DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
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 acceptable inorganic or organic acids.

The term " Ritonavir " 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 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, 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 the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, 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 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.

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 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.

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 includes, 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, 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 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 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 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.

The term "excipient" means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.

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.

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 %.

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

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 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", "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.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Nirmatrelvir or pharmaceutically acceptable salt thereof having reduced particle, 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 = 50 µm, D50 = 200 µm and D90 = 400µm, wherein the 10th volume percentile particle size (D10) is less than about 50 µm, the 50th volume 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.

In certain embodiments, the present invention relates to a pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein, pharmaceutical composition is in the form of solid dosage form, semi-solid dosage form and liquid dosage form,

In certain embodiments compounds described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, or lotions and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to lotions, ointments, creams, and gels.

In another embodiment, the solid oral pharmaceutical composition is in the form of tablet comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, in combination with ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of capsule comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, in combination with ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to solid oral pharmaceutical composition comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, in combination with ritonavir and diluent, lubricant, disintegrants, binders and one or more pharmaceutically acceptable excipients.

In yet another embodiment, the pharmaceutical composition of the present invention can be formulated as dosage forms which include, but are not limited to, powders, granules, pills, tablets, coated tablets, capsules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

In another embodiment, the pharmaceutical composition of the present invention can be formulated as oral dosage forms selected from powders, granules, tablets, and capsules, powders for reconstitution, granules for reconstitution.

In another embodiment, the present invention relates to the oral stable pharmaceutical composition comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof in combination with ritonavir, wherein the composition is in the form of tablet or capsule.

In another aspect, the present invention relates to the unit dosage comprising 10 mg to 500mg Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with 50mg to 100mg Ritonavir or pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients used for the treatment of Covid-19 disease.

In another aspect, the present invention relates to the unit dosage comprising 300 mg Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with 100mg Ritonavir or pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients used for the treatment of Covid-19 disease.

In another aspect, the present invention relates to the unit dosage comprising 300mg Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with 50mg Ritonavir or pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients used for the treatment of Covid-19 disease.

In another aspect, the present invention relates to the unit dosage comprising 150mg Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with 100mg Ritonavir or pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients used for the treatment of Covid-19 disease.

In another aspect, the present invention relates to the unit dosage comprising 150mg Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with 50mg Ritonavir or pharmaceutically acceptable salt thereof and one or more pharmaceutical acceptable excipients used for the treatment of Covid-19 disease.

In another embodiment, the present invention composition relates to the oral stable pharmaceutical composition having excellent stability, good purity profile with improved dissolution profile and bioavailability.

In further embodiments of the present invention, the pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Nirmatrelvir, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, alone or in combination with ritonavir.

The composition of the present invention can be produced by sizing and milling a mixture of the drug substance with excipients. For example, one method for the production includes mixing the Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, alone or in combination with ritonavir with the materials for the preparation by a suitable mixer, and lubrication the mixture to tablet or capsule.

The pharmaceutical compositions can be prepared by using any suitable 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.

In an another embodiment, the present invention relates a stable pharmaceutical composition comprising Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with ritonavir and one or more pharmaceutically acceptable excipient. Where in the formulation process does not involve any complex process like bilayer tableting or tedious process like multiple granulations The present invention further provides process for preparation of Nirmatrelvir in combination with ritonavir composition with co-granulation.

In an another embodiment, the present invention relates a pharmaceutical composition comprising a stable pharmaceutical composition comprising Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with ritonavir one or more pharmaceutically acceptable excipient, where in the process for preparation of Nirmatrelvir in combination with ritonavir composition by top spraying the drug solution of ritonavir on Nirmatrelvir granules.

In an another embodiment, the present invention relates to oral stable composition of Nirmatrelvir in combination with ritonavir wherein said composition comprises:
(a) Nirmatrelvir or its pharmaceutical salt thereof,
(b) ritonavir or its pharmaceutical salt thereof
(b) One or more diluents;
(c) One more disintegrant;
(d) One or more binder;
(e) One or more lubricant; and
(f) Optionally one or more pharmaceutical acceptable excipients.

In an another embodiment, the present invention relates to oral stable composition of Nirmatrelvir in combination with ritonavir wherein said composition comprises:
(a) from about 20% to about 60% of Nirmatrelvir or its pharmaceutical salt thereof,
(b) from about 1% to about 30% of ritonavir or its pharmaceutical salt thereof
(b) from about 10 % to about 60 % of one or more diluents;
(c) from 5 % to about 15 % of disintegrant;
(d) from about 1 % to about 10 % binder;
(e) from about 0.5 % to about 2 % lubricant; and
(f) optionally one or more pharmaceutical acceptable excipients.

In an another embodiment, the present invention relates to oral stable composition of Nirmatrelvir in combination with ritonavir wherein said composition comprises:
(a) Nirmatrelvir or its pharmaceutical salt thereof,
(b) ritonavir or its pharmaceutical salt thereof
(b) one or more diluents;
(c) one or more disintegrant;
(d) one or more binder;
(e) one or more lubricant; and
(f) optionally one or more pharmaceutical acceptable excipients.

Where in the above said composition is prepared by co-granulation where both the drugs are granulated together or by top spray granulation where the ritonavir solution is sprayed on Nirmatrelvir granules.

In an another embodiment, the present invention the above mentioned granules are punched in to tablets or filled in capsules of required size.

In an another embodiment, the present invention relates to the oral stable pharmaceutical composition of Nirmatrelvir or pharmaceutically acceptable salt thereof in combination with ritonavir as defined above is used for the treatment of Covid-19 disease.

In yet another embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising Nirmatrelvir or pharmaceutically acceptable salts or derivatives thereof, in combination with ritonavir, microcrystalline cellulose, Lactose monohydrate, Sodium starch glycolate, Hydroxy propyl cellulose, Colloidal silicon dioxide, Co-povidone, Croscarmellose sodium, Sodium stearyl fumarate, Calcium Hydrogen Phosphate Anhydrous, Calcium Hydrogen Phosphate di-hydrate and Steric acid and one or more pharmaceutically acceptable excipients.

According embodiment, Nirmatrelvir pharmaceutically acceptable salt thereof has a particle size distribution with the D90 is less than 500 µm, preferably less than 200 µm and more preferably less than 100 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 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 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 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, 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.

According embodiment, the pharmaceutical composition is meant for once daily, twice daily or thrice daily administration.

In another embodiment, the present invention relates to a pharmaceutical stable dosage form 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

Comparative dissolution profile of market sample PAXLOVID co-packaged for oral use, and test product of Ritonavir tablets IP 100mg.

Product name Market sample- PAXLOVID
co-packaged Test product
Ritonavir tablet IP 100MG
Strength 100mg
Dissolution condition 900ml of a solution prepared by dissolving 15.7 g of polyoxyethylene 10-lauryl ether in 1000ml of a 0.85 percent v/v solution of Hydrochloric acid at 100RPM with paddle.
Batch number FP9607 RTNT11-0201-008
Time point (Min) % Drug release
15 38 25
30 71 53
45 89 73
60 96 87

Examples:
S.No. Ingredients Functional category Qty per Unit (mg)
150 mg % w/w
Intra granular
1 Nirmatrelvir API 150.00 20.00
2 Ritonavir API 100.00 24.00
3. Microcrystalline cellulose 101
(Pharmacel 101) Diluent 185 24.65
4. Lactose Monohydrate
(Pharmatose 200 M) Diluent 85.00 24.67
5. Croscarmellose sodium
(Primellose) Disintegrant 22.50 3.00
6. Colloidal silicon dioxide
(Aerosil 200 M) Glidant 7.50 1.00
7. Sodium stearyl fumarate
(PRUV) Lubricant 7.50 1.00
Extra granular
7. Sodium stearyl fumarate
(PRUV) Lubricant 7.50 1.00
Uncoated tablet weight (mg) 565.00 100.00
Film Coating (3.0 % w/w weight build up, 15.0% w/w solid content)
8. Opadry Pink 03F540440 Coating material 22.50 --
9. Purified Water Solvent q.s --
Coated tablet weight (mg) 587.50 --
Opadry Pink 03F540440 contains Hydroxy propyl methyl cellulose, Talc, Polyethylene glycol, Titanium dioxide and Iron oxide red.
MANUFACTURING PROCESS:
Sifting:
i. Co-sift Nirmatrelvir, Ritonavir, 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 (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 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 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.
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. A pharmaceutical formulation comprising fixed dose combination of Nirmatrelvir and Ritonavir or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical formulation as claimed in claim 1, where in the formulation comprising:
(a) Nirmatrelvir or its pharmaceutical salt thereof,
(b) Ritonavir or its pharmaceutical salt thereof
(b) one or more diluents;
(c) one or more disintegrant;
(d) one or more lubricant;
(e) Optionally a binder; and
(f) one or more pharmaceutical acceptable excipients.

3. The pharmaceutical formulation as claimed in claim 1, where in the formulation is a unit dosage composition of Nirmatrelvir and Ritonavir.

4. The pharmaceutical formulation as claimed in claim 1, where in the immediate release formulation is prepared by co-granulation of Nirmatrelvir and Ritonavir by dry-granulation or wet granulation method.

5. The pharmaceutical formulation as claimed in claim 1, where in the pharmaceutical excipients are used in the composition is microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate.

6. The pharmaceutical formulation as claimed in claim 1, where in the process of granulation preparation contain top spraying the drug solution of ritonavir on Nirmatrelvir granules.

7. The pharmaceutical formulation as claimed in claim 1, where in the Nirmatrelvir and Ritonavir having D90 is less than 200 µm.

8. The process for the preparation of fixed dose combination of Nirmatrelvir and Ritonavir comprising of sifting the Nirmatrelvir, Ritonavir with other excipients, blending the mixture, granulating the above mixture with suitable granulation technique, lubricated the obtained granules and compress the lubricated granules in to tablets.

9. An immediate release pharmaceutical formulation as claimed in claim 1, where in the composition is used for the treatment of Covid-19 disease.