CN109985000B - 克立硼罗微乳组合物 - Google Patents
克立硼罗微乳组合物 Download PDFInfo
- Publication number
- CN109985000B CN109985000B CN201711471716.XA CN201711471716A CN109985000B CN 109985000 B CN109985000 B CN 109985000B CN 201711471716 A CN201711471716 A CN 201711471716A CN 109985000 B CN109985000 B CN 109985000B
- Authority
- CN
- China
- Prior art keywords
- microemulsion
- kreb
- emulsifier
- solution
- composition
- 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
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 169
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 239000002245 particle Substances 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 30
- 150000002148 esters Chemical class 0.000 claims abstract 2
- 238000003756 stirring Methods 0.000 claims description 57
- 238000002360 preparation method Methods 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000007957 coemulsifier Substances 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 14
- 229920000053 polysorbate 80 Polymers 0.000 claims description 14
- 239000008213 purified water Substances 0.000 claims description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 9
- -1 alkyl oleate Chemical compound 0.000 claims description 9
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 9
- 229940093471 ethyl oleate Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940049964 oleate Drugs 0.000 claims description 6
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 229940105132 myristate Drugs 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- 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 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 235000021360 Myristic acid Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 36
- 208000010668 atopic eczema Diseases 0.000 abstract description 21
- 206010012434 Dermatitis allergic Diseases 0.000 abstract description 19
- 201000008937 atopic dermatitis Diseases 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 13
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 6
- 239000000194 fatty acid Substances 0.000 abstract description 6
- 229930195729 fatty acid Natural products 0.000 abstract description 6
- 231100000245 skin permeability Toxicity 0.000 abstract description 6
- 150000004665 fatty acids Chemical class 0.000 abstract description 5
- 230000014759 maintenance of location Effects 0.000 abstract description 4
- 229920000136 polysorbate Polymers 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 85
- 239000003921 oil Substances 0.000 description 31
- 229940079593 drug Drugs 0.000 description 18
- 210000003491 skin Anatomy 0.000 description 13
- 239000006071 cream Substances 0.000 description 10
- 239000013022 formulation composition Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000009826 distribution Methods 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 6
- 229940043234 carbomer-940 Drugs 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 238000002651 drug therapy Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 4
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 229940074928 isopropyl myristate Drugs 0.000 description 4
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 4
- 229940075495 isopropyl palmitate Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 3
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000001087 glyceryl triacetate Substances 0.000 description 3
- 235000013773 glyceryl triacetate Nutrition 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 229960002622 triacetin Drugs 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 2
- 229960004866 mycophenolate mofetil Drugs 0.000 description 2
- 238000000554 physical therapy Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229940082484 carbomer-934 Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- USZAGAREISWJDP-UHFFFAOYSA-N crisaborole Chemical compound C=1C=C2B(O)OCC2=CC=1OC1=CC=C(C#N)C=C1 USZAGAREISWJDP-UHFFFAOYSA-N 0.000 description 1
- 229950008199 crisaborole Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940088592 immunologic factor Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 description 1
- 229960005330 pimecrolimus Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了克立硼罗微乳组合物,所述克立硼罗微乳组合物包括:以重量百分比计,包括:克立硼罗0.5%~5.0%,油相5%~20%,乳化剂10%~40%,助乳化剂5%~30%,水30%~70%,其中油相为选自C10‑C18的脂肪酸单酯,三羧酸甘油酯中的一种或多种的组合,乳化剂为选自吐温系乳化剂。本发明克立硼罗微乳溶液稳定性好,具有理想微乳粒径,可有效提高药物皮肤渗透性;克立硼罗微乳凝胶相比克立硼罗微乳溶液,可进一步提高皮肤渗透性和滞留量,可提高过敏性皮炎临床治疗顺应性并起到缓释效果。
Description
技术领域
本发明属于生物医药领域,具体涉及一种克立硼罗微乳溶液和微乳凝胶剂及其制备方法,该微乳组合物可以包载克立硼罗透过皮肤角质层,具有高皮肤渗透性、高皮肤药物滞留量、残留物易清洗的特征,主要用于治疗过敏性皮炎(湿疹)。
背景技术
过敏性皮炎(AD,atopic dermatitis),俗称湿疹。是一种与遗传过敏素质密切相关的皮肤炎症性疾病,患者人群广泛分布。特征是皮肤瘙痒,皮疹多形性并伴有渗出倾向。除具有湿疹的临床表现外,还具有以下特点:有容易患哮喘、过敏性鼻炎、湿疹的家族倾向;对异种蛋白过敏;血清免疫球蛋白E(IgE)增高以及血液中嗜酸粒细胞增多。
过敏性皮炎的病因与发病机制尚未完全明确。通常认为是由各种内、外因素刺激及相互作用导致发病,包括遗传因素、免疫因素以及环境因素等。过敏性皮炎具有明显的家族聚集性,并且60%~90%患者受季节影响明显,冬重夏轻。冷、热及环境气候的急剧变化,突然大量出汗亦可为恶化或诱发因素。接触羊毛、纺织品、粉尘和高温作业的职业发病率也较高。过敏性皮炎分布于各年龄段,婴儿与青少年居多,统计显示60%的过敏性皮炎呈现早期发生的特点,并伴有终生性。目前发达国家,过敏性皮炎的发病率维持在10~20%,并呈现逐年增加的趋势。
根据疾病特点以及目前疾病诱因的研究结果,过敏性皮炎的治疗方式主要包括***药物治疗、物理治疗及局部药物治疗。1)***药物治疗:基于过敏性皮炎的免疫学发病机制的全身用药,包括口服及注射给药。口服药物主要包括环孢素A(CyA)、麦考酚酯 (MMF)等,其特点是疗效确切可靠,作为免疫抑制剂,肝肾毒性、严重的胃肠道反应以及中性粒细胞减少极大的限制了其应用,另一类口服药物以抗细菌及抗真菌药物为主,主要局限性在于耐药性以及疾病的反复性;注射类药物主要是免疫调节剂,代表药物有干扰素-γ以及免疫球蛋白(HdIVIG),其特点是起效快,效果明显,但长期用药安全性数据不完善。2)物理治疗:基于病理学研究,针对过敏性皮炎的病灶部位的外部物理干预方式,代表方式有光疗(中、高剂量的紫外光照),其特点是安全无明显不良反应,但确切的疗效极大限制其临床应用。3)局部药物治疗:过敏性皮炎作为局部性病变,因其疾病特点,局部药物治疗(外用药物)为首选治疗方案。目前局部治疗的药物主要包括他克莫司、匹美克莫司、辣椒辣素、多塞平搽剂。局部治疗药物的局限性为药物渗透性差,疗效有限,药物作用机制不明确,容易复发。
2016年上市的克立硼罗作为外用小分子硼类药物,对过敏性皮炎治疗的意义重大。基于过敏性皮炎发病机制的研究,通过抑制磷酸二酯酶4(PDE4)和促炎症细胞因子这两个炎症靶标,从而达到抑制多种炎症介质的活性,降解环磷酸腺苷,以达到治疗过敏性皮炎的效果。
克立硼罗上市剂型为乳膏剂(商品名:EUCRISA),需每日给药2次。根据过敏性皮炎疾病特点,长时间持续给药在临床上顺应性差,乳膏剂主要为油性基质,给药后皮肤表面油腻感强,与衣物等接触后,难以清洗,临床用药顺应性差,乳膏剂的生产工艺复杂,药物配制及分包装需进行热处理,并且需要特殊包材。
理想的外用制剂是借助制剂技术,以简单稳定的处方工艺,以物理的方式促进药物穿过皮肤角质层,提高渗透性以达到提高治疗效率的目的,减小药物本身毒副作用,提高安全性,并且提高用药的临床顺应性。
微乳(micro emulsion,ME)是水,油,表面活性剂和助表面活性剂按适当的比例混合,自发形成的各向同性,透明,热力学稳定的分散体系。微乳液首先由schulman等发现并命名。已知将药物制成微乳经皮给药制剂可以提高制剂的载药量和稳定性,延长药物作用时间,提高生物利用度,而且微乳表面张力较低,容易润湿皮肤,使角质层结构发生变化,使药物易于穿透角质层被人体吸收。目前市场上也已有微乳经皮给药制剂的成功案例。然而,微乳制剂的效果发挥与具体的药物成分,所用的表面活性剂以及微乳粒子的大小密切相关,此外,微乳制剂自身的稳定性也非常重要,现有技术中出现的乳剂或霜剂中的油相一般为凡士林或脂肪醇,然而使用上述油相的制剂,稳定性不好,透皮渗透性也较差。对于某特定药物来说,能否获得具有优异稳定性且效果显著提升的微乳制剂是无法预期的。
发明内容
发明要解决的问题
本发明的目的是针对现有技术的不足,提供一种稳定性好且具有理想微乳粒径的克立硼罗微乳组合物。
用于解决问题的方案
一种克立硼罗微乳组合物,所述克立硼罗微乳组合物包括:以重量百分比计,克立硼罗0.5%~5.0%,油相5%~20%,乳化剂10%~40%,助乳化剂5%~30%,水30%~70%,其中油相为选自C10-C18的脂肪酸单酯,三羧酸甘油酯中的一种或多种的组合,乳化剂为选自吐温系乳化剂。所述脂肪酸单酯为1mol脂肪酸与1mol醇通过酯化反应形成的脂肪酸酯,所述的三羧酸甘油酯为3mol羧酸与1mol甘油通过酯化反应所形成的三羧酸甘油酯。
进一步的,所述克立硼罗微乳组合物为克立硼罗微乳溶液或克立硼罗微乳凝胶剂,其中,以重量百分比计,所述克立硼罗微乳溶液包括:克立硼罗0.5%~5.0%,油相5%~20%,乳化剂10%~40%,助乳化剂5%~30%,水30%~70%,其中油相为选自C10-C18的脂肪酸单酯,甘油三酯中的一种或多种的组合,乳化剂为选自吐温80和吐温60中的一种或多种的组合;所述克立硼罗微乳凝胶剂包含所述克立硼罗微乳溶液和凝胶材料。
进一步的,所述克立硼罗微乳溶液,以重量百分比计,克立硼罗1.0%~2.0%,油相 8%~15%,乳化剂15%~30%,助乳化剂10%~25%,水40%~60%,优选为克立硼罗1.5%~2.0%,油相8%~10%,乳化剂20%~30%,助乳化剂10%~20%,水40%~50%。
进一步的,所述油相为选自油酸酯、三羧酸甘油酯、棕榈酸酯和肉豆蔻酸酯中的一种或多种,优选的,所述油酸酯为油酸烷基酯,所述的烷基为C1-C6的烷基,所述的三羧酸甘油酯为含C1-C6的羧酸,所述的棕榈酸酯为棕榈酸烷基酯,所述的烷基为C1-C6 的烷基,所述的肉豆蔻酸酯为肉豆蔻烷基酯,所述的烷基为C1-C6的烷基。
进一步的,所述油相为油酸乙酯、三乙酸甘油酯、棕榈酸异丙酯和肉豆蔻酸异丙酯中的一种或多种的组合。
进一步的,所述助乳化剂为选自甲醇、乙醇、丙醇、异丙醇、丙二醇和聚乙二醇400中的一种或多种的组合。
进一步的,所述油相为油酸乙酯,所述乳化剂为吐温80,所述助乳化剂为乙醇,优选为无水乙醇。
进一步的,所述的凝胶材料为卡波姆、甲基纤维素或羧甲基纤维素钠中的一种或多种,优选为卡波姆940、卡波姆934、卡波姆941,更优选为卡波姆940,所述凝胶材料的添加重量是所述克立硼罗微乳溶液的添加重量的0.5%~2.5%。
进一步的,所述的克立硼罗微乳溶液中微乳粒子粒径为5-50nm。
进一步的,所述的克立硼罗微乳溶液中微乳粒子粒径为5-30nm。
本发明还提供了一种克立硼罗微乳组合物的制备方法,所述方法包括如下步骤:(1) 取所述油相、乳化剂、助乳化剂,搅拌均匀,加入克立硼罗,搅拌,加水,即得克立硼罗微乳溶液,(2)任选地加入凝胶材料,充分溶胀,混合均匀,即得克立硼罗微乳凝胶剂。
进一步的,步骤(1)为取所述油相、乳化剂、助乳化剂,搅拌均匀,加入克立硼罗,继续搅拌至溶解,加入纯化水,搅拌至澄明,待气泡消尽得澄清透明溶液,即为克立硼罗微乳溶液,其中,加入纯化水时,采用机械搅拌器来搅拌,搅拌速度为500~5000rpm
进一步的,所述反应的反应温度为20-100℃,优选为20-80℃。
发明的效果
1)本发明的克立硼罗微乳溶液稳定性好,具有理想微乳粒径,微乳离子表面带正电荷,且已被实验证明能够有效提高药物组合物的皮肤渗透性,可望提高克立硼罗的治疗效果;
2)本发明的克立硼罗微乳凝胶在克立硼罗微乳溶液的基础上,改善微乳的皮肤粘附性、涂展性及滞留时间问题,增加了药物在皮肤表面粘附性、提高药物皮肤滞留量,可提高过敏性皮炎临床治疗顺应性,而且同时还可防止微乳中药物析出,提高药物稳定性,延长药物的释放时间,实现缓释效果,达到了减少用药频率的目的。
3)本发明的克立硼罗微乳或微乳凝胶是O/W体系,药物体系兼具粘附性、涂展性及渗透性等优势的同时,具有易于清洗,不污染衣物等有点,具备良好的临床应用顺应性。
4)本发明的克立硼罗微乳溶液或微乳凝胶制备简单、过程可控。
附图说明
图1实施例1-3的克立硼罗微乳溶液粒度分布稳定性。
图2实施例4-6和对比例1的克立硼罗微乳溶液粒度分布稳定性。
具体实施方式
克立硼罗,英文名为Crisaborole,2016年获得美国FDA批准上市,是一种磷酸二酯酶-4(PDE-4)抑制剂。
本发明提供一种克立硼罗微乳组合物。具体而言,该组合物为克立硼罗微乳溶液或克立硼罗微乳凝胶剂,其中,以重量百分比计,克立硼罗微乳溶液的原料配方包括:克立硼罗1.0%~2.0%,油相8%~15%,乳化剂15%~30%,助乳化剂10%~25%,水40%~60%,其中油相为选自油酸乙酯、三乙酸甘油酯、棕榈酸异丙酯和肉豆蔻酸异丙酯中的一种或多种的组合,乳化剂为选自吐温80、吐温60中的一种或多种的组合,助乳化剂为选自无水乙醇、丙二醇和聚乙烯醇400中的一种或多种的组合;所述克立硼罗微乳凝胶剂的原料配方包含克立硼罗微乳溶液和凝胶材料。
在一项优选的实施方案中,所述克立硼罗微乳溶液的原料配方为:克立硼罗1.5%~2.0%,油相8%~10%,乳化剂20%~30%,助乳化剂10%~20%,水相40%~50%。
在一项优选的实施方案中,所述油相为油酸乙酯,乳化剂为吐温80,且助乳化剂为无水乙醇。该配方条件下,所制备的克立硼罗微乳溶液的微粒大小,稳定性最为优异,相应的皮肤渗透性最好,且同时无任何副作用。进一步地,克立硼罗微乳溶液的原料配方为:克立硼罗约2.0%,油相约8%,乳化剂约30%,助乳化剂约10%,水相约50%。
本发明的克立硼罗微乳溶液可以按照本领域所知晓的微乳溶液的一般方法来制备,然而优选地,本发明克立硼罗微乳溶液通过以下步骤制得:取配方量的所述油相、乳化剂、助乳化剂,在室温或加热条件下搅拌均匀,加入配方量的克立硼罗,继续搅拌至溶解,然后在持续搅拌条件下,不断加入纯化水,不断搅拌至澄明,待气泡消尽得澄清透明溶液,即为克立硼罗微乳溶液。该方法制备得到的克立硼罗微乳溶液为水包油型微乳,且微乳液滴表面带有电荷。
在一项优选的实施方案中,加入纯化水时,采用机械搅拌器来搅拌,搅拌速度为500~5000rpm,在该条件下,所获得微乳粒子的微粒大小比较理想而且均一性较好。
在一项优选的实施方案中,根据本发明,所述的克立硼罗微乳溶液中微乳粒子粒径在 5-50nm之间,优选为5-30nm,更优选为5-20nm。其中粒度分布的测试方法为:取微乳溶液,纯化水稀释一倍,采用Nicomp388激光粒度仪测定粒度分布。P.I值为方差 (Variance),为多次测量的波动系数,其与平均粒度同为检测报告结果。
作为本发明的进一步优选方案,所述克立硼罗微乳组合物为克立硼罗微乳凝胶剂,其与克立硼罗微乳溶液相比,通过凝胶材料稳定的网状结构可以防止微乳中药物析出,同时增加药物体系在皮肤表面的粘合性、涂展性,延长药物滞留时间,提高用药顺应性。
进一步地,克立硼罗微乳凝胶剂中,凝胶材料的添加重量是所述克立硼罗微乳溶液的添加重量的0.5%~2%。
优选地,所述凝胶材料为卡波姆,例如卡波姆940。
克立硼罗微乳凝胶剂的一种简单的制备方法为:取所述克立硼罗微乳溶液,加入凝胶材料,充分溶胀,混合均匀,即得。
根据本发明的另一个方面,该克立硼罗微乳溶液的制备方法为:1)取配方量的克立硼罗、油相、乳化剂、助乳化剂于室温或加热至60~80℃至溶解;2)持续搅拌条件下,将水相不断加入至油相中,不断搅拌、待气泡消尽,得到澄清透明微乳溶液。
进一步地,本发明所提供的微乳组合物中还可以加入常用的抑菌剂、香精等。
以下将结合具体的实施例来进一步阐述本发明中的技术方案。应当理解的是,下列实施例仅用于解释和说明本发明,而并不用于限制本发明的保护范围。除非另有说明,下列实施例中使用的仪器、材料和试剂等均可通过常规商业手段获得。
实施例1-1:克立硼罗微乳溶液的制备
按表1中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)室温下,取油酸乙酯、吐温80、无水乙醇,采用高效机械搅拌器,搅拌速度500rpm,搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表1
所得微乳溶液的平均粒度为16.5±0.6nm,P.I.0.127。
实施例1-2:克立硼罗微乳溶液的制备
本实施例基本同实施例1-1,不同的是,其中吐温80为吐温60替代,无水乙醇为聚乙二醇400替代,所得微乳溶液平均粒度为23.4±0.7nm,P.I.0.185。
实施例1-3:克立硼罗微乳溶液的制备
本实施例基本同实施例1-1,不同的是,其中吐温80为卵磷脂替代,无水乙醇为丙二醇替代,所得微乳溶液平均粒度为22.5±0.8nm,P.I.0.215。
实施例2:克立硼罗微乳溶液的制备
按表2中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)室温下,取油酸乙酯、吐温80、无水乙醇,采用高效机械搅拌器,搅拌速度2500rpm,搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表2
所得微乳溶液的平均粒度为7.7±0.3nm,P.I.0.251。
实施例3:克立硼罗微乳溶液的制备
按表3中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)室温下,取肉豆蔻酸异丙酯、吐温80、聚乙二醇400、无水乙醇,采用高效机械搅拌器,搅拌速度3000rpm,搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表3
所得微乳溶液的平均粒度为16.8±0.5nm,P.I.0.225。
实施例4:克立硼罗微乳溶液的制备
按表4中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)室温下,取三乙酸甘油酯、吐温80、无水乙醇,采用高效机械搅拌器,搅拌速度4000rpm搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至黄色澄清透明溶液。
表4
所得微乳溶液的平均粒度为19.8±0.8nm,P.I.0.187。
对比例1克立硼罗微乳溶液的制备
按表5中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)取棕榈酸异丙酯、聚氧乙烯氢化蓖麻油40、无水乙醇,油浴加热至45℃,采用高效机械搅拌器,搅拌速度4000rpm搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表5
所得微乳溶液的平均粒度为257.0±19.4nm,P.I.0.388,静置24h后,溶液发生分层,有部分油滴沉积和晶体析出。
实施例5:克立硼罗微乳溶液的制备
按表6中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)取油酸乙酯、吐温80、无水乙醇,采用高效机械搅拌器,搅拌速度5000rpm搅拌均匀,加热至60~80℃,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表6
所得微乳溶液的平均粒度为17.4±0.6nm,P.I.0.158。
实施例6:克立硼罗微乳溶液的制备
按表7中的配方组成和以下制备步骤制备克立硼罗微乳溶液:
1)取油酸乙酯、吐温80、无水乙醇,采用高效机械搅拌器,搅拌速度5000rpm搅拌均匀,加入克立硼罗,继续搅拌至溶解;
2)持续搅拌条件下,将纯化水不断加至油相,不断搅拌至澄明,待气泡消尽得无色至淡黄色澄清透明溶液。
表7
所得微乳溶液的平均粒度为26.5±0.8nm,P.I.0.271。
实施例7:克立硼罗微乳凝胶剂的制备
按表8中的配方组成和以下制备步骤制备克立硼罗微乳凝胶剂:
室温下,取克立硼罗微乳溶液,加入配方量卡波姆940,待其充分溶胀后,混合均匀。
表8
本例配方1所得的克立硼罗微乳凝胶剂粘度为3120±60mPa.s,配方2所得的克立硼罗微乳凝胶剂粘度为8780±80mPa.s,配方3所得的克立硼罗微乳凝胶剂粘度为12370±110mPa.s。
实施例8:克立硼罗微乳凝胶剂的制备
按表9中的配方组成和以下制备步骤制备克立硼罗微乳凝胶剂:
室温下,取克立硼罗微乳溶液,加入配方量卡波姆940,待其充分溶胀后,混合均匀。
表9
本例配方4所得的克立硼罗微乳凝胶剂粘度为7960±50mPa.s,配方5所得的克立硼罗微乳凝胶剂粘度为13890±430mPa.s,配方6所得的克立硼罗微乳凝胶剂粘度为23000±800mPa.s。
实施例9:克立硼罗微乳凝胶剂的制备
按表10中的配方组成和以下制备步骤制备克立硼罗微乳凝胶剂:
室温下,取克立硼罗微乳溶液,加入配方量卡波姆940,待其充分溶胀后,混合均匀。
表10
配方7所得的克立硼罗微乳凝胶剂粘度为14560±290mPa.s,配方8所得的克立硼罗微乳凝胶剂粘度为24380±690mPa.s,配方9所得的克立硼罗微乳凝胶剂粘度为42000 ±1100mPa.s。
实施例10:克立硼罗微乳凝胶剂的透皮吸收试验
分别采用实施例1-1的克立硼罗微乳溶液、对比例1的克立硼罗微乳溶液、实施例8中配方6制备的颗粒硼罗微乳凝胶剂以及参考克立硼罗乳膏剂专利文本(US20170152273A1)中的乳膏剂制备方法制备得到的2%克立硼罗乳膏剂,进行离体皮肤渗透性试验。
以上述样品进行人工皮肤膜渗透试验。取人工皮肤膜,固定于Franz扩散池的供应室,接受室中加入20%聚乙二醇400的pH 7.4磷酸盐缓冲液作为释放介质,保持人工膜内衬与溶液密切接触。取定量样品置供给室内,调节水浴使外套层温度恒定于37±1℃,搅拌速度为100r/min,测定接受室内药物含量,结果见表11。
表11
结果表明:克立硼罗微乳及其凝胶剂具备更好的透皮渗透性。克立硼罗微乳溶液虽可以促进药物的透皮吸收,但由于用药部位特殊性,使其不能较长的在皮肤表面滞留,需进行持续给药;克立硼罗乳膏剂虽可以满足持续给药,但皮肤渗透性差于微乳及其凝胶剂,同时其由大量油脂性基质组成,给药部位清洁及衣物清洁麻烦,用药顺应性差。因此,综合比较,克立硼罗微乳凝胶具有较好的皮肤粘附性及皮肤渗透性、并具备一定缓释作用,其特性有利于改善临床用药顺应性。
实施例11克立硼罗微乳溶液的稳定性实验
将制备的克立硼罗微乳溶液于室温下(25±2℃、65±5%RH)贮存,分别于5、10、30天考察微乳溶液稳定性。观察微乳溶液性状及外观变化表12、粒度分布表13及图1 和图2。
表12克立硼罗微乳溶液性状稳定性
表13克立硼罗微乳溶液粒度分布稳定性
结果表明:克立硼罗微乳溶液具备较好的稳定性。室温贮存下,保持澄清透明的均相体系。粒度分布稳定,未发生乳滴聚集、破裂。因此,按本技术制备的克立硼罗乳液具有良好的稳定性。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (12)
1.一种克立硼罗微乳组合物,其特征在于,所述克立硼罗微乳组合物为克立硼罗微乳溶液或克立硼罗微乳凝胶剂,其中,以重量百分比计,所述克立硼罗微乳溶液由克立硼罗0.5%~5.0%,油相5%~20%,乳化剂10%~40%,助乳化剂5%~30%,水30%~70%组成,其中油相选自油酸酯、三羧酸甘油酯、肉豆蔻酸酯中的一种或多种,乳化剂选自吐温80和吐温60中的一种或多种的组合,助乳化剂选自甲醇、乙醇、丙醇、异丙醇、丙二醇和聚乙二醇400中的一种或多种的组合;所述克立硼罗微乳溶液中微乳粒子粒径为5-50nm;所述克立硼罗微乳凝胶剂由所述克立硼罗微乳溶液和凝胶材料组成,其中所述凝胶材料选自卡波姆、甲基纤维素或羧甲基纤维素钠中的一种或多种。
2.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,以重量百分比计,所述克立硼罗微乳溶液由克立硼罗1.0%~2.0%,油相8%~15%,乳化剂15%~30%,助乳化剂10%~25%,水40%~60%组成。
3.根据权利要求2所述的克立硼罗微乳组合物,其特征在于,以重量百分比计,所述克立硼罗微乳溶液由克立硼罗1.5%~2.0%,油相8%~10%,乳化剂20%~30%,助乳化剂10%~20%,水40%~50%组成。
4.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,所述油酸酯为油酸烷基酯,其中所述烷基为C1-C6的烷基;所述三羧酸甘油酯中的羧酸为含C1-C6的羧酸;所述肉豆蔻酸酯为肉豆蔻酸烷基酯,其中所述烷基为C1-C6的烷基。
5.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,所述油相为油酸乙酯。
6.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,所述克立硼罗微乳凝胶剂的粘度为2000-30000mPa.s。
7.根据权利要求6所述的克立硼罗微乳组合物,其特征在于,所述克立硼罗微乳凝胶剂的粘度为3000-25000mPa.s。
8.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,所述凝胶材料的添加重量是所述克立硼罗微乳溶液的添加重量的0.5%~2.5%。
9.根据权利要求1所述的克立硼罗微乳组合物,其特征在于,所述克立硼罗微乳溶液中微乳粒子粒径为5-30nm。
10.一种权利要求1-9任一项所述的克立硼罗组合物的制备方法,其特征在于,所述方法包括如下步骤:(1)取所述油相、乳化剂、助乳化剂,搅拌均匀,加入克立硼罗,搅拌,加水,即得克立硼罗微乳溶液,(2)任选地加入凝胶材料,充分溶胀,混合均匀,即得克立硼罗微乳凝胶剂。
11.根据权利要求10所述的克立硼罗组合物的制备方法,其特征在于,步骤(1)为取所述油相、乳化剂、助乳化剂,搅拌均匀,加入克立硼罗,继续搅拌至溶解,加入纯化水,搅拌至澄明,待气泡消尽得澄清透明溶液,即为克立硼罗微乳溶液,其中,加入纯化水时,采用机械搅拌器来搅拌,搅拌速度为500~5000rpm,反应温度为20-100℃。
12.根据权利要求11所述的克立硼罗组合物的制备方法,其特征在于,所述反应温度为20-80℃。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711471716.XA CN109985000B (zh) | 2017-12-29 | 2017-12-29 | 克立硼罗微乳组合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711471716.XA CN109985000B (zh) | 2017-12-29 | 2017-12-29 | 克立硼罗微乳组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109985000A CN109985000A (zh) | 2019-07-09 |
CN109985000B true CN109985000B (zh) | 2022-09-02 |
Family
ID=67108546
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711471716.XA Active CN109985000B (zh) | 2017-12-29 | 2017-12-29 | 克立硼罗微乳组合物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109985000B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113504158A (zh) * | 2021-07-14 | 2021-10-15 | 山东诺明康药物研究院有限公司 | 一种含硼类皮炎药物的体外透皮试验方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20170152273A1 (en) * | 2015-11-30 | 2017-06-01 | Anacor Pharmaceuticals Inc. | Topical Pharmaceutical Formulations For Treating Inflammatory-Related Conditions |
-
2017
- 2017-12-29 CN CN201711471716.XA patent/CN109985000B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20170152273A1 (en) * | 2015-11-30 | 2017-06-01 | Anacor Pharmaceuticals Inc. | Topical Pharmaceutical Formulations For Treating Inflammatory-Related Conditions |
Also Published As
Publication number | Publication date |
---|---|
CN109985000A (zh) | 2019-07-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Yu et al. | Tacrolimus nanoparticles based on chitosan combined with nicotinamide: enhancing percutaneous delivery and treatment efficacy for atopic dermatitis and reducing dose | |
Li et al. | A more efficient ocular delivery system of triamcinolone acetonide as eye drop to the posterior segment of the eye | |
Mirza et al. | A vaginal drug delivery model | |
US20040147578A1 (en) | Use of lipoaminoacids as absorption promoters in a pharmaceutical composition | |
EP1957087A1 (en) | Compositions for external application, containing adenosyl cobalamin for improvement of skin diseases | |
JPH04501123A (ja) | 脱水/水補給リポソームに被嚢されたペプチド/タンパク質の局所送達 | |
CN101703468A (zh) | 维生素e油纳米乳制剂与制备方法 | |
CN114870016B (zh) | 一种jak抑制剂的微乳泡沫剂及其应用 | |
Wang et al. | Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: Simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects | |
CN109069418A (zh) | 包含他克莫司的局部组合物 | |
Huang et al. | A novel hyaluronic acid-based dissolving microneedle patch loaded with ginsenoside Rg3 liposome for effectively alleviate psoriasis | |
El-Salamouni et al. | Evaluation of chamomile oil and nanoemulgels as a promising treatment option for atopic dermatitis induced in rats | |
EP3957300A1 (en) | Cationic hyaluronic acid modified lipoid vesicle and preparation and application thereof | |
JP2023520273A (ja) | 治療化合物、製剤、およびその使用 | |
Lu et al. | Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid | |
JPH10513181A (ja) | 経皮製剤 | |
CN101428009A (zh) | 胰岛素经鼻吸入粉雾剂 | |
CN109985000B (zh) | 克立硼罗微乳组合物 | |
Yao et al. | Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis | |
Lv et al. | Solid lipid nanoparticle delivery of rhynchophylline enhanced the efficiency of allergic asthma treatment via the upregulation of suppressor of cytokine signaling 1 by repressing the p38 signaling pathway | |
Gupta et al. | Design and evaluation of thermoreversible in situ gelling system of forskolin for the treatment of glaucoma | |
CN112972381B (zh) | 一种液晶包覆晶型药物的载药乳液及其制备方法 | |
Lalan et al. | Atopic dermatitis: Drug delivery approaches in disease management | |
CN101422431A (zh) | 胰岛素经鼻给药制剂 | |
Sheng et al. | Oxybutynin nanosuspension gel for enhanced transdermal treatment for overactive bladder syndrome |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: 215123 10th Floor, Building D, No. 398 Ruoshui Road, Suzhou Industrial Park, Jiangsu Province Patentee after: Suzhou Wangshan Wangshui Biopharmaceutical Co.,Ltd. Country or region after: China Address before: 215123 10th Floor, Building D, No. 398 Ruoshui Road, Suzhou Industrial Park, Jiangsu Province Patentee before: SUZHOU VIGONVITA LIFE SCIENCES Co.,Ltd. Country or region before: China |