Solid pharmaceutical compositions comprising pirfenidone

Abstract

The present invention relates to a composition comprising pirfenidone or pharmaceutically acceptable salt thereof prepared by spray granulation, wherein the composition is free of glidant.

Description

[0001]SOLID^PHARMACEUTICAL^COMPOSITIONS^COMPRISING^PIRFENIDONE^ ^ Field^of^invention^ The present invention relates to a composition comprising pirfenidone or pharmaceutically acceptable salt thereof prepared by spray granulation, wherein the composition is free of glidant. ^ Background^of^the^invention^ Pirfenidone is a synthetic pyridone drug. It is an antifibrotic agent with anti-inflammatory and antioxidant properties that is used to treat idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive form of interstitial pneumonia. Pirfenidone has a chemical name as 5-methyl-1-phenylpyridin-2-one and its chemical structure is shown in below. It^has molecular weight of 185.22 g / mol. US3839346, filed 18.12.1972, describes the pirfenidone molecule. In pharmaceutical industry, the oral administration route is prevalent and it has many advantages especially about patient compliance. One of the oral administration ways used commonly is tablet form. Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms. General properties of tablet dosage forms; ^ Tablet should have elegant product without any cracks, discoloration or contamination. 1    ^ Mechanical strength should be sufficient for production packaging, shipping and dispensing. ^ Physical properties should maintain the chemical and physical stability. ^ Tablet form should have predictable and reproducible manner for releasing the active ingredients. In view of the foregoing, there is a need to improve powder flowability and tablet compression in compositions comprising pirfenidone and free of glidant, in the state of the art and to produce tablets with spray granulation of a specifically desired quality and dissolution profile. The present invention provides a solution to these problems by providing novel compositions of pirfenidone with glidant free compositions. These solutions will be described in detail. Brief^Description^of^The^Figures Figure^1: Graph of dissolution profile of pirfenidone Summary^of^the^invention^ The present invention provides a pharmaceutical composition prepared by spray granulation, comprising pirfenidone or a pharmaceutically acceptable salt thereof wherein particle size of pirfenidone is 160 µm ≤ D90 ≤ 300 µm, where composition is free of glidant and comprises 6.0 % (w / w) to 8.0% (w / w) binder. The composition dosage form can be a tablet or a capsule, preferably can be a tablet.   In other embodiment, d90 particle size of pirfenidone can be 200 µm.   In other embodiment, the pharmaceutical composition comprises 6.5% to 7.5% binder by weight of composition. In other aspect of invention, a spray granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Sieving and mixing pirfenidone, filler and disintegrant, b. Spray granulation in fluid bed dryer with purified water comprising binder, c. Sieving and drying granules d. Sieving disintegrant and lubricant and mixing with granules, 2    e. Compressing tablet and film coating. In other aspect of invention, a pharmaceutical composition for use in the treatment of idiopathic pulmonary fibrosis (IPF). Detailed^Description^of^the^Invention^ The present invention relates a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof and relevant excipients. The present invention relates a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof with a specific interval of pirfenidone particle size, and relevant excipients. The present invention relates a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof with a specific interval of pirfenidone particle size and the pharmaceutical composition comprising a binder, and relevant excipients. The present invention relates a a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof with a specific interval of pirfenidone particle size and the pharmaceutical composition comprising a binder, without a glidant and relevant excipients. The present invention relates a a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof with a specific interval of pirfenidone particle size and the pharmaceutical composition comprising a binder, without glidant wherein the composition is prepared by spray granulation. The present invention relates to a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof prepared by spray granulation wherein the composition is free of glidant. The present invention provides a pharmaceutical composition comprising pirfenidone or pharmaceutically acceptable salt thereof, the particle size of pirfenidone is 160 µm ≤ D90 ≤ 300 µm, the pharmaceutical composition comprising from 6.0 % (w / w) to 8.0% (w / w) 3    binder, wherein the composition is free of glidant wherein the composition is prepared by spray granulation. The present invention relates to a process for pharmaceutical composition comprising pirfenidone 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 aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the pirfenidone as defined hereinbefore and hereinafter. 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. Excipients that are used in tablet dosage form are diluent, binder, disintegrants, lubricant, viscosity enhancer agent and solvent except active ingredient. The term "particle size" as used herein refers to the volume diameter of valsartan particles, as determined by laser light scattering using a Malvern-Mastersizer Apparatus MS 2000. Methods of determining the size of particles are well known in the art. For example, Laser Diffraction, Dynamic Light Scattering, Image Particle Analysis, Acoustic Spectroscopy etc. The dxvalue indicates that a certain percentage X of the particles has a size below a certain limit. d90means that 90% of particles (V / V) have a higher volume diameter than the indicated value. 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 4    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. In the present invention, the particle size of pirfenidone can be 160 µm ≤ d90 ≤ 300 µm. More specifically, d90 particle size of pirfenidone herein may be 160 µm, 165 µm, 170 µm, 175 µm, 180 µm, 185 µm, 190 µm, 195 µm, 200 µm, 205 µm, 210 µm, 215 µm, 220 µm, 225 µm, 230 µm, 235 µm, 240 µm, 245 µm 250 µm, 255 µm, 260 µm, 265 µm, 270 µm, 275 µm, 280 µm, 285 µm, 290 µm, 295 µm or 300 µm. Even more specifically, d90 particle size of pirfenidone can be 200 µm. The inventors surprisingly have found that the pharmaceutical composition comprises pirfenidone which d90 value is 200 µm, and 7.0 % binder by weight of the composition wherein composition is free of glidant wherein the composition prepared by spray granulation improves powder blend uniformity, tablet compressibility, dissolution and produces tablets with the desired properties. In other embodiment pharmaceutical composition comprises pirfenidone in an amount of 83.5-85.5 % based on the total weight of the composition. 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 croscarmellose sodium. The disintegrants can be comprised in an amount in a range of about 3.5-6.5% based on the total weight of the composition. Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, 5    polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, polyvinylpyrrolidone (PVP) and pregelatinized starch. The preferred binder is polyvinylpyrrolidone (PVP). The binders can be comprised in an amount in a range of about 6.0-8.0% based on the total weight of the composition. More preferably can be in an amount of 7.0% based on the total weight of the composition. 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. More preferably diluent is microcrystalline cellulose. The fillers or diluents can be comprised in an amount in a range of about 2.0-4.0% based on the total weight of the composition. Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate. The lubricants can be comprised in an amount in a range of about 0.1-1.1% based on the total weight of the composition. 6    Table 1: Pirfenidone film coated tablet composition Ingredients Ratio (%) API 83.5-85.5 Disintegrant 3.5-6.5 Binder 6.0-8.0 Filler 2.0-4.0 Lubricant 0.1-1.1 100,00In other aspect of invention, a spray granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Sieving and mixing pirfenidone, filler and disintegrant, b. Spray granulation in fluid bed dryer with purified water comprising binder, c. Sieving and drying granules d. Sieving disintegrant and lubricant and mixing with granules, e. Compressing tablet and film coating. In other aspect of invention, a pharmaceutical composition for use in the treatment of idiopathic pulmonary fibrosis (IPF). Examples^ Example^1^ The tablet composition according to the preferred embodiment of the present invention is given in Table 2 below. ^ Table^2:^Pirfenidone film coated tablet composition Ingredients^^ Ratio^(%)^Pirfenidone 83.5-85.5 Croscarmellose Sodium 3.5-6.5 Povidone 6.0-8.0 Microcrystalline 2.0-4.0 Cellulose Magnesium Stearate 0.1-1.1 Total 100,00 7    The composition in Table 2 were prepared by spray granulation. Pirfenidone, microcrystalline cellulose and croscarmellose sodium were sieved and mixed. Spray granulation was done with purified water which comprises binder. Granulation was done in a fluidized bed dryer. Dried granules were sieved and dried. Croscarmellose sodium and magnesium stearate were sieved and mixed with granules. The tablets were compressed and film coated. ^ Invitro^Studies^ Pirfenidone^ Dissolution results of present invention compositions comprising pirfenidone which d90 particle size was 200 µm were evaluated. Dissolution reached up to 100% at 10 minutes, and the desired value was achieved (Figure 1). Table^3: Dissolution profile of pirfenidone Time^ Dissolution^ (min)^ (%)^ 0 0,0 5 22,1 10 81,3 15 96,8 20 99,1 30 99,4 45 100,9 60 101,0 8

Claims

CLAIMS^ 1. A pharmaceutical composition prepared by spray granulation, comprising pirfenidone or a pharmaceutically acceptable salt thereof characterized in that particle size of pirfenidone is 160 µm ≤ D90 ≤ 300 µm, where composition is free of glidant and comprises 6.0 % (w / w) to 8.0% (w / w) binder.

2. The pharmaceutical composition according to claim 1, wherein the composition dosage form is tablet or capsule.

3. The pharmaceutical composition according to claim 2, wherein the composition dosage form is tablet.

4. The pharmaceutical composition according to claim 1, wherein the particle size of pirfenidone is 200 µm.

5. The pharmaceutical composition of claim 1, wherein the composition comprises 6.5% to 7.5% binder by weight of composition.

6. A pharmaceutical composition according to any one of the previous claims for use in the treatment of idiopathic pulmonary fibrosis (IPF).

7. A spray granulation process for manufacturing a pharmaceutical composition according to claim 1, characterized in comprising steps of: a. Sieving and mixing pirfenidone, filler and disintegrant, b. Spray granulation in fluid bed dryer with purified water comprising binder, c. Sieving and drying granules d. Sieving disintegrant and lubricant and mixing with granules, e. Compressing tablet and film coating.

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