DD249186A1 - METHOD OF MANUFACTURING A NEW GLIBENCLAMID MEDICAMENT WITH HIGHER BIODEGRADABILITY - Google Patents

Abstract

The invention relates to a method for producing a peroral administered Glibenclamid drug form with high bioavailability, in which the drug is embedded in stable roentgenamorphher form in a hydrophilic Traeger consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol or b-cyclodextrin; It leads to a rapid onset of action and the same blood sugar reduction as previous preparations at a significantly reduced dose / dosage form due to improved absorption and high bioavailability and improves the treatment of diabetes mellitus.

Description

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Field of application of the invention

The invention relates to an industrially applicable process for the preparation of a peroral administered Glibenclamid drug form with rapid onset and high bioavailability at significantly reduced dosage for the treatment of diabetes mellitus.

Characteristic of the known technical solutions

The sulfonylurea derivative glibenclamide is a highly effective agent of oral antidiabetics in a dosage of 1 to 5mg per tablet worldwide in drug traffic and is used advantageously for the treatment of diabetes mellitus. Glibenclamide is a weak acid with a pK _a value of 6.7 and a low solubility in gastric juice or water of 0.4 and 1 mg / 100 ml, respectively. Since the low dissolution rate and saturation solubility in the gastric environment are not sufficient for complete resorption and absorption a rapid onset of action, according to the state of the art, the dissolution rate of the drug z. B. by Feinstmahlung (Borchert, HH and Associated Pharmacy 31,307 [1976], Rupp, WO and colabor. Arzneimittel-Forsch., 22,471 [1972], Schmidt, HAE Arzneimittel-Forsch., 19,1422 [1969]) or more recently by microfiltration in surfactant-containing media (DE-OS 2348334) are increased, resulting in dosage forms with improved dissolution characteristics and bioavailability.

Carrying out a microfiltration or dusting (dustproofing!) Is a costly additional operation to provide the active ingredient in optimum particle size, which has been further described for processing with molten polyglycols and capsule-forming surfactants, but with the active ingredient subjected to an additional critical temperature stress is (DE-OS 2355743, GB Pat 2118040). In addition, solid glibenclamide dosage forms are described in which the active ingredient is present in non-crystalline form on a solid insoluble carrier (DE-OS 3326167), with no solution improvement but only a resorption improvement to occur. Since no information on storage stability is included, it is expected that a recrystallization of the drug leads to a reduction in the dissolution and absorption rate.

Object of the invention

The aim of the invention is the industrially simple production of a stable, perorally administrable glibenclamide dosage form, which allows a rapid and complete drug absorption, whereby suitable, industrially available, pharmaceutically technologically easy to process water-soluble and non-toxic excipients should be applied.

Explanation of the essence of the invention

The invention has for its object to produce a glibenclamide dosage form containing the active ingredient in stable X-ray amorphous embedding in water-soluble carriers and secures after disintegration an immediate, complete drug dissolution in the gastro-intestinal fluids and a high absorption rate.

Surprisingly, it has been found that, while avoiding operations to reduce its particle size, the active substance is easily converted into corresponding hydrophilic carrier materials (eg polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol) by spray drying using common drug adjuvant solutions in stable X-ray amorphous form. Embedding 3-cyclodextrin) and can deform primarily with the addition of other excipients with explosive effect to solid compacts, after application immediate complete drug dissolution, in addition an increase in solubility by formation of highly supersaturated solutions and thus a rapid onset of action and the same potency as internationally introduced preparations only about 20% of the dose of the crystalline active substance result (see Fig. 1 and 2).

embodiment

The method according to the invention is illustrated by the following examples and the dissolution behavior in vitro and the lowering of blood sugar in vivo on the rat test animal are shown in FIGS. 1 and 2, respectively.

example 1

For the preparation of 100 g of a 50% active ingredient embedding in polyvinylpyrrolidone K30 is dissolved 50 g of the active ingredient and excipient, for example in about 21 of the solvent mixture chloroform / methanol (7: 3, V: V), sprayed this solution in NIRO atomizing dryer and The powdered product dries 24h to 2O ⁰ C for 24 h. The resulting X-ray amorphous active ingredients! η bedding is pressed with the addition of tabletting excipients on a circular press at a pressing force of 8 to 12kN to tablets with a diameter of 8mm.

Recipe Formula Tablet (mg):

50% glibenclamide-polyvinylpyrrolidone embedding (10),

Heweten 12N (75), Ultraamylopectin (10), Talcum (5).

Example 2

The tableting excipients (500 g lactose, 250 g potato starch, 100 g Hweten 12 N) for a total of Tabletten000 tablets are dry, e.g. mixed in WSG and granulated by spraying a solution of 50g glibenclamide and 50g polyvinylpyrrolidone K30 in the solvent mixture chloroform / methanol (7: 3, V: V).

The dry granules thus obtained can be used directly as an application form or compressed with the addition of 50 g talcum to tablets of 100 mg mass with a diameter of 8 mm.

Legend Fig. 1

In vitro glibenclamide release in the paddle apparatus according to USPXX (400.00 ml of phosphate buffer pH 7.0, 37 ° C. ± 1 K) from internationally introduced preparations (o, x) and glibenclamide tablets according to Example 1 (above) ) for each one or ^ D two or □ 4 tables / dissolution test and display of the drug concentrations achieved in the test medium in / xg / ml (mean curves, η = 10)

Legend Fig. 2

Blood glucose level in the fed rat (o control) after administration of model tablets (rat)

example 1

• tablet (1): dose 1 tablet (a 1mg crystalline

Glibenclamide commercial product) tablet (2): dose 1 tablet (a 0.5 mg glibenclamide 1 mg of the

50% active ingredient embedded in

Polyvinylpyrrolidone K30 tablet (3): dose 1 tablet (a 0.2 mg glibenclamide ^ 0.4 mg of the

50% active ingredient embedded in

Polyvinylpyrrolidone K30

Claims (8)

1. A process for the preparation of a glibenclamide dosage form with rapid onset and high bioavailability, characterized in that the active ingredient in a hydrophilic indifferent water-soluble carrier, such as. As polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, / 3-cyclodextrin embedded by spray drying of common drug adjuvant solutions in X-ray amorphous form stable and then processed by direct tableting with tablet disintegrants and fillers to solid briquettes. 2. The method according to item!, Characterized in that the common drug-excipient solution to the further tabletting excipients z. B. is sprayed in WSG, followed by direct tabletting of the granules.  3. The method according to item 1 and 2, characterized in that polyvinylpyrrolidones having average molecular weights of from 17,000 to 90,000, preferably 40,000, are used as the carrier, wherein the drug content is from 1 to 80%. 4. Process according to items 1 and 2, characterized in that polyvinyl alcohols are used as carriers, preferably in partially hydrolyzed form, the proportion of drug being from 1 to 50%. 5. The method according to item 1 and 2, characterized in that are used as the carrier polyethylene glycols having average molecular weights of 5,000 to 20,000, wherein the active ingredient content is 1 to 3%. 6. The method according to item 1 and 2, characterized in that are used as the carrier cyclodextrins, preferably / 3-Cyclödextrin, wherein the active ingredient content is 1 to 9%. 7. The method according to item 1 and 2, characterized in that are used as the solvent ethanol, methanol, dimethylformamide, chloroform or solvent mixtures such as ethanol-water mixtures, methanol-water mixtures or chloroform-methanol mixtures. 8. The method according to item 1 and 2, characterized in that as tablets hi If ingredients cellulosic powder, lactose, potato starch, ultraamylopectin and talcum are used.