DD275399B5 - MEDICAMENTAL TECHNOLOGY FOR THE PREPARATION OF A GLIBENCLAMID DRUG MODEL - Google Patents

Description

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

It is known from DE-PS 2348334 that finely divided glibenclamide with a particle surface s 3m ² / g (Teilchen particle size <2 pm) 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. Glibenclamide is brought to DE-PS 2348334 by precipitation or grinding on a particle surface of 3 to 10mVg (measured by BET Methodo) and mixed with a pharmacologically acceptable wetting agent.

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

EP131950 describes the use of glibenclamide having a surface area of from 0.8 to 1.4 m 3 / g in combination with polyethylene glycol (m.w. 6000-35000) and strongly alkalizing trometamol. The mixture is homogenized at 500 to 800U / min at 50 ⁰ C, granulated and the granules compressed 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 less than 2pm, the particles must be stabilized in a non-crystalline state or the known solubilizing effect of polyethylene glycol in combination with a strong alkalizing addition, the own, in this case not harmless pharmacological effect is used.

The aim of the invention is the industrially simple preparation of a per os administered glibencamide-containing dosage form 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.

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 salary range and sufficient stability of drug release. In response to this object, a process for the preparation of a glibenclamide-containing per os-administrable solid dosage form with high bioavailability was found using glibenclamide with a specific particle surface ^ 3mVg and using a mixture of conventional amounts of lactose, starch, silica and sodium carboxymethylcellulose Carriers, 0.5 to 5 parts by weight of crystalline glibenclamide having a specific surface area of 0.5 to 2.5 mVg be suspended in an aqueous solution containing 0.05 to 0.5 parts by mass of sodium carboxymethyl cellulose and this suspension in a fluidized bed method to a mixture of the per se sprayed on known carriers and dried.

The dry granules may be further Hiifsstoffe, for example, magnesium stearate or other flow, lubricating and release agents are added. The granules can be compressed into tablets or filled into hard gelatin capsules or capsule-shaped starch containers (Capill).

example 1

5,4g glibenclamide with a particle size index d '= 0,01 (according to Rosin-Rammler-Sperling) and a specific surface of 1,0m ^! / g in 100 ml of 1% sodium carboxymethylcellulose solution with a Koruma mill (grit 80) suspended. With the suspension diluted with water to 290 ml, a mixture of 195 g lactose, 92 g potato starch, 32.5 g sodium carboxymethyl cellulose and 10.5 Supiasil® in the fluidized bed is granulated 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.

Example 2

2.78g of glibenclamide are suspended in 70ml of 1% NaCMC solution with a corumamine grinder (or a suitable stirrer). With the suspension diluted to 200 ml with water, a mixture of 195 g lactose, 92 g potato starch,

Granulated and dried 32.5 g of NaCMC and 7.8 g of silica in the fluidized bed. After adding 0.75 g Magnesiumsteart the granules are pressed with a mass of 110mg

 Jode tablet contains 0.0mg glibenclamide.

Example 3

10.8 g of glibenclamide are suspended in 150 ml of 1% NaCMC solution with a Korumamühle (or a suitable stirrer). With the suspension diluted to 350 ml with water, a mixture of 192 g lactose, 90 g potato starch, 32.5 g NaCMC and 10.8 g silicon dioxide in the fluidized bed is granulated and dried. After adding 0.75 g of magnesium stearate, the granules are pressed with a mass of 110 mg. Each tablet contains 3.5mg 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 as an in vitro criterion is decisive:

The test for the release of glibenclamide on tablets 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

0-0 18 months after production

100-

ί so

10 ZO 30

These data confirm the stability of the dosage form.

60 left LmIn]

Comparative bioavailability data

The bioavailability was investigated successively on 12 healthy volunteers after a single oral administration of the tablets according to the invention according to the embodiment with a dosage of 1.75 mg / tablet (T) against an internationally recognized top preparation with a dosage of 3.5 mg / tablet (S) and following Results obtained:

T _m, x (h) ml " ¹ ) 1.9 ± 0.1 2.2 ± 0.2 Cmäxlng- • h-ml " ¹ ! 128 ± 15 273 ± 25 AUC (ng \ 448 + 58 891 ± 117

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

Claims (1)

A process for the preparation of a glibenclamide-containing, per os-administrable solid dosage form with high bioavailability, using glibenclamide with a specific particle surface <3m ² / g and using a mixture of conventional amounts of lactose, starch, silica and sodium carboxymethylcellulose as carriers, characterized in that 0.5 to 5 parts by weight of crystalline glibenclamide having a specific surface area of 0.5 to 2.5 m ² / g are suspended in an aqueous solution containing 0.05 to 0.5 parts by weight of sodium carboxymethylcellulose, and this suspension is fluidized to a mixture of sprayed on known carriers and dried. For this 8 pages drawings