SK280799B6 - Solid forms of a drug containing 8-chloro-1-methyl-6-phenyl-4h- -[1,2,4]triazolo[4,3-a][1,4]bezodiazepin and method of manufacturing the same - Google Patents

Abstract

Solid forms of a drug with reliable control-release of a therepeutially active component alprazolam (8-chloro-1-methyl- -6-phenyl-4h-[1,2,4]triazolo[4,3-a][1,4]bezodiazepin) contain: 0.1 - 15 mg, preferably 0.25 - 5 mg of alprazolam; a carrier comprising from 0.1 to 80 mg of water-soluble alpha-, beta- or gama-cyclodextrin, mono-, di-, oligo- or polysaccharide or polyvinylpyrrolidone (PVP) of average mol.wt. 25000 - 120000; water-insoluble hydrophilic porous or non-porous SiO2, TiO2 or Al2O3; and/or 0.01 - 15 mg of non-ionic surfactant having an HLB value of 13 - 18, prefereably 14.5 - 15.5; and a disintegrant comprising sodium starch glycolate, crosslinked PVP or sodium carboxymethyl cellulose.

Description

Technical field

The invention relates to solid dosage forms with the reliable release of the therapeutically active component of alprazolam - 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine and method of their preparation. Alprazolam is a well known anxiolytic.

BACKGROUND OF THE INVENTION

In order to achieve optimal absorption and thus an optimal therapeutic effect, the appropriate dissolution kinetics of the active ingredient are determined. When using a therapeutically active ingredient such as alprazolam, low solubility and dissolution rate are a common problem. Due to regulatory requirements, the most appropriate solution to the problem of low solubility and dissolution rate is the physical approach, which means that both dissolution parameters are adjusted by technological procedures in which the main focus is on the rate and dissolution profile.

U.S. Pat. No. 4,721,709 describes the preparation of benzodiazepine adsorbents on a pharmaceutically acceptable water-insoluble carrier. The principle consists in mixing the active ingredient solution with the carrier and then precipitating the adsorbent with a solvent in which neither the active ingredient nor the carrier is soluble. The adsorbent obtained has a substantially higher solubility of the active ingredient. This patent does not disclose or address the problem of alprazolam polymorphism and its effect on dissolution rate and dissolution profile and bioavailability.

The present invention differs from the prior art in that the active ingredient is applied together with a surfactant to the water-soluble carrier particles. Unlike the process disclosed in U.S. Patent 4,721,709, the entire process is carried out in one phase and is therefore more economical and easier to apply in industry.

It is well known that the solubility and dissolution rate of a therapeutically active ingredient is also affected by its polymorphism. Metastable modifications most often have a higher solubility and dissolution rate due to the lower lattice energy of the crystals. It is therefore appropriate to select a metastable modification for the preparation of therapeutic compositions containing a water-soluble therapeutically active ingredient. However, the physical and chemical stability of the metastable modification of the active ingredient (the ingredient itself, as well as the formulation) can cause problems. During the technological preparation process or during aging, metastable modifications often change to more stable forms, which in turn leads to a change in the biopharmaceutical characteristics (as well as the bioavailability). Polymorphism and polymorphic transformations of the finished formulation are particularly important for therapeutically active ingredients that are administered at very low doses and whose solubility and dissolution rate are very low.

In the literature (U.S. Patent No. 4,721,709) a technological process is described which achieves rapid dissolution of benzodiazepines, including alprazolam.

However, this patent does not disclose or address the problem of alprazolam polymorphism and its effect on dissolution rate and dissolution profile and bioavailability.

SUMMARY OF THE INVENTION

The present invention relates to a solid dosage form with a reliable release of the active ingredient alprazolam and to a process for its preparation and to the preparation of a formulation into a capsule, a classic film-coated tablet, and a dragee. This method eliminates the polymorphism problem of the active ingredient used, i. j. alprazolam, and provides a stable and rapid release that does not depend on the physical characteristics of the active ingredient used. The term release refers to the dissolution kinetics and solubility of the active ingredient. The formulation and method of preparing the present invention provides a very fast and reliable release of alprazolam from the formulation whose rate or solubility profile does not depend on the physical characteristics of the starting alprazolam and the process is simpler than that described in said US patent.

The present invention provides solid dosage forms with a reliable release of the therapeutically active component of alprazolam -8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine, which contain 0.1 to 15 mg, preferably 0.25 to 5 mg of alprazolam, 0.1 to 80 mg of a water-soluble carrier such as α, B and δ-cyclodextrins, mono-, di-, oligo- and polysaccharides or polyvinylpyrrolidone with an average molecular weight of 25,000 to 120,000 and water-insoluble hydrophilic carriers such as porous and non-porous silica, titanium dioxide and alumina, 0.01 to 15 mg nonionic surfactants having an HLB value of 13 to 18, preferably 14.5 to 15, 5, and a disintegrant in a concentration of 2 to 20% selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

The present invention also provides a process for the preparation of solid dosage forms with a reliable release of the therapeutically active component of alprazolam, such that 0.1-80 mg of a carrier selected from a water-soluble or water-insoluble hydrophilic carrier is mechanically dispersed with 0.1-15 mg of alprazolam in a solvent solution selected from water. and organic solvents whose boiling point is less than 100 ° C under normal pressure, the solvent is evaporated under reduced pressure or by spraying the dispersion in a spray drier, or applied to a fluidized bed in the presence of 0.1 to 15 mg of nonionic surfactant and disintegrant. Preferably, the solvent is ethanol or a mixture of ethanol and water at a concentration of 50 to 96% by volume. The solvents used are water and organic solvents whose temperature warns below 100 ° C under normal pressure. Preferably ethanol and ethanol-water mixtures are used in concentrations of 50 to 96 vol. ethanol.

The added pharmaceutically acceptable vehicles guarantee the disintegration of the therapeutic forms - tablets of the invention - at t <1 minute and are selected from corn starch (0 to 70%), lactose (0 to 70%), colloidal silica (0 to 10%), magnesium stearate (0-5%), stearic acid (0-5%) and polyvinylpyrrolidone (0-20%).

The addition of a superdisintegrator has a critical effect on tablet disintegration and thus also on the solubility kinetics of alprazolam. Cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose or sodium starch glycolate may be used as the superdisintegrator, preferably cross-linked polyvinylpyrrolidone. Said components are combined in the formulation to provide an optimal dissolution kinetics of alprazolam, i. 90% in 10 minutes.

In our preliminary study, we found that alprazolam exists in at least two polymorphic modifications currently on the market. Due to the present invention, the problem of various polymorphic modifications no longer exists on the market.

BRIEF DESCRIPTION OF THE DRAWINGS

The figure is actually a diagram showing the effect of the type of carrier on the dissolution profile of alprazolam from coatings, where a is alprazolam itself, b is lactose, c is mannitol, d is colloidal silica and e is bentonite.

DETAILED DESCRIPTION OF THE INVENTION

1. Alprazolam coatings on lactose

1. alprazolam 10% lactose to 100% ethanol (96% v / v) q.s.

Alprazolam was dissolved in ethanol. The method of applying the active ingredient to the lactose as carrier is carried out in one of the following ways:

Evaporating the solvent from the solution under reduced pressure, or

B - spraying the dispersion in a spray drier, or C - spraying on a fluid bed

The product is then pulverized and sieved through a 600 µm sieve.

II. alprazolam 10%

Tween ^R 80 1% (Tween ^R 80 = polyethylene oxide sorbitan monooleate) lactose up to 100% ethanol (96% v / v) qs

Method of preparation identical to point I.

2. Tablets coated with alprazolam on carriers preferably 0.25 to 5 mg alprazolam, 0.1 to 80 mg water-soluble carrier such as α, β and δ-cyclodextrins, mono-, di-, oligo- and polysaccharides or polyvinylpyrrolidone with an average a molecular weight of 25,000 to 120,000 and water-insoluble hydrophilic carriers such as porous and non-porous silica, titanium dioxide and alumina, 0.01 to 15 mg nonionic surfactants having an HLB value of 13 to 18, preferably 14.5 to 15.5 , and a disintegrant at a concentration of 2 to 20% selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

A process for the preparation of solid dosage forms with a reliable release of the therapeutically active component of alprazolam according to claim 1, characterized in that 0.1 to 80 mg of a carrier selected from a water-soluble or water-insoluble hydrophilic carrier is mechanically dispersed with 0.1 to 15 mg of alprazolam in solution. a solvent selected from water and organic solvents whose boiling point is less than 100 ° C under normal pressure, the solvent is evaporated under reduced pressure or by spraying the dispersion in a spray drier, or applied to a fluidized bed in the presence of 0.1 to 15 mg nonionic surfactant component and disintegrator.

A process according to claim 2, wherein the solvent is ethanol or a mixture of ethanol and water at a concentration of 50 to 96% by volume.

drawing Alprazolam coating (5%) 7.70% corn starch 24.00% lactose 62.25% polyvinylpyrrolidone 3.00% magnesium stearate 0.05% dye 0.004% cross-linked sodium carboxymethylcellulose 3.00%

Tablets are prepared by direct compression of the ingredients.

3. Comparison of dissolution profiles of alprazolam with different carriers (Fig.)

Claims (1)

PATENT CLAIMS Solid dosage forms with the reliable release of the therapeutically active component of alprazolam - 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine, characterized in that containing 0.1 to 15 mg,