FI56486C - FOERFARANDE FOER FRAMSTAELLNING AV EN UREA PHARMACEUTICAL COMPOSITION TILL ANVAENDNING FOER UTVAERTES BRUK PAO MAENNISKOKUD - Google Patents

Description

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C, .c, Patent granted II C2 1933 Patent oeddeiat ^ τ ^ (51) Kv.lk. '/ Int.CI. * A 61 K 9/10 {}, A 61 K 31/17 FINLAND —FINLAND (21) Patent application - Patencansöltnlng 11 i + 5/73 (22) Filing date - Ansttknlngsdag 11.0U.73 (23) Starting date - Giltighetsdag 11.0U.73

(41) Made public - Bllvit offentllg 12.10.7U

Patent and Registration Office .... ........ . . , • (44) To be seen and heard. publication date -

Patent and registration authorities Ansökan utlagd och utl.skriften publicerad 31.10.79 (32) (33) (31) Privilege claimed — Begärd prloritet (71) Vymatt SA, U, Via Bossi, Lugano 6900, Ticino, Swiss Switzerland (CH) (72) Steven Leigh, Thorpe, Surrey, England-England (GB) (7U) Leitzinger Oy (5U) Process for the preparation of a pharmaceutical urea-containing mixture for topical application to human skin -Förfarande för framställning av en uramide innehällande pharmaceutical composition composition användning The present invention relates to a process for the preparation of a pharmaceutical composition containing urea for external application to human skin. [Icy mixtures can be used to treat dry, hyperkeratotic skin conditions associated with atopic eczema, ichthyosis-like skin diseases, and ichthyosis.

In hyperkeratotic conditions, water-binding, low-molecular-weight substances are often absent from the horn-like layer of the skin. These low molecular weight substances can be urea and betaine. As a result, the skin becomes dry and often flakes. Increasing the concentration of urea on the skin promotes water retention and the skin becomes softer and more natural looking. It has been clinically shown that 10% urea applied externally in a suitable medium adequately fulfills this function. Such prior external preparations containing urea are usually prepared without preparation by first dissolving urea in an aqueous solution which is emulsified as an oily or fatty carrier containing a mixture of molten waxes, fatty acids / alcohols with various emulsifiers. The resulting cream may be of either the oil-in-water or water-in-oil type, depending on the properties of the emulsifiers used. Unfortunately, such urea preparations have two major disadvantages.

2 56486 (a) Because urea is volatile in water, it tends to decompose, releasing ammonia and carbon dioxide.

(b) In aqueous solution, it causes stinging, especially on broken skin.

Because most people with atopic eczema also have broken or cracked skin, this unwanted side effect severely interferes with ongoing treatment. Stabilizers, for example buffer salts added to some latent formulations to reduce urea degradation, often increase the stinging side effect.

In order to obtain a stable urea formulation, it is possible to either disperse or dissolve the urea in a non-aqueous non-aqueous solvent, for example glycerol or propylene glycol or propylene glycol. This dispersion or solution is subsequently made into a non-aqueous medium which forms a cream or paste. However, such a preparation is pharmaceutically inelegant and aesthetically unsatisfactory. In addition, it is not certain whether urea can affect the entire physiological effect on the skin.

It is an object of the present invention to provide a urea formulation which is both substantially stable and effective and which, moreover, does not cause significant stinging when applied to broken skin.

Studies have shown that this can be accomplished if urea is initially adsorbed onto a pharmaceutically inert powder matrix, which is then dispersed in a fine non-aqueous semi-solid petrolatum base, the powder cream formulation feels "non-greasy" on the skin and is suitable for cosmetics. Urea has been shown to be stable in this form and, more importantly from a clinical point of view, the product does not cause stinging when applied to broken skin.

The process of the invention is characterized by mixing in any order: (a) a pharmaceutically acceptable, fluid, semi-solid, gel or solid, hydrophobic substance, (b) an aqueous solution of urea, and (c) a water-insoluble powder which is inert to the hydrophobic substance and urea. , to obtain a mixture comprising a hydrophobic phase of a hydrophobic substance in which an inert powder is dispersed, into the particles of which an aqueous solution of urea is adsorbed, the mixture containing 1 to 20% by weight of urea, 5 to 0% by weight of water-insoluble powder and 20 to 50% by weight of hydrophobic substance.

„*, ·!, · I 3 56486

In order to formulate such a preparation, it is essential that the urea is initially dissolved in as little water as possible without the use of heat. This urea solution is then adsorbed onto an inert powder matrix. Examples of suitable inert materials or matrices are starch and talc. In practice, it has been found that the stability and physiological functions of the preparation can be greatly improved if part of the water is replaced by an alcohol such as ethyl alcohol, propylene glycol or glycerol, while the cosmetic properties are enhanced by the addition of modifying oils and waxes such as oleic alcohol and isopropyl myrrh.

The following examples illustrate the urea powder ointment of the invention by way of example without limiting it.

Example 1

Urea 10 g

Water 10 g Starch 30 g

White ground wax ad. 100 g

Urea is completely soluble in 10 g of water at room temperature. This solution is adsorbed on the starch, and the starch is then uniformly dispersed in a white earth wax substrate.

4

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Example 2

Urea 10 g

Water 10 g Starch 30 g

Allyl alcohol 5 g

Or overnight ground wax 100 g

It has been found that the physical appearance of the final product can be improved; if a modifying oil such as oleyl alcohol is added. Oleyl alcohol is added in the final stage of mixture preparation.

Example 3

It has further been found that a substrate can be made more hydrophilic by adding a surfactant having an HLB value of between 9 and 14. An example of such a surfactant is polyoxyethylene nonyl ether having an HLB value of about 11.

Urea 10 g

Water 10 g Starch 30 g

Polyoxyethylene nonyl- 1 g ether 01 ί-yl alcohol 5 g

White jiaavax ad. 100 g

Polyoxyethylene nonyl ether is best added to the powdered intermediate mixture of starch and urea.

Example 4

To improve the chemical stability of the urea powder ointment, it is often desirable to dissolve the urea in water and a solvent. to a solution of ethyl alcohol, propylene glycol or glycerol. Thus, in this example, propylene glycol has been used to replace some of the water.

5 S6486

Carbamici 10 j

Water 8 g

Propylene glycol 5 g Starch 35 g

Polyoxyethylene nonyl 2 g ether

Oleyyl alcohol 4 g

White ground wax ad. 100 g

Urea is dissolved in a water / propylene glycol mixture without the use of heat. Example 5

Urea 10 g)

Water 7.5 g I A

Ethyl alcohol 10 g)

Starch 35 g) B

Polyoxyethylene nonyl 2 g) ether j

Oleyyl alcohol 4- £)

White; .lava ad. 100 g ^

The urea is dissolved in a water / alcohol mixture as intermediate A. A is then adsorbed onto B and allowed to dry at room temperature until a free-flowing intermediate is obtained. This is mixed evenly with C to form a urea powder cream.

Example 6

Urea 10 g

Water 7 g j A

Ethyl alcohol 8 5)

Propylene glycol 5 g)

Starch HO g) B

Plyoxyethylene nonyl ether 2 g

Oleyyl alcohol kg) ^

White r.i-idvahd ad. 100 g) 6 S6486 In this example, propylene glycol is added to the water / alcohol mixture. The preparation method is similar to Example 5.

Example 7

Xarbamide (urea) 10%

Water 14%

Dry starch (poly- 27% sakkaricii)

White wax 26%

Sorbitol 1%

Polyoxyethylene fatty ester 9%

Sorbitan ironolaurate 2%

Isopropyl myristate 10%

Hydrocortisone and / or 1% fluorinated corticosteroids

The percentages given above and below are approximate weight percentages of the mixture.

The amount of starch forming the inert matrix can range from 5 to 60 I. When a smaller amount of starch is used, a "wet" powder matrix is obtained when the urea solution is added, while when used. a higher percentage of starch is obtained as a free-flowing powder. The amount of starch used should be between 25 and 50% of the final weight as recommended. Instead of starch, an alternative inert substance, e.g. talc, can be used. In fact, it is often desirable to use a combination or blend of starch and talc in some suitable ratio.

At least most of the starch and / or talc particles are preferably less than 30 microns in size. The powder should preferably be able to absorb at least half of its weight of water and other urea solvent and still remain substantially powder.

The following ranges of ingredients have been found to be suitable in the mixture:

Urea 1 - 20%

Water (including other solvents, e.g. ethyl alcohol, propylene.i- 2 - 40% y] yol or ylycerol) 7 §6486 7 "rl · ']' 'e ly s (including talc or nuu 5-60¾ primer a. uh e)

White on the face (including other liquid paraffin v petrolatum or high alcohol 20 to 50 l)

Sorbitol (or nuu moisturizer) 0-5%

Polyoxyethylene fatty ester, polyoxyethylene nonyl ether or other water-miscible. surfactant

Sorbitan monolaurate, sorbitan monostearate or other oil-miscible surfactant 0-5% ta-active substance

Isopropyl myristate j. oleyl alcohol 0-15% or other modifying oil or wax

Hydrocortisone, fluorinated corticosteroids or other ingredients for the treatment of inflammation 0-2%

The final mixture is best a powder, ointment, salve or solution with a pH between 5 and 9 and no stinging on the skin.

Claims (11)

A process for the preparation of a urea-containing pharmaceutical composition for use for topical use on human skin, characterized in that it mixes in any order: (a) a pharmaceutically acceptable, liquid, semi-solid, gelatinous or solid hydrophobic material, (b) an aqueous solution of urea and (c) a water-insoluble powder inert to the hydrophobic material and to the urea to form a composition comprising a hydrophobic phase of the hydrophobic material in which the inert powder is dispersed, on whose particles an aqueous solution of the urea is adsorbed, the composition containing 1-20% by weight urea, 5-60% by weight water-insoluble powder and 20-50% by weight hydrophobic substance. 2. A process according to claim 1, characterized in that the inert powder is starch and / or tannic and that at least most of the powder particles are below 30 microns. Method according to claim 1 or 2, characterized in that said hydrophobic substance is white earth wax, liquid paraffin, petroleum jelly or higher alcohol. 4. A process according to any one of claims 1-3, characterized in that the urea has been dissolved in water and the solution obtained has been adsorbed in the powder matrix, the final product containing 2-40% by weight water. Process according to claim 4, characterized in that the water is partially replaced with one or more solvents for urea, e.g. with ethyl alcohol, propylene glycol or glycerol. 6. A process according to any one of claims 1-5, characterized in that, in addition to the composition, one or more non-ionic surfactants, water-soluble surfactants or substances, e.g. polyoxyethylenonyl ether or polyoxyethylene fatty ethers, the proportion of which in the composition is preferably not more than 10% by weight, and in oil miscible surfactant or substances, e.g. sorbitan monolaurates or sorbitan monostearates, the proportion of which