A CN100500151C CN 100500151 C CN100500151 C CN 100500151C CN B2004100307482 A CNB2004100307482 A CN B2004100307482A CN 200410030748 A CN200410030748 A CN 200410030748A CN 100500151 C CN100500151 C CN 100500151C
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- China
- Prior art keywords
- sublingual
- water
- tablet
- sorbitol
- hydrochloride
- 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.)
- Expired - Lifetime
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- 239000003814 drug Substances 0.000 title claims abstract description 22
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 238000009472 formulation Methods 0.000 title 1
- 239000006190 sub-lingual tablet Substances 0.000 claims abstract description 25
- SKYZYDSNJIOXRL-BTQNPOSSSA-N (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol;hydrochloride Chemical compound Cl.C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 SKYZYDSNJIOXRL-BTQNPOSSSA-N 0.000 claims abstract description 21
- 229960003990 apomorphine hydrochloride Drugs 0.000 claims abstract description 21
- 229940098466 sublingual tablet Drugs 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- 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 17
- 239000000600 sorbitol Substances 0.000 claims description 17
- 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 13
- 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 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 11
- 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 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- 239000004376 Sucralose Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 235000019408 sucralose Nutrition 0.000 claims description 6
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 6
- 230000000149 penetrating effect Effects 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 3
- 229930003268 Vitamin C Natural products 0.000 claims description 3
- 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 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 235000019154 vitamin C Nutrition 0.000 claims description 3
- 239000011718 vitamin C Substances 0.000 claims description 3
- MSWMMJONWLTTGS-UHFFFAOYSA-N 2-hydroxy-2-oxoacetate;triethylazanium Chemical compound OC(=O)C(O)=O.CCN(CC)CC MSWMMJONWLTTGS-UHFFFAOYSA-N 0.000 claims 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 abstract description 14
- 229960003088 loratadine Drugs 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000003826 tablet Substances 0.000 abstract description 9
- XRHDQSKAXOSHGA-DTUSRQQPSA-N ypu5b72ooi Chemical compound Cl.O([C@H]1[C@@]2(OC)CC[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O XRHDQSKAXOSHGA-DTUSRQQPSA-N 0.000 abstract description 2
- 229960001889 buprenorphine hydrochloride Drugs 0.000 abstract 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- 239000011230 binding agent Substances 0.000 description 14
- 239000008187 granular material Substances 0.000 description 13
- 239000002671 adjuvant Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
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- 239000011812 mixed powder Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
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- 238000003756 stirring Methods 0.000 description 6
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- 229960004046 apomorphine Drugs 0.000 description 4
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 230000007797 corrosion Effects 0.000 description 3
- 238000005260 corrosion Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 241000581835 Monodora junodii Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 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 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- BRTSNYPDACNMIP-FAWZKKEFSA-N dihydroetorphine Chemical compound O([C@H]1[C@@]2(OC)CC[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O BRTSNYPDACNMIP-FAWZKKEFSA-N 0.000 description 2
- 210000005225 erectile tissue Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
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- 239000000314 lubricant Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
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- 210000000056 organ Anatomy 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
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- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 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 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical compound CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
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- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 239000004202 carbamide Substances 0.000 description 1
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- 235000012730 carminic acid Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
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- 229910017053 inorganic salt Inorganic materials 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 229940085605 saccharin sodium Drugs 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
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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 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a water-soluble medicine sublingual tablet prescription composition. Said medicine tablet can be sublingually slowly-dissolved within 10-20 min. The water-soluble effective component of said tablet preparation can be apomorphine hydrochloride, buprenorphine hydrochloride, dihydroetorphine hydrochloride and loratadine, its optimum is apomorphine hydrochloride.
Description
Invention field
The prescription that the present invention relates to a kind of preparation of the water soluble drug that is used for Sublingual or buccal administration is formed.
Background of invention
First pass effect and active drug for fear of liver play a role fast, and some water soluble drug example hydrochloric acid apomorphine (apomorhine hydrochloride), buprenorphin hydrochloride (burenophinehydrochloride), dihydroetorphine hydrochlorate (dihydroetorphine hydrochloride), loratadine (loratadine) etc. adopt the Sublingual administration.The regulation that existing Chinese Pharmacopoeia version in 2000 is made Sublingual tablet: " principal agent and adjuvant should be soluble in water "; Sublingual tablet needs " dissolving in 5 minutes by the disintegrating method method ", promptly can see through sieve aperture at the disintegration tester Chinese medicine tablet.For satisfying pharmacopeia external " dissolving in 5 minutes " regulation, should select the disintegrate adjuvant, still, and disintegrate adjuvant imbibition, it is interior water-soluble but to be difficult to the short time, runs counter to pharmacopeia and answers regulation soluble in water about principal agent and adjuvant.
Therefore, Sublingual tablet is often selected water soluble adjuvant for use in preparation process, yet the easy moisture absorption of water soluble adjuvant can cause the technological problems of sticking; The normal hardness of selecting to reduce tablet in the big in addition production technology, this has caused practical difficulty to commercial production, packing and transportation.
Apomorphine can be used for the treatment of male sexual disorder, i.e. so-called " sexual impotence ".Sexual impotence refers to male's can not reach and keep to be satisfied with erection of sexual intercourse, is also referred to as " erectile dysfunction ".Erectile dysfunction may be by psychological factor or organ factor, the perhaps composition of the two.The organ factor comprises physiological, neural blood vessel and hormone pathology, the perhaps combination of the two.The neural impulse of loose signal takes place by acting on the central nervous system in apomorphine hydrochloride to some muscle.Can stop blood to flow into penis during these muscular tones.When these were of flaccid muscles, the blood flow that flows into penis obviously increased.The blood flow increase makes three kinds of erectile tissues of penis be full of blood, makes penis become strong, and the full adjacent vein of erectile tissue compressing prevents blood to flow out penis, prevents blood to flow out penis and can keep continuing to erect.
Segraves, R, T, studies show that to follow usually for the dosage that reaches the needed apomorphine that erects of et al.J Urology 145:1174-1175 (1991) felt sick and other undesirable serious adverse such as hypertension flushing and perspiration.In addition, too fast if said preparation dissolves, apomorphine is soluble in water, and sublingual administration is swallowed by the patient easily, and can not fully absorb in the Sublingual.Therefore, medicine should not dissolve too fast in the Sublingual.The slow stripping of Sublingual tablet means medicine at the uniform velocity stripping in 10～20 minutes.
In sum, the prescription that the purpose of this invention is to provide a kind of suitable water soluble drug sublingual administration is formed and preparation technology, should meet 2000 editions regulations of existing Chinese Pharmacopoeia, solve the soft problem of big production technology again, and can slowly dissolve in 10～20 minutes in the Sublingual and make the drug slow stripping to reduce its side effect, improve bioavailability of medicament simultaneously.
Summary of the invention
For solving the difficulty that water soluble drug sublingual administration medicament development exists, the present invention is devoted to overcome in the following aspects:
1. the speed of rate.2000 editions dissolution rates of Sublingual tablet being controlled medicine with the regulation of " press the disintegrating method method, dissolve in 5 minutes " and " principal agent and adjuvant should be soluble in water " of existing Chinese Pharmacopoeia.But the solution time in Sublingual should be more than 10 minutes in vivo in this pharmaceutical preparation, and should the slow corrosion in the Sublingual, to reduce the drug side effect of not expecting and to improve bioavailability of medicament.Therefore there is certain contradiction with in vitro tests in the body.The solution time of the tablet that patent CN1271276A produces in disintegration tester is about 8 minutes, exceeded the regulation of Chinese Pharmacopoeia; And wherein used insoluble microcrystalline cellulose excipients, run counter to the guideline of " principal agent and adjuvant should be soluble in water ".
2. the operability of production technology.This preparation prescription is formed and preparation technology is devoted to reduce difficulty in the suitability for industrialized production, as the combination of sticking, Hardness Control, packing or above several difficulties etc.
3. Sublingual process in leaching.This preparation is dispersed in aqueous soluble active constituent in the compositions of water soluble adjuvant, for example sorbitol, mannitol, sucrose and lactose etc., or the compositions of above several adjuvants, by regulating corrosion speed control medicine slowly stripping in the time range of suitable sublingual administration of adjuvant.
Having developed a kind of prescription of water soluble drug sublingual administration preparation forms.
Biological active substances of the present invention is a water soluble drug, comprises apomorphine hydrochloride, buprenorphin hydrochloride, dihydroetorphine hydrochlorate, loratadine; Preferred apomorphine hydrochloride.
Penetrating agent can be sucrose, lactose, sorbitol, mannitol, fructose, xylitol, glucose or their compositions, and the ratio in prescription is 45%～95%; The compositions of preferred sorbitol, mannitol and lactose, wherein to account for the ratio of compositions be 40%～80% to sorbitol, preferred proportion is 60%.Experimental result shows that the ratio of sorbitol in compositions is vital: the ratio of sorbitol is too high, is easy to generate the problem of sticking, and this is because sorbitol very easily absorbs water; The ratio of sorbitol is too low, and it is too slow to cause Sublingual tablet to dissolve easily, and this is because lactose and mannitol penetrating power are not enough.Also can add glycerol, carbamide, organic salt and inorganic salt such as sodium chloride etc. in case of necessity.
Can further add other conventional adjuvants among the present invention, as correctives, binding agent, coloring agent, lubricant and stabilizing agent etc.
Correctives contains intense sweetener, comprises aspartame, sucralose, saccharin sodium, stevioside, cyclamate or their combination; Essence comprises apple essence, flavoring orange essence, grape essence, strawberry essence, citric acid and their combination.Preferred correctives comprises sucralose, green apple powdered flavor and citric acid.
Binding agent comprises: polyvidone aqueous solution, water, starch slurry, the aqueous solution of hydroxypropyl emthylcellulose.
Coloring agent comprises light green, light blue, and carmine, greyish purple.
Lubricant comprises micropowder silica gel, Pulvis Talci, magnesium stearate, fumaric acid sodium stearyl.Preferred magnesium stearate and Pulvis Talci.
Stabilizing agent comprises: antioxidant, as vitamin C; Complexing of metal ion agent such as disodiumedetate.Preferred stabilizing agent is vitamin C and disodiumedetate.
Preferred version describes in detail:
At apomorphine hydrochloride, apomorphine hydrochloride is a kind of unstable compounds in the presence of light and oxygen.But, test discovery said preparation compositions by the influence factor and give apomorphine hydrochloride stability.And the corrosion of sorbitol, mannitol and lactose can make apomorphine hydrochloride stripping slowly in the Sublingual; Can satisfy in disintegration tester simultaneously and dissolve in five minutes, to meet 2000 editions requirements of Chinese Pharmacopoeia the Sublingual tablet solution time.In addition, the proportioning of suitable penetrating agent makes stripping, suitability for industrialized production sticking and the unmanageable problem of hardness obtain solution.The pressure change of finding solution time and tablet simultaneously is irrelevant, the essentially no difference of external solution time of the tablet of hardness 20N and the tablet of 100N.Cover the bitterness except adding sweeting agent, citric acid and green apple powdered flavor can further improve taste of medicine.The antioxidative effect has also been played in the adding of antioxidant and complexing of metal ion agent.
Embodiment
Be that example illustrates the present invention with apomorphine hydrochloride and loratadine respectively, but be not limited only to following examples.
Table 1:
Embodiment 1
The supplementary material consumption is with reference to table 1.Apomorphine hydrochloride and citric acid are mixed, and then, the principle and the sorbitol that progressively increase by equivalent mix, and mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.Disodiumedetate, sucralose be dissolved in 70% the alcohol-water solution, add an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stampings, hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, basket method 50 is changeed, and does stripping and measures.Stripping curve as shown in Figure 1.
In the disintegration tester, 37 degrees centigrade, do and dissolve test.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 2 (n=6).
The stripping curve of Fig. 1 apomorphine hydrochloride sublingual tablets
The solution time of table 2 apomorphine hydrochloride sublingual tablets
Embodiment 2
The supplementary material consumption is with reference to table 1.Apomorphine hydrochloride and citric acid are mixed, and then, the principle and the sorbitol that progressively increase by equivalent mix, and mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.Disodiumedetate, sucralose be dissolved in 70% the alcohol-water solution, add an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stampings, hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, to do stripping and measure, basket method 50 is changeed.Stripping curve as shown in Figure 2.
In the disintegration tester, 37 degrees centigrade, do and dissolve test.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 3 (n=6).
The stripping curve of Fig. 2 apomorphine hydrochloride sublingual tablets
The solution time of table 3 apomorphine hydrochloride sublingual tablets
Embodiment 3
The supplementary material consumption is with reference to table 1.Apomorphine hydrochloride and citric acid are mixed, and then, the principle and the sorbitol that progressively increase by equivalent mix, and mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.Disodiumedetate, sucralose be dissolved in 70% the alcohol-water solution, add an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stampings, hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, to do stripping and measure, basket method 50 is changeed.Stripping curve as shown in Figure 3.
In the disintegration tester, 37 degrees centigrade, do and dissolve test.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 4 (n=6).
The stripping curve of Fig. 3 apomorphine hydrochloride sublingual tablets
The solution time of table 4 apomorphine hydrochloride sublingual tablets
Table 5
Embodiment 4
The supplementary material consumption is with reference to table 5.Loratadine and citric acid are mixed, and then, the principle and the sorbitol that progressively increase by equivalent mix, and mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.In 70% the alcohol-water solution, add an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stampings, hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, to do stripping and measure, basket method 50 is changeed.Stripping curve as shown in Figure 4.
In the disintegration tester, 37 degrees centigrade, do the external test of dissolving.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 6 (n=6).
The stripping curve of Fig. 4 loratadine Sublingual tablet
The solution time of table 6 loratadine Sublingual tablet
Embodiment 5
The supplementary material consumption is with reference to table 5.Loratadine and citric acid are mixed, and then, the principle and the sorbitol that progressively increase by equivalent mix, and mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.In 70% the alcohol-water solution, add an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stamping hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, to do stripping and measure, basket method 50 is changeed.Stripping curve as shown in Figure 5.
In the disintegration tester, 37 degrees centigrade, do and dissolve test.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 7 (n=6).
Embodiment 5
The stripping curve of Fig. 5 loratadine Sublingual tablet
The solution time of table 7 loratadine Sublingual tablet
Embodiment 6
The supplementary material consumption is with reference to table 5.Loratadine and citric acid are mixed, then, mix by progressively increase principle and sorbitol of equivalent, mixed powder is placed on mixing in the quick mixer granulator, adds the lactose and the mannitol of recipe quantity again, mixes fast.70% alcohol-water solution adds an amount of light blue, as binding agent.In the powder of quick stirring, add binding agent.Stirred 5 minutes fast.Soft material is crossed 24 mesh sieves and is granulated.The air blast oven dry.Dried granule 20 mesh sieve granulate.Seven millimeters scrobicula stampings, hardness 50N.
Use digestion instrument, 500ml water, 37 degrees centigrade, to do stripping and measure, basket method 50 is changeed.Stripping curve as shown in Figure 6.
In the disintegration tester, 37 degrees centigrade, do and dissolve test.Get a slice and place the Sublingual, do the oral cavity and dissolve test.The results are shown in Table 8 (n=6).
Embodiment 6
The stripping curve of Fig. 6 loratadine Sublingual tablet
The solution time of table 8 loratadine Sublingual tablet
Embodiment 7 hardness and the time relationship external, that dissolve in the Sublingual
To be pressed into the different tablet of hardness by the granule of above each prescription, solution time is shown in table 9 and table 10.
Table 9 Sublingual tablet hardness and external, Sublingual solution time table (n=6)
Table 10 Sublingual tablet hardness and external, Sublingual solution time table (n=6)
Claims (2)
1. water soluble drug Sublingual tablet, it is characterized in that comprising aqueous soluble active constituent and penetrating agent, it can slowly dissolve in 10～20 minutes in the Sublingual, and solution time and firmness change are irrelevant, described aqueous soluble active constituent is an apomorphine hydrochloride, and described penetrating agent is the compositions of sorbitol, mannitol and lactose; The composition of this water soluble drug Sublingual tablet is apomorphine hydrochloride, sorbitol, lactose, mannitol, citric acid, sucralose, light blue, ethanedioic acid triethylammonium tetrakis disodium, vitamin C, magnesium stearate and Pulvis Talci, and the part by weight of each composition is: a, 1:70:10:14:1:0.07:0.015:0.02:1:0.5:3; B, 15:40:20:20:1:0.07:0.015:0.02:1:0.5:3; Or c, 30:20:25:30:1:0.07:0.015:0.02:1:0.5:3.
2. according to the Sublingual tablet of claim 1, it is characterized in that described aqueous soluble active constituent content is 1mg～30mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100307482A CN100500151C (en) | 2004-04-02 | 2004-04-02 | Water-soluble medicine sublingual-medicating formulation |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100307482A CN100500151C (en) | 2004-04-02 | 2004-04-02 | Water-soluble medicine sublingual-medicating formulation |
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| CN1676130A CN1676130A (en) | 2005-10-05 |
| CN100500151C true CN100500151C (en) | 2009-06-17 |
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| PT2651357T (en) * | 2010-12-16 | 2020-06-17 | Sunovion Pharmaceuticals Inc | Sublingual films |
| GB201309654D0 (en) | 2013-05-30 | 2013-07-17 | Euro Celtique Sa | Method |
| CN113304177A (en) * | 2021-06-01 | 2021-08-27 | 金华寿仙谷药业有限公司 | Wall-broken ganoderma lucidum spore powder extract and preparation method and application of disintegrating tablet thereof |
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