FI83837C - FOERFARANDE FOER OEKNING AV STABILITETEN HOS VATTENHALTIGA KOMPOSITIONER SOM INNEHAOLLER ANTRALIN. - Google Patents

Description

! 83837

A method for increasing the stability of anthralin-containing aqueous compositions

The invention relates to a method for increasing the stability of anthralin-containing aqueous compositions.

Anthralin, also known as ditranol, has been a common component in compositions used to treat percutaneously psoriasis, a skin condition characterized by thickened, reddish, silvery-gray scaly patches of skin that may be a few small wounds or cover large areas. in the body.

Although dermatologists have made 15 some more recent attempts to treat psoriasis in recent years, the large number of therapeutic agents and diets used indicates that most of them have no long-term effect. A large number of topical drugs have been used to treat psoriasis, for example, tars, tar derivatives, anthralins, mercury compounds, corticosteroids, and keratolytics.

Many dermatologists treating psoriasis still consider anthralin as an alternative treatment. Anthraline is commonly used as the primary form of treatment for inpatients and outpatients in most hospitals. The preparation used for this purpose generally contains 0.05 to 5% by weight of anthralin, based on the total weight of the composition. Unless otherwise stated, the percentage by weight used hereinafter means the percentage by weight based on the total weight of the composition. Used properly, anthralin is very effective and has at most minimal side effects.

Although anthralin is generally known to be very effective in the treatment of psoriasis, it still has three main 35 major disadvantages: instability, skin and clothing 2 83837 staining, and skin irritation. When catalyzed by light, anthraine is oxidized, dimerized, and / or chemically degraded to form 1,8-dihydroxyanthraquinone and 1,8,1 ', 8'-tetrahydroxy-10,10'-diantrone and other unidentified by-products.

Anthralin has been shown to be sensitive to degradation by self-oxidation (namely, free radical oxidation). Its degradation products are believed to be inactive in chemotherapy for psoriasis. Skin irritation or anthralin-10 renal edema is believed to be primarily caused by the anthralin free radical intermediates that are initially formed. Anthralin-induced skin staining is believed to be due to its oxidation products, namely 1,8-dihydroxyananthraquinone or dimer.

15 Many solutions to the problem of ant ralin stability have been reported in the industry in the past, but none have been sufficiently satisfactory. Typical prior art solutions are disclosed in U.S. Patents 4,203,969 and 4,287,214. U.S. Patent 4,203,969 discloses the criticality of water-soluble, oil-insoluble acid oxidation

the use of an inhibitor or the use of a combination of an acid and a water-soluble, oil-insoluble antioxidant in the continuous aqueous phase of the cream. U.S. Patent 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, whereas certain alpha-hydroxy acids stabilize it satisfactorily. Ponce-Waelch and Hulsebosch, Arch. Derm. 30 Forsch. 249, (1974) 141-152 disclose Lactacyd pH2® ointment adjuvant with anthralin. Ko. Table 1 of the reference describes the lack of stability of such a preparation as analyzed by UV spectroscopy and thin layer chromatography. Although Caron and Shroot, J. Pharm. Sci. 70:11 35 (1981) 1 205-1 207 describe the addition of 0.44% salicylic acid to a composition containing 3,83837 anthralins, which also contains cetyl alcohol, sodium lauryl sulphate, paraffin and petrolatum, there is in fact no clear indication that the composition contains water, and the stabilizing effect of anthralin 5 has not been evaluated by any component of the composition and no concentration ranges have been mentioned where such components could be used to prepare a stable, aqueous and anthralin-containing composition having an effective anti-psoriasis effect.

When the stability of anthralin is determined by high performance liquid chromatography (HPLC) using the method described in Caron et al., J. Pharm. Sci. 70:11 (1981) 1205 or in the Pharmacopeial 15 Forum, May-June 1982, pages 1956-1957, instead of the more commonly used stability test method described in The United States Pharmacopeial Convention, Inc., the United States Pharmacopeia (USP), it is found that the lower methods for stabilizing anthralin are not entirely satisfactory and the stability they cause is less than previously thought. In contrast to the USP method, which is less than satisfactory for determining anthralin stability, the HPLC method is a selective, sensitive, and reproducible method for determining anthralin stability. Recent publications, such as those referred to so far, have raised serious questions as to whether the USP and British Pharmacopeia (BP) methods are indicative of anthralin stability. It is expected that the USP and BP in the near future will change their test methods for all anthralin-containing preparations to HPLC.

In most commercial applications, concentrations of anthralin in excess of 0.5% by weight are rarely, if ever, marketed for outpatient use because such compositions result in rapid loss of activity and oxidation of 4,83837 anthralins. When spotted psoriasis affected more than 20% of the body surface area, hospitalization was necessary to avoid normal skin irritation when in contact with products with a high anthralin content and to control the stability of the product to ensure rapid treatment. One major drawback in preparations with a low anthralin content, i.e. about 0.5% or less, is that it is impossible to provide rapid treatment, which is possible with preparations with a higher anthralin content.

It has been previously shown in the art that: a. Anthralin is susceptible to degradation by self-oxidation (free radical oxidation) and its degradation products are inactive in chemotherapy for psoriasis.

15 b. Anthralinic arthritis or skin irritation is mainly due to the initial intermediates of anthralin, which are biologically active free radicals.

c. Anthaline-induced skin and clothing staining is due to its oxidation products, such as its colored dimer or 1,8-dihydroxyanthraquinone.

Previous attempts in the art to stabilize anthralin against oxidation included traditional methods of contraception such as the use of ascorbic acid BHA, BHT, EDTA (ethylenediaminetetraacetic acid) or citric acid, acidification of pH 25, lowering the process temperature, and removal of peroxides. However, none of the above attempts to stabilize anthraline previously described in the art have been appropriate.

It is clear from the above that anthralin degradation products or original free radical intermediates cause an irritation and staining problem which has hitherto been considered a necessary consequence of anthralin therapy. If the stability of anthralin could be improved, the problems of irritation and staining indirectly caused by the degradation products of anthralin could be solved at the same time.

Although new anthralin product formulations have been developed to provide better tolerability, greater comfort, and less color loss, the instability of anthralin 5 in such formulations, as evidenced by loss of activity and discoloration from light yellow to brown or black, has remained an unsolved problem. No anthralin preparation has yet been available in which the stability of the anthralin itself is long lasting and the preparation is physically stable and has a pleasing appearance and acceptable color. It is well known that the color of commercially available anthralin products disappears in a short time, and the appearance becomes very unpleasant and unacceptable to the user.

It has now been found that the desired stabilization of anthralin in compositions suitable for superficial application in the treatment of psoriasis can be achieved by adding an anthralin stabilizing amount of an acid-resistant, water-soluble anionic surfactant to the composition containing water, anthralin and optionally an oil-soluble antioxidant.

The method of the invention for increasing the stability of anthralin-containing aqueous compositions is characterized in that a dermatologically acceptable acid is added to the aqueous composition containing from about 0.1% to about 5.0% by weight of anthralin, based on the total weight of the composition, in an amount sufficient to control pH 5.3 or less, and from about 0.05 to about 30% by weight, based on the total weight of the composition, of a surfactant selected from the group consisting of alkyl sulfate, alkyl sulfonate, alkyl benzene sulfonate, sulfonyl fatty acid, alkyl phosphate, dioctyl sulfosuccinate, isethionate, alkyl ether sulfate, methyl sarcosine or the like non-soap anionic surfactant 6,83837.

The composition to be treated by this method may further optionally contain a water-soluble antioxidant in the aqueous phase. The presence of a water-soluble oxidation inhibitor in the aqueous phase has now been found, contrary to the teachings of U.S. Patent 4,203,969, not critical to the long-term stability of anthralin in the compositions of this invention. The presence of water-soluble oxidation may be desirable, although not critical.

The composition to be treated by the process of the invention has an anthralin content of up to about 5.0% by weight. Preferably, compositions containing from about 0.1% to about 3.0% by weight of anthralin that can be used for surface application are treated, and more preferably, compositions containing from about 0.5% to about 2.0% by weight of anthralin are treated.

Of course, compositions with a higher anthralin content could be stabilized by the method of the invention, but care must be taken in the use of such compositions to avoid normal skin irritation.

The anionic surfactant is used in an amount sufficient to stabilize the anthraine in an amount of about 0.05 to about 10% by weight, preferably 0.1 to 5.0% by weight, and most preferably 0.3 to 1.0%. % by weight, based on the total weight of the composition.

Although it is previously known in the art that anthralin is more stable at acidic pH and that the pH of anthralin-containing compositions can be controlled using any dermatologically acceptable acid, it is preferred to use citric or salicylic acid. Compositions comprising the process of the invention with an acid-resistant, water-soluble anionic surfactant have a pH of 5.3 and below. Is . It is preferred to use lower pH values, and the limiting factor is skin irritation. Preferably less than pH 4.0 and more preferably less than 3.4 pH are used.

The process of the invention provides an anthraline product with long-term anthralin stability, cosmetic fineness, better tolerability, and substantially no color loss after storage when properly packaged. It can be used successfully as well as in low-intensity, long-term outpatient treatment of psoriasis and in intensive, short-10 hospitalization.

It is contemplated that the present invention may work because oil particles or droplets dispersed in a liquid medium can be charged in two ways. The first method concerns the reactive adsorption of certain ions present in solution. In the case of water, it may be a hydronium or hydroxyl ion. Most of the oil droplets or particles dispersed in the aqueous medium achieve a negative charge due to the preferential adsorption of the hydroxyl ion. Another way involves charges with oil particles or droplets, the charges arising from the ionization of surfactant functional groups, such as phosphates, carboxylates, sulphates and sulphonates, which may be on the surface of the particle or at the interface between the oil and water phases. : 25 la.

Molecules and ions that are adsorbed by the surfaces or interfaces are referred to as surfactants. An alternative term is amphiphile, suggesting that a molecule or ion has a certain affinity for both polar and non-polar solvents.

The amphiphilic nature of the surfactant molecules or ions causes them to adsorb to the interface, which may be a liquid / gas or liquid / liquid surface.

35 The chemical structure of anthralin is shown as follows: 8 83837

OH OH

_ | ^^ NS * v // ^ S p> || hydrophilic side lipophilic side

H H

Anthralin is an amphiphilic-type molecule; that is, anthralin has a certain affinity for both polar and non-polar groups. The amphiphilic nature of anthralin molecules also causes them to concentrate on the surface or interface where they are exposed to easy attack. Under such conditions, oxidation initiators such as oxygen, light, hydrogen ions or metal ions readily attack the anthralin and / or accelerate its degradation by free radical self-oxidation. The high surface or interface concentration of anthralin molecules also accelerates dimer formation due to the intermolecular effect.

It is believed that the present invention provides particles, oil droplets, or micelles having a predominantly anionic charge on the surface created by either the anionic surfactant alone or one or more nonionic surfactants and one or more anionic surfactants. 25 combination of its surfactant. The negatively charged surface has functional groups, e.g., sulfonate, sulfate, phosphate, and carboxylate groups from anionic surfactants. The anionic groups ad-30 of acid-resistant surfactants are sorbed to the surface at the oil / water interface, leaving a negatively charged surface on the oil-oil particle, droplet or micelle. The negatively charged surface attracts cations from the aqueous phase, and rejects the anions of the solution, such as hydroxyl, once the initial adsorption has gone to the final 35 wood. In addition to these electrical forces, the thermal motion tends to achieve an ionic uniform distribution of all ions in the solution. The result is an equilibrium state and the system as a whole is electrically neutral.

The distribution ratio of anthralin between oil and water 5 is about 5,000 to 10,000 in favor of the oily phase. Therefore, in oil-based preparations the emulsion is in the case of based preparations, e.g. creams and gels or emulsified creams, the anthralin molecules dissolve and remain in the oil phase. When the initial adsorption on the surface is complete, the surface is filled with anionic and / or nonionic surfactant molecules. Anthralin molecules do not concentrate on surfaces and are completely protected by a negatively charged surface and reject the approach of hydroxyl ions or other degradation initiators. Such a situation can be illustrated by the diagram shown in Figure 1, in which the anthralin molecules remain in the oil phase and the line a, a 'is the surface of the particle, oil silicon or micelle. Adsorbed ions, which give the surface its negative charge, are called potency-determining ions and come from anionic surfactants. Immediately adjacent to this surface layer is a region of tightly bound molecules from the continuous aqueous phase of one with some positive ions, mostly hydronium ions, which are also tightly bound to the surface. The boundary of this range is marked by the line b, b '. The potential on line b, b 'is still negative, but it has fewer cations than in the bound negative layer. In the region bounded by lines b, b 'and c, c' there is an excess of negative ions-30 and. On the other side of the line c, c ', the ion distribution is uniform, and electrical neutrality is achieved. The line d, d 'indicates the outer boundary.

*: The anionic surfactant used as a stabilizer for anthralin compositions in accordance with this invention causes a strong increase in anthralin stability. It is believed that the anionic surfactant protects the anthralin molecules from attack by creating a negatively charged surface that forms micelles or by surface insulation. Although the anionic surfactant used in an anthralin stabilizing amount provides the advantages of this invention, as mentioned earlier, stabilization can be further enhanced by the use of antioxidants previously used in anthralin-containing compositions.

The acid-resistant, water-soluble, anionic surfactants used in this invention are readily available compounds, typically non-soap surfactants such as alkyl sulfates, alkyl sulfonates, alkyl benzene sulfonates, alpha-sulfonyl fatty acids, alpha-sulfonyl fatty acids, alkyl fatty acids, alkyl fatty acids, , alkyl ether sulfates, methyl sarcosines, etc. Preferably, sodium lauryl sulfate, sodium octoxynol-3-sulfonate, sodium dodecylbenzenesulfonate, sodium lauryl sulfosyl-20-succinate, DEA-oleyl ethylene-3-phosphate (diethanolamine ammonium polyol) isothionate, sodium laureth sulfate and sodium lauryl sarcosinate, etc. Mixtures of such surfactants may also be used.

Contrary to previous teachings in the art, the treatment of this invention provides the composition with long-term stability without the use of water-soluble antioxidants, although they may be added to improve results.

It has further been found that the anionic surfactants used in accordance with this invention, when used in combination with oil-soluble antioxidants, greatly increase the stability of anthralin. Typical such antioxidants are asb of 83837 corbyl palmitate, hydroquinone, propyl gallate, nor-dihydroguaiacetic acid, BHT, BHA, alpha-tocopherol, phenylalpha-naphthylamine and lecithin. It has also been found that water-soluble antioxidants can additionally be used in the aqueous phase. Typical such oxidation inhibitors include sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, acetone sodium metabisulfite, as-corbic acid, isoascorbic acid, thiosoric acid, thiosgorol, thioglycerol, thioglycerol,

The anionic surfactants used in accordance with this invention can also be used with nonionic surfactants, such as polyalkoxy ethers, polyalkoxy esters and polyalkoxyamides, poly-alcoholic alcohols and fatty acid esters of fatty alcohols, which reduce the potential skin irritation caused by anions. If desired, anionic surfactants can also be used in combination with suitable thickeners such as methylcellulose, tragacan-20, sodium alginate, bentonite from Carbopol 934 (CTFA; crosslinked polymer of acrylic acid), carboxymethylcellulose and Vee-gum; aluminum silicate). CTFA means that the name used is the nomenclature set forth in the CTFA Cosmetic Ingredient Directory, 3rd Edition, published by CTFA Association Inc.

In the past, due to the poor stability of anthralin in dermatological compositions, anthralin-containing compositions were rarely, if ever, sold with an anthralin content of more than 0.5% by weight. As a result of the improved anthralin stability provided by this invention, it is now possible to provide very stable preparations both in terms of anthralin content and the physical stability of the preparation itself, and such preparations are very effective in the topical treatment of psoriasis. Such preparations may have anthralin contents of 0.1 to 5.0% by weight or more and are useful in the outpatient treatment of psoriasis. In addition, the results of accelerated storage stability studies at high temperatures and the Arrhenius curves of the results obtained with the above preparations made it possible to project the stability of both anthralin and the preparations for more than two years for storage at room temperature by HPLC. For the purposes of these studies, the maintenance of anthralin levels below 90% was unsatisfactory.

To demonstrate the stability of anthralin-containing products treated in accordance with this invention, gel compositions containing 1% by weight of anthralin (plus 0.05% by weight excess) were prepared according to the method for preparing the basic gel composition described in Example 1 below. compositions were consistent with the base gel composition 20 and were identical except for the surfactant used. In addition to the gel compositions prepared using acid-resistant, water-soluble anionic surfactants, for comparison, gel compositions were prepared using Kati-25one amine surfactant, Richamate 1655 (product of Richardson Company; cocamidopropyldimethylamine-nipropionate) and using triethionate an unsustainable, water-soluble anionic surfactant to demonstrate a lack of anthralin stability in gels containing members of such classes of surfactants. Samples were evaluated at storage temperatures at room temperature, 35 ° C, and 45 ° C.

i3 83837

Example 1 Basic gel composition

Part A grams 5 mineral oil (USP) 164 propyl gallate 0.5 BHT 2.0 salicylic acid 2.0 oleth-2 (CTFA; oleyl alcohol poly-10 ethylene glycol ether) 60.0

Isoceteth-20 (CTFA; polyethylene glycol ether of isocetyl alcohol) 200.0 ascorbyl palmitate 1.0 anthralin 0.5 15

Part B

PEG-8 (CTFA; polyethylene glycol) 50.0 sorbitol solution (70%) 20.0 EDTA (ethylenediaminetetraacetic acid) 1.0 sodium bisulfite 1.0 ascorbic acid 10.0 surfactant 5.0 purified water (USP) q.s. 1,000.0

The compositions were prepared by mixing Part A

components and heating to 90 ° C. Stirring was continued until all solids were mixed. The components of Part B were mixed in a separate vessel and heated to 90 ° C with continuous stirring until all 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 packaged in an inert gas in aluminum tubes suitably coated with si-35 fibers so that they did not react with the product.

83837

table 1

Stability of anthralin

Corresponding to the surfactant storage- 45 days 215 medium_temperature 1 ^ at the beginning_false_ A. sodium lauryl RT 1.05% 1.027% 1.09% lisulfate 35 ° C 1.05% * 0.95% 45 ° C 1.05 % 1.006% 0.718% B. Cationic RT 1.05% 0.529% 0.42% Amine 35 ° C 1.05% 0 O (Richamate 1655) 45 ° C 1.05% 0 0 C. Triethanolamine RT 1.05 % 0.599% 0.084% nistearate 35 ° C 1.05% * 0 45 ° C 1.05% 0.00343% 0.058% D. sodium dioctyl RT 1.05% 1.045% 1.07% lisulfosuccin- 35 ° C 1, 05% * 0.989% sodium 45 ° C 1.05% 0.978% 0.762% E. sodium alkyl RT 1.05% 1.080% 1.06% olefin sulfo-35 ° C 1.05% * 0.935% sodium 45 ° C 1, 05% 1.012% 0.800% F. sodium cosyl RT 1.05% 1.076% 1.09% isothionate 35 ° C 1.05% * 0.958% 45 ° C 1.05% 1.026% 0.833% G. DEA-ol-3 - RT 1.05% 1.091% 1.09% phosphate 35 ° C 1.05% * 0.989% 45 ° C 1.05% 1.049% 0.777% H. sodium laureth RT RT 1.05% 1.089% 1.094% sulphate 35 ° C 1.05% * 0.982% 45 ° C 1.05% 1.046% 0.585% I. sodium lau RT 1.05% 1.069% 1.054% rylsulfo- 35 eC 1.05% * 0.928% sodium 45 ° C 1.05% 0.943% 0.781% J. sodium octoct RT 1.05% 1.378% 0.994% synole-3-sul- 35 ° C 1 .05% * 0,936% phonate 45 ° C 1,05% 1,019% 0,785% RT * room temperature * not determined * * although the 45 and 215 day data show that is 83837 215 day samples had greater stability at 45 days, this is due to the fact that the analytical method is not sensitive enough to detect differences at these low concentrations.

The base gel composition of Example 1 was used with higher surfactant concentrations to demonstrate the upper limits of the range in which acid-resistant water-soluble anionic surfactants can be used. While even higher concentrations are possible, skin irritation is a limiting factor. The following Table II describes the results of this study.

Table II

The storage stock of the combination 15 surface-activity temperature 45 days 215 days at the beginning of the sulfur sulfur-RT 1.05% 1.068% 1.09% ryl sulfate 35 ° C 1.05% * * ti (5%) 45 ° C 1.05% 0.978% 0.136% Sodium laurel RT 1.05% 1.01% 1.03% Ryl sulfate 35 ° C 1.05% * 0.932% «df« n »« n * ti (10% ) 45 ° C 1,05% 0,389% 0,119% The loss of 25 *** activity in these samples is probably due to leaks in the pipes due to poor seals and loss of viscosity at high temperatures.

* no determination was made.

i6 83837

Example 2

A satisfactory gel combination was made by the following formula:

Part A grams of 5 anthralin (including 15% overrun) 1.15

Isoceteth-20 (CTFA) 20.0 Mineral Oil (USP) 16.0

Oleth-2 (CTFA) 6.0 salicylic acid 0.2 10 ascorbyl palmitate 0.1 BHT 0.1 propyl gallate 0.01

Part B grams 15 PEG-8 (CTFA) 5.0 sorbitol solution 2.0 ascorbic acid 1.0 sodium lauryl sulfate 0.3 citric acid 0.1 sodium bisulfite 0.05 EDTA 0.01 purified water q.s. 100.00

The gel was prepared by mixing the components of Part A and heating to 90 ° C. Stirring was continued until all solids were mixed. In a separate vessel, the components of Part B were mixed and heated to 90 ° C with continued stirring until all solids had dissolved. Part B was mixed with Part A and stirring was continued for 10 minutes maintaining the temperature at 90 ° C. The resulting gel was cooled to packing temperature and packed in an inert atmosphere in aluminum tubes with a non-reactive coating on the inner surfaces.

The composition of Example 2 was evaluated clinically in chickens. The same composition was used in all cases.

i7 83837 but the anthralin content varied. Clinical researcher experience in the evaluation of drugs used in the treatment of psoriasis.

These clinical studies show that the gel compositions treated according to the present invention with 0.5 to 2% by weight of anthralin give particularly good results in patients receiving a short-term treatment of 10 to 20 minutes each time for six weeks. In patients treated in this way, psori-10 asis ranged from local areas to areas that covered most of their body surface area. These patients were evaluated after six weeks. The results of such evaluations are shown in Table III below and clearly demonstrate the efficacy of a gel containing 0.5-2% by weight of anthralin stabilized by the means of this invention.

Table III

20 lhokoske- Patient-

Anthralization time clinical treatment_ (min) _distribution_reaction_researcher

1% Week 1 20 size good 9 Dr. H

2% 5 weeks 10 for body 25

1% Week 1 20 only excellent- Dr. Dr. R

* 2% for 5 weeks for 10 rio nen

0.5% Week 1 20 only excellent- Dr. Dr. E

* 1% for 5 weeks for 10 rio nen 30

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

* 5 weeks for 10 rio nen

0.5% Week 1 20 only excellent- Dr. Dr. B

* 35 1% 5 weeks for 10 ries nen ie 83837 * application to the whole body was started, but the irritation of healthy skin was such that the treatment was returned only to the injured areas after which there were no more problems.

5 ** As used herein, good means medium to significant cleansing of the skin and excellent means significant to complete cleansing of the skin.

It should be noted here that a clinical evaluation of the composition 10 of Example 6 has begun. Preliminary results show no difference in clinical efficacy in the short-term treatment of psoriasis between the composition of Example 2 (with a water-soluble antioxidant in the aqueous phase) and the composition of Example 6 (without a water-soluble antioxidant in the aqueous phase).

It should be noted here that the solution of the anthralin stability problem by this invention promotes the use of short-term therapy and is very advantageous in the treatment of psoriasis.

20 Example 3

A satisfactory ointment preparation was prepared by the following formula:

Part A Grams 25 Vaseline 200.0 Mineral Oil (USP) 50.0

Steareth-2 (CTFA, stearyl alcohol polyethylene glycol ether) 12.5

Steareth-100 (CTFA stearyl alcohol poly-30 ethylene glycol ether) 2.5 anthralin 11.5+ (containing 15% excess) salicylic acid 3.5 propyl gallate 0.05 35 BHT 0.5 ascorbyl palmitate 0.5 i 83 8337

Part B Grams 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 Purified Water (USP) q.s. 500.00 10 The ointment was prepared by mixing the components of Part A and heating to 70 ° C. Stirring was continued until all solids were mixed. In a separate vessel, the components of Part B were mixed and heated to 70 ° C with continued stirring until all solids had dissolved. Part B was mixed with Part A and stirring was continued at 70 ° C until the parts were completely mixed. The resulting ointment was cooled to packing temperature and packaged.

20 Example 4

A satisfactory stick combination was prepared by the following formula: grams

Syncrowax HGL-C (Croda; Cie.36 carboxylic acid triglyceride) 45.0

Syncrowax ERL-C (Croda; glycol ester of C18.36 carboxylic acid) 15.0 Vaseline 310.0 Mineral oil (USP) 120.0 30 Salicylic acid 0.5 Propyl gallate 0.05 BHT 0.25 Ascorbyl palmitate 0.5 Sodium lauryl sulfate 2.5 35 ascorbic acid 0.25 anthralin 5.75 purified water (USP) 4.0 20 8 3 8 37

Sodium lauryl sulfate and ascorbic acid were dissolved in water and added to the other components premixed at 80 ° C and then cooled to 75 ° C. The composition was then poured into molds, allowed to stand and settle and packaged.

Example 5

A satisfactory ointment composition was prepared by the following formula: 10 grams of cetostearyl alcohol 280.0 white soft paraffin 500.0 liquid paraffin 200.00 sodium lauryl sulfate 5.0 salicylic acid 2.0 ascorbyl palmitite 1.0 BHA 0.5 EDTA 0.05 ascorbic acid 0.05 20 anthralin 11.5 purified water (USP) 4.00

All components except anthralin were vigorously mixed with water at 75 ° C until bubbling lak-25 kasi. Anthralin was then added and stirring was continued for another 30 minutes. The composition was cooled to 55 ° C and packaged.

Examples 6 and 7 show two more gel compositions which can be prepared by the method described in Example 1 and are very stable under prolonged storage.

2i 83837

Example 6

Part A grams of anthralin 11.5 5 Isoceteth-20 (CTFA) 200.0 01eth-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 grams PEG-8 (CTFA) 50.0 15 sorbitol (70% solution) 20.0 EDTA 0.2 citric acid 5.5 sodium lauryl sulfate 5.0 purified water (USP) q.s 1,000.0 20

Example 7

Part A grams of anthralin 10.5 25 Isoceteth-20 (CTFA) 200.0

Oleth-2 (CTFA) 60.0 Mineral oil (USP) 160.0 Propyl gallate 0.5 BHT 2.0 30 Salicylic acid 2.0 Ascorbyl palmitate 1.0 22 83837

Part B grams 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. Although the anthrelin compositions treated in accordance with this invention may be formulated and used in the form of an ointment, gel, ointment or stick, for ease of use, ointment or gel forms are preferred.

Having described the present invention with reference to the foregoing description, reference is made to the following claims to determine the scope of the invention.

Claims (4)

A process for increasing the stability of aqueous compositions containing anthralin, characterized in that an aqueous composition containing about 0.1 - about 5.0% by weight of anthralin, calculated on the total weight of the composition, puts a dermatologically acceptable acid in an amount sufficient to adjust the pH to 5.3 or less, and about 0.05 to 10% by weight, based on the total weight of the composition, a surfactant which is alkyl sulfate, alkyl sulfonate, alkylbenzenesulfonate, sulfonyl fatty acid, alkyl phosphate, dioctyl sulfosuccinate, isetionate, alkyl ether sulfate, methyl sarcosine or similar nonionic surfactant. 2. A process according to claim 1, characterized in that the composition contains an oil-insoluble antioxidant. Method according to claim 1 or 2, characterized in that the composition contains, based on the total weight of the composition, about 0.5 - 2.0% by weight of antraline and added to the composition about 0.3 - 1.0% by weight. -% the surfactant. Process according to any one of claims 1-3, characterized in that the composition is an oil-in-water or water-in-oil type emulsion and the oil phase contains an amount of oil-soluble antioxidant sufficient to increase the anthralin instability.