DESC:FIELD OF INVENTION
The present invention relates to a pharmaceutical compositions of dasatinib and processes for the preparation of the same.
Furthermore, the present invention relates to the pharmaceutical composition comprising dasatinib and at least one hydrophobic meltable material.
Furthermore, the present invention relates to the pharmaceutical composition comprising dasatinib, at least one hydrophobic meltable material and one or more of pharmaceutically acceptable excipients.
Furthermore, the present invention relates to the pharmaceutical composition comprising dasatinib, at least one hydrophobic meltable material and one or more of pharmaceutically acceptable excipients used for the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia.
BACKGROUND
Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain. As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.
CML and ALL is largely treated with targeted drugs called tyrosine-kinase inhibitors (TKIs) which have led to dramatic improved long-term survival rates since 2001. These drugs have revolutionized treatment of this disease and allow most patients to have a good quality of life when compared to the former chemotherapy drugs.
Therefore, there is an unmet medical need for methods, medicaments and pharmaceutical compositions with a good efficacy.
Dasatinib is a protein tyrosine kinase inhibitor, including Src Kinase, Bcr/Abl inhibitor, and is also known as a Src/Abl inhibitor and is useful in the treatment of oncological and immunologic diseases.
SPRYCEL® tablets contains dasatinib and chemically known as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-yridiminyl] amino]-5-thiazolecarboxamide.
US Patent No. 6,596,746 discloses cyclic compounds and salts thereof, to methods of using such compounds in treating protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders, and to pharmaceutical compositions containing such compounds.
The PCT application WO 2005/077945 discloses processes for preparing 2-aminothiazole-5aromatic carboxamides which are useful as kinase inhibitors, such as inhibitors of protein tyrosine kinase and p38 kinase, intermediates and crystalline forms which are designated as monohydrate, butanol solvate, ethanol solvate, crystalline neat form (N-6) and crystalline neat form (T1H1-7).
US Patent publication No. 2006/0251723 Covers a pharmaceutical composition comprising dasatinib a pharmaceutically acceptable carrier; wherein compositions having a non-reactive coating.
The change in the Form of dasatinib e.g. solvate form of dasatinib, anhydrous and the like dramatically increases its solubility. The problem is to get the desired dissolution profile from the pharmaceutical composition comprising such forms of dasatinib. Surprisingly, it has been found that pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material provide desired dissolution profile.
Surprisingly, it has been found that pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material in specific ratio provide desired dissolution profile.
Surprisingly, it has been found that pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material provide desired dissolution profile when prepared by specific process.
Surprisingly, it has also been found that pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material; wherein the ratio of dasatinib and and at least one hydrophobic meltable material and process of preparation of compositions is playing a major role in dissolution dasatinib from the final dosage forms.
SUMMARY OF INVENTION
The present invention relates to a pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients, wherein dasatinib and hydrophobic meltable material are in ratio of 1:0.1 to 1:2.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients wherein pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, lubricant, glidant, coating agents.
Furthermore the present invention relates to a process of preparing pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical compositions comprising dasatinib, wherein composition is used for the treatment of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).
DETAILED DESCRIPTION
In an aspect, present invention relates to a pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material.
In an aspect, the present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients.
In an aspect, the present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients wherein hydrophobic meltable material is selected from Hydrogenated castor oil, Carnuba wax, Cetyl palmitate, Glycerin monostearate, Paraf!n wax, Stearic acid, Glyceryl behenate, Glyceryl palmitostearate, Glyceryl stearate, Beeswax, Microcrystalline wax, Stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol and lauryl alcohol, hydrogenated vegetable oil, glycerol monooleate, acetylated mono glyceride, tristearin, tripalmitin, cetyl ester wax, glyco wax and castor wax preferably from Hydrogenated Vegetable Oil, Carnauba wax, Glyceryl Behenate, Hydrogenated castor oil.
In an aspect, the present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients wherein hydrophobic meltable material is selected from hydrogenated vegetable oil, carnauba wax, glyceryl behenate, hydrogenated castor oil.
In an aspect, the present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients wherein hydrophobic meltable material is hydrogenated castor oil.
In an aspect, the present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients, wherein dasatinib and hydrophobic meltable material are in ratio of 1:0.1 to 1:2.
In a further preferred embodiment, the weight ratio of dasatinib and at least one hydrophobic meltable material is about 1 :0.1 , 1 :0.2, 1 :0.3, 1 :0.4, 1 :0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1. 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2. In a further preferred embodiment, the weight ratio of dasatinib and at least one hydrophobic meltable material is about 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8 or 1:0.9.
The term “dasatinib” as used in the context of the present invention relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, propylene glycol solvate and the like.
The term “pharmaceutically acceptable excipients” include, but not limited to, any one or more of diluents, disintegrants, binders, lubricants, glidants, acidifying agent, alkalizing agent, stabilizers, rate controlling polymers, surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers, coloring agents and the like.
The term “composition” as used in the context of the present invention includes pharmaceutical dosage forms such as tablets, capsules, pills, sachets, granules and the like.
The term “hydrophobic meltable material” include, but not limited to Hydrogenated castor oil, Carnuba wax, Cetyl palmitate, Glycerin monostearate, Paraf!n wax, Stearic acid, Glyceryl behenate, Glyceryl palmitostearate, Glyceryl stearate, Beeswax, Microcrystalline wax, Stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol and lauryl alcohol, hydrogenated vegetable oil, glycerol monooleate, acetylated mono glyceride, tristearin, tripalmitin, cetyl ester wax, glyco wax and castor wax and the like.
Suitable diluents, may be selected from, but not limited to the group consisting of different grades of starches, such as maize starch, potato starch, rice starch, wheat starch, Pregelatinised starch, fully Pregelatinised starch; cellulose derivatives, such as microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such as Mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose; oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium hydrogenphosphate; particularly preferably the fillers are selected from the group consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, spray dried lactose, and anhydrous lactose and the like.
Suitable disintegrants may be selected from, but not limited to the group consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate, crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted hydroxypropylcellulose, and disintegrating aids such as magnesium alumino-metasilicate and ion exchange resins like polacrilin potassium; particularly preferably the disintegrants are selected from the group consisting of sodium starch glycolate, croscarmellose sodium and crospovidone and the like.
Suitable binders may be selected from, but not limited to the group consisting of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and the like.
Suitable lubricants may be selected from, but not limited to the group consisting of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl fumarate and the like.
Suitable glidants, may be selected from, but not limited to the group consisting of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc and the like.
Suitable surfactants as component can be selected from, but not limited to the group consisting of anionic surfactants, preferably sodium lauryl sulphate; polyethylene glycols (PEGs), preferably those PEGs having molecular weight in the range of about 2000 to 10000, more preferably PEG 3350, PEG 4000, PEG 6000, PEG 8000; Polysorbates, preferably Tween 20, Tween 80 or Span 80; fatty acid esters, preferably propylene glycol caprylates such as Capmul PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleates and caprylates (Capmul MCM); esters of polyethylene glycol and fatty acids, such as Labrasol and Solutol; castor oil ethoxylate (glycerol polyethylene glycol ricinoleate) such as Cremophor EL and Cremophor RH 40. More preferably the surfactant is selected from the group consisting of sodium lauryl sulphate; PEG 3350, PEG 4000, PEG 600 or, PEG 8000 and preferably PEG 6000; Tween 20 or Tween 80; and esters of polyethylene glycol and fatty acids, most preferably sodium lauryl sulphate and PEG 6000 and in particular sodium lauryl sulphate and the like.
Suitable sweeteners may be selected from, but not limited to the group consisting of aspartame, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic material and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical compositions can be film coated with one or more coating agents, and the like.
Suitable film-forming agents and coating materials, if used, may include, but are not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, polyvinylalcohol,, methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, shellac, liquid glucose, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate such as Kollidon® VA64 BASF, copolymers of acrylic and/or methacrylic acid esters with trimethylammoniummethylacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid methylester and the like.
Suitable plasticizers, if used, may include, but are not limited to polyethylene glycol, diethyl phthalate and glycerol. Preference is given to polyethylene glycol and the like.
In an aspect the pharmaceutical composition can be prepared by one or more of various methods, but not limited, to methods of preparing said compositions include one or more of processes such as direct compression, wet granulation, dry granulation (roller compaction), solvent evaporation, hot melt granulation, hot melt extrusion, fluid bed granulation, spray drying, extrusion-spheronization and the like.
In an aspect the present invention relates to a pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material prepared by hot melt extrusion.
In an aspect the present invention relates to a pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material, prepared by twin screw extrusion.
In an aspect the present invention relates to a pharmaceutical compositions comprising dasatinib and at least one hydrophobic meltable material, prepared by using any process wherein the drug comes in contact with melted hydrophobic meltable material. It can be prepared in rapid mixer granulator by spraying molten hydrophobic meltable material or mixed in a jacketed rapid mixer granulator by increasing the temperature or spraying the molten hydrophobic material on dry mixed or using twin screw extrusion or using hot melt extrusion and the like.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients, wherein pharmaceutical compositions can be prepared in the form of tablets, granules, matrix tablets, multilayered tablets, powders, pellets, capsules, minitablets, microcapsules, multiple unit particles, and the like.
In an aspect the present invention relates to pharmaceutical compositions comprising
a) about 10- about 40% of dasatinib,
b) about 1-about 80% hydrophobic meltable material
c) about 10- about 80% diluent,
d) about 0 - about 10% binder,
e) about 1- about 25% disintegrant,
f) about 0.05- about 10% lubricant and/or glidant;
In an aspect the present invention relates to pharmaceutical compositions comprising
g) about 10- about 40% of dasatinib,
h) about 1-about 80% hydrophobic meltable material
i) about 10- about 80% microcrystalline cellulose and / or lactose,
j) about 0 - about 10% binder,
k) about 1- about 25% croscarmellose sodium,
l) about 0.05- about 10% colloidal silicon dioxide and/or magnesium stearate;
In an aspect the present invention relates further relates to processes for the preparation of the compositions. It can be prepared in rapid mixer granulator by spraying molten hydrophobic meltable material or mixed in a jacketed rapid mixer granulator by increasing the temperature or spraying the molten hydrophobic material on dry mixed or using twin screw extrusion or using hot melt extrusion and the like.
In an aspect, the present invention relates to methods of preparing a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients comprising the steps of:
a). Sifting and mixing dasatinib, at least one hydrophobic meltable material, diluent, optionally part of glidant and
b). Resultant material is then processed through twin screw extruder to make granules, and mill the granules
c) Addition of extra-granular materials
In an aspect, the present invention relates to methods of preparing a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients comprising the steps of:
a). Sifting and mixing dasatinib, at least one hydrophobic meltable material, part of microcrystalline cellulose, part of colloidal silicon dioxide,
b). Resultant material is then processed through twin screw extruder to make granules,
c). Compact remaining quantity of microcrystalline cellulose using roll Compactor,
d). Blending and milling dasatinib extrudes and compacted microcrystalline cellulose,
e). Sifting anhydrous lactose, croscarmellose sodium and remaining quantity of colloidal silicon dioxide,
f). Blending of step d) and step e).
g). lubrication with magnesium stearate
h). optionally, compress the tablets using appropriate tooling.
i). optionally, coat the tablets with coating material
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients, wherein the percentage of dasatinib is released not less than about 80% within about 15 minutes when subjected to an in vitro dissolution study.
The present invention relates to a pharmaceutical compositions comprising dasatinib, at least one hydrophobic meltable material and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical compositions are stable throughout shelf life of the compositions and provide the desired therapeutic concentration of the active agent for the intended duration.
In an aspect, the present invention relates to pharmaceutical composition of dasatinib can be used for treatment of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).
The following example illustrates certain specific aspects and embodiments of the invention and demonstrates the practice and advantages thereof. It is to be understood that the examples are provided solely for purposes of illustration and should not be regarded as limiting the scope of the invention in any manner.
S.No. Material name mg/
unit mg/
unit mg/
unit mg/
unit mg/
unit mg/
unit mg/
unit mg/
unit
1 Dasatinib 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
2 Hydrogenated Castor oil 100.00 - - - 50.00 - - -
3 Hydrogenated Vegetable Oil - 100.00 - - - 50.00 - -
4 Carnauba wax - - 100.00 - - - 50.00 -
5 Glyceryl Behenate - - - 100.00 - - - 50.00
6 Microcrystalline cellulose 210.00 210.00 210.00 210.00 260.00 260.00 260.00 260.00
7 Anhydrous lactoase 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00
8 Croscarmellose sodium 13.50 13.50 13.50 13.50 13.50 13.50 13.50 13.50
9 Colloidal Silicon dioxide 5.50 5.50 5.50 5.50 5.50 5.50 5.50 5.50
10 Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
11 Opadry white 13.50 13.50 13.50 13.50 13.50 13.50 13.50 13.50
12 Purified water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Procedure:
1. Sifting and blending of Dasatinib, hydrophobic meltable material (Hydrogenated Castor oil / Hydrogenated vegetable oil / Carnauba wax / Glyceryl Behenate), part quantity of Colloidal Silicon dioxide and part quantity of microcrystalline cellulose.
2. Process the resultant material through twin screw extruder to make granules.
3. Compact remaining quantity of microcrystalline cellulose using roll Compactor.
4. Blend dasatinib extrudes and compacted microcrystalline cellulose in blender.
5. Milling of dasatinib extrudes and compacted microcrystalline cellulose through Quadro comill using appropriate Screen.
6. Sift anhydrous lactose, croscarmellose sodium and remaining quantity of colloidal silicon dioxide through appropriate Screen.
7. Blend step 5 and step 6 in Blender.
8. Sift the Magnesium stearate through appropriate screen and lubricate step 7 material.
9. Compress the tablets using appropriate tooling.
10. Coat the tablets with coating material

We claim:
1. A pharmaceutical composition comprising dasatinib and at least one hydrophobic meltable material.
2. A pharmaceutical composition according to claim 1, wherein at least one hydrophobic meltable material is selected from Hydrogenated castor oil, Carnuba wax, Cetyl palmitate, Glycerin monostearate, Paraf!n wax, Stearic acid, Glyceryl behenate, Glyceryl palmitostearate, Glyceryl stearate, Beeswax, Microcrystalline wax, Stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol and lauryl alcohol, hydrogenated vegetable oil, glycerol monooleate, acetylated mono glyceride, tristearin, tripalmitin, cetyl ester wax, glyco wax and castor wax preferably from Hydrogenated Vegetable Oil, Carnauba wax, Glyceryl Behenate, hydrogenated castor oil.
3. A pharmaceutical composition according to claim 1, wherein at least one hydrophobic meltable material is selected from hydrogenated vegetable oil, carnauba wax, glyceryl behenate, hydrogenated castor oil.
4. A pharmaceutical composition according to claim 1, wherein it is prepared by twin screw extrusion.
5. A pharmaceutical composition according to claim 1, wherein dasatinib and at least one hydrophobic meltable material are in ratio of 1:0.1 to 1:2.
6. A pharmaceutical composition according to claim 1, wherein dasatinib and at least one hydrophobic meltable material is used for the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia.
,CLAIMS:We claim:
1. A pharmaceutical composition comprising dasatinib and at least one hydrophobic meltable material.
2. A pharmaceutical composition according to claim 1, wherein at least one hydrophobic meltable material is selected from Hydrogenated castor oil, Carnuba wax, Cetyl palmitate, Glycerin monostearate, Paraf!n wax, Stearic acid, Glyceryl behenate, Glyceryl palmitostearate, Glyceryl stearate, Beeswax, Microcrystalline wax, Stearyl alcohol, cetostearyl alcohol, cetyl alcohol, myristyl alcohol and lauryl alcohol, hydrogenated vegetable oil, glycerol monooleate, acetylated mono glyceride, tristearin, tripalmitin, cetyl ester wax, glyco wax and castor wax preferably from Hydrogenated Vegetable Oil, Carnauba wax, Glyceryl Behenate, hydrogenated castor oil.
3. A pharmaceutical composition according to claim 1, wherein at least one hydrophobic meltable material is selected from hydrogenated vegetable oil, carnauba wax, glyceryl behenate, hydrogenated castor oil.
4. A pharmaceutical composition according to claim 1, wherein it is prepared by twin screw extrusion.
5. A pharmaceutical composition according to claim 1, wherein dasatinib and at least one hydrophobic meltable material are in ratio of 1:0.1 to 1:2.
6. A pharmaceutical composition according to claim 1, wherein dasatinib and at least one hydrophobic meltable material is used for the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia.