Anhydrous crystalline form of the hydrochloride r(-)-n-(4,4-di (3-methyltin-2-yl) but-3-enyl)-nicotinebuy acid, its preparation, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to an anhydrous crystalline form of the hydrochloride R(-)-M-(4,4-di(3-methyltin-2-yl)but-3-enyl)-nicotinebuy acid, free from associated organic solvent (1), which is nephroscopes and thermally stable under normal storage conditions. Connection (1) inhibits the absorption of gamma-aminobutyric acid and can be used in medicine to treat epilepsy. 4 C. and 1 C.p. f-crystals.

The invention relates to an anhydrous crystalline form of the hydrochloride R(-)-N-(4,4-di(3-methyltin-2-yl)but-3-enyl)- nicotinebuy acid, its preparation and use as therapeutic agent.

U.S. patent N 5,010,090 reveals a new class of compounds that demonstrate the properties of inhibiting the uptake of gamma-aminobutyric acid, and therefore these compounds are valuable for use in therapy for the treatment of epilepsy and other diseases associated with the absorption of gamma-aminobutyric acid.

In the present invention, R(-)-N-(4,4 - di(3-methyltin-2-yl) but-3-enyl)-nikotinova acid will hereinafter be called Tiagabine (Tiagabin (INN).

In U.S. patent 5,354,760 described tiagabine ghidrah is otinovaa acid and its pharmaceutically acceptable derivatives disclosed in WO 95/31976.

However, the monohydrate, which is stable at normal room temperature in a dry atmosphere without access of light, is less stable at elevated temperatures. Monohydrate at elevated temperatures ranging from about 50oC, gives the water that leads to its complete dehydration at the melting temperature of 80-85oC. Such properties monohydrate are very uncomfortable when receiving drugs based on it. Alternative product, which is described in U.S. patent 5,010,090 (column 8, line 62) can be obtained only time consuming method using ethyl acetate as described in the patent.

In addition, the analysis showed that the products obtained in this way contain undesirable quantities to make solvent.

Other organic solvents can be used to highlight the product, but organic solvents always form clathrates, i.e., the solvate of the hydrochloride of tiagabine and appropriate organic solvent.

Such solvents are undesirable, because they are either toxic to humans, or can interact (react with other ingredients in the pharmaceutical prepacyte trudnorastvorim used in organic solvents, which is very inconvenient when industrial production of drugs.

It was found that the anhydrous form can be obtained from aqueous solutions in special conditions where selective education anhydrate with high purity and yield.

Anhydrous form of the hydrochloride of tiagabine is nephroscopes and thermally stable under normal storage conditions.

Anhydrous form of the present invention is highly suitable for use in pharmaceutical preparations and stable in normal conditions the way they are received.

Anhydrous hydrochloride of tiagabine characterized by a specific x-ray diffraction pattern and a typical IR spectrum in KBr crystals.

Profile anhydrate obtained using differential scanning calorimetry (DSC) shows only 1 peak, indicating the melting of the compound at a temperature of from 190 to 200oC.

The invention also provides a method for obtaining anhydrous crystalline hydrochloride of tiagabine, which includes the crystallization of the hydrochloride of tiagabine from aqueous chloride-hydrogen acid at a concentration of chloride-hydrogen of the acid is not less than 0.55 M above the 50oC.

Crystallization can be initiated by using seed crystals, but this is optional, since crystallization can begin spontaneously.

The crystals can be separated by conventional means, for example by filtration or centrifugation. The crystals may be washed with water or dilute chloride-hydrogen acid, then dried either under reduced pressure or under normal pressure, at room temperature or at elevated temperature.

It was found that the anhydrous form of the hydrochloride, N-(4,4-di(3-methyl-Tien-2-yl)but-3-enyl)-nicotinebuy acid, obtained as described in this application solves the problems arising in the manufacture of medicines using monohydrate form. The invention also provides a pharmaceutical composition comprising anhydrous crystalline form of the hydrochloride R(-)-N-(4,4-di(3-methyltin-2-yl)but-3-enyl)-nicotinebuy acid and a pharmaceutically acceptable carrier.

The composition according to the invention is generally intended for oral administration, however, compositions, intended for dissolution for parenteral administration, transdermal delivery, or the replacement of the t standard dosage form, containing 0.1 to 3000 mg of the compounds according to the invention for oral administration. The usual dose for oral administration for the treatment of epilepsy ranges from 1.0 to 500 mg, preferably 1 to 1,000 mg per day, more preferably 1-100 mg per day, either as a single dose or divided into 2 or 3 doses.

Preferred standard dosage forms include solid form of tablets or capsules, in liquid form solutions, suspensions, emulsions, elixirs, or capsules filled with them, the patches are intended for transdermal administration, or sterile solutions for injection.

The composition of the invention receive the usual galenic preparations ways.

Conventional excipients are pharmaceutically acceptable organic and inorganic substances suitable for parenteral and oral administration, which have no harmful effects when interacting with the active connection.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, syrup, peanut oil, olive oil, gelatin, lactose, white clay, sucrose, agar, pectin, gum acacia, amylases the esters of fatty acids and pentaerythritol, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, disintegrators, stabilizers, wetting agents, emulsifiers, salts, influencing the osmotic pressure, buffer substances and/or dyes, etc. that have no harmful effects when interacting with the active connection.

For parenteral administration, in particular, are suitable solutions or suspensions for injection, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

For oral administration are particularly suitable are tablets, coated tablets or capsules containing talc and/or hydrocarbon carrier or binder, or etc., while the carrier is preferably lactose and/or corn starch and/or potato starch. You can use syrup or elixir or similar when using sweetened media.

A typical tablet obtained in the usual way tabletting, includes:

The total mass of the tablet, mg - 320

Talc, Heb.Pharm. - 16,0

The invention also provides a method of treating diseases associated with the absorption of gamma-aminobutyric acid in mammals, including humans, the method includes introducing an effective amount of an anhydrous crystalline form of the hydrochloride R(-)-N-(4,4-di(3-methyltin-2-yl) but-3-enyl)-nicotinebuy acid.

Further, the invention provides pharmaceutically acceptable anhydrous crystalline form of the hydrochloride R(-)-N-(4,4-di(3-methyltin-2-yl)but-3 - enyl)-nicotinebuy acid for therapeutic use in the treatment of epilepsy and other diseases associated with the absorption of gamma-aminobutyric acid.

EXAMPLE 1

Tiagabine hydrochloride (anhydrous)

100 g of the hydrochloride monohydrate of tiagabine dissolved in 700 ml of 0.2 N. chloride-hydrogen acid at 55oC. the Concentration of chloride-hydrogen acid was adjusted to 1.3 n by adding concentrated chloride-hydrogen acid. Crystallization of the product begins spontaneously in the process of adding acid. Stirring is continued for 17 hours at 50oC. the Product is filtered and dried in vacuum, obtaining 95% of the hydrochloride of tiagabine.

The water content according to Karl is IU.

EXAMPLE 2

Tiagabine hydrochloride (anhydrous)

Tiagabine hydrochloride are dissolved in 7 ml of 0, 25 N. HCl per gram of tiagabine when 55oC. the Solution was adjusted to 0.8 n using concentrated chloride-hydrogen acid. Then the solution load of 0.5 g/l of the seed crystals and the solution stirred for 18 hours at 52oC. the Product is filtered and dried at room temperature, obtaining a yield of 85%.

The results of x-ray analysis correspond to the anhydrous crystalline form of the product.

EXAMPLE 3

Tiagabine hydrochloride (anhydrous)

75 g of the hydrochloride monohydrate of tiagabine dissolved in 613 ml of water at 65oC. the Solution is filtered and added 37 g of concentrated chloride-hydrogen acid dissolved in 115 g of water.

The solution is cooled to 52oC and stirred over night.

The suspension is cooled to 40oC and then the product is filtered. The filter cake is washed with 2 times 55 g of water, then dried in vacuum at 30oC.

Water content by Karl-Fischer: 0%.

The results of x-ray analysis: corresponds to the anhydrous crystalline form.

DSC (differential scanning cal is svodnyy)

10 g of the hydrochloride monohydrate of tiagabine stirred with 100 ml of 1 N. chloride-hydrogen acid at 70oC. the Mixture is cooled to room temperature and stirred over night, getting a crystalline suspension.

The product is filtered and washed with water, then dried in vacuum at 40oC.

Yield: 9 g ~95%

HPLC: purity 99.9% of

DSK: the beginning 197,8oC

Thermal gravimetric analysis (TGA): weight loss of 0.15% at 160oC.

The results of x-ray analysis: corresponds to the anhydrous crystalline form.

EXAMPLE 5

Tiagabine hydrochloride (anhydrous)

In a flask with a capacity of 1 l load 50 g of ethyl ester of tiagabine, 750 ml of water and 11 g of concentrated chloride-hydrogen acid. The mixture is heated under reflux for 2 hours and then distilled ethanol/water (total 400 ml) for 4 hours. The remaining solution was stirred at a temperature of distillation during the night. Cooled to 55-60oC, then for 5 minutes add the additional amount of 37.5 g of chloride-hydrogen acid. The solution is cooled down to 50-52oC and stirred at this temperature for 18 hours. The precipitate of going to lorida of tiagabine.

Yield: 86%.

Water content by Karl-Fischer: 0,4%.

The results of x-ray analysis correspond to the anhydrous crystalline form.

EXAMPLE 6

Tiagabine hydrochloride (anhydrous)

In a flask with a capacity of 1 l load 50 g of ethyl ester of tiagabine, 575 ml of water and 25 g of concentrated chloride-hydrogen acid. The mixture is heated under reflux for 1 hour, then evaporated ethanol/water (total 200 ml) for 4 hours. The reaction solution is cooled to 88oC and add more of 23.5 g of concentrated chloride-hydrogen acid. The solution is gradually cooled to room temperature (22oC) while stirring the reaction mixture for 18 hours. The resulting precipitate is collected by filtration and washed with 20 ml of water. The product is dried in vacuum at room temperature, receiving 42,0 g of the hydrochloride of tiagabine.

Yield: 90%.

Water content by Karl-Fischer: 0,1%.

The results of x-ray analysis correspond to the anhydrous crystalline form.

1. Anhydrous crystalline form of the hydrochloride R(-)-N-(4,4-di(3-methyltin-2-yl)but-3-enyl)-nicotinebuy acid, free from associated organizes illien-2-yl)but-3-enyl)-nicotinebuy acid, includes (a) dissolving the hydrochloride of tiagabine in aqueous hydrochloric acid solution, b) precipitation of the hydrochloride of tiagabine from aqueous hydrochloric acid solution having a concentration of not less than 1.3 m

3. Pharmaceutical composition having anti-epileptic activity comprising a therapeutically effective amount of crystalline salts under item 1 and a pharmaceutically acceptable carrier or diluent.

4. The pharmaceutical composition under item 3 in the form of standard dosage forms, containing about 1.0 to 1500 mg of the active ingredient.

5. Treatment indications associated with the treatment of epilepsy in a mammal, comprising introducing an effective amount of a crystalline salt of p. 1.

 

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