DD275399A1 - MEDICAMENTAL TECHNOLOGY FOR THE PREPARATION OF A GLIBENCLAMID DRUG MODEL - Google Patents

Abstract

The pharmaceutical technology process for the preparation of a glibenclamide-containing dosage form with high bioavailability, very good content uniformity and sufficiently stable drug release is characterized in that crystalline glibenclamide having a specific surface of 0.5 to 2.0 m2 / g suspended in aqueous Natriumcarboxymethylcelluloseloesung and this suspension in a mixture of lactose, starch, sodium carboxymethylcellulose and silica is distributed homogeneously by spraying.

Description

Application of the invention

The invention relates to a medicament technology process for producing a glibenclamide-containing, per os-administrable drug form with high bioavailability, stable release of the drug and very good content uniformity. The pharmaceutical technology process can find application in the pharmaceutical industry.

Characteristic of the known state of the art

It is known from DE-PS 2348334 that finely dispersed glibenclimide having a particle surface area> 3m ² / g (particle size S2pm) is a highly effective, rapidly absorbable form which achieves 100% bioavailability which permits it to reduce the dosage from 5mg to 3.5mg per tablet. Gübenclamid is nech DE-PS 2348334 brought by precipitation or grinding on a particle surface of 3 to 10mVg (measured by BET method) and mixed with a pharmacologically acceptable wetting agent.

In DE-OS 3228384 it is described that glibenclamide is prepared and stabilized in a non-crystalline state, preferably with sorbitol, mannitol and xylitol or polyvinylpyrrolidones and / or copolymers of vinylpyrrolidone and vinylazeiate or colloidal silica or cellulose and / or cellulose derivatives, and others Substances, such as emulsifiers, preferably nonionic emulsifiers are added.

EP 131950 describes the use of glibenclamide having a surface area of from 0.8 to 1.4 mVg in combination with polyethylene glycol (mol. Wt. 6000-35000) and strongly alkalizing trometamol. The mixture is homogenized at 500 to 800 rpm at 50 ° C., granulated and the granules are pressed into tablets. However, the increase in solubility of glibenclamide with increasing pH is well known.

In the known technical solutions, it is therefore essential that the Glibenclamidteilchengröße must be smaller than 2μιη, the particles must be stabilized in a non-crystalline state or the known solubilizing effect of Poiyethylenglycols in combination with a strong alkalizing additive, its own, in this case not harmless pharmacological effect is used.

Ziolder invention

The aim of the invention is the industrially simple preparation of a dosage form containing glibenclamide per os with high bioavailability, very good content uniformity and sufficient stability of the drug release. Furthermore, the disadvantages to be eliminated by additional process steps, such as micronization or spray drying and the use of alkalizing additives.

Explanation of the essence of the invention

The invention was based on the object of developing a technically simple and economical process without the use of strongly alkalizing additives and without micronization or spray drying for the preparation of per os administrable glibenclamide-containing dosage forms with high bioavailability, very good content uniformity and sufficient stability of the drug release.

In a solution to this problem, a process has been found in which a suspension of crystalline glibenclamide having a specific surface area of from 0.5 to 2.multidot./m, preferably from 0.5 to 2.0 m.sup.2 / g, in aqueous sodium curboxymethylcellulose solution a mixture au ;. Milk sugar, starch, sodium carboxymethyl cellulose and silica homogeneously distributed and this mixture is granulated.

The homogeneous distribution and granulation are advantageously carried out by spraying off the abovementioned suspension which contains 0.5 to 5 parts, preferably 1.5 to 3.5 parts of glibenclamide and 0.05 to 0.5 parts, preferably 0.15 to 0.35 parts of sodium carboxymethylcellulose to a mixture of 30 to 120 parts, preferably 55 to 65 parts lactose, 10 to 60 parts, preferably 22 to 26 parts starch, 5 to 50 parts, preferably 8 to 12 parts sodium carboxymethylcellulose and 0.5 to 10 parts, preferably 1 , 5 to 3.5 parts of silica. The dry granules Kingsnon other adjuvants, such as magnesium stearate or other flow, lubricants and release agents can be added.

The granules can be pressed into tablets ν or filled into hard geomembrane capsules or capsule-shaped starch containers (Capill).

embodiment

5.4 g of glibenclamide with a particle size index d '= 0.01 (according to Rosin-Rammler-Sperling) and a specific surface area of 1, OmVg are suspended in 100 ml of 1% sodium carboxymethylcellulose solution with a Koruma-Mühie (grain size 80). With the suspension diluted to 290 ml with water, a mixture of 195 g lactose, 92 g potato starch, 32.5 g sodium carboxymethylcellulose and 10.5% Suprasil® is granulated in the fluidized bed and dried. After admixing 0.75 g of magnesium stearate, the granules are pressed into tablets having a mass of 110 mg. Each tablet contains 1.75 mg glibenclamide.

Result of testing for uniform drug content:

1.851 mg (s ² = 0.001)

The variance of the estimated stochastic homogeneity according to Poole is Gr = 0.0024.

This proves the very good content uniformity as a result of the procedure.

For a consistently good bioavailability over the lifetime of the preparation, the stable release of the active ingredient is decisive as an in vitro criterion:

The test for liberation of glibenclamide on tablets obtained according to the embodiment is carried out in a paddle apparatus at pH 7.8 and the glibenclamide content is determined spectrophotometrically.

Result of the release studies:

x-x after production

o-o 18 months after production

f-i

100-

£ so ·

10 ZO

60 LeitLmin]

These data confirm the stability of the dosage form.

Comparative data of bioavailability

The bioavailability was investigated successively on 12 healthy subjects after a single oral administration of the tablets according to the invention according to the embodiment with a dosage of 1, / 5 mg / tablet (T) against an internationally recognized top preparation with a dosage of 3.5 mg / tablet (S) and following Results obtained:

ml " ¹ y T 1.8 ± 0.1 S 2.2 ± 0.2 tm "(h) •H ml " ¹ ) 128 + 15 273 ± 24 c _max (ng · 448 ± 58 891 ± 117 AUC (ng

The above-mentioned data relevant for the assessment of the bioavailability do not differ significantly considering the applied dose. This proves that the same effect is achieved with the simple method according to the invention.

Claims (4)

1. A process for the preparation of a glibenclamide-containing, peros administrable drug form with high bioavailability using a dispersing or wetting agent and a specific surface area of the active ingredient of less than 3m ² / g, characterized in that 0.5 to 5 parts, preferably 1 , 5 dis 3.5 parts of glyburide, in crystalline form having a specific surface area of 0.5 to 2.5 m ² / g, preferably 0.5 to 2.0 m ² / g in a 0.05 to 0.5 parts, preferably 0.15 to 0.30 parts of sodium carboxymethylcellulose-containing aqueous solution are suspended, and this suspension is sprayed on tablet excipients, such as, for example, lactose, starch, sodium carboxymethylcellulose, silicon dioxide. 2. The method according to claim 1, characterized in that the Glibenclamidsuspension to a mixture of 30 to 120 parts, preferably 55 to 65 parts lactose, 10 to 60 parts, preferably 22 to 26 parts of starch, 5 to 50 parts, preferably 1.5 sprayed to 3.5 parts of silica and dried. 3. The method according to claim 1, characterized in that the Glibenc'amidmischung or the granules flow, lubricants and release agents, for example magnesium stearate, are added. 4. The method according to claim 1, characterized in that 0.05 to 0.7 parts, mainly 0.2 to 0.3 parts of magnesium stearate are added.