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WO1998030215A1 - Formulation topique de tretinoine a base de liposomes - Google Patents

Formulation topique de tretinoine a base de liposomes Download PDF

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Publication number
WO1998030215A1
WO1998030215A1 PCT/IB1998/000206 IB9800206W WO9830215A1 WO 1998030215 A1 WO1998030215 A1 WO 1998030215A1 IB 9800206 W IB9800206 W IB 9800206W WO 9830215 A1 WO9830215 A1 WO 9830215A1
Authority
WO
WIPO (PCT)
Prior art keywords
liposome
based formulation
tretinoin
lecithin
cholesterol
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.)
Ceased
Application number
PCT/IB1998/000206
Other languages
English (en)
Inventor
Rainer Naeff
Sandro Delmenico
Michael Corbo
Jan Ondracek
Frank Floether
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cilag AG
Original Assignee
Cilag AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Cilag AG filed Critical Cilag AG
Priority to AU57774/98A priority Critical patent/AU5777498A/en
Publication of WO1998030215A1 publication Critical patent/WO1998030215A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61Q19/08—Anti-ageing preparations
    • 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
    • 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
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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

Definitions

  • the present invention relates to a liposome based topical formulation of tretinoin, particularly a formulation providing good penetration of biological active substances into the skin, suitable for the treatment of acne, psoriasis and photoaging.
  • the invention relates to a liposome based tretinoin formulation with superior stability prepared by means of an ethanol injection technique.
  • retinoic acid and its derivatives are effective therapeutic agents in topical treatment of acne and other skin disorders, because it decreases the cohesiveness of follicular epithelial cells and induces proliferation of the follicular epithelium. More recently, retinoic acid has been used topically for the treatment of photoaging of the skin.
  • the topical formulations in use are preferably conventional creams, liquids or gel based formulations which are marketed in the United States under the trade names RETIN- A® and RENO V A®. These products contain tretinoin (trans-retinoic acid) in concentrations of 0.025%, 0.05% and 0.1% creams and 0.01% and 0.025% gels.
  • Liposomes are small vesicles comprising amphipathic lipids arranged in spherical bilayers. Liposomes may contain many concentric lipid bilayers separated by aqueous channels (multilamellar vesicles or MLVs), or alternatively, they may contain a single membrane bilayer (unilamellar vesicles), which may be small unilamellar vesicles (SUNs) or large unilamellar vesicles (LUVs).
  • the lipid bilayer is composed of two lipid monolayers having a hydrophobic "tail” region and a hydrophilic "head” region. In the membrane bilayer, the hydrophobic "tails" of the lipid monolayers orient towards the center of the bilayer, whereas the hydrophilic "heads” orient toward the aqueous phase.
  • Liposomes may be used to encapsulate a variety of materials by trapping hydrophilic compounds in the aqueous interior or between bilayers, or by trapping hydrophobic compounds within the bilayer. As such, they are particularly useful to deliver biologically active materials by encapsulating compounds which exhibit poor aqueous solubility or which exhibit unacceptable toxicity at therapeutic dosages.
  • Topical liposome formulations have been known for years and topical retinoic acid liposomal preparations have been proposed.
  • U.S. Patent 5,034,228 discloses liposomal low dose tretinoin formulations in which the liposomes are prepared by methods involving the use of dichloromethane solvents and spray drying followed by size homogenization with ultrasounds or high pressure homogenization.
  • the goal of the present invention therefore was to provide a topical application form suitable for tretinoin, which is cosmetically elegant and minimizes irritating side effects, and which provides good skin penetration abilities yet minimizes skin permeation and systemic absorption.
  • the formulation should also provide superior long term stability for an extended shelf life in comparison with known formulations.
  • a liposome-based composition for use in the topical treatment of skin disorders comprising: (a) an effective amount of an active ingredient comprising tretinoin or its pharmaceutically acceptable derivatives;
  • lipidic phase comprising:
  • lecithin or hydrogenated lecithin and (ii) cholesterol or a derivative thereof selected from cholesterol esters, polyethylene glycol derivatives of cholesterol (PEG- cholesterols), and organic acid derivatives of cholesterols; and
  • composition comprises single bilayered liposomes made by preparing an alcoholic solution of the lipidic phase and the active ingredient and injecting the solution under pressure into an aqueous electrolyte solution contained in a high speed homogenizer.
  • a lower alcohol preferably ethanol
  • the active ingredient is tretinoin (all trans retinoic acid) and its derivatives, salts and esters.
  • tretinoin all trans retinoic acid
  • the active ingredient is tretinoin (all trans retinoic acid) and its derivatives, salts and esters.
  • tretinoin all trans retinoic acid
  • these compounds, their chemistry, and synthesis, are described in Frickel, F., Chemistry and Physical Properties of Retinoids: THE RETINOIDS, Sporn, Roberts, Goodman eds., Academic Press, p. 7-145 (1984), hereby incorporated by reference.
  • the liposomal tretinoin compositions prepared under the mild conditions described herein exhibit improved stability, i.e. the liposomes themselves are stable and at the same time the chemical degradation of the biologically effective substance is minimized.
  • the liposomal tretinoin compositions of the instant invention provide a high level of skin penetration to achieve the therapeutic effect while allowing virtually no skin permeation thereby minimizing the risk of systemic side effects.
  • FIGURE 1 - shows the results of in vitro skin permeation studies of various formulations showing the level of tretinoin in the skin 24 hours following application of the formulation
  • FIGURE 2 - shows the results of in vitro skin permeation studies of various formulations showing the level of tretinoin which had permeated through the skin to the receptor 24 hours following application of the formulation.
  • the active ingredients used in the present invention are the tretinoin (all trans retinoic acid) compounds in general, their salts and esters or mixtures thereof.
  • the compositions are useful in treating dermatological disorders including acne, photoaging, wrinkles, hyperkeratosis, psoriasis, to lighten or remove pigmental skin spots, and the like.
  • photoaging means damage to essential structural and functional components of the skin resulting from chronic exposure to ultraviolet radiation.
  • Clinical signs of photodamage include wrinkling, mottled hyperpigmentation and roughness accompanied by histologic changes such as epidermal atypia, breakdown of elastin and collagen fibers in the dermis and increased melanocytic activity.
  • the liposome compositions generally contain from about lOmg to about lOOOmg of the retinoic acid compound per 100 grams of composition.
  • Such a formulation particularly produced according to the process described in EP 0 253 619, which is herein incorporated by reference, shows very good penetration abilities of retinoic acid and its derivatives and related compounds, particularly tretinoin, when applied in topical application.
  • Lecithin can either be used as natural lecithin in purified form or, preferably, as the more stable hydrogenated lecithin, whereby the use of the latter allows a reduction of the concentration of the stabilizing agents.
  • the lecithin component is generally present in an amount from about 1.0 to 10 grams per 100 grams of composition.
  • the hydrogenated lecithin should be of good quality without detectable levels of catalysts which can influence the stability of tretinoin and liposomes in a negative manner.
  • Cholesterol is employed as the liposome stabilizing agent in amounts ranging from 0.1 to 1.0 grams per 100 grams of composition.
  • other cholesterol derivatives may be employed such as cholesterol esters, polyethylene glycol derivatives of cholesterol (PEG-cholesterols), as well as organic acid derivatives of cholesterols, for example cholesterol hemisuccinate.
  • the alcohol component is a lower alkanol of one to six carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like in amounts ranging from 0.5 to about 8.0 grams per 100 grams of composition. Ethanol is preferred.
  • a gelling agent in the composition to provide a less fluid product.
  • Various gelling agents may be employed and are within the scope of this invention including cellulose derivatives such as hydroxypropyl methylcellulose.
  • a liposomal formulation as described above, but additionally comprising one or more a polyacrylate(s) such as carboxypolymethylene (carbomer) as gelling agent makes possible a much better skin penetration of the active ingredient than do paraffin ointment bases or liposome- based formulations with other gelling agents such as xanthan gum.
  • polyacrylate(s) as gelling agent(s)
  • the penetration abilities of the highly fluid liposome-based formulations are at least reached or even enhanced.
  • a topical retinoic acid composition it is important to achieve the proper balance of skin penetration of the active ingredient while minimizing the permeation of the active ingredient through the skin where it can be systematically absorbed.
  • topical compositions such as creams
  • the skin penetration is rather low.
  • permeation is also high and therefore the danger of systemic effects is a problem.
  • the instant invention in contrast, provides good skin penetration to achieve the therapeutic effect while allowing virtually no skin permeation. In this manner, the number of administrations per day can be minimized due o higher penetration and delivery of the active ingredient to the skin while minimizing side effects due to systemic absorption.
  • the tcpical tretinoin compositions currently marketed have limited shelf-life of not more than three years.
  • stability measurements of only up to six months could be found.
  • carbomer gelling agent exhibit improved stability, i.e. the liposomes themselves are stable and at the same time the decomposition of the biologically effective substance is minimized.
  • a shelf-life of up to five years has been achieved which is very important for industrial application.
  • This improved stability may be attributable to the superior mild manufacturing technology of the present invention and the ingredients and composition of the formulation (both from a qualitative and quantitative point of view when compared with the formulations described in the literature).
  • the normally high pressure homogenization or the french press methods used in other prior art methods of manufacturing liposomes result in high temperatures (up to more than 100°C) and pressures (up to 800 bar) which may have a negative impact on the stability of Tretinoin.
  • the stability of the composition can be further enhanced by the addition of antioxidants such as tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, or edetates such as e.g. disodium edetate, with the edetates additionally binding possibly present heavy metals.
  • the stability can furthermore be enhanced by the addition of preserving agents such as benzoic acid and parabens, e.g. methylparaben, and/or propylparabene.
  • the desired pH is preferably stabilized by a buffer system.
  • a citric acid buffer such as citric acid monohydrate or a phosphate buffer, particularly a buffer of potassium dihydrogen phosphate and disodium hydrogen are suitable.
  • the protons that are liberated upon thickening or cross-linkage, respectively, of the polyacrylate e.g. Carbomer 974 P
  • a base preferably sodium hydroxide.
  • One or more additional substances which have therapeutic affects on the skin may also be incorporated into the liposome compositions of the present invention.
  • additional substances which may be incorporated include compounds capable of inducing epitheliazation, such as the chromanols such as Vitamin E.
  • Anti-bacterial agents such as erythromycin, clindamycin, minocycline and the like may also be included for treatment of acne.
  • Anti-inflammatory agents such as corticosteroids may also be advantageously included in the composition.
  • the liposome-based compositions of the present invention are prepared by applying the methods known in the art for manufacturing liposome compositions described in EP 253619, hereby incorporated by reference.
  • single bilayered liposomes are prepared by preparing an ethanolic solution of a phospholipid and the active ingredient and injecting the solution under pressure into an aqueous electrolyte solution contained in a high speed homogenizer.
  • the liposomes are formed spontaneously providing liposomes having a diameter of less than l ⁇ m.
  • the liposomes are manufactured by forming an aqueous electrolyte solution of the methylparaben, propylparaben and disodium edetate in purified water.
  • the retinoic acid active ingredient, the lecithin and cholesterol are dissolved in an alcoholic solution such as ethanol.
  • the aqueous solution is connected to a high performance homogenizer to effect circulation and the alcoholic solution containing the active ingredient is directly injected into the homogenizer. Liposomes of less than l ⁇ m are formed spontaneously.
  • a liposome-based dispersion of the following composition was produced according to the method described in EP 0 253 619:
  • Methylparaben and propylparaben and the disodium edetate were dissolved in purified water at 80°C (kettle I).
  • Tretinoin, tocopherol, lecithin, and cholesterol were dissolved in ethanol in a separate kettle (kettle II) at 55°C-70°C under agitation.
  • the ethanol solution was purged with nitrogen during the whole procedure.
  • the water phase was cooled to 55°C-70°C.
  • Kettle 1 was connected to a high-performance homogenizer (Megatron MT-48; manufacturer: Kinematica, Littau, Lucerne, Switzerland) to effect circulation of the aqueous solution.
  • the ethanol solution was injected through a tube from kettle II directly into the homogenizer. Liposomes having a diameter of less than 1 mm were spontaneously formed and collected in kettle I.
  • the production of the liposome-based gel was performed as the one of the dispersion according to Example 1 with the exception that after the liposome formation according to Example 1 the Carbomer 934 P was admixed, followed by a sodium hydroxide solution.
  • Homogenizer speed up to 13,000 rpm
  • Tretinoin The skin penetration of Tretinoin from the products produced as described in Example was determined in vitro and compared with that of commercially available gel and cream products.
  • Diffusion Cells Franz Cell, 10 ml volume, 0.636 cm 2 surface area
  • Receptor Media 25% Isopropanol in pH 5.6 Buffer with 0.025% BHT Conditions: Cells covered with aluminum foil, under yellow light at 37°C
  • FIG. 1 A summary of the amount of tretinoin remaining in the skin after 24 hours for each formulation investigated is shown in FIG. 1.
  • FIG. 2 A summary of the amount of drug permeating through the full thickness of the skin and entering into the receptor media is shown in FIG. 2.
  • the liposomal and cream formulations produced no detectable levels of tretinoin in the receptor, suggesting that a vast majority of the applied dose remained in or on the skin.
  • the liposomal gel of the present invention achieved tretinoin skin levels approximately 4-fold higher than the cream formulation yet no tretinoin was detected in the receptor compartment.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Birds (AREA)
  • Dispersion Chemistry (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

L'invention concerne une formulation de trétinoïne à base de liposomes permettant une bonne pénétration du principe actif dans la peau. Cette formulation est particulièrement appropriée pour le traitement de l'acné ou du photovieillissement.
PCT/IB1998/000206 1997-01-13 1998-01-08 Formulation topique de tretinoine a base de liposomes Ceased WO1998030215A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57774/98A AU5777498A (en) 1997-01-13 1998-01-08 Liposome-based topical tretinoin formulation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3493797P 1997-01-13 1997-01-13
US60/034,937 1997-01-13

Publications (1)

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WO1998030215A1 true WO1998030215A1 (fr) 1998-07-16

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2787997A1 (fr) * 1998-12-31 2000-07-07 Obagi Europ Agent cosmetique pour le rajeunissement de la peau, compositions et procede de mise en oeuvre
WO2001001963A1 (fr) * 1999-07-05 2001-01-11 Idea Ag Procede d'amelioration du transport a travers des barrieres adaptables semi-permeables
EP1067920A4 (fr) * 1998-04-02 2003-01-02 Univ Michigan Procedes et compositions de reduction de l'inhibition de la synthese de collagene induite par un rayonnement uv dans la peau humaine
US6683069B1 (en) 1998-04-02 2004-01-27 Regents Of The University Of Michigan Methods and compositions for reducing UV-induced inhibition of collagen synthesis in human skin
US7175850B2 (en) 1998-12-23 2007-02-13 Idea Ag Formulation for topical non-invasive application in vivo
EP1214926B1 (fr) * 2000-12-12 2007-03-14 Kabushiki Kaisha Kishohin Kagaku Kaiho Kenkyujo Composition à usage topique
EP1967180A1 (fr) * 2007-03-06 2008-09-10 Almirall Hermal GmbH Composition topique contenant un agoniste du recepteur de rétinoides
US7473432B2 (en) 2002-10-11 2009-01-06 Idea Ag NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
EP1888036A4 (fr) * 2005-06-07 2010-09-22 Reddys Lab Ltd Dr Preparations pour liberation de medicament
US20110142922A1 (en) * 2002-04-30 2011-06-16 Ferndale Ip, Inc. Stabilized composition and method for dermatological treatment
CN111658599A (zh) * 2020-07-17 2020-09-15 广东芭薇生物科技股份有限公司 一种脂质体防晒化妆品及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253619A2 (fr) * 1986-07-15 1988-01-20 Cilag Ltd. Procédé de préparation de liposomes singuliers à deux couches
WO1990014833A1 (fr) * 1989-06-07 1990-12-13 Bazzano Gail S Vehicules a liberation lente reduisant au minimum l'irritation dermique due a des compositions a usage local
US5034228A (en) * 1985-12-11 1991-07-23 Moet-Hennessy Recherche Pharmaceutical composition, in particular dermatological or cosmetic, comprising hydrous lipidic lamellar phases or liposomes containing a retinoid or a structural analogue thereof such as a carotenoid
WO1995035095A1 (fr) * 1994-06-22 1995-12-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions destinees a l'application de substances actives sur la peau

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5034228A (en) * 1985-12-11 1991-07-23 Moet-Hennessy Recherche Pharmaceutical composition, in particular dermatological or cosmetic, comprising hydrous lipidic lamellar phases or liposomes containing a retinoid or a structural analogue thereof such as a carotenoid
EP0253619A2 (fr) * 1986-07-15 1988-01-20 Cilag Ltd. Procédé de préparation de liposomes singuliers à deux couches
WO1990014833A1 (fr) * 1989-06-07 1990-12-13 Bazzano Gail S Vehicules a liberation lente reduisant au minimum l'irritation dermique due a des compositions a usage local
WO1995035095A1 (fr) * 1994-06-22 1995-12-28 Yissum Research Development Company Of The Hebrew University Of Jerusalem Compositions destinees a l'application de substances actives sur la peau

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XP002900110 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1067920A4 (fr) * 1998-04-02 2003-01-02 Univ Michigan Procedes et compositions de reduction de l'inhibition de la synthese de collagene induite par un rayonnement uv dans la peau humaine
US6683069B1 (en) 1998-04-02 2004-01-27 Regents Of The University Of Michigan Methods and compositions for reducing UV-induced inhibition of collagen synthesis in human skin
US7175850B2 (en) 1998-12-23 2007-02-13 Idea Ag Formulation for topical non-invasive application in vivo
FR2787997A1 (fr) * 1998-12-31 2000-07-07 Obagi Europ Agent cosmetique pour le rajeunissement de la peau, compositions et procede de mise en oeuvre
WO2001001963A1 (fr) * 1999-07-05 2001-01-11 Idea Ag Procede d'amelioration du transport a travers des barrieres adaptables semi-permeables
WO2001001962A1 (fr) * 1999-07-05 2001-01-11 Idea Ag. Procede d'amelioration du transport a travers des barrieres semi-permeables compatibles
US7459171B2 (en) 1999-07-05 2008-12-02 Idea Ag Method for the improvement of transport across adaptable semi-permeable barriers
US7591949B2 (en) 1999-07-05 2009-09-22 Idea Ag Method for the improvement of transport across adaptable semi-permeable barriers
EP1214926B1 (fr) * 2000-12-12 2007-03-14 Kabushiki Kaisha Kishohin Kagaku Kaiho Kenkyujo Composition à usage topique
US20140105967A1 (en) * 2002-04-30 2014-04-17 Ferndale Ip, Inc. Stabilized composition and method for dermatological treatment
US20110142922A1 (en) * 2002-04-30 2011-06-16 Ferndale Ip, Inc. Stabilized composition and method for dermatological treatment
US7473432B2 (en) 2002-10-11 2009-01-06 Idea Ag NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
EP1888036A4 (fr) * 2005-06-07 2010-09-22 Reddys Lab Ltd Dr Preparations pour liberation de medicament
US20120041029A1 (en) * 2005-06-07 2012-02-16 Dr. Reddy's Laboratories, Inc. Compositions for drug delivery
US8603539B2 (en) 2005-06-07 2013-12-10 Dr. Reddy's Laboratories Limited Compositions for drug delivery
WO2008107193A1 (fr) * 2007-03-06 2008-09-12 Almirall Hermal Gmbh Composition topique contenant un agoniste du récepteur rétinoïde pour le traitement de l'acné
EP1967180A1 (fr) * 2007-03-06 2008-09-10 Almirall Hermal GmbH Composition topique contenant un agoniste du recepteur de rétinoides
CN111658599A (zh) * 2020-07-17 2020-09-15 广东芭薇生物科技股份有限公司 一种脂质体防晒化妆品及其制备方法

Also Published As

Publication number Publication date
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