DESC:It is difficult to formulate an active such as pirfenidone having high solubility such that the release of active from the formulation is controlled at a predetermined rate. The selection of suitable excipients incorporated in a suitable amount is critical parameter for formulating such actives having high solubility.

Thus, the present invention provides a sustained release formulation of pirfenidone which is comprising of at least 25-30% by weight of pirfenidone, release controlling agents and optionally coated with non-functional coating membrane. Tablets according to the invention surprisingly provide for the administration of pirfenidone in a smaller unit dose of pirfenidone. The tablets of the invention are, despite the high drug loading, small, and, therefore, convenient to administer.

The present inventors provide sustained release formulations of pirfenidone that not only release the active agent continuously in a predetermined manner and lessen the frequency of dosing but also reduce peak-trough fluctuations thereby maintaining desired therapeutic concentrations for longer duration of time and minimizing side effects otherwise associated immediate release tablets. The formulations of the present invention are stable, easy or convenient to prepare, and provide the desired in vitro release and bioavailability.

The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.

The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "controlled release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Pirfenidone is released at a predetermined rate that is slower than the immediate release formulation. AUC, as used herein, refers to the area under the curve that represents changes in blood concentrations of Pirfenidone over time. Cmax, as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of Pirfenidone over time. Tmax, as used herein, refers to the time that it takes for pirfenidone blood concentration to reach the maximum value. T 1/2, as used in this disclosure, refers to the time that it takes for pirfenidone blood concentration to decline to one-half of the maximum level. Collectively AUC, Cmax, Tmax, and T1/2 are the principle pharmacokinetic parameters that characterize the pharmacokinetic responses of a particular drug product such as pirfenidone in an animal or human subject.

The term pirfenidone as employed herein refers is used in broad sense to include not only “pirfenidone free base” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.

The term "salt" as used herein, refers to salts derived from inorganic or organic acids. Examples of suitable salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, fumarate, hydrochloride, carbonates, bicarbonates, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, mandelate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, salicylate, succinate, sulfate, nitrates, tartrate, sulfonates, thiocyanate, tosylate, mesylate, and undecanoate.

Pharmaceutically effective amount of pirfenidone is employed in the composition of the present invention. The term "effective amount" refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect. In one embodiment the amount of pirfenidone in the composition can vary from about 1 weight % to about 90 weight %, based on the total weight of the composition.

In another embodiment the amount of pirfenidone in the composition can vary from about 5 weight % to about 85 weight %, based on the total weight of the composition.

In still another embodiment the amount of Pirfenidone in the composition can vary from about 10 weight % to about 80 weight %, based on the total weight of the composition. Preferably, pirfenidone is present in an amount of 70.0% if total weight of composition. In one embodiment the compositions of the present invention comprise about 200 mg to about 1750 mg of pirfenidone in total weight of composition, preferably 250mg to 1500mg of total weight of formulation, preferably 300mg to 1500mg of total weight of formulation. In a most preferred embodiment, the pirfenidone is present in an amount of 1200mg of total weight of formulation.

In one embodiment, the pirfenidone employed for present invention is in the form of free acid or free base or pharmaceutically acceptable prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable salts of prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof.

In one embodiment of the present invention is to provide a sustained release pharmaceutical formulation comprising Pirfenidone and excipient as given below.

Ingredients mg/tablet
1200 mg
Pirfenidone 1200.00
Microcrystalline cellulose 50.00
Croscarmellose sodium 11.00
Povidone K- 90 14.00
Purified water q.s
Hydroxy propyl methyl cellulose 120.00
Magnesium stearate 5.00

The sustained release compositions of the present invention comprise along with pirfenidone comprises of at least one release controlling agent. The term "release controlling agent" as used herein means any excipient that can retard the release of active agent and includes, but is not limited to, polymeric release controlling agent, nonpolymeric release controlling agent or combinations thereof.

Suitable polymeric release controlling agent may be employed in the compositions of the present invention. In an embodiment, the polymeric release controlling agent employed in the compositions of the present invention may be swelling or non-swelling. In a further embodiment, polymeric release controlling agents that may be employed in the compositions of the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, polyalkylene oxides and derivatives thereof, maleic copolymers, acrylic acid derivatives or the like or any combinations thereof. Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carb oxy methyl ethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

Saccharides or polysaccharides include but not limited to guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Vinyl derivatives, polymers and copolymers thereof include, but are not limited to, polyvinylacetate aqueous dispersion (Kollicoat® SR) copolymers of vinyl pyrrolidone, copolymers of polyvinyl alcohol, mixture of polyvinyl acetate and polyvinylpyrrolidone (e.g. Kollidon® SR), polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP), or combinations thereof. Polyalkylene oxides and derivatives thereof include, but are not limited to, polyethylene oxide and the like or any combinations thereof. The term "polyethylene oxide polymer" or "PEO" as used herein includes all forms and MWs of PEO polymers. Sources of PEO polymers include, e.g., Polyox WSR-303™.

Acrylic acid derivatives include but not limited to methacrylic acids, poiymethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butylmethacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate methymethacrylate copolymer), Eudragit® L 100 and Eudragit® S (methacrylic acid'methyl methacrylate copolymer), Eudragit® L 100-55 (methacrylic acid'ethyl acrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof. Maleic copolymer based polymeric release controlling agent includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and the like, or combinations thereof. In one embodiment, polymers with low viscosity are employed in the compositions of the present invention as release controlling agent such as, but not limited to, Methocel K4M, and the like or combinations.

The term "non-polymeric release controlling agent" as used herein refers to any excipient that can retard the release of an active agent and that does not comprise of repeating units of monomers. Suitable non-polymeric release controlling agents employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, resins and the like or combinations thereof. Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids that may be employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment, the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Suitable long chain monohydric alcohols include, but are not limited to, acetyl alcohol, stearyl alcohol or mixtures thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes that may be employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof. Mixtures of these waxes with the fatty acids may also be used. Waxes are also monoglyceryl esters, diglyceryl esters, or tri glyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxy! groups of glycerol is substituted by a fatty acid. Glycerides that may be employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl di stearate,
glyceryl tri stearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyri state, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, or mixtures thereof.

Resins employed in the compositions of the present invention include, but are not limited to, shellac and the like or any combinations thereof. In one embodiment the non-polymeric release controlling agent employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil, Croduret® (Hydrogenated castor oil), Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil), Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated cottonseed oil), Softisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof.
In preferred embodiment, the formulation of present invention comprises of combination of hydroxypropyl methyl cellulose and polyethylene oxide as release rate controlling agents.

The amount of release controlling agent used in the sustained release formulations of the present invention may vary depending upon the degree of controlled or sustained release desired. In an embodiment, release controlling agent is present in the composition in an amount from about 1% to about 50 % by weight of the dosage form. In a preferred embodiment, release controlling agent is present in the formulation in an amount from about 10% to about 30% by weight of the dosage form, preferably 25% by weight of total tablet weight.

In one embodiment, pirfenidone is in the form of, but not limited to, powder, granules, pellets, beads, mini tablets or the like is treated with at least one release controlling agent. In a further embodiment the active agent may be in micronized form. The active ingredient may be treated by any of the techniques known in the art such as, but not limited to, melt granulation, hot melt extrusion, fluid bed coating, wet granulation, spray drying, extrusion-spheronization, dry granulation or roll compaction. In an embodiment, pirfenidone is blended or physically mixed with release controlling agent.

In addition to the above discussed excipients, the controlled release compositions of the present invention comprise at least one pharmaceutically acceptable excipients, such as, but not limited to diluents, glidants, lubricants, disintegrants, stabilizers, preservatives, colorants and the like or combinations thereof.

Diluents are inert ingredients sometimes used as bulking agents in order to decrease the concentration of the active ingredient in the final formulation. Suitable diluents used in the present invention are selected from, not limited to, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminium silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, ethyl cellulose, the preferred filler is microcrystalline cellulose. In a preferred embodiment, the amount of glidant included in present formulation is from about 0.1% to about 10% by weight based on total weight of formulation, preferably from 4% by weight of total weight of tablet.

Suitable glidants included in the present formulation can be selected from the group consisting of silica, fumed silica, silicified cellulose, sodium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, and physical or compressed combinations thereof. The glidant can be silica, and can be a hydrophilic fumed silica (colloidal silicon dioxide). In a preferred embodiment, the amount of glidant included in present formulation is from about 0.1% to about 10% by weight based on total weight of formulation.

Examples of suitable lubricants of present invention include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate or mixtures thereof. In a preferred embodiment, the amount of lubricant included in present formulation is from about 0.1% to about 10% by weight based on total weight of formulation, preferably from about 0.5% to about 1% by weight based on total weight of formulation.

Suitable disintegrants be employed in the formulations of the present invention include but not limited to croscarmellose sodium, crospovidone, sodium starch glycolate, starch or combinations thereof.

The formulation of present invention is substantially free of binder. By " substantially free" of excipient it is meant that the formulation contains less than about 15 % by weight, more preferably less than about 8% by weight, and most preferably less than about 2 % by weight of binder based on the total weight of the formulation on a dry basis (i.e., excluding moisture as hereinafter defined). In an embodiment, the binder should be essentially absent, present in an amount of not more than about 0.1% by weight, and preferably totally absent from the formulation of present invention. The examples of binder for the understanding of this invention include other than microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, and polyvinylpyrrolidone.

The formulation of present invention comprising Pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipient is in the form of tablet. In another embodiment according to the invention, the sustained release formulation may be optionally coated. Surface coatings may be employed for aesthetic purposes or for dimensionally stabilizing the dosage form. The coating may be carried out using any conventional technique employing conventional ingredient. A surface coating can, for example, be obtained using a quick dissolving film using conventional polymers such as, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, poly methacrylates or the like or combinations thereof. Tablets of the present invention may vary in shape including, but not limited to, oval, triangle, almond, peanut, parallelogram, pentagonal. It is contemplated within the scope of the invention that the dosage form can be encapsulated. Tablets in accordance with the present invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, dry granulation, wet granulation, extrusion hot melt granulation, screw granulation and the like. Preferably, the sustained release tablet formulation of present invention is prepared by extrusion by hot melt granulation, screw granulation. The formulations of present invention comprising high load of Pirfenidone and other excipients is administered to the patient twice a day, most preferably once a day. The formulations of present invention having an effective amount of pirfenidone and pharmaceutically acceptable excipients when administered in a patient is capable of sustaining a measurable pharmacokinetic response. In vitro drug release was measured by in vitro dissolution experiments. These studies were carried out using USP apparatus II at a paddle speed of 100 in 1000 ml dissolution medium from Examples 1 to 10. Drug release was evaluated with either Simulated Gastric Fluid (SGF), pH=1.2 or Simulated Intestinal Fluid (SIF), pH=7.5, both prepared according to USP without enzyme added. Tablet sinkers were applied in all experiments. At predetermined time intervals, a sample was withdrawn from the vessel and assayed using a UV-VIS spectrophotometer at a wavelength of 240 nm.

The present invention also provides a method of treating idiopathic pulmonary fibrosis which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The present invention also provides a use of the pharmaceutical composition in the manufacture of a medicament for the treatment of idiopathic pulmonary fibrosis.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1: Composition of Pirfenidone sustained release tablets.
S.No. Ingredients Functional category mg/tablet % w/w
1200 mg
Intra-granular agents
1. Pirfenidone API 1200.00 85.71
2. Microcrystalline cellulose PH 101 Diluent 50.00 3.57
3. Croscarmellose sodium Disintegrant 11.00 0.79
Binder solution
4. Povidone K- 90 Binding agent 14.00 1.00
5. Purified water Solvent q.s --
Extra granular agents
6. Hydroxy propyl methyl cellulose K 100 M Rate-controlling polymer for
sustained release 120.00 8.57
7. Magnesium stearate Lubricant 5.00 0.36
Total weight of uncoated tablets 1400.00 100.00
Film coating ( 3.0% w/w weight build up)
8. Instacoat Universal (IC-U-3849) white Film coating material 42.00 --
9. Purified water Solvent q.s --
Total weight of film coated tablets 1442.00 --
Manufacturing Process:
Sifting:
I. Co-sift Pirfenidone, Microcrystalline cellulose 101 and Croscarmellose sodium through 30 # mesh.
II. Load the step i into Rapid mixer granulator and dry mix for 10 minutes.
Binder preparation:
III. Add required quantiry of Purified water, to this add weighed quantity of Povidone K-90 under stirring and continue stirring upto clear solution was formed.
Granulation:
IV. Granulate the step ii with step iii to attain desired granules and dried the wet granules to attain desired % LOD @ 105°C NMT 1 - 3 % w/w.
Sizing and Milling:
V. Sift the dried granules through 20# mesh and mill the retains with 1.50 mm screen until all the dried granules passes through 20# mesh.
Extragranular agents:
VI. Sift Hydroxy propyl methyl cellulose K 200 M through 30# mesh.
VII. Sift Magnesium stearate through 60# mesh.
Lubrication:
VIII. Load the granules of step v and to this add step vi material and blend for 15 minutes
IX. Add step vii to the step viii and again blend for 5 minutes.
Compression:
X. Compress the step ix blend according to their individual weights by using suitable punches.

Table 1: Comparative In-vitro dissolution profile of test product in 0.1 N HCL for Pirfenidone.
Dissolution conditions: 0.1 N HCl/900 mL/Basket/75 RPM
Time (in hrs.) % drug released
2 18
4 27
8 42
12 54
16 73
20 90
,CLAIMS:We claim:
1) An oral pharmaceutical composition containing sustained release Pirfenidone in an amount sufficient to deliver 1200 mg having at least one release controlling agent and one or more pharmaceutically acceptable excipients.

2) An oral pharmaceutical composition as claimed in claim 1, where in the Pirfenidone is used in an amount of 80-95% from the total weight of the composition.

3) An oral pharmaceutical composition as claimed in claim 1, where in the release controlling agent is Hydroxy propyl methyl cellulose is used 7-25% from the total weight of the composition.

4) An oral pharmaceutical composition as claimed in claim 1, where in the pharmaceutical acceptable excipients are used in the composition is diluent, disintegrant, binding agent, rate controlling polymer and lubricant.

5) An oral pharmaceutical composition as claimed in claim 1, where in the pharmaceutical acceptable excipients is microcrystalline cellulose, croscarmellose sodium, povidone, hydroxypropylmethylcellulose and magnesium stearate.

6) An oral pharmaceutical composition as claimed in claim 1, where in the pharmaceutical acceptable excipients are below:

Pirfenidone 1200.00
Microcrystalline cellulose 50.00
Croscarmellose sodium 11.00
Povidone K- 90 14.00
Purified water q.s
Hydroxy propyl methyl cellulose K 100 M 120.00
Magnesium stearate 5.00

7) An oral pharmaceutical composition as claimed in claim 1, where in the release controlling polymer is used to achieve the sustained release mechanism of Pirfenidone.

8) An oral pharmaceutical composition as claimed in claim 1, where in Pirfenidone is in the form of tablet or capsule or granules.

9) A process for preparation of oral pharmaceutical composition as claimed in claim 1, co-sift Pirfenidone microcrystalline cellulose, croscarmellose sodium and perform granulation, prepare binder solution and granulate the above step, sizing and milling the dried granules and shift hydroxy propyl methyl cellulose, perform the lubrication and compress the above mixture in a suitable blend using suitable punches.

10) An oral pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment and prevention of Idiopathic pulmonary fibrosis.