CS217143B1 - Medicinal preparation containing the pentoxyfylin - Google Patents

Abstract

The present invention relates to an oral, lump preparation containing pentxifylline, blood flow in the central and peripheral blood stream and from which it is effective the substance is gradual, over several hours release. This effect is made possible by use of a new auxiliary flying copolymer ester methacrylic acid content quaternary ammonium groups. Auxiliary the fabric contains both the core and the shell coated tablets. Apply to granules respectively. finished matrix tablets in the mold spraying using a nozzle.

Description

The present invention relates to an oral, unitary preparation containing pentoxifylline (3,7-dimethyl-1- (5-oxo-heyl) -xanthine), wherein said drug is gradually released over a period of several hours and a process for its preparation. The gradual release of the drug substance is provided by copolymerisate of esters of acrylic and methacrylic acid containing quaternary ammonium groups.

By means of a technological procedure and speoial excipients, it has been achieved below that the drug substance is gradually released upon contact of the solid dosage form with the liquid. This is particularly important when it is a drug and a tenuous half-life or irritant effect on the gastrointestinal tract wall.

It has long been known that methylxanthines / caffeine, theophylline / irritate the stomach wall as well as pentoxifylline, which also has a short half-life (Hinze, HJ (1972)) 3,7-dimethyl-1- (5-oxo-hexyl) parmakokinetics (xanthine) (BL 191) in humans. 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 the fact that it had to be administered very often at high doses, yet night drug levels in the blood practically dropped to zero.

For this reason, various attempts have been made to keep the blood level of the drug high and balanced. For example, NSR 2,520,978 (Personally Applicable Solid Dosage Formulations of Water-Soluble Xanthine Derivatives) discloses (page 3) that hydroxyethylcellulose was used as an excipient. In this case, the cellulose derivative upon contact with the fluid forms a hydrogel from which the water-soluble xanthine derivative is then gradually released.

The disadvantage is that the unit form prepared by hydroxyethylcellulose after its contact with the fluid increases its volume several times and becomes uncontrolled through the water. and a short peak of drug concentration in the blood. This effect has been demonstrated in the trial of Trental 400 (Albert-Boussel Pharma 6mbH trademark, Wiesbaden, Germany) for a 400 mg pentoxifylline medicinal product in hydroxyethylcellulose base (see below).

1, 2, graph 1 / in preclinical testing. The maximum blood level was in both cases after eo and 2 hours after administration with a very sharp peak, followed by a sharp decrease in concentration.

This adverse effect has been addressed by selecting a new excipient which allows a higher degree of regulation of drug delivery in the gaatrointestinal tract. These are two types of copolymers of acrylic and methacrylic acid esters containing quaternary araonic groups.

The first type contains the ratio of copolymerizate of (meth) acrylic acid to quaternary ammonium groups 1 <20 / Eudragit RL / second type 1 * 40 / Eudragit RS / / Eudragit R is a trademark of Rfthm GmbH, Darmstadt, Germany upon contact with the liquid, they swell and become water-impermeable independent of the pH of the environment. D.t A969 / Permeable acrylic resins for the preparation of depot dosage forms, Pharm.Ind.

31. 319-322 /. The advantage over hydroxyethylcellulose is that the transfer of water to the dosage form resp. the transfer of the drug substance from the dosage form is precisely controllable as the individual excipients differ in permeability for water type RL is easy, RS is slightly permeable.

Because of the solubility of the drug substance g of the amount of each type of copolymer, the transfer of pentoxifylline into the gastrointestinal tract is precisely controllable. 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 sprayed in a fluidizing apparatus with water using a high-pressure nozzle after homogenization. The granulate formed was dried and then sprayed with a solution of Eudragit RL and RS (isopropanol-methylene chloride solution). After drying, talc, calcium or magnesium stearate was added to the granulate, and after mixing it was tableted to a matrix.

217 143 tablets. The tablets were sprayed in a suitable machine with a solution of Eudragit RI and ES with the addition of mastenoid or magnesium stearate as an anti-adhesive and polyethylene glycol / m.h. 6000) glycerin triacetate or castor oil as a plasticizer.

Pharmacokinetic follow-ups were transferred to a paooh of 10-15 kg. * They were divided into two groups of 7 dogs each. Group A was administered orally 800 mg of Trental ^R - 400 mg / tablet / tab.1 / group B 800 mg of pentoxifylline prepared by the above method using a copolymerizate of (meth) acrylic acid esters / tab.2. followed by time intervals after administration of the drug preparation 1 h, 2 h, h, 6 h, 8 h, 12 h, 20 h, 16 h, 24 h.

The concentration of pentoxifylline in the blood was monitored by high pressure liquid chromatography. Extraction was performed as follows and blood samples were also centrifuged at 4000 rpm for 10 minutes. 3 ml of de-centrifuged plasma was mixed with 100 µl of an aqueous solution of 1- (3-oxobutyl) -3,7-dimethylxanthine (internal Standard) conentration from 0.5 µg to 1.5 µg.

To this mixture was added the following solutions of 250 µl of 0.1N hydrochloric acid or 250 TEL 0.1N NaOH and 6 ml of a 5% isopropanol / chloroform mixture. The solution was mixed using a high speed mixer and after phase separation of 5 ml of the organic phase, 5 ml of a new extraction agent were replaced. This operation was repeated a total of three times. The combined organic solutions were evaporated, the residue was dissolved in 30 µl of chloroform. The sample prepared in this way was chromatographed on a high-pressure liquid chromatograph (Hewled-Peckard). The measurement was carried out by means of a built-in spectrophotometer and integrator (Speotra Physics-Minlgrator). The target was 60.5 µm (Gauge), 20 MPa pressure, chloroform-isopropanol-acetic acid (96.5 12.5 µl), absorption maximum 273 mm, detection limit 5 µg / ml plasma. Figure 1 is a graph of blood levels of pentoxifylline in dogs where the solid line represents Pentoxifylin in the base with an acid / meth / acrylic ester copolymer and the dashed line represents Pentoxifylin in the hydroxyethylcellulose base.

-1 - -. ----- ... - -A Pentoxifylline in methacrylate base time / h / 1 2 4 6 8 12 16 20 24 28 Cono-pentoxifylline in blood ug / ml 2.18 4.99 4.67 2.19 0.47 0.39 0.22 0.14 0.01 0.34 • pentoxifylline in ethyl cellulose base time / h / Τ ' 2 4 6 8th 12 16 20 24 28 Cono.pentoxifylline in blood ug / inj 4.36 5.77 3.18 - 2, C 0.96 0.17 0.13 0.11 0.21 0.09

As a result, the two types of dosage forms studied differ in the release of the active substance in vivo. The formulation containing pentoxifylline in the hydroxyethylcellulose base reaches its highest blood level after 2 hours, with a very sharp shake, after which the pentoxifylline level drops sharply. This phenomenon is very disadvantageous from a therapeutic point of view since the pharmacological effect of hemorrheic agents is related to the blood level of the drug.

The dosage form contains pentoxifylline and the copolymerizate of the acid / mat / acrylic acid releases the drug more slowly, more evenly, the highest levels are maintained at the same level practically for two hours * The area under the curve has also increased by 10% * the form containing pentoxifylline and (meth) acrylic acid copolymer is, from a therapeutic point of view, more advantageous than a combination of pentoxifylline and hydroxyethyl cellulose because it gives more balanced levels of the active substance in the blood and the bioavailability is increased,

In the foregoing, the invention is illustrated by three examples without being limited to these.

217 143

Example 1.

Kernel composition. pentoxifylline Eudragit RL Eudragit RS Polyvinylpyrrolidone 400 0000 mg 37.500 mg 37.500 mg 16.000 mg talc Calcium stearate 6.500 mg 2.500 mg Film obalt Eudragit RL Eudragit RS talc Polyethylene glycol 6000 2.03125 mg 2.03125 mg 4.45000 mg 0.44500 mg

Example 1 - Preparation Method

The pentoxifylline, a portion of Eudragit RL and RS, the mass of tenoa and polyvinylpyrrolidone, adjusted to a suitable particle size, are introduced into the fluidization apparatus. The mixture is sprayed in a fluidized state at 60 ° C and 2.00 MPa spray pressure with distilled water. After drying, the granulate is coated with a second early organic solvent soluble Eudragit RL and RS. After drying, the coated granulate is treated, a second portion of raasten and calcium stearate is added. It is tabletted to a total tablet weight of 500.0 mg. The finished matrix tablets are coated in a suitable machine with a mixture of the copolyraerisate esters of the acid / meth / acrylic esters with the addition of an anti-sticking talc and a polyethylene glycol plasticizer 6000.

Example 2

Core composition t pentoxifylline Eudragit RL 400.0000 mg 65.0000 mg Eudragit RS 10,0000 mg polyvinylpyrrolidone 16,0000 mg LIastanec 6,5000 mg Magnesium stearate 2,5000 mg Film cover t Eudragit RL 3.15025 mg Eudragit RS 1,00000 mg talc 12,13450 mg glycerol 0.51000 mg

Example 2 - Preparation Method

Pentoxifylline, a portion of Eudragit RL and RS, a portion of talc and polyvinylpyrrolidone treated to a suitable particle size are introduced into the fluidization apparatus. The mixture is sprayed with distilled water in a suitable coating apparatus. After drying, the granulate is coated with a second portion of eudragit RL and RS dissolved. After drying, the granulate is treated, the second part of the rash and magnesium stearate is added. It is ground into matrix tablets. The finished tablets are coated with Eudragit RL and RS with the addition of talc and a glycerol triacetate plasticizer.

Example 3

Core composition »Pentoxifylín 400

400, 0000 mg

Film cover 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

217 143

Example 3 - Preparation Method

Pentoxifylline, a portion of Eudragit RL and RS, talc and polyvinylpyrrolidone are introduced into the fluidization apparatus. Anes are sprayed with distilled water at an injection pressure of 0.3 MPa. After drying, the granulate is coated with a second portion of the copolymer dissolved in an organic solvent. After drying, a second portion of talc and stearin are added. It is tabletted to a total weight of 500 mg. The finished matrix tablets are coated with a mixture of Eudragit RL and RS with the addition of an anti-adhesive magnesium stearate and a castor oil softener.

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.