DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

10 The term "Nirmatrelvir" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically
15 acceptable inorganic or organic acids.

The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents,
20 antioxidants, solubilizer, plasticizers or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "binder" employed in a composition of the present invention is capable for holding
25 the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or
5 lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.
10
The term " Glidant" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The Glidant of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, Colloidal Silicon dioxide (fumed silica), hydrophilic silica, calcium sulphate or dicalcium
15 phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

20 The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention include, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol,
25 mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "disintegrant" employed in a composition of the present invention is capable of
30 facilitating the breakup of a pharmaceutical composition prepared from the composition when

placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, powdered cellulose or croscarmellose; iron exchange resin such as amberlite, gums such as agar, locust
5 bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2- pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate or starch.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein
10 synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

15 The term "disintegrant" employed in a composition of the present invention is capable of the dissolving the drug (Nirmatrelvir), especially in water. The Solubilizers of instant invention includes, but are not limited to include polyethylene glycols, caffeine, xanthene, gentisic acid, cyclodextrins, citric acid, tartaric acid, benzoic acid, polyethylene glycol, ethanol, propylene glycol, glycerin, n-methyl 2-pyrrolidone, dimethyl acetamide, beeswax, d-a tocopherol, oleic
20 acid, mono and di glycerides, cremphor, Tween 20, sorbitan monooleate , peppermint oil, polysorbate, peanut oil, corn oil, soybean oil, sesame oil, olive oil, cotton seed oil, a- cyclodextrins, b-cyclodextrins, g-cyclodextrins, sulfobutylether-cyclodextrin, hydroxypropyl - cyclodextrin, glycerol, choline, distearoyl phosphalidylglycerol (DSPG), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG),
25 Macrogol 15 Hydroxystearate or a combination thereof.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
30

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to
11 % and about 40 % means 36 % to 44 %.

5 The term "oral dosage forms" includes all conventional oral solid dosage forms like a tablet, capsule, Oral disintegrating films or tablets, syrups, suspension, granules, pill, caplet, pellets, powder or sachet, or any other orally ingestible dosage form comprising Nirmatrelvir and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

10 The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at
15 least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising",
20 "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The term “particles” refers to individual drug substance particles whether the particles exist
25 singly or are agglomerated. Thus, a composition comprising particulate Nirmatrelvir may contain agglomerates that are well beyond the size limit of about 500 µm specified herein. However, if the mean size of the primary drug substance particles (i.e., Nirmatrelvir) comprising the agglomerate are less than about 500 µm individually, then the agglomerate itself is considered to satisfy the particle size constraints defined herein and the composition is within
30 the scope of the invention.

The “Nirmatrelvir particles” refers to particles of Nirmatrelvir that do not include an added excipient. Nirmatrelvir particles are different than “particles containing Nirmatrelvir”, which are particles that contain Nirmatrelvir and at least one added excipient. Nirmatrelvir particles
5 of the disclosure exclude a polymeric, wax or protein excipient and are not embedded, contained, enclosed or encapsulated within a solid excipient. Nirmatrelvir particles of the disclosure may, however, contain impurities and byproducts typically found during preparation of Nirmatrelvir. Even so, Nirmatrelvir particles comprise at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% Nirmatrelvir or a pharmaceutically acceptable salt thereof,

10 meaning the Nirmatrelvir particles consist of or consist essentially of substantially pure Nirmatrelvir or pharmaceutically acceptable salt thereof.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Nirmatrelvir or pharmaceutically acceptable salt thereof having
15 reduced particle size and one or more pharmaceutical acceptable excipients.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Nirmatrelvir or pharmaceutically acceptable salt thereof having
20 particle size (D90) less than 200µm, and one or more pharmaceutical acceptable excipients.

According to embodiment, present invention to provide a particle size distribution of the Nirmatrelvir may have from D10 = 10 µm, D50 = 200 µm and D90 = 400µm, wherein the 10th volume percentile particle size (D10) is less than about 50 µm, the 50th volume
25 percentile particle size (D50) is less than about 200 µm, or the 90th volume percentile particle size (D90) is less than about 400 µm, or any combination thereof.

According to embodiment, present invention to provide a particle size distribution of the Nirmatrelvir may have particle size (D90) is less than 500 µm, preferably less than 200 µm,
30 and more preferably less than100 µm are combination thereof.

According to embodiment, present invention to provide a particle size distribution of the Nirmatrelvir may have particle size (D90) is less than 100 µm, preferably less than 50 µm, and more preferably less than 10 µm are combination thereof.
5
In one embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising an intra-granular portion and an extra-granular portion, the intra- granular portion comprising Nirmatrelvir or pharmaceutically acceptable salt thereof having D90 less than 500µm and one or more pharmaceutically acceptable excipients, and the extra-
10 granular portion comprising one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising an intra-granular portion and an extra-granular portion, the intra- granular portion comprising Nirmatrelvir or pharmaceutically acceptable salt thereof having
15 D90 less than 200µm and one or more pharmaceutically acceptable excipients, and the extra- granular portion comprising one or more pharmaceutically acceptable excipients.

In certain exemplary embodiments, the pharmaceutical composition comprises, Nirmatrelvir or its pharmaceutically acceptable salt thereof, as generally described below. Some preferred,
20 but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids.

In one embodiment, the present invention relates to a stable pharmaceutical composition
25 comprising Nirmatrelvir or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients; wherein Nirmatrelvir or pharmaceutically acceptable salt thereof is crystalline form or amorphous form.

In another embodiment, the oral pharmaceutical composition is in the form of tablet or capsule or Syrups or Suspension comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

5 In yet another embodiment, the present invention relates to oral pharmaceutical composition comprising
(a) Intra-granular composition comprising Nirmatrelvir or its pharmaceutical salt thereof, Lubricant, Glidant, and optionally one or more pharmaceutically acceptable excipients;
(b) Extra-granular composition comprising Lubricant and optionally one or more
10 pharmaceutically acceptable excipients.

According embodiment, the present invention relates to oral stable composition of Nirmatrelvir, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 10 % to about 40 % of Nirmatrelvir or its
15 pharmaceutical salt thereof having reduced particle size;
(1) from 0.1 % to about 5 % one or more Glidants;
(2) from 0.1 % to about 5 % one or more Lubricants;
(3) from about 20 % to about 80 % one or more Diluents;
(4) from about 1 % to about 8 % one or more Disintegrants;
20 (5) from about 0 % to about 10 % one or more Solubilizers;
(b) Extra-granular portion comprising;
(1) from 0.1 % to about 5 % one or more Lubricants; and
(2) optionally one or more pharmaceutical acceptable excipients;

25 According embodiment, the present invention relates to oral tablet composition of Nirmatrelvir, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 20 % to about 30 % of Nirmatrelvir or its pharmaceutical salt thereof having reduced particle size;
(1) from 20 % to about 60 % of Microcrystalline cellulose;
30 (2) from about 15 % to about 30 % one or more Lactose Monohydrate;

(3) from about 1 % to about 8 % one or more Croscarmellose sodium;
(4) from 0.1 % to about 5 % one or more Colloidal silicon dioxide;
(5) from 0.1 % to about 5 % one or more Sodium stearyl fumarate; and
(6) optionally one or more pharmaceutical acceptable excipients;
5 (b) Extra-granular portion comprising;
(1) from 0.1 % to about 5 % one or more Sodium stearyl fumarate; and
(2) optionally one or more pharmaceutical acceptable excipients;

According embodiment, Nirmatrelvir or pharmaceutically acceptable salt thereof has a particle
10 size distribution with the D90 is less than 500 µm, preferably less than 300 µm, more preferably less than 200 µm.

Particle size analysis can be carried out via different methods. Non-limiting examples of the methods include, but are not limited to, sieve technique, wet dispersion method with laser
15 diffraction analysis, dry dispersion method with laser diffraction analysis, or a combination thereof. Particle size analysis is not limited to the methods described herein and can be carried out using any method known to one skilled in the art. In one embodiment, particle size analysis can be performed via a sieve technique. In another embodiment, particle size analysis can be performed using a wet dispersion method (e.g., water as the dispersing agent, and analysis by
20 laser diffraction using, e.g., Sympatec equipment). In yet another embodiment, particle size analysis can be performed using a dry dispersion method and analyzed by laser diffraction using, e.g., Sympatec equipment.

The pharmaceutical compositions as mentioned above can be prepared by using any suitable
25 method known in the art such as direct compression, dry or wet granulation (aqueous/non- aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

According embodiment of the present invention relates to the process of preparation of an oral
30 stable composition of Nirmatrelvir, wherein the said Nirmatrelvir or its pharmaceutical salt

thereof, is added to the in intra-granular portion in about 10 % to about 40 % of the total weight of composition.

According embodiment of the present invention relates to the process of preparation of an oral
5 stable composition of Nirmatrelvir, which is prepared by using dry granulation method.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Nirmatrelvir, which is prepared by using wet granulation method.

10 According embodiment of the present invention relates to the process of preparation of an oral stable composition of Nirmatrelvir, which is prepared by direct compression method.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Nirmatrelvir having reduced particle size, which is prepared by mixing
15 Nirmatrelvir, microcrystalline cellulose, Croscarmellose sodium, Colloidal silicon dioxide and Sodium stearyl fumarate. The above composition is blended for 20- 25 minutes. The above mixture is compacted using roller compactor, the slugs obtained were passed through sieve to obtain desired granule size, the granules obtained in the above step are mixed with Sodium stearyl fumarate is added and lubricated again. The lubricated granules are then filled into
20 capsules or sachets or punched in to suitable size tablets and coated with a suitable film coating.

According embodiment of the present invention relates to the process of preparation of an oral stable composition of Nirmatrelvir having reduced particle size, which is prepared by mixing Nirmatrelvir, microcrystalline cellulose, Croscarmellose sodium, Colloidal silicon dioxide, the
25 above mixture is granulated by adding granulation fluid (consisting of binder and solvent) and obtained granules are lubricated with Sodium stearyl fumarate. The above composition is blended for 20- 25 minutes. The lubricated granules are then filled into capsules or sachets or punched in to suitable size tablets and coated with a suitable film coating.

According to one of the embodiment, the present invention relates to the process of preparation of an oral stable composition comprising Nirmatrelvir or its pharmaceutical salt thereof having reduced particle size, which is prepared by using direct compression.

5 According embodiment, the present invention composition relates to the oral stable pharmaceutical composition comprising Nirmatrelvir or its pharmaceutical salt thereof having better stability, good purity profile, dissolution profile and better bioavailability.

The pharmaceutical composition is meant for once daily, twice daily or thrice daily
10 administrations.

According embodiment, the present invention relates to the oral stable composition comprising Nirmatrelvir or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.
15
According embodiment, the present invention relates to the oral stable composition comprising Nirmatrelvir or its pharmaceutical salt thereof, having dissolution more than 98% within 30 minutes.

20 According embodiment, the present invention relates to the pharmaceutical composition comprising Nirmatrelvir or its pharmaceutical salt thereof for the treatment of Covid-19 disease.

In a yet another embodiment, pharmaceutical compositions disclosed herein are contemplated
25 to be administered in combination with other the agent(s) such as, CYP3A4 inhibitor, selected from ritonavir, nelfinavir, delavirdine or combinations thereof for treatment of Covid-19 disease,

In another embodiment, the present invention relates to a pharmaceutical stable dosage form
30 composition comprising immediate release tablet.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Comparative dissolution profile of market sample PAXLOVID co-packaged for oral use and test product of Nirmatrelvir tablet 150Mg.

Product name Market sample- PAXLOVID
co-packaged Test product
Nirmatrelvir tablet
Strength 150mg
Dissolution condition 900ml of pH 4.5 acetate buffer with 0.2% SDS at 75 RPM with paddle
Batch number FP9607 NMTT11-0200-017
Time point (Min) % Drug release
5 50 64
10 68 78
15 77 85
20 83 90
30 89 93
60 97 94

5
Examples:

S.No. Ingredients Functional
category Qty per Unit (mg)
150 mg 300mg % w/w
Intra granular
1 Nirmatrelvir API 150.00 300mg 31.00

2 Microcrystalline cellulose 101
(Pharmacel 101)
Diluent
185.00
370.00
38.33
3. Lactose Monohydrate
(Pharmatose 200 M) Diluent 100.00 200.00 20.67
4. Croscarmellose sodium
(Primellose) Disintegrant 22.50 45.00 4.00
5. Colloidal silicon dioxide
(Aerosil 200 M) Glidant 7.50 15.00 1.50
6. Sodium stearyl fumarate
(PRUV) Lubricant 7.50 15.00 1.50
Extra granular
7. Sodium stearyl fumarate
(PRUV) Lubricant 7.50 15.00 1.50
Uncoated tablet weight (mg) 480.00 940.00 100.00
Film Coating (3.0 % w/w weight build up, 15.0% w/w solid content)
8. Opadry Pink 03F540440 Coating
material 22.50 22.50 --
9. Purified Water Solvent q.s q.s --
Coated tablet weight (mg) 502.5 962.5 --
Opadry Pink 03F540440 contains Hydroxy propyl methyl cellulose, Talc, Polyethylene glycol, Titanium dioxide and Iron oxide red.

10 MANUFACTURING PROCESS: Sifting:

i. Co-sift Nirmatrelvir, Lactose monohydrate, Croscarmellose sodium and colloidal silicon dioxide with half quantity of microcrystalline cellulose PH 101 through sieve # 30 ASTM (600 µm).
ii. Co-sift step no. i material with remaining half quantity of microcrystalline cellulose 101
5 (Pharmacel 101) through sieve # 30 ASTM (600 µm).
iii. Sift step no. ii material through sieve # 30 ASTM (600 µm).
iv. Sift Sodium stearyl fumarate through sieve # 60 ASTM (250 µm).
Pre Mixing
v. Load the sifted material of step-iii into the blender and mix for 20 minutes at suitable
10 rpm.
vi. Load the sifted material of step-iv into the blender of step v and mix for 5 minutes at suitable rpm.
Dry granulation
vii. Compact the step vi with roll compactor and milled with 1.00 mm screen in multi-mill
15 to attain desired granules and continued compaction and milling process until all the granules passes through 30# mesh.
viii. Sift Sodium stearyl fumarate through 60# mesh.
Lubrication:
ix. Blend the step vii materials with step viii for 5 mins.
20 Compression:
x. Compress the above blend by using suitable punches.
Coating:
Prepare the coating dispersion by dispersing Opadry pink in purified water under stirring and coat the compressed tablets of step x with the coating dispersion.
,CLAIMS:1. The pharmaceutical composition comprising Nirmatrelvir or pharmaceutically acceptable salt thereof where in the particle size D90 is less than 200µm.

2. The pharmaceutical composition as claimed in claim 1, where in the composition is free of Crospovidone.

3. The pharmaceutical composition as claimed in claim 1, where in the composition comprising
a) Intra-granular portion comprising from about 10 % to about 40 % of Nirmatrelvir or its pharmaceutical salt thereof having reduced particle size;
(1) from 0.1 % to about 5 % one or more Glidants;
(2) from 0.1 % to about 5 % one or more Lubricants;
(3) from about 20 % to about 80 % one or more Diluents;
(4) from about 1 % to about 10 % one or more Disintegrants;
(5) from about 0 % to about 10 % one or more Solubilizers;
(b) Extra-granular portion comprising;
(1) from 0.1 % to about 5 % one or more Lubricant; and
(2) optionally one or more pharmaceutical acceptable excipients.

4. The pharmaceutical composition as claimed in claim 1, where in the composition comprising Nirmatrelvir or its salts in the range of 10 % to about 40 % of the total weight of the composition.

5. The pharmaceutical composition as claimed in claim 1, wherein the ration between the Nirmatrelvir and croscarmellose sodium is 1:10.

6. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate.

7. The pharmaceutical composition as claimed in claim 1, where in the composition is prepared by dry granulation method.

8. The pharmaceutical composition as claimed in claim 1, where in the composition contain reduced particle size of Nirmatrelvir.

9. The pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment of Covid-19 and corona virus disease.