Indian Patents. 212733:A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE

Title of Invention	A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE
Abstract	"A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE" The present invention discloses a pharmaceutical composition in the form of micro-tablets or micro-pellets and comprising at least one alkyl hydrogen fumarate of the formula and, optionally, at least one pharmaceutically-acceptable excipient or carrier.

Full Text	1 A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE" The present invention relates to the use of the free acid form. of certain fumaric acid monoalkyl esters (a kyl hydrogen. fumarates} either aicne or in combination with a dialkyl fumarate for preparing a pharmaceutical composition in the form of micro - tablets for treaning psouriasis, psoriatic arthritis, neurodermat tis and en-teritis regionalis Crohn. Pharmaceutical preparations which, as a result of bio- logical degradation after administration, lead into the citric acid cycle or belong do that cycle are increas-ingly gaining significance in generally high dosages, since it is possble to relieve or cure cryptogenotic diseases with, their aid. Thus, fumaric acid inhibits the growth of the Ebrlich ascites tumour in mice, reduces the toxic effects of Mitomyein C and Aflatoxin [cf. K. Kuroda, M. Akao, Bio-chem. Pharmacol. 29, 2839 - 2844 (198C) / Gann. 12, 777 782 (1981) / Cancer Res. 3_6, 1900 - 1903 (l976). anci has a both anti-psoriatic and antimicrobial effect. [C. X. Huhtsner, C. food Sci 48, 1574 (1983) / M.N. Islam, US-A-4,346/ 118 / C.A. 97, 161317b (198?.)]. When administered by the parenteral, dermal and par ticularly the oral route, high dosages of the funaric acid derivatives previously known for this purpose such as dihydroxy fumaric acid, fumaramide and fumaronitrial c have such an unacceptable rate of side effects and high 2 toxicity [P. Holland, R.G. White, Brit. J. Dermatol. 85, 259 - 263 (1971) / M. Hagedorn, K.W. Kalkoff, G. Kiefer, D. Baron, J. Hug, J. Petres, Arch. Derm. Res. 254, 67 - 73, (1975)] that such a therapy usually had to be disregarded. EP-A-0 188 749 already describes fumaric acid deriva-tives (salts) and pharmaceutical compositions contain-ing the same for the treatment of psoriasis. Pharmaceutical compositions for treating psoriasis which contain a mixture of fumaric acid and other fu-maric acid derivatives are known from DE-A-25 30 372. A content of fumaric acid is obligatory. DE-A-26 21 214 describes drugs for treating psoriasis which contain fumaric acid monoethyl ester and mineral salts thereof as the active ingredient. Moreover, EP-A-0 312 697 describes the use of various fumaric acid monoalkyl ester salts for the therapy of psoriasis, psoriatic arthritis, neurodermatitis and enteritis re-gionalis Crohn. The use of fumaric acid monoethyl ester salts (Ca, Zn, Mg) and fumaric acid dimethyl ester for the treatment of psoriasis is known from the publication "Hautarzt" (1987), 279 - 285. Since, in a psoriatic epidermis, the activity of phos-phoslipase A2 is changed, the fact that this enzyme is stimulated by fumaric acid is one possible explanation of the mechanism of the compositions according to the invention. Surprisingly, we have now found that the treatment of psoriasis with alkyl hydrogen fumarates even without salt formation can be achieved with a pharmaceutical 3 composition which contains the free acid form of one or several C-1-5-alkyl hydrogen fumarates and, optionally, pharmaceutically acceptable excipients and carriers and is presented in the form of micro-tablets or micro-pellets. Optionally, these compositions may also con-tain one or several dialkyl fumarates. The compositions in the form of micro-tablets or micro-pellets permit the administration of the free acid in-stead of its salt without the occurrence of the known side effects, especially the formation of ulcers. This is probably due to the fact that micro-tablets or mi-cro-pellets permit a uniform distribution in the stom-ach, thus avoiding irritating local concentrations of the monoalkyl hydrogen fumarate in the form of the free acid. Compositions containing the free acid of the alkyl hy-drogen fumarate in an amount of 20 to 300 mg are par-ticularly suitable for oral administration, the total weight of the active ingredients being 100 to 300 mg. For the systemic start of a therapy or the cessation thereof, respectively, a low dosage containing 100 of 120 mg of active ingredient, e.g. 30.0 mg to 35.0 mg of dimethyl fumarate and 70 to 90 mg of methyl hydrogen fumarate, is advantageous. 190 to 210 mg of active ingredient, e.g. in the form of 120.0 mg of dimethyl fumarate and 90.0 mg of monoethyl fumarate, are an example of a therapeutic dosage after the initial phase. The compositions according to the invention are admin-istered orally in the form of micro-tablets or encapsu-lated micro-tablets or micro-pellets, the solid single dosage drug forms dissolving in the stomach within a 4 few minutes and uniformly releasing the active ingredi-ents from the drug form. A lower dosage is required for the start or cessation of systemic treatment and a higher dosage for therapeutic treatment after the ini-tial phase. The micro-tablets according to the invention are made by methods known in the prior art, such as granulation, screening, extrusion/spheronisation and such like. In addition to the active ingredient, they may contain customary excipients and carriers such as lactose, PVP and such like. The micro-tablets or micro-pellets pref-erably have a size of 300 - 2,000 urn, preferably 500 to 1,500 µm and even more preferably 1,000 µm. To facilitate administration of the single dosage, the micro-tablets or micro-pellets may be encapsulated, for example in gelatinous capsules. Optionally, the micro-tablets or micro-pellets may be provided with a coating which is resistant to gastric acid. Such a coating may be applied with known processes, e.g. by application or spraying in a fluidised bed apparatus or in the form of a film coating. Example Production of encapsulated micro-pellets containing 50.0 mg of methyl hydrogen fumarate (corresponding to a total of 44.6 mg of fumaric acid) Taking the necessary precautions (breathing mask, gloves, protective suit), 5,000 kg of methyl hydrogen fumarate are crushed by means of a #400 screen and ho-mogenised. In addition, 2 1 of a 20 % (m/v) polyvinyl pyrrolidone (Kollidon K30) solution in ethanol are pre-pared. 7.250 kg of Nonpareilles pellets are introduced into a coating pan and sprayed with part of the Kolli-don K-30 solution until slightly humid. Then the active 5 ingredient mixture is added in portions until the pel-lets are dry. This procedure of humidifying/drying is continued until all of the active ingredient mixture has been added. Finally, the pellets are moved around until fully dry. After that, the pellets are filled into hard gelatine capsules (126.5 mg pellets/capsule). It was found that the preparations according to the in-vention have an effect similar to that of preparations containing the known fumaric acid derivatives in salt form against various clinical forms of psoriasis, pso-riatic arthritis, neurodermatitis and enteritis region-alis Crohn (morbus Crohn), but are free of the side ef-fects known from the administration of the free acid. Examination of acute toxicity Before the clinical trial, the acute toxicity of methyl hydrogen fumarate was tested by oral administration to rats. The results show a very low toxicity of the fu-maric acids used (cf. Table 2) . Table 1 Acute toxicity on rats (oral administration) Sex Methyl hydrogen fumarate LD50 Male Female 2,606.8 1,777.8 Lowest lethal dose in mg/kg Male Female 2, 150.0 1,470.0 Pharmaceutical equivalency Comparison of the pharmaco-kinetic data of Fumaderm forte (example 4 from European patent 0 312 697 Bl) and monomethyl fumarate or monoethyl fumarate, respec-tively, as calcium salt. 6 Table 2 Equivalency Substance Species Dosage Methyl hydro- administered (mg/kg gen fumarate body-wt.) level (Cmax) / (µg/ml) Fumaderm forte Rat 30 8,99 Methyl hydrogen Rat 100 male: 69.9 fumarate female: 84,8 Methyl hydrogen Rat 100 male; 51.3 fumarate calcium salt female: 107,0 Fumaderm forte: This mixture contains 120 mg of di-methyl fumarate, 87 mg of monoethyl fumarate calcium salt, 5 mg of monoethyl fumarate magnesium salt, 3 mg of monoethyl fumarate zinc salt. -7-We claim: 1. A pharmaceutical composition in the form of micro-tablets or micro-pellets and comprising at least one alkyl hydrogen fumarate of the formula wherein R is a C1-5 alkyl, optionally in admixture with dialkyl fumarate of the formula and, optionally, at least one pharmaceutically-acceptable excipient or carrier. 2. A composition, as claimed in claim 1, wherein an active ingredient used in forming in said composition is methyl hydrogen fumarate. 3. A composition, as claimed in claim 1, wherein active ingredients used in forming said composition are methyl hydrogen fumarate mixed with dimethyl fumarate. 4. A composition, as claimed in any of claims 1 to 3, wherein the pharmaceutical composition is adapted for oral administration, and the total weight of the active ingredient(s) per dosage of said composition is 20 to 300 mg. -8- 5. A composition, as claimed in any of claims 1 to 3, wherein said composition contains 10 to 290 parts by weight of methyl hydrogen fumarate and 290 to 10 parts by weight of dimethyl fumarate. 6. A composition, as claimed in any of claims 1 to 3, wherein the pharmaceutical composition is adapted for oral administration, and the micro- tablets or micro-pellets are provided with an enteric coating. 7. A composition, as claimed in any of claims 1 to 3, wherein the micro- tablets or micro-pellets have a size of 300 to 2,000 urn. 8. A composition, as claimed in any of claims 1 to 3, wherein the pharmaceutical composition is adapted for oral administration, and the total weight of the active ingredients in said composition per dosage is 20 to 300 mg, and in that said composition contains per dosage 10 to 290 parts by weight of methyl hydrogen fumarate and 290 to 10 parts by weight of dimethyl fumarate. 9. A composition, as claimed in claim 8, wherein in that the micro-tablets or micro-pellets are provided with an enteric coating. 10. A composition, as claimed in any of claims 8 to 9, wherein the micro- tablets or micro-pellets have a size of 300 to 2,000 urn. 11. A composition, as claimed in claim 1, wherein said composition is useful for treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalis Crohn. "A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE" The present invention discloses a pharmaceutical composition in the form of micro-tablets or micro-pellets and comprising at least one alkyl hydrogen fumarate of the formula and, optionally, at least one pharmaceutically-acceptable excipient or carrier.

Full Text

1
A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE"
The present invention relates to the use of the free acid form. of certain fumaric acid monoalkyl esters (a kyl hydrogen. fumarates} either aicne or in combination with a dialkyl fumarate for preparing a pharmaceutical composition in the form of micro - tablets for treaning psouriasis, psoriatic arthritis, neurodermat tis and en-teritis regionalis Crohn.
Pharmaceutical preparations which, as a result of bio- logical degradation after administration, lead into the citric acid cycle or belong do that cycle are increas-ingly gaining significance in generally high dosages, since it is possble to relieve or cure cryptogenotic diseases with, their aid.
Thus, fumaric acid inhibits the growth of the Ebrlich ascites tumour in mice, reduces the toxic effects of Mitomyein C and Aflatoxin [cf. K. Kuroda, M. Akao, Bio-chem. Pharmacol. 29, 2839 - 2844 (198C) / Gann. 12, 777
782 (1981) / Cancer Res. 3_6, 1900 - 1903 (l976). anci has a both anti-psoriatic and antimicrobial effect. [C. X. Huhtsner, C. food Sci 48, 1574 (1983) / M.N. Islam, US-A-4,346/ 118 / C.A. 97, 161317b (198?.)].
When administered by the parenteral, dermal and par ticularly the oral route, high dosages of the funaric acid derivatives previously known for this purpose such as dihydroxy fumaric acid, fumaramide and fumaronitrial c have such an unacceptable rate of side effects and high
2
toxicity [P. Holland, R.G. White, Brit. J. Dermatol. 85, 259 - 263 (1971) / M. Hagedorn, K.W. Kalkoff, G. Kiefer, D. Baron, J. Hug, J. Petres, Arch. Derm. Res. 254, 67 - 73, (1975)] that such a therapy usually had to be disregarded.
EP-A-0 188 749 already describes fumaric acid deriva-tives (salts) and pharmaceutical compositions contain-ing the same for the treatment of psoriasis.
Pharmaceutical compositions for treating psoriasis which contain a mixture of fumaric acid and other fu-maric acid derivatives are known from DE-A-25 30 372. A content of fumaric acid is obligatory.
DE-A-26 21 214 describes drugs for treating psoriasis which contain fumaric acid monoethyl ester and mineral salts thereof as the active ingredient. Moreover, EP-A-0 312 697 describes the use of various fumaric acid monoalkyl ester salts for the therapy of psoriasis, psoriatic arthritis, neurodermatitis and enteritis re-gionalis Crohn.
The use of fumaric acid monoethyl ester salts (Ca, Zn, Mg) and fumaric acid dimethyl ester for the treatment of psoriasis is known from the publication "Hautarzt" (1987), 279 - 285.
Since, in a psoriatic epidermis, the activity of phos-phoslipase A2 is changed, the fact that this enzyme is stimulated by fumaric acid is one possible explanation of the mechanism of the compositions according to the invention.
Surprisingly, we have now found that the treatment of psoriasis with alkyl hydrogen fumarates even without salt formation can be achieved with a pharmaceutical
3
composition which contains the free acid form of one or several C-1-5-alkyl hydrogen fumarates and, optionally, pharmaceutically acceptable excipients and carriers and is presented in the form of micro-tablets or micro-pellets. Optionally, these compositions may also con-tain one or several dialkyl fumarates.
The compositions in the form of micro-tablets or micro-pellets permit the administration of the free acid in-stead of its salt without the occurrence of the known side effects, especially the formation of ulcers. This is probably due to the fact that micro-tablets or mi-cro-pellets permit a uniform distribution in the stom-ach, thus avoiding irritating local concentrations of the monoalkyl hydrogen fumarate in the form of the free acid.
Compositions containing the free acid of the alkyl hy-drogen fumarate in an amount of 20 to 300 mg are par-ticularly suitable for oral administration, the total weight of the active ingredients being 100 to 300 mg.
For the systemic start of a therapy or the cessation thereof, respectively, a low dosage containing 100 of 120 mg of active ingredient, e.g. 30.0 mg to 35.0 mg of dimethyl fumarate and 70 to 90 mg of methyl hydrogen fumarate, is advantageous.
190 to 210 mg of active ingredient, e.g. in the form of 120.0 mg of dimethyl fumarate and 90.0 mg of monoethyl fumarate, are an example of a therapeutic dosage after the initial phase.
The compositions according to the invention are admin-istered orally in the form of micro-tablets or encapsu-lated micro-tablets or micro-pellets, the solid single dosage drug forms dissolving in the stomach within a
4
few minutes and uniformly releasing the active ingredi-ents from the drug form. A lower dosage is required for the start or cessation of systemic treatment and a higher dosage for therapeutic treatment after the ini-tial phase.
The micro-tablets according to the invention are made by methods known in the prior art, such as granulation, screening, extrusion/spheronisation and such like. In addition to the active ingredient, they may contain customary excipients and carriers such as lactose, PVP and such like. The micro-tablets or micro-pellets pref-erably have a size of 300 - 2,000 urn, preferably 500 to 1,500 µm and even more preferably 1,000 µm.
To facilitate administration of the single dosage, the micro-tablets or micro-pellets may be encapsulated, for example in gelatinous capsules. Optionally, the micro-tablets or micro-pellets may be provided with a coating which is resistant to gastric acid. Such a coating may be applied with known processes, e.g. by application or spraying in a fluidised bed apparatus or in the form of a film coating.
Example
Production of encapsulated micro-pellets containing 50.0 mg of methyl hydrogen fumarate (corresponding to a total of 44.6 mg of fumaric acid)
Taking the necessary precautions (breathing mask, gloves, protective suit), 5,000 kg of methyl hydrogen fumarate are crushed by means of a #400 screen and ho-mogenised. In addition, 2 1 of a 20 % (m/v) polyvinyl pyrrolidone (Kollidon K30) solution in ethanol are pre-pared. 7.250 kg of Nonpareilles pellets are introduced into a coating pan and sprayed with part of the Kolli-don K-30 solution until slightly humid. Then the active
5
ingredient mixture is added in portions until the pel-lets are dry. This procedure of humidifying/drying is continued until all of the active ingredient mixture has been added. Finally, the pellets are moved around until fully dry. After that, the pellets are filled into hard gelatine capsules (126.5 mg pellets/capsule).
It was found that the preparations according to the in-vention have an effect similar to that of preparations containing the known fumaric acid derivatives in salt form against various clinical forms of psoriasis, pso-riatic arthritis, neurodermatitis and enteritis region-alis Crohn (morbus Crohn), but are free of the side ef-fects known from the administration of the free acid.
Examination of acute toxicity
Before the clinical trial, the acute toxicity of methyl hydrogen fumarate was tested by oral administration to rats. The results show a very low toxicity of the fu-maric acids used (cf. Table 2) .
Table 1 Acute toxicity on rats (oral administration)

Sex Methyl hydrogen fumarate
LD50 Male Female 2,606.8 1,777.8
Lowest lethal dose in mg/kg Male Female 2, 150.0 1,470.0
Pharmaceutical equivalency
Comparison of the pharmaco-kinetic data of Fumaderm forte (example 4 from European patent 0 312 697 Bl) and monomethyl fumarate or monoethyl fumarate, respec-tively, as calcium salt.
6
Table 2 Equivalency

Substance Species Dosage Methyl hydro-
administered (mg/kg gen fumarate
body-wt.) level (Cmax) /
(µg/ml)
Fumaderm forte Rat 30 8,99
Methyl hydrogen Rat 100 male: 69.9
fumarate female: 84,8
Methyl hydrogen Rat 100 male; 51.3
fumarate calcium salt female: 107,0
Fumaderm forte: This mixture contains 120 mg of di-methyl fumarate, 87 mg of monoethyl fumarate calcium salt, 5 mg of monoethyl fumarate magnesium salt, 3 mg of monoethyl fumarate zinc salt.
-7-We claim:
1. A pharmaceutical composition in the form of micro-tablets or micro-pellets and comprising at least one alkyl hydrogen fumarate of the formula

wherein R is a C1-5 alkyl, optionally in admixture with dialkyl fumarate of the formula

and, optionally, at least one pharmaceutically-acceptable excipient or carrier.
2. A composition, as claimed in claim 1, wherein an active ingredient
used in forming in said composition is methyl hydrogen fumarate.
3. A composition, as claimed in claim 1, wherein active ingredients used
in forming said composition are methyl hydrogen fumarate mixed with
dimethyl fumarate.
4. A composition, as claimed in any of claims 1 to 3, wherein the
pharmaceutical composition is adapted for oral administration, and the total
weight of the active ingredient(s) per dosage of said composition is 20 to 300
mg.
-8-
5. A composition, as claimed in any of claims 1 to 3, wherein said
composition contains 10 to 290 parts by weight of methyl hydrogen fumarate
and 290 to 10 parts by weight of dimethyl fumarate.
6. A composition, as claimed in any of claims 1 to 3, wherein the
pharmaceutical composition is adapted for oral administration, and the micro-
tablets or micro-pellets are provided with an enteric coating.
7. A composition, as claimed in any of claims 1 to 3, wherein the micro-
tablets or micro-pellets have a size of 300 to 2,000 urn.
8. A composition, as claimed in any of claims 1 to 3, wherein the
pharmaceutical composition is adapted for oral administration, and the total
weight of the active ingredients in said composition per dosage is 20 to 300
mg, and in that said composition contains per dosage 10 to 290 parts by
weight of methyl hydrogen fumarate and 290 to 10 parts by weight of dimethyl
fumarate.
9. A composition, as claimed in claim 8, wherein in that the micro-tablets
or micro-pellets are provided with an enteric coating.
10. A composition, as claimed in any of claims 8 to 9, wherein the micro-
tablets or micro-pellets have a size of 300 to 2,000 urn.
11. A composition, as claimed in claim 1, wherein said composition is
useful for treating psoriasis, psoriatic arthritis, neurodermatitis and enteritis
regionalis Crohn.
"A PHARMACEUTICAL COMPOSITION COMPRISING ALKYL HYDROGEN FUMERATE"
The present invention discloses a pharmaceutical composition in the form of micro-tablets or micro-pellets and comprising at least one alkyl hydrogen fumarate of the formula

and, optionally, at least one pharmaceutically-acceptable excipient or carrier.

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Patent Number

212733

Indian Patent Application Number

IN/PCT/2000/00094/KOL

PG Journal Number

50/2007

Publication Date

14-Dec-2007

Grant Date

12-Dec-2007

Date of Filing

20-Jun-2000

Name of Patentee

FUMAPHARM AG

Applicant Address

KHALDENSTRASSE 24A, 6006 LUZERN

Inventors:

#	Inventor's Name	Inventor's Address
1	JOSHI KUMAR RAJENDRA	ALTSTETTERSTR 224, 8048, ZURICH
2	STREBEL HANS-PETER	MATTENWEG 7, 5630 MURI

PCT International Classification Number

A 61 K 31/225

PCT International Application Number

PCT/EP98/07956

PCT International Filing date

1998-12-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	19814358.3	1998-03-31	Germany