CN113509438A - 一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 - Google Patents
一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 Download PDFInfo
- Publication number
- CN113509438A CN113509438A CN202110467569.9A CN202110467569A CN113509438A CN 113509438 A CN113509438 A CN 113509438A CN 202110467569 A CN202110467569 A CN 202110467569A CN 113509438 A CN113509438 A CN 113509438A
- Authority
- CN
- China
- Prior art keywords
- parts
- emulsion
- water
- saffron
- oil
- 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.)
- Pending
Links
- 239000000839 emulsion Substances 0.000 title claims abstract description 123
- 244000124209 Crocus sativus Species 0.000 title claims abstract description 71
- 235000015655 Crocus sativus Nutrition 0.000 title claims abstract description 71
- 235000013974 saffron Nutrition 0.000 title claims abstract description 69
- 239000004248 saffron Substances 0.000 title claims abstract description 69
- 239000000203 mixture Substances 0.000 title claims abstract description 26
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 title claims abstract description 23
- 206010022437 insomnia Diseases 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 112
- 235000019198 oils Nutrition 0.000 claims abstract description 83
- 239000003814 drug Substances 0.000 claims abstract description 31
- 241000222336 Ganoderma Species 0.000 claims abstract description 17
- 240000008866 Ziziphus nummularia Species 0.000 claims abstract description 15
- 239000000796 flavoring agent Substances 0.000 claims abstract description 15
- 244000303040 Glycyrrhiza glabra Species 0.000 claims abstract description 13
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 claims abstract description 13
- 244000197580 Poria cocos Species 0.000 claims abstract description 13
- 235000008599 Poria cocos Nutrition 0.000 claims abstract description 13
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 12
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 12
- 235000011477 liquorice Nutrition 0.000 claims abstract description 12
- 239000000284 extract Substances 0.000 claims abstract description 9
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 9
- 239000003765 sweetening agent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 7
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 5
- 239000012071 phase Substances 0.000 claims description 137
- 238000000034 method Methods 0.000 claims description 31
- 239000000706 filtrate Substances 0.000 claims description 28
- 239000007788 liquid Substances 0.000 claims description 27
- 239000000890 drug combination Substances 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 18
- 230000002572 peristaltic effect Effects 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 12
- 239000008346 aqueous phase Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 235000012907 honey Nutrition 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 235000019634 flavors Nutrition 0.000 claims description 8
- 210000003022 colostrum Anatomy 0.000 claims description 7
- 235000021277 colostrum Nutrition 0.000 claims description 7
- 210000000582 semen Anatomy 0.000 claims description 7
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 6
- 240000008790 Musa x paradisiaca Species 0.000 claims description 6
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 6
- 235000001188 Peltandra virginica Nutrition 0.000 claims description 6
- 241001619461 Poria <basidiomycete fungus> Species 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- 238000000265 homogenisation Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 235000013336 milk Nutrition 0.000 claims description 5
- 239000008267 milk Substances 0.000 claims description 5
- 210000004080 milk Anatomy 0.000 claims description 5
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 4
- 239000007764 o/w emulsion Substances 0.000 claims description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 238000007873 sieving Methods 0.000 claims description 3
- 238000000194 supercritical-fluid extraction Methods 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 239000001116 FEMA 4028 Substances 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 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 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 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 claims description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 2
- 229960004853 betadex Drugs 0.000 claims description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- 229940083466 soybean lecithin Drugs 0.000 claims description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 claims 1
- 239000007968 orange flavor Substances 0.000 claims 1
- 239000003921 oil Substances 0.000 abstract description 65
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- 230000007547 defect Effects 0.000 abstract description 4
- 239000000341 volatile oil Substances 0.000 abstract description 3
- 230000009977 dual effect Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 34
- 238000012360 testing method Methods 0.000 description 15
- AEDDIBAIWPIIBD-ZJKJAXBQSA-N mangiferin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(OC=2C(=CC(O)=C(O)C=2)C2=O)C2=C1O AEDDIBAIWPIIBD-ZJKJAXBQSA-N 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 238000011068 loading method Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 210000000056 organ Anatomy 0.000 description 10
- 230000037396 body weight Effects 0.000 description 9
- 238000004945 emulsification Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 230000007958 sleep Effects 0.000 description 9
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- YWQSXCGKJDUYTL-UHFFFAOYSA-N Mangiferin Natural products CC(CCC=C(C)C)C1CC(C)C2C3CCC4C(C)(C)CCCC45CC35CCC12C YWQSXCGKJDUYTL-UHFFFAOYSA-N 0.000 description 7
- 150000004676 glycans Chemical class 0.000 description 7
- 210000002216 heart Anatomy 0.000 description 7
- 229940043357 mangiferin Drugs 0.000 description 7
- 229920001282 polysaccharide Polymers 0.000 description 7
- 239000005017 polysaccharide Substances 0.000 description 7
- 239000002131 composite material Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000032798 delamination Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000004622 sleep time Effects 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 244000111489 Gardenia augusta Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 4
- 238000011047 acute toxicity test Methods 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 229960001412 pentobarbital Drugs 0.000 description 4
- 229960002275 pentobarbital sodium Drugs 0.000 description 4
- 230000004620 sleep latency Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229940126680 traditional chinese medicines Drugs 0.000 description 4
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 235000018958 Gardenia augusta Nutrition 0.000 description 3
- 229960000796 barbital sodium Drugs 0.000 description 3
- FTOAOBMCPZCFFF-UHFFFAOYSA-N barbitone sodium Natural products CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 3
- 229940125717 barbiturate Drugs 0.000 description 3
- 235000009508 confectionery Nutrition 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- RGHFKWPGWBFQLN-UHFFFAOYSA-M sodium;5,5-diethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC1(CC)C([O-])=NC(=O)NC1=O RGHFKWPGWBFQLN-UHFFFAOYSA-M 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 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 description 2
- 206010033557 Palpitations Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000031971 Yin Deficiency Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000008216 herbs Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006996 mental state Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 235000020926 24-h fasting Nutrition 0.000 description 1
- 241000605445 Anemarrhena asphodeloides Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- SEBIKDIMAPSUBY-ARYZWOCPSA-N Crocin Chemical group C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)OC(=O)C(C)=CC=CC(C)=C\C=C\C=C(/C)\C=C\C=C(C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1)O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SEBIKDIMAPSUBY-ARYZWOCPSA-N 0.000 description 1
- SEBIKDIMAPSUBY-JAUCNNNOSA-N Crocin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)OC1OC(COC2OC(CO)C(O)C(O)C2O)C(O)C(O)C1O)C=CC=C(/C)C(=O)OC3OC(COC4OC(CO)C(O)C(O)C4O)C(O)C(O)C3O SEBIKDIMAPSUBY-JAUCNNNOSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010013954 Dysphoria Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 240000008397 Ganoderma lucidum Species 0.000 description 1
- 235000001637 Ganoderma lucidum Nutrition 0.000 description 1
- 235000017443 Hedysarum boreale Nutrition 0.000 description 1
- 235000007858 Hedysarum occidentale Nutrition 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 241000112528 Ligusticum striatum Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 241001107098 Rubiaceae Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000001914 calming effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 235000021316 daily nutritional intake Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 235000020828 fasting Nutrition 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 239000001947 glycyrrhiza glabra rhizome/root Substances 0.000 description 1
- 238000010262 high-speed countercurrent chromatography Methods 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000009396 suanzaoren Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8964—Anemarrhena
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
- A61K36/074—Ganoderma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
- A61K36/076—Poria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/484—Glycyrrhiza (licorice)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
- A61K36/725—Ziziphus, e.g. jujube
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Botany (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dispersion Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种用于治疗失眠的西红花药物组合乳剂及应用,所述乳剂由如下质量配比的原料制成:油相0.5‑2份,水相8.5‑10份,乳化剂0.1‑5.0份,矫味剂0.01‑5份、甜味剂0.1‑10份、食用香精0.1‑1.5份;所述油相为酸枣仁油;所述水相为知母4‑8份、茯苓4‑8份、甘草2‑4份、灵芝1‑4份、西红花0.1‑1份的水提物;本发明以酸枣仁油和中药复方提取液分别替代乳剂中必不可少的油相和水相,实现药辅两用,既减少了辅料的用量,节约了成本,又增加了乳剂的载药量,突破乳剂载药量低的缺陷,减少了用药剂量,增加了患者的顺应性。
Description
(一)技术领域
本发明涉及一种治疗失眠的中药制剂组合物及制备方法,具体涉及一种治疗失眠的口服中药乳剂及其制备方法与应用。
(二)背景技术
目前,失眠症是当前发病率最高的几个病症之一。失眠已经成为临床上的常见病,多发病,其发病趋势已逐渐趋向年轻化,并影响人们的日常生活和工作,严重者会诱发抑郁等精神疾患,对于失眠的治疗已经成为了人们关注和重视的问题,当前的治疗多以苯二氮卓等镇定类药物为主,起效快,但不良反应较大,长时间使用会让患者产生依赖性、成瘾性和其他不良反应。应用中医药对失眠进行治疗是当下的发展趋势,也是治疗失眠的根本所在。中医学对失眠早有记载,在《难经》中首次记载“不寐”的病名,关于对失眠的辨证论治,历代医家持有不同的观点,但大多人认为失眠与心、肝、脾、肺、肾的气血阴阳失调密切相关。
中药的有效成分分为脂溶性成分和水溶性成分,油脂属于脂溶性有效成分,油脂主要存在于种子类中药中,如酸枣仁,具有除烦安眠,补中益气等功效。目前对种子类中药中的油脂,有两种处理方式,一是用水提取种子类中药中水溶性成分,而油脂还存在于种子类药物的药渣中,二是用压榨法压取油脂或用极性小的溶剂提取,但油脂与水溶性有效成分不能互溶,而出现油水分层,不符合均一制剂的要求。此外,乳剂制备过程中易出现分散相液滴上浮或下沉的现象,导致药物制剂稳定性差。将油脂性成分和水溶性成分制备成乳剂是实现油水互溶的关键技术,但是目前乳剂,尤其是中药复方乳剂普遍出现载药量低、乳化剂用量高、乳剂稳定性差等缺点,限制了乳剂在中药复方中的应用。
在乳剂的制备中,常规的搅拌和乳化形成的乳滴较大,乳滴容易聚集,乳剂稳定性差。高速逆流一直被用于液-液分配色谱分离技术中,其原理为利用两相溶剂体系在高速旋转的螺旋管内建立起一种特殊的单向性流体动力学平衡,当其中一相作为固定相,另一相作为流动相,在连续逆向流动的过程中能实现分配。在运用的过程中,两相溶剂的性质非常重要,如果一项为油相,一项为水相,则容易乳化,是高速逆流方法运用的主要难题之一。
(三)发明内容
本发明目的是提供一种用于治疗失眠的西红花药物组合乳剂及其制备与应用,西红花药物组合乳剂粒径均匀、载药量高、稳定性好;本发明药物与辅料的配比,以药效成分酸枣仁油替代乳剂中必不可少的油相辅料,以中药复方水提物作为水相,药辅两用,显著增加了西红花药物组合乳剂的载药量。本发明还将高速逆流工艺进行改进,将油相和乳化剂从逆流罐一端高速射入,水相从逆流罐相对的另一端高速射入,在逆流罐中经高压匀质,此过程可形成内循环,反复射入和匀质,通过控制逆流速度、逆流压力和逆流时间,实现油水两相的充分乳化,最终形成均一的稳定乳剂,所得乳剂的乳滴小且均匀,不易聚集,乳剂稳定性好。
本发明采用的技术方案是:
本发明提供一种用于治疗失眠的西红花药物组合乳剂,所述乳剂由如下质量配比的原料制成:油相0.5-2份,水相8.5-10份,乳化剂0.1-5.0份,矫味剂0.01-5份、甜味剂0.1-10份、食用香精0.1-1.5份;所述油相为酸枣仁油;所述水相为知母4-8份、茯苓4-8份、甘草2-4份、灵芝1-4份和西红花0.1-1份的水提物;所述乳化剂为伯洛沙姆188、吐温80、大豆磷脂或水溶性单甘酯中的一种或几种;所述甜味剂为阿斯巴甜、甜蜜素或蜂蜜中的一种或几种;所述矫味剂为羧甲基纤维素钠或β-环糊精中的一种或两种。所述食用香精为香蕉香精、橙子香精或奶香香精中的一种。
进一步,所述水相按如下方法制备:按配方量,将知母、茯苓、甘草、灵芝和西红花混合,先用6-10倍量水回流1-3小时(优选8倍量水回流2小时),一次过滤,得一次滤液和一次滤渣;一次滤渣再用5-8倍量水回流1-3小时(优选6倍量水回流1.5小时),二次过滤,得二次滤液和二次滤渣,合并一次滤液和二次滤液,60℃旋蒸至原体积的10-15%(优选12%),即为水相。
进一步,所述酸枣仁油按如下方法制备:将酸枣仁粉碎过40目筛,然后加入超临界流体萃取仪的反应釜中进行超临界CO2流体萃取,以二氧化碳作为萃取流体,萃取时间为80-120min,萃取压力为20-40MPa,萃取温度为30℃-50℃,得酸枣仁油。优选萃取条件为:萃取时间为100min,萃取压力为30MPa,萃取温度为45℃。
进一步,优选所述西红花药物组合乳剂由如下质量配比的原料制成:油相0.5-1份,水相8.5-9.5份,乳化剂0.1-2.0份,矫味剂0.01-2份、甜味剂1-5份、食用香精0.1-1.5份;所述水相为知母5-8份、茯苓5-8份、甘草3-4份、灵芝2-4份、西红花0.1-0.5份的水提物。
更进一步,优选所述西红花药物组合乳剂由如下质量配比的原料制成:油相0.8份,水相9.1份,水溶性单甘酯0.1份,羧甲基纤维素钠0.02份、蜂蜜1份、香蕉香精0.5份;所述水相为知母6份、茯苓6份、甘草3份、灵芝3份、西红花0.1份的水提物。
本发明还提供一种所述西红花药物组合乳剂的制备方法,所述方法包括:(1)按配方量,将知母、茯苓、甘草、灵芝和西红花混合,先用6-10倍量水回流1-3小时(优选8倍量水回流2小时),一次过滤,得一次滤液和一次滤渣;一次滤渣再用5-8倍量水回流1-3小时(优选6倍量水回流1.5小时),二次过滤,得二次滤液和二次滤渣,合并一次滤液和二次滤液,60℃旋蒸至原体积10-15%(优选12%),即为水相;(2)采用高速逆流装置,所述高速逆流装置由密封逆流灌6、油相转轮3、水相转轮4、油相流量阀7、水相流量阀8、初乳流量阀9组成;所述油相转轮3和水相转轮4置于密封逆流罐6内并设有逆流间隙5;所述密封逆流罐6一端设有油相进液口1,另一端设有水相进液口2,侧面设有初乳液出口;所述油相进液口1处设有与蠕动泵驱动器(型号:BT300-2J)连接的油相流量阀7,所述水相进液口2处设有与蠕动泵驱动器(型号:BT300-2J)连接的水相流量阀8,所述初乳液出口处设有初乳液流量阀9,所述油相流量阀7、水相流量阀8和初乳液流量阀9通过管路连通;将油相与乳化剂由外接蠕动泵驱动器(型号:BT300-2J)经橡胶管从油相进液口射入,同时水相由另一相同外接蠕动泵驱动器(型号:BT300-2J)经橡胶管摄入从水相进液口高速射入,在油相转轮和水相转轮的带动下反方向运转,经高压匀质,此过程可形成内循环,反复射入和匀质,最终形成均一的稳定水包油型乳剂;将水包油型乳剂与甜味剂和矫味剂均匀混合,添加食用香精制成不同风味的乳剂,即得西红花药物组合乳剂。
所述油相转轮3和水相转轮4均为可控速转轮,速度范围是0-4000rpm,油相和水相射入的速度均为300-500ml/min,所述油相转轮3和水相转轮4运转方向相反,油相转轮3逆时针运转,水相转轮4顺时针运转。所述高压匀质条件为转速500-2000rpm、压力5-20MPa、时间为10-80min。
本发明还提供一种所述西红花药物组合乳剂在制备治疗失眠药物中的应用,本西红花药物组合乳剂在使用剂量范围内安全有效,成年人(60kg)日用量为不超过10-15g。
酸枣仁汤主治肝阴虚,肝郁化火型失眠,加入西红花可以治疗阴虚火旺型失眠。酸枣仁有效成分是皂苷类和黄酮类,是非常重要的养血安神的药物,其性味甘、平、酸,入心、肝经,具有养心益肝,安神,敛汗之功效。临床可用于心肝血虚引起的失眠多梦,惊悸怔忡。甘草味甘甜,性平和,入心、脾、肺、胃四经。生用偏凉,可泻火解毒、缓急止痛;炙用偏温,能散表寒、补中益气。此外,甘草还善于调和药性,解百药之毒。茯苓性甘、淡、平。入心、脾、肺、肾经。渗湿利水,健脾和胃,宁心安神。知母味苦,入肺、胃、肾经。滋阴降火,润燥滑肠。治烦热消渴,骨蒸劳热,肺热咳嗽,大便燥结,小便不利。西红花具有解郁安神、疏肝理气的功效,有效成分是西红花苷。灵芝对于增强人体免疫力,调节血糖,控制血压,辅助肿瘤放化疗,保肝护肝,促进睡眠等方面均具有显著疗效。栀子是茜草科植物栀子的果实。栀子的果实是传统中药,属卫生部颁布的第l批药食两用资源,具有护肝、利胆、降压、镇静、止血、消肿等作用。
与传统工艺相比,本发明具有以下突出的有益效果:
1、本发明制备的西红花药物组合乳剂是一种O/W型分散体,外观为乳黄色液体;制成口服乳剂,便于现代人携带使用。
2、本发明以酸枣仁油和中药复方提取液分别替代乳剂中必不可少的油相和水相,实现药辅两用,既减少了辅料的用量,节约了成本,又增加了乳剂的载药量,突破乳剂载药量低的缺陷,减少了用药剂量,增加了患者的顺应性。
3、本发明针对高速逆流色谱两相溶剂易发生乳化的缺点,首次将高速逆流技术应用于乳剂的制备,采用高速逆流装置,实现油水两相反复多次逆流匀质,通过控制逆流速度、逆流压力、逆流时间,保证所制备的乳剂乳滴小且均匀,乳剂的稳定性好,不易聚集。
4、本发明低温稳定性好,离心稳定性好,载药量高且安全有效。
(四)附图说明
图1高速逆流装置。
图2西红花药物组合乳剂外观图。
图3西红花药物组合乳剂紫外吸收曲线。
图4西红花药物组合乳剂高效液相色谱图。
图5芒果苷标准曲线。
图6西红花药物组合乳剂粒径测定图。
图7西红花药物组合乳剂日均采食量曲线。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
参照图1,本发明采用的高速逆流装置由密封逆流灌6、油相转轮3、水相转轮4、油相流量阀7、水相流量阀8、初乳流量阀9组成;所述油相转轮3和水相转轮4置于密封逆流罐6内并设有逆流间隙5;所述密封逆流罐6一端设有油相进液口1,另一端设有水相进液口2,侧面设有初乳液出口;所述油相进液口1处设有与蠕动泵驱动器(型号:BT300-2J)连接的油相流量阀7,所述水相进液口2处设有与蠕动泵驱动器(型号:BT300-2J)连接的水相流量阀8,所述初乳液出口处设有初乳液流量阀9,所述油相流量阀7、水相流量阀8和初乳液流量阀9通过管路连通。所述油相转轮3和水相转轮4均为可控速转轮,速断范围是0-4000rpm,所述油相转轮3和水相转轮4运转方向相反,油相转轮3逆时针运转,水相转轮4顺时针运转。
油相和乳化剂由外接蠕动泵驱动器(型号:BT300-2J)经橡胶管射入油相进液口1,同时水相由另一相同外接蠕动泵驱动器(型号:BT300-2J)经橡胶管射入水相进液口2,分别在油相转轮和水相转轮的带动下量进行逆流乳化,初乳由初乳流量阀9放出,再分别经油相流量阀7、水相流量阀8进入密封逆流罐6,高速逆流一段时间后由初乳流量阀放出,即得水包油型乳剂。
实施例1
1、质量配方:酸枣仁油0.8份、知母6.0份、茯苓6.0份、甘草3.0份、灵芝3.0份、西红花0.1份、水溶性单甘酯0.1份、蜂蜜1份、羧甲基纤维素钠0.02份,香蕉香精0.5份。
2、制备方法:
(1)油相:将50g酸枣仁粉碎过40目筛至粉末粒度为0.32mm,然后加入超临界流体萃取仪(型号:ASI spe-ed SFE-2)的反应釜中进行超临界CO2流体萃取,以二氧化碳作为萃取流体,萃取时间为100min,萃取压力为30MPa,萃取温度为45℃,得酸枣仁油15g,作为油相。
(2)水相:按配方量,将知母6.0g、茯苓6.0g、甘草3.0g、灵芝3.0g、栀子3.0g、西红花0.1g混合,先用8倍量水回流2小时,一次过滤,得一次滤液和一次滤渣;一次滤渣再用6倍量水回流1.5小时,二次过滤,得二次滤液和二次滤渣,合并一次滤液和二次滤液,60℃旋蒸至30ml,得水相27.885g。
(3)乳剂:采用图1所示高速逆流装置进行逆流乳化,取0.8g酸枣仁油与0.1g水溶性单甘酯混合经橡胶管由蠕动泵驱动器从油相进液口1以400ml/min的流量射入,9.1g水相经橡胶管由蠕动泵驱动器从水相进液口2以400ml/min的流量射入,后开启转轮,设定油相转轮和水相转轮的速度均为1000rpm,压力为10MPa,时间为30min,乳化结束后,获得水包油型乳剂;将全部水包油型乳剂中加入1g蜂蜜,0.02g羧甲基纤维素钠,充分混合,搅拌均匀,加入0.5g香蕉香精,即得香蕉口味西红花药物组合乳剂11.52g,西红花药物组合乳剂外观为乳黄色均匀液体(图2)。
3、性能测试
离心稳定性研究:将步骤2制备的西红花药物组合乳剂进行离心处理(低速离心TD5A),转速为3500r/min,所制乳剂30min未出现分层,满足药典规定的15min不得出现分层的要求,说明稳定性良好。
冻融稳定性研究:将实施例2制备的西红花药物组合乳剂进行冻融实验,放入-20℃冰箱12小时,取出溶解,反复三次,未出现分层现象,说明稳定性良好。
总多糖含量测定:采用紫外分光光度法(紫外可见分光光度计UV1800)对西红花药物组合乳剂进行总多糖含量测定,测定条件为分光光度法(中国药典2010版一部附录V),测定结果见图3。
载药量测定:采用高效液相色谱法(高效液相色谱仪Agilent 1260,色谱柱SB-C18,温度:30℃),根据表1检测西红花药物组合乳剂中芒果苷峰面积,根据芒果苷标准曲线获得西红花药物组合乳剂载药量,测定结果见图4。芒果苷标准曲线方程为见图5。
粒径测定:采用马尔文粒度仪(纳米粒度及Zeta Brookhave)对其粒径进行测定,测定条件为稳定时间30s,检测时间60s,检测范围0-100nm,测定结果见图6。
结果显示本发明所制备的乳剂D90=36.2μm,总多糖含量为6.4%,总芒果苷载药量为8.85ug/g,远远大于常规乳剂的载药量。
表1高效液相色谱法检测条件
时间(min) | 0 | 4 | 8 | 15 | 20 |
乙腈(%) | 5 | 12 | 16 | 25 | 5 |
0.1%磷酸(%) | 95 | 88 | 84 | 75 | 95 |
实施例2
1、配方:酸枣仁油0.9份、知母6.5份、茯苓6.5份、甘草3.4份、灵芝3.4份、西红花0.1份、大豆磷脂0.1份、蜂蜜1份、羧甲基纤维素钠0.02份、橙子香精0.4份。
2、制备方法
(1)酸枣仁油制备同实施例1。
(2)水相:按配方量,将知母6.5g、茯苓6.5g、甘草3.4g、灵芝3.4g、西红花0.1g,先用8倍量水回流1小时,一次过滤,得一次滤液和一次滤饼,一次滤饼再用6倍量水回流1.5小时,二次过滤,获得二次滤液和二次滤饼,合并一次滤液和二次滤液,60℃旋蒸至30ml,得水相27.885g。
(3)乳剂:采用实施例1高速逆流装置进行逆流乳化,将0.9g酸枣仁油与0.1g大豆磷脂混合经橡胶管由蠕动泵驱动器从油相进液口1以300ml/min的流量射入,9.0g水相经橡胶管由另一个蠕动泵驱动器从水相进液口2以300ml/min的流量射入,设定油相转轮和水相转轮的速度均为800rpm,逆流压力为15MPa,逆流时间为20min,乳化结束,获得水包油型乳剂;将全部水包油型乳剂中加入1g蜂蜜,0.02g羧甲基纤维素钠,充分混合,搅拌均匀,加入0.4g橙子香精,即得橙子口味西红花药物组合乳剂11.42g。
3、性能检测
离心稳定性研究:采用实施实例1方法检测所制乳剂30min未出现分层,满足药典规定的15min不得出现分层的要求,说明稳定性良好。
冻融稳定性研究:采用实施实例1方法将制备的西红花药物组合乳剂进行冻融实验,未出现分层现象,说明稳定性良好。
总多糖含量、载药量、粒径检测方法同实施实例1。本发明所制备的乳剂D90=38.2μm,总多糖含量为7.3%,总芒果苷载药量为7.73ug/g,远远大于常规乳剂的载药量。
实施例3
1、配方:酸枣仁油1.0份、知母6.8份、茯苓6.8份、甘草3.4份、灵芝3.4份、西红花0.1份、伯洛沙姆0.1份、蜂蜜1份、羧甲基纤维素钠0.02份、奶香香精0.5份。
2、制备方法:
(1)油相制备同实施例1。
(2)水相:按配方量,将知母6.8g、茯苓6.8g、甘草3.4g、灵芝3.4g、西红花0.1g,先用8倍量水回流1.5小时,一次过滤,得一次滤液和一次滤饼,一次滤饼再用6倍量水回流1.5小时,二次过滤,得二次滤液和二次滤饼,合并一次滤液和二次滤液,60℃旋蒸至30ml,得水相27.885g。
(3)乳剂:采用实施例1高速逆流装置进行逆流乳化,将1.0g酸枣仁油与0.1g伯洛沙姆188混合经橡胶管由蠕动泵驱动器从从油相进液口1以500ml/min的流量射入,8.9g水相经橡胶管由另一个蠕动泵驱动器从水相进液口2以500ml/min的流量射入,设定油相转轮和水相转轮的速度均为1500rpm,压力为10MPa,时间为60min,乳化结束后,获得水包油型乳剂;将全部水包油型乳剂加入1g蜂蜜,0.02g羧甲基纤维素钠,充分混合,搅拌均匀,再加入1滴(0.5g)奶香香精,即得奶香口味西红花药物组合乳剂11.52g。
3、性能检测
离心稳定性研究:采用实施实例1方法检测所制乳剂30min未出现分层,满足药典规定的15min不得出现分层的要求,说明稳定性良好。
冻融稳定性研究:采用实施实例1方法将制备的西红花药物组合乳剂进行冻融实验,未出现分层现象,说明稳定性良好。
总多糖含量、载药量、粒径检测方法同实施实例1。本发明所制备的乳剂D90=41.24μm,总多糖含量为7.2%,总芒果苷载药量为8.03ug/g,远远大于常规乳剂的载药量。
实施例4、西红花药物组合物乳剂与酸枣仁汤的药效学比较研究。
1实验动物:BALB/c 4周龄雄性SPF级小鼠70只,体重18-22g,根据体重随机分为7组,组间体重经t检验无显著差异(P>0.05)
实验药物:西红花药物组合乳剂为实施例1方法制备。酸枣仁汤为炒酸枣仁15g,甘草3g,知母6g,茯苓6g,川芎6g,加入800mL水,煎煮2h至一半倍体积,取煎煮液,即得。
2实验方法:
2.1给药方法
将实验动物70只小鼠按体质量排序,按随机数字表法随机分为7组:空白对照组、酸枣仁汤低、中、高剂量组(即1-S低、1-S中、1-S高剂量组)以及西红花药物组合乳剂低、中、高剂量组(即1-X低、1-X中、1-X高剂量组),每组10只小鼠。根据人和动物按体表面积折算的等效剂量比值折算,酸枣仁汤及上述实施例1西红花药物组合乳剂配置成低、中、高剂量组分别为0.23g/ml、1.16g/ml、2.31g/ml,按0.2ml/10g·BW体积给小鼠灌胃,每天1次,连续30天。空白对照组灌胃予以等体积的蒸馏水。
2.2测定方法
2.2.1延长戊巴比妥钠诱导的小鼠睡眠时间试验。于末次给药后15min,给各组小鼠腹腔注射45mg/kg体重戊巴比妥钠,注射量为0.1ml/10g体重。以小鼠翻正反射消失为睡眠指标,观察受试物能否延长巴比妥钠诱导的睡眠时间。试验在夜间进行。
2.2.2阈下剂量戊巴比妥钠睡眠发生率试验。于末次给药后15min,给各组小鼠腹腔注射30mg/kg体重戊巴比妥钠,注射量为0.1ml/10g体重。以小鼠翻正反射消失达1min以上者为入睡标准,记录30min内入睡动物数。试验在夜间进行。观察受试物能否提高戊巴比妥钠阈下睡眠发生率。
2.2.3巴比妥钠睡眠潜伏期试验。于末次给药后15min,给各组动物腹腔注射300mg/kg体重巴比妥钠,注射量为0.1ml/10g体重。以小鼠翻正反射消失为睡眠指标,观察受试物对巴比妥钠睡眠潜伏期的影响。
表2酸枣仁汤和西红花药物组合乳剂的保健功能评价
注:与正常对照组比较,*P<0.05,**P<0.01。“1-S低剂量组”中“S”指酸枣仁汤;“1-X低剂量组”中“X”指西红花药物组合乳剂。
由表2可知,酸枣仁汤和西红花药物组合乳剂均能显著延长戊巴比妥钠诱导的睡眠时间,提高戊巴比妥钠诱导的睡眠发生率以及缩短巴比妥钠诱导的睡眠潜伏期且除低剂量的酸枣仁汤对睡眠时间的影响显著(P<0.05)外,其他剂量下的酸仁汤和西红花药物组合乳剂对睡眠的影响均表现出极显著差异(P<0.01)。其中低剂量的西红花药物组合乳剂对戊巴比妥钠诱导的睡眠时间和睡眠潜伏期的协同作用最强;中剂量的西红花药物组合乳剂对睡眠发生率影响最大。同等剂量的酸枣仁汤和西红花药物组合乳剂对巴比妥类的协同作用表现出一致性,但从数据的平均值来看,西红花药物组合乳剂的效果比原汤剂好,实施实例2和3具有同样效果。可推测,西红花药物组合乳剂经过除杂等一系列工艺后,比原汤剂更容易吸收,药效更好。
实施例5、西红花药物组合物乳剂的最大耐受量实验。
1最大耐受量的测定方法。BALB/c 4周龄雄性SPF级小鼠正常预饲养7d后,采用随机数字表法将小鼠分为对照组与耐受组,每组10只。禁食24h,耐受组小鼠分3次灌服浓度为3g/ml的实施例1方法制备的西红花药物组合乳剂(以灌胃形式灌服,以蒸馏水为溶剂配制),每次间隔8h,第一次0.2ml/10g·BW体积、第二次0.7ml/10g·BW、第三次0.9ml/10g·BW,共3次,总量为180000mg/kg;对照组小鼠在相同时间灌服相同剂量蒸馏水。观察各组小鼠行为及活动情况,连续观察14d,并称量体重。脏器指数=脏器重量/小鼠体重×100%。绘制进食量曲线。
2统计数据:试验数据采用SPSS 23.0软件进行处理,数据以“平均值±标准差”表示,组间采用方差分析进行显著性比较,P<0.01表示差异极显著,P<0.05表示差异显著,P>0.05表示差异不显著。
3最大耐受量各项指标测定结果
最大耐受量计算公式:小鼠的最大耐受量倍数=每只小鼠的耐受药量/小鼠平均体重(20g)×成人平均体重(50kg)/成人每日用量,每只小鼠的耐受药量是灌胃3次的累计给药量。成人每日用量是本乳剂的规定数值,按药典规定的知母有效成分的日用量确定,具体用量为12g/60kg/d。
小鼠日均采食量计算公式:日均采食量=(每只日粮添加量-日粮回收量)/小鼠数量,计算日均进食量并绘制曲线(见图7)。
表3最大耐受小鼠脏器指数
在最大耐受量试验中,最后一次灌胃后耐受组小鼠有炸毛现象,灌胃后采食量明显减少,24h后恢复正常;连续观察14d,各组小鼠行为活动、食欲、精神状态、粪便、尿液等均无明显差异。剖检解剖未见各脏器病变,小鼠两组间脏器指数差异不显著(P>0.05);耐受试验中每日口服剂量增加到了180000mg/kg,计算所得小鼠的最大耐受量倍数为250倍时小鼠未死亡,小鼠能耐受人用量100倍以上即认为中药组方安全,并且实施实例2和3小鼠耐受人用量同样达到100倍以上。因此可认为西红花药物组合乳剂日常服用剂量内安全无毒。
实施例6、西红花药物组合物乳剂的急性毒理性实验。
1急性毒性实验方法
BALB/c 4周龄雄性SPF级小鼠正常预饲养7d后,将40只小鼠随机分为4组,分别为低、中、高剂量组及对照组,每组10只。禁食24h后将浓度为2g/ml、2.5g/ml、3g/ml的实施例1方法制备的西红花药物组合乳剂(蒸馏水配制),按0.2ml/10g·BW体积分别给低、中、高剂量组小鼠灌胃,每天1次,连续7d,高剂量组给药量累积达到60000mg/kg,观察动物的中毒症状,采用加权法测得LD50。灌胃结束后观察14d,解剖观察各组织器官的变化,计算脏器指数(脏器重量/小鼠体重×100%)。
2统计数据
试验数据采用SPSS 23.0软件进行处理,数据以“平均值±标准差”表示,组间采用方差分析进行显著性比较,P<0.01表示差异极显著,P<0.05表示差异显著,P>0.05表示差异不显著。
3急性毒性实验各指标测定结果
3.1LD50测定
表4小鼠急性毒理性实验
4小鼠脏器指数
表5急性毒性脏器指数
实验过程首次灌胃各组小鼠均表现挣扎,肌肉震颤。灌胃后高剂组小鼠精神萎靡,喜蜷缩扎堆,约12h后各组小鼠状态恢复正常。连续观察14d,各组小鼠行为活动、食欲、精神状态、粪便、尿液等均无明显差异,并且实施实例2和3给药的小鼠与空白组也无明显差异。剖检各组小鼠心脏、肝脏、脾脏、肺脏和肾脏均未见明显病变,计算其脏器指数也无显著差异(P>0.05)。急性毒性试验主要测定半数致死量(LD50),在LD50测定试验中4组小鼠均未见死亡,未成功测得西红花药物组合乳剂的LD50,但是按照毒理学评价标准,如果LD50>10000mg/kg,则属于无毒性物质。而本试验中每日口服剂量增加到了60000mg/kg,小鼠未死亡,说明该复方中药制剂对小鼠安全无毒。
Claims (10)
1.一种用于治疗失眠的西红花药物组合乳剂,其特征在于所述乳剂由如下质量配比的原料制成:油相0.5-2份,水相8.5-10份,乳化剂0.1-5.0份,矫味剂0.01-5份、甜味剂0.1-10份、食用香精0.1-1.5份;所述油相为酸枣仁油;所述水相为知母4-8份、茯苓4-8份、甘草2-4份、灵芝1-4份、西红花0.1-1份的水提物;所述乳化剂为伯洛沙姆188、吐温80、大豆磷脂或水溶性单甘酯中的一种或几种;所述甜味剂为阿斯巴甜、甜蜜素或蜂蜜中的一种或几种;所述矫味剂为羧甲基纤维素钠或β-环糊精中的一种或两种。
2.如权利要求1所述的西红花药物组合乳剂,其特征在于所述食用香精为香蕉香精、橙子香精或奶香香精中的一种。
3.如权利要求1所述的西红花药物组合乳剂,其特征在于所述水相按如下方法制备:按配方量,将知母、茯苓、甘草、灵芝和西红花混合,先用6-10倍量水回流1-3小时,一次过滤,得一次滤液和一次滤渣;一次滤渣再用5-8倍量水回流1-3小时,二次过滤,得二次滤液和二次滤渣,合并一次滤液和二次滤液,60℃旋蒸至原体积的10-15%,即为水相。
4.如权利要求1所述的西红花药物组合乳剂,其特征在于所述酸枣仁油按如下方法制备:将酸枣仁粉碎过40目筛,然后加入超临界流体萃取仪的反应釜中进行超临界CO2流体萃取,以二氧化碳作为萃取流体,萃取时间为80-120min,萃取压力为20-40MPa,萃取温度为30℃-50℃,得酸枣仁油。
5.如权利要求1所述的西红花药物组合乳剂,其特征在于所述西红花药物组合乳剂由如下质量配比的原料制成:油相0.5-1份,水相8.5-9.5份,乳化剂0.1-2.0份,矫味剂0.01-2份、甜味剂1-5份、食用香精0.1-1.5份;所述水相为知母5-8份、茯苓5-8份、甘草3-4份、灵芝2-4份、西红花0.1-0.5份的水提物。
6.如权利要求1所述的西红花药物组合乳剂,其特征在于所述西红花药物组合乳剂由如下质量配比的原料制成:油相0.8份,水相9.1份,水溶性单甘酯0.1份,羧甲基纤维素钠0.02份、蜂蜜1份、香蕉香精0.5份;所述水相为知母6份、茯苓6份、甘草3份、灵芝3份、西红花0.1份的水提物。
7.一种权利要求1所述西红花药物组合乳剂的制备方法,其特征在于所述方法包括:(1)按配方量,将知母、茯苓、甘草、灵芝和西红花混合,先用6-10倍量水回流1-3小时,一次过滤,得一次滤液和一次滤渣;一次滤渣再用5-8倍量水回流1-3小时,二次过滤,得二次滤液和二次滤渣,合并一次滤液和二次滤液,60℃旋蒸至原体积10-15%,即为水相;(2)采用高速逆流装置,所述高速逆流装置由密封逆流灌、油相转轮、水相转轮、油相流量阀、水相流量阀、初乳流量阀组成;所述油相转轮和水相转轮置于密封逆流罐内并设有逆流间隙;所述密封逆流罐一端设有油相进液口,另一端设有水相进液口,侧面设有初乳液出口;所述油相进液口处设有与蠕动泵驱动器连接的油相流量阀,所述水相进液口处设有与蠕动泵驱动器连接的水相流量阀,所述初乳液出口处设有初乳液流量阀,所述油相流量阀、水相流量阀和初乳液流量阀通过管路连通;将油相与乳化剂由蠕动泵驱动器经橡胶管从油相进液口射入,同时水相由另一相同蠕动泵驱动器经橡胶管摄入从水相进液口射入,在油相转轮和水相转轮的带动下反方向运转,经反复射入和高压匀质,形成均一的稳定水包油型乳剂;将水包油型乳剂与甜味剂和矫味剂均匀混合,添加食用香精制成不同风味的乳剂,即得西红花药物组合乳剂。
8.如权利要求7所述的方法,其特征在于所述所述油相转轮和水相转轮速度范围均是0-4000rpm,油相和水相射入的速度均为300-500ml/min。
9.如权利要求7所述的方法,其特征在于所述高压匀质条件为转速500-2000rpm、压力5-20MPa、时间为10-80min。
10.一种权利要求1所述西红花药物组合乳剂在制备治疗失眠药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110467569.9A CN113509438A (zh) | 2021-04-28 | 2021-04-28 | 一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110467569.9A CN113509438A (zh) | 2021-04-28 | 2021-04-28 | 一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113509438A true CN113509438A (zh) | 2021-10-19 |
Family
ID=78063687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110467569.9A Pending CN113509438A (zh) | 2021-04-28 | 2021-04-28 | 一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113509438A (zh) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101229247A (zh) * | 2007-12-28 | 2008-07-30 | 重庆工学院 | 一种治疗失眠的药物制剂及其制备方法 |
WO2012027882A1 (zh) * | 2010-08-30 | 2012-03-08 | 河北以岭医药研究院有限公司 | 治疗失眠的药物组合物及其制备方法 |
CN103340407A (zh) * | 2013-07-23 | 2013-10-09 | 四川省中医药科学院 | 具有改善睡眠功效的组合物、制备方法及用途 |
CN104383461A (zh) * | 2014-12-08 | 2015-03-04 | 杨其义 | 一种治疗血瘀性失眠的中药组合物 |
CN105213548A (zh) * | 2015-11-05 | 2016-01-06 | 南京中医药大学 | 一种具有防治早老性痴呆作用的植物油组合物及其制备方法与应用 |
CN105381059A (zh) * | 2015-11-28 | 2016-03-09 | 史克勇 | 可以改善睡眠障碍的药物 |
CN107349375A (zh) * | 2017-06-01 | 2017-11-17 | 曾爱忠 | 一种中药口服微乳剂的制备方法及中药口服微乳剂 |
-
2021
- 2021-04-28 CN CN202110467569.9A patent/CN113509438A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101229247A (zh) * | 2007-12-28 | 2008-07-30 | 重庆工学院 | 一种治疗失眠的药物制剂及其制备方法 |
WO2012027882A1 (zh) * | 2010-08-30 | 2012-03-08 | 河北以岭医药研究院有限公司 | 治疗失眠的药物组合物及其制备方法 |
CN103340407A (zh) * | 2013-07-23 | 2013-10-09 | 四川省中医药科学院 | 具有改善睡眠功效的组合物、制备方法及用途 |
CN104383461A (zh) * | 2014-12-08 | 2015-03-04 | 杨其义 | 一种治疗血瘀性失眠的中药组合物 |
CN105213548A (zh) * | 2015-11-05 | 2016-01-06 | 南京中医药大学 | 一种具有防治早老性痴呆作用的植物油组合物及其制备方法与应用 |
CN105381059A (zh) * | 2015-11-28 | 2016-03-09 | 史克勇 | 可以改善睡眠障碍的药物 |
CN107349375A (zh) * | 2017-06-01 | 2017-11-17 | 曾爱忠 | 一种中药口服微乳剂的制备方法及中药口服微乳剂 |
Non-Patent Citations (4)
Title |
---|
吴正红: "《现代中药制剂设计》", 30 April 2020, 中国医药科技出版社 * |
葛洪等: "《新编临床药物学》", 31 March 2018, 吉林科学技术出版社 * |
蔡宛如: "《药食同源》", 31 August 2019, 浙江科学技术出版社 * |
黄锁义: "《天然产物的提取分离技术及其发展研究》", 31 March 2020, 吉林大学出版社 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102048933B (zh) | 一种治疗小儿腹泻的中药组合物及其制备方法 | |
US5324516A (en) | Galenic composition for decreasing blood alcohol concentration | |
CN101822704B (zh) | 一种祛斑药物组合物及其制备方法 | |
CN102198262A (zh) | 一种治疗小儿轮状病毒性肠炎的中药制剂及其制备方法 | |
CN106605915A (zh) | 一种老年润肠通便保健食品及其制备方法 | |
CN105031517A (zh) | 一种降三高的铁皮石斛保健茶及其制备方法 | |
CN108524776A (zh) | 一种治疗气阴两虚型糖尿病的药物及其制备方法 | |
CN111840394B (zh) | 一种用于失眠的药物组合物及其制备方法 | |
CN100571740C (zh) | 一种降血糖、降血脂的中药组合物及制法和应用 | |
CN113509438A (zh) | 一种用于治疗失眠的西红花药物组合乳剂及其制备与应用 | |
CN105434738A (zh) | 一种治疗小儿多动症的中药组合物及其制备方法 | |
CN104383183A (zh) | 一种治疗非酒精性脂肪肝的药物组合物 | |
CN101015655A (zh) | 小儿抗痫药物 | |
CN103007145B (zh) | 一种治疗小儿轮状病毒肠炎的中药组合物及其制备方法 | |
CN105412424A (zh) | 一种含有艾叶的润肠通便的药物制剂及其制备方法 | |
CN105727089A (zh) | 含艾叶的药物组合物用于制备治疗肠易激综合症药物中的用途 | |
CN101884700A (zh) | 一种含茶的中药组合物 | |
CN105560984B (zh) | 一种益气健脾的中药组合物 | |
CN115414439B (zh) | 一种治疗功能性便秘的中药组合物 | |
CN114432411B (zh) | 一种治疗慢性肾病蛋白尿的中药组合物及其制备方法与应用 | |
CN105920447A (zh) | 一种抗抑郁的保健品及其制备方法 | |
CN108404068B (zh) | 一种治疗和/或预防腹泻的药物组合物及其制备方法 | |
CN105381414A (zh) | 一种治疗乳房肿块及囊性增生的中药制剂及其制备方法 | |
CN104940693A (zh) | 一种降三高的铁皮石斛中药组合物及其制备方法 | |
CN104547945A (zh) | 一种治疗淋巴结核的中药制剂及其制备方法 |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211019 |