CN114767559B - Azelaic acid liposome whitening cream and preparation method thereof - Google Patents
Azelaic acid liposome whitening cream and preparation method thereof Download PDFInfo
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- CN114767559B CN114767559B CN202210523259.9A CN202210523259A CN114767559B CN 114767559 B CN114767559 B CN 114767559B CN 202210523259 A CN202210523259 A CN 202210523259A CN 114767559 B CN114767559 B CN 114767559B
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- azelaic acid
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- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 title claims abstract description 232
- 239000002502 liposome Substances 0.000 title claims abstract description 69
- 239000006071 cream Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 230000002087 whitening effect Effects 0.000 title claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 14
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000011187 glycerol Nutrition 0.000 claims abstract description 7
- 229940057995 liquid paraffin Drugs 0.000 claims abstract description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 7
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008117 stearic acid Substances 0.000 claims abstract description 7
- 239000003871 white petrolatum Substances 0.000 claims abstract description 7
- 239000011159 matrix material Substances 0.000 claims abstract description 5
- 229940075507 glyceryl monostearate Drugs 0.000 claims abstract description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 28
- 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 24
- 238000003756 stirring Methods 0.000 claims description 14
- 235000012000 cholesterol Nutrition 0.000 claims description 12
- 239000002504 physiological saline solution Substances 0.000 claims description 12
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 claims description 11
- 239000012528 membrane Substances 0.000 claims description 9
- 150000003904 phospholipids Chemical class 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 208000003351 Melanosis Diseases 0.000 claims description 5
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 5
- 239000002537 cosmetic Substances 0.000 claims description 5
- 239000011148 porous material Substances 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 238000009210 therapy by ultrasound Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000036571 hydration Effects 0.000 claims description 4
- 238000006703 hydration reaction Methods 0.000 claims description 4
- -1 liquid paraffin Chemical compound 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims 1
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 16
- 238000010521 absorption reaction Methods 0.000 abstract description 12
- 230000002500 effect on skin Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 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 5
- 230000001815 facial effect Effects 0.000 description 5
- 239000000787 lecithin Substances 0.000 description 5
- 235000010445 lecithin Nutrition 0.000 description 5
- 229940067606 lecithin Drugs 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- 206010000496 acne Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000011162 core material Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000000823 artificial membrane Substances 0.000 description 2
- 150000001536 azelaic acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000000887 hydrating effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- 208000020154 Acnes Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010014970 Ephelides Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 235000010254 Jasminum officinale Nutrition 0.000 description 1
- 240000005385 Jasminum sambac Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000186429 Propionibacterium Species 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 240000001341 Reynoutria japonica Species 0.000 description 1
- 235000018167 Reynoutria japonica Nutrition 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- 235000017089 Scutellaria baicalensis Nutrition 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003255 anti-acne Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940059958 centella asiatica extract Drugs 0.000 description 1
- 229940119217 chamomile extract Drugs 0.000 description 1
- 235000020221 chamomile extract Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 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 1
- 239000001947 glycyrrhiza glabra rhizome/root Substances 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000001198 melaleuca alternifolia leaf oil Substances 0.000 description 1
- 230000036564 melanin content Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 231100000957 no side effect Toxicity 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000001331 rosmarinus officinalis leaf Substances 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000037394 skin elasticity Effects 0.000 description 1
- 244000005714 skin microbiome Species 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/362—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/06—Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/31—Hydrocarbons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/345—Alcohols containing more than one hydroxy group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
- A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
- A61K8/553—Phospholipids, e.g. lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/82—Preparation or application process involves sonication or ultrasonication
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Birds (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses an azelaic acid liposome cream and a preparation method thereof, wherein the liposome cream comprises an azelaic acid liposome solution and a cream matrix, and the matrix comprises the following components in parts by weight: 20-100 parts of glyceryl monostearate, 50-100 parts of liquid paraffin, 20-50 parts of stearic acid, 10-30 parts of white vaseline, 10-50 parts of glycerin, 10-20 parts of triethanolamine and 15-50 parts of water. The azelaic acid active ingredient in the azelaic acid liposome solution exists in the form that the azelaic acid active ingredient is free azelaic acid or DSPE-PEG-azelaic acid. Compared with the conventional free azelaic acid cream, the azelaic acid liposome cream provided by the invention has good transdermal absorption effect, can obviously inhibit skin melanin generation, and does not generate side effect on skin.
Description
Technical Field
The invention belongs to the technical field of cosmetics, and particularly relates to azelaic acid liposome whitening cream and a preparation method thereof.
Background
Azelaic acid is also known as azaleic acid, and is commonly found in wheat, barley, etc., and contains two carboxyl groups with the structural formulaIs generally used for preventing and treating skin diseases, and has the effects of inhibiting or killing anaerobic bacteria and aerobic bacteria on skin. In vivo experiments show that the azelaic acid cream is applied for 2-3 months continuously and has the effects of obviously reducing the number of skin bacteria and bacteria of propionibacterium in hair follicles, thus indicating that the azelaic acid cream has direct antibacterial effect.
In addition to the antibacterial effect, studies have shown that azelaic acid has selective action on abnormal melanocytes, inhibits melanin activity, and plays a role in whitening. The mechanism of azelaic acid for whitening is that it blocks the synthesis of DNA in melanocytes and has a milder anti-tyrosinase effect. After being combined with other components, the efficacy is better than that of hydroquinone with the concentration of 2 percent. Based on this, research on whitening and spot-lightening products of azelaic acid is becoming hotter, and sales of related products are rising year by year.
With respect to the safety of azelaic acid, previous studies have shown that it is safe, and that animal tests administered orally in excess of 4g/kg dose, do not show any toxic reactions, nor teratogenicity and mutagenicity. Although the human body local application test does not show systemic adverse reaction, a part of subjects can have side effects such as erythema, pruritus, burning sensation and the like after administration.
Patent CN202110985696.8 discloses an azelaic acid anti-acne and anti-inflammatory gum comprising azelaic acid, butylene glycol, polyacrylate crosslinked polymer-6, t-butanol, salicylic acid, pullulan, dextrin, xanthan gum, butylene glycol, centella asiatica extract, polygonum cuspidatum root extract, scutellaria baicalensis root extract, tea extract, glycyrrhiza glabra root extract, chamomile extract, rosemary leaf extract, PEG-40 hydrogenated castor oil, melaleuca alternifolia leaf oil and water. In fact, azelaic acid is used in the acne-removing anti-inflammatory adhesive, and the antibacterial activity of azelaic acid is mainly seen.
Patent CN201911265889.5 discloses an azelaic acid microcapsule, which consists of a wall material and a core material, wherein the wall of the microcapsule adopts inorganic material calcium carbonate, the core material adopts azelaic acid with the effects of whitening, removing freckles and removing acnes and jasmine essential oil with the effects of increasing skin elasticity and enabling skin to be tender, and the mass ratio of the core wall material is 1 (4-9). The microcapsule can realize effective utilization of azelaic acid and absorption of azelaic acid by human skin, and greatly improves stability and compatibility of azelaic acid. However, whether microcapsules using calcium carbonate as a wall material are advantageous for absorption by human skin is certainly considered.
In order to truly improve the transdermal absorption effect of azelaic acid and to improve the bioavailability thereof, the present invention provides a liposome cream containing azelaic acid, which has a good transdermal absorption effect, is capable of remarkably inhibiting skin melanin formation, and has substantially no side effects on the skin as compared with conventional free azelaic acid cream.
Disclosure of Invention
The invention aims to provide azelaic acid liposome cream and a preparation method thereof, and another aim of the invention is to provide application of the azelaic acid liposome cream in the field of whitening and skin care products.
In a first aspect, the present invention provides an azelaic acid liposome cream comprising an azelaic acid liposome solution and a cream base, the mass ratio of azelaic acid liposome solution to cream base being 1: (0.8-1), wherein the matrix comprises the following components in parts by weight: 20-100 parts of glyceryl monostearate, 50-100 parts of liquid paraffin, 20-50 parts of stearic acid, 10-30 parts of white vaseline, 10-50 parts of glycerin, 10-20 parts of triethanolamine and 15-50 parts of water.
The azelaic acid liposome solution is prepared from phospholipid, cholesterol, DSPE-mPEG2000, an azelaic acid active ingredient and liposome dispersion, wherein the azelaic acid active ingredient is free azelaic acid or DSPE-PEG-azelaic acid.
The liposome dispersion liquid is selected from one or more than two of physiological saline and phosphate buffer with pH=7.4.
The phospholipids include, but are not limited to, one or a combination of two or more of lecithin, cephalin, soybean phospholipids, hydrogenated soybean phospholipids, phosphatidylethanolamine.
A situation: when the azelaic acid active ingredient is free azelaic acid, the azelaic acid liposome is prepared by the following method:
(1) Dissolving azelaic acid, phospholipid, cholesterol and DSPE-mPEG2000 in chloroform methanol solution, and performing rotary evaporation at 35-37 ℃ under reduced pressure to form a film;
(2) Adding physiological saline for hydration for 1-2 hours;
(3) Performing ultrasonic treatment;
(4) Centrifuging;
(5) Filtering with 0.8 μm pore size filter membrane, and re-suspending in liposome dispersion to obtain azelaic acid concentration of 1-10%.
Preferably, in the step (1), azelaic acid, phospholipid, cholesterol and DSPE-mPEG2000 in mass ratio of (3-7): (30-40): (5-10): 1.
A situation: when the azelaic acid active ingredient is DSPE-PEG-azelaic acid, the azelaic acid liposome is prepared by the following method:
(1) Dissolving azelaic acid in DMF, adding EDC and NHS for activation, dripping DSPE-PEG-NH 2, reacting overnight, and dialyzing to obtain DSPE-PEG-azelaic acid;
(2) Dissolving DSPE-PEG-azelaic acid, phospholipid, cholesterol and DSPE-mPEG2000 in chloroform methanol solution, and performing rotary evaporation at 35-37deg.C under reduced pressure to form a film;
(3) Adding physiological saline for hydration for 1-2 hours;
(4) Performing ultrasonic treatment;
(5) Centrifuging;
(6) Filtering with 0.8 μm pore size filter membrane, and re-suspending in liposome dispersion to obtain azelaic acid concentration of 1-10%.
The molar mass ratio of azelaic acid to DSPE-PEG-NH 2 in the step (1) is (1.1-1.2) 1, and the molecular weight of DSPE-PEG-NH 2 can be 200, 400, 600, 800 and the like.
In a preferred embodiment of the invention, DSPE-PEG-NH 2 has a molecular weight of 200.
Preferably, in the step (2), the mass ratio of the DSPE-PEG-azelaic acid, the phospholipid, the cholesterol and the DSPE-mPEG2000 is (5.5-13): (25-35): (5-10): 1.
In a second aspect, the present invention provides a process for the preparation of an azelaic acid liposome cream comprising: heating and melting glycerin monostearate, liquid paraffin, stearic acid and white vaseline to obtain an oil phase, adding glycerin and triethanolamine into water, stirring to obtain a water phase, adding azelaic acid liposome into the water phase, rapidly stirring, adding the oil phase into the water phase, and stirring to condense to obtain milky azelaic acid liposome cream.
In a third aspect, the invention provides an azelaic acid liposome cream for preparing a whitening and freckle removing cosmeceutical or skin care product.
The azelaic acid liposome cream provided by the invention has the following advantages:
(1) The concentration of the drug in the azelaic acid product sold for the treatment of acne is 20%, which is unacceptable for skin care products requiring prolonged use. Conventional azelaic acid cream has poor transdermal absorption performance and has certain limitation in use as a whitening agent. The cream prepared by adding azelaic acid into a cream matrix to prepare the liposome preparation has obviously increased transdermal absorption performance.
(2) The liposome prepared by coating free azelaic acid in a liposome membrane material has poor stability, and on the basis, the azelaic acid is modified by the technician of the invention by using distearoyl phosphatidylethanolamine-polyethylene glycol-NH 2, and the modified azelaic acid is prepared into the liposome according to a conventional method, so that the stability is obviously improved, and the transdermal absorption capacity of the medicament is almost linearly increased along with the time.
(3) According to the invention, azelaic acid is added into the cream in a liposome form, so that a relatively remarkable whitening and freckle removing effect can be achieved at a relatively low drug concentration (2-4%).
Drawings
FIG. 1 cream transdermal penetration vs. time curve
FIG. 2 subject facial melanin value-time curve
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Preparation of azelaic acid liposome
Preparation example 1
Liposome preparation by thin film hydration method routinely used by those skilled in the art, azelaic acid 3g, lecithin 40g, cholesterol 5g and 1g DSPE-mPEG2000 are dissolved in chloroform methanol solution (chloroform: methanol=4:1V/V), and the solution is formed by rotary evaporation under reduced pressure at 37 ℃; adding physiological saline, hydrating at 37deg.C for 2 hr, and performing ultrasonic treatment on ice with an ultrasonic breaker; 18000g was centrifuged for 3 minutes, and the mixture was filtered through a 0.8 μm pore size filter to obtain azelaic acid liposome, which was redispersed in physiological saline to form a liposome solution (azelaic acid concentration: 3g/100 g).
Preparation example 2
The preparation method and raw materials are the same as in preparation example 1, 5g of azelaic acid is added into the preparation system, the rest raw materials are used in the same amount as in preparation example 1, azelaic acid liposome is prepared, and the liposome is dispersed into physiological saline to form a solution with azelaic acid concentration of 5g/100 g.
Preparation example 3
The preparation method and raw materials are the same as in preparation example 1, azelaic acid 7g is added into the preparation system, the rest raw materials are used in the same amount as in preparation example 1, azelaic acid liposome is prepared, and the liposome is dispersed into physiological saline to form a solution with azelaic acid concentration of 7g/100 g.
Preparation example a
S1: weighing 22.56g (0.12 mol) of azelaic acid, dissolving in a proper amount of DMF, adding EDC and NHS for activation, adding 2 g (M=200, 0.1 mol) of DSPE-PEG-NH, vibrating and reacting overnight, dialyzing, and freeze-drying to obtain DSPE-PEG-azelaic acid;
S2: dissolving 5.5g of DSPE-PEG-azelaic acid, 34g of lecithin, 5g of cholesterol and 1gDSPE-mPEG2000 in chloroform methanol solution (chloroform: methanol=4:1V/V), and performing reduced pressure rotary evaporation at 37 ℃ to form a film; adding physiological saline, hydrating at 37deg.C for 2 hr, and performing ultrasonic treatment on ice with an ultrasonic breaker; 18000g was centrifuged for 3 minutes, and the mixture was filtered through a 0.8 μm pore size filter to obtain azelaic acid liposome, which was redispersed in physiological saline to form a liposome solution (azelaic acid concentration: 3g/100 g).
Preparation example b
The preparation method and the raw materials are the same as in preparation example a, except that 9.3g of DSPE-PEG-azelaic acid, 30g of lecithin, 5g of cholesterol and 1g of DSPE-mPEG2000 are added into the preparation system in the step S2 to prepare azelaic acid liposome, and the liposome is dispersed into physiological saline to form a solution with azelaic acid concentration of 5g/100 g.
Preparation example c
The preparation method and the raw materials are the same as in preparation example a, except that 13g of DSPE-PEG-azelaic acid, 27g of lecithin, 5g of cholesterol and 1g of DSPE-mPEG2000 are added into the preparation system in the step S2 to prepare azelaic acid liposome, and the liposome is dispersed into physiological saline to form a solution with the azelaic acid concentration of 7g/100 g.
Preparation of azelaic acid liposome cream
Example 1
The formulation of the cream is shown below, with an azelaic acid content of 1.67g/100g.
The preparation method comprises the following steps: according to the weight shown in the table, heating and melting glycerin monostearate, liquid paraffin, stearic acid and white vaseline to obtain an oil phase, adding glycerin and triethanolamine into purified water, stirring uniformly to obtain a water phase, adding azelaic acid liposome solution into the water phase, adding the oil phase into the water phase under rapid stirring, and stirring until the oil phase is condensed to obtain the milky azelaic acid liposome cream.
Example 2
The formulation of the cream is shown below, and the preparation method is the same as in example 1, with azelaic acid content of 2.78g/100g.
Example 3
The formulation of the cream is shown below, and the preparation method is the same as in example 1, with azelaic acid content of 3.89g/100g.
Example 4
The formulation of the cream is shown below, and the preparation method is the same as in example 1, with azelaic acid content of 1.67g/100g.
Example 5
The formulation of the cream is shown below, and the preparation method is the same as in example 1, with azelaic acid content of 2.78g/100g.
Example 6
The formulation of the cream is shown below, and the preparation method is the same as in example 1, with azelaic acid content of 3.89g/100g.
Comparative example 1
The formulation of the cream is shown below, with an azelaic acid content of 1.67g/100g.
The preparation method comprises the following steps: according to the weight shown in the table, heating and melting glycerin monostearate, liquid paraffin, stearic acid and white vaseline to obtain an oil phase, adding glycerin and triethanolamine into purified water, stirring uniformly to obtain a water phase, adding free azelaic acid into the water phase, stirring to dissolve, adding the oil phase into the water phase under a rapid stirring state, and stirring to condense to obtain the milky azelaic acid liposome cream.
Comparative example 2
The formulation of the cream is shown below, the preparation method is the same as that of comparative example 1, and the azelaic acid content is 2.78g/100g.
Comparative example 3
The formulation of the cream is shown below, the preparation method is the same as that of comparative example 1, and the azelaic acid content is 3.89g/100g.
Azelaic acid liposome cream effect verification
1. Evaluation of transdermal absorption Property of cream
Test device: the modified Franz diffusion cell, the diffusion membrane was a cellulose acetate membrane (artificial membrane) device with a transdermal area of 3.57cm 2 and a receiving chamber volume of 10mL. The receiving liquid is normal saline.
The test method comprises the following steps: 1.50g of the cream prepared in examples 1-6 and comparative examples 1-3 was uniformly smeared on the surface of an artificial membrane, 10mL of a receiving solution was added to a receiving tank, and the solution was placed in a constant temperature water bath at 37.+ -. 0.5 ℃ with a stirring speed of 300r/min.
Sample collection: and respectively taking 0.1mL of receiving solution at 4 time points of 0.5, 1,2 and 3 hours after coating, taking 2 parts of receiving solution in parallel at each time point, and supplementing the receiving solution into a receiving chamber after sampling, and filtering by a microporous filter membrane of 0.22 mu m to be tested.
Drawing a standard curve of high performance liquid chromatography: the standard curve is obtained by taking azelaic acid standard solution of 10 mug/mL, 20 mug/mL, 40 mug/mL, 80 mug/mL and 100 mug/mL of each concentration, and carrying out linear regression by taking peak area as an ordinate and concentration as an abscissa.
Sample detection: 20 mu L of the receiving liquid is precisely sucked, peak area parameters are obtained under the same detection condition, the peak area parameters are brought into a standard curve to obtain azelaic acid concentration, and an average value is recorded.
TABLE 1 transdermal penetration of cream
Comparative examples 1-3 are products obtained by mixing free azelaic acid directly into a cream base, which are common in the prior art, and as can be seen from the data of table 1 and the transdermal drug delivery profile shown in fig. 1, in the drug release profile, the product prepared by directly adding azelaic acid in free form into the cream base, the release profile was rapid before 2 hours and gentle after 2 hours.
The transdermal amount of azelaic acid in the creams of examples 1-3 was not large in 0-2 hours compared to the comparative examples, because a certain time is required for transdermal permeation of the liposome membrane after azelaic acid is coated with the liposome membrane, but drug release is rapid after transdermal permeation, and drug release is rapid in 2-3 hours. However, the liposome has poor stability under normal conditions, and demulsification is easy to occur due to the change of external environment.
Based on the above, the inventor modifies azelaic acid connected with distearoyl phosphatidylethanolamine-polyethylene glycol, and prepares the modified azelaic acid into liposome. As shown in the data of examples 4-6, the cream has no obvious drug release in 0-2 hours, which indicates that the liposome has a certain slow release effect, the drug release curve in 2-3 hours is greatly improved, the drug release curve is larger than that of examples 1-3, which indicates that the transdermal property of the modified liposome is better, and the transdermal absorption almost linearly increases with time, and the regularity is good.
2. Evaluation of whitening Effect of cream
Test object: 9 female subjects with dark complexion, chloasma and no allergy history are selected and randomly divided into 3 groups of 3 people.
The testing method comprises the following steps: 3 groups of subjects used the creams prepared according to example 3, example 6 and comparative example 3, respectively; the cosmetic is used once each day after cleansing the face in the morning and evening, and is continuously used for 36 weeks, so that other cosmetics are avoided being used in the period; the number of melanin was measured at the same place of the face by using the skin melanin tester MEXAMETERMX probe from germany CK company at weeks 0, 12, 24 and 36, respectively, with the number of measurements being 3-5, excluding the difference data, and taking the average value, and the results are shown in the following table.
Table 2 data for cream whitening effect detection
As can be seen from the above table data in combination with fig. 2, the tendency of reduction in the amount of facial melanin in the subjects of the groups of example 3 and example 6 was more remarkable, and the amount of facial melanin in the user of the cream of comparative example 3 was most slowly reduced, mainly because the transdermal absorption effect of the cream of comparative example 3 was inferior to that of examples 3 and 6. And comparative example 3 showed a remarkable effect in the first 12 weeks, and the facial melanin values of the latter subjects decreased very slowly.
Analysis of the melanin decline curves of example 3 and example 6 showed that the melanin decline was very slow for the example 3 cream user after 24 th, while the melanin content was still continuously declining for the example 6 cream user after 24 weeks. This result indicates that azelaic acid liposome in the cream prepared in example 3 is likely to be unstable during storage, demulsification occurs, azelaic acid is dispersed in the cream in a free form, transdermal absorption performance is deteriorated, and the effect of the drug is not obvious after 24 weeks.
In addition, the safety data of the subjects in this test were counted, and none of the 9 subjects showed severe allergic reaction, and only 1 subject in the cream-applied group of comparative example 3 showed mild facial itching at 24 weeks, and no erythema, pimple or edema.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (3)
1. An azelaic acid liposome cream comprising an azelaic acid liposome solution and a cream base, the mass ratio of azelaic acid liposome solution to cream base being 1: (0.8-1), wherein the matrix comprises the following components in parts by weight: 20-100 parts of glyceryl monostearate, 50-100 parts of liquid paraffin, 20-50 parts of stearic acid, 10-30 parts of white vaseline, 10-50 parts of glycerin, 10-20 parts of triethanolamine and 15-50 parts of water;
The azelaic acid liposome solution is prepared from phospholipid, cholesterol, DSPE-mPEG2000, an azelaic acid active ingredient and liposome dispersion, wherein the azelaic acid active ingredient is DSPE-PEG-azelaic acid; the liposome dispersion is normal saline;
The azelaic acid liposome solution is prepared by the following method:
(1) Dissolving azelaic acid in DMF, adding EDC and NHS for activation, dripping DSPE-PEG-NH 2, oscillating for reaction overnight, dialyzing, and lyophilizing to obtain DSPE-PEG-azelaic acid;
(2) Dissolving DSPE-PEG-azelaic acid, phospholipid, cholesterol and DSPE-mPEG2000 in chloroform methanol solution, and performing rotary evaporation at 35-37deg.C under reduced pressure to form a film;
(3) Adding physiological saline for hydration for 1-2 hours;
(4) Performing ultrasonic treatment;
(5) Centrifuging;
(6) Filtering with 0.8 μm pore size filter membrane, and suspending in liposome dispersion to make azelaic acid concentration 1-10%;
The molar mass ratio of azelaic acid to DSPE-PEG-NH 2 in the step (1) is (1.1-1.2) 1; in the step (2), the mass ratio of DSPE-PEG-azelaic acid, phospholipid, cholesterol and DSPE-mPEG2000 is (5.5-13): (27-34): 5:1.
2. A process for the preparation of the azelaic acid liposome cream of claim 1 comprising: heating and melting glycerin monostearate, liquid paraffin, stearic acid and white vaseline to obtain an oil phase, adding glycerin and triethanolamine into water, stirring to obtain a water phase, adding azelaic acid liposome solution into the water phase, adding the oil phase into the water phase under rapid stirring, and stirring to condense to obtain milky azelaic acid liposome cream.
3. Use of the azelaic acid liposome cream of claim 1 in the preparation of a whitening, freckle-removing cosmetic.
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