DESC:FIELD OF THE INVENTION

The present invention relates to the pharmaceutical composition comprising a solid dispersion containing Pirtobrutinib or a pharmaceutically acceptable salt, Hydroxypropyl methylcellulose phthalate, and one or more pharmaceutically acceptable excipients. Further, the present invention relates to a process for the preparation of the said pharmaceutical composition.

BACKGROUND OF THE INVENTION

Pirtobrutinib is a small molecular drug that has recently been developed for the treatment of certain types of cancer. It belongs to a class of medications known as tyrosine kinase inhibitors, which work by blocking specific proteins that promote the growth and spread of cancer cells. Pirtobrutinib specifically targets a protein called Bruton's tyrosine kinase (BTK), which is involved in the survival and proliferation of cancer cells. By inhibiting BTK, Pirtobrutinib helps to slow down or stop the growth of cancer cells, ultimately leading to the shrinkage of tumors. This drug is approved for the treatment of mantle cell lymphoma (MCL).

In terms of Bio-pharmaceutics Classification System (BCS), Pirtobrutinib falls under Class II. Class II drugs have low solubility and high permeability, which refers to class of drugs which are poorly soluble in water but can easily pass through biological membranes. This classification is important for understanding the drug's absorption, distribution, metabolism, and excretion characteristics, which can influence its pharmacokinetics and therapeutic efficacy. Pirtobrutinib is a white to practically white to yellow to brown solid powder. The aqueous solubility of Pirtobrutinib is considered practically insoluble, or insoluble, across the pH 1 to pH 7 range.

Pirtobrutinib is marketed as brand name of JAYPIRCA® and it is approved for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. JAYPIRCA® (Pirtobrutinib tablets) are supplied as 50 mg or 100 mg film-coated tablets for oral administration. Each JAYPIRCA® tablet contains croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and silicon dioxide. HPMC phthalate is not used in currently marketed pharmaceutical composition.

The chemical name for Pirtobrutinib is 5-amino-3-{4-[(5-fluoro-2-methoxybenz amido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carbox amide. Pirtobrutinib has the molecular formula C22H21F4N5O3 and molecular weight of 479.44. The chemical structure of Pirtobrutinib is given below:

(Pirtobrutinib)

US10342780 patent discloses kinase inhibitors, which covers Pirtobrutinib as a composition of matter and general formulation of it.

US10695323 patent discloses different compounds having effect as kinase inhibitors, which covers Pirtobrutinib by general structure and method of use of kinase inhibitor.

WO2020028258 patent application discloses pharmaceutical composition of Pirtobrutinib comprising Hydroxypropyl methylcellulose acetate succinate (HPMCAS) and other excipients and process for preparation thereof.

Considering the prior efforts as disclosed in the background, a need still exists to provide alternate pharmaceutical compositions which would address the issues relating to solubility and stability of Pirtobrutinib.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients, wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more glidants, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.

Another object of the present invention is to provide a process for preparation of pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients; wherein the said composition is use in the treatment of cancer selected from the group consisting of: mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia, and marginal zone lymphoma.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients. Further, the present invention provides a process for the preparation of pharmaceutical composition comprising solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention provides a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients.

The term “Pirtobrutinib” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with composition.

The term “Hydroxypropyl methylcellulose phthalate” refers to a phthalic acid ester of hydroxypropyl methylcellulose. The hydroxypropyl methylcellulose phthalate can be present in an amount of from about 15% to about 70% by weight of the total weight of the composition.

In accordance with the present invention, the term “about” shall mean a variation up to 10% (plus or minus 10%) of the particular term.

The term “Dissolution” refers to a dissolution of Pirtobrutinib formulation by using paddle type dissolution test apparatus, at the speed of 75 RPMs, sodium phosphate buffer pH 6.8 as dissolution media and 900 ml dissolution media. According to the present invention, at least about 85% of the Pirtobrutinib is dissolved within about 30 minutes as determined in an in vitro dissolution test conducted using a USP Dissolution Apparatus 2 (Paddle Apparatus), 900 mL dissolution volume, Sodium Phosphate Buffer pH 6.8 dissolution medium, and paddle rotation of 75 RPM.

The term “formulation’ refers to final pharmaceutical dosage form of Pirtobrutinib for oral administration (i.e., Tablet, Capsule, Granules).

In one of the embodiments, the present invention provides a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients.

In one of the embodiments, Pirtobrutinib is present in an amount between about 5% w/w and about 30% w/w of the total weight of the composition. In some embodiments, the ratio of the Pirtobrutinib to the hydroxypropyl methylcellulose phthalate is about 1:1 to about 1:6. More specifically, the ratio of Pirtobrutinib to the hydroxypropyl methylcellulose phthalate is about 1:1 to 1:3.

In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients, wherein the said pharmaceutical composition is preferably a solid oral pharmaceutical composition.

According to the present invention, the pharmaceutical composition is preferably solid oral pharmaceutical composition in the form of, but not limited to, tablets, capsules, mini-tablets, granules, and pills.

In one of the embodiment, the present invention is to provide a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients, wherein the said one or more pharmaceutical acceptable excipient is selected from one or more diluents, one or more glidants, one or more disintegrants, one or more solvents, one or more lubricants or the mixtures thereof.

The diluent can be selected from the group comprising of, but not limited to, sucrose, lactose, microcrystalline cellulose, dibasic calcium phosphate methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, corn starch pregelatinized starch xylitol, sorbitol, mannitol, polyvinylpyrrolidone, a polyethylene glycol, a polyvinyl alcohol, a polymethacrylate, or mixtures thereof. The diluents can be present in an amount of from about 5% to about 60% by weight of the total weight of the composition.

The glidant can be selected from the group comprising of, but not limited to, colloidal silicon dioxide, magnesium silicate, starch, talc, tribasic calcium phosphate, polyethylene glycol, carnauba wax or mixtures thereof. The glidant can be present in an amount of from about 0.2% to about 4% by weight of the total weight of the composition.

The disintegrant can be selected from the group comprising of, but not limited to, sodium starch glycolate, crospovidone, alginic acid, sodium alginate, croscarmellose sodium, an ion exchange resin, and combinations thereof. The disintegrant can be present in an amount of from about 0.5% to about 10% by weight of the total weight of the composition.

The lubricant can be selected form the group comprising of, but not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, a hydrogenated vegetable oil, sodium stearyl fumarate, colloidal silicon dioxide, sodium benzoate, sodium oleate, sodium acetate, talc, zinc stearate or mixtures thereof. The lubricant can be present in an amount of from about 0.2% to about 5% by weight of the total weight of the composition.

In some embodiments, the solvent is one or more organic solvents. In some embodiments, the organic solvent is selected from the group comprising of ethanol, acetone, dichloromethane, isopropyl alcohol and combinations thereof. In some embodiments, the solvent is a mixture of an organic solvent and water.

In some embodiments, the said pharmaceutical composition is optionally coated with a coating. The said coating can be film coating, sugar coating, enteric coating, etc., and the type of coating would depend on the type of pharmaceutical composition. The coating mentioned herein are well documented in the art.

In another embodiment, the present invention provides a process for the preparation of pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate (HPMCP) and other excipients; wherein the said process comprises of, but not limited to, hot melt extrusion, spray drying, lyophilization, co-precipitation, solvent evaporation, wet granulation, dry granulation, direct compression, and coating. The processes mentioned herein for the preparation of solid dispersion as per the present invention are well documented in the art.

In another embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion of Pirtobrutinib, Hydroxypropyl methylcellulose phthalate and one or more pharmaceutically acceptable excipients; wherein the said pharmaceutical compositions are used in the treatment of cancer selected from the group comprising of mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom’s macroglobulinemia, and marginal zone lymphoma.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope, and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.

Example 1: Formulation and process of Pirtobrutinib tablet (% range)

Ingredients % w/w
Pirtobrutinib 5 - 30
Hydroxypropyl methylcellulose phthalate (HPMCP) 15 - 70
Diluent 5 - 60
Solvent q.s.
Disintegrant 0.5 - 10
Glidant 0.2 - 4
Lubricant 0.2 - 5
Film Coating(Optional) 0.1 - 10
Purified water q.s.
Total weight of the pharmaceutical composition 100

Manufacturing process:
1) Dissolve the dispensed quantity of HPMCP in required quantity of suitable solvent system under stirring.
2) Add Pirtobrutinib to above solution under stirring to get clear solution.
3) Add diluent to Fluid Bed Processor and spray the solution of HPMCP and API onto the diluent with suitable processing parameters.
4) After spraying the solution, dry the granules in Fluid Bed Processor to get desired quality of dried granules on loss on drying.
5) Mill the dried granules.
6) Mix the quantity of disintegrant, glidant and dried granules obtained in step 5.
7) Lubricate the mixture obtained in step 6 with lubricant to obtain a lubricated blend.
8) Compress the lubricated blend into tablets using compression machine using suitable punches.
9) Coat the core tablets with Opadry blue dispersion as applicable using auto coater.

Example 2: Formulation and process of Pirtobrutinib 50 mg tablet

Ingredients Quantity (mg)
Pirtobrutinib 50
Hydroxy propyl Methylcellulose Phthalate (HPMCP) 50 - 150
Lactose Monohydrate 12.5 - 112.50
Solvent q.s.
Croscarmellose Sodium 4.50 - 7.50
Silicon Dioxide 1.00 - 2.50
Magnesium Stearate 1.00 - 3.00
Opadry Blue Coating Material 7
Purified water q.s.

Manufacturing process:
1) Sift the dispensed quantity of lactose monohydrate through ASTM # 40 sieve.
2) Dissolve the dispensed quantity of HPMCP in required quantity of suitable solvent system under stirring. Add Pirtobrutinib to above solution under stirring to get clear solution.
3) Add the sifted lactose monohydrate to Fluid Bed Processor and spray the solution of step 2 onto lactose monohydrate with suitable processing parameters.
4) After spraying the solution, dry the granules in Fluid Bed Processor.
5) Mill the dried granules of step 4 through Co-mill/ Lab Co-mill.
6) Sift croscarmellose sodium and colloidal silicon dioxide through ASTM # 40 sieve and mix with sized granules of step 5.
7) Sift magnesium stearate through ASTM # 60. Lubricate the blend of step 6 with sifted magnesium stearate of step 6 to obtain lubricated blend.
8) Compress the lubricated blend of step 7 into tablets using compression machine using suitable punches.
9) Coat the core tablets with Opadry Blue dispersion as applicable using auto coater.

Example 3: Formulation and process of Pirtobrutinib 100 mg tablet

Ingredients Quantity (mg)
Pirtobrutinib 100
Hydroxy propyl Methyl cellulose Phthalate (HPMCP) 100 - 300
Lactose Monohydrate 25 - 225
Solvent q.s.
Croscarmellose Sodium 9 -14
Silicon Dioxide 2 - 5
Magnesium Stearate 2 - 6
Opadry Blue Coating Material 14
Purified water q.s.

Manufacturing process:
1) Sift the dispensed quantity of lactose monohydrate through ASTM # 40 sieve.
2) Dissolve the dispensed quantity of HPMCP in required quantity of suitable solvent system under stirring. Add Pirtobrutinib to above solution under stirring to get clear solution.
3) Add the sifted lactose monohydrate to Fluid Bed Processor and spray the solution of step 2 onto lactose monohydrate with suitable processing parameters.
4) After spraying the solution, dry the granules in Fluid Bed Processor.
5) Mill the dried granules of step 4 through Co-mill/ Lab Co-mill.
6) Sift croscarmellose sodium and colloidal silicon dioxide through ASTM # 40 sieve and mix with sized granules of step 5.
7) Sift magnesium stearate through ASTM # 60. Lubricate the blend of step 6 with sifted magnesium stearate of step 6 to obtain lubricated blend.
8) Compress the lubricated blend of step 7 into tablets using compression machine using suitable punches.
9) Coat the core tablets with Opadry Blue dispersion as applicable using auto coater.

Example 4: Formulation of Pirtobrutinib (Top spray granulation Trial 1)

Ingredients Quantity (mg)
Intragranular Ingredients
Lactose Monohydrate 76.80
Microcrystalline Cellulose (pH-302) 153.20
Croscarmellose Sodium 12.00
Drug-Polymer Solution
Pirtobrutinib 100.00
Hypromellose phthalate (HPMC HP-55) 100.00
Iso Propyl Alcohol Q.S.
Acetone Q.S.
Extragranular Ingredients
Croscarmellose Sodium 12.00
Aerosil 200 6.00
Magnesium Stearate 6.00
Film Coating Ingredients
Opadry 03K105008 Blue 14.00
Purified Water Q.S.
Weight of Coated Tablets (mg) 480.00

Example 5: Formulation of Pirtobrutinib (Top spray granulation Trial 2)

Ingredients Quantity (mg)
Intragranular Ingredients
Lactose Monohydrate 76.80
Croscarmellose Sodium 11.50
Drug-Polymer Solution
Pirtobrutinib 100.00
Hypromellose phthalate (HPMC HP-55) 100.00
Iso Propyl Alcohol Q.S.
Acetone Q.S.
Extragranular Ingredients
Microcrystalline Cellulose (pH-302) 155.60
Croscarmellose Sodium 11.50
Aerosil 200 2.30
Magnesium Stearate 2.30
Film Coating Ingredients
Opadry 03K105008 Blue 12.800
Purified Water Q.S.
Weight of Coated Tablets (mg) 480.00

Example 6: Formulation of Pirtobrutinib (Top spray granulation Trial 3)

Ingredients Quantity (mg)
Intragranular Ingredients
Lactose Monohydrate 76.80
Croscarmellose Sodium 11.50
Drug-Polymer Solution
Pirtobrutinib 100.00
Hypromellose phthalate (HPMC HP-55) 200.00
Iso Propyl Alcohol Q.S.
Acetone Q.S.
Extragranular Ingredients
Microcrystalline Cellulose (pH-302) 55.60
Croscarmellose Sodium 11.50
Aerosil 200 2.30
Magnesium Stearate 2.30
Weight of Coated Tablets (mg) 480.00

Example 7: Formulation of Pirtobrutinib (Rotary Evaporation Trial 4)

Ingredients Quantity (mg)
Intragranular Ingredients
Lactose Monohydrate 10.00
Microcrystalline Cellulose (pH-302) -
Croscarmellose Sodium -
Drug-Polymer Solution
Pirtobrutinib 100.00
Hypromellose phthalate (HPMC HP-55) 100.00
Iso Propyl Alcohol Q.S.
Acetone Q.S.
Extragranular Ingredients
Lactose Monohydrate 66.80
Microcrystalline Cellulose (Emcocel 90M) 155.60
Croscarmellose Sodium 23.00
Aerosil 200 2.30
Magnesium Stearate 2.30
Weight of Coated Tablets (mg) 460.00

Example 8: Step wise procedure for preparation of formulation of Pirtobrutinib (example 4 to 7)

Step 1. Binder Solution preparation
a. Mix Acetone & Iso propyl alcohol together under stirring.
b. Dissolve HPMC HP 55 in above solvent mixture under stirring to get clear solution.
c. Dissolve Pirtobrutinib in above polymer solution under stirring to get clear solution.
d. Dissolve HPMC HP 55 & Pirtobrutinib in to Acetone under stirring to get clear solution & than dispersed lactose monohydrate in solution. (Trial 4)

Step 2. Granulation
a. Co sift Lactose monohydrate, Microcrystalline cellulose & Crosscarmellose sodium through ASTM # 40 Sieve & Load in FBP Bowl. (Trial 1)
b. Co Sift Lactose monohydrate & Crosscarmellose sodium through ASTM # 40 sieve & Load in FBP bowl. (Trial 2 ,3)
c. Spray solution of step no. 1 on above blend in FBP followed by drying to obtained dry granules.
d. Binder solution loaded in Rotary evaporator & drying is continued till solvent evaporated completely. (Trial 4)
e. Mill above dried granules through suitable screen size using Co-mill.

Step 3. Blending & Lubrication
a. Co-sift Colloidal anhydrous silica and Croscarmellose Sodium through ASTM 40# Sieve & mix with step no. 2 granules in blender for 10 minutes. (Trial 1)
b. Co-sift Colloidal anhydrous silica, Microcrystalline cellulose and Croscarmellose Sodium through ASTM 40# Sieve & mix with step no. 2 granules in blender for 10 minutes. (Trial 2,3)
c. Co-sift Lactose monohydrate, Colloidal anhydrous silica, Microcrystalline cellulose and Croscarmellose Sodium through ASTM 40# Sieve & mix with step no. 2 granules in blender for 10 minutes. (Trial 4)
d. Sift Magnesium stearate through ASTM 60# sieve & Mix with above Blend in Blender for 5 minutes.

Step 4. Compression
a. Compress lubricated blend of step 3 with suitable sets of tooling using Rotary tablet compression machine.

Step 5. Coating
a. Disperse Opadry 03K105008 Blue in purified water under stirring.
b. Core tablet of step 4 is coated using coating solution in Autocoater.

Example 9: Dissolution study of top spray granulation tablets of example 4, 5, 6 and (Trial 1, 2, 3) and marketed preparation of Pirtobrutinib (Jaypirca®)

Dissolution Data:
Dissolution Test Apparatus: Paddle (USP Dissolution Apparatus 2)
Speed (RPMs): 75
Medium: Sodium Phosphate Buffer pH 6.8
Volume: 900 ml
Sampling Times (minutes): 5, 10, 15, 20, 30, 45 and 60

Result of Dissolution:
Time Points % Drug Release
Jaypirca® Example 4 Example 5 Example 6
5 62 40 55 55
10 85 57 73 68
15 94 68 81 74
20 97 76 87 79
30 100 87 94 85
45 100 95 98 91
60 100 -- 99 93
Recovery
(15 min at 200 RPM) 100 100 101 95

Based on the above dissolution profile, the innovator product (Jaypirca®) and our samples are complying. The formulation of example 4 to 6 satisfies the condition of at least about 85% of the Pirtobrutinib is dissolved within about 30 minutes as determined in an in vitro dissolution test conducted using a Paddle Apparatus, 900 mL dissolution volume, Sodium Phosphate Buffer pH 6.8 dissolution medium, and paddle rotation of 75 RPM. ,CLAIMS:We Claims:

1. A pharmaceutical composition comprising solid dispersion of pirtobrutinib or its pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose phthalate and one or more pharmaceutical acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the pirtobrutinib is present in an amount of about 5% to 30% by weight of the composition.

3. The pharmaceutical composition as claimed in claim 1, wherein the hydroxypropyl methylcellulose phthalate is present in an amount of about 15% to 70% by weight of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the pirtobrutinib or its pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose phthalate are present in a ratio of 1:1 to 1:6.

5. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutical acceptable excipient is selected from one or more diluents and surfactant.

6. The pharmaceutical composition as claimed in claim 1, wherein the said one or more diluent is selected from lactose, calcium phosphate, microcrystalline cellulose, starch, sucrose and/or mannitol.

7. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is a coated tablet.

8. The pharmaceutical composition as claimed in claim 1, further comprising one or more pharmaceutical acceptable excipients selected from one or more diluents, one or more solvents, one or more glidants, one or more lubricants or the mixtures thereof.

9. The pharmaceutical composition as claimed in claim 1, wherein at least about 85% of the pirtobrutinib is dissolved within about 30 minutes as determined in an in vitro dissolution test conducted using a USP Dissolution Apparatus 2 (Paddle Apparatus), 900 mL dissolution volume, Sodium Phosphate Buffer pH 6.8 dissolution medium, and paddle rotation of 75 RPM.

10. A process for preparation of pharmaceutical composition of pirtobrutinib comprising pirtobrutinib or its pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose phthalate and one or more pharmaceutical acceptable excipients, comprising following steps:
1) Sifting one or more diluent and mixing it to obtain a blend.
2) Dissolve the hydroxypropyl methylcellulose phthalate in required quantity of suitable solvent system and stirring.
3) Add pirtobrutinib to above solution of step 2 under stirring to get clear solution.
4) Add the blend of step 1 to Fluid Bed Processsor and spray the solution of step 3 onto the blend of step 1.
5) After spraying of solution, dry the granules in Fluid Bed Processor to get solid dispersion.
6) Mix the granules of step 5 with diluent and lubricant.
7) Compress the mixture of step 6 into tablets using compression machine.
8) Coat the core tablets with appropriate coating solution using auto coater.