IE910068A1 - Topical compositions - Google Patents

Topical compositions

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Publication number
IE910068A1
IE910068A1 IE006891A IE6891A IE910068A1 IE 910068 A1 IE910068 A1 IE 910068A1 IE 006891 A IE006891 A IE 006891A IE 6891 A IE6891 A IE 6891A IE 910068 A1 IE910068 A1 IE 910068A1
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IE
Ireland
Prior art keywords
composition
accordance
agent
water
alcohol
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IE006891A
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IE65371B1 (en
Inventor
Subhas Chandra Kundu
Noel Mark Meltzer
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Hoffmann La Roche
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Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of IE910068A1 publication Critical patent/IE910068A1/en
Publication of IE65371B1 publication Critical patent/IE65371B1/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Abstract

The stability of topical pharmaceutical preparations in emulsion form with 1 alpha ,25-dihydroxycholecalciferol as active ingredient is increased when the pH of the preparation is 6.5 - 7.5.

Description

The present invention relates to topical pharmaceutical compositions comprising la,25-dihydroxycholecalciferol in a suitable topical pharmaceutical carrier wherein said topical compositions are emulsions having a pH of about 6.5 to about 7.5. Compositions of the invention include aesthetically elegant vanishing creams. Compositions of the invention have excellent stability at both room temperature and elevated temperatures.
In the past, topical pharmaceutical compositions con15 taining la,25-dihydroxycholecalciferol have had stability problems due to the sensitive nature of the la,25-dihydroxycholecalcif erol . It has been unexpectedly found that the stability of topical pharmaceutical compositions which contain la,25-dihydroxycholecalciferol and which are emulsions can be improved by adjusting the pH the aqueous phase so that the range of the pH of the topical compositions is about 6.5 to about 7.5, preferably about 6.8 to about 7.2. The most preferred pH of the topical compositions is about 7.0.
As used herein emulsions include oil-in-water emulsions, water-in-oil emulsions, and multiple emulsions.
As used herein a topical pharmaceutical carrier comprises a mixture of a viscosity agent, a lipophilic solubilizing agent, a hydrophilic solubilizing agent, an emulsifier, an emollient, a preservative, an antioxidant, a chelating agent, and a humectant.
Grn/25.10.90 Compositions of the invention include skin creams, vanishing skin creams, gels, and lotions.
Skin creams may be oil-in-water emulsions, water-in-oil 5 emulsions, or multiple emulsions. Vanishing skin creams are either oil-in-water or water-in-oil emulsions. Lotions are usually oil-in-water emulsions.
The preferred compositions of the invention are 10 aesthetically elegant oil-in-water vanishing skin creams and water-in-oil skin creams.
The pH of the compositions of the invention is in the range of about 6.5 to about 7.5, preferably about 6.8 to about 7.2. The most preferred pH of the compositions of the invention is about 7.0. To achieve this pH, the aqueous phase of a composition of the invention is adjusted, preferably buffered to a pH of about 7.0 to about 8.0. In this manner the resulting pH of the final composition is in the range of about 6.5 to about 7.5, preferably 7.0.
As used herein, the term % (w/w) or % (wt/wt)" refers to % weight/weight. Thus. 10 grams of ingredient A in 100 grams of composition is present at 10 % (w/w).
It is known that topical pharmaceutical compositions containing la,25-dihydroxycholecalciferol can be utilized in the treatment of skin conditions such as psoriasis. This is disclosed, for example, in U.S. Patent 4.610,978.
The topical pharmaceutical compositions of the present invention comprise la,25-dihydroxycholecalciferol in topical pharmaceutical carrier materials.
In particular, aesthetically elegant, vanishing skin creams of the invention are buffered oil-in-water emulsions which comprise, la,25-dihydroxycholecalciferol. a IE 9168 - 3 viscosity agent, a lipophilic solubilizing agent, a hydrophilic solubilizing agent, an emulsifier, an emollient, a preservative, an antioxidant, a chelating agent, a humectant, and a buffering agent.
Topical pharmaceutical compositions of the present invention may also contain conventional additives used in topical pharmaceutical formulations. Such additives include, for example, fragrances and substantive agents such as polymers. (Substantive agents are agents which allow for prolonged contact time between the topical pharmaceutical composition and the skin.) Viscosity agents are also referred to in this specification as bodying agents. The viscosity agent may be an alcohol selected from the group consisting of cetyl alcohol, stearyl alcohol, ceteostearyl alcohol, and myristyl alcohol. The viscosity agent may also be xanthan gum, a magnesium aluminum silicate like veegum. carbomer, glyceryl stearate, hydrogenated castor oil. cetyl palmitate, stearic acid; a combination of synthetic and semisynthetic wax; a combination of glyceryl stearate, cetearyl alcohol, cetyl palmitate and cocoglycerides blend; or a combination of glyceryl hydroxystearate, cetyl palmitate and trihydroxystearin blend. The viscosity agent may also be two or more of any of the viscosity agents mentioned above. The viscosity agent is preferably a combination of cetyl and stearyl alcohol.
The hydrophilic solubilizer can be dimethyl isosorbide or transcutol; or an aliphatic alcohol selected from the group consisting of ethyl alcohol, isopropyl alcohol, polyethylene glycol, or more preferably propylene glycol.
The lipophilic solubilizer can be castor oil; isopropyl myristate; an alcohol selected from the group consisting of octyl dodecanol, isocetyl alcohol, oleyl alcohol, oleyl IE 9168 - 4 cetyl alcohol, or triglycerides of medium chain length vegetable fatty acids such as Miglyols which are mixtures of caprylic and capric triglyceride, propylene glycol dicaprylate and dicaprate, or a mixture of caprylic and capric triglyceride; or Neobee M-5. The lipophilic solubilizer more preferably is mineral oil.
The emulsifier can be a polysorbate selected from the group consisting of Polysorbate 20, Polysorbate 40, Polysorbate 60 and Polysorbate 80; a sorbitan selected from the group consisting of sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan trioleate or sorbitan tristearate. The emulsifier can also be glyceryl monostearate, polyoxyethylene stearate, polyoxyethylene lauryl ether, PEG-20 glyceryl stearate, ceteareth-12, ceteareth-20, ceteareth-30, PPG-2-Ceteareth-9. polyethylene glycol ethers of oleyl alcohol such as oleth-5, oleth-10, a mixture of oleth-5 and oleth-10, sterols such as soya sterol, PEG-5 soya sterol, PEG-10 sterol, PEG-16 soya sterol, PEG-25 soya sterol, and also the emulsifier can be sodium cetearyl sulfate, or PEG-40 hydrogenated castor oil. The emulsifier is preferably a mixture of Span 60. which is sorbitan monostearate, Arlacel -165 which is glyceryl monostearate and polyoxyethylene stearate blend and Tween 60, which is polysorbate 60.
The emollient can be an ester such as oleyl oleate, octyl stearate, myreth-3 myristate, hexyl laurate. dibutyl adipate, isocetyl stearate, octyldodecyl stearate, PEG-7-glyceryl cocoate, oleyl erucate, a mixture of coco-caprylate and caprate. myristal myristate. cetearyl isonanoate. decyl oleate, a mixture of caprylic and capric triglyceride. PEG-5-Laureth-5, trihydroxymethoxy stearin, and a mixture of propylene glycol dicaprylate and dicaprate. The emollient can also be castor oil or dioctyl cyclohexane or mineral oil. The emollient is preferably IE 9168 mineral oil.
The preservative can be cis-1-(3-chloroethyl)-3,5.7triaza-l-azoniaadamantane chloride; sorbic acid; potassium sorbate; benzyl alcohol; benzalkonium chloride; dichlorobenzyl alcohol; N-(hydroxymethyl)-N-(l,3-dihydroxymethy1-2.5-dioxo-4-imidazolidinyl)-N-hydroxymethylJurea; boric acid; chlorobutanol; monothioglycerol; methyl paraben; propyl paraben; or more preferably a mixture of methyl and propyl parabens.
The anti-oxidant can be propyl gallate; butylated hydroxytoluene; ascorbyl palmitate; sodium ascorbate; α-tocopherol; or more preferably butylated hydroxyanisole.
The chelating agent can be dimercaprol; ascorbic acid; diphenylthiocarbazone, versene acid, or more preferably disodium edetate.
The humectant can be glycerin; elastin; hyaluronic acid; or more preferably sorbitol.
The topical pharmaceutical carrier materials of the invention are slightly acidic. Accordingly, in order to obtain a topical pharmaceutical composition within the desired pH range of about 6.5 to about 7.5, it is necessary that the aqueous phase be adjusted to that pH. Suitable agents for adjusting the pH to the desired range are sodium hydroxide or potassium hydroxide or buffering agents e.g. a mixture of sodium citrate and citric acid; a mixture of tris (hydroxymethyl) aminomethane and tris(hydroxymethyl) aminomethane hydrochloride; or disodium phosphate. Other buffers which are compatible with topical pharmaceutical compositions may also be used. The buffering agent is preferably disodium phosphate. Determining the pH for the aqueous phase, which will be mixed with particular pharmaceutical carrier materials, so that a final pH between about 6.5 to about 7.5 is achieved, is within the skill of the ordinary artisan. Ordinarily, when the pH of the aqueous phase is in the range of about 7.0 to about 8.0 this will result in a final topical pharmaceutical composition whose pH is in the range of about 6.5 to about 7.5.
In the procedure for preparing the topical pharmaceutical compositions of the present invention, the la,25-dihydroxy- cholecalciferol is dissolved in the oil phase. The oil phase and the aqueous phase are then mixed to form the final emulsion.
The topical pharmaceutical compositions of the present invention contain from about 0.00001% (w/w) to about 0.1% (w/w) preferably 0.0005 % (w/w) to about 0.005 % (w/w) of la, 25-dihydroxycholecalciferol. The topical pharmaceutical compositions of the invention which are oil-in-water emulsions can be prepared by incorporating la,25-dihydroxycholecalciferol into carrier formulations, by mixing in the following steps: Step 1: la,25-dihydroxycholecalciferol is dissolved in a hydrophilic solubilizer such as propylene glycol under nitrogen. It is preferred to keep the resulting solution at about room temperature until its use in Step 4 below so as to avoid degradation of the la,25-dihydroxycholecalciferol.
Step 2: All hydrophilic ingredients are weighed out, and added to water. The pH of the mixture is adjusted to the range of about 7.0 to about 8.0. The resulting mixture is heated with stirring until a maximum temperature of about 70°C to about 75°C is achieved. The resulting solution is the aqueous phase of the final emulsion.
Step 3: All lipophilic ingredients are mixed together, and heated with stirring until a maximum temperature of about 70°c to about 75°C is achieved. The resulting IE 9168 solution is the oil phase of final emulsion.
Step 4: Under nitrogen, the solution from Step 1 is then added to the oil phase of Step 3 while stirring is continued and the temperature is maintained at about 70° to about 75°C. Additional propylene glycol is used to wash the vessel which contained the solution from Step 1. This wash is added to the mixture of Step 4.
Step 5: Under nitrogen, the oil phase from Step 4 is added to the aqueous phase from Step 2 using a homogenizer to disperse the resulting emulsion. Homogenization is continued until the droplet size of the oil droplets in the emulsion is about 1 to about 20 microns. Then homogenization is stopped, and gentle stirring is conducted until the emulsion cools to room temperature.
The above procedure for preparing topical pharmaceutical compositions of the invention is further exemplified in the examples below.
The topical pharmaceutical compositions of the invention are used by applying an effective amount to the areas to be treated, for example, by rubbing the composition into the psoriatic skin or spreading the composition on the psoriatic skin.
The following examples serve to illustrate in more detail but are not intended to limit the invention.
IE 9168 Example 1 Ια.25(ΟΗ)2Ρ3* Buffered Oil-in-Water — Topical Cream Components Ranqes % (w/w) la,25(OH)2D3 0.00001 - 0.1 Long Chain Alcohol/Viscosity Agent 0.1 - 20.0 Lipophilic Solubilizing Agent 0.2 - 40.0 Hydrophilic Solubilizing Agent 0.2 - 40.0 Emulsifiers 0.5 - 30.0 Emollient 1.0 - 20.0 Preservative Systems 0.001 - 10.0 Antioxidant 0.001 - 5.0 Chelating Agent 0.001 - 5.0 Humectant 0.1 - 10.0 Water 50 - 95.0 Buffering Agent 2.0 - 12.0 PH pH 6.5 - 7.5 * As used throughout the specification la,25(OH)2D3 refers to la,25-dihydroxycholecalciferol.
Example 2 Oil-in-Water Cream % (w/w) la,25-dihydroxycholecalciferol Cetyl Alcohol Stearyl Alcohol Sorbitan Monostearate Mineral Oil Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend Polysorbate 60 Propylene Glycol Propylparaben Butylated Hydroxyanisole (BHA) Sorbitol Solution Edetate Disodium 3θ Methylparaben Water q.s. to pH adjusted with Sodium Hydroxide Solution 0.00001-0.1 1.5 2.5 2.0 4.0 4.0 1.0 .0 0.05 0.05 2.0 0.01 0.18 100.0 pH 6.5-7.5 The topical pharmaceutical compositions of the present invention are preferably packaged for example, in epoxy-lined aluminum tubes sealed with phenyloxy sealant.
Such packaging keeps oxygen and light from contacting the compositions. Alternatively, topical pharmaceutical compositions of the invention may be packaged, for example, in porcelain ointment jars or glaminate tubes.
E9168 1α,25(ΟΗ)_Ρ3 0,0005 % (w/w) Oil-in-Water Cream - 10 Example 3 Quantitative Composition The left hand column below gives the quantitative composition of a topical pharmaceutical composition of the invention that was made.
Also given in the center column of this example are reasonable variations of this composition. are actual amounts of 6,180 grams that was : in amounts of the different components Also given components made. in the right hand column for a batch of cream of Ingredients % (w/w) Reasonable Variations % (w/w) Typical Batch, Gm la.25(OH)2D3 0.00055** 0.033 Purified Water, USP 80.61945*** 70-90 4,837.167 Methylparaben, USP 0.18 0.14-0.22 10.8 Propylparaben. USP 0.05 0.04-0.06 3.0 Sorbitol Solution, USP 2.00 1-3 120.0 Edetate Disodium, USP 0.10 0.075-0.125 6.0 Cetyl Alcohol. USP/NF 1.50 0.5-2.5 90.0 Stearyl Alcohol, USP/NF 2.50 1.5-3.5 150.0 Glyceryl Monostearate and Polyoxyethylene Stearate Blend (Arlacel 165) 4.00 3-5 240.0 Sorbitan Monostearate (Spunge) 2.00 1-3 120.0 Polysorbate 60 (Tween 60) r USP/NF 1.00 0.5-1.5 60.0 Mineral Oil. Light. USP 4.00 3-5 240.0 Propylene Glycol. USP 5.00 4-6 300.0 Butylated Hydroxyanisole (BHA). USP 0.05 0.03-0.07 3.0 TOTAL 103.00 gm 6.180 gm ** Includes a 10% excess *** Includes a 3% excess to compensate for water loss during the manufacturing process.
The aqueous phase of the above cream was adjusted to pH 7.5-8.0 using sodium hydroxide solution.
The Manufacturing Procedure: 1. The Cetyl Alcohol. Stearyl Alcohol. Sorbitan Monostearate. Glyceryl Monostearate and Polyoxyethylene Stearate Blend. Polysorbate 60, Mineral Oil and a portion of Propylene Glycol were mixed in a suitable container and were melted with a waterbath. 2. Butylated Hydroxyanisole and Propylparaben were added to the material from step 1, dissolved and maintained at 70-75°C. 3. In a suitable container, the Edetate Disodium and Methylparaben were dissolved in a preheated solution of the Sorbitol Solution and Purified Water. 4. The la,25(OH)2D3 was dissolved in the balance of the Propylene Glycol and added to the material from step 2.
Note: A nitrogen atmosphere was maintained above the product during this and subsequent steps.
. The pH of the solution from Step 3 was adjusted to about 7.5-8.0. The oil phase from step 4 was added to the aqueous phase from step 3 while emulsifying with a high shear mixer. 6. The product was cooled to room temperature.
Example 4 Oil-in-Water Buffered Cream Ingredients la,25(OH)2D3 Cetyl Alcohol Stearyl Alcohol Sorbitan Monostearate (Span 60) Mineral Oil Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 10 Polysorbate 60 (Tween 60) Propylene Glycol Propylparaben Butylated Hydroxyanisole (BHA) Sorbitol Solution Edetate Disodium Methylparaben Water q.s. pH adjusted with disodium phosphate. pH % (w/w) 0.0005 1.5 2.5 2.0 4.0 4.0 1.0 .0 0.05 0.05 2.0 0.01 0.18 100.0 7.0 Manufacturing Procedure: 1. In a suitable container the Cetyl Alcohol. Stearyl Alcohol. Sorbitan Monostearate. Glyceryl Monostearate and Polyoxyethylene Stearate Blend, Polysorbate 60, Mineral Oil and a portion of Propylene Glycol were melted in a waterbath. 2. Butylated Hydroxyanisole and Propylparaben were added to the material from step 1, dissolved and maintained at 70-75°C. 3. In a suitable container the Edetate Disodium and Methylparaben were dissolved in the preheated solution of the Sorbitol Solution and Purified Water. 4. The la.25(OH)2D3 was dissolved in the balance of the Propylene Glycol and added to the material from step Note: A nitrogen atmosphere was maintained above the product during this and subsequent steps.
. The pH of the solution from Step 3 was adjusted to about 7.5-8.0. The oil phase from step 4 was added to the aqueous phase from step 3 while emulsifying with a high shear mixer. 6. The product was cooled to room temperature.
Example 4a Oil-in-Water Buffered Cream Ingredients % (w/w) la.25(OH)2D3 Cetyl Alcohol Stearyl Alcohol Sorbitan Monostearate (Span 60) Mineral Oil Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) Polysorbate 60 (Tween 60) Propylene Glycol Propylparaben Butylated Hydroxyanisole (BHA) Sorbitol Solution Edetate Disodium Methylparaben Water q.s. pH adjusted with disodium phosphate. pH 0.005 1.5 2.5 2.0 4.0 4.0 1.0 .0 0.05 0.05 2.0 0.01 0.18 100.0 7.0 The above cream can be made using a procedure analogous to that of Example 4.
Example 5 Oil-in-Water Buffered Cream Ingredients % (w/w) la,25(OH)2D3 0.0005 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 Polysorbate 60 (Tween 60) 1.0 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 Water q.s. 100.0 pH adjusted with Tris (hydroxymethyl) aminomethane and Tris (hydroxymethyl) aminomethane hydrochloride pH 7.4 The above cream was made using a procedure analogous to that of Example 4.
Example 6 Oil-in-Water Buffered Cream Ingredients % (w/w) let, 25 (OH) 2D3 0.0005 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 Polysorbate 60 (Tween 60) 1.0 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 Qc- Water q.s. to 100.0 pH adjusted with Sodium Hydroxide Solution pH 6.6 The above cream was made using a procedure analogous to that of Example 4.
Example 7 Oil-in-Water Buffered Cream Ingredients la.25(OH)2D3 Cetyl Alcohol Stearyl Alcohol Sorbitan Monostearate (Span 60) Mineral Oil Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) Polysorbate 60 (Tween 60) 13 Propylene Glycol Propylparaben Butylated Hydroxyanisole (BHA) Sorbitol Solution Edetate Disodium Methylparaben Water q.s. to pH adjusted with Sodium Hydroxide Solution % (w/w) 0.005 1.5 2.5 2.0 4.0 4.0 1.0 .0 0.05 0.05 2.0 0.01 0.18 100.0 pH 7.1 The above cream was made using a procedure analogous to that of Example 4.
Example 8 Ranges Water-in-Oil Cream Ingredients % (w/w) % (w/w) Functions la,25(OH)2D3 0. 00055-0.0055 0.00001-0.1 Active Hydroxylated Lanolin Mineral Oil, and Lanolin 2.5 1.75-3.25 Emulsifier Alcohol 16.5 11.55-21.45 Emulsifier Mineral Oil, Light Microcrystalline Wax 20.0 14.0-26.0 Emollient 170-175° m.p. 16.0 11.2-20.8 Thickener Propylparaben 0.05 0.04-0.06 Preservative Propylene Glycol 5.00 4.0-6.0 Solubilizer Methylparaben 0.18 0.14-0.22 Preservative Edetate Disodium 0.10 0.075-0.125 Chelating Agent Butylated Hydroxyanisole 0.05 0.03-0.07 Antioxidant Water 39.62 28.0-52.0 Vehicle pH 6.5-7.0 Manufacturing Procedure: 1. In a suitable container melt the hydroxylated lanolin, Λ mineral oil and lanolin alcohol, light mineral oil, v microcrystallme wax and a portion of propylene glycol m a waterbath at 70-75°C. 2. Add the butylated hydroxyanisole and propylparaben to the mixture from step 1, dissolve and maintain at 70-75°C. 3. In a suitable container dissolve the edetate disodium and 25 methylparaben in the preheated purified water. 4. Dissolve la,25(OH)2D3 in the balance of the propylene glycol and add to the material from step 2.
Note: Maintain a nitrogen atmosphere above the product during this and subsequent steps.
. Adjust pH to about 7.5-8.0. The buffer used to adjust the pH is disodium phosphate. Add the oil phase from step 4 to the aqueous phase from step 3 while emulsifying with a high shear mixer . 6. Cool the product to room temperature.
Example 9 Water-in-Oil Cream Ranges Ingredients % (w/w) % (W/W) Functions la.25(OH)2D3 0 .00055-0. 0055 0.00001-0.1 Active Petrolatum, Lanolin and Lanolin alcohol 7.0 4.9-9.1 Ingredient Emulsifier Mineral Oil, Light 12.0 8.4-15.6 Emollient Microcrystalline Wax 170-175° m.p. 9.0 6.3-11.7 Thickener Sorbitan Sesquioleate 2.0 1.4-2.6 Emulsifier Propylparaben 0.05 0.04-0.06 Preservative Butylated Hydroxyanisole 0.05 0.04-0.06 Sulubilizer Propylene Glycol 5.00 4.0-6.0 Solubilizer Methylparaben 0.18 0.14-0.22 Preservative Edetate Disodium 0.10 0.075-0.125 Chelating Water 64.62 45.0-84.0 Agent Vehicle PH 6.5-7 .0 - This cream is made in the same manner as the cream in Example 8. The buffering agent is disodium phosphate.
The following data compare the stability of la,25dihydroxycholecalcif erol in unbuffered oil-in-water vanishing creams and in buffered oil-in-water vanishing creams of the invention. The data below, were obtained from analyzing vanishing creams which were stored in 15g epoxy-lined aluminum tubes with white polyethylene caps.
A 0.0005 % (w/w) vanishing cream made in the same manner as described in Example 3 but without being buffered (pH .5-6.0) was stored for 12 months at 25°C and showed a loss of potency of la,25-dihydroxycholecalciferol of 11%. By contrast the 0.0005 % (w/w) vanishing cream of Example 3 (pH 6.5) when stored for 12 months at 25°C showed a loss of potency of la,25-dihydroxycholecalciferol of only 2%.
A 0.005 % (w/w) vanishing cream made in the same manner as described in Example 7 but without being buffered (pH .5-6.0) was stored for 6 months at 25°C and showed a loss of potency of 7%. By contrast a 0.005 % (w/w) vanishing cream of Example 7 (pH 7.1) when stored for 6 months at 25°C showed no loss of potency.
A 0.005 % (w/w) vanishing cream made in the same manner as in Example 7 but without being buffered (pH 5.5-6.0) was stored for 6 months at 37°C and showed a loss of potency of 18%. By contrast a 0.005 % (w/w) vanishing cream of Example 7 (pH 7.1) when stored for 6 months at 37°C showed a loss of potency of 4%.
The above data demonstrate that compositions of the invention are more stable than compositions of the prior art

Claims (10)

1. WE CLAIM:
1. A topical pharmaceutical composition in the form of an emulsion which comprises from about 0.00001 to about 0.1 % 5 (w/w) of la,25-dihydroxycholecalciferol in combination with an agent adjusting the pH of the composition to the range of about 6.5 to about 7.5 and a pharmaceutical acceptable carrier. 10
2. A composition in accordance with claim 1, wherein the pH is within the range of about 6.8 to about 7.2.
3. A composition in accordance with claim 1 wherein the pH is about 7.0.
4. A composition in accordance with claim 1, 2. or 3 wherein said pH adjusting agent is selected from the group consisting of sodium hydroxide; potassium hydroxide; disodium phosphate; and tris(hydroxymethyl)aminomethane and 20 tris(hydroxymethyl)aminomethane hydrochloride.
5. A composition in accordance with claim 1. 2, or 3 wherein the la,25-dihydroxycholecalciferol is present in a dosage range of from about 0.0005 to about 0.005 % (w/w).
6. A composition in accordance with claim I, 2, or 3 selected from the group consisting of a gel. a lotion, and a vanishing skin cream. 30
7. A composition in accordance with claim 1. 2, or 3 which is a vanishing skin cream.
8. A composition in accordance with claim 7, comprising Ingredients Ranqes (w/w la.25(OH) 2 D 3 0.00001 - 0. Long Chain Alcohol/Viscosity Agent 0.1 - 20.0 Lipophilic Solubilizing Agent 0.2 - 40.0 Hydrophilic Solubilizing Agent 0.2 - 40.0 Emulsifiers 0.5 - 30.0 Emollient 1.0 - 20.0 Preservative Systems 0.001 - 10.0 Antioxidant 0.001 - 5.0 Chelating Agent 0.001 - 5.0 Humectant 0.1 - 10.0 Water 50 - 95.0 Buffering Agent 2.0 - 12.0 PH 6.5 - 7.5
9. A composition in accordance with claim 7, comprising Ingredients % (w/w) la,25(OH) 2 D 3 0.0005 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 Polysorbate 60 (Tween 60) 1.0 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 Water q.s. to 100.0 pH adjusted with disodium phosphate 7.0
10. A topical pharmaceutical composition according to claim 1, substantially as hereinbefore described and exemplified.
IE6891A 1990-01-10 1991-01-09 Topical compositions IE65371B1 (en)

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EP (1) EP0437225B1 (en)
JP (1) JPH0739345B2 (en)
AT (1) ATE104554T1 (en)
AU (1) AU629445B2 (en)
CA (1) CA2033726A1 (en)
DE (1) DE59101404D1 (en)
DK (1) DK0437225T3 (en)
FI (1) FI910112A (en)
IE (1) IE65371B1 (en)
IL (1) IL96903A (en)
NO (1) NO178286C (en)
NZ (1) NZ236710A (en)
PH (1) PH27567A (en)
ZA (1) ZA91115B (en)

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CH684681A5 (en) * 1992-09-03 1994-11-30 Keane Jr & Cie coricide composition.
IL103224A (en) * 1992-09-18 1998-08-16 Teva Pharma Stabilized pharmaceutical compositions containing derivatives of vitamins d2 and d3
DE19549243A1 (en) * 1995-12-21 1997-06-26 Schering Ag Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues
JP4387465B2 (en) * 1997-12-09 2009-12-16 中外製薬株式会社 Lotion containing vitamin D3 derivative
AU743486B2 (en) * 1997-12-09 2002-01-24 Chugai Seiyaku Kabushiki Kaisha Creams containing vitamin D3 derivatives
WO2000059470A1 (en) * 1999-04-05 2000-10-12 Senju Pharmaceutical Co., Ltd. Emulsion and process for producing the same
BR9917389B1 (en) * 1999-06-25 2013-04-24 Typical formulations comprising skin penetrating agents and their use.
RU2271810C2 (en) * 2000-10-27 2006-03-20 Лео Фарма А/С Compositions for topical using comprising at least one vitamin d or one vitamin d analog and at least one corticosteroid
JP2006525959A (en) * 2003-02-05 2006-11-16 ガルデルマ・リサーチ・アンド・デヴェロップメント・エス・エヌ・セ Inverse emulsion type composition comprising at least one active agent sensitive to the presence of water and its use in cosmetics and dermatology

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CA1272953A (en) * 1984-10-08 1990-08-21 Yuji Makino Pharmaceutical composition for external use containing active-type vitamin d.sub.3
JPS6351312A (en) * 1986-08-20 1988-03-04 Pola Chem Ind Inc Skin beautifying cosmetic
JPS63145211A (en) * 1986-12-05 1988-06-17 Piasuaraizu Kk Vitamin-containing cosmetic
US4855294A (en) * 1988-09-06 1989-08-08 Theratech, Inc. Method for reducing skin irritation associated with drug/penetration enhancer compositions

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IE65371B1 (en) 1995-10-18
NO910102D0 (en) 1991-01-09
ATE104554T1 (en) 1994-05-15
EP0437225B1 (en) 1994-04-20
IL96903A (en) 1995-03-15
DK0437225T3 (en) 1994-06-27
DE59101404D1 (en) 1994-05-26
JPH0739345B2 (en) 1995-05-01
FI910112A0 (en) 1991-01-09
NO178286C (en) 1996-02-28
NZ236710A (en) 1993-04-28
CA2033726A1 (en) 1991-07-11
NO178286B (en) 1995-11-20
NO910102L (en) 1991-07-11
EP0437225A1 (en) 1991-07-17
AU6922891A (en) 1991-07-11
ZA91115B (en) 1991-09-25
PH27567A (en) 1993-08-18
JPH04210903A (en) 1992-08-03
IL96903A0 (en) 1992-03-29
FI910112A (en) 1991-07-11
AU629445B2 (en) 1992-10-01

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