NO171623B - PROCEDURE FOR AA WEEK STABILITY FOR ANTI-CONTAINING PREPARATIONS - Google Patents

Description

The present invention relates to a method for increasing the stability of anthralin-containing preparations.

Anthralin, also known as dithranol, has been a common component in preparations used for the percutaneous treatment of psoriasis, a dermatological disorder characterized by thickened, reddish, silver-scale-like patches of skin, which may appear as small lesions or which may cover large areas of the body.

Although in recent years dermatologists have used a number of new methods for the treatment of psoriasis, the majority of the used therapeutic agents and cures lack a sustained effect. A number of different topical treatments have been used to treat psoriasis, for example tar, tar derivatives, anthralin, mercury compounds, corticosteroids and keratolytics.

Anthralin is still the treatment of choice for many dermatologists when treating psoriasis. Generally, anthralin is used as a "mainline" treatment of inpatients and ambulatory patients in most hospitals. For this purpose, the anthralin is usually used in concentrations varying from 0.05 to 5 weight-Sé, calculated on the total weight of the preparation.

Unless otherwise stated below, weight-£ means percent weight based on the total weight of the preparation. When used correctly, anthralin is extremely effective, and its use is accompanied by minimal or no side effects.

Although it is generally recognized that anthralin is very effective in the treatment of psoriasis, the agent nevertheless suffers from three main problems, namely instability, staining of skin and clothing and skin irritation. Anthralin is sensitive to light-catalyzed oxidation, dimerization and/or chemical degradation, whereby 1,8-dihydroxy-anthraquinone and 1,8,1',8'-tetrahydroxy-10,10'-dianthrone and other unidentified by-products are formed.

It has been reported that anthralin is susceptible to auto-oxidative degradation (ie free radical oxidation). The breakdown products are believed to be inactive in the chemotherapy of psoriasis. Skin "irritation" or "anthralin erythema" is believed to be primarily caused by the initial free radical intermediates of anthralin. The "staining" of the skin by anthralin is believed to be attributable to the oxidation products of anthralin, i.e. 1,8-dihydroxyanthraquinone or its dimer.

Many solutions to the problem of anthralin stability have been mentioned in the prior art, but none of these proposals have been sufficiently satisfactory. Typical known solutions are those described in US-PS 4,203,969 and 4,287,214. US-PS 4,203,969 mentions the critical aspect of the use of a water-soluble, oil-insoluble acid antioxidant or a combination of an acid and a water-soluble, oil-insoluble antioxidant in the continuous aqueous phase of a cream. US-PS 4,287,214 describes that antioxidants such as ascorbic acid, BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene) and other chemicals such as salicylic acid do not satisfactorily stabilize anthralin, while certain α-hydroxy acids do. Ponce-Waelsch and Hulsebosch in "Arch. Derm. Forsch.", 249, 141-152 (1972) describe a "Lactacyd pH2®" cream carrier containing anthralin. Table 1 in this reference shows the lack of stability of such a preparation when analyzed with an ultraviolet spectroscope! and thin-layer chromatography. Although Caron and Shroot, "J. Pharm. Sei.", 70:11, 1205-1207 (1981) mention salicylic acid in a 0.44 SÉ ug anthralin-containing preparation which also contains cetyl alcohol, sodium lauryl sulfate, paraffin, and petroleum jelly, there is actually no clear description that the preparation contains any water, nor is there any emphasis on any anthralin-stabilizing effect provided by any of the preparation's components or the concentration intervals, where such components could be used to provide a stable water- and anthralin-containing preparation in anti-psoriasis-effective amounts.

When anthraline instability is determined using high pressure liquid chromatography (HPLC) using the method described by Caron et al. in "J. Pharm. Sei.", 70:11, 1205 (1981) or in "Pharmacopeial Forum", May-June 1982, pages 1956-1957, The United States Pharmacopeial Convention, Inc., instead of that in United States Pharmacopeia (USP) more generally used methods for stability determinations, it turns out that the previously known methods for stabilizing anthralin are not completely satisfactory as they generally give less stability than previously assumed. In contrast to the USP method, which is less satisfactory for the determination of anthraline instability, the HPLC method is a selective, sensitive and reproducible method for the determination of anthraline instability. Useful publications such as those discussed above have raised serious questions about whether the USP and British Pharmacopeia (BP) methods actually indicate anthralin instability. It is expected that USP and BP will soon change their test method to HPLC for all anthralin-containing preparations.

For most commercial applications, anthralin concentrations of more than 0.5 wt-# are marketed relatively rarely, if at all, for ambulatory treatment, as such preparations rapidly undergo loss of activity and oxidation of anthralin. Where plaque psoriasis has attacked more than 20$ of the body's surface area, treatment during a hospital stay was necessary, to avoid irritation of normal skin in contact with anthralin preparations in the higher concentrations, and to control product stability during rapid treatment. A significant disadvantage of preparations with a low concentration, i.e. 0.5£ or less, is that it is impossible to carry out the rapid treatment, which is possible with preparations containing higher concentrations of anthralin.

The prior art seems to show that

a) Anthralin is sensitive to auto-oxidative degradation (free-radical oxidation), and the degradation products are

inactive in the chemotherapy of psoriasis,

b) Skin irritation, or anthralin erythema, is mostly caused by the initial biologically active free radical intermediates of anthralin, c) Staining of skin and clothes from anthralin is due to oxidation products such as the colored dimer or 1,8-dihydroxy-anthraquinone.

Attempts to date to stabilize anthralin against oxidation include the traditional prevention methods such as the use of ascorbic acid, BHA, BHT, EDTA (ethylene-diamine-tetraacetic acid), citric acid, setting the pH value to an acidic pH value, reducing the process temperature, removal of peroxides and protection from light. However, none of the previous attempts, as described in the prior art, to stabilize anthralin have been sufficient.

It is clear from the foregoing that the anthralin breakdown products or the initial free radical intermediates cause the irritation and staining problem which has hitherto been assumed to be an inevitable side effect of anthralin therapy. If anthralin instability could be improved, the irritation and staining problems indirectly caused by anthralin breakdown products would be solved at the same time.

Although new compositions of anthralin products have been developed for better patient tolerance, more convenience and less discoloration, the instability of anthralin in such preparations, manifested by loss of activity and a certain change of the hazard from pale yellow to brown to black, has so far remained an unsolved problem . No anthralin preparation has so far been available which provides long-term stability of anthralin as such and physical stability of the preparation together with an attractive appearance and an acceptable colour. It is well known that commercially available anthralin products become discolored within a short time with an appearance that is extremely unattractive and not acceptable to the user.

It has now been shown that the desired stabilization of anthralin in preparations for topical application in the treatment of psoriasis can be achieved by a method of the kind mentioned at the outset, which is characterized by adding to an aqueous preparation containing 0.1 to 5.0 weight-56 anthralin, calculated on the total weight of the preparation, an oil-soluble antioxidant, a dermatologically acceptable acid is added in an amount sufficient to adjust the pE value to 5.3 or below, and 0.05 to 10 weight-£, calculated on the total weight of the preparation, of an acid-stable, water-soluble, anionic surfactant which is alkyl sulfate, alkyl sulfonate, alkylbenzene sulfonate, sulfonyl fatty acid, alkyl phosphate, dioctyl sulfosuccinate, isethionate, alkyl ether sulfate or methyl sarcosine.

The presence of a water-soluble antioxidant in the aqueous phase has now, in contrast to what is described in US-PS 4,203,969, proven not to be critical for long-term stability of anthralin in the preparations according to the present invention. Although not critical, the presence of a water-soluble antioxidant may be desirable.

Preferably, anthralin according to the present invention will be used in a concentration of up to 5.0 wt. More preferably, 0.1 to 3.0% by weight of anthralin can be used in preparations suitable for topical application, and most preferably 0.5 to 2.0% by weight can be used.

Higher concentrations of anthralin can of course also be stabilized using the invention, but care must be taken when using such preparations to avoid irritation of normal skin.

The anionic surfactant is used in an amount sufficient to stabilize the anthralin. Preferably, the anionic surfactant is used in a concentration of 0.05 to 10% by weight, more preferably 0.1 to 5.0% by weight and most preferably 0.3 to 1.0% by weight.

Although it is known from the prior art that anthralin is more stable at an acidic pH value, and that the pH value of anthralin-containing preparations can be adjusted using any dermatologically acceptable acid, it is preferred as acid to use citric or salicylic acid. The pE value for anthralin-containing preparations containing an acid-stable, water-soluble anionic surfactant in accordance with the present invention is 5.3 or lower. It is preferred to use a lower pE value, as the limiting factor is skin irritation. Preferably, a pH value below 4.0 is used and most preferably a pE value below 3.4.

The present invention provides an anthralin product with long-term anthralin instability, cosmetic elegance, better patient tolerance and essentially no discoloration after storage in suitable packaging. It can be used with good results both for long-term outpatient treatment at low strength and for short-term treatment during hospital stay of psoriasis with high strength.

It is believed that the present invention can work because particles or droplets of oil dispersed in liquid media can be charged in one of two ways. The first involves reactive adsorption of particular ions, which are present in solution. In the case of water, it can be hydronium or hydroxyl ions. The proportion of oil particles or

—droplets dispersed in an aqueous medium acquire a negative charge due to preferential adsorption of

hydroxyl ions. The second way involves charges on particles or droplets of oil, where the charges are due to the ionization of functional groups of surfactants, for example the phosphates, carboxylates, sulphates and sulphonates, which may be on the surface of the particle or the interface between the oil and water surfaces.

Molecules and ions, which are adsorbed to surfaces or interfaces, are called surfactants. An alternative term is amphiphilic, which suggests that the molecule or ion has a certain affinity, both for polar and non-polar solvents. It is the amphiphilic nature of surface-active molecules or ions, which causes these to be adsorbed at the interface, which can be liquid/gas or liquid/liquid.

The chemical structure of anthralin is as follows:

Anthralin is an amphiphile-type molecule, and in other words, anthralin has a certain affinity towards both polar and non-polar groups. The amphiphilic nature of anthralin molecules also causes them to concentrate at the surface or interface where they are exposed to the attack. Under such conditions, oxidation initiators such as oxygen, light, hydrogen ions or metal ions will easily attack the anthralin and/or accelerate its degradation by free radical auto-oxidation. High surface or interfacial concentration of anthralin molecules also accelerates dimer formation due to the intramolecular reaction.

It is believed that according to the present invention, particles, droplets of oil or micelles are created, the surface of which contains a mostly anionic charge, which is provided either by the anionic surfactant alone, or by the combination of nonionic surfactants and anionic surfactants . The negatively charged surface is provided by the functional groups, for example sulphonates, sulphates, phosphates, carboxylates and others in the anionic surfactant(s). The anionic groups of acid-stable surfactants are adsorbed on the surface at the oil/water interface, forming a negatively charged surface on the oil particle, droplet or micelle. Cations in the aqueous phase will be attracted to the negatively charged surface, which also rejects all anions in the solution such as hydroxyl, once the first adsorption has occurred. Besides these electrical forces, the thermal motion tends to produce a uniform distribution of all the ions in solution. As a result, an equilibrium situation is formed and the system as a whole is electrically neutral.

The distribution ratio for anthralin between oil and water is in favor of the oily phase to an extent of approx. between 5,000 - 10,000 to 1. In the case of oil-in-water emulsion-based preparations, for example creams, gels and so on or emulsified ointment, the anthralin molecules are therefore dissolved in and practically retained in the oil phase. Once the initial adsorption on the surface is complete, the surface area is occupied by anionic and/or non-ionic surfactant molecules. The anthralin molecules will not be concentrated at the surfaces, and they are completely protected from the negatively charged surface, which repels the approach of hydroxyl ions or other decomposition initiators.

Such a situation can be described with reference to the drawing, where the anthralin molecules are retained in the oil phase, and the line a,a' is the surface of the particle, oil drop or micelle. The adsorbing ions, which give the surface its negative charge, are called potential determining ions, and they come from the anionic surfactant. Immediately in the vicinity of this surface layer there is an area of tightly bound molecules from the continuous water phase together with some positive ions, mostly hydronium ions, which are also tightly bound to the surface. The boundary of this area is indicated by the line b,b'. The potential at b,b' is always negative, with fewer cations than at the adjacent negative layers. In the area bounded by the lines b,b' and c,c' there is an excess of negative ions. Along the line c,c', the distribution of ions is uniform, and electrical neutrality is achieved. The line d,d' shows the outer boundary.

The anionic surfactant(s), which are used as a stabilizer for the anthralin preparations produced according to the invention, produce a dramatic increase in the anthralin's stability. It is believed that the anionic surfactant protects anthralin molecules from attack by creating a negatively charged surface, which forms micelles, or by surface separation. Although the anionic surfactant when used in an anthralin-stabilizing amount will produce the advantage of the present invention, as discussed above, the stabilization can be further increased by the use of antioxidants, which have previously been used in anthralin-containing preparations.

The acid-stable, water-soluble anionic surfactants, which are used in the method according to the present invention, are readily available compounds that are characteristically selected from surfactants that are not soaps such as alkyl sulfates, alkyl sulfonates, alkylbenzene sulfonates, o-sulfonyl fatty acids, alkyl phosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulfates, methylsarcosines and the like. Preferably, sodium lauryl sulfate, sodium octoxynol-3-sulfonate, sodium dodecylbenzene sulfonate, sodium lauryl sulfonate, DEA-oleth-3-phosphate, sodium dioctyl sulfosuccinate, sodium cocyl isothionate, sodium lauryl sulfate and sodium lauryl sarcosinate and the like are used. Mixtures of such surfactants can also be used.

In contrast to the known technique, the preparations obtained according to the present invention have long-term stability without water-soluble antioxidants, although such can be added to achieve improved results.

It has also been shown that the anionic surfactants in question greatly increase anthralin stability when they are used in combination with oil-soluble antioxidants. Typical of such antioxidants are ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, BHT, BHA, α-tocopherol, phenyl-oc-naphthylamine and lecithin.

It has also been shown that water-soluble antioxidants can further be used in the aqueous phase. Characteristic of such antioxidants are sodium sulphite, sodium etabisulphite, sodium bisulphite, sodium thiosulphate, sodium formaldehyde sulphoxylate, acetone sodium metabisulphite, ascorbic acid, isoascorbic acid, thioglycerol, thiosorbitol, thiourea, thioglycolic acid and cysteine hydrochloride.

The anionic surfactants in question can also be used with non-ionic surfactants such as polyalkylene ethers, polyalkylene esters, polyalkylene amides, fatty acid esters of polyvalent alcohols and fatty alcohols, which minimize the degree of skin irritation caused by the anions. If desired, anionic surfactants can also be used in combination with compatible thickeners such as methylcellulose, tragacanth, sodium alginate, "Carbopol 934" (CTFA), bentonite, carboxymethylcellulose and V-gum (eng.: Vee-gum) (CTFA). As used herein and elsewhere, (CTFA) means that the name used is a nomenclature from the CTFA Cosmetic Ingredient Directory, 3rd ed., published by the CTFA Association Inc.

Because of the poor stability of anthralin in dermatological preparations, anthralin-containing preparations were rarely, if ever, sold with anthralin concentrations of more than 0.5 wt.

As a result of the improved anthralin stability achieved by means of the invention, it is now possible to offer very stable preparations both with regard to anthralin concentration and physical stability of the preparations themselves, which preparations are particularly effective for the topical treatment of psoriasis. Such preparations can have anthralin concentrations of 0.1 to 5.0 wt-5é, or more, and are useful for ambulatory treatment of psoriasis. Furthermore, the results of studies on the stability at high temperature storage as well as Arrhenius plots of the results obtained on such preparations, have made it impossible to predict the stability of both anthralin and the preparations for a period of more than 2 years under room temperature storage, when the stability was measured by means of HPLC - method. In connection with these studies, a maintenance of less than 90% of the anthralin concentration was considered to be unacceptable.

In order to demonstrate the stability of the anthralin-containing products, gel preparations containing 1 wt-# of anthralin (plus 0.05 wt-5é excess) are prepared in accordance with the base gel composition shown below in example 1. All such gel preparations corresponded to the base gel composition and were identical apart from the surfactant used. In addition to gel preparations made with the acid-stable, water-soluble anionic surfactants, gel preparations are made using the cationic amine surfactant "Richamate 1655", a product of The Richardson Company, and using triethanolamine stearate, an acid-labile, water-soluble anionic surfactant, to demonstrate the lack of anthralin stability in gels containing substances from such groups of surfactants. Samples were assessed under storage conditions at room temperature, 35°C and 45°C.

Example 1

Basls gel preparation

The preparations are made by mixing the components in part A and heating to a temperature of 90'C. Stirring was continued until all the solids were mixed. The components from Part B were combined in a separate container and heated to 90°C with continuous stirring until all the solids were dissolved. Part B was added to Part A and the resulting mixture was stirred. Stirring was continued for 10 minutes, as the temperature was maintained at 90° C. The resulting gel was cooled to packaging temperature, and packaged under an inert gas in aluminum tubes that were suitably coated on the inside so that they did not react with the product. The base gel composition of Example 1 was used at higher concentrations of surfactant to demonstrate the upper limits of the range in which the acid-stable, water-soluble, anionic surfactants can be used. Although even higher concentrations are possible, skin irritation is a limiting factor. The following Table II shows the results of this study.

Example 2

A satisfactory gel preparation was prepared from the following recipe:

The gel is prepared by mixing the components from part A and heating to a temperature of 90°C. Stirring was continued until all the solids were mixed. In a separate container, the components from part B were mixed and heated to 90°C with continuous stirring, until all the solids had dissolved. Part B was mixed with Part A and stirring was continued for 10 minutes while the temperature was maintained at 90°C. The resulting gel was cooled to packing temperature and packaged in aluminum tubes with a non-reactive inner coating under a gas atmosphere.

The preparation from example 2 was subjected to clinical testing. In all cases, the same composition was used, except that the anthralin concentration was varied. Clinical studies were carried out by clinical dermatologists with extensive experience in evaluating drugs used in the treatment of psoriasis.

These studies show that the gel preparations containing 0.5 to 2% by weight of anthralin produce particularly good results in patients who undergo a short-term therapy of 10 to 20 minutes once a day during a 6-week treatment period. The patients thus treated had psoriasis varying from local lesions to lesions over a larger part of the body surface. The patients were assessed after 6 weeks. The results of such evaluations are shown in Table III below and clearly show the effectiveness of 0.5 to 2 wt-56 anthralin-containing gel stabilized 1 in accordance with the invention.

It is worth noting here that clinical evaluation of the preparations according to example 6 has already begun. Preliminary results show no difference in terms of clinical effectiveness in the short-term treatment of psoriasis between the preparation according to example 2 (containing water-soluble antioxidant in the aqueous phase) and the preparation according to example 6 (not containing water-soluble antioxidant in the aqueous phase).

It must be emphasized here that the solution to the stability problem of anthralin by means of the preparations obtained according to the present invention facilitates the use of short-term therapy and is particularly useful in the treatment of psoriasis.

Example 3

A satisfactory cream preparation was prepared from the following recipe:

The cream was prepared by mixing the components from part A and heating to a temperature of 70°C. Stirring was continued until all the solids were mixed. In a separate container, the components from part B were mixed and heated to 70°C with continued stirring until all solids were dissolved. Part B was mixed with Part A and stirring was continued, maintaining a temperature of 70°C, until both parts were thoroughly mixed. The resulting cream was cooled to packaging temperature and packaged.

Example 4

A satisfactory stick preparation was prepared on the basis of the following recipe:

Sodium sulfate and ascorbic acid were dissolved in the water and added to the remaining components which had been premixed at 80°C and then cooled to 75°C. The preparation was poured into moulds, cooled and allowed to solidify and then packaged.

Example 5

A satisfactory ointment preparation was prepared on the basis of the following recipe:

All components with the exception of the anthralin mixed thoroughly with water at 75°C until bubbling ceased. The anthralin was then added and stirring was continued for another 30 minutes. The preparation was cooled to 55°C and packaged.

Examples 6 and 7 show two further preparations which can be prepared using the method indicated in example 1, and which are particularly stable under long-term storage conditions.

Example 6

Example 7

Although the anthralin preparations obtained according to the invention can be formulated and used in the form of cream, gel, ointment or stick, the cream and gel forms are the most preferred, as they are the easiest to apply.

Claims (7)

1. Process for increasing the stability of anthralin-containing preparations, characterized in that an oil-soluble antioxidant, a dermatologically acceptable acid in an amount which is sufficient to adjust the pH value to 5.3 or below, and 0.05 to 10 weight-Sé, calculated on the total weight of the preparation, of an acid-stable, water-soluble, anionic surfactant that is alkylsulfate, alkylsulfonate, alkylbenzenesulfonate, sulfonyl fatty acid, alkyl phosphate, dioctyl sulfosuccinate, isothionate, alkyl ether sulfate or methyl sarcosine. 2. Method according to claim 1, characterized in that the pH value is adjusted to 4 or lower. 3. Method according to claim 1 or 2, characterized in that the pH value is adjusted to 3 or 4. 4. Method according to any one of claims 1-3, characterized in that the pH value is adjusted to 3.2. 5. Method according to any one of claims 1-4, characterized by the addition of the surfactant in an amount of 0.1 to 5.0 wt-#, preferably 0.3 to 1.0 wt-£, the preparation containing a anthralin amount of 0.1 to 5.0 wt-#, preferably 0.1 to 3.0 wt-# and most preferably 0.5 to 2.0 wt-%, whereby the wt-# portion is calculated on the total weight of the preparation. 6. Method according to any one of claims 1-5, characterized by adding a surfactant selected from among sodium lauryl sulfate, sodium dioctyl sulfosuccinate, sodium alkylolefin sulfonate, sodium cocyl isothionate, DEA oleth-3-phosphate, sodium laureth sulfate, sodium lauryl sulfonate and sodium octoxynol-3-sulfonate. 7. Process according to claim 6, characterized in that sodium lauryl sulfate is added as surfactant.