FR2547725A1 - COMPOSITIONS AND METHOD FOR STABILIZING ANTHRALINE - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION IS A PHARMACEUTICALLY ACCEPTABLE COMPOSITION FOR TOPICAL TREATMENT OF PSORIASIS. THIS COMPOSITION CONTAINS WATER, AN ANTI-OXIDANT SOLUBLE IN OIL AND ANTHRALIN IN SUFFICIENT QUANTITY TO ENSURE ANTI-PSORIASIS ACTION, AN ANIONIC SURFACTANT, ANIONIC, WATER-SOLUBLE, STABLE WITH RESPECT TO ACIDS IN SUFFICIENT AMOUNT TO STABILIZE THE ANTHRALIN.

Description

AT

  COMPOSITIONS AND METHOD FOR STABILIZING ANTHRALINE

  Anthralin, also known as dithranol, is a common component of formulations used for the treatment of psoriasis, a dermatological condition characterized by scaly, silvery, reddish and thick skin patches that may occur either in the form of small lesions or cover with

wide areas of the body.

  Although dermatologists in recent years have considered a number of new approaches to the treatment of psoriasis, the large number of therapeutic agents and regimens used attest to the lack of sustained efficacy of the majority of these. psoriasis has resulted in the use of a wide variety of topical medications, eg tars, tar derivatives, anthralin, mercury compounds, corticosteroids

and keratolytic agents.

  Anthralin is still the treatment of choice for many dermatologists treating psoriasis In general, anthralin is used in most hospitals as a "basic treatment" for hospitalized patients or ambulant patients. For this purpose, anthralin is generally employed in concentrations ranging from 0.05% to 5% by weight relative to the total weight of the composition. Unless otherwise indicated, in the use that will be made hereinafter, "percentage by weight" means the percentage by weight. weight when compared to the total weight of the composition When used correctly, anthralin is extremely effective and its use is accompanied by an absence or

minimum of adverse reactions.

  Although anthralin is generally considered highly effective in the treatment of psoriasis, it nevertheless suffers from three major disadvantages: its instability, skin and clothing stains, and skin irritation. photo-catalyzed oxidation, dimerization and / or chemical decomposition, which lead to the production of 1,8-dihydroxyanthraquinone, 1,8,1 ', 8'-tetrahydroxy-10,10' -dianthranone and other by-products

unidentified.

  Anthralin has been reported to be susceptible to degradation by auto-oxidation (i.e., radical oxidation); its degradation products are considered inactive in the chemotherapy of psoriasis The "irritation" or "erythema due to anthralin" of the skin are estimated as being caused firstly by the initial 10 free radical intermediates of the skin. anthralin The "stains" of the skin produced by anthralin are thought to be attributable to its oxidation products, ie to 1,8-dihydroxyanthraquinone or

to the dimer.

  Many solutions to the problem of stability of the anthra 15 line have been mentioned in the prior art but none of them have been found to be sufficiently satisfactory. As typical solutions of the prior art, mention may be made of those described in US Pat. US 4,203,969 and 4,287,214. US Pat. No. 4,203,969 describes the criticality in the continuous aqueous phase of a cream of using a soluble acidic antioxidant in the water. and water-insoluble or a combination of an acid and a water-soluble and oil-insoluble oxidizer US Pat. No. 4,287,214 discloses that oxidizers such as ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) and other chemicals such as salicylic acid, do not adequately stabilize anthralin, while some alpha- hydroxy do Ponce-Waelsch and Hulse bosch, Arch Derm Forsch 249, 141-152 (1974) describe a creamy Lactacyd vector of p H 2 containing anthralin. Table 1 in this publication shows the lack of stability of such a formation when analyzed. Ultraviolet Spectroscopy and Thin Layer Chromatography Although Caron and Shroot, J Pharm. Sci 70/11, 1205-1207 (1981) describe salicylic acid in a composition containing 0.44% anthralin and also containing cetyl alcohol, sodium lauryl sulphate, paraffin and paraffin oil. paraffin, it is, in fact, not clearly stated that the composition may contain water or is given any appreciation of a possible stabilizing effect of anthralin caused by any of the components of the composition or ranges of concentration for which such components could be employed to obtain a stable composition containing water and

  anthralin at effective anti-psoriatic levels.

  When determining the stability of anthralin by high pressure liquid chromatography (HPLC) using the method described by Caron et al., J Pharm Sci 70/11, -1205 (1981) or that described in US Pat. the Pharmacopeial Forum, May and June 1982, pages 1956-1957, of the United States Pharmacopeial Convention, Inc., instead of the United States Pharmacopeia (USP) method more commonly used to determine this stability, it is found that the methods of The prior art for stabilizing anthralin is not completely satisfactory and generally gives a lower stability than was thought to be achieved. In contrast to the USP method, which is less than satisfactory for determining the stability of anthralin, the HPLC method is selective, sensitive and reproducible for determining the stability of anthralin. Recent publications such as those mentioned above have raised serious questions about indicative of the stability of anthralin in the USP and BP (British Pharmacopeia) methods USP and BP 20 can be expected to rapidly modify their test methods to employ HPLC for

  formulations containing anthralin.

  For most commercial applications, anthralin concentrations greater than 5% by weight are rare, if any, in ambulatory applications since such compositions experience a rapid loss of activity and give rise to Anthralin oxidation When psoriasis plaques affect more than 20% of the body surface, treatment of patients requires hospitalization to avoid irritation of healthy skin due to contact with higher concentration of anthralin formulations. to control the stability of the product while allowing a rapid treatment A major drawback of the formulations at low concentrations, that is to say at about 0-5% or less, is that they do not allow rapid treatment whereas this is possible with formulations containing higher concentrations of anthralin. It is apparent from the prior art that: anthralin is likely to be degraded by auto-oxidation (free radical oxidation) and these degradation products are inactive in psoriasis chemotherapy; b irritation or erythema of the skin due to anthralin is mainly due to the initial, free radical, biologically active intermediates of anthralin; c the tasks on the skin and clothing caused by anthra5 line are due to its oxidation products such as its dimer

  colored or 1,8-dihydro-anthraquinone.

  Prior art assays for stabilizing anthralin against oxidation include conventional methods of prevention such as the use of ascorbic acid, BHA, BHT, EDTA (ethylene diamine tetracetic acid), citric acid, pH adjustment to acidic value, process temperature reduction, peroxide removal and light shielding However, none of these earlier attempts to stabilize the anthralin as described

  previously did not prove adequate.

  It is clear from the foregoing that anthralin degradation products or initial free-radical intermediates cause irritation and task problems that were thought to be now an unavoidable therapy-related incident. At Vanthraline If the stability of anthralin can be improved, the problems of irritation and of tasks indirectly caused by the degradation products of anthralin, should be solved concomitantly Although new formulations of the products based on anthralin has been developed to ensure better patient tolerance, to make these products more suitable and to decrease discolouration, the instability of anthralin in such formulations as manifested by the loss of activity and a change in color from pale yellow to brown and black, has so far remained unresolved. An anthralin-based treatment which gives rise to long-term stability of the anthralin per se and a physical stability of the formulation associated with an attractive appearance and an acceptable color. It is well known that products based on anthralin commercially available will fade

  in a short period of time, which results in a very unpleasant appearance which is unacceptable to the user.

  It has now been found that the desired stabilization of anthralin in compositions suitable for topical application in the treatment of psoriasis can be achieved by adding an anthralin-stabilizing amount of an acid-stable and acid-soluble anionic surfactant. water, in a composition containing water, anthralin and an oil soluble antioxidant and having a pH of 5, 3 or less, such a composition optionally containing, in addition, a water-soluble oxidant In the aqueous phase, it has now been found that the presence of a water-soluble antioxidant in the aqueous phase, contrary to US Pat. No. 4,203,969, is not critical to the stability of the aqueous phase.

  In the formulations according to the present invention, although not critical, the presence of a water-soluble antioxidant may be desirable.

  Preferably, the anthralin employed according to the present invention will be at a concentration of up to about 5.0% by weight. Preferably, from about 0.1% to about 3.0% by weight of anthralin in compositions suitable for topical application

  and more preferably from about 0.5% to 2.0% by weight.

  Of course higher concentrations of anthralin can also be stabilized according to the present invention but

  in the use of such compositions care should be taken to avoid irritation of the healthy skin.

  The anionic surfactant is used in an amount sufficient to stabilize the anthralin Preferably, the anionic surfactant is employed in a content of 0.05% to 10% by weight, preferably 0.1% to 5.0% by weight, and more preferably from 0.3% to 1.0% by weight. Although it is known from the prior art that anthralin is more stable to an acidic pH and that the pH of anthraquinone-containing compositions can be controlled by the use of any dermatologically acceptable acid. It is preferable to employ an acid such as citric or salicylic acid. The compositions containing anthraquinone, a stable acid and a soluble anionic surfactant are

  water, according to the present invention, is a pH of 5.3 or lower.

  It is preferred to use lower pH values, the limiting factor being skin irritation. Preferably, a pH of less than 4.0 is

  used and preferably less than 3.4.

  The subject of the present invention is an anthralin-based product in which the anthralin has a long-lasting stability which is an attractive presentation, which gives rise to a better tolerance for the patient and which hardly gives rise to discolouration. after storage in suitable packaging This product can be successfully used for both mild treatments, long-term ambulatory psoriasis treatments and treatments.

  intensive and short hospitalized patients.

  It can be hypothesised that the present invention is effective because particles or drops of oil dispersed in the

  liquid medium can be loaded in two ways.

  The application of specific ions in the solution in the case of water may be hydronium or hydroxyl ion. Most of the particles or drops of dispersed oils may be present in the solution. in the aqueous medium acquire a negative charge due to adsorption

  preferential hydroxyl ion.

  The second involves charges on the particles or drops of oil when the charges arise from the ionization of the functional groups of surfactants such as phosphates, carboxylates, sulfates and sulfonates, which may be located on the surface of the surface. particle or

  the interface between the oily and aqueous phases.

  Molecules and ions that adsorb to surfaces or interfaces are referred to as surfactants or surfactants. Another expression is "amphiphilic," which suggests that the molecule or ion has some affinity for both polar solvents and non-polar solvents It is the "amphiphilic" nature of the molecules or surfactant ions which causes them to be adsorbed at the interface, which can be

liquid / gas or liquid / liquid.

  The chemical structure of anthralin is as follows:

OH O OH

  hydrophilic face <9 lipophilic face IL H Anthralin is an amphiphilic molecule; in other words, anthralin has some activity for both polar and non-polar groups. The nature of the amphiphilic molecules of ana thralin also causes them to concentrate at the surface or interface where they occur. In such conditions, oxidation initiators such as oxygen, light, hydrogen ions or metal ions will readily attack anthralin.

  and / or accelerate its degradation by self-oxidation to free radicals.

  High concentration of surface or interface anthralin molecules also accelerates dimer formation due to the intramolecular interaction. It can be hypothesised that the present invention leads to the creation of particles, oil drops or micelles whose surface has an essentially anionic charge created either by the sole anionic surfactant or by the combination of the nonionic surfactants with the anionic agent (s) The negatively charged surface is obtained by functional groups such as sulphonates, sulphates, phosphates, carboxylates, etc. of the anionic surfactant (s). Anionic groups of stable surfactants Acids are adsorbed on the surface of the oil / water interface, creating a negatively charged surface on drops, micelles or oil particles Cations in the aqueous phase will be attracted to the negatively charged surface which also repels in the solution the anions such as the hydroxyls once the initial adsorption is complete In addition to these forces el electric, a thermal movement tends to produce an equal distribution of all ions in the solution.

  equilibrium situation and that the system as a whole is electrically neutral.

  The partition ratio of anthralin between water and oil favors the oily phase in a range of approximately 5,000 to 10,000 for 1. Thus, in the case of emulsion-based preparations, oil in the water, for example creams, gels, etc., or emulsified ointments, the anthralin molecules are dissolved in the oily phase and are virtually retained therein. Once the initial adsorption to the surface is complete, that It is occupied by anionic and / or nonionic surfactant molecules. Anthralin molecules will not be concentrated on surfaces and are

  fully protected by the negatively charged surface which prevents the approach of hydroxyl ions or other degradation initiators.

  Such a situation can be described by the scheme of FIG. 1, in which the anthralin molecules are retained in the oily phase and the aa 'line is the surface of the particle, the drop of oil or the micelle. adsorbed which give the surface its negative charge are indicated as potential-determining ions and come from the anionic surfactant (s). In the immediate vicinity of the surface layer is a region of highly bound molecules of the aqueous continuous phase with some positive ions, mainly hydronium ions also closely related to the surface The boundary of this region is given by the line b, b 'The potential on the line b, b' is still negative but there are fewer cations than in the layer of In the region bounded by lines b, b 'and c, there is a negative ion excess. Above line c, c', the ion distribution is uniform and

  electrical neutrality The line d, d 'represents the outer limit.

  The anionic surfactant (s) used as stabilizers for the anthralin-based compositions according to the present invention produce a significant increase in the stability of the anthralin. The anionic surfactant (s) can be considered to protect the It is important that the anionic agent (s), when employed in anthralin-stabilizing amount, provide the benefits of the present invention by providing a negatively charged surface which forms micelles or by surface separation. invention as mentioned above; stabilization can

  to be further improved by using antioxidants which have been used in the past in compositions containing anthralin.

  The acid-stable, water-soluble anionic surfactants used in the present invention are readily available compounds, typically selected from surfactants which are not soaps such as alkyl sulphates, alkylsulfonates, alkylbenzenesulfonates, alpha-sulphonyl fatty acids, alkylphosphates, dioctylsulphosuccinate, isethionates, alkylethersulphates, methylsarcosines and the like. Sodium lauryl sulphate, sodium octoxynol-3-sulphonate, is preferably used. sodium dodecyl benzene sulphonate, sodium lauryl sulphonate, DEA oleth-3-phosphate, sodium dioctyl sulphosuccinate, sodium cocyl isothionate, sodium laureth sulphate and sodium lauryl sarcosinate and the like.

  may also employ mixtures of such surfactants.

  Contrary to the teachings of the prior art, the compositions according to the present invention have a long-term stability when they do not contain a water-soluble antioxidant, although

  it can be added to improve the results.

  It has also been found that the anionic surfactants according to the present invention, when used in combination with oil-soluble antioxidants, remarkably enhance the stability of anthralin as anti-oxidants characteristics. there may be mentioned: ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, BHT, BHA,

  alphatocopherol, phenylalphanaphthylamine and lecithin.

  Water-soluble antioxidants have also been found to be soluble in water

  may be used additionally in the aqueous phase.

  As characteristic anti-oxidants, mention may be made of sodium sulphite, sodium metabisulphite, sodium bisulfite, sodium thiosulfate, sodium formamide dehydoxylate, acetone sodium metabisulfite, ascorbic acid, isoascorbic acid , thioglycerol, thiosorbitol, thiourea, thioglycolic acid and

cysteine hydrochloride.

  The anionic surfactants according to the present invention can also be used with nonionic surfactants such as polyalkoxyethers, polyalkoxy esters, polyalkoxyamides, fatty acid esters of polyalcohols and fatty alcohols, which reduce the potential for skin irritation caused by anions. When desired, the anionic surfactants can also be used in combination with compatible thickening agents such as methylcellulose, tragacanth, alginate

  sodium, Carbopol 934 (CTFA), bentonite, carboxymethylcellulose and Vee-gum (CTFA). As used herein or elsewhere in this specification, the term "CTFA" indicates that the name is

  used in the CTFA nomenclature: Cosmetic Ingredient Directory, 3rd edition, published by the CTFA Association, Inc. Previously, since the low stability of anthralin in dermatological compositions, compositions containing seldom sold, even if they were, at concentrations of anthralin greater than 0.5% by weight. It results from the increased stability of anthralin according to the present invention that it is now possible to offer preparations highly stable both with respect to the concentration of anthralin and the physical stability of the compositions themselves, such compositions being extremely effective in the topical treatment of psoriasis Such compositions may have anthralin concentrations of 0.1% to 5, 0% by weight and more and are useful for the outpatient treatment of psoriasis In addition, the results of stability studies at the conservat High temperature accelerated ion and Arrhenius curves of data resulting from such compositions allowed projections of the stability of both anthralin and compositions for a period exceeding two years under storage conditions at room temperature when stability was tested according to the method of

  HPLC For these studies, retention of less than 90% concentration of anthralin was considered unacceptable.

  To demonstrate the stability of the anthralin products according to the present invention, gelled compositions containing 1% by weight of anthralin (plus a surplus of 0.05% by weight) were prepared as the composition of the present invention. base gel set forth in Example 1 All gel compositions were in accordance with the composition of the base gel and were identical except for the surfactant used. In addition to gel compositions prepared with water-soluble, acid-stable anionic surfactants in accordance with the present invention, the gel compositions were prepared using a cationic amine surfactant, Richamate 1655, a product of Richardson Company, and using triethanolamine stearate, an acid-labile and water-soluble anionic surfactant to demonstrate the lack of stability of anthralin in the gels containing elements of such categories of surfactants Samples have been

  studied under conditions of storage at room temperature, at 30 ° C. and at 45 ° C.

EXAMPLE 1

  Composition of base gel Part A grams of mineral oil (USP) 164 propyl gallate 0.5

BHT 2.0

  Salicylic acid 2.0 oleth-2 (CTFA) 60.0 isoceteth-20 (CTFA) 200.0 ascorbyl palmitate 1.0 anthralin 10.5 Part B

PEG-8 (CTFA) 50.0

sorbitol solution (70%) 20.0

At EDTA 1.0

  sodium bisulfite 1.0 Ascorbic acid 10.0 surfactant 5.0 purified water (USP) qs 1000.0 The compositions are prepared by mixing the constituents of Part A and heating to a temperature of 90 ° C. The stirring is continued until all the solids are mixed. The components of Part B are mixed in a separate vessel and heated at 90 ° C., with continuous stirring, until all the solids have dissolved. B is added to Part A and the resulting mixture is stirred. Stirring is continued for 10 minutes, the temperature being maintained at 90 ° C. The resulting gel is cooled to the conditioning temperature and conditioned under inert gas in test tubes. aluminum suitably lined internally

  so that they do not react with the product.

TABLE I

  Stability of anthralin Temperature Composition surfactant A laurylsodium sulfate - cationic amine (Richamate 1655) C storage triethanolamine stearate RT

350 C 45 C

RT

 C 45 C

RT

 C 45 C

Initial

  1.05% 1.05% 1.05% 1.05% 1.05% 1.05% 1.05% 1.05% 1.05%

Equivalent (%) 45 to 215 days

1,027 1,09

0.96

1.006 0.718

0.529 o 0.42

0.599 0.084

O

0.0034 0.058

  D dioctyl sodium sulfosuccinate E alkylsodium olefin sulfonate RT

 C 450 C RT 35 C 45 C

  1.05% 1.05% 1.05% 1.05% 1.05% 1.05%

1,045 0,978 1,080 1,012

1.07

0.989 0.762 1.06 0.935

0.800 F cocyl isothionate sodium

RT 35 C

 C RT 35 C 45 C

  1.05% 1.05% 1.05% 1.05% 1.05% 1.05%

1.076 * 1.1 **

0,958

1,026 0.833 1,091 1.09

0.989

1,049 0,777

  G oleth-3 phosphate DEA H lauryl sulphate sodium I lauryl sulphonate sodium

RT 35 C 450 C

RT 35 C 45 C RT

 C 45 C

1.05% 1.05% 1.05% 1.05%

1.05% 1.05% 1.05% 1.05% 1.05%

1,089 1,046

1,094 0.982 0.585

1,069 1,054

0.982

0.943 0.781 1.378 0.994

0.936

1,019 0,785

  Sodium octoxynol-3-sulfonate * the determination was not made; ** Although the results for 45 days and 215 days indicate that the samples at 215 days have a higher stability than at 45 days, this is attributed to the fact that the analytical method is not sensitive enough to distinguish

  differences at such low concentrations.

  The base gel composition of Example 1 is employed at higher surfactant concentrations to demonstrate the upper limits of the range for which the water-soluble, acid-stable anionic surfactants of the present invention are present. Although even higher concentrations can be used, skin irritation is a factor in

  limitation The following table II illustrates the results of this study.

TABLE II

  Composition Temperature equivalent to storage surfactant Initial 45 days 215 days i 5 sodium lauryl sulfate RT 1.05% 1.068% 1.09%

(5%) 35 C 1.05% * 0.136%

  450 C 1.05% O e 978% 09136% Sodium lauryl sulfate RT 1.05% 1.01% 1.03% (10%) 35 C 1.05% * 0.932%

 C 1.05% 0.389% 0.119%

  *** the loss of activity in these samples appears to be due to leaks in the tubes due to faulty joints and high viscosity losses at high temperatures;

  * the determination has not been made.

35

EXAMPLE 2

  A satisfactory gel composition consisting of: Part A Anthralin grams (including a 15% excess) 1.15 isoceteth-20 (CTFA) 20.0 mineral oil (USP) 16.0 oleth-2 (CTFA) 6.0 Salicylic acid 0.2 ascorbyl palmitate 0.1 is prepared from

BHT 0.1

propyl gallate 0.01 Part B

PEG-8 (CTFA) 5.0

  sorbitol solution (70%) 2.0 ascorbic acid 1.0 sodium lauryl sulfate 0.3 citric acid 0.1 sodium bisulfite 0.05

EDTA 0.01

  purified water (USP) qs 100.0 The gel is prepared by mixing the components of Part A and heating to a temperature of 90 ° C. Stirring is continued until all of the solids are mixed in a separate vessel. the constituents of part B are mixed and heated to 90 C, under

  stirring continues until all the solids are dissolved.

  Part B is mixed in Part A and stirring is continued for 10 minutes while maintaining the temperature of 90 ° C. The resulting gel is cooled to the conditioning temperature and packaged in aluminum tubes having a coating. internal no

  reagent in an inert gas atmosphere.

  The composition of Example 2 is subjected to a clinical evaluation. In all cases, the same composition is used, except

  that the concentration of anthralin is changed Clinical studies are performed by dermatologists with extensive experience evaluating drugs used in the treatment of psoriasis.

  These clinical studies demonstrate that the gel compositions according to the present invention, containing 0.5 to 2% by weight of anthranil, provide good results on patients who are administered by 30 daily doses in short-term therapy of 10 at 20 minutes, for a six-week treatment period Patients treated with psoriasis from localized binding to most of their body connections Patients are assessed after six weeks The results of these 35 evaluations are shown in Table III below and clearly demonstrate the efficacy of a gel containing 0.5 to

  2% by weight stabilized according to the present invention.

TABLE III

  Duration Treatment of Anthralin Contact with Number (%) Skin Applied Physician Response (mn) to Clinical ** Patients 1% Lsw 20 All Good 9 Dr H 2% 5 Weeks 10 of Body 1% 1 Week 20 only excellent 10 Dr. R 2% 5 weeks 10 lesions 0.5% lr sem 20 only excellent 10 Dr E 1% 5 weeks 10 lesions * 0.5% lr sem 20 only excellent 20 Dr. V / E 1% 5 weeks Lesions * 0.5% 1st week 20 only excellent 11 Dr. B 1% 5 weeks 10 lesions * * whole body application started but the degree of irritation of the uninvolved skin was that the protocol was amended so that only the lesions

  problem was found later.

  ** in this example, "good" indicates a moderate improvement to

  significant and "excellent" indicates an improvement from significant to total.

  It should be noted that the clinical evaluation of the composition of Example 6 has been initiated. Preliminary results indicate no difference as regards the clinical efficacy of the short-term treatment of psoriasis between the composition of the example 2 (containing a water-soluble anti-oxidant in aqueous phase) and the composition of Example 6 (not containing a water-soluble antioxidant)

in aqueous phase).

  It should be noted that solving the problem of the stability of anthralin by the compositions of the present invention facilitates

  use of short-term therapy and is extremely beneficial in the treatment of psoriasis.

EXAMPLE 3

  A suitable cream preparation was prepared from the following formula: Part A grams petrolatum 200.0 mineral oil (USP) o 50.0 steareth-2 (CTFA) 12.5 steareth-100 (CTFA) 2.5 anthralin 11.5 + (including an excess of 15%) salicylic acid 3.5 propyl gallate 0.05

BHT 0.5

  ascorbyl palmitate 0.5 Part B Sodium Lauryl Sulfate 1.50 Ascorbic Ascorbic Acid 2.0

PEG-8 (CTFA) 60.0

dried sodium phosphate 0.75

EDTA 0.5

  sorbic acid 0.5 xanthic gum (USP) 3.25 purified water (USP) - qs 500.00 The cream is prepared by mixing the constituents of part A and heating to a temperature of 70 ° C. Stirring is continued until All the solids are mixed In an independent container, the constituents of Part B are mixed and heated at 70 ° C. with continuous stirring, until all the solids are dissolved. Part B is mixed in the mixture. part A and stirring continues while maintaining the mixture at a temperature of 70 C,

  until both parts A and B are thoroughly mixed.

  The resulting cream is cooled to the conditioning temperature and packaged.

EXAMPLE 4

  A suitable stick composition is prepared from the following components: grams Syncrowax HGL-C (Croda) 45.0 Syncrowax ERL-C (Croda) 15.0 Petrolatum 310.0 mineral oil (USP) 120.0 salicylic acid 0, 5 propyl gallate 0.05

BHT 0.25

  ascorbyl palmitate 0.5 sodium lauryl sulphate 2.5 ascorbic acid 0.25 anthralin 5.75 purified water (USP) 4.0 Sodium lauryl sulphate and ascorbic acid are dissolved in water and added to the rest components which are premixed at C and then cooled to 75 ° C. The composition is then poured into

  mussels and allowed to cool and take in mass, then condition.

EXAMPLE 5

  A suitable balm composition is prepared from the following formula: grams cetostearyl alcohol 280.0 white soft paraffin 500.0 liquid paraffin 200.0 sodium lauryl sulphate 5.0 salicylic acid 2.0 ascorbyl palmitate D 1, 0

BHA 0.5

EDTA 0.05

  ascorbic acid 0.05 anthralin 11.5 purified water (USP) 4.00 All constituents with the exception of anthralin are vigorously mixed in water at 75 C until bubble formation is interrupted. anthralin is then added and stirring is continued for an additional 30 minutes. The composition is

  cooled to 55 C and conditioned.

  Examples 6 and 7 describe two other gel compositions that can be prepared by the method described in Example 1 and are extremely stable under long-term storage conditions. EXAMPLE 6

15 20 25 30

  Part A anthralin. isoceteth-20 (CTFA). oleth-2 (CTFA). mineral oil (USP). propyl gallate Bl T. salicylic acid. ascorbyl palmitate Part B PEG-8 (CTFA). sorbitol (70% solution). EDTA citric acid. sodium lauryl sulphate with purified water (USP) q s. EXAMPLE 7 Part A anthralin isoceteth-20 (CTFA) oleth-2 (CTFA) mineral oil (USP). propyl gallate BHT salicylic acid. ascorbyl palmitate grams 11.5

, 0 60.0 165.0 0.1 1.0 2.0 1.0

, 0 20.0 0.2 5.5 5.0 1000.0

grams

, 5,200.0 60.0 160.0

0.5 2.0 2.0 1.0

2 47725

Part B

PEG-8 (CTFA) 50.0

  Sorbitol (70% solution) 20.0 Ascorbic acid 10.0 sodium bisulfite 1.0

At EDTA 1.0

  With Sodium Lauryl Sulfate 5.0 With Purified Water (USP) qs 1000.0 Although the anthralin compositions of the present invention are capable of being formulated and used as a cream, gel, balm or stick, it is preferred for each applications the forms of

gel or cream.

  Naturally, the present invention is not limited to the embodiments described and shown, but it is capable of many variants accessible to those skilled in the art without it being possible to

  departs from the spirit of the invention.

Claims (27)

  1. A pharmaceutically acceptable composition for topical treatment of psoriasis and containing water, an oil-soluble antioxidant and anthralin in an amount sufficient to provide an anti-psoriatic action, the improvement comprising introducing into said composition an acid-stable, water-soluble anionic surfactant in an amount of   sufficient to stabilize anthralin.   2. The composition according to claim 1, characterized in that the surfactant is stable at a pH of less than or equal to about 5.3.   3. The composition of claim 1, characterized in that the surfactant is stable at a pH less than or equal to about 4. The composition according to claim 1, characterized in that   that the surfactant is stable at a pH between 3 and 4.   5. The composition according to claim 1, characterized in that   that the surfactant is stable at a pH of about 3.2.   6. The composition according to any one of claims 2, 3, 4 or 5, further comprising anthralin in a proportion of about   From about 0.5% to about 5% by weight and said surfactant being present in an amount of about 0.05% to about 10% by weight;   weight being expressed relative to the total weight of the composition.   7. The composition according to claim 2, 3, 4 or 5, characterized in that it contains anthralin in a proportion of about 0.1% to about 3.0% by weight and said surfactant active in a proportion of about 0.1% to about 5.0% by weight, this weight percentage   being expressed relative to the total weight of the composition.   8. The composition according to claim 2, 3, 4 or 5, characterized in that it contains anthralin in a proportion of about 0.5% to about 2.0% by weight and said surfactant active in a proportion of the order of 0.3% to about 1.0% by weight, this weight percentage   being expressed relative to the total weight of the composition.   9. The composition according to any one of claims 2, 3, 4 or 5, characterized in that it contains from about 0.1% to about   3.0% by weight of anthralin and in that the surfactant is selected from the group consisting of alkyl sulphates, alkyl sulphonates, alkyl benzenesulfonates, sulphonylated fatty acids, alkyl phosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulphates, methyl sarcosines and unsaponified anionic surfactants of the same type, said weight percentage being expressed by weight total of the composition.   The composition of any one of claims 2, 3,   4 or 5, characterized in that it contains from about 0.5% to about 2.0% by weight of anthralin and that the surfactant is selected from the group consisting of alkyl sulfates alkyl sulphonates, alkyl benzene sulphonates, sulphonyl fatty acids, alkyl phosphates, dioctyl sulphosuccinate, isethionates, alkyl ether sulphates, methyl sarcosines and unsaponified anionic surfactants of the same type, said weight percentage being expressed in relation to weight total of the composition.   11. The composition according to any one of claims 2, 3, 4 or 5, characterized in that it contains from about 0.1% to about   , 0% by weight of anthralin and that the surfactant is in a proportion of about 0.05% to 10.0% by weight and is selected from the group consisting of alkyl sulfates, sulfonates alkyl, alkyl benzene sulphonates, sulphonyl fatty acids, alkyl phosphates, dioctyl sulphosuccinate, isethionates, alkyl ether sulphates, methyl sarcosines and unsaponified anionic surfactants of the same type, said weight percentage being expressed by relative to the total weight of the composition   12. The composition according to any one of claims 2, 3,   4 or 5, characterized in that it contains from about 0.1% to about 3.0% by weight of anthralin and that the surfactant is in a proportion of about 0.1% to 5.0% by weight and is selected from the group consisting of alkyl sulfates, alkyl sulfonates, alkyl benzenesulfonates, sulfonyl fatty acids, alkyl phosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulfates unsaponified anionic surfactants, methylsarcosines and surfactants of the same type,   weight being expressed relative to the total weight of the composition.   13. The composition according to any one of claims 2, 3,   4 or 5, characterized in that it contains from about 0.5% to about 2.0% by weight of anthralin and that the surfactant is in a proportion of about 0.3 % to 1.0% by weight and is selected from the group consisting of alkyl sulfates, alkyl sulfonates, alkyl benzenesulfonates, sulfonyl fatty acids, alkyl phosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulfonates, methylsarcosines and unsaponified anionic surfactants of the same type,   weighting being expressed with respect to the total weight of the composition.   14. The composition according to claim 11, characterized in that   said surfactant is sodium lauryl sulphate.   The composition according to claim 1, characterized in that said composition is an oil-in-water emulsion and what   said emulsion does not contain an antioxidant in the aqueous phase.   16. The composition according to any one of claims 1 to   , characterized in that it is in solid form.   The composition according to any one of claims 1 to   , characterized in that it is in the form of cream.   18. The composition according to any one of claims 1 to   , characterized in that it is in gel form.   19. The composition according to any one of claims 1 to 15, characterized in that it is in the form of balm.   20. The composition according to claim 1, characterized in that the composition is an oil-in-water or water-in-oil emulsion and that the oily phase contains a proportion of antioxidant   soluble in oil sufficient to increase the stability of thrombinus.   21. The composition according to claim 20, characterized in that   that said composition is a water-in-oil emulsion.   22. The composition according to claim 20, characterized in that the composition contains an amount of hydrosoluble antioxidant in the aqueous phase sufficient to increase the stability of the anthralin. 23. The composition according to claim 1, characterized in that the surfactant is a mixture of two or more agents.   suitable anionic surfactants.   A method for increasing the stability of anthralin-containing compositions comprising adding to said composition a   amount of a water-soluble, acid-stable anionic surfactant sufficient to stabilize said anthralin.   25. The method of claim 24 which further comprises adjusting the pH of said compositions to a pH of 5.3 or lower.   26. The process according to claim 24, which further comprises adding to said compositions an oil-soluble antioxidant.   when the emulsion contains an oily phase.   27. The method of claim 26 which comprises adding a water-soluble antioxidant to said composition.