CN115089636B - 一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 - Google Patents
一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 Download PDFInfo
- Publication number
- CN115089636B CN115089636B CN202210789356.2A CN202210789356A CN115089636B CN 115089636 B CN115089636 B CN 115089636B CN 202210789356 A CN202210789356 A CN 202210789356A CN 115089636 B CN115089636 B CN 115089636B
- Authority
- CN
- China
- Prior art keywords
- parts
- traditional chinese
- chinese medicine
- stirring
- hours
- 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 103
- 239000000203 mixture Substances 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 206010020751 Hypersensitivity Diseases 0.000 title abstract description 12
- 208000026935 allergic disease Diseases 0.000 title abstract description 10
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 33
- 239000013543 active substance Substances 0.000 claims abstract description 29
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 14
- 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 abstract description 7
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 7
- 229940083466 soybean lecithin Drugs 0.000 claims abstract description 7
- 230000000172 allergic effect Effects 0.000 claims abstract description 5
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 20
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000001704 evaporation Methods 0.000 claims description 14
- 239000002502 liposome Substances 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 235000001361 Styrax officinalis Nutrition 0.000 claims description 12
- 235000019382 gum benzoic Nutrition 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 235000001405 Artemisia annua Nutrition 0.000 claims description 10
- 240000000011 Artemisia annua Species 0.000 claims description 10
- 235000004032 Centella asiatica Nutrition 0.000 claims description 10
- 244000146462 Centella asiatica Species 0.000 claims description 10
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 claims description 10
- 244000303040 Glycyrrhiza glabra Species 0.000 claims description 10
- 229920002873 Polyethylenimine Polymers 0.000 claims description 10
- 238000009210 therapy by ultrasound Methods 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 235000003261 Artemisia vulgaris Nutrition 0.000 claims description 9
- 240000006891 Artemisia vulgaris Species 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000004471 Glycine Substances 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 235000011438 Albizia odoratissima Nutrition 0.000 claims description 7
- 239000001525 mentha piperita l. herb oil Substances 0.000 claims description 7
- 235000019477 peppermint oil Nutrition 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 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 description 6
- 235000011477 liquorice Nutrition 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 238000002791 soaking Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 239000012943 hotmelt Substances 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 229940126680 traditional chinese medicines Drugs 0.000 claims description 2
- 240000000559 Albizia odoratissima Species 0.000 claims 2
- 244000303379 Styrax officinalis Species 0.000 claims 2
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 claims 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 claims 1
- 206010070834 Sensitisation Diseases 0.000 claims 1
- 229940010454 licorice Drugs 0.000 claims 1
- 229920006289 polycarbonate film Polymers 0.000 claims 1
- 230000008313 sensitization Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 28
- 230000035699 permeability Effects 0.000 abstract description 5
- 230000007815 allergy Effects 0.000 abstract description 4
- 208000030961 allergic reaction Diseases 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 24
- 238000012360 testing method Methods 0.000 description 16
- 210000003491 skin Anatomy 0.000 description 11
- 241001060310 Styracaceae Species 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 235000008216 herbs Nutrition 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000001976 improved effect Effects 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 210000000952 spleen Anatomy 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000003306 harvesting Methods 0.000 description 6
- 241000220433 Albizia Species 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 244000246386 Mentha pulegium Species 0.000 description 4
- 235000016257 Mentha pulegium Nutrition 0.000 description 4
- 235000004357 Mentha x piperita Nutrition 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 235000001050 hortel pimenta Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- -1 polydimethylsiloxane Polymers 0.000 description 4
- 235000019633 pungent taste Nutrition 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000341 volatile oil Substances 0.000 description 4
- 235000003392 Curcuma domestica Nutrition 0.000 description 3
- 244000008991 Curcuma longa Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 244000165082 Lavanda vera Species 0.000 description 3
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 235000019658 bitter taste Nutrition 0.000 description 3
- 235000003373 curcuma longa Nutrition 0.000 description 3
- 229930003935 flavonoid Natural products 0.000 description 3
- 150000002215 flavonoids Chemical class 0.000 description 3
- 235000017173 flavonoids Nutrition 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000001102 lavandula vera Substances 0.000 description 3
- 235000018219 lavender Nutrition 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000004745 nonwoven fabric Substances 0.000 description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 description 3
- 239000005020 polyethylene terephthalate Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 210000000434 stratum corneum Anatomy 0.000 description 3
- 235000019640 taste Nutrition 0.000 description 3
- 235000013976 turmeric Nutrition 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 2
- 241000208173 Apiaceae Species 0.000 description 2
- 241000208838 Asteraceae Species 0.000 description 2
- 244000107602 Corymbia citriodora Species 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 235000004722 Eucalyptus citriodora Nutrition 0.000 description 2
- 241000220485 Fabaceae Species 0.000 description 2
- 241000628997 Flos Species 0.000 description 2
- 235000000554 Glycyrrhiza uralensis Nutrition 0.000 description 2
- 240000008917 Glycyrrhiza uralensis Species 0.000 description 2
- 244000062245 Hedychium flavescens Species 0.000 description 2
- 235000017443 Hedysarum boreale Nutrition 0.000 description 2
- 235000007858 Hedysarum occidentale Nutrition 0.000 description 2
- 239000004831 Hot glue Substances 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 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 2
- 230000002929 anti-fatigue Effects 0.000 description 2
- 229940030225 antihemorrhagics Drugs 0.000 description 2
- 239000000227 bioadhesive Substances 0.000 description 2
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 2
- 229940116229 borneol Drugs 0.000 description 2
- 239000010624 camphor oil Substances 0.000 description 2
- 229960000411 camphor oil Drugs 0.000 description 2
- 239000010634 clove oil Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- 150000002212 flavone derivatives Chemical class 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 239000001947 glycyrrhiza glabra rhizome/root Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000002874 hemostatic agent Substances 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000001289 litsea cubeba fruit oil Substances 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 229940100640 transdermal system Drugs 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 2
- 239000009637 wintergreen oil Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 235000011468 Albizia julibrissin Nutrition 0.000 description 1
- 240000007185 Albizia julibrissin Species 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 244000061520 Angelica archangelica Species 0.000 description 1
- 241000213006 Angelica dahurica Species 0.000 description 1
- 241001435059 Artemisia argyi Species 0.000 description 1
- 235000010894 Artemisia argyi Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920000832 Cutin Polymers 0.000 description 1
- 235000001287 Guettarda speciosa Nutrition 0.000 description 1
- 241000142952 Hamamelidaceae Species 0.000 description 1
- 241000382951 Hansenia forbesii Species 0.000 description 1
- 241000533388 Hansenia weberbaueriana Species 0.000 description 1
- 241000207923 Lamiaceae Species 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- OQILCOQZDHPEAZ-UHFFFAOYSA-N Palmitinsaeure-octylester Natural products CCCCCCCCCCCCCCCC(=O)OCCCCCCCC OQILCOQZDHPEAZ-UHFFFAOYSA-N 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 235000003713 Rhodiola rosea Nutrition 0.000 description 1
- 244000042430 Rhodiola rosea Species 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- 229930190125 Sanguisorbin Natural products 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000019229 Spleen disease Diseases 0.000 description 1
- 241001656988 Styrax chinensis Species 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- GJQLBGWSDGMZKM-UHFFFAOYSA-N ethylhexyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(CC)CCCCC GJQLBGWSDGMZKM-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940089161 ginsenoside Drugs 0.000 description 1
- 229930182494 ginsenoside Natural products 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000000171 lavandula angustifolia l. flower oil Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003860 sleep quality Effects 0.000 description 1
- 230000036578 sleeping time Effects 0.000 description 1
- 208000027140 splenic disease Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
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)
- A61K36/185—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)
-
- 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)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
-
- 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)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/237—Notopterygium
-
- 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)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
- A61K36/282—Artemisia, e.g. wormwood or sagebrush
-
- 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
-
- 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)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- 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
- A61K9/127—Liposomes
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Alternative & Traditional Medicine (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Inorganic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Toxicology (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法。该中药组合物包括如下重量份组分:60~80份中药活性物质、2~7份助剂、250~350份大豆卵磷脂、60~90份胆固醇。本发明还提供了包含该组合物的无过敏性透皮贴剂的制备方法。与现有技术相比,本发明制备的无过敏性透皮贴剂可以提神醒脑,药物渗透性好,无过敏反应。
Description
技术领域
本发明涉及药物制剂技术领域,尤其涉及一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法。
背景技术
经皮给药系统是将药物涂布或敷贴于皮肤,经由皮肤毛细血管吸收进入体循环产生全身或局部治疗或预防作用的药物递送系统。与常规给药系统相比,可避免肝首关效应及胃肠灭活,且具有血药浓度水平较稳定,可随用随停,无创伤性,给药方法简单、方便,患者依从性高等独特优势。中药透皮贴剂是基于中医药理论的指导,将中药经过粉碎或提取、纯化等工艺所得到的提取物、有效部位或有效成分,与适宜的辅料相混合而制成的供黏贴在完整皮肤上的能起全身作用的一种薄片状柔性制剂,由背衬层、药物贮库层、黏贴层和用前需除去的保护层构成,与普通经皮给药制剂相比,透皮贴剂在皮肤顺应性、药物透皮率和释药速率可控性等方面应更具优势。
公开号为CN113952405A的发明专利公开了一种抗疲劳的组合物、制备方法及贴剂,该组合物主要包括按重量份数计的以下原料:黄姜50~70份、薄荷5~8份、薰衣草25~30份以及矿物盐1~3份。其以黄姜作为主要功能成分,具有暖身驱寒、促进新陈代谢、提升免疫力以及抗疲劳的效果,并以薰衣草改善睡眠质量,以薄荷提神醒脑、解除困乏;以矿物盐提高其他原料的吸收利用率,维持皮肤角质正常代谢,协同达到抗疲劳效果。而且,黄姜、薄荷以及薰衣草具有芳香味,能够提升使用者的使用兴趣。该组合物的制备方法能够将原料中的有效成分溶出,提升吸收利用率。以该组合物制成的贴剂能够在自发热层的发热作用下增强机体对有效成分的吸收效果。但是该组合物制备的贴剂需要利用热层的发热作用增强机体对药物有效成分的吸收,在经皮给药系统中,利用敷热打开毛孔促进药物渗透的作用并不显著,可见其药物透皮性不佳。
公开号为CN114191527A的发明专利公开了一种中正平和的提神醒脑中药组合物、医用固定贴及其制备方法,该中药组合物包括:温热性药物:姜黄、当归、丁香油、柠檬桉和冷榨芝麻油;和寒凉性药物:冬青油、桉叶油、山苍子油、樟脑油、薄荷脑和冰片。该中药组合物提神抗疲劳,辨证施治,不仅补虚扶正,也祛疲安神,利用当归、冷榨芝麻油、丁香油、姜黄和柠檬桉的温热性来降低冰片、冬青油、山苍子油、樟脑油和薄荷脑的寒凉性,使提神中药组合物药性中正平和,避免了寒凉性提神药使人心率过快、体质虚寒的副作用,为虚寒人群的提神用药提供了新选择。但是该固定贴的药物利用率较低,同时易发生皮肤过敏现象。
公开号为CN109674841A的发明专利公开了一种提神醒脑乳液,该乳液由水、卡波姆、甘油、人参皂甙、红景天提取物、肉豆蔻酸异丙酯、海藻糖、丙二醇、氢氧化钠、聚二甲基硅氧烷、角鲨烷、棕榈油甘油酯、辛酸/癸酸甘油三酯、棕榈酸乙基己酯、薰衣草油组成,能够明显降低人的起效时间和提高提神醒脑的持续时间,能够有效缓解人们的疲劳度。但是该乳液可能会导致过敏。
发明内容
有鉴于现有技术中出现的提神醒脑、抗疲劳中药贴剂中药物活性物质的透皮性不佳、药物利用率低、易过敏的问题,本发明所要解决的技术问题是提供一种可以提神醒脑,集中注意力,药物渗透性好,无过敏反应的中药透皮贴剂。
为实现上述目的,本发明提供了一种中药组合物,其特征在于,包括如下重量份组分:60~80份中药活性物质、2~7份助剂、250~350份大豆卵磷脂、60~90份胆固醇。
优选的,所述中药活性物质的制备方法如下,所述份数均为重量份:将15~30份甘草、20~45份陈皮、20~35份青蒿、10~20份艾叶、10~15份羌活、20~40份积雪草、5~10份合欢花、15~30份苏合香混合破碎至粒径为10~20mm,加入1500~2500份水,超声30~60分钟后浸泡1.5~2.5小时,在100~110℃温度下以300~500转/分钟搅拌并冷凝回流4~6小时,停止冷凝回流,冷却至20~30℃,得到初混合物;将初混合物在50~65℃下加热冷凝,收集挥发溶液和剩余混合物;将挥发溶液冷冻干燥,与3~8份薄荷油混合,得到活性挥发物质;将剩余混合物在90~110℃温度下加热蒸发至体积减少3/5~4/5,加入2000~3500份无水乙醇,70~85℃加热冷凝回流1~2小时,过滤,收集液体,80~110℃浓缩至开始出现固体,60~85℃真空干燥8~12小时,与活性挥发物质混合,得到中药活性物质。
优选的,所述过滤为0.22~0.45微米滤膜过滤。
优选的,所述助剂制备方法如下,所述份数均为重量份:
S1、将10~30份2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯、7~21份甘氨酸、4.5~10份对甲苯磺酸加入到150~300份无水乙醇中,加热搅拌冷凝回流10~14小时,80~110℃温度下蒸发去除无水乙醇,加入20~60份乙酸乙酯,300~500转/分钟搅拌10~30分钟,加水洗涤,萃取,收集上层液体,50~80℃旋转蒸发去除乙酸乙酯,得到物质A;
S2、将15~45份步骤S1制备的物质A、25~75份聚乙烯亚胺加入300~600份水中,以300~500转/分钟搅拌10~20分钟,在20~30℃温度下,以3~10mL/s通入氮气,继续以300~500转/分钟搅拌45~55小时,透析,60~80℃真空干燥3~5天,得到助剂。
优选的,步骤S1中加热搅拌冷凝回流温度为130~145℃,搅拌转速为300~500转/分钟。
优选的,步骤S2所述透析的截留分子量为3500~8000Da。
所述中药组合物的制备方法如下,所述份数均为重量份:
步骤1将250~350份大豆卵磷脂、60~90份胆固醇、60~80份中药活性物质在600~1000份溶剂中溶解,超声90~180秒,在35~45℃温度下蒸发至开始出现固体,35~45℃温度下真空干燥8~12小时后,加入25~35份水,搅拌20~40分钟,超声6~15分钟,继续搅拌1~2小时,依次过150~250nm和80~120nm聚碳酸纤维脂膜,得到脂质体;
步骤2、将2~7份助剂加入8~25份水中,以300~500转/分钟搅拌10~30分钟,再加入65~85份步骤1制备的脂质体,在20~30℃温度下,以3~10mL/s通入氮气,继续以300~500转/分钟搅拌45~55小时,得到中药组合物。
优选的,步骤1所述溶剂为二氯甲烷与甲醇体积比为3:2~5:2的混合物。
本发明还提供了一种包含上述中药组合物的无过敏透皮贴剂的制备方法,包括如下步骤,所述份数均为重量份:将80~85份压敏胶在100~160℃加热熔融,加入15~20份所述中药组合物,以400~600转/分钟搅拌均匀,得到混合物,保持混合物温度在85~100℃下涂布于防黏层,冷却后压覆背衬材料,得到中药透皮贴剂。
优选的,所述压敏胶为熔点为100~160℃的热熔型压敏胶。
优选的,所述防黏层为聚对苯二甲酸乙二酯薄膜;背衬材料为弹性无纺布。
优选的,上述中药透皮贴剂载药浓度为1~3g/cm2。
优选的,所述中药透皮贴剂还能利用上述中药组合物经过其他贴剂制备方法制得。
本发明通过甘草、陈皮、青蒿、艾叶、羌活、薄荷油、积雪草、合欢花、苏合香制备得到中药活性物质,将中药活性物质制备成载药脂质体,再利用助剂进行修饰,得到中药组合物,最后再利用中药组合物制备出中药透皮贴剂。苏合香中含大量树脂,在贴剂制备过程中,可起到天然黏性剂的作用,还能与助剂连接,促进中药活性物质的透皮性,同时中药活性物质还具有开窍、解暑、抗菌、提神的作用。助剂采用2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯与甘氨酸酯化,甘氨酸的链长增长,提高对药物的透皮性,具有良好的生物相容性。然后再与聚乙烯亚胺反应,将聚乙烯亚胺变为氨基酸的连接剂,2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯中的碳碳双键与聚乙烯亚胺的伯胺基团结合,使助剂具有两性特性,改变角质层中蛋白的二级结构,促进亲水药物的经皮渗透性。将助剂与载药脂质体混合,与载药脂质体中的中药活性物质连接,形成助剂修饰载药脂质体,进一步提高药物的透皮性,促进中药活性物质作用,增强药效和提高对药物的利用。
甘草:豆科植物甘草、胀果甘草或光果甘草的干燥根及根茎。秋季采挖,趁湿切去茎基、串条、枝杈、须根等,放干燥处风干。亦有将外面栓皮削去者,称为粉甘草。性平,味甘。归心经、胃经、脾经、肺经。具有补脾益气、止咳祛痰、缓急定痛、调和药性的功效。属补虚药下分类的补气药。
陈皮:芸香科植物橘和其栽培变种的成熟果皮。采摘成熟果实,剥取果皮,晒干得到,常纵剖成整齐3瓣,基部相连。味辛、味苦,性温。归脾经、肺经。具有理气开胃,燥湿化痰,治脾胃病的作用。属理气药。
青蒿:菊科植物黄花蒿的地上部分,夏、秋季花盛开或结果时采收。割取地上部分,除去老茎,阴干或晒干。性寒,味苦、辛。归胆经、肝经。具有抗菌、抗病毒、抗寄生虫、抗肿瘤、解热的作用;可以调节机体免疫功能,减慢心率,抑制心肌收缩力,降低冠脉流量,降低血压,且有一定抗心律失常作用;还能保护肝脏,防护辐射,缩短戊巴比妥睡眠时间等。
艾叶:菊科植物艾的叶,夏季花未开时采摘,除去杂质,晒干。性温,味苦、辛。归肝经、脾经、肾经。具有散寒止痛、温经止血的作用。属止血药下属分类的温经止血药。
羌活:伞形科植物羌活或宽叶羌活的干燥根茎和根,春、秋二季采挖,除去须根及泥沙,晒干,性温,味辛、苦。具有解表散寒,祛风除湿,止痛的功效,属解表药下属分类的辛温解表药。
薄荷:唇形科植物薄荷的地上部分。通常收割2次,第1次收割在小暑后大暑前(7月中下旬),主要提取薄荷油用;第2次收割在霜降之前(10月中下旬),主要作药材用,晒干或阴干。性凉,味辛。归肺经、肝经。具有宣散风热、清头目、透疹的作用。属解表药下属分类的辛凉解表药。
积雪草:伞形科植物积雪草的全草。夏、秋季采收全草,除去泥杂,晒干或鲜用。性寒,味苦、辛。归肝经、脾经、肾经。具有清湿热、解毒消肿、活血利尿的功效。属清热药下分类的清热燥湿药。
合欢花:豆科植物合欢的初开放的花序或花蕾。夏季花开放时择晴天采收或花蕾形成时采收,摊于竹匾内迅速晒干,2~3天后花由红白色转变成黄褐色即可。性平,味甘。归心经、肝经。具有解郁安神的作用。属安神药下属分类的养心安神药。
苏合香:金缕梅科植物苏合香树的树干渗出的香树脂,经加工精制而成。性温,味辛。归心经、脾经。具有开窍、辟秽、止痛的作用。属开窍药。
由于采用以上技术方法,本发明与现有技术相比具有以下优点:1)利用甘草、陈皮、青蒿、艾叶、羌活、薄荷油、积雪草、合欢花、苏合香制备的中药活性物质,药物性质温和,无过敏现象,通过经皮系统给药,具有提神醒脑,解暑的作用,还能防止出现皮肤因长时间覆盖贴剂导致的皮肤接触面瘙痒红斑问题;苏合香的加入,不仅可提高药物的透皮性,还能在中药透皮贴剂中起到天然黏性剂的作用;2)利用2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯增加甘氨酸的链长,再与聚乙烯亚胺结合,制备得到助剂,使助剂具有两性特征,提高助剂的促经皮渗透性,助剂与载药脂质体中的中药活性物质连接,提高药物的透皮性和有效利用率,增强药物作用效果,同时助剂对皮肤无刺激性,还能促进皮肤吸收中药活性物质。
具体实施方式
实施例和对比例中原料来源:
大豆卵磷脂:上海添阔生物科技有限公司,含量:99%。
胆固醇:河南冠琪生物科技有限公司,含量:99%,货号:a8547。
甘草产自辽宁丹东。
陈皮、青蒿、积雪草、合欢花产自广东湛江市。
艾叶产自湖北黄冈市。
羌活产自四川都江堰。
苏合香产自土耳其。
聚乙烯亚胺:武汉卓创远航化工有限公司,分子量:600。
压敏胶:佛山市顺德区奇固热熔胶有限公司,型号:1331,粘度:3000mpa·s/160℃,软化点:75±5℃。
聚对苯二甲酸乙二酯薄膜:东莞市鸿万鑫橡胶制品科技有限公司,货号:lxm-015,厚度:0.1mm。
弹性无纺布:平湖展鹏热熔胶有限公司,主要成分:聚氨酯,克重:75g/m2,货号:LM-0007。
实施例1
一种中药组合物,其制备方法如下:
步骤1、将300g大豆卵磷脂、80g胆固醇、75g中药活性物质在800g体积比为2:1的二氯甲烷与甲醇的混合物中溶解,超声120秒,在40℃温度下蒸发至开始出现固体,40℃温度下真空干燥10小时后,加入30g水,搅拌30分钟,超声10分钟,继续搅拌1.5小时,依次过200nm和100nm聚碳酸纤维脂膜,得到脂质体;
步骤2、将5g助剂加入15g水中,以400转/分钟搅拌20分钟,再加入75g步骤1制备的脂质体,在25℃温度下,以6mL/s通入氮气,继续以400转/分钟搅拌50小时,得到中药组合物。
所述中药活性物质采用如下方法制备得到:
将25g甘草、30g陈皮、25g青蒿、15g艾叶、12g羌活、30g积雪草、7g合欢花、20g苏合香混合破碎至粒径为15mm,加入1800g水,超声45分钟后浸泡2小时,在105℃温度下以400转/分钟搅拌并冷凝回流5小时,停止冷凝回流,冷却至25℃,得到初混合物;将初混合物在60℃下加热冷凝,收集挥发溶液和剩余混合物;将挥发溶液冷冻干燥,与5g薄荷油混合,得到活性挥发油;将剩余混合物在100℃温度下加热蒸发至体积减少7/10,加入2500g无水乙醇,80℃加热冷凝回流1.5小时,0.45微米滤膜过滤,收集液体,90℃浓缩至开始出现固体,70℃真空干燥10小时,与活性挥发油混合,得到中药活性物质。
所述助剂制备方法如下:
S1、将20g 2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯、14g甘氨酸、6g对甲苯磺酸加入到200g无水乙醇中,135℃温度下以400转/分钟搅拌冷凝回流12小时,100℃温度下蒸发去除无水乙醇,加入50g乙酸乙酯,400转/分钟搅拌20分钟,加水洗涤,萃取,收集上层液体,60℃旋转蒸发去除乙酸乙酯,得到物质A;
S2、将25g步骤S1制备的物质A、40g聚乙烯亚胺加入400g水中,以400转/分钟搅拌15分钟,在25℃温度下,以7mL/s通入氮气,继续以400转/分钟搅拌50小时,4500Da透析袋透析,70℃真空干燥4天,得到助剂。
包含上述中药组合物的中药透皮贴剂采用如下方法制备:
将83g压敏胶在140℃加热熔融,加入17g中药组合物,以500转/分钟搅拌均匀,得到混合物,保持混合物温度在90℃下涂布于面积为8.5cm2的聚对苯二甲酸乙二酯薄膜,冷却后压覆弹性无纺布,得到中药透皮贴剂。
对比例1
一种中药组合物,其制备方法与实施例1基本相同,唯一的区别在于:中药活性物质的制备方法不同。
所述中药活性物质制备方法如下:
将25g甘草、30g陈皮、25g青蒿、15g艾叶、12g羌活、30g积雪草、7g合欢花、20g苏合香混合破碎至粒径为15mm,加入1800g水,超声45分钟后浸泡2小时,在105℃温度下以400转/分钟搅拌并冷凝回流5小时,停止冷凝回流,冷却至25℃,得到初混合物;将初混合物在60℃下加热冷凝,收集挥发溶液和剩余混合物;将挥发溶液冷冻干燥,与5g薄荷油混合,得到活性挥发油;将剩余混合物在100℃温度下加热蒸发至体积减少7/10,加入2500g无水乙醇,80℃加热冷凝回流1.5小时,0.45微米滤膜过滤,收集液体,90℃浓缩至开始出现固体,70℃真空干燥10小时,与活性挥发油混合,得到中药活性物质。
包含上述中药组合物的中药透皮贴剂的制备方法与实施例1相同。
对比例2
一种中药组合物,其制备方法与实施例1基本相同,唯一的区别在于:助剂的制备方法不同。
所述助剂制备方法如下:
S1、将20g 2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯、6g对甲苯磺酸加入到200g无水乙醇中,135℃温度下以400转/分钟搅拌冷凝回流12小时,100℃温度下蒸发去除无水乙醇,加入50g乙酸乙酯,400转/分钟搅拌20分钟,加水洗涤,萃取,收集上层液体,60℃旋转蒸发去除乙酸乙酯,得到物质A;
S2、将25g步骤S1制备的物质A、40g聚乙烯亚胺加入400份水中,以400转/分钟搅拌15分钟,在25℃温度下,以7mL/s通入氮气,继续以400转/分钟搅拌50小时,4500Da透析袋透析,70℃真空干燥4天,得到助剂。
包含上述中药组合物的中药透皮贴剂的制备方法与实施例1相同。
对比例3
一种中药组合物,其制备方法与实施例1基本相同,唯一的区别在于:助剂的制备方法不同。
所述助剂制备方法如下:
S1、将20g 2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯、14g甘氨酸、6g对甲苯磺酸加入到200g无水乙醇中,135℃温度下以400转/分钟搅拌冷凝回流12小时,100℃温度下蒸发去除无水乙醇,加入50g乙酸乙酯,400转/分钟搅拌20分钟,加水洗涤,萃取,收集上层液体,60℃旋转蒸发去除乙酸乙酯,得到物质A;
S2、将25g步骤S1制备的物质A加入400份水中,以400转/分钟搅拌15分钟,在25℃温度下,以7mL/s通入氮气,继续以400转/分钟搅拌50小时,4500Da透析袋透析,70℃真空干燥4天,得到助剂。
包含上述中药组合物的中药透皮贴剂的制备方法与实施例1相同。
测试例1
透皮渗透试验:
参考硕士论文(TPGS修饰的地榆皂苷I长循环脂质体的制备及质量评价,作者:宋婷婷,遵义医科大学,2021年)测试具体步骤如下:
1)本试验以总黄酮作为测试指标,采用HPLC法检测本发明中药透皮贴剂样品中的总黄酮质量m。
1)取健康SD大鼠断颈处死,用电剃刀除去腹部鼠毛,剥离并处理腹部鼠皮,处理好的腹部鼠皮固定于样品池与接收池之间,将本发明制备的中药透皮贴剂贴在小鼠角质层面(SD大鼠角质层面接触载药层面积9cm2);
2)在TK6-500透皮扩散试验仪上进行透皮试验,试验仪同时设置3个扩散池,池结构同Franz池,尺寸按比例减小,池口面积约9cm2,每个接收池体积预先标定,各池体积在8~8.6mL范围;
3)配制0.9wt%生理盐水作为接收液,固定样品池,恒温(32±0.5)℃,分别于1、2、4、6、8小时时取样,每次取样0.5mL,并补充等体积接收液,采用HPLC法检测接收液中总黄酮的浓度,通过式1计算得到总黄酮的累积透过率Q,测试结果见表1。
其中:V0为取样总体积,Ci和Cn为第i和第n时间点取样时测得的药物质量浓度(mg/mL),Vi为取样体积(mL),m表示样品中总黄酮的总质量。
测试例2
提神醒脑测试:
选取200名身体健康情况接近,男女比例为1:1,年龄在25~35岁之间,长时间从事办公室文字撰写工作,白天易犯困的的人员,在犯困的时候贴一剂本发明制备的中药透皮贴剂,分为4组,每组男女比例为1:1,分别对应实施例1、对比例1、对比例2、对比例3四个试验组,每组50人,每人每天只能贴一剂,每次贴2小时,以60天计,结束后登记各组受试者的犯困情况,以显著、不明显进行登记,计算贴过本发明制备的中药透皮贴剂效果显著的受试人员占比k,通过式2计算,结果见表1。
其中,n为每组认为使用本发明制备的中药透皮贴剂效果显著的人数。
测试例3
过敏性测试:
1)取不同窝健康小鼠80只,雌雄各半,分为4组,分别对应实施例1、对比例1、对比例2、对比例3四个试验组。用电剃刀在不伤小鼠皮肤的过程中小心除去小鼠腹部左右两侧鼠毛,各侧去毛区面积为3.5cm×3.5cm;
2)测试的空白对照与试验采用同一受体左右侧对比进行,在左侧涂抹等量生理盐水并用纱布和胶带覆盖固定,右侧贴本发明制备的中药透皮贴剂,给药测试14次。初次给药时间为1小时,后面给药时间均为12小时,给药中间间隔时间为12小时,给药结束后清洗给药残留表面,观察并记录小鼠皮肤给药部位红斑、水肿等过敏反应指征。结果见表1。
表1测试结果
通过对比实施例1与对比例1~3发现,实施例1中药物活性物质的透过率和透皮贴剂的提神醒脑效果均优于对比例1~3,可能是实施例1中加入的苏合香和助剂之间结合具有促进药物活性物质经皮渗透的作用,同时制备的中药活性物质性质温和,通过经皮系统给药,具有提神醒脑,解暑的作用,防止了皮肤因长时间覆盖贴剂导致的皮肤过敏问题;由2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯增加甘氨酸的链长,再与聚乙烯亚胺结合制备的助剂可提高助剂的促经皮渗透性,同时,助剂与载药脂质体中的中药活性物质连接,进一步提高药物的透皮性,从而提高了药物的有效利用率,增强药物作用效果。
Claims (6)
1.一种中药组合物,其特征在于,包括如下重量份组分:60~80份中药活性物质、2~7份助剂、250~350份大豆卵磷脂、60~90份胆固醇;
所述中药活性物质包含以下成分制备:甘草、陈皮、青蒿、艾叶、羌活、积雪草、合欢花、苏合香;
所述中药活性物质制备方法如下,以重量份计:将15~30份甘草、20~45份陈皮、20~35份青蒿、10~20份艾叶、10~15份羌活、20~40份积雪草、5~10份合欢花、15~30份苏合香混合破碎至粒径为10~20mm,加入1500~2500份水,超声30~60分钟后浸泡1.5~2.5小时,在100~110℃温度下搅拌并冷凝回流4~6小时,冷却至20~30℃,得到初混合物;将初混合物在50~65℃下加热冷凝,收集挥发溶液和剩余混合物;将挥发溶液冷冻干燥,与3~8份薄荷油混合,得到活性挥发物质;将剩余混合物在90~110℃温度下加热蒸发至体积减少3/5~4/5,加入2000~3500份无水乙醇,70~85℃加热冷凝回流1~2小时,过滤,收集液体,80~110℃浓缩至开始出现固体,60~85℃真空干燥8~12小时,与活性挥发物质混合,得到中药活性物质;
所述助剂制备方法如下:
S1、将2-甲基-2-丙烯酸-2-(膦酰基氧基)乙酯、甘氨酸、对甲苯磺酸加入到无水乙醇中,加热搅拌冷凝回流10~14小时,80~110℃温度下蒸发去除无水乙醇,加入乙酸乙酯,搅拌10~30分钟,加水洗涤,萃取,收集上层液体,50~80℃蒸发去除乙酸乙酯,得到物质A;
S2、将步骤S1制备的物质A、聚乙烯亚胺加入水中,搅拌10~20分钟,在20~30℃温度下,以3~10mL/s通入氮气,继续搅拌45~55小时,透析,60~80℃真空干燥3~5天,得到助剂。
2.如权利要求1所述的一种中药组合物,其特征在于:所述步骤S1中加热搅拌冷凝回流温度为130~145℃;步骤S2所述透析的截留分子量为3500~8000Da。
3.如权利要求1所述的一种中药组合物,其特征在于,采用如下方法制备得到:
步骤1、将大豆卵磷脂、胆固醇、中药活性物质在溶剂中溶解,超声90~180秒,在35~45℃下蒸发至开始出现固体,35~45℃下真空干燥8~12小时后,加入水,搅拌20~40分钟,超声6~15分钟,继续搅拌1~2小时,依次过150~250nm和80~120nm聚碳酸酯膜,得到脂质体;
步骤2、将助剂加入水中,搅拌10~30分钟,再加入步骤1制备的脂质体,在20~30℃下,以3~10mL/s通入氮气,继续搅拌45~55小时,得到中药组合物。
4.如权利要求3所述的一种中药组合物,其特征在于:所述步骤1所述溶剂为二氯甲烷与甲醇按照3:2~5:2的体积比混合而成。
5.一种无过敏性透皮贴剂的制备方法,其特征在于,使用了如权利要求1~4任一项所述的中药组合物,具体包括如下步骤:将熔点为100~160℃的热熔型压敏胶在100~160℃加热熔融,加入所述中药组合物搅拌均匀,得到混合物,保持混合物温度在85~100℃下涂布于防黏层,冷却后压覆背衬材料,得到中药透皮贴剂。
6.一种无过敏性透皮贴剂,其特征在于:采用如权利要求5所述的无过敏性透皮贴剂的制备方法制备得到。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210789356.2A CN115089636B (zh) | 2022-07-06 | 2022-07-06 | 一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210789356.2A CN115089636B (zh) | 2022-07-06 | 2022-07-06 | 一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115089636A CN115089636A (zh) | 2022-09-23 |
CN115089636B true CN115089636B (zh) | 2023-12-08 |
Family
ID=83297285
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210789356.2A Active CN115089636B (zh) | 2022-07-06 | 2022-07-06 | 一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115089636B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998003188A1 (de) * | 1996-07-19 | 1998-01-29 | Basf Aktiengesellschaft | Pflanzenextrakthaltige arzneiformen |
WO2018004490A1 (en) * | 2016-07-01 | 2018-01-04 | Bioarge Bitiksel Kozmetik Arastirma Gelistirme Muhendislik Ltd. Sti. | Enhanced oil dispersion and transdermal delivery |
CN112022919A (zh) * | 2020-07-20 | 2020-12-04 | 云南中医药大学 | 经皮吸收的苍艾油传递体凝胶及其制备方法 |
CN113633672A (zh) * | 2020-04-23 | 2021-11-12 | 北京博爱堂中医药研究所 | 一种组合物及其制备方法和用途 |
-
2022
- 2022-07-06 CN CN202210789356.2A patent/CN115089636B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998003188A1 (de) * | 1996-07-19 | 1998-01-29 | Basf Aktiengesellschaft | Pflanzenextrakthaltige arzneiformen |
WO2018004490A1 (en) * | 2016-07-01 | 2018-01-04 | Bioarge Bitiksel Kozmetik Arastirma Gelistirme Muhendislik Ltd. Sti. | Enhanced oil dispersion and transdermal delivery |
CN113633672A (zh) * | 2020-04-23 | 2021-11-12 | 北京博爱堂中医药研究所 | 一种组合物及其制备方法和用途 |
CN112022919A (zh) * | 2020-07-20 | 2020-12-04 | 云南中医药大学 | 经皮吸收的苍艾油传递体凝胶及其制备方法 |
Non-Patent Citations (1)
Title |
---|
α-细辛醚的黏胶分散型经皮贴剂研究;胡英;吴遥遥;吴争;梁文权;高建青;;中国新药杂志;18(10);949-952、916 * |
Also Published As
Publication number | Publication date |
---|---|
CN115089636A (zh) | 2022-09-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI501772B (zh) | 具抗關節炎活性的到手香精萃物 | |
CN103041173B (zh) | 一种治疗皮炎、湿疹的中药外用制剂及其制备方法 | |
CN100542585C (zh) | 一种具有镇痛和抗炎作用的外用药物组合物 | |
WO2011026267A1 (zh) | 用于消炎消肿止痛的中草药组合物、制备方法及其应用 | |
CN104784507A (zh) | 一种具有多重美容功效的中药组合物及其制备方法和应用 | |
CN102988264A (zh) | 银杏叶祛斑美白霜及其制备方法 | |
KR101412500B1 (ko) | 대나무 통 한방 발효 추출물을 유효 성분으로 함유하는 아토피 피부 개선 화장료 조성물 및 그의 제조방법 | |
CN106176784B (zh) | 一种用于皮炎的药物组合物、应用、制剂及其制备方法 | |
KR20110016611A (ko) | 아토피 피부 개선용 조성물 및 이의 제조방법 | |
CN108785200B (zh) | 一种抗菌、祛痘、抗皱的银离子保湿面膜液、面膜及其制备方法 | |
JPH0616530A (ja) | 化粧料 | |
CN115089636B (zh) | 一种中药组合物、包含该组合物的无过敏性透皮贴剂及其制备方法 | |
CN107569421A (zh) | 一种可溶性祛斑微针 | |
CN108403932B (zh) | 一种治疗激素依赖性皮炎的中药复方外用制剂及其制备方法和应用 | |
CN115518127A (zh) | 一种抑菌抗炎消肿止痒乳膏及其制备方法 | |
CN115192552B (zh) | 一种有效缓解风湿疼痛的中药透皮贴剂及其制备方法 | |
CN108653431B (zh) | 防治鼻炎的药物组合物、制备方法及其应用和制剂 | |
CN101953951B (zh) | 一种手足保健美容液及其制备方法 | |
CN105561098A (zh) | 一种治疗糜烂性脚气的药物 | |
CN105343660A (zh) | 一种治疗周围性眩晕的中药制剂及其制造方法 | |
CN110507712A (zh) | 一种外用治疗关节炎的白头翁提取物及其制备方法 | |
JP5030366B2 (ja) | アレルギー性疾患治療用組成物 | |
CN104352866A (zh) | 一种治疗火毒伤津型烧伤的中药制剂及其制备方法 | |
KR102533237B1 (ko) | 한방복합추출물을 유효성분으로 함유하는 탈모방지 또는 두피개선용 화장료 조성물 | |
CN108743813B (zh) | 一种抗鼻咽癌中药纳米乳液 |
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 | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20231114 Address after: 518000 No.501, 504, No.2 factory building, Shenfeng Road Industrial Zone, Henggang street, Longgang District, Shenzhen City, Guangdong Province Applicant after: SHENZHEN GUFANG TRADITIONAL MEDICINE DECOCTION PIECES CO.,LTD. Address before: 518000 1701-1704, building D3, Nanshan Zhiyuan, No. 1001, Xueyuan Avenue, Changyuan community, Taoyuan Street, Nanshan District, Shenzhen, Guangdong Applicant before: Xinling Pharmaceutical Technology (Shenzhen) Co.,Ltd. |
|
TA01 | Transfer of patent application right | ||
GR01 | Patent grant | ||
GR01 | Patent grant |