SK90894A3 - Solid drug forms with reliable releasing active substance of alprazolam and preparation method thereof - Google Patents

Abstract

Solid alprazolam formulations comprise: (i) a carrier comprising (a) 0-70 wt.% water-soluble ~a-, ~b or ~c-cyclodextrin, mono-, di-, oligo- or polysaccharide or polyvinylpyrrolidone (PVP) of average mol.wt. 25000-120000; (b) 0-10 wt.% water-insoluble hydrophilic porous or non-porous SiO2, TiO2 or Al2O3; and/or (c) 0-10 wt.% non-ionic surfactant having an HLB value of 13-18; and (ii) 2-20 wt.% disintegrant comprising sodium starch glycolate, crosslinked PVP or sodium carboxymethyl cellulose.

Description

The present invention is concerned with new solid dosage forms with a reliable release of the active ingredient alprazolam (chemical name: 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1, 4] benzoazepine) and a novel process for 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 a therapeutically active ingredient is used, e.g. alprazolam, represent a low solubility and dissolution rate 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 using technological procedures in which the main focus is on the dissolution rate and profile.

SUMMARY OF THE INVENTION

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 exhibit higher solubility and dissolution rate, which is due to the lower lattice energy of the crystals. It is therefore appropriate to choose a metastable modification for the preparation of therapeutic compositions containing a water-soluble therapeutically active ingredient. Nevertheless, 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 process of preparation or aging, metastable modifications often change to more stable forms, which in turn leads to a change in the biopharmaceutical characteristics (as well as 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 (US Patent No. 4,721,709) a technological process is described which achieves rapid dissolution of benzodiazepines, including alprazolam. Even so, this patent does not describe or solve the problem of alprazolam polymorphism and its effect on dissolution rate and dissolution profile and bioavailability.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a technological process for preparing the formulation and making the formulation into a solid dosage form (capsules, tablets (both classical and film-coated) and dragees) that eliminates the problem of polymorphism of the active ingredient used, i. 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 process of its preparation as described in the present invention provide 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 of preparation is simpler than that described in the aforementioned US Patent.

A first object of the present invention are solid dosage forms with a reliable release of the therapeutically active ingredient of alprazolam (chemical name: 8-chloro-1-methyl-63 to 15 mg, preferably from

0.1 to 80 mg of water-soluble gamma-cyclodextrins, mono- or polyvinylpyrrolidone by weight of hydrophilic phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine), contain from 0.1 alprazolam, from alpha-, beta-, aa polysaccharides molecular and water-insoluble and non-porous silica, an oxide further from 0.01 to 15 mg of nonionic with an HLB value between 13 and 18, is a disintegrant in a concentration of sodium starch polyvinylpyrrolidone carboxymethylcellulose, polyvinylpyrrolidone.

New solid dosage forms of the therapeutically active component of alprazolam in one of the following ways:

1. The carrier is dispersed with mechanical alprazolam in a selected solvent, and evaporated under reduced pressure.

2. The carrier is dispersed with mechanical alprazolam in a selected solvent, sprayed in a spray drier.

3. Prepare the solvent to be the selected carrier.

Another subject of drug which

0.25 to 5 mg of a carrier such as di-, oligo-, with an average of up to 120,000 being porous alumina,

000 carriers as titanium and surfactant preferably between 14.5 and 15.5% to 20%, which is selected by glycolate, cross-linked and cross-linked sodium salt preferably used cross-linked releasable are prepared by mixing into a solution which is then stirred into a solution then the alprazolam solution is then applied to the fluidized bed of the invention is a process for preparing new solid dosage forms with a reliable release of the therapeutically active ingredient of alprazolam (chemical name: 8-chloro-1-methyl-6-phenyl-4H- [1,2, 4] triazolo [4,3-a] [1,4] benzodiazepine), characterized in that the active ingredient is applied to the surface of the carrier from the solution by evaporating the solution under reduced pressure or by spraying in a spray drier or fluidized bed. Water and organic solvents whose boiling point is less than 100 ° C under normal pressure are used as solvents. Preferably, ethanol and ethanol-water mixtures are used in concentrations of from 50 to 96% by volume. ethanol.

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

The addition of a super disintegrator 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 ensure 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.

DETAILED DESCRIPTION OF THE INVENTION

1. Alprazolam coatings on lactose

I.

alprazolam lactose to ethanol (96% v / v)

10%

100%

qs

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

Spraying the dispersion in a spray drier, or

C - application of the fluidized bed

The product is then pulverized and passed through a 30 mesh screen.

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

alprazolam coating (5%) 7.70% maize starch 24.00% lactose 62.25% polyvinylpyro1idón 3:00% magnesium stearate 00:05% coloring 0.004% cross-linked sodium carboxy- methylcellulose 3:00%

Tablets are prepared by direct compression of the above ingredients.

3. Comparison of dissolution profiles of alprazolam with different carriers (Fig. 1)

Claims (3)

PATENT CLAIMS Solid dosage forms with the reliable release of the therapeutically active ingredient of alprazolam (chemical name: 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine), characterized in that they contain from 0.1 to 15 mg, preferably from 0.25 to 5 mg of alprazolam, from 0.1 to 80 mg of a water-soluble carrier such as alpha, beta, and gamma-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, further from 0.01 to 15 mg non-ionic surfactants with an HLB value between 13 and 18, preferably between 14.5 and 15.5 and a disintegrant in a concentration of from 2 to 20%, which is selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. 2. A process for the preparation of solid dosage forms with a reliable release of the active ingredient alprazolam (chemical name: 8-chloro-1-methyl-6-phenyl-4H- [1,2,4] triazole), from 0.1 to 15 mg of alprazolam being applied to a selected from water-soluble and gamma-cyclodextrins, mono-, di-, oligo-, and polysaccharides or polyvinylpyrrolidone with an average molecular weight of 25,000 to 120,000 and a water-insoluble hydrophilic carrier such as porous and non-porous silica, titanium dioxide and alumina , from a solution of a solvent selected from water and organic solvents having a boiling point below 100 ° C under normal pressure, by evaporating the solvent under reduced pressure or by spraying the dispersion in a spray drier or [4,3-a] [1,4] benzodiazepine) characterized by that therapeutically active ingredient a surface area of 0.1 to 80 mg of a carrier carrier such as alpha, beta, by application to a fluidized bed in the presence of from 0.1 to 15 mg of a nonionic surfactant The active ingredient has an HLB value between 13 and 18, preferably between 14.5 and 15.5, and a disintegrant in a concentration of 2 to 20%, which is selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. Method according to claim 2, characterized in that ethanol or a mixture of ethanol and water in concentrations of 50-96% by volume are used as solvent. qot - 9 - The legend: ------- ο ------ alprazolam ----- --------- 2.5% lactose 200 (b) ------------------- 2.5% mannitol (c) ------- & -------- Aerosil 200 (d) ~ -------- Bentonite (e) Fig. 1: Effect of carrier type on the dissolution profile of alprazolam from coatings (a - alprazolam itself, b - lactose, c - mannitol, d - colloidal silica, e - bentonite)