CS217143B1 - Medicinal product containing pentoxifylxn - Google Patents

Abstract

The invention relates to an oral, piece preparation containing pentoxifylline, which causes increased blood flow in the central and peripheral blood vessels and from which the active substance is gradually released over several hours. This effect is made possible by the use of a new auxiliary substance of a copolymer of esters of /meth-/ acrylic acid containing quaternary ammonium groups. The said auxiliary substance is contained in both the core and the coating of the coated tablet. It is applied to granules or finished matrix tablets in the form of spraying using a nozzle.

Description

217 143 ϊ

The present invention relates to an oral, pentoxifylline (3,7-dimethyl-1-A-oxo-heyl) -xanthine-containing pentoxifylline formulation, wherein said drug substance is graded over a period of one hour to produce it. The sequential release of the drug substance is ensured by the copolymerization of acrylic acid esters of methacrylic acid containing quaternary ammonium groups.

Technological processes and special auxiliaries make it possible for the drug to be released gradually upon contact of the solid dosage form with the liquid. This is particularly important when it is a drug with tame biological half-life or gastrointestinal wall irritation.

It has long been known that methylxanthines / caffeine, theophylline / gastric wall irritants as well as pentoxifylline, which in addition has a short half-life (Hinze, HJ / 1972 / Parmakokinetics 3,7-dimethyl-1- (5-oxo-hexyl)) -xanthine / BL 191 / u. Arzneim.Porsch. 22, 1144-1151 /.

Pentoxifylline belongs to a group of drugs that increase blood circulation in the peripheral and central blood vessels * This effect is achieved by increased erythrocyte flexibility and reduced blood viscosity. The disadvantage was that it had to be applied very often and in high doses, yet night blood levels of the drug practically dropped to zero. In this regard, attempts were made to make the blood level of the drug high and level. For example, in German Patent Specification 2,520,978 / Personally Applicable Solid Dosage Forms of Water Soluble Xanthine Derivatives (see page 3), hydroxyethylcellulose was used as the excipient. In this case, the cellulose derivative forms a hydrogel upon contact with the liquid, from which the water-soluble xanthine derivative is subsequently released.

A disadvantage is that the lump mold prepared with hydroxyethylcellulose, upon contact with the liquid, increases its volume several times and becomes uncontrolled by water permeability. If the dosage form thus prepared contains a highly water-soluble substance, such as pentoxifylline, rapid leaching occurs. it produces a sharp and short peak in the concentration of drug in the blood. This effect has been demonstrated by the Trental 400 / Albert-Boussel Pharma 6mbH, Wiesbaden, NSR, medicinal product containing 400 mg of pentoxifylline in hydroxyethyl cellulose base (on proteins and / or tab.). 1, 2, graph 1 / in a preclinical trial. The maximum blood level in both cases was about 2 hours after administration with a large sharp peak, followed by a sharp decrease in concentration.

Said adverse effect was solved by selecting a new excipient that allows a higher degree of regulation of drug delivery in the gastrointestinal tract. These are twenty copolymers of acrylic acid esters of methacrylic containing quaternary araenoic groups.

The first type comprises the ratio of the (meth / acrylic acid) ester copolymer to the quaternary ammonium groups. 1/20 / Eudragit RL / second type 1 40 / Eudragit RS / Eudragit R is the trademark of Rfthm GmbH, Darmstadt, Germany. with fluid, they become water-impermeable and independent of the pH of the environment (Lehmann, K., Dreher,. D.t. A969 / · Permeable acrylic resins for depot drug formulations, Pharm.Ind. 31, 319-322]. An advantage over hydroxyethylcellulose is that the water is transferred to the dosage form of the drug. the transfer of the drug substance from the dosage form is precisely regulated as the individual excipients differ in the water permeability) the RL type is easy, the RS diffusely. The solubility rates of the drug substance g the amount of individual types of copolymers is accurately controllable in the gastrointestinal tract. The excipient may be coated with granules or tablets.

The procedure was as follows a mixture of pentoxifylline, mastenoa, polyvinylpyrrolidone, powdered Budraglt RL and RS was homogenized in water by means of a high pressure nozzle in the fluidization apparatus. The granulate formed was dried and further sprayed with a solution of the Eudragit RL and RS / isopropanol-methylene chloride mixtures. After drying, talc, calcium or magnesium stearate was added to the granules and, after mixing, tableted to matrix 217 143 2 tablets. The tablets are sprayed with a solution of Budragit RI and ES with the addition of mastene or magnesium stearate as an antiadhesive and polyethylene glycol / m.h. 6000 /, glycerol acetate or castor oil as a plasticizer.

Pharmacokinetic follow-ups were transferred to a weight of 10-15 kg * They were divided into two groups of 7 dogs · Group A 800 mg of TrentalR was administered - 400/2 tablets / tab.1 / group B 800 mg of pentoxifylline prepared by the method by means of the acid ester / racetrail / acrylic ester / polymer / pentoxifyin level in the blood was followed at intervals of 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 20 h , 16 h, 23 h.

Blood pentoxifylline concentrations were monitored by high pressure liquid chromatography. Bxtrakoia was transferred as follows. Blood samples were centrifuged at 4000 to / ml rain. 3 ml of centrifuged plasma was mixed with 100 µl of aqueous solution of 1- (3-oxobutyl) -3,7-dimethylxanthine / internal standard / concentration from 0.5 to 1.5 µg. To this mixture, 250 µl of 0.1 N hydrochloric acid or 250 µl of 0.1 N NaOH and 6 ml of 5% isopropanol in chloroform were added followed by solutions. The solution was stirred using a high speed mixer and 5 ml of the new extractant was exchanged after phase separation of 5 ml of the organic phase. This operation was repeated three times. The combined organic solutions were evaporated, the residue was dissolved in 30 µl cloroform. The sample thus prepared was chromatographed on a high pressure liquid chromatograph (Hewled-Peckard). The measurement was performed using a built-in spectrophotometer and integrator / Speotra Physios-Minigrator The chromatographic details were as follows: Column length: 250 mm, Inner diameter: 3 mm, Carrier: Total diameter: 60.5 µm (Merck), Pressure: 20 MPa, Elution system: chloroform-isopropanol-acetic acid: 96 Figure 5 shows a graph of "Pentoxifylline Blood Level in Dogs", where the solid line indicates "Pentoxifylline based on an acid ester / meth / copolymer base". acrylic and interrupted line means "Pentoxifylline in hydroxyethylcellulose base" -1 - -. ----- ... - -AA, Pentoxifylline in methacrylate base time / h / 1 2 4 6 8 12 16 20 24 28 Blood xiophilia ug / m l 2,18 4,99 4,67 2,19 0,47 0,39 0,22 0,14 0,01 0,34 • Pentoxifylline in ethylcellulose base 1 time / h / Τ '2 4 6 8. 12 16 20 24 28 Concentration of xifylin in blood ug / inj 4.36 5.77 3.18 • 2, Cl 0.96 0.17 0.13 0.11 0.21 0.09

As can be seen from the results, the two types of drug form in question are cast in a release agent in vivo. The formulation containing pentoxifylline in hydroxyethylcellulose bases reaches its highest blood level after 2 hours with very sharp peaks after which the level of pentoxifylline decreases sharply. This phenomenon is very disadvantageous from a therapeutic point of view, since the pharmacological action of hemorrhage-adjusting agents is bound to blood-level drugs.

The dosage form containing pentoxifylline and the acid / acrylic acid copolymer releases the drug substance more slowly, more equally, the highest levels being maintained at the same level of practitioner for two hours. concluded that the dosage form containing pentoxifylline and the (meth) acrylic acid copolymer is more favorable from a therapeutic point of view than the combination of pentoxifylline and hydroxyethylcellulose, since it gives more balanced levels of the active ingredient in the blood and the bioavailability is increased. The subject matter of the invention is illustrated in three examples without limiting it to the third one. 3 217 143 Example 1.

Core composition. Pentoxifylline Eudragit RL Eudragit RSPolyvinylpyrrolidone 400 0000 mg37.500 mg37.500 mg16.000 mg Talc Calcium stearate 6.500 mg 2.500 mg Film coating Eudragit RL Eudragit RS Talc Polyethylene glycol 6000 2.03125 mg2.03125 mg4.45000 mg0.44500 mg Example 1 - Method preparation

The pentoxifylline, the Eudragit RL chassis and RS, the polyvinylpyrrolidone and the polyvinylpyrrolidone adapted to the appropriate particle size are introduced into the fluidization apparatus. The precipitate is sprayed in a fluidized state at 60 ° C and 2.00 MPa of spray pressure with distilled water. After drying, the granulate is coated with a second early Eudragit RL and RS, soluble in the organic solvent. After drying, the coated granulate is adjusted, a second portion of the batter and calcium stearate are added. The total tablet weight is 500.0 mg. The finished matrix tablets are coated with a mixture of copolymers of methacrylic acid esters with the appropriate anti-adhesive agent mastanoa and a plasticizer of polyethylene glycol 6000 in a suitable apparatus.

Core composition t Eudragit RL 400,0000 mg65,0000 mg Eudragit RS 10,0000 mg Polyvinylpyrrolidone 16,0000 mg Liestan 6.5000 mg Magnesium stearate 2.5000 mg Eudragit RL 3.15025 mg Eudragit RS 1.00000 mg Talc 12.13450 mg Glycerin triacetate 0.51000 mg Example 2 - Preparation method

Pentoxifylline, part of Eudragit RL and RS, a portion of the butter and polyvinylpyrrolidone treated with a suitable particle size are introduced into the fluidization apparatus. The mixture is sprayed with distilled water in a suitable auctioning apparatus. After drying, the granulate is coated with a second time-fragment RL and RS dissolved in an organic solvent. After drying, the granulate is adjusted, a second portion of mastene and magnesium stearate are added. It packs into matrix tablets. The ready-made tablets are coated with Eudragit RL and RS with the addition of talc and a glycerol triacetate softener. Example 3

Core composition »Pentoxifylline 400 400, 0000 mg

Film packaging i

Eudragit RL 3.0000 mg Eudragit RS 72.0000 mg Polyvinylpyrrolidone 16.0000 mg Talc 4.5000 mg Stearin 4.5000 mg Eudragit RL 0.50020 mg Eudragit RS 4.21000 mg Magnesium stearate 4.22000 mg Castor oil 0.34500 mg

Claims (2)

OBJECT OF THE INVENTION Medicinal product containing pentoxifylline as active substance, excipients in particular vinylpyrrolidone, raasteneo, polyethylene glycol or glycerin triacetate or castor oil, calcium or magnesium stearate or stearin, characterized in that it additionally contains copolymers of methacrylic acid and acrylic acid groups 11 to 21.2 wt. % based on the weight of the formulation, of which 10 to 20% is present in the core in the filter shell of 1.0 to 1.2%. from 2) A method for preparing a medicament according to claim 1, characterized in that a granulate comprising methacrylic acid / acrylic acid copolymers containing a quaternary ammonium group in an amount of 5 to 10% is prepared, then a solution of said copolymerizates in an organic solvent in an amount of 5 to 10% of the granules are then compressed into matrix tablets, which are sprayed with a solution of said copolymers in an organic solvent in an amount of 1.0 to 1.2%, the organic solvent solution also contains excipients.