CN112089848A - 叶酸的环糊精包合物及其制备方法 - Google Patents
叶酸的环糊精包合物及其制备方法 Download PDFInfo
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- CN112089848A CN112089848A CN202011163093.1A CN202011163093A CN112089848A CN 112089848 A CN112089848 A CN 112089848A CN 202011163093 A CN202011163093 A CN 202011163093A CN 112089848 A CN112089848 A CN 112089848A
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- folic acid
- cyclodextrin
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 203
- 239000011724 folic acid Substances 0.000 title claims abstract description 102
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 102
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims abstract description 101
- 229960000304 folic acid Drugs 0.000 title claims abstract description 101
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 74
- 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 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 14
- 239000000661 sodium alginate Substances 0.000 claims abstract description 14
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 14
- 239000012046 mixed solvent Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
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- 238000000034 method Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 19
- 229960004853 betadex Drugs 0.000 description 19
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 18
- 239000003814 drug Substances 0.000 description 10
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
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- 229940097362 cyclodextrins Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- AEMOLEFTQBMNLQ-AZLKCVHYSA-N (2r,3s,4s,5s,6r)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@@H]1O[C@@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-AZLKCVHYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-SYJWYVCOSA-N (2s,3s,4s,5s,6r)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-SYJWYVCOSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000219315 Spinacia Species 0.000 description 1
- 235000009337 Spinacia oleracea Nutrition 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
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- XKGHIDSAMUQOSZ-WWPIYYJJSA-L disodium (2S)-2-[amino(benzoyl)amino]pentanedioate Chemical compound C1=CC=C(C=C1)C(=O)N([C@@H](CCC(=O)[O-])C(=O)[O-])N.[Na+].[Na+] XKGHIDSAMUQOSZ-WWPIYYJJSA-L 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
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- 229940014144 folate Drugs 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
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- 229960002989 glutamic acid Drugs 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- 210000001630 jejunum Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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Abstract
本发明涉及一种叶酸的环糊精包合物及其制备方法。包括叶酸、环糊精或羟丙基‑β‑环糊精,质量比为1:2~1:50。还添加海藻酸钠,促进环糊精对叶酸的包合,提升环糊精包合物在冻干之后的复溶速度。用量是叶酸质量的1/4‑1/3。制备方法是将环糊精和叶酸溶于水和有机溶剂的混合溶剂中,然后置于60℃的微波中反应2~3分钟,过滤,除去游离物原料,真空干燥所得。本发明利用环糊精包合作用,将叶酸包合,形成稳定的包合物,增大叶酸的溶解度和生物利用度。
Description
技术领域 :
本发明涉及医药技术领域,具体涉及一种叶酸环糊精及环糊精衍生物的包合物及其制备方法。
背景技术:
叶酸(Folic Acid)属于B族维生素,化学名为 N-[4-[(2-氨基-4-氧代-1,4-二氢-6-蝶啶)甲氨基]苯甲酰基]-L-谷氨酸,结构式如下:
因为从菠菜中发现了这种生物因子,所以被命名为叶酸。叶酸主要在十二指肠及近端空肠部位吸收,经尿和粪便排出体外。叶酸在空气中稳定,但受紫外光照射即分解失去活力,在酸性溶液中对热不稳定,其钠盐溶于水后受光照会分解为喋啶和氨基苯甲酰谷氨酸钠。叶酸在水中的溶解度极小,在25℃水中的溶解度仅0.0016mg/mL(pH为4.8-4.8),按照中国药典溶解度划分等级,属于微溶药物,生物利用度较低,因此,提高其溶出速率和生物利用度具有重要意义。因此,对于叶酸制剂,提高其对光的稳定性、在胃酸环境的稳定性、胃肠道内的生物利用度是极其必要的。
公开号为CN 105796498 B的中国专利公布了 一种粉末包衣叶酸及其制备方法,所述粉末包衣叶酸由叶酸和包衣材料经流化床底喷粉末包衣法制备而成,包衣材料优选为羟丙基纤维素或聚乙二醇,所得粉末包衣叶酸具有良好的光、湿稳定性;且溶出良好,利于机体对叶酸的吸收。
公开号为CN102000345A的中国专利申请文件公开了包合态的叶酸/β-环糊精组合物及其制备方法。该组合物是由β-环糊精与叶酸组成,β-环糊精与叶酸的质量比为4~7∶1。制备方法是,称取β-环糊精和叶酸,加入纯水混合成混悬液或溶液,在加热搅拌条件下反应,反应液静置冷却至固体物充分析出,过滤,过滤后滤饼干燥(干燥方式是直接干燥、或流化床干燥、或真空干燥、或冷冻干燥)即得固体包合态的叶酸/β-环糊精组合物;该发明使叶酸包埋于β-环糊精的筒状空腔结构中,成为叶酸-β-环糊精包合物,包合态的叶酸/β-环糊精组合物的用于制备成片剂、胶囊剂、颗粒剂、口服液和注射液等剂型,解决了叶酸稳定性差、水溶性低等缺点。
公开号为CN101806795A的中国专利申请文件公开一种肿瘤靶向性的功能化量子点及其制备方法。该功能化量子点是由叶酸、环糊精和量子点共同构成,叶酸分子有一部分包含于环糊精的疏水空腔内形成叶酸-环糊精包合物,再进一步结合到量子点表面。制备该功能化量子点时,首先将叶酸与γ-环糊精结合形成包合物,再将γ-环糊精叶酸包合物修饰到量子点表面,即得具有优异荧光特性和肿瘤靶向性的双功能的纳米尺寸材料。由于用γ-环糊精包合叶酸,改善了叶酸的水溶性和分散性。再通过一种有效的方法将叶酸和量子点连接起来,所得的荧光探针可用于肿瘤细胞的生物学研究,具有低毒性、选择性高等特点。
发明内容:
为了克服常规叶酸环糊精包合物的包和率低,采用冻干法干燥后复溶难的问题,本发明提供一种叶酸环糊精的包合物及其制备方法。利用环糊精包合作用,将叶酸包合,形成稳定的包合物,增大叶酸的溶解度和生物利用度,而且具有较高的包合率,且易于复溶。
一种叶酸的环糊精包合物,包括叶酸、环糊精或其衍生物,质量比为1:2~1:50,优选质量比为:1:5~1:40,更优选1:15~1:30。
在上述包合物中,还添加海藻酸钠,用量是叶酸质量的1/4-1/3。添加海藻酸钠后,一方面促进环糊精对叶酸的包合,另一方面提升了环糊精包合物在冻干之后的复溶速度。
环糊精衍生物为羟丙基-β-环糊精,与环糊精相比较,羟丙基-β-环糊精更好地提升了对叶酸的包合率。
采用该环糊精包合物进一步制备的液体、半固体或固体制剂,克服叶酸原料药水溶性差、生物利用度低的缺点,提高药物的疗效和安全性。
上述叶酸的环糊精包合物,是采用微波辐射法制得,具体如下:首先将环糊精和叶酸溶于水和有机溶剂的混合溶剂中,然后置于60℃的微波中反应 2~3分钟,过滤,用等量的混合溶剂洗去游离的叶酸或环糊精,真空干燥得包合物。
上述混合溶剂是水与乙醇或者乙二醇的等体积混合物,较佳地,添加碱性溶液方便叶酸的溶解。该碱性溶液可以是氨水、碳酸钠、碳酸氢钠、氢氧化钠的任意一种,或使得混合溶剂的pH在6.8-11.0。
有益效果:
(1)由于环糊精内疏水、外亲水的结构特点,β-环糊精的疏水空腔(分子空腔内径尺寸:6.0~6.5 A°,高7.9 A°)能够容纳叶酸分子(宽度小于3.7),从而形成稳定的包合物,而羟丙基-β-环糊精中羟丙基的引入打破了β-环糊精的分子内环状氢键,在保持环糊精空腔的同时更好地提升了包合物的水溶性。
(2)环糊精的包结过程中包结物的稳定性受到水、主客体分子尺寸相匹配、极性和电荷、介质、氢键等的影响。海藻酸钠的分子是由β-D-甘露糖醛酸(M单元)与α-L-古洛糖醛酸(G单元)依靠β-1,4-糖苷键连接并由不同比例的GM、MM和GG片段组成的共聚物,其溶于水,不溶于乙醇、乙醚、氯仿等有机溶剂。在酸性条件下,-COO-转变成-COOH,电离度降低,海藻酸钠的亲水性降低,分子链收缩,pH值增加时,-COOH基团不断地解离,海藻酸钠的亲水性增加,分子链伸展,在本发明中,所采用的混合溶剂采用碱性化合物调整pH为碱性,海藻酸钠用于提升环糊精对叶酸的包合率,提升环糊精包合物在冻干之后的复溶速度。
(3)叶酸分子被环糊精包合后,在海藻酸钠的作用下,更好地达到稳定状态,叶酸稳定性和溶解度均得到提高。
具体实施方式:
为了更好的说明本发明的技术方案,特给出以下实施例,但本发明不仅限于此。
实施例 1
称取 β- 环糊精 2.5g,在搅拌条件下,缓慢加入到加100ml的水中,使之饱和,称取叶酸0.5g,用0.5%氨水溶解后,缓慢滴加到β-环糊精饱和溶液中,然后置于 60℃的微波中反应 2~3分钟,过滤,用等量的0.5%氨水洗去游离的药物或环糊精,真空干燥后,过80目筛。即得叶酸β- 环糊精包合物。
实施例1-8所采用的工艺条件对比以及结果如表1所示:
注:实施例1、2在于考察环糊精种类的影响,实施例2、3在于考察是否添加海藻酸钠对性能的影响,实施例2、3、4在于考察海藻酸钠的不同用量对性能的影响。
实施例9 包合可行性的验证:
叶酸难溶于乙醇,水中溶解度也不高 (0.082mg/ml)。水溶液中,叶酸在 283nm nm的波长处有最大吸收,加入自身无紫外吸收的各种环糊精后, 药物吸光度随环糊精浓度的增加呈现规律性增强,表明水溶液中,环糊精与叶酸存在明显的包合作用。通过环糊精浓度与药物吸光度的变化,根据公式1/ΔA=1/(ΔAmaxKa/[CD]o)+1/ΔAmax和ΔA=-(1/Ka )(ΔA/[CD]o)+ Δε/Δ[G]o,可以测得表观包合常数,结果见表 2( 测定条件:pH =4.65;pH=6.75; pH=9.00的 0.1mol·L-1 磷酸缓冲液,检测波长283nm)。
表2 : 叶酸的表观包合常数 Ka(283nm, 15±5℃ )
表2的结果表明,环糊精包合叶酸效果与介质的酸度有关,碱性水溶液中有较大的表观包合常数,各种环糊精均能与叶酸形成稳定的包合物,这对提高叶酸的稳定性、改善叶酸的药剂学性质十分有利。酸性条件下(pH=4.65),叶酸易质子化,分子极性增强,导致包合能力下降,因此,不利于产生稳定的包合物。
实施例10 溶解度试验
采用相溶解度法考察环糊精对叶酸溶解度的影响,试验结果见表3:
表3 不同包合物溶解度试验结果
结果表明,饱和β-环糊精使叶酸溶解度增加4倍 ;羟丙基-β-环糊精溶液增加5倍以上,优于单一β-环糊精,显示出更好的溶解性,添加海藻酸钠后溶解性更好。
实施例11样品稳定性试验
将实施例1所得叶酸的环糊精包合物 (包合比为1∶15)、实施例3所得叶酸的羟丙基-β-环糊精包合物(包合比为为 1∶20) 与叶酸原料分别置于 40℃热和 4500±500LX 光下进行十天稳定性实验。分别于第 5 和 10 天取样, HPLC含量检测。相对含量 ( 以 0 天100%计 )和有关物质 检测结果 见表 4,表5。
HPLC测试条件:仪器:戴安UltiMate3000;色谱柱:Shim-pack VP-ODS5μm 250L×4.6;检测器:VWD-3100,检测波长:256nm;流动相:甲醇-水-冰醋酸(30:70:0.4);流速;1.0mL/min,柱温:30℃。
表 4 : 样品中叶酸相对百分含量
表5样品中叶酸有关物质
试验结果表明:表4中样品中叶酸相对百分含量显示,光、热条件下非包合的叶酸原料药含量下降3%-5% ;而包合物中叶酸含量相对稳定。说明,环糊精包合使叶酸的稳定性得到明显提高。 另外,对比不同环糊精制备的包合物,β- 环糊精制备的包合物稳定性低于羟丙基-β-环糊精制备的包合物。
实施例12生物利用度试验 :
1、 受试药物 :实施例1所得叶酸/β-环糊精包合物、实施例2所得叶酸/羟丙基-β-环糊精、对照例叶酸原料( CMC-Na 混悬液给药) ,共3个供试样品。
2、动物实验 : 试验动物SD大鼠分为3组,按照“化学药物非临床药代动力学研究技术指导原则 (【H】GPT5-1)”的要求设计方案开展试验, HPLC 法测定血药浓度,结果分别见表6。
表6: 实验样品的药代动力学参数
*代表与对照例有显著差异, P < 0.05.
表6的结果显示,对照例中叶酸CMC-Na悬液口服生物利用度最低,实施例1、2生物利用度有所提高,证明包合状态的叶酸具有一定的加快口服吸收效果。对照例混悬状态叶酸不易分解、稳定性差,助悬剂副作用强,而且制剂不易保存、使用携带不便,产业化难度高。叶酸的环糊精包合物口服效果良好,实施例3,添加海藻酸钠的羟丙基-β-环糊精包合物复溶效果最好,缩短了达峰时间。
Claims (6)
1.一种叶酸的环糊精包合物,其特征在于,包括叶酸、环糊精或羟丙基-β-环糊精,两者的质量比为1:2~1:50;
还添加海藻酸钠,用量是叶酸质量的1/4-1/3。
2.权利要求1所述的叶酸的环糊精包合物的制备方法,是采用微波辐射法制得,其特征在于,首先将环糊精和叶酸溶于水和有机溶剂的混合溶剂中,然后置于60℃的微波中反应2~3分钟,过滤,用相同的混合溶剂洗去游离的叶酸、环糊精或其衍生物,真空干燥所得。
3.根据权利要求2所述的叶酸的环糊精包合物的制备方法,其特征在于,所述混合溶剂是水与乙醇或者乙二醇的等体积混合物。
4.根据权利要求2所述的叶酸的环糊精包合物的制备方法,其特征在于,所述混合溶剂添加碱性溶液方便叶酸的溶解。
5.根据权利要求4所述的叶酸的环糊精包合物的制备方法,其特征在于,所述的碱性溶液是氨水、碳酸钠、碳酸氢钠、氢氧化钠的任意一种,使得混合溶剂的pH在6.8-11.0。
6.一种药物组合物,其特征在于,包含权利要求1所述的环糊精包合物及药学上可接受的药物载体,剂型是液体、半固体或固体制剂。
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