Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2000-06-27
2002-06-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S489000, C424S502000, C514S846000, C514S847000
Reexamination Certificate
active
06399082
ABSTRACT:
The present invention relates to the use of a combination of a diol and an alpha-hydroxy acid for the topical treatment of hyperkeratotic skin diseases.
BACKGROUND OF THE INVENTION
Chronic hyperkeratotic skin diseases are characterised by a disturbance in the keratinisation process and include among other diseases psoriasis, hyperkeratotic eczema and ichthyosis.
Psoriasis is characterised by reddened flaking skin lesions. The disease, has as a rule, a chronic course. Topical agents for the treatment thereof are often smeary and or discoloring, e.g. dithranol and tar. Steroid preparations are cosmetically attractive but have important side-effects. Emollient preparations containing e.g. salicylic acid and urea in a cream or ointment base have a certain peeling effect but are not separately sufficiently active.
Hyperkeratotic eczema is characterised by thickened scaling skin often with chaps (rhazades).
Lamellar ichthyosis is a rare congenital genodermatosis characterised by generalised hyperkeratosis intense dryness of the skin and large scales especially over the extremities (H. Traupe, ed. (1989) The Ichthyoses: A guide to clinical diagnosis, genetic counseling and therapy, 1st ed., Springer Verlag, Berlin). Though usually not life-threatening, the disease can be very disfiguring and causes considerable distress to the sufferers throughout life. The treatment of lamellar ichthyosis involves oral vitamin A derivatives (retinoids) combined with adjuvant topical treatment with different emollient formulations containing e.g. urea, propylene glycol and alpha-hydroxy acids (AHA). However, the therapeutic results like in other hyperkeratotic skin diseases, are often disappointing and associated with side-effects.
E. J. Van Scott et al. (1974) Arch. Derrnatol. 110: 586-590 pioneered in using alpha-hydroxy acids against ichthyotic conditions. Further E. J. Van Scott et al. (1984) J. Am. Acad. Dermatol. 11: 867-879 described a keratolytic gel (5-10% alpha-hydroxy acid in a vehicle consisting of water, ethanol and propylene glycol (4:4:2), which however fell in oblivion since it was irritating and not suitable for whole body application.
In EP-0292495 compositions, consisting essentially of a mixture of propylene glycol, urea and optionally lactic acid, were disclosed. The compositions after topical application to the skin were said to have a beneficial effect on hyperkeratotic skin diseases. Simple application of the said mixture to the skin is possible, but in practice proved to be very difficult to achieve effectively. The mixture is fluid and slow to dry (evaporate) and the use of plasters and/or bandages is deemed necessary. This procedure is considered to be too inconvenient for general use. Besides that, due to the high concentrations of propylene glycol (40-80%) and urea (5-20%), side-effects, such as irritation, may occur, which also are a serious draw-back for daily application of such preparations during a prolonged period of time.
U.S. Pat. No. 4,105,783 discloses compositions containing a product, prepared by reacting, in aqueous or alcoholic aqueous solution, one or more of an alpha-or a beta-hydroxy acid and a base selected from the group consisting of ammonium hydroxide and an organic alkylamine, in a total amount of from 1 to 20% for the topical treatment of dry skin disorders, such as psoriasis and ichthyosis. The bases are successfully used to raise the pH of the compositions containing the hydroxy acids without compromising the therapeutic activity of the active ingredients, thereby reducing the skin irritation. Although it was stated that the reaction products, viz the ammonium salts and amides, thus formed, need no isolation procedure and can be directly incorporated into the therapeutic composition, good manufacturing and clinical practices nowadays require a careful assessment of the active ingredient both qualitatively and quantitatively and extensive pharmacological and toxicological testing of the reaction product formed.
There thus still exists a need for an effective product based on well-known and well-defined active ingredients or a method which can be topically applied to hyperkeratotic skin without causing serious side-effects, such as irritation.
SUMMARY OF THE INVENTION
The object of the present invention is to provide the use of compositions containing a combination of a diol and an alpha-hydroxy acid in a vehicle, which has semi-occluding properties, for topical treatment of hyperkeratotic skin diseases.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that compositions containing a combination of a diol and an alpha-hydroxy acid in a semi-occluding vehicle on topical application to the skin of patients, having a hyperkeratotic skin disease, are effective and show a considerable reduction of side-effects, such as irritation, as compared with compositions, containing the same amounts of the diol and the alpha-hydroxy acid in a non-occluding vehicle, such as a gel. In addition thereto the compositions of the invention show a remarkably greater efficacy than compositions comprising either the diol or the alpha-hydroxy acid in the same amount.
Examples of diols which may be used are propylene glycol, butylene glycol, pentanediol and hexylene glycol. There is a preference for propylene glycol and hexylene glycol, which may be used in a concentration of up to 40% and preferably from 10-20%.
Examples of the alpha-hydroxy acids or derivatives thereof are lactic acid, citric acid, glycolic acid, glucuronic acid, galacturonic acid, pyruvic acid etc, but preferably lactic acid is used. The alpha-hydroxy acid may be used in an amount of up to 10%, but preferably up to 5% is used.
The semi-occluding vehicles to be used are characterised by the fact that in in vitro and in vivo tests an occluding activity is observed, which is lower than for white soft paraffin, which is considered to be an occluding vehicle. The lower limit for the occluding activity is determined by values which are obtained for preparations, known to be non-occluding. E.g. in the in vitro test as disclosed in example 7 preparations having an occlusion factor below about 70 are considered to be non-occluding preparations. A proper in vivo test, wherein the effectiveness of topical preparations in restoring a cutaneous barrier function of diseased skin is assessed, is disclosed in example 8. Examples of such semi-occluding vehicles are fatty creams, containing a certain amount of occluding fats, such as white soft paraffin, or creams, containing an aqueous suspension of solid lipid nanoparticles, e.g. wherein the solid lipid is hard paraffin, having a melting point range from 54 to 57° C.
The combination of only 5% lactic acid and 20% propylene glycol in a fatty cream base is readily acceptable by most patients and has proved to be much more effective and less irritating than monotherapy with either of the two compounds in the same or even at twice these concentrations. The astonishingly potent effect of the mixture of the diol and the alpha-hydroxy acid in the semi-occluding vehicle suggests that the ingredients act synergistically in reverting hyperkeratosis.
The compositions according to the invention can be used in several stages of the treatment of hyperkeratotic skin diseases. In the pretreatment of psoriatic plaques before initiation of treatment with e.g. corticosteroids the compositions have proven to be equally good as the standard product, which is 5% of salicylic acid in white soft paraffin. However, the cosmetic properties of the compositions according to the invention were considered by the patients to be superior over those of the standard product. The treatment of lamellar ichthyosis normally consists of systemic therapy with retinoids combined with adjuvant topical treatment. The compositions according to the invention have proven to be advantageously used in such adjuvant topical treatment. For less severe hyperkeratotic skin disorders the compositions according to the invention can be used without systemic therapy.
Although the foregoing invention has been describe
Bennett Rachel M.
McDonnell & Boehnen Hulbert & Berghoff
Yamanouchi Europe B.V.
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