Microtablets based on fumaric acid

 

Proposed: microtablets based alilovic esters of fumaric acid of General formula (1) or (2) for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and regional enteritis Crohn's. The invention can dramatically reduce the side effects of traditional tablets with the stated active ingredient in relation to the gastrointestinal tract and expands the Arsenal of tools specified destination. 9 C.p. f-crystals, 1 PL.

and a represents a divalent cation, n=1 or 2.

The invention relates to the use of certain salts monoalkyl esters of fumaric acid individually or in combination with dialkylamino to obtain microtablets for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and regional enteritis (Crohn's disease).

In European application EP-A-0188749 already described derivatives of fumaric acid and containing pharmaceutical compositions for the treatment of psoriasis. From the application DE-A-2530372 also known pharmaceutical compositions for the treatment of psoriasis, which contain a mixture of fumaric acid and other derivatives of fumaric acid. Share free fumaric acid e is s tools for the treatment of psoriasis, which as biologically active substances contain monotropy ester of fumaric acid and its inorganic salts. From the publication of Hautarzt, S. 279-285 (1987) is also known the use of salts of calcium, zinc and magnesium of monoethylene ester of fumaric acid, and dimethyl ester of fumaric acid for the treatment of psoriasis.

Finally, in the European patent EP 0312697 describes pharmaceutical compositions that contain one or more compounds selected from the salts of calcium, magnesium, zinc and iron nanometrology ester of fumaric acid individually or preferably in a mixture with (C1-C5-alkylphenolate. The preparation described in example 4 of this patent contains 87,5 mg of monoethylfumarate calcium, 120,0 mg dimethylfumarate, 5.0 mg of monoethylfumarate magnesium and 3.0 mg of monoethylfumarate zinc, which corresponds to 164 mg of fumaric acid. The drug is in the form resistant to gastric juice tablets and approved and is available on sale in Germany under the trade name of fumaderm (Fumaderm). During phase 3 clinical studies and subsequent study of the marketing of this drug found that approximately 60% of patients is in the form of diarrhea, pain in the stomach and the presence of feelings of fullness. As another side effect, in addition, often the so-called surge of blood, as well as disorders of vision and feeling hot.

Although tablets, tend to be relatively well tolerated, however, especially in the beginning of the treatment ever again faced with these disabilities. In the course of treatment often appear again unwanted side effects. However, there are patients who receive fumaderm causes severe disturbances in the area of the gastrointestinal tract. Occurring disorders in the stomach and intestines hurt that patient mode and regimens and able to provide patients a negative influence to such an extent that they are part of the reason for discontinuation of treatment.

The objective of the present invention to provide a pharmaceutical composition, which can be used to avoid these side effects, particularly violations in the area of the gastrointestinal tract, while the introduction of the same, forming part of the composition of pharmaceutical substances.

Studies of the applicant have shown that methylhydroquinone representing metabolite dimethylfumarate, the actor tumor necrosis in human mononuclear peripheral blood cells (periphere blood mononuclear cells=RWMS-cells) and in isolated monocytes. When multiple repeated exposure come to reduce the increasing allocation of alpha-tumor necrosis factor induced by endotoxin, therefore, the effect of habituation.

This initial induction of alpha-tumor necrosis factor possibly responsible for known side effects of the drug fumaderm as violations in the area of the gastrointestinal tract or symptoms tide of blood. The tendency to reduce stimulated by endotoxin allocation alpha tumor necrosis factor after repeated exposure of methylhydroquinone can be explained by habituation effect, i.e. the reduction of side effects during long-term treatment with fumaderm. Accordingly, in order to further research was primarily inhibition of excretion of alpha-tumor necrosis factor using other medicines and controlling because of this side effects with the introduction of fumaderm.

Research unexpectedly shown that the dosage form of biologically active substances in the form of microtablets can significantly reduce violations in the area of the gastrointestinal tract. The problem is solved according to the invention use one or n is necessary in a mixture with dialkylamino formulaand a represents the divalent cation of a number of Sa, SB, Zn or Fe or a monovalent cation from the series Li, Na or K and n represents the number 1 or 2 depending on the kind of cation and, if necessary, conventional pharmaceutical auxiliaries and carriers for pharmaceutical compositions in the form of microtablets or microphyll for the treatment of psoriatic arthritis, neurodermatitis, psoriasis and regional enteritis Crohn's.

Value or the average diameter of microphyll or microtablets preferably is in the range from 300 to 2000 μm, in particular in the region from 500 to 1500 μm and most particularly preferably 1000 μm.

Microtablets or MicroProse can be filled capsules or sachets and take in this form. Next, microtablets or capsules can be provided with a coating resistant to gastric juice. This coating is applied by conventional means. In the case of capsules we can talk about hard or soft gelatin capsules.

Preferred compositions according to the invention contain calcium salt nanometrology ester of fumaric acid and/or calcium salt of monoethylene ester of fumaric acid, if necessary in a mixture with dimethylfuran which preferably contains 10-290 wt. parts monoalkyl ester of fumaric acid (calcium salt) and 290-10 wt. parts dimethylfumarate. According to another variant embodiment of the invention, the composition also may contain 1-50 wt. parts zinc salt monoalkyl ester of fumaric acid.

Another preferred composition is in the form of microtablets contains 1-250 wt. parts monoalkyl ester of fumaric acid (calcium salt), 250-10 wt. parts dimethylfumarate, 1-50 wt. parts monoalkyl ester of fumaric acid (magnesium salt) and 1-50 wt. parts monoalkyl ester of fumaric acid (zinc salts), and the total mass of biologically active substances is 30-300 mg

For system start treatment, and also, conversely, to end of treatment (gradually decreasing the dosage) preferred low dosage. It may consist of 30 mg dimethylfumarate, 20 mg of monoethylfumarate calcium and 3 mg of monoethylfumarate or monomethylfumarate zinc. For therapeutic doses after the initial phase can be used, for example, the dosage of 20 mg dimethylfumarate, 87 mg of monoethylfumarate calcium and 3.0 mg of monoethylfumarate or monomethylfumarate zinc.

Used according to the invention derivatives of fumaric kalkaska reasoning, assume that the violations in the area of the gastrointestinal tract can be caused by local irritation in the epithelial cells of the intestine, which induce the release of alpha-tumor necrosis factor. Probably the normal admission tablets included in the tablets of the substance locally released in the intestine in too high concentrations, causing local irritation of the mucous membrane of the intestine. Because of this, local irritation in the short term can be released very high concentrations of alpha-tumor necrosis factor, which may be responsible for the gastrointestinal side effects. With the introduction of resistant to gastric juice microtablets capsules, compared with that achieved locally low concentrations of biologically active substances in the epithelial cells of the intestine. Microtablets from the stomach gradually, due to the peristalsis of the stomach, fall into the small intestine and thus is a better distribution of biologically active substances.

Resistant to gastric juice microtablets same dosage, therefore, are distributed in the stomach and therefore portions fall into the intestine, where biologically different cells of the intestine, as well as the release of alpha-tumor necrosis factor. Hence, probably, should better portability of microtablets stomach and intestine compared with conventional tablets. However, it was impossible to expect that a mere change galenical forms of the drug will lead to such a dramatic reduction in side effects.

Obtaining and principle of the proposed according to the invention of microtablets explained using the following examples.

The examples of the preparation EXAMPLE 1. Getting resistant to the action of gastric juice microtablets capsules containing a 87.0 mg of monoethylfumarate calcium, 120,0 mg dimethylfumarate, 5.0 mg of monoethylfumarate magnesium and 3.0 mg of monoethylfumarate zinc, which corresponds, in General, 164 mg of fumaric acid.

8,700 kg of monoethylfumarate calcium, 12,000 kg dimethylfumarate, 0.500 kg of monoethylfumarate magnesium and 0.30 kg of monoethylfumarate zinc crushed, intensively mixed and with appropriate precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. Prepare a mixture of excipients the following composition: 18,00 kg derived starch (STA-RX1500), 0.30 kg microcrystalline 2D/chr/174.gif" align="BASELINE">120), 4,00 kg Primogel, 0.25 kg of colloidal silicic acid (Aerosil). A powder mixture is mixed with a mixture of biologically active substances, homogenized with 200 sieve, using a 2% aqueous solution of polyvinylpyrrolidone (KollidonK25) in the usual way processed into granulate binder in the dried state is mixed with the external phase, which consists of 0.50 kg of magnesium stearate and 1.50 kg of talc. A powder mixture was then usual pressed with obtaining convex microtablets gross weight of 10.0 mg and a diameter of 2.0 mm Instead of these classical methods tablete testing you can also use other ways of getting tablets, as a direct tableting, as well as the preparation of solid dispersions by the method of melting and spray drying method.

Resistant to gastric juice coating can be applied in classical drageeing boiler by spraying or using a vacuum, and in the apparatus with fluidized bed. To achieve resistance to the action of gastric juice in this case is prepared, e.g. the SELINE">HP 50) in a mixture of the following solvents: 13,00 l of acetone, 13,50 l of ethanol (96% denatured with 2% ketone) and 1.50 l of demineralized water. To a ready solution as a plasticizer add 0,240 kg of castor oil and as usual portions is applied to the core tablets.

After drying then in the same apparatus as film coating is applied, the suspension of the following composition: 0,340 kg of talc, 0,400 kg of titanium oxide(VI) Cronus RN 56, 0,324 kg red lacquer Farblack L 86837, 4,800 kg 12,5% Eudragit E (Eudragit E), and 0.120 kg of polyethylene glycol 6000 (pH. 11 (XI) in a solvent mixture of the following composition: 8,170 kg propan-2-ol, 0,200 kg of demineralised water and 0,600 kg glyceryltrinitrate (triacetin).

Resistant to gastric juice microtablets then bring in a detachable hard gelatin capsules in an amount up to 500.0 mg net mass and close.

EXAMPLE 2. Getting resistant to the action of gastric juice microtablets capsules containing a 87.0 mg of monoethylfumarate calcium 120 mg dimethylfumarate, 5.0 mg of monoethylfumarate magnesium and 3.0 mg of monoethylfumarate zinc, which corresponds in General, 164 mg of fumaric acid.

8,700 kg of monoethylfumarate calcium, 12,000 kg dimethylfumarate, 0.500 kg monoethylether precautions (breathing mask, gloves, protective clothing and so on) homogenized using a sieve 800. Prepare a mixture of excipients the following composition: 24,70 kg of microcrystalline cellulose (AvicelPH 200), 3.00 kg nutritionnelles (AC-Di-SOL SD-711), 2,50 kg of talc, 0,10 kg anhydrous silicon dioxide (Aerosil200) and 1.00 kg of magnesium stearate. All the mixture of excipients are mixed with a mixture of biologically active substances and stirred to obtain a homogeneous mixture. Powdery mixture then by direct tabletting press with obtaining convex microtablets gross weight of 10.0 mg and a diameter of 2.0 mm Instead of these classical methods tabletting you can also use other ways of getting tablets, as the preparation of solid dispersions by the method of melting and spray drying method or tableting granules binder.

Resistant to gastric juice coating can be applied in classical drageeing boiler by spraying or using a vacuum, and in the apparatus with fluidized bed. In this case, for example, prepare a solution of 0.94 g of Eudragit L (Eudragitswinging nuclei tablets.

Then prepare a dispersion of 17,32 kg Eudragit (EudragitL D-55) and the mixture 2,80 kg of micro-talc, 2.00 kg of macrogel 6000 and 0.07 kg of Dimethicone in water and applied by spraying to the kernel.

Resistant to gastric juice microtablets then bring in a detachable hard gelatin capsules in an amount up to 760,0 mg net mass and close.

Examples of treatment According to the above examples was prepared microtablets containing the same 4 biologically active substances in the same quantitative composition contained in the commercial product fumaderm (Fumaderm). Resistant to gastric juice tablet fumaderm corresponds to approximately 102 is resistant to the action of gastric juice to microtelecom of the same composition. For practical use these microtablets fill capsules, as described in the above examples. Two capsules correspond to one tablet of fumaderm.

For a better comparison of the two patients who suffered severe disabilities in the area of the gastrointestinal tract in the treatment of tablets fumaderm, had been treated with resistant to the action of gastric juice by mikrotabletkami in the area of the gastrointestinal tract, observed when taking the regular tablets. Improvement in respect of psoriasis was reached, as in the treatment with tablets fumaderm known from the prior art, however, depending on the circumstances, to achieve clinical success sufficient a smaller dose when taken in the form of microtablets.

The results of treatment are presented in the table.

The table shows that taking microtablets even in high-dose (9 capsules daily) does not cause any side effects or shall result in only minor side effects, while already a lower dosage of the drug trade fumaderm leads to serious disturbances in the region of the gastrointestinal tract.

From the results of the treatment also shows that microtablets in relation to its effectiveness for the treatment of psoriasis in at least the same drug, if you do not have the superior effect. In General, therefore, proposed according to the invention the dosage form derivatives of fumaric acid in the form of microtablets shows a clear improvement compared to treatment with conventional tablets.


Claims

1. Pharmaceutical composition for the treatment of psoriatic is and microphyll, containing one or more salts monoalkyl esters of fumaric acid of General formula

if necessary, mixed with dialkylamino formula

where a represents the divalent cation of a number of CA, Mg, Zn or Fe or a monovalent cation from the series Li, Na or K;
n represents the number 1 or 2 depending on the kind of cation
as biologically active substances in the amount of 10-300 mg and pharmaceutical excipients.

2. The composition according to p. 1, characterized in that it contains calcium salt of monoecious or nanometrology ester of fumaric acid.

3. Composition under item 1 or 2, characterized in that it contains calcium salt monoalkyl ester of fumaric acid in a mixture with dimethylfumarate.

4. The composition according to p. 1, characterized in that it contains calcium and zinc salts monoalkyl ester of fumaric acid in a mixture with dimethylfumarate.

5. The composition according to p. 1, characterized in that it contains calcium, magnesium and zinc salts of monoethylene ester of fumaric acid in a mixture with dimethylfumarate.

6. The composition according to p. 3, characterized in that it contains 10-290 wt. including the calcium salt monoalkylated is made from 20 to 300 mg.

7. The composition according to p. 4, characterized in that it contains 10-250 wt. including the calcium salt monoalkyl ester of fumaric acid, 1-50 wt. including dimethylfumarate and 1-50 wt. including zinc salts monoalkyl ester of fumaric acid, and the total mass of biologically active substances is from 20 to 300 mg.

8. Composition according to any one of paragraphs. 1-5, characterized in that it contains 10-250 wt. including the calcium salt monoalkyl ester of fumaric acid, 250-10 wt. including dimethylfumarate, 1-50 wt. including magnesium salts monoalkyl ester of fumaric acid and 1-50 wt. including zinc salts monoalkyl ester of fumaric acid, and the total mass of biologically active substances is from 30 to 300 mg.

9. Composition according to any one of paragraphs. 1-8, characterized in that it is made in the form of microtablets or microphyll, provided with a coating resistant to gastric juice.

10. Composition according to any one of paragraphs. 1-9, characterized in that it is made in the form of microtablets or microphyll placed in capsules or sachets.

 

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