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
  • A61Q19/004—Aftersun preparations
• • 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
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • 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
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/522—Antioxidants; Radical scavengers
• • 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
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms

Definitions

• This invention relates to skin care compositions containing retinoids which generally improve the quality of the skin, particularly human facial skin. More particularly, the present invention relates to chemically stable skin care compositions containing a non-phosphoiipid liposome formulation and certain retinoids.
• Retinoic acid also known as Vitamin A acid or tretinoin
• Vitamin A acid or tretinoin is well-known for the treatment of such skin conditions as acne and products containing retinoic acid are commercially available in various forms.
• Such products include Retin A* creams, an oil-in-water emulsion of retinoic acid containing an oil-soluble antioxidant, butylated hydroxytoluene (BHT); Retin A* liquid, commercially available from Ortho Pharmaceutical Corporation of Raritan, New Jersey, which is a solution of retinoic acid in a polyethylene glycol/ethanol solvent employing BHT as an antioxidant; and Retin A* gel, which comprises retinoic acid in a gel vehicle comprising ethyi alcohol as the solvent, hydroxypropyl cellulose as the thickener or gelling agent and BHT as an antioxidant.
• BHT butylated hydroxytoluene
• Retin A* gel which comprises retinoic acid in a gel vehicle comprising ethyi alcohol as the solvent, hydroxypropyl cellulose as the thickener or gelling agent and BHT as an antioxidant.
• U.S. Patent No. 4,603,146 suggests the use of Vitamin A acid in an emollient vehicle as a treatment for ameliorating the effects of photoda age. Further, U.S. Patent No. 4,877,805, suggests that a number of retinoids are useful for restoring and reversing sun damage of human skin.
• retinoids such as, for example, retinol (Vitamin A alcohol), retinal
• Retinol is an endogenous compound naturally occurring in the human body and essential for good growth, differentiation of epithelial tissues and reproduction. Retinol is also preferred because it is safer and less irritating to the skin than other retinoids, such as retinoic acid. Additionally, excess retinol is stored in the human body largely in an inactive ester form, e.g. retinyl palmitate and, to some extent, retinyl acetate.
• the aldehyde, retinal also a preferred form, is an active metabolite of retinol and is needed for visual function.
• compositions which contain these preferred, naturally occurring retinoids which have similar properties to existing retinoic acid formulations, i.e., providing a composition which is aesthetically pleasing and which can deliver active ingredients after a substantial shelf life.
• existing formulations containing retinoids are oil-in-water emulsions in which the retinoic acid is carried within the oil phase and is protected from oxidation by employing an oil-soluble antioxidant.
• Oil-in- water emulsions are generally considered preferable to water-in-oil emulsions because they are nonocclusive, non-greasy, compatible with other such emulsion products, easy to remove from the skin and are regarded as more aesthetically pleasing as well as being more economical to manufacture.
• the chemical stability of the active retinoic acid ingredient is quite good in that the oil phase protects the retinoic acid, especially when an oil-soluble antioxidant is present.
• the aforementioned Retin A* cream is an oil-in-water emulsion containing retinoic acid and BHT, an oil-soluble antioxidant.
• BHT an oil-soluble antioxidant
• U.S. Patent 3,906, 108 there is disclosed an emulsion of retinoic acid which may include an oil-soluble antioxidant such as BHT o r d l- ⁇ -toco p hero l a n d a c -. k --.t i n g agent e.g.ethylenediaminetetraacetic acid (EDTA).
• EDTA ethylenediaminetetraacetic acid
• a tanning composition is described which may include, among other ingredients Vitamin A in an oil-in-water emulsion containing Vitamin E and citric acid.
• U.S. Patent 4,247,547 still another form of a retinoic acid containing composition, namely a gel, is disclosed and is protected by an antioxidant selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole (BHA) , ascorbic acid (Vitamin C) , propyl gallate, and oc -tocopherol (Vitamin E).
• an antioxidant selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole (BHA) , ascorbic acid (Vitamin C) , propyl gallate, and oc -tocopherol (Vitamin E).
• retinoids including, for example, retinol, retinal and retinyl esters such as retinyl acetate and retinyl palmitate.
• compositions emulate the formulas of commercial retinoic acid compositions: they are oil-in-water emulsions protected by oil-soluble antioxidants.
• the retinoids other than retinoic acid in such compositions quickly lose their activity and either oxidize or isomerize to non-efficacious chemical forms with the result that the amount of retinoid actually available to provide the beneficial effects of the product is reduced, in an unacceptably short period of time, to an ineffective quantity and eventually only to trace quantities.
• retinoids such as retinol, retinyl acetate and retinyl palmitate are formulated in water-in-oil emulsions.
• retinoids such as retinol, retinyl acetate and retinyl palmitate are formulated in water-in-oil emulsions.
• Patent 4,826,828 describes a stable composition comprising retinol, retinyl acetate and retinyl palmitate may consist of retinol in a water-in-oil emulsion wherein the emulsion further include two oil-soluble antioxidants, BHT and BHA.
• Avon Products, Inc. the assignee of U.S. 4,826,828, sells two skin care products called Bioadvance and Bioadvance 2000. Each of these products is supplied in two bottles, portions of which are mixed together just prior to use. The first bottle contains what is called a "skin lotion”, while the second bottle contains what is called a "fortifier”.
• the “skin lotion” is a water-in-oil emulsion having a number of ingredients which include water, emulsifiers, siiicone and vegetable oils, preservatives, emollients and butylated hydroxytoluene (BHT)
• the "fortifier” is a non- aqueous solution which contains a number of ingredients including cyciomethicone (a siiicone oith denatured ethanol, an emulsifier (Polysorbate 20), retinol, retinyl acetate, retinyl palmitate, BHT and BHA.
• U.S. 4,720,353 to Bell describes water-in-oil emulsion carriers for various medicaments and drugs intended for topical application to the skin.
• Water soluble, miscible or dispersible drugs may be incorporated into the aqueous phase of the emulsion.
• Oil-soluble, miscible or dispersible drugs may be incorporated into the oil phase.
• Drugs which may be incorporated into the emulsion include derivatives of retinoic acid.
• Ingredients which may optionally be added to the emulsion include a preservative such as methyl paraben, propyl paraben or imidazolidinyi urea or an antioxidant such as butylated hydroxyanisole and a water or oil soluble vitamin such as vitamin C, tocopherol linoleate and the like.
• a preservative such as methyl paraben, propyl paraben or imidazolidinyi urea
• an antioxidant such as butylated hydroxyanisole
• a water or oil soluble vitamin such as vitamin C, tocopherol linoleate and the like.
• EP 0 343 444 A2 discloses cosmetic preparations based on retinyl palmitate.
• Example 3 discloses a night cream in the form of an water-in-oil type emulsion comprising retinyl palmitate and butylated hydroxyanisole (BHA).
• Example 4 discloses a water-in-oil emulsion comprising retinyl acetate and a-Tocopherol (Vitamin E).
• EP 0 330 496 A2 to Ban is directed to skin treatment compositions comprising a topically acceptable base and an effective amount of at least one ester of retinol, said compositions being useful in the treatment of photoaged skin.
• Example 6 discloses a water-in-oil emulsion comprising Vitamin A propionate and BHT, an oil soluble antioxidant.
• Jonas C.T. Wang, et.al in pending application USSN 719,764 filled November 15, 1993 disclose the stabilization of retinol in a water-in-oil emulsion, in which retinol was dispersed and protected in oil phase.
• oil-in-water emulsions are much more preferred than water-in-oil emulsions based on the cosmetic performance. This is due to the fact that oil-in-water emulsions, in general, are less occlusive, less greasy, compatible with make-up and easy to be removed from the skin leading to a more aesthetically pleasing feel.
• oil-in-water formulations are less costly considering the ingredient composition and the manufacturing process.
• retinoids including retinoic acid, retinal, retinol, and retinyl esters to enhance the broad usage of retinol for skin treatment.
• Another object of this invention is to provide a method for making a stable skin care composition containing retinoids, which retains its activity over a long time period.
• Figure 1 is a graph depicting the effect of pH on stability of retinol in non- phosphoipid liposome formulations.
• Figure 2 is a graph depicting the amount of retinol released from the formulation of Example 8C compared with that of a water-in-oil formulation.
• Figure 3 is a graph depicting the amount of active ingredient which permeates the epidermis and dermis from the formulations of Examples 8C and 6 in comparison with that of a water-in-oil formulation.
• Figure 4 is a graph depicting the sensory perceptions of certain formulations of this invention in comparison with other skin care compositions.
• retinoids may be successfully stabilized against chemical degradation by incorporating them into non-phospholipid liposomes using a specifically defined stabilizing system and process.
• the retinoids which can be stabilized against chemical degradation in accordance with the principles of the present invention include retinol (Vitamin A alcohol) , retinal (Vitamin A aldehyde), retinyl acetate, retinyl palmitate and mixtures thereof.
• the "chemical stability" or "stability" of a retinoid is defined in terms of the percentage of the specified retinoid which is retained in its original chemical form after the composition has been stored for a specified period of time at a specified temperature.
• the concentration of all-trans retinol in an absolute ethanol solution were 0.20% by weight and, after two (2) weeks storage at room temperature (21 * C ⁇ 1 * C) , the concentration of all-trans retinol were 0.18% by weight, then the original solution of ail-trans retinol in absolute ethanol would be characterized as having a chemical stability of retinol of 90% after two weeks storage at room temperature.
• the non- phospholipid liposome form in combination with the selection of a stability - 10 - system from those described herein, will produce compositions having a chemical stability of 80% after 13 weeks' storage at 50" C.
• the present invention also provides a system for stabilizing retinoids, unexpectedly, without the presence of a water-soluble antioxidant.
• a skin care composition comprising a non-phospholipid liposome and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said composition further comprising a stabilizing system selected from the group consisting of:
• an oil-soluble antioxidant a) an oil-soluble antioxidant; and b) a chelating agent and at least one oil-soluble antioxidant;
• composition has a pH from at least about 5 to about 10, said composition retaining at least about 80% of said retinoids after 13 weeks storage at 50 * C.
• compositions of this invention can be endowed with material changes resulting in a controll ⁇ d-releas ⁇ of active agent from the liposome carrier.
• the compositions of this invention may also be moderated in order to enhance or diminish penetration of the active ingredient into the skin.
• compositions of the present invention containing a relatively high level of surfactants exhibit irritation at the same level as that experienced by individuals exposed to a water-in- ⁇ i cream ccr taining 2% surfactant.
• composition of the invention is in the form of a particular type of liposome, namely, a non-phospholipid liposome.
• compositions such as the ones containing retinoic acid are oil-in-water emulsion systems.
• certain retinoid compounds in particular, retinol, retinal, and the retinyl esters tend to be chemically unstable, i.e. they degrade, either by way of oxidation or isomerization, and are, therefore, not available to perform in their desired manner. While this is not clearly understood, it is believed that this degradation occurs as a result of the rapid diffusion of oxygen through the external water phase to the internal oil phase containing the retinoid. The oxygen is readily available to degrade the retinoid. Because the diffusion of oxygen is greater in a water phase than an oil phase, an oil-in-water system is more prone to such degradation.
• compositions of the present invention overcome these difficulties and instead, provide a non-phospholipid liposome composition containing at least one retinoid compound wherein both the physical stability of the liposome and the chemical stability of the active ingredients are maintained at high levels.
• Liposomes are spherical, self-closed structures composed of curved lipid bilayers which entrap part of the solvent, in which the , ireely float, into their interior. They may consist of one or several concentric membranes. Liposomes are made predominantly from amphiphiles, ⁇ -. special class of surface active molecules, which are characterized by having a hydrophilic 1194 PCMJS96/04557
• liposome technology has been concerned mostly with vesicles composed of phospholipid.
• Phosphotipids are labile and expensive to purify or synthesize.
• manufacture of phospholipid liposome is difficult and costly to scale up.
• Certain double-chain synthetic surfactants with non-ionic polar heads and single-chain surfactants in mixture with cholesterol can form non-ionic liposome. They have increased chemical stability over natural phospholipid and are easy to make in large, commercial quantities.
• the structure of these aggregates involves the ordering of lipid molecules: the hydrophilic part tends to be in contact with water while the hydrophobic hydrocarbon chains prefer to be hidden from water in the interior of the structures.
• One of the most frequently encountered aggregate structures is a lipid bilayer. On the surface of either side are polar heads which shield non-polar tails in the interior of the lamella from water. At higher lipid concentrations these biia ⁇ ers from lamellar crystalline phases where two-dimensional planar lipid bilayers alternate with water layers. Upon dilution, these lipid biiayers form liposomes. These liposomes can entrap hydrophilic materials in the aqueous compartments and lipophilic materials in the bilayers.
• Liposomes that are entrapped in the bilayers are sometimes referred to as "cargo molecules". Lipophilic entrapment is severely limited by the ability of the bilayer to entrap the cargo molecule. Liposomes can be large or small and may be composed of from one to several hundred concentric bilayers. With respect to the size and the number of lamellae, they are distinguished as large multilamellar vesicles (MLV's) and large and small unilamellar vesicles (LUV's and SUV's respectively). Most of the research to date have centered on above mentioned type of vesicles.
• MMV's multilamellar vesicles
• LUV's and SUV's large and small unilamellar vesicles
• PLV paucilameilar lipid vesicles
• the invention describes the PLV's consisting of 2 to 8 peripheral bilayer surrounding a large unstructured central cavity which can be filled wholly or in part with an apolar oil or wax.
• the multiple lipid bilayer and an apolar core of the PLV'S provide PLV'S with the capacity to transport a greater amount of lipophilic materials.
• U.S. 5, 147,723 to Donald F. H. Wallach describes the non- phospholipid surfactants which can form paucilameilar lipid vesicles.
• the surfactant can be selected from a group consisting of polyoxyethylene fatty esters having the formula R.-COO(C 2 H 4 O) n H where R 1 is a radical of lauric, myristic, cetyl, stearic or oleic acid and n is an integer from 2 to 10; polyoxyethylene fatty acid ethers, having the formula R 2 -CO(C 2 H 4 O) m H where R 2 is a radical of lauric, myristic, or cetyl acids, single or double unstaurated octadecyl acids, or double unsaturated eicodienic acids and m is an integer from 2 to 4; polyoxyethylene (20) sorbitan mono- or trioieate; and polyoxyethylene glyceryl monostearate with from 1 to 10 polyoxy
• the oil-soluble antioxidants which are useful in the compositions of the present invention include butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), a-tocopherol, phenyl- a-naphth ⁇ lamine, hydroquinone, propyl gallate, nordih ⁇ droguiaretic acid, and mixtures thereof as well as any other known oil-soluble antioxidant compatible with the other components of the compositions.
• BHT butylated hydroxytoluene
• BHA butylated hydroxyanisole
• a-tocopherol phenyl- a-naphth ⁇ lamine
• hydroquinone propyl gallate
• nordih ⁇ droguiaretic acid and mixtures thereof as well as any other known oil-soluble antioxidant compatible with the other components of the compositions.
• the oil-soluble antioxidants useful in the compositions of this invention should be utilized in a stabilizing effective amount and may range in total from about 0.001 to* about 5% based on the weight of the total composition, preferably from about 0.01 to about 1 %.
• the amount of antioxidants utilized in the compositions of the present invention is dependent in part on the specific antioxidants selected, the amount of and specific retinoid being protected and the processing conditions.
• a retinol formulation should include BHT in the amount of from about 0.01 % to about 1 % by weight.
• a retinal formulation should include BHT in the amount of from about 0.01 % to about 1 % by weight.
• the compositions may include a cheiating agent during the scale-up process to ⁇ r- ..imize metal ion contamination.
• the retinoid compounds of this invention are sensitive to metal ions and in particular to bi- and t ⁇ -vaieni cations and in certain instances, appear degrade rapidly in their presence.
• the chelating agent forms a complex with the metal ions thereby inactivating them and preventing them from affecting the retinoid compounds.
• Chelating agents which are useful in the compositions of the present invention include ethylenediamine tetraacetic acid (EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, citric acid, tartaric acid, and mixtures thereof.
• the chelating agents should be utilized in a stabilizing effective amount and may range from about 0.01 to about 2% based on the weight of the total composition, preferably from about 0.05 to about 1 %.
• the retinoid compounds which are useful in the compositions of the present invention consist of Vitamin A alcohol (retinol) , Vitamin A aldehyde (retinal) and Vitamin A esters (retinyl acetate and retinyl palmitate). These retinoids are utilized in the compositions of the present invention in a therapeutically effective amount that may range from about 0.001 to about 5% by weight of the total compositions, preferably from about 0.001 to about 1 %.
• the skin care compositions of the present invention comprising a non- phospholipid can be in the format of cream or lotion formulations, as desired, by varying the relative quantities of the lipid and water phases of the emulsion.
• the pH of the compositions should be in the range of from at least about 5 to about 9, and preferably from about 5 to about 7.
• any of the many formulations or compositions of the cream or lotion type currently utilized in skin care preparations can be employed provided that it is in a non-phospholipid and is chemically compatible with the retinoid compounds.
• the ratio of the oil phase of the non-phospnolip.d liposome to the water phase can be from about 5:95 to about 40:60. The actual ratio of the two phases will depend on the desired final product.
• retinol (Vitamin A alcohol) were prepared having the % w/w compositions set forth in Table 1.
• Table 1 the interpretation "o/w” indicates an oil-in-water composition.
• These emulsions were prepared according to the following procedure.
• the ingredients shown under the heading "Aqueous Phase Ingredients” were added to a first glass container equipped with a stainless steel stirrer and heated with stirring to 75 * C-85 " C under an argon gas blanket.
• the ingredients shown under the heading "Oil Phase Ingredients” were added to a second glass container equipped with a stainless steel stirrer and heated with stirring to about from 85 * C to 90 "C under an argon gas blanket.
• the Retinoid Mixture was added with stirring.
• the emulsion was blanketed under argon gas and the temperature was maintained at about 50 * C-53 " C during the addition of the Retinoid Mixture.
• the emulsion was gradually cooled, with stirring and under an argon blanket, to room temperature (approximately 21 "Q.
• the finished emulsion was then transferred under argon gas blanketing to blind end aluminum tubes (2 ounce size) which were promptly crimped and tightly capped. The closed tubes were then set aside for determination of retinol stability after storage for various time periods at various temperatures.
• Retinol degrades under the influence of UV light. Accordingly, care must be taken at all stages of the emulsion preparation process to protect the retinol from exposure to UV light. This can be accomplished by turning out the lights in the processing area or by conducting the various handling and processing steps under yellow light.
• Polysorbate 61 (Tween 61 ) 1 .20 1 .20 1.25
• the ingredient in the Oil Phase Ingredients designated as Mixture A consisted of 1 .50 ' g myristyl myrista ⁇ e; 1.25 g oteic acid (Emersol 228); 1.25g glyceryl stearate (Emerest 2400); .25 g stearic add (Emersol 132); 1.00 g isopropyl palmitate; 1.00 stearoxytrimethylsilane (Dow Corning 580 Wax); 0.50 synthetic beeswax; 0.50 g stearyl alcohol; and 0.50 g cetyl alcohol.
• Mixture A consisted of 1 .50 ' g myristyl myrista ⁇ e; 1.25 g oteic acid (Emersol 228); 1.25g glyceryl stearate (Emerest 2400); .25 g stearic add (Emersol 132); 1.00 g isopropyl palmitate; 1.00 stearoxytrimethyls
• Mixture A was prepared by mixing the indicated ingredients in a glass container, stirring with heat until all m ⁇ re ⁇ ie ⁇ ts were liquefied and uniformly mixed; pouring the liquefied mixture into shallow containers; and allowing the mixture to cool to ambient temperature.
• Concentrations of all-trans retinol in oil-in-water samples A, B and C in Table 1 were determined after storage for various time periods at various temperatures. Concentrations of retinol and other retinoids such as retinal (vitamin A aldehyde), retinyl acetate and retinyl palmitate can be determined by any suitable analytical procedure. As reported herein, we determined retinoid concentrations by a stability indicating high performance liquid chromatography (HPLC) procedure in which the chromatograph was equipped with a reversed phase 5 micron C-8 column (25 cm in length x 4.6 mm in diameter) and a UV detector at 340nm.
• HPLC high performance liquid chromatography
• the sample to be analyzed was diluted with a solution of 50% by weight methanol and 50% by weight ethyl acetate to a concentration of 18 micrograms/ml and the retinoid ⁇ was detected at 340nm.
• the gradient mobile phase consisted of an organic portion composed of 5 percent tetrahydrofuran in acetonitriie and an aqueous portion consisting of 0.05N ammonium acetate.
• the solvent program has an initial composition of 70% organic/30% aqueous which increases linearly to 80% organic/20% aqueous at 13 minutes, then again increases linearly to 100% organic at 15 minutes, where it stays until 19 minutes.
• the analytical conditions were run at a flow rate of 2 ml/min and thermostatically regulated at 40 * C.
• the retention time of retinol (Vitamin A alcohol) is about 6.4 minutes.
• the retention times of retinal (Vitamin A aldehyde), retinyl acetate, and retinyl palmitate are ⁇ out 7.5 mins., 10.1 mins. and 18.7 mins. , respectively.
• the HPLC results were found to be reproducible to better than a 3% range of standard deviation.
• emulsion comprising all-trans retinol, BHT and disodium EDTA (a chelating agent) does not have acceptable chemical stability.
• a phospholipid liposomal formulation of retinol (Vitamin A alcohol) was prepared having the % w/w composition set forth in Table 2 at CILAG AG. After four weeks aging at 50 " C, only 64.87% of the original amount of retinol was found in the formulation which does not meet the stability criteria. Table 2:
• a phospholipid liposomal formulation of retinol (Vitamin A alcohol) was prepared by BioZone according to U.S Patents Nos. 4,485,054 and 4,761 ,288. After four weeks aging at 50 * C, only 64.61 % of the original amount of retinol was found in the formulation which does not meet the stability criteria.
• a non-phospholipid liposomal formulation of retinol (Vitamin A alcohol) was prepared by Micro Vesicular Systems, Inc. of New Jersey according to U.S. Patent No. 4,91 1 ,928. After 12 weeks aging at 50" C, 40 * C and room temperature only 58.1 % , 79.4% and 89.3% respectively of the original amount of retinol was found in the formulation which does not meet the stability criteria.
• retinol was more stable in both phospholipid and non-phospholipid liposome type formulation than in the oil-in-water emulsion. Although retinol was partially stabilized by formulation type change from o/w to non-phospholipid liposome, the shelf- life at ambient temperature was only 12 weeks, that is still chemically unacceptable.
• Retinol was encapsulated in the non-phospholipid liposome formulation with the following composition in accordance with the procedure set forth below.
• the pH of the final formulation was about 5.6.
• Example 5 Example 6
• Polysorbate 80 1.00% 1.05%
• the oil phase components were mixed together and heated to a temperature of aboui S5°C.
• the water phase components were then mixed together and heated to a temperature of about 85 °C and then cooled to 60°C before phasing, the water phase was then purged with argon to remove oxygen.
• a Novosome" liposome maker commercially available from Micro Vesicular Systems of New Jersey and described in U.S Patent Number 4,895,452 was equilibrated to a temperature of about 60°C by pumping the water phase through the equipment. 1 .13% of retinol (45% active was added to the oil phase.
• Example 7 The data summarized in Table 5 suggest that the stability of retinol in Example 7 was comparable to Example 5 which was prepared without ascorbic acid and disodium EDTA but under yellow light and Argon blanket. The results also suggest that the addition of ascorbic acid/disodium EDTA might enhance the chemical stability of retinol in Novasome * liposomes without the need for using an argon blanket.
• water-soluble antioxidants may also be utilized in the compositions of this invention such as ascorbic acid, sodium sulfite,* sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfox ⁇ late, isoascorbic acid, thiogl ⁇ cerot, thiosorbitol, thiourea, thiogl ⁇ colic acid, cysteine hydrochloride, 1-4-diazobicyclo-(2,2,2)octane and mixtures thereof.
• the non- phospholipid liposomal formulation of retinol (Example 8A ) was physically mixed with various proportions of 30% w/w cyclomethicone loaded non- phospholipid liposome (Example 8B).
• the stability results are summarized in Tables 6 through 8.
• Example 8C (50% Example 8A & 50% Example 8B)
• Example 8D (60% Example 8A and 40% Example 8B)
• Example 8E (70% Example 8A and 30% Example 8B)
• Example 8D To define the pH range most useful for retinol-containing compositions of this invention, the pH of Example 8D was adjusted to pH's ranging from 3.6 to 7.4 with dilute hydrochloric acid or dilute sodium hydroxide. The samples were stored at different temperatures (4 * C, 30 * C, 40 "C and 50 * C). Samples were taken periodically for both physical and chemical evaluation. The results in Figure 1 clearly showed that optimal pH range for retinol cream at 50 * C was above 5 .
• Skin bioimplicationabiiity which is defined by the availability of drug released from the formulation as well as the extent of skin penetration after application, usually serves as a good indicator for drug efficacy.
• the in-vitro bioavailability of retinol was determined by standard in-vitro release and skin penetration tests using FRANZ diffusion cells. For the release study, a weighed amount of cream was applied on a synthetic membrane mounted on each of the FRANZ diffusion cells. The synthetic membrane functioned as a cream supporter and did not cause significant resistance to the drug release. Samples were taken from the receptor chamber at predetermined intervals. The amount of retinol released from the formulation to the receptor solution was determined by High Pressure Liquid Chromatography (HPLC) .
• HPLC High Pressure Liquid Chromatography
• Example 8C which is a 50:50 mixture of 0.34% retinol loaded non-phospholipid liposome and 30% cyclomethicone loaded non-phospholipid
• Example 6 (0.15 % retinol loaded non-phospholipid) provided similar skin penetration to RoC s.a product ( Figure 3).
• Retinol-containing non-phospholipid liposome formulations were evaluated for dermal irritation and were also compared with a water-in-oil retinol formulation. Scope and Procedure
• the modified Draize Rabbit Primary Dermal Irritation Test is a procedure for predicting the ability of test articles to elicit inflammatory responses upon prolonged occluded contact with intact and intentionally-abraded New Zealand white rabbit skin. Following a timed exposure period, the test articles are removed and the application sites were evaluated. From this data, a Primary Dermal Irritation (PDI) Index is calculated for each test article and a classiflcation is assigned.
• PDI Primary Dermal Irritation
• test article was applied with 0.25-0.30g to 25mm Hilltop Chambers containing non-woven Webril pads. The chambers were then applied to the appropriate test sites and held in place with strips of Dermicel tape. The trunk of the animals were wrapped to occlude the sites and to keep the test articles in place. After the 4 hours of exposure, the test articles were removed and readings were taken after one hour in order to allow the skin to equilibrate. After the equilibration period, the sites were examined and then again reexa ined after 72 hours of application for signs of dermal irritation and were graded using a scale as follows:
• Placebo negative 1.2 Mild Irritant control
• the irritancy of topical formulation arises from both the active and the surfactants.
• the results in Table 9 show that 0.15 % retinol w/o formulations, which contain approximately 2% surfactants, exhibit mild or marginally moderate irritancy.
• the results suggest that non- phospholipid liposome formulations may have a potential to reduce the irritancy from the ingredients of the formulations.
• the products of this invention unexpectedly provide chemical stability enhancement, bioavailabihty programmability of retinoids to the skin, as well as improvement of the cosmetic elegance of the vehicle, which can all be achieved in a single non-phospholipid liposome formulation.

Landscapes

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

Priority Applications (7)

Applications Claiming Priority (2)

Publications (3)

Family

ID=23648011

Family Applications (1)

Country Status (15)

Cited By (37)

Families Citing this family (9)

Citations (1)

• 1996
  • 1996-04-03 CN CN96194264A patent/CN1185729A/zh active Pending
  • 1996-04-03 HU HU9801607A patent/HUP9801607A3/hu unknown
  • 1996-04-03 NZ NZ306694A patent/NZ306694A/xx not_active IP Right Cessation
  • 1996-04-03 EP EP96912539A patent/EP0818988A2/en not_active Ceased
  • 1996-04-03 AU AU55322/96A patent/AU5532296A/en not_active Abandoned
  • 1996-04-03 CA CA002217201A patent/CA2217201A1/en not_active Abandoned
  • 1996-04-03 EA EA199700289A patent/EA199700289A1/ru unknown
  • 1996-04-03 BR BR9604954A patent/BR9604954A/pt not_active Application Discontinuation
  • 1996-04-03 CZ CZ973119A patent/CZ311997A3/cs unknown
  • 1996-04-03 PL PL96322624A patent/PL322624A1/xx unknown
  • 1996-04-03 JP JP8530447A patent/JPH11503165A/ja not_active Ceased
  • 1996-04-03 AP APAP/P/1997/001101A patent/AP789A/en active
  • 1996-04-03 WO PCT/US1996/004557 patent/WO1996031194A2/en not_active Application Discontinuation
  • 1996-04-03 KR KR1019970707067A patent/KR19980703668A/ko not_active Application Discontinuation
• 1997
  • 1997-10-03 OA OA70096A patent/OA10520A/en unknown

Patent Citations (1)

Also Published As

Similar Documents

Legal Events