WO2020217235A1

WO2020217235A1 - Solid dosage form of dasatinib

Info

Publication number: WO2020217235A1
Application number: PCT/IB2020/054601
Authority: WO
Inventors: Vijay Joguparthi; Srikanth Polasa; Kishore KUMAR CHINTAKINDI
Original assignee: Aizant Drug Research Solutions Private Limited
Priority date: 2019-04-24
Filing date: 2020-05-15
Publication date: 2020-10-29

Abstract

The present invention relates to delayed release solid dosage forms of dasatinib wherein the delayed release profile is achieved by using hydrophobic or lipophilic material or a suitable polymer in the granulation of the ingredients of composition. The present invention also relates to a process for preparation of delayed release solid dosage forms of Dasatinib where the hydrophobic material or polymers are used in specific proportion to their concentration in the formulation, for delaying the release of active component. The said formulation is stable and does not change to other polymorphic forms.

Description

SOLID DOSAGE FORM OF DASATINIB

CROSS REFERENCE

[0001] This application claims priority to an Indian provisional patent application no. 201941016156, filed April 24, 2019, the contents of which are incorporated herein by reference in their entireties.

FIELD OF INVENTION

[0002] The present invention relates to a solid state dosage form of Dasatinib with pharmaceutically acceptable excipients and its method of preparation. The present invention also relates to use of specific polymers and hydrophobic material to provide a delayed release profile of a Dasatinib dosage form.

BACKGROUND

[0003] Dasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2- methyl-4-pyrimidinyl]amino]-l,3-thiazole-5-carboxamide a compound having the following chemical structure:

[0004] 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®. Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinases inhibitor and is useful in the treatment of oncological diseases. It is approved for use in patients with chronic myelogenous leukemia (CML) after Imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-i- ALL).

[0005] US20060251723 and US20130122093 disclose formulation of Dasatinib, specifically monohydrate form and PEG is incorporated into coating to avoid decomposition of Dasatinib. W02017144109 A1 discloses an oral dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, together with at least one disintegrant.

[0006] US20140343073A1 discloses process for the preparation of amorphous form of dasatinib by milling. US7491725 B2 discloses crystalline monohydrate of dasatinib and their solid dosage forms. US8680103 B2 discloses pharmaceutical compositions of dasatinib crystalline monohydrate with pharmaceutically acceptable carriers, including binder, diluent, disintegrant, and/or a lubricant. US2008275009 A1 discloses pharmaceutical composition of dasatinib with at least one acid pH modifier as an excipient. WO2017103057 discloses a tablet composition comprising anhydrous dasatinib and one or more pharmaceutically acceptable excipients, wherein the tablet is film coated with a coating composition comprising an organic ester as plasticizer. WO 2006/121742 also describes the specific film coated tablets of dasatinib.

[0007] To further come up with a better formulation there are several approaches like using various solid state forms like amorphous and crystalline forms, many crystalline forms of dasatinib known and described in literature. W02005077945 discloses a crystalline monohydrate of dasatinib and a butanol solvate of dasatinib. The marketed product Sprycel® contains the crystalline monohydrate of dasatinib. Other crystalline forms are disclosed in W02005077945 (crystalline ethanol solvate and two anhydrous forms of dasatinib), others are disclosed in W02009053854, W02010062715, W02010067374, WO2011095059 and W02012014149. Some of the described forms do contain unwanted solvents.

[0008] However it is well known that such crystalline forms, especially under humid conditions or in presence of moisture tend to become unstable. Further Dasatinib monohydrate is a BCS class II compound, exhibiting low solubility and high permeability. Its low aqueous solubility affects various formulation paradiagram like the dissolution behaviour, flow property, storage stability and real time processing during preparation of dosage forms. A skilled reader would also be aware that the presence and associated amounts of specific excipients has an effect on the dissolution of an active pharmaceutical ingredient as present in a dosage form.

[0009] Thus in view of the prior art cited above, there is still a need for a stable pharmaceutical compositions with adequate dissolution comprising Dasatinib, which is suitable for production on commercial scale. The inventors in the present invention have however now found that by careful use of excipients in specific pattern or process using hydrophobic material or specific polymers can be used for providing a better and modified release profile of dasatinib from solid state forms and maintain the stability of the dosage from.

[0010] According to the present invention therefore, there is provided a solid state dosage form comprising dasatinib, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable hydrophobic excipient or polymer in proportion to the formulation for getting a modified or delayed release profile of the drug.

SUMMARY OF THE INVENTION

[0011] The present is related to a Dasatinib solid oral dosage from prepared with hydrophobic or lipophilic polymers for achieving a stable and pharmaceutically advantageous formulation. The said formulation uses lipophilic materials or polymers in proportion to their concentration that inherently provides a delaying effect on the release of the active component from the pharmaceutical formulation.

[0012] In another aspect, the present invention provides dasatinib formulation with polymers having melting point less than 200°C, for delaying the drug release. The property of polymers was used inherently in a process of preparation of dosage forms for controlling the dasatinib release rate in the present invention.

[0013] In yet another aspect, the present invention provides solid state dosage forms of Dasatinib with at least one lipophilic / hydrophobic material or pharmaceutically acceptable polymer.

[0014] In a further aspect, the present invention provides solid state dosage forms of Dasatinib with a plurality of other pharmaceutically acceptable excipients in specific quantity and combinations, for both stabilizing and delaying the release of the active agent and forming a long acting pharmaceutical composition.

[0015] In another aspect, the present invention provides a tablet or pellet composition of Dasatinib with at least one lipophilic or hydrophobic excipient and having delayed or modified drug release.

[0016] The present invention further contemplates pharmaceutical composition of dasatinib with at least on lipophilic excipient, at least one diluent, disintegrant and a lubricant with an optional coating to provide a controlled or specific delayed release oral dosage form of Dasatinib.

[0017] In yet another aspect, the present invention solid dosage forms of Dasatinib comprises of intra-granular and extra-granular part wherein the hydrophobic material or a polymer is characteristically in Intra-granular part. However the composition may comprises of hydrophobic material in the extra-granular part.

[0018] In a further aspect; the hydrophobic material used in the composition may be in both intra and extra-granular part in 1:1 or 1:10 to 10:1 ratio.

[0019] In another aspect, the present composition comprises of intra-granular part with active ingredient, at least one diluent and at least one hydrophobic material and the extra-granular part may or may not have any hydrophobic material.

[0020] In a further aspect, the present invention provides a tablet or pellet composition of Dasatinib with at least one polymer/hydrophobic material, having delayed or modified drug release.

[0021] The present composition may further be coated with a film coating or any other suitable coating wherein the coating may or may not have a delayed release property.

[0022] In an object, the present composition can be a delayed release or modified release composition, wherein the release profile is mainly attributed to the preparation process and the hydrophobic or polymeric material used during the granulation.

[0023] In a further aspect, the present invention provides a process for preparing a controlled/ delayed release dosage form of dasatinib wherein the process comprises of homogeneously mixing Dasatinib, a hydrophobic / lipophilic carrier or polymeric material and a suitable diluent in a jacketed Rapid mixer granulator with simultaneous heating during mixing to the melting point of the lipophilic carrier or polymeric material to obtain spherical granules. Then they were cooled to the room temperature and the obtained granules were sized and mixed with the extra-granular excipients followed by compressing into tablets.

BRIEF DESCRIPTION OF FIGURES

[0024] Figure-1: Shows comparative dissolution data of the test formulation prepared using various techniques like direct compression, melt granulation with carnauba wax and melt granulation with hydrogenated castor oil in pH 4.5 Acetate buffer as dissolution media.

[0025] Figure-2: Shows comparative dissolution data of the test formulation prepared using various techniques like direct compression, melt granulation with carnauba wax and melt granulation with hydrogenated castor oil in pH 1.2 buffer as dissolution media. [0026] Figure-3: Shows comparative dissolution data of test formulation prepared using melt granulation with carnauba wax in different dissolution mediums.

[0027] Figure-4: Shows comparative dissolution profile of formulation prepared by direct compression and melt granulation using stearic acid concentrations in pH 4.5 buffer as dissolution media.

[0028] Figure-5: Shows comparative dissolution profile of formulation prepared by direct compression and melt granulation using stearic acid concentrations in pH 4.0 + 1% Triton X 100 as dissolution media.

[0029] Figure-6: Shows XRD graphs:

(a) Overlay of Placebo and Melt granulation formulation using Amorphous API.

(b) Overlay of Crystalline API and melt granulation formulation using Amorphous API.

DESCRIPTION OF THE INVENTION

[0030] The present disclosure is herein described with reference to embodiments, which form a part here. Other embodiments may be used and/or other changes may be made without departing from the spirit or scope of the present disclosure. The illustrative embodiments described in the description are not meant to be limiting of the subject matter presented here.

[0031] The inventors in the present invention have explored the use of various hydrophobic materials like camauba wax, hydrogenated castor oil, stearic acid, sterayl alcohol, glyceryl monostearate, glyceryl palmitostearate and other polymers like Eudragit RS PO, Eudragit RL PO, Eudragit EPO, Ethyl cellulose or polymers having melting point less than 200°C, for delaying the drug release. The inventors have found that when these lipophilic materials or polymers are used in proportion to their concentration in the formulation, a delaying effect on the release of the active component from the pharmaceutical formulation is obtained. This property was used for controlling the dasatinib release rate in the present invention.

[0032] The present invention pertains to solid state dosage forms of Dasatinib with at least one lipophilic / hydrophobic material or pharmaceutically acceptable polymer. In combination therewith is a plurality of other pharmaceutically acceptable excipients in specific quantity and combinations, for both stabilizing and delaying the release of the active agent and forming a long acting pharmaceutical composition. [0033] In another embodiment, the present invention provides a tablet or pellet composition of Dasatinib with at least one lipophilic or hydrophobic excipient and having delayed or modified drug release.

[0034] In yet another preferred embodiment, the present invention provides a pharmaceutical composition of dasatinib with specific quantity of at least on lipophilic excipient, at least one diluent, at least one disintegrant and a lubricant with an optional coating to provide a controlled release oral dosage form of Dasatinib.

[0035] In yet another embodiment the present composition comprises of intragranular and extragranular part wherein the hydrophobic material is characteristically in Intragranular part. In yet another embodiment the present composition comprises of hydrophobic material in the extragranular part. In yet another embodiment the hydrophobic material may be in both intra and extragranular part in 1:1 or 1:10 to 10:1 ratio.

[0036] In a further preferred embodiment the present composition comprises of intragranular part with active ingredient, at least one diluent and at least one hydrophobic material and the extragranular part may or may not have any hydrophobic material.

[0037] In a further embodiment, the present invention provides a tablet or pellet composition of Dasatinib with at least one polymer having delayed or modified drug release.

[0038] In yet another preferred embodiment, the present invention provides a pharmaceutical composition of dasatinib with specific quantity of polymers or polymers having melting point less than 200°C, at least one diluent, at least one disintegrant and a lubricant with an optional coating to provide a controlled release oral dosage form of Dasatinib.

[0039] In yet another embodiment the present composition comprises of intragranular and extragranular part wherein the polymer is characteristically in Intragranular part. In yet another embodiment the present composition comprises of polymer in the extragranular part.

[0040] In yet another embodiment the polymer may be in both intra and extragranular part in 1:1 or 1:10 to 10:1 ratio.

[0041] In a further preferred embodiment the present composition comprises of intragranular part with active ingredient, at least one diluent and at least one polymeric material and the extragranular part may or may not have any polymeric material. [0042] In one another embodiment the present composition is coated with a film coating or any other suitable coating wherein the coating may or may not have a delayed release property.

[0043] In one of the preferred embodiment the present invention pertains to a process for making solid oral dosage forms in which the therapeutic compound is a dasatinib

(amorphous). The process features the use of melt granulation in Rapid mixer granulator.

More specifically, the present invention discloses a simple coating or binding Dasatinib with hydrophobic materials like Carnauba wax, Hydrogenated Castor oil, Stearic acid, Stearyl alcohol, Glyceryl monostearate, Glyceryl palmitostearate there by means of melt granulation in order to effectively cover and delay the release of Active pharmaceutical ingredient specifically Dasatinib.

[0044] In yet another preferred embodiment the present invention pertains to a process for making solid oral dosage forms in which the therapeutic compound is a dasatinib

(amorphous) and the process features the use of polymers in Rapid mixer granulator. More specifically, the present invention discloses a simple coating or binding Dasatinib with polymers like Eudragit RS PO, Eudragit RL PO, Eudragit EPO, Ethyl cellulose or polymers having melting point less than 200°C, there by means of melt granulation in order to effectively cover and delay the release of Active pharmaceutical ingredient specifically Dasatinib.

[0045] In another embodiment the present composition may be a delayed release or modified release composition, wherein the release profile is mainly attributed to the preparation process and the hydrophobic or polymeric material used during the granulation.

[0046] In a further embodiment the present invention provides a process for preparing a controlled release dosage form of dasatinib wherein the process comprises of homogeneously mixing Dasatinib, a hydrophobic / lipophilic carrier or polymeric material and a suitable diluent in a jacketed Rapid mixer granulator with simultaneous heating during mixing to the melting point of the lipophilic carrier or polymeric material to obtain spherical granules. Then they were cooled to the room temperature and the obtained granules were sized and mixed with the extragranular excipients followed by compressing into tablets.

[0047] In another embodiment the present invention provides a process for manufacturing the claimed composition comprising of following steps: i. Sifting Dasatinib, microcrystalline cellulose (Avicel pH 112) and hydrophobic material or a polymer through suitable sieve;

ii. Loading the sifted material from step i) in to a Jacketed Rapid mixer granulator and mixing for suitable period of time at slow impeller speed;

iii. Connecting the circulating hot water bath to the Jacketed Rapid mixer granulator, wherein the temperature of water is 80-100°C;

iv. The dry mix material within the RMG attains a temperature of 75-100°C, which leads to start of the melting and formation of granules;

v. The granules formed in step iv) are then dried and milled through Oscillating granulator;

vi. Then to step v) milled granules, lactose monohydrate / microcrystalline cellulose and croscarmellose sifted through suitable sieve are added and blended for suitable period of time;

vii. Then the lubricant magnesium stearate is sifted through suitable sieve and added to step vi) blend and lubricated for suitable period of time;

viii. Thereafter the lubricated blend form step vii) is compressed into tablets with suitable tooling to achieve desired tablet properties; and

ix. Resulting core tablets from step viii) were then coated with Opadry till desired weight gain is achieved.

[0048] The Dasatinib used in the present invention is selected from crystalline, amorphous, anhydrous, or any other suitable form, solvate or pharmaceutically acceptable salt thereof.

[0049] The present invention also contemplates use of any other active pharmaceutical ingredient other than Dasatinib, for preparing solid state dosage forms of Active ingredient using polymer / hydrophobic material prepared using melt-granulation.

[0050] The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct blending & filling/compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or uncoated. Coating of compositions such as tablets and caplets is well known in the art.

[0051] Pharmaceutically acceptable excipients may be utilized as required for conversion of the granules into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, sweeteners, taste modifying agents, flavoring agents and other additives that are commonly used in solid pharmaceutical dosage form preparations.

Non limiting examples of excipients that can be used in the composition are:

Diluents:

[0052] Various useful fillers or diluents include but are not limited to starches, lactose, mannitol, cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PHI 12 microcrystalline cellulose 114, and microcrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, magnesium aluminometasilicate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:

[0053] Various useful binders include but are not limited to hydroxypropyl celluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropylmethylcelluloses, also called hypromelloses or HPMC (Methocel™ ) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP- K29, PVP-K30, and PVP-K90), Plasdone™ S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol.TM.), methylcelluloses, polymethacrylates, magnesium aluminometasilicate and starches.

Disintegrants:

[0054] Various useful disintegrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not limited to crosslinkedpovidone, Kollidon™ CL, magnesium aluminometasilicate like neusilin, Polyplasdone™ XL, XI- 10, and INF- 10 and low-substituted hydroxypropylcelluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low- substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Stabilizers:

[0055] Various useful stabilizers include basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples of basic inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(0H)16.C03.4H20], aluminum hydroxide- magnesium [2.5Mg0.Al₂0₃.xH₂0], and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Physical form Stabilizers:

[0056] Various useful physical form stabilizers include various polymers such as but not limited to povidones like povidone k25, k30, k90 and the like, cellulose derivatives such as but not limited to hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetyl succinate; silicate derivatives such as but not limited to colloidal silicon dioxide, magnesium alumino meta silicate and the like.

Surface- Active Agents:

[0057] Useful surface- active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface- active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethylenically treated sorbitan esters (TWEEN™), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenolamine stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yolk.

Lubricants:

[0058] An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

Glidants:

[0059] One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations, can be used. Useful glidants include but are not limited to silicon dioxide, aerosol, talc, neusilin and combinations thereof.

Coloring Agents:

[0060] Coloring agents can be used to color code the compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the like.

Flavoring agents:

[0061] The flavoring agents may comprise one or more synthetic or natural flavouring or aromatizing agents. Flavoring agents may be selected from essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit comprising mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavour of the fruit, e.g., strawberry, raspberry and black currant; artificial and natural flavours of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds, nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger.

Sweetening agents:

[0062] Sweetening agents are added essentially to improve the taste, and comprise one or more synthetic or natural sugars, i.e., any form of carbohydrates suitable for use as sweetener, as well as so called artificial sweeteners such as saccarin, sodium saccarin, aspartame, e.g., NutraSweet.RTM., acesulfame K or acesulfame, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, stevside.

Useful additives for coatings include but are not limited to plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

[0063] Various useful plasticizers include but are not limited to substances such as castor oil, diacetylated monoglycerides, dibutylsebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like titanium dioxide may also be present, typically in an amount ranging from about 10% to about 20% based on the total weight of the coating.

[0064] Hydrophobic materials used include but are not limited to Carnauba wax, Hydrogenated castor oil, Stearic acid, Stearyl alcohol, Glyceryl monostearate, Glyceryl palmitostearate, palmitic acid, polyoxyethylene monostearates, other hydrogenated vegetable oils and fats, stearic acid and combinations thereof.

[0065] Polymeric material used include but are not limited to Eudragit RS PO, Eudragit RL PO, Eudragit EPO, Ethyl cellulose or any suitable polymers having melting point less than 200°C, and combinations thereof.

EXAMPLES

[0066] The following examples are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention. [0067] Example 1: Dasatinib tablet Dosage Form with hydrophobic material using melt granulation technique

[0068] Manufacturing procedure:

Dispensing:

i. Weighing the raw material to be used in the preparation;

Sifting:

ii. Sifting Dasatinib, microcrystalline cellulose (Avicel pH 112) and hydrophobic material through suitable sieve;

Granulation:

iii. Loading the sifted material from step ii) in to a Jacketed Rapid mixer granulator and mixing for suitable period of time at slow impeller speed;

iv. Connecting the circulating hot water bath to the Jacketed Rapid mixer granulator, wherein the temperature of water is 80-95°C;

v. The dry mix material within the RMG attains a temperature of 75-90°C, which leads to start of the melting and formation of granules;

vi. The granules formed in step v) are then dried and milled through Oscillating granulator;

vii. Then to step vi) milled granules, lactose monohydrate / microcrystalline cellulose and croscarmellose sifted through suitable sieve is added and blended for suitable period of time; viii. Then the lubricant magnesium stearate is sifted through suitable sieve and added to step vii) blend and lubricated for suitable period of time;

ix. Thereafter the lubricated blend form step viii) is compressed into tablets with suitable tooling to achieve desired tablet properties; and

Coating:

x. Resulting core tablets from step ix) were then coated with Opadry till desired weight gain is achieved.

[0069] Example 2: Dasatinib tablets prepared using melt granulation technique with carnauba wax

[0070] Preparation procedure:

i. 10 gram of Dasatinib, 10 gram of Carnauba wax and 5 gram of Microcrystalline cellulose were homogeneously mixed in jacketed Rapid mixer granulator; ii. The above mixing was continued with simultaneous heating to the melting point of carnauba wax to form spherical granules;

iii. Then the above granules were cooled to the room temperature, followed by sizing and mixing with the extragranular excipients;

iv. Then the above mixture is compressed into tablets and coated. [0071] Example 3: Dasatinib tablets prepared using melt granulation technique with hydrogenated castor oil

[0072] Preparation procedure:

i. 10 gram of Dasatinib, 10 gram of hydrogenated castor oil and 5 gram of Microcrystalline cellulose were homogeneously mixed in jacketed Rapid mixer granulator;

ii. The above mixing was continued with simultaneous heating to the melting point of hydrogenated castor oil to form spherical granules;

iv. Then the above mixture is compressed into tablets and coated.

[0073] Example 4: Dasatinib tablets prepared using melt granulation technique with stearic acid

[0074] Preparation procedure:

i. 10 gram of Dasatinib, 10 gram of stearic acid and 5 gram of Microcrystalline cellulose were homogeneously mixed in jacketed Rapid mixer granulator; ii. The above mixing was continued with simultaneous heating to the melting point of stearic acid to form spherical granules;

iv. Then the above mixture is compressed into tablets.

[0075] Example 5: Dasatinib tablet dosage form with polymeric material using melt granulation technique

[0076] Manufacturing procedure:

Dispensing:

i. Weighing the raw material to be used in the preparation;

Sifting:

ii. Sifting Dasatinib, microcrystalline cellulose (Avicel pH 112) and Eudragit RS PO (Polymer) through suitable sieve;

Granulation:

iv. Connecting the circulating hot water bath to the Jacketed Rapid mixer granulator, wherein the temperature of water is 95-100°C;

v. The dry mix material within the RMG attains a temperature of 90-100°C, which leads to start of the melting and formation of granules;

vii. Then to step vi) milled granules, lactose monohydrate / microcrystalline cellulose and croscarmellose sifted through suitable sieve is added and blended for suitable period of time;

viii. Then the lubricant magnesium stearate is sifted through suitable sieve and added to step vii) blend and lubricated for suitable period of time;

Coating:

[0077] Example 6: Dasatinib tablets prepared using melt granulation technique with

Eudragit EPO

[0078] Preparation procedure:

i. 10 gram of Dasatinib, 5 gram of Eudragit EPO polymer and 10 gram of Microcrystalline cellulose were homogeneously mixed in jacketed Rapid mixer granulator;

ii. The above mixing was continued with simultaneous heating to the glass transition temperature (57°C) or melting point (250°C) of polymer to form spherical granules, which lead to binding of polymer to the drug or API;

iv. Then the above mixture is compressed into tablets and coated.

[0079] Example 7: Dissolution Analysis of the Dosage Form

The applicant has further compared the dissolution profiles of the Dasatinib dosage form prepared as per the present invention and reported the data as shown in below tables:

Table 1: Comparative dissolution data of different test formulation in pH 4.5 Acetate buffer:

60 94 47 42

(Refer Figure- 1)

Table 2: Comparative Dissolution data of different test formulation in pH 1.2 buffer:

(Refer Figure-2)

Table 3: Comparative Dissolution data of test formulation in buffer having different pH:

(Refer Figure- 3) Note: Infinity (data collected at 200 RPM)

[0080] Example 8: Dasatinib tablets prepared using melt granulation technique with different concentration of stearic acid:

a. Stearic acid 70 mg batch:

[0081] Preparation procedure:

i. 100 gram of Dasatinib, 70 gram of stearic acid and 7.5 gram of Neusilin were homogeneously mixed in jacketed Rapid mixer granulator;

ii. The above mixing was continued with simultaneous heating to the melting point of stearic acid to form spherical granules;

iv. Then the above mixture is compressed into tablets. b. Stearic acid 60 mg batch:

[0082] Preparation procedure: Same as 70 mg batch above in (a). [0083] Manufacturing procedure:

Dispensing:

a. Weighing the raw material to be used in the preparation;

Sifting:

h. Sifting Dasatinib, Neusilin and Stearic acid through suitable sieve;

Granulation:

c. Loading the sifted material from step b) in to a Jacketed Rapid mixer granulator and mixing for suitable period of time at slow impeller speed;

d. Connecting the circulating hot water bath to the Jacketed Rapid mixer granulator, wherein the temperature of water is 60-70°C;

c. The dry mix material within the RMG attains a temperature of 60-70°C, which leads to start of the melting and formation of granules;

T The granules formed in step e) are then cooled, dried and milled through Oscillating granulator;

Then to step f) milled granules, Croscarmellose and Aerosil were sifted through suitable sieve and blended for suitable period of time;

In Then the lubricant magnesium stearate is sifted through suitable sieve and added to step g) blend and lubricated for suitable period of time;

L Thereafter the lubricated blend form step h) is compressed into tablets with suitable tooling to achieve desired tablet properties; and

Coating:

. Resulting core tablets from step i) were then coated with Opadry till desired weight gain is achieved.

[0084] Example 9: Dissolution Analysis of the stearic acid Dosage Forms:

The applicant has further compared the dissolution profiles of the Dasatinib dosage form prepared as per the procedure in Example-8 and reported the data as shown in below tables:

Table 4: Comparative dissolution data of different test formulation in pH 4.5 Acetate buffer:

_

(Refer Figure-4)

The above table and figure-4, clearly shows, that with stearic acid formulation prepared by direct compression shows more than 85% drug release in the medium, whereas the formulation prepared with melt granulation shows only 40% drug release (delayed release) which is due to binding of the hydrophobic carrier to the drug, inherent feature of the present process.

Table 5: Comparative Dissolution data of different test formulation in pH 4.0 buffer with Triton:

(Refer Figure- 5)

The above table and figure-5, shows that the formulation prepared by direct compression and hot melt granulation shows more than 85% drug release in the medium.

[0085] Example 10: XRD analysis

Also the Applicant further performed XRD analysis for the formulations prepared with stearic acid using hot melt extrusion process. Placebo samples and Crystalline API were also analysed and the XRD overlays are provided in Figure 6 (a), (b). The XRD analysis depicted that the formulation made with melt granulation doesn’t show any extra peaks other than the placebo peaks (Figure-6a). Further the overlay of Dasatinib crystalline API and formulations made with Hot melt granulation in Example 8, doesn’t show any peaks related to Crystalline form peaks (Figure-6b. So from the XRD analysis it can be concluded that the amorphous nature is retained in the formulation during the hot melt granulation process without changing into crystalline form. Thus the formulation prepared using present process was found to be stable and resistant to form changes which are a major drawback of prior art literature.

Claims

CLAIMS:

1. A pharmaceutical dosage form comprising of Dasatinib with at least one hydrophobic or lipophilic component and a pharmaceutically acceptable excipient.

2. The pharmaceutical dosage form as claimed in claim 1 , wherein the said hydrophobic or lipophilic component is a pharmaceutically acceptable polymer or excipient.

3. The pharmaceutical dosage form as claimed in claim 1, wherein the said dosage form comprises of intragranular and extragranular components and the polymer may be present either in intragranular part or extragranular part or in both intragranular and extragranular part.

4. The pharmaceutical dosage form as claimed in claim 1 , wherein the said hydrophobic or lipophilic component is selected from a group comprising of carnauba wax, hydrogenated castor oil, stearic acid, sterayl alcohol, glyceryl monostearate, glyceryl palmitostearate, polymers like Eudragit RS PO, Eudragit RL PO, Eudragit EPO, Ethyl cellulose or combinations thereof, and the said components are having melting point less than 200°C.

5. The pharmaceutical composition as claimed in claim 1, wherein the said composition with at least on lipophilic component, further comprises of diluent, disintegrant, glidant, carrier and a lubricant with an optional coating to provide a controlled release oral dosage form of Dasatinib.

6. The pharmaceutical dosage form as claimed in claim 1 , wherein the said dosage form is a delayed release, modified release or controlled release dosage form.

7. The pharmaceutical dosage form as claimed in claim 1 , wherein the said dosage form is prepared by dry granulation, wet granulation, hot melt granulation, direct blending & filling/compression, double compression, extrusion spheronization or layering.

8. A hot melt granulation process for preparation of a solid dosage form of Dasatinib with at least on lipophilic polymer, wherein the said process comprises of: i. Sifting Dasatinib, and at least one excipient and a hydrophobic material or a polymer through suitable sieve;

ii. Loading the sifted material from step i) in to a Jacketed Rapid mixer granulator and mixing at slow impeller speed;

iii. Connecting the circulating hot water bath to the Jacketed Rapid mixer granulator, wherein the temperature of water is 60-100°C;

iv. Dry mixing the material within the RMG and attaining a temperature of 75- 100°C, which leads to the start of melting and formation of granules; v. Then the granules formed in step iv) are dried and milled through Oscillating granulator;

vi. Then to step v) milled granules, suitable diluent, disintegrant and glidant is added after sifting through suitable sieve and blended;

vii. Then a suitable lubricant is sifted through suitable sieve and added to step vi) blend and lubricated;

viii. Thereafter the lubricated blend form step vii) is compressed into tablets; and ix. Resulting core tablets from step viii) were then coated with Opadry.

9. The process as claimed in claim 8, wherein the excipient used in the process are pharmaceutically acceptable excipient used in the manufacturing of solid dosage forms comprising diluent, binders, carriers, disintegrants, lubricants, glidants, solvent or their combinations.

10. The process as claimed in Claim 8, wherein said heating in the process characteristically melts the lipophilic component, which on cooling produce inherently coated or covered active ingredient granules for delayed release of active ingredient.

11. A hot melt extrusion process for delaying the drug release from a Dasatinib solid dosage form, wherein the said process comprises of heating the drug and at least one pharmaceutically acceptable excipient with a lipophilic or hydrophobic polymer, wherein the said heating produces an inherent coating or covering over the drug which inherently delays the drug release from the solid dosage form.

12. The process as claimed in claim 11 , wherein the said pharmaceutically acceptable excipient can be a diluent, binder, disintegrant or glidant.

13. The process as claimed in claim 11 , wherein the said lipophilic or hydrophobic polymer is a pharmaceutical acceptable excipient selected from a group comprising of carnauba wax, hydrogenated castor oil, stearic acid, sterayl alcohol, glyceryl monostearate, glyceryl palmitostearate, polymers like Eudragit RS PO, Eudragit RL PO, Eudragit EPO, Ethyl cellulose or combinations thereof, and the said excipient is having melting point less than 200°C.

14. A pharmaceutical composition of Dasatinib with a modified dissolution profile, wherein the said composition comprises of a holt melt extrusion granules prepared by heating Dasatinib, a lipophilic or hydrophobic polymer and a pharmaceutically acceptable excipient to suitable temperature for melting the lipophilic or hydrophobic polymer in which the remaining component form a uniform dispersion, wherein on cooling the polymer forms a coating or covering on the drug.

15. The composition as claimed in claim 14, wherein the said coting or covering inherently causes delayed release of the drug from the composition.