Paroxetine cholate or salts of cholic acid derivatives and composition containing paroxetine and cholic acid or cholic acid derivatives

FIELD: chemistry.

SUBSTANCE: claimed invention describes paroxetine cholate or salt of cholic acid derivative and composition, which contains paroxetine and cholic acid or its derivative. Also described is pharmaceutical composition for treatment of depressive states, containing paroxetine salt or composition. Pharmaceutical composition can be part of peroral medication, swallowed without water, on form of disintegrating in mouth paroxetine tablet.

EFFECT: obtaining paroxetine cholate or salt of cholic acid derivative, which can be used in pharmacology.

19 cl, 38 ex, 12 tbl

 

The scope of the invention

This invention relates to paroxetine holata or salts derived holeva acid and compositions containing paroxetine and cholic acid or its derivative.

Background of the invention

Paroxetine has a chemical formula of (-)-(3S,4R)-4-(p-forfinal)-3-[(3,4-methylenedioxy)phenoxy]-methyl]piperidine and its use as a therapeutic agent for treating depression, panic disorder, premenstrual dysphoric disorder, and social phobia using the typical mechanism selectively acting inhibitor absorption of serotonin (5-HT) (selective serotonin (5-HT) reuptake inhibitor, SSRI).

It was reported that since conventional antidepressants, including paroxetine, cause patients napriazhennosti for the reception of medicines, the development of oral formulations and swallow them without water, will improve the administration of the medicine patients by reducing sensation in the introduction of this drug. According to clinical results Remeron SolTab (manufactured by Janssen under the brand name of Mirtazapine (Mirtazapine)), which is first developed in the world oral antidepressant and swallow them without water, long-term treatment of depression without stopping at the initial stage is referred to as a critical factor in improving symptoms of depression the th patient. A study on patients who were injected Remeron SolTab showed that patients preferred drugs SolTab other normal tablets. This study also showed that the number of patients choosing SolTab, 6 times higher than the number of patients who choose other tablets. These results show that the use of antidepressants and swallow them without water, improves compliance sick mode and regimens and, therefore, you can expect the best results when treating depression and preventing relapse of depression.

However, paroxetine has a very bitter taste even at low concentrations it, while at high concentrations of paroxetine, due to its inherent properties, it causes an irritating painful sensation together with a very bitter taste. Thus, paroxetine is limited in its ability to be used in solid oral formulations and swallow them without water. Although paroxetine can be covered with membrane or to include substances, such as polymers and cyclodextrins using known General methods, bitter taste paroxetine not completely masked. In particular, if paroxetine is included with the tablet, the form covered or included granules may partially destroyed emitting content of the granules to the outside, which has an unpleasant sensation in the mouth. To and fully and partially block the bitter and irritating taste of paroxetine it is necessary to apply large quantities of fillers. Thus, it is impossible to develop orally disintegrating tablet.

PCT Pubtication WO 95/020964 describes the process of creating the liquid preparation (liquid for medical treatment) by dispersion in water insoluble in it ion-exchange resin to obtain a disperse system with the drug, thereby masking the bitter taste of the drug. However, since the ion-exchange resin insoluble in water, it is not uniformly distributed in the aqueous phase and, consequently, the bitter taste of a drug cannot be fully masked.

Attempts to mask the inherent paroxetine taste another flavor - glycyrrhizic acid or salts of glycyrrhizic acid is available in PCT applications WO 03/013470 and WO 03/013529. In these publications refer to the fact that since the glycyrrhizinate, as the main ingredient of licorice, he has a strong sweet taste of licorice, it can assist in masking the bitter taste of paroxetine. In fact, the abstracts of the publications describe that because of the intensity of the taste of licorice even when the composition is introduced glycyrrhizinate, other flavoring additives may be desirable to modify licorice taste of the composition.

Was actively undertaken a number of studies for the lei paroxetine. For example, U.S. patent No. 4721723 and PCT application WO 99/32484 describe paroxetine hydrochloride; PCT application WO 99/52901 describes paroxetine maleate; PCT application WO 99/55699 describes paroxetine camphorsulfonate; PCT WO 99/55698 describes paroxetine ascorbate; PCT application WO 00/01694 describes paroxetine methanesulfonate; bids PC T WO 03/013470 and WO 03/013529 describe glycyrrhizinate or salts of glycyrrhizic acid; PCT application WO 99/40084 describes salts of paroxetine with acids, including sulfuric, tartaric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, 4-methylbenzenesulfonate, posterolateral, milk and almond acid without a detailed explanation in respect salts; and PCT application WO 00/01692 describes salts of paroxetine with the acidic group. However, none of the above patent publications not mentioned about the improvement of the taste associated with the use of salts of paroxetine.

In addition to these salts of paroxetine in PCT application WO 95/20964 applying liquid oral drug that uses paroxetine-Amberley complex. However, amberlith resin is not monomolecular substance, and is a polymeric substance, carrying a lot of charges in one molecule, and in particular, it is insoluble in water or solvents. The molecular weight of the polymers can be expressed only average mole is usrnam weight, due to the properties of the polymers. Thus, the binding molar ratio amberlite resin to medicinal drug it is impossible to achieve, unlike monomolecular salts, and thus, it is difficult to argue that paroxetine-Amberley complex is a salt. In addition, the taste - masking of the polymer resin caused by dispersion in water of a water-insoluble complex of the resin - drug. Thus, the action of the complex differ from the action of salts of paroxetine.

Until now, little has been reported, proposed or experimentally confirmed that there would be no taste and pain paroxetine and significant improvement in stability paroxetine through education salts of paroxetine. In particular, there are no messages on paroxetine holata and salts derived holeva acid.

Thus, the purpose of this invention to provide salt of paroxetine or composition of paroxetine can cause changes of the characteristic properties of molecular units paroxetine with altered gustatory properties, so that in salt or composition disappeared bitter taste of paroxetine, even after its complete dissolution in water.

Another purpose of this invention is to propose a drug paroxetine for oral administration and swallow them without water, namely, p is sadalsuud mouth tablet, containing salt of paroxetine or composition of paroxetine.

Description of the invention

In accordance with one aspect of the present invention is proposed paroxetine Holt or salt derived holeva acid. Particularly preferred salt of paroxetine holata.

In accordance with another aspect of the present invention features a composition comprising paroxetine and cholic acid or its derivative.

Cholic acid and its derivatives correspond to the formula 1:

Formula 1

where R1, R2and R3independently represent a hydrogen atom or a hydroxyl group;

and X has the following values-OH, -ONa, -NH-(CH2)n-SO3H, -NH-(CH2)n-SO3Na, -NH-(CH2)n-SO3K, -NH-(CH2)n-CO2H, -NH-(CH2)n-CO2Na or-NH-(CH2)n-CO2K (where n is an integer from 1 to 3),

or formula 2:

Formula 2

where X has the meanings given in formula 1.

Cholic acid, described in this invention, has the chemical formula 3α,7α,12α-trihydroxypregn-24-OIC acid, and also indicates the extract medical bile (bovine), Holloway acid, Hollin or Holloway acid.

Examples of relevant derivatives holeva acid, described in this invented and, include 3α,12α-dihydroxyfuran-24-OIC acid (deoxycholic acid, 3,7,12-trioxolane-24-OIC acid, dehydrocholic acid), 3α,7α-dihydroxyfuran-24-OIC acid (chenodeoxycholic acid), 3α,7β-dihydroxyfuran-24-OIC acid (ursodeoxycholic acid), 3α-hydroxypoly-24-OIC acid (lithocholic acid), 2-[(3α,7α,12α-trihydroxy-24-Oklahoman-24-yl)amino]econsultancy acid (human beings need it to acid), 2-(3α,7α,12α-trihydroxy-24-Oklahoman-24-yl)glycine (glikoholeva acid), etc. of alkali metal Salts and other derivatives, which can be obtained from these derivatives holeva acid, are also within the scope of of the present invention. These derivative holeva acids have a steroid structure in the form of a shared source cycle and related to steroid acids containing carboxyl group. Acidic substances with steroid source cycle, which can be extracted from the bile of humans and animals, and their salts with ions of alkali metals are also within the scope of this invention.

Cholic acid and its derivatives, produced by a living organism, known as the main ingredients of bile secreted in the gastrointestinal tract and is re-absorbed in a volume of 500 ml daily. From about 20 g to 30 g holeva acid is its derivative, calculated on dry basis, contains daily volume (500 ml) of bile secreted in the upper part of the small intestine, which is about 0.5 g is separated in the form of excrement during intestinal re-absorption. To compensate for the loss by the body is produced about 400 mg daily. Accordingly, if paroxetine Holt or salt derived holeva acid, described in this invention, administered orally for the treatment of depression in people, the number holeva acid or its derivatives is limited to a maximum of 40 mg per day at steady state. As the range of doses holeva acid or its derivative in the form of the above salt of paroxetine corresponds to 0.13%-0,2% of the total number please bile in the intestines of humans, toxicity and side effects cannot be taken into account. Therefore, cholic acid and its derivatives are highly suitable as salts of drugs. In particular, cholic acid, or an extract medical bile (bovine) currently used as an emulsifier for food in Japan and is classified in the list of FDA in the United States as harmless (generally recognized as safe, GRAS).

Paroxetine Holt or salt derived holeva acid, according to this invention is a crystalline, non-crystalline or polycrystalline form. Suppose the equipment crystalline or non-crystalline form. In the drug paroxetine cholate or salt derived holeva acid molar ratio holeva acid or its derivative to paroxetine in free base form is from 0.25:1 to 5:1 and preferably from 0.5:1 to 2:1.

Paroxetine Holt or salt derived holeva acid, according to this invention, can be obtained in accordance with the following procedure.

Paroxetine Holt or salt derived holeva acid can be obtained by a simple interaction of the free base of paroxetine with holeva acid or its derivative at a given molar ratio. In this case, it is preferable that the free base would be in solution. More preferably, when the free base and cholic acid or its derivative are in solution. In particular, paroxetine Holt or salt derived holeva acid can be prepared by dissolving the free base of paroxetine in an appropriate solvent and then dissolving holeva acid or its derivative in the solution; or by dissolving holeva acid or its derivative in an appropriate solvent separately and then mixing the resulting solution with a solution previously dissolved free base of paroxetine.

Paroxetine used to obtain salt may be in the oily form of a free OS is Finance, in which the salt component is removed from the salt of paroxetine, or in the form of the salt of paroxetine. When applied directly to the salt of paroxetine, it is advantageous in terms of efficient separation and purification, when the salt component of the volatile or has a high solubility in solvents.

Suitable solvents used to obtain salt is not specifically limited, as they can easily dissolve the free base. The solvents can be used for dissolving holeva acid or its derivative. Examples of appropriate solvents include water and organic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyl-acetamide", she methyl acetate, ethyl acetate, isopropylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, dichloromethane, dichloroethane and diethyl ether. These solvents can be used as such or in combination with two or more solvents. Remove the used solvent can be performed by conventional means, for example, drying under reduced pressure or in vacuum, evaporation, spray drying, lyophilization (drying, freezing), cold filtering and combining these methods for p is obtaining crystalline solid, non-crystalline or polycrystalline paroxetine cholate or salt derived holeva acid. Drying under reduced pressure or in vacuum, evaporation and cold filtering is preferably used for obtaining a crystalline salt of paroxetine. Meanwhile, spray drying and lyophilization is preferably used to obtain non-crystalline salt of paroxetine.

To obtain the salt in solid form in the presence of solvent in the beginning paroxetine and cholic acid or its derivative is dissolved in simple or mixed solvent. Then the resulting solution is kept at a temperature of 0°or other solvent is mixed with solution for planting salt of paroxetine. The precipitate is filtered, washed with cold solvent and dried with getting ready paroxetine cholate or salt derived holeva acid. Used in this invention is a cold solvent selected from solvents that can be mixed with single or mixed solvent, but can not easily dissolve ready paroxetine Holt or salt derived holeva acid.

Thus, the prepared paroxetine Holt can be obtained in anhydrous form or in the form of a hydrate. If the salt of paroxetine get in the form of MES, evaporation of intermolecular solvent is carried out in a drying Cabinet is whether, to delete MES, spend the displacement of solvent.

With the aim of increasing output paroxetine cholate or salt derived holeva acid can conduct heat to increase the concentration of free base and holeva acid or its derivative in solution. Alternatively, the free base and cholic acid or its derivative is dissolved in an appropriate solvent and then part of the solvent can be removed by drying in vacuum or evaporation. You can also enter the seed to stimulate the deposition of salt of paroxetine.

This invention also relates to compositions containing paroxetine and cholic acid or its derivative.

Although paroxetine in free base form or in salt form is brought into contact with holeva acid or its derivative at a specific molar ratio with or without water or organic solvent and, if you have full or partial change of the physical properties of the salts, which will reduce the taste or painful sensation caused by paroxetine, they will also be within the scope of this invention.

In the composition according to this invention the molar ratio holeva acid or its derivative to the free base of paroxetine is from 0.25:1 to 5:1 and preferably from 0.5:1 to 2:1. what a song, described in this invention can be prepared by uniformly mixing paroxetine and cholic acid or its derivative in water or an organic solvent, followed by drying. The solvent used for the preparation of compositions described in this invention, identical to the solvent used for the preparation of salts of paroxetine.

This invention provides a pharmaceutical composition comprising paroxetine Holt or salt derived holeva acid and pharmaceutically acceptable filler. This invention also provides a pharmaceutical composition comprising paroxetine, cholic acid or its derivative and a pharmaceutically acceptable excipient. The pharmaceutical compositions described in this invention can be part of the oral drugs and swallow them without water. A pharmaceutical composition comprising a salt of paroxetine and composition of paroxetine (including paroxetine, cholic acid or its derivative) is also within the scope of this invention.

Pharmaceutically acceptable filler may be at least a filler selected from diluents, binders, disintegrators, coloring agents, sweeteners, fragrances, preservatives, lubricants, etc. can Also be used fillers the functions of a composite material. In particular, the pharmaceutically acceptable excipient can be, at least, the agent is selected from fillers, with character thinners and disintegrators and demonstrating the properties of fast decay, for example, the products sold under the trade names Pharmaburst and Pharmagum. The diluent may be, at least, a diluent selected from lactose, dextrose, microcrystalline cellulose, starch, etc.; binder may be at least a binder selected from polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl-methylcellulose, hydroxyethyl cellulose, dicalcium phosphate, sodium alginate, etc.; a disintegrator may be at least disintegrator selected from sodium croscarmellose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, gelatinising starch, malonamate hydroxy-propylethylene etc; dye may be at least a dye, selected from water-soluble dyes, tar dyes, etc.; sweetening substance may be at least sweetener selected from dextrose, sorbitol, mannitol, aspartame, Acesulfame, citric acid and so on; Corrigendum may be, at least, corrigent, choose from orange, grape, strawberry, Czernin the x corrigent powders, etc.; the preservative may be, at least, a preservative, selected from benzoic acid, methylparaben, ethylparaben, propyl paraben, etc.; the lubricant may be at least a lubricating substance selected from magnesium stearate, talc, crude anhydrous silica, fatty acid esters, sucrose, etc..

The pharmaceutical composition described in this invention can be prepared using standard pharmaceutically suitable procedures, such as mixing the various components, mixing, screening, filling and pressing.

The pharmaceutical composition described in this invention can be prepared in conventional dosage forms, such as: solid oral preparations such as tablets, capsules, granules and powders; liquid oral preparations such as syrups, suppositories and vials for injection. For oral administration, the preferred tablets, capsules and syrups.

The pharmaceutical composition described in this invention, can be entered in any convenient way, for example, oral, sublingual, buccal, rectal, transdermal, parenteral, intravenous, intramuscular, etc. Oral, sublingual and buccal injection is suitable for the purposes of this invention, the composition dissolves in the mouth Il is eaten without water.

The pharmaceutical composition described in this invention may be administered for the treatment of depressive disorders in an amount such that the content of the paroxetine would be 20˜50 mg/day; in such a quantity that the content of the paroxetine would be 40 mg/day up to a maximum amount of 60 mg/day, starting with 20 mg/day for the treatment of obsessive-compulsive disorders; in such a quantity that the content of the paroxetine would be 40 mg/day up to a maximum quantity of 50 mg/day, starting from 10 mg/day for the treatment of panic disorders; in such a quantity that the content of the paroxetine would be up to a maximum quantity of 50 mg/day, starting with 20 mg/day, if necessary, increasing the dose of 10 mg/day for the treatment of disorders social phobia and post-traumatic stress disorder; and in such quantity that the content of the paroxetine would be 20 mg/day for the treatment of disorders generalized anxiety.

The best way of carrying out the invention

The compositions and processes described in this invention will be explained in more detail with reference to the following examples. However, these examples should not be construed as limiting the scope of invention.

Example 1

1, 0 g oily free base of paroxetine and 1.24 g holeva acid is completely dissolved in 20 ml of methanol by heating to 40° C and shaken for 2 hours. The solvent was removed under reduced pressure and the residue was then dried in vacuum, obtaining 2.2 g of solid paroxetine holata in the form of a white powder.

Example 2

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in a mixed solvent of methanol (10 ml) and acetone (40 ml) and heated to 40°and With shaking for 30 minutes. The solution was left to stand at room temperature for 24 hours to obtain salt. Salt was filtered and dried in vacuum to obtain 2.0 g of a solid paroxetine holata in the form of white crystals.

Example 3

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in 10 ml of methanol by heating to 40°and With shaking for one hour. The solution is slowly dropwise added to 100 ml of diethyl ether with planting solids was stirred at 0°C for 3 hours and filtered. The filter cake was washed with 30 ml of diethyl ether and dried in vacuum to obtain 1.89 g of solid paroxetine holata in the form of a light gray powder.

Example 4

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in a mixed solvent of ethanol (20 ml) and isopropylacetate (30 ml) and heated to 50°and Stra is Ivanyi within 2 hours. The solution was left to stand at -20°C for 48 hours, filtered and dried in vacuum to obtain 1.9 g of solid paroxetine holata in the form of a light gray powder.

Example 5

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid suspended in 50 ml of isopropanol. After boiling the suspension under stirring for 3 hours, it was slowly stirred at 25°C for 2 hours, filtered, and then dried in vacuum, obtaining 2.15 g of solid paroxetine holata in the form of white crystals.

Example 6

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in a mixed solvent of purified water (5 ml) and methanol (30 ml) with stirring for 2 hours. The solution was left to stand at 0°C for 48 hours, filtered and dried in vacuum to obtain 1.8 g of solid paroxetine holata in the form of a white powder.

Example 7

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in a mixed solvent of ethanol (30 ml) and dichloromethane (50 ml) and heated to 50°and With shaking for 3 hours. After distillation of the solution under reduced pressure to remove dichloromethane, it was left to stand at 25°C for 8 hours, filtered and dried in vacuum to obtain 1,94 g solid paroxeti holata in the form of white crystals.

Example 8

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in 10 ml of N,N-dimethylformamide under stirring for 10 minutes. The solution is slowly dropwise added to 100 ml of isopropylacetate with planting solids was stirred at 0°C for 3 hours and filtered. The filter cake was washed with 30 ml of diethyl ether and dried in vacuum to obtain 1.84 g of solid paroxetine holata in the form of a light gray powder.

Example 9

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in 10 ml of N,N-dimethylacetamide when heated to 40°and With shaking for 20 minutes. The solution is slowly dropwise added to 100 ml of diethyl ether with planting solids was stirred at 0°C for 3 hours and filtered. The filter cake was washed with 30 ml diethyl ether, dried in vacuum, obtaining of 1.75 g of solid paroxetine holata in the form of a light gray powder.

Example 10

1.0 g of the oily free base of paroxetine and 1.24 g holeva acid was completely dissolved in 10 ml of dimethyl sulfoxide with stirring for 5 minutes. The solution is slowly dropwise added to 100 ml of purified water with planting solids was stirred at 0°C for 3 hours and filtered. From filtrowanie precipitate was washed with 30 ml of diethyl ether and dried in vacuum to obtain 1.7 g of solid paroxetine holata in the form of a white powder.

Example 11

1.0 g of the oily free base of paroxetine and 1.19 g deoxycholic acid was completely dissolved in 10 ml of methyl ethyl ketone by heating to 40°and With shaking for one hour. The solution was left to stand at -20° ˜ 0°within 24 hours for planting crystals and filtered. The filter cake was washed with chilled methanol to 0°or lower and dried in vacuum to obtain 2.1 g of a solid of paroxetine deoxycholate in the form of a white powder.

Example 12

0.8 g of oily free base of paroxetine and 1.13 g glycocholic acid was completely dissolved in 20 ml of ethanol under heating to 40°and With shaking for 3 hours. After concentrating the solution under reduced pressure until the distilled 5 ml of solvent, the solution is further left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filter cake was washed with chilled methanol at 0°or lower and dried in vacuum to obtain 1.6 g of solid paroxetine glycocholate in the form of a light gray powder.

Example 13

0.8 g of oily free base of paroxetine and 1.31 g human beings need it to acid was completely dissolved in a mixed solvent of purified water (5 ml) and ethanol (20 ml) and heated to 40°and With shaking for one what about the hours. After concentrating the solution under reduced pressure until the distilled 5 ml of solvent was left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filter cake was washed with chilled methanol to 0°or lower and dried in vacuum to obtain 1.8 g of solid paroxetine taurocholate in the form of a light gray powder.

Examples 14-17

After paroxetine Holt, dicalcium phosphate, microcrystalline cellulose and sodium to croscarmelose mixed together with the respective compositions of examples 14 and 15 below in table 1, each mixture was passed through a standard sieve of 30 mesh. Then to properly sifted mixture was added magnesium stearate in amounts shown in table 1, and optionally mixed, and the mixture was pressed into tablets using conventional techniques.

Meanwhile, after paroxetine Holt, dicalcium phosphate, aspartame and powder orange flavor mixed together with the respective compositions of examples 16 and 17, shown below in table 1, each mixture was passed through a standard sieve of 30 mesh. Then to properly sifted mixture was added Pharmagum S and magnesium stearate in amounts shown in table 1, and optionally mixed, and the mixture is pressed the Ali into tablets using conventional techniques. Tablets for oral administration can take or swallow without water, avoiding the bitter taste, despite the rapid disintegration in the mouth.

Table 1
The pharmaceutical compositions of examples 14-17
Example 14Example 15Example 16Example 17
Paroxetine Holt20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Dicalcium phosphate (DCP)80.0 mg120,0 mg40,0 mg60,0 mg
Microcrystalline cellulose50.0 mg75,0 mg--
Sodium crosscarmellose10.0 mg15,0 mg--
Pharmagum SH--240,0 mg360,0 mg
Aspartame--0.2 mg0.3 mg
Powder orange flavour--0.5 mg0.75 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg
HPharmagum S: brand quickly disintegrating filler commercially available from the firm SPI Pharma

Examples 18-21

After paroxetine glycocholate, microcrystalline cellulose, sodium to croscarmelose and L-hydroxypropylcellulose mixed together with the respective compositions of examples 18 and 19, shown below in table 2, each mixture was passed through a standard sieve of 30 mesh and pereirae with linking solution prepared by dissolving in water Povidone K-30 (Povidone K-30) in the amount indicated in table 2. Each of the ground mixtures were dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve 18 mesh to obtain granulated particles with a size 18 mesh or less. To the corresponding granular particles was added magnesium stearate in amounts shown in table 2, and additionally mixed, and the final mixture was pressed into tablets using conventional techniques.

Meanwhile, after paroxetine glycocholate and microcrystalline cellulose were mixed with the respective compositions of examples 20 and 21, shown below in table 2, each mixture was passed through standardmonitor 30 mesh and pereirae with binding solution, prepared by dissolution in water of Povidone K-30 (Povidone K-30) in the amount indicated in table 2.

Each of the ground mixtures were dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve of 24 mesh with obtaining the granulated particles with a size of 24 mesh or less. To the corresponding granular particles were added Pharmaburst X powder to taste grape powder citric acid with a particle size of 30 mesh or less, and magnesium stearate in amounts shown in table 2, and additionally mixed, and the mixture was pressed into tablets using conventional techniques. Tablets for oral administration can take or swallow without water, avoiding the bitter taste, despite the rapid disintegration in the mouth.

Table 2
The pharmaceutical compositions of examples 18-21
Example 18Example 19Example 20Example 21
Paroxetine glycocholate20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Povidone K-300,0 mg 15,0 mg15,0 mg22,5 mg
Microcrystalline cellulose100.0 mg150,0 mg100.0 mg150,0 mg
Sodium crosscarmellose10.0 mg15,0 mg--
L-Hydroxypropyl cellulose30.0 mg40,0 mg--
Pharmaburst X*--240,0 mg320,0 mg
Powder to taste grapes--1.0 mg1.5 mg
Citric acid--1.0 mg1.5 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg
*Pharmaburst X: brand quickly disintegrating filler commercially available from the firm SPI Pharma

Examples 22-25

After paroxetine taurocholate, microcrystalline cellulose, sodium to croscarmelose and L-hydroxypropylcellulose mixed together with the respective compositions of examples 22 and 23, shown below in table 3, each mixture was passed through a standard sieve of 30 mesh and pereirae with binding solution, you need a kitchen is by dissolution in water of Povidone K-30 (Povidone K-30) in number, specified in table 3. Each of the ground mixtures were dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve 18 mesh to obtain granulated particles with a size 18 mesh or less. To the corresponding granular particles was added magnesium stearate in amounts shown in table 3, and additionally mixed, and the mixture was pressed into tablets using conventional techniques.

Meanwhile, after paroxetine taurocholate and microcrystalline cellulose were mixed and then mixed with the respective compositions of examples 24 and 25, shown below in table 3, each mixture was passed through a standard sieve of 30 mesh and pereirae with linking solution prepared by dissolving in water Povidone K-30 (Povidone K-30) in the amount indicated in table 3.

Each of the ground mixtures were dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve of 24 mesh with obtaining the granulated particles with a size of 24 mesh or less. To the corresponding granular particles were added Pharmaburst X powder to taste grape powder citric acid with a particle size of 30 mesh or less, and magnesium stearate in amounts shown in table 2, and optionally mixed and ready the second mixture was pressed into tablets using conventional techniques. Tablets for oral administration can take or swallow without water, avoiding the bitter taste, despite the rapid disintegration in the mouth.

Table 3
The pharmaceutical compositions of examples 22-25
Example 22Example 23Example 24Example 25
Paroxetine taurocholate20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Povidone K-3010.0 mg15,0 mg16,0 mg23,0 mg
Microcrystalline cellulose90,0 mg130,0 mg110,0 mg150,0 mg
Sodium crosscarmellose15,0 mg20.0 mg--
L-Hydroxypropyl cellulose30.0 mg40,0 mg--
Pharmaburst X*--260,0 mg340,0 mg
Powder to taste grapes--2.0 mg2.5 m the
Citric acid--1.0 mg1.5 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg
*Pharmaburst X: brand quickly disintegrating filler commercially available from the firm SPI Pharma

Examples 26 and 27

After paroxetine Holt, dicalcium phosphate, microcrystalline cellulose and sodium to croscarmelose mixed together with the respective compositions of examples 14 and 15 above in table 1, each mixture, respectively, for examples 26 and 27 were passed through a standard sieve of 30 mesh. Then to properly sifted mixture was added magnesium stearate in amounts shown in table 1, and optionally mixed, and ready the mixture was filled in capsules No. 2 using conventional techniques.

Examples 28 and 29

After paroxetine glycocholate, microcrystalline cellulose, sodium to croscarmelose and L-hydroxypropylcellulose mixed together with the respective compositions of examples 18 and 19 above in table 2, each mixture was passed through a standard sieve of 30 mesh and pereirae with linking solution prepared by dissolving in water Povidone K-30 (Povidone K-30) in amounts shown in table 2 above, with the responsibility for examples 28 and 29. Each of the ground mixtures were dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve 18 mesh to obtain granulated particles with a size 18 mesh or less. To appropriately granular particles was added magnesium stearate in amounts shown in table 2, and optionally mixed and ready mixture was filled in capsules No. 2 using conventional techniques.

Examples 30 and 31

Every 1.51 g and to 3.02 g of salt of paroxetine hydrochloride was stirred until a homogeneous mass of 1.65 g holeva acid and then pereirae with 0.7 g and 1 g of binder solution prepared by dissolving in ethyl alcohol Povidone K-30 (Povidone K-30) in an amount of 30 weight./vol.%, accordingly, for examples 30 and 31. The ground mixture was dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve of 30 mesh to obtain granulated particles with a size of 30 mesh or less. Ready granulated particle was used as compositions paroxetine containing cholic acid.

Examples 32 and 33

After you have selected the sample, corresponding to 20 mg of the free base of paroxetine from the corresponding compositions paroxetine prepared in examples 30 and 31, each of the samples plumage is shivali with dukellis phosphate, microcrystalline cellulose and sodium croscarmelose together with the composition of example 14, above, in table 1, and sieved through a standard sieve of 30 mesh, respectively, for examples 32 and 33. To properly sifted mixture was added magnesium stearate in the amounts given in example 14, and additionally mixed, and the mixture was pressed into tablets using conventional techniques.

Example 34

To 1.33 g of the free base of paroxetine was added 0.5 g of ethanol to obtain a suspension, and then thereto was added 3.3 grams holeva acid. The resulting mixture was pereirae, dried in a drying Cabinet at 40°With the loss of mass on drying (loss of drying, LOD) 2% or less, and was passed through a standard sieve of 30 mesh to obtain granulated particles with a size of 30 mesh or less, which was used as a composition paroxetine containing cholic acid.

Example 35

After you have selected the sample, corresponding to 20 mg of the free base of paroxetine composition of paroxetine prepared in example 34, the sample was mixed with dukellis phosphate, aspartame and powder orange flavour together with the composition of example 16, above, in table 1, and sieved through a standard sieve of 30 mesh. To the sifted mixture was added Pharmagum S and magnesium stearate in the amounts given in example 16, and optionally mixed; and the mixture was pressed into tablets using conventional techniques. Tablets for oral administration, it is possible to chew or swallow without water, avoiding the bitter taste, despite the rapid disintegration in the mouth.

Comparative example 1: Comparison of taste

After took 5 mg of the drug in the solid state from each of the medicinal composition is shown in table 4, without any filler, water or other solvents, is out of line evaluated the taste of the medicinal product with the help of three members of the selected group for 10 minutes. Originally paroxetine retains the characteristic bitter taste, even in small quantities and then calls annoying pain along with unbearable bitter taste for a certain period of time.

According to experimental results (table 4) other salts of paroxetine, with the exception of paroxetine holata and paroxetine glycocholate, initially maintained a bitter taste and caused an irritating painful sensation along with a bitter taste in a certain period of time. In particular, currently being sold or approved paroxetine hydrochloride and paroxetine methanesulfonate kept the bitter taste inherent in the paroxetine, and subjected to a strong rejection by members of the selected group. On the contrary,paroxetine Holt and paroxetine glycocholate, described in this invention, eliminates the bitter taste and a painful sensation inherent paroxetine, and is not subjected to strong rejection by members of the selected group. In addition, it was confirmed that the reduction of the characteristic taste and pain paroxetine can only be achieved by mixing paroxetine with holeva acid. Thus, paroxetine Holt or salt derived holeva acid and a composition comprising paroxetine and cholic acid or its derivative, described in this invention, suitable as disintegrating in the mouth tablets antidepressants.

Table 4
The initial taste (within one minute)Later taste (after one minute)
Paroxetine HoltWithout tasteWithout pain
A mixture of paroxetine and holeva acid (1:1, molar ratio)Slightly bitter tasteWithout pain
Paroxetine glycocholateWithout tasteWithout pain
Paroxetine the glucuronateBitter tasteCaused an irritating painful experienced is e
Paroxetine HClVery bitter tasteCaused an irritating painful sensation
Paroxetine methanesulfonateVery bitter tasteCaused an irritating painful sensation
Paroxetine tartrateVery bitter tasteCaused an irritating painful sensation
Paroxetine napsylateVery bitter tasteCaused an irritating painful sensation

Comparative example 2: Comparison of stability

Each of the drugs listed in table 5, were completely dissolved in 0.3%hydrogen peroxide solution at a concentration of 1 mg/ml During storage under stress conditions at 80°With controlled changes in the content of drugs. a 0.3%solution of hydrogen peroxide solution is usually used to quickly determine the stability of drugs, and provides stress conditions for artificial acidification of drugs. Quantitative analysis was performed using HPLC according to the quantitative analysis of paroxetine listed in the U.S. Pharmacopoeia (USP).

HPLC analysis showed that paroxetine Holt and paroxetine glycocholate have high what kind of stability compared to other salts of paroxetine. In particular, the contents of the currently marketed or approved paroxetine hydrochloride and paroxetine methanesulfonate quickly reduced to 54% or below within 48 hours and up to about 15% or below within 120 hours of storage. The results show that these drugs cause almost complete loss of it within 120 hours. On the contrary, salt, described in this invention, maintained the levels of 89% or more within 48 hours and 54% or more than 120 hours of storage. Thus, salts, described in this invention, it was surprisingly stable. In addition, it was confirmed that the improvement in stability can also be achieved by mixing paroxetine with holeva acid.

Table 5
Comparison of the stability of salts of paroxetine under severe conditions (Luggage at 80°and 0.3%hydrogen peroxide)
Original24 hours48 hours72 hours120 hours144 hours
Paroxetine Holt100,0%of 98.2%92,4%-66,3%-
Mixture100,0%97,4%90,3%- 63,9%-
paroxetine and holeva acid (1:1,molar ratio)
Paroxetine glycocholate100,0%96,8%89,6%-54,3%-
Paroxetine the glucuronate100,0%92,8%59,0%-12,3%-
Paroxetine HCl100,0%84,5%53,8%-13,4%-
Paroxetine methanesulfonate100,0%74,4%31,8%16,6%--
Paroxetine tartrate100,0%81,3%-28,3%-4,8%
Paroxetine napsylate100,0%60,4%-16,1%-3,5%

Industrial application

As is evident from the above description, the new salts of paroxetine and composition of paroxetine described in this invention, the bitter taste inherent in the paroxetine disappears completely, and not by masking the bitter taste of pomomusings, using ion-exchange resin; clathrates using cyclodextrins; coatings, applying polymers; and other substances with an intense fragrance and flavor properties, etc. other such conventional methods, and with the salt of paroxetine with holeva acid or its derivatives with a slightly bitter taste. I.e. this path described in this invention, consists in the complete destruction of the taste paroxetine without modification of the taste. Thus, it suddenly fixes the characteristic taste and painful feeling caused by paroxetine.

In addition, unlike glycyrrhizic acid or salts of glycyrrhizic acid, is described in PCT applications WO 03/013470 and WO 03/013529, where the intense smell and taste of licorice causes changes of the taste of paroxetine salt described in this invention, use cholic acid or its derivatives with a slightly bitter taste to completely remove the inherent paroxetine bitter taste without any taste changes.

In addition, paroxetine Holt and salt of paroxetine derivative holeva acid, described in this invention have excellent stability to oxidation, which is considered as the main factor reducing the content of drug in assessing its stability compared with other salts paroxet is on.

Therefore, paroxetine Holt and salt of paroxetine derivative holeva acid, described in this invention, are suitable as vehicles for oral administration and swallow them without water, especially hard drugs, and can be used for liquid drugs owing to their excellent stability.

In addition, taste and excellent stability paroxetine can be achieved not only through education salt of paroxetine, but also by mixing paroxetine with holeva acid or its derivatives.

Although the preferred variants of the present invention is described for illustrative purposes, the person skilled in the art understand that various modifications, additions and substitutions without deviating from the scope and nature of the invention as described in the attached claims.

Examples synthesis

(101) 0.8 g of Oily free base of paroxetine and 1.18 g glycocholate sodium was completely dissolved in 20 ml of ethanol under heating to 40°and With shaking for 3 hours. The solution was concentrated under reduced pressure until the distilled 5 ml of solvent, the solution is further left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filter cake was washed with chilled methanol at 0°or lower and dried under vacuum Poluchenie 1.5 g of solid paroxetine glycocholate in the form of a light gray powder.

(102) 1.0 g of the oily free base of paroxetine and 1.19 g of lithocholic acid was completely dissolved in 10 ml of methyl ethyl ketone by heating to 40°and With shaking for 1 hour. The solution was left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 1.9 g of solid paroxetine lithonate in the form of a white powder.

(103) 1.0 g of the oily free base of paroxetine and 1.14 g chenodeoxycholic acid was completely dissolved in 10 ml of methyl ethyl ketone by heating to 40°and With shaking for 1 hour. The solution was left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 2.0 g of a solid paroxetine chenodeoxycholic in the form of a white powder.

(104) 1.0 g of the oily free base of paroxetine and 1.14 g of ursodeoxycholic acid was completely dissolved in 20 ml of ethanol under heating to 40°and With shaking for 3 hours. The solution was concentrated under reduced pressure until the distilled 5 ml of solvent, the solution is further left to stand at -20° ˜ 0°within 24 hours the La planting crystals, then was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 1.5 g of solid paroxetine ursodeoxycholate in the form of a light gray powder.

(105) 0.8 g of oily free base of paroxetine and 1.31 g human beings need it to acid was completely dissolved in a mixture of purified water (5 ml) and ethanol (20 ml) and heated to 40°and With shaking for 1 hour. The solution was concentrated under reduced pressure until the distilled 5 ml of solvent, the solution is further left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 1.8 g of solid paroxetine taurocholate in the form of a light gray powder.

(106) 0.8 g of oily free base of paroxetine and 1.36 g taurocholate sodium was completely dissolved in a mixture of purified water (5 ml) and ethanol (20 ml) and heated to 40°and With shaking for 1 hour. The solution was concentrated under reduced pressure until the distilled 5 ml of solvent, the solution is further left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in Vacu the IU obtaining 1.8 g of solid paroxetine taurocholate in the form of a light gray powder.

(107) 1.0 g of the oily free base of paroxetine and 1.14 g dehydrocholic acid was completely dissolved in 10 ml of methyl ethyl ketone by heating to 40°and With shaking for 1 hour. The solution was left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 2.0 g of a solid paroxetine dehydrocholate in the form of a white powder.

(108) 1.0 g of the oily free base of paroxetine and 1.26 g of deoxycholate sodium was completely dissolved in 10 ml of methyl ethyl ketone by heating to 40°and With shaking for 1 hour. The solution was left to stand at -20° ˜ 0°within 24 hours for planting crystals, after which it was filtered. The filtered residue was washed with cold methanol at 0°or lower and dried in vacuum to obtain 2.0 g of a solid of paroxetine deoxycholate in the form of a white powder.

(109) 1.0 g of the oily free base of paroxetine and 1.22 g dehydrocholic acid was completely dissolved in a mixture of purified water (5 ml) and ethanol (30 ml) and was shaken for 2 hours. The solution was left to stand at 0°at 48 hours, was filtered and dried under vacuum to obtain 2.0 g of a solid paroxetine dehydrocholate in the form of a white powder.

(11) 1.0 g of the oily free base of paroxetine and 1.30 grams cholate sodium was completely dissolved in a mixture of purified water (5 ml) and ethanol (30 ml) and was shaken for 2 hours. The solution was left to stand at 0°at 48 hours, was filtered and dried under vacuum to obtain 2.1 g of a solid paroxetine holata in the form of a white powder.

Examples of pharmaceutical preparations

(201) except that paroxetine Holt replaced with paroxetine lithocholate, tablets prepared in much the same way as in examples 14-17 in formulas Table 6.

0.2 mg
Table 6
Formula 1Formula 2Formula 3Formula 4
Paroxetine lithocholate20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Dicalcium phosphate (DCP)80.0 mg120,0 mg40,0 mg60,0 mg
Microcrystalline cellulose50.0 mg75,0 mg--
Sodium crosscarmellose10.0 mg15,0 mg--
Pharmagum S--240,0 mg360,0 mg
Aspartame--0.3 mg
Powder orange flavour--0.5 mg0.75 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg

(202) except that paroxetine Holt replaced with paroxetine dehydrocholate, tablets prepared in much the same way as in examples 14-17 in formulas Table 7.

Table 7
Formula 1Formula 2Formula 3Formula 4
Paroxetine dehydrocholate20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Dicalcium phosphate (DCP)80.0 mg120,0 mg40,0 mg60,0 mg
Microcrystalline cellulose50.0 mg75,0 mg--
Sodium crosscarmellose10.0 mg15,0 mg--
Pharmagum S--240,0 mg36,0 mg
Aspartame--0.2 mg0.3 mg
Powder orange flavour--0.5 mg0.75 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg

(203) except that paroxetine Holt replaced with paroxetine chenodeoxycholic, tablets prepared in much the same way as in examples 18-21 in the formulas of Table 8.

Table 8
Formula 1Formula 2Formula 3Formula 4
Paroxetine chenodeoxycholic20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Povidone K-3010.0 mg15,0 mg15,0 mg22,5 mg
Microcrystalline cellulose100.0 mg150,0 mg100.0 mg150,0 mg
Sodium crosscarmellose10.0 mg15,0 mg--
-Hydroxypropyl-cellulose 30.0 mg40,0 mg--
Pharmaburst X--240,0 mg320,0 mg
Powder to taste grapes--1.0 mg1.5 mg
Citric acid--1.0 mg1.5 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg

(204) except that paroxetine Holt replaced with paroxetine ursodesoxycholic, tablets prepared in much the same way as in examples 18-21 in formulas Table 9.

Table 9
Formula 1Formula 2Formula 3Formula 4
Paroxetine ursodesoxycholic20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
Povidone K-3010.0 mg15,0 mg15,0 mg22,5 mg
Microcrystalline cellulose100.0 mg150 mg 100.0 mg150,0 mg
Sodium crosscarmellose10.0 mg15,0 mg--
L-Hydroxypropyl cellulose30.0 mg40,0 mg--
Pharmaburst X--240,0 mg320,0 mg
Powder to taste grapes--1.0 mg1.5 mg
Citric acid--1.0 mg1.5 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg

(205) except that paroxetine Holt replaced with paroxetine deoxycholate, tablets prepared in much the same way as in examples 18-21 in formulas Table 10.

Povidone K-30
Table 10
Formula 1Formula 2Formula 3Formula 4
Paroxetine deoxycholate20.0 mg (as free base)30.0 mg (as free base)20.0 mg (as free base)30.0 mg (as free base)
10.0 mg15,0 mg15,0 mg22,5 mg
Microcrystalline cellulose100.0 mg150,0 mg100.0 mg150,0 mg
Sodium crosscarmellose10.0 mg15,0 mg--
L-Hydroxypropyl cellulose30.0 mg40,0 mg--
Pharmaburst X--240,0 mg320,0 mg
Powder to taste grapes--1.0 mg1.5 mg
Citric acid--1.0 mg1.5 mg
Magnesium stearate1.5 mg2.25 mg1.5 mg2.25 mg

Additional experimental examples

Experimental example 1. Comparison of taste

After took 5 mg of the drug in the solid state from each of the medicinal composition is shown in table 11, with no filler, water or other solvents, the taste of the drug was evaluated out of line with three members specially selected group within 10 minutes. Originally paroxetinenet characteristic bitter taste, even in small quantities and then calls annoying pain along with unbearable bitter taste for a certain period of time.

According to experimental results (table 11), the remaining salt of paroxetine, with the exception of paroxetine holata, paroxetine lithocholate, paroxetine dehydrocholate, paroxetine chenodeoxycholic, paroxetine ursodeoxycholate, paroxetine of deoxycholate, paroxetine taurocholate and paroxetine glycocholate initially maintained a bitter taste and caused an irritating painful sensation along with a bitter taste in a certain period of time. In particular, currently being sold or approved paroxetine hydrochloride and paroxetine methanesulfonate kept the bitter taste inherent in the paroxetine, and subjected to a strong rejection by members of the selected group.

On the contrary, paroxetine Holt, paroxetine lithocholate, paroxetine dehydrocholate, paroxetine chenodeoxycholic, paroxetine ursodesoxycholic, paroxetine deoxycholate, paroxetine taurocholate and paroxetine glycocholate described in this invention, eliminates the bitter taste and a painful sensation inherent paroxetine, and is not subjected to strong rejection by members of the selected group.

Table 11
Tastes salts of paroxetine
The initial taste (within one minute) Later taste (after one minute)
Paroxetine HoltWithout tasteWithout pain
Paroxetine lithocholateWithout tasteWithout pain
Paroxetine dehydrocholateWithout tasteWithout pain
Paroxetine chenodeoxycholicWithout tasteWithout pain
Paroxetine ursodesoxycholicWithout tasteWithout pain
Paroxetine deoxycholateWithout tasteWithout pain
Paroxetine taurocholateWithout tasteWithout pain
Paroxetine glycocholateWithout tasteWithout pain
Paroxetine hydrochlorideVery bitter tasteCaused an irritating painful sensation
Paroxetine methanesulfonateVery bitter tasteCaused an irritating painful sensation
Paroxetine tartrateVery bitter tasteCaused an irritating painful sensation
Paroxetine napsylateVery bitter tasteCaused an irritating painful sensation

Experimental example 2. Comparison of stability

Each of the drugs listed in table 12, were completely dissolved in 0.3%hydrogen peroxide solution at a concentration of 1 mg/ml During storage under stress conditions at 80°With controlled changes in the content of drugs. a 0.3%solution of hydrogen peroxide solution is usually used to quickly determine the stability of drugs, and provides stress conditions for artificial acidification of drugs. Quantitative analysis was performed using HPLC according to the quantitative analysis of paroxetine listed in the U.S. Pharmacopoeia (USP).

HPLC analysis showed that paroxetine Holt, paroxetine lithocholate, paroxetine dehydrocholate, paroxetine chenodeoxycholic, paroxetine ursodesoxycholic, paroxetine deoxycholate, paroxetine taurocholate and paroxetine glycocholate have high stability compared to other salts of paroxetine.

In particular, the contents of the currently marketed or approved paroxetine hydrochloride and paroxetine methanesulfonate quickly reduced to 54% or below within 48 hours and up to about 15% or below within 120 hours of storage. The results show that these drugs cause almost complete loss of it within 120 hours. In contrast, salt. described in this invention, maintained the levels of 89% or more within 48 hours and 54% or more than 120 hours of storage. Thus, salts, described in this invention, it was surprisingly stable.

Table 12
Original24 hours48 hours72 hours120 hours144 hours
Paroxetine Holt100.0%98.2%92.4%-66.3%-
Paroxetine lithocholate97.6%91.5%-65.6%-
Paroxetine dehydrocholate98.3%92.1%-65.9%-
Paroxetine chenodeoxycholic96.8%90.8%-64.1%-
Paroxetine ursodesoxycholic97.1%91.4%-5.5% -
Paroxetine deoxycholate98.0%91.9%-63.2%-
Paroxetine taurocholate97.5%91.6%-55.3%-
Paroxetine glycocholate96.8%89.6%-54.3%-
Paroxetine hydrochloride84.5%53.8%-13.4%-
Paroxetine methanesulfonate74.4%31.8%16.6%--
Paroxetine tartrate81.3%-28.3%-4.8%
Paroxetine napsylate60.4%-16.1%-3.5%

1. Paroxetine Holt or salt derived holeva acid, in which cholic acid and its derivative correspond to the formula 1

where R1, R2and R3independently are hydrogen atoms or hydroxyl groups, and X represents-OH, -ONa, -NH-(CH2) n-SO3N, -NH-(CH2)n-SO3Na. -NH-(CH2)n-SO3To, -NH-(CH2)n-CO2H, -NH-(CH2)n-CO2Na or-NH-(CH2)n-CO2K (where n is an integer from 1 to 3), or formula 2

where X has the meanings given in formula 1.

2. Salt according to claim 1, in which the salt is a salt of paroxetine holata.

3. Salt according to claim 1 or 2, in which the salt of paroxetine is in crystalline form.

4. Salt according to claim 1 or 2, in which the salt of paroxetine is in a noncrystalline form.

5. Pharmaceutical composition for the treatment of extensive depressive disorder, obsessive-compulsive disorder, panic and General anxiety disorder or post-traumatic stress disorder, containing salt of paroxetine according to claim 1 or 2, and pharmaceutically acceptable filler.

6. The composition according to claim 5, which is part of the oral drug and swallow them without water.

7. Pharmaceutical composition for the treatment of extensive depressive disorder, obsessive-compulsive disorder, panic and General anxiety disorder or post-traumatic stress disorder, contains paroxetine and cholic acid or its derivative, in which cholic acid and its derivative correspond to the formula 1

where R1, R2and R3independently are hydrogen atoms or hydroxyl groups, and X represents-OH, -ONa, -NH-(CH2)n-SO3N, -NH-(CH2)n-SO3Na, -NH-(CH2)n-SO3K, -NH-(CH2)n-CO2H, -NH-(CH2)n-CO2Na or-NH-(CH2)n-CO2K (where n is an integer from 1 to 3), or formula 2

where X is-HE.

8. The composition according to claim 7, in which the molar ratio holeva acid or its derivative to the paroxetine is from 0.5:1 to 2:1.

9. The composition according to claim 7 or 8, obtained by uniformly mixing paroxetine and holeva acid or its derivative in water or an organic solvent with subsequent drying.

10. A pharmaceutical composition comprising the composition according to claim 7 or 8 and a pharmaceutically acceptable filler.

11. The pharmaceutical composition according to claim 9, further containing a pharmaceutically acceptable filler.

12. The pharmaceutical composition of claim 10, part oral drug and swallow them without water.

13. The pharmaceutical composition according to item 11, is included with oral medication, swallow them without water.

14. A method of treating depression, comprising introducing a therapeutically effective amount of parkas is etin cholate or salt derived holeva acid according to claim 1 person who needs such treatment.

15. A method of treating depression, comprising introducing a therapeutically effective amount of a composition according to claim 7 to a person who needs such treatment.

16. The use of paroxetine cholate or salt derived holeva acid according to claim 1 for the treatment of depression.

17. The use of a composition according to claim 7 for the treatment of depression.

18. The use of paroxetine cholate or salt derived holeva acid according to claim 1 in the manufacture of medicaments for the treatment of depression.

19. The use of a composition according to claim 7 in the manufacture of medicaments for the treatment of depression.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicinal industry, sterols.

SUBSTANCE: invention relates, in particular, to the improved method for producing sterols - lanosterol and cholesterol from wooly fat that can be used in preparing medicinal and cosmetic preparations. Method is carried out by alkaline hydrolysis of raw, extraction of unsaponifiable substances, removal of solvent and successive isolation of lanosterol and cholesterol. Alkaline hydrolysis of raw is carried out with a mixture of ethanol, sodium hydroxide, pyrogallol and water at temperature 70°C for 4 h at stirring in the following ratio of components: raw : ethanol : sodium hydroxide : pyrogallol : water = 100.0:(300.0-350.0):(30.0-35.0):(0.01-0.05):(7.5-12.0), respectively, with the indicated mixture with addition of toluene in the following ratio: raw : ethanol : sodium hydroxide : pyrogallol : toluene : water = 100.0:(220.0-255.0):(30.0-38.0):(0.05-0.12):(100.0-137.0):(2.5-7.0), respectively, and lanosterol is isolated by precipitation from mixture of methylene chloride and ethanol in the ratio = 1:1. Before removal of solvent unsaponifiable substances are extracted at temperature 50°C for 2-3 h at stirring. Invention provides increasing yield of the end product, enhancing qualitative indices and reducing cost of production.

EFFECT: improved producing method.

2 cl, 3 ex

FIELD: organic chemistry, chemistry of steroids.

SUBSTANCE: invention relates to a new method for synthesis of 6β-formyl-B-norcholestane-3β,5β-diol of the formula (I): by constricting six-membered B-ring of cholesterol. Method involves photooxidation of cholesterol with air oxygen at irradiation by visible light in the presence of porphyrine photosensibilizing agent immobilized on low-molecular fraction of copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonylfluoride octene-1 in the mass ratio porphyrine photosensibilizing agent : cholesterol = 1:(12-15). As porphyrine photosensibilizing agent 5,10,15,20-tetraphenylporphyrine can be used. Method shows technological simplicity, it doesn't require rigid conditions and provides the high yield of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)

wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.

EFFECT: valuable medicinal properties of compounds.

22 cl, 7 tbl, 41 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to substituted phenylalkylamines, their pharmaceutically acceptable salts and physiologically functional derivatives

The invention relates to an improved method of direct esterification of Stanlow/sterols interaction of stanol/sterols and acid taken in stoichiometric ratio, in the presence of a sufficient amount of catalyst, which can be acidic or basic, and in the presence of a sufficient amount of decolorizing agent, preferably activated carbon

The invention relates to the field of biologically active substances from plant material, in particular to a method of simultaneously receiving 20-hydroxyecdysone but also of inokosterone, ecdysone, magisteria And having the following structural formula:

20-hydroxyecdysone - R1=OH, R2=H, R3=OH, R4=H

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)

wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.

EFFECT: valuable medicinal properties of compounds.

22 cl, 7 tbl, 41 ex

FIELD: organic chemistry, chemistry of steroids.

SUBSTANCE: invention relates to a new method for synthesis of 6β-formyl-B-norcholestane-3β,5β-diol of the formula (I): by constricting six-membered B-ring of cholesterol. Method involves photooxidation of cholesterol with air oxygen at irradiation by visible light in the presence of porphyrine photosensibilizing agent immobilized on low-molecular fraction of copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonylfluoride octene-1 in the mass ratio porphyrine photosensibilizing agent : cholesterol = 1:(12-15). As porphyrine photosensibilizing agent 5,10,15,20-tetraphenylporphyrine can be used. Method shows technological simplicity, it doesn't require rigid conditions and provides the high yield of the end product.

EFFECT: improved preparing method.

2 cl, 3 ex

FIELD: medicinal industry, sterols.

SUBSTANCE: invention relates, in particular, to the improved method for producing sterols - lanosterol and cholesterol from wooly fat that can be used in preparing medicinal and cosmetic preparations. Method is carried out by alkaline hydrolysis of raw, extraction of unsaponifiable substances, removal of solvent and successive isolation of lanosterol and cholesterol. Alkaline hydrolysis of raw is carried out with a mixture of ethanol, sodium hydroxide, pyrogallol and water at temperature 70°C for 4 h at stirring in the following ratio of components: raw : ethanol : sodium hydroxide : pyrogallol : water = 100.0:(300.0-350.0):(30.0-35.0):(0.01-0.05):(7.5-12.0), respectively, with the indicated mixture with addition of toluene in the following ratio: raw : ethanol : sodium hydroxide : pyrogallol : toluene : water = 100.0:(220.0-255.0):(30.0-38.0):(0.05-0.12):(100.0-137.0):(2.5-7.0), respectively, and lanosterol is isolated by precipitation from mixture of methylene chloride and ethanol in the ratio = 1:1. Before removal of solvent unsaponifiable substances are extracted at temperature 50°C for 2-3 h at stirring. Invention provides increasing yield of the end product, enhancing qualitative indices and reducing cost of production.

EFFECT: improved producing method.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention describes paroxetine cholate or salt of cholic acid derivative and composition, which contains paroxetine and cholic acid or its derivative. Also described is pharmaceutical composition for treatment of depressive states, containing paroxetine salt or composition. Pharmaceutical composition can be part of peroral medication, swallowed without water, on form of disintegrating in mouth paroxetine tablet.

EFFECT: obtaining paroxetine cholate or salt of cholic acid derivative, which can be used in pharmacology.

19 cl, 38 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to synthesis of biologically active substances, in particular specifically, to improved method of producing 2,3-monoacetonide 20-hydroxyecdysone of formula found in very small amounts in some plants, e.g. Rhaponticum carthamoides. Method is implemented by interaction of 20- hydroxyecdysone (1.0 g, 2.08 mmole) and acetone with phosphomolybdic acid (PMA) added. As suspension is effected by mother compound in PMA acetone (0.3 g, 0.16 mmole), after 5 min homogenisation of reaction mixture is observed to be steamed by neutralisation with 0.1% sodium hydrocarbonate solution with following ethyl acetate and chromatography extraction of the end product, thus resulting in isolation of the end 2,3-monoacetonide 20- hydroxyecdysone of 32% yield.

EFFECT: method is highly selective and single-stage.

2 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula [I], where X represents halogen, trifluoromethyl, C1-C7alkyl, substituted with phenyl, C2-C9alkenyl, optionally substituted with C1-C7alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C1-C7alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, phenyl or benzoyl, where C1-6alkyl is optionally substituted with one or more halogens, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or C1-6alkoxy; Q1 represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q2 represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

FIELD: production processes.

SUBSTANCE: invention refers to wood working and wood chemical industries. Birch bark is broken down, mixed with liquid, the mixture is held at temperature higher than mixture freezing temperature, then triterpene compounds are separated from lingo-adipic residue with the following filtration and drying. Birch bark is additionally broken down by method of impact-abrasing and/or abrasing effect till obtaining birch bark flour. Birch bark flour is mixed with liquid with density of 0.999-0.958 kg/m3. Mixture is held for 0.1-10 hours and then separated by flotation to hydrophobic and hydrophilous fraction. Solution remaining after separation is condensed and dried. Obtained hydrophobic fraction - mixture of triterpene compounds - is exposed to recrystallisation in ethanol with activated charcoal and then betuline, solution of triterpene compounds in ethanol and mixture of triterpene and polyphenol compounds at carbon matrix is obtained. Or triterpene compounds mixture is separated to fractions in carbon-dioxide extractor and betuline, dry mixture of triterpene and polyphenol compounds are obtained. Hydrophilous fraction - lingo-adipic flour - is separated from liquid and dried out.

EFFECT: increase of environmental safety and method effectiveness.

6 cl, 4 ex, 3 dwg

FIELD: medicine.

SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.

EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.

9 cl, 3 ex

Up!