WO2020115774A1 - High drug load extended release formulations - Google Patents

Abstract

The present invention pertains to a high drug load tablet comprising pirfenidone as active ingredient in an amount from about 30% to 80% in weight of the active moiety based on the total weight of the tablet.

Description

“HIGH DRUG LOAD EXTENDED RELEASE FORMULATIONS”

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to co-pending Indian Provisional Patent Application Serial Number 201821046100 filed on December 6, 2018. This application is incorporated herein by reference, in its entirety.

Field of Invention:

The present invention relates to pharmaceutical formulations of pirfenidone. Particularly, the present invention relates to oral high drug load extended release formulations of pirfenidone or pharmaceutically acceptable salts thereof and processes for preparing such formulations. Further provided are methods of using such extended release formulation in the treatment and prevention of fibrotic diseases.

Background of invention:

Idiopathic pulmonary fibrosis (IPF), the most common form of the idiopathic interstitial pneumonias, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown cause. IPF occurs in middle-aged and elderly adults (median age at diagnosis 66 years, range 55-75 years), is limited to the lungs, and is associated with a histopathological or radiological pattern typical of usual interstitial pneumonia. Patients with IPF usually seek medical attention because they suffer chronic and progressive exertional dyspnoea and cough.

The annual incidence of IPF is rising and is estimated to be between 4-6 and 16-3 per 100 000 people and the prevalence is 13 to 20 cases per 100 000. There is a higher predominance of the disease in men (1 -5 to 1 -7: 1) than in women and the frequency increases with age. Due to rapid progress and poor prognosis, the disability and mortality of the disease are extremely high. The average life expectancy of the patient is 3-5 years after diagnosis, or 4-6 years after the onset of symptoms. For a long time, idiopathic pulmonary fibrosis, like other interstitial pneumonia, was considered to be an inflammatory disease of the lungs. However, with the deepening of its pathogenesis research, the treatment strategy has shifted from anti-inflammatory to the specific aspects of the pathophysiology of idiopathic pulmonary fibrosis.

Pirfenidone, the first drug to be licensed, was approved for use by the National Institute for Health and Care Excellence (NICE) in 2013 and by USFDA in 2014 for the treatment of idiopathic pulmonary fibrosis. Pirfenidone is a non-peptide synthetic molecule with a molecular weight of 185.23 daltons. Its chemical name of pirfenidone is 5-methyl- 1 -phenyl-2- l(H)-pyridone. It has a molecular formula of C12H11NO and a molecular weight of 185.23. The structural formula of pirfenidone is:

While the precise the mechanism of pirfenidone is incompletely understood, it exhibits both anti-inflammatory and antifibrotic effects. Much attention has been focused on the antifibrotic effect of the drug. An important aspect of the antifibrotic mechanism of pirfenidone is associated with decreased TNF-a expression, decreased PDGF expression, and decreased collagen expression.

Pirfenidone is an achiral, non-hygroscopic white to pale yellow powder. Pirfenidone is BCS class 1 drug i.e it has been shown to have high solubility and high permeability and high Bioavailability as approximately 80%. The elimination half life is 3-4 hours with single dosing and decreases upon multiple dosing. Pirfenidone is available in the form of immediate release tablets and capsules with the name ESBREIT for oral administration. US7988994B2 describes the said marketed formulation as capsule comprising a pharmaceutical formulation of 70-95% pirfenidone and 5-30% of pharmaceutically acceptable excipients. The excipients include disintegrators, binders such as microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, and polyvinylpyrrolidone, fillers, and lubricants.

The recommended daily maintenance dosage of ESBRIET is 801 mg three times daily for a total of 2403 mg/day. Doses should be taken with food at the same time each day. The recommended dosage regimen is tailored dosing pattern until patients are established on a stable dose of pirfenidone. The recommended starting dose is 1 x 267-mg capsule three times daily for 1 week, followed by 2 ^c 267-mg capsules three times daily for 1 week, followed by the maintenance dosage of 3 x 267-mg capsules three times daily. Also, some recommended precautions needed to be taken are that dosages above 2403 mg/day are not to be taken by any patient, patients should not take 2 doses at the same time to make up for a missed dose and patients should not take more than 3 doses per day. Thus, pirfenidone is high dose molecule. It also has a very poor compressibility. Manufacturing the tablet formulation with such high dose active generally requires many excipients such as filler, disintegrants, binder etc. in the formulation for process suitability. Further, the effectiveness of a formulation may be determined by a plurality of factors, including the amount of pirfenidone it contains, the kinds and relative amounts of pharmacologically acceptable excipients used, and the target patient profile.

Clinical pharmacokinetic (PK) studies have demonstrated that, after oral administration of pirfenidone in various oral formulations, peak plasma pirfenidone concentration (C max) and area under the plasma concentration versus time curve (AUC) are significantly higher in a fasted versus a fed state. The observed reduction in C max in the fed state is of clinical benefit as pirfenidone- related side effects such as nausea, dizziness, headache and vomiting were associated with C max .Therefore, prescribing information recommends taking pirfenidone with food.

Thus, there is a problem of medication adherence, which is defined as the degree to which patients follow recommendations on the timing, dosage and frequency of their medications. The need for multiple dosings in a day, present patient compliance problems and also cause fluctuations in serum concentrations of the active agents and toxicity. Poor adherence is associated with worse health outcomes. The prescribed number of dose units of medication daily is an important factor in influencing adherence, with an increasing number of doses associated with poorer adherence.

Extended release formulations generally control the rate of drug absorption, so as to avoid excessive drug absorption while maintaining effective blood concentration of the drug to provide a patient with a consistent therapeutic effect over the extended time. Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, extended released dosage forms generally help reduce side effects caused by a drug and enhance the patient's compliance.

Extended release formulations of pirfenidone can provide patients stable plasma levels, improved predictability of absorption and reduced inter-individual variability smooth and stable plasma levels compared to immediate release, improved tolerability for long term administration, Cmax related ales may reduce due to blunted Cmax, which can potentially allow dosing, irrespective of fasting or fed condition, improved safety profile will improve long term adherence to therapy and better patient compliance resulting into reduction in adverse events. The pill burden of taking 1 ^c 801 -mg tablet three times a day can be reduced by taking extended release formulation and hence has the potential to increase adherence in the patients. Thus, extended release dosage form of pirfenidone or pharmaceutically acceptable salts thereof are needed that would enable better patient compliance and offer advantages over conventional immediate release formulations. Extended release formulations would also lessen or prevent potentially undesirable effects by reducing peak blood levels (Cmax) and' increase drug efficacy (Cmin) by maintaining desired therapeutic plasma concentrations for longer period.

Some modified release formulations of pirfenidone have been provided such as US9408836 relates to a composition in sustained-release tablet form comprising 600.0 mg pirfenidone, 118.8 mg microcrystalline cellulose, 70.0 mg low viscosity hydroxy propylmethylcellulose (HPMC), 46.5 mg high viscosity hydroxypropylmethyl- cellulose (HPMC), 8.5 mg silicium dioxide, and 6.2 mg sodium stearyl fumarate, wherein the sustained-release tablet has a bioavailability of up to 12 hours. A considerably high amount of excipients specifically microcrystalline cellulose, HPMC are used to formulate the sustained release tablets.

WO2018088886 relates to the use of a pharmaceutical composition in the form of prolonged release tablets comprising lOOmg, 200mg, 300mg, 400mg or 600mg of pirfenidone for reversion and treatment of alcoholic and nonalcoholic steatohepatitis (NAFLD / NASH). However, it does not provide the details of formulations used for the treatment.

US20170281609 discloses a granulate formulation comprising pirfenidone and a glidant and optionally one or more additional pharmaceutically acceptable excipients admixed with the granules intragranularly , extragranularly such as binders, disintegrants, glidants, lubricants, and fillers.

Thus, although some attempts have been made to formulate pirfenidone formulations with modified release of active, none of the formulations have high amount of pirfenidone with substantially less amount of excipients specifically binder and incorporating specific excipients which help to release pirfenidone in a controlled manner at an extended time.

Need therefore exists to provide oral extended release formulations of pirfenidone that would enable better patient compliance by reducing the number of dosage, providing increased adherence with regimen and still is bioavailable during an extended period of long hours from its administration effectively optimizing the anti-fibrotic and anti-inflammatory action of pirfenidone, uses substantially less amount of excipient thereby lessening the drug- excipient interaction and can be produced by simple manufacturing techniques.

Object of invention:

An object of the present invention is to provide an extended release pharmaceutical formulation comprising high load of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients capable of advantageous therapeutic actions.

Another object of the present invention is to provide an extended release pharmaceutical formulation comprising high load of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

Yet another object of the present invention is to provide an extended release pharmaceutical formulation comprising high dose of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients, is substantially free of binder and release active for a longer period of time.

Still another object of present invention is to provide an extended release pharmaceutical formulation comprising high dose of pirfenidone substantially free of binder which release the active at a rate comparable to the release rate of formulation with binder. Another object of the present invention is to provide a process for manufacturing a pharmaceutical composition in extended release formulation comprising pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients in such a way as to make the drug bioavailable during a prolonged period of time of at least 12 hours from its administration. Thus, the anti-fibrotic and anti-inflammatory action of the drug pirfenidone is optimized.

Another object of the present invention is to provide a method for treatment of fibrotic disorders administering an extended release pharmaceutical formulation comprising pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

Summary of invention:

An aspect of the present invention is to provide an extended release pharmaceutical formulation comprising high load of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients capable of advantageous therapeutic actions.

Another aspect of the present invention is to provide an extended release pharmaceutical formulation comprising high dose of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

Yet another aspect of the present invention is to provide an extended release pharmaceutical formulation comprising high dose of pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients, is substantially free of binder and release active for a longer period of time.

Still another aspect of present invention is to provide an extended release pharmaceutical formulation comprising high dose of pirfenidone substantially free of binder which release the active at a rate comparable to the release rate of formulation with binder. Another aspect of the present invention is to provide a process for manufacturing a pharmaceutical composition in extended release formulation comprising pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients in such a way as to make the drug bioavailable during a prolonged period of time of at least 12 hours from its administration. Thus, the anti-fibrotic and anti-inflammatory action of the drug pirfenidone is optimized.

Another aspect of the present invention is to provide a method for treatment of fibrotic disorders administering an extended release pharmaceutical formulation comprising pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

Detailed description of invention:

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.

After considerable experimentation, the inventors of present invention found that, although a high loading of pirfenidone, upwards of 65%, was desired, in order to achieve a final dosage form of a reasonable size for oral administration, nonetheless the presence of a binder was a prime found to be cause of the difficulties which were experienced. This discovery was quite contrary to conventional practice which teaches that a binder component is essential particularly when drug loadings of the level which we were using are required.

It is contemplated that the binder was in some way interfering to prevent the moisture control agent from acting in the desired way, and also it appeared that the binder was tending to stick the forming particles together whereby large agglomerates resulted. Based on the experimental work, the inventors have now developed a new extended release formulation of pirfenidone.

The inventors have found that the pirfenidone may itself act as its own binder to enable the desired high drug loading to be achieved. The inventors suggest that a proportion of the pirfenidone dissolves during the wet blending step to form liquid bridges between the particles. On drying, removal of the water will leave interparticulate bonds within the structure of the pellets, whereby the pellets retain their coherency.

Thus, the present invention provides a new extended release formulation of pirfenidone which is substantially free of binder and comprising of at least 25% 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 size than was hitherto possible for a gives unit dose of pirfenidone. The tablets of the invention are, despite the high drug loading, small, and, therefore, convenient to administer. Hus leads to a better patient compliance.

The present inventors provide extended 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 comprises 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.

The extended 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 are 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 30D , 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 are 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 butyl

methacrylate, (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, cetyl 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, minitablets 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 comprises 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 fro , not limited to, sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatine, starch, pregelatinised starch, mieroerystalline cellulose, magnesium aluminium silicate, carboxymethylcellulose sodium (CMC sodium), methylcellulose, etiiylcellulose, The preferred filler is mieroerystalline 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 silioaluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, and physical or coprocessed 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 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 extended 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 extended 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 extended release tablets

Table 1

Process of preparation:

Pirfenidone and HPMC through specified mesh. Granulated the sifted materials in suitable granulator using water. Dried and sized the granules using suitable equipment and blend in suitable blender. Polyox, Aerosil 200 were sifted through specified mesh and blended with dried granules of drug. Magnesium Stearate was sifted through specified mesh and blended with granules in suitable blender. The lubricated blend was compressed as tablet dosage form.

Example 2: Comparative dissolution profile of formulations with and without binder

Table 2: Composition of formulation with and without binder

Process of preparation:

Formula 1 : Pirfenidone, polyox, aerosil 200 and microcrystalline cellulose were sifted through specified mesh were sifted. Povidone was dissolved in water to form clear solution. Granulated the sifted materials in suitable granulator using povidone binder solution. Dried and sized the granules using suitable equipment and blend in suitable blender magnesium Stearate was sifted through specified mesh and blended with blend of granules in suitable blender. The lubricated blend was compressed to form tablet dosage form.

Formula 2: same as example 1

Dissolution profile:

Dissolution media: USP type- 1 (basket) / 900 ml 0.1N HC1 / 75rpm / 37°c /20 hrs and infinity

Table 4: Result of dissolution profile

Observation: dissolution profile found comparable for formulations with and without binder. Also, tableting parameters are found to be satisfactory for formulations without binder as compared with formulations with binder.

Example 3: Pirfenidone extended release tablet prepared by wet granulation process

Manufacturing process:

All the materials were sifted through selected sieve. Intra-granular material was dry- mixed in rapid mixer granulator and granulated using Povidone. The granules were dried using fluidized bed processor and milled through suitable screen to get uniform sized granules. Blended the sized granules with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine. Example 4 - Pirfenidone extended release tablet prepared by wet granulation process

Manufacturing process:

All the material through selected sieve were sifted. Mixed intra-granular material and granulated using Rapid Mixer Granulator. Dried the above granules using Fluidized Bed Processor and milled through suitable screen to obtain uniform sized granules. Blended the sized granules with extra-granular material using octagonal blender. Lubricated the blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine.

Example 5 - Pirfenidone extended release tablet prepared by wet granulation process

Manufacturing process:

Sifted all the material through selected sieve. The intra-granular material was dried and granulated using Rapid Mixer Granulator. The above granules were dried using Fluidized Bed Processor and milled through suitable screen to get desired sized granules. The sized granules were blended with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine.

Example 6 - Pirfenidone extended release tablet prepared by dry granulation process

Manufacturing process:

Sifted all the material through selected sieve. Granulated the intra-granular material using Roller compactor to form uniform ribbons. The above ribbons were milled through suitable screen attached to integrated mill to obtain uniform sized granules. Blended the sized granules with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the lubricated blend into tablets using compression machine. Example 7 - Pirfenidone extended release tablet prepared by direct compression process

Manufacturing process:

Sifted all the material through selected sieve. Blended the drug with intra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate.

Compressed the above lubricated blend into tablets using compression machine.

Example 8 - Pirfenidone extended release tablet prepared by hot melt granulation process

Manufacturing process:

Sifted all the material through selected sieve. Granulated pirfenidone and diluent using Hot Melt Extruder to form granules. Dried the above granules and mill the above granules through suitable screen to get uniform sized granules. Blended the sized granules with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine.

Example 9 - Pirfenidone extended release tablet prepared by screw granulation process

Manufacturing process: Screw Granulation

Sifted all the material through selected sieve. Granulated the drug and diluent using Purified water as binder in Hot Melt Extruder to form granules. Dried the above granules and milled the above granules through suitable screen to obtain uniform sized granules. Blended the sized granules with extra-granular material using octagonal blender. Lubricated the above blend using Magnesium stearate. Compressed the above lubricated blend into tablets using compression machine.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,”“comprising,” or“having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

Claims

We Claims,

1. A high drug load extended release tablet formulation comprising pirfenidone in an amount of from about 50 to about 90% by weight based on the total weight of the tablet, at least one release controlling agent and optionally pharmaceutically acceptable excipients.

2. The formulation as claimed in claim 1 wherein the release controlling agent is polymeric release controlling agent selected from cellulose derivative, saccharide or polysaccharide, poly(oxyethylene)- poly(oxypropylene) block copolymer, vinyl derivative or polymer or copolymer thereof, polyalkylene oxide and derivative thereof, maleic copolymer, acrylic acid derivative, or any combination thereof.

3. The formulation as claimed in claim 1 wherein the release controlling agent is selected from cellulose derivatives such as hydroxymethyl cellulose, hydroxypropylcellulose, polyvinylpyrrolidone or combination thereof , polyalkylene oxide or derivatives thereof and combination thereof.

4. The formulation of claim 1, wherein the amount of release controlling agent is from about 10% to about 50% by weight of total weight of tablet.

5. The formulation of claim 1, wherein said excipients further comprise one or more excipients selected from diluents, glidants, lubricants or combination thereof.

6. The formulation of claim 1, wherein diluents are selected from sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatine, starch, pregelatinised starch, microcrystalline cellulose, magnesium aluminium silicate, carboxymethylcellulose sodium, methylcellulose, ethylcellulose, and combination thereof.

7. The formulation of claim 6, wherein the diluent is microcry talline cellulose present in an amount from about 0.2% to about 10% by weight based of total weight of tablet.

8. The formulation of claim 5, wherein said glidants comprise one or more selected from silica, fumed silica, silicified cellulose, sodium stearate, magnesium aluminum silicate, pyrogenic silica, hydrated sodium silioaluminate, cellulose, calcium phosphate, sodium lauryl sulfate, pregelatinized starch, talc, and physical or coprocessed combinations thereof.

9. The formulation of claim 8 wherein the said glidant is present in an amount from about 0.2% to about 10% by weight of total weight of tablet formulation.

10. The formulation of claim 5, wherein said lubricants are selected from magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate or mixtures thereof.

11. The formulation of claim 10 wherein the said lubricant is present in an amount from about 0.5% to about 3% by weight of total weight of tablet formulation.

12. The formulation of claim 1, wherein the formulation is administered to the patient once a day or twice a day.

13. The formulation of claim 1, wherein the high load pirfenidone formulation is prepared by process selected from wet granulation, dry granulation, direct compression, hot melt granulation, screw granulation or combination thereof.

14. The formulation of claim 1 wherein the formulation does not contain binder.

15. The formulation of claim 1, wherein the dissolution profile tablet formulation not comprising binder is comparable with that of the tablet formulation comprising binder.

16. The formulation of claim 1 wherein the formulation is used for the treatment of fibrotic condition.

17. A high drug load extended release tablet formulation comprising 70% pirfenidone, 25% release controlling agent, 4% diluent, 0.3% disintegrants, 0.7% lubricant based on total weight of tablet formulation.

18. A high drug load extended release tablet formulation comprising :

i. 70% pirfenidone,

ii. 25% release controlling agent selected from hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyoxyethylene oxide or combination thereof,

iii. 4% microcrystalline cellulose,

iv. 0.3% colloidal silicon dioxide and

v. 0.7% magnesium stearate

based on total weight of tablet formulation wherein the tablet is prepared by process selected from wet granulation, dry granulation, hot melt granulation, screw granulation or combination thereof.