CN100482220C - Oral preparation of bilobalide with high bioavailability and preparation method thereof - Google Patents
Oral preparation of bilobalide with high bioavailability and preparation method thereof Download PDFInfo
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- CN100482220C CN100482220C CNB2007100200968A CN200710020096A CN100482220C CN 100482220 C CN100482220 C CN 100482220C CN B2007100200968 A CNB2007100200968 A CN B2007100200968A CN 200710020096 A CN200710020096 A CN 200710020096A CN 100482220 C CN100482220 C CN 100482220C
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- bilobalide
- ginkalide
- active component
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- adjuvant
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- MOLPUWBMSBJXER-YDGSQGCISA-N bilobalide Chemical compound O([C@H]1OC2=O)C(=O)[C@H](O)[C@@]11[C@@](C(C)(C)C)(O)C[C@H]3[C@@]21CC(=O)O3 MOLPUWBMSBJXER-YDGSQGCISA-N 0.000 title claims abstract description 144
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 241000218628 Ginkgo Species 0.000 claims abstract description 7
- 235000011201 Ginkgo Nutrition 0.000 claims abstract description 7
- 235000008100 Ginkgo biloba Nutrition 0.000 claims abstract description 7
- 210000002784 stomach Anatomy 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 37
- 238000009472 formulation Methods 0.000 claims description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000002671 adjuvant Substances 0.000 claims description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 7
- -1 hydroxypropyl Chemical group 0.000 claims description 7
- 150000002596 lactones Chemical class 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 238000007907 direct compression Methods 0.000 claims description 6
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 6
- 229920001249 ethyl cellulose Polymers 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 5
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 239000004088 foaming agent Substances 0.000 claims description 5
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 5
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 230000003196 chaotropic effect Effects 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 3
- 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 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 239000000783 alginic acid Substances 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 229960001126 alginic acid Drugs 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 235000019700 dicalcium phosphate Nutrition 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
- 238000005516 engineering process Methods 0.000 claims description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000001095 magnesium carbonate Substances 0.000 claims description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 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
- 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 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000007908 dry granulation Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 9
- 238000001035 drying Methods 0.000 abstract description 4
- 238000000227 grinding Methods 0.000 abstract 2
- 239000002245 particle Substances 0.000 abstract 2
- 229930063422 Bilobalide A Natural products 0.000 abstract 1
- SQOJOAFXDQDRGF-ZMVGXLHTSA-N ginkgolide b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-ZMVGXLHTSA-N 0.000 abstract 1
- 238000009736 wetting Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000007779 soft material Substances 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical group 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a method for preparing bilobalide tablet with high biological utilization, which is characterized in that it is prepared from bilobalide drug as active component and relative findings, wherein, the bilobalide drug can be bilobalide or bilobalide B that treated by powdering technique, and the findings contain the components which can hold the drug in the stomach. The mass ration between the bilobalide drug and the findings is 1:0.3-30. The bilobalide drug is extracted from ginkgo leaf. And the preparation is characterized in that processing bilobalide drug via powdering treatment, and the finding is screened via the screen at 80-100 deals to be mixed uniformly and pressed into tablet or drops, or using wetting particle making technique or drying particle technique to press the tablet or drops.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof, more particularly, relate to a kind of oral formulations and preparation thereof of bilobalide of high bioavailability.
Background technology
Along with the development of Folium Ginkgo research, now prove: the active component of Folium Ginkgo mainly is flavone and lactone compound.Wherein, bilobalide is that a class of only finding in Folium Ginkgo has the important component of special construction and remarkable pharmacologically active, does not find as yet so far to be present in other any plants.The more important thing is that they have unique pharmacological action and therapeutic value, have proved that bilobalide is strong platelet activating factor (plateletacllvatfactor, PAF) receptor antagonist.The monomer of bilobalide has similar ring-type mother nucleus structure, generally the bilobalide mixture is called bilobalide at present, from monomer difference called after ginkalide A, ginkalide B, ginkalide C, bilobalide M, bilobalide J and the bilobalide of wherein having purified, wherein the activity of ginkalide B is the strongest.Along with effective medicinal ingredient clear and definite in the Folium Ginkgo, its lactone composition becomes the competitively new drug target of exploitation of countries such as France, Britain, Germany and the U.S. in recent years.At present both at home and abroad all to drug effect, toxicity, the clinical further investigation of bilobalide, the monomer ginkalide B has also entered II, III phase at state place clinical, be used for tests such as shock, burn, apoplexy, transplant rejection and hemodialysis, also may prevent and treat allergic asthma.
The physicochemical property of bilobalide is special, under alkali condition, the ring-type mother nucleus structure of bilobalide can open loop causes that its structural deterioration, polarity diminish, water solublity strengthens, thereby be difficult in intestinal, (referring to duodenum and following position, be alkaline environment) absorb, thereby bilobalide or the oral bioavailability not high (only being about 3～10%) of ginkalide B, generally should be made into the injection type administration.But drug administration by injection patient compliance is low, the administration inconvenience.
Summary of the invention
The objective of the invention is to provide a kind of oral formulations and preparation thereof of bilobalide of high bioavailability at above-mentioned weak point, solve bilobalide or the low problem of ginkalide B oral administration bioavailability, improved the bioavailability of bilobalide oral administration, to give full play to its therapeutical effect, making things convenient for patient's medication, is purpose of the present invention.
A kind of mixture of bilobalide of high bioavailability or ginkalide B oral formulations and preparation thereof are to take following scheme to realize:
A kind of oral formulations of bilobalide of high bioavailability is characterized in that: it is formulated by active component bilobalide and adjuvant, and wherein the active component bilobalide is through micronization processes; The active component bilobalide comprises bilobalide or ginkalide B; Contain the pharmaceutic adjuvant that impels medicine to be trapped in stomach in its adjuvant; The weight proportion of active component bilobalide and pharmaceutic adjuvant is 1:0.3～30.
The oral formulations of the bilobalide of described a kind of high bioavailability is characterized in that the active component bilobalide is to extract the bilobalide that obtains from Folium Ginkgo, or is further purified the ginkalide B that obtains; Bilobalide wherein is the mixture of ginkalide A, ginkalide B, ginkalide C, bilobalide, total lactone content 70%～100%; Ginkalide B is that its content is 95%～100% from the further refining ginkalide B monomer that obtains of bilobalide.
Described adjuvant comprises delay agent, suspending agent, foaming agent, chaotropic agent, filler, lubricant, binding agent; A kind of or its mixture in hydroxypropyl emthylcellulose (HPMC), carboxymethyl starch sodium (CMS), methylcellulose (MC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), carbomer, chitosan, the alginic acid sugar is selected in the delay agent for use; Suspending agent is selected a kind of or its mixture of octadecanol, hexadecanol, Polyethylene Glycol, acroleic acid resin for use; Foaming agent is selected sodium bicarbonate, calcium carbonate, magnesium carbonate for use, can use separately, also can be used in combination with citric acid or tartaric acid; Chaotropic agent is selected sodium lauryl sulphate, Tween 80 for use; Filler is selected a kind of or its mixture in microcrystalline Cellulose, lactose, sucrose, glucose, mannitol, calcium hydrogen phosphate, polyvinylpolypyrrolidone (PVPP), the ethyl cellulose (EC) for use; The adjuvant that lubricant, binding agent etc. use for the tablet permission includes but not limited to micropowder silica gel, magnesium stearate, Pulvis Talci, dehydrated alcohol, polyvinylpyrrolidone, can use use also capable of being combined separately.
A kind of preparation method of oral formulations of bilobalide of high bioavailability is: with active component bilobalide or ginkalide B process micronization processes, adjuvant is crossed 80～100 mesh sieves, mix homogeneously, direct compression makes, perhaps adopt wet granulation technique or dry granulation technology, tabletting or pill and get.
The preparation method of the oral formulations of the bilobalide of described a kind of high bioavailability is characterized in that its tablet or pill can carry out coating, and coating material is selected acroleic acid resin for use, or Opadry.
The oral formulations of the bilobalide of described a kind of high bioavailability is characterized in that containing the active component bilobalide in every preparation or ginkalide B is 1mg～240mg.
The oral formulations of the bilobalide of described a kind of high bioavailability is characterized in that dosage form comprises tablet, capsule, pill and pellet.
The oral formulations of the bilobalide of described a kind of high bioavailability is characterized in that active component bilobalide or ginkalide B bioavailability in vivo is higher than 30%.
The present invention has overcome existing bilobalide or ginkalide B oral administration biological utilisation is low, generally adopts the deficiency of drug administration by injection, provides suitable oral Preparation of a kind of bilobalide or ginkalide B and preparation method thereof, convenient drug administration.
The present invention through micronization processes, quickens drug absorption speed with active ingredient; Select suitable excipients for use, particularly being detained agent can form density that high-molecular gel makes preparation and alleviate or adhere to coat of the stomach in water, suspending agent and foaming agent alleviate the density of preparation, facilitate pharmaceutical preparation to be in the top of gastric juice, slow down pharmaceutical preparation with the speed that the gastric juice emptying enters intestinal, pharmaceutical preparation is detained for a long time at stomach, avoid the destruction of high pH environment active ingredient, finally make the oral administration biaavailability of active ingredient increase substantially, can give full play to its drug effect.
Studies show that, the conventional oral formulations of bilobalide or ginkalide B (refers to without micronization processes, or add special adjuvant and be trapped in stomach to impel medicine) absorption in gastrointestinal tract is very low, mainly be the variation that can not solve bilobalide-like substances physicochemical property under high pH, thereby finally cause its bioavailability low because of conventional oral formulations.The invention solves the conventional low problem of bioavailability when oral of bilobalide, the oral administration biaavailability of gained preparation obviously improves, and its drug effect is given full play in clinical practice, and does not have the awkward shortcoming of injection.The properties of samples that makes is stable, does not have tangible catabolite, meets the prescription of country to oral drugs.
The specific embodiment
By the following examples, further specify the present invention, following embodiment only is used to the present invention is described and to the present invention without limits.
Embodiment 1: get bilobalide (total lactone content〉70%) 100g, adopt jet mill that medicine is crushed to granularity between 5～10 μ m; Get hydroxypropyl emthylcellulose (HPMC) 200g, hexadecanol 200g crosses 80 mesh sieves respectively; With the supplementary material mix homogeneously, be binding agent with the ethanol solution of 10% polyvinylpyrrolidone (PVP), and add a small amount of Tween 80, the system soft material, the wet grain of the 20 mesh sieve systems of crossing, wet grain is put after 40 ℃ of dryings, cross 18 mesh sieve granulate, add a small amount of magnesium stearate, tabletting behind the mixing.
Embodiment 2: get ginkalide B (content〉95%) 10g, be crushed to granularity between 5～10 μ m through the high speed rotating bump; Get hydroxypropyl emthylcellulose (HPMC) 1.5g, carboxymethyl cellulose (CMC) 3.5g, calcium carbonate 1.5g, sodium lauryl sulphate 0.8g crosses 80 mesh sieves respectively; With the supplementary material mix homogeneously, add a small amount of micropowder silica gel, dry method direct compression behind the mixing.
Embodiment 3: get bilobalide (total lactone content〉70%) 100g, adopt jet mill that medicine is crushed to granularity between 5～10 μ m; Get carbomer 15g, sodium bicarbonate 20g, lactose 30g is binding agent with the ethanol solution of 10% polyvinylpyrrolidone (PVP), and adds a small amount of Tween 80, the system soft material, the wet grain of the 20 mesh sieve systems of crossing, wet grain is put after 50 ℃ of dryings, crosses 18 mesh sieves, add a small amount of magnesium stearate, fill is in capsule behind the mixing.
Embodiment 4: get ginkalide B (content〉95%) 10g, adopt ball mill that medicine is crushed to granularity between 5～10 μ m; Get hydroxypropyl emthylcellulose (HPMC) 4g, carboxymethyl cellulose (CMC) 2g, calcium carbonate 0.5g, magnesium carbonate 0.4g, mannitol 0.2g crosses 80 mesh sieves respectively; Add Pulvis Talci and sodium lauryl sulphate, with the supplementary material mix homogeneously, directly fill is in capsule.
Embodiment 5: get bilobalide (total lactone content〉70%) 100g, adopt jet mill that medicine is crushed to granularity between 5～10 μ m; Get hydroxypropyl cellulose (HPC) 10g, carboxymethyl cellulose (CMC) 10g, ethyl cellulose (EC) 5g, calcium carbonate 5g crosses 80 mesh sieves respectively; With the supplementary material mix homogeneously, add a small amount of micropowder silica gel and sodium lauryl sulphate, dry method direct compression behind the mixing.
Embodiment 6: get ginkalide B (content〉95%) 10g, adopt and stir mill with drug micronization; Get hydroxypropyl emthylcellulose (HPMC) 40g, carbomer 20g, Polyethylene Glycol 20g, sodium bicarbonate 30g, citric acid 20g, magnesium stearate 10g, micropowder silica gel 20g, starch 100g, sucrose 20g crosses 80 mesh sieves respectively; With above-mentioned supplementary material mixing, with dehydrated alcohol (10%) the solution solution system soft material of polyvinylpyrrolidone (PVP) 20g, the wet grain of the 30 mesh sieve systems of crossing, wet grain is put immediately and is rotated 40～60min in the coating pan, take out oven dry, get 20～30 purpose micropills after sieving, in the hard capsule of packing into.
Embodiment 7: get bilobalide (total lactone content〉70%) 100g, adopt jet mill that medicine is crushed to granularity between 5～10 μ m; Get chitosan 450g, octadecanol 30g, calcium hydrogen phosphate 20g crosses 80 mesh sieves respectively; With the supplementary material mix homogeneously, add a small amount of micropowder silica gel and sodium lauryl sulphate, dry method direct compression behind the mixing.Tablet surface is wrapped the alcoholic solution with acroleic acid resin, drying again.
Embodiment 8: get ginkalide B (content〉95%) 10g, adopt jet mill that medicine is crushed to granularity between 5～10 μ m; Get alginic acid sugar 5g, methylcellulose 5g, hydroxyethyl-cellulose 12g, acroleic acid resin 50g, sodium bicarbonate 1g crosses 80 mesh sieves respectively; With the supplementary material mix homogeneously, add a small amount of micropowder silica gel and sodium lauryl sulphate, dry method direct compression behind the mixing.
Claims (5)
1, a kind of oral formulations of bilobalide of high bioavailability is characterized in that: it is formulated by active component bilobalide and adjuvant, and wherein the active component bilobalide is through micronization processes; The active component bilobalide is a bilobalide, or ginkalide B; Contain the pharmaceutic adjuvant that impels medicine to be trapped in stomach in its adjuvant; The weight proportion of active component bilobalide and pharmaceutic adjuvant is 1:0.3～30;
Described active component bilobalide or ginkalide B bioavailability in vivo are higher than 30%;
Described adjuvant comprises delay agent, suspending agent, foaming agent, chaotropic agent, filler, lubricant, binding agent; A kind of or its mixture in hydroxypropyl emthylcellulose (HPMC), carboxymethyl starch sodium (CMS), methylcellulose (MC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), carbomer, chitosan, the alginic acid sugar is selected in the delay agent for use; Suspending agent is selected a kind of or its mixture of octadecanol, hexadecanol, Polyethylene Glycol, acroleic acid resin for use; Foaming agent is selected sodium bicarbonate, calcium carbonate, magnesium carbonate for use, uses separately, or is used in combination with citric acid or tartaric acid; Chaotropic agent is selected sodium lauryl sulphate or Tween 80 for use; Filler is selected a kind of or its mixture in microcrystalline Cellulose, lactose, sucrose, glucose, mannitol, calcium hydrogen phosphate, polyvinylpolypyrrolidone (PVPP), the ethyl cellulose (EC) for use; Lubricant, binding agent are the adjuvant that tablet allows use, select micropowder silica gel, magnesium stearate, Pulvis Talci, dehydrated alcohol, polyvinylpyrrolidone for use, use separately, or are used in combination;
Described dosage form is tablet, capsule, pill or pellet.
2, the oral formulations of the bilobalide of a kind of high bioavailability according to claim 1, it is characterized in that the active component bilobalide is to extract the bilobalide that obtains from Folium Ginkgo, or be further purified the ginkalide B that obtains; Bilobalide wherein is the mixture of ginkalide A, ginkalide B, ginkalide C, bilobalide, total lactone content 70%～100%; Ginkalide B is that its content is 95%～100% from the further refining ginkalide B monomer that obtains of bilobalide.
3, the preparation method of the oral formulations of the bilobalide of the described a kind of high bioavailability of claim 1, it is characterized in that its preparation method is: with active component bilobalide or ginkalide B process micronization processes, adjuvant is crossed 80～100 mesh sieves, mix homogeneously, direct compression makes, perhaps adopt wet granulation technique or dry granulation technology, tabletting or pill and get.
4, the preparation method of the oral formulations of the bilobalide of a kind of high bioavailability according to claim 3 is characterized in that its tablet or pill carry out coating, and coating material is selected acroleic acid resin for use, or Opadry.
5, the oral formulations of the bilobalide of a kind of high bioavailability according to claim 1 is characterized in that containing the active component bilobalide in every preparation or ginkalide B is 1mg～240mg.
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| CN105663073A (en) * | 2016-04-06 | 2016-06-15 | 刘建军 | Method for preparing traditional Chinese medicine tablet granulated by adhesive foam state |
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