CZ90096A3 - Process for preparing solid dispersions or coatings as well as solid forms with lime antagonists of dihydropyridine type - Google Patents

Abstract

There is described a process for the preparation of solid dispersions and deposits with dihydropyridine type calcium antagonists containing as the active substance one or more 1,4-dihydropyridine derivatives such as nitrendipine, nimodipine and lacidipine and as a carrier one or more water-soluble derivatives of mono-, di-, oligo- and polysaccharides, and, if required, also polymer substances, which are swellable in contact with water, selected from polacrilin potassium, sodium starch glycolate and/or cross-linked carboxy methyl cellulose, and anionogenic or non-ionogenic type surfactants selected from sodium lauryl sulfate, poloxamers and/or higher fatty acids polyoxyethylene sorbitan esters, whereat from the dispersion, preferably a solution and/or suspension of active substance(s), and if required one or more water-soluble adjuvants, selected from mono, di and oligosaccharides, and surfactants selected from sodium lauryl sulfate, poloxamers and/or polyoxyethylene sorbitan esters of higher fatty acids with 12 to 18 carbon atoms, in a solvent selected from lower aliphatic alcohols with 1 to 4 carbon atoms, preferably ethanol and 1-propanol and if required in mixture with water, the solvent is removed by spraying of dispersion under the stream of the heat air and if required to the carrier, selected from one or more of the water-soluble mono, di, oligo and polysaccharides and if required the water-swellable polymer substances from the group of disintegrators, and the anionic or nonionic surfactants. Furthermore, there is described a process for the preparation of solid medicinal forms of dihydropyridine type calcium antagonists, whereat the mentioned solid dispersions and (or) deposits are mixed in a suitable manner with disintegrators and lubricant, and if required the other adjuvants such as carriers and binders, and then by such a mixture there are formed preferably tablets and capsules.

Description

Technical field

The present invention relates to a process for the preparation of solid dispersions, deposits and solid dosage forms comprising, as an active ingredient, dihydropyridine type calcium antagonists.

Too slow dissolution rate of drug active ingredients from solid formulations may lead to incomplete absorption and hence low drug bioavailability.

The simplest solution to the stated requirements in connection with the problem of slow dissolution is the pharmaceutical-technological addition of micronization. However, in the case of strongly aerophilic active substances, which also include 1,4-dihydropyridine derivatives having calcium channel receptor antagonistic effects, micronization does not always lead to an increase in the dissolution rate. Therefore, when developing formulations containing one or more 1,4-dihydropyridine derivatives with low solubility and low dissolution rate in water, this approach cannot be used.

BACKGROUND OF THE INVENTION

It is known that the dissolution rate of the drug active ingredients is directly influenced by the surface area of the dissolving particles and the solubility of the active ingredient. The patent literature contains technological solutions to increase the dissolution rate by micronization. DE 3310649 and EP 14256X BAYER AG protect the particle size of a micronized formulation comprising a dihydropyridine type calcium antagonist.

Higher dissolution rates can also be achieved with solid dispersions containing the active ingredients and suitable hydrophilic biologically inactive compounds such as colloidal silicon dioxide, PVP, sugars, etc. Among these dispersions, so-called solid surface dispersions (adsorbates and deposits) on However, the preparation of these dispersions on an industrial scale is difficult or even impractical (YU patent 44 291), as it often involves the vaporization step of a large number of silicas. organic solvents and use

- ^Λ - ~ voluminous carrier unsuitable for the preparation of solid formulations of the active ingredient dose exceeding 10 mg. From a physical point of view, the active ingredient is unstable in these dispersions. Mechanical handling changes the dispersion and often results in a decrease in dissolution rate.

DE 3419128 describes a process for the preparation of preparations containing 1,4-dihydropyridine derivatives from which the active ingredient is released rapidly and reliably. The cited application protects a classical method of granulating an active ingredient selected from 1,4-dihydropyridine derivatives with water-soluble excipients such as lactose, sucrose, fructose, glucose, mannitol, sorbitol, some alkali metal or alkaline earth metal salts of organic acids and other excipients such as starch, cellulose, FVP, and colloidal silica.

EP-A-0 176 773, similar to the above-mentioned DE 3419128, describes a process for the preparation of well-absorbable nitrendipine-containing solid preparations. The method comprises granulating a drug mixture, ie, nitredipine, starch, lactose and microcrystalline cellulose with an aqueous solution of a surfactant and PVP. The main features of the process are: solvent is water, addition of binder, i.e. PVP, and granular product; the question is therefore the granulation process.

A substantially similar concept is also disclosed in EP-A-0 001 247 which claims stable and readily absorbable solid dosage forms of nifedipine. These forms are more resistant to photochemical degradation and retain good resorption

2a by plasma. According to a preferred embodiment of the invention, nifedipine is stabilized in the formulations by attaching a solution of nitendipine in polyethylene glycol to a porous inorganic or organic carrier such as aluminosilicate, dry aluminum hydroxide, etc., or in another preferred embodiment a non-crystalline dispersion of solid nifendipine solution is prepared. and PVP, and the organic solvents present from the solution of nipedipine and PVP are removed, e.g., the solvents are evaporated and the residue further powdered, or the solution is sprayed onto the excipient particles in a fluid bed to form granules. In summary, the first embodiment does not include the need for drying and in the second embodiment the solvent is removed from the solution containing the binder, in particular PVP.

SUMMARY OF THE INVENTION A group of mono-, oligolecular forms in preparation

The present invention provides a process and processes for preparing solid dispersions and / or deposits containing one or more 1,4-dihydropyridine derivatives and suitable pharmacologically inactive compounds selected from and polysaccharides, and a process for preparing solids containing these dispersions and / or deposits, said solid dispersions and deposits. a process comprising spraying colloidal silica or microcrystalline cellulose into a dispersion (solution or suspension) containing one or more 1,4-dihydropyridine derivatives and a suitable carrier selected from mono-, oligo- and polysaccharides is used. Spraying is carried out according to one of the following procedures:

spraying in a dryer, or

- fluidized bed spraying.

In other words, solid formulations in connection with the present application are preferably:

1. solid dispersions in which the drug (one or more 1,4-dihydropyridine derivatives) is homogeneously dispersed in a matrix or pharmacologically inactive substances comprising one or more water-soluble mono-, di-, oligo and / or polysaccharides, surfactants and one or more disintegrators;

2. soluble deposits wherein the drug or drug together with the surfactant is bound to the surface of the carrier (s) selected from one or more mono-, di-, oligo- or polysaccharides, preferably in admixture with one or more disintegrators; or

3. a combination of a solid dispersion and a soluble deposit in which the dispersion containing the drug, the mono-, di-, oligo and / nobo polysaccharides water-soluble and the surfactant is bound to the surface of a carrier selected from one or more mono-, di-; oligo- or polysaccharides, preferably in admixture with one or more disintegrators.

The above-described solid formulations according to the present invention can be prepared by a process comprising:

spraying a mixture comprising all components dispersed in alcohols, preferably a mixture of alcohols with water in a dryer, or spraying a suspension or solution comprising a mixture of one or more 1,4-dihydropyridine derivatives, at least one surfactant and one or more water-soluble mono- , di-, oligo- or polysaccharides and an alcohol, preferably a mixture of alcohol and water, onto a hydrophilic carrier consisting of one or more mono-, di-, oligo- or polysaccharides, preferably in admixture with one or more fluid bed disintegrators, or solvent evaporation from a dispersion of all components in an alcohol or preferably in an alcohol-water mixture under reduced pressure.

Of the solid preparations prepared by the above processes and containing 1 to 75%, preferably 2.5 to 25% by weight. 1,4-dihydropyridine derivatives having calcium channel receptor antagonist activity can be prepared by adding a superdisintegrant selected from the group consisting of sodium starch glycolate, methacrylic-divinyl-benzene copolymer (polacrillin potassium), cross-linked carboxymethylcellulose and cross-linked PVP and adding anionic and / / or nonionic surfactants and other known adjuvants, solid dosage forms such as capsules, tablets (conventional or coated) or dragees.

Accordingly, the present invention provides a process for the preparation of said formulations comprising 1,4-dihydropyridine derivatives comprising:

(a) preparing a solution or suspension comprising one or more 1,4-dihydropyridine derivatives, one or more water-soluble mono-, di-, oligo- or polysaccharides and preferably one or more surfactants in a hydrophilic solvent; ) providing at least one carrier selected from mono-, di-, oligo- or polysaccharides, which is preferably mixed with one or more disintegrators, (c) evaporating the solvent by spraying the solution or suspension (a) onto the carrier (b) in a stream of hot air.

Another object of the present invention is a process for preparing solid preparations containing derivatives

1,4-dihydropyridine comprising:

(i) preparing a solution or suspension containing one or more 1,4-dihydropyridine derivatives, one or more water-soluble mono-, di-, oligo- or polysaccharides in a hydrophilic solvent, the solution or suspension preferably further comprising one or more surface-active agents and / or one or more disintegrators, and (ii) evaporating the solvent.

The surfactant may be selected from the group consisting of sodium lauryl sulfate, substituted and unsubstituted polyoxyethylene polyoxypropylene block polymers, and polyoxyethylene sorbitan esters of higher C12-C18 fatty acids, the preferred surfactant is sodium lauryl sulfate, α-hydro-o-hydroxypoly (oxyethylene) block polymer, and - poly- (oxypropylene) b-poly (oxyethylene) _a , wherein a is 80 or 101 and b is 27 or 56, and polyoxyethylene sorbitan monooleate.

The water-soluble carbohydrates in steps (a) and (i) and the carbohydrates in step (b) may be soluble starch, lactose, mannitol, sorbitol, and / or glucose, preferably sorbitol, mannitol and / or lactose.

The disintegrator may be selected from the group consisting of potassium methacrylic-divinyl-benzene copolymer (polacrilin potassium), sodium starch glycolate and cross-linked carboxymethylcellulose, preferably sodium starch glycolate and cross-linked carboxymethylcellulose.

As 1,4-dihydropyridine derivatives, e.g.

nitrendipine, nimodipine and / or lacidipine.

As the hydrophilic solvent, lower aliphatic C1 -C * alcohols containing from 0 to 50% by volume of water can be used.

release issues

Lower aliphatic alcohols are preferably ethanol and / or 1-propanol.

The process of step (c) uses a fluidized bed.

The solvent is removed by spraying with simultaneous drying or drying under reduced pressure and higher temperature.

The present process process and the ingredients used provide a comparable or higher release rate of the active ingredient from the solid dosage forms than the formulation in DE 341912Θ, which also addresses and addresses the need for micronizing the active ingredient. The present process is less energy intensive, results in less active substance loss and results in higher homogeneity of the final solid dosage form.

The present invention also encompasses the preparation of solid dosage forms such as capsules, tablets (conventional or coated) or dragees containing at least one of the following 1,4-dihydropyridine derivatives: nitrendipium, nimodipine and lacidipine in an amount of 2 to 240 mg per dose, these solids The dosage forms stably release the active ingredient rapidly. In addition to one or more of said active ingredients, the present compositions further comprise one or more adjuvants selected from the group of mono-, di-oligo- and polysaccharides, preferably sorbitol, lactose, water-soluble starch and mannitol in concentrations of 5 to 90% by weight; one or more of the disintegrants, preferably sodium starch glycolate, potassium salt of methacrylic-divinyl-benzene copolymers (polacrilin potassium), cross-linked carboxymethylcellulose and / or cross-linked polyvinylpyrrolidone at a concentration of 5 to 20% by weight; one or more anionic or nonionic surfactants selected from the group consisting of sorbic esters and ethers, polyethylene glycol and polypropylene glycol, poloxamers, alkali. salts of alkylsulfonic acids in a concentration of 0.05 to 10% by weight; and other commonly known additives selected from the group consisting of. binders, preferably microcrystalline cellulose, lubricants, preferably magnesium or aluminum stearate.

The benefit of preparing the solid dosage forms containing the dihydropyridine-type calcium antagonists of the present invention, when compared to other patented or commercial processes, is the use of near nontoxic solvents and the speed and efficiency of the process in addition to the improved pharmacokinetic properties of the formulation.

Since 1,4-dihydropyridine derivatives are poorly water soluble, especially nitrendipine, nimodipine and lacidipine have significantly lower solubilities than nifedipine, it was necessary to develop a more efficient dissolution method applicable generally to 1,4-dihydropyridine derivatives than that described in of document EP-A-0 001.247. Surprisingly, it has been found that very rapid dissolution can be achieved in formulations where a solution containing the drug, soluble carbohydrates, surfactants, hydrophilic solvent but no binder has been attached to the surface of hydrophilic carriers selected from the group of mono-, di-, oligo- Alternatively, a solution containing one or more drugs, soluble carbohydrates, surfactants, hydrophilic solvent but no binder can be evaporated very rapidly - according to appended claim 2 - by an innovative process that is not granulation, resulting in either individual carrier particles (s) coated with a solid dispersion of the drug or individual particles of solid dispersion with a large surface area, allowing them to dissolve very quickly without further treatment, e.g., further dusting. The presence of hydrophilic substances such as mono-, di-, oligo- or polysaccharides soluble in water reduces the hydrophobic properties of the system. As shown in Examples 4, 6 and 7 of EP-A-0 001 247, PVP is always used as a binder, no mono-, di-, oligo- or polysaccharides are added to reduce the hydrophobic properties of the system, and granules are the product of the process. further need to be further powdered for proper solubility, water and digestive juices (Example 7).

DETAILED DESCRIPTION OF THE INVENTION

I) Dispersions / deposits

Example 1 nitrendipine 100.0 g mannitol 900.0 g ethanol (96% v / v) q.s.

Nitrendipine was dissolved in ethanol and mannitol dispersed in the resulting solution. The solvent was from the dispersion

Spray removed into the hot air stream. Final the product was a pig sieve having a mesh size of 200 µm. Example 2 nitrendipine 100.0 g lactose 900.0 g ethanol (96% v / v) with water 2 + 1 q.s. Nitrendipine and lactose were dissolved in a mixture of ethanol with water and followed the procedure of Example 1.

Example 3

nitrendipine 250.0 G lactose 750.0 G ethanol mixture (96% v / v) with water 2 + 1 q.S. Dispersion was prepared as of Example 2

Example 4 nimodipine

100.0 g lactose ________________. 890.0 g ------------------- - ...........

sodium lauryl sulfate 10.0 g mixture of ethanol (96 fc by volume) with water q.s.

Preparation process:

a) All solids were dissolved in a solvent mixture. The solvents were removed as in Example 2,

b) One or more 1,4-dihydropyridine derivatives and sodium lauryl sulfate were dissolved in a solvent mixture. The solution was then sprayed in a stream of hot air onto lactose. The prepared dispersion was passed through a 200 µm sieve.

Example 5 nitrendipine 10.0 g lactose 120.0 g cereal starch 128.0 g microcrystalline cellulose 43 0 g calcium carbonate 35.0 g sodium lauryl sulfate 1.0 g

The ingredients were mixed in a planetary mixer and granulated with an aqueous solution of PVP. The granulate was dried to a final moisture content of 4.5% by weight.

II) Preparation of solid dosage forms

Example 6

The granulate prepared according to Example 5 and 5.0 g of magnesium stearate were compressed into tablets.

Example 7 nitrendipine 20 mg tablets ------ dispersion according to example 2 200.0 g sodium lauryl sulfate 10.0 g PVP CL 14.0 g microcrystalline cellulose 24.0 g aluminum stearate 2.0 g

Procedure: The ingredients were mixed homogeneously and the mixture was directly tabletted.

Example 8: nimodipine 30 mg tablets dispersion according to example 4b 300.0 g sodium starch glycolate 35.0 g microcrystalline cellulose 62.0 g magnesium stearate 3.0 g

The procedure was the same as in Example 7.

Figures 1 to 3 show a comparison of the dissolution profiles of the dispersions of Examples 2 and 5 versus the dissolution profile of micronized nitrendipine; Fig. 2 shows a comparison of the thermograms of the dispersion of Example 2 against the granulate of Example 5; of Examples 6 and 7.

Industrial applicability

The present process for the preparation of solid dispersions, deposits and solid dosage forms containing as active ingredient. dihydropyridine type calcium antagonists solve the problem of dissolution rate of the active ingredient of the formulation. The preparation is useful as a medicine.

Claims (6)

Ρ A Τ Ε Ν Τ Ο YEARS A process for the preparation of solid preparations containing 1,4-dihydropyridine derivatives, characterized in that it comprises; (a) preparing a solution or suspension comprising one or more 1,4-dihydropyridine derivatives, one or more water-soluble mono-, di-, oligo- or polysaccharides and preferably one or more surfactants in a hydrophilic solvent; one carrier selected from mono-, di ™, oligo- or polysaccharides, which is preferably admixed with one or more disintegrators, (c) evaporating the solvent by spraying solution or suspension (a) onto the carrier (b) in a stream of hot air. 2. Process for preparing solid preparations containing derivatives 1,4-dihydropyridine comprising: (i) preparing a solution or suspension containing one or more 1,4-dihydropyridine derivatives and one or more water-soluble mono-, di-, oligo- or polysaccharides in a hydrophilic solvent, and preferably the solution or suspension further comprises one or more surfactants and / or one or more disintegrators, and (ii) evaporating the solvent by spraying the solution or suspension (i) into a hot air stream. Method preparation according to claims 1 or i, v y z n and c i s e t í m that povxc ·, active the substance is volena from a group comprising sodium lauryl sulfate, substituted and unsubstituted block polymers polyoxyethylene-polyoxypropylene and polyoxyethylene sorbitan esters higher C10-C18 fatty acids, preferably surface the active substance is sodium iauryl sulphate, block, polymer of α-hydro-o-hydroxypoly (oxyethylene) α-poles (oxypropylene) & -poly (oxyethylene) _a . wherein a is 80 or 101 and b is 27 or 56, and polyoxyethylene sorbitan monooleate. A preparation process according to any one of claims 1 to 3, characterized in that the soluble water-soluble carbohydrates in steps (a) and (i) and the soluble carbohydrates in step (b) can be soluble starch, lactose, mannit, or sorbit, lactose. or glucose, preferably sorbitol, mannitol 5. Method preparation according to any of claims 1 to 4, v y z n a č u j ici se t wherein the disintegrator may be selected from the group consisting of potassium methacrylic-divinyl-benzene copolymer (polacrilin potassium), sodium starch glycolate and cross-linked carboxymethyl- cellulose, preferably starch glycolate carboxymethylcellulose. sodium and reticulated 6. The preparation process of any one of from claims 1 to 5, characterized by as derivatives 1,4-dihydropyridine can be used e.g. nimodipine and / or lacidipine. n i t r e n d i p i η, 7. The preparation process of any one of: Claims 1 to 6 characterized in that: as hydrophilic the solvent can be used lower aliphatic C 1 -C 4 alcohols containing 0 to 50 vol% water. Process according to claim 7, characterized in that the lower aliphatic alcohols are ethanol and / or 1-propanol. 9. The process of claim 1 wherein step (c) utilizes a fluidized bed. Process according to claim 2, characterized in that the solvent is removed by spraying with simultaneous drying or by drying under reduced pressure and at a higher temperature.