CA2033726A1 - Topical compositions - Google Patents
Topical compositionsInfo
- Publication number
- CA2033726A1 CA2033726A1 CA002033726A CA2033726A CA2033726A1 CA 2033726 A1 CA2033726 A1 CA 2033726A1 CA 002033726 A CA002033726 A CA 002033726A CA 2033726 A CA2033726 A CA 2033726A CA 2033726 A1 CA2033726 A1 CA 2033726A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- accordance
- agent
- water
- oil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
ABSTRACT OF THE DISCLOSURE
Topical, pharmaceutical compositions comprising 1.alpha.,25-dihydroxycholecalciferol and a pharmaceutically acceptable carrier wherein the pharmaceutical composition is an emulsion buffered at a pH in a range of about 6.5 to about 7.5 are described. The topical pharmaceutical compositions of the invention have good stability.
Topical, pharmaceutical compositions comprising 1.alpha.,25-dihydroxycholecalciferol and a pharmaceutically acceptable carrier wherein the pharmaceutical composition is an emulsion buffered at a pH in a range of about 6.5 to about 7.5 are described. The topical pharmaceutical compositions of the invention have good stability.
Description
RAN _05]/23 Z~ 6 The present invention relat:es to topical pharmaceutical compositions comprising lu,25-clihydroxycholecalciferol in a suitable topical pharmaceutic:al carrier wherein said topical compositions are emulsions having a pH of about 6.5 to about 7.5. Compositions of the invention include 10 aesthetically elegant vanishins~ creams. Compositions o~ the invention have excellent stability at both room temperature and elevated temperature6.
In the past, topical pharmaceutical compositions con-taining 1~,25-dihydroxycholecalciferol ha~e had s~ability problems due to the sensitive nature of the 1,25-di-hydroxycholecalciferol. It has been unexpectedly found tha~
the stability of topical pharmaceutical compositions which contain 1,25-dihydroxycholecalciferol and which are 20 emulsions can be improved by adjusting the pH the aqueous phase so that the range of the pH of the topical compo-sitions is about 6.5 to about 7.5, preferably about 6.B to about 7.2. The most preferred p~ of the topical compo-sitions is about 7Ø
As used herein emulsions include oil-in-water emulsions, water-in-oil emulsions, and multiple emulsions.
As used herein a topical pharmaceutical carrier 30 compeises a mixture of a viscosity agent, a lipophilic solubilizing agent, a hydrophilic solubilizing agent, an emulsifier, an emollient, a preservative, an antio~idant, a chelating agent, and a humectant.
35 Grn/25.10.90 ,~
In the past, topical pharmaceutical compositions con-taining 1~,25-dihydroxycholecalciferol ha~e had s~ability problems due to the sensitive nature of the 1,25-di-hydroxycholecalciferol. It has been unexpectedly found tha~
the stability of topical pharmaceutical compositions which contain 1,25-dihydroxycholecalciferol and which are 20 emulsions can be improved by adjusting the pH the aqueous phase so that the range of the pH of the topical compo-sitions is about 6.5 to about 7.5, preferably about 6.B to about 7.2. The most preferred p~ of the topical compo-sitions is about 7Ø
As used herein emulsions include oil-in-water emulsions, water-in-oil emulsions, and multiple emulsions.
As used herein a topical pharmaceutical carrier 30 compeises a mixture of a viscosity agent, a lipophilic solubilizing agent, a hydrophilic solubilizing agent, an emulsifier, an emollient, a preservative, an antio~idant, a chelating agent, and a humectant.
35 Grn/25.10.90 ,~
- 2 - ~ ~33'~
Compositions of the invention include skin creams, vanishing skin creams, gels, and lotion6.
Skin creams may be oil-in-~ater emulsion6, water-in-oil emulsions, or multiple emulsion6. 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 ~.8 to 15 about 7.2. The most preferred pH of the compositions of the invention is about 7Ø To achieve this pH, the a~ueous phase of a composition of the invention is adjusted, preferably buffered to a pH of about 7.0 to about ~Ø In this manner the resulting pH of the final composition is in the range of about 6.5 to about 7.5, preferably 7Ø
As used herein, the term "% (w/w)" or "~ (wt/wt)" refers to % weight/weight. Thus, lO grams of ingredient A in lO0 grams of composition is present at lO ~ (w/w).
It is known that topical pharmaceutical composition6 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 4,610,97~.
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 emulsion6 which comprise, la,25-dihydroxycholecalciferol, a 3 ~3~'Y;~:~
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 10 a~ polymers. (Substantive asents are agents which allow for prolonged contact time between the topical pharmaceutical composition and the skin.) Viscosity agents are also referred to in this 15 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 20 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 3t~6 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 ~rom the group consisting of Polysorbate 20, Polysorbate 40, 10 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 20 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 lal.~rate, dibutyl adipate, isocetyl stearate, octyldodecyl stearate, 30 PEG-7-glyceryl cocoate, oleyl erucate, a mixture o~
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 35 dicaprate. The emollient can also be castor oil or dioctyl cyclohexane or mineral oil. The emollient is preferably - 5 ~ 3'726 mineral oil.
The preservative can be cis-1-(3-chloroethyl)-3,5,7-tria~a-l-azoniaadamantane chloride: sorbic acid: potassium sorbate: benzyl alcohol: benzalkonium chloride:
dichlorobenzyl alcohol; N-thydroxymethyl)-N-(1,3-dihydroxy-methyl-2,5-dioxo-4-imidazolidinyl)-N-hydroxymethyl)urea;
boric acid: chlorobutanol: monothioglycerol: methyl paraben:
propyl paraben: or more preferably a mixture of methyl and 10 propyl parabens.
The anti-oxidant can be propyl gallate: butylated hydroxytoluene: ascorbyl palmitate: sodium ascorbate:
a-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 25 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 30 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 35 preferably disodium phosphate. Determining the pH for the aqueous phase, ~hich will be mixed with particular pharmaceutical carrier materials, so that a final p~I between about 6.5 to about 7.5 is achieved, is within ~he 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 prepa,ring the topical pharmaceutical compositions of the present invention, the la,Z5-dihydroxy- cholecalciferol is dissolved i~ 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 l,25-dihydroxycholecalciferol into carrier formulations, 20 by mixing in the following steps:
Step ~: la,25-dihydroxycholecalciferol is dissolved in a hydrophilic solubilizer such as propylene glycol under nitrogen. It is preferred to keep the resulting solution at 25 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 30 the range of about 7.0 to about 8Ø The resulting mixture is heated with stirring until a maximum temperature of about 70C to about 75C is achieved. The resulting solution is the aqueous phase of the final emulsion.
Step 3: ~ll lipophilic ingredients are mixed together, and heated with stirring until a maximum temperature of about 70C to about 75C is achieved. The resulting - 7 - ~ 3'~
solution is the oil phase of final emulsion.
Step ~: Under nitrogen, the solution from Step 1 i6 then added to the oil phase of Step 3 while stirring iB
continued and the temperature is maintained at about 70 to about 75C. Additional propylene glycol is used to wash the vessel which contained the solution from Step 1. This wash i5 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 ~ 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 homogeniæation is stop~ed, and gentle stirring is conducted until the emulsion cools to room temperature.
The above procedure for prepaeing topical pharmaceutical compositions of the invention is further exemplified in the 20 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 2~ 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.
- 8 ~ 2~
Example 1 1,25(OH12D3* Buffered Oil-in~Water ~opical Cream CQmPonents Ran~es % (w/w) 1,25(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 10 Antioxidant 0.001 - 5.0 Chelating Agent O.001 - 5.0 Humectant 0.1 - 10.0 Water 50 - 95.0 Buf f ering 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 O.O0001-O.l Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate 2.0 Mineral Oil 4.0 25 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend 4.0 Polysorbate 60 1.0 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2OO
Edetate Disodium 0.01 30 Methylparaben 0.18 ~ater q. 6 . to 100.0 pH adjusted with Sodium Hydroxide Solution pH 6.5-7.5 The topical pharmaceutical compositions of the present invention are preferably packaged for example, in 35 epoxy-lined aluminum tubes ~ealed with phenyloxy sealant.
Such packaging keeps oxygen and light ~rom contacting the compositions. Alternatively, topical pharmaceutical compositions of the invention may be packaged, for example, in porcelain ointment jars or glaminate tube6.
:~ 25 3~7;~
~ le 3 la,25(0H)2D3 0.0005 % ~w/w) Oil-in-Water Cream Quantitative Com~osition The left hand colum~ below gives the quantitative composition of a topical phacmaceutical composition of the invention that was made.
Also given in the center column o~ this example are reasonable variations in amounts of the different com~onents of this composition. Also given in the right hand column are actual amounts of components for a batch of cream of 6,180 grams that was made.
Reasonable VariationsTypical Inqredients % (w/w) ~ (w~w)Batch, ~m 1,25(OH)zD3 0.00055** - 0.033 Purified Water, USP80.61945~**70-904,837.167 Methylparaben, USP 0.18 0.1~-O.Z2 10.8 Propylparaben, USP 0.05 0.04-0.06 3.0 Sorbitol Solution, USP 2.00 1-3 120.0 Edetate Disodium, USP 0.100.075-0.125 6.0 Cetyl Alcohol, USP/MF 1.50 0.5-2.5 go.o 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), 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 O.05 0.03-0.07 3.0 TOTAL103.00 gm 6,180 gm ** Includes a 10% excess *** Includes a 3% excess to compensate for water loss during the manufacturing process.
.
, .
- ' ~
.
- 11 - 2~33~
The aqueous phase of the above cream was adjusted to p~
7.5-8.0 using sodium hydroxide solution.
The Manufacturina Procedure:
l. The Cetyl Alcohol, Stearyl ~lcohol, Sorbitan Monos~earate, 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 l, dissolved and maintained at 70-750C.
3. In a suitable container, the Edetate Disodium and Methylparaben were dissolved in a preheated solution of the Sorbitol Solution and Purified Water.
Compositions of the invention include skin creams, vanishing skin creams, gels, and lotion6.
Skin creams may be oil-in-~ater emulsion6, water-in-oil emulsions, or multiple emulsion6. 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 ~.8 to 15 about 7.2. The most preferred pH of the compositions of the invention is about 7Ø To achieve this pH, the a~ueous phase of a composition of the invention is adjusted, preferably buffered to a pH of about 7.0 to about ~Ø In this manner the resulting pH of the final composition is in the range of about 6.5 to about 7.5, preferably 7Ø
As used herein, the term "% (w/w)" or "~ (wt/wt)" refers to % weight/weight. Thus, lO grams of ingredient A in lO0 grams of composition is present at lO ~ (w/w).
It is known that topical pharmaceutical composition6 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 4,610,97~.
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 emulsion6 which comprise, la,25-dihydroxycholecalciferol, a 3 ~3~'Y;~:~
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 10 a~ polymers. (Substantive asents are agents which allow for prolonged contact time between the topical pharmaceutical composition and the skin.) Viscosity agents are also referred to in this 15 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 20 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 3t~6 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 ~rom the group consisting of Polysorbate 20, Polysorbate 40, 10 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 20 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 lal.~rate, dibutyl adipate, isocetyl stearate, octyldodecyl stearate, 30 PEG-7-glyceryl cocoate, oleyl erucate, a mixture o~
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 35 dicaprate. The emollient can also be castor oil or dioctyl cyclohexane or mineral oil. The emollient is preferably - 5 ~ 3'726 mineral oil.
The preservative can be cis-1-(3-chloroethyl)-3,5,7-tria~a-l-azoniaadamantane chloride: sorbic acid: potassium sorbate: benzyl alcohol: benzalkonium chloride:
dichlorobenzyl alcohol; N-thydroxymethyl)-N-(1,3-dihydroxy-methyl-2,5-dioxo-4-imidazolidinyl)-N-hydroxymethyl)urea;
boric acid: chlorobutanol: monothioglycerol: methyl paraben:
propyl paraben: or more preferably a mixture of methyl and 10 propyl parabens.
The anti-oxidant can be propyl gallate: butylated hydroxytoluene: ascorbyl palmitate: sodium ascorbate:
a-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 25 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 30 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 35 preferably disodium phosphate. Determining the pH for the aqueous phase, ~hich will be mixed with particular pharmaceutical carrier materials, so that a final p~I between about 6.5 to about 7.5 is achieved, is within ~he 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 prepa,ring the topical pharmaceutical compositions of the present invention, the la,Z5-dihydroxy- cholecalciferol is dissolved i~ 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 l,25-dihydroxycholecalciferol into carrier formulations, 20 by mixing in the following steps:
Step ~: la,25-dihydroxycholecalciferol is dissolved in a hydrophilic solubilizer such as propylene glycol under nitrogen. It is preferred to keep the resulting solution at 25 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 30 the range of about 7.0 to about 8Ø The resulting mixture is heated with stirring until a maximum temperature of about 70C to about 75C is achieved. The resulting solution is the aqueous phase of the final emulsion.
Step 3: ~ll lipophilic ingredients are mixed together, and heated with stirring until a maximum temperature of about 70C to about 75C is achieved. The resulting - 7 - ~ 3'~
solution is the oil phase of final emulsion.
Step ~: Under nitrogen, the solution from Step 1 i6 then added to the oil phase of Step 3 while stirring iB
continued and the temperature is maintained at about 70 to about 75C. Additional propylene glycol is used to wash the vessel which contained the solution from Step 1. This wash i5 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 ~ 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 homogeniæation is stop~ed, and gentle stirring is conducted until the emulsion cools to room temperature.
The above procedure for prepaeing topical pharmaceutical compositions of the invention is further exemplified in the 20 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 2~ 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.
- 8 ~ 2~
Example 1 1,25(OH12D3* Buffered Oil-in~Water ~opical Cream CQmPonents Ran~es % (w/w) 1,25(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 10 Antioxidant 0.001 - 5.0 Chelating Agent O.001 - 5.0 Humectant 0.1 - 10.0 Water 50 - 95.0 Buf f ering 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 O.O0001-O.l Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate 2.0 Mineral Oil 4.0 25 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend 4.0 Polysorbate 60 1.0 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2OO
Edetate Disodium 0.01 30 Methylparaben 0.18 ~ater q. 6 . to 100.0 pH adjusted with Sodium Hydroxide Solution pH 6.5-7.5 The topical pharmaceutical compositions of the present invention are preferably packaged for example, in 35 epoxy-lined aluminum tubes ~ealed with phenyloxy sealant.
Such packaging keeps oxygen and light ~rom contacting the compositions. Alternatively, topical pharmaceutical compositions of the invention may be packaged, for example, in porcelain ointment jars or glaminate tube6.
:~ 25 3~7;~
~ le 3 la,25(0H)2D3 0.0005 % ~w/w) Oil-in-Water Cream Quantitative Com~osition The left hand colum~ below gives the quantitative composition of a topical phacmaceutical composition of the invention that was made.
Also given in the center column o~ this example are reasonable variations in amounts of the different com~onents of this composition. Also given in the right hand column are actual amounts of components for a batch of cream of 6,180 grams that was made.
Reasonable VariationsTypical Inqredients % (w/w) ~ (w~w)Batch, ~m 1,25(OH)zD3 0.00055** - 0.033 Purified Water, USP80.61945~**70-904,837.167 Methylparaben, USP 0.18 0.1~-O.Z2 10.8 Propylparaben, USP 0.05 0.04-0.06 3.0 Sorbitol Solution, USP 2.00 1-3 120.0 Edetate Disodium, USP 0.100.075-0.125 6.0 Cetyl Alcohol, USP/MF 1.50 0.5-2.5 go.o 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), 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 O.05 0.03-0.07 3.0 TOTAL103.00 gm 6,180 gm ** Includes a 10% excess *** Includes a 3% excess to compensate for water loss during the manufacturing process.
.
, .
- ' ~
.
- 11 - 2~33~
The aqueous phase of the above cream was adjusted to p~
7.5-8.0 using sodium hydroxide solution.
The Manufacturina Procedure:
l. The Cetyl Alcohol, Stearyl ~lcohol, Sorbitan Monos~earate, 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 l, dissolved and maintained at 70-750C.
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(0H)2D3 was dissolved in the balance of the Propylene Glycol and added to the material from step 2.
Note: A nitrogen a~mosphere was maintained above the product during this and subsequent steps.
Note: A nitrogen a~mosphere was maintained above the product during this and subsequent steps.
5. The pH of the solution from Step 3 was adjusted to about 7.5-8Ø 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.
~33~
-- lZ --Exam~le 4 oi 1- in-Water Buffered Cream Inqredients % tW/W2 la,25(H)2D3 0.0005 Cetyl Alcohol 1.5 Stearyl ~lcahol z.5 Sorbitan Monostearate (Span 60j 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Steaeate Blend (~rlacel 165) 4.0 10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) O.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 1~ Water q.s. lOO.O
pH adjusted with disodium phosphate, pH 7.0 Manufacturin~ Procedure:
l. In a suitable container the Cetyl Alcohol, Stearyl Alcohol, Sorbitan Monostearate, ~lyceryl Monosteara~e 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 l, dissolved and maintained at 70-75C.
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(0H)2D3 was dissolved in the balance of the Propylene Glycol and added to the material from step 2.
~3~
Note: A nitrogen atmosphere was maintained above the product during this and subsequent steps.
5. The pH of the solution from Step 3 was adjusted ~o about 7.5-8Ø 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 15 Inqredients (w/w~
la,25(OH)2D3 0.005 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4,0 20 Glyceryl Monostearate and Polyoxye~hylene 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 z.o 25 Edetate Disodium 0.01 Methylparaben 0.18 Water q.s. 100 0 pH adjusted with disodium phosphate~ pH 7 0 The above cream can be made using a procedure analogous to that of Example 4.
~xample 5 Oil-in-Water Buffered Cream Inqredients % (w/w) la, 25(OH)2D3 0.0005 Cetyl Alcohol l.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (~rlacel 165) 4.0 10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0 PLopylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2.0 Edetate Disodium O.Ol Methylparaben 0.18 15 Water q.s. lOO.o 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.
Exam~le 6 Oil-in-Water Buffered Cream Inqredient8 % (W/WL__ 25 la,25(0H)zD3 0.0005 Cetyl Alcohol l.5 Stearyl Alcohol 2.5 Sorbitan ~onostearate (Span 60) ~.o Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 30 Polysorbate 60 (Tween 60) l.O
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 lOO.O
pH adjus~ed with Sodium Hydroxide Solution pH 6.6 ~)3~'7~26 The above cream was made using a procedure analogous to that of Example 4.
_ample 7 Oil-in-Water Bu~fered Cream . Inqredients % (w/w) 10 la,25(OH)2D3 0 005 Cetyl ~lcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl ~onostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 Polysorbate 60 (Tween 60) 1.0 15 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BE~A) 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 ~ Methylparaben 0.18 : Water q.s. to 100.0 pH adjusted with Sodium Hydroxide Solution pH 7.1 The above cream was made using a procedure analogous to that of Example 4.
33~7~2~
Example 8 Water-in=Oil Cream Ranges Inqredients % (w~w) _ % (w/wl _ Functions 1~,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active Hydroxylated Lanolir 2.5 1.75-3.25 Emulsifier ~ineral Oil, and Lanolin Alcohol 16.511.55-21.45 Emulsifier Mineeal Oil Light 20.0 14.0-26.0 Emollient Microcrystailine Wax 170-175~ m.p. 16.0 ll.Z-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 0.100.075-0.125 Chelating Agent 15 Butylated Hydroxyanisole 0.05 0.03-0.07 Antioxidant Water 39.6228.0-52.0 Vehicle pH 6.5-7.0 - -Manufacturinq Procedure:
1. In a suitable container melt the hydroxylated lanolin, mineral oil and lanolin alcohol, light mineral oil, microcrystalline wax and a portion of propylene glycol in a waterbath at 70-75~C.
2. Add the butylated hydroxyanisole and propylparaben to the mixture from step 1, dissolve and maintain at 70-75C.
3. In a suitable container dissolve the edetate disodium and methylparaben in the preheated purified water.
4. Dissolve la,25(0H)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.
5. Adjust pH to about 7.5-8Ø 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.
~. :
.. .
.. . . . . . .
~033i7r~
Example 9 Water-i.n-Oil Cream Ranges Inqredients % (w/w) % (w/w) Func~ions 1,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active Petrolatum, Lanolin In.gredient and Lanolin alcohol7.0 4.9-9.1 Emulsifier Mineral Oil, Light12.0 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 Pro~ylparaben 0.05 0.04-0.06 Preservative Butylated Hydroxyanisole 0.05 0.04-0.06 Sulubilizer Propylene Glycol5.00 4.0-6.0 Solubilizer Methylparaben 0.18 0.14-0.22 Preservative 15 Edetate Disodium0.10 0.075-0.125 Chelating Agent Water 64.62 45.0-84.0 Vehicle pH 6.5-7.0 This cream i8 made in the same manner as the cream in Example 8. The buffering agent is disodium phosphate.
The following data compare tha stability of la,25~
dihydroxycholecalciferol in unbuffered oil-in-water vanishing creams and in buffered oil-in-water vanishing creams of the invention. The data below, were obtained fro~
Z5 analyzing vanishing c~eams 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 tpH
5.5-6.0) was stored for 12 months at Z5C 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 25C showed a 106s of potency of la,25-dihydroxycholecalciferol of only 2%.
~3~
A 0.005 % (w/w) vanishing cream made in the same manner as described in Example 7 but without being buffered (pH
5.5-6.0) was stored for 6 months at 25C and showed a 10s6 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 Z5C
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 37C and showed a loss of potency Oe 18%. By contrast a 0.005 ~ (w/w) vanishing cream of Examele 7 (pH 7.1) when stored for 6 months at 37C showed a 1068 of potency of 4%.
The above data demonstrate that compositions of the invention are more stable than compositions of the prior art.
-
~33~
-- lZ --Exam~le 4 oi 1- in-Water Buffered Cream Inqredients % tW/W2 la,25(H)2D3 0.0005 Cetyl Alcohol 1.5 Stearyl ~lcahol z.5 Sorbitan Monostearate (Span 60j 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Steaeate Blend (~rlacel 165) 4.0 10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BHA) O.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 Methylparaben 0.18 1~ Water q.s. lOO.O
pH adjusted with disodium phosphate, pH 7.0 Manufacturin~ Procedure:
l. In a suitable container the Cetyl Alcohol, Stearyl Alcohol, Sorbitan Monostearate, ~lyceryl Monosteara~e 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 l, dissolved and maintained at 70-75C.
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(0H)2D3 was dissolved in the balance of the Propylene Glycol and added to the material from step 2.
~3~
Note: A nitrogen atmosphere was maintained above the product during this and subsequent steps.
5. The pH of the solution from Step 3 was adjusted ~o about 7.5-8Ø 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 15 Inqredients (w/w~
la,25(OH)2D3 0.005 Cetyl Alcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4,0 20 Glyceryl Monostearate and Polyoxye~hylene 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 z.o 25 Edetate Disodium 0.01 Methylparaben 0.18 Water q.s. 100 0 pH adjusted with disodium phosphate~ pH 7 0 The above cream can be made using a procedure analogous to that of Example 4.
~xample 5 Oil-in-Water Buffered Cream Inqredients % (w/w) la, 25(OH)2D3 0.0005 Cetyl Alcohol l.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (~rlacel 165) 4.0 10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0 PLopylparaben 0.05 Butylated Hydroxyanisole (BHA) 0.05 Sorbitol Solution 2.0 Edetate Disodium O.Ol Methylparaben 0.18 15 Water q.s. lOO.o 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.
Exam~le 6 Oil-in-Water Buffered Cream Inqredient8 % (W/WL__ 25 la,25(0H)zD3 0.0005 Cetyl Alcohol l.5 Stearyl Alcohol 2.5 Sorbitan ~onostearate (Span 60) ~.o Mineral Oil 4.0 Glyceryl Monostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 30 Polysorbate 60 (Tween 60) l.O
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 lOO.O
pH adjus~ed with Sodium Hydroxide Solution pH 6.6 ~)3~'7~26 The above cream was made using a procedure analogous to that of Example 4.
_ample 7 Oil-in-Water Bu~fered Cream . Inqredients % (w/w) 10 la,25(OH)2D3 0 005 Cetyl ~lcohol 1.5 Stearyl Alcohol 2.5 Sorbitan Monostearate (Span 60) 2.0 Mineral Oil 4.0 Glyceryl ~onostearate and Polyoxyethylene Glycol Stearate Blend (Arlacel 165) 4.0 Polysorbate 60 (Tween 60) 1.0 15 Propylene Glycol 5.0 Propylparaben 0.05 Butylated Hydroxyanisole (BE~A) 0.05 Sorbitol Solution 2.0 Edetate Disodium 0.01 ~ Methylparaben 0.18 : Water q.s. to 100.0 pH adjusted with Sodium Hydroxide Solution pH 7.1 The above cream was made using a procedure analogous to that of Example 4.
33~7~2~
Example 8 Water-in=Oil Cream Ranges Inqredients % (w~w) _ % (w/wl _ Functions 1~,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active Hydroxylated Lanolir 2.5 1.75-3.25 Emulsifier ~ineral Oil, and Lanolin Alcohol 16.511.55-21.45 Emulsifier Mineeal Oil Light 20.0 14.0-26.0 Emollient Microcrystailine Wax 170-175~ m.p. 16.0 ll.Z-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 0.100.075-0.125 Chelating Agent 15 Butylated Hydroxyanisole 0.05 0.03-0.07 Antioxidant Water 39.6228.0-52.0 Vehicle pH 6.5-7.0 - -Manufacturinq Procedure:
1. In a suitable container melt the hydroxylated lanolin, mineral oil and lanolin alcohol, light mineral oil, microcrystalline wax and a portion of propylene glycol in a waterbath at 70-75~C.
2. Add the butylated hydroxyanisole and propylparaben to the mixture from step 1, dissolve and maintain at 70-75C.
3. In a suitable container dissolve the edetate disodium and methylparaben in the preheated purified water.
4. Dissolve la,25(0H)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.
5. Adjust pH to about 7.5-8Ø 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.
~. :
.. .
.. . . . . . .
~033i7r~
Example 9 Water-i.n-Oil Cream Ranges Inqredients % (w/w) % (w/w) Func~ions 1,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active Petrolatum, Lanolin In.gredient and Lanolin alcohol7.0 4.9-9.1 Emulsifier Mineral Oil, Light12.0 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 Pro~ylparaben 0.05 0.04-0.06 Preservative Butylated Hydroxyanisole 0.05 0.04-0.06 Sulubilizer Propylene Glycol5.00 4.0-6.0 Solubilizer Methylparaben 0.18 0.14-0.22 Preservative 15 Edetate Disodium0.10 0.075-0.125 Chelating Agent Water 64.62 45.0-84.0 Vehicle pH 6.5-7.0 This cream i8 made in the same manner as the cream in Example 8. The buffering agent is disodium phosphate.
The following data compare tha stability of la,25~
dihydroxycholecalciferol in unbuffered oil-in-water vanishing creams and in buffered oil-in-water vanishing creams of the invention. The data below, were obtained fro~
Z5 analyzing vanishing c~eams 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 tpH
5.5-6.0) was stored for 12 months at Z5C 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 25C showed a 106s of potency of la,25-dihydroxycholecalciferol of only 2%.
~3~
A 0.005 % (w/w) vanishing cream made in the same manner as described in Example 7 but without being buffered (pH
5.5-6.0) was stored for 6 months at 25C and showed a 10s6 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 Z5C
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 37C and showed a loss of potency Oe 18%. By contrast a 0.005 ~ (w/w) vanishing cream of Examele 7 (pH 7.1) when stored for 6 months at 37C showed a 1068 of potency of 4%.
The above data demonstrate that compositions of the invention are more stable than compositions of the prior art.
-
Claims (9)
1. A topical pharmaceutical composition in the form of an emulsion which comprises from about 0.00001 to about 0.1 %
(w/w) of 1a,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.
(w/w) of 1a,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.
2. A composition in accordance with claim 1, wherein the pH
is within the range of about 6.8 to about 7.2.
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 7Ø
is about 7Ø
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 tris(hydroxymethyl)aminomethane hydrochloride.
disodium phosphate: and tris(hydroxymethyl)aminomethane and tris(hydroxymethyl)aminomethane hydrochloride.
5. A composition in accordance with claim 1, 2, or 3 wherein the 1.alpha.,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 1, 2, or 3 selected from the group consisting of a gel, a lotion, and a vanishing skin cream.
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 Ranges (w/w %) 1.alpha..25(0H)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 6.5 - 7.5
9. A composition in accordance with claim 7, comprising Ingredients % (w/w) 1.alpha.,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. to 100.0 pH adjusted with disodium phosphate 7.0
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46310290A | 1990-01-10 | 1990-01-10 | |
| US463,102 | 1990-01-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2033726A1 true CA2033726A1 (en) | 1991-07-11 |
Family
ID=23838868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002033726A Abandoned CA2033726A1 (en) | 1990-01-10 | 1991-01-07 | Topical compositions |
Country Status (14)
| Country | Link |
|---|---|
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1991
- 1991-01-04 DK DK91100142.8T patent/DK0437225T3/en active
- 1991-01-04 DE DE59101404T patent/DE59101404D1/en not_active Expired - Fee Related
- 1991-01-04 AT AT9191100142T patent/ATE104554T1/en not_active IP Right Cessation
- 1991-01-04 EP EP91100142A patent/EP0437225B1/en not_active Expired - Lifetime
- 1991-01-07 CA CA002033726A patent/CA2033726A1/en not_active Abandoned
- 1991-01-07 ZA ZA91115A patent/ZA91115B/en unknown
- 1991-01-07 NZ NZ236710A patent/NZ236710A/en unknown
- 1991-01-08 PH PH41826A patent/PH27567A/en unknown
- 1991-01-08 AU AU69228/91A patent/AU629445B2/en not_active Ceased
- 1991-01-08 IL IL9690391A patent/IL96903A/en not_active IP Right Cessation
- 1991-01-08 JP JP3060742A patent/JPH0739345B2/en not_active Expired - Lifetime
- 1991-01-09 FI FI910112A patent/FI910112A/en not_active Application Discontinuation
- 1991-01-09 NO NO910102A patent/NO178286C/en unknown
- 1991-01-09 IE IE6891A patent/IE65371B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| 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 |
| IE910068A1 (en) | 1991-07-17 |
| FI910112A0 (en) | 1991-01-09 |
| NO178286C (en) | 1996-02-28 |
| NZ236710A (en) | 1993-04-28 |
| 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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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |