RS52580B - TWO-TABLETS OF CARBAMAZEPINE CONTROLLED RELEASE - Google Patents

Abstract

Pharmaceutical formulation of two-layer tablets, containing as active ingredient carbamazepine, in a concentration of 50-75%, which in equal amounts is included in the composition of the first and second layers, matrix agents, in the first layer low-viscosity cellulose HPMC K 100LV at a concentration of 2-10%, in the second layer high viscosity cellulose HPMC K 4M at a concentration of 15-25%, one or more binders, which are part of the first and second layer, at a concentration of 2-10% and are selected of polyvinylpyrrolidone, a derivative of cellulose, gelatin, tragacanth, starch paste, polyethylene glycol and alginate, a top-up and second layer supplement selected from lactose at a concentration of 10-20% and corn starch at a concentration of 3-8 %, the intragranular disintegrants are included in the composition of the first and second layers, selected from, sodium starch glycolate at a concentration of 2- 5%, microcrystalline cellulose at a concentration of 2-7%, starch into a concentrate 3-7%, glidant, colloidal silicon dioxide, at a concentration of 0.1-1%, or lubricants, which are part of the first and second layers, are added extragranularly, at a concentration of 0.1-2% , selected from stearic acid, magnesium stearate, paraffin, talc, oil, waxes, polyethylene glycol or silicone.The application contains 4 more patent claims.

Description

1.Technical field

The invention belongs to the field of pharmaceutical technology, more specifically to the field of manufacturing a pharmaceutical preparation in the form of tablets for human medicine. According to the International Classification of Patents, the invention belongs to class A 61 K.

2. Technical problem

This invention protects a new pharmaceutical form, bilayer tablets, with carbamazepine as an active component. The specificity of the formulation is in the malrix system, which consists of cellulose derivatives of different viscosity and other auxiliary substances that ensure the controlled release of carbamazepine during 8 hours, while maintaining a certain level of the active substance in the plasma.

During the first hour, about 50% of the active substance is released, and the rest is released gradually over the next 7 hours, which was confirmed by a clinical study. This release profile was achieved by applying a modern procedure for the production of two-layer tablets, where one layer contains cellulose derivatives of low viscosity, and the other carefully selected cellulose derivatives of high viscosity.

3. State of the art

Preparations with carbamazepine, an anticonvulsant with a psychotropic effect, are particularly effective in controlling focal and tonic-clonic generalized seizures. The mechanism of its action has not been fully elucidated. It has an analgesic effect in trigeminal and glossopharyngeal neuralgia.

US patent 6,572,889 describes a solid dosage form containing carbamazepine as an active substance, rheologically modified copolymers based on acrylic or maleic acid, a cross-linking agent (sucrose allyl ether or pentaerythritol, polyalcohols, divinyl glycol, diallyl phthalate, divinyl benzene, allyl methacylate, ethylene glycol dimethyl acrylate, diallyl fumarate, diallyl maleate, castor oil, polyols or their combinations), surfactant (sodium lauryl sulfate, potassium or magnesium n-dodecyl sulfate) and other auxiliary substances (microcrystalline cellulose, dicalcium phosphate, lactose monohydrate, tricalcium phosphate, lactose, sucrose, sorbitol, mannitol, magnesium starch, cellulose derivatives or stearate). Capsules and tablets made by direct compression or wet granulation methods are suggested as a dosage form.

In the PCT application with publication number WO 03/075830, tablets with controlled release of carbamazepine are described, which contain a hydrophobic polymer (cellulose derivatives such as ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate or their mixtures), a hydrophilic polymer from the group of vinyl pyrrolidone and auxiliary substances.

In patent US 6,162,466, tablets with a delayed release of carbamazepine are described, the particles of which are coated with a hydrophilic coating, the composition of which includes methacrylic polymers Eudragit RS, RL aqueous dispersion Eudragit RS30D, RL30D or their mixtures and at least one auxiliary substance (starch, pregelatinized starch, croscarmellose sodium and sodium starch glycolate). The carbamazepine particles are coated with a polymer dispersion to form coated granules which are mixed with a disintegrant, bulking agent and lubricant and compressed into tablets.

According to the invention in the patent GB 2,193,632 of the company Ciba-Geigy, a therapeutic system for the controlled release of carbamazepine contains a core coated with a semipenneable coating. The core consists of fine particles of carbamazepine. a protective colloid that prevents crystal growth in the presence of water, a swelling hydrophilic polymer (vinylpyrrolidone, vinylacetate and ethylene oxide homopolymer) and a water-soluble component (sodium or potassium chloride, glucose or mannitol) that induces the process of osmosis through the barrier.

Ketzendler et al. in US patent 5,980,942 disclose an erodible matrix tablet with extended release of carbamazepine containing the active substance, hydrophilic polymers from the group of cellulose derivatives with viscosities between 5 and 100,000 cps and a hydrophobic component. The formulation also includes additives from the group of proteins, polysaccharides, hydrophilic derivatives of polyacrylamide and methacrylic acid. After per os application of the mentioned system, and in contact with digestive fluids, the formulation erodes, releasing carbamazepine with zero-order kinetics.

The erodible dosage form of carbamazepine containing at least one biocompatible hydrophilic polymer from the group of polyalkyl oxides, cellulose polymers, polymers of acrylic and methacrylic acid and their mixtures is described in patent application US 20030091630. Particles of the medicinal substance are coated with an enterosolvent coating containing a hydrophilic polymer, and the resulting granules are compressed into tablets or filled into capsules.

Park et al. in patent application US 20030180362 describe a system with controlled and targeted release of carbamazepine that consists of an inner matrix coated with a film coating or layer that provides a modified release of the active principle and is applied once or twice a day. Granules, 0.1 - 1 mm in size, consist of an active substance and a carrier. Depending on the solubility of the medicinal substance, carriers can be hydrophobic substances such as fatty acids and their esters, alcohols, glycerides, waxes if the solubility of the medicinal substance is greater than 1 mg/ml or hydrophilic substances such as polyalkylglycol, carboxyvinyl hydrophilic polymer or their mixtures if the solubility is less than 1 mg/ml. The inner matrix is surrounded by a kidney-erodible polymer (hydrophobic polymers-ethylcellulose, shellac, copolymers of methacrylic acid, hydrophilic polymers-hydroxyalkylcellulose and hydroxypropylalkylcellulose, pH-dependent polymers-hydroxyalkylcellulose phthalate, hydroxyalkylmethylcellulose phthalate, cellulose acetyl phthalate, anionic copolymers of methacrylic acid). The layer providing the modified release can be composed of a hydrophobic, hydrophilic, pH-dependent polymer or a mixture thereof. The release proceeds according to zero-order kinetics.

In patent application US 20030180357, sublingual tablets are given which consist of an active substance, including carbamazepine, fillers (lactose and/or starch), binders, disintegrants, wetting agents and others that are most commonly used. Different types of rubber are used to coat and achieve controlled release.

The innovation described in patent application US 20030050620 includes granules, pellets or tablets as systems with controlled release of various medicinal substances. Carbamazepine is mentioned among the numerous active substances. The membrane through which the transport is carried out and which controls the release may be of cellulose esters. ether, polyethylene oxide, dextran, gelatin, hydroxypropylmethyl cellulose. The release can take place according to zero, first or pseudo-first order kinetics.

A formulation with controlled release of carbamazepine for one-day use is described in patent application US 20030175341. Controlled release is achieved by the use of cellulose-based polymers (HPMC, HEC, NaCMC or their mixtures). They are listed as a dosage form

tablets made by wet granulation or capsules.

4. Essence of the invention

This invention protects a new pharmaceutical form, bilayer tablets, with carbamazepine as an active component. The specificity of the formulation is in the matrix system, which consists of cellulose derivatives of different viscosity and other auxiliary substances that ensure the controlled release of carbamazepine during 8 hours, which has the effect of maintaining a certain level of the active substance in the plasma.

During the first hour, about 50% of the active substance is released, and the rest is released gradually over the next 7 hours (Table 1), which was confirmed by a clinical study. This release profile was achieved by applying a modern procedure for the production of two-layer tablets, where one layer contains low-viscosity cellulose derivatives, and the other carefully selected high-viscosity cellulose derivatives.

The physico-chemical properties of the active substance have a significant influence on the release rate of the active substance from a certain dosage form. There is a direct relationship between the surface area of the particle in contact with the dissolution medium and the dissolution rate. As the surface area increases with decreasing particle size, faster dissolution can be expected when the particles are smaller, especially when dealing with poorly soluble medicinal substances. According to our solution, the particle size for the production of two-layer tablets is up to 200 μm with a representation of 95%. The content of carbamazepine in the formulation is 50-75%, and equal amounts are included in the composition of the first and second layers.

Many stages in the tablet manufacturing process can affect the release and dissolution rate of the active substance. Granulation procedure, granulate moisture, compression force applied during tableting. they can change the properties of the final product. Pharmaceutical-technological properties of tablets such as firmness and disintegration time, among others, will depend on the behavior of the material during tableting at the above-mentioned stages. Research has shown that the wet granulation process can have a positive effect on the dissolution rate of a difficult-to-dissolve active substance in terms of its potentiation, and that is why it was chosen for the production of tablets. Purified water was used as a solvent, the application of which not only makes the product cheaper, but is also the most environmentally friendly. As part of the wet granulation procedure, the mixed powder substances are pre-granulated with the addition of binding agents. Granulate drying is carried out in a fluid dryer.

As part of our technical solution, two-layer tablets were developed in which carbamazepine is part of both the first and second layers.

Most substances in the form of powder do not have a sufficiently good flowability or compressibility necessary to obtain a high-quality dosage form without prior processing, i.e. granulation. By adding some liquid for granulation or a solution of binding material (adhesive, sticky) to the powder mixture and turning it into granulate, the mentioned difficulties are eliminated.

One or more binders can be used in the formulation in concentrations of 2 - 10%, and it is part of both the first and second layers. Examples of binders suitable for use in the formulation according to the invention include polyvinylpyrrolidone, gelatin, tragacanth, glucose syrup, starch, cellulose derivatives, polyethylene glycols with a molecular weight of 1000-5000.

When formulating two-layered tablets, special attention was paid to the mechanical connection of the two layers in order to reduce the possibility of their separation during the intended period of validity of the preparation. Within our invention, the problem is solved by compressing the first layer at the minimum value of the compression force. In this way, when compressing the second layer, and by applying a higher compression pressure, stronger mechanical forces are established between the layers, which reduces the tendency of their subsequent separation.

Fillers should improve the flow and binding properties of the powder mixture. Lactose is mostly used for these purposes today. As part of our technological solution, lactose enters the composition of the first layer in a concentration of 10 - 20%. In order to prevent the tendency of tablets to harden during standing, which has a negative effect on disintegration, lactose is combined with corn starch in a concentration of 3 - 8%.

The purpose of the disintegrant is to allow the active substance to be released from the skin after application

tablets, which is a prerequisite for resorption or local action. It must resist the action of the binding agent used in the tablet and the physical forces of compression that were required to form the tablet. There are two basic methods of adding a disintegrant to a granulate: extragranular and intragranular. The intragranular addition, which was applied in our case, should enable the disintegration of the granules into fine, small powder particles. The molecular structure of the disintegrant also affects the disintegration process of the tablet. The representative of the super agent for disintegration is sodium starch glycolate, which is obtained by cross-linking and carboxylation of compressed starch, and enters the composition of the first layer in a concentration of 2 - 5% and, thanks to the pronounced capillary effect and swelling, enhances the disintegration of tablets even more. At the same time, microcrystalline cellulose is applied, in a concentration of 2 - 7%, which can rapidly absorb water thanks to capillary action. Its synergistic effect with corn starch was used in the first layer where it was applied in a concentration of 2 - 7%, and starch in a concentration of 3 - 7%.

Matrix tablets are compressed dosage forms composed of active substance, matrix agent and other auxiliary substances. By using water-soluble celluloses as polymers that control the release of the active principle, they are relatively easy to formulate. In order to achieve a controlled release, it is necessary to wet the polymer, its hydration and dissolution. Penetrating into the tablet, water causes the formation of a thick gel layer. The mechanism of release of soluble active substances is diffusion through the gel layer, and in the case of poorly soluble substances. first, there is erosion of the tablet surface, and then diffusion of the active principle. There are certain differences in the degree of hydration of different polymers, which should be taken into account when formulating tablets. K type hydroxypropylmethyl cellulose (HPMC) is recommended due to very fast hydration, and the particle size is such that it ensures adequate mass flow during the tableting process. The use of celluloses with higher molecular weights slows down the release of the active substance, because a viscous gel is formed that dissolves more slowly and through which diffusion takes place more slowly. In order to achieve a modified release in our technological solution, we combined HPMC of different viscosity. The composition of the first layer contains HPMC of low viscosity in a concentration of 2 - 10%, so the release of the active substance from this layer is fast. The composition of the second layer includes HPMC of high viscosity, in a concentration of 15 - 25%. It provides sustained release of carbamazepine. Expected release profile: after 2 hours: 50-70%, after 4 hours: 65-85%, after 6 hours: 75-95%, after 8 hours: at least 85%.

In order to ensure the flowability of granules or powders, colloidal silicon dioxide (0.1-1.0%), or lubricants such as magnesium stearate, stearic acid, paraffin, talc, vegetable and animal fats, oils and waxes, PEG molecular weight 1000-5000 or silicones in a concentration of 0.1-2.0% can be used.

The use of the mentioned auxiliary substances ensures the desired mechanical characteristics, a short disintegration time, i.e. controlled release of the active substance from the tablet, as well as the stability of the preparation within the expected shelf life.

By using contact packaging, a blister made of PVC/PVDC foil intended for moisture-sensitive products, the influence of ambient moisture on the degradation of carbamazepine and possible mechanical delamination of the tablet is significantly reduced, thus achieving a longer shelf life of the product compared to a hard PVC blister.

The invention will further be illustrated by way of examples, without intending to be limited thereto.

EXAMPLE 1.

First layer

Granulate:

Second layer

Granulate:

Making bilayer tablets

I Preparing the first layer

Polyvinylpyrrolidone (10.00g) is dissolved in purified water (40.00g) so that a clear solution is obtained. The following powdery substances are mixed: carbamazepine (200.00g), lactose (42.50g), microcrystalline cellulose (1 l.00g), HPMC K 100LV (10.00g), sodium starch glycolate (8.00g) and corn starch (15.00g), and then the homogeneous mixture of powders is moistened with a previously prepared granulation solution. The agglomerated mass is dried in a fluidization dryer, in the temperature range from 20°C to 70°C, until a maximum 2% loss of granulate is achieved. The dried granulate is sifted on an oscillatory granulator. The following are added to the sieved dry granulate: talc (1.70g) and magnesium stearate (0.80g), and then the homogeneous mixture of powders is used to compress the first layer of the tablet, on a rotary machine for

tableting.

II Preparing the second layer

Polyvinylpyrrolidone (10.00g) is dissolved in purified water (40.00g) so that a clear solution is obtained. The following powdered substances are mixed: carbamazepine (200.OOg), microcrystalline cellulose (10.00g), HPMC K 4M (57.50g) and corn starch (5.00g), and then the homogeneous mixture of powders is wetted with a previously prepared granulation solution. The agglomerated mass is dried in a fluidization dryer, in the temperature range from 20°C to 70°C, until a maximum 2% drying loss of the granulate is achieved. The dried granulate is sifted on an oscillatory granulator. The following are added to the sifted dry granulate: talc (1.70g) and magnesium stearate (0.80g). The resulting mixture is used to make the second layer. Tablets are compressed on a machine for making two-layer tablets, by successively compressing the first and then the second layer. Tablets have the following characteristics:

The tablets are packed in blisters made of ALU/PVC and PVC/PVDC strips.

EXAMPLE 2.

First layer

Granulate:

Other auxiliary substances are added extragranularly:

Second layer

Granulate:

Other auxiliary substances are added extragranularly:

Making bilayer tablets

I Preparing the first layer

Polyvinylpyrrolidone (10.00g) is dissolved in purified water (40.00g) so that a clear solution is obtained. The following powdery substances are mixed: carbamazepine (200.00g), lactose (40.00g), microcrystalline cellulose (13.50g), HPMC K 100LV (10.00g), sodium starch glycolate (10.00g) and corn starch (13.00g), and then the homogeneous mixture of powders is moistened with a previously prepared granulation solution. The agglomerated mass is dried in a fluidization dryer, in the temperature range from 20°C to 70°C, until a maximum 2% loss of granulate is achieved. The dried granulate is sifted on an oscillatory granulator. Magnesium stearate (2.50g) is added to the sieved dry granulate, and then the homogeneous mixture of powders is used to compress the first layer of the tablet, on a rotary machine for

tableting.

II Preparing the second layer

Polyvinylpyrrolidone (7.00g) is dissolved in purified water (30.00g) so that a clear solution is obtained. The following powdered substances are mixed: carbamazepine (200.OOg), microcrystalline cellulose (12.00g), HPMC K 4M (55.50g) and corn starch (8.00g), and then the homogeneous mixture of powders is wetted with a previously prepared granulation solution. The agglomerated mass is dried in a fluidization dryer, in the temperature range from 20°C to 70°C, until a maximum 2% loss of granulate is achieved. The dried granulate is sifted on an oscillatory granulator. Magnesium stearate (2.50g) is added to the sifted dry granulate. The resulting mixture is used to make the second layer. Tablets are compressed on a machine for making two-layer tablets, by successively compressing the first and then the second layer. Tablets have the following characteristics:

Claims (4)

1. Pharmaceutical formulation of two-layer tablets, indicated by the fact that it contains as an active substance carbamazepine, in a concentration of 50-75%, which in equal quantities enters into the composition of both the first and second layers, the matrix agent, namely in the first layer low-viscosity cellulose HPMC K 100LV in a concentration of 2-10%, in the second layer high-viscosity cellulose HPMC K 4M in a concentration of 15-25%, one or more binders, which are included in the composition of the first and second layers, in a concentration of 2-10% and are selected from polyvinylpyrrolidone, cellulose derivatives, gelatin, tragacanth, starch paste, polyethylene glycol and alginate, filling agents, which are included in the composition of the first and second layers, selected from lactose in a concentration of 10-20% and corn starch in a concentration of 3-8%. disintegrants, which are added intragranularly, enter the composition of the first and second layers, selected from sodium starch glycolate in a concentration of 2-5%, microcrystalline cellulose in a concentration of 2-7%. starch in a concentration of 3-7%, a sliding agent, colloidal silicon dioxide, in a concentration of 0.1-1%, or lubricants, which are included in the composition of the first and second layers, are added extragranularly, in a concentration of 0.1-2%. selected from stearic acid, magnesium stearate. paraffin, talc, oil, waxes, polyethylene glycol or silicone. 2. Pharmaceutical formulation according to claim 1, characterized in that it contains carbamazepine particles up to 200 μm, with a representation of at least 95%. 3. Pharmaceutical formulation of two-layer tablets according to claim 1, characterized by the fact that the first layer contains carbamazepine in the amount of 200.00 mg, HPMC K 100LV 10.00 mg, lactose 42.50 mg, microcrystalline cellulose 11.00 mg, sodium starch glycolate 8.00 mg, corn starch 15.00 mg, polyvinylpyrrolidone 10.00 mg, and extragranularly added auxiliary substances, talc 1.70mg and magnesium stearate 0.80mg, and the second layer contains carbamazepine in the amount of 200.00mg, HPMC K 4M 57.50mg, microcrystalline cellulose 10.00mg, corn starch 5.00mg, polyvinylpyrrolidone 10.00mg and extragranularly added auxiliary substances, talc 1.70mg and magnesium stearate 0.80 mg. 4. The procedure for making a pharmaceutical formulation of two-layer tablets according to claims 1-3, indicated by the fact that the tablets are compressed on a machine for making two-layer tablets, by successively compressing the first and then the second layer, which are obtained by the process of wet granulation, in which purified water is used as a solvent to dissolve binders, and with that solution agglomerate: a. in the first layer, a powdery mixture composed of carbamazepine, low-viscosity cellulose HPMC K 100LV, fillers, and disintegrants, the agglomerate is dried in a fluid dryer at a temperature of 20°C to 70°C, to a drying loss of no more than 2%, sieved on an oscillatory granulator, and then lubricants are added and compressed into the first layer of biconvex tablets of minimum solid lkN, b. in the second layer, a powdery mixture composed of carbamazepine, high-viscosity cellulose HPMC K 4M, fillers, and disintegrants, the agglomerate is dried in a fluid dryer at a temperature of 20°C to 70°C, to a maximum drying loss of 2%, sieved on an oscillatory granulator, and then lubricants are added and compressed into the second layer, which is applied to the first layer of a biconvex two-layer tablet of minimum hardness 30 kN. S. Pharmaceutical formulation according to claims 1-3, characterized in that it is packed in a blister pack, composed of ALU/PVC and PVC/PVDC tape.