DESC:FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients. It further provides a process for the preparation of said pharmaceutical composition, and their use to treat certain fibrosis diseases.

BACKGROUND OF THE INVENTION

Pirfenidone is a non-peptide synthetic molecule, and it is chemically known as 5-Methyl-1-phenylpyridin-2-one. Its empirical formula is C12H11NO and the molecular weight is 185.22 g/mol. The chemical structure of Pirfenidone is shown in formula below:

Currently, Pirfenidone capsule and tablet is available under the brand name of Esbriet®, for the treatment of idiopathic pulmonary fibrosis.

The U.S. Patent No. 3,839,346 disclosed the Pirfenidone (AMR-69). Pirfenidone is manufactured and being evaluated clinically as a broad-spectrum anti-fibrotic drug. The half-life (Tl/2) of pirfenidone is approximately 3 hours in healthy subjects. This patent mentions about a tablet dosage form of 5 methyl-l-phenyl-2-(IH) pyridine with polyvinylpyrrolidone, silicic acid, corn starch, magnesium stearate, talc and milk sugar as excipients. Further this patent also discloses that formulation with pirfenidone can also be prepared in the form of pills, dragees, capsules, chachets, suppositories sustained release pulvules and similar pharmaceutical forms.

The U.S. Patent No. 9,561,217 describes the tablet dosage form comprising microcrystalline cellulose, colloidal anhydrous silica, povidone, croscarmellose sodium, magnesium stearate, titanium dioxide, talc.

The U.S. Patent No. 7,767,225 describes the capsule dosage form comprising microcrystalline cellulose, croscarmellose sodium, povidone, and magnesium stearate.

There are many factors which determine the effectiveness of a formulation like amount of pirfenidone in formulation, pharmacologically inert excipients used in formulation and the target dissolution profile of the formulation. All these factors affect the pharmacokinetic responses in the patient. Therefore, it is desirable to have a stable and effective pharmaceutical composition of pirfenidone, which provides drug release characteristics similar to the reference drug product, and also comply with high purity needs of regulatory agencies.

Thus, there is a need, in general, for effective pharmaceutical compositions that provide desirable pharmacokinetic responses in patients and having drug release characteristics similar to the reference drug product Esbriet®, thereby optimizing therapeutic actions of pirfenidone.

OBJECTS OF THE INVENTION

The primary object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone, and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients, wherein the said copovidone acts as a binder in the said composition.

Another object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients, wherein the said composition is present in the form of granules which can be either filled in capsule or compressed into tablet with optional film coating.

Another object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone, and one or more pharmaceutically acceptable excipients, wherein the said excipients further comprise at least one diluent, at least one disintegrant, at least one lubricant or mixtures thereof.

Another object of the present invention is to provide a process for the preparation of pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients, wherein the copovidone acts as a binder in the said composition and is responsible for providing similar dissolution profile to the reference drug product Esbriet®.

Further, the said composition is present in the form of granules, which can be either filled in capsule or compressed into tablet with optional a film coating. Also, the present invention discloses process for the preparation of said pharmaceutical composition, and their use to treat certain fibrosis diseases.

DETAILED DESCRIPTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

The term “pharmaceutical composition” for the purpose of the invention, means a composition of granules which can be either filled in capsule or can be compressed into tablet with optional film coating. The pharmaceutical composition of the present invention provides similar dissolution profile to the reference drug product, commercially available as Esbriet® (Pirfenidone; Oral tablets and capsules).

The term “AUC” for the purpose of the invention, means the area under the curve that represents changes in blood concentrations of pirfenidone over time.

The term “Cmax” for the purpose of the invention, means the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of pirfenidone over time.

The term “Tmax” for the purpose of the invention, means the time that it takes for pirfenidone blood concentration to reach the maximum value.

The term “Tl/2” for the purpose of the invention, means the time that it takes for pirfenidone blood concentration to decline to one-half of the maximum level.

The term “Pharmacokinetic Parameter” for the purpose of this invention, means parameter like AUC, Cmax, Tmax and Tl/2 that characterizes the pharmacokinetic responses of a particular drug product.

The term “film coat” for the purpose of the invention, means a thin polymer-based coat applied to a solid dosage form such as a tablet or capsule, so as to provide aesthetic look and moisture barrier.

The primary object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone, and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients, wherein the copovidone acts as a binder in the said composition.

Not bound to any theory, the term "binder" for the purpose of the invention, means a pharmaceutically acceptable excipient that substantially hold the active pharmaceutical ingredient and excipients together in a cohesive mix. The binder, as used hereinbefore, refers to an excipient that holds the pirfenidone in a cohesive mix and control pirfenidone release that results in slow building up plasma concentration of pirfenidone and provides drug release characteristics similar to the reference drug product.

The inventors of the present invention tried to use the commonly used binder in the pharmaceutical composition containing pirfenidone, such that it provides drug release characteristics similar to the reference drug product. However, it was found that granules formulated using copovidone, gives stable and effective pharmaceutical composition of pirfenidone which provides drug release characteristics similar to the reference drug product.

The copovidone may be added as dry binder during dry mixing and/or wet binder during the granulation process. Further, pharmaceutical composition of the present invention may also comprise optionally additional binders which can be selected form the group consisting of microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, pregelatinized starch, hypromellose, copovidone and polyvinylpyrrolidone or mixture thereof.

In one of the preferred embodiment, the pharmaceutical composition of the present invention comprises pirfenidone with copovidone, wherein copovidone is present at concentration of at least 2 to 5 % w/w of the said pharmaceutical composition.

In one of the embodiment, the pharmaceutical composition of the present invention comprises 100-1200 mg of pirfenidone.

In one of the preferred embodiment, the pharmaceutical composition of the present invention is present in the form of granules, which can be filled in capsule or can be compressed into tablet with optional film coating.

In another preferred embodiment, the capsule shell may be made of hard gelatin, which may be clear or opaque, and white or different color. The size of capsule is 1 in a preferred embodiment. Other sizes may be adopted in alternative embodiments.

In one of the embodiment, the compressed tablets are further coated with a film coating. The film coating comprises water-soluble film former polymer with plasticizers, colorants, opacifiers and coating solvents. Preferably the film coating composition comprises polyvinyl alcohol, titanium dioxide, talc, iron oxide yellow, iron oxide black, iron oxide red, Glycerol esters of fatty acids and sodium lauryl sulfate (SLS).

In addition to the above-mentioned ingredients, pharmaceutical composition of the present invention may also comprise one or more pharmaceutically acceptable excipients such as at least one diluent, at least one disintegrant, at least one lubricant or mixtures thereof, which can be provided as intragranular and/or extragranular components. It is known to a person skilled in the art that the excipients can perform more than one function in the pharmaceutical composition.

The diluent can be selected form the group consisting of calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrates, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol or mixture thereof

The disintegrant can be selected form the group consisting of agar-agar, algins, calcium carbonate, carboxymethylcellulose, cellulose, clays, colloidal silicon dioxide, croscarmellose sodium, crospovidone, gums, magnesium aluminium silicate, methylcellulose, polacrilin potassium, sodium alginate, low substituted hydroxypropylcellulose, and cross-linked polyvinylpyrrolidone, hydroxypropylcellulose, sodium starch glycolate, and starch or mixture thereof.

The lubricant can be selected form the group consisting of agar, calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycols, sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearic acid, talc, and zinc stearate or mixture thereof.

In a preferred embodiment, pharmaceutically acceptable excipients of the present invention include, non-limiting examples such as lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, gelatin or mixture thereof.

The pharmaceutical composition of the present invention may be prepared by a conventional process known in the art, such as wet granulation and dry granulation. Preferably the method for preparation of the said pharmaceutical composition is wet granulation.

According to present invention a pirfenidone granules are prepared by wet granulation comprising following steps:

(a) sifting of pirfenidone, one or more diluent, one or more disintegrant through appropriate mesh and mixing in a suitable mixer,
(b) dissolving a binder in a solvent to produce a granulation liquid,
(c) granulating the sifted blend using granulation liquid of step (b) in Rapid Mixture Granulation,
(d) after completion of the granulation, drying and optionally, screening the granulate obtained in step (c),
(e) optionally blending the granulate obtained in step (d) with additional excipients; and,
(f) lubricating the blended granules obtained in step (e) to prepare the final composition.

In one of the embodiment, the lubricated granules prepared according to the present invention are further either filled in capsule or compressed into tablet with optional film coating.

In one of the embodiment, the pharmaceutical composition of the present invention can be used in treatment of Idiopathic pulmonary fibrosis.

In one of the embodiment, the pharmaceutical composition of the present invention remains stable and total impurity remains in acceptable limit when pharmaceutical composition of the present invention kept on 40°C / 75% RH for 180 days. Acceptable limits of the said total impurities of pirfenidone according to the present invention are not more than 1% w/w, when determined after 180 days when kept at 40°C / 75% RH.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

EXAMPLE - 1: Pharmaceutical Composition of Pirfenidone.
Ingredient %w/w
Pirfenidone 60-95%
Copovidone 2-5 %
Binder 2-30%
Diluent 2-30%
Disintegrant 2-10%
Lubricant 0.3-0.8%

Brief Manufacturing Process:
1. Co-Sift pirfenidone, diluent and copovidone through #30 ASTM.
2. Granulate sifted blend using purified water in RMG followed by drying.
3. Sift dried granules through #30 ASTM. Mill the oversized granules through multi mill using 1.00 mm screen.
4. Blend the dried granules with disintegrant and lubricant.
5. Lubricated granules either filled in capsule or compressed into tablet with optional film coating.

EXAPMLE – 2: Pharmaceutical Composition of Pirfenidone tablet and capsule
mg/tablet mg/capsule
Strength 267 mg 801 mg 267 mg
Dry mix
Pirfenidone 267.00 801.00 267.00
Lactose Monohydrate 27.60 82.80 27.60
Copovidone 16.000 48.000 16.000
Binder solution
Purified water q.s. q.s. q.s.
Lubrication
Croscarmellose sodium 6.40 19.20 2.00
Magnesium Stearate 3.00 9.00 0.94
Core tablet / capsule weight (mg) 320.00 960.00 320.00
Tablet compression / Capsule Filling
Size 1 HCG - - 75.00
Filled Capsule weight (mg) - - 395.00
Film Coating of compressed tablets
Opadry II (Polyvinyl alcohol, Macrogol, Titanium dioxide, Talc, ferric oxide) 10.00 30.00 -
Coated tablet weight (mg) 330.00 990.00 -

Brief Manufacturing Process:
1. Co-Sift Pirfenidone, lactose monohydrate and copovidone through #30 ASTM.
2. Granulate sifted blend using purified water in RMG followed by drying.
3. Sift dried granules through #30 ASTM. Mill the oversized granules through multi mill using 1.00 mm screen.
4. Blend the dried granules with croscarmellose sodium and magnesium stearate.
5. Compress the lubricated blend using compression machine into tablet or fill the lubricated blend in hard gelatin capsule shells.
6. Coat the compressed tablets with the suspension of Opadry II in purified water.

EXAMPLE - 3: Dissolution Profile of Pirfenidone tablets
Time (min) Dissolution Profile: Media – Deionized water, Apparatus – Paddle 50 RPM, 1000 mL
Esbriet® Tablet
(267 mg) Pirfenidone Tablet
(Copovidone as a binder) 267 mg Esbriet® Tablet
(801 mg) Pirfenidone Tablet
(Copovidone as a binder) 801 mg
5 79 (58-85) 81 (76-87) 67 (64-69) 80 (78-82)
10 92 (91-93) 99 (98-100) 86 (85-87) 95 (94-96)
15 96 (95-97) 100 (99-100) 92 (90-93) 98 (97-99)
20 98 (97-98) 100 (100-101) 94 (93-96) 99 (99-100)
30 99 (99-99) 100 (100-101) 96 (95-97) 100 (97-101)
45 100 (100-101) 101 (100-102) 98 (97-98) 100 (98-101)
60 101 (100-101) 102 (101-102) 99 (98-100) 101 (100-102)
Note: Results are in Mean (Minimum – Maximum)

EXAMPLE - 4: Dissolution Profile of Pirfenidone capsules
Time (min) Dissolution Profile: Media – Deionized water, Apparatus – Paddle 50 RPM, 1000 mL
Esbriet® Capsule (267 mg) Pirfenidone Capsule (Copovidone as a binder) 267 mg
5 52 (41-60) 51 (47-57)
10 72 (67-81) 85 (74-92)
15 80 (75-90) 96 (90-100)
20 88 (82-96) 99 (97-102)
30 94 (82-96) 101 (100-101)
45 97 (94-99) 101 (101-102)
60 98 (97-99) 101 (100-102)
Note: Results are in Mean (Minimum – Maximum)

In above Example 3 and 4, the dissolution test were performed with pirfenidone capsule and tablet (with copovidone) and Esbriet® (with povidone) respectively. Here, the dissolution profile of pirfenidone capsule and tablet with copovidone shows equivalent dissolution profile as that of Esbriet® (reference product).

Further the pirfenidone capsule is tested for bioequivalence study and the results are shown in example 5.

EXAMPLE - 5: Bioequivalence study results of Pirfenidone capsule
Study Confidence Interval 90%
(Fasting) Confidence Interval 90%
(Fed)
No of subjects 18 18
Cmax 96.6 (80.55-115.72) 109.2 (98.97-120.57)
AUC 0-t 97.0 (88.57-106.31) 108.0 (97.33-119.78)
AUC 0-8 97.0 (88.44-106.37) 107.8 (97.21-119.55)
Tmax 1.109 (T); 0.874 (R) 1.887 (T); 1.964 (R)

EXAMPLE - 6: Bioequivalence study results of Pirfenidone tablet
Study Confidence Interval 90%
(Fasting) Confidence Interval 90%
(Fed)
No of subjects 18 18
Cmax 90.2 (81.58-99.69) 104.0 (94.71 -114.23)
AUC 0-t 92.9 (85.94-100.45) 105.7 (97.11 -115.04)
AUC 0-8 93.1 (86.05-100.67) 105.9 (97.27 -115.27)
Tmax 0.701 (T); 0.647 (R) 2.838 (T); 3.019 (R)

The pharmaceutical composition of the present invention met the bioequivalence criteria of 90% Confidence Interval (80% to 125%) when compared with Esbriet® Capsules and tablet in fasting and fed state based on Cmax, AUC 0-t, AUC 0-8 and Tmax.

The stability study for total pirfenidone impurities along with dissolution study of example 2 were carried out at 40°C / 75% RH for 180 days.

EXAMPLE - 6: Total impurity profile and dissolution study results of pirfenidone capsule
Stability condition 40°C/75% RH
Tests Initial 30 days 60 days 90 days 180 days
Pack HDPE Bottles
Assay 99.30% 100.70% 99.30% 98.20% 99.20%
Water 1.32% 1.70% 1.18% 1.23% 1.02%
Total Impurity 0.006% 0.006% 0.008% ND 0.007%
Dissolution
45 minutes 96%
(90-100) 101%
(99-102) 100%
(98-101) 99%
(99-100) 100 %
(99-101)

EXAMPLE - 7: Total impurity profile and dissolution study results of pirfenidone Tablet
Stability Condition 40°C/75% RH
Tests Initial 30 days 60 days 90 days 180 days
Pack HDPE Bottles
Assay 100.80% 98.20% 98.40% 99.50% 99.60%
Water content 1.42% 1.29% 1.68% 1.20% 1.34%
Total Impurity 0.006% 0.007% ND ND ND
Dissolution
45 minutes 101%
(100-102) 101%
(100-103) 99%
(96-100) 100%
(99-102) 101%
(100-102)

Total impurity profile and dissolution profile of the pharmaceutical compositions according to example 2 meets the acceptance criteria of total impurities and dissolution limit as disclosed hereinabove. ,CLAIMS:We claim,

1. A stable oral pharmaceutical composition comprising,
i. pirfenidone;
ii. copovidone; and
iii. one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the amount of pirfenidone in the composition is 100 mg to 1200 mg.

3. The pharmaceutical composition as claimed in claim 1, wherein the amount of copovidone in the composition is at least 2.5 % w/w to 5 % w/w.

4. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutically acceptable excipient is selected from the group comprising diluent, disintegrant or lubricant or mixture thereof.

5. The pharmaceutical composition as claimed in claim 1, wherein the said composition is present in the form of granules which can be either filled in capsule or compressed into tablet with optional film coating.

6. The pharmaceutical composition as claimed in claim 1, wherein the total impurity in said composition are not more than 1% w/w when kept at 40°C / 75% RH for 180 days.

7. A process for the preparation of stable oral pharmaceutical composition comprising pirfenidone, copovidone and one or more pharmaceutically acceptable excipients; wherein the method comprises the steps of:

(a) mixing pirfenidone, one or more diluent, one or more disintegrant in a suitable mixer;
(b) dissolving a Copovidone in a solvent to produce a granulation liquid;
(c) granulating the sifted blend using granulation liquid of step (b) in Rapid Mixture Granulation;
(d) drying the granulate obtained in step (c);
(e) optionally blending the granulate obtained in step (d) with additional excipients; and,
(f) lubricating the blended granules obtained in step (e) to prepare the final composition.