DE3421510A1 - PHARMACEUTICAL AGENTS - Google Patents

Description

PROF. DR. DR. J. REITSTÖT "> ER DR-WE ¹ RNER KINZEBACH DR. ING. WOLFRAM BUNTE (ι _β8β -ιβ7β)

REITSTÖTTER. KINZEBACH Be PARTNER PATENTANWÄLTE POST BOX 78Ο. D-BOOO MÜNCHEN 43 APPROVED REPRESENTATIVES AT

EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE (OB9) 2 71 OB 83 CABLES: PATMONDIAL MUNICH TELEX: Ο52152Ο8 ISAR D TELEKOP: (O8S) 271 OO 63 (CR. Il + 111) BAUERSTRASSE 22. DBOOO MUNICH

June 8, 1984

OUR FILES:

OURREF: M / 25 107

REFERENCE: RE

Bristol-Myers Company

345, Park Avenue

New York 10154 USA

PHARMACEUTICAL PRODUCTS

POSTAL ADDRESS; D-8OOO MUNICH 43. POST BOX 78Ο

- β "

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Pharmaceutical agent

The invention relates to pharmaceutical compositions for topical use Treatment of psoriasis and methods of stabilizing anthralin in pharmaceutical compositions.

Anthralin, also known as pithranol, is a common ingredient in formulations used for percutaneous treatment used by psoriasis. Psoriasis is a dermatological disease that characterizes is characterized by thickened, reddened, silvery-scale-like patches of skin that appear as a few small lesions occur or cover large areas of the body.

Even if dermatologists have been the Having tried treating psoriasis in many ways, such is the large number that have come into play therapeutic agents and procedures are a sign that the majority of them are effective is missing. A large number of topical agents have been used to treat psoriasis, such as tar preparations, Tar derivatives, anthralin, mercury compounds, corticosteroids and keratolytics.

Anthralin is still the treatment of choice for psoriasis for many dermatologists. In the Most hospitals will use anthralin in general

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• 3.

used as "basic means" for treatment in hospital and for home treatment. Used for this purpose one anthralin in general in concentrations of 0.05 to 5 wt .-%, based on the total weight of the relevant means. Unless otherwise stated,% by weight mean% by weight in the following, based on the Total weight of the agent. When used correctly, anthralin is extremely effective and has minimal levels or no side effects.

Despite its effectiveness in treating psoriasis, anthralin has three disadvantages: it is unstable, soils the skin and clothing and is irritating to the skin. Anthralin easily succumbs to one light-catalyzed oxidation, dimerization and / or chemical decomposition, with 1,8-dihydroxyanthraquinone and 1,8,1 ', 8'-tetrahydroxy-10,10'-dianthrone and others unidentified by-products arise.

It has been described that anthralin can undergo an autoxidative degradation reaction (via oxidation, involving free radicals). It is believed that the breakdown products in psoriasis chemotherapy are ineffective. Further, it is believed that the "irritation" or "anthraline theme" of the skin is chief caused by the initial intermediate products of anthralin breakdown, which are free radicals

gQ den. Anthralin will "pollute" the skin its oxidation products, namely 1,8-dihydroxyanthraquinone or the dimer.

Various attempts have been made to solve the problem of anthralin instability, and one that has been satisfactory

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However, the solution has not yet been found. Typical of the prior art are those in US Patents 4,203,969 and US Pat 4,287,214 suggested solutions. US Pat. No. 4,203,969 describes the problem with use a water-soluble, oil-insoluble acid antioxidant or a combination of an acid and one water-soluble, oil-insoluble antioxidant in the continuous aqueous phase of a cream. US Pat. No. 4,287,214 states that antioxidants, such as ascorbic acid, BHA (butylated hydroxyanisole) and BHT (butylated hydroxytoluene) and other chemical compounds, like salicylic acid, in contrast to α-hydroxy acids, do not stabilize anthralin in a satisfactory manner. Ponce-Waelsch and Hulsebosch, "Arch. Derm. Forsch 249, 141-152 (1974) describe a lactacyd pH2® Cream carrier containing anthralin. From Table 1 of this publication, the lack of stability is a Such a formulation can be seen if one looks at it by means of UV spectroscopy and thin layer chromatography analyzed. Caron and Shroot, J. Pharm. Sci., 70:11, 1205-1207 (1981) describe the use of salicylic acid in an agent containing 0.44% anthralin and also cetyl alcohol, sodium lauryl sulfate, paraffin and petroleum, but there is no suggestion that it contains water that any the constituents of the agent have a stabilizing effect on the anthralin or that within the concentration ranges, in which these components can be used, with antipsoriatic effects Quantities of stable water and anthralin containing agent is present.

If you determine the stability of the anthraline, that is

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by high pressure liquid chromatography (HPLC) using the method described by Caron et al. "J. Pharm. Sex."
70:11, 1205 (1981) or using the method described in "Pharmacopeial Forum", May-June 1982, pages 1956-1957, The United States Pharmacopeial
Convention, Inc. instead of the more commonly used method for determining stability according to the United States Pharmacopeia

(USP), it turns out that the known processes for stabilizing anthralin are not entirely satisfactory are. The stability is generally lower than previously assumed. In contrast to the

USP method used to determine the stability of the
Anthraline is insufficient, represents the HPLC method
a selective, sensitive and reproducible method for determining the stability of anthraline. In
Recent publications, such as those mentioned above, have raised the question of whether those in the USP

and British Pharmacopeia (BP) described the method to determine the stability of the anthraline.
It is believed that in the USP and the BP shortly for
all formulations containing anthralin the HPLC

Method is introduced.

Commercially available applications with an anthralin concentration of more than 0.5% by weight are rare if
at all, brought onto the market for outpatient treatment because such agents suffer a rapid loss of activity and oxidation of the anthraline takes place. In cases where plaque psoriasis spreads over 20% of the body surface, inpatient hospital treatment was required to avoid skin irritation because of the higher anthralin levels

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to avoid and to ensure the stability of the product and rapid handling. One major disadvantage of formulations with a low concentration of anthralin, i.e. about 0.5% or less, is that rapid treatment as with formulations containing higher anthralin concentrations is not possible is.

From the state of the art it can be seen that:

a) Anthralin is accessible to an autoxidative degradation reaction (oxidation with the participation of free radicals) and the breakdown products in psoriatic chemotherapy are ineffective;

b) the skin irritation or the anthralinist theme in the

in most cases through initially biologically active anthraline intermediates in the form of free ones Causing radicals;

c) the oxidation products of anthraline, such as its colored dimer or 1,8-dihydroxyanthraquinone, are responsible for soiling skin and clothing.

Attempts were made to apply anthralin against oxidation conventional methods, such as the use of ascorbic acid, BHA, BHT, EDTA (ethylenediaminetetraacetic acid), Citric acid, setting an acidic pH value, lowering the temperature, removing peroxides and Protection from light, stabilize. However, none of these known attempts was to stabilize the Anthraline suitable.

On the basis of the above, it is certain that the anthralin breakdown products or the first intermediate products

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in the form of free radicals which cause skin irritation and pollution, which was previously considered inevitable was accepted in anthraline therapy. If the anthralin stability could be improved, would at the same time, the skin irritation and pollution caused by the anthralin breakdown products avoided will.

Even if new formulations of anthralin products have been developed that are better tolerated by patients and are more comfortable and which are less discolored, the instability of anthraline arises in such formulations, which are characterized by a loss of activity and a change in color of slightly yellow to brown and black documented, but as an unsolved problem. So far there is none Anthralin formulation available in which the anthralin per se is stable over a long period of time and at the physical stability with an appealing Appearance and acceptable color is coupled. It is known that there are commercially available anthralin products discolor in a short time and take on an appearance that is unattractive and unacceptable for the end user is.

It has now been found that the desired stabilization of anthralin in compositions for topical treatment of psoriasis can be achieved by using an acid stable, water soluble anionic surfactant Agent in an anthralin-stabilizing amount to a composition that contains water, Contains anthralin and an oil-soluble antioxidant, and which has a pH of 5.3 or less. One Such a composition can, if desired, additionally contain a water-soluble antioxidant in the aqueous

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-Ali.

Phase included. Contrary to the teaching of U.S. Pat. No. 4,230,969, it has been found that the presence of a water-soluble antioxidant in the aqueous phase is not critical with regard to long-term stability of the anthraline in the formulations according to the invention. Even if it is not critical / can the presence a water-soluble antioxidant may be desirable.

10

Preferably the anthralin comes in the inventive Agents in a concentration of up to about 5.0% by weight are used. Particularly preferably used about 0.1 to about 3.0% by weight of anthralin, most preferably about 0.5 to 2.0% by weight, in the pharmaceutical agents suitable for topical administration.

According to the invention, anthralin can also be used in higher concentrations be stabilized, but the use of such agents must be done with care to avoid skin irritation to avoid. .

The anionic surfactant is used in an amount sufficient to stabilize the anthralin. Preferably the anionic surfactant comes Agent in an amount of 0.05 to 10% by weight, particularly preferably 0.1 to 5% by weight, and am most preferably 0.3 to 1.0 wt%, for use.

30th

Although it is known that anthralin is more stable at acidic pH and that the pH of anthralin containing agents can be controlled by using a dermatologically acceptable acid, it is preferable to use an acid such as lemon

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or salicylic acid. The pH of the invention Anthralin-containing agents with an acid-stable, water-soluble anionic surfactant is 5.3 and less. Lower pH values are preferred, with the risk of irritating the area however limited. The pH is preferably set to 4.0, particularly preferably to less than 3.4 a.

According to the invention, an anthralin product is created, wherein the anthralin is stable over a long period of time. This product is cosmetically acceptable for that Patients tolerate better and it does not discolor significantly when stored if it is in a suitable manner Way of packing. It can be used for long-term outpatient treatment of psoriasis with low anthralin doses, as well as for a short-term inpatient treatment with high doses of anthraline.

It is believed that the invention is based on the fact that oil particles or droplets in a liquid medium in charge one of two ways. The first possibility involves reactive adsorption of certain in Dissolution of existing ions. In the case of water, this can be the hydronium or hydroxyl ion. The majority of the oil particles or droplets dispersed in a water medium take due to the preferred Adsorption of the hydroxyl ion takes on a negative charge. The second way of charging involves charges on oil particles or droplets, the charges from the ionization of functional groups of surface-active Agents originate, e.g. phosphates, carboxylates, sulfates and sulfonates, which are on the surface

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of the particles or in the intermediate layer of the oil-water phases.
5

Molecules and ions that are adsorbed on the surfaces or in the intermediate layers are called as surfactants or surfactants. Another term is amphiphile, which suggests that the molecule or ion is a particular one Has affinity for both polar and non-polar solvents. The amphiphilic nature of the surface-active molecules or ions caused their adsorption in the interlayer between Liquid / gas or liquid / liquid can occur.

Anthralin has the following chemical structural formula:

OH 0 OH

hydrophilic side

lipophilic side

^{H H}

Anthralin is an amphiphilic molecule and therefore has a certain affinity for both polar and also non-polar groups. The amphiphilic nature of the anthralin molecules causes them to settle on the surface or enrich the intermediate layer. There they are easily exposed to attack. Under such conditions Oxidation initiators, such as oxygen, light, hydrogen or metal ions, attack Anthralin slightly and / or accelerate its decline

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build by autoxidation via free radicals. A high concentration of anthralin molecules on the surface or the intermediate layer also accelerates the dimer formation due to the intramolecular interaction.

It is believed that particles, oil droplets or micelles are formed based on the present invention whose surface carries predominantly an anionic charge, either from the anionic surface-active Agent alone or from the combination of non-ionic surfactant (s) with one or more anionic surfactants. The negatively charged surface originates from the functional groups of the anionic surfactant (s), e.g. sulfonates, Sulfates, phosphates, carboxylates, etc. The anionic groups of the acid-stable surface-active Agent is applied to the surface of the oil / water interlayer adsorbed, whereby the oil particles, droplets or micelles have a negatively charged surface is awarded. This negatively charged surface then attracts cations from the aqueous phase and repels other anions in the solution, such as hydroxyl ions, when the initial adsorption is complete. In addition to these electrical forces, thermal motion appears to be uniformly distributed of all ions in solution to cause. This leads to an equilibrium situation, so that the system as a whole is electrically neutral.

There is more anthralin in the oil phase Distribution ratio of the anthraline between oil and Water is about 5,000 to 10,000: 1. In case of

Preparations based on an oil-in-water emulsion, for example a cream or gel, etc. or im In the case of emulsified ointments, the anthralin molecules are dissolved in the oil phase and essentially become therein δ retained. As soon as the first adsorption on the surface is complete, the surface is through molecules the anionic and / or non-ionic surface-active Busy means. The anthralin molecules do not accumulate on the surface and are through the negatively charged surface is protected, which repels hydroxyl ions or other degradation initiators.

Such a situation can be described by the diagram shown in FIG. From this diagram it can be seen that the anthralin molecules are retained in the oil phase. The line a, a '' means the surface of the particle, the oil drop or the Micelle. The adsorbed ions, which give the surface its negative charge, are called potential denotes determinant ions and originates from the anionic surfactant (s). Direct Adjacent to this surface layer is a region of firmly bound molecules of the continuous water phase along with some positive ions, mostly hydronium ions, which are also are firmly bound to the surface. The limit of this area is indicated by the line b, b '. The potential on the line b, b 'is negative, but there are fewer cations there than on the bound one negative layer. There is an excess in the area bounded by lines b, b 'and c, c' of negative ions. Beyond the line c, c 'there is an even distribution and electrical neutrality before. The line d, d 'is the outer limit.

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The anionic (s) used according to the invention to stabilize anthralin-containing agents surface-active agent (s) leads to a significant increase in the stability of the anthraline. It is believed that the anionic surfactant or the means the AnthraVin by surface separation or protects by creating a negatively charged surface that forms micelles. Even if already the anionic surfactant or agents when put in one of the anthralin Applying a stabilizing amount, is responsible for the advantages of the agents according to the invention the stabilization is still achieved through the use of antioxidants already contained in anthralin Compositions used are further increased.

The acid-stable, water-soluble, anionic surfactants useful in the present invention are easily available. For example, they can be selected from non-soap surfactants Agents such as alkyl sulfates, alkyl sulfonates, alkylbenzenesulfonates, a-sulfonyl fatty acids, alkyl phosphates, Dioctyl sulfosuccinate, isethionates, alkyl ether sulfates, methyl sarcosines, and the like. Preferably if you use sodium lauryl sulfate, sodium octoxynol-3-sulfonate, Sodium dodecylbenzenesulfonate, sodium laurylsulfonate, DEA-oleth-3-phosphate, sodium dioctylsulfosuccinate, Sodium cocyl isothionate, sodium laureth sulfate and sodium lauryl sarcosinate and the like. Mixtures of the surfactants can also be used be used.

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In contrast to previously known preparations, the agents according to the invention have long-term stability without Use water-soluble antioxidants, even if these are added for even better results can.

It has also been found that those used according to the invention anionic surfactants in combination with oil-soluble antioxidants increase stability of the anthraline increase significantly. Typical examples of such antioxidants are ascorbylpamitate, hydroquinone, Propyl gallate, nordihydroguaiaretic acid, BHT, BHA, a-tocopherol, phenyl-a-naphthylamine and lecithin.

It has also been found that water-soluble antioxidants are also used in the aqueous phase can. Typical examples of such antioxidants are sodium sulfite, sodium metabisulfite, sodium bisulf it, sodium thiosulfate, sodium formaldehyde. sulfoxylate, Acetone Sodium Metabisulfite, Ascorbic Acid, Isoascorbic Acid, Thioglycerin, Thiosorbitol, Thiourea, Thioglycolic acid and cysteine hydrochloride.

The anionic surface-active agents used according to the invention can also be used together with nonionic surfactants such as polyalkoxy ethers, Polyalkoxyesters, polyalkoxyamides, fatty acid esters of polyalcohols and fatty alcohols are used will. The nonionic surfactants minimize those caused by the anions Skin irritation. If desired, the anionic surfactants may be compatible in combination with Thickeners, such as methyl cellulose, tragacanth,

Sodium alginate, Carbopol 934 (CTFA), bentonite, carboxymethyl cellulose and Vee rubber (CTFA) can be used. (CTFA) means the name used in the nomenclature in the CTFA Cosmetic Ingredient Directory, 3rd Edition, published by the CTFA Association, Inc.

Due to the low stability of anthralin in dermatological preparations, anthralin-containing So far, preparations rarely, if ever, with an anthralin concentration of more than 0.5% by weight in the Trade brought. Because of the improved anthralin stability according to the invention, it is now possible, very much stable preparations with regard to the anthralin concentration and the physical stability of the formulations itself, with such formulations being extremely useful in the topical treatment of psoriasis are effective. These preparations can have anthralin concentrations of 0.1 to 5.0% by weight or more and are useful for the outpatient treatment of psoriasis. They also have short term high temperature storage stability studies and Arrhenius plots of obtained on the basis of such preparations Data show that both anthralin and the preparations are stable for more than two years at room temperature are. The stability was determined by means of the HPLC method. As part of these investigations, the retention less than 90% of the anthralin concentration is considered unacceptable.

In order to demonstrate the stability of the anthralin-containing agents according to the invention, gel compositions were which contained 1% by weight of anthralin (plus 0.05% by weight surcharge). The production took place according to the basic composition of the gel given in Example 1 below. All gel compositions

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spoke of this base gel composition and were except for the surfactant used identical. In addition to the gel compositions according to the invention based on the acid-stable, water-soluble anionic surfactants have been made gel compositions using the cationic amine surfactant, Richamate 1655, a product of the Richardson Company, and using triethanolamine stearate, an acid-unstable, water-soluble anionic surfactant Means made. These experiments should show that in the gels containing the latter Classes of surfactants include that anthralin,: is unstable. "- The samples were stored at room temperature, 35 ° C and 45 ° C and then rated.

example 1

Composition of the base gel

Part A

Mineral oil (USP) 164 g

Propyl gallate 0.5 g

BHT 2.0 g

Salicylic acid 2.0 g

Oleth-2 (CTFA) 60.0 g

Isoceteth-20 (CTFA) 200.0 g

Ascorbyl palmitate 1 »0 g

Anthralin. 10/5 g

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- 25th

part B

PEG-8 (CTFA) 50, supra

Sorbitol solution (70%) 20.0 g

EDTA 1.0 g

Sodium bisulfite 1.0 g

Ascorbic acid 10.0 g

surfactant 5.0 g

Purified water (USP) ad 1000.0 g

The compositions are prepared by mixing the ingredients of Part A and heating to 90 ° C. Stirring is continued until all of the solids are mixed. The components of part B are mixed in a separate vessel and heated to 90 ° C with stirring until all solids are dissolved are. Part B is added to Part A and the resulting mixture is stirred. The mixture is stirred for a further 10 min, with the temperature is kept at 90 C. The gel obtained is cooled to packaging temperature and under an inert gas packed in aluminum tubes with a suitably coated interior so that it does not react with the Product can be made.

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TABLE I. Anthralin instability

Surface-active storage anthralin agent tein content

rature

corresponding

45 days 215 days

A. Sodium lauryl
sulfate RT
350c
45 ° C 1
1
1 .05%
.05%
.05% 1,027-0 / 0
*
1.006-0 / 0 1
O
O .09%
, 96%
, 718% B. cationic amine
(Richamate 1655) RT
35 ° C
45 ° C 1
1
1 .05%
.05%
.05% 0.529-0 / 0
0-0 / 0
0-0 / 0 O
O
O , 42% C. Triethanolamine
stearate RT
35 ° C
45 ° C 1
1
1 .05%
.05%
.05% 0.599-0 / 0
*
0.00343-0 / 0 O
O
O, .084%
_r O58% D. Sodium dioctyl
sulfosuccinate RT
350c
45 ° C 1
1
1 .05%
.05%
.05% 1.045-0 / 0
0.978-0 / 0 1,
0,
0, . 07%
_r 989%
, 762% E. Sodium alkyl
olefin sulfonate RT
350C
450c 1,
1,
1, _r 05%
.05%
_r 05% 1,080-0 / 0
*
1,012-0 / 0 1,
O ₁
O ₁ . 06%
, 935%
, 800% F. Sodium cocyl
isothionate RT
35 ° C
45 ° C 1,
1, _r 05%
.05%
.05% 1,076-0 / 0
*
1,026-0 / 0 1,
0,
0, 09% **
958%
833% G. DEA-oleth-3-
phosphate RT
. 350c
45 ° C 1,
1,
1. .05%
.05%
05% 1,091-0 / 0
*
1,049-0 / 0 1,
0,
0, O9%
989%
777% H. Sodium laureth
sulfate RT
35 ° C
45 ° C 1,
1,
1" 05%
05%
05% 1,089-0 / 0
*
1,046-0 / 0 1,
0,
0, 094%
982%
585% I. Sodium lauryl
sulfonate RT
35 ° C
45 ° C 1,
1,
1, 05%
05%
05% 1,069-0 / 0
*
0.943-0 / 0 1,
0,
0, 054%
928%
781% J. Sodium octoxynol
3-sulfonate RT
35 ° C
450c 1/
1,
1, 05%
05%
05% 1.378-0 / 0
*
1,019-0 / 0 0,
0,
0, 994%
936%
785%

*not determined.

** The data for 45 days and 215 days, respectively, suggest that the samples stored for 215 days are more stable than the samples stored for 45 days. This is explained by the fact that the analytical method is not sensitive enough to these differences to detect at such low concentrations.

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Based on the base gel composition of the example 1, preparations with higher concentrations of surface-active agent are prepared, around the upper limit to show the range in which the acid-stable, water-soluble, anionic surfactants can be used. Although even higher concentrations are possible, notes the occurrence of skin irritation is a limit. Table II below shows the results of this Research compiled ..

TABLE II

Boundary surface-active s middle

Storage anthraline temperature content
rature

corresponding

45 days 215 days

Sodium lauryl sulfate (5%)

Sodium Lauryl Sulphate (10%)

RT 1.05%

35 ° C 1.05%

45 ° C ** 1.05%

RT 1.05%

35 ° C 1.05%

45 ° C ** 1.05%

1.068% 1.09% * *

0.978% 0.136%

1.01% 1.03%

* 0.932% 0.389% 0.119%

*not determined.

** The loss of activity of these samples is due to damaged areas in the tubes, which are caused by defective seals originate from, and can be attributed to a loss of viscosity at high temperature-

1.15 G 20.0 G 16.0 G 6.0 G 0.2 G 0.1 G 0.1 G 0.01 G

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Example 2

A gel is prepared on the basis of the following Formu-5

deration:

Part A

Anthralin (including 15% surcharge) Isoceteth-20 (CTFA)
Mineral oil (USP)
Oleth-2 (CTFA)
Salicylic acid
Ascorbyl palmitate

15 ^BHT

Propyl gallate

part B

PEG-8 (CTFA). 5.0 g

Sorbitol solution (70%) 2.0 g

Ascorbic acid 1.0 g

Sodium Lauryl Sulphate 0.3 g

Citric acid 0.1 g

Sodium bisulfite 0.05 g

EDTA 0.01 g

Purified water (USP) ad 100.00g

The gel is prepared by mixing the ingredients of Part A and heat it to 90 ⁰ C. Continue stirring until all of the solids are mixed. The components of part B are mixed in a separate vessel and heated to 90 ° C. with stirring until all solids have dissolved. Part B and part A are mixed and the mixture is stirred for a further 10 minutes, the temperature being kept at 90.degree. The gel obtained is brought to packaging temperature

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cools and under an inert gas atmosphere in aluminum tubes, which have a non-reactive coating on the inside.

The formulation according to Example 2 was clinically evaluated. The composition was that in all cases same, only the anthralin concentration varied. The clinical examinations were conducted by dermatologists with great experience in the evaluation of drugs for the treatment of psoriasis.

The clinical studies show that the gel compositions according to the invention containing 0.5 to 2% by weight Anthralin contain particularly good results in patients who receive short-term therapy once a day for a 6-week period of 10-20 min. Patients treated in this way suffered from psoriasis that ranged from local lesions to lesions over most of the body surface. The state of Patient was assessed after 6 weeks. The results are summarized in Table III and clearly show the effectiveness of the gel stabilized according to the invention with 0.5 to 2% by weight of anthralin.

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-2η- • £% ■

TABLE III

Anthralin (%) skin applied: clinical number evaluating treatment con- Anspre- tender

permanent takt chen * pa doctor

(min) tien-

th

1%
2% 1 .
5 week
Weeks 20th
10 on entire
body Well 9 Dr .H 1%
2% 1 .
5 week
Weeks 20th
10 only on
Lesions excellent
net 10 Dr .R 0.5%
1% 1
5 .Week
Weeks 20th
10 only on
Lesions excellent
net 10 Dr .E 0.5%
1 % 1
5 .Week
Weeks 20th
10 only on
Lesions excellent
net 20th Dr • V / E 0.5%
1% 1
5 .Week
Weeks 20th
10 only on
Lesions excellent
net 11th Dr .B

* "good" means moderate to significant clearing, "Excellent" means significant to complete Clearing.

In the meantime, the clinical evaluation of the composition started according to example 6. First "with the composition according to Example 6 (without a water-soluble Antioxidant in the aqueous phase) results obtained differ with respect to the clinical

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Efficacy in the short-term treatment of psoriasis not from those with the composition according to the example 2 (containing a water-soluble antioxidant in the aqueous phase).

The present invention solves the problem of anthralin instability. The agents according to the invention thus facilitate short-term therapy and are therefore particularly useful for treating Psoriasis.

! 5 Example 3

A cream is prepared according to the following formulation:

Part A

Petrolatum ²⁰ mineral oil (USP

Steareth-2 (CTFA) Steareth-100 (CTFA) Anthralin

contains 15% surcharge 25 salicylic acid

Propyl gallate

BHT

As corbyl palmitate

200.0 G 50.0 G 12.5 G 2.5 G 11.5 G 3.5 G 0.05 G 0.5 G 0.5 G

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part B

Sodium Lauryl Sulphate 1.50 g

Ascorbic acid 2.0 g

PEG-8 (CTFA) 60.0 g

dried sodium phosphate 0.75 g

EDTA 0.5 g

Sorbic acid 0.5 g

Xanthan Gum (USP) 3.25 g

Purified water (USP) ad 500.00 g

The cream is prepared by mixing the ingredients of Part A and heating to 70 ° C. One stirs continue until all solids are mixed. The components of the are mixed in a separate vessel Part B and heat with stirring to 70 ° C until all solids are dissolved. Part B and Part A are mixed together. Stirring is continued, while maintaining the temperature of 70 ° C, until the two parts are thoroughly are mixed. The cream obtained is cooled to packaging temperature and packaged.

25 Example 4

A stick composition is made according to the following formulation manufactured:

Syncrowax HGL-C (Croda) 30 Syncrowax ERL-C (Croda)

Petrolatum

Mineral oil (USP)

Salicylic acid

Propyl gallate
35 BHT

45.0 G 15.0 G 310.0 G 120.0 G 0.5 G 0.05 G 0.25 G

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Ascorbyl palmitate 0.5 g

Sodium Lauryl Sulphate 2.5 g

Ascorbic acid 0.25 g

Anthralin 5.75 g

Purified Water (USP) 4.0 g

The sodium lauryl sulfate and the ascorbic acid are dissolved in water and added to the remaining, pre-mixed at 80 ⁰ C components. The mixture is then cooled to 75 ^° C. The composition is then poured into molds, allowed to cool and settle and packaged.

Example 5

An ointment is prepared according to the following formulation:

Cetostearyl alcohol 20 white soft paraffin

liquid paraffin

Sodium lauryl sulfate

Salicylic acid

Ascorbyl Palmitate 25 BHA

EDTA

Ascorbic acid

Anthralin

purified water (USP)

All components except the Anthralins be mixed violently with water at 75 ⁰ C until the bubbling ceases. The anthralin is then added and the mixture is stirred for a further 30 minutes, and the composition is cooled

35 55 ⁰ C and unpacks.

280.0 G 500.0 G 200.0 G 5.0 G 2.0 G 1.0 G 0.5 G 0.05 G 0.05 G 11.5 G 4.00 G

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Examples 6 and 7 describe two further gel compositions, which can be prepared according to the method described in Example 1 and which are in prove to be extremely stable in a long-term storage test.

Example 6

Part A

Anthralin 11.5 g

Isoceteth-20 (CTFA) 200.0 g

Oleth-2 (CTFA) 60.0 g

. r. Mineral oil (USP) 165.0 g

Propyl gallate 0.1 g

BHT 1f 0 g

Salicylic acid 2.0 g

Ascorbyl palmitate 1.0g

part B

PEG-8 (CTFA) 50.0 g

Sorbitol (70% solution) 20.0 g

EDTA 0.2 g

Citric acid 5.5 g

Sodium Lauryl Sulphate 5.0 g

Purified water (USP) ad 1000.0 g

M / 25107

Example 7

Part A

Anthralin Isoceteth-20 (CTFA) Oleth-2 (CTFA) Mineral oil (USP) propyl gallate BHT

Salicylic acid ascorbyl palmitate

part B

PEG-8 (CTFA)

Sorbitol (70% solution)

As corb in acidic sodium bisulfite EDTA

Sodium lauryl sulfate

purified water (USP) ad

The anthraline compositions according to the invention can can be formulated and used as a cream, gel, ointment, or stick. Because of the easy application they are preferably used as a cream or gel.

10.5 G 200.0 G 60.0 G 160.0 G 0.5 G 2.0 G 2.0 G 1.0 G 50.0 G 20.0 G 10.0 G 1.0 G 1.0 G 5.0 G 1000.0 G

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Claims (27)

M / 25107 PATENT CLAIMS 1. Pharmaceutical agent for the topical treatment of psoriasis, the water, an oil-soluble antioxidant and contains an antipsoriatic effective amount of anthralin, characterized that it is an acid stable, water soluble anionic surfactant in an amount sufficient to stabilize the anthraline. 2. Composition according to claim 1, characterized in that the surface-active Agent is stable at a pH of about 5.3 and below. 3. Composition according to claim 1, characterized in that the surface-active Agent is stable at a pH of about 4 and below. 4. Composition according to claim 1, characterized in that the surface-active Agent is stable at a pH of about 3 to 4. 5. Composition according to claim 1, characterized in that the surface-active Agent is stable at a pH of about 3.2. M / 25107 6. Agent according to claims 2, 3, 4 or 5, characterized in that it, based on the total weight of the agent, about 0.5 to 5.0% by weight of anthralin and about 0.05 to contains about 10% by weight of the surfactant. jQ 7. Means according to claims 2, 3, 4 or 5, d a through characterized in that it, based on the total weight of the agent, about 0.1 to about 3.0 wt .-% anthralin and about 0.1 to about 5.0% by weight of the surfactant , contains p-means. 8. Agent according to claims 2, 3, 4 or 5, characterized in that it, based on the total weight of the agent, approximately 2Q 0.5 to about 2.0 wt% anthralin and about Contains 0.3% to about 1.0% by weight of the surfactant. 9. Means according to claims 2, 3, 4 or 5, since ₂ c characterized in that it, based on the total weight of the agent, about 0.1 to about 3.0 wt .-% anthralin and a contains surfactant selected from alkyl sulfates, alkyl sulfonates, alkyl benzenesulfonates, sulfonyl fatty acids, alkylphospha-30 ten, dioctyl sulfosuccinate, isethionates, alkyl ether sulfates, Methyl sarcosines and similar non-soap anionic surfactants Means. M / 25107 10. Means according to claims 2, 3, 4 or 5, d a characterized in that it, based on the total weight of the composition, about 0.5 to about 2.0 wt .-% anthralin and a surfactant Contains agents selected from alkyl sulfates, sulfonates, alkylbenzenesulfonates, Sulfonyl fatty acids, alkyl phosphates, dioctyl sulfosuccinate , Isethionates, alkyl ether sulfates, Methyl sarcosines. and like non-soap anionic surfactants. 11. Means according to claims 2, 3, 4 or 5, d a through characterized in that it, based on the total weight of the agent, about 0.1 to 5.0 wt .-% anthralin and about 0.05 to Contains 10.0% by weight of the surfactant selected from alkyl sulfates, sulfonates, Alkylbenzenesulfonates, sulfonyl fatty acids, alkyl phosphates, dioctyl sulfosuccinate, isethionates, Alkyl ether sulfates, methyl sarcosines. and the like non-soap, anionic surfactants Means. 12. Means according to claims 2, 3, 4 or 5, characterized in that it, based on the total weight of the agent, approximately Contains 0.1 to 3.0% by weight of anthralin and about 0.1 to 5.0% by weight of the surfactant, which is selected from alkyl sulfates, sulfonates, alkylbenzenesulfonates, sulfonyl fatty acids, alkyl phosphates, Dioctyl sulfosuccinate, isethionates, alkyl ether sulfates, methyl sarcosines and the like non-soap anionic surfactants. M / 25107 13. Means according to claims 2, 3, 4 or 5, characterized in that it, based on the total weight of the agent, approximately 0.5 to 2.0% by weight of anthralin and approximately 0.3 to 1.0% by weight of the surfactant selected from alkyl sulfates, Sulfonates, alkylbenzenesulfonates, sulfonyl fatty acids, Alkyl phosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulfates, methyl sarcosines and like non-soap anionic surfactants. 14. Composition according to claim 11, characterized in that the surface-active Agent is sodium lauryl sulfate. 15. Means according to claim 1, characterized in that - indicates that it is present as an oil-in-water emulsion and the emulsion in the aqueous Phase does not contain an antioxidant. 16. Agent according to one of claims 1 to 15 in solid form. 17. Composition according to one of claims 1 to 15 in the form of a cream. 18. Agent according to one of claims 1 to 15 in the form of a gel. 19. Agent according to one of claims 1 to 15 in the form an ointment.
35 M / 25107 20. Means according to claim 1, characterized in that it is an oil-in-water or water-in-oil emulsion is present and the oil phase an amount of an oil soluble one sufficient to increase the stability of the anthraline Contains antioxidant. 21. Composition according to claim 20, characterized in that it is an oil-in-water emulsion is present. 22. Means according to claim 20, characterized in that that there is a sufficient amount of a water-soluble antioxidant in the anthraline to increase its stability Contains water phase. 23. Composition according to claim 1, characterized in that the surface-active anionic agents a mixture of two or more suitable anionic surfactants Means is. 24. A method for increasing the stability of agents containing anthralin, characterized that such agents have a sufficient amount of an acid-stable to increase the stability of the anthraline water-soluble, anionic surfactant added. 25. The method according to claim 24, characterized in that the pH of the M / 25107 Means adjusts to 5.3 or below. 26. The method according to claim 24, characterized in that the means an oil-soluble antioxidant is added if the emulsion contains an oil phase. 27. The method according to claim 26, characterized that one adds a water-soluble antioxidant to the agent.