EP1255565A1

EP1255565A1 - Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary

Info

Publication number: EP1255565A1
Application number: EP01942307A
Authority: EP
Inventors: Sven Schreder; Karen Schamp; Claudia Wildner
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2000-01-13
Filing date: 2001-01-05
Publication date: 2002-11-13
Also published as: AU2001228454A1; WO2001051089A1; US20030153585A1; AR027512A1

Abstract

The invention relates to pharmaceutical preparations containing at least one medical agent and 2-pyrrolidone as the dissolving intermediary.

Description

PHARMACEUTICAL PREPARATIONS CONTAINING 2-PYRROLIDONE AS A SOLUTION AGENT

The invention relates to pharmaceutical preparations containing at least one active pharmaceutical ingredient and 2-pyrrolidone as solubilizer.

Active pharmaceutical ingredients which are sparingly soluble in water are preferably used, in particular 4- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid or one of the pharmaceutically acceptable salts, 4- [4- (3-chloro-4-hydroxy-

10 benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one of the pharmaceutically acceptable salts or 5- [1- (3,4-dimethoxy-benzoyi) -1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3,6-dihydro- [1,3,4] thiadiazin-2-one. The preparations according to the invention are preferably administered orally. Subject of

15 invention is also the use of 2-pyrrolidone as

Solubilizer in pharmaceutical preparations for oral administration in human medicine.

Many chemical substances show poor water solubility.

20 If these poorly soluble compounds act as active pharmaceutical ingredients

Should be used, they must be made available to the human organism in a suitable manner so that the active ingredient can be taken up. The bioavailability of an active pharmaceutical ingredient often depends to a considerable extent on galenics

25 of the preparation.

If the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability lies, i.e. the proportion of the drug that remains unchanged in the systemic blood, i.e. gets into the big cycle, at 100%.

30 When a poorly soluble active pharmaceutical ingredient is administered orally, it must first dissolve so that it can overcome the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum, or can be resorbed by the body. Theoretically the best

Dosage form for oral administration is a solution, because in this formulation the active ingredient does not require a dissolution step before it can be absorbed.

One way to increase the solubility of a poorly soluble active pharmaceutical ingredient and thereby improve absorption is by comminuting the poorly soluble compound. The particle size is reduced to the nanometer range and the active ingredient is "nanonized" in the formulation. By reducing the particle size, the surface available for resolution is enlarged. Furthermore, reagents are added which modify the surface of the particles and thus prevent reaggregation. These measures increase the rate of dissolution and the concentration gradient between the active ingredient solution, for example in the stomach, and the blood increases. Known formulations in which the particle size of the drug substance is in the "nanonized" type and methods for nanonization are described in US Pat. No. 5,145,684, US Pat. No. 5,534,270, US Pat. No. 5,585,108, US Pat. No. 5,662,883, US Pat. No. 5,665,331 or US Pat.

The dissolution rate can also be increased by adding a solubilizer, for example alcohols, glycerol, propylene glycol, polyethylene glycol or sorbitol.

Another possibility is the production of microemulsions in which the active ingredient is present in solution. Known formulations using this technique apply, as well as methods for the preparation of microemulsions are described in US 5,141,961, US 5,376,688, US 5,430,017, US 5,688,761, US 5,505,961, US 5,707,648, US 5,759,566 or US 5,912,011.

The object of the invention was to develop new pharmaceuticals in the form of pharmaceutical preparations for the oral administration of active pharmaceutical ingredients, in particular 4- [4- (3-chloro-4-methoxy-benzylamino) -benzo [4,5] thieno [2,3 -d] pyrimidin-2-yl] - cyclohexane carboxylic acid or its pharmaceutically acceptable salts, 4- [4- (3-chloro-4-hydroxy-benzylamino) -benzo [4,5] thieno [2,3-d] pyrimidin- 2-yl] -cyclohexane carboxylic acid or its pharmaceutically acceptable salts or 5- [1 - (3, 4-dimethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3, To provide 6-dihydro- [1, 3,4] thiadiazin-2-one, which have a very good bioavailability and at the same time allow the active ingredient to flood into the body quickly.

5- [1- (3,4-Dimethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3,6-dihydro- [1,3,4] thiadiazine -2-one is a compound known from EP 0 294 647 (Example 5) with positive inotropic activity. The substance has a vasodilating effect and therefore promotes blood circulation and antithrombotic.

It can be used in particular to combat heart muscle diseases or heart failure.

The solubility of this compound in water is 2 μg / ml. 5- [1- (3,4-Dimethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3,6-dihydro- [, 3,4] thiadiazine 2-one is a classic example of a sparingly soluble

Compound, the solubility of which is the determining step for bioavailability.

The compound 4- [4- (3-chloro-4-methoxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyhmidin-2-yl] τcyclohexane carboxylic acid or its Poorly soluble pharmaceutically acceptable salts, especially the ethanolamine salt, are effective inhibitors of cGMP phosphodiesterase (PDE V inhibitors). This compound, its pharmaceutically acceptable salts and a process for its preparation are described in WO 99/55708 (Example 2 or p. 9, lines 1-34). The

Compounds are suitable for the treatment of diseases of the cardiovascular system, in particular heart failure and for the treatment and / or therapy of erectile dysfunction. The solubility of the ethanolamine salt is 22 ng / ml in phosphate buffer (pH 1.0), 19 ng / ml in phosphate buffer (pH 7.0) and in the gastrointestinal tract, i.e. under physiological conditions, 10 ng / ml. The solubility of the ethanolamine salt in artificial gastric juice is 1 mg / 100 ml, in artificial intestinal juice 6 mg / 100 ml in phosphate buffer (pH 1.0) 22 ng / ml, in phosphate buffer (pH 6) 1.6 ng / ml and in phosphate buffer (pH 10) 11.4 µg / ml.

Analogous to the above explanations, the solution of the active pharmaceutical ingredient determines the rate of bioavailability.

The first metabolite of 4- [4- (3-chloro-4-methoxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or the pharmaceutically acceptable salts of 4 - [4- (3-Chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid is 4- [4- (3-chloro-4 -hydroxy-benzylamino) -benzo [4,5] thieno [2,3-d] pyhmidin-2-yl] cyclohexane carboxylic acid. 4- [4- (3-

Chloro-4-hydroxy-benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or its pharmaceutically acceptable salts are also effective inhibitors of cGMP phosphodiesterase (PDE V inhibitors) , Other poorly soluble active pharmaceutical ingredients that are suitable for a preparation according to the invention are active pharmaceutical ingredients whose solubility in water is less than 100 μg / ml. Examples of poorly soluble active pharmaceutical ingredients which are suitable for a preparation according to the invention are triamteren, phenytoin, mebendazole,

Glibenclamide, naproxen, nabumetone, medroxyprogesterone acetate, estradiol, lovastatin, clotrimazole, danazol, cinnarizine, loratadine, sitosterol or probucol.

The object was achieved by finding the preparations according to the invention.

The invention relates to a pharmaceutical preparation containing at least one active pharmaceutical ingredient, in particular a poorly soluble active pharmaceutical ingredient, and 2-pyrrolidone as

Solubilizers. The pharmaceutical preparation is preferably administered orally.

The invention relates to a pharmaceutical preparation containing at least one active pharmaceutical ingredient, in particular a poorly soluble active pharmaceutical ingredient, a lipid-like auxiliary and 2-pyrrolidone as a solubilizer.

The invention also relates to a pharmaceutical preparation containing at least one active pharmaceutical ingredient, in particular a poorly soluble active pharmaceutical ingredient, a carrier and 2-pyrrolidone as a solubilizer.

The invention relates to a pharmaceutical preparation, as described above, containing at least 4- [4- (3-chloro-4-methoxy- benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid or one of the poorly soluble pharmaceutically acceptable salts, and 2-pyrrolidone as solubilizer.

4- [4- (3-Chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid ethanolamine salt is preferably used.

The invention relates to a pharmaceutical preparation containing at least 4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one the poorly soluble pharmaceutically acceptable salts, 2-pyrrolidone as a solubilizer and a lipid-like auxiliary or a carrier material.

The invention relates to a pharmaceutical preparation containing at least 4- [4- (3-chloro-4-hydroxy-benzylamino) - beπzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one the pharmaceutically acceptable salts and 2-pyrrolidone as solubilizer.

The invention relates to a pharmaceutical preparation containing at least 4- [4- (3-chloro-4-hydroxy-benzylamino) -benzo [4,5] thieπo [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one the poorly soluble pharmaceutically acceptable salts, 2-pyrrolidone as a solubilizer and a lipophilic auxiliary or a carrier material.

The invention relates to a pharmaceutical preparation containing at least 5- [1- (3,4-dimethoxy-benzoyl) -1, 2,3,4-tetrahydro- quinolin-6-yl] -6-methyl-3,6-dihydro- [1,3,4] thiadiazin-2-one and 2-pyrrolidone as solubilizers.

The invention relates to a pharmaceutical preparation containing at least 5- [1- (3,4-dimethoxy-beπzoyl) -1, 2,3,4-tetrahydroquinolin-6-yl] -6-methyl-3,6-dihydro - [1, 3,4] thiadiazin-2-one, 2-pyrrolidone as solubilizer and a lipophilic excipient or a carrier material.

Surprisingly, it was found that the preparation according to the invention enables a very good bioavailability of a drug active substance which is sparingly soluble in water and gastric juice, as well as a rapid flooding of the active substance. In particular, in the preparation according to the invention, there is no nanonization of the active ingredient or the production of a microemulsion.

Important parameters for the characterization of bioavailability are listed below:

AUC means area under the curve, where concentration means the concentration of the drug in the plasma, which is plotted against time. The AUC value is proportional to the amount of the active substance that has entered the systemic circulation. AUC (0-6h) refers to the area of the concentration-time curve, which is determined in the time immediately after ingestion up to 6 h. In AUC (0-inf), inf means "an infinit".

The absolute bioavailability (BV) results from the comparison with the AUC _iv measured after intravenous administration:

BV = AUC / AUC _jv . The relative bioavailability (BV) results from the comparison of two pharmaceutical preparations A and B: V _re | - AU _{preparation A} / AUC _{preparation B.}

The maximum drug concentration c _max in the plasma and the associated time t _max serve to further characterize concentration-time curves.

To determine the characteristic data, as just described, both in vitro tests and in vivo studies are carried out.

The release data as an in vitro test method are carried out analogously to USP XXIII Method II, USP, 1995, vol. 23 / NF18, 1792, in a paddle apparatus (50 rpm) at 37 ° C.

The in vivo investigations are carried out according to the Standard Operating Procedures (SOP) of the Institute of Toxicology or the Institute of

Pharmacokinetics and metabolism Grafing carried out by Merck KGaA as a 5-fold cross-over study.

The corresponding formulations according to the invention are administered orally to five male beagle dogs in the unfeeded state and in the fed state. After 15 or 30 minutes, as well as 1, 2,

4, 6 and 24 hours whole blood is taken and the concentration of the

Active pharmaceutical ingredient in the blood plasma determined according to conventional analysis methods known to those skilled in the art.

2-pyrrolidone is a known solubilizer, e.g. in US 4,081,528 for stabilizing antibiotic aqueous solutions and in WO 97/26895 for the solution of avermectin.

No. 4,710,497 describes pyrrolidones which, in combination with a promoter, improve the permeability of active substances through the skin. No. 5,811,130 describes the use of 2-pyrrolidone as cosolvent in aqueous pharmaceutical solutions for injection.

Surprisingly, the use of 2-pyrrolidone in the pharmaceutical preparations according to the invention has a very good effect

Bioavailability of the poorly soluble active pharmaceutical ingredients and rapid flooding of the active ingredient, characterized by the maximum concentration c _max . The characteristic values or release data of a selection of formulations according to the invention, described in Examples 1 or 3, in comparison to a selection of formulations according to the technologies of the prior art, described in Examples 2 or 4, are disclosed in Examples 5 and 6.

In addition to the property of 2-pyrrolidone as a solubilizer, 2-pyrrolidone is also compatible with lipid-like auxiliaries or other suitable carrier materials.

According to the invention, this leads to fixation of the sparingly soluble active pharmaceutical ingredients dissolved in 2-pyrrolidone in a matrix of a lipid-like auxiliary substance or in a matrix of a further suitable carrier material. As a rule, semi-solid pastes are formed which contain the drug substance which is sparingly soluble in water and dissolved in 2-pyrrolidone, which in turn can be processed in a suitable manner into a capsule, tablet or dragee.

In particular, the formulation according to the invention is filled into capsules, for example hard gelatin or soft gelatin capsules.

The formulation according to the invention in the semi-solid state can also be mixed with further carrier materials and after spray solidification by spray drying can be filled in as granules in hard gelatin or soft gelatin capsules, or with suitable tabletting aids Tablets are pressed. These tablets can also be provided with suitable film coatings. Suitable coating materials are, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, vinyl copolymers such as polyvinylpyrrollidone or polyvinyl acetate or acrylate-methacrylate polymers.

The pharmaceutical preparation containing at least one poorly soluble active pharmaceutical ingredient, selected from the group 4- [4- (3-chloro-4-methoxy-benzylamino) -benzo [4,5] thieno [2,3-d] pyrimidin-2-yl ] - cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts, 4- [4- (3-chloro-4-hydroxy-benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yi] cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts or 5- [1- (3,4-dimethoxy-benzoyl) -1, 2,3,4-tetrahydro-chiolin-6-yl] -6-methyl-3,6-dihydro- [1 , 3,4] thiadiazin-2-one, 2-pyrrolidone and / or a lipid-like auxiliary or a carrier material, can also be used in the semi-solid state according to the invention in ointments or gel-like pharmaceutical forms which can be applied to mucous membranes.

Lipid-like excipients include, for example, glycerides from

Polyoxyethylene or hydroxypolyoxyethylene and fatty acids with 12, 13, 14, 15, 16, 17 or 18 carbon atoms, for example oleoyl-macrogol-6-glyceride, linoleoyl-macrogol-6-glycide, lauroyl-macrogol-6-glyceride, caprylocaproyl- Macrogol-8-glyceride, lauroyl-macrogol-32-glyceride or stearoyl-macrogol-32-glyceride, glycerin-polyethylene glycol oxystearate, propylene glycol monolaurate or diethylene glycol monoethyl ether. Other lipid-like substances are, for example, Miglyol® neutral oils, ie glycerol esters of fatty acids with 8, 9 or 10 carbon atoms, or capricilic, capric or diglyceryl succinate. A commercial product of a Miglyol® neutral oil is Miglyol® 829. Usual trade names of the lipid-like ones described above

Excipients are LABRAFIL® M 1944 CS, LABRAFIL® M 2130 CS,

LABRAFIL® M 2125 CS, LABRASOL®, LAUROGLYCOL®, GELUCIRE®

44/14, GELUCIRE® 50/13 or TRANSCUTOL® P from Gattefosse. Glyceride 1 is Oleoyl-Macrogol-6-Glycehd or LABRAFIL® M 1944

CS understood.

Glyceride 2 is Linoleoyl-Macrogol-6-Glycerid or LABRAFIL® M

2125 CS understood.

Glyceride 3 means lauroyl-macrogol-6-glyceride or LABRAFIL® M 2130 CS.

Glyceride 4 is Caprylocaproyl-Macrogol-8-Glycerid or

LABRASOL® understood.

Glyceride 5 is lauroyl-macrogol-32-glyceride or GELUCIRE®

44/14 understood. Glyceride 6 is Stearoyl-Macrogoi-32-Glycerid or GELUCIRE®

50/13 understood.

Glyceride 3, glyceride 5 or glyceride 6 are particularly suitable for the preparation according to the invention. Glyceride 5 is particularly preferably used.

Suitable carrier materials, in addition to the lipid-like carrier materials, for example glyceride 5, are also sorbitol or microcrystalline cellulose. Glyceride 5 or sorbitol is particularly preferably used.

The invention relates to a pharmaceutical preparation as described above, wherein the carrier material and / or the lipophilic auxiliary, selected from the group consisting of glyceride 5, sorbitol or glyceride 3, is contained. If appropriate, further solubilizers can be part of the preparation according to the invention. Suitable solubilizers are, for example, polyethylene glycols (PEG), for example PEG 1000, PEG 400 or PEG 200 or polyethylene glycol succinates, for example D-α-tocopheryl-polyethylene glycol 1000 succinate with the trade name Vitamin E-TPGS®.

Other carriers or additives can be added, e.g. Binder, colorants, lubricants, sweeteners and / or flavorings.

As lubricants or lubricants e.g. Talc, metal stearates, for example magnesium or calcium stearate, magnesium lauryl sulfate, polyglycols, glycerol mono- or distearates, paraffin, cocoa butter, macrogol or leucine are suitable. Magnesium stearate is preferably used.

Preferred embodiments of the preparation according to the invention contain 5 to 500 mg, in particular 10, 25, 50, 100 or 500 mg of active pharmaceutical ingredient. They particularly preferably contain 25, 50 or 100 mg of active pharmaceutical ingredient.

The proportion of 2-pyrrolidone in the preparation according to the invention is 1 to 30 percent by weight, preferably 10 to 20 percent by weight, particularly preferably 11 to 14 percent by weight.

The invention also relates to a pharmaceutical preparation as described, characterized in that it contains 1 to 30 percent by weight of 2-pyrrolidone.

The invention also relates to a process for the preparation of a pharmaceutical preparation comprising an active pharmaceutical ingredient selected from the group 4- [4- (3-chloro-4-methoxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts, 4- [4- (3-chloro-4-hydroxybenzylamino) benzo [4, 5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts or 5- [1 - (3,4-dimethoxy-benzoyl) -1, 2,3,4-tetrahydro- quinolin-6-yl] -6-methyl-3,6-dihydro- [1, 3,4] thiadiazin-2-one and 2-pyrrolidone, characterized in that the poorly soluble active pharmaceutical ingredient is dissolved in 2-pyrrolidone and the solution stirred into a melt of the other auxiliaries. The mixture can subsequently be filled into capsules at the mixing temperature or after cooling.

The poorly water-soluble active pharmaceutical ingredient is dissolved in 2-pyrrolidone at temperatures between 10 ° and 40 ° C., preferably between 15 ° and 25 ° C., particularly preferably at room temperature.

The other auxiliaries of the preparation according to the invention are melted at temperatures between 40 ° and 100 ° C., preferably between 50 ° and 70 ° C., particularly preferably at 60 ° C., and the solution, containing the water-poorly soluble active pharmaceutical ingredient and 2-pyrrolidone, into the Melt stirred.

The mixture according to the invention produced in this way is poured into the hard or soft gelatin capsules immediately after the components have been mixed in the liquid state or after a certain cooling time. Filling in the liquid state by volumetric metering is preferred.

The following examples relate to the production and the composition of the pharmaceutical preparation according to the invention and the production and the composition of comparative preparations according to the prior art. In the following examples, 4- [4- (3-chloro-4-methoxy-benzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt is abbreviated with ethanolamine salt. 2-Pyrrolidone was used in the form of the commercial product Soluphor® P.

Example 1 :

Pharmaceutical preparations containing 4- [4- (3-chloro-4-methoxybenzylamino) benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt as active pharmaceutical ingredient. The abbreviation PEG stands for polyethylene glycol.

1. Formulation 1:

Ethanolamine salt 50 mg 2-pyrrolidone 100 mg

Glyceride 5 780 mg

production:

A solution of 5 g of ethanolamine salt in 11 g of 2-pyrrolidone is stirred into a melt of 78 g of glyceride 5 at 60 ° C. The resulting mixture is poured into a hard gelatin capsule in the liquid state, so that one capsule contains the composition of the above-mentioned formulation as a single dose.

2. Formulation 2:

Ethanolamine salt 50 mg

2-pyrrolidone 100 mg

Vitamiπ-E-TGPS® 310 mg

Glyceride 3 160 mg PEG 1000 350 mg production:

31 g Vitamin-E-TGPS®, 16 g glyceride 3 and 11 g polyethylene glycol 1000 are melted at 50-70 ° C to a homogeneous mixture. A solution of 5 g of ethanolamine salt in 11 g of 2-pyrrolidone is stirred into this melt. The mixture is poured into a hard gelatin capsule in the liquid state, so that one capsule contains the composition of the above-mentioned formulation as a single dose.

3. Formulation 3:

Ethanolamine salt 50 mg

2-pyrrolidone 50 mg

PEG 200 100 mg

Sorbitol 200 mg

production:

A mixture of 10 g sorbitol, 5 g polyethylene glycol 200 and 2.5 g 2-pyrrolidone is heated to 40-50 ° C. 2.5 g of ethanolamine salt are added with stirring. The mixture is poured into a hard gelatin capsule in the liquid state, so that one capsule

Composition of the above formulation as a single dose.

Example 2: Comparative solution containing 4- [4- (3-chloro-4-methoxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] cyclohexane carboxylic acid, ethanolamine salt as a poorly soluble active pharmaceutical ingredient (abbreviated to ethanolamine salt), for oral administration, the theoretically optimal dosage form, since the active ingredient does not require a dissolving step, but can be absorbed immediately: Formulation 4:

Ethanolamine salt 50 mg

Hydroxypropyl-ß-CD 500 mg. Where CD means cyclodextrin,

Water, purified 2783 mg

production:

50 mg of ethanolamine salt and 500 mg of hydroxypropyl-β-cyclodextrin are dissolved in 2783 mg of water.

Formulation 5: microemulsion

Ethanolamine salt 56.3 mg

Glycerol stearate 100 mg

Glyceride 4,300 mg

Glyceride 1 300 mg

Diethylene glycol monoethyl ether 72 mg

Propanediol-1,250 mg finely divided silica 21.7 mg

production:

A mixture of 1.1 g of glycerol stearate used as a commercial product Imwitor® 960, 3.3 g of glyceride 4, 3.3 g of glyceride 1, 792 mg of diethylene glycol monoethyl ether and 550 mg of 1,2-propanediol is heated to 45.degree. 62 mg of ethanolamine salt are added to this solution and dissolved with stirring. The highly disperse silicon dioxide is sieved over 196M / cm ² and added to the mixture. The resulting microemulsion is poured into hard gelatin capsules so that the individual dosage corresponds to the formulation mentioned above. Example 3:

Pharmaceutical preparation containing 5- [1- (3,4-dimethoxy-benzoyl) - 1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3,6-dihydro- [1, 3, 4] thiadiazin-2-one as a poorly soluble active pharmaceutical ingredient (hereinafter abbreviated as thiadiazinon).

1. Formulation 6:

Thiadiazinon 30 mg

2-pyrrolidone 100 mg glyceride 5 780 mg

production:

A solution of 3 g of thiadiazinone in 11 g of 2-pyrrolidone is stirred into a melt of 78 g of glyceride 5 at 60 ° C. The resulting mixture is poured into a hard geiatine capsule in the liquid state, so that one capsule contains the composition of the above-mentioned formulation as a single dose.

2. Formulation 7:

Thiadiazinon 30 mg

2-pyrrolidone 100 mg

Glyceride 6 780 mg

Preparation: A solution of 3 g thiadiazinon in 11 g 2-pyrrolidone is in a

Melt 78 g of glyceride 6 at 60 ° C. The resulting mixture is poured into a hard gelatin capsule in the liquid state, so that one capsule contains the composition of the above-mentioned formulation as a single dose. 3. Formulation 8:

Thiadiazinon 30 mg

2-pyrrolidone 100 mg

Vitamin E TGPS® 310 mg

Glyceride 3 160 mg

PEG 1000 350 mg

production:

31 g of vitamin E TGPS®, 16 g of glyceride 3 and 11 g of polyethylene glycol 1000 are melted at 50-70 ° C to a homogeneous mixture. A solution of 3 g of thiadiazinone in 11 g of 2-pyrrolidone is stirred into this melt. The mixture is poured into a hard gelatin capsule in the liquid state, so that one capsule contains the composition of the above-mentioned formulation as a single dose.

Example 4:

Comparative preparation: mixture of thiadiazinone and lactose

Formulation 9: Thiadiazinon 30 mg

Lactose 270 mg

production:

30 m g of thiadiazinone and 270 mg of lactose are mixed and filled into a capsule.

Example 5:

The values obtained from the cross-over study on fed and non-fed animals are listed in Tables 1 and 2: Table 1: 50 mg of ethanolamine salt, administered to the unlined animal in formulations 1 to 4

Table 2: 50 mg of ethanolamine salt, administered to the fed animal in formulations 1 to 8 according to Example 5

The absolute bioavailability BV [%] results from the comparison with the AUC _IV measured after _{IV administration} . The animals were given 1 mg / kg of ethanolamine salt iv.

The mean body weight of the animals is 14.4 kg per animal for the calculation of the bioavailability.

Example 6:

The following in vitro data from thiadiazinon have been obtained in various

Release media at 37 ° C and 50 rpm in a paddle apparatus (USP Method II) released. The release volume is always 900 ml. The target dose is 30 mg thiadiazinon, the "IST" dose is determined on the basis of 6 capsules of a batch. The "Isf" dose is the percentage of the released amount. Formulation 9 serves as a comparison.

Description of the release media: 1. SGF / T

pH = 1, 2

Triton X 100 means polyethylene glycol mono- [p- (1,1,3,3-tetramethylbutyl) phenyl] ether.

2. fAssif (fasted state simulated intestinal fluid)

pH = 6.5

3. fEssif (fed State simulated intestinal fluid)

pH = 5.0

4. bidistilled water (Aqua bidest). 5. Texapon solution, a solution of sodium lauryl sulfate in bidist. Water (12.5 mmol / l).

Table 3: Release data of formulation 6 in the release media fAssif and fEssif, as previously described:

Table 4: Release data of formulation 7 in the release media SGF / T and fEssif, as previously described:

Continuation of table 4:

Table 5: Release data of formulation 8 in the release media SGF / T and fEssif, as previously described:

Table 6: Release data of formulation 9 in the release media SGF / T, fAssif and fEssif, as previously described:

Claims

claims

1. Pharmaceutical preparation containing at least one active pharmaceutical ingredient and 2-pyrrolidone as solubilizer.

2. Pharmaceutical preparation according to claim 1, containing at least the drug active ingredient 4- [4- (3-chloro-4-methoxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts.

3. Pharmaceutical preparation according to claim 1, containing at least the active pharmaceutical ingredient 4- [4- (3-chloro-4-hydroxy-benzylamino) - benzo [4,5] thieno [2,3-d] pyrimidin-2-yl] - cyclohexane carboxylic acid or one of its pharmaceutically acceptable salts.

4. Pharmaceutical preparation according to claim 1, containing at least 5- [1- (3,4-dimethoxy-benzoyl) -1, 2,3,4-tetrahydro-quinolin-6-yl] -6-methyl-3,6- dihydro- [1, 3,4] thiadiazin-2-one.

5. Pharmaceutical preparation according to claims 1 to 4, characterized in that a carrier material and / or a lipophilic auxiliary is included.

6. Pharmaceutical preparation according to claim 5, characterized in that glyceride 5, sorbitol or glyceride 3 is contained.

7. A process for the preparation of a pharmaceutical preparation according to claims 1 to 6, characterized in that the active pharmaceutical ingredient is dissolved in 2-pyrrolidone, the solution is stirred into a melt of the further auxiliaries. Use of 2-pyrrolidone as a solubilizer in pharmaceutical preparations for oral administration in human medicine.