PHARMACEUTICAL COMPOSITION COMPRISING VENETOCLAX

This application claims priority to Indian Provisional No. 201921018227, filed May 7, 2019, the content of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The field of the invention relates to pharmaceutical compositions comprising venetoclax or a pharmaceutically acceptable salt thereof and process for their preparation.

BACKGROUND OF THE SUBJECT MATTER

Venetoclax is a selective inhibitor of BCL-2 protein chemically designated as 4-(4-{ [2-(4-chlorophenyl)-4,4dimethylcyclohex-l-en-l-yl]methyl}piperazin- l-yl)-N-({ 3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl} sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) corresponding to the molecular formula C45H50C1N7O7S, molecular weight of 868.44 and the following structure:

In the United States, venetoclax is available as 10 mg, 50 mg and 100 mg film-coated tablets under the brand name VENCLEXTA®. Venetoclax exists as light yellow to dark yellow solid, with very low aqueous solubility and limited bioavailability because of which it may be classified as BCS Class IEIV compound.

For a poorly soluble drug, one of the main challenges is to increase its solubility/bioavailability through formulation. Solid dispersion is one of these methods, which is applied to improve the solubility, dissolution rates and consequently, the bioavailability of poorly soluble drugs. The solid dispersion is based on the concept that the drug is dispersed in an inert carrier at solid state. Quite often, the drug in solid dispersion is in an amorphous state, which has increased solubility compared to the crystalline state. However, one of the main challenges in utilization of solid dispersion is to maintain the amorphous state of the drug and avoid crystallization, as this may negate the solubility/bioavailability improvements achievable by the amorphous state. Another challenge in utilization of solid dispersion is precipitation of amorphous drug to crystalline state in the gastrointestinal tract, which may again lead to decreased or non-reproducible solubility/bioavailability.

Advancements in solid dispersion science have led to some solutions to the aforementioned challenges. For example, a review by Vasconcelos et al., entitled“Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs,” Drug Discovery Today, Volume 12, Numbers 23/24, December 2007, reports a solid dispersion system termed“Third generation solid dispersions,” which contains surfactant as an additional ingredient apart from the carrier/polymer and poorly soluble drug. It is reported that the inclusion of surfactants in solid dispersion containing a polymeric carrier may help to prevent precipitation and/or formation of larger hydrophobic particles by agglomeration of fine crystalline precipitate. Vasconcelos further reports that drug recrystallization is a major barrier to the marketing success of conventional solid dispersions, and this could be prevented by usage of third generation solid dispersion strategies.

However, presence of surfactant inside solid dispersion containing drugs brings its own challenges, such as processing and manufacturability. U.S. Patent Publication No. US 2015/0148331 discloses solid dispersion comprising venetoclax, water soluble polymer and surfactant prepared by hot melt extrusion technique. This publication emphasizes the presence of surfactant in the solid dispersion along with drug and hydrophilic polymer. However, it also teaches that although higher surfactant level leads to faster drug release rate, greater surfactant level may affect the manufacturability of the extrudates in the preparation of solid dispersions.

U.S. Patent No. 10,213,433 discloses the preparation of solid dispersion comprising venetoclax, water soluble polymer and surfactant by solvent evaporation technique.

WO 2017/212431 discloses various polymorphic forms of venetoclax and processes of preparing them. It also discloses solid dispersions of venetoclax prepared generally by solvent evaporation technique. It does mention hot-melt extrusion to prepare solid dispersion but does not provide any information regarding such processes. The examples are provided with only solvent evaporation technique.

Formulators often face challenges with solid dispersions such as re-crystallization, precipitation of drug, instability and lack of clarity i.e. opaqueness. Hence, there remains a need of a solid dispersion comprising venetoclax that is devoid of one or more of such disadvantages.

In addition, hot melt extrusion process to prepare a solid dispersion is often constrained by manufacturability and scalability challenges. Such issues in many cases depend on the composition mix that is to be processed. Therefore, there is a need of a solid dispersion comprising venetoclax that is amenable to an improved, faster process which is continuous, uses less energy and is economical.

During the course of formulation development, it was found that the difficulties associated with a composition comprising a solid dispersion of venetoclax may be overcome by preparing a composition comprising either (i) a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, at least two different water soluble polymer and free of a surfactant, or (ii) a mixture of at least two solid dispersions, i.e., a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and a water soluble polymer and free of a surfactant, and a solid dispersion free of venetoclax or a pharmaceutically acceptable salt thereof comprising a water soluble polymer and a surfactant. These compositions may have one or more or all of following advantages:

1) Improved dissolution,

2) Improved chemical stability (for example, reduced relative substances),

3) Improved stability of amorphous venetoclax (for example, less crystallinity),

4) Improved manufacturability,

5) Bio-equivalency with VENCLEXTA®, which contains a solid dispersion component containing venetoclax, a water soluble polymer and a surfactant.

SUMMARY OF THE SUBJECT MATTER

An object of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers.

An object of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers.

An object of the present subject matter is to provide a stable solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, wherein amorphous state of venetoclax or a pharmaceutically acceptable salt thereof is retained during stability.

An object of the present subject matter is to provide a stable solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, wherein amorphous venetoclax or a pharmaceutically acceptable salt thereof does not exhibit significant crystallinity.

An object of the present subject matter is to provide a stable solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, wherein venetoclax or a pharmaceutically acceptable salt thereof does not undergo significant degradation.

An object of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, wherein the solid dispersion is prepared by hot melt extrusion with improved manufacturability.

An object of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers.

An object of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers.

An object of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers, wherein the pharmaceutical composition is bioequivalent to VENCLEXTA®.

In an embodiment, the solid dispersion comprising venetoclax disclosed herein may be devoid of a surfactant.

In an embodiment, the solid dispersion comprising venetoclax disclosed herein may comprise a surfactant.

In an embodiment, the solid dispersion disclosed herein is prepared using amorphous form of venetoclax or a pharmaceutically acceptable salt thereof.

In an embodiment, the subject matter provides a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, a first polymer, a second polymer, and optionally one or more pharmaceutically acceptable excipients.

In an embodiment, the subject matter provides a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, a first polymer, a second polymer, and optionally one or more pharmaceutically acceptable excipients, wherein the solid dispersion is devoid of any surfactant.

In an embodiment, the first polymer and the second polymer are not the same.

In an embodiment, first and second polymers may be selected from hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

In an embodiment, the first polymer is a hydrophilic water soluble polymer and the second polymer is an enteric coating polymer.

In an embodiment, the first polymer is an enteric coating polymer and the second polymer is a hydrophilic water soluble polymer.

In an embodiment, both first polymer and second polymers are hydrophilic water soluble polymers.

In an embodiment, the second water soluble polymer is a hydrophilic water soluble polymer other than first water soluble polymer.

In an embodiment, the first polymer is a vinyl based polymer and second polymer is a cellulose derivative.

In an embodiment, the first polymer is co-povidone or povidone and second polymer is hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

In an embodiment, the present subject matter provides a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, co-povidone, hydroxypropyl cellulose and, optionally one or more pharmaceutically acceptable excipient, wherein the solid dispersion is devoid of any surfactant.

In an embodiment, the subject matter provides a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, a water soluble polymer, and is free of a surfactant.

In an embodiment, the subject matter provides a solid dispersion comprising a water soluble polymer, a surfactant and is free of venetoclax or a pharmaceutically acceptable salt thereof.

In an embodiment, the subject matter provides a pharmaceutical composition comprising a mixture of at least two solid dispersions and optionally one or more pharmaceutically acceptable excipients, the first solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and a polymer, and the second solid dispersion comprising a polymer, a surfactant and is free of venetoclax or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the first solid dispersion is free of a surfactant. In a further embodiment, the first and second solid dispersions comprise the same polymer. In a further preferred embodiment, the polymer is a water soluble polymer.

In an embodiment, the subject matter provides a pharmaceutical composition comprising a solid dispersion and optionally one or more pharmaceutically acceptable excipients, the solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, at least two polymers, and is free of a surfactant. In a preferred embodiment, the polymers are different. In a further preferred embodiment, the polymers are water soluble polymers.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative image of extrudates obtained by the method of Example 1A.

Figure 2 is an illustrative image of extrudates obtained by the method of Example IB.

Figure 3 is an illustrative image of extrudates of Solid Dispersion I obtained by the method of Example 4.

Figure 4 is an illustrative image of extrudates of Solid Dispersion II obtained by the method of Example 4.

Figure 5 is an illustrative X-ray powder diffraction pattern of the venetoclax composition prepared in Example 4, the amorphous venetoclax prepared in Example 5, and a placebo composition similar to Example 4 without venetoclax.

DETAILED DESCRIPTION OF THE SUBJECT MATTER

While various aspects and features of certain embodiments have been summarized above, the following detailed description illustrates a few exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments. The described examples are provided for illustrative purposes and are not scope limiting.

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 practiced without some of these specific details.

A pharmaceutical composition comprising venetoclax or a pharmaceutically acceptable salt thereof is provided. Further provided a process for preparing such composition.

The terms “composition”, “pharmaceutical composition” or “formulation” are synonymously used in the present specification and may be in the form of, e.g., tablet, capsule or granules.

The term "tablet" refers to tablet without a coating or tablet with one or more coatings. Furthermore, the term“tablet” comprises tablets having one, two, three or even more layers and press-coated tablets, wherein each of the before mentioned types of tablets may be without or with one or more coatings.

Unless otherwise indicated, all numbers used herein to express quantities, dimensions, and so forth used should be understood as being modified in all instances by the term“about.” As used in this specification, the singular forms“a”,“an”, and“the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to“a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth

For the purpose of the present subject matter, active pharmaceutical ingredient (API) venetoclax is a base or a pharmaceutically acceptable salt or hydrate thereof and is in crystalline or amorphous forms thereof. However, the amorphous form of venetoclax base is preferred in a solid dispersion.

The terms pharmaceutically acceptable excipients, pharmaceutically compatible excipients, and excipients are used interchangeably in this disclosure. They refer to non-API substances such as diluents or fillers, disintegrating agents, binders, surfactants, lubricants and glidants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.

The term“stability” refers to physical and/or chemical stability.

Physical stability of solid dispersion and/or composition comprising such solid dispersion refers to presence of amorphous form of venetoclax. Said solid dispersion and/or composition

is considered to be stable if venetoclax is present in an amorphous form. Said solid dispersion and/or composition does not exhibit significant crystallinity.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof and/or composition comprising such solid dispersion retains at least 90% w/w, at least 95% w/w, at least 99% w/w or about 100% w/w of venetoclax or a pharmaceutically acceptable salt thereof in amorphous form. Said solid dispersion and/or composition retains about 90% w/w, about 91% w/w, about 92% w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about 97% w/w, about 98% w/w, about 99% w/w or about 100% w/w of venetoclax or a pharmaceutically acceptable salt thereof in amorphous form.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof and/or composition comprising such solid dispersion exhibit not more than 10% w/w of crystallinity, not more than 9% w/w of crystallinity, not more than 8% w/w of crystallinity, not more than 7% w/w of crystallinity, not more than 6% w/w of crystallinity, not more than 5% w/w of crystallinity, not more than 4% w/w of crystallinity, not more than 3% w/w of crystallinity, not more than 2% w/w of crystallinity, or not more than 1% w/w of crystallinity.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof and/or composition comprising such solid dispersion lacks crystallinity at initial time point.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt and/or composition comprising such solid dispersion lacks crystallinity at least for 6 months when stored at 40 °C/ 75% RH.

The term“chemical stability” relates to no or an acceptable level of drug-related impurities (also known as related substances) in terms of total impurity, maximum individual unknown impurity and single maximum individual impurity. Moreover, a pharmaceutical composition is defined to have chemical stability when active agents therein exhibit good stability as determined by a standard potency test such as assay and the like. A composition of the subject matter retains at least 90% w/w of the initial potency for at least 6 months when stored at 40 °C/ 75% RH.

The term "impurity" relates to any compound having a retention time that differs from that of venetoclax or a pharmaceutically acceptable salt thereof by at least the detection limit of the chromatography apparatus used to determine the retention time. The different retention time may be measured, for example, by HPLC.

An aspect of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers.

In an embodiment, the weight percentage of venetoclax or a pharmaceutically acceptable salt thereof is about 1% w/w to about 20% w/w based on the total weight of the solid dispersion. Venetoclax or a pharmaceutically acceptable salt thereof may comprise about 1 % w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w, about 15% w/w, about 16% w/w, about 17% w/w, about 18% w/w, about 19% w/w or about 20% w/w based on the total weight of the solid dispersion. Venetoclax or a pharmaceutically acceptable salt thereof may be present in an amount of about 12 % w/w to about 15% w/w based on the total weight of the solid dispersion.

In an embodiment, the solid dispersion disclosed herein is prepared using amorphous form of venetoclax or a pharmaceutically acceptable salt thereof.

A suitable polymer as per the present subject matter is a hydrophilic water soluble polymer, water insoluble polymer or enteric coating polymer and combinations thereof.

Examples of hydrophilic water soluble polymers for use in the solid dispersion include cellulose derivatives such as hydroxypropyl cellulose (e.g. marketed as Klucel), hydroxyethyl cellulose (e.g. marked as Natrosol), hydroxypropyl methyl cellulose (e.g. marketed as Methocel), methyl cellulose; vinyl based polymers such as Polyvinylpyrrolidone (e.g. marketed as Kollidon 30), copovidone (co-povidone) (e.g. marketed as Kollidon VA64); oligo and polysaccharides such as carrageenans, galactomannans and xanthan gum; cyclodextrins; polyethylene glycols; polyethylene oxides; copolymers and graft copolymers of polyethylene glycols or polyethylene oxides such as graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus®), and mixtures thereof.

Examples of water insoluble polymers for use in the solid dispersion include oils, beeswax, carnauba wax, microcrystalline wax, fatty alcohols, cetostearyl alcohol, stearyl alcohol, cetyl alcohol, myristyl alcohol, fatty acid esters, glyceryl monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, celluloses, ethylcellulose, low substituted hydroxypropyl cellulose (L-HPC), cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono cellulose alkanylates, di cellulose alkanylates, tri cellulose alkanylates, mono cellulose arylates, di cellulose arylates, tricellulose arylates, mono cellulose alkenylates, di cellulose alkenylates, tri cellulose alkenylates, carboxymethylcellulose sodium (carmellose sodium), croscarmellose sodium, acacia, tragacanth, propylene glycol alginate, agar powder, gelatin, starch, partly pregelatinized starch, oil, sodium starch glycolate, phospholipid (lecithin), glucomannans, polymethacrylic acid based polymers, zein, aliphatic polyesters, Poly (D, L-lactide) (PLA), Poly (D,L-lactide, co-glycolide acid (PLGA), and mixtures thereof.

Examples of enteric polymers for use in the solid dispersion include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, and combinations thereof.

In an embodiment, the weight percentage of polymer is about 35% w/w to about 90% w/w based on the total weight of the solid dispersion. Polymer may comprise about 40-85% w/w, about 40-80% w/w, about 50-85% w/w, about 50-80% w/w, about 55-85% w/w, about 55-80% w/w, about 60-85% w/w or about 60-80% w/w based on the total weight of the solid dispersion.

In an embodiment, the weight percentage of polymer in solid dispersion comprising of venetoclax or a pharmaceutically acceptable salt thereof is about 35% w/w to about 90% w/w based on the total weight of the solid dispersion. Polymer in solid dispersion comprising of venetoclax may contain about 40-85% w/w, about 40-80% w/w, about 50-85% w/w, about 50-80% w/w, about 55-85% w/w, about 55-80% w/w, about 60-85% w/w or about 60-80% w/w based on the total weight of the solid dispersion.

In an embodiment, the weight percentage of polymer in solid dispersion free of venetoclax or a pharmaceutically acceptable salt thereof is about 40% w/w to about 60% w/w based on the total weight of the solid dispersion. Polymer may be present in an amount of 50-55% w/w based on the total weight of the solid dispersion.

In an embodiment, the ratio of venetoclax or a pharmaceutically acceptable salt thereof to polymer in the solid dispersion is from about 1: 1 to about 1: 15. The ratio of venetoclax or a pharmaceutically acceptable salt thereof to polymer is about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1: 10, about 1: 11, about 1: 12, about 1: 13, about 1: 14 or about 1: 15.

In an embodiment, the solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and a polymer is devoid of a surfactant.

An aspect of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers.

In an embodiment, a solid dispersion comprises venetoclax or a pharmaceutically acceptable salt thereof, a first polymer, a second polymer, and optionally one or more pharmaceutically acceptable excipients.

In an embodiment, a solid dispersion comprises venetoclax or a pharmaceutically acceptable salt thereof, a first polymer, a second polymer, and optionally one or more pharmaceutically acceptable excipients, wherein the solid dispersion is devoid of any surfactant.

In an embodiment, the first polymer and the second polymer are not the same.

In an embodiment, the solid dispersion comprising two different polymers is free of surfactant.

In an embodiment, first and second polymers may be selected from hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

In an embodiment, the first polymer is a hydrophilic water soluble polymer and the second polymer is an enteric coating polymer.

In an embodiment, the first polymer is an enteric coating polymer and the second polymer is a hydrophilic water soluble polymer.

In an embodiment, both first polymer and second polymers are hydrophilic water soluble polymers.

In an embodiment, the second water soluble polymer is a hydrophilic water soluble polymer other than first water soluble polymer.

In an embodiment, the first polymer is a vinyl based polymer and second polymer is a cellulose derivative.

In an embodiment, the first polymer is co-povidone or povidone and second polymer is hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

In an embodiment, the first polymer is co-povidone and second polymer is co-povidone.

In an embodiment, ratio of venetoclax or a pharmaceutically acceptable salt thereof to the first polymer in the solid dispersion is from about 1: 1 to about 1: 15. The ratio of venetoclax or a pharmaceutically acceptable salt thereof to the first polymer is about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1: 10, about 1:11, about 1: 12, about 1: 13, about 1: 14 or about 1: 15.

In an embodiment, the ratio of venetoclax or a pharmaceutically acceptable salt thereof to the second polymer in the solid dispersion is from about 1:0.05 to about 1: 10. The ratio of venetoclax or a pharmaceutically acceptable salt thereof to the second polymer is about 1:0.1 to about 1:5. The ratio of venetoclax or a pharmaceutically acceptable salt thereof to the second polymer is about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises co-povidone as the first polymer.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises povidone as the first polymer.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises hydroxypropyl cellulose as the second polymer.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises hydroxypropyl methylcellulose as the second polymer.

In an embodiment, the present subject matter provides is a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, co-povidone, hydroxypropyl cellulose and, optionally one or more pharmaceutically acceptable excipients, wherein the solid dispersion is devoid of any surfactant.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises co-povidone, hydroxypropyl cellulose and a glidant.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises povidone, hydroxypropyl cellulose and a glidant.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises co-povidone, hydroxypropyl methylcellulose and a glidant.

In an embodiment, a solid dispersion of venetoclax or a pharmaceutically acceptable salt thereof comprises povidone, hydroxypropyl methylcellulose and a glidant.

In an embodiment, ratio of second polymer to first polymer in the solid dispersion is from about 1: 1 to about 1: 100. The ratio of second polymer to first polymer in the solid dispersion is about 1: 1, about 1:5, about 1: 10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90 or about 1:100. The ratio of second polymer to first polymer in the solid dispersion is from about 1: 1 to about 1: 10. The ratio of second polymer to first polymer in the solid dispersion is about 1: 1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 or about 1: 10.

Glidants aid in the processing of powder materials. Suitable glidants include, but not limited to silicon dioxide particularly colloidal silicon dioxide (e.g. Aerosil®, Cab-O-Sil®), calcium silicate, magnesium silicate, magnesium trisilicate, talc, starch, mixtures thereof or the like.

In an embodiment, a solid dispersion comprises venetoclax or a pharmaceutically acceptable salt thereof, co-povidone, hydroxypropyl cellulose and colloidal silicon dioxide wherein the solid dispersion is devoid of surfactant.

In an embodiment, a solid dispersion comprises about 1-10% w/w of glidant. The glidant is present in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w or about 10% w/w based on the weight of solid dispersion. The glidants may be present in an amount of about 2% w/w based on the weight of solid dispersion.

In an embodiment, a solid dispersion comprising venetoclax comprises about 0.5-10% w/w of glidant. The glidant is present in an amount of about 0.5% w/w, 0.7% w/w, 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w or about 10% w/w based on the weight of solid dispersion. The glidants may be present in an amount of about 2% w/w based on the weight of solid dispersion.

In an embodiment, a solid dispersion free of venetoclax comprises about 15-25 % w/w of glidant based on the weight of solid dispersion.

In an embodiment, the solid dispersion disclosed herein may comprise a surfactant. Suitable surfactants useful in the present subject matter include anionic or non-ionic surfactants or mixtures.

Suitable anionic surfactant include alkyl sulfates (e.g., sodium lauryl sulfate), alkylcarboxylates, alkylbenzole sulfates, secondary alkane sulfonates, and mixtures thereof.

Suitable non-ionic surfactants includes polyoxyethylene castor oil derivatives such as PEG-35 castor oil, PEG-40 hydrogenated castor and PEG-60 hydrogenated castor oil; fatty acid monoesters of sorbitan, for example sorbitan monooleate (e.g., Span™ 80), sorbitan monostearate (e.g., Span™ 60), sorbitan monopalmitate (e.g., Span™ 40) and sorbitan monolaurate (e.g., Span™ 20); other fatty acid esters of sorbitan, for example, sorbitan tristearate and sorbitan trioleate; fatty acid monoesters of polyoxyethylene sorbitan (polysorbates) such as PEG-20 sorbitan monooleate (polysorbate 80, e.g., Tween™ 80) PEG-20 sorbitan monostearate (polysorbate 60, e.g., Tween™ 60), PEG-20 sorbitan monopalmitate (polysorbate 40, e.g., Tween™ 40), or PEG-20 sorbitan monolaurate (polysorbate 20, e.g., Tween™ 20); other fatty acid esters of polyoxyethylene sorbitan, for example, polyoxyethylene (20) sorbitan tristearate (Tween 65), polyoxyethylene (20) sorbitan trioleate (Tween 85); fatty acid ester of polyalkylene glycols such as, for example, PEG 660 hydroxy-stearic acid (polyglycol ester of 12-hydroxy stearic acid (70 mol %) with 30 mol % ethylene glycol); polyalkoxylated ethers of fatty alcohols such as, for example, PEG (2) stearyl ether (Brij 72), macrogol 6 cetylstearyl ether or macrogol 25 cetylstearyl ether; tocopherol compounds such as a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS); or mixtures thereof.

In an embodiment, surfactant is present as a part of solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, one or more polymers.

In an embodiment, solid dispersion of surfactant and one or more polymers is prepared in addition to solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers. That is, the one solid dispersion comprises one or more polymers and at least one surfactant but no venetoclax or a pharmaceutically acceptable salt thereof, while the solid dispersion comprises venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers with or without surfactant. In a preferred embodiment, the second solid dispersion is free of surfactant.

In an embodiment, the solid dispersion comprises venetoclax or a pharmaceutically acceptable salt thereof, one or more polymers, surfactant and a pharmaceutically acceptable excipient.

In an embodiment, the solid dispersion disclosed herein is devoid of glidant.

An aspect of the present subject matter is to provide a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof with improved manufacturability.

In certain embodiments, solid dispersion is prepared by suitable technique such as a melting process including co-melting, an extrusion technique such as hot melt extrusion or a solvent removal process. The solvent removal process may include without limitation solvent evaporation, rotary evaporation and spray-drying.

In a preferred embodiment, the solid dispersion is prepared by hot melt extrusion of venetoclax or a pharmaceutically acceptable salt thereof with one or more polymers. In a further preferred embodiment, the input venetoclax or a pharmaceutically acceptable salt thereof is amorphous, or substantially so.

With respect to hot melt extrusion, the melting and mixing takes place in extruders or kneaders. Suitable extruders include single-screw extruders and multi-screw extruders, for example twin-screw extruders, which can be co-rotating or counter-rotating and, optionally, equipped with kneading disks or other screw elements for mixing or dispersing the components of the melt.

The elevated temperature attained during this part of the process can suitably be between about 70° C to about 200° C, such as for example about 70° C to about 180° C, about 70° C to about 160° C, about 80° C to about 180° C, about 80° C to about 160° C, about 90° C to about 180° C, about 90° C to about 160° C, about 100° C to about 180° C, and 100° C to about 160° C.

In an aspect, a process of preparing a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof comprises the steps of:

a) Mixing and co-sifting venetoclax or a pharmaceutically acceptable salt thereof, a first polymer and second polymer,

b) Blending the sifted material of step (a), and

c) Loading the blend of step (b) into twin screw hot melt extruder and making the extrudes with suitable parameters.

In a preferred embodiment, the process comprises the steps of:

a) Mixing and co- sifting venetoclax or a pharmaceutically acceptable salt thereof, a first hydrophilic water soluble polymer, a second different hydrophilic water soluble polymer, and a glidant, without surfactant

b) Blending the sifted material of step (a), and

c) Loading the blend of step (b) into a twin screw hot melt extruder Pharma 11 by Thermo Scientific and making the extrudes with suitable parameters including a zone temperature ranging from 700C to 1600C.

In an aspect, a process of preparing a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof comprises the steps of:

a) Sifting a polymer,

b) Co-sifting venetoclax or a pharmaceutically acceptable salt thereof with material of step a),

c) Re- sifting material of step b) and blending, and

d) Loading the blend of step (c) into a twin screw hot melt extruder and making the extrudes with suitable parameters.

In a preferred embodiment, the process comprises the steps of:

a) Co- sifting a hydrophilic water soluble polymer and a glidant,

b) Co-sifting venetoclax or a pharmaceutically acceptable salt thereof with material of step a),

c) Re- sifting material of step b) and blending, and

d) Loading the blend of step (b) into a twin screw hot melt extruder Pharma 11 by Thermo

Scientific and making the extrudes with suitable parameters including a zone temperature ranging from 800C to 1600C.

In an aspect, a process of preparing a solid dispersion free of venetoclax comprises the steps of:

a) Sifting a polymer,

b) Mixing a surfactant and a glidant,

c) Co-sifting of mixture (b) with polymer of step (a) and blending, and

d) Loading the blend of step (c) into twin screw hot melt extruder and making the extrudes with suitable parameters.

In a preferred embodiment, the process comprises the steps of:

a) Sifting a hydrophilic water soluble polymer and a glidant separately,

b) Adsorbing a surfactant onto the glidant of step a) in a rapid mixer granulator,

c) Co-sifting granules of step b) with the hydrophilic water soluble polymer of step a) and blending, and

d) Loading the blend of step (c) into a twin screw hot melt extruder of Pharma 11 by Thermo Scientific and making the extrudes with suitable parameters including a zone temperature ranging from 800C to 1300C.

Without bound by any theory, it is hypothesized that less residence time may lead to less impurity levels (related substances). Accordingly, usage of two water soluble polymers provided better feed rate and higher screw speed because of less torque, which decreased the residence time of the mixture inside the machine, thus leading to production of less related substances.

In an embodiment, the present subject matter results in lesser time for processing and thus enables faster manufacturability and scalability of the extmdates.

Manufacturability of the extmdates can be evaluated using generated torque during manufacturing, which is indicative of the ease with which the input material is processed. Manufacturability can also be evaluated by appearance of extmdates, i.e. clarity, which is indicative of homogeneity of solid dispersion.

Torque is the resistance provided by the material to the screw in the hot melt extruder during melting process. Generally, the equipment will stop when torque reaches 100%. Moreover, torque can vary with different compositions. Therefore, at predetermined zone temperature, less torque value even at higher screw speed indicates that the process is smooth. Less torque value implies the selection of higher feed rate and faster screw speed. In other words, manufacturability is also dependent on the choice of composition.

The clarity of extmdates is indicative of complete molecular dispersion of venetoclax in the polymer matrix. The better clarity of extrudes directly affects the nature of the molecular dispersion, which in turn increases solubility of the API and improves bioavailability.

Moreover, the faster feed rate reduces the process time, resulting in higher production per unit time, which in turn increases scalability of the process.

In one embodiment, it was found that addition of a different water soluble second polymer in solid dispersion comprising a first water soluble polymer may result in one or more of following with regard to a venetoclax composition:

1) Improved dissolution,

2) Improved chemical stability (for example, reduced relative substances),

3) Improved stability of amorphous venetoclax (for example, less crystallinity),

4) Improved manufacturability,

5) Bio-equivalency with VENCLEXTA®, which contains a solid dispersion component containing venetoclax, a water soluble polymer and a surfactant.

It was found that addition of a second different hydrophilic water soluble polymer to a first hydrophilic water soluble polymer in solid dispersion may result in one or more of following with regard to a venetoclax composition:

1) Less torque value at higher screw speed indicating smooth processing,

2) Improved clarity of extrudates indicating complete molecular dispersion of venetoclax in the polymer matrix,

3) Improved dissolution,

4) Improved stability indicating less impurity generation.

In another embodiment, the presence of two solid dispersions in the venetoclax composition, i.e., a first solid dispersion comprising venetoclax, a water soluble polymer and free of surfactant, and a second solid dispersion comprising a water soluble polymer, a surfactant and free of venetoclax, may provide improved dissolution/bioavailability compared to a composition comprising one solid dispersion. It may also resolve the incompatibility of venetoclax with surfactant/s as both are part of separate solid dispersions. Additionally, such a system is likely to avoid the need of using two separate polymers.

An aspect of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and one or more polymers.

An aspect of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers.

An aspect of the present subject matter is to provide a pharmaceutical composition comprising a solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof and at least two polymers, wherein the pharmaceutical composition is bioequivalent to VENCLEXTA®.

In an embodiment, the composition comprises solid dispersion of venetoclax and at least one pharmaceutically acceptable excipient selected from polymer, diluents, disintegrating agents, binders, surfactants, lubricants and glidants.

In an embodiment, a composition comprises solid dispersion of venetoclax or pharmaceutically acceptable salt thereof and a polymer.

In an embodiment, the weight percentage of venetoclax or a pharmaceutically acceptable salt thereof is about 1% w/w to about 15% w/w based on the total weight of the composition. Venetoclax or a pharmaceutically acceptable salt thereof may comprise about 1 % w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, about 10% w/w, about 11% w/w, about 12% w/w, about 13% w/w, about 14% w/w or about 15% w/w based on the total weight of the composition. Venetoclax or a pharmaceutically acceptable salt thereof may be present in an amount of about 10% w/w based on the total weight of the composition. Venetoclax or a pharmaceutically acceptable salt thereof is preferably present in the composition in a mass amount of 10 mg, 50 mg or 100 mg.

Suitable polymers as per the present subject matter are hydrophilic water soluble polymers, water insoluble polymers, enteric coating polymers, and combinations thereof.

In an embodiment, the weight percentage of the polymer is about 35% w/w to about 90% w/w based on the total weight of the composition. The polymer comprises about 40-85% w/w, about 40-80% w/w, about 50-85% w/w, about 50-80% w/w, about 55-85% w/w, about 55-80% w/w, about 60-85% w/w or about 60-80% w/w, about 65-85% w/w or about 65-80% w/w based on the total weight of the composition. The polymer comprises about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w or about 85% w/w based on the total weight of the composition. The polymer may be present in an amount of about 70% w/w based on the total weight of the composition.

In an embodiment, a composition comprises a solid dispersion of venetoclax and a diluent.

Examples of suitable diluents (also referred to as fillers) as per the present subject matter are lactose, in particular lactose monohydrate, cellulose and derivatives, such as powdered cellulose, microcrystalline or silicified microcrystalline cellulose, cellulose acetate, starches and derivatives such as pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, sterilizable maize, sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium phosphate, calcium sulphate, dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide, sugars and derivatives such as confectioner's sugar, fructose,

sucrose, dextrates, dextrin, D-sorbitol sulfobutylether b-cyclodextrin, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin, sorbitol, inulin, xylitol, erythritol, isomalt, kaolin, lactitol, and mixtures thereof.

In an embodiment, a pharmaceutical composition comprises solid dispersion of venetoclax and microcrystalline cellulose.

In an embodiment, a pharmaceutical composition comprises about 5-50% w/w of diluents based on total weight of the composition. Diluents comprise an amount of about 5-40% w/w, about 5-30% w/w, about 5-20% w/w, or about 5-10% w/w based on total weight of the composition. Diluents comprise an amount of about 5 % w/w, about 6 % w/w, about 7 % w/w, about 8 % w/w, about 9 % w/w or about 10 % w/w based on total weight of the composition. Diluents may be present in an amount of about 7% w/w based on total weight of the composition.

In an embodiment, a pharmaceutical composition comprising a first solid dispersion with venetoclax and a second solid dispersion without venetoclax, may comprise about 2-50% w/w of diluents based on total weight of the composition. Diluents comprise an amount of about 2-40% w/w, about 2-30% w/w, about 2-20% w/w, or about 2-10% w/w based on total weight of the composition. Diluents comprise an amount of about 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, about 6 % w/w, about 7 % w/w, about 8 % w/w, about 9 % w/w or about 10 % w/w based on total weight of the composition. Diluents may be present in an amount of about 7% w/w based on total weight of the composition.

In an embodiment, a composition comprises a solid dispersion of venetoclax and a surfactant.

In an embodiment, a composition comprises a solid dispersion of venetoclax and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent and a polymer.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent and a surfactant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a polymer and a surfactant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a polymer and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a polymer and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a surfactant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a surfactant and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a glidant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer and a surfactant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a surfactant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a surfactant and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a glidant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer, a surfactant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer, a surfactant and a glidant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer, a glidant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a surfactant, a glidant and a lubricant.

In an embodiment, a composition comprises a solid dispersion of venetoclax, a diluent, a polymer, a surfactant, a lubricant and a glidant.

In an aspect, a composition comprises a mixture of a solid dispersion comprising venetoclax and a solid dispersion free of venetoclax.

In an embodiment, the solid dispersion comprising venetoclax comprises venetoclax, a water soluble polymer and optionally, a glidant.

In an embodiment, the solid dispersion free of venetoclax comprises a water soluble polymer, a surfactant and optionally, a glidant.

In an embodiment, the solid dispersion comprising venetoclax is free of surfactant.
CLAIMS:

1. A solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable polymer and optionally at least one pharmaceutically acceptable glidant, wherein the solid dispersion is devoid of surfactant.

2. The solid dispersion of claim 1, wherein venetoclax or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 20% by weight.

3. The solid dispersion of claim 1, wherein at least one polymer is present in an amount of about 35% to about 90% by weight.

4. The solid dispersion of claim 1, wherein at least one polymer is selected from group consisting of hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

5. The solid dispersion of claim 1, wherein at least one polymer is selected from group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, co-povidone, carrageenans, galactomannans and xanthan gum, cyclodextrins, polyethylene glycols, polyethylene oxides, copolymers and graft copolymers of polyethylene glycols or polyethylene oxides, , ethylcellulose, low substituted hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate.

6. The solid dispersion of claim 1, wherein at least one polymer is co-povidone.

7. The solid dispersion of claim 1, wherein at least one glidant comprises colloidal silicon dioxide.

8. A pharmaceutical composition comprising a mixture of: (a) first solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable polymer and optionally at least one pharmaceutically acceptable glidant; and (b) second solid dispersion comprising at least one pharmaceutically acceptable polymer, at least one surfactant and optionally at least one pharmaceutically acceptable glidant, wherein the second solid dispersion is free of venetoclax

9. The composition of claim 8, wherein the first solid dispersion is devoid of surfactant.

10. The composition of claim 8, wherein venetoclax or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 20% by weight of first solid dispersion.

11. The composition of claim 8, wherein at least one polymer in first solid dispersion is present in an amount of about 35% to about 90% by weight of first solid dispersion.

12. The composition of claim 8, wherein at least one polymer is selected from group consisting of hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

13. The composition of claim 8, wherein at least one polymer is selected from group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, co-povidone, carrageenans, galactomannans and xanthan gum, cyclodextrins, polyethylene glycols, polyethylene oxides, copolymers and graft copolymers of polyethylene glycols or polyethylene oxides, , ethylcellulose, low substituted hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate.

14. The composition of claim 8, wherein at least one polymer is co-povidone.

15. The composition of claim 8, wherein at least one glidant is colloidal silicon dioxide.

16. The composition of claim 8, wherein at least one surfactant is selected from group consisting of anionic or non-ionic surfactants or mixtures thereof.

17. The composition of claim 8, wherein at least one surfactant is selected from group consisting of PEG-35 castor oil, PEG-40 hydrogenated castor, PEG-60 hydrogenated castor oil, sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sorbitan tristearate, sorbitan trioleate, PEG-20 sorbitan monooleate, PEG-20 sorbitan monostearate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monolaurate, polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20) sorbitan trioleate, PEG (2) stearyl ether, macrogol 6 cetylstearyl ether or macrogol 25 cetylstearyl ether, a-tocopheryl polyethylene glycol succinate or mixtures thereof.

18. The composition of claim 8, wherein at least one surfactant is polysorbate 80.

19. The composition of claim 8, wherein at least one surfactant is present in an amount of about 1% to about 10% by total weight of the composition.

20. The composition of claim 9, wherein venetoclax or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 20% by weight of first solid dispersion.

21. The composition of claim 9, wherein at least one polymer in first solid dispersion is present in an amount of about 35% to about 90% by weight of first solid dispersion.

22. The composition of claim 9, wherein at least one polymer is selected from group consisting of hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

23. The composition of claim 9, wherein at least one polymer is co-povidone.

24. The composition of claim 9, wherein at least one glidant is colloidal silicon dioxide.

25. The composition of claim 9, wherein at least one surfactant is selected from group consisting of anionic or non-ionic surfactants or mixtures.

26. The composition of claim 9, wherein at least one surfactant is polysorbate 80.

27. The composition of claim 9, wherein at least one surfactant is present in an amount of about 1% to about 10% by weight of the composition.

28. A solid dispersion comprising venetoclax or a pharmaceutically acceptable salt thereof, at least two pharmaceutically acceptable polymers and optionally at least one pharmaceutically acceptable glidant, wherein the solid dispersion is devoid of surfactant.

29. The solid dispersion of claim 28, wherein venetoclax or a pharmaceutically acceptable salt thereof is present in an amount of about 1% to about 20% by weight.

30. The solid dispersion of claim 28, wherein at least two polymers are present in an amount of about 35% to about 90% by weight.

31. The solid dispersion of claim 28, wherein at least two polymers are selected from group consisting of hydrophilic water soluble polymers, enteric coating polymers and water insoluble polymers.

32. The solid dispersion of claim 28, wherein at least two polymers are selected from group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, co-povidone, carrageenans, galactomannans and xanthan gum, cyclodextrins, polyethylene glycols, polyethylene oxides, copolymers and graft copolymers of polyethylene glycols or polyethylene oxides, , ethylcellulose, low substituted hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl

acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate.

33. The solid dispersion of claim 28, wherein the at least two pharmaceutically acceptable polymers are different and are water soluble.

34. A solid dispersion comprising at least one polymer, a surfactant, and optionally one or more pharmaceutically acceptable glidants, wherein the solid dispersion is free of venetoclax or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a solid dispersion free of surfactant comprising venetoclax or a pharmaceutically acceptable salt thereof, at least two different polymers and optionally one or more pharmaceutically acceptable glidants.

36. The solid dispersion as described herein prepared by hot melt extrusion.

37. The solid dispersion of claim 36, wherein the input venetoclax or a pharmaceutically acceptable salt thereof is at least substantially amorphous.

38. A pharmaceutical composition as described herein in tablet form and bioequivalent to Venclexta®

39. A pharmaceutical composition as described herein wherein the venetoclax or a pharmaceutically acceptable salt remains at least substantially amorphous after storage for 6 months at 40 °C / 75% RH substantially as shown in Figure 5.

40. A pharmaceutical composition as described herein wherein which exhibits the dissolution profile substantially as shown in Table 11.