A solid pharmaceutical composition comprising dolutegravir

Abstract

The present invention relates to a pharmaceutical composition comprising dolutegravir or a pharmaceutically acceptable salt thereof and mannitol as a diluent wherein dolutegravir or pharmaceutically acceptable salt thereof is used in the specific d90 values to obtain an improved stability improved powder flowability and tablet compression.

Description

[0001]DESCRIPTION A SOLID PHARMACEUTICAL COMPOSITION COMPRISING DOLUTEGRAVIR Field of Invention The present invention relates to a pharmaceutical composition comprising dolutegravir or a pharmaceutically acceptable salt thereof and mannitol as a diluent wherein dolutegravir or pharmaceutically acceptable salt thereof is used in the specific d90 values to obtain an improved stability improved powder flowability and tablet compression. Background of the Invention Human immunodeficiency virus (HIV) is an infection that causes illness on the body’s immune system, specifically the white blood cells called CD4 cells. These CD4 cells are destroyed by HIV, and the immune system is weakened against opportunistic infections, such as tuberculosis and fungal infections, severe bacterial infections and some cancers. Dolutegravir is an orally bioavailable integrase strand-transfer inhibitor (INSTI) and take effect therapeutically against human immunodeficiency virus type 1 (HIV-1) infection. Through oral use, dolutegravir binds to the active site of integrase, an HIV enzyme that catalyzes the transfer of viral genetic material into human chromosomes. This avoids integrase from binding to retroviral deoxyribonucleic acid (DNA), and blocks the strand transfer step, which is required for the HIV replication cycle. This prevents HIV-1 replication. Dolutegravir is approved for use in the majority of HIV-infected patients. It can be used to treat HIV-infected adults who have been never cured with HIV therapy (treatment-naive) and HIV- infected adults who have been previously cured with HIV therapy (treatment-experienced), including those who have been cured with other integrase strand transfer inhibitors. Dolutegravir and its preparation method was described in EP1874117. Dolutegravir has a chemical name as (4R,12aS) - N - (2,4-difluorobenzyl) - 7 – hydroxy – 4 -methyl-6, 8 - dioxo - 3,4,6,8,12,12a – hexahydro - 2H-pyrido [1',2':4,5] pyrazino [2,1-b] [1,3] oxazine - 9 - carboxamide and its chemical structure is shown below. Dolutegravir has molecular weight of 419.4 g / mol. Dolutegravir Different forms have been observed for Dolutegravir. As reference for Dolutegravir sodium, crystalline form is described in EP3177629 and amorphous form is described in EP2742051. Furthermore, detailed description about various forms of Dolutegravir can be achieved also in EP3337479 patent application. As stated in EP1874117, the present compound can be administered orally or parenterally. In the case of oral use, Dolutegravir or pharmaceutically acceptable salt thereof can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like; an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In the case of parenteral use, Dolutegravir or pharmaceutically acceptable salt thereof can be used as an aqueous or oily suspension injectable, or a nasal drop. Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like may be preferentially used. As an anti-HIV drug, particularly, an oral agent is preferable. A preparation of EP1874117 is prepared by combining (e.g. mixing) a therapeutically effective amount of Dolutegravir or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent. EP1874117 has also stated that a dose of the present invention is different depending on an administration method, an age, a weight and condition of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05mg to 3000mg, preferably about 0.1 mg to 1000 mg may be administered per adult a day, if necessary, by dividing the dose. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05mg to 500mg is administered per adult a day. The brand name of Dolutegravir is Tivicay, which is an anti-retroviral medication used together with other medication, to treat HIV / AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is for oral use. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naive or treatment-experienced but have not previously taken other integrase strand transfer inhibitors. It is indicated in the European Union, in combination with other anti-retroviral medicinal preparations, for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children above six years of age. The indication for dolutegravir in the US was updated in June 2020, to include children at least four weeks old and weighing at least 3 kg. In view of the foregoing, there is a need to improve powder flowability and tablet compression in compositions comprising dolutegravir or a pharmaceutically acceptable salt thereof in the state of the art and to produce tablets of a specifically desired quality and specifications. The present invention provides a solution to these problems by providing novel compositions containing dolutegravir or a pharmaceutically acceptable salt thereof. These solutions will be described in detail. Brief Description of The Figures Figure 1: Graph of dissolution profiles of dolutegravir comparison between dolutegravir with d (90) = 6 µm and dolutegravir with d (90) = 60 µm. Summary of the Invention The present invention provides a wet granulation process for solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof is between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol is between 10 µm and 50 µm. More preferably particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof can be 5 µm ≤ d (90) ≤ 25 µm. More preferably the average particle size of the mannitol can be between 20 µm and 30 µm, even more preferably can be 25 µm. A process for preparing solid pharmaceutical composition of the present invention, said process comprises the steps below: a. Adding dolutegravir or its pharmaceutically acceptable salt thereof mannitol, second diluent, a disintegrant as a component of intra-granular phase, a binder and a diluent to the granulator chamber, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a solvent thereby forming the intra- granular phase, d. Drying the granules obtained in step c, e. Sieving the granules obtained in step d, f. Adding the remaining amount of a disintegrant as a component of extra-granular phase and adding a lubricant, g. Mixing a disintegrant and a lubricant with the granules obtained in step e, h. Sieving sodium stearyl fumarate as a component of extra-granular phase, and i. Tablet compression and film coating of the tablet. The solid pharmaceutical composition for oral administration can be a tablet, a film coated tablet or a capsule. The solid pharmaceutical composition for oral administration can be a film coated tablet. A solid pharmaceutical composition obtainable by the process according to any of preceding claims. A solid pharmaceutical composition of the present invention for use in the treatment of Human Immunodeficiency Virus (HIV) infections. Detailed Description of the Invention The aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the dolutegravir or a pharmaceutically acceptable salt thereof as defined hereinbefore and hereinafter. As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected. Suitable diluents according to the present invention are selected from the group including, but are not limited to, lactose, microcrystalline cellulose, starches, calcium phosphates, sucrose, maltodextrin, mannitol, sorbitol, and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred diluents are mannitol, microcrystalline cellulose or mixture thereof. Mannitol can be selected as a first diluent. Microcrystalline cellulose can be selected as second diluent. In other embodiment mannitol in present invention, for example mannitol 25 C (average particle size 25 µm), mannitol 200 SD (average particle size 150 µm), Mannitol 160 C (average particle size 160 µm) and mannitol nonpareil 108 (average particle size 200 µm) can be exemplified. Mannitol 25 C can be preferred mannitol type. The present invention relates to a process for pharmaceutical composition comprising Dolutegravir or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein the excipients are selected from the group including, but are not limited to solvents, diluents, lubricants, fillers, disintegrants, binders, surfactants, and other materials known to one of ordinary skill in the art and the mixtures thereof. The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, in The D90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. One can determine the average particle size of a solid from a knowledge of its surface area per unit weight and its density. The present invention provides a wet granulation process for solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof is between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol is between 10 µm and 50 µm. The inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol is between 10 µm and 50 µm, improves powder blend uniformity and tablet compressibility. More preferably particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is 5 µm ≤ d (90) ≤ 25 µm. Preferably the average particle size of the mannitol be between 20 µm and 30 µm, even more preferably the average particle size of mannitol can be 20 µm, 21 µm, 22 µm, 23 µm, 24 µm or 25 µm, 26 µm, 27 µm, 28 µm, 29 µm or 30 µm. The particle size of dolutegravir or a pharmaceutically acceptable salt thereof can be 2 µm ≤ d (90) ≤ 35 µm. More specifically it can be 5 µm ≤ d (90) ≤ 25 µm. Even more specifically, the particle size herein may be 5 µm, 6 µm, 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm or 25 µm. In other embodiment solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof can be between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol can be between 20 µm and 30 µm. The inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol is between 20 µm and 30 µm, improves powder blend uniformity and tablet compressibility. In other embodiment solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof can be between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol can be 25 µm. The inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 2 µm ≤ d (90) ≤ 35 µm and wherein the average particle size of the mannitol is between 25 µm, improves powder blend uniformity and tablet compressibility. In further embodiment solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof can be between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol can be between 10 µm and 50 µm In other embodiment the inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol is between 10 µm and 50 µm, improves powder blend uniformity and tablet compressibility. In further embodiment solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof can be between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol can be between 20 µm and 30 µm. The inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol is between 20 µm and 30 µm, improves powder blend uniformity and tablet compressibility. In other embodiment solid pharmaceutical composition comprising dolutegravir or pharmaceutically acceptable salt thereof and mannitol as a diluent wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof can be between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol can be 25 µm In further embodiment the inventors have found that present invention compositions the particle size distribution of dolutegravir or a pharmaceutically acceptable salt thereof is between 5 µm ≤ d (90) ≤ 25 µm and wherein the average particle size of the mannitol is between 25 µm, improves powder blend uniformity, tablet compressibility and produces tablets with the desired properties. Lubricants can also be used in the process. Lubricants are used for preventing adhesion of the tablet material to the surfaces of the die and punches. This helps to reduce the wear and tear on the tableting equipment and to prevent the formation of tablet defects, such as cracks or chips. Suitable lubricants according to the present invention are selected from a group including, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred lubricant is sodium stearyl fumarate. Disintegrants can also be used in the process. Disintegrants are used for disintegrating tablets into fine particles in gastric and intestinal fluid, so that the other components of the composition can be quickly dissolved and absorbed to have a desired effect. Most of these substances have good water absorption and expansion, so as to achieve the disintegration of tablets. Suitable disintegrants for this inventive formulation can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose, sodium starch glycolate, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinized starch, sodium alginate, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used. The preferred disintegrant is sodium starch glycolate. Binders can also be used in the process. Binder excipients are formulated to act as an adhesive to literally “bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. They can also give volume to low active dose tablets. Suitable binders according to the present invention are selected from the group including, but are not limited to, microcrystalline cellulose, starches, lactose, sugar alcohols like mannitol, mannitol 25 C, polymers like polyvinylpyrrolidone, polyethylene glycol, isomalt, hypromellose (hydroxypropyl methylcellulose) and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred binder is povidone (polyvinylpyrrolidone). Solvents can also be used in the process. Solvents are excipients used to enhance solubility, taste, anti-microbial effectiveness or stability, to reduce dose volume (such as oral, injections). Conversely, solvents can be used to optimize insolubility (if taste of an active pharmaceutical ingredient is an issue). Diluents or fillers or bulking agents can also be used in the process. Increases dosage form, volume, or weight of a pharmaceutical product with Spectrum's wide selection of diluent excipients. Because most dosages require only very small quantities of Active Pharmaceutical Ingredients (APIs), diluents often comprise a significant proportion of the dosage form. Suitable diluents according to the present invention are selected from the group including, but are not limited to, lactose, microcrystalline cellulose, starches, calcium phosphates, sucrose, maltodextrin, mannitol, sorbitol, and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred diluents are mannitol, microcrystalline cellulose or mixture thereof. Suitable solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water. In other embodiment the pharmaceutical composition according to the present invention may be in the form of a tablet, capsule, caplet, film-coated tablet, enteric tablet, controlled-release tablet and any similar solid oral dosage forms. The preferred dosage form according to the present invention is film-coated tablet form. Commonly available coating materials may be used for coating of tablets. A process for preparing solid pharmaceutical composition of the present invention, said process comprises the steps below: a. Adding dolutegravir or a pharmaceutically acceptable salt thereof mannitol, second diluent, a disintegrant as a component of intra-granular phase, a binder and a diluent to the granulator chamber, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a solvent thereby forming the intra- granular phase, d. Drying the granules obtained in step c, e. Sieving the granules obtained in step d, f. Adding the remaining amount of a disintegrant as a component of extra-granular phase and adding a lubricant, g. Mixing a disintegrant and a lubricant with the granules obtained in step e, h. Sieving sodium stearyl fumarate as a component of extra-granular phase, and i. Tablet compression and film coating of the tablet. In other embodiment solid pharmaceutical compositions of the present invention are prepared by direct compression, dry granulation or wet granulation. Preferably, by wet granulation. In other embodiment film coated tablet compositions of the present invention are prepared by direct compression, dry granulation or wet granulation. Preferably, by wet granulation. A process for preparing solid pharmaceutical composition of the present invention, said wet granulation process comprises the steps below: a. Adding dolutegravir or a pharmaceutically acceptable salt thereof mannitol, second diluent, a disintegrant as a component of intra-granular phase, a binder and a diluent to the granulator chamber, b. Mixing the substances from step a, c. Granulation of the mixture from step b with a solvent thereby forming the intra- granular phase, d. Drying the granules obtained in step c, e. Sieving the granules obtained in step d, f. Adding the remaining amount of a disintegrant as a component of extra-granular phase and adding a lubricant, g. Mixing a disintegrant and a lubricant with the granules obtained in step e, h. Sieving sodium stearyl fumarate as a component of extra-granular phase, and i. Tablet compression and film coating of the tablet. Preferably, active ingredient in the present invention composition is dolutegravir or a pharmaceutically acceptable salt thereof. More preferably is dolutegravir sodium. The particle size of dolutegravir or a pharmaceutically acceptable salt thereof can be 2 µm ≤ d (90) ≤ 35 µm. More specifically it can be 5 µm ≤ d (90) ≤ 25 µm. Even more specifically, the particle size herein may be 6 µm, 7 µm, 8 µm, 9 µm, 10 µm, 11 µm, 12 µm, 13 µm, 14 µm, 15 µm, 16 µm, 17 µm, 18 µm, 19 µm, 20 µm, 21 µm, 22 µm, 23 µm, 24 µm or 25 µm. Preferably, one or more diluents can be selected from mannitol, mannitol 25 C microcrystalline cellulose or mixtures thereof. More preferably first diluent can be selected as mannitol 25 C and second diluent can be selected as microcrystalline cellulose. In other embodiment, one or more diluents may be present in an amount from about 35% w / w to about 90% w / w of the total weight of the composition. In other embodiment, mannitol can be selected as first diluent. Mannitol may be present in an amount from about 25.00% w / w to about 60.00% w / w of the total weight of the composition, preferably, from 40.00% to 55.00% of the total weight of the composition, more preferably in an amount of about 48,47% of the total weight of the composition. In other embodiment, mannitol 25 C can be selected as first diluent. Mannitol 25 C may be present in an amount from about 25.00% w / w to about 60.00% w / w of the total weight of the composition, preferably, from 40.00% to 55.00% of the total weight of the composition, more preferably in an amount of about 48,47% of the total weight of the composition. In another preferred embodiment, the pharmaceutical composition according to invention: Table 1: Dolutegravir compositions Ingredients % weight Dolutegravir or a pharmaceutically acceptable salt thereof5.00%-20.00%One or more disintegrants 4.00%-10.00% One or more diluents 35.00%-90.00% One or more binders 3.00%-7.00% One or more lubricants 1.00%-2.50% One or more solvents q.s. Total 100.00% In other aspect of present invention, a solid pharmaceutical composition for use in the treatment of Human Immunodeficiency Virus (HIV) infections. In another aspect of an invention pharmaceutical compositions comprising dolutegravir or a pharmaceutically acceptable salt thereof and mannitol as a diluent for use in the treatment of HIV (Human Immunodeficiency Virus) infection. In-vitro Tests Dissolution results of present invention compositions comprising different d90 value of dolutegravir were compared. For dolutegravir compositions with a particle size above 35 µm d90, which d (90) is 60 µm invention, dissolution reached up to 92%, but the desired value was not achieved. The desired dissolution values were achieved with compositions in which Dolutegravir defined within the scope of the invention has a particle size of d (90) = 6 µm. Table 2: Dissolution values d (90) = 6 µm particle size for dolutegravir Time (min) Dissolution (%) 10 51 15 75 20 84 30 91 45 98 60 100 When the values described above are analyzed in Figure 1, it will be understood that the desired dissolution is achieved when the particle size of dolutegravir d90 is 6 µm as described in the invention. Comparative Data Between Mannitol 25 C and Mannitol 200 SD Dolutegravir compositions were prepared with mannitol 25 C with the specific value specified below. The prepared compositions were compared with mannitol 200 SD, which is average particle 150 µm. The desired dissolution values were achieved in the compositions of the invention prepared with mannitol at 25 C with the following specific values. Since mannitol 25 C has a small particle size, there was no incompatibility problem with dolutegravir in the composition of the invention. Table 3: Technical Specifications of Mannitol 25 C Technicial Specifications III Amount of Mannitol 25 C in the formulation (%) %48,47 Average Particle Size (µm) 25 µm Bulk Density (g / mL) 0.36 g / mL Tap density 0.71 g / mL It was observed that mannitol 200 SD, which average particle size, could not form homogeneous compositions with dolutegravir. Due to particle size incompatibility with dolutegravir, the desired dissolution could not be achieved in compositions containing mannitol 200 SD. Table 4: Technical Specifications of Mannitol 200 SD Technicial Specifications III Amount of Mannitol 200 SD in the formulation (%) %48,47 Average Particle Size (µm) 150 µm Bulk Density (g / mL) 0.49 g / mL Tap density 0.6 g / mL In summary, mannitol 200 SD, having a large particle structure, average particle size is 150 µm, caused the film tablet to disperse very quickly. The desired dissolution profile could not be obtained.

Claims

CLAIMS 1. A pharmaceutical composition prepared by wet granulation comprising dolutegravir or a pharmaceutically acceptable salt thereof and mannitol as diluent, characterized in that the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof is 2 µm ≤ d (90) ≤ 35 µm and the average particle size of mannitol is between 10 µm and 50 µm.

2. The pharmaceutical composition according to claim 1, wherein the particle size distribution of the dolutegravir or a pharmaceutically acceptable salt thereof is 5 µm ≤ d (90) ≤ 25 µm.

3. The pharmaceutical composition according to claim 1 or 2, wherein the average particle size of the mannitol is between 20 µm and 30 µm.

4. The pharmaceutical composition according to any of the preceding claims, wherein the average particle size of the mannitol is 25 µm.

5. The pharmaceutical composition according to any preceding claims, wherein the composition dosage form is film coated tablet.

6. The pharmaceutical composition according to claim 1, for use in the treatment of Human Immunodeficiency Virus (HIV) infections.

7. Method for preparing the composition according to Claim 1 comprising steps of a. Adding dolutegravir or a pharmaceutically acceptable salt thereof, mannitol, second diluent, a disintegrant as a component of intra granular phase, a binder and a diluent to the granulator chamber, b. Mixing the substances from step a, c. Granulation of the mixture from step b with adding solvent, thereby forming the intra- granular phase, d. Drying the granules obtained in step c, e. Sieving the granules obtained in step d, f. Adding the remaining amount of a disintegrant as a component of extra-granular phase and adding a lubricant, g. Mixing the disintegrant and the lubricant with the granules obtained in step e, h. Adding a lubricant as a component of extra-granular phase, i. Tablet compression and film coating of the tablet

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