WO2017108605A1 - Pharmaceutical composition comprising amorphous dasatinib - Google Patents

Pharmaceutical composition comprising amorphous dasatinib Download PDF

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Publication number
WO2017108605A1
WO2017108605A1 PCT/EP2016/081369 EP2016081369W WO2017108605A1 WO 2017108605 A1 WO2017108605 A1 WO 2017108605A1 EP 2016081369 W EP2016081369 W EP 2016081369W WO 2017108605 A1 WO2017108605 A1 WO 2017108605A1
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Prior art keywords
dasatinib
tablet composition
composition according
polymer
acid
Prior art date
Application number
PCT/EP2016/081369
Other languages
French (fr)
Inventor
Sonia GARCIA JIMENEZ
Lisardo Alvarez Fernandez
Jose VELADA CALZADA
Original Assignee
Synthon B.V.
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Publication date
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Publication of WO2017108605A1 publication Critical patent/WO2017108605A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • CML chronic myelogenous leukaemia
  • ALL Philadelphia chromosome- positive acute lymphoblastic leukaemia
  • Ph+ Philadelphia chromosome positive chronic myelogenous leukaemia
  • Dasatinib was discovered by Bristol-Myers Squibb and is disclosed in EP1169038. Dasatinib is the active ingredient in the medicinal product sold under the brand name Sprycel ® .
  • WO2005077945 discloses a crystalline monohydrate of dasatinib and a butanol solvate of dasatinib.
  • the marketed product Sprycel ® contains the crystalline monohydrate of dasatinib.
  • WO2005077945 further discloses a crystalline ethanol solvate and two anhydrous forms of dasatinib.
  • Other forms of dasatinib are disclosed in WO2009053854, WO2010062715, WO2010067374, WO2011095059 and WO2012014149. Some of the described forms do contain unwanted solvents. Moreover, it was experienced in our laboratory that, especially under humid conditions, some of these forms are rather unstable.
  • Dasatinib monohydrate is a BCS class II compound, exhibiting low solubility and high permeability. Its low aqueous solubility affects the dissolution behavior of dasatinib monohydrate negatively.
  • solubility of amorphous forms is higher compared to the solubility of crystalline forms, thus it would be desirable to have dasatinib available in amorphous form.
  • WO2009053854 provides processes to prepare amorphous dasatinib.
  • WO2015049645 discloses processes to prepare several hydrated forms of amorphous dasatinib.
  • CN104327067 provides a process to prepare amorphous dasatinib by dissolving the compound in a solvent/co-solvent system followed by spray-drying.
  • amorphous dasatinib as such is not stable and therefore not suitable for use on pharmaceutical production scale.
  • WO2013105894 and WO2013105895 disclose pharmaceutical compositions comprising stable amorphous hybrid nanoparticles comprising dasatinib and a polymeric stabilizing and matrix-forming component and processes to prepare them.
  • the process to obtain said particles involves the provision and mixing of several pressurized streams. Such a treatment could easily affect the physical stability of dasatinib and is moreover rather costly.
  • CN 104367557 discloses a process to prepare solid dispersions comprising dasatinib and polyvinylpyrrolidone by dissolving dasatinib and the polymer in a mixture of methanol and water followed by spray drying. Since the solubility of dasatinib in this solvent mixture is low, large amounts of solvent are used. The disclosed process is therefore not suitable for production on commercial scale.
  • the present invention relates to a tablet composition
  • a solid dispersion of dasatinib and a polymer wherein the composition is obtained by:
  • polymer is selected from polyvinylpyrrolidone, copovidone and hydroxypropyl cellulose.
  • Said tablet composition may be used as a medicament, particularly in the treatment of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
  • CML chronic myeloid leukaemia
  • ALL acute lymphoblastic leukaemia
  • Sprycel ® contains the monohydrated form of dasatinib as disclosed in WO2005077945, the so-called form "Hl-7".
  • Dasatinib monohydrate is a very stable compound, but being a BCS class II compound, it exhibits low aqueous solubility which affects dissolution behavior.
  • dasatinib has been disclosed in the prior art. Many of these forms are solvated forms of dasatinib and some of them do contain unwanted (e.g. toxic) solvents. Moreover, some of the forms as disclosed in the prior art are rather unstable.
  • solid dispersion has been defined as a dispersion of one or more Active Pharmaceutical Ingredients (APIs) in an inert carrier or matrix at the solid state, prepared by a solvent or melting process or a combination of the two.
  • APIs Active Pharmaceutical Ingredients
  • the solid dispersions are divided into crystalline solid dispersions and amorphous solid dispersions respectively.
  • Amorphous carriers used are mostly polymers.
  • the API is dispersed in very small size and exists in supersaturated state in amorphous carriers because of forced degradation.
  • the amorphous carriers can increase the wettability and dispersibility of drugs as well as inhibit the precipitation process of drugs when amorphous solid dispersions are dissolved in water. These properties along with the fast dissolution rate of amorphous carriers due to the low thermodynamic stability of amorphous state carriers, enhance the drug solubility and release rate.
  • the number of marketed products arising from solid dispersion approaches is very low. This low number is mainly due to scale-up problems and physicochemical instability in the manufacturing process or during storage leading to phase separation and crystallization (Vo et. al, Eur. J. Pharm. Biopharm., 85 (2013) 799-813).
  • the process selected to prepare the tablet compositions of the present invention is the solvent evaporation method, because in this method problems related to decomposition, as frequently occurring in the melting method, are prevented.
  • An important prerequisite of the solvent evaporation method is the sufficient solubility of the drug and the carrier in the solvent system. Finding a suitable non-toxic solvent is sometimes difficult because carriers are hydrophilic whereas drugs are hydrophobic.
  • the present invention provides a tablet composition comprising a solid dispersion of dasatinib and a polymer, wherein the composition is obtained by:
  • the polymers to be used in accordance with the present invention are selected from polyvinylpyrrolidone (PVP), copovidone and hydroxypropyl cellulose.
  • PVP polyvinylpyrrolidone
  • Commonly used polymers like polyethylene glycol, Eudragit ® and hydroxypropyl methylcellulose were found to be unsuitable to be used in the present invention for various reasons. Some of the polymers did not result in fully amorphous solid dispersions, while other polymers did give rise to amorphous solid dispersions but wherein dasatinib started to crystallize over time. Moreover, some polymers were found to be unsuitable to be used in accordance with the present invention due to their solubility/gelling behavior in the solvent system.
  • Polyvinylpyrrolidone is a particularly preferred polymer to be used in accordance with the present invention.
  • the weight ratio of dasatinib to polymer in the solid dispersion ranges from about 1: 1 to about 1:6, preferably from 1: 1 to 1:3.
  • the tablet composition of the present invention is obtained by dissolving, in the first step of the process, dasatinib and the polymer in a solvent mixture.
  • the non-toxic solvent mixture in accordance with the present invention comprises water, an alcohol and at least one molar equivalent of acid with respect to dasatinib. Both dasatinib and the polymer dissolve well in the solvent mixture upon heating at a temperature ranging from 45 to 70°C.
  • the acid used in accordance with the present invention is a mineral acid.
  • the acid is hydrochloric acid.
  • the amount of acid present in the solvent mixture may range. However, at molar ratios of acid to dasatinib below 1: 1, dissolution is insufficient, while at too high ratios, gelling was observed.
  • the molar ratio of acid to dasatinib is ranging from 1: 1 to 3: 1. More preferably, the molar ratio of acid to dasatinib is ranging from 1: 1 to 2: 1.
  • the alcohol used in the solvent mixture of the present invention is selected from methanol, ethanol and isopropanol. Ethanol is a particularly preferred alcohol.
  • the volume ratio water to alcohol in the solvent mixture may vary, but is preferably ranging from 2:3 to 1:4. At these ratios, optimal solubility is achieved.
  • the resulting solution is added to a diluent.
  • the addition of the solution to the diluent is performed by spraying the solution over the diluent.
  • the diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art.
  • the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol.
  • Microcrystalline cellulose is a particularly preferred diluent.
  • the solvent is evaporated.
  • the evaporation is carried out by techniques known to a person of ordinary skill in the art.
  • the resulting blend is then mixed with further excipients.
  • the tablet compositions according to the present invention comprise, besides a diluent, further pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well4inown and are those excipients which are conventionally used by the person skilled in the art.
  • the pharmaceutically acceptable excipients are chosen from one or more binders, disintegrants, glidants or lubricants. Most preferably, the further excipients are chosen from one or more disintegrants and one or more lubricants.
  • the disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of
  • croscarmellose sodium is a particularly preferred disintegrant.
  • the lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant.
  • the final blend is compressed into tablets, using equipment and methods well-known in the art.
  • the tablet composition of the present invention exhibits excellent long term stability. Even after 3 months at 40°C/75% RH, no conversion into any crystalline form of dasatinib was observed. Moreover, the tablet composition of the present invention is cost effective and very suitable for production on commercial scale.
  • the tablet composition of the present invention display dissolution behavior typical for immediate-release formulations.
  • the composition of the present invention exhibits a dissolution rate of at least 85% in 15-30 minutes when tested in 500 ml 0.01 N hydrochloric acid pH 2.0 in a USP apparatus II at 75 rpm, 25°C.
  • the tablet composition in accordance with the present invention may be used as a medicament.
  • the pharmaceutical composition typically may be used in the treatment of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
  • CML chronic myeloid leukaemia
  • ALL acute lymphoblastic leukaemia
  • the tablets comprising a solid dispersion of dasatinib and a polymer were prepared by wet granulation and have the composition as given in table 1.
  • Table 1 tablet composition of tablets comprising a solid dispersion of dasatinib and a polymer
  • microcrystalline cellulose in a fluid bed dryer.
  • the solvent was evaporated by using a top spraying/drying process. During spraying/drying the temperature was adjusted to 45-80°C, depending on the polymer used.
  • the resulting blend was sieved through an appropriate mesh size sieve. 14.00 g of croscarmellose sodium was sieved through a suitable mesh size sieve for deagglomeration and mixed with the blend.
  • Magnesium stearate was sieved through an appropriate sieve to deagglomerate and mixed with the powder mix.
  • the homogeneous powder obtained, was compressed using a rotating tablet press using appropriate punches. The tablets were stored at 40°C/75% RH (open dish). Stability results:

Abstract

The present invention relates to a tablet composition comprising a solid dispersion of dasatinib and a polymer, wherein the composition is obtained by: (1) Dissolving dasatinib and the polymer in a solvent mixture comprising water, an alcohol and at least one molar equivalent of acid with respect to dasatinib at a temperature ranging from 45 to 70ºC; (2) Adding the resulting solution to a diluent; (3) Evaporating the solvent; (4) Mixing the resulting blend with further excipients; (5) Compressing the final blend into tablets, what wherein the polymer is selected from polyvinylpyrrolidone, copovidone and hydroxypropyl cellulose. The invention further relates to the use of said tablet composition as a medicament, particularly in the treatment of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).

Description

PHARMACEUTICAL COMPOSITION COMPRISING AMORPHOUS
DASATINIB BACKGROUND OF THE PRESENT INVENTION
Dasatinib, chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- piperazinyl]-2-methyl-4-pyrimidinyl] amino] -5-thiazolecarboxamide of formula (I),
Figure imgf000002_0001
is a pharmaceutically active compound used for the treatment of adult patients with chronic myelogenous leukaemia (CML) after imatinib treatment, Philadelphia chromosome- positive acute lymphoblastic leukaemia (ALL) and newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase.
Dasatinib was discovered by Bristol-Myers Squibb and is disclosed in EP1169038. Dasatinib is the active ingredient in the medicinal product sold under the brand name Sprycel®.
Several crystalline forms of dasatinib are known and described in literature.
WO2005077945 discloses a crystalline monohydrate of dasatinib and a butanol solvate of dasatinib. The marketed product Sprycel® contains the crystalline monohydrate of dasatinib. WO2005077945 further discloses a crystalline ethanol solvate and two anhydrous forms of dasatinib. Other forms of dasatinib are disclosed in WO2009053854, WO2010062715, WO2010067374, WO2011095059 and WO2012014149. Some of the described forms do contain unwanted solvents. Moreover, it was experienced in our laboratory that, especially under humid conditions, some of these forms are rather unstable.
Dasatinib monohydrate is a BCS class II compound, exhibiting low solubility and high permeability. Its low aqueous solubility affects the dissolution behavior of dasatinib monohydrate negatively.
The solubility of amorphous forms is higher compared to the solubility of crystalline forms, thus it would be desirable to have dasatinib available in amorphous form.
WO2009053854 provides processes to prepare amorphous dasatinib. WO2015049645 discloses processes to prepare several hydrated forms of amorphous dasatinib. CN104327067 provides a process to prepare amorphous dasatinib by dissolving the compound in a solvent/co-solvent system followed by spray-drying. However, amorphous dasatinib as such is not stable and therefore not suitable for use on pharmaceutical production scale.
WO2013105894 and WO2013105895 disclose pharmaceutical compositions comprising stable amorphous hybrid nanoparticles comprising dasatinib and a polymeric stabilizing and matrix-forming component and processes to prepare them. The process to obtain said particles, involves the provision and mixing of several pressurized streams. Such a treatment could easily affect the physical stability of dasatinib and is moreover rather costly.
CN 104367557 discloses a process to prepare solid dispersions comprising dasatinib and polyvinylpyrrolidone by dissolving dasatinib and the polymer in a mixture of methanol and water followed by spray drying. Since the solubility of dasatinib in this solvent mixture is low, large amounts of solvent are used. The disclosed process is therefore not suitable for production on commercial scale.
Thus in view of the prior art cited above, there is still a need for stable pharmaceutical compositions with adequate dissolution comprising dasatinib, which are suitable for production on commercial scale. BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a tablet composition comprising a solid dispersion of dasatinib and a polymer, wherein the composition is obtained by:
(1) Dissolving dasatinib and the polymer in a solvent mixture comprising water, an alcohol and at least one molar equivalent of acid with respect to dasatinib at a temperature ranging from 45 to 70°C;
(2) Adding the resulting solution to a diluent;
(3) Evaporating the solvent;
(4) Mixing the resulting blend with further excipients;
(5) Compressing the final blend into tablets,
wherein the polymer is selected from polyvinylpyrrolidone, copovidone and hydroxypropyl cellulose.
Said tablet composition may be used as a medicament, particularly in the treatment of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Sprycel® contains the monohydrated form of dasatinib as disclosed in WO2005077945, the so-called form "Hl-7". Dasatinib monohydrate is a very stable compound, but being a BCS class II compound, it exhibits low aqueous solubility which affects dissolution behavior.
Other forms of dasatinib have been disclosed in the prior art. Many of these forms are solvated forms of dasatinib and some of them do contain unwanted (e.g. toxic) solvents. Moreover, some of the forms as disclosed in the prior art are rather unstable.
Various approaches to overcome the poor aqueous solubility of drug candidates have been investigated in drug research and development. Since the solubility of amorphous forms is higher compared to the solubility of crystalline forms, it would be desirable to have the drug candidate available in amorphous form. However, drugs that can exist in either amorphous or crystalline form tend to crystallize over time when present in amorphous state because the crystalline form of the drug is a lower-energy state than the amorphous form.
One of the most successful strategies to improve the dissolution of poorly soluble drugs is the preparation of a solid dispersion. The term solid dispersion has been defined as a dispersion of one or more Active Pharmaceutical Ingredients (APIs) in an inert carrier or matrix at the solid state, prepared by a solvent or melting process or a combination of the two. Depending on the physical state of the carrier, which is crystalline or amorphous, the solid dispersions are divided into crystalline solid dispersions and amorphous solid dispersions respectively. Amorphous carriers used are mostly polymers. In amorphous solid dispersions, the API is dispersed in very small size and exists in supersaturated state in amorphous carriers because of forced degradation. The amorphous carriers can increase the wettability and dispersibility of drugs as well as inhibit the precipitation process of drugs when amorphous solid dispersions are dissolved in water. These properties along with the fast dissolution rate of amorphous carriers due to the low thermodynamic stability of amorphous state carriers, enhance the drug solubility and release rate. Despite the high active research interests, the number of marketed products arising from solid dispersion approaches is very low. This low number is mainly due to scale-up problems and physicochemical instability in the manufacturing process or during storage leading to phase separation and crystallization (Vo et. al, Eur. J. Pharm. Biopharm., 85 (2013) 799-813).
It is not self-evident that a given drug will form an amorphous solid dispersion with just any polymer, and that, even in the event the solid dispersion is formed, it will be stable over time. Factors playing a role herein are the physicochemical properties of both API and polymer, the ratio of API to polymer used and the technique used to prepare the solid dispersion. Techniques to prepare solid dispersions often require very specific conditions for each combination of API and polymer.
In order to obtain tablet compositions comprising a solid dispersion of dasatinib and a polymer, exhibiting adequate dissolution and excellent long term stability, which are suitable for production on commercial scale, the use of several polymers has been investigated. Only some of them appeared to be suitable to be used in accordance with the present invention. Use of some of the polymers resulted in tablet compositions wherein dasatinib was present only partially in amorphous form. Other polymers did provide tablet compositions comprising solid dispersions wherein dasatinib was present in fully amorphous form, but wherein upon storage dasatinib converted into its crystalline form(s).
The process selected to prepare the tablet compositions of the present invention is the solvent evaporation method, because in this method problems related to decomposition, as frequently occurring in the melting method, are prevented. An important prerequisite of the solvent evaporation method is the sufficient solubility of the drug and the carrier in the solvent system. Finding a suitable non-toxic solvent is sometimes difficult because carriers are hydrophilic whereas drugs are hydrophobic.
The present invention provides a tablet composition comprising a solid dispersion of dasatinib and a polymer, wherein the composition is obtained by:
(1) Dissolving dasatinib and the polymer in a solvent mixture comprising water, an alcohol and at least one molar equivalent of acid with respect to dasatinib at a temperature ranging from 45 to 70°C;
(2) Adding the resulting solution to a diluent;
(3) Evaporating the solvent;
(4) Mixing the resulting blend with further excipients;
(5) Compressing the final blend into tablets, wherein the polymer is selected from polyvinylpyrrolidone, copovidone and hydroxypropyl cellulose.
The polymers to be used in accordance with the present invention are selected from polyvinylpyrrolidone (PVP), copovidone and hydroxypropyl cellulose. Commonly used polymers like polyethylene glycol, Eudragit® and hydroxypropyl methylcellulose were found to be unsuitable to be used in the present invention for various reasons. Some of the polymers did not result in fully amorphous solid dispersions, while other polymers did give rise to amorphous solid dispersions but wherein dasatinib started to crystallize over time. Moreover, some polymers were found to be unsuitable to be used in accordance with the present invention due to their solubility/gelling behavior in the solvent system. Polyvinylpyrrolidone is a particularly preferred polymer to be used in accordance with the present invention.
The weight ratio of dasatinib to polymer in the solid dispersion ranges from about 1: 1 to about 1:6, preferably from 1: 1 to 1:3.
The tablet composition of the present invention is obtained by dissolving, in the first step of the process, dasatinib and the polymer in a solvent mixture. The non-toxic solvent mixture in accordance with the present invention comprises water, an alcohol and at least one molar equivalent of acid with respect to dasatinib. Both dasatinib and the polymer dissolve well in the solvent mixture upon heating at a temperature ranging from 45 to 70°C.
Preferably, the acid used in accordance with the present invention is a mineral acid. Most preferably, the acid is hydrochloric acid. The amount of acid present in the solvent mixture may range. However, at molar ratios of acid to dasatinib below 1: 1, dissolution is insufficient, while at too high ratios, gelling was observed. Preferably, the molar ratio of acid to dasatinib is ranging from 1: 1 to 3: 1. More preferably, the molar ratio of acid to dasatinib is ranging from 1: 1 to 2: 1. The alcohol used in the solvent mixture of the present invention is selected from methanol, ethanol and isopropanol. Ethanol is a particularly preferred alcohol. The volume ratio water to alcohol in the solvent mixture may vary, but is preferably ranging from 2:3 to 1:4. At these ratios, optimal solubility is achieved.
After the first step of dissolving dasatinib and the polymer in the solvent mixture, the resulting solution is added to a diluent. In a preferred embodiment of the present invention, the addition of the solution to the diluent is performed by spraying the solution over the diluent. The diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art. Particularly, the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol. Microcrystalline cellulose is a particularly preferred diluent.
After the step of adding the solution, comprising of dasatinib and the polymer in the solvent mixture, to a diluent, the solvent is evaporated. The evaporation is carried out by techniques known to a person of ordinary skill in the art.
The resulting blend is then mixed with further excipients. The tablet compositions according to the present invention comprise, besides a diluent, further pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well4inown and are those excipients which are conventionally used by the person skilled in the art. The pharmaceutically acceptable excipients are chosen from one or more binders, disintegrants, glidants or lubricants. Most preferably, the further excipients are chosen from one or more disintegrants and one or more lubricants.
The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of
croscarmellose sodium, crospovidone or sodium starch glycolate. Croscarmellose sodium is a particularly preferred disintegrant. The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant.
After mixing the blend, comprising of the solid dispersion of dasatinb and the polymer, with further excipients, the final blend is compressed into tablets, using equipment and methods well-known in the art.
The tablet composition of the present invention exhibits excellent long term stability. Even after 3 months at 40°C/75% RH, no conversion into any crystalline form of dasatinib was observed. Moreover, the tablet composition of the present invention is cost effective and very suitable for production on commercial scale.
The tablet composition of the present invention display dissolution behavior typical for immediate-release formulations. The composition of the present invention exhibits a dissolution rate of at least 85% in 15-30 minutes when tested in 500 ml 0.01 N hydrochloric acid pH 2.0 in a USP apparatus II at 75 rpm, 25°C.
The tablet composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
EXAMPLES
The tablets comprising a solid dispersion of dasatinib and a polymer were prepared by wet granulation and have the composition as given in table 1. Table 1: tablet composition of tablets comprising a solid dispersion of dasatinib and a polymer
Figure imgf000010_0001
87.5 g of the polymer was dissolved in a heated solution (60°C) of ethanol 96%
(v/v):aqueous hydrochloric acid (3M):water 60:5:35. 87.5 g of dasatinib was added. The total solution volume was 1250 ml. The resulting solution was added to 159.25 g of
microcrystalline cellulose in a fluid bed dryer. The solvent was evaporated by using a top spraying/drying process. During spraying/drying the temperature was adjusted to 45-80°C, depending on the polymer used. The resulting blend was sieved through an appropriate mesh size sieve. 14.00 g of croscarmellose sodium was sieved through a suitable mesh size sieve for deagglomeration and mixed with the blend. Magnesium stearate was sieved through an appropriate sieve to deagglomerate and mixed with the powder mix. The homogeneous powder obtained, was compressed using a rotating tablet press using appropriate punches. The tablets were stored at 40°C/75% RH (open dish). Stability results:
Table 2: Stability results at 40°C/75% RH open dish for tablets comprising dispersion of ' dasatinib:polyvinylpyrrolidone 1:1
Figure imgf000011_0001

Claims

A tablet composition comprising a solid dispersion of dasatinib and a polymer, wherein the composition is obtained by:
(1) Dissolving dasatinib and the polymer in a solvent mixture comprising water, an alcohol and at least one molar equivalent of acid with respect to dasatinib at a temperature ranging from 45 to 70°C;
(2) Adding the resulting solution to a diluent;
(3) Evaporating the solvent;
(4) Mixing the resulting blend with further excipients;
(5) Compressing the final blend into tablets,
wherein the polymer is selected from polyvinylpyrrolidone, copovidone and hydroxypropyl cellulose.
The tablet composition according to claim 1, wherein the diluent is microcrystalline cellulose.
The tablet composition according to claim 1 or 2, wherein the polymer is
polyvinylpyrrolidone.
The tablet composition according to any one of claims 1 to 3, wherein the weight ratio of dasatinib to polymer is ranging from 1: 1 to 1:3.
The tablet composition according to any one of claims 1 to 4, wherein the alcohol is selected from methanol, ethanol and isopropanol.
The tablet composition according to any one of claims 1 to 5, wherein the alcohol is ethanol.
The tablet composition according to any one of claims 1 to 6, wherein the volume ratio water to alcohol in the solvent mixture is ranging from 2:3 to 1:4.
8. The tablet composition according to any one of claims 1 to 7, wherein the molar ratio of acid to dasatinib is ranging from 1: 1 to 3: 1.
9. The tablet composition according to any one of claims 1 to 8, wherein the acid is a
mineral acid.
10. The tablet composition according to any one of claims 1 to 9, wherein the acid is
hydrochloric acid.
11. The tablet composition according to any one of claims 1 to 10, wherein the further excipients are chosen from one or more disintegrants and one or more lubricants.
12. The tablet composition according to any one of claims 1 to 11 exhibiting a dissolution rate of at least 85% in 15-30 minutes when tested in aqueous hydrochloric acid pH 2.0 in a USP apparatus II at 75 rpm, 25°C.
13. The tablet composition according to any one of claims 1 to 12, for use as a medicament.
14. The tablet composition according to claim 13 for use in the treatment of chronic
myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL).
PCT/EP2016/081369 2015-12-22 2016-12-16 Pharmaceutical composition comprising amorphous dasatinib WO2017108605A1 (en)

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EP15202074 2015-12-22

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209908A1 (en) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
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WO2019209908A1 (en) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
US11440908B2 (en) 2018-04-25 2022-09-13 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
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US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
CN111217807A (en) * 2018-11-26 2020-06-02 安礼特（上海）医药科技有限公司 Dasatinib amorphous form and preparation method thereof
CN111904933A (en) * 2019-05-08 2020-11-10 北京化工大学 Transparent water-dispersible dasatinib nanoemulsion and preparation method thereof
CN111904933B (en) * 2019-05-08 2023-06-13 北京化工大学 Transparent water-dispersed dasatinib nanoemulsion and preparation method thereof
US11202778B2 (en) 2020-01-24 2021-12-21 Nanocopoeia, Llc Amorphous solid dispersions of dasatinib and uses thereof
US11298356B1 (en) 2020-01-24 2022-04-12 Nanocopoeia, Llc Amorphous solid dispersions of dasatinib and uses thereof
US11324745B2 (en) 2020-01-24 2022-05-10 Nanocopoeia, Llc Amorphous solid dispersions of dasatinib and uses thereof
WO2021150981A1 (en) * 2020-01-24 2021-07-29 Nanocopoeia, Llc Amorphous solid dispersions of dasatinib and uses thereof
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US11633398B2 (en) 2020-01-24 2023-04-25 Nanocopoeia, Llc Amorphous solid dispersions of dasatinib and uses thereof
US11389450B2 (en) 2020-01-31 2022-07-19 Nanocopoeia, Llc Amorphous nilotinib microparticles and uses thereof
US11559485B2 (en) 2020-04-30 2023-01-24 Nanocopoeia, Llc Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib
US20220175774A1 (en) * 2020-12-07 2022-06-09 Alembic Pharmaceuticals Limited Bioavailable Oral Dosage Form Of Tyrosine-Kinase Inhibitor
WO2022157308A1 (en) * 2021-01-21 2022-07-28 Xspray Pharma Ab (Publ) Fast dissolving pharmaceutical compositions of dasatinib
US11529351B2 (en) 2021-01-21 2022-12-20 Xspray Pharma Ab Fast dissolving pharmaceutical compositions
WO2022254033A1 (en) 2021-06-04 2022-12-08 Bend Research, Inc. Formic acid as processing aid in spray drying for basic drugs

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