TREATMENT OF SKIN CONDITIONS USING HIGH KRAFFT TEMPERATURE ANIONIC SURFACTANTS

Abstract

The present invention is a method and composition for the treatment of skin conditions where the epidermal barrier has decreased function such as when the patient is suffering from eczema, in particular, Atopic Dermatitis. Epidermal barrier function can be significantly improved and the extraction of epidermal lipids can be reduced by using formulations containing high Krafft temperature surfactants, preferably, anionic surfactants.

Claims

1. A method for treating an epidermal barrier with decreased function, comprising topically administering a composition comprising a high Krafft temperature surfactant, a moisturizer and water to a patient in need of such treatment, wherein said composition does not include roflumilast or a keratolytic agent.

2. The method according to claim 1, wherein said high Krafft temperature surfactant is in an amount of 0.1-20% w/w.

3. The method according to claim 1, wherein said composition is selected from the group consisting of an oil in water emulsion, a water in oil emulsion, a microemulsion or nanoemulsion, and a hydrophilic or hydrophobic ointment.

4. The method according to claim 1, wherein said composition further comprises at least one additional component selected from the group consisting of a solvent, moisturizer, polymer or thickener, antifoaming agent, preservative, antioxidant, sequestering agent, stabilizer, buffer, pH adjusting solution, skin penetration enhancer, film former, dye, pigment, aerosol forming agent and fragrance.

5. The method according to claim 1, wherein said composition has a pH of 3.5-9.0.

6. The method according to claim 1, wherein said composition comprises carriers suitable for topical administration.

7. The method according to claim 1, wherein said composition further comprises an active pharmaceutical ingredient.

8. The method according to claim 7, wherein said active pharmaceutical agent is selected from the group consisting of Anthralin, Azathioprine, Tacrolimus, Coal tar, Methotrexate, Methoxsalen, Ammonium lactate, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids, Corticotropin, Vitamin D analogues, Acitretin, Tazarotene, Cyclosporine, Resorcinol, Colchicine, Adalimumab, Ustekinumab, Infliximab, antibiotics, phosphodiesterase-4 inhibitors, and combinations thereof.

9. The method according to claim 1, wherein said patient with an epidermal barrier with decreased function is suffering from eczema.

10. The method according to claim 9, wherein said patient is suffering from atopic dermatitis, contact dermatitis, and/or seborrheic dermatitis.

11. A pharmaceutical composition comprising white petrolatum, isopropyl palmitate, a high Krafft temperature surfactant, diethylene glycol monoethyl ether, methylparaben, propylparaben and water, wherein said composition does not include roflumilast or a keratolytic agent.

12. The pharmaceutical composition according to claim 11, wherein said high Krafft temperature surfactant is a mixture of cetostearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate.

13. The pharmaceutical composition according to claim 12, further comprising hexylene glycol.

14. The pharmaceutical composition according to claim 11, wherein said high Krafft temperature surfactant is an anionic surfactant.

15. The pharmaceutical composition according to claim 11, wherein said high Krafft temperature surfactant has a Krafft temperature above 48° C.

16. The pharmaceutical composition according to claim 15, wherein said high Krafft temperature surfactant has a Krafft temperature above 50° C.

17. The pharmaceutical composition according to claim 16, wherein said high Krafft temperature surfactant has a Krafft temperature above 52° C.

18. The pharmaceutical composition according to claim 11, wherein said composition does not contain an active pharmaceutical ingredient.

19. A composition comprising TABLE-US-00007 White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (49.75%) wherein said composition does not contain an active pharmaceutical ingredient.

20. A composition comprising TABLE-US-00008 White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.75%) wherein said composition does not contain an active pharmaceutical ingredient.

21. A method for reducing the extraction of epidermal lipids and increasing epidermal barrier function, comprising topically administering a formulation comprising a high Krafft temperature surfactant, a moisturizer and water to a patient in need of such treatment.

22. The method according to claim 21, wherein said high Krafft temperature surfactant is an anionic surfactant.

23. The method according to claim 21, wherein said high Krafft temperature surfactant has a Krafft temperature above 48° C.

24. The method according to claim 23, wherein said high Krafft temperature surfactant has a Krafft temperature above 50° C.

25. The method according to claim 24, wherein said high Krafft temperature surfactant has a Krafft temperature above 52° C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows the results of treating excised skin with a high Krafft temperature formulation and a low Krafft temperature formulation. Treatment with the cream formulation containing high Krafft temperature phosphate surfactants (Krafft temperature 53° C., Formulation 2 from EXAMPLE 2) did not result in ceramide extraction. Treatment with the cream containing the low Krafft temperature sodium cetostearyl sulfate surfactant (Elidel Cream Vehicle, Formulation 5 from EXAMPLE 2) was most efficient in extracting ceramides from human skin. A greater quantity of ceramides were extracted from Formulation 5 treated skin after 3 warm water washes than from the 4% sodium lauryl sulfate positive control.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Epidermal barrier compromised skin can be treated using emollient emulsions containing one or more high Krafft temperature anionic surfactants without decreased clinical efficacy over time. The surfactants emulsify the composition and help wet the surface of any actives or excipients in the formulation. As used herein the term “surfactant” means an amphiphile (a molecule possessing both polar and nonpolar regions which are covalently bound) capable of reducing the surface tension of water and/or the interfacial tension between water and an immisicible liquid. Any anionic surfactant with a Krafft temperature above 48° C. can be used in the present invention. The Krafft point of an anionic surfactant can be determined using methods known in the art, for example, see Li, et al., “Property Prediction on Surfactant by Quantitative Structure-Property Relationship: Krafft Point and Cloud Point”, Journal of Dispersion Science and Technology, 26: 799-808, 2005. Such surfactants may include but are not limited to alkyl aryl sodium sulfonate, ammonium lauryl sulfate, cocamide ether sulfate, cocamine oxide, coco betaine, coco diethanolamide, coco monoethanolamide, coco-caprylate/caprate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, docusate sodium, sodium dodecylbenzenesulfonate, sodium palmitate, sodium hexadecyl sulfonate, sodium stearyl sulfate, sodium stearate, sodium xylene sulfonate, potassium cetyl phosphate, potassium C9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate, lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphate oleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10 phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethyl phosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeyl phosphate and tristearyl phosphate.

TABLE-US-00001 Commonly Used Anionic Surfactants and Their Krafft Temperatures Krafft Temperature Surfactant ° C. C.sub.10H.sub.21SO.sub.3.sub.− Na.sup.+ Sodium decyl sulfonate 22.5 C.sub.12H.sub.25SO.sub.3.sub.− Na.sup.+ Sodium dodecyl sulfonate 38.0 C.sub.14H.sub.29SO.sub.3.sub.− Na.sup.+ Sodium myristyl* sulfonate 48.0 C.sub.16H.sub.33SO.sub.3.sub.− Na.sup.+ Sodium hexadecyl sulfonate 57.0 C.sub.10OSO.sub.3.sub.− Na.sup.+ Sodium decyl sulfate 8.0 C.sub.12H.sub.25OSO.sub.3.sub.− Na.sup.+ Sodium lauryl sulfate (SLS) Sodium dodecyl sulfate (SDS) 16.0 C.sub.14H.sub.29OSO.sub.3.sub.− Na.sup.+ Sodium myristyl sulfate 30.0 C.sub.16H.sub.33OSO.sub.3.sub.− Na.sup.+ Sodium cetyl sulfate 45.0 C.sub.18H.sub.37OSO.sub.3.sub.− Na.sup.+ Sodium stearyl sulfate 56.0 C.sub.12H.sub.25(OCH.sub.2CH.sub.2)OSO3− Na+ Sodium laureth sulfate (SLES) <0 C.sub.12H.sub.25OSO.sub.3.sub.− NH.sub.4.sub.+ Ammonium lauryl sulfate (ALS) 10 C.sub.12COO.sup.−Na.sup.+ Sodium laurate Dodecanoic acid sodium salt 21.5 C.sub.14COO.sup.−Na.sup.+ Sodium myristate Tetradecanoic acid, sodium salt 39 C.sub.16COO.sup.−Na.sup.+ Sodium palmitate Hexadecenoic acid, sodium salt 69 C.sub.18COO.sup.−Na.sup.+ Sodium stearate Octadecanoic acid, sodium salt 71 C.sub.12H.sub.25(C.sub.6H.sub.4)SO.sub.3.sub.−Na.sup.+ Sodium dodecylbenzenesulfonate 52 C.sub.12OPO.sub.3.sub.− Na.sup.+ Sodium lauryl phosphate Sodium dodecyl phosphate (SDP) 31.5 Ceteth - 10 phosphate 53 Dicetyl phosphate 58 Sodium cetostearyl sulfate Blend of cetyl and stearyl sulfate 41 *sodium tetradecyl sulfate is a commonly used (but incorrect) synonym for 7-ethyl-2-methyl-4-undecanyl sulfate sodium which is an anionic surfactant sclerosing agent.

[0016] In a preferred embodiment, the emulsifier blend of cetearyl alcohol (CAS 67762 30 0), dicetyl phosphate (CAS 2197 63 9) and ceteth-10 phosphate (CAS 50643-20-4) which is manufactured by Croda under the tradename CRODAFOS™ CES, is used. This commercially available emulsifier blend is a self-emulsifying wax that is predominately the waxy material cetearyl alcohol (which is a mixture cetyl alcohol (C.sub.16H.sub.34O) and stearyl alcohol (C.sub.18H.sub.38O)) combined with 10-20% dicetyl phosphate and 10-20% ceteth-10 phosphate. Self-emulsifying waxes form an emulsion when blended with water. When CRODAFOS™ CES is added to water it spontaneously forms an emulsion having a pH of about 3. Agents which adjust the pH can be added to increase or decrease the pH to the desired value. The pH of the formulation can be adjusted depending on the optimal pH of the components. The pH should be between 3.5-9.0, preferably between 4.0-8.0.

##STR00001##

[0017] Preferably, the compositions according to the present invention are in one of the following forms:

[0018] An oil-in-water emulsion: The product may be an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, salts, surfactants, emulsifiers, and other components. These emulsions may include water-soluble or water-swellable polymers that help to stabilize the emulsion.

[0019] A water-in-oil emulsion: The compositions may be an emulsion that includes a continuous phase of a hydrophobic component and an aqueous phase that includes water and optionally one or more polar hydrophilic carrier(s) as well as salts or other components. These emulsions may include oil-soluble or oil-swellable polymers as well as one or more emulsifier(s) to help to stabilize the emulsion.

[0020] A hydrophilic or hydrophobic ointment: The compositions are formulated with a hydrophobic base (e.g. petrolatum, thickened or gelled water insoluble oils, and the like) and optionally having a minor amount of a water soluble phase. Hydrophilic ointments generally contain one or more surfactants or wetting agents

[0021] A microemulsion: These are clear, thermodynamically stable isotropic liquid systems that contain oil, water and surfactants, frequently in combination with a cosurfactant. Microemulsions may be water continuous, oil continuous or bicontinuous mixtures. The formulations may optionally also contain water up to 60% by weight. Higher levels may be suitable in some compositions. Classes of cosurfactants include short-chain alcohols, alkane diols and triols, polyethylene glycols and glycol ethers, pyrrolidine derivatives, bile salts, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters. Suitable hydrophilic components for use in a microemulsion include one or more glycols such as polyols such as glycerin, propylene glycol, butylene glycols, polyethylene glycols (PEG), random or block copolymers of ethylene oxide, propylene oxide, and/or butylene oxide, polyalkoxylated surfactants having one or more hydrophobic moieties per molecule, silicone copolyols, blend of ceteareth-6 and stearyl alcohol as well as combinations thereof, and the like.

[0022] An aerosol foam or spray: The product may be an alcohol/solvent based solution containing an emulsifying wax or an emulsion comprising a discrete phase of a hydrophobic component and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, surfactants, emulsifiers, and other components. These solvent or emulsion foam concentrates may include water-soluble or water-swellable polymers that help to stabilize the emulsion and corrosion inhibitors to improve compatibility between the formulation and the package. A hydrocarbon, hydrochlorofluorocarbon (HCFC) or chlorofluorocarbon (CFC) aerosol propellant can be added to the solvent or emulsion foam concentrate in packaging designed to maintain pressure until the foam or spray product is dispensed for application.

Solvents

[0023] Compositions according to the present invention may include one or more solvents or co-solvents which modify skin permeation or the activity of other excipients contained in the formulation. Solvents include but are not limited to ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, oleyl alcohol, polyethylene glycol, glycerol, propylene glycol and SD alcohol.

Moisturizers

[0024] Compositions according to the present invention may include additional moisturizers to increase the level of hydration. The moisturizer can be a hydrophilic material including humectants or it can be a hydrophobic material including emollients. Suitable moisturizers include but are not limited to: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, and stearyl alcohol.

Polymers and Thickeners

[0025] For certain applications, it may be desirable to formulate a product that is thickened with soluble, swellable, or insoluble organic polymeric thickeners such as natural and synthetic polymers or inorganic thickeners such as acrylates copolymer, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, acrylamide/sodium acryloyldimethyl taurate copolymer, carboxy vinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methylcellulose,

Additional Components

[0026] Compositions according to the present invention may be formulated with additional components such as fillers, carriers and excipients conventionally found in cosmetic and pharmaceutical topical products. Additional components including but not limited to antifoaming agents, preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol, phenylmercury salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting agents (preferably agents which result in an acidic pH, including but not limited to gluconolatone, citric acid, lactic acid, and alpha hydroxyacids), skin penetration enhancers, skin protectants (including but not limited to petrolatum, paraffin wax, dimethicone, glyceryl monoisostearate, isopropyl isostearate, isostearyl isostearate, cetyl alcohol, potassium cetyl phosphate, cetyl behenate and behenic acid), chelating agents, film formers, dyes, pigments, diluents, bulking agents, fragrances, aerosol producing agents and other excipients to improve the stability or aesthetics, may be added to the composition. Though alcohol is known to irritate and extract water and lipids from the skin, alcohol can be included in formulations which include high Krafft temperature surfactants in view of the improvement in epidermal barrier function. Alcohol can be included to improve the solubility and to increase the absorption of active pharmaceutical agents.

[0027] Compositions according to the present invention may be formulated with or without pharmaceutically active agents depending on the condition being treated. The additional active agents include but are not limited to Anthralin (dithranol), Azathioprine, Tacrolimus, Tapinarof, Coal tar, Methotrexate, Methoxsalen, Ammonium lactate, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g. Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), Corticotropin, Vitamin D analogues (e.g. calcipotriene, calcitriol), Acitretin, Tazarotene, Cyclosporine, Resorcinol, Colchicine, Adalimumab, Ustekinumab, Infliximab, phosphodiesterase-4 inhibitors (PDE-4 inhibitors) such as Roflumilast, and antibiotics (e.g. erythromycin, ciprofloxacin, metronidazole).

Administration and Dosage

[0028] The compositions according to the present invention can be administered by any suitable administration route including but not limited to cutaneously (topically), transdermally, and mucosally (e.g. sublingual, buccal, nasally). In a preferred embodiment, the composition is administered topically.

[0029] Suitable pharmaceutical dosage forms include but are not limited to emulsions, creams, lotions, foams, microemulsions and nanoemulsions.

[0030] The composition can be administered one or more times per day, preferably the composition is administered 1-2 times per day.

[0031] The composition can be used in veterinary and in human medicine for the treatment of all diseases and conditions associated with epidermal barrier dysfunction, such as proliferative, inflammatory and allergic dermatoses. Such dermatoses include but are not limited to Inflamed Keratinization Disorders such as atopic dermatitis, psoriasis (vulgaris), eczema, acne, Lichen simplex, sunburn, pruritus, seborrheic dermatitis, Darier disease, Hailey-Hailey disease, hypertrophic scars, discoid lupus erythematosus, and pyodermias. In a preferred embodiment, the dermatoses to be treated is atopic dermatitis.

[0032] The following examples are provided to enable those of ordinary skill in the art to make and use the methods and compositions of the invention. These examples are not intended to limit the scope of what the inventor regards as the invention. Additional advantages and modifications will be readily apparent to those skilled in the art.

Example 1

[0033] Creams were prepared according to the following formulations.

Formulation 1

[0034]

TABLE-US-00002 White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (49.75%)

Formulation 2

[0035]

TABLE-US-00003 White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Crodafos CES 10.0% w/w Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.75%)

Formulation 3

[0036]

TABLE-US-00004 White Petrolatum 10.0% w/w Isopropyl Palmitate 5.0% w/w Sodium Dodecyl Sulfate 2.0% w/w Cetearyl Alcohol 8.0% w/w Hexylene glycol 2.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 25.0% w/w Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.75%)
Formulation 4 (U.S. Pat. No. 10,195,160—Formulation for Tapinarof 2b in Table 1)

TABLE-US-00005 Medium Chain Triglycerides 10.0% w/w Steareth-2 1.8% w/w Steareth-20 1.1% w/w Polysorbate 80 1.5% w/w Propylene glycol 10.0% w/w Diethylene glycol monoethyl ether (Transcutol P) 2.0% w/w Benzoic acid 0.25% w/w Butylated hydroxytoluene 0.1% w/w Disodium ethylene diamine tetraacetic acid 0.1% w/w Citrate/citric acid buffer 0.27% w/w Purified Water q.s. ad 100 (64.68%)

Formulation 5 (Formulation for Elidel Cream Vehicle Example 14 EP 0 786986)

[0037]

TABLE-US-00006 Mono- and di-glycerides 2.0% w/w Medium-chain triglycerides 15.0% w/w Sodium cetostearyl sulphate 1.0% w/w Propylene glycol 5.0% w/w Cetyl alcohol 4.0% w/w Benzyl alcohol 1.0% w/w Stearyl alcohol 4.0% w/w Oleyl alcohol 10.0% w/w Citrate/citric acid buffer 0.05% w/w 10% NaOH or 10% HCl Solution as needed for pH = 5.3 + 0.3 Purified Water q.s. ad 100 (57.95%)

Example 2

[0038] 0.0012 grams of ceteth-10 phosphate (Moravek Lot 671-144-000-A-20190821-JHO) was weighed into a 20 mL glass scintillation vial. 10.0113 grams of distilled water was added to the scintillation vial and the vial was tightly capped and placed in a water bath. The temperature was gradually increased from 36.0° C. to 56.0° C. After equilibrating at 52.5° C. for 150 minutes the ceteth-10 phosphate had not dissolved and the sample did not froth when vigorously shaken. The surfactant remained as waxy particles sedimented on the bottom of the vial. After equilibration at 53.0° C. for 435 minutes, ceteth-10 phosphate had dissolved and the sample frothed when shaken. The Krafft temperature of a 0.012% ceteth-10 phosphate aqueous solution was determined to be 53.0° C.

[0039] 0.0019 grams of dicetyl phosphate (Sigma dihexadecyl phosphate lot STBH2863) was weighed into a 20 mL glass scintillation vial. 11.2262 grams of distilled water was added to the scintillation vial and the vial was tightly capped and placed in a water bath. The temperature was gradually increased from 51.0° C. to 65.0° C. After equilibrating at 57° C. for 120 minutes the dicetyl phosphate had not dissolved and the sample did not froth when vigorously shaken. After equilibration at 58.0° C. for 450 minutes, dicetyl phosphate had dissolved and the sample frothed when shaken. The Krafft temperature of a 0.017% dicetyl phosphate aqueous solution was determined to be 58.0° C. 0.0024 grams of sodium cetostearyl sulfate (BASF Lanette E Granules Lot 0021826181) was weighed into a 20 mL glass scintillation vial. 17.0763 grams of distilled water was added to the scintillation vial and the vial was tightly capped and placed in a water bath. The temperature was gradually increased from 35.0° C. to 42.5° C. After equilibrating at 40.0° C. for 805 minutes the sodium cetostearyl sulfate had not dissolved and the sample slightly frothed when vigorously shaken. After equilibration at 42.5° C. for 365 minutes, sodium cetostearyl sulfate had dissolved and the sample frothed when shaken. The Krafft temperature of a 0.014% sodium cetostearyl sulfate aqueous solution was determined to be 41.0° C.

Example 3

[0040] The ability of cream formulations containing emulsifiers having a range of Krafft temperatures, to extract epidermal lipids can be determined using excised human cadaver skin dermatomed to a target thickness of 500 microns. Excised human skin was obtained frozen from a US tissue bank and stored at −20° C. until use. The skin was loaded onto vertical Franz cells with a diameter of 8 mm having a 0.503 cm.sup.2 extraction area and a receptor chamber filled with 3.0 ml of 4% BSA in water containing 0.01% gentamicin sulfate thermostated at 32° C. (receptor solution). Using a positive displacement pipette, a 5-microliter dose of cream was added to each Franz Cell (10 mg cream per cm.sup.2 of skin tissue). The diffusion cells were maintained at a skin surface temperature of 32±1° C. After 24-hour incubation, the skin surface was cleaned with Q-tips (wet Q-tip and dry Q-tip for three cycles) to remove any surface residue of the applied test article. The skin surface was then washed with 45° C. warm water for three cycles. Skin tissues were then removed from the Franz Cell and tape stripped. The first two tape strips were discarded. The tape-stripping process was continued for an additional 15 times. The 15-tape strips were collected, quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS), and labelled “stratum corneum”. Epidermis and dermis layers were separated using a scalpel. The epidermis was collected, and the lipids extracted from any remaining stratum corneum and the epidermis using baths containing chloroform/methanol mixtures. The baths were gathered, evaporated, and dissolved into an appropriate mobile phase for quantitation by HPLC/MS/MS analysis.

[0041] According to the literature (ref), there are twelve common ceramides in human skin. N-lignoceroyl-phytosphingosine (Ceramide NP) and N-(2′-(R)-hydroxylignoceroyl)-D-erythro-phytosphingosine (Ceramide AP) are among the most abundant ceramides in human skin. In addition to quantifying Ceramides NP and AP in this lipid extraction study, N-Lignoceroyl-D-erythro-Sphingosine (Ceramide NS) and N-lignoceroyl-D-erythro-sphinganine (Ceramide NDS) were also quantified from the tape strips and epidermal extraction baths described in this example. The total nanograms of Ceramides NP, AP, NS and NDS extracted from the samples labeled “stratum corneum” and “epidermis” after three warm (45° C.) water rinses were added together and normalized to one square centimeter of human skin. As shown in FIG. 1, treating the skin with a cream formulation containing high Krafft temperature phosphate surfactants (Formulation 2 from EXAMPLE 2) did not result in ceramide extraction. After three warm water washes the amount of ceramides remaining in Formulation 2 treated skin was the same as excised skin dosed with 5 microliters of water (inert control) 24-hours prior to the warm water washes. The skin treated with the cream containing the low Krafft temperature sodium cetostearyl sulfate surfactant (Formulation 5 from EXAMPLE 2) was most efficient in extracting ceramides from human skin. A greater quantity of ceramides were extracted from Formulation 5 treated skin after 3 warm water washes than from the 4% sodium lauryl sulfate positive control.

Example 4

[0042] Atopic dermatitis clinical studies use the Eczema Area and Severity Index (EASI) as a validated scoring system to measure the efficacy of topically applied products. The EASI score assesses objective physician estimates of two dimensions of atopic dermatitis: 1) disease extent and 2) clinical signs. Scoring the extent of disease is accomplished by assigning a numerical score of 0 to 6 linked to the percentage of skin affected: Score of 0=0% of skin affected; score of 1=1-9% of skin affected; score of 2=10-29% skin affected; score of 3=30-49% of skin affected; score of 4=50-69% skin affected; score of 5=70-89% skin affected and score of 6=90-100% of skin affected. The disease extent score is combined with scoring of the severity of four clinical signs (erythema, induration/papulation, excoriation, and lichenification) each on a scale of 0 to 3 (0=none, absent; 1=mild; 2=moderate; 3=severe) at four body sites (head and neck, trunk, upper limbs, and lower limbs). Half scores are allowed. Each body site will have a score that ranges from 0 to 72, and the final EASI score will be obtained by averaging these four scores (using multipliers 0.2 for head and neck and upper limbs and 0.3 for trunk and lower limbs). Hence, the final EASI score will range from 0 to 72 for each time point that the patient is evaluated in the clinic. EASI scores reported as “percent change from baseline” is a standard way of clinically evaluating improvement or worsening of atopic dermatitis lesions over the time course of topical product application. As an example a 1% increase in EASI % CFB at 4 weeks of treatment would imply that on average all patients treated with this cream had their atopic dermatitis worsen. Alternatively a 55% decrease in EASI % CFB at 4 weeks of treatment would mean dramatic improvement in either disease extent or clinical signs, or typically significant improvement in both disease extent and clinical signs of atopic dermatitis lesions.

[0043] It is a drug product's ability to treat atopic dermatitis significantly better than the vehicle (the same cream formulation without the active pharmaceutical ingredient) that results in pharmaceutical product approval at the FDA. Thus, EASI scores are published for both pharmaceutical products and their vehicle control topical cream products clinically evaluated for the treatment of atopic dermatitis.

[0044] Formulation 2 from EXAMPLE 2 was dosed once daily for four weeks to 45 atopic dermatitis patients. The EASI % CFB was reduced by 55.8% for AD patients treated with this blend of high Krafft temperature surfactants (53.0° C. for ceteth-10 phosphate and 58.0° C. for dicetyl phosphate) and only one patient complained of application site burning. This is in contrast to the Elidel® vehicle formulation that had 1% increase in EASI % CFB after twice daily dosing of 136 AD patients for 4 weeks. According to the Elidel® package insert this cream vehicle formulation contains the low Krafft temperature surfactant (41° C.) sodium cetostearyl sulfate and had 17 patients complain of application site burning.