Pharmaceutical preparations for treating psoriasis, psoriatic arthritis, neurodermitis and enteritis regionalis Crohn.

The invention relates to pharmaceutical preparations for the treatment of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn (Crohn's disease) for the systemic therapy of these diseases.

Pharmaceutical preparations which, after administration, when they biodegrade or belong to the citric acid cycle, usually gain more and more therapeutic value in high doses, since they can be used to alleviate or heal cryptogenic diseases.

For example, fumaric acid inhibits the growth of Ehrlich's ascetic tumor in mice, reduces the toxic effects of mitomycin C and aflotoxin (K. Kuroda, M. Akao, Biochem. Pharmacol. <u style="single">29</u>, 2839-2844 (1980) / Gann. <u style="single">72</u>, 777-782 (1981) / Cancer Res. <u style="single">36</u>, 1900-1903 (1976)) and has an antipsoriatic and antimicrobial effect (CN Huhtsnen, J. Food Sci. <u style="single">48</u>, 1574 (1983) / MN Islam, U.S. Patent 4,346,118 of Aug. 24, 1982 / CA <u style="single">97</u>, 161317b (1982)).

High administration doses of fumaric acid or its previously known derivatives such as dihydroxyfumaric acid, fumaramide and fumaronitrile have such an unacceptable rate of side effects and high toxicity when administered parenterally, dermally, but especially perally (P. Holland, RG White, Brit. J. Dermatol. <u style="single">85</u>, 259-263 (1971) / M. Hagedorn, KW Kalkoff, G. Kiefer, D. Baron, J. Hug, J. Petres, Arch. Derm. Res. <u style="single">254</u>, 67-73 (1975)) that up to now such therapy has had to be avoided.

European patent application No. 85 116 011.9 dated December 16, 1985 already describes fumaric acid derivatives and pharmaceutical preparations containing them for the treatment of psoriasis. It has now surprisingly been found that an overall significantly improved effect can be achieved by mixed preparations which contain one or more compounds from the group of the calcium, magnesium, zinc and iron salts of fumaric acid monoalkyl esters of the general formula<chemistry id="chem0001" num="0001"><img file="EP0312697A2_D0001.tif" /></chemistry> alone or preferably in a mixture with dialkyl fumarate of the formula<chemistry id="chem0002" num="0002"><img file="EP0312697A2_D0002.tif" /></chemistry> and customary pharmaceutically acceptable auxiliaries and carriers.

Preferred mixed preparations according to the invention contain the calcium salt of fumaric acid monoethyl ester, the calcium salt of fumaric acid monoethyl ester in a mixture with dimethyl fumarate, the calcium and zinc salt of fumaric acid monoethyl ester in a mixture with dimethyl fumarate or the calcium, magnesium and zinc salt of fumaric acid monoethyl in a mixture with dimethyl fumarate.

Mixed preparations which contain the calcium salt of the fumaric acid monoalkyl ester in an amount of 100 to 300 mg are particularly suitable for oral administration, the total weight of the active ingredients being 100 to 300 mg.

Further preferred oral forms of administration contain 10 to 290 parts by weight of the calcium salt of the fumaric acid monoalkyl ester and 290 to 10 parts by weight of dimethyl fumarate, 10 to 250 parts by weight of the calcium salt of the fumaric acid monoalkyl ester, 1 to 50 parts by weight of dimethyl fumarate and 1 to 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester or 10 to 250 parts by weight of the calcium salt of the fumaric acid monoalkyl ester, 250 bois 10 parts by weight of dimethyl fumarate, 1 up to 50 parts by weight of the magnesium salt of the fumaric acid monoalkyl ester and 1 to 50 parts by weight of the zinc salt of the fumaric acid monoalkyl ester, the total weight of the active ingredients in each case being 100 to 300 mg.

A low dosage is advantageous for the systemic entry into the treatment or the exit, for example from 30.0 mg of dimethyl fumarate, 67.0 mg of the calcium salt of monoethyl fumarate, 5.0 mg of the magnesium salt of monethyl fumarate and 3.0 mg of the zinc salt of monoethyl fumarate contains.

A dose of 120.0 mg of dimethyl fumarate, 87.0 mg of the calcium salt of the monoethyl fumarate, 5.0 mg of the magnesium salt of the monoethyl fumarate and 3.0 mg of the zinc salt of the monoethyl fumarate can be used for the therapeutic dosage after an initial phase.

The fumaric acid derivatives contained in the preparations according to the invention are obtained, for example, by using a compound of the following formula<chemistry id="chem0003" num="0003"><img file="EP0312697A2_D0003.tif" /></chemistry><ul id="ul0001" list-style="none"><li>a) condensed with 2 mol of alkyl alcohol (ROH) to the diester and then hydrolyzed in a controlled manner to form the monoester, or</li><li>b) condensed with 1 mol of a corresponding alkyl alcohol (ROH) and the monoacid chloride obtained hydrolyzed to the acid, or</li><li>c) fumaric acid is directly condensed with 2 mol of alkyl alcohol (ROH) according to claim 1 to a diester and then hydrolyzed in a controlled manner to form the monoester, or</li><li>d) maleic acid or maleic anhydride is directly condensed with 1-2 moles of the corresponding alkyl alcohol (ROH) according to claim 1 to form a mono- or diester and then isomerized catalytically to the corresponding fumaric acid derivative.</li></ul>

The salts of the fumaric acid monoalkyl esters can be obtained by using a compound of the general formula<chemistry id="chem0004" num="0004"><img file="EP0312697A2_D0004.tif" /></chemistry> in which R is a C₁-C₅ alkyl group, with half a mole of Ca, Mg or Zn hydroxide or oxide in toluene to react and the water formed during the reaction is removed azeotropically.

example 1

Production of film-coated tablets with a stomach-resistant coating containing 210 mg of monoethyl fumarate Ca salt, corresponding to 150 mg of fumaric acid:

21,000 kg of monoethyl fumarate calcium salt are crushed, mixed and homogenized using a sieve 800 with appropriate precautions (respiratory mask, gloves, protective suit, etc.). An auxiliary mixture of the following composition is then produced: 20,000 kg of starch derivative (STA-RX 1500^R), 2,000 kg microcrystalline cellulose (Avicel PH 101 ^R), 0.600 kg polyvinylpyrolidone (PVP, Kollidon ^R 25), 4,000 kg Primogel ^R, 0.300 kg of colloidal silica (Aerosil ^R). The entire powder mixture is mixed with the active ingredient and homogenized using a sieve 200 and with a 2% aqueous solution of polyvinylpyrolidone (Kollidon^RK30) processed in the usual way to a binder granulate and mixed in a dry state with the outer phase. This consists of 2,000 kg of a so-called FST complex, containing 80% talc, 10% silica and 10% magnesium stearate. It is then pressed in the usual way into curved tablets of 500 mg in weight and 11.5 mm in diameter. Instead of these classic tableting methods, other methods for producing tablets can also be used, direct tableting and solid dispersions using the melting method and the spray drying method.

Stomach resistance:

A solution of 2.250 kg of hydroxypropylmethyl cellulose phthalate (HPMCP, Pharmacoat HP 50 ^R) in a solvent mixture of 2.50 l demineralized water, 13.00 l acetone Ph.Helv.VII and 13.00 l ethanol 94% by weight and 0.240 kg castor oil (Ph. Eur. II) was added to the solution. In the coating pan, the solution is traditionally poured onto the tablet cores in portions or sprayed on or applied in a fluidized bed apparatus of the appropriate construction.

After appropriate drying, the <u style="single">Film cover</u> appropriate. This consists of a solution from Eudragit^R E 12.5% ​​4,800 kg. Color lacquer ZLT 2 blue (Siegle) 0.210 kg, titanium (VI) oxide Kronos RN 56 0.520 kg. Talc (Ph. Eur.) 0.340 kg and polyethylene glycol 6000 Ph. Helv. VII 0.120 kg. in a solution mixture of 8,200 kg 2-propanol, Ph. Helv. VII, 0.060 kg glycerol triacetate and 0.200 kg Aqua demineralisata. After homogeneous distribution in the coating pan or fluidized bed, the mixture is dried and polished in the customary manner.

Example 2

Production of stomach-resistant capsules containing 86.5 mg of monoethyl fumarate Ca salt and 110.0 mg of dimethyl fumarate, corresponding to a total of 150 mg of fumaric acid

8.650 kg of monoethyl fumarate Ca salt and 11,000 kg of dimethyl fumarate are mixed with a mixture consisting of 15,000 kg of starch, 6,000 kg of lactose Ph. Helv. VII, 2,000 kg of microcrystalline cellulose (Avicel ^R), 1,000 kg polyvinylpyrolidone (Kollidon ^R 25) and 4,000 kg Primogel ^R mixed intensively and homogenized using a sieve 800, taking appropriate protective measures (respiratory mask, gloves, protective suit etc.) into account. The entire powder mixture is mixed with a 2% aqueous solution of polyvinylpyrolidone (Kollidon^R 25) processed in the usual way to form a binder granulate and mixed with the outer phase in the dried state. This consists of 0.350 kg of colloidal silica (Aerosil^R), 0.500 kg of Mg stearate and 1.500 kg of talcum Ph. Helv. VII. The homogeneous mixture is then filled into appropriate capsules in 500.0 mg portions, which are then coated in the usual way with a stomach-resistant coating consisting of hydroxypropylmethyl cellulose stearate and castor oil Plasticizers. Instead of hard gelatin capsules, they can also be filled into appropriate gastro-resistant capsules, consisting of a mixture of cellulose acetate phthalate (CAP) and hydroxypropylethyl cellulose phthalate (HPMCP).

Example 3

Production of gastro-resistant capsules containing 203.0 mg of monoethyl fumarate Ca salt and 5.0 mg of monoethyl fumarate Mg salt and 3.0 mg of monoethyl fumarate Zn salt, corresponding to a total of 150 mg of fumaric acid

20.300 kg of monoethyl fumarate Ca salt as well as 0.500 kg of monoethyl fumarate Mg salt and 0.300 kg of monoethyl fumarate Zn salt are crushed, mixed intensively and homogenized with appropriate protective measures (breathing mask, gloves, protective suit, etc.) using a sieve 800. A homogeneous powder mixture of the following composition is mixed into this active substance mixture: spray-dried lactose 12,900 kg, colloidal silica 1,000 kg, microcrystalline cellulose (Avicel^R) 2,000 kg, magnesium stearate (Ph. Helv. VII) 1,000 kg and talc (Ph. Helv. VII) 2,000 kg. The entire powder mixture is homogenized again using a sieve 200 and then filled into hard gelatin capsules with a net weight of 400 mg and sealed. The coating with a stomach-resistant coating takes place as in Example 2.

Example 4

Preparation of stomach-resistant tablets containing 87.0 mg monoethyl fumarate Ca salt, 120.0 mg dimethyl fumarate, 5.0 mg monoethyl fumarate Mg salt and 3.0 mg monoethyl fumarate Zn salt corresponding to 164 mg fumaric acid ("Forte" tablets)

12,000 kg dimethyl fumarate, 8,700 kg monoethyl fumarate Ca salt, 0.500 kg monoethyl fumarate Mg salt and 0.300 kg monoethyl fumarate Zn salt are crushed, mixed intensively and homogenized using a sieve 800, taking appropriate protective measures (respiratory mask, gloves, protective suit etc.) into account. An excipient mixture of the following composition is produced, in a similar manner to that listed in Example 1: Starch derivative (STA-RX 1500^R) 18,000 kg, microcrystalline cellulose (Avicel pH 101 ^R) 0.300 kg, polyvinyl pyrolidones (PVP, Kollidon ^R 120) 0.750 kg, Primogel ^R 4,000 kg and colloidal silica (Aerosil ^R) 0.250 kg. Excipients and active ingredient mixture are mixed intensively and homogenized using a sieve 200. The whole is with a 2% aqueous solution of polyvinyl pyrolidone (Kollidon^R K25) processed in the usual way to a binder granulate and mixed with the outer phase in the dried state. This consists of 0.500 kg Mg stearate (Ph. Eur.) And 1.500 kg talc (Ph. Eur. II). The whole granulate is then pressed in the usual way into curved tablets of 500 mg gross mass and 11.5 mm in diameter. Instead of this classic tabletting method, other methods of tablet production can also be used, such as direct tableting and solid dispersions using the melt and spray drying methods.

The enteric coating can be poured on or sprayed on in a classic coating pan and can also be applied in a fluidized bed apparatus. A solution of 2.250 kg of hydroxypropylmethylcellulose phthalate (HPMCP, Pharmacoat HP 50^R) dissolved in a mixture of the following solvents: acetone 13.00 l, ethanol 94% by weight denatured with 2% ketone 13.50 l and aqua demineralisata 2.50 l. Castor oil Ph. Eur. 0.240 kg is added to the finished solution as a plasticizer and applied in portions to the convex tablet cores in the usual way.

Filmcoat: After drying is completed, a suspension of the following composition is then drawn up as a filmcoat in the same apparatus: Talcum Ph. Eur. II 0.340 kg, titanium (VI) oxide Cronus RN 56 ^R 0.400 kg, color varnish L-red varnish 86237 N 0.324 kg, Eudragit E 12.5% ^R 4,800 kg and polyethylene glycol 6000 pH 11 XI 0.120 kg in a mixed solution of the following composition: 2-propanol DAB 8.170 kg, Aqua demineralisata 0.200 kg glycerol triacetate (triacetin ^R) 0.060 kg.

Example 5

Preparation of stomach-resistant film-coated tablets containing 67.0 mg monoethyl fumarate Ca salt, 30.0 mg dimethyl fumarate, 5.0 mg monoethyl fumarate Mg salt and 3.0 mg monoethyl fumarate Zn salt corresponding to 75 mg fumaric acid ("Mite" tablets)

3.000 kg of dimethyl fumarate, 6.700 kg of monoethyl fumarate Ca salt, 0.500 kg of monoethyl fumarate Mg salt and 0.300 kg of monoethyl fumarate Zn salt are comminuted, mixed intensively and homogenized using a sieve 800. Appropriate protective measures such as a breathing mask, gloves, protective suit, etc. should be used. Then a mixture consisting of 30,000 kg of starch derivative (STA-RX 1500^R), 3,000 kg microcrystalline cellulose (Avicel pH 101 ^R), 0.750 kg polyvinylpyrolidone (PVP Kollidon ^R 25), 4,000 kg Primogel ^R, 0.250 kg colloidal silica (Aerosil ^R) offset. The mixture of active ingredients is mixed in homogeneously, passed through a sieve 200 and worked up with a 2% aqueous solution of polyvinylpyrolidone (K 25) in the customary manner to give a binder granulate. A powder mixture of the following auxiliaries is added to the dried granules as the outer phase: 0.500 kg Mg stearate Ph. Eur. II and 0.800 kg talc Ph. Helv. VII.

The homogeneous mixture of granules is compressed into curved tablet cores weighing 500.0 mg and 11.5 mm in diameter in the usual way. In addition to the binder methods, other tableting methods according to Examples 1 and 4 can also be used.

The tablet cores are coated with a stomach-resistant coating and with a film coat in a manner analogous to that described in Examples 1 and 4.

The preparations according to the invention are preferably administered orally in the form of tablets or capsules, these solid single-dose medicinal forms preferably being provided with a stomach-resistant coating which, after passage through the stomach in the small intestinal juice, dissolves in the small intestine within a few minutes and releases the active principle from the pharmaceutical form. For systemic entry or Exit requires a low dose (middle), for the therapeutic dose after the entry phase a higher dose (forte).

It was found that the mixed preparations according to the invention, after oral administration, have a considerably improved action against the most diverse clinical manifestations of psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn (Crohn's disease).

Since the activity of phospholipase A₂ is changed in a psoriatic epidermis, a possible explanation of the mechanism of action of the mixed preparations according to the invention is that this enzyme is stimulated by calcium monoethyl fumarate, with Mg and Zn cations for the skin metabolism of psoriasis patients of great Importance.

In addition to orally administrable preparations in the form of capsules, granules and tablets, the invention relates to cutaneous and transdermal administration in the form of ointments, plasters, lotions and shower products, to parenteral administration in the form of aqueous microdispersions, O / W emulsions or oily ones Solutions for rectal administration as suppositories or micro enemas as well as for the medicinal treatment of hair, fingernails and toenails.

Therapeutic treatment of psoriasis with the preparation according to Example 4 and its results

In an intraindividual Velaufs study over a year, the outpatient oral treatment of psoriasis was tested on a total of 24 patients (see Table 1). All patients previously responded poorly to conventional drugs and forms of therapy, so that of one<u style="single">negative selection</u> can be spoken.

Half of all orally and outpatient patients objectively showed a significant improvement, which usually only occurred after several weeks of treatment.

No serious objective side effects, in particular kidney and liver dysfunction or changes in blood count, were found.

Acute toxicity was assessed orally in mice and rats prior to clinical testing. The results showed a very low toxicity of the fumaric acid derivatives used (see Table 2).<tables id="tabl0001" num="0001"><img file="EP0312697A2_D0005.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0312697A2_D0006.tif" /></tables>

The following describes the treatment of patients with neurodermatitis and enteritis regionalis Crohn (Crohn's disease) and their therapeutic result:

HM - female - 1951

- Disease: Enteritis regionalis Crohn - Dose: 3 tablets / day (formulation according to Example 5) - Duration: 7.5.86 - 27.11.86 - Success: Since then, the bowel has been calm without medication

EL - female - 1919

- Disease: Enteritis regionalis Crohn - Start of therapy: 24.3.84 - Dose: 3 tablets / day (formulation according to Example 5) - Success: intestinal bleeding and ulcers come to rest

WCh - female - 1945

- Disease: Enteritis regionalis Crohn - Start of therapy: 9.4.1988 - Dose: 3 tablets / day (formulation according to Example 5) - Success: everything calmer, but too early to judge

NK - male - 1971

Disease: neurodermatitis - Duration of the disease: 16 years - Start of therapy: 16.12.87 - Dose: 3 tablets / day (formulation according to Example 4) - Success: very good

DN - female - 1926

- Disease: neurodermatitis - Duration of the disease: 40 years - Start of therapy: 4.9.86 - Dose: 2 tablets / day (formulation according to Example 4) - Success: good

AS - female - 1941

- Disease: neurodermatitis - Duration of the disease: 20 years - Start of therapy: 16.12.87 - Dose: 6 tablets / day (formulation according to Example 5) - Success: very good

DE - female - 1960

Disease: ichthyosis - Start of therapy: March 15, 1988 - Dose: 6 tablets / day (formulation according to Example 5) - Success: good