WO2019053500A1

WO2019053500A1 - Pharmaceutical composition of solid dosage form containing pazopanib and process for its preparation

Info

Publication number: WO2019053500A1
Application number: PCT/IB2018/000399
Authority: WO
Inventors: Nicole LIU; Angus TSENG; Jaya Abraham; Bhasin Singh PARMINDER; Patil ATUL
Original assignee: Alvogen Malta Operations (Row) Ltd
Priority date: 2018-04-17
Filing date: 2018-04-17
Publication date: 2019-03-21

Abstract

The invention relates to a pharmaceutical composition of solid dosage form containing a pazopanib, which is used in pharmacy and medicine, in particular for the treatment of advanced renal cell carcinoma and sarcoma of soft tissue, and to a process for its preparation. The pharmaceutical composition comprise pazopanib in an amount of 50 to 80 w/w % with a specific particle surface area of 1000 -2000 m2/kg, distributed by size D90 35-45 μιτι, D 50 5-12 and D10 NMT 1-3 μιη and as excipients microcrystalline cellulose, povidone, sodium starch glycolate and magnesium stearate. An advantage of a pharmaceutical composition according to the invention is its good pharmaceutical and biological availability and the process for its preparation is easily manageable and controllable and ensures the preparation of a stable dosage form with a good rate and degree of release of the active substance.

Description

PHARMACEUTICAL COMPOSITION OF SOLID DOSAGE FORM CONTAINING PAZOPANIB AND PROCESS FOR ITS PREPARATION

TECHNICAL FIELD

The invention relates to a pharmaceutical composition of solid dosage form containing a pazopanib, which is used in pharmacy and medicine, in particular for the treatment of advanced renal cell carcinoma and sarcoma of soft tissue, and to a process for its preparation. BACKGROUND ART

Pazopanib is a pyrimidine derivative with the chemical name 5 - [[4 - [(2,3- dimethyl-2H-indazol-6-yl) methylamino-2- pyrimidinyl] amino] -2- methylbenzenesulfonamid. The substance pazopanib is a potent and selective multi- target receptor tyrosine kinase inhibitor that blocks tumor growth. It is an angiogenesis inhibitor that targets the receptors of VEGFR-1, VEGFR-2, VEGFR-3 and growth factor receptors derived from PDGFR-a, PGDFR-3 and c-Kit platelets.

Pazopanib is seen to be received by Glaxo and was first described in his patent WO02059110. It is known to use pazopanib in the form of a hydrochloride salt which is a white to pale yellow solid, very slightly soluble in water at pH 1 and practically insoluble above pH 4. Based on its physical properties, according to the Biopharmaceutical Classification System (BCS), the pazopanib is classified as a Class II active substance (a substance with high permeability and poor solubility). This means that the particle size is what is expected to affect the dissolution and hence its bioavailability.

It is known that the most commonly used method for improving solubility is the micronization of the active substance. The micronized substance has better solubility and provides high rate of absorption, higher bioavailability, and a better therapeutic effect.

PCT patent application WO2009100176 describes a solid dosage form in which the active ingredient is a tyrosine kinase inhibitor and is included in the solid dispersion composition together with a pharmaceutically acceptable polymer and a surfactant that aids dissolution and the tablet form includes as excipients a disintegrant, filler and lubricant. Patent application WO2013066616 describes a granular dosage form useful as an aqueous suspension. The drug formulation is designed for pediatric use and adult patients. The active substance pazopanib is micronized, with more than 90% of its particle size being from 0.61 to 10 pm. The micronized pazopanib is present in the composition in an amount of 35 to 50 w w % and the composition includes as excipients guar gum used as a thickener and PVP or hypromellose as a suspending agent. The composition may also include a buffer, a preservative, a surfactant, a sweetener and a flavor.

Patent application WO2015145157 describes a pharmaceutical composition of a tablet formulation comprising pazopanib or a pharmaceutically acceptable derivative thereof in which the active substance is in the form of nanoparticles having a particle size of less than 2000 nm. The nanoparticles of the active ingredient are stabilized by addition of surfactant in an amount of 2 to 10 w w % and viscosity modifying agent in an amount of 2 to 15 w/w %. The composition also includes at least one polymer as well as a disintegrant.

There is a product named Votrient®, commercially available, in the form of film-coated tablets. The tablet core of this product includes 200 mg micronized Pazopanib hydrochloride and the excipients: microcrystalline cellulose, sodium starch glycolate, povidone K30 and magnesium stearate. The tablet core is coated with a film of titanium dioxide, hypromellose, macrogol, red iron dioxide, and polysorbate 80. (EU / 3/06/382 and FDA, N022465).

It is an object of the invention to provide a pharmaceutical composition of a solid dosage form containing pazopanib with good pharmaceutical and biological availability and the process of its preparation to be easily manageable and controllable and to ensure the preparation of a stable pharmaceutical form at a good rate and degree of release of the active substance.

DISCLOSURE OF INVENTION

The task is solved by a pharmaceutical composition of a solid dosage form comprising from 50 to 80 w/w % of pazopanib with a specific particle surface of 1000-2000 m²/kg, distributed in a size of D90 35-45 pm, D50 5-12 pm and D10 NMT 1-3 pm, and the excipients in the solid dosage form are microcrystalline cellulose in an amount of 5-25 w/w %, povidone in an amount of 1-5 w/w %, sodium starch glycolate in an amount of 2-15 w/w % and magnesium stearate in an amount of 0.5- 1.5 w/w %. The required specific surface area of the active substance pazopanib and its corresponding size distribution of the components in the pharmaceutical composition is achieved by mixing from 1 :1 to 3:7 of non-micronized and micronized pazopanib. The solid dosage form may be film-coated.

The achieved particle size distribution of pazopanib is determined by the laser diffraction method. This particle size of pazopanib was found to release at least 30% of this active substance for 15 minutes and no more than 70 % of it for 60 minutes with an identified biorelevance determined by the USP II methodology in a solvent with pH 2.1 HCI, with a volume of 500 mL and a stirring speed of 50 rpm.

In one embodiment, the active substance pazopanib is present in composition in an amount from 60 w/w % to 70 w/w %. In one most preferred embodiment, the active substance pazopanib is in an amount from 65 w/w % to 70 w/w %.

According to one another embodiment, the mean particle size of the active substance pazopanib in the pharmaceutical composition of the solid dosage form, according to the invention, D50 is less than 8 μιη.

According to another preferred embodiment of the present invention, the disintegrant sodium starch glycolate, included in the pharmaceutical composition of pazopanib, is present in an amount ranging from 4 to 12 w/w %, more preferably from 8 to 12 w/w %.

Pazopanib according to the invention is selected from pharmaceutically acceptable derivatives. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes, etc. Pazopanib is preferably in the form of a hydrochloride.

The pharmaceutical composition according to the invention contains less than 800 mg pazopanib and is administered once a day. More preferably, the composition of the invention contains from about 100 mg to about 800 mg pazopanib. Most preferably, the composition of the invention contains from about 125 mg to about 700 mg of pazopanib. The pharmaceutical composition of the present invention may contain from about 175 mg to about 600 mg pazopanib or from about 225 mg to about 500 mg pazopanib.

For preparing of solid dosage form according to the invention, the required amount of pazopanib, microcrystalline cellulose and sodium starch glycolate are sieved, mixed and preheated using hot air in the fluid bed processor (FBP). In a separate vessel, povidone is dissolved in purified water to obtain from 50 to 150 w/w % of the granulating liquid, based on the weight of the tablet blend, preferably about 100 w/w %. The resulting granulating fluid is sprayed onto the fluidized powder mixture using the top spray granulation technique. The rate of spraying of the granulating liquid depends on the size of the equipment and the air flow. The spray rate is maintained from 20 to 300 g/min to achieve a granule of the desired properties. The relative velocity of air and liquid droplets is high, so wetting is effective and drying begins almost immediately. The dried and sieved granules are impregnated with magnesium stearate and compressed as a tablet using a tablet press. The tablet core can be coated with an Opadry film coating with immediate release in a coated tablets tank.

An advantage of a pharmaceutical composition of the solid dosage form containing pazopanib according to the invention, is its good pharmaceutical and biological availability and the process for its preparation is easily manageable and controllable and ensures the preparation of a stable dosage form with a good rate and degree of release of the active substance.

BRIEF DESCRIPTION OF THE FIGURES

The pharmaceutical composition and its properties have been investigated and the results of the studies carried out are presented graphically in the following figures:

Figure 1 is a graphical representation of the results of the comparative study of the film-coated tablet composition dissolution profile according to the invention and film- coated tablets with identical composition but made using only micronized pazopanib (D90 less than 10 μπι) and only non-micronized pazopanib /D90 less than 40 μηη/. Figure 2 graphically reflects the In vitro Dissolution Rate of the pharmaceutical composition containing 200 mg pazopanib HCI, determined in a pH of 2.1 HCI (USP II), with a volume of 500 ml_, a stirring speed of 50 rpm: (T - R)/R. Figure 3 presents a graphical image of the observed and calculated in vivo profile of the pharmaceutical composition, according to the invention, that has been created based on the absorption of a mixture of micronized and non-micronized pazopanib hydrochloride in the ratio of 6:4 using the plasma profiles of micronized pazopanib hydrochloride and non-micronized pazopanib hydrochloride.

Figure 4 presents a graphically simulated, based on the concentration, in vivo profile, created using the plasma profiles of micronized pazopanib hydrochloride and non-micronized pazopanib hydrochloride mixed in a ratio of 6:4.

Figure 5 presents graphically simulated, based on in vivo concentration profiles, created using the plasma profiles of micronized and non-micronized pazopanib hydrochloride mixed in a ratio of 7:3.

EXAMPLES

The pharmaceutical composition of the solid dosage form containing pazopanib according to the invention is illustrated by the following exemplary embodiments:

Example 1. Preparation of a pharmaceutical composition of a film-coated tablet formulation containing 200 mg of Pazopanib with a particle surface area of 1000- 2000 m²/kg, distributed over size D90 35-45 μιη, D50 5-12 m and D10 NMT 1-3 pm.

The pharmaceutical composition of the tablet formulation containing 200 mg of active substance pazopanib is prepared using the following components:

For preparation of the tablet formulation, the required amounts of pazopanib hydrochloride, microcrystalline cellulose and sodium starch glycolate are sieved and blended and preheated using hot air in the Fluid bed processor (FBP).

In a separate vessel, 100 w/w % of the granulating liquid is prepared, based on the weight of the tablet mixture, upon dissolving the required amount of povidone in the purified water. The resulting granulating fluid is injected at a spray rate of 150 g/min on the fluidized powder mixture using the top spray granulation technique. The relative velocity of air and liquid droplets is high, so wetting is effective and drying begins almost immediately. The dried and sieved granules are powdered with magnesium stearate and compressed as a tablet using a tablet press. The tablet core is covered with an Opadry film coating with immediate release in a coated tablets tank.

Example 2 Comparative studies to determine the dissolution profile of the film- coated tablet formulations prepared using the rapid mixer granulation technique (RMG), and top spray granulation FBP respectively.

There were prepared batches to make a comparative analysis in order to establish the effect of selected degree of micronization of the active ingredient particles and of the selected process for the preparation of the pharmaceutical composition according to the invention. In Table 1 are shown the results of the dissolution profile of the film-coated tablets containing the active substance pazopanib, with the mixing limits, of the micronized with non-micronized active substance, compared to the use of only micronized or non-micronized active substance.

The batches prepared are of the same quantitative and qualitative composition as mentioned in Example 1 and are obtained by applying the two alternative granulation methods.

The dissolution profile of pazopanib film tablets was determined in order to assess the quality of the pharmaceutical forms and was performed in accordance with the FDA requirement of paddle agitator device with 50 rpm and volume of 500 ml at pH 2.1 HCI. Tests of the pazopanib film tablets were conducted under the same test conditions, samples were taken at the same time interval: 5-10-15-30-45 and 60 minutes.

The results of the conducted study over a period of time of 60 min with each of the prepared formulations are shown in Table 1. Table 1. Comparative Dissolution tests of film coated tablet including pazopanib with a different particle size and with identical quality and quantity compositions, received by different processes of production

The USP II methodology using a solvent of pH 2.1 HCI, with a volume of 500 mL and a stirring speed of 50 rpm, provides a good correlation with the in vivo observations of formulations containing pazopanib.

The analysis of the results reported in Table 1 also shows that in order to achieve a target dissolution profile comparable to that of the reference product, pazopanib hydrochloride in the tablet formulation should have a particle size specific, a 1 :1 mixture to 7:3 micronized to non-micronized pazopanib hydrochloride, and for the granulation to be use the FBP method.

The results obtained from this comparative study are shown graphically in Figure 1.

Figure 2 is shown graphically in vitro dissolution profile of film-coated tablets containing 200 mg pazopanib hydrochloride. It is formed on the basis of studies prepared by the methodology USP II using a solvent with a pH of 2.1 HCI and a volume of 500 mL and a stirring speed of 50 rpm. Example 3. Simulation of in vivo particle profiles of the active substance pazopanib obtained by mixing the micronized and non-micronized pazopanib hydrochloride within the range defined by the invention.

For the mixtures with a selected optimum particle size of the active substance pazopanib obtained by mixing the micronized and non-micronized pazopanib hydrochloride, which also showed a good dissolution profile, simulation of in vivo profile was performed. The simulation illustrates the complex mechanisms of absorption of pazopanib hydrochloride in vivo in the gastrointestinal tract. It is prepared on the basis of the plasma profiles of micronized and non-micronized pazopanib hydrochloride and has presented graphically in Figures 3, 4 and 5. Based on the in vivo simulation, according to the present invention, the critical particle size of pazopanib hydrochloride is determined as a mixture of the active substance with different size of the particles to achieve bioequivalence of the medicinal composition. Example 4. Preparation of film-coated tablets containing 200 mg of pazopanib hydrochloride with PSD: D90 35-45 microns, D50 5-12 microns, D10 NMT 5 microns For the preparation of the film-coated tablets the following ingredients are used:

The solid pharmaceutical form is prepared by the method described in Example 1. The granulating liquid is prepared in an amount of 120 w/w %, based on the weight of the tablet blend, and sprayed at a rate of 200 g/min.

A comparative study of the dissolution profile of the film-coated tablets, obtained according to Example 4 of the invention, and film-coated tablets of the reference product at pH 2.1 HCl (USP), 500 mL, paddle 50 rpm was performed. The results of this study are shown in Table 3 as follows:

Table 3. Results of the comparative study of the dissolution profile of the film-coated tablets

according to the invention and those of the reference product.

The results obtained in the study show that the pharmaceutical composition according to the invention has good physical properties, good rate and degree of dissolution, which is a prerequisite for its good bioavailability.

Claims

PATENT CLAIMS

1. A pharmaceutical composition of a solid dosage form comprising pazopanib and as excipients microcrystalline cellulose, povidone, sodium starch glycolate and magnesium stearate, characterized in that the pazopanib is present in an amount of 50 to 80 w/w % having a specific particle surface area of 1000 -2000 m²/kg , the pazopanib particles are distributed by size D90 35-45 pm, D 50 5-12 pm and D10 NMT 1-3 pm, obtained by mixing of non- micronized and micronized pazopanib in a ratio of 1 :1 to 3:7, and the excipients in the solid dosage form are in the following ratios w/w %: 5-25 microcrystalline cellulose, 1-5 povidone, 2-15 sodium starch glycolate and 0,5-1 ,5 magnesium stearate.

2. A pharmaceutical composition of a solid dosage form according to claim 1 , characterized in that the pazopanib is in an amount of 60 to 70 w/w %, preferably from 65 to 70 w/w %.

3. A pharmaceutical composition of a solid dosage form according to claims 1 and 2, characterized in that the pazopanib particles are in an average size D50 of less than 8 pm.

4. A pharmaceutical composition of a solid dosage form according to claims from 1 to 3, characterized in that the sodium starch glycolate is in an amount of 4 to 12 w/w %, preferably 8 to 12 w/w %.

5. A pharmaceutical composition of solid dosage form according to claims from 1 to 4, characterized in that the pazopanib in the pharmaceutical composition is in the form of the hydrochloride salt.

6. Process for the preparation of the pharmaceutical composition of the solid dosage form according to any one of claims from 1 to 5, characterized in that the necessary amounts of pazopanib, microcrystalline cellulose and sodium starch glycolate are sieved, mixed and preheated using of hot air, then separately prepared granulation solution of povidone in purified water in an amount of 50-150 w/w %, towards the weight of the tablet blend, preferably about 100 w/w % is sprayed onto the fluidized powder mixture at a rate of 20 to 300 g/min, so that the drying of the fluidized powder mixture to start simultaneously with the wetting of the fluidized powder mixture, and the dried granules are sieved, powdered with magnesium stearate and compressed into a tablet.