EA018867B1 - Method of producing pharmaceutical composition and product therefrom - Google Patents

Abstract

The invention relates to chemical-pharmaceutical industry, in particular to a method of producing a pharmaceutical composition as tablets for oral administration and to a product prepared according to the above method. According to the invention the method provides wet granulation to produce tablets with high content of an active ingredient with no adhesion during pressing operation providing improved hardness, low fragility and rapid disintegration.

Description

The technical field to which the invention relates.

The invention relates to the field of the pharmaceutical industry, and in particular to a method for producing a pharmaceutical composition, which is a solid dosage form for oral administration, and a product obtained in accordance with the specified method.

Information about the prior art.

Known pharmaceutical granular composition and method for its preparation (RF patent No. 2025121). The composition includes a water-soluble refractory crystalline drug substance (96.0-98.0 wt.%), A binder (0.5-2.0 wt.%), A lubricant (0.5-1.0 wt.%) And water ( 1.0-3.0 wt.%). A method of obtaining a pharmaceutical composition consists in pre-granulating the drug substance with its solution, subsequent granulation with a solution of the binder in water or in an organic solvent, drying the obtained granulate and dusting it with a lubricant. The method for producing this pharmaceutical composition does not provide tablets in the absence of adhesion during compression, providing improved hardness, low brittleness and quick disintegration time.

Known compositions for the preparation of tablets (US patent No. 3873713, 4016254), which include microcapsules consisting of crystals of a drug substance, coated with a shell of a polymeric material. From microcapsules mixed with excipients (excipients), tablets are pressed. Methods for preparing the compositions include applying film-forming membranes to the drug crystals, adding lubricating components, and then compressing the tablets. These decisions are not intended to provide improved fluidity or flowability of the powder and uniformity in weight, to prevent the tablets from sticking together during the compaction process, to ensure low tablet fragility and suitable hardness.

A method for producing a pharmaceutical composition for the manufacture of sustained-release tablets is described, including the preparation of microcapsules by coating a film-forming substance on non-agglomerated particles of a drug substance, adding a lubricant and a cultivator in the form of a finely dispersed fraction of the active principle (RF patent No. 2171673). Introduction to the composition of the ripper allows you to add porosity to the manufactured tablets, which helps to reduce the time of their disintegration. Changing the concentration of the cultivator and its implementation from the drug substance allows you to adjust the duration of the disintegration of the dosage form and helps to maintain a high content of the drug substance in the drug. Since the ripper is made from a substance that is the active principle of the tablet, the drug and the ripper have the same physical parameters, in particular solubility. Due to the same solubility, the tablet does not decompose into its constituent particles, and its gradual dissolution without increasing the dissolution surface. However, the described method is intended for the manufacture of sustained release tablets with disintegration in the range from 10 to 30 minutes for sublingual administration.

It is known to obtain tablet cores by the method of traditional wet granulation: mixing powders of the substance pentoxifylline and excipients, moisturizing, granulating, drying and grinding. The nuclei obtained by this method have a number of significant drawbacks, and, first of all, insufficient strength and porosity, which complicates the process of coating the nuclei with a shell. The method of wet granulation, as is known, is a laborious and lengthy process, which does not always make it possible to obtain granules that are homogeneous in terms of particle size distribution and, therefore, high-quality tablets. When granulating in a fluidized bed, the powder, and then the granulate formed, are continuously in motion, which makes it possible to obtain tablets with the best physicomechanical and pharmaceutical characteristics (Sadchikova N.P. et al. Pharmaceutical Chemistry Journal: 2003, No. 10, p. 27-30). However, the described method does not provide tablets, characterized by a high load of the active ingredient, rapid disintegration and storage stability.

Moreover, the selection of appropriate excipients for specific pharmaceutically active ingredients and the determination of the correct combination of active ingredients and excipients in the manufacturing process takes a lot of time and leads to a significant delay in the process of creating a pharmaceutical product.

SUMMARY OF THE INVENTION

A method for producing a pharmaceutical composition representing a solid dosage form (tablet) is provided, which provides tablets characterized by a high loading of the active ingredient, low brittleness, rapid disintegration and storage stability, moreover, the method achieves improved fluidity or flowability of the powder, uniformity in weight of the granules and sticking of tablets is prevented.

Another aspect of the invention relates to a pharmaceutical composition in the form of tablets for oral administration, obtained according to the proposed method, containing the active principle and excipients, including fillers, binders, surfactants, disintegrants, agglutinants, lubricating components.

The proposed method for producing a pharmaceutical composition in the form of tablets, presenting

- 1 018867 wet granulation, which includes the following stages: mixing the substances and grinding or grinding into fine powder, moistening the powder with a solution of binders, granulating and calibrating the granules, mixing the granules with sliding or lubricating substances and disintegrating agents or disintegrants, followed by pressing the resulting mass, characterized in that after mixing the granules with moving substances and cleaving agents, additionally grinding the mixed powder, followed by the addition of a sliding substance and grinding, the active substance, diluent and binder are granulated to ensure agglomeration of fine powder particles and to obtain granules containing 75 wt.% or less granules larger than 150 μm in size, and then the granulate is mixed with a disintegrant and a sliding substance for at least 5 minutes and no more than 10 minutes to obtain a homogeneous mixture, the sliding substance is added by mixing for at least 3 and not more than 5 minutes, ensuring its distribution on the porous surface granules.

The proposed method provides, in comparison with known technical solutions, improved flowability of the powder, uniformity in weight, low brittleness and suitable hardness of the tablets and prevents sticking of the tablets, which improves the production yield in each batch.

The product obtained in accordance with the claimed method is a solid dosage form (tablet) and contains, in a preferred embodiment, the following substances as fillers: lactose monohydrate, starch and povidone as a binder, colloidal silicon dioxide as a glidant, and croscarmellose sodium as disintegrant, magnesium stearate and microcrystalline cellulose as a binder.

List of figures

The present invention is illustrated by the following drawings, where in FIG. 1 shows the dissolution profile of a tablet according to the invention, presents average data obtained from the dissolution profile of twelve tablets; in FIG. 2A and 2B show the process occurring with mixed powder A in a high shear granulator.

Information confirming the possibility of carrying out the invention

The method according to the invention provides for wet granulation and provides tablets with a high load of the active ingredient without sticking during pressing, providing improved hardness, low brittleness and quick disintegration time.

The proposed method for producing a pharmaceutical composition in the form of a tablet, which is granulation in the wet state and comprising the following stages: mixing the substances and grinding into a fine powder, moistening the powder with a solution of binders, granulating and calibrating the granules, mixing the granules with glidants and disintegrating agents, followed by pressing the resulting mass, characterized in that after mixing the granules with moving substances and cleaving agents additional o carry out the grinding of the mixed powder, followed by the addition of a sliding substance and grinding, and the active substance, diluent and binder are granulated to ensure the agglomeration of fine powder particles and to obtain granules containing 75 wt.% or less granules in size greater than 150 microns, and then granulate is mixed with a disintegrant and a sliding substance for at least 5 minutes and no more than 10 minutes to obtain a homogeneous mixture, and the sliding is added by mixing for at least 3 and not more than 5 minutes, ensuring its distribution division on the porous surface of the granules.

In accordance with the proposed method, the production of granules from the powder is carried out by applying low compression, mixing granules and fine particles with the formation of a compact mass. These fine particles fill the spaces between the larger granules, thereby increasing the density of the granulation.

A tablet obtained in accordance with the claimed method has the following properties: contains a low percentage of water or hydrogen bonds or bridges, has a fast disintegration time, contains a small amount of a lubricant that is not evenly distributed over the tablet, and a high load of the active ingredient.

Excipients include lubricants or lubricants, agglutinating agents, diluents, disintegrating or disintegrating agents, binders. Lubricants or lubricants are used to improve ejection after pressing the mixture, thereby preventing the tablets from sticking to the pressing surfaces.

Binders are added to improve the fluidity of the powder, which helps to fill the mold during compression molding and achieve better uniformity in weight.

Diluents are mainly used to reduce the concentration of the active ingredient in the composition or to increase the final weight of the tablet.

Disintegrants or disintegrants play an important role in providing the desired disintegration or disintegration of the tablets in a liquid medium such as water or gastric juice, and the subsequent release of the active ingredient.

Agglutinating substances are designed to maintain the integrity of the tablets. They can

- 2 018867 able to bind all the ingredients present in the composition.

The raw materials used in the granulation process of the present invention typically include excipients and the active ingredient in the form of fine particles. The average particle size of the powder is about 100, 50 or 20 microns. The minimum size of the fine particles present in the powder is 2-20 microns, the maximum particle size is 75-150 microns.

The average particle size can be measured, for example, by using a series of grating filters. In the case of very fine powders, a microscope is used. The fluidity of such powders is usually insufficient for their use in compression molding.

Some small particles (for example, 3, 5, 10 or more) agglomerate to form granules of a maximum size of 50, 100 or 75 microns (hereinafter referred to as small granules). Granules with a size larger than the maximum designate as granules acceptable for use. The granules remaining after removal by a gas stream of small particles and small granules are called accepted granules.

The possibility of carrying out the invention is shown by the example of the manufacture of a tablet containing 5'-deoxy-5-fluoro-Y - [(pentyloxy) carbonyl] cytidine (capecitabine) as an active principle.

Capecitabine is a prodrug of 5'-deoxy-5-fluoruridine for oral administration, is prescribed for malignant neoplasms of the rectum and mammary gland.

In a preferred embodiment of the inventive method, capecitabine, monohydrate lactose, povidone, microcrystalline cellulose and croscarmellose sodium are mixed and ground in a mixer with a U-shaped body (ν-blender) for 5 minutes to obtain a mixed powder A. Then starch, water (15 wt.%) Are added. , mixed, granulated in a high shear granulator and calibrated. Crossscarmellose sodium and colloidal silicon dioxide are added, ground in an ν blender to obtain a mixed powder B. Then magnesium stearate is added, ground in an ν blender to obtain a mixed powder C. The process that takes place with mixed powder A in a high shear granulator is shown in FIG. 2A and 2B.

As the liquid content increases, the process taking place in the granulator can be divided into three stages of granule growth or enlargement. Analysis of samples taken from the granulator at different time intervals showed that in the first stage after wetting, primary granulation or the formation of nuclei of granules occurs. During this process, small particles or agglomerates are created, on the one hand, and enlargement (growth) of small particles occurs as a result of their agglomeration or layering of small particles to larger ones, on the other hand. At the second stage, the growth of granules occurs by randomly layering agglomerates of small particles on the surface of other granules, as well as compaction of the granules and the transport of a binder onto the surface of the granules. When the agglomerates of small particles are completely layered, at the third stage, mainly coalescence of small and large granules occurs.

The product obtained in accordance with the claimed method is a solid dosage form (tablet) and contains, in a preferred embodiment, the following substances as fillers: lactose monohydrate, starch, povidone as a binder, colloidal silicon dioxide as a sliding substance, crosscarmellose sodium as a disintegrant, magnesium stearate and microcrystalline cellulose as a binder, in ratios as follows.

Active ingredient / fillers % Capecitabine 80.9 Starch 2.0 Lactose Monohydrate 5.1 Povidone 3.0 Colloidal silicon dioxide 0.7 Crosscarmelose Sodium 4.5 Magnesium stearate 1.7 Microcrystalline cellulose 2.0

The tablets obtained in accordance with the claimed method are characterized by the fact that there are essentially no hydrogen bridges linking the solid particles in the granules used to make the tablets. Additionally, tablets are characterized by a high load of the active ingredient, content in small quantities of a lubricant, and storage stability.

High loading of the active ingredient means, for example, that a tablet may contain at least 40, 60 or 80% of the active ingredient relative to the total weight of the tablet.

A lubricant is present in less than 1.0, 0.5, 0.3, or 0.2% of the total tablet weight. It is well known that a lubricant, such as magnesium stearate, usually has an adverse effect on the time of disintegration and / or dissolution. When the granules are mixed with a lubricant, the latter tends to form a film surrounding the granules. Such a film can prevent the formation of appropriate bonds between the granules during

- 3 018867 compression pressing. The use of very small quantities of a granular lubricant in accordance with the present invention improves tablet plasticity and disintegration time. The soft and porous surface of the granules can prevent the formation of a film, since the granules interact with a large amount of lubricant and have fewer areas of connection with each other. Thus, the properties of the resulting tablets of the claimed method are improved.

Lubricants are mainly distributed on the porous surface of the granules in the manufacture of tablets. Thus, only small amounts of lubricants are found inside the core of the granule. For example, lubricants can be distributed such that more than 90, 80, or 70% of the lubricants remain on the surface of the cross section of the tablet, representing, respectively, less than 10, 20, or 30% of the total cross section of the tablet. The localization of lubricating particles on the cross-sectional surface of a tablet can, for example, be determined using a system including an electronic scanning microscope and additional equipment that allows specific identification of particles containing lubricants.

The fast disintegration time can be less than 600, 120, or 30 s when the tablet is placed in water at a temperature similar to body temperature (i.e., about 37 ° C). For a tablet containing not less than 5, 20 or 30 wt.% And not more than 95, 80 or 30 wt.% Of at least one pharmaceutically active ingredient, to ensure a low disintegration time, the content of the disintegrant is not less than 1, 3 or 5% and / or not more than 7, 10 or 20 wt.% disintegrant. In some embodiments of the invention, the percentage of disintegrant may be higher than 20%, for example, starch or carboxymethyl cellulose, or a combination thereof, can be used.

Stability during long-term storage may mean, for example, that the weight of the tablet increases with respect to its original weight by less than 2.0, 1.5 or 1.0% after storage for 4 months at 40 ° C and at a relative humidity of 75% .

The tablets may also contain not less than 1, 5 or 10% and not more than 60, 80 or 94% by weight of a diluent such as microcrystalline cellulose. The pharmaceutically active ingredient, disintegrant and diluent may be granulated together or separately.

The tablets are uniform in content, i.e. the standard deviation of the components by weight is lower than 3.0, 2.0 or 1.0% of the average.

The present invention is illustrated by the following examples.

Examples 1-3.

The compositions used in examples 1-3 are presented in table. one

Table 1

Examples No. 1 Number 2 No. 3 Components G G G Capecitabine 1626.51 1626.51 1626.51 Lactose Monohydrate 95.55 95.55 95.55 Povidone 40.18 40.18 40.18 Crosscarmelose Sodium 90.07 90.07 90.07 Starch 40.18 40.18 40.18 Colloidal silicon dioxide 14.90 14.90 14.90 Magnesium stearate 34,99 34,99 34,99

During the granulation process in all three examples, a powder mass of approximately 2.0 kg and containing 80% capecitabine was mixed, granulated and dried. During processing, the samples were tested for various types of granules obtained by changing the time of movement of the mixer. The results are presented in table. 2.

table 2

Examples No. 1 ΝΊ No. 3 Impeller Movement Time 30 min. 60 min 90 min % retention Filter (sifter) No. 40 48 63 75 % retention Filter (sifter) N ° 100 one one 3 % retention 51 36 22

The aim was to obtain granules from a powder with an optimal distribution size, good fluidity and good compressibility.

During pressing, each mixture was exposed to 3 different compression forces, the results are presented in table. 3.

- 4 018867

Table 3

Examples Number 1 Number 2 No. 3 Compression force kg / cm ² The core porosity of the tablet m ² / g The core porosity of the tablet m ² / g The core porosity of the tablet m ² / g 450 4.23 4.34 4.88 1000 4.27 4.95 4.92 2000 4.25 4.25 4.78

The porosity results indicate that with an increase in the compression force from 450 to 1000 kg / cm ^{2 the} core porosity increases, while with an increase in the compression force from 1000 to 2000 kg / cm ^{2 the} core porosity decreases. The preferred level of porosity is determined on the basis of disintegration data (Table 4) and friability or brittleness (Table 5).

Table 4

Examples Number 1 Number 2 No. 3 Compression force % % % kg / cm2 disintegration (10 min) disintegration (10 min) disintegration (10 min) 450 twenty thirty 40 1000 25 45 42 2000 fifteen twenty 43

Table 5

Examples No. 1 Number 2 No. 3 Compression Strength kg / cm2 % flowability % flowability % flowability 450 0.8 0.7 0.9 1000 0.5 0.1 0.6 2000 0.9 1.3 1,2

If the compressive forces are too weak (450 kg / cm ² ), the particles agglomerate and the disintegration of the tablet is low. On the other hand, when the compressive forces are too high (2000 kg / cm ² ), the particles bind together irreversibly, requiring more energy to separate.

In a most preferred embodiment, the tablet mixture of Example 2 and a compression force of 1000 kg / cm ^{2 are used} .

In one of the embodiments of the proposed method using a four-shaft granulator, where two rotating shafts (rollers) are located on each side of the apparatus axis, the compression force between the first pair of shafts is preferably from 100 to 1000 kg / cm ² , which ensures the removal of air present in mixtures, and an increase in the contact surface between particles. The compression force between the second pair of main shafts is preferably from 600 to 1000 kg / cm ² , which ensures the compaction of the powder and the formation of bonds between the particles.

Claims (8)

1. A method of obtaining a pharmaceutical composition representing a solid dosage form, comprising mixing the substances and grinding into a fine powder, moistening the powder with a solution of binders, granulating and calibrating the granules, drying, mixing the granules with sliding substances and disintegrating agents, followed by pressing the resulting mass, characterized in that after mixing the granules with moving substances and cleaving agents, grinding of the mixed powder with the last by adding the sliding substance and grinding, and the active substance, diluent and binder are granulated to ensure agglomeration of fine powder particles and to obtain granules containing 75 wt.% or less granules larger than 150 μm in size, and then the granulate is mixed with a disintegrant and a sliding substance less than 5 minutes and not more than 10 minutes to obtain a homogeneous mixture, and the sliding substance is added by mixing for at least 3 minutes and no more than 5 minutes, ensuring its distribution on the porous surface of the granules. 2. The method according to claim 1, characterized in that during the drying process, the moisture content of the granulate is not less than 1 and not more than 2%. 3. The method according to claim 1, characterized in that the compression force when pressing the tablet mixture with the formation of a compact porous body is from 100 to 1000 kg / cm ² . 4. The method according to claim 3, characterized in that the compression force during compression of the compact body is from 600 to 1000 kg / cm ² . 5. The product obtained in accordance with the method according to claim 1, representing a tablet containing - 5 018867 with an active substance content of up to 80%, a lubricant content of less than 1% and a disintegration time of less than 600 s. 6. The product according to claim 5, characterized in that it has a hardness of from 8 to 11 kgf. 7. The product according to claim 5, characterized in that it has a flowability of not more than 1 wt.%. 8. The product according to claim 5, characterized in that it has a disintegration rate of 600, 120 or 30 s in water at a temperature of about 37 ° C.