DK163028B - STABILIZED ANTHRALINE PREPARATION AND PROCEDURE FOR PREPARING THEREOF - Google Patents

Description

in

DK 163028 B

Anthralin, also known as dithranol, has been a common component of preparations used for the percutaneous treatment of psoriasis, a dermatological disorder characterized by thickened, reddish, silver scaly-like skin pieces that can appear as a few small lesions or can cover large areas of the body.

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

Anthralin remains the preferred treatment for many dermatologists in the treatment of psoriasis. In general, an-15 thraline is used as a "main line" treatment for stay patients and ambulatory patients in most hospitals. For this purpose, the anthralin is generally used at concentrations ranging from 0.05 to 5% by weight based on the total weight of the preparation.

Unless otherwise stated below, weight percent means 20 percent by weight based on the total weight of the composition. With proper use, anthralin is extremely effective and its use is accompanied by minimal to no side reactions.

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

It has been disclosed that anthralin is susceptible to auto-oxidation degradation (i.e., free radical oxidation). Its degradation products are thought to be inactive in the chemotherapy of psoriasis. The skin's "irritation" or "anthralin erythema" is thought to be primarily caused by the initial free radical intermediates of anthralin. The skin's "stain" of anthralin is believed to be attributable to its oxidation products, i.e.

1,8-dihydroxy-anthraquinone or the dimer.

Many solutions to the problem of anthralin stability have been provided in the prior art, but none have been sufficient 2

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satisfying. Typical known solutions are those disclosed in U.S. Patent Nos. 4,203,969 and 4,287,214. U.S. Pat.

No. 4,203,969 discloses the critical use of a water-soluble, oil-soluble acid antioxidant or a combination of an acid and a water-soluble, oil-soluble antioxidant in the continuous aqueous phase of a cream. U.S. Patent No. 4,287,214 discloses 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 alpha βίο hydroxy acids do. GB Patent No. 2,107,587 discloses a composition in the form of a shampoo for the treatment of skin diseases, which contains anthralin, a fatty acid ester, water and an anionic or nonionic surfactant. The preparation is stable to oxidation for one week when stored at approx. + 4 ° C. Ponce-Waelsch and 15 Hulsebosch, Arch.Derm.Forsch. 249, 141-152 (1974) disclose a "Lactacyd® pH2" cream vehicle containing anthralin. Table 1 of this reference shows the lack of stability of such a preparation by analysis by UV spectroscopy and thin layer chromatography. Although Caron and Shroot, J.Pharm.

Sci. 70:11, 1205-1207 (1981) disclose salicylic acid in a 0.44% anthralin-containing preparation which also contains cetyl alcohol, sodium lauryl sulfate, paraffin and vaseline, there is actually no clear description that the composition contains any nor is there any accentuation of any anthralin-stable serous effect provided by any of the composition's components or the concentration ranges in which such 25 components could be used to provide a stable water- and anthralin-containing composition in anti-psoriasis-effective amounts.

When anthralin stability is determined using high pressure liquid chromatography (HPLC) using the procedure described in Caron, et al., J.Pharm.Sci. 70:11, 1205 (1981), or that described in Pharmacopeia! Forum, May-June 1982, pages 1956-1957, The United States Pharmacopeial Convention,

Inc., instead of the more commonly used method of stability determination in United States Pharmacopeia (USP), it appears that the prior art methods of stabilizing anthralin are not completely satisfactory, generally providing less stability than previously believed. . Unlike the USP method, which is less satisfactory for the determination of the anthral instability, the HPLC method is a selective, sensitive and reproducible method.

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cerbar method for determining anthralin stability. Recent publications, such as those mentioned above, have raised serious questions about whether the methods of USP and British Pharmacopeia (BP) actually indicate anthralin stability. It is expected that USP and BP 05 will soon change their test method to HPLC for all anthralin-containing preparations.

For most commercial applications, anthralin concentrations greater than 0.5% by weight are rarely, if at all, marketed for ambulatory therapy, as such preparations undergo rapid loss of activity and oxidation of anthralin. Where plaque psoriasis had attacked more than 20% of the body's surface area, treatment at hospital stays was necessary to avoid irritation of normal skin in contact with the higher concentrations of anthralin and to control product stability during rapid treatment. One major disadvantage of low concentration preparations, i.e. 0.5% or less is that it is impossible to undertake the rapid treatment possible with preparations containing higher concentrations of anthralin.

The prior art seems to show that: 20 a. Anthralin is susceptible to auto-oxidation degradation (free radical oxidation) and its degradation products are inactive in the chemotherapy of psoriasis, b. The skin irritation or anthralin erythema is mostly caused by the initial biologically active free radical intermediates of anthralin, c. The staining of anthraline skin and clothing is due to its oxidation products such as its colored dimer or 1,8-dihydroxy-anthraquinone.

Previous attempts to stabilize anthralin against oxidation included the traditional prevention methods such as the use of ascorbic acid, BHA, BHT, EDTA (ethylenediaminetetraacetic acid), citric acid, pH adjustment to an acidic pH, reduction of 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 degradation products or the initial free radical intermediates cause it 4

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irritation and staining problem, which has hitherto been assumed to be an inevitable consequence of anthralin therapy. If anthralin stability could be improved, the irritation and staining problems indirectly caused by anthralin degradation products would be solved simultaneously.

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, as manifested by loss of activity and a change in color from pale yellow 10 to brown to black, has so far remained a unsolved problem. No anthralin preparation has so far been available which will cause long term stability of anthralin as such and physical stability of the preparation as well as an attractive appearance and acceptable color. It is well known that commercially available anthralin products are discolored in a short time with a resultant appearance that is highly unattractive and unacceptable to the end user.

It has now been found that the desired stabilization of anthralin in compositions suitable for topical use in the treatment of psoriasis can be achieved by adding an anthralin stabilizing amount of an acid-stable, water-soluble anionic surfactant to a composition containing water. , anthralin and an oil-soluble antioxidant, and having a pH of 5.3 or less, which optionally further contains a water-soluble antioxidant in the aqueous phase. The presence of a water-soluble antioxidant 25 in the aqueous phase has now, contrary to that disclosed in U.S. Patent No. 4,203,969, has not been found to be critical to the long-term stability of anthralin in the compositions of the present invention. Although not critical, the presence of a water-insoluble antioxidant may be desirable.

Preferably, according to the present invention, anthralin will be used at a concentration of up to approx. 5.0% by weight.

More preferably, ca. 0.1 to approx. 3.0% by weight of anthralin is used in compositions suitable for topical application, and most preferably about 0.5 to 2.0% by weight is used.

Of course, higher concentrations of anthralin can also be stabilized by the present invention, but care must be taken in the use of such preparations to avoid irritation 5

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of normal skin.

The anlonic surfactant is used in an amount sufficient to stabilize the anthralin. Preferably, the anionic surfactant is used at 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.

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

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

It is believed that the present invention may work because particles or droplets of oil dispersed in liquid media can be charged in one of two ways. The first way involves reactive adsorption of particular ions present in solution. In the case of water, it may be the hydronium or hydroxyl ion. The majority of oil particles or droplets dispersed in an aqueous medium take up a negative charge due to preferential adsorption of the hydroxyl ion. The second way involves charges on particles or droplets of oil, the charges being due to the ionization of functional groups of surfactants, e.g. the phosphates, carboxylates, sulfates and sulfonates, which may be on the surface of the particle or interphase of the oil-water phases.

35 Molecules and ions adsorbed to surfaces or interfaces are called surfactants. An alternative term is amph ifil, indicating that the molecule or ion has some affinity for both

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6 polar and non-polar solvents. It is the amphiphilic nature of surfactant molecules or ions which causes them to be adsorbed at the interphase, which may be liquid / gas or liquid / liquid.

The chemical structure of anthralin is as follows: 05

HO O OH

AJLl Hydrofilside

Lipophilic side 10

Anthralin is an amphiphilic-type molecule, and in other words, anthralin has some affinity for both polar and non-polar groups. The amphiphilic nature of anthraim molecules also causes them to be concentrated at the surface or interphase where they are exposed to light attack. Under such conditions, oxidation initiators such as oxygen, light, hydrogen ions or metal ions will readily attack the anthralin and / or accelerate its degradation through free radical auto-oxidation. High surface or interphase concentration of anthra-lin molecules also accelerates dimer formation due to the intramolecular interaction.

It is believed that the present invention creates particles, droplets of oil or micelles whose surface contains a mostly anionic charge 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 sulfonates, sulfates, phosphates, carboxylates, etc. in the anionic surfactant (s). The anionic groups of acid-stable surfactants are adsorbed on the surface at the oil / water interface to form 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, until the initial adsorption is complete. In addition to 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 created and the system as a whole is electrically neutral.

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The distribution ratio of anthraline between oil and water is in favor of the oily phase to an extent of approx. Therefore, in the case of oil-in-water emulsion-based preparations, such as creams, gels, etc. or emulsified ointment, the anthralin-05 molecules are dissolved in and practically retained in the oil phase. Once initial surface adsorption is complete, the surface area is occupied by anionic and / or nonionic surfactant molecules. The anthralin molecules will not be co-centered at the surfaces and are fully protected by the negatively charged surface which rejects the approximation of hydroxyl ions or other degradation initiators.

Such a situation can be described with reference to Figure 1, where the anthralin molecules are retained in the oil phase and the line a, a * is the surface of the particle, oil droplet or micelle. The 15 adsorbing ions that give the surface its negative charge are called potential determining ions and they come from the anionic surfactant. Immediately near this surface layer is a region of tightly bound molecules from the continuous aqueous phase along with some positive ions, mostly 20 hydronium ions, which are also tightly bound to the surface.

The boundary of this area is indicated by line b, b '. The potential at line b, b 'is still negative, but there are fewer cations than at the adjacent negative layer. In the region bounded by lines b, b 'and c, c' there is an excess of negative ions. Following line c, c ', the distribution of ions is uniform and electrical neutrality is obtained. The line d, d * shows the outer boundary.

The anionic surfactant (s) used as a stabilizer for anthralin compositions in accordance with the present invention produces a dramatic increase in the stability of anthralin. It is believed that the anionic surfactant protects anthralin molecules from attack by creating a negatively charged surface that forms micelles or by surface separation. Although the anionic surfactant when used in an anthralin stabilizing amount will produce the benefits of the present invention as discussed above, the stabilization can be further enhanced by the use of antioxidants previously used in anthralin-containing compositions.

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δ

The acid-stable, water-soluble anionic surfactants used in the present invention are readily available compounds typically selected from non-soap surfactants such as alkyl sulfates, alkyl sulfonates, alkylbenzenesulfonates, alpha sulfonyl fatty acids, alkyl phosphates, dioctylsulfosuccinate, isethionates, alkylethersulfates, methylsarcosins and the like. Preferably, sodium lauryl sulfate, sodium octoxynol-3-sulfonate, sodium dodecylbenzenesulfonate, sodium lauryl sulfonate, DEA-oleth-3-phosphate, sodium dioctyl sulfosuccinate, sodium cocyl isothionate and sodium laurethsulfate and sodium laurethsulfate Mixtures of such surfactants may also be used.

Contrary to the prior art, the compositions of the present invention have long-term stability without water-soluble antioxidants, although these can be added for improved results.

It has further been found that the anionic surfactants in question greatly increase anthralin stability when used in combination with oil-soluble antioxidants. Typical of 20 such antioxidants are ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, BHT, BHA, alpha-tocopherol, phenyl-alpha-naphthylamine and lecithin.

It has also been found that water-insoluble antioxidants can be further used in the aqueous phase. Typical of such antioxidants are sodium sulphite, sodium metabisulphite, sodium bisulphite, sodium thiosulphate, sodium formaldehyde sulphoxylate, acetone sodium metabulphite, ascorbic acid, isoascorbic acid, thioglycerol, thiosorbitol hydrochloride, thiourea

The present anionic surfactants may also be used with nonionic surfactants such as polyalkoxy ethers, polyalkoxy esters, polyalkoxyamides, fatty acid esters of polyhydric alcohols and fatty alcohols which minimize the degree of skin irritation caused by the anions. If desired, the anionic surfactants may also be used in combination with compatible thickeners such as methyl cellulose, tragacanth, sodium alginate, "Carbopol 934" (CTFA), bentonite, carboxymethyl cellulose and Vee gum (CTFA) . As used here and elsewhere means 9

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(CTFA) that the name used is a nomenclature from the CTFA Cosmetic Ingredient Directory, 3rd ed., Published by the CTFA Association, Inc.

Due to the poor stability of anthralin in dermatological 05 preparations, anthralin containing preparations were rarely, if at all, sold with anthralin concentrations greater than 0.5% by weight. Due to the improved anthralin stability provided by the present invention, it is now possible to offer very stable compositions both with respect to anthralin concentration and physical stability of the compositions themselves, which are highly effective for topical treatment. of psoriasis. Such preparations may have anthralin concentrations of 0.1 to 5.0% by weight or more and are useful for the outpatient treatment of psoriasis. Furthermore, the results of accelerated 15 high temperature storage stability studies and Arrhenius plots of the results obtained in such preparations have made predictions for the stability of both anthralin and the preparations for a period of more than 2 years under room temperature storage conditions when the stability was measured by the HPLC method. For 20 of these studies, retention of less than 90% of the anthralin concentration was considered unacceptable.

To demonstrate the stability of the anthralin-containing products of the present invention, gel compositions containing 1% by weight of anthralin (plus 0.05% by weight of excess) were prepared according to the base gel composition of Example 1. All such gel compositions corresponded to the basic gel composition phrase and were identical except for the surfactant used. In addition to gel compositions prepared with the acid-stable, water-soluble anionic surfactants of the present invention, gel compositions were prepared using the cationic amine surfactant "Richamate 1655", a product of The Richardson Company, and using triethanolamine stearate, a acid-unstable, water-soluble anionic surfactant to detect the lack of anthralin stability in gels containing substances from such groups of surfactants.

Samples were evaluated under storage conditions at room temperature, 35 ° C and 45 ° C.

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Example 1 Basls Gel Preparation S_

Part A

05 Mineral Oil (USP) 164

Propyl gallate 0.5 BHT 2.0

Salicylic acid 2.0

Oleth-2 (CTFA) 60.0 10soceteth-20 (CTFA) 200.0

Ascorbyl palmitate 1.0

Anthralin 10.5

Part B

PEG-8 (CTFA) 50.0

Sorbitol solution (70%) 20.0 EDTA 1.0

Sodium bisulfite 1.0

Ascorbic Acid 10.0 Surfactant 5.0

Purified Water (USP) q.s. 1000.0

The compositions were prepared by mixing the components of Part A and heating to a temperature of 90 ° C. Stirring was continued until all the solids were mixed. The components of Part B were mixed in a separate container and heated to 90 ° C with continuous stirring until all the solids dissolved. Part B was added to Part A and the resulting mixture was stirred. Stirring was continued for 10 minutes, keeping the temperature at 90 ° C. The resulting gel was cooled to packing temperature and embalmed under an inert gas in aluminum tubes which were suitably coated internally so that they did not react with the product.

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Table I

Anthralin stability

Keep- Similar to ringing voice - -

Surfactant Perature Initial 45 days 215 days 05 - ---- - A. Sodium lauryl sulfate RT 1.05% 1.027% 1.09% 35 ° C 1.05% * 0.96% 45 ° C 1.05% 1.006% 0.718% B. Cationic amine RT 1.05% 0.529% 0.42% ("Richamate 1655") 35 ° C 1.05% 0 0 ° A 45 ° C 1.05% 0 0 10 C. Triethanolamine stearate RT 1, 05% 0.599% 0.084% 35 ° C 1 05% * 0 45 ° C θ'5% 0.00343% 0.058% D. Sodium dioctyl sulfate RT 1.05% 1.045% 1.07% succinate 35 ° C 1.05% * 0.989% 45 ° C 1.05% 0.978% 0.762% E. Sodium Al Chylolefin RT 1.05% 1.080% 1.06% Sulfonate 35 ° C 1.05% * 0.935% 45 ° C 1.05% 1.012 % 0.800% F. Sodium cocyl isothionate RT 1.05% 1.076% ** 1.09% ** 35 ° C 1.05% * 0.958% 45 ° C 1.05% 1.026% 0.833% G. DEA-oleth-3 -phosphate RT 1.05% 1.091% 1.09% 35 ° C 1.05% * 0.989% 45 ° C 1.05% 1.049% 0.777% H. Sodium laureth sulfate RT 1.05% 1.089% 1.094% 35 ° C 1.05% * 0.982% 45 ° C 1.05% 1.046% 0.585% I. Sodium lauryl sulfonate RT 1.05% 1.069% 1.054% 35 ° C 1.05% * 0.928% 45 ° C 1.05% 0.943% 0.791 % J. Sodium octoxynol-3-RT 1.05% 1.378% 0.994% sul phonate 35 ° C 1.05% * 0.936% 45 ° C 1.05% 1.019% 0.785% * Determination not made.

** Although the results after 45 days and 215 days show that 215 35-day samples had greater stability than after 45 days, this is because the analytical method is not sufficiently sensitive to distinguish differences at low concentrations.

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The base gel composition of Example 1 was used with higher surfactant concentrations to detect the upper limits of the range in which the acid-stable, water-soluble, anionic surfactants of the present invention can be used. Although even higher concentrations are possible, skin irritation is a limiting factor. Subsequent Table II shows the results of this study.

Table II

10 Keep- Similar to ringing voice - -

Surfactant perature Initial 45 days 215 days

Sodium lauryl sulfate (5%) RT 1.05% 1.068 1.09% 35 ° C 1.05% * 45 ° C *** 1.05% 0.978% 0.136% Sodium lauryl sulfate (10%) RT 1.05% 1 , 01% 1.03% 35 ° C 1.05% * 0.932% 45 ° C *** 1.05% 0.389% 0.119% *** The loss of activity in these samples is thought to be due to leaks in the tubes due to defects seals and because of high temperature viscosity loss.

* Determination was not made.

Example 2 A satisfactory gel preparation was prepared from the following specification:

Part A

Anthralin (including 15% excess) 1.15 lsoceteth-20 (CTFA) 20.0

Mineral Oil (USP) 16.0

Oleth-2 (CTFA) 6.0

Salicylic Acid 0.2

Ascorbyl palmitate 0.1 BHT 0.1

Propyl gallate 0.01 13

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Part B

PEG-8 (CTFA) 5.0

Sorbitol Solution 2.0

Ascorbic acid 1.0 05 Sodium lauryl sulfate 0.3

Citric acid 0.1

Sodium bisulfite 0.05 EDTA 0.01

Purified Water (USP) q.s. 100.00 10

The gel was prepared by mixing the components of 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 together and heated to 90 ° C under continuous stirring until all the solids were dissolved. Part B was mixed with Part A and stirring was continued for 10 minutes while maintaining the temperature at 90 ° C. The resulting gel was cooled to packing temperature and packaged in aluminum tubes with a non-reactive interior coating under a gas atmosphere.

The preparation of Example 2 was subjected to clinical testing. IN

in all cases the same composition was used except that the anthralin concentration varied. Clinical studies were performed by clinical dermatologists with extensive experience in the evaluation of drugs used in the treatment of psoriasis.

These clinical studies show that the gel compositions of the present invention, containing 0.5 to 2% by weight anthracline, produce particularly good results in patients undergoing short-term therapy of 10 to 20 minutes once daily over a 6-week treatment period. . The patients thus treated had 30 psoriasis varying from local lesions to lesions over a larger portion of their body surface. Patients were assessed at 6 weeks. The results of such assessments are shown in Table III below and clearly show the efficacy of 0.5 to 2% by weight of anthralin-containing gel stabilized in accordance with the present invention.

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Table 111

Anthralin Skin Con- Number (%) rate, time Clinical pa- Sub-treatment (minutes) Added reaction ** patients seeking 05 - - - - -

1% 1st week 20 very good 9 Dr. H

2% 5 weeks 10 body

1% 1st week 20 read only excellent 10 Dr. R

2% 5 weeks 10 sions

iA 0.5% 1st week 20 read only excellent 10 dr. E

1% 5 weeks 10 sions *

0.5% 1st week 20 only read excellent 20 Dr. V / E

1% 5 weeks 10 sions *

0.5% 1st week 20 read only excellent 11 Dr. B

1% 5 weeks 10 sessions * 15 * The application was started on the entire body, but the degree of irritation in uninvolved skin was such that the schedule changed to only lesions, after which there were no problems.

20 ** As used herein, "good" indicates moderate to significant improvement, and "excellent1 * signifies significant to complete improvement. 1 2 3 4 5 6 7 8 9 10 11

It is worth noting here that clinical assessment of the preparation of Example 6 has already begun. Preliminary results 3 show no difference in clinical efficacy in 4 short-term treatment of psoriasis between the preparation of Example 25 (containing water-soluble antioxidant in the aqueous phase) and the preparation of Example 6 (not containing water-soluble antioxidant 7 in the aqueous). phase).

8

It should be emphasized here that the solution to anthralin's stability problem by means of the compositions of the present invention facilitates the use of short-term therapy and is particularly useful in the treatment of psoriasis.

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Example 3

A satisfactory cream preparation was prepared according to the following regulation: £ 1_

05 Part A

Vaseline 200.0

Mineral Oil (USP) 50.0

Steareth-2 (CTFA) 12.5

Steareth-100 (CTFA) 2.5 10 AnthraJin 11.5+ (includes 15% excess)

Salicylic acid 3.5

Propyl gallate 0.05 BHT 0.5 Ascorbyl palmitate 0.5

Part B

Sodium lauryl sulfate 1.50

Ascorbic Acid 2.0 20 PEG-8 (CTFA) 60.0 Dried Sodium Phosphate 0.75 EDTA 0.5

Sorbic Acid 0.5

Xanthan Gum (USP) 3.25 Purified Water (USP) q.s. 500.00

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 together and heated to 70 ° C

with continued stirring until all the solids were dissolved. Part B was mixed in 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.

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©

Example 4

A satisfactory pin preparation to be made on the basis of the following specification: S_ 05 "Syncrowax HGL-C" (Croda) 45.0 "Syncrowax ERL-C" (Croda) 15.0

Vaseline 310.0

Mineral Oil (USP) 120.0

Salicylic acid 0.5 Propyl gallate 0.05 BHT 0.25

Ascorbyl palmitate 0.5

Sodium lauryl sulfate 2.5

Ascorbic Acid 0.25 Anthraline 5.75

Purified Water (USP) 4.0

The sodium sulfate and ascorbic acid were dissolved in the water and added to the remaining components premixed at 80 ° C and then cooled to 75 ° C. The preparation was poured into molds, cooled and solidified and packaged.

Example 5

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

Cetostearylal carbon 280.0

White soft paraffin 500.0

Liquid paraffin 200.0 Sodium lauryl sulfate 5.0

Salicylic acid 2.0

Ascorbyl palmitate 1.0 BHA 0.5 EDTA 0.05 Ascorbic acid 0.05

Anthralin 11.5

Purified Water (USP) 4.00 17

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

05

Examples 6 and 7 show two additional compositions which can be prepared by the method of Example 1 and which are extremely stable under prolonged storage conditions.

Example 6

Part A

Anthralin 11.5 lsoceteth-20 (CTFA) 200.0 Oleth-2 (CTFA) 60.0

Mineral Oil (USP) 165.0

Propyl gallate 0.1 BHT 1.0

Salicylic acid 2.0 Ascorbyl palmitate 1.0

Part B

PEG-8 (CTFA) 50.0

Sorbitol (70% solution) 20.0 EDTA 0.2

Citric acid 5.5

Sodium lauric sulfate 5.0

Purified Water (USP) e.g. 1000.0 1 35 18

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Example 7 2_

Part A

Anthralin 10.5 05 lsoceteth-20 (CTFA) 200.0

Oleth-2 (CTFA) 60.0

Mineral Oil (USP) 160.0

Propyl gallate 0.5 BHT 2.0 Salicylic acid 2.0

Ascorbyl palmitate 1.0

Part B

PEG-8 (CTFA) 50.0 Sorbitol (70% solution) 20.0

Ascorbic Acid 10.0

Sodium Bisulfite 1.0 EDTA 1.0

Sodium Lauryl Sulfate 5.0 Purified Water (USP) q.s. 1000.0

Although the anthrain compositions of the present invention can be formulated and used in the form of cream, gel, ointment or stiff, the cream and gel forms are preferred as they are most easily applied. 1 35

Claims (16)

A pharmaceutically acceptable composition suitable for topical treatment of psoriasis and containing water and anthralin in an amount sufficient to provide an anti-psoriasis action, characterized in that the composition contains an oil-soluble antioxidant and an acid-stable, water-soluble anionic surfactant in an amount sufficient to stabilize the anthralin at pH 5.3 and below, and optionally a water-soluble antioxidant in the aqueous phase. 10 Composition according to claim 1, characterized in that it has a pH of approx. 4 and below. Composition according to claim log2, characterized in that it has a pH of approx. 3 to approx. 4th Composition according to claims 1 to 3, characterized in that it has a pH of approx. 3.2. 5. A composition according to claims 1 to 4, characterized in that it contains anthralin in an amount of approx. 0.5 to approx. 5.0% by weight and the surfactant in an amount of approx. 0.05 to approx. 10% by weight, the weight percentages being based on the weight of the entire composition. Composition according to claim 5, characterized in that it contains anthralin in an amount of approx. 0.1 to approx. 3.0% by weight and the surfactant in an amount of approx. 0.1 to approx. The weight percentages are based on the weight of the entire composition. Composition according to claim 6, characterized in that it contains anthralin in an amount of approx. 0.5 to approx. 2.0% by weight and the surfactant in an amount of approx. 0.3 to approx. The weight percentages are based on the weight of the entire composition. Composition according to claims 1 to 7, characterized in that the surfactant is selected from the group consisting of alkyl sulfates, alkyl sulfonates, all alkyl benzenesulfonates, sulfonyl fatty acids, all alkyl phosphates, dioctylsulfosuccinate, isethionates, alkyl ether sulfates, DK 1630 nonionic anionic surfactants or mixtures thereof. Composition according to claim 8, characterized in that the surfactant is sodium lauryl sulphate. A composition according to claims 1 to 9, characterized in that it is an oil-in-water emulsion and that the emulsion does not contain antioxidant in the aqueous phase. 10 Composition according to claims 1 to 9, characterized in that it is an oil-in-water emulsion or water-in-oil emulsion and that the oil phase contains the oil-soluble antioxidant in an amount sufficient to increase anthralin stability. 15 Composition according to claim 11, characterized in that it is an oil-in-water emulsion. Composition according to claim 11, characterized in that it contains a water-soluble antioxidant in the aqueous phase in an amount sufficient to increase anthralin stability. A composition according to claims 1 to 13, characterized in that it is in solid, cream, gel or ointment form. 25 Process for increasing the stability of anthralin-containing compositions, characterized in that an oil-soluble antioxidant and an acid-stable, water-soluble anionic surfactant are added to such compositions in an amount sufficient to stabilize the anthralin, at pH 5.3 and below, and optionally a water-soluble antioxidant in the aqueous phase. Process according to claim 15, characterized in that a water-soluble antioxidant is added. 35