Claims:We Claim:
1. A reservoir-matrix dosage delivery system comprising Pirfenidone or its pharmaceutically acceptable salt thereof.
2. Reservoir-matrix dosage delivery system according to claim 1, comprises excipients selected from diluents, binders, disintegrants,
3. The reservoir-matrix dosage delivery according to claim 1, wherein the manufacturing process by granulation technique, most preferably wet granulation method.
4. A composition according to claim 1, wherein the carrier particles contain diameter (0.9) is not more than 150 microns, preferably diameter (0.9) is not more than 70 microns and most preferable diameter (0.9) is not more than 50 microns.
5. A composition according to claim 1, wherein the functional coating systems contains Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 and Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 , ethyl cellulose derivatives and its combination or alone.
6. A composition according to claim 1, wherein the reservoir coating system contains water soluble pore former like hypromellose, povidone, triethyl citrate, polysorbate 80 or any.
7. A composition according to claim 1, wherein the dissolution is carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.
, Description:FIELD OF THE INVENTION:

The present invention relates to pharmaceutical compositions comprising Pirfenidone with a reservoir-matrix dosage delivery system for treating pulmonary fibrosis.

BACKGROUND OF THE INVENTION:

Pirfenidone is chemically known as 5-methyl-1-phenyl-2-(1H)-pyridone. It is indicated for the treatment of Idiopathic pulmonary fibrosis. Pirfenidone is a pyridone analog that works by inhibiting collagen synthesis and fibroblast growth in a dose-dependent manner. The chemical structure of Pirfenidone is as depicted below:

Pirfenidone is sold under brand name Esbriet® has been approved for treatment of fibrotic disorder and is effectively treated by administering the dose three times a day. However, the three times a day dosing regimen is quite cumbersome for the patient. Studies have shown that patient compliance increases as the dosing regimen decreases and is higher if it is once a day. Therefore, a dosage form that reduces the Pirfenidone daily dosing regimen, while maintaining a stable plasma level of Pirfenidone, i.e., an extended release form particularly, a reservoir matrix type formulation, would be advantageous.

US Patent No. 3,839,346, describes the synthesis of Pirfenidone. Oral preparations of Pirfenidone are disclosed in US Patent No.’s 7,767,225 B2; 9,017,722 B2; 9,408,836 B2 and 10,188,637 B2.

PCT International Publication No. WO 2020/115774 A1 discloses a high drug load extended release tablet formulation comprising about 50 to about 90 w/w% Pirfenidone, at least one release controlling agent and optionally pharmaceutically acceptable excipient(s) wherein the release controlling agent is incorporated within the core of the tablet.

KR Patent Application Pub. No. 10-2019-0018584 A discloses a delayed release tablet composition comprising Pirfenidone, a polymer having a viscosity of 1,000 cPs or more and a molecular weight of 10,000 g/mol or more; and a channelling agent prepared by wet granulation method.

Chinese Patent Application Pub. No. 102488660 A discloses a slow release micropill comprising Pirfenidone and auxillary materials wherein said slow-release micro-pill comprises sphere, medicine layer, slow release layer and pastille release layer from inside to outside successively.

Chinese Patent Application Pub. No. 101972236 A discloses a sustained-release tablet composition which comprises active component Pirfenidone, sustained-release matrix material and additives.

Drug release is a complex interplay of the coating and the drug core. Reservoir matrix systems has gained increasing attention in recent years because of limitations of conventional drugs formulations as these systems provide a significant advantage over immediate release compositions to both clinicians and patients.

In a matrix delivery system, the drug is either molecularly dissolved or dispersed inside a matrix and the reservoir system is enveloped with a rate limiting membrane. This type of drug delivery has been at the centre of research due to its many benefits over conventional dosage forms. These dosage forms are administered to patients in much fewer daily doses than their immediate release counterparts and generally achieve desired therapeutic effect and efficiency in the fewer daily doses. For example, if a drug is administered multiple times a day it will be difficult for a patient who swallows and there may be chances that the patient may skip the dose unknowingly. If the drug is formulated as reservoir matrix type dosage form it would rather decrease dosing frequency and the patient may not have fear of missing the dose.

Henceforth, the object of the present invention is to provide an extended release pharmaceutical composition comprising Pirfenidone for once a day administration and which can deliver the drug in a controlled manner.

Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, this type of dosage forms generally helps to reduce side effects caused by the drug as these dosage forms deliver the drug in a slow, incremental amounts besides high and low concentrations of immediate release formulations which is easier for a patient's body to digest the drug, thereby avoiding undesirable side-effects.

Numerous patents teach modified release drug delivery systems of which US patent No. 9,408,836 list Pirfenidone as a suitable candidate for modified release. However, such systems do not allow for the peculiar properties of Pirfenidone owing to its lower maintenance dose and thus yield less than ideal extended release formulations. Further, these systems do not allow for the balance that must be made between the amount of the drug immediately released and the amount of time over which the remaining drug in the sustained release portion is released.

For example, if too much Pirfenidone is present in the immediate release portion, the result is essentially the same as that obtained with the commercially available tablets, i.e., an immediate release formulation. Conversely, if too little Pirfenidone is present in the immediate release portion, the resulting formulation exhibits poor bioavailability. Furthermore, most formulations which claim twelve-hour potency release almost the entire drug within six to eight hours, making the formulation less therapeutically effective towards the end of the twelve-hour period. To prevent blood serum concentrations of active drug from falling below a therapeutically effective level at extended time periods, many manufacturers increase the drug strength of the dosage form. The increase in drug strength, however, results in a concomitant increase in side-effects. Therefore, it requires expertise and skill to present the dose with desired properties while maintaining the dosage strength and achieve therapeutic benefit.

Without being bound by any theory, the inventors of the present invention surprisingly found that the pharmaceutical compositions prepared according to the invention achieves required dissolution profile and bioavailability, particularly with extended release formulations comprising Pirfenidone administered once a day, which is highly cost effective.

The present invention has the following advantages:

? For patients who self-administer therapies, reservoir matrix type dosage forms generally result in greater compliance due to the lower frequency of dosing, lower quantity of dosage units to be consumed, and reduced undesired side-effects.
? The release of the drug is kept constant even if the coating accidentally ruptures.
? There is a lower risk of dose dumping and the possibility of improvement of aqueous drug solubility.
? Drug-polymer interactions can occur and bring benefits in terms of mechanical properties such as plasticizing effect.
? The main advantage of these type of systems include fast initial release and complete drug release in a defined time. In addition, matrix systems were found suitable to control drug release of a highly soluble drug.
? Easy to manufacture and cost is low.

Therefore, the inventors of the present invention developed an extended release pharmaceutical composition comprising Pirfenidone as active ingredient which is administered once a day and achieves enhanced bioavailability.

OBJECTIVE OF THE INVENTION:

The object of the present invention relates to pharmaceutical composition comprising Pirfenidone with reservoir-matrix dosage delivery systems for the treatment of pulmonary fibrosis.

SUMMARY OF THE INVENTION:

The first aspect of the present invention is to provide pharmaceutical compositions comprising Pirfenidone with reservoir-matrix dosage delivery systems for the treatment of pulmonary fibrosis.

Second aspect of the present invention is to provide an extended release pharmaceutical composition of Pirfenidone comprising a matrix core component and a reservoir coating or a pharmaceutically acceptable salt thereof.

The other aspect of the present invention is to provide an extended release pharmaceutical composition of Pirfenidone comprising a matrix core component and a reservoir coating or a pharmaceutically acceptable salt thereof.

Third aspect of the present invention is to provide reservoir-matrix dosage delivery using the manufacturing process by granulation technique, most preferably wet granulation method.

Fourth aspect of the present invention is to provide the carrier particles having a diameter (0.9) not more than 150 microns, preferably diameter (0.9) not more than 70 microns and most preferably diameter (0.9) is not more than 50 microns.

Fifth aspect of the present invention is to provide the dissolution of the pharmaceutical composition to be carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an extended release pharmaceutical composition comprising Pirfenidone and the process for its preparation thereof. Further, the said pharmaceutical composition is useful for the treatment of pulmonary fibrosis.

As used herein, the term ‘active ingredient’ includes any compound or any agent that has therapeutic properties that is known to or that is useful for treatment for the corresponding disease. The most preferred active ingredient is Pirfenidone.

As used herein, the term ‘salt’ or ‘pharmaceutically acceptable salt’ refers to salts of active ingredient which are well known in the art that include salts of sodium, calcium, potassium, magnesium, hydrochloride, hydrobromide, furoate, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and laurate.

As used herein, the term ‘pharmaceutical composition’ refers to the therapeutic compound with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in order to prevent, treat or control a particular disease or condition affecting the mammal. This includes orally administrable formulations as well as formulations administrable by other means. The term pharmaceutical composition can be used interchangeably with the term ‘composition’ or ‘formulation’.

As used herein, the term ‘dosage form’ referring to the solid drug products such as capsules or tablets in all its variations that contains an amount sufficient to produce a therapeutic effect with a single administration. The dosage form of the present invention is for oral administration.

As used herein, the term ‘excipient’ or ‘pharmaceutically acceptable excipients’ is intended to denote all the components of the tablet other than the biologically active substance approved by regulatory authorities or which are regarded as safe for human or animal use. The term inactive pharmaceutical ingredient is used herein synonymously for pharmaceutical excipient.

As used herein, the term ‘immediate release’ refers to a part or layer or all of a dosage form that releases active agent substantially immediately upon contact with gastric environment and that results in substantially complete dissolution within about 1 hour. When used in association with the dissolution profiles discussed herein, the term ‘immediate release’ refers to that portion of a dosage form according to the present invention that delivers active agent over a period of time less than 1 hour.

As used herein, the term ‘extended release’ refers to refers to a composition in which a drug is released over an extended period of time, such as over 4, 6, 10, 12, 15, 18, 20 or 24 hours, specifically over a period of up to 20 hours and is taken to encompass sustained release, controlled release, modified release, prolonged release, delayed release and the like.
As used herein, the term “matrix core component” means an uncoated, compressed tablet. The tablet core of the dosage form of the present invention comprises a matrix of a drug and a controlled release polymer. Once the tablet exits the highly acidic environment of the stomach and enters the intestine, the coating dissolves there from, and the core continues to release drug in a controlled fashion.

As used herein, the term “reservoir system” is when drug diffusion through the coating is a limiting step and drug dissolution is much faster than diffusion. The entire release process of such a system can be divided into two distinctive phases. The ?rst phase is typi?ed by a zero-order release pro?le due to the presence of a constant reservoir, i.e., the drug concentration in the core is above drug solubility Cs. The second phase is characterized by a ?rst-order release pro?le owing to a non-constant reservoir, i.e., only dissolved drug exists in the system which is gradually depleted.

As used herein, the term "functional coating" is a coating that modifies the release properties of the total formulation.

As used herein, the term ‘wet granulation’ refers to any process comprising the steps of addition of a liquid to powdered materials, agitation, and drying to yield a solid dosage form. The resulting granulated drug product may be further processed into various final dosage forms.

As used herein, the term ‘dissolution’ refers to the process by which the active ingredient is being dissolved from the dosage form in the presence of a solvent. In the present invention dissolution is carried out in 900 ml of pH 6.8 phosphate buffer as dissolution medium in a Paddle (Type II) apparatus at 50 RPM.

As used herein, the term ‘stability’ refer to the ability of a composition to withstand degradation or decomposition when kept at a particular temperature for a specified period of time, preferably under inert atmosphere. In the present invention stability is carried out at 40ºC±2ºC/ 75% ±5%RH and 25ºC±2ºC/ 60%±5% RH for a period of one month, two months, three months, six months, nine months, twelve months thereof.

As used herein, the term “effective amount” or “therapeutically effective amount” is well known in the art. It is meant to describe a non-toxic but sufficient amount of the agent capable of providing a desired therapeutic effect. An appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.

As used herein, the term ‘treating’ or ‘treatment’ refers to the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by Pirfenidone in a mammal.
As used herein, the term ‘subject’ includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.

As used herein, the singular forms "a," "an," and "the" include the plural reference unless the context clearly indicates otherwise.

In one embodiment of the present invention is to provide an extended release pharmaceutical composition of Pirfenidone comprising a matrix core component or a pharmaceutically acceptable salt thereof.

In an embodiment of the present invention is to provide an extended release pharmaceutical composition of Pirfenidone comprising a matrix core component and a reservoir coating or a pharmaceutically acceptable salt thereof.

Accordingly, preferred embodiment of the present invention is to provide an extended release pharmaceutical composition of Pirfenidone comprising about 30% to about 90% by weight of Pirfenidone based on total amount of tablet.

In another embodiment of the present invention is to provide an extended release pharmaceutical composition comprising Pirfenidone, a suitable diluent, a suitable disintegrant, a suitable polymer, a suitable binder, a suitable glidant, and optionally a pharmaceutical acceptable excipient.

In a preferred embodiment of the present invention is to provide a pharmaceutical composition comprising an extended release pharmaceutical composition containing Pirfenidone, maltodextrin, sodium starch glycolate, hypromellose, povidone, colloidal silicon dioxide and magnesium stearate.

In yet an embodiment of the present invention is to provide a pharmaceutical composition comprising an extended release pharmaceutical composition containing Pirfenidone, maltodextrin, sodium starch glycolate, hypromellose, povidone, colloidal silicon dioxide, magnesium stearate, seal coating and functional coating.

Excipient means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling, storage, disintegration, dispersion, dissolution, release or organoleptic properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.

Pharmaceutical compositions of the present invention comprise Pirfenidone and one or more excipients selected from the group consisting of control release polymers, diluents, disintegrants, binders, lubricants, glidants, film formers, surfactants, plasticizers and solvents; and substances added to improve appearance of the composition.

Diluents as used herein, make up the required bulk of solid dosage form. Diluents may include, but are not limited to, microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, or combinations thereof. Most preferred diluent is maltodextrin.

Binders as used herein, means substances used to provide adhesion of powder particles in tablet granulations. Binders include cellulose derivatives such as microcrystalline cellulose, methylcellulose, carboxymethycellulose sodium, HPMC, hydroxyethyl cellulose, and hydroxypropyl cellulose, povidone, polyvinyl pyrrolidone, gelatin, natural gums, starch, pregelatinized starch, sucrose, corn syrup, polyethylene glycols, and sodium alginate, ammonium calcium alginate, magnesium aluminum silicate, polyethylene glycols. Most preferred binder is povidone.

Disintegrants as used herein, means a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, but are not limited to, mannitol, alginic acid, carboxymethylcellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone, Mg aluminum silicate, methylcellulose, povidone, sodium alginate, sodium starch glycolate and starch. Most preferred disintegrant is sodium starch glycolate.

Surfactants as used herein, refers to a substance or compound that reduces surface tension when dissolved in water or water solutions, or that reduces interfacial tension between two liquids, or between a liquid and a solid. The term “surfactant” thus includes cationic, anionic, nonionic, zwitterionic, and amphoteric agents and combinations thereof. Examples include, but are not limited to, sodium lauryl sulfate, sodium dioctylsulfosuccinate (DOSS), lecithin, cetrimide, polysorbate, poloxamer, spans, polyoxyethylene resin oil, polyoxyethylene fatty acid glycerides, betacyclodextrin, polyethoxylated castor oil, polyethylene glycol, propylene glycol monolaurate and combinations thereof. The most preferred surfactant polysorbate.

Plasticizer as used herein, means a compound used in solid dosage forms to provide the desired plasticity to the coating. Exemplary plasticizers include, but are not limited to, propylene glycol, polyethylene glycol, triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate, benzyl benzoate, chlorbutanol, dextrin, glycerin, glycerin monostearate, mannitol, lanolin alcohol, 2-pyrrolidine, sorbitol, triacetin, diacetylated monoglyceride, tri butyl citrate, triethanolamine, and the like and mixtures thereof. Most preferred plasticizer is triethyl citrate.

Lubricant as used herein, means substances used in tablet formulations to reduce friction during tablet compression. Lubricants typically include hydrogenated vegetable oils (such as corn oil), hydrogenated mineral oils, polyethylene glycols, salts of stearic acid, talc, inorganic salts, organic salts and polyvinyl alcohols. Most preferred lubricant is magnesium stearate.
Glidants as used herein, means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Glidants are selected from, but not limited to, talc, colloidal silicon dioxide, silicates, powdered cellulose, starch, tribasic calcium phosphate, silicon hydrogel. Most preferred glidant is colloidal silicon dioxide.

Film formers as used herein, are used in the formulation process to apply a coating layer to provide a range of functionalities. Suitable film formers may include one or more of hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, acrylates and the like. Most preferred film former is hydroxypropyl methyl cellulose.

Control release polymers as used herein, are substances which control the release of a drug from the dosage form for an extended period of time. The rate controlling agents or control release polymers may include a hydrophilic or a hydrophobic substance. Suitable hydrophilic substances are selected from, but not limited to one or more of cellulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose sodium; polyacrylates, methyl acrylates, Eudragit, polyethylene oxides, polyethylene glycols, starch derivatives, polyurethanes, pectin, gelatin, hyaluronic acid, acrylamide derivatives and the like. Suitable hydrophobic substances are selected from, but not limited to one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnauba wax, hydrogenated vegetable oil and its derivatives, acrylate and phthalate polymers and copolymers. Most preferred control release polymer is hydroxypropyl methylcellulose.

Solvents as used herein, is applied to a large number of chemical substances which are used to dissolve or dilute other substances or materials. Suitable solvents may include one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride and the like.

The tablets or granules prepared according to the invention are coated with suitable coating agents. Coatings may be employed for aesthetic purpose or for stabilizing the tablets or for retarding the drug-release.

The tablet core of the dosage form of the present invention is coated with an functional coating. A functional coating modifies the release properties of the total formulation in the presence of rate control agents/ control release polymers.
The invention further provides for unit dose extended release pharmaceutical composition of 250 mg to 750 mg Pirfenidone comprising about 5% to about 30% by weight of a controlled release excipient for once a day oral administration.

In yet another embodiment of the present invention, the extended release pharmaceutical composition comprising Pirfenidone is prepared by granulation technique.

In yet another preferred embodiment of the present invention, the extended release pharmaceutical composition comprising Pirfenidone is prepared by granulation technique; preferably wet granulation.

Compositions having enhanced compressibility and flow characteristics are obtained using wet granulation. The granulation may be carried out by aqueous or non-aqueous method. A wet granulation process comprises the steps of dry mixing Pirfenidone with one or more excipients, wet granulating the dry mix using a binder solution to form granules, followed by drying, lubricating the dried granules, followed by compression into tablets.

In further an embodiment there is provided a process of preparing an extended release pharmaceutical composition comprising matrix core component and functional coating:

Matrix core component
a) blending Pirfenidone, a suitable diluent, a suitable disintegrant and a suitable polymer
b) dissolving a suitable binder in water under continuous stirring,
c) granulating the blend of step a) with binder solution of step b)
d) drying the granules obtained in step c)
e) blending the granules obtained in step d) with a suitable polymer and a suitable glidant,
f) lubricating the blend obtained in step e) with a suitable lubricating agent,

Compression
g) blending and/ or compressing the lubricated blend of step f)
h) optionally, coating the tablet.
Functional coating
i) obtaining a solution by mixing suitable solvents and dividing the mixture into two equal parts
j) dissolving a suitable polymer(s) in one part of step i) to obtain first solution
k) dissolving a suitable plasticizer, a suitable surfactant and a suitable glidant in other part of step i) to obtain second solution
l) mixing the solution of step j) with solution of step k)
m) coating the compressed tablet.
In a preferred embodiment, there is provided a process of preparing an extended release pharmaceutical composition comprising:

Matrix core component
a) blending Pirfenidone, maltodextrin, sodium starch glycolate and hypromellose
b) dissolving povidone in water under continuous stirring,
c) granulating the blend of step a) with binder solution of step b)
d) drying the granules obtained in step c)
e) blending the granules obtained in step d) with hypromellose and colloidal silicon dioxide;
f) lubricating the blend obtained in step e) with magnesium stearate,

Compression
g) blending and/ or compressing the lubricated blend of step f)
h) optionally, coating the tablet.

Functional coating component
i) obtaining a solution by mixing acetone, isopropyl alcohol and dividing the mixture into two equal parts
j) dissolving Eudragit of different grades in one part of step i) to obtain first solution
k) dissolving triethyl citrate, polysorbate and talc in in other part of step i) to obtain second solution
l) mixing the solution of step j) with solution of step k)
m) coating the compressed tablet.

In an embodiment, the extended release pharmaceutical composition according to the invention exhibits a release profile characterized in that at least about 5% of Pirfenidone is released after 1 hour, at least about 15% of Pirfenidone is released after 2 hours, at least about 20% of Pirfenidone is released after 4 hours, at least about 30% of Pirfenidone is released after 6 hours, at least about 40% of Pirfenidone is released after 8 hours, and at least about 70% of Pirfenidone is released after 12 hours in 900 ml of phosphate buffer having pH 1.2, 2.0, 4.5 and 6.8; paddle type apparatus and at 50 RPM.

In another embodiment, the extended release pharmaceutical composition comprising Pirfenidone is in the form of laminated tablet, beads, pellets, granules and powder to be administered in a capsule.

In further an embodiment, the extended release pharmaceutical composition comprising Pirfenidone for oral administration for the treatment of pulmonary fibrosis.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLES

Example 1:
Table – 1

S.No Ingredients % w/w
Matrix core component
Intra granular
1 Pirfenidone 73.78
2 Maltodextrin 3.44
3 Sodium starch glycolate 0.98
4 Hypromellose (4000 to 15000 cps) 2.46
Binder solution
5 Povidone K-30 1.97
6 Purified water QS
Extragranular
7 Hypromellose (100,000 cps) 9.34
8 Colloidal silicon dioxide 0.49
9 Magnesium Stearate 0.98
Seal Coating
10 HPMC 5 cps 1.87
11 Purified water QS
Functional coating
12 Eudragit RS PO (Ammonio methacrylate copolymers) 1 : 2 : 0.2 1.11
13 Eudragit RL PO (Ammonio methacrylate copolymers) 1 : 2 : 0.1 1.40
14 Talc 1.49
15 Triethyl citrate 0.47
16 Polysorbate 80 0.20
17 Acetone Q.S
18 Isopropyl Alcohol Q.S
19 Water Q.S
Total 100 %

Manufacturing Procedure:

Matrix core component
a) Pirfenidone, maltodextrin, sodium starch glycolate and hypromellose were blended together,
b) Povidone was dissolved in water under stirring,
c) The blend of step a) was granulated with binder solution of step b),
d) The wet mass obtained in step c) was dried at 50 °C in fluidized bed dryer up to loss on drying 1 to 4%w/w,
e) The granules obtained in step d) were blended with hypromellose and colloidal silicon dioxide,
f) The blend obtained in step e) was lubricated with magnesium stearate.

Compression
g) The lubricated blend of step f) was compressed into tablets
h) Compressed tablets were coated

Seal coating
i) Hypromellose is mixed in purified water and stirred the solution for 45 minutes until clear solution was formed.

Reservoir coating
j) Mixed the acetone, isopropyl alcohol and water as per proposed formula and divided into two equal quantities.
k) Poly (ethyl acrylate, methyl methacrylate, Trimethyl ammonioethyl methacrylate chloride 1 : 2 : 0.2 and Poly (ethyl acrylate, methyl methacrylate, Trimethyl ammonioethyl methacrylate chloride 1 : 2 : 0.1 was added in one portion and stirred for 30 minutes until clear solution was formed.
l) triethyl citrate, polysorbate 80 and talc were added in another solvent portion and stirred for 30 minutes.
m) Mixed Step k) and Step l) in a suitable vessel and stirred for 30 minutes.

Example 2:
Table - 2
S.No Ingredients % w/w
Matrix core component
Intra granular
1 Pirfenidone 75.21
2 Lactose monohydrate 3.51
3 Sodium starch glycolate 1.01
4 Hypromellose (4000 to 15000 cps) 2.51
Binder solution
5 HPMC 5 cps 2.01
6 Purified water Q.S
Extragranular
7 Hypromellose (100,000 cps) 9.53
8 Colloidal silicon dioxide 0.501
9 Magnesium Stearate 1.01
Seal coating
10 HPMC E5 LV 1.90
11 Purified water Q.S
Functional coating
12 Ethyl cellulose 1.13
13 Hypromellose E3 LV 0.82
14 PEG 4000 0.48
15 Polysorbate 80 0.20
16 Dibutyl sebacate 0.20
17 Ethanol Q.S
18 Purified water Q.S
Total 100 %

Manufacturing Procedure:

Matrix core component
a) Pirfenidone, lactose monohydrate, sodium starch glycolate and hypromellose were blended together,
b) Hypromellose was dissolved in water under stirring,
c) The blend of step a) was granulated with binder solution of step b),
d) The wet mass obtained in step c) were dried at 50 °C in fluidised bed dryer up to loss on drying 1 to 4%w/w
e) The granules obtained in step d) were blended with hypromellose and colloidal silicon dioxide;
f) The blend obtained in step e) was lubricated with magnesium stearate.
Compression
g) The lubricated blend of step f) was compressed into tablets,
h) Compressed tablets were seal coated.
Seal coating
i) Hypromellose was mixed in purified water and stirred the solution for 45 minutes until clear solution was formed.
Reservoir coating
j) Mixed ethanol and water as per proposed formula and divided into two equal quantities.
k) Hypromellose & ethyl cellulose was added in one portion and stirred for 30 minutes until clear solution was formed.
l) Polyethylene glycol, dibutyl sebacate and polysorbate 80 were added in another solvent portion and stirred for 30 minutes.
m) Mixed Step k) and Step l) in a suitable vessel and stirred for 30 mins.
n)
Example 3:
Table – 3

S.No Ingredients % w/w
Matrix core component
Intra granular
1 Pirfenidone 74.70
2 Microcrystalline cellulose 3.49
3 Croscarmellose sodium 0.99
4 Hypromellose (4000 to 15000 cps) 2.49
Binder solution
5 HPMC 5 cps 1.99
6 Purified water Q.S
Extragranular
7 Hypromellose (100,000 cps) 9.46
8 Colloidal silicon dioxide 0.49
9 Magnesium Stearate 0.99
Seal coating
10 HPMC E5 LV 1.89
11 Purified water Q.S
Functional coating
12 Ethyl cellulose dispersion 2.49
13 Povidone 0.20
14 PEG 4000 0.40
15 Polysorbate 80 0.20
16 Dibutyl sebacate 0.20
17 Ethanol Q.S
18 Purified water Q.S
Total 100 %

Manufacturing Procedure:
Matrix core component
a) Pirfenidone, microcrystalline cellulose, croscarmellose sodium and hypromellose were blended together,
b) Hypromellose was dissolved in water under stirring,
c) The blend of step a) was granulated with binder solution of step b),
d) The wet mass obtained in step c) were dried at 50 °C in fluidised bed dryer up to loss on drying 1 to 4 % w/w,
e) The granules obtained in step d) were blended with hypromellose and colloidal silicon dioxide,
f) The blend obtained in step e) was lubricated with magnesium stearate,
Compression
g) The lubricated blend of step f) was compressed into tablets,
h) Compressed tablets were seal coated
Seal coating
i) Mixed hypromellose in purified water and stirred the solution for 45 minutes until clear solution was formed.
Reservoir coating component
j) Mixed polyethylene glycol, dibutyl sebacate and polysorbate 80 in water as per proposed formula and stirred for 30 minutes.
k) Added ethyl cellulose dispersion to above solution and stirred for 30 minutes until uniform suspension was obtained.

Example 4:
Dissolution Method:
In vitro dissolution studies on Pirfenidone extended release tablets according to example: 1-3 were carried out using USP apparatus 2 (Paddle type) at 50 RPM in 900 ml of phosphate buffer having pH 1.2, 2.0, 4.5 and 6.8 as a dissolution medium maintained at a temperature of 37±0.5 °C.

Dissolution profiles of example 1 Pirfenidone extended release tablets at different pH scale are given in the below tables:
Table 4: Dissolution- pH 1.2, 900 ml, Paddle, 50 RPM

Time points (hr) 1 2 4 6 8 10 12 18
Example-1 NMT 7 NMT 25 Between 20 to 40 Between 35 to 55 Between 40 to 60 Between 55 to 75 NLT 75 NLT 85

Table 5: Dissolution- pH 2.0, 900 ml, Paddle, 50 RPM

Time points (hr) 1 2 4 6 8 10 12 18
Example-1 NMT 7 NMT 25 Between 20 to 40 Between 35 to 55 Between 40 to 60 Between 55 to 75 NLT 75 NLT 85

Table 6: Dissolution- pH 4.5, 900 ml, Paddle, 50 RPM

Time points (hr) 1 2 4 6 8 10 12 18
Example-1 NMT 7 NMT 25 Between 20 to 40 Between 35 to 55 Between 40 to 60 Between 55 to 75 NLT 75 NLT 85

Table 7: Dissolution- pH 6.8, 900 ml, Paddle, 50 RPM

Time points (hr) 1 2 4 6 8 10 12 18
Example-1 NMT 7 NMT 25 Between 20 to 40 Between 35 to 55 Between 40 to 60 Between 55 to 75 NLT 75 NLT 85

Example 5:
Stability studies:
Stability studies of extended release tablets prepared according to the present invention were carried out in sealed HDPE containers. The sealed HDPE containers were stored in accelerated stability conditions at 40°C ±2°C & 75% ±5% RH and 25°C ±2°C & 60% ±5% RH for a period of one month, two months, three months and six months.