SI9300504A - Process for preparation solid dispersions and deposits of calcium antagonist dihidropyrimidine derivates and pharmaceutical compositions comprising the same - 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

PROCEDURE FOR THE PREPARATION OF SOLID DISPERSIONS AND DEPOSITS AND SOLID MEDICINAL FORMS WITH CALCIUM DIHYDROPYRIDINE TYPE ANTAGONISTS

Technical field of the invention

The present invention relates to a process for the preparation of solid dispersions and deposits and solid pharmaceutical forms with dihydropyridine type calcium antagonists.

A technical problem

Insufficient rate of dissolution of active substances from solid medicinal preparations can lead to their incomplete absorption and low bioavailability.

Due to regulatory requirements, the most appropriate pharmaceutical-technological approach is to solve the dissolution rate that is too low. The easiest way to do this is through micronisation. However, when it is highly aerophilic, including 1,4-dihydropyridine derivatives with antagonistic action on receptors in Ca channels, it does not always increase the rate of dissolution. Therefore, we could not apply this approach to formulations involving one or more 1,4 dihydropyridine derivatives characterized by very poor solubility and low dissolution rate in water.

The state of the art

It is known that the rate of dissolution of the active substance is directly influenced by the surface of the dissolved particles and the solubility of the active substance. The patent literature describes technological solutions for increasing the rate of dissolution by micronization. The patents of Bayer DE 3310649 and EP 142561 protect the particle size of micronized dihydropyridine type calcium antagonists.

The dissolution rate is also increased by the preparation of solid dispersions of the active ingredient with the corresponding hydrophilic biologically inactive compound e.g. colloidal silica, PVPjem, sugars, etc. Among the dispersions mentioned above are particularly topical. solid surface dispersions (adsorbates and deposits), for which the theoretical and practical basis was mainly developed by Rupprecht et al., especially for the use of silicon-based carriers (natural and man-made). The preparation of such dispersions is often difficult or impracticable on an industrial scale (Yu. Patent Application P1089 / 86), as it often involves the evaporation phase of large quantities of organic solvents and the use of bulk carriers that are not suitable for the production of higher-dose solid forms. of 10 mg. On the other hand, the physical state of the active substance is unstable in the dispersions thus prepared. Mechanical processing often changes, which is reflected in a lower dissolution rate.

German patent application DE 3419128 describes a process for the manufacture of a 1,4-dihydropyridine derivative formulation from which the active substance is rapidly and reliably released. This application protects the classical process of granulation of an active ingredient selected from 1,4-dihydropyridine derivatives with water-soluble excipients such as: lactose, sucrose, fructose, glucose, mannitol, sorbitol, certain alkali and alkaline earth salts of organic acids and other excipients such as starch, whole , PVP and colloidal silica.

DESCRIPTION OF THE TECHNICAL PROBLEM SOLUTION

The present invention includes technological processes and methods that enable the preparation of solid dispersions and (or) deposits of one or more 1,4-dihydropyridine derivatives with suitable pharmacologically indifferent compounds selected from mono-, di-, oligo- and polysaccharides and the preparation of solid dosage forms with incorporated dispersions and (or) deposits. In the manufacture of the aforementioned solid dispersions and deposits, we employ methods in which the dispersion (solution or suspension) consisting of one or more 1,4 dihydropyridine derivatives and a suitable selected carrier from: mono-, di-, oligo- and polysaccharides, colloidal silica or microcrystalline are used cellulose, by one of the following methods:

- Spray dryer spray or

- by spraying in a vortex layer.

From the dispersions thus prepared, containing a total of 1-75% (preferably 2.5 to 25%) of 1,4-dihydropyridine derivatives with antagonistic action on calcium channel receptors, followed by the addition of a superdisintegrant selected from sodium starch glycolate, potassium polyacrylamine, cross-linked sodium carboxime and cross-linked PVP, anionic and (or) nonionic surfactants, and other known excipients, form solid drug forms: capsules, tablets (classic or lacquered) or more expensive.

The technological processes and the ingredients used of the present invention provide a comparative or. even faster release of the active ingredient from the solid dosage form than in the case of the formulation of patent application DE 3419128; the problem of micronisation of the active substance. This results in less energy consumption, less active substance loss and greater homogeneity of the final solid dosage form.

Our invention also includes the manufacture of solid dosage forms: capsules, tablets (classic or lacquered) or dragees containing at least one of the following 1,4-dihydropyridine derivatives: nitrendipine, nimodipine and lacidipine in an amount

2-240 mg pro dosi and provide rapid and stable release of the active substance from the formulation. In addition to one or more of the aforementioned active ingredients, the invention also includes one or more excipients selected from: water-soluble carriers selected from mono, di, oligo and polysaccharides, preferably sorbitol, lactose, water-soluble starch and mannitol in a concentration of 5-90%; one or more substances of the disintegrant group, preferably sodium starch glycolate, potassium polyacryline, cross-linked sodium carboxymethylcellulose and (or) cross-linked polyvinylpyrrolidone at a concentration of 5-20%; one or more surfactants of anionic or non-ionic substances of esters and ethers of sorbitan, polyethylene and polypropylene glycol, pooxamers, alkali salts of alkylsulfonic acids in a concentration of 0.05 to 10% and other commonly known excipients selected from the group of binders, preferably microcrystalline cellulose, and dyscrystalline cellulose preferably magnesium or aluminum stearate.

The advantages of the present process for the preparation of solid dosage forms with dihydropyridine type calcium antagonists over other patented or In addition to the improved pharmacokinetic properties of the formulation, commercial processes include the use of practically non-toxic solvents, the speed and cost-effectiveness of the process.

EXECUTIVE EXAMPLES

I) dispersions / deposits:

Example 1:

nitrendipine 100.0 g mannitol 900.0 g ethanol (96 vol.%) q.s.

Nitrendipine is dissolved in ethanol and mannitol is dispersed into the solution.

Dispersions are removed by dispersing the solvent in a stream of heated air.

The final product is sieved through a 200 μπι sieve.

Example 2:

nitrendipine 100.0 g lactose 900.0 g mixture ethanol (96 vol.%) / water 2 + 1 q.s.

Nitrendipine and lactose were dissolved in an ethanol / water mixture and continued in the same manner as in 1.

Example 3: Nitrendipine lactose

250.0 g 750.0 g ethanol mixture (96 vol%) / water 2 + 1 q.s.

The process of preparing the dispersion is the same as under 2.

Example 4:

nimodipine lactose

100.0 g 890.0 g sodium iavril sulfate 10.0 g ethanol mixture (96% vol) / water

q.s.

Preparation process:

a) dissolve all the solid components in a solvent mixture and remove them according to the same procedure as under 2.

b) dissolve one or more 1,4-dihydropyridine derivatives and sodium Iavril sulfate in a solvent mixture. The solution was then sprayed with lactose in warm air stream. The resulting dispersion was sieved through a 200 µm sieve.

Example 5: nitrendipine lactose corn starch microcrystalline cellulose calcium carbonate sodium iavril sulfate

10.0 g

120.0 g 128.0 g 43.0 g

35.0 g 1.0 g

The above ingredients are mixed in a planetary mixer and grinded with an aqueous PVP solution. Dry the granulate to 4.5% humidity.

II) Examples of manufacturing solid dosage forms

Example 6:

The granulate of Example 5 was compressed into tablets with the addition of 5.0 g of magnesium stearate.

Example 7: nitrendipine 20 mg tablets: the dispersion of 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 components are homogeneously mixed and directly tableted

Example 8: nimodipine 30 mg tablets:

dispersion under 4b 300.0 g sodium starch glycolate 35.0 g microcrystalline cellulose 62.0 g magnesium stearate 3.0 g

The same procedure as for 7.

Example 9: Comparison of the dissolution profiles of the dispersions of Examples 2 and 5 with the dissolution profile of micronized nitrendipine.

t (min)

Example 10: Comparison of thermograms of the dispersion sample from Example 2 and

Example 11; Comparison of dissolution profiles of 20 mg nitrendipine tablets from examples 6 and 7 of dissolved nitrendipine

Claims (2)

PATENT APPLICATIONS A process for the preparation of solid dispersions and deposits with calcium dihydropyridine type antagonists containing, as active ingredient, one or more 1,4-dihydropyridine derivatives as nitrendipine, nimodipine and lacidipine, and as a carrier of one or more water-soluble mono-, di-, oligo derivatives - and polysaccharides, preferably soluble starch, lactose, mannitol, sorbitol and glucose, optionally mixed with one or more disintegrants selected from potassium polyacrylin, sodium starch glycolate and (or) cross-linked carboxymethyl cellulose, dispersed or sprayed 1,4-dihydropyridine derivatives and, if necessary, one or more excipients from the group of water-soluble mono-, di- and oligosaccharides and, where appropriate, a wettable selected from anionic and (or) non-ionic surfactants, preferably sodium lauryl sulfate, poloxamer 68 or ( and) 127 and (or) higher fatty acid polyoxyethylene sorbitan esters, characterized in that dispersion, preferably solution and (or) suspension of the active ingredient (s) and, if necessary, one or more water-soluble excipients selected from mono-, di- and oligosaccharides and surfactants selected from sodium lauryl sulfate, poloxamers and (or) polyoxyethylene sorbitan esters fatty acids of 12 to 18 carbon atoms, in a solvent selected from lower aliphatic alcohols of 1 to 4 carbon atoms, preferably of ethanol and 1-propanol, optionally mixed with water in a concentration of 50 to 100% by volume, the solvent is removed by spraying dispersions in warm air flow, if necessary, to a carrier selected from one or more water-soluble mono-, di-, oligoin polysaccharides and, if necessary, a swellable polymeric substance selected from potassium polyacrylin, sodium starch glycolate and (or) cross-linked carboxymethylcellulose and surface active substances such as sodium lauryl sulfate, poloxamer and (or) polyoxyethylene sorbitan esters of higher fatty acids . 2. A process for the preparation of solid dosage forms based on the solid dispersions and (or) deposits of claim 1, characterized in that the dispersion and (or) deposit in the mixer is mixed together with a disintegrant selected from potassium polyacryline, sodium starch glycolate and (or) crosslinked. carboxymethyl cellulose, glidants, preferably magnesium stearate, and, where appropriate, other commonly known excipients such as fillers and binders, and by the known methods make the desired solid dosage forms, preferably tablets or capsules.