CN105380900B - 一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 - Google Patents
一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 Download PDFInfo
- Publication number
- CN105380900B CN105380900B CN201510824766.6A CN201510824766A CN105380900B CN 105380900 B CN105380900 B CN 105380900B CN 201510824766 A CN201510824766 A CN 201510824766A CN 105380900 B CN105380900 B CN 105380900B
- Authority
- CN
- China
- Prior art keywords
- nano
- preparation
- oxide
- minocycline
- added
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 208000002874 Acne Vulgaris Diseases 0.000 title claims abstract description 16
- 206010000496 acne Diseases 0.000 title claims abstract description 16
- 238000002653 magnetic therapy Methods 0.000 title claims abstract description 8
- 229960004023 minocycline Drugs 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 22
- 239000002105 nanoparticle Substances 0.000 claims abstract description 19
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003292 glue Substances 0.000 claims abstract description 8
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 7
- 229960001631 carbomer Drugs 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 3
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 claims abstract 5
- 238000003756 stirring Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- 102000009027 Albumins Human genes 0.000 claims description 6
- 108010088751 Albumins Proteins 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000693 micelle Substances 0.000 claims description 5
- 230000002441 reversible effect Effects 0.000 claims description 5
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002122 magnetic nanoparticle Substances 0.000 claims description 4
- 239000004530 micro-emulsion Substances 0.000 claims description 4
- 239000004246 zinc acetate Substances 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000007872 degassing Methods 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 238000005352 clarification Methods 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims 1
- 238000002604 ultrasonography Methods 0.000 claims 1
- 229910044991 metal oxide Inorganic materials 0.000 abstract description 10
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 9
- 229920002988 biodegradable polymer Polymers 0.000 abstract description 6
- 239000004621 biodegradable polymer Substances 0.000 abstract description 6
- 238000010382 chemical cross-linking Methods 0.000 abstract description 6
- 239000003431 cross linking reagent Substances 0.000 abstract description 6
- 238000013268 sustained release Methods 0.000 abstract description 3
- 239000012730 sustained-release form Substances 0.000 abstract description 3
- 239000011159 matrix material Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000004706 metal oxides Chemical class 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 18
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 15
- 241000186427 Cutibacterium acnes Species 0.000 description 9
- 229940055019 propionibacterium acne Drugs 0.000 description 8
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 210000003780 hair follicle Anatomy 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000013980 iron oxide Nutrition 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 206010040882 skin lesion Diseases 0.000 description 4
- 231100000444 skin lesion Toxicity 0.000 description 4
- 229960001727 tretinoin Drugs 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000001732 sebaceous gland Anatomy 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940040944 tetracyclines Drugs 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 241000555688 Malassezia furfur Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000186429 Propionibacterium Species 0.000 description 1
- 241000882890 Renova Species 0.000 description 1
- -1 Salicylic acid Compound Chemical class 0.000 description 1
- 206010039792 Seborrhoea Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940022880 bentoquatam Drugs 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 229940126678 chinese medicines Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229940056319 ferrosoferric oxide Drugs 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229960002421 minocycline hydrochloride Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229940059527 renova Drugs 0.000 description 1
- 229940002683 retin-a Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 210000004378 sebocyte Anatomy 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- 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
-
- 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
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用，原料包括药物米诺环素、纳米金属氧化物、生物可降解高分子材料、卡波姆胶940、化学交联剂；重量百分比为：米诺环素0.05％～0.5％(W/W)，生物可降解高分子材料20％～25％(W/W)，纳米金属氧化物0.2％～4％(W/W)，卡波姆胶CBM‑940 60％～79％(W/W)，化学交联剂为0.01％～0.02％(W/W)；以生物可降解高分子材料包裹米诺环素及纳米金属氧化物制成金属氧化物‑米诺环素纳米粒，以卡波姆940(carbopol‑940)为基质制成缓释凝胶；所述纳米金属氧化物为纳米氧化铁、纳米氧化锌的混合物。
Description
技术领域
本发明涉及纳米材料与抗菌药物协同作用的临床研究，用于制备皮肤科用药品，特别用于治疗痤疮等皮肤疾病。
背景技术
痤疮是毛囊皮脂腺单位的一种慢性炎症性皮肤病，好发于青少年，愈后易遗留疤痕，对青少年的心理和社交影响很大。据估计，全球对治疗青春痘药物的需求每年可达约18.7亿英镑的(约合190亿元人民币)市值。痤疮发病机制较为复杂，目前研究认为毛囊中含有糠秕马拉色菌、凝固酶阴性葡萄球菌、格兰阴性杆菌以及痤疮丙酸杆菌等多种微生物，其中痤疮丙酸杆菌产生的脂酶分解皮脂生成游离脂肪酸，同时趋化炎症细胞和介质，是诱导痤疮发生的关键因素。临床上痤疮的主要疗法是局部或系统使用抗生素或维A酸类药物，但痤疮丙酸杆菌日益增多的耐药性以及维A酸类药物的不良反应，大大限制了其在临床上的使用。
2005年《全球痤疮联盟》指南明确指出“选择药物治疗痤疮时应尽可能针对多种发病机制”，因此既能抑制痤疮丙酸杆菌繁殖又兼顾非特异性抗炎症作用的抗生素应当优先考虑。但是，只有活的痤疮丙酸杆菌与炎症形成有关，而皮损部位分离的痤疮丙酸杆菌会对四环素类或大环内酯类抗生素耐药，因此，有效抑制活的细菌才能从根本上控制炎症反应。抗生素需有效渗透至毛囊及皮脂腺，才能获得较高的抗菌效果，由于药物的分子质量及亲脂性存在较大差别，导致在毛囊、皮脂腺中的分布浓度有差别。结合抗生素药代动力学特别是选择分布皮脂溢出部位，应首选四环素类抗生素。对于痤疮患者耐药性携带情况分析发现四环素类耐药率为四环素＞多西环素＞米诺环素，同时研究发现米诺环素在毛囊、皮脂腺中的浓度高，所以米诺环素是治疗寻常痤疮的首选抗生素。
目前已有口服米诺环素与维A酸类药物、水杨酸类化合物以及过氧苯胺酰等外用制剂协同作用的报道。但口服米诺环素每日剂量最少为100mg，肝肾毒性较强，而外用米诺环素会产生耐药性，不能长期使用；维A酸类药物遇光和氧化剂易分解，诱发皮炎；水杨酸类化合物和强氧化剂过氧苯胺酰皮肤刺激性较强。如何寻找出一种安全、有效、彻底、耐受性好的治疗药物或治疗方法，是当今皮肤科医生所面临的难题之一。
发明内容
本发明的目的是为解决现有技术上的问题，提供了一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用，本产品在抗菌药物及缓释材料的选择上进行优化，使其具有药效好、副作用小、定向作用准、易于操作、成本低等优点。
本发明是通过以下方式实现的：
一种治疗痤疮的纳米磁疗外用凝胶的制备方法，原料包括药物米诺环素、纳米金属氧化物、生物可降解高分子材料、卡波姆胶940、化学交联剂；重量百分比为：米诺环素0.05％～0.5％(W/W)，生物可降解高分子材料20％～25％(W/W)，纳米金属氧化物0.2％～4％(W/W)，卡波姆胶CBM-94060％～79％(W/W)，化学交联剂为0.01％～0.02％(W/W)；以生物可降解高分子材料包裹米诺环素及纳米金属氧化物制成金属氧化物-米诺环素纳米粒，以卡波姆940(carbopol-940)为基质制成缓释凝胶；所述纳米金属氧化物为纳米氧化铁、纳米氧化锌的混合物。
所述的制备方法，金属氧化物-米诺环素纳米粒尺寸大小在500nm以下。
所述的制备方法，所述生物可降解高分子材料包括白蛋白、聚乳酸(PLA)、羧甲基纤维素盐(CMC-Na)、海藻酸盐多种材料中的一种或多种。
所述的制备方法，所述纳米金属氧化物为纳米氧化铁和纳米氧化锌，纳米氧化铁与纳米氧化锌质量比为1∶4～1∶10。
所述的制备方法，所述的化学交联剂包括甲醛、戊二醛、多聚甲醛中的一种或几种。
所述的制备方法，所述含药磁性纳米粒的具体制备步骤如下：
1)、将米诺环素溶于水中配制成水溶液后将该水溶液加入磷酸盐缓冲液中，制成米诺环素质量浓度为0.05～50％的溶液，pH＝8，加入所述的纳米金属氧化物及所述的生物可降解高分子材料，搅拌使之形成悬浊液；
2)、向步骤(1)所得悬浊液中加入有机相，水相与有机相的体积比为1∶4～1∶5，并加入所述化学交联剂，搅拌30min，待其充分固化后离心，洗涤得金属氧化物-米诺环素纳米粒。
所述的制备方法，所述缓释凝胶的制备步骤如下：取卡波姆胶固体，加入蒸馏水，水浴搅拌至固体完全溶解；冷却至室温后，放置到搅拌器中，边搅拌边加入质量分数为0.05％～10％的金属氧化物-米诺环素纳米粒，搅拌混匀，逐滴滴加三乙醇胺调节pH值，pH值为7时形成透明凝胶，超声波脱气后即得目标产品。
所述的制备方法，所述的有机相为乙醇。
根据任一所述制备方法制备获得的纳米磁疗外用凝胶。
所述的纳米磁疗外用凝胶在制备治疗痤疮药物中的应用。
本发明将米诺环素药物分子与具有抗菌作用的纳米氧化锌粒子相结合制成外用凝胶，利用纳米粒子携带药物分子通过内吞作用进入毛囊、皮脂腺细胞的特定部位，直接作用于病菌，提高了靶区的药物浓度、药物利用率和疗效，同时利用微量元素疗法与抗生素治疗的协同作用，降低药物的毒副作用及不良反应，由于减少了米诺环素用量，因此可以降低细菌耐药性的发生机率。
附图说明
图1是活性氧化物-米诺环素纳米粒透射电镜图；
图2是本发明的体外实验结果：活性氧化物-米诺环素纳米粒凝胶细胞毒性研究；
图3是本发明的体外实验结果：活性氧化物-米诺环素纳米粒凝胶的抑菌性能测试；
具体实施方式
以下结合具体实施例，对本发明进行详细说明。
实施例1：纳米氧化铁-米诺环素纳米级凝胶
一、纳米氧化锌反胶束微乳液的制备
精确配置1mol/L乙酸锌水溶液待用，然后称取0.3655g的十六烷基三甲基溴化胺(CTAB)，加入到10ml的环己烷中；随后向溶液中精确低价5ml的异丙醇(IPA)，持续搅拌至形成均匀的乳白色乳液，继续搅拌，并加入乙酸锌水溶液直至溶液体系瞬间澄清，说明两项体系已经形成反胶束微乳液，继续滴加乙酸锌溶液保持澄清即停止。
二、纳米氧化铁-纳米氧化锌-米诺环素白蛋白纳米粒的制备
1)取50％浓度的米诺环素0.1ml溶液于0.9ml缓冲溶液中配置成pH＝8含药5％混合液，加入混合液体积比0.5％的白蛋白，即5mg白蛋白，放置于西林瓶中，再将混合液加入西林瓶中，匀速搅拌10min，转速600rpm。
2)各加入0.1mg纳米氧化铁(四氧化三铁)固体和0.5ml纳米氧化锌胶束后，再各加入无水乙醇4ml继续搅拌30s。
3)加入戊二醛20μl后继续搅拌30min得到所要制备的纳米粒溶液。
三、含药纳米凝胶的制备
取卡波姆胶固体1g于250mL烧杯中，加入100mL蒸馏水，置于40℃水浴搅拌至固体完全溶解。冷却至室温后，放置到搅拌器中，边搅拌边加入质量分数为0.05％、0.5％、5％、10％等不同浓度的含药磁性纳米粒，搅拌混匀，逐滴滴加三乙醇胺调节pH值，pH值为7时形成透明凝胶，超声波脱气30min后即得目标产品。
透射电镜实验结果显示(图1)，活性氧化物-米诺环素白蛋白纳米粒粒径小于100nm，属于纳米粒。
细胞毒性：收集对数期L929小鼠成纤维细胞，加入96孔平底板，每孔加入100μl，在5％CO2，37℃孵育至细胞单层铺满孔底。加入浓度梯度的药物，5％CO2，37℃孵育16～48小时，倒置显微镜下观察。每孔加入20μl MTT溶液(5mg/ml，即0.5％MTT)，继续培养4h后终止培养，小心吸去孔内培养液。每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪OD 490nm处测量各孔的吸光值，计算细胞存活率。图2是本发明的体外细胞毒性实验结果：研究结果表明该凝胶可以降低盐酸米诺环素的细胞毒性，不会对机体产生毒性、过敏反应及免疫作用。
抑菌能力：以疮疱丙酸杆菌(Propionibacterium acnes)为待测菌种，用打孔法来评价水凝胶的抑菌效果。将痤疮丙酸菌接种到琼脂平板上，用直径为4mm的打孔器在营养琼脂平板上均匀打出4个孔。用微量移液器加入25μl配置好的不同纳米氧化锌含量的凝胶。静置，倒置培养皿于37℃培养24h后，用游标卡尺测量抑菌直径。如图3所示，是本发明的抑菌性能体外实验结果：抑菌圈直径大于7mm视为有抑菌活性。由结果能看出凝胶对痤疮丙酸杆菌的抑菌能力随纳米氧化锌含量增加逐步增大，当纳米氧化锌含量大于0.6％时抑菌能力较为稳定。
临床疗效：治疗组外用活性氧化物-米诺环素凝胶(含米诺环素纳米粒质量分数为0.6％，米诺环素含量为0.005％，每日1次，凝胶5mg/次；对照组口服盐酸米诺环素胶囊(惠氏制药有限公司，批准文号：国药准字H10960010)50mg/次，每日2次；空白组外用空白卡波姆胶，5mg/次，均为每日一次。连续治疗6周，每2周复诊1次，观察并记录皮损变化。
疗效判断标准分为显效、改善和无效。显效：皮损消退70～99％；改善：皮损消退30～69％；无效：治疗后皮损消退不足30％或无明显好转。
表1 凝胶法治疗痤疮与普通对照法对比
应当理解的是，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，而所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (1)
1.一种治疗痤疮的纳米磁疗外用凝胶的制备方法，其特征在于，包括以下步骤：
一、纳米氧化锌反胶束微乳液的制备
配制1mol/L乙酸锌水溶液待用，然后称取0.3655g的十六烷基三甲基溴化铵，加入到10mL的环己烷中；随后向溶液中滴加5mL的异丙醇，持续搅拌至形成均匀的乳白色乳液，继续搅拌，并加入乙酸锌水溶液直至溶液体系瞬间澄清，说明两相体系已经形成反胶束微乳液，继续滴加乙酸锌溶液保持澄清即停止；
二、含药磁性纳米粒的制备
1)取50％浓度的米诺环素0.1mL溶液于0.9mL缓冲溶液中配制成pH＝8含药5％混合液，5mg白蛋白放置于西林瓶中，再将混合液加入西林瓶中，匀速搅拌10min，转速600rpm；
2)加入0.1mg纳米四氧化三铁和0.5ml纳米氧化锌反胶束后，再加入无水乙醇4mL继续搅拌30s；
3)加入戊二醛20μl后继续搅拌30min得到所要制备的纳米粒溶液；
三、含药纳米凝胶的制备
取卡波姆胶固体1g于250mL烧杯中，加入100mL蒸馏水，置于40℃水浴搅拌至固体完全溶解；冷却至室温后，放置到搅拌器中，边搅拌边加入质量分数为0.05％、0.5％、5％或10％的含药磁性纳米粒，搅拌混匀，逐滴滴加三乙醇胺调节pH值，pH值为7时形成透明凝胶，超声波脱气30min后即得。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510824766.6A CN105380900B (zh) | 2015-11-25 | 2015-11-25 | 一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510824766.6A CN105380900B (zh) | 2015-11-25 | 2015-11-25 | 一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105380900A CN105380900A (zh) | 2016-03-09 |
| CN105380900B true CN105380900B (zh) | 2018-05-29 |
Family
ID=55414083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510824766.6A Expired - Fee Related CN105380900B (zh) | 2015-11-25 | 2015-11-25 | 一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105380900B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494426B (zh) * | 2020-06-08 | 2022-02-18 | 西南大学 | 僵蚕醇提物及其应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288673A (zh) * | 2007-09-30 | 2008-10-22 | 西北工业大学 | 一种盐酸米诺环素微球及其制备方法以及在制药中的应用 |
| WO2014083311A1 (en) * | 2012-11-27 | 2014-06-05 | Hovione International Ltd | Tetracycline topical formulations, preparation and uses thereof |
-
2015
- 2015-11-25 CN CN201510824766.6A patent/CN105380900B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288673A (zh) * | 2007-09-30 | 2008-10-22 | 西北工业大学 | 一种盐酸米诺环素微球及其制备方法以及在制药中的应用 |
| WO2014083311A1 (en) * | 2012-11-27 | 2014-06-05 | Hovione International Ltd | Tetracycline topical formulations, preparation and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸米诺环素微球凝胶的制备;高迎春等;《中国医院药学杂志》;20061231;第26卷(第1期);第79-80页，尤其是第2.1.2和2.3节 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105380900A (zh) | 2016-03-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rusu et al. | Recent advances regarding the therapeutic potential of adapalene | |
| Mou et al. | Hydrogel containing minocycline and zinc oxide-loaded serum albumin nanopartical for periodontitis application: preparation, characterization and evaluation | |
| Bai et al. | Solvothermal synthesis of ZnO nanoparticles and anti-infection application in vivo | |
| Rani et al. | Antidiabetic activity enhancement in streptozotocin+ nicotinamide–induced diabetic rats through combinational polymeric nanoformulation | |
| Madan et al. | Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies | |
| Ayyanaar et al. | ROS-responsive chitosan coated magnetic iron oxide nanoparticles as potential vehicles for targeted drug delivery in cancer therapy | |
| Wang et al. | Pd-Cu nanoalloy for dual stimuli-responsive chemo-photothermal therapy against pathogenic biofilm bacteria | |
| Thotakura et al. | Aspartic acid derivatized hydroxylated fullerenes as drug delivery vehicles for docetaxel: An explorative study | |
| Hussein-Al-Ali et al. | Novel kojic acid-polymer-based magnetic nanocomposites for medical applications | |
| CN101422432B (zh) | 一种替米考星纳米乳抗菌药物的制备方法 | |
| Chen et al. | Fabrication of supercritical antisolvent (SAS) process-assisted Fisetin-encapsulated poly (vinyl pyrrolidone)(PVP) nanocomposites for improved anticancer therapy | |
| Zhang et al. | A stable quaternized chitosan-black phosphorus nanocomposite for synergetic disinfection of antibiotic-resistant pathogens | |
| Orylska-Ratynska et al. | Tetracyclines—an important therapeutic tool for dermatologists | |
| Zhang et al. | A Prussian blue alginate microparticles platform based on gas-shearing strategy for antitumor and antibacterial therapy | |
| Patil et al. | Generation of sustained release chitosan nanoparticles for delivery of ketorolac tromethamine: a tubular microreactor approach | |
| Chen et al. | Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes | |
| Lin et al. | Different dimensional copper-based metal–organic frameworks with enzyme-mimetic activity for antibacterial therapy | |
| Pagano et al. | Emulgel loaded with flaxseed extracts as new therapeutic approach in wound treatment | |
| Kumari et al. | Nanoscale calcium oxide and its biomedical applications: a comprehensive review | |
| Mutalik et al. | Gold-based nanostructures for antibacterial application | |
| CN105380900B (zh) | 一种治疗痤疮的纳米磁疗外用凝胶及其制备方法和应用 | |
| Khan et al. | Antibacterial and Wound-Healing Activities of Statistically Optimized Nitrofurazone-and Lidocaine-Loaded Silica Microspheres by the Box–Behnken Design | |
| Song et al. | Ciprofloxacin-releasing ROS-sensitive nanoparticles composed of poly (ethylene glycol)/poly (D, L-lactide-co-glycolide) for antibacterial treatment | |
| Gegel et al. | Thermosensitive chitosan-containing hydrogels: their formation, properties, antibacterial activity, and veterinary usage | |
| Abou-Taleb et al. | Chitosan/solid-lipid nanoparticles hybrid gels for vaginal delivery of estradiol for management of vaginal menopausal symptoms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| CB03 | Change of inventor or designer information |
Inventor after: Mou Jie Inventor after: Pei Dongsheng Inventor after: Zhao Bonan Inventor after: Lu Jianwu Inventor after: Xu Mingdi Inventor after: Gao Gan Inventor after: Gao Junhong Inventor after: Jiang Liqun Inventor after: Yang Dongzhi Inventor before: Mou Jie Inventor before: Pei Dongsheng Inventor before: Zhao Bonan Inventor before: Lu Jianwu Inventor before: Xu Mingdi Inventor before: Gao Gan Inventor before: Gao Junhong Inventor before: Jiang Liqun |
|
| COR | Change of bibliographic data | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160519 Address after: 221004 Xuzhou Medical College, No. 209 copper hill road, Jiangsu, Xuzhou Applicant after: Xuzhou Medical College Address before: 221004 Xuzhou Medical College, No. 209 copper hill road, Jiangsu, Xuzhou Applicant before: Mou Jie |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210111 Address after: 221000 room 710, block C, Central Plaza, Yongjia new town, Yunlong District, Xuzhou City, Jiangsu Province Patentee after: Xuzhou Hanxiang Biotechnology Research Institute Co.,Ltd. Address before: Xuzhou Medical College, 209 Tongshan Road, Xuzhou City, Jiangsu Province, 221004 Patentee before: XUZHOU MEDICAL College |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180529 |