CN109381433B - 一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 - Google Patents
一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 Download PDFInfo
- Publication number
- CN109381433B CN109381433B CN201811092142.XA CN201811092142A CN109381433B CN 109381433 B CN109381433 B CN 109381433B CN 201811092142 A CN201811092142 A CN 201811092142A CN 109381433 B CN109381433 B CN 109381433B
- Authority
- CN
- China
- Prior art keywords
- eutectic solvent
- hydrogen bond
- insoluble
- polymer microspheres
- insoluble flavonoid
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 40
- 229940079593 drug Drugs 0.000 title claims abstract description 36
- 239000002904 solvent Substances 0.000 title claims abstract description 34
- 230000005496 eutectics Effects 0.000 title claims abstract description 33
- 229930003935 flavonoid Natural products 0.000 title claims abstract description 33
- 235000017173 flavonoids Nutrition 0.000 title claims abstract description 33
- 239000004005 microsphere Substances 0.000 title claims abstract description 21
- 229920000642 polymer Polymers 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 20
- 150000002215 flavonoids Chemical class 0.000 title claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- -1 flavonoid compound Chemical class 0.000 claims abstract description 16
- 229920002678 cellulose Polymers 0.000 claims abstract description 14
- 239000001913 cellulose Substances 0.000 claims abstract description 14
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims abstract description 11
- 235000019743 Choline chloride Nutrition 0.000 claims abstract description 11
- 229960003178 choline chloride Drugs 0.000 claims abstract description 11
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical group [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims abstract description 10
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Chemical group C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims abstract description 8
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical group C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims abstract description 8
- 229960003237 betaine Drugs 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000004898 kneading Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- GZSOSUNBTXMUFQ-NJGQXECBSA-N 5,7,3'-Trihydroxy-4'-methoxyflavone 7-O-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 GZSOSUNBTXMUFQ-NJGQXECBSA-N 0.000 claims description 15
- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 claims description 15
- 229960004352 diosmin Drugs 0.000 claims description 15
- IGBKNLGEMMEWKD-UHFFFAOYSA-N diosmin Natural products COc1ccc(cc1)C2=C(O)C(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 IGBKNLGEMMEWKD-UHFFFAOYSA-N 0.000 claims description 15
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 claims description 15
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims description 5
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 claims description 5
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims description 5
- 239000000835 fiber Substances 0.000 claims description 5
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims description 5
- 235000005493 rutin Nutrition 0.000 claims description 5
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 claims description 5
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 claims description 5
- 229960004555 rutoside Drugs 0.000 claims description 5
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 claims description 5
- 229960004245 silymarin Drugs 0.000 claims description 5
- 235000017700 silymarin Nutrition 0.000 claims description 5
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 235000017166 Bambusa arundinacea Nutrition 0.000 claims description 3
- 235000017491 Bambusa tulda Nutrition 0.000 claims description 3
- 241001330002 Bambuseae Species 0.000 claims description 3
- 235000015334 Phyllostachys viridis Nutrition 0.000 claims description 3
- 239000011425 bamboo Substances 0.000 claims description 3
- 229920000742 Cotton Polymers 0.000 claims description 2
- 230000000857 drug effect Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 15
- 239000002994 raw material Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000005357 flat glass Substances 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N flavone Chemical group O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Virology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药技术领域，具体涉及一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法。所述方法步骤为：S1：将氢键受体氯化胆碱或甜菜碱与氢键供体低聚甘油按照一定比例混合，混合物置于90‑100℃的恒温水浴锅中边加热边搅拌2‑3小时，直至反应体系变为无色透明液体，冷却至室温即得低共熔溶剂；S2：向该低共熔溶剂中加入难溶性黄酮类化合物，50‑60℃搅拌均匀后，用一定量纤维素进行吸附，经捏合，即得载药高分子微球。本发明所制备的低共熔溶剂能够使黄酮类化合物易于以无定形的形态高度分散在低共熔溶剂中，有效提升难溶性黄酮类药物的溶解性和药效。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法。
背景技术
低共熔溶剂的研究一直受到人们广泛关注，自Abbott等人2003年首次成功制备低共熔溶剂，各种与低共熔溶剂相关的研究报道接踵而至。低共熔溶剂是指由氢键受体(如氯化胆碱、甜菜碱等)和氢键供体(如尿素、苯酚、甘油等)按一定化学计量比组合而成的两组分或三组分低共熔混合物，它不但具有与离子液体相似的化学性质，而且这种溶剂无毒性、可生物降解，合成过程原子利用率达100％，是一种新型的绿色溶剂。
黄酮类化合物是一类具有2-苯基色原酮结构的植物次级代谢产物，在植物界广泛存在。其在植物体内通常与糖类结合形成苷，少部分以游离态的苷元形式存在。黄酮类化合物具有抗菌、抗病毒、抗肿瘤、抗心脑血管疾病、保肝和治疗骨质疏松等药理活性。然而黄酮类化合物大多具有低溶解性和高渗透性的特点，其生物利用度受其溶解性的限制，即使较小的溶出速率的增加都会使生物利用度大幅度提高，因而，黄酮类化合物的研究一直是国内外生物类和医药类研究的热门课题。
本实验室发现氯化胆碱、甜菜碱和低聚甘油制备的低共熔溶剂，对黄酮类化合物有很好的溶解性。高聚物纤维素在低共熔溶剂中能够溶胀，分子结构变得松散，可以吸附难溶性药物，使药物更加稳定。因纤维素在胃里很难分解，从而达到药物的缓释作用。因而，用低共熔溶剂溶解难溶的黄酮类化合物，然后用纤维素进行吸收，制备负载难溶黄酮类药物的高分子微球，对于提高难溶性黄酮类化合物的溶解性和新的药物制剂的开发具有极大的现实可行性。
发明内容
本发明的目的就是利用氯化胆碱、甜菜碱与低聚甘油制备新型的低共熔溶剂，利用该种低共熔溶剂溶解难溶性黄酮类化合物，然后用纤维素等高聚物进行吸附，制备负载黄酮类药物的高分子微球，能够有效的提高黄酮类药物的溶解性和稳定性。
本发明是通过以下技术方案实现的：
一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法如下：氯化胆碱或甜菜碱与低聚甘油按照一定比例混合，混合物置于90-100℃的恒温水浴锅中边加热边搅拌2小时，直至反应体系变为无色透明液体，冷却至室温即得低共熔溶剂，向该低共熔溶剂中加入难溶性黄酮类化合物，50-60℃搅拌均匀后，用一定量纤维素进行吸附，捏合，即得载药高分子微球。
本发明所制备的低共熔溶剂，氢键受体为氯化胆碱、甜菜碱；氢键供体为低聚甘油。氯化胆碱或甜菜碱与低聚甘油共混，通过氢键作用结合形成分子复合体，增大体系的黏度，降低体系的熔点。
作为优选，所述氢键的供体与受体摩尔比范围为1-5。
作为优选，黄酮类化合物为芦丁、水飞蓟素、地奥司明等难溶性化合物。
所述纤维素的添加量为氢键供体与氢键受体总量的2-3倍，纤维素具体选自棉纤维、竹纤维或棕榈纤维。
所述低聚甘油聚合度范围为2-20。
本发明所制备的低共熔溶剂能够使黄酮类化合物易于以无定形的形态高度分散在低共熔溶剂中，有效提升难溶性黄酮类药物的溶解性和药效。
本发明采用的纤维素，在低共熔溶剂中溶胀，分子结构变得松散，进而吸附难溶性黄酮类药物，使药物更加稳定。且纤维素在胃里很难被分解，吸附药物后可达到药物的缓释作用。
具体实施方式：
下面通过具体实施方式对本发明做进一步说明，但本发明的保护范围并不仅限于此。
实例1：
按氯化胆碱与低聚甘油的摩尔比为1∶1，分别称取5g氯化胆碱和5.95g二聚甘油于100ml烧杯中混合，混合物置于100℃的恒温水浴锅中边加热边搅拌2小时，直至反应体系变为无色透明液体，冷却至室温即得低共熔溶剂。向该低共熔溶剂中加入0.5g地奥司明，80℃加热搅拌均匀后，加入20g粒径为80目的竹纤维，然后开启捏合机捏合1小时，即得载药高分子微球。
分别称取原料药地奥司明20mg和低共熔溶剂溶解后的地奥司明20mg，用研钵将两样品研细至手感无颗粒感即可。将样品架置于一个干净的平板玻璃上，把研细的样品填入样品架的内框中，然后将一平面用力压实，样品的背面要均匀平整，作为衍射面。将装好样品的样品架小心放置到样品架座上，用X射线粉末衍射仪进行扫描，记录数据。
参照2015版《中国药典》四部通则0931“溶出度与测定度释放法”规定中的第二法(桨法)，测定载药高分子微球在500ml蒸馏水中的体外溶出度，桨转速为75r/min，水浴温度(37.0±0.5)℃。精密称取载药高分子微球300mg，用研钵研细至手感无颗粒感，加入蒸馏水中，分别于5、15、30、45、60min取样5mL，用0.45um微孔滤膜过滤，取续滤液进样分析。并即时补加同体积、同温度的溶出介质。精密吸取不同时间段的溶出介质滤液20uL注入高效液相色谱仪分析测定，记录峰面积。另取等量地奥司明原料，同法检测并记录。
实施例2-6
采用与实例1相同的制备方法和检测方法，保持氯化胆碱用量(5g)不变，改变低聚甘油的聚合度和用量，记录各个时刻地奥司明的峰面积。
根据峰面积，利用外标法计算实施例1-6溶出介质中的药物含量，算出各个时间段地奥司明的累积溶出率，所得结果见表1。
表1各个时间段地奥司明的累积溶出率
经X射线衍射法扫描检测可知，原料药地奥司明经扫描后出现明显的特征峰，而微球经扫描没有特征峰，说明微球中的地奥司明以无定形的形态分散其中，该分散形态有助于提高药物的溶出度。
根据表1可知，实例1-6中载药高分子微球的在各个时间段的溶出度相较于地奥司明原料都有提高，且实例1、3、4效果更佳，60min的累积溶出度高达87％，相比同时间段地奥司明原料药的溶出度显著提升，说明用低共熔溶剂溶解地奥司明可显著提升其溶出度，且地奥司明的溶出度与氢键供体的聚合度、氢键受体和供体的摩尔比密切相关。
按照实施例1所述方法，制备含有芦丁和水飞蓟素的载药高分子微球，参照2015版《中国药典》四部通则0931“溶出度与测定度释放法”规定中的第二法(桨法)，检测二者在各个时间段的溶出度，并与原料药进行对比，结果证明用低共熔溶剂溶解的芦丁和水飞蓟素在各个时间段的溶出度均显著增加，且氢键受体与供体摩尔比为1∶1时效果更佳，说明低共熔溶剂溶解难溶性黄酮类化合物能显著提升该类药物的溶出度、增加其药效。
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (4)
1.一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法，其特征在于，所述方法步骤为：
S1：将氢键受体氯化胆碱或甜菜碱与氢键供体低聚甘油按照一定比例混合，混合物置于90-100℃的恒温水浴锅中边加热边搅拌2-3小时，直至反应体系变为无色透明液体，冷却至室温即得低共熔溶剂；
S2：向该低共熔溶剂中加入难溶性黄酮类化合物，50-60℃搅拌均匀后，用一定量纤维素进行吸附，经捏合，即得载药高分子微球；
其中，所述难溶性黄酮类化合物为芦丁、水飞蓟素或地奥司明。
2.根据权利要求1所述利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法，其特征在于，所述氢键供体与氢键受体的摩尔比范围为1-5。
3.根据权利要求1所述利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法，其特征在于，所述纤维素的添加量为氢键供体与氢键受体总量的2-3倍，纤维素具体选自棉纤维、竹纤维或棕榈纤维。
4.根据权利要求1所述利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法，其特征在于，所述低聚甘油聚合度范围为2-20。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811092142.XA CN109381433B (zh) | 2018-09-18 | 2018-09-18 | 一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811092142.XA CN109381433B (zh) | 2018-09-18 | 2018-09-18 | 一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109381433A CN109381433A (zh) | 2019-02-26 |
| CN109381433B true CN109381433B (zh) | 2021-05-14 |
Family
ID=65418825
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811092142.XA Active CN109381433B (zh) | 2018-09-18 | 2018-09-18 | 一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109381433B (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111569466B (zh) * | 2020-05-09 | 2022-06-14 | 浙江工业大学 | 一种中草药提取液中单宁酸的去除方法 |
| CN113907355B (zh) * | 2021-10-19 | 2023-04-21 | 江西省华宝芯荟科技有限公司 | 一种水相结晶型油包水乳液及其制备方法 |
| CN114432274B (zh) * | 2022-01-11 | 2024-02-23 | 季华实验室 | 一种载药促渗一体化经皮药物传递系统基质的制备方法及应用 |
| CN115745897B (zh) * | 2022-11-09 | 2024-03-22 | 武汉科技大学 | 一种氯氮平重结晶方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016135385A1 (en) * | 2015-02-27 | 2016-09-01 | Teknologian Tutkimuskeskus Vtt Oy | Process for producing shaped articles based on cellulose |
| CN108497497A (zh) * | 2018-04-23 | 2018-09-07 | 广东省农业科学院蚕业与农产品加工研究所 | 桑叶活性物质的提取和保存方法 |
-
2018
- 2018-09-18 CN CN201811092142.XA patent/CN109381433B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016135385A1 (en) * | 2015-02-27 | 2016-09-01 | Teknologian Tutkimuskeskus Vtt Oy | Process for producing shaped articles based on cellulose |
| CN108497497A (zh) * | 2018-04-23 | 2018-09-07 | 广东省农业科学院蚕业与农产品加工研究所 | 桑叶活性物质的提取和保存方法 |
Non-Patent Citations (1)
| Title |
|---|
| "Green and efficient extraction of rutin from tartary buckwheat hull by using natural deep eutectic solvents";Huang Y.，et al.;《Food Chemistry》;20161103;第221卷;第1401页左栏第20-26,39-42行、表1，第1402页左栏第22-25行、表2，摘要 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109381433A (zh) | 2019-02-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109381433B (zh) | 一种利用低共熔溶剂制备负载难溶黄酮类药物的高分子微球的方法 | |
| CN104829572B (zh) | 达格列净新晶型及其制备方法 | |
| CN103012430B (zh) | 美洛西林钠化合物及其药物组合物 | |
| CN102827293A (zh) | 一种炔基羟丙基纤维素及其温敏性水凝胶的制备方法与应用 | |
| CN105542185A (zh) | 一种制备聚乙烯醇-聚己内酯-聚对二氧环己酮双接枝共聚物胶束的方法 | |
| CN110183338B (zh) | 一种硫脲甜菜碱共晶及其制备方法与应用 | |
| CN110575439A (zh) | 高分子/低共熔物乳液的构建方法及在黄酮类药物增溶中的应用 | |
| CN111217372B (zh) | 手性介孔核-壳结构二氧化硅纳米粒及其制备方法和应用 | |
| CN103145735B (zh) | 一种注射用盐酸头孢甲肟化合物及其药物组合物 | |
| CN104688678A (zh) | 一种甘精胰岛素注射液的制备方法及其制备的甘精胰岛素注射液 | |
| CN108586332B (zh) | 一种异烟肼与柚皮素的共晶及其制备方法 | |
| CN102499922B (zh) | 一种注射用盐酸头孢甲肟组合物及其制剂 | |
| CN110305131A (zh) | 利格列汀新晶型及其制备方法 | |
| CN103509001B (zh) | 一种埃索美拉唑镁三水合物及其制备方法 | |
| CN102144984A (zh) | 一种易于溶出的拉米夫定片及其制备方法 | |
| Choi et al. | A glucose-triggered solubilizable polymer gel matrix for an insulin delivery system | |
| CN102451168B (zh) | 一种柚皮素片制备方法 | |
| CN108250381A (zh) | 含硒酚醛树脂微球的制备方法及其应用 | |
| CN105542186A (zh) | 一种制备聚乙烯醇-聚己内酯-聚肽双接枝共聚物胶束的方法 | |
| CN103239411B (zh) | 一种头孢地尼及枸橼酸和枸橼酸钠干混悬剂组合物 | |
| CN106727385A (zh) | 一种新的阿莫西林片 | |
| CN108570045A (zh) | 氢溴酸山莨菪碱的晶型、其制备方法、药物组合物 | |
| CN102641302A (zh) | 一种提高中药提取物浸膏粉软化点的方法 | |
| CN106822026A (zh) | 一种新的阿莫西林胶囊 | |
| CN114315797B (zh) | 一种高晶型纯度艾司奥美拉唑镁二水合物晶体的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |