GRANULES OF MAVACAMTEN FOR ORAL ADMINISTRATION FIELD OF THE INVENTION The present invention relates to a composition in the form of granules comprising Mavacamten. BACKGROUND OF THE INVENTION Camzyos
® is approved in Europe as hard capsules containing 2.5 mg, 5 mg, 10 mg or 15 mg of Mavacamten per capsule, as an active substance. Mavacamten may be used as a medicament for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). The hard capsules are of size 2 and can accommodate 216 mg to 432 mg of formulation of bulk density from 0.6 g/ml to 1.2 g/ml. The U.S. patent 9,585,883 suggests many different compositions for Mavacamten like tablets, chewable tablets, effervescent powder and effervescent tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, troches, hard or soft capsules, emulsions, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, etc. It also discloses that formulations for oral use may be in the form of hard gelatin capsules where the active ingredient is mixed with a solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium. There is no guidance on preparation of composition containing the required dose of Mavacamten and suitable to be filled in capsules of size 2 or smaller. Similarly, it generally discloses that tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients. There is no other guidance regarding preparing smaller size tablets or reducing excipient burden or preparing mini-tablets that can be filled in a capsule. The below mentioned PCT applications disclose conventional Mavacamten compositions. PCT publication no. WO 2021/154904A1 discloses Mavacamten in many different polymorphic forms. It also generally discloses that a composition for tableting or capsule filling can be prepared by wet granulation. It suggests that in wet granulation, the active ingredients and excipients in powder form are blended and then further mixed in the presence of water, that causes the powders to clump into granules. The granulate can be screened and/or milled, dried, and then screened and/or milled to the desired particle size. A crystalline Form A of Mavacamten is disclosed in PCT publication no. WO 2021/092598 A1 by Myokardia. PCT publication no. WO 2022/162701 A1 suggests that dissolution profile can be improved by providing new polymorphic forms and solvates of active compound or salts
thereof. It suggests preparation of new polymorphic forms to improve the performance characteristics of a pharmaceutical product. Generally, it is not advisable to micronize an active substance for preparation of solid dosage forms. Reducing particle size alters the morphology of the active substance. It changes the surface area and affects porosity of the active substance. It may result in different crystalline polymorphs, amorphous active substance, or a mixture of crystalline and amorphous active substance. The flow properties of the active substance may be adversely affected when micronized. Also, there may be a build-up of electrostatic charge upon micronization of the active substance due to its increased surface area. Similar is the observation with Mavacamten. The flow of Mavacamten used in the present invention is affected when micronized. It was observed that desired fill weight could not be obtained if micronized Mavacamten, separately or in a mixture with pharmaceutically acceptable excipients, was attempted to be filled into capsules. Technical difficulties like rat holing were observed in the hopper, as the stagnant material formed an internal holding around the inner walls of hopper. However, in spite of the challenges involved, and against the conventional teachings mentioned in the literature cited above; the present invention used micronized Mavacamten and modulated the density of the granules. The density of granules was increased due to closely packed micronized Mavacamten particles having the disclosed particle size distribution, to achieve the objects of the invention, without detrimentally affecting the stability of polymorphic form of Mavacamten. Increasing the bulk density of Mavacamten granules as compared to conventional Mavacamten granules has resulted in a viable option for preparation of newer dosage forms of Mavacamten like tablets and granules for oral suspensions. This has not been taught or disclosed in literature prior to the invention. There is no observed alteration in the polymorphic form of Mavacamten, in the disclosed granule compositions during storage and handling. Besides, the granulate of the present invention provides a drug release pattern in a dissolution medium, that can match that of marketed Mavacamten capsules. It can be understood that Mavacamten is firmly crammed when filled inside the capsule shell. Therefore, assisting the release of Mavacamten from the capsules would probably need the addition of release promoting agent like a surfactant to the composition. However, it is observed that the compositions of the present invention do not require addition of release promoting agents like surfactants to enhance the rate of dissolution of Mavacamten. In the process of addressing the problems related to delivery of Mavacamten from the oral solid dosage forms, the inventors have provided novel solid dosage forms of Mavacamten. The solid dosage forms of the invention can be granules for oral suspension or tablets. It is
desirable to have tablets with low porosity and high mechanical resistance which can be optionally filled in capsules. The compositions of the present invention are also suitable to prepare such tablets. There is also a strong need to provide a pharmaceutical composition comprising Mavacamten, which is stable. Especially stable at harsh temperature and humidity conditions, in terms of resisting polymorphic conversion, during pharmaceutical processing and storage. The present invention has provided such pharmaceutical compositions. OBJECT OF THE INVENTION An object of the present invention is to provide granules of Mavacamten to prepare compositions suitable for oral administration. It is another object of the invention to provide tablets of Mavacamten. The Mavacamten granules disclosed herein, can be compressed to prepare tablets. It is another object of the invention to provide granules of Mavacamten for preparation of oral suspension. More particularly, the present invention relates to compositions, in the form of granules comprising crystalline Mavacamten; which release the Mavacamten into a dissolution medium at a faster rate than conventional Mavacamten compositions. Further, the invention also relates to the granules of higher bulk density and good flow properties suitable for capsule filling, sachet filling; as well as compressing into tablets. The granules are prepared using Mavacamten in a micronized form. These granules exhibit faster drug release as compared to the conventional compositions prepared from coarser Mavacamten. Due to high bulk density, the granules are suitable to be filled in capsules of size smaller than size 2 capsules. SUMMARY OF THE INVENTION The present invention provides granules of Mavacamten to prepare pharmaceutical compositions, suitable for oral administration. In an embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; wherein the granules have a bulk density within the range of 0.4 g/ml to 0.6 g/ml. In preferred aspects of the embodiment, the present invention provides the granules comprising Mavacamten of different bulk density values (in g/ml), such as 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.540.55, 0.56, 0.57, 0.58, 0.59 or 0.6. In another embodiment, the present invention provides a composition in the form of granules, comprising: Mavacamten; and one or more pharmaceutically acceptable excipients;
wherein the granules have a bulk density within the range of 0.4 g/ml to 0.6 g/ml; wherein the granules exhibit a release of Mavacamten of at least 30% after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% sodium lauryl sulfate; and wherein 90% of the Mavacamten particles had a particle size below 50 microns before granulation. In another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten wherein 90% of the Mavacamten particles had a particle size below 50 microns and 50% of the Mavacamten particles had a particle size below 10 microns before granulation. In preferred aspects of the embodiment, the present invention provides the granules comprising Mavacamten; and one or more pharmaceutically acceptable excipients; of different bulk density values (in g/ml), such as 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.540.55, 0.56, 0.57, 0.58, 0.59 or 0.6. In another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; and one or more pharmaceutically acceptable excipients; wherein 90% of the Mavacamten particles had a particle size below 10 microns and/or 50% of the Mavacamten particles had a particle size below 5 microns before granulation. In another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; and one or more pharmaceutically acceptable excipients; wherein the granules have a tapped density within the range of 0.5 g/ml to 1 g/ml; and wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% w/v of sodium lauryl sulfate. In yet another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; and one or more pharmaceutically acceptable excipients; wherein the granules have a Hausner ratio within the range of 1.2 to 1.8; and wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% w/v of sodium lauryl sulfate. In yet another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; and one or more pharmaceutically acceptable excipients; wherein the granules have a compressibility index within the range of 15% to 40%; and wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% w/v of sodium lauryl sulfate. In an alternative embodiment, the present invention provides the composition according to any one of the above embodiments, wherein the granules exhibit a release of at least 50%
Mavacamten, after 10 minutes in a dissolution medium of pH 6.8 containing 0.05% w/v of sodium lauryl sulfate. In an alternative embodiment, the present invention provides the composition according to any one of the above embodiments, wherein the granules exhibit a release of at least 80% Mavacamten, after 30 minutes in a dissolution medium of pH 6.8 containing 0.05% w/v of sodium lauryl sulfate. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 20 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 10 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns and 50% of the Mavacamten particles by volume have a particle size below 20 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 20 microns and 50% of the Mavacamten particles by volume have a particle size below 10 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 10 microns and 50% of the Mavacamten particles by volume have a particle size below 5 microns.
In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns and 50% of the Mavacamten particles by volume have a particle size below 20 microns and 10% of the Mavacamten particles by volume have a particle size in the range of 0.1 to 2 microns. In an aspect, the present invention provides use of the composition according to any one of the above embodiments, for the preparation of a solid dosage form; wherein the solid dosage form further comprises of one or more pharmaceutically acceptable excipients. In an alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments or aspects; wherein the dosage form is granules, tablets or capsules. In an alternative aspect, the present invention provides a composition according to any one of the above embodiments, wherein the composition is filled into a sachet; wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from a group consisting of a flavor, a sweetener and a taste-masking agent. In an alternative aspect, the present invention provides a tablet comprising the composition according to any one of the above embodiments, wherein the granules have a compressibility index within the range of 15% to 40%; and wherein the one or more pharmaceutically acceptable excipients are selected from a diluent, a binder, a disintegrant, a glidant and a lubricant. In another alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments or aspects; wherein the dosage form comprises of Mavacamten in an amount of about 0.5% w/w to 7.5% w/w; a diluent in an amount of about 60% w/w to 90 % w/w; a disintegrant in an amount of about 2% w/w to 8 % w/w; a binder in an amount of about 0.5 % w/w to 5% w/w; a glidant in an amount of about 0.1 % w/w to 2 % w/w and a lubricant in an amount of about 0.5 % w/w to 2 % w/w of the dosage form. In another alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments or aspects; wherein the dosage form comprises of Mavacamten in an amount of about 0.5% w/w to 7.5% w/w; a diluent in an amount of about 60% w/w to 70 % w/w; a disintegrant in an amount of about 3% w/w to 5 % w/w; a binder in an amount of about 0.5 % w/w to 2% w/w; a glidant in an amount of about 0.3 % w/w to 1 % w/w and a lubricant in an amount of about 0.5 % w/w to 1 % w/w of the dosage form.
In another alternative aspect, the present invention provides the composition according to any one of the above embodiments or aspects; wherein the composition is devoid of the salts calcium carbonate, calcium phosphate and the clays like kaolin. In another alternative aspect, the present invention provides the composition according to any one of the above embodiments or aspects; wherein the composition is devoid of a release promoting agent, especially a surfactant. In another alternative aspect, the present invention provides the composition according to any one of the above embodiments, wherein the Mavacamten is crystalline. In another alternative aspect, the present invention provides the composition according to any one of the above embodiments, wherein the Mavacamten is a crystalline form A of Mavacamten. BRIEF DESCRIPTION OF THE DRAWINGS Fig 1 provides the X-ray Powder Diffraction (XRPD) pattern of crystal Form A of Mavacamten. Fig 2 provides the X-ray Powder Diffraction (XRPD) pattern of initial samples of Mavacamten capsules as per Example 1. Fig 3 provides the X-ray Powder Diffraction (XRPD) pattern of samples of Mavacamten capsules as per Example 1 after subjecting the capsules to temperature and humidity conditions of 40°C and 75% relative humidity for 6 months in a HDPE bottle pack. Fig 4 provides the X-ray Powder Diffraction (XRPD) pattern of initial placebo samples of capsules having composition similar to Example 1. Fig 5 provides the X-ray Powder Diffraction (XRPD) pattern of Mavacamten used for Example 1 DETAILED DESCRIPTION OF THE INVENTION The present invention provides granules of Mavacamten suitable for oral administration. The term “granules” as used herein refers to granules or granulate and does not exclude granulates made by comminution of extruded composition containing Mavacamten. Granules as per present invention, are orally administrable, and they include pharmaceutically acceptable excipients. In order to make a denser granulate, the inventors have devised a method to avoid flow problems and to prepare granules which have a high bulk density using micronized particles of Mavacamten. Porosity of the granulate is thereby reduced. The reduction in porosity enables better packing of the Mavacamten particles in a single granule. This provides a suitable option to address the poor flow of Mavacamten
particles. Besides this, a higher amount of Mavacamten can be loaded in the granules. The size of Mavacamten active substance for preparing the granules is selected such that 90% of the Mavacamten particles by volume have a particle size below 50 microns. Such fine particles are suitably granulated by a wet granulation method, hot melt extrusion (followed by comminution) or roller compaction. Release of Mavacamten in dissolution medium from a pharmaceutical dosage form is an important aspect of formulation and is directly proportional to the porosity of the granules. However, even though the dense packing of Mavacamten in the granules is generally expected to hamper drug release, the granules of present invention are able release the Mavacamten at a faster rate such that, at least 30% of Mavacamten is released in 5 minutes. There are various methods to measure the bulk density and tapped density of powders. A publication by United States Pharmacopoeial Convention entitled “<616> Bulk Density and tapped density of Powders” stage 6 Harmonization; official August 1, 2015; discloses standard methods for determining bulk density, tapped density, Hausner ratio and Compressibility index values. These methods are suitable for determining the same values for granules also. Method I disclosed in the said publication is suitable for determining bulk density of granules. The bulk density of granules is the ratio of the mass of an untapped sample of granules and its volume. The bulk density is expressed in grams per mL (g/mL). The tapped density is an increased bulk density attained after mechanically tapping a container containing the granules. Tapped density is obtained by mechanically tapping a graduated measuring cylinder containing the granules. Method I disclosed in the said publication is suitable for determining tapped density of granules. The tapped density is expressed in grams per mL (g/mL). The Hausner Ratio and Compressibility index are calculated by the formulas Compressibility Index— 100(V0 - VF)/V0 V0 = unsettled apparent volume of granules V
F = final tapped volume of granules and, Hausner Ratio— V
0/VF In an embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; wherein the granules have a bulk density within the range of 0.4 g/ml to 0.6 g/ml; wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 with 0.05% sodium lauryl sulfate.
In preferred aspects of the embodiment, the present invention provides the granules comprising Mavacamten with different bulk density values (in g/ml), such as 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.540.55, 0.56, 0.57, 0.58, 0.59 or 0.6. Tapped density of granules is also an important indicator. It is an increased bulk density attained by the granules after being mechanically tapped for a specified period of time in a container. The tapped density of granules of the present invention is desired to be in the range of 0.4 g/ml to 1.1 g/ml, preferably in the range of 0.5 g/ml to 1 g/ml. This property can be determined for the granules and selection of the granules for preparation of the oral composition can be based on it. In another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; wherein the granules have a tapped density within the range of 0.5 g/ml to 1 g/ml; wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 with 0.05% sodium lauryl sulfate. Hausner ratio and compressibility index are the indicators to predict the natural tendency of a given sample of granules to be compressed and can be used to select the granules for preparation of the oral composition. For example, as a part of tableting procedure to prepare compressed tablets, filling of the tablet die with uniform flow of granules is essential to maintain uniformity of weight of the tablet. In yet another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; wherein the granules have a Hausner ratio within the range of 1.2 to 1.8; wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% sodium lauryl sulfate. In yet another embodiment, the present invention provides a composition in the form of granules comprising Mavacamten; wherein the granules have a compressibility index within the range of 15% to 40%, wherein the granules exhibit a release of at least 30% Mavacamten, after 5 minutes in a dissolution medium of pH 6.8 with 0.05% sodium lauryl sulfate. Based on the above embodiments, various compositions of Mavacamten can be prepared, that can achieve different drug release rates and patterns. The drug released in a dissolution medium can be measured at suitable intervals of 5, 10 and 30 minutes to evaluate the rate of drug release. In an alternative embodiment, the present invention provides the composition according to any one of the above embodiments, wherein the granules exhibit a release of at least 50% Mavacamten, after 10 minutes in a dissolution medium of pH 6.8 containing 0.05% sodium lauryl sulfate.
In an alternative embodiment, the present invention provides the composition according to any one of the above embodiments, wherein the granules exhibit a release of at least 80% Mavacamten, after 30 minutes in a dissolution medium of pH 6.8 containing 0.05% sodium lauryl sulfate. These granules provide an easy means to adjust the release of Mavacamten from the oral compositions. In a method, the rate of release of Mavacamten is modulated by changing the particle size distribution of the Mavacamten which is used to prepare the granules. Particle size distribution of Mavacamten used to prepare the granules; has an impact on the dissolution behavior of the granules. Two separate batches of Mavacamten granules were made using Mavacamten having 2 different particle size distributions. The batches had the same quantitative and qualitative composition and were made with the same granulation process. The results of dissolution studies performed on both the batches indicated that the granules made using micronized Mavacamten with a narrow particle size distribution exhibited a faster rate of release of Mavacamten. The narrow particle size distribution was such that 90% of Mavacamten particles had a particle size less than 50 microns. On the other hand, the batch of granules made using coarser Mavacamten with a particle size distribution where 50 % particles were greater than 50 microns, exhibited a slow release of Mavacamten of less than 10% in 60 minutes. The particle size distribution preferred by the inventors is a very narrow distribution to minimize oversized particles and fines. Micronized Mavacamten that is used herein, has a particle size distribution such that; 90% of Mavacamten particles are below 50 microns; preferably below 20 microns; and most preferably below 10 microns. Such fine particles are difficult to handle and are suitably granulated by a wet granulation method or roller compaction. These granulation methods are well known to a person skilled in the art. Other suitable methods of granulation are fluid bed granulation and melt extrusion/ melt granulation, which are well known to a person skilled in the art. The granules having a high bulk density prepared from micronized Mavacamten, are suitable for filling in smaller capsules. The density is increased and voids between particles are decreased due to close packing of the Mavacamten particles in the granules. As explained above, the density of the granulate and its flow properties are modulated by a wet granulation process for preparation of the granulate and also by using micronized Mavacamten of a suitable particle size distribution. The particle size reduction of Mavacamten is carried out by milling using suitable ball or hammer or roller milling. The particle size distribution is measured by laser diffraction using an equipment such as a Malvern Mastersizer 3000 from Malvern Panalytical.
In another embodiment, the present invention provides a composition in the form of granules, comprising: Mavacamten; and one or more pharmaceutically acceptable excipients; wherein the granules have a bulk density within the range of 0.4 g/ml to 0.6 g/ml; wherein the granules exhibit a release of Mavacamten of at least 30% after 5 minutes in a dissolution medium of pH 6.8 containing 0.05% sodium lauryl sulfate; and wherein 90% of the Mavacamten particles had a particle size below 50 microns before granulation. In another embodiment, the present invention provides a composition in the form of granules, wherein the one or more pharmaceutically acceptable excipients are selected from a diluent, a disintegrant, a binder, a glidant and a lubricant. In an alternative aspect, the present invention provides a composition according to any one of the above embodiments, wherein the composition is filled into a sachet; wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from a group consisting of a flavor, a sweetener and a taste-masking agent. In an alternative aspect, the present invention provides a tablet comprising the composition according to any one of the above embodiments, wherein the granules have a compressibility index within the range of 15% to 40%; and wherein the one or more pharmaceutically acceptable excipients are selected from a diluent, a binder, a disintegrant, a glidant and a lubricant. In another embodiment, the present invention provides a composition in the form of granules, wherein the Mavacamten is in a range of 0.5% w/w to 7.5% w/w; the diluent is in a range of 60% w/w to 90 % w/w; the disintegrant is in a range of 2% w/w to 8 % w/w; the binder is in a range of 0.5 % w/w to 5% w/w; the glidant is in a range of 0.1 % w/w to 2 % w/w and the lubricant is in a range of 0.5 % w/w to 2 % w/w. In another embodiment, the present invention provides a composition in the form of granules, wherein the diluents are selected from lactose, sucrose, mannitol, sorbitol, xylitol, calcium phosphate, calcium carbonate, calcium sulfate, dry starch, microcrystalline cellulose and silicified microcrystalline cellulose; binders are selected from starch, pregelatinized starch, xanthan gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, hypromellose, sodium carboxymethylcellulose, polyethylene glycol and methylcellulose; disintegrants are selected from starch, methyl cellulose, hydroxypropyl cellulose, croscarmellose, cross-linked polyvinylpyrrolidone and sodium starch glycolate; glidant are selected from colloidal silicon dioxide and talc; lubricants are selected from talc, magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate and polyethylene glycol, and magnesium stearate. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 20 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 10 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns and 50% of the Mavacamten particles by volume have a particle size below 20 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 20 microns and 50% of the Mavacamten particles by volume have a particle size below 10 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 10 microns and 50% of the Mavacamten particles by volume have a particle size below 5 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten particles have a particle size distribution such that 90% of the Mavacamten particles by volume have a particle size below 50 microns and 50% of the Mavacamten
particles by volume have a particle size below 20 microns and 10% of the Mavacamten particles by volume have a particle size in the range of 0.1 microns to 2 microns. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten is crystalline. In an aspect, the present invention provides use of Mavacamten particles for the preparation of the granules according to any one of the above embodiments, wherein the Mavacamten is crystalline Form A of Mavacamten. The crystalline Form A of Mavacamten is disclosed in US 2023/0158027 A1. Fig 1 provides the X-ray Powder Diffraction (XRPD) spectrum of crystal Form A of Mavacamten. In an aspect, the present invention provides use of the composition according to any one of the above embodiments, for the preparation of a solid dosage form; wherein the solid dosage form further comprises of one or more pharmaceutically acceptable excipients. The granules comprising Mavacamten are prepared by compounding one or more pharmaceutically acceptable excipients together with Mavacamten. Suitable pharmaceutically acceptable excipients like one or more binder, disintegrant and diluent are used to prepare the granules. Examples of binders that can be included are starch, pregelatinized starch, xanthan gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, hypromellose, sodium carboxymethylcellulose, polyethylene glycol and methylcellulose. Some of the preferred binders are polyvinylpyrrolidone and hypromellose. Examples of diluents that can be included are lactose, sucrose, mannitol, sorbitol, xylitol, calcium phosphate, calcium carbonate, calcium sulfate, dry starch, microcrystalline cellulose and silicified microcrystalline cellulose. Some of the preferred diluents are mannitol and spray dried mannitol. Examples of disintegrants that can be included are starch, methyl cellulose, hydroxypropyl cellulose, croscarmellose, cross-linked polyvinylpyrrolidone and sodium starch glycolate. Some of the preferred disintegrants are croscarmellose and sodium starch glycolate. In an alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments and/or aspects; wherein the dosage form is granules, tablets or capsules. Suitable lubricants and glidants are blended with the granules to aid the lubrication of granules and assist the flow through the hopper of the capsule filling or tableting machine, while filling into capsules or punching into tablets. The granules blended with lubricants and glidants can also be easily filled into capsules of capacity less than or equal to 0.4 ml. For
example, a suitable glidant is colloidal silicon dioxide or talc; and suitable lubricants include talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate and polyethylene glycol, and magnesium stearate. In another alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments and/or aspects; wherein the dosage form comprises of Mavacamten in an amount of about 0.5% w/w to 7.5% w/w; a diluent in an amount of about 60% w/w to 90 % w/w; a disintegrant in an amount of about 2% w/w to 8 % w/w; a binder in an amount of about 0.5 % w/w to 5% w/w; a glidant in an amount of about 0.1 % w/w to 2 % w/w and a lubricant in an amount of about 0.5 % w/w to 2 % w/w of the dosage form. The preferable solid dosage forms are granules, tablets or capsules. In another alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments and/or aspects; wherein the dosage form comprises of Mavacamten in an amount of about 0.5% w/w to 7.5% w/w; a diluent in an amount of about 60% w/w to 70 % w/w; a disintegrant in an amount of about 3% w/w to 5 % w/w; a binder in an amount of about 0.5 % w/w to 2% w/w; a glidant in an amount of about 0.3 % w/w to 1 % w/w and a lubricant in an amount of about 0.5 % w/w to 1 % w/w of the dosage form. The preferable solid dosage forms are granules, tablets or capsules. In another alternative aspect, the present invention provides the composition according to any one of the above embodiments; wherein the composition is devoid of the salts calcium carbonate and calcium phosphate and the clays like kaolin. Although, the compositions according to present invention do not require a release promoting agent to aid the rate of dissolution and release of Mavacamten; in an alternative aspect, a release promoting agent may be added to the compositions according to any one of the above embodiments or aspects; wherein the release promoting agent is a surfactant. Suitable surfactants can be selected from sodium oleate, sodium lauryl sulfate, poloxamer and polysorbate. Preferred surfactants are sodium lauryl sulfate, poloxamer and polysorbate. In another alternative aspect, the present invention provides the composition according to any one of the above embodiments or aspects; wherein the composition is devoid of a release promoting agent, especially a surfactant. Wet granulation is one of the methods to prepare compositions of the present invention. The method involves mixing together of ingredient present in the granules and Mavacamten in a suitable equipment like a rapid mixer granulator. The mixture is wetted with binder solution, preferably in purified water and granulated in the granulator. The wet granules are dried in a fluid bed dryer or a fluid bed processor with loss on drying as an indicator for desired dryness
of the granules. The dried granules are lubricated with glidant and/or lubricant and either compressed into tablets or filled into capsules. In an alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments and/or aspects; wherein the dosage form is granules comprising Mavacamten, filled in a sachet, or a bottle; and supplied with or without water for reconstitution. The granules of Mavacamten can be prepared as per any one of the embodiments and examples disclosed herein. Suitable sweeteners, flavours and taste-masking agents could be incorporated into granules comprising Mavacamten; or mixed with granules of Mavacamten; or coated on the granules of Mavacamten. Suitable examples of flavors include black cherry flavor, peppermint flavor, orange flavor, menthol, vanilla or combinations thereof. Preferably, peppermint flavor. Suitable examples of sweeteners include aspartame, acesulfame potassium, sucrose, sucralose, sodium saccharin or combinations thereof. Preferably, aspartame. In an alternative aspect, the present invention provides a solid dosage form according to any one of the above embodiments and/or aspects; wherein the polymorphic form of Mavacamten in the dosage form remains the same, after subjecting the dosage forms to temperature and humidity conditions of 40°C and 75% relative humidity for 6 months. In an alternative aspect, the present invention provides capsules according to any one of the above embodiments and/or aspects; wherein the polymorphic form of Mavacamten in the dosage form remains the same, after subjecting the dosage forms to temperature and humidity conditions of 40°C and 75% relative humidity for 6 months. Fig 2 provides the X-ray Powder Diffraction (XRPD) pattern of initial samples of Mavacamten capsules as per Example 1. Fig 3 provides the X-ray Powder Diffraction (XRPD) pattern of samples of Mavacamten capsules as per Example 1 after subjecting the capsules to temperature and humidity conditions of 40°C and 75% relative humidity for 6 months in a HDPE bottle pack. From the XRPD pattern in the Figures 2-4 and the Table A; it can be seen that, maximum relative intensity of peaks is observed at below mentioned 2θº angles for the Mavacamten API (Active Ingredient) i.e., Form A polymorphic form and the compositions (Mavacamten capsules (initial); and Mavacamten capsules (stored in HDPE bottle pack of 30's, for 6 months at 40°C/75%RH)). The 2θº values of the compositions are closely similar to 2θº values of Mavacamten API (Active Ingredient); which confirms there is no change in the polymorphic form in the drug product during manufacturing and stability. TABLE A: Result summary of XRPD analysis:
Samples Position (2θº) (major) Mavacamten (Active Ingredient) 11.7049°, 17.4344°, 20.0492°, 22.4105° and 31.6778° Mavacamten Capsules 15 mg of Example 1 11.7122°, 17.4238°, 20.0630°, 22.4128° Initial and 31.6858° Mavacamten Capsules 15 mg of Example 1 11.7840°, 17.5125°, 20.0933°, 22.4405° HDPE bottle pack of 30's, 6 month, and 31.4555° 40°C/75%RH Mavacamten Capsules 15mg Placebo
$ 10.5067°, 14.6544°, 18.8013°, 20.4782°, 21.0491°, 23.4336°, 28.3519°, 29.5127°, 31.7831°, 33.4273°, 33.6120°, 38.5557°, and 38.7134° $ Placebo has the same qualitative composition as that of the Example 1 except Mavacamten. The present invention and its embodiments and aspects will be further explained in detail by the following non-limiting examples. EXAMPLES EXAMPLE 1: Quantitative Composition Ingredients mg Granule contents Mavacamten 15.00 Spray Dried Mannitol 186.30 Croscarmellose Sodium 11.00 Hypromellose 4.40 Lubrication Silicon dioxide 1.10 Magnesium Stearate 2.20 Total Filled content weight 220 Size # 2 (Hard gelatin capsules, ACG) 63 Filled capsule weight 283 Mavacamten particle size distribution d(10):0.37µm, d(50):3.75 µm & d(90):9.66 µm Table 2: Quantitative composition for 15 mg Mavacamten capsules (Example 1)
Procedure: 1. Mavacamten, mannitol, croscarmellose sodium and hypromellose were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water. 3. The mixture of step 1 was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3 were dried in fluid bed processor/dryer. 5. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve. 6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend. 7. The lubricated blend was filled into capsule of size 2. COMPARATIVE EXAMPLE 1: Quantitative Composition Ingredients mg Granule contents Mavacamten (Coarser API) 15.00 Spray dried mannitol 186.30 Croscarmellose Sodium 11.00 Hypromellose 4.40 Lubrication Silicon dioxide 1.10 Magnesium Stearate 2.20 Total Filled content weight 220 Size # 2 (Hard gelatin capsules) 63 Filled capsule weight 283 Mavacamten coarser API- Particle size distribution d(10):10.4 µm, d(50):52.2 µm & d(90):167.0 µm d(90) = 90% of particles by volume are smaller than the d(90) value d(50) = 50% of particles by volume are smaller than the d(50) value d(10) = 10% of particles by volume are smaller than the d(10) value Table 1: Quantitative composition for 15 mg Mavacamten capsules (Comparative Example 1) Procedure:
1. Mavacamten, mannitol, croscarmellose sodium and hypromellose were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water. 3. The mixture of step 1 was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3 were dried in fluid bed processor/dryer. 5. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve. 6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend. 7. The lubricated blend was filled into capsule of size 2. DISSOLUTION STUDIES OF COMPARATIVE EXAMPLE 1 & EXAMPLE 1 Dissolution parameters: Drug Name Mavacamten Dosage Form Capsule USP Apparatus II (Paddle) Speed (RPMs) 50 Dissolution Medium 0.05%(w/v) SLS in 50 mM Sodium Phosphate, pH 6.8 Volume (mL) 900 Recommended Sampling 5, 10, 15, 20, 30, 45 and 60 Times (minutes) Table 3: Dissolution parameters The content of Mavacamten released was measured in the samples by High Performance Liquid Chromatography (HPLC). HPLC operation is well known to a person skilled in the art. Standard: Standard solution containing 0.006 mg/ml of Mavacamten was prepared in dissolution medium. Dissolution method and sample: One capsule was placed in each of the 6 dissolution vessels of the apparatus containing 900 ml of dissolution medium. The dissolution apparatus was run as per the dissolution parameters. At specified time interval, 10 ml sample aliquot from each dissolution vessel was withdrawn and replaced with 10 ml fresh dissolution medium maintained at 37 ⁰C. Chromatography conditions: Equipment: HPLC system equipped with UV/PDA detector Column: Inertsil ODS 3V, 150 mm x 4.6 mm, 5 micron Flow rate: 1 ml/minute; Wavelength: 267 nm; Injection column: 50 µl
Column oven temperature: 40 ⁰C; Auto sampler temperature: 25 ⁰C Run time: 10 minutes; Retention time: about 5.5 minutes; Mobile phase: Water: acetonitrile 60:40 v/v Where, AT = Area of Mavacamten peak in sample preparation chromatogram, AS = Average area of Mavacamten peak in standard preparation chromatogram, WS = Weight of Mavacamten reference/working standard in mg P = % Purity of Mavacamten reference/working standard on as is basis, LC = Label Claim in mg, CF = Correction factor Note: Determine amount of drug dissolved at various time intervals making necessary correction for amount of dissolution medium withdrawn and replaced.
Where, X = % release calculated at each interval before applying CF. The results are mentioned below: T
ime Mavacamten Capsule 15mg Mavacamten Capsule 15mg COMPARATIVE EXAMPLE 1 EXAMPLE 1 (Minutes) % Release % RSD % Release % RSD 5 2.0 8.9 36.9 25.8 10 3.8 6.1 63.6 7.3 15 4.8 3.3 76.4 10.0 20 5.5 2.2 80.4 9.9 30 6.5 3.7 88.8 6.9 45 7.5 5.9 91.6 10.5 60 8.6 8.4 94.3 8.6 RSD = Relative Standard Deviation
Table 4: Dissolution study results for 15 mg Mavacamten capsules of Comparative Example 1 and Example 1 Observations: It can be clearly observed that the capsules of Example 1 have exhibited a significantly higher % release of Mavacamten at all the time points mentioned in Table 4, as compared to the capsules of the Comparative Example 1. EXAMPLE 2: Quantitative Composition Ingredients 15 mg/tab Dry mix Mavacamten 15.00 Mannitol 205.20 Croscarmellose Sodium 12.00 Binder Hypromellose 4.80 Purified water* q.s Lubrication Colliodal Silicon Dioxide (Aerosil 200) 0.60 Magnesium Stearate 2.40 Total fill content weight (mg) 240.00 Empty Hard gelatin capsule Size 2 63.00 Total weight of capsule 303.00 Mavacamten particle size distribution d(10): 0.301 µm; d(50): 2.34 µm; d(90): 7.71 µm * not in the final composition Table 5: Quantitative composition for 15 mg Mavacamten capsules (Example 2) Procedure: 1. Mavacamten, Mannitol & Croscarmellose sodium were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water. 3. The mixture of step 1 was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3 were dried in fluid bed processor/dryer.
5. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve. 6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend. 7. The lubricated blend was filled into capsule of size 2. EXAMPLE 3: Quantitative Composition of Capsules Ingredients 15 mg/tab Dry mix Mavacamten 15.00 Mannitol 260.25 Croscarmellose Sodium 15.00 Binder Hypromellose 6.00 Purified water* q.s Lubrication Colliodal Silicon Dioxide (Aerosil 200) 0.75 Magnesium Stearate 3.00 Total fill content weight (mg) 300.00 Empty Hard gelatin capsule Size 2 63.00 Total weight of capsule 363.00 Mavacamten particle size distribution d(10): 0.301 µm; d(50): 2.34 µm; d(90): 7.71 µm * not in the final composition Table 6: Quantitative composition for 15 mg Mavacamten capsules (Example 3) Procedure: 1. Mavacamten, Mannitol & Croscarmellose sodium were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water. 3. The mixture of step 1, was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3, were dried in fluid bed processor/dryer. 5. The dried granules were sized by passing through a mill, and sifting through 40# mesh sieve.
6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend. 7. The lubricated blend was filled into capsule of size 2. EXAMPLE 4: Quantitative Composition of Tablets: Ingredients 15 mg/tab Dry mix Mavacamten (Micronized API) 15.00 Mannitol 205.20 Croscarmellose Sodium 4.80 Binder Hypromellose 4.80 Purified Water* q.s Pre-Lubrication Croscarmellose Sodium 7.20 Colloidal silicon dioxide 0.60 Lubrication Magnesium Stearate 4.80 Total Tablet Weight 242.40 Mavacamten particle size distribution d(10): 0.301 µm; d(50): 2.34 µm; d(90): 7.71 µm * not in final composition Table 7: Quantitative composition for 15 mg Mavacamten tablets Procedure: 1. Mavacamten, Mannitol & Croscarmellose sodium were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water. 3. The mixture of step 1 was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3 were dried in fluid bed processor/dryer. 5. The dried granules were sized by passing through a mill and sifting through 40# mesh sieve. 6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend.
7. The lubricated blend was compressed into tablets. Dissolution studies were carried in a similar to those for Example 1, and the results are reported below. Dissolution test: Camzyos
® Capsules 15 mg Mavacamten tablets (Example 4) Time (Min) % Release % RSD % Release % RSD 5 45.9 11.0 64.9 3.2 10 72.3 4.7 86.0 1.0 15 78.7 2.0 93.3 1.4 20 81.6 1.8 96.0 1.9 30 85 1.4 97.5 2.0 45 88.5 1.1 98.0 2.1 60 90.7 1.1 98.4 2.2 RSD = Relative Standard Deviation Table 8: Comparative dissolution test results Camzyos
® capsules 15 mg versus Mavacamten tablets (Example 4) EXAMPLE 5: Quantitative Composition of granules for oral suspension Ingredients 15 mg/ 5 ml Dry mix Mavacamten 15.00 Sucrose 216.60 Binder Isopropyl Alcohol* q.s. Blending Xanthan Gum 7.20 Peppermint flavor 1.20 Total Weight 240.00 Mavacamten particle size distribution d(10): 0.301 µm; d(50): 2.34 µm; d(90): 7.71 µm * not in final composition Table 9: Quantitative composition for 15 mg Mavacamten granules Procedure:
1. Mavacamten and Sucrose were co-sifted through sieve #40 and mixed in a rapid mixer granulator for 10 minutes. 2. The material of step 1 was granulated using isopropyl alcohol as binder to form granules. 3. The granules were dried in a fluid bed dryer and subsequently sized through a mill using suitable screen and sieves. 4. Xanthan Gum & Peppermint flavor through 40# and mixed with the granules of step 3 in a blender for another 10 minutes. 5. These granules are suitable for reconstitution with water to prepare a suspension having strength 15mg/5ml. EXAMPLE 6: Quantitative Composition of Capsules: Ingredients 15 mg/capsule Dry mix Mavacamten (Micronized API) 15.00 Mannitol 186.85 Croscarmellose Sodium 11.00 Binder Hypromellose 4.40 Purified Water* q.s Lubrication Colloidal silicon dioxide 0.55 Magnesium Stearate 2.20 Total Fill Weight 220.00 Mavacamten particle size distribution d(10): 0.301 µm; d(50): 2.34 µm; d(90): 7.71 µm * not in final composition Table 10: Quantitative composition for 15 mg Mavacamten capsules (Example 6) Procedure: 1. Mavacamten, Mannitol & Croscarmellose sodium were sifted through 20# mesh sieve and mixed in a Rapid Mixer Granulator. 2. A binder solution was prepared by dissolving hypromellose in sufficient quantity of purified water.
3. The mixture of step 1, was granulated using binder solution in the rapid mixer granulator. 4. The wet granules of step 3, were dried in fluid bed processor/dryer. 5. The dried granules were sized by passing through a mill, and sifting through 40# mesh sieve. 6. The sized granules were lubricated by mixing with magnesium stearate & colloidal silicon dioxide in a blender to prepare a lubricated blend. 7. The lubricated blend was filled into capsule of size 2. Dissolution studies were carried in a similar to those for Example 1, and the results are reported below. Time Camzyos
® Capsules 15 mg Mavacamten capsules Example 6 (Min) % Release % RSD % Release % RSD 5 45.9 11.0 43.0 11.3 10 72.3 4.7 81.7 2.7 15 78.7 2.0 87.0 1.6 20 81.6 1.8 89.7 2.1 30 85 1.4 92.0 2.4 45 88.5 1.1 94.4 2.9 60 90.7 1.1 95.6 3.0 RSD = Relative Standard Deviation Table 11: Comparative dissolution test results Camzyos
® capsules 15 mg versus Mavacamten capsules (Example 6) Physical properties of granules for the Examples 1-6 and Comparative Example 1 are given below Bulk density Tapped density Compressibility Hausner g/ml g/ml Index ratio Example 1 0.440 0.532 17.391 1.210 Comparative 0.394 0.476 17.308 1.209 Example 1 Example 2 0.478 0.693 30.952 1.448 Example 3 0.538 0.665 19.048 1.235 Example 4 0.519 0.721 28 1.389 Example 5 0.573 0.716 20 1.250 Example 6 0.513 0.646 20.558 1.259 Table 12: Physical properties of granules for the Examples 1-6 and comparative Example 1