Pharmaceutical composition having depigmentating and antiphotoaging activity

Abstract: The object of the present invention is a product based on a trans-retinoic acid (tretinoin) and azelaic acid combination having depigmentating effect and, more generally, antiphotoageing effect. After clinical and instrumental comparative analysis (clinical and photographic reports and skin mould profilometry), the action on physiological and/or photoinduced skin ageing obtained with the combination of the invention has been compared with the one noticeable after the treatment with azelaic acid or retinoic acid only. Better results were obtained using the azelaic-retinoic combination. The depigmentating action of the combination is superimposable to the one observed by using separately the two active ingredients, but it can be achieved in a surprisingly shorter time (from six to three months).

Description: The present invention relates to dermatologic preparations containing trans-retinoic acid (tretinoin) and azelaic acid as active ingredients. Recent studies documented the depigmentating action of both trans-retinoic acid and azelaic acid; this property is utilized for the preparation of compositions effective for the treatment of some unaesthetic forms of skin hyperchromatism (melanosis), well visible especially on face and hands. It has now been found that the trans-retinoic acid and azelaic acid combination exhibits a depigmentating action analogous to the one obtained utilizing the two active ingredients separately but that the results are already evident after three months of therapy. On the contrary, with the two substances used separately, a treatment of at least six months is necessary to observe the desired effect. Trans-retinoic acid (U.S. Patent 4,603,146, EP-A-0230498) and, to a less extent, azelaic acid (EP-A-0336880), exercise a preventive and reparative action of tissues which run into morphological alterations ascribable to physiological ageing and to damages caused by chronic exposure to actinic radiation. The antiageing and antiphotoaging actions of retinoic acid take place through the control of mechanisms that govern the regulation of the normal cell replication at the skin level, and in parallel, stimulating the slowed function of structures present in the dermis (fibroblasts, microcirculation, etc.). The clinical expression of these tissural alterations consists in the appearance of wrinkledness (of variable intensity), anomalous pigmentations, focal hyperkeratosis, folliculate ostia marked evidence, skin compactness and tonicity modifications, etc. The combination of trans-retinoic and azelaic acids proved to be therapeutically more effective than the separate active ingredients in exercising a control and reparative action towards skin structures altered by ageing and photoexposure. Therefore, the pharmaceutical compositions of the present invention can be used by subjects of any age for whom the treatment of skin modifications (visible and non visible) that respond well to trans-retinoic and azelaic acids and to their combination is suitable. The compositions object of the present invention, which are suitable for topical administration, can be prepared resorting to well-known techniques and excipients, such as, for instance, those described in "Remington's Pharmaceutical Sciences Handbook", Mack Pub.Co. N.Y. USA. Examples of suitable formulations comprise creams, ointments, gels, lotions, emulsions and the like. The weight-percentage of trans-retinoic acid can range from 0.005% to 0.05%, preferably from 0.01% to 0.025%, compared to the total amount of the formulation, while the azelaic acid amount can range from 10% to 30%, preferably from 15% to 25%. The administration form and the treatment length will usually be determined by a physician, but, generally, 1 or 2 applications a day, for a period from 1 to 6 months, will be sufficient to obtain clinically evident results. Hereinafter, some examples of formulations are reported in a table form; the results obtained in a clinical experimentation compared with the active ingredients not combined each other are reported as well. A product in the form of a cream containing 20% azelaic acid and retinoic acid in two different concentrations (0.01% and 0.025%) was tested on 120 people to evaluate antiphotoageing effect and depigmentating activity. The evaluation of antiphotoaging effect was performed on 90 patients (two of them were male) while the evaluation depigmentating activity was carried out on 30 female patients suffering from face melanosis. The patients were photographed after the 1 st , 3 rd , and 6 th months of the treatment. Latero-orbital region skin moulds with silicone material were performed on about 50% of the patients under antiphotoaging treatment at time 0 and after 6 months. Cutaneous moulds were examined with the computer profilometric analysis technique. During the experimentation 18 dropouts occurred (due to personal and not to tolerability reasons). Possible problems of tolerability to the product (burning sensation, slight colour) occurred only during the first days of the treatment and were easily overcome by alternating the evening application of the product with a one day rest. DEPIGMENTATING ACTIVITY The product depigmentating activity was evidenced already after the 3 rd month in about 1/3 of the treated cases, and it was comparable to that obtained in former experiments with azelaic acid or retinoic acid alone, after a much longer period of treatment (6 months or longer). ANTIPHOTOAGEING ACTIVITY The antiphotoageing activity of the product was evaluated not only clinically (by photography) but also by sophisticated profilometric analysis of cutaneous moulds and compared to analogous observations carried out on moulds of patients treated with azelaic acid or retinoic acid only. The results are hereinafter reported. Instrumental evaluation of the antiphotoageing effect of the azelaic and retinoic acid combination by topical use. PROFILOMETRIC ANALYSIS In the group of patients treated with the association the analysis was performed on 15 moulds, selected among the available 52 ones. 17 moulds of subjects of the same age, subjected to the topical treatment with 0.05% retinoic acid and 12 moulds of subjects treated with 20% azelaic acid were analyzed by comparison for the same period. Summarizing: a) 20% azelaic acid = 12 patients b) 0.05% retinoic acid = 17 patients c) retinoic-azelaic acid combination = 15 patients To perform the profilometric study, silicone hard resin counter-moulds were prepared before and after the treatment, on the same skin portion, considering two main wrinkles as the reference point. The following parameters were considered: 3 for wrinkledness (RA, RZD, RT), 2 for peak density (NR, D) and one for profile length (Lo). The results obtained for the various parameters can be summarized as following: RT parameter Maximum wrinkledness. The distance between the lines tangent to the peaks and to the grooves, within the length of the measured profile. RZD parameter Mean deepness The mean value of the filtered profile width, measured within five adjacent bases lengths. RA parameter Wrinkledness mean value. Mean value of all the ordinates of the filtered profile (from form and corrugation errors), in absolute magnitude, within the length of measure). After the treatment, skin microwrinkledness is reduced in a statistically significative manner by using the retinoic acid and azelaic acid combination. Also by using trans-retinoic acid or azelaic acid alone for a six months period a wrinkledness reduction was obtained for the considered parameters but it was statistically no significative. NR parameter . Peaks number The peaks number was counted with the density criterion D but referred to 10 mm of profile. D parameter Density Filter and profile peaks (or grooves) number, gathered within a set out band delimitated by the secants parallel to the mean line and named c₁ (upper) and c₂ (lower) and related to the measured length. LO Parameter Profile development Filtered profile development length. From the above data it is evident that the application of the trans-retinoic and azelaic acid combination induced an increase in peak density; this means a return to the "juvenile" type skin texture. Azelaic and trans-retinoic acids alone showed no better activity in increasing peak density parameters as compared to their association. The results from the clinical and laboratory researches performed to demonstrate the efficacy of the cream containing the 20% azelaic acid and 0.01% to 0.025% trans-retinoic acid combination allow to express the following observations: 1) the enhanced depigmentating activity of the combination is nearly superimposable to the one achieved with products based only on azelaic acid which were formerly tested (about 35% of regression of the lesions), but the depigmentating activity occurs faster with the combination (about 3 months against 6). 2) Remarkable antiaging activity is unquestionably reported from profilometric analysis of moulds which enables to put in evidence how the azelaic and trans-retinoic acids combination induces a lowering of skin microwrinkledness higher than the one achieved with azelaic or trans-retinoic acid alone. In conclusion, the combination warrants fast and satisfying depigmentating activity on face melanosis and proves to be particularly efficient in reducing the skin microwrinkledness, one of the most significant clinical expressions of skin damage originated from photoexposure and from ageing processes.

Claims: Claims for the following Contracting States : DE, GB, FR, IT, NL, SE, LI, CH, BE, AT, LU, DK, ES, GR Dermatologic compositions based on an azelaic and trans-retinoic (tretinoin) acid combination. Dermatologic compositions according to claim 1, in which azelaic acid and trans-retinoic acid are present in concentrations ranging from 10% to 30% and from 0.005% to 0.05% (w/w) respectively. Dermatologic compositions according to claim 1, in which azelaic acid and trans-retinoic acid are present in 20% and 0.01% (w/w) concentrations respectively. Dermatologic compositions according to claim 1, in which azelaic acid and trans-retinoic acid are present in 20% and 0.025% (w/w) concentrations respectively. Dermatologic compositions according to the preceding claims, under the form of day-cream, night-cream, lotions, serum, gels, masks. The use of a azelaic and trans-retinoic acid combination to prepare a dermatologic composition for antiphotoaging and depigmentating skin treatment.

Inventors: CAPUTO RUGGERO, CAPUTO, RUGGERO
Applicants: CILAG SPA, SCHERING SPA, CILAG S.P.A.
Application year: 1991
Main classification: A61K31
IPC codes: A61K8, A61K31, A61Q19, A61P17