CS213652B1 - A method for producing stable solid lump oral dosage forms - Google Patents

Abstract

The invention relates to a method for producing stable solid piece oral dosage forms containing mutually incompatible active ingredients, in such a way that on cores containing at least two mutually compatible active ingredients, indifferent layers are formed alternately with layers containing active ingredients incompatible with the active ingredients in the core. This method is suitable, for example, for polyvitamin and polyenzymatic preparations.

Description

The invention relates to a method for producing stable solid piece oral saline tablets containing mutually incompatible active ingredients, the release of which in different places of the digestive tract can be controlled.

In common practice, there are a number of solid pharmaceutical preparations for oral use that contain multiple active ingredients. It is very common for these substances to be mutually incompatible, to react with each other, thereby significantly reducing the stability and therapeutic effect of the preparation. Active ingredients are also very often sensitive to external influences, especially moisture, atmospheric oxygen or light.

Protection against external influences is relatively simple. The preparations are produced in the form of coated tablets, i.e. dragees or coated tablets, which consist of a core containing active and auxiliary substances and a coating that provides protection against adverse external influences. Various auxiliary substances are used to create the coating; in the case of dragees, it is mainly formed by a layer of sugar, in the case of coated tablets, by a layer of high-molecular substances, in most cases cellulose derivatives. In practice, two fundamentally technological processes for creating coatings are used. In the production of dragees, the cores are coated in a rotating coating pan with a coating suspension, the basis of which is an aqueous solution of sucrose; on top of the coating, they are sometimes sprinkled with other auxiliary substances and the water is evaporated by the action of hot air. Coated tablets are usually produced in a fluidized method. In a suitable device, the cores are blown with an air stream At a certain temperature, the particles are brought into suspension and in this state, a solution of a film-forming substance in a suitable solvent or mixture of solvents is sprayed onto them, which is evaporated by warm air.

The situation is much more complicated when it is necessary to protect the individual components contained in the tablet against mutual interaction. This is usually solved in several ways. Extruded tablets are prepared from several granulates, with some active substances in the granulate or the entire granule being protected by covering with a suitable inert substance. The disadvantage of this method is that the covering layer of the extruded tablets is partially disrupted by the pressing pressure, and thus unwanted contact with the other components contained in the extrudate is restored.

Another option is the production of sandwich-type layered tablets. To produce such tablets, it is necessary to have special tableting machines. However, here too, incompatible components meet at the contact surfaces. Sometimes this deficiency is solved by another indifferent intermediate layer, which further complicates the situation, the demands on the equipment and its function.

There is also a known method in which some active substances are applied to the core during coating, i.e. incorporated into the sugar coating layer. ^However , this method cannot process substances sensitive to moisture.

The aim of the invention was to eliminate the alleged disadvantages and shortcomings of the previous methods and to enable the production of composite preparations containing mutually incompatible components, especially polyvitamin and polyenzymatic preparations. Systematic study of this issue led to new findings that helped to solve the given task. For example, it was found that it is very advantageous to first create a core from granulate, which contains active (mutually compatible) and auxiliary substances, then apply an inert intermediate layer to the core using a fluid technique and then a suspension or solution of one or more active substances that are incompatible with the substances in the core, in a solution of a suitable cellulose derivative in a suitable organic solvent or mixture of solvents. After evaporation of the organic solvent, a layer is formed on the core that contains a homogeneously dispersed active substance or substances, the individual particles of which are perfectly protected from contact with the active substances contained in the core and therefore no mutual undesirable reactions can occur. To ensure immediate effect, it is necessary to choose a hydrophilic high-molecular substance; if it is a question of achieving controlled release, it is possible to choose a combination of hydrophilic and hydrophobic substances, or to use a substance whose dissolution is influenced by the pH value of the environment.

The subject of the invention is therefore a method for producing stable, solid, piecewise, oral dosage forms containing mutually incompatible active ingredients; the essence of this method lies in the fact that an indifferent lubricating layer is formed on cores containing at least two active mutually compatible substances, provided, if desired, with an acid-resistant layer, from a hydrophilic cellulose derivative, preferably hydroxypropylmethylcellulose, optionally in a mixture with a hydrophobic cellulose derivative, preferably ethylcellulose, on this mixture at least one layer containing one or more active substances incompatible with the active substances in the core is formed, followed by another indifferent intermediate layer or a final covering layer. The individual layers are expediently formed in a floating manner, i.e. by a fluid technique.

When implementing the method according to the invention, the best procedure is, for example, to dissolve the active substances to be applied to the core in a 2 to 10%, preferably 4% solution of the aforementioned cellulose derivatives, usually in a mixture of an alcohol with 1 to 3 carbon atoms, for example ethanol, with a chlorinated alkane with 1 to 2 carbon atoms, for example dichloromethane, in a volume ratio of 1:3 to ₍ 3:1), preferably in a mixture of ethanol and dichloromethane in a ratio of 1:1. This solution is applied to the cores either by spraying in a suspension, or by spraying and pouring in a coating pan. In the last phase, the finished cores are given a definitive treatment by coating or by coating with a final covering layer that protects the product against external influences.

The method according to the invention allows, using conventional technology, to produce solid piece oral dosage forms, which may contain several mutually incompatible substances, without jeopardizing their stability, and thus the stability of the entire preparation.

The following examples provide further details of the method according to the invention, which are intended to illustrate the method but are not intended to limit the materials, apparatus, procedure or conditions disclosed therein.

Example 1

Using the usual method for producing taMet (by pressing granulate), 56 kg of lenticular-shaped cores with a diameter of 10.5 mm are prepared. The individual cores have the following composition (in mg):

Choline bitartrate 170,- D, L-methionine 25,- inositol 50,- tocopherol acetate 5,- pyridoxine 1.5 thiamine 1.5

213 652 nicotinamide 5, cyanocobalamin 0.003 excipients (starch, lactose, gelatin, colloidal silicon dioxide) up to 350

The cores are then introduced into the working chamber of the fluid spraying device, where the following solutions or suspensions are gradually sprayed onto them:

1.

2.

hydroxypropylmethylcellulose 1,120 kg ethanol 13.5 liter dichloromethane 13.5 liter propylene glycol 0.120 kg hydroxypropylmethylcellulose 0.280 kg ethanol 12.5 liter dichloromethane 12.5 liter propylene glycol 0.028 kg riboflavin 0.244 kg colloidal silicic acid 0.244 kg

3rd solution same as sub 1.

Evaporation of the solvents gradually creates three separate layers. The resulting cores are coated and polished in the usual way in coating boilers. A polyvitamin preparation in the form of a dragee is created. In addition to the active ingredients in the core, individual dragees also contain 1.5 mg of rihořlavin in the outer layer, which is completely isolated and cannot cause instability of the other components due to its catalytic effect.

Example 2

The following solutions or suspensions are applied sequentially to the cores prepared according to Example 1 in a fluidized bed coating device:

1. solution 1, according to example 1, 2. solution 2. according to example 1, 3. hydroxypropylmethylcellulose 0.280 kg ethanol 6,- liters dichloromethane 6,- liters propylene glycol 0.028 kg pantothenic acid 0.490 kg 4. japanese wax solution 1. according to example 1. 0.049 kg

Evaporation of the solvents gradually creates 4 separate layers, the coated cores are then coated and polished in the usual way in coating kettles. A multivitamin preparation in the form of a dragee is obtained, which, in addition to the substances contained in the core, also contains 1.5 mg of riboflavin and 3 mg of

J/

213 B52 pantothenol. Both substances are isolated from each other and from each other, which guarantees stability

of the preparation, as can be seen from the table. thiamine content in wt.% contents pantothenol in % wt. commercial procedure according to commercial procedure according to preparation invention preparation invention default state 100% 100% 100% 100% 90 days 25°C 85% 92% 100% 100«« 90 days 38°C 67% 85% 87% 9» «

Example 3

By pressing the previously prepared granulate, 60 kg of cores with a diameter of 5.5 mm are prepared, with the following composition (in mg):

thiamine 2 pyridoxine 1 nicotinamide 20 excipients (starch, lactose, gelatin, colloidal silicon dioxide) up to 60

The cores are introduced into the working chamber of a fluidized bed tablet coating machine, where layers are gradually formed on them by applying the following solutions:

hydroxypropylmethylcellulose 1.5 kg ethanol 15,- liters dichloromethane 15,- liters propylene glycol 0.15 kg hydr oxypr opylme thylc elulo sa 2,- kg ethanol 25,- liters dichloromethane 25,- liters propylene glycol 0.2 kg riboflavin 2,- kg colloidal silicic acid 2,- kg pantothenic acid 3,- kg japanese wax 0.2 kg

3. solution same as sub. 1.

The resulting cores are then coated in the usual way in coating boilers. The result is a multivitamin preparation in the form of a dragee. In addition to the substances listed in the core, individual dragees contain 2 mg of riboflavin and 3 mg of pantothenic acid in the package. These substances are protected from contact with other components, which gives the preparation its stability.

Example 4

For 60 kg of kernels, of the same composition as in example 3 and produced by the same method,

213 8S2 individual layers are formed by applying solutions 1 to 3 by pouring or spraying onto rotating cores in a coating pan. A polyvitamin preparation in the form of a dragee is obtained as in example 3.

Example 5

As in example 3, ao produces 60 kg of cores of the same composition. On these cores, ee creates layers in a fluidized bed for tablet coating by successively applying the following solutions:

1. solution 1. according to example 3, 2. solution 2. according to example 3, 3. hydroxypropylmethylcellulose 1.5 kg ethanol 15,- liters dichloromethane 15,- liters pigment paint 0.15 kg propylene glycol 0.150 kg japanese wax 0.150 kg The last layer is the covering layer and the product is no longer bids. Get a multivitamin supplement ¹ prehistory in the form of coated tablets the same composition as in example 3* Here too, the stability is

This is due to the fact that riboflavin and pantothenic acid are completely separated from each other and from the other components.

Claims (2)

SCOPE OF YOURSELF j A process for the production of stable solid unit dosage forms, comprising: mutually incompatible active ingredients, characterized in that indifferent intermediate layers are formed on cores containing at least two active mutually compatible substances, provided, if desired, with an acid-corrosive layer. % of the hydrophilic cellulose derivative, preferably hydroxypropylmethylcellulose, optionally in admixture with the hydrophobic cellulose derivative, preferably ethylcellulose, at least one layer comprising one or more active ingredients incompatible with the 8 active ingredients in the core is formed on this interlayer followed by another indifferent interlayer or final layer. 2. Method according to claim 1, characterized in that the individual spindles are formed in a hover.