DESC:DETAILED DESCRIPTION OF THE INVENTION

Description provided herein is not meant to be limited. Embodiments and different ways to practise the invention of the present application are expressly included and variations in those embodiments are considered part of the present invention.
In the following description, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the described embodiments. It will be apparent to one skilled in the art, however, that other aspects of the embodiments provided herein may be practised without some of these specific details.
In one aspect, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to immediate release pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients in the form of granules.
In one aspect, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, such as diluents, binders, disintegrants, glidants and lubricants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.
In another embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said composition comprises an intra-granular portion and an extra-granular portion.
In another embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said composition comprises an intra-granular portion and an extra-granular portion, wherein said excipients may include, but not limited to diluents, binders, disintegrants, glidants and lubricants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof.
In one embodiment, the present invention provides a pharmaceutical composition comprising an intragranular portion and an extragranular portion, said intragranular portion consisting of the drug and one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising an intra-granular portion and an extra-granular portion, said extra-granular portion consisting of one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising an intragranular portion and an extragranular portion, said intragranular portion consisting of the drug and pharmaceutically acceptable excipients, and said extra-granular portion consisting of pharmaceutically acceptable excipients.
In one embodiment, the present invention provided a pharmaceutical composition comprising an intra-granular portion with an extra-granular portion, wherein said intra-granular portion consisting of the drug and pharmaceutically active component and pharmaceutically acceptable excipient component, wherein, said extra-granular portion consisting of pharmaceutically acceptable excipients, wherein said excipients may include, but not limited to, diluents, binders, disintegrants, glidants and lubricants, surfactants, pH adjusters, coating agents, colorants, or combinations thereof include diluents, binders, disintegrants, glidants and lubricants.
In one embodiment, both intra-granular portion and extra-granular portion of a pharmaceutical composition described herein may comprise the drug.
One aspect of the present invention comprises solid oral pharmaceutical dosage forms wherein the solid dosage forms are formulated using a diluent or diluents. One aspect of the present invention comprises pharmaceutical capsules, wherein the capsules are formulated using a diluent or diluents.
In one embodiment, diluents provide bulk to a composition, may aid in processing. Examples of diluents suitable for use in the composition of the present invention include, but not limited to, calcium phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, lactose, cellulose (e.g., microcrystalline cellulose, powdered cellulose), pregelatinized starch, starch, lactitol, mannitol, sorbitol, xylitol, dextrin, maltodextrin, isomalt, powdered sugar, compressible sugar, dextrates, sucrose, dextrose, fructose, maltitol, erythritol, maltose, raffinose, polydextrose, trehalose and inositol, chitin, chitosan, bicarbonate, sodium carbonate, or combinations thereof. Typically a diluent may be present in any amount upto 80% w/w. In an embodiment, a diluent may be present in an amount of upto about 60% w/w
In one embodiment, binders impart cohesive properties to the powdered material. Examples of binders suitable for use in the composition of the present invention include, but not limited to, starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), polymethacrylates, natural and synthetic gums (e.g., acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein), cellulose derivatives [such as carboxymethyl cellulose and salts thereof, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, bentonites, or combinations thereof. In one embodiment of the present invention, the binder comprises hydroxypropyl cellulose (HPC). In one embodiment of the present invention, the binder comprises hydroxypropyl methyl cellulose (HPMC). In one embodiment of the present invention, the binder comprises polyvinylpyrrolidone (PVP).
The composition of the present invention typically comprise up to about 8% binder. In an embodiment, the compositon may suitably comprise up to about 6.5%, suitably up to about 5% binder.
In one embodiment, lubricants are generally used to enhance processing, for example, to prevent adhesion of the composition material to manufacturing equipment, reduce interparticle friction, improve rate of flow of the formulation, and/or assist ejection of the composition from the manufacturing equipment. Examples of lubricants suitable for use in the present invention include, but are not limited to, talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, myristic acid, palmitic acid, hydrogenated vegetable oils, glyceryl behanate, tribehenin, glyceryl dibehenate, glyceryl monostearate, polyethylene glycol, glyceryl palmitostearate, a mixture of benenate esters of glycerine, myristic acid, ethylene oxide polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate), or combinations thereof.
The composition of the present invention typically comprise up to about 5% lubricant. In an embodiment, the composition may suitably comprise up to about 3%lubricant.
In one embodiment, disintegrants are employed to facilitate breakup or disintegration of the formulation after administration. Examples of disintegrants suitable for use in the present invention include, but not limited to, starches such as corn starch, potato starch, pregelatinized starch, modified corn starch, sodium starch glycolate, celluloses such as methyl cellulose, microcrystalline cellulose, cellulose, carboxymethylcellulose, modified cellulose gum or crosslinked sodium carboxymethylcellulose (e.g., Ac-Di-Sol R), gums such as gellan gum, xanthan gum, agar, guar gum, alginic acid and alginates, bentonite, montmorillonite clay, crosslinked polymers such as croscarmellose sodium, crospovidone, effervescent agents, such as sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid, silicates such as calcium silicate, magnesium aluminum silicate, hydrous aluminum silicate, Veegum HV and other agents such as chitosan, natural sponge, cation exchange resins, ion exchange resins (e.g., polyacrin/ polacrilin potassium), citrus pulp, or combinations thereof.
The composition of the present invention typically comprise up to about 8% w/w of disintegrant. In an embodiment, the composition may suitably comprise up to about 4% w/w disintegrant.
In one embodiment, glidants are used to improve flow. Because of the shape and size of the particles, glidants improve flow in low concentrations. Most commonly used glidants are alkali metal stearates, colloidal silicon dioxide (CAB-O-SIL®, SYLOID®, AEROSIL®), and talc, calcium silicate, magnesium silicate, magnesium trisilicate, starch, sodium stearyl fumarate, or combinations thereof.
The composition of the present invention typically comprise up to about 8% w/w of disintegrant. In an embodiment, the composition may suitably comprise up to about 4% w/w disintegrant.
In one embodiment, the present invention provides a pharmaceutical composition comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, about 30% to 60% w/w of a diluent, about 2% to 8% w/w of a binder, about 0.5% to 4% w/w of a glidant, about 1.5% to 4% disintegrant, about 0.5% to about 3% lubricant, or one or more combinations thereof. In another embodiment said composition may further comprise one or more other pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, said composition comprising:
a) intragranular portion comprising about 25% to 50% w/w of a diluent, about 2% to 8% w/w of a binder, about 0.5% to 2.5% w/w of a glidant, about 1.5% to 4% w/w of a disintegrant, and about 0.5% to about 2% w/w of a lubricant; and
b) extragranular portion comprising about 10% to about 25% w/w of a diluent, about 0.5% to 3% w/w of a glidant, about 1.5% to 4% w/w of a disintegrant, and about 0.5% to about 1.5% w/w of a lubricant; wherein the larotrectinib is present either in the intragranular portion or both intragranular and extragranular portions. In another embodiment, said composition may further comprise optionally one or more other pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a pharmaceutical composition comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, said composition comprising:
a) intragranular portion comprising about 30% to 60% w/w of a diluent, about 2% to 8% w/w of a binder, about 0.5% to 2.5% w/w of a glidant, about 1.5% to 4% w/w of a disintegrant, and about 0.5% to about 2% w/w of a lubricant; and
b) extragranular portion comprising about 0.5% to 3% w/w of a glidant, and about 0.5% to about 1.5% w/w of a lubricant; wherein the larotrectinib is present either in the intragranular portion or both intragranular and extragranular portions.
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients such as microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, or combinations thereof, said excipients suitably present in intragranular or extragranular portions or both.
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof, said composition comprising: a) intragranular portion comprising one or more pharmaceutically acceptable excipients such as microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, or combinations thereof, and b) extragranular portion comprising one or more pharmaceutically acceptable excipients such as microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, or combinations thereof, said composition optionally comprising one or more other pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib, said composition comprising: a) intragranular portion consisting of larotrectinib or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, hydroxypropyl cellulose, or combinations thereof, and b) extragranular portion consisting of microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, or combinations thereof.
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib, said composition comprising: a) intragranular portion consisting of larotrectinib or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, and hydroxypropyl cellulose and b) extragranular portion consisting of microcrystalline cellulose, sodium starch glycolate, magnesium stearate and colloidal silicon dioxide.
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib, said composition comprising: a) intragranular portion consisting of larotrectinib or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, and hydroxypropyl cellulose and b) extragranular portion consisting of magnesium stearate and colloidal silicon dioxide.
In one embodiment, the present invention provides a pharmaceutical composition comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, said composition comprising:
a) intragranular portion comprising about 25% to 50% w/w of microcrystalline cellulose, about 2% to 8% w/w of hydroxypropyl cellulose, about 0.5% to 2.5% w/w of colloidal silicon dioxide, about 1.5% to 4% w/w of sodium starch glycolate, and about 0.5% to about 2% w/w of magnesium stearate; and
b) extragranular portion comprising about 10% to about 25% w/w of microcrystalline cellulose, about 0.5% to 3% w/w of colloidal silicon dioxide, about 1.5% to 4% w/w of sodium starch glycolate, and about 0.5% to about 1.5% w/w of magnesium stearate; wherein the larotrectinib is present either in the intragranular portion or both intragranular and extragranular portions. In another embodiment, said composition may further comprise one or more other pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising a) intragranular portion comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, about 25% to 50% w/w of microcrystalline cellulose, about 2% to 8% w/w of hydroxypropyl cellulose, about 0.5% to 2.5% w/w of colloidal silicon dioxide, about 1.5% to 4% w/w of sodium starch glycolate, and about 0.5% w/w to about 2% w/w of magnesium stearate; and
b) extragranular portion comprising about 10% w/w to about 25% w/w of microcrystalline cellulose, about 0.5% to 3% w/w of colloidal silicon dioxide, about 1.5% to 4% w/w of sodium starch glycolate, and about 0.5% w/w to about 1.5% w/w of magnesium stearate. In another embodiment, said composition may further comprise one or more other pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a pharmaceutical composition comprising a) intragranular portion comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, about 30% to 60% w/w of microcrystalline cellulose, about 2% to 8% w/w of hydroxypropyl cellulose, about 0.5% to 2.5% w/w of colloidal silicon dioxide, about 1.5% to 4% w/w of sodium starch glycolate, and about 0.5% to about 2% w/w of magnesium stearate; and
b) extragranular portion comprising about 0.5% to 3% w/w of colloidal silicon dioxide, and about 0.5% w/w to about 1.5% w/w of magnesium stearate. In another embodiment, said composition may further comprise one or more other pharmaceutically acceptable excipients.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 34.5 % to 47 % w/w of Larotrectinib; (ii) 39 % to 52.5 % w/w of microcrystalline cellulose; (iii) 4.25 % to 5.75 % w/w of hydroxypropyl cellulose; (iv) 0.85 % w/w to 1.15 % w/w of colloidal silicon dioxide; (v) 2.55 % to 3.45 % w/w of sodium starch glycolate; (v) 1.27 % to 1.72 % w/w of magnesium stearate;
b) extragranular portion comprising (i) 1.7 % to 2.3 % w/w of colloidal silicon dioxide and (ii) 0.42 % to 0.57 % w/w of magnesium stearate.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising: a) intragranular portion comprising (i) 36.8 % to 45.05 % w/w of Larotrectinib; (ii) 41.43 % to 50.64 % w/w of microcrystalline cellulose; (iii) 4.5 % to 5.5 % w/w of hydroxypropyl cellulose; (iv) 0.9 % to 1.1 % w/w of colloidal silicon dioxide; (v) 2.7 % to 3.3 % w/w of sodium starch glycolate; (v) 1.35 % to 1.65 % w/w of magnesium stearate;
b) extragranular portion comprising (i) 1.8 % to 2.2 % w/w of colloidal silicon dioxide and (ii) 0.45 % to 0.55 % w/w of magnesium stearate.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) 38.91 % to 43.0 % w/w of Larotrectinib; (ii) 43.73 % to 48.34 % w/w of microcrystalline cellulose; (iii) 4.75 % to 5.25 % w/w of hydroxypropyl cellulose; (iv) 0.95 % to 1.05 % w/w of colloidal silicon dioxide; (v) 2.85 % to 3.15 % w/w of sodium starch glycolate; (v) 1.42 % to 1.57 % w/w of magnesium stearate;
b) extragranular portion comprising (i) 1.9 % to 2.1 % w/w of colloidal silicon dioxide and (ii) 0.47 % to 0.52 % w/w of magnesium stearate.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) about 40.96 % w/w of Larotrectinib; (ii) about 47.04 % w/w of microcrystalline cellulose; (iii) about 4 % w/w of hydroxypropyl cellulose; (iv) about 1 % w/w of colloidal silicon dioxide; (v) about 3 % w/w of sodium starch glycolate; (v) about 1.50 % w/w of magnesium stearate;
b) extragranular portion comprising (i) about 2 % w/w of colloidal silicon dioxide and (ii) about 0.50 % w/w of magnesium stearate.
In another embodiment, the present invention provides an oral pharmaceutical composition comprising:
a) intragranular portion comprising (i) about 41 % w/w of Larotrectinib; (ii) about 32.83 % w/w of microcrystalline cellulose; (iii) about 5 % w/w of hydroxypropyl cellulose; (iv) about 1 % w/w of colloidal silicon dioxide; and (v) about 1.50 % w/w of magnesium stearate;
b) extragranular portion comprising (i) about 14.16 % w/w of microcrystalline cellulose; (ii) about 1 % w/w of colloidal silicon dioxide; (iii) about 3 % w/w of sodium starch glycolate and (iv) about 0.50 % w/w of magnesium stearate.
In one embodiment, the choice of particular type and amount of an excipient, and capsulation technique employed depends on the further properties of pharmaceutical active component and the excipients, e.g., compressibility, flowability, particle size, compatibility, and density. The capsules may be prepared according to methods known in the art, suitably filling a standard hard gelatin capsule with pharmaceutical active component admixed with excipients, suitably filling a standard hard gelatin capsule with the composition prepared according to the present invention, on a scale suitable for commercial production. Suitable capsules comprise composition comprising pharmaceutically active component and one or more of fillers, binders, disintegrants, glidants, and/or lubricants and optionally other pharmaceutically acceptable excipients, that is filled into capsules.
The capsule referred to herein may be taken orally. Capsules may be designed with a telescoping cap and body manufactured from e.g. gelatin or cellulose. In an embodiment said encapsulation of the drug composition or drug substance may be carried out by filling said composition or drug substance inside the capsules. In an embodiment the filling process may be carried out by suitable techniques and equipment which are known in the art at various scales of operation such as lab scale, scale-up and industrial scale operations.
In an embodiment, the present invention provides a process of pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said process comprises preparing larotrectinib granules using any granulation method known in the art such as dry granulation methods, e.g. slugging or roller compaction, wet granulation methods, e.g., high-shear granulation (or rapid mixer granulation) or top spray granulation (using fluidized bed processor), or other granulation techniques such as twin screw granulation, etc., or one or more combinations thereof. In a preferred embodiment, said process comprises a dry granulation technique. In one embodiment, said granules are prepared in the presence of a binder. In another embodiment, said granules are prepared in the absence of a binder.
In one embodiment, the composition provided in the present invention, prepared by granulation process, comprises intra and extra granular portions, wherein, intragranular portion comprises Larotrectinib or its salt, filler or diluent, binder, disintegrant, glidant and lubricant, and wherein, extragranular portion comprises lubricant and glidant, and optionally other pharmaceutically acceptable excipients.
In one embodiment, the composition provided in the present invention, prepared by granulation process, comprises intra and extra granular portions, wherein, intragranular portion comprises Larotrectinib or its salt, filler or diluent, binder, disintegrant, glidant and lubricant, and wherein, extragranular portion comprises filler or diluent, disintegrant, lubricant and glidant.
In general, granulation is a process of particle size enlargement of powdered ingredients which is carried out to confer fluidity, and optionally compressibility, to powder systems. Ideally, granulation should be relatively dust free (reduced dustiness minimises losses, inhalation and explosion risks during further use of the granules, such as tabletting) and provide an as small percentage of both fine and coarse particles as possible, and granules should be robust enough to withstand handling without breaking down. Other desired properties of granulated products include improved flow and handling which facilitates controlled metering; increased bulk density; reduced pressure loss for fluid flow through a packed bed; controlled dissolution rates; and substantially maintained surface area of the original particles.
In one embodiment, the composition of the present invention is prepared through wet granulation process, wherein the method comprising preparing a granulate comprising an active ingredient and one or more carriers, further comprising processing the granules into an oral solid dosage formulation. In other words the present invention relates to a wet granulation method for preparing an oral solid dosage formulation comprising an active ingredient and one or more carriers, the method comprising a) formation of a mixture of the active ingredient and one or more carriers, b) granulation of the mixture with a binder liquid (solution or suspension), c) drying the mixture, and d) processing the granulate into an oral solid dosage formulation, wherein the granulation is performed in a high shear mixing means. In one embodiment the oral solid dosage formulation is a tablet. In another embodiment the oral solid dosage formulation is a capsule.
In one embodiment, the present invention is prepared through wet granulation process. In another embodiment, a wet method for the preparation of solid dosage form is the wet granulation process which involves a number of stages as follows.
a) The drug substance is blended, if needed, with an inert diluent or filler in a powder mixer in order to produce a uniform dispersion of the drug in the filler.
b) The blended mixture is wetted by means of a liquid phase or solvent including, if needed, a binder (also known as adhesive or granulating agent or binding agent). The liquid phase or solvent must be volatile, so that it can be easily removed by drying, and non-toxic. It may be for instance water or a lower alcohol, such as isopropanol, ethanol or methanol, either alone or in combination.
c) The binder is usually introduced as a solution or dispersion in the liquid phase, or the binder may also be mixed in the dry powder (the so-called “dry binder addition”).
d) The wetting step is usually carried out in the same apparatus as the blending step. The damp mass obtained is then passed through a coarse sieve, usually of mesh size 1-2 mm, yielding particles, for instance by means of an oscillating granulator in which a rotor oscillating about its horizontal axis passes the damp material through the screen, or by means of a comminutor containing a number of rapidly revolving blades.
e) After the granulation step, granules are dried by means of a tray drier or a fluidised bed drier or by vacuum or microwave, resulting in a coarse free-flowing solid. The granule size at this point being usually considerably larger, a sizing step including a comminution stage followed by sieving will usually be needed for breaking agglomerates of granules and removing the fine material which can be recycled.
f) After the sizing step, granules are ready for blending, if needed, with additives such as lubricants, glidants, disintegrants, flavours, colorants and the like.
In one embodiment, the present invention provided is prepared through dry granulation process. Dry granulation is used, for example, when materials have sufficient inherent binding or cohesive properties to form granules. Dry granulation refers to the process of granulating without the use of liquids. In order for a material to be dry granulated at least one of its constituents, either the active ingredient or a diluent, must have cohesive properties. Alternately, dry granulation may also be performed by using a dry binder in the mixture to be granulated to impart said cohesive properties to the mixture.
In one embodiment, dry granulation may be performed by a process known as “slugging.” In “slugging” the material to be granulized is first made into a large compressed mass or “slug” typically by way of a tablet press. A fairly dense slug may be formed by allowing sufficient time for the air to escape from the material to be compacted. Compressed slugs are then comminute through a desired mesh screen manually or automatically as, for example, by way of a comminuting mill. Formation of granules by “slugging” is also known as precompression.
In another embodiment, dry granulation may also be performed using a “roller compactor.” In a roller compactor material particles are consolidated and densified by passing the material between two high-pressure rollers. The densified material from a roller compactor is then reduced to a uniform granule size by milling. The uniform granules may then be mixed with other substances, such as a lubricant, to tablet the material (as, for example, by way of a rotary tableting machine).
The powder materials being processed, especially during pharmaceutical manufacturing processes, must possess good flow properties in order for the manufacturing process to be successful.
It was surprisingly found that the pharmaceutical composition described herein in the present invention provides an advantage of improved flow properties in comparison to the flow properties of larotrectinib API and formulation blends disclosed in the prior art, e.g., US Pat. No. 10,799,505, as measured by Angle of Repose, Carr's index or Carr's Compressibility Index (CI), and/or Hausner ratio (HR). Therefore, in one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof with improved flow properties as measured by Angle of Repose, Carr's index or Carr's Compressibility Index (CI), and/or Hausner ratio (HR). The method of analysing Carr’s index or Carr's Compressibility Index is a well-known method to a person skilled in the art.
Examples of basic, conventional flow tests are as follows:
Angle of Repose:
One popular test is the static angle of repose test. This test measures the “angle of repose,” which can be defined as the constant, three-dimensional angle relative to a horizontal base that is assumed by a cone-like pile of material formed by any of several different methods. A lower angle of repose value indicates better powder flow. The angle of repose is formed by permitting powder to drop through a funnel onto a fixed, vibration-free base that includes a retaining lip to retain a layer of powder on the base. The height of the funnel is varied during the test in order to carefully build up a symmetrical cone of powder. Typically, the funnel height is maintained approximately 2 to 4 cm from the top of the powder pile as it is being formed in order to minimize the impact of falling powder on the tip of the cone. Alternatively, the funnel could be kept fixed while the base is permitted to vary as the pile forms.
The angle of repose is the angle formed by the horizontal base of the surface and the edge of a cone-like pile of granules. It is calculated from the following equation:
? = Tan-1(h/r)
The Carr's Index was calculated according to the following equation:
CI = (?tap- ?bulk /?tap) x 100
?bulk: Bulk density
?tap: Tap density
The Hausner Ratio was calculated with the following equation:
HR = ?tap/?bulk
The values obtained as a result of this test are believed to be measures of the cohesiveness of a powder as it forms an arch in a hopper and the ease with which such an arch could be broken. In one variation, the rate of consolidation is also, or alternatively, measured. Factors influencing the methods used to obtain the compressibility index and the Hausner ratio include the diameter of the cylinder used, the number of times the powder is tapped to achieve the tapped density, the mass of material used in the test, and rotation of the sample during tapping.
The flow properties of the formulation blends to be processed into finished dosage forms may be further termed as shown below in Table 1, based on the obtained values of Angle of Repose, Hausner Ratio, and Compressibility Index (%).
Table 1: Reference values
Reference Values
Flow Character Angle of Repose Hausner Ratio Compressibility Index (%)
Excellent 25-30o 1.0 - 1.11 =10
Good 31-350 1.12 – 1.18 11 – 15
Fair 36-400 1.19 – 1.25 16 – 20
Passable 41-450 1.26 – 1.34 21 – 25
Poor 46-550 1.35 – 1.45 26 – 31
Very poor 56-650 1.46 – 1.59 32 – 37
Very very poor =660 =1.60 =38

The commercially available larotrectinib product (VITRAKVI® capsule) contains only API in crystalline form without any excipients. The US Pat. No. 10,799,505 (‘505 patent), discloses that the crystalline API was found to have poor flow based on angle of repose values, and only ‘passable’ flow properties based on Carr’s Compressibility Index and Hausner ratio values. This suggests there may be a need of an alternate composition of larotrectinib or its salt, with improved flow properties compared to commercially available larotrectinib product containing only crystalline API without any excipients. It is further noted that the formulation blends containing larotrectinib including excipients disclosed in the patent were found ‘poor’ flow. This further suggests that there is a need of alternate compositions in addition to those disclosed in the ‘505 patent which may provide improved flow properties.
It was surprisingly found that the pharmaceutical composition described herein in the present invention provides an advantage of improved flow properties in comparison to the flow properties of larotrectinib sulfate API and formulation blends disclosed in the prior art, e.g., the blends disclosed in US Pat. No. 10,799,505, as measured by Angle of Repose, Carr's index or Carr's Compressibility Index (CI), and/or Hausner ratio (HR).
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable slat thereof with improved flow properties as measured by Angle of Repose, Carr's index or Carr's Compressibility Index (CI), and/or Hausner ratio (HR).
In one embodiment, the present invention provides a pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein said composition exhibits desirable dissolution and stability comparable to the commercially available larotrectinib composition.
In one embodiment, the pharmaceutical composition comprising larotrectinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients as described herein above in one or more embodiments remains stable at least for a period of 3 months under the conditions of 40°C ± 2°C/75% RH ± 5% RH, and the total amount of impurities at the end of three months under such conditions, may not exceed 10% w/w. More preferably the total amount of impurity is < 8% w/w or <5% w/w or < 2% w/w, at the end of three months or six months. Further, said stable composition retains at least about 90% w/w of the drug under said conditions. In some embodiments said composition remains stable at least for a period of 6 months. In some embodiments said composition remains stable at least for a period of 12 months.
The composition of the present invention may be represented by the following Examples, which are to be construed as merely illustrative and not a limitation of the scope of the present invention.
EXAMPLES
All the excipients utilized herein are standard pharmaceutical grade excipients available from numerous manufacturers well known to those in the art.
S. No. Name of the ingredient Example 1 (%w/w) Example 2 (%w/w) Example 3 (%w/w)
Intragranular:
1 Larotrectinib Sulfate 41 41 40.96
2 Microcrystalline cellulose (Avicel PH101) 37.83 32.83 47.04
3 Hydroxylpropyl cellulose (HPC) - 5 4.00
4 Colloidal silicon dioxide (Aerosil 200) 1 1 1.00
5 Sodium starch glycolate - - 3.00
6 Magnesium stearate 1.5 1.5 1.50
Extra granular:
7 Microcrystalline cellulose (Avicel PH 101) 14.16 14.16 -
8 Colloidal silicon dioxide (Aerosil 200) 1 1 2.00
9 Sodium starch glycolate 3 3 -
10 Magnesium stearate 0.5 0.5 0.50
100.00 100.00 100.00
Capsule filling: Empty hard gelatin capsule shells size ‘2’; size ‘0’

Manufacturing procedure:
1. Weighed required quantities of all the ingredients like, pharmaceutical active, diluent or filler, binder, glidant, disintegrant and lubricant.
2. Larotrectinib, microcrystalline cellulose, hydroxypropyl cellulose, colloidal silicon dioxide, sodium starch glycolate and magnesium stearate was mixed together in high shear mixture to form a powder blend form step 1.
3. The aforementioned ingredients of step 2 was subjected to compact into ribbons using a roller compaction to form intragranular portion.
4. The slugs or ribbons or intragranular portion of step 3 was milled and screened through 0.6mm mesh screen. The screened mixture was mixed in a blender with extragranular excipients colloidal silicon dioxide and magnesium stearate.
5. The lubricated blend of step 4 was then filled in hard gelatin capsules.
Alternatively the granulation of the above compositions may be performed by wet granulation method or any other suitable method as known to a person skilled in the art or as described herein in the present invention.
Example - 4
Dissolution testing:
For capsule dissolution testing, a sample of each capsule was placed in a 0.1N HCL buffer media and the dissolution of the capsule was measured over time. Dissolution for these samples was measured according to United States Pharmacopeia (USP) Type I apparatus using a speed of 100 rpm in 500 mL of 0.1N HCL buffer at a pH of about 1.
Table 2: Comparison of dissolution profile of Vitrakvi® and present composition.
Time (min) % Drug release
Vitrakvi® Example 3
10 102 86
15 102 92
20 102 94
30 102 95
45 103 94

Example – 5
Comparison of flow properties of prior art composition vs present composition
The flow properties of the blends of present composition were compared with the flow properties of crystalline larotrectnib sulfate and larotrectinib sulfate formulation blends disclosed in the prior art, i.e., US Pat. No. 10,799,505 (the ‘505 patent) as reproduced in the following Table 3.
Table 3: Comparison of flow properties of Example 3 composition blend and the composition blends disclosed in the US Pat. No. 10,799,505.
Parameters The US Pat. No. 10,799,505 Example 3
Crystalline larotrectinib sulfate Formulations Blends (4 different blends)
Angle of Repose 50.280 40.27 & above 35.5
Hausner Ratio 1.28 1.43 & above 1.241
Carr’s Index 22% 30% & above 19.44%

As provided in the above table, the composition/formulation blends of the present invention apparently produces improved flow properties when compared to the formulations known in the prior art.
Example – 6
Stability studies: Capsule dosage form prepared according to Example 1 was subjected to accelerated stability testing as per the ICH guidelines at temperature 40°±2°C and relative humidity of 75%±5% for 3 months. The capsules were placed in a high density polyethylene (HDPE) bottles exposed to above mentioned condition and the capsules were analyzed for drug content, water content and impurities.
Table 4: Stability studies
Test Specification Initial 3 M
40°C/75%RH
(HW HDPE ) 3 M 40°C/75%RH (HW HDPE + 1 g SG)
Assay 90.0% -110.0% 100.8 99.9 100.2
Water content NMT 6.0 % w/w 3.1 4.55 3.89
Related Substances
Any unspecified degradation products NMT-0.2 % ND 0.029 0.024
Total degradation products NMT-0.5 % ND 0.097 0.094
NMT- Not more than
The studies show that the formulation of the present invention not only has improved flow properties but also achieved desired dissolution and stability upon storage at accelerated stability conditions as described herein.

Dated this: 28th March 2025

(Signature):

Saritha Bommakanti
For Alembic Pharmaceuticals Limited
,CLAIMS:We Claim:

1. A pharmaceutical composition comprising about 25% to 50% w/w of larotrectinib or a pharmaceutically acceptable salt thereof, said composition comprising:
a) an intragranular portion comprising about 30% to 60% w/w of a diluent, about 2% to 8% w/w of a binder, about 0.5% to 2.5% w/w of a glidant, about 1.5% to 4% w/w of a disintegrant, and about 0.5% to about 2% w/w of a lubricant; and
b) an extragranular portion comprising about 0.5% to 3% w/w of a glidant, and about 0.5% to about 1.5% w/w of a lubricant; wherein larotrectinib is present either in the intragranular portion or both intragranular and extragranular portions.

2. The composition as claimed in claim 1, wherein one or more diluents are selected from calcium phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, kaolin, lactose, microcrystalline cellulose, powdered cellulose, pregelatinized starch and starch or combinations thereof.

3. The composition as claimed in claim 1, wherein one or more binders are selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and polyethylene glycol or combinations thereof.

4. The composition as claimed in claim 1, wherein one or more disintegrants are selected form croscarmellose sodium, crospovidone, sodium starch glycolate and ion exchange resins or combinations thereof.

5. The composition as claimed in claim 1, wherein one or more glidants are selected form alkali metal stearates, colloidal silicon dioxide, talc, magnesium trisilicate, starch and sodium stearyl fumarate or combinations thereof.

6. The composition as claimed in claim 1, wherein one or more lubricants are selected from talc, magnesium stearate, calcium stearate, glyceryl monostearate and sodium stearyl fumarate or combinations thereof.

7. A pharmaceutical composition comprising:
a) intragranular portion comprising: (i) about 40-42 % w/w of Larotrectinib; (ii) about 46-48 % w/w of microcrystalline cellulose; (iii) about 3-4 % w/w of hydroxypropyl cellulose; (iv) about 0.5-2 % w/w of colloidal silicon dioxide; (v) about 2-4 % w/w of sodium starch glycolate; (v) about 1-3 % w/w of magnesium stearate; and
b) extragranular portion comprising (i) about 1-3 % w/w of colloidal silicon dioxide and (ii) about 0-2 % w/w of magnesium stearate.

8. The composition as claimed in claim 1, wherein the composition is prepared by dry granulation method.

Dated this: 28th March 2025

(Signature):

Saritha Bommakanti
For Alembic Pharmaceuticals Limited