LU85411A1 - COMPOSITIONS AND METHOD FOR STABILIZING ANTHRALIN - Google Patents

Description

i

DESCRIPTIVE MEMORY

FILED IN SUPPORT OF A REQUEST • H

OF

PATENT

FORMED BY

BRISTOL-MYERS COMPANY, for

Compositions and method for stabilizing anthralin.

h • n Anthralin, also known as dithranol, has been a common active ingredient in compositions intended for the percutaneous treatment of psoriasis, which is a dermatosis characterized by bright, reddened, thickened scaly patches of the skin which may appear in the form of small, scattered lesions or CD.YD.F - 1 - WW-0031 can cover large areas of the body.

In recent years "dermatologists have followed many new approaches to the treatment of psoriasis, but the very large number of therapeutic agents and regimens applied attest to the lack of long-term efficacy of most of them. The treatment of psoriasis has been tried using many topical medications such as tars, derivatives thereof, anthralin, mercury compounds, corticosteroids and keratolytics.

Anthralin remains the agent of choice for the treatment of psoriasis in the opinion of many dermatologists. In general, anthralin is used for the main treatment in most clinics and hospitals. To this end, anthralin is generally taken in concentrations of 0.05% to 5% by weight, based on the total weight of the composition. Unless otherwise indicated, for the purposes of the invention, the percentage by weight means the percentage by weight relative to the total weight of the composition. Properly administered, anthralin is extremely effective and causes little or no side reactions.

Although anthralin is recognized as highly effective for the treatment of psoriasis, it has three major drawbacks, namely instability, the appearance of spots on the skin and clothing, and skin irritation. Anthralin is subject to oxidation, dimerization and / or light-catalyzed chemical decomposition giving rise to 1,8-dihydroxyanthraquinone and 1,8,1 ', 8'-tetrahydroxy-10, 10'-dianthrone, as well as other unidentified side products.

Anthralin has been described as being susceptible to degradation by auto-oxidation (oxidation by free radicals). These degradation products appear inert for the chemotherapy of psoriasis. "Irritation" or "skin erythema from anthralin" is believed to be caused primarily by the early intermediaries of free radical oxidation of anthralin. The formation of spots on the skin by anthralin is believed to be due to its oxidation products, namely 1,8-dihydroxyanthraquinone or the dimer.

Numerous solutions have already been proposed to remedy the instability of anthralin, but none has been sufficiently effective. Examples of the known solutions proposed are given in U.S. Patents 4,203,969 and 4,287,214. According to the E.U.A. 4,203,969, it is critical to use an acidic antioxidant soluble in water and insoluble in oil or a combination of an acid and an antioxidant soluble in water and insoluble in oil in continuous aqueous phase of a cream. The E.U.A. 4,287,214 specifies that antioxidants, such as ascorbic acid, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), and other chemical agents such as salicylic acid, do not stabilize anthralin in satisfactorily, whereas; some alpha hydroxy acids do this. Ponce-Waelsch and ^ Hulsebosch, describe in Arch. Derm. Forsch., 249 141-152 (1974), Lactacyd pH 2 (D which is a vehicle

T

for cream containing anthralin. Table I of the article shows the absence of stability of such a composition during the examination by UV spectroscopy and thin layer chromatography. Caron and Shroot, J. Pharm. Sci., 70:11, 1205-1207, (1981) mention salicylic acid in a 0.44% anthralin composition which also contains cetyl alcohol, CD.YD.F - 3 - WW-0031 * sodium lauryl sulfate, paraffin and petrolatum, but there is no clear indication that the composition contains any amount of water and no assessment is given on the stabilization of the anthralin by any of the components of the composition, nor over the concentration ranges over which these components could be used to form a stable aqueous anthralin composition effective against psoriasis.

The determination of the stability of anthralin by high pressure liquid chromatography (HPLC) according to the method described by Caron et al., J. Pharm. Sci, 70:11, 1205 (1981) or that described in Pharmacopeial Forum, May-June 1982, pages 1956-1957; The United States Pharmacopeial Convention, Inc., rather than the more common method of the United States Pharmacopoeia (USP), shows that the known methods for stabilizing anthralin are not perfectly satisfactory, the stability conferred being lower than that assumed so far. Unlike the USP method, which leaves something to be desired for determining the stability of anthralin, the HPLC method is a selective, sensitive and reproducible method for determining the stability of anthralin. Recent publications, such as those referred to, have seriously questioned the fact that the USP and BP (British Pharmacopoeia) methods indicate the stability of anthralin. It is expected that the USP and BP methods will soon be replaced by an HPLC assay method for all compositions containing 11anthralin.

For most applications, anthralin concentrations greater than 0.5% by weight are not or hardly available on the market for treatment at the dispensary, CD.YD.F - 4 - WW-0031, because these compositions undergo a rapid loss of activity and oxidation of anthralin. When psoriasis reaches more than 20% of the surface of the body, treatment in a hospital environment is necessary to avoid irritation of normal skin in contact with anthralin compositions in higher concentrations and to control the stability of the product providing treatment i. fast. A major drawback of compositions at low concentrations, that is to say about 0.5% if not less, is that they do not lend themselves to the rapid treatment which is possible with compositions having higher concentrations of anthralin.

The known state of the art reveals that: a. anthralin is susceptible to degradation by auto-oxidation (oxidation by free radicals) and that its degradation products are inert for the chemotherapy of psoriasis; b. skin irritation or erythema from anthralin is most often induced by the first free, biologically active free radical intermediates of anthralin; vs. the stains due to anthralin on the skin and clothing are due to its oxidation product such as the colored dimer or 1,8-dihydroxyanthraquinone.

The stabilization of anthralin against oxidation has been tried by conventional preventive means such as the use of ascorbic acid, BHA, BHT, ethylenediamine tetraacetic acid (EDTA), citric acid, adjusting the pH to a value in the acid range, lowering the preparation temperature, removing peroxides and protecting against light. However, no CD.YD.P - 5 - WW-0031 "of these known attempts to stabilize the anthra-line appeared to be adequate.

It thus appears clearly that the degradation products of anthanthine or its first radical intermediates are at the origin of the irritation and of the spots envisaged until now as a ".

inevitable incident with anthralin treatment. If the stability of anthralin could be improved, the irritation and the appearance of spots indirectly induced by the degradation products of anthralin would be eliminated.

Although new anthralin compositions have been developed for better tolerance, greater convenience and lower coloring, the lack of stability of anthralin in these compositions, resulting in the loss of activity and the shift from light yellow to brown and black, remained an unresolved difficulty. It has not yet been possible to prepare an anthralin composition ensuring the long-term stability of anthralin, having physical stability and having a pleasant appearance and an acceptable coloration. It is indeed well known that the anthralin compositions sold change color in a short time and take on a highly unpleasant and unacceptable appearance for the consumer.

The Applicant has now discovered that the desired stabilization of anthralin in compositions for topical use for the treatment of psoriasis can be ensured by adding, in a quantity capable of stabilizing anthralin, of an anionic surfactant which is acid stable and soluble. in water to a composition containing water, anthralin and an oil-soluble antioxidant and having a pH of 5.3 or less, the composition optionally containing, CD.YD.F - 6 - WW -0031 "in addition, in the aqueous phase, a water-soluble antioxidant. The presence of a water-soluble antioxidant in the aqueous phase appeared, contrary to the indications of the E.U.A. 4,203,969, as not critical for the long-term stability of anthralin in the compositions according to the invention. Although not critical, the presence of a water-soluble antioxidant may be desirable.

> ·. Preferably, anthralin is used in a concentration of up to about 5.0% by weight according to the invention. Anthralin can be used in compositions for topical use more advantageously in a concentration of from about 0.1% to about 3.0% and especially from about 0.5% to 2.0% by weight.

It is obvious that anthralin in higher concentrations can also be stabilized according to the invention, but care must be taken in the use of these compositions to avoid irritation of normal skin.

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

It is known that anthralin is more stable at an acidic pH and that the pH of compositions containing anthralin can be adjusted by means of any dermatologically acceptable acid, but it is preferable to use an acid such as citric or salicylic acid. The composition pH containing anthralin and an acid-stable, water-soluble anionic surfactant according to the present invention is 5.3 if not less. It is preferable to choose lower pH values, CD.YD.F - 7 - WW-0031 * limiting factor being skin irritation. Preferably, the pH is less than 4 and more advantageously it is less than 3.4.

The subject of the invention is an anthralin composition which ensures the long-term stability of anthralin, has a good appearance, is better tolerated by patients and does not undergo substantially any discoloration when stored when it is * packed properly. The composition makes it possible to successfully treat psoriasis in the patient treated long term in the dispensary with low concentrations and in the patient treated in the hospital short term with high concentrations.

The hypothesis put forward is that the invention gives good results because the particles or droplets of oil dispersed in a liquid medium can be charged in one of two ways. The first is the reactive adsorption of particular ions that are present in the solution. In the case of water, it can be the hydronium ion or the hydroxyl ion. Most of the particles or droplets of oil dispersed in an aqueous medium take a negative charge by preferential adsorption of the hydroxyl ion. The second way involves, on the particles or droplets of oil, charges which result from the ionization of functional radicals of surfactants, such as phosphates, carboxy-lates, sulfates and sulfonates, which can be found in the surface of the particles or at the interface between the oily phase and the aqueous phase.

The molecules and ions that are adsorbed on a surface or at an interface are called surfactants. A different term is that of amphipathic agent which suggests that the molecule or ion has a certain affinity for polar solvents and CD.YD.P - 8 - WW-0031 also for non-polar solvents. It is the amphipathic nature of the surfactant molecules and ions that causes them to adsorb at the interface, which can be a liquid-gas or liquid-liquid limit.

The chemical structure of anthralin is as follows:

· *. OH OH OH

L _, \ hydrophilic side 11 ^ lipophilic side

H H

Anthralin is an amphipathic molecule, that is to say that it has a certain affinity for polar radicals and also for non-polar radicals. The amphipathic nature of anthralin molecules also makes them concentrate on the surface or interface where they are easy to destroy. Under these conditions, oxidation initiators such as oxygen, light, hydrogen ions and metal ions readily attack anthralin and / or accelerate its degradation by free radical self-oxidation. A high surface or interfacial concentration of the anthralin molecules also accelerates the formation of the dimer through intramolecular interactions.

The hypothesis proposed is that, in the case of the invention, particles, droplets or micelles of oil are formed, the surface of which carries a mainly anionic charge provided by the anionic surfactant alone or by the combination of one or more nonionic surfactants with one or more anionic surfactants. The negatively charged surface consists of functional radicals, for example sulfo-CD.YD.F - 9 - WW-0031 nates, sulfates, phosphates, carboxylates, etc. of the anionic surfactant (s). The anionic radicals of acid-stable surfactants are adsorbed at the oil-water interface and thus constitute a surface with a negative charge on the droplet, particle or micelle of oil. The cations of the aqueous phase are attracted to the negatively charged surface which w ^ repels, moreover, any anions of the solution, such as hydroxyl ions, when the initial adsorption is completed. Apart from these electrical forces, the thermal movement tends to cause a uniform distribution of all the ions in the solution. As a result, a balance is struck and the system is electrically neutral overall.

The coefficient of partition of anthralin between oil and water is in favor of the oily phase in a ratio of about 5,000 to 10,000: 1. Consequently, in the case of preparations based on an oil-in-water emulsion, such as creams, gels, etc., or emulsion ointments, the anthralin molecules are dissolved and are virtually retained in the oily phase. . When the initial adsorption to the surface is complete, the surface is occupied by anionic and / or nonionic surfactant molecules. The anthralin molecules are not concentrated on the surface and are completely protected by the negatively charged surface which repels hydroxyl ions and other degradation initiators.

Such a situation can be explained using the diagram in FIG. 1, where the anthralin molecules are retained in the oily phase and the line a, a 'represents the surface of the particle, droplet or micelle of oil. The adsorbed ions which give its negative charge to the surface are called CD.YD.F - 10 - WW-0031 ions determining the potential and come from the anionic surfactant (s). In the immediate vicinity of this surface layer, there is a region of closely attracted molecules of the continuous aqueous phase with some positive ions, mainly hydronium ions, which are also firmly attracted to the surface. The boundary of this region is indicated by the line ^ „b, b '. The potential at line b, b 'is still negative, but there are fewer cations than on the fixed negative layer. In the region delimited by lines b, b 'and c, c', there is an excess of negative ions. Beyond the line c, c ', the distribution of the ions is uniform and the electrical neutrality is established. Line d, d is the outer limit.

The anionic surfactant (s) used as stabilizers for the anthralin compositions of the invention greatly increase the stability of anthralin. The hypothesis is that the anionic surfactant (s) protect the anthralin molecules against attack by establishing a surface with negative charge which forms mi ones or by separation of the surfaces. Although the anionic surfactant (s), when used in an amount suitable for stabilizing anthralin, provide the advantages specific to the invention, as indicated above, stabilization can be further improved with the aid of antioxidants which have already been used in compositions containing anthralin.

v The acid-stable and water-soluble anionic surfactants used according to the invention are easy to obtain compounds, normally chosen from non-soapy surfactants, such as alkyl sulfates, alkyl sulfonates, alkylbenzene sulfonates, alpha-sulfonylated fatty acids, alkylphos-phates, dioctylsulfosuccinates, isethionates, alkyl- CD.YD.F - 11 - WW-0031 ethersulfates, methylsarcosinates, etc. Preference is given to sodium lauryl sulfate, sodium octoxynol-3-sulfonate, sodium dodecylbenzenesulfonate, sodium lauryl sulfonate, DEA oleth-3-phosphate, sodium dioctylsulfosuccinate, sodium cocylisethionate, sodium laurethsulfate, sodium laurylsarcosinate, etc. Mixtures of these surfactants are also suitable.

Contrary to indications of the known state: of the art, the compositions of the invention are stable for the long term in the absence of water-soluble antioxidants, although these can be added for improvement results.

The Applicant has further discovered that the anionic surfactants of the invention, used in conjunction with oil-soluble antioxidants, greatly increase the stability of anthralin. Examples of these antioxidants are ascor-byle palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, BHT, BHA, alpha-tocopherol, phenyl-alpha-naphthylamine and lecithin. It has also been discovered that water-soluble antioxidants can be used in addition in the aqueous phase. Typical examples of these antioxidants are sodium sulfite, sodium metabi-sulfite, sodium bisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, sodium metabisulfite-acetone, ascorbic acid, isoascorbic acid, thioglycerol, thiosorbitol, thiourea, thioglycolic acid and cysteine hydrochloride.

The anionic surfactants of the invention can also be used with nonionic surfactants, such as polyalkoxy ethers, polyalkoxy-esters, polyalkoxyamides, esters of fatty acids CD.YD.F - 12 - WW-0031 of polyhydric alcohols and fatty alcohols, which reduce the skin irritation caused by anions. When desired, anionic surfactants can also be used in conjunction with compatible thickeners such as methylcellulose, gum tragacanth, sodium alginate, Carbopol 934 (CTFA), bentonite, and carboxymethylcellulose. Vee-gum (CTFA). For the purposes of the invention, the abbreviation CTFA indicates that the name used belongs to the nomenclature of the CTFA Cosmetic Ingredient Directory, 3rd edition, published by the CTFA Association, Inc.

Previously, due to the poor stability of anthralin in dermatological compositions, it rarely, if ever, happened to sell compositions having an anthralin concentration of more than 0.5% by weight. Due to the better stability of the anthralin provided by the invention, it is now possible to obtain very stable compositions with regard to the anthralin concentration and the physical stability of the compositions themselves, which are extremely effective for topical treatment of psoriasis. These compositions can have anthralin contents of 0.1% to 5.0% by weight or more and are useful for the treatment of psoriasis in non-hospitalized patients. In addition, the results of accelerated studies on the stability at high temperature storage and the Arrhenius diagrams established using these results for these compositions make it possible to predict for anthralin and the compositions a stability of more than two years at room temperature, stability being evaluated by HPLC. For these studies, a persistence of less than 90% of the anthralin titer is considered unacceptable.

To demonstrate the stability of the CD.YD.F - 13 - WW-0031 * anthralin compositions of the invention, gels were prepared containing 1% by weight of anthralin (plus 0.05% by weight of surtitle) in accordance with the constitution of the base gel given below in Example 1. All of these gels conform to the composition of the base gel and are identical, except as regards the surfactant. In addition to the gels prepared with the acid-soluble and water-soluble anionic surfactants v * of the invention, gels were prepared using Richamate 1655, i which is a cationic surfactant amine produced by the

Société Richardson Company, and using triethanolamine stearate, which is an anionic acid-soluble and water-soluble surfactant, to show the lack of stability of anthralin in gels containing surfactants of these particular classes . The samples were examined after storage at room temperature, 35 ° C and 45 ° C.

EXAMPLE 1, -

Basic gel composition.

Part A £

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

Ascorbyle palmitate 1.0

Anthralin 10.5k

Part B

PEG-8 (CTFA) 50.0

Sorbitol 70% solution 20.0 EDTA 1.0

Sodium bisulfite 1.0

Ascorbic acid 10.0

Surfactant 5.0 CD.YD.F - 14 - WW-0031

Purified water (USP) to make 1000.0

The compositions are prepared by mixing the components of Part A and heating them to 90 ° C. Stirring is continued until all the solids are mixed. The components of part 4 B are mixed in a separate container and heated to 90 ° C

continuing stirring until all solids are dissolved. Part B is added to part A and the resulting mixture is stirred. Stirring is continued for 10 minutes while maintaining the temperature at 90 ° C. The gel is cooled to packaging temperature and packaged, under inert gas, in aluminum tubes suitably coated on the inside so that it does not react with the product.

TABLE I

Anthralin stability

Composition Temperature Ini- Equivalent to tial 45 215 surfactant storage days days A. Laurylsulfate TA 1.05% 1.027% 1.09% sodium 35 ° C 1.05% * 0.96% 45 eC 1.05% 1.006 % 0.718% B. Cationic amine TA 1.05% 0.529% 0.42% s. (Richamate 1655) 35 ° C 1.05% 0% 0% 45 ° C 1.05% 0% 0% C. MT stearate 1.05% 0.599% 0.084% triethanolamine 35 ° C 1.05% * 0% 45 ° C 1.05% 0.343% 0.058% D. Dioctylsulfosuc- TA 1.05% 1.045% 1.07% sodium cinate 35 ° C 1.05% * 0.989% 45 ° C 1.05% 0.978% 0.762% CD.YD.F - 15 - WW-0031 E. Alkylolefin TA 1.05% 1.080% 1.06% sulfonate 35 ° C 1.05% * 0.935% sodium 45 ° C 1.05% 1.012% 0.800 % F. Cocylisethionate TA 1.05% 1.076% 1.09% ** sodium 35eC 1.05% * 0.958% 45eC 1.05% 1.026% 0.833% G. Oleth-3-phosphate TA 1.05% 1.091% 1.09% - ”. DEA 35eC 1.05% * 0.989% α 45 ° C 1.05% 1.049% 0.777% H. Laurethsulfate TA 1.05% 1.089% 1.0 94% sodium 35 ° C 1.05% * 0.982 % 45 ° C 1.05% 1.046% 0.585% I. Laurylsulfonate TA 1.05% 1.069% 1.054% sodium 35 ° C 1.05% * 0.928% 45eC 1.05% 0.943% 0.781% J Octoxynol-3-sul- TA 1.05% 1.378% 0.994% sodium fonate 35eC 1.05% * 0.936% 45 ° C 1.05% 1.019% 0.785% * Determination not carried out.

** Although the data for 45 days and 215 days indicates that the 215-day samples have greater stability than the 45-day samples, this is due to the fact that the analytical technique is not sensitive enough to reveal differences in these weak concentrations.

The base gel composition of Example 1 is used with higher surfactant concentrations to show the upper limits of the range where the acid-stable and water-soluble anionic surfactants according to the invention CD.YD .F - 16 - WW-0031 * can be used. Although even higher concentrations are possible, skin irritation is a limiting factor. Table II below summarizes the results of this study.

TABLE II

^ * Composition Temperature Ini- Equivalent to tial 45 215 surfactant conservation days days A. Laurylsulfate TA 1.05% 1.068% 1.09% sodium (5%) 35 ° C 1.05% - * - * 45 ° C *** 1.05% 0.978% 0.136% B. Laurylsulfate TA 1.05% 1.01% 1.03% sodium (10%) 35 ° C 1.05% - * 0.932% 45 ° C ** * 1.05% 0.389% 0.119% *** The loss of activity in these samples seems to result from leaks in the tubes due to defective seals and the decrease in viscosity at high temperature.

* Determination not carried out.

EXAMPLE 2.-

A satisfactory gelled composition of the following constitution is prepared: 'Part A g i Anthraline (including 15% surtitling) 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 BHT 0.1

Propyl gallate 0.01 CD.YD.F - 17 - WW-0031

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) to make 100.00

The gel is prepared by mixing the components of part A and heating them to 90 ° C. Stirring is continued until all the solids are homogeneous. In a separate container, the components of part B are mixed and heated to 90 ° C., continuing to agitate until all the solids have dissolved. Part A is mixed with Part B and stirring is continued for 10 minutes while maintaining the temperature at 90 ° C. The resulting gel is cooled to packaging temperature and packed in aluminum tubes with an inert inner coating in an atmosphere of inert gas.

The composition of Example 2 is subjected to clinical evaluation. In all cases, the same composition is used, but by modifying the concentration of anthralin. Clinical studies are carried out by clinical dermatologists with long experience in the evaluation of drugs used for the treatment of psoriasis.

These clinical studies demonstrate that the gels according to the invention which contain 0.5 to 2% by weight of anthralin give particularly good results in patients who are treated once a day for a period of 10 to 20 minutes during '' a treatment extending over 6 weeks. Patients treated in this way develop psoriasis. CD.YD.F - 18 - WW-0031 ranging from localized lesions to lesions reaching most of the surface of the body. The condition of the patients is evaluated after 6 weeks. The results of the evaluations are collated in Table III and clearly show the effectiveness of a gel containing 0.5 to 2% by weight of anthralin which is stabilized in accordance with the invention.

v N.

CD.YD.F - 19 - WW-0031 M Μ ι oc Φ

ho u

• H Ο P μ · η D'd) η ΜΗ 'Φ „Ε Π χ (0

d W Ο D

η · · · C. w · Ί <0 φ φ 5% ® 5 »» h ί ë -¾.¾ ΐ ε ° Q ° ο 0 ϋ | * Η Η Μ ν =, Η φ φ ^ Μ 2 4J Β £ £> "i" .S σ '2 2 ° 3 Ε <= · Ϊ a φ φ Η ο. 'g 10 ο c +>,.

Φ C -Ρ ε φ ® φ φ φ φ ε ε

Sc ωΠΒΠβϋ ^> ïïcr 2 φ φ φ φ · η -η 2 Η * b Η Η Η Η 'Φ (0 +1

Sc * R Η Η Η Η -P Ρ Φ ft-H 2 Φ Φ Φ Φ 'Φ · Ρ Ο u ΪΗ ^ UUOU · Η £ «Ο X X X X Φ φ Μ-Ι Ü φ Φ Φ Φ Η · Η

Η MC

, _ ft φ * Ο1 Η ^ * * * h η Μ · Η S S + J Ο Η'Φ Φ

^ 9 03 rn ß m + * m-P rn -Ρ CJ ^ -P

d vi a S® Sc ïn ïïc φη · ί0 § £ ^ g g g §1 o | § | £ η £ E-I U 2 y. H S H 5 -H * · Η 5 H ^ Φ • H 9 ü M S, M § M S “S φ ®“ μ '®

H ^ m 'Φ h H' Φ H 'Φ & φ -P qj P

6 ® HS * 3 * 3 S_5 '® £ »g g g ÏÏ® · 0 g 3 3 3 π'® φ ß φ Μ M Ό Φ 10 6

φ> ^ <0 _ W O

^ ^ Φ φ ΗΦπί M + JÏti oo oo oo oo oo φ ï ft g at NH CM H CN H CM H CMH -P ft "ε φ p c_“ 2 φ -ph "c 9" 'Φ' 1 ow ft ' 2 »up φ φ § v- d V Φ

M P

> Μ Φ Φ

C Φ ft -H

^ Φ Φ Φ 0 C * P · <* P C C C · Η * H ·. -H φ ^ 4) φ φ -H -H -H · Ρ Φ · Ρ Ch Π C C Φ Φ Φ φ M C ft Φ φ φ -H Μ · Η M Ë M ËM ËM Ο φ · Η +)

Cg ΦΦ ΦΦ φφ ΦΦ Φ Φ * H M ε Φ O

-ΗΦ Ë C ë ß WC WC WC η φ φ -Ρ Η -Ρ φ Η φ · Η · Η · Η * Η OjH C Φ

φ · Η Μφ Μφ ΦΦ ΦΦ ΦΦ ft-Pt? CC

ρ φ ë ερ ^ ΡΕΡεΦΡ-Ηοο £ 14 φφ φ φ / φ φ / φ φ / φ φ - Φ C Ο · Η 4- »Ε-ι PM Ρ Μ HM HM HM ΡΊ ft C Cq + -> d # φ / φ <; Hin Hin öp m <κ> in op m m in m * OP OP OP OP “OP“ OP “OP * *

H CM H CM OH OH OH

CD.YD.F - 20 - WW-0031 y

It is interesting to observe that the clinical evaluation of the composition of Example 6 was undertaken. Preliminary results revealed no difference in clinical efficacy in short-term treatment of psoriasis between the composition of Example 2 (the aqueous phase of which contains a water-soluble antioxidant) and the composition of Example 6 (the aqueous phase of which * does not contain any water-soluble antioxidant.

It should be observed that the solution provided to the problem of the stability of anthralin by the compositions of the invention facilitates short-term treatment and is very favorable for the treatment of psoriasis.

EXAMPLE 5.-

A satisfactory cream of the following constitution is prepared:

Part A çj

Vaseline 200.0

Mineral oil (USP) 50.0

Steareth-2 (CTFA) 12.5

Steareth-100 (CTFA) 2.5

Anthralin (including 15% surcharge) 11.5+

Salicylic acid 3.5

Propyl gailate 0.05 BHT 0.5 ^ Ascorbyl palmitate 0.5

s. Part B

Sodium lauryl sulfate 1.50

Ascorbic acid 2.0 PEG-8 (CTFA) 60.0

Dried sodium phosphate 0.75 EDTA 0.5

Sorbic acid 0.5

Xanthan gum (USP) 3.25 CD.YD.F - 21 - WW-0031

Purified water (USP) to make 500.00

The cream is prepared by mixing the components of part A by heating them to 70 ° C. Stirring is continued until all the solids are homogeneous. In a separate container, the components of Part B are mixed and heated to 70 ° C with further stirring until all the solids are dissolved. Part B is mixed with Part A and the stirring is continued, maintaining a temperature of 70 ° C. until complete homogenization. The resulting cream is cooled to packaging temperature and packaged.

EXAMPLE 4.-

A satisfactory stick composition of the following constitution is prepared: 2

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

0.25 ascorbic acid

Anthralin 5.75 ÿ Purified water (USP) 4.0

Sodium lauryl sulfate and ascorbic acid are dissolved in water and added to the other components which have been preheated to 80 ° C, then cooled to 75 ° C. The composition is then poured into molds where it is allowed to cool and solidify before packaging.

CD.YD.F - 22 - WW-0031 t EXAMPLE 5, -

A satisfactory ointment of the following constitution is prepared:

Cetostearyl alcohol 280.0

Soft white paraffin 500.0

Liquid paraffin 200.0 K “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

All the components, except the anthralin, are thoroughly mixed with water at 75 ° C. until no more bubbles appear. Anthralin is then added and stirring is continued for another 30 minutes. The composition is cooled to 55 ° C. and packaged.

Examples 6 and 7 illustrate two additional gels which can be prepared according to the method of Example 1 and which are extremely stable over the long term.

EXAMPLE 6.-

Part A cj

Anthralin 11.5

Isoceteth-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

Ascorbyle palmitate 1.0 CD.YD.F - 23 - WW-0031

Part B

PEG-8 (CTPA) 50.0

Sorbitol (70% solution) 20.0 EDTA 0.2

Citric acid 5.5

Sodium lauryl sulfate 5.0

Purified water (USP) to make 1000.0 v EXAMPLE 7, -

Part A çj * Anthraline 10.5

Isoceteth-20 (CTFA) 200.0 01eth-2 (CTFA) 60.0

Mineral oil (USP) 160.0

Propyl gallate 0.5 BHT 2.0

Salicylic acid 2.0

Ascorbyle palmitate 1.0

Part B

PEG-8 (CTFA) 50.0

Sorbitol (70% solution) 20.0

Ascorbic acid 10.0

Sodium bisulphite 1.0 EDTA 1.0

Sodium lauryl sulfate 5.0

Purified water (USP) to make 1000.0

Although the anthralin compositions of the invention can be presented and used in the form of creams, gels, ointments or sticks, the preference is given to creams and gels because of the ease of application.

Although various embodiments and details have been described to illustrate the invention, it goes without saying that it is susceptible of numerous variants and modifications without departing from its scope.

CD.YD.F - 24 - WW-0031

Claims (22)

2. Composition according to claim 1, characterized in that the surfactant is stable at a pH of about 5.3 and below. 3. Composition according to claim 1, characterized in that the surfactant is stable at a pH of about 4 and below. 4. Composition according to claim 1, characterized in that the surfactant is stable at a pH of about 3-4. 5. Composition according to claim 1, characterized in that the surfactant is stable at a pH of around 3.2. 6. Composition according to claim 2, 3, 4 or 5, characterized in that it comprises anthralin in a concentration of about 0.5% by weight to 5.0% by weight and the surfactant in a concentration of about 0.05% by weight to about 10% by weight, the percentages by weight being related to the full weight * V · of the composition. 7. Composition according to claim 2, 3, 4 or 5, characterized in that it comprises anthralin in a concentration of about 0.1% by weight to 3.0% by weight and the surfactant in a concentration of about 0.1% by weight to about 5.0% by weight, the percentages by weight being based on the full weight CD.YD.P - 25 - WW-0031 of the composition. 8. Composition according to claim 2, 3, 4 or 5, characterized in that it comprises the anthra-line in a concentration of approximately 0.5% by weight to 2.0% by weight and the active surf in a concentration of from about 0.3% by weight to about 1.0% by weight, the percentages by weight being based on the complete weight of the composition. 9. Composition according to claim 2, 3, '4 or 5, characterized in that it comprises the anthraline in a concentration of about 0.1% to about 3.0% by weight and the surfactant is chosen among alkyl sulfates, alkyl sulfonates, alkylbenzenesulfonates, sulfonylated fatty acids, alkylphosphates, dioctylsulfosuccinates, isethionates, alkylethersulfates, methylsarcosinates and anionic analogous surfactants other than soaps, the percentages by weight being related to full weight of the composition. 10. Composition according to claim 2, 3, 4 or 5, characterized in that it comprises an-thraline in a concentration of approximately 0.5% to approximately 2.0% by weight and the surfactant is chosen from »alkylsulfates, alkylsulfonates, alkylbenzene sulfonates, sulfonylated fatty acids, alkylphosphates, dioctylsulfosuccinates, isethionates, alkylethersulfates, methylsarcosinates and anionic surfactants analogous other than soaps, the percentages by weight being based on the total weight the composition. 11. Composition according to claim 2, 3, 4 or 5, characterized in that it comprises an-thraline in a concentration of approximately 0.1% to approximately 5.0% by weight and the surfactant in a concentration from about 0.05% to about 10.0% by weight, the surfactant CD.YD.F - 26 - WW-0031 "# being chosen from alkylsulfates, alkylsulfonates, alkylbenzenesulfonates, sulfonylated fatty acids, alkylphosphates, dioctylsulfosuccinates, isethionates, alkylethersulfates, methylsarcosinates and anionic surfactants analogous other than soaps, the percentages by weight being based on the complete weight of the composition. 12. Composition according to claim 2, s 3, 4 or 5, characterized in that it comprises antraline in a concentration of about 0.1% to about 3.0% by weight and the surfactant in a concentration of about 0.1% to about 5.0% by weight, the surfactant being chosen from alkyl sulfates, alkyl sulfonates, alkylbenzenesulfonates, sulfonylated fatty acids, alkylphosphates, dioctylsulfosuccinates, isethionates, alkyl ether sulfates, methyl sarcosinates and analogous anionic surfactants other than soaps, the percentages by weight being based on the complete weight of the composition. 13 - A composition according to claim 2, 3, 4 or 5, characterized in that it comprises antraline in a concentration of about 0.5% to about 2.0% by weight and the surfactant in a concentration of about 0.3% to about 1.0% by weight, the surfactant being chosen from alkylsulfates, alkylsulfonates, alkylbenzenesulfonates, sulfonylated fatty acids, alkylphosphates, dioctylsulfosucci-W * f (^ nates , isethionates, alkylethersulfates, methylsarcosinates and anionic surfactants analogous other than soaps, the percentages by weight being based on the full weight of the composition 14, - Composition according to claim 11, characterized in that the surfactant is lauryl- Sodium sulfate 15., - Composition according to claim 1, CD.YD.F - 27 - WW-0031 "" characterized in that it is an oil-in-water emulsion and the emulsion does not contain antioxidant in the aqueous phase. 16. Composition according to any one of claims 1 to 15, characterized in that it is in solid form. 17. Composition according to any one of the vc. Claims 1 to 15, characterized in that it is% in the form of a cream. 18. Composition according to any one of claims 1 to 15, characterized in that it is in the form of a gel. 19. Composition according to any one of claims 1 to 15, characterized in that it is in the form of an ointment. 20. Composition according to claim 1, characterized in that it is an oil-in-water or water-in-oil emulion and the oily phase contains, in an amount sufficient to increase the stability of anthralin, an antioxidant soluble in oil. 21. Composition according to claim 20, characterized in that it is an oil-in-water emulsion. > 22.- Composition according to claim 20, characterized in that it contains, in the aqueous phase, an antioxidant soluble in water in an amount sufficient to increase the amount of anthralin. 23. Composition according to claim 1, characterized in that the anionic surfactant is a mixture of two or more suitable anionic surfactants. 24. Method for increasing the stability of compositions containing anthralin, characterized in that an anionic surfactant, acid-stable and water-soluble in CD.YD.F - 28 - WW-0031 is added to these compositions "sufficient to stabilize anthralin. 25. The method of claim 24, characterized in that the pH of the compositions is further adjusted to 5.3 or below. 26. The method of claim 24, characterized in that an oil-soluble antioxidant is added to the compositions when the emulsion '^ contains an oily phase. 27. The method of claim 26, characterized in that a water-soluble antioxidant is added to the composition. u / CD.YD.F - 29 - WW-0031