HRP940417A2 - Solid curative forms with reliable release of alprazolame active substance and a process of the production thereof - Google Patents

Description

Technical field of the invention

The presented invention relates to new solid medicinal forms with reliable release of the active substance alprazolam (chemical: 8-chloro-1-methyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4 ]benzodiazepine) and to a new procedure for their preparation. Alprazolam is a well-known anxiolytic.

Technical problem

In order to achieve optimal absorption and thus optimal therapeutic efficacy, it is necessary to ensure the appropriate dissolution kinetics of the active substance. When using therapeutically active substances, eg alprazolam, low solubility and dissolution rate are often a problem. Due to regulatory requirements, the most suitable physical approach is to solve the problem of low solubility and dissolution rate, which means that with formulation technological solutions we influence both parameters of solubility, and the main emphasis is on the speed and profile of solubility.

State of the art

It is well known that the solubility and dissolution rate of the active substance, among other things, is influenced by its polymorphism. Metastable modifications very often show higher solubility and dissolution rate, which is a consequence of the lower energy of the crystal lattice.

For the formulation of therapeutic preparations with a poorly water-soluble therapeutically active substance, it would be convenient to choose metastable modifications. Of course, the physical and chemical stability of the metastable modification of the active substance (only substances as well as formulations) can be a problem. During the technological process of preparation of the formulation or during aging, metastable modifications very often change into more stable forms, which changes the biopharmaceutical characteristics (also biological availability). Polymorphism and polymorphic changes in finished formulations are of particular importance in the case of therapeutically active substances that are applied in small doses and whose solubility and dissolution rate are very low.

In the literature (US patent number 4,721,709) a technological procedure is described, which achieved the rapid dissolution of benzodiazepines, among them, the aforementioned alprazolam. That patent neither describes nor solves the problem of polymorphism of alprazolam and its effect on the rate and profile of dissolution and bioavailability.

Description of the solution to the technical problem

The presented invention includes technological preparation procedures as well as the composition of solid medicinal forms [capsules, tablets (classic and film-tablets) and dragees], which eliminates the problem of polymorphism of the active substance used, i.e. alprazolam, and thus ensures a stable and rapid release of the active substance, which it does not depend on the physical characteristics of the active substance used. The term "release" refers to the dissolution and solubility kinetics of the active substance. The formulation and the technological process of its preparation are described in the proposed invention, whereby fast and reliable dissolution of alprazolam from the formulation is ensured, and the dissolution rate and profile are independent of the physical characteristics of the starting alprazolam, while at the same time the technological process of preparing that formulation is more unique than that described in the cited US patent.

The first object of the presented invention are solid medicinal forms with a reliable release of the therapeutically active substance alpralose (chemically: 8-chloro-1-methyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4 ]benzodiazepine) containing 0.1 to 15 mg, preferably 0.25 to 5 mg of alpralose, 0.1 to 80 mg of water-soluble substrates such as alpha-, beta- and gamma-cyclodextrin, mono-, di-, oligo- and polysaccharides and polyvinyl pyrrolidone with an average molecular weight of 25,000 to 120,000, and water-insoluble hydrophilic substrates such as porous or non-porous silica, titanium dioxide, and aluminum oxide, and 0.01 to 15 mg of nonionic surfactants with an HLB value of 13 to 18, preferably 14.5 to 15.5, and a disintegrant in a concentration of 2 to 20% chosen from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone is preferred.

New solid medicinal forms with reliable release of the therapeutically active substance alprazolam were prepared according to one of the following procedures:

1. - the substrate is dispersed, by mechanical mixing, into a solution of alprazolam in the selected solvent, which is then evaporated under reduced pressure.

2. - the substrate is dispersed, by mechanical mixing, in a solution of alprazolam in the chosen solvent. The dispersion is then sprayed in a spray dryer.

3. - a solution of alprazolam is prepared in the selected solvent and it is then sprayed onto the selected substrate in a fluidized bed.

The next subject of the invention is the process of preparing the previously mentioned new solid medicinal forms with reliable release of the therapeutically active substance alprazolam (chemical: 8-chloro-1-methyl-6-phenyl-4H[1,2,4]triazolo[4,3-a] [1,4]benzo diazepine) which is carried out so that the active substance is brought from the solution to the surface of the substrate by evaporation under reduced pressure or by spraying in a "spray dryer" or by deposition in a fluidized bed. Water and organic solvents with a boiling point below 100ºC at normal atmospheric pressure are used as solvents. It is advantageous to use ethanol and ethanol-water mixtures at a concentration of 50 to 96% by volume of ethanol.

Additional pharmaceutically acceptable excipients ensure the disintegration of therapeutic forms - tablets according to the invention - in t < 1 minute and are chosen from corn starch (0 - 70%), lactose (0 - 70%), colloidal silicon dioxide (0 - 10%), magnesium stearate (0 - 5%), stearic acid (0 - 5%), polyvinylpyrrolidone 0 - 20%).

The addition of superdisintegrators has a critical influence on the disintegration of tablets and thus on the dissolution kinetics of alprazolam. Network-linked polyvinylpiperolidone, network-linked sodium carboxymethylcellulose or sodium starch glycolate can be used as a superdisintegrator; it is advantageous to use cross-linked polyvinylpyrrolidone. The mentioned substances were combined in the formulation in such a way as to ensure optimal alprazolam dissolution kinetics, i.e. 90% in 10 minutes. In our reformulation studies, alprazolam was found to occur in at least two polymorphic modifications, both of which are present on the market. With the help of the presented invention, we naturally solve the problem of various polymorphic modifications present on the market.

Examples

1. Deposit of alprazolam on lactose

Ι. alprazolam 10%

lactose up to 100%

ethanol (96%) q.s.

Alprazolam dissolves in ethanol. The process of deposition of the active substance on lactose as a substrate was carried out by one of the following procedures:

A - by the process of evaporation of the solvent from the dispersion under reduced pressure, or

B - by the process of spraying the dispersion in a "Spray dryer", or

C - by the process of deposition in a fluidized bed.

The product is then pulverized and sieved through a 30-mesh sieve.

ΙΙ. alprazolam 10%

TweenR 80 1% (TweedR 80 is polyethylene oxide sorbitan monooleate)

lactose up to 100%

ethanol (96%) q.s.

The preparation procedure is the same as under Ι.

2. Tablets with alprazolam deposits on the substrates

alprazolam deposit (5%) 7.70%

corn starch 24.00%

lactose 62.25%

polyvinylpyrrolidone 3.00%

magnesium stearate 0.05%

color 0.004%

cross-linked CMC-Na 3.00%

The tablets were prepared by direct pressing of the previously mentioned ingredients.

3. Comparison of the dissolution profile of alprazolam with different substrates (Figure 1).

Claims (3)

1. Solid medicinal forms with reliable release of the therapeutically active substance alprazolam (chemical: 8-chloro-1-methyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) , indicated by the fact that it contains 0.1 to 15 mg, preferably 0.25 to 5 mg of alprazolam, 0.1 to 80 mg of water-soluble substrates such as alpha-, beta- and gamma-cyclodextrin, mono-, di-, oligo - and polysaccharides or polyvinylpyrrolidone with an average molecular weight of 25,000 to 120,000, and water-insoluble hydrophilic substrates such as porous and non-porous silica, titanium dioxide, and aluminum oxide, and furthermore 0.01 to 15 mg of nonionic surface-active substance with an HLB value 13 to 18, preferably 14.5 to 15.5, and a disintegrant in a concentration of 2 to 20% chosen from sodium starch glycolate, crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose. 2. The process of preparing solid medicinal forms with reliable release of the active substance alprazolam (chemical: 8-chloro-1-methyl-6-phenyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine ), indicated by the fact that 0.1 to 15 mg of the therapeutically active substance alprazolam was applied to the surface of 0.1 mg to 80 mg of a substrate chosen from water-soluble substrates such as alpha-, beta- and gamma-cyclodextrin, mono-, di-, oligo- and polysaccharides or polyvinylpyrrolidone with an average molecular weight of 25,000 to 120,000, and water-insoluble hydrophilic substrates such as porous or non-porous silica, titanium dioxide and aluminum oxide, from a solution in a solvent chosen between water and organic solvents with a boiling point below 100ºC at normal atmospheric pressure, by evaporation of the solvent at reduced pressure or by spraying in a "spray dryer" or by deposition in a fluidized bed in the presence of 0.01 to 15 mg of a nonionic surface-active substance with an HLB value of 13 to 18, preferably 14.5 to 15.5 and in acc the presence of a disintegrant in a concentration of 2 to 20% selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. 3. The method according to claim 2, characterized in that the solvent used is ethanol or an ethanol-water mixture in a concentration of 50 to 96% by volume of ethanol.