CN116919939A - 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 - Google Patents
一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN116919939A CN116919939A CN202210351303.2A CN202210351303A CN116919939A CN 116919939 A CN116919939 A CN 116919939A CN 202210351303 A CN202210351303 A CN 202210351303A CN 116919939 A CN116919939 A CN 116919939A
- Authority
- CN
- China
- Prior art keywords
- component
- composition
- lipid material
- bpo
- dispersed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 239000004342 Benzoyl peroxide Substances 0.000 title claims abstract description 79
- 235000019400 benzoyl peroxide Nutrition 0.000 title claims abstract description 78
- 239000000203 mixture Substances 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 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 title claims abstract description 19
- 229960001727 tretinoin Drugs 0.000 title claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 52
- 150000002632 lipids Chemical class 0.000 claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000004203 carnauba wax Substances 0.000 claims description 8
- 235000013869 carnauba wax Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- 230000008018 melting Effects 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003349 gelling agent Substances 0.000 claims description 7
- 229940049654 glyceryl behenate Drugs 0.000 claims description 7
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 5
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 4
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 4
- 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 description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 4
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 3
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- 229940076810 beta sitosterol Drugs 0.000 claims description 2
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 2
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 2
- 229940082483 carnauba wax Drugs 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 229940107161 cholesterol Drugs 0.000 claims description 2
- XHRPOTDGOASDJS-UHFFFAOYSA-N cholesterol n-octadecanoate Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCCCC)C2 XHRPOTDGOASDJS-UHFFFAOYSA-N 0.000 claims description 2
- XHRPOTDGOASDJS-XNTGVSEISA-N cholesteryl stearate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)C1 XHRPOTDGOASDJS-XNTGVSEISA-N 0.000 claims 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 claims description 2
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 2
- 229950005143 sitosterol Drugs 0.000 claims description 2
- 239000001993 wax Substances 0.000 claims description 2
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 24
- 239000002994 raw material Substances 0.000 description 19
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 13
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 11
- 208000002874 Acne Vulgaris Diseases 0.000 description 11
- 206010000496 acne Diseases 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 238000000576 coating method Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000227 grinding Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229940075507 glyceryl monostearate Drugs 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 241000186427 Cutibacterium acnes Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000003093 cationic surfactant Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229940055019 propionibacterium acne Drugs 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000020154 Acnes Diseases 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000001126 Keratosis Diseases 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 150000004492 retinoid derivatives Chemical class 0.000 description 2
- 210000001732 sebaceous gland Anatomy 0.000 description 2
- -1 silicate anions Chemical class 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NLMOYOROJZUUMN-UHFFFAOYSA-N 2,3-dihydroxypropyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO.CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO NLMOYOROJZUUMN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- YMSGUPPAXLHXHG-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO YMSGUPPAXLHXHG-UHFFFAOYSA-N 0.000 description 1
- 208000002506 Darier Disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010059866 Drug resistance 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
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 206010035116 pityriasis rubra pilaris Diseases 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
- A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明提供一种维A酸和过氧化苯甲酰组合物及其制备方法和用途,所述组合物包含组分(i)过氧化苯甲酰;组分(ii)维A酸;和(iii)一种脂质材料。所述组合物具有优良的稳定性,且制剂工艺简单,易于放大化生产。
Description
技术领域
本发明属于组合物制剂领域,具体涉及一种维A酸和过氧化苯甲酰组合物及其制备方法和用途。
背景技术
痤疮是一种好发于青春期并主要累及面部的毛囊皮脂腺单位慢性炎症性皮肤病。痤疮发病机制仍未完全阐明。遗传背景下激素诱导的皮脂腺过度分泌脂质、毛囊皮脂腺导管角化异常、痤疮丙酸杆菌等毛囊微生物增殖及炎症和免疫反应等与之相关。
外用维A酸类药物具有改善毛囊皮脂腺导管角化、溶解微粉刺和粉刺、抗炎、预防和改善痤疮炎症后色素沉着和痤疮瘢痕等作用。此外,还能增加皮肤渗透性,在联合治疗中可以增加外用抗菌及抗炎药物的疗效。外用维A酸类药物可作为轻痤疮的单独一线用药,中度痤疮的联合用药以及痤疮维持治疗的首选。常用维A酸类药物包括维A酸和异维A酸。
过氧化苯甲酰可缓慢释放出新生态氧和苯甲酸,具有杀灭痤疮丙酸杆菌、抗炎及轻度溶解粉刺作用,该药目前尚无针对痤疮丙酸杆菌的耐药性出现,可作为炎性痤疮首选外用抗菌药物,可以单独使用,也可联合外用维A酸类药物或外用抗生素使用。药物有2.5%~10%不同浓度及洗剂、乳剂或凝胶等不同剂型可供选择。
维A酸和过氧化苯甲酰在治疗痤疮领域均显示出较好的效果,但是维A酸和过氧化苯甲酰存在配伍禁忌。维A酸为还原剂,而过氧化苯甲酰为氧化剂,在同一处方中会发生氧化还原反应而导致两种药物降解。
现有文献中已有关于维A酸和过氧化苯甲酰的制剂报道,例如,专利申请CN101754677B公开了一种用于以金属氧化物涂布固体水不溶性颗粒物质的方法,其中,固体水不溶性颗粒包括维A酸、过氧化苯甲酰等API,所述方法包括(1)研磨:API与阳离子表面活性剂高速研磨,形成悬浊液,阳离子表面活性剂覆盖在API表面,粒径控制在几十纳米;(2)涂布:加入硅酸钠溶液,500rpm搅拌,调节pH,使硅酸盐负离子与阳离子结合,吸附在药物表面上并聚合形成二氧化硅层;(3)重复涂布:重复涂布过程,依次添加阳离子表面活性剂和硅酸盐,形成二氧化硅囊壳,5-100次;(4)老化:室温,一定pH条件下搅拌24~96h。由于硅酸盐负离子与阳离子结合是一个被动吸附过程,重复涂布形成的二氧化硅囊壳重现性差,另外24-96h的老化过程极其耗时。采用该方法制剂,无论是重复涂布还是长时间的老化过程,在商业化生产上均较难实现,质量控制难度大,对设备要求高,成本高。
因此,需要开发一种稳定、安全无刺激且适于工业化生产的维A酸和过氧化苯甲酰组合物。
发明内容
为解决现有技术存在的问题,第一方面,本发明提供一种组合物,包含组分(i)过氧化苯甲酰;组分(ii)维A酸;和(iii)一种脂质材料。
根据本发明的实施方案,所述脂质材料选自巴西棕榈蜡,山嵛酸甘油酯、胆固醇、β固谷甾醇、棕榈酸甘油酯、胆固醇硬脂酸酯、蓖麻油蜡中的一种,两种或更多种。
根据本发明的实施方案,所述组合物进一步包含凝胶剂。所述凝胶剂选自HPMC、卡波姆、纤维素衍生物如HPMC,MC,CMC-Na、壳聚糖中的一种,两种或更多种。
根据本发明的实施方案,所述组合物进一步包含抗氧化剂,所述抗氧化剂选自丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)、叔丁基对苯二酚(TBHQ)、抗坏血酸棕榈酸酯中的一种,两种或更多种。
根据本发明的实施方案,所述组分(i)占组合物总量的约2.0%至约10.0%(w/w),例如2.0%,2.5%,3.0%,3.5%,4.0%,4.5%,5.0%,5.5%,6.0%,优选的,所述组分(i)占组合物总量的约2.0%至约3.0%(w/w)。
根据本发明的实施方案,所述组分(ii)占组合物总量的约0.01%至约0.30%(w/w),例如0.01%,0.025%,0.05%,0.1%,0.15%,0.20%(w/w),优选的,所述组分(ii)组分(i)占组合物总量的约0.025%至约0.20%(w/w)。
根据本发明的实施方案,所述凝胶剂占组合物总量的约5%至30%(w/w),例如,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,优选的,所述凝胶剂占组合物总量的约15%至约25%(w/w)。
根据本发明的实施方案,所述抗氧化剂占组合物总量的约0.01%至约0.50%(w/w),例如,0.01%,0.02%,0.025%,0.05%,0.1%,0.15%,0.20%(w/w)优选的,所述组分(i)占组合物总量的约0.02%至约0.30%(w/w)。
根据本发明的实施方案,所述组分(i)和组分(ii)分散在所述脂质材料中。在一些实施方案中,所述组分(i)和组分(ii)分别分散在脂质材料中。在一些实施方案中,所述分散组分(i)的脂质材料与组分(i)的质量比为0.5-3:1,例如为0.5:1,0.6:1,0.7:1,0.8:1,0.9:1,1.0:1,1.1:1,1.2:1,1.3:1,1.4:1,1.5:1,1.6:1,1.7:1,1.8:1,1.9:1,2.0:1,2.5:1,3:1;优选的为0.9-1.1:1。在一些实施方案中,所述分散组分(ii)的脂质材料与组分(ii)的质量比为6-15:1,例如为6:1,7:1,8:1,9:1,10:1,11:1,12:1,13:1,14:1,15:1;优选的为7-9:1。
根据本发明的实施方案,所述组分(i)分散在脂质材料中的制备步骤如下:将BPO和脂质材料混合,加热熔融搅拌均匀,冷却至室温。在一些实施方案中,所述加热熔融的温度为60-100℃,优选的,为75-85℃;在一些实施方案中,冷却至室温后,将所得材料经研磨后过40-100目筛,优选的,过60目筛。
根据本发明的实施方案,所述组分(ii)分散在脂质材料中的制备步骤如下:将RA和脂质材料混合,加热熔融搅拌均匀,冷却至室温。在一些实施方案中,所述加热熔融的温度为70-110℃,优选的,为85-95℃;在一些实施方案中,冷却至室温后,将所得材料经研磨后过60目筛;在一些实施方案中,将RA和脂质材料混合后进一步加入抗氧化剂。
第二方面,本发明提供所述组合物的制备方法,包括如下步骤:
(a)将组分(i)和组分(ii)分别分散在所述脂质材料中;
(b)将所述凝胶剂溶于水中,加热,加入被脂质材料分散的组分(i)和被脂质材料分散的组分(ii)。
根据本发明的实施方案,所述组分(i)、组分(ii)分散在脂质材料中的制备步骤分别如前所述。
根据本发明的实施方案,所述凝胶剂溶于水的质量百分比为15-25%,例如为15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,优选的为18-22%。
根据本发明的实施方案,所述步骤(b)中,加热温度为60-100℃,优选为75-85℃。
第三方面,本发明提供所述组合物在制备用于预防/缓解/治疗皮肤类疾病的药物中的用途。所述皮肤类疾病包括痤疮,银屑病、鱼鳞病、扁平苔癣、毛发红糠疹、毛囊角化病、鳞状细胞癌及黑色素瘤等。
有益效果
本发明提供了一种维A酸和过氧化苯甲酰的组合物制剂,具有优良的稳定性,且制剂工艺简单,易于放大化生产。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
材料和试剂缩写
RA:维A酸
BPO:过氧化苯甲酰
BHT:丁羟甲苯
CW:Carnauba Wax,巴西棕榈蜡
GB:Glyceryl Behenate,山嵛酸甘油酯
GT:Glycerol Tristearate,三硬脂酸甘油酯(硬脂)
GM:Glyceryl Monostearate,单硬脂酸甘油酯
以下实施例中的“%”,除非另有说明,均指质量百分数
实施例1RA/CW+BPO/CW组合物制备
1.以巴西棕榈蜡为脂质材料的RA、BPO中间体制备
I.取适量RA和BPO,分别进行适当研磨使药物尽量研细,过100目筛。
II.取上述RA 0.1g,以RA:巴西棕榈蜡:丁羟甲苯=1:8:1称量原辅料放入50ml EP管中,适当混匀,90℃加热熔融搅拌均匀,冷却至室温,再经研磨后过60目筛,即得0.1g包被RA中间体(RA/CW),其中,RA的理论含量10%。
III.取上述BPO(BPO原料标识含量为70%)0.4285g,以BPO:巴西棕榈蜡=1:1称量原辅料放入50ml EP管中,适当混匀,80℃加热熔融搅拌均匀,冷却至室温,再经研磨后过60目筛,即得0.857g包被BPO中间体(BPO/CW),其中,BPO的理论含量1*0.7/(1+1)=35%。
2.凝胶组合物制备
称取20g HPMC+80g水,加热到80℃,即得20%HPMC空白凝胶100g。
3.RA/BPO凝胶制备
按照下表A-1处方取RA原料(或RA/CW)、BPO原料(或BPO/CW),并加入处方量空白凝胶,搅拌均匀,即得10g凝胶。该凝胶组合物中,RA和BPO的理论含量分别为0.1%和3.0%。
表A-1
实施例2RA/GB+BPO/GB组合物制备
1.以山嵛酸甘油酯为脂质材料的RA、BPO中间体制备
I.取适量RA与BPO,分别进行适当研磨使药物尽量研细,过100目筛。
II.取上述RA0.1g,以RA:山嵛酸甘油酯:丁羟甲苯=1:8:1称量原辅料放入50mlEP管中,适当混匀,90℃加热熔融搅拌均匀,冷却至室温,再经研磨后过60目筛,即得0.1g包被RA中间体(RA/GB),其中,RA理论含量10%。
III.取上述BPO(BPO原料标识含量为70%)0.4285g,以BPO:山嵛酸甘油酯=1:1称量原辅料放入50ml EP管中,适当混匀,80℃加热熔融搅拌均匀,冷却至室温,再经研磨后过60目筛,即得0.857g包被BPO中间体(BPO/GB),其中,BPO的理论含量1*0.7/(1+1)=35%。
2.凝胶组合物制备
称取20g HPMC+80g水,加热到80℃,即得20%HPMC空白凝胶100g。
3.RA/BPO凝胶制备
按照下表B-1处方取RA原料(或RA/GB)、BPO原料(或BPO/GB),并加入处方量空白凝胶,搅拌均匀,即得10g凝胶。该凝胶组合物中,RA和BPO的理论含量分别为0.1%和3.0%。
表B-1
实施例3RA、BPO含量稳定性检测
1.样品处理方法
该操作需全程避光,取凝胶样品100mg,加入20mg亚硫酸钠,再加1ml水,涡旋10min破凝胶并反应掉BPO,再加2ml异丙醇超声20min提取,甲醇4ml,超声4min,13000rpm离心沉淀后取上清进样检测RA。
BPO的提取不加亚硫酸钠,其余操作同前,进样检测BPO。
2.维A酸(RA)检测方法
RA的HPLC检测方法参考中国药典(2020版):色谱柱:C18柱(150mm×4.6mm,5μm);流动相:甲醇-2%冰醋酸溶液(81:19);柱温:30℃;检测波长:350nm;流速:1mL/min;进样量:20μL。同一样品平行制备2份,取平均值。
3.过氧化苯甲酰(BPO)检测方法
BPO的HPLC检测方法为:色谱柱:C18柱(150mm×4.6mm,5μm);流动相:乙腈-水(1:1);柱温30℃,检测波长为254nm,流速1mL/min;进样量10μL。同一样品平行制备2份,取平均值。
4.巴西棕榈蜡包被效果测试:采用依据实施例1表A-1处方制备的RA/BPO凝胶,其活性成分含量如下表A-2所示。
表A-2处方中活性成分质量(g)
样品 | RA形式 | RA质量 | BPO形式 | BPO质量 |
Rx1-P | RA/CW | 0.01ga | BPO/CW | 0.3ga |
Rx2-P | RA/CW | 0.01ga | BPO | 0.3g |
Rx3-P | RA | 0.01g | BPO/CW | 0.3ga |
Control | RA | 0.01g | BPO | 0.3g |
注:上标a代表为理论计算的质量。
稳定性结果如下表A-3、A-4所示,其中,活性成分含量随检测时间点变化的比值以w/w%表示:
表A-3.室温下稳定性
表A-4.40℃加速稳定性
5.山嵛酸甘油酯包被效果测试
采用依据实施例1表B-1处方制备的RA/BPO凝胶,其活性成分含量如下表B-2所示。
表B-2
样品 | RA形式 | RA质量 | BPO形式 | BPO质量 |
Rx1-C | RA/GB | 0.01ga | BPO/GB | 0.3ga |
Rx2-C | RA/GB | 0.01ga | BPO | 0.3g |
Rx3-C | RA | 0.01g | BPO/GB | 0.3ga |
Control | RA | 0.01g | BPO | 0.3g |
注:上标a代表为理论计算的质量。
稳定性结果如下B-3、B-4所示:
表B-3.室温下稳定性
表B-4.40℃加速稳定性
实施例4.凝胶性能测定
对于巴西棕榈蜡和山嵛酸甘油酯包被的RA-BPO复方组合物,进行外观形状测定,观察色泽,粘稠度,均匀度,涂布性能,结果如下所示:
色泽与形态 | 涂布 | |
Rx1-P | 淡黄色凝胶,黏度适中,流动性好 | 易涂抹,质地细腻均匀,无颗粒感 |
Rx1-C | 淡黄色凝胶,黏度适中,流动性好 | 易涂抹,质地细腻均匀,无颗粒感 |
对比例1
参照实施例1,仅将脂质材料替换为三硬脂酸甘油酯(硬脂),制备得到以三硬脂酸甘油酯为脂质材料包被的RA中间体(RA/GT)和以三硬脂酸甘油酯为脂质材料包被的BPO中间体(BPO/GT),并依据实施例1的RA/BPO凝胶制备方法,分别制备四组样品:Rx1-H、Rx2-H、Rx3-H和control组,活性成分含量如下表C-1所示
表C-1
样品 | RA形式 | RA质量 | BPO形式 | BPO质量 |
Rx1-H | RA/GT | 0.01ga | BPO/GT | 0.3ga |
Rx2-H | RA/GT | 0.01ga | BPO | 0.3g |
Rx3-H | RA | 0.01g | BPO/GT | 0.3ga |
Control | RA | 0.01g | BPO | 0.3g |
注:上标a代表为理论计算的质量。
参照实施例3对所述样品中RA、BPO含量进行稳定性测试,结果如下表C-2、C-3所示:
表C-2.室温下稳定性
表C-3.40℃加速稳定性
结论:硬脂包被活性成分后,组合物制剂在40℃加速稳定性测试中,RA降解太快,外观性状明显变化,颜色从最初的淡黄色变为接近白色。
对比例2
参照实施例1,仅将脂质材料替换为单硬脂酸甘油酯,制备得到以单硬脂酸甘油酯为脂质材料包被的RA中间体(RA/GM)和以单硬脂酸甘油酯为脂质材料包被的BPO中间体(BPO/GM),并依据实施例1的凝胶组合物制备方法,分别制备四组样品:Rx1-M、Rx2-M、Rx3-M和control组,活性成分含量如下表D-1所示
表D-1
注:上标a代表为理论计算的质量。
参照实施例3对所述样品中RA、BPO含量进行稳定性测试,结果如下表D-2、D-3所示:
表D-2室温下稳定性
表D-3.40℃加速稳定性
结论:单硬脂酸甘油酯包被活性成分后,制剂在40℃加速实验中,RA迅速降解,颜色也从最初的淡黄色变为接近白色。
以上,对本发明示例性的实施方式进行了说明。但是,本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种组合物,包含组分(i)过氧化苯甲酰;组分(ii)维A酸;和(iii)一种脂质材料。
2.根据权利要求1所述的组合物,其特征在于,所述脂质材料选自巴西棕榈蜡,山嵛酸甘油酯、胆固醇、β固谷甾醇、棕榈酸甘油酯、胆固醇硬脂酸酯、蓖麻油蜡中的一种,两种或更多种。
3.根据权利要求1或2所述的组合物,其特征在于,所述组合物进一步包含凝胶剂,优选的,所述凝胶剂选自HPMC、卡波姆、纤维素衍生物如HPMC,MC,CMC-Na、壳聚糖中的一种,两种或更多种。
4.根据权利要求1-3任一项所述的组合物,其特征在于,所述组合物进一步包含抗氧化剂,优选的,所述抗氧化剂选自丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)、叔丁基对苯二酚(TBHQ)、抗坏血酸棕榈酸酯中的一种,两种或更多种。
5.根据权利要求1-4任一项所述的组合物,其特征在于,
所述组分(i)占组合物总量的约2.0%至约10.0%(w/w),优选的,所述组分(i)占组合物总量的约2.0%至约3.0%(w/w);
所述组分(ii)占组合物总量的约0.01%至约0.30%(w/w),优选的,所述组分(ii)组分(i)占组合物总量的约0.025%至约0.20%(w/w);
所述凝胶剂占组合物总量的约5%至30%(w/w),优选的,所述凝胶剂占组合物总量的约15%至约25%(w/w);
所述抗氧化剂占组合物总量的约0.01%至约0.50%(w/w),优选的,所述组分(i)占组合物总量的约0.02%至约0.30%(w/w)。
6.根据权利要求1-5任一项所述的组合物,其特征在于,所述组分(i)和组分(ii)分散在所述脂质材料中。
7.根据权利要求1-6任一项所述的组合物,其特征在于,所述组分(i)和组分(ii)分散在所述脂质材料中;优选的所述分散组分(i)的脂质材料与组分(i)的质量比为0.5-3:1;所述分散组分(ii)的脂质材料与组分(ii)的质量比为6-15:1。
8.根据权利要求7所述的组合物,其特征在于,所述组分(i)分散在脂质材料中的制备步骤如下:将BPO和脂质材料混合,加热熔融搅拌均匀,冷却至室温;所述组分(ii)分散在脂质材料中的制备步骤如下:将RA和脂质材料混合,加热熔融搅拌均匀,冷却至室温。
9.根据权利要求1-8任一项所述的组合物的制备方法,其特征在于,包括如下步骤:
(a)将组分(i)和组分(ii)分别分散在所述脂质材料中;
(b)将所述凝胶剂溶于水中,加热,加入被脂质材料分散的组分(i)和被脂质材料分散的组分(ii)。
10.根据权利要求1-8任一项所述的组合物在制备用于预防/缓解/治疗皮肤类疾病的药物中的用途。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210351303.2A CN116919939A (zh) | 2022-04-02 | 2022-04-02 | 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 |
PCT/CN2023/084164 WO2023185761A1 (zh) | 2022-04-02 | 2023-03-27 | 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210351303.2A CN116919939A (zh) | 2022-04-02 | 2022-04-02 | 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116919939A true CN116919939A (zh) | 2023-10-24 |
Family
ID=88199165
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210351303.2A Pending CN116919939A (zh) | 2022-04-02 | 2022-04-02 | 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116919939A (zh) |
WO (1) | WO2023185761A1 (zh) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2910320B1 (fr) * | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | Emulsion comprenant au moins un retinoide et du peroxyde de benzole |
EA201200347A1 (ru) * | 2009-12-31 | 2012-07-30 | Сол-Джел Текнолоджиз Лтд. | Микрокапсулы со стабилизированным ядром, способ их получения и их применение |
EP2726067B1 (en) * | 2011-06-29 | 2020-02-19 | Sol-Gel Technologies Ltd. | Stabilized topical formulations containing core-shell microcapsules |
CN106729722B (zh) * | 2016-11-21 | 2020-05-12 | 成都山信药业有限公司 | 一种制备稳定复方制剂的方法及复方制剂 |
US20190015368A1 (en) * | 2017-07-12 | 2019-01-17 | Sol-Gel Technologies Ltd. | Method of acne treatment by concomitant topical administration of benzoyl peroxide and tretinoin |
-
2022
- 2022-04-02 CN CN202210351303.2A patent/CN116919939A/zh active Pending
-
2023
- 2023-03-27 WO PCT/CN2023/084164 patent/WO2023185761A1/zh unknown
Also Published As
Publication number | Publication date |
---|---|
WO2023185761A1 (zh) | 2023-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Li et al. | Curcumin–piperine mixtures in self-microemulsifying drug delivery system for ulcerative colitis therapy | |
Sansone et al. | Flavonoid microparticles by spray-drying: Influence of enhancers of the dissolution rate on properties and stability | |
Wang et al. | A cost-effective method to prepare curcumin nanosuspensions with enhanced oral bioavailability | |
Sermkaew et al. | Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata | |
Zu et al. | Preparation and characterization of amorphous amphotericin B nanoparticles for oral administration through liquid antisolvent precipitation | |
CN102451179B (zh) | 一种含番茄红素,白藜芦醇或褪黑素的肠溶固体制剂及其制备方法 | |
Jin et al. | Enhanced oral absorption of 20 (S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies | |
CA2571606C (en) | Triterpene-containing oleogel-forming agent, triterpene-containing oleogel and method for producing a triterpene-containing oleogel | |
Del Gaudio et al. | Nanospray drying as a novel tool to improve technological properties of soy isoflavone extracts | |
Jin et al. | Novel breviscapine nanocrystals modified by panax notoginseng saponins for enhancing bioavailability and synergistic anti-platelet aggregation effect | |
CN103110648A (zh) | 钙泊三醇倍他米松软膏及其制备方法 | |
CN102038672B (zh) | 一种用于治疗痤疮的药物组合物 | |
CN105106968B (zh) | 一种胃溶型薄膜包衣预混剂及其制备方法 | |
Li et al. | Development and evaluation of optimized sucrose ester stabilized oleanolic acid nanosuspensions prepared by wet ball milling with design of experiments | |
EP2568966B1 (en) | New particles of tetracyclines and protecting agent | |
CN116919939A (zh) | 一种维a酸和过氧化苯甲酰组合物及其制备方法和用途 | |
CN114796110A (zh) | 一种不含乙醇的难溶性药物浓缩液以及由其制备的胶束溶液 | |
TW201513894A (zh) | 含埃克替尼的皮膚外用藥物組合物及其應用 | |
CN103070825A (zh) | 一种肌内或皮下注射用姜黄素微粒混悬液及其制备方法和用途 | |
CN102885781B (zh) | 一种牛蒡苷元的固体分散体及口服固体制剂 | |
CN113508819A (zh) | 一种氟啶虫酰胺·螺虫乙酯混配制剂及其应用 | |
JP2016034918A (ja) | 難水溶性抗酸化物質送達用組成物 | |
WO2004084862A1 (en) | Process for the production of cross-linked gelatin beadlets | |
EP3501497B1 (en) | Dispersion process of adapalene in a gel preparation | |
Zhao et al. | Solid lipid nanoparticle as an effective drug delivery system of a novel curcumin derivative: formulation, release in vitro and pharmacokinetics in vivo |
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 |