IE62117B1 - Salicyclic acid containing agents for treating scaly skin diseases - Google Patents

Description

The invention relates to an agent containing salicylic acid for local therapy of lepidosis in the field of human and veterinary medicine. Psoriasis, tinea amiantacea and seborrhoea sicca are examples of such lepidosis.

Prom, for example, E. Mutschler, Arzneimittelwirkungen, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1975» p. 575» it is known that salicylic acid causes removal of scales and softening of keratinous material and is used in the form of salicyl vaseline, salicyl spirit and salicyl collodion. Salicyl lard, salicyl eucerin and salicyl gel, among others, are in use as further agents for treating the abovementioned lepidosis.

From the publication by U. Adams and P. Neuwald in Pharm. Ind. Vol. 44, No. 6, pages 625 to 629, 1982, the use of 15 medium-chain triglyceride gels is known for producing salicylic acid containing ointments, if desired, with the addition of emulsifiers like wool wax alcohols. Such gels contain medium-chain triglycerides and an organic modified, layered lattice silicate of magnesium as gelling agent.

In EP-A-0 065 870 there are described anti-inflammatory ointments containing antiinflammatory substances like indomethacin, steroids and the like in an ointment base essentially comprising medium-chain triglycerides (glycerides of 0θ to 0^2 carboxylic acids), a carboxyvinyl polymer and water in the ratio of 1-25 J 0.3-3 : 75-99 as well as a gelling agent like isopropanolamine.

Moreover, it is also known to use solutions of salicylic acid in fatty oils such as olive oil, castor oil and others for treating the abovementioned lepidosis.

From DE-A-762 726 it is known that the solubility of 10 salicylic acid in fats and oils as well as ointments can he increased hy the addition of higher molecular aliphatic alcohols (Cq - Ο^θ) or their ethers with polyhydric alcohols containing at least one free hydroxyl group.

During use of the known salicylic acid containing agents 15 it has been found that these known agents are not or only little acceptable in use fbr the thus treated patients for a number of reasons including, for example, considerable smell irritation caused by the fatty oils turning rancid during the treatment, and, in practice, render the desired result actually only by stationary treatment. However, this is of particular importance for the patients treated with the agents, also for psychological reasons.

It is the object of the invention to provide a salicylic acid containing agent of the initially mentioned type, which agent has good acceptability without disadvantageous effects on the patients and enables non-stationary treat- ? ment. v According to the invention, this object is achieved in that the agent contains, each in percent by weight of the total weight of the agent = 100, 1 to 15 percent salicylic acid, 1 to 15 percent aliphatic 1,2-diol and 70 to 98 percent ester formed by a dihydric alcohol and at least one fatty acid selected from the group of saturated mediumchain fatty acids and the group of saturated long-chain, branched fatty acids.

Furthermore, according to the invention, this object is achieved by 1 to 15 percent salicylic acid, 1 to 15 percent aliphatic 1,2-diol and 7θ to 98 percent triglyceride of at least one fatty acid, selected from the group of saturated long-chain, branched fatty acids or their mixture with saturated medium-chain fatty acids, each in percent by weight of the total weight of the agent = 100.

The object is further achieved by salicylic acid in the range of 1 to 15 percent, an aliphatic 1,2-diol in the range of 1 to 15 percent, and a triglyceride of at least one fatty acid selected from the group of saturated medium-chain fatty acids, in the range of 70 to 98 percent, each in percent by weight of the total weight of the agent = 100.

* Finally, the object is also achieved by using a composition containing 1 to 15 percent salicylic acid, 1 to percent aliphatic 1,2-diol, and 7θ to 98 percent ester formed by a monohydric alcohol and at least one fatty acid, selected from the group of saturated medium-chain fatty acids and saturated long-chain, branched fatty acids, each in percent hy weight of the total weight of the agent = 100, for the manufacture of a medicament for local therapy of lepidosis in the field of human and veterinary medicine.

The saturation concentration of salicylic acid in fatty oils or mixtures thereof is in the range of 3 % to about 6 %. While salicylic acid is soluble in castor oil up to about 10 percent, this is, however, not a useful solvent within the scope of the invention due to its high viscosity and susceptibility to oxidation (turning rancid).

The solubility of salicylic acid in aliphatic 1,2-diols is much higher and amounts to about 20 percent in, for instance, propane-1,2-diol. However, such aliphatic 1,2diols are immiscible with the aforementioned fatty oils.

Surprisingly, it has now been found that clear and monophase solutions are obtained when the aforementioned esters, aliphatic 1,2-diols and salicylic acid are mixed with each other in the aforenoted mixing ratios. Therefore, various aliphatic 1,2-diols may be brought to use, whereby propane1,2-diol and the different butylene glycols having adjacent hydroxyl groups have proven particularly favourable.

In the agent according to the invention there may be used esters formed by mono-hydric or multihydric alcohols, especially of propane-1,2-diol, and saturated fatty acids of medium or greater chain length, particularly evennumbered and odd-numbered, branched or non-branched mediumchain (Οθ to fatty acids or branched long-chain (0^2 to C/jq) fatty acids or their mixtures, or triglycerides of the same acids. Particularly preferred therein are single or mixed esters of caprylic acid, capric acid, nonanoic acid and isostearic acid (mixture of branched-chain octadecanoic acids; see Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor, Aulendorf, 1981, p. 505). Instead of the aforementioned triglycerides there may also be employed common fatty oils, preferably vegetable fatty oils.

The agents according to tbe invention also have good acceptability during long-time application; up to now, no allergic reactions have been observed even in longtime applications. During such treatment, high effectiveness is achieved; in particular, total removal of scales, i.e. freedom from symptoms, which is maintained upon corresponding follow-up treatment, is already achieved after relatively short application time, depending on the severity of the illness.

A particularly effective, preferred agent according to the invention contains, each in percent by weight of the agent, 4- to 7·5 percent salicylic acid, 1 to 4-.5 percent pronane-1,2-diol and 88 to 95 percent triglycerides of caprylic acid, capric acid or a mixture thereof.

The proportion of propane-1,2-diol therein is so high that salicylic acid is present in nearly saturated solution.

An important reason for the high effectiveness of the agents according to the invention possibly resides in that the selected solvent mixtures act in a particularly favourable therapeutical manner on the diseased skin and thereby constitute a very effective carrier for conveying the salicylic acid to its site of action.

Furthermore, the treatment with the agents according to the invention is not connected with undesired and inacceptable burdens on the patients because the agents according to the invention are rapidly and completely resorbed by the skin. Thus, there are no smell irritations unbearable for the patient due to the fact that the fats or fatty oils become rancid and no undesired soiling of clothes or bed linen. A further very important advantage of the agents according to the invention is that it is no longer necessary to stay in hospital in most of the cases. Altogether, this results in a very high acceptance by the patients.

Preferred embodiments of the invention will be described hereinbelow in connection with the instruction for their preparation.

Salicylic acid in quantities of 1 to 15 parts by weight is triturated with 1 to 15 parts by weight of an aliphatic 1,2-diol like propane-1,2-diol in conventional manner. Subsequently, 98 to 7θ parts by weight of the particularly selected ester of the monohydric or multihydric alcohol are added; the mixture is stirred until a clear, oily solution is formed. Preferably, the aliphatic 1,2-diol is employed in an amount which increases with the amount of salicylic acid in correspondence with the ester which is selected as the lipid phase.

According to a preferred exemplary embodiment, salicylic acid is weighed in quantities of 4, 5» 7*5 and 10 g and triturated in usual manner with quantities of 1, 2, 4.5 and 7 g °f propane-1,2-diol, respectively. Subsequently, there are added to the 5, 7» 12 and 17 g of the propane1,2-diol trituration 95» 93» 88 and 83 g, respectively, of a single or mixed ester formed by propane-1,2-diol or glycerin and saturated medium-chain (CQ to C12) fatty acids like caprylic acid, capric acid or nonanoic acid or branched long-chain to 01θ) fatty acids like isostearic acid or the like and the mixture is stirred until a clear, oily solution is formed. These agents thus contain, each in percent by weight of the total weight = 100, salicylic acid 4 propane-1,2-diol 1 ester 95 7.5 10 4.5 7 88 85 Instead of these esters, there may also be employed esters of fatty alcohols, fatty oils, particularly vegetable fatty oils.

Preferably, the procedure is such that - starting from the saturation concentration of salicylic acid in the ester propane-1,2-diol is utilized in an amount such that there is just obtained a saturated or almost saturated solution of the desired amount of salicylic acid in the mixture of propane-1,2-diol and ester. In any case, it has been proved favourable for the treatment if saturated or almost saturated solutions of salicylic acid are employed.

These agents have been used in the manner described hereinbelow for treatment of lepidosis like psoriasis, tinea amiantacea, seborrhoea sicca on humans and mange and other forms of lepidosis on, for example, ponies. Altogether, in these and other comparable investigations, it has been found that the agents containing 4 to 7-5 percent by weight salicylic acid, 1 to 4.5 percent by weight aliphatic 1,2diol and 88 to 95 percent by weight ester, have the relatively best effect in terms of acceptability, effectiveness and duration of treatment until freedom of symptoms.

During further investigations it has been found that instead of propane-1,2-diol also the different butylene glycols having adjacent hydroxyl groups and, if desired, also other aliphatic 1,2-diols can be used.

The therapeutical application of an exemplary embodiment which contains 5 percent by weight salicylic acid, 2 percent by weight propane-Ί,2-diol and 95 percent by weight medium-chain triglycerides (total weight of the agent = 100) is described hereinbelow with respect to a patient group of 150 persons which primarily suffered from psoriasis and, to a smaller part, from other forms of lepidosis, for example seborrhoeic eczema. The treatment comprised, a) in the case of scalp diseases, applying the agent two or three times per week to the affected scalp locations; the treatment may be effected by using a plastic shower cap having a closing rubber rim and a commercially available surgical cap for over-night fixing, and b) in the case of body diseases, applying the agent one or two times per day to the affected locations; the agent is resorbed by the skin after 10 to 15 minutes of action.

In the case of 8 persons of the patient group the treatment was prematurely discontinued for reasons unrelated to the actual treatment. In the case of 5θ persons of the patient group, total descaling and, thus, the desired freedom from symptoms was achieved, depending on the severity of the original disease, after a treatment period of month in the case of light original disease, up to 5 months in the case of medium original disease, and up to 4 months in the case of severe original disease, and the onset of descaling began already during the first weeks of treatment.

In most of the remaining 92 patients, descaling was advanced very far after a treatment duration up to one year and, also in these cases, total descaling and, thus, the desired freedom from symptoms, can be expected.

Allergic reactions were not observed and the patients have accepted the treatment excellently. This is certainly affected by the fact that the agent is neutral in odor and quickly absorbed by the skin, whereby there is no soiling of clothes or bed linen, and also by the fact that the stay in a hospital is only required in particular circumstances and in the case of very severe diseases.

The same or similar effects were achieved when the triglycerides were replaced with others of the aforementioned esters.

As a very advantageous side effect, a clearly recognizable, increased hair growth has been found, also in the field of veterinary medicine.

The once achieved freedom from symptoms can also be maintained subsequently. Therefore, a follow-up therapy is recommended using commercially available agents such as dithranol for reducing new scale formation, in alternation with the herebefore described agents.

It will be appreciated the preparations according to the invention also have application as cosmetic agents.

Claims (22)

Claims

1. Salicylic acid containing agent for local therapy of lepidosis in the field of human and veterinary medicine, characterised by 1 percent to 15 percent of salicylic acid, 1 percent to 15 percent of an aliphatic 1,2-diol, and 70 percent to 98 percent of an ester formed by a dihydric alcohol and at least one fatty acid selected from the group consisting of saturated medium-chain fatty acids and saturated long-chain, branched fatty acids, each in percent by weight of the agent.

2. Agent according to claim 1, characterised in that the concentration of the aliphatic 1,2-diol contained therein increases with increasing concentration of salicylic acid.

3. Agent according to claim 1 or 2, characterised in that the aliphatic 1,2-diols are selected from the group consisting of propane 1,2-diol and butylene glycol containing vicinal hydroxy groups.

4. Agent according to any one of claims 1 to 3, characterised in that the ester is formed from propane 1,2-diol.

5. Agent according to claim 4, characterised in that the agent contains salicylic acid in the range of 4 percent to 7.5 percent, propane 1,2-diol in the range of 1 percent to 4.5 percent, and propane 1,2-diol ester of a medium-chain saturated fatty acid in the range of 88 percent to 95 percent, each in percent by weight of the agent.

6. Agent according to any one of claims 1 to 5, characterised in that the saturated medium-chain fatty acids are selected from caprylic acid, capric acid, nonanoic acid or mixtures thereof.

7. Agent according to any one of claims 1 to 5, characterised in that the saturated long-chain, branched fatty acid is isostearic acid.

8. Agent according to any one of the preceding claims, characterised in that the proportion of the aliphatic 1,2diol is selected such that the salicylic acid is present in at least almost saturated solution.

9. Salicylic acid containing agent for local therapy of lepidosis in the field of human and veterinary medicine, characterised by 1 percent to 15 percent of salicylic acid, 1 percent to 15 percent of an aliphatic 1,2-diol, and 70 percent to 98 percent of a triglyceride of at least one fatty acid selected from the group consisting of saturated long-chain, branched fatty acids or their mixture with saturated medium-chain fatty acids, each in percent by weight of the agent.

10. Agent according to claim 9, characterised in that the concentration of the aliphatic 1,2-diol contained therein increases with increasing concentration of salicylic acid.

11. Agent according to claim 9 or 10, characterised in that the aliphatic 1,2-diols are selected from the group consisting of propane 1,2-diol and butylene glycol containing vicinal hydroxy groups.

12. Agent according to any one of claims 9 to 11, characterised in that the saturated medium-chain fatty acids are selected from caprylic acid, nonanoic acid or mixtures thereof. capric acid, Agent according to any one of characterised in that the saturated fatty acid is isostearic acid. claims 9 to 12, long-chain, branched

13. 14. Agent according to any one of claims 9 to 13, characterised in that the proportion of the aliphatic 1,210 diol is selected such that salicylic acid is present in at least almost saturated solution.

14. 15. Salicylic acid containing agent for local therapy of lepidosis in the field of human or veterinary medicine characterised by salicylic acid in the range of 1 percent to 15 percent, an aliphatic 1,2-diol in the range of 1 percent to 15 percent, and a triglyceride of at least one fatty acid selected from the group consisting of saturated medium-chain fatty acids in the range of 70 percent to 98 percent, each in percent by weight of the agent.

15. 16. Agent according to claim 15, characterised in that the concentration of the aliphatic 1,2-diol contained therein increases with increasing concentration of salicylic acid.

16. 17. Agent according to claim 15 or 16, characterised in that the aliphatic 1,2-diols are selected from the group consisting of propane 1,2-diol and butylene glycol containing vicinal hydroxy groups.

17. 18. Agent according to any one of claims 15 to 17, characterised in that the saturated medium-chain fatty acids are selected from caprylic acid, capric acid, nonanoic acid or mixtures thereof.

18. 19. Agent according to any one of claims 15 to 18, characterised in that the triglyceride is selected from the group of vegetable triglycerides.

19. 20. Agent according to any one of claims 15 to 19, characterised in that the proportion of the aliphatic 1,2diol is selected such that salicylic acid is present in at least almost saturated solution.

20.

21. Agent according to any one of claims 1 to 8, characterised by the addition of an agent reducing new lepidosis formation.

22. Agent according to