DESC:A PHARMACEUTICAL ANTI-CANCER COMBINATION AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical combination comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor optionally with antiprotozoal drug for the treatment of cancer. Further, the present invention also relates to a pharmaceutical composition comprising Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor and/or antiprotozoal drug along with one or more pharmaceutically acceptable excipients. Moreover, the present invention also relates to the process of preparing such composition thereof.

BACKGROUND OF THE INVENTION

Breast cancer and melanoma are two distinct yet significant forms of cancer that affect many individuals worldwide. Breast cancer is the most commonly diagnosed cancer among women, with both men and women risk. It primarily originates in the breast tissue and can be detected through regular screenings like mammograms. On the other hand, melanoma is a type of skin cancer that arises from melanocytes, the cells responsible for producing pigment in the skin. Unlike breast cancer, melanoma is often visible on the skin’s surface and can develop from moles or appear as new, irregular shaped growths. Melanoma cancers are highly aggressive and malignant tumors, contributing significantly to the global burden of disease (GBD) and posing a severe threat to global health. Both diseases underscore the importance of early detection and awareness, as prompt diagnosis and appropriate treatment can greatly improve the chances of successful outcomes for those affected by these cancers. Regular self-examinations, screenings, and sun protection measures are key components of prevention and early intervention. Current treatment options for these cancers is limited, and evidence indicates that monotherapies often suffer from poor or short-lived responses. Recently, scientists have developed combination therapies designed to target multiple pathways simultaneously, aiming to enhance efficacy and address the limitations of single -agent treatments

Dasatinib is used to treat certain type of chronic myeloid leukemia as a first treatment and in adults who can no longer benefit from other leukemia medications including imatinib or in those who cannot take these medications because of side effects.

Simvastatin, also known as the brand name product Zocor, is a lipid-lowering drug derived synthetically from a fermentation product of Aspergillus terreus. It belongs to the statin class of medications, which are used to lower the risk of cardiovascular disease and manage abnormal lipid levels by inhibiting the endogenous production of cholesterol in the liver.

Quinacrine, marketed under the brand name Quinacrine or Atabrine, is a medication with a multifaceted history and varied applications. Originally developed as an antimalarial drug, quinacrine played a significant role in combating malaria during World war II. However, its usage for malaria prevention has diminished over the year due to the emergence of more effective antimalarial drugs.

Wee1 is a kinase protein involved in checkpoint regulation that in response to DNA-damage or replication stress can halt the cell cycle progression in S- and G2 phases by adding inhibitory phosphorylation (Tyr15) on cyclin-dependent kinases CDK2 and CDK1, respectively. Wee1 has been reported to overexpress in different cancers and Wee1 kinase Inhibitors are currently in clinical trials for cancer treatment as single agents and in combination with radiation or chemo-therapy. Although mono-targeting of Wee1 has shown antitumor effect in some cancer cell lines, a stronger effect has been observed when Wee1 inhibitors were combined with Chk1/2 protein inhibitors.

Simvastatin, 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase inhibitor, is a cholesterol-lowering drug and used in the prevention of cardiovascular disease. It has been reported that simvastatin can induce apoptosis and inhibit proliferation alone or act synergistically. It has been reported that simvastatin caused a dose-dependent increase in S phase cell cycle and induced significant apoptosis, which was associated with inhibition of Chk1 expression, downregulation of Cdc25A, cyclin A and CDK2 expression.

Dasatinib, is a BCR-ABL tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Dasatinib was approved for medical use in the United States and in the European Union in 2006. In a recent study aimed to identify potential Wee1 kinase inhibitors from FDA-approved drugs using in silico approach, dasatinib demonstrated significant inhibition of Wee1. Since Wee1 kinase inhibitors and CHK1/2 inhibitors showed synergistic effects in reported studies, therefore Dasatinib (as Wee1 inhibitor) plus Simvastatin (as CHK1 inhibitor) are expected to show synergistic effects.

Quinacrine (QNC) is an antiprotozoal drug commonly used against Malaria and Giardiasis. QNC has been demonstrated the anticancer effect via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. As already discussed, Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC induced cell death via cell cycle arrest. Hence, proposed combination Dasatinib (as Wee1 inhibitor) plus Quinacrine (as CHK1/2 inhibitor) is expected to show synergistic effect.

Although various combinations are known from prior known references, there still remains a need for pharmaceutical combination using Tyrosine kinase inhibitor along with HMG-CoA reducing agent, or antiprotozoal drug to treat or prevent the cancer.

The combination of Tyrosine kinase inhibitor and HMA-CoA reducing agent or antiprotozoal drug has advantageous properties which make these combinations suitable for treating & preventing cancer including breast cancer, melanoma, colorectal cancer, non-small cell lung cancer.

OBJECTIVES OF THE INVENTION

An objective of the present invention to provide a pharmaceutical combination comprising therapeutically effective amount of Tyrosine kinase inhibitor and HMG-CoA reductase inhibitor.

Another objective of the present invention to provide a pharmaceutical composition comprising therapeutically effective amount of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor and one or more pharmaceutically acceptable excipients.

Another objective of the present invention to provide a pharmaceutical composition comprises of therapeutically effective amount of Dasatinib, simvastatin and one or more pharmaceutically acceptable excipients.

Another objective of the present invention to provide a pharmaceutical combination comprising therapeutically effective amount of Tyrosine kinase inhibitor and antiprotozoal drug.

Another objective of the present invention to provide a pharmaceutical composition comprising therapeutically effective amount of Tyrosine kinase inhibitor and antiprotozoal drug along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention to provide a pharmaceutical composition comprises of therapeutically effective amount of dasatinib and quinacrine along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a pharmaceutical combination comprises of Tyrosine kinase inhibitor and HMG CoA reductase inhibitor, wherein the combination is administered either simultaneously or separately or sequentially.

Another objective of the present invention is to provide a pharmaceutical combination comprises of Tyrosine kinase inhibitor and antiprotozoal drug, wherein the combination is administered either simultaneously or separately or sequentially.

Further objective of the present invention to provide a pharmaceutical combination for cancer, wherein the combination shows a synergistic effect and significantly reduces the time required to treat and prevent the disorders related to cancer as compared to treatment with Dasatinib, Simvastatin or Quinacrine alone.

Another objective of the present invention to provide a pharmaceutical composition comprising of tyrosine kinase inhibitor and HMG CoA reductase inhibitor or antiprotozoal drug used for the treatment of cancer such as breast cancer, melanoma, colorectal cancer, non-small cell lung cancer.

Additional objectives and embodiments of the invention will be set forth in part of the description, or may be learned by practice of the invention.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a pharmaceutical combination comprising Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor optionally along with antiprotozoal drug.

In an aspect the present invention relates to a pharmaceutical composition comprising;
(a) therapeutically effective amount of Tyrosine kinase inhibitor;
(b) therapeutically effective amount of HMG-CoA reductase inhibitor; and
(c) one or more pharmaceutically acceptable excipients.

In an aspect the present invention relates to a pharmaceutical composition comprising;
(a) therapeutically effective amount of Tyrosine kinase inhibitor;
(b) therapeutically effective amount of antiprotozoal drug; and
(c) one or more pharmaceutically acceptable excipients.

In an aspect the present invention relates to a pharmaceutical combination of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, wherein the tyrosine kinase inhibitor is selected from the group comprising of Dasatinib, Imatinib, Nilotinib, Ponatinib, Bosutinib, Bosutinib.

In an aspect the present invention relates to a pharmaceutical combination of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, wherein the Tyrosine kinase inhibitor is Dasatinib.

In an aspect the present invention relates to a pharmaceutical composition comprising Tyrosine kinase inhibitor and HMG-CoA reductase inhibitor along with one or more pharmaceutically acceptable excipients, wherein the HMG-CoA reductase inhibitor is selected from the group of Simvastatin, Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastin.

In an aspect the present invention relates to a pharmaceutical composition comprising Tyrosine kinase inhibitor and HMG-CoA reductase inhibitor along with one or more pharmaceutically acceptable excipients, wherein the HMG-CoA- reductase inhibitor is Simvastatin.

In an aspect the present invention relates to a pharmaceutical composition comprising Tyrosine kinase inhibitor and antiprotozoal drug along with one or more pharmaceutically acceptable excipients, wherein the antiprotozoal drug is selected from the group of quinacrine, metronidazole, nifurtimox, atovaquone, pentamidine, benznidazole, dehydroemetine, sodium stibogluconate.

In an aspect the present invention relates to a pharmaceutical composition comprising Tyrosine kinase inhibitor and antiprotozoal drug along with one or more pharmaceutically acceptable excipients, wherein the antiprotozoal drug is Quinacrine.

In an aspect the present invention relates to a pharmaceutical composition comprising Dasatinib, simvastatin or quinacrine along with one or more pharmaceutically acceptable excipients.

In one aspect, the present invention provides the use of combination of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor or antiprotozoal drug in the preparation of medicines for the prevention and/or treatment of cancer related disorders.

In one more aspect, the present invention provides a use of a pharmaceutical composition for the prevention and/or treatment of cancer, wherein the said composition comprising:
a) therapeutically effective amount of Tyrosine kinase inhibitor;
b) therapeutically effective amount of HMG-CoA reductase inhibitor;
c) one or more pharmaceutically acceptable excipients.

In an aspect of the present invention, the said Dasatinib is in the range of 20-180 mg, the said HMG-CoA reductase inhibitor preferably be Simvastatin is in the range of 5-40 mg and the said antiprotozoal drug is Quinacrine is in the range of 100-400 mg.

In one more aspect, the present invention provides a pharmaceutical combination for prevention and/or treatment of cancer by administering:
a) therapeutically effective amount of Tyrosine kinase inhibitor;
b) therapeutically effective amount of HMG-CoA reductase inhibitor or antiprotozoal drug or metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters, solvate thereof,
wherein the said Tyrosine kinase inhibitor is administered in range of about 20-180 mg and the said HMG-CoA reductase inhibitor is administered in the range of 5-40 mg, or the antiprotozoal drug in the range of 100-400 mg.

According to another aspect, the present invention provides a method of treating or prevention of cancer by administering therapeutically effective amount of Tyrosine kinase inhibitor and therapeutically effective amount of HMG-CoA reductase inhibitor or antiprotozoal drug either simultaneously, or concurrently or alternately or sequentially.

According to one more aspect, the present invention relates to a pharmaceutical composition comprising dasatinib and simvastatin for the treatment of cancer, wherein the pharmaceutical composition comprising about 20mg to 180mg of dasatinib, and about 5mg to about 40mg of simvastatin.

According to another aspect, the present invention provides a pharmaceutical composition comprising of dasatinib, and quinacrine for the treatment of cancer, wherein said pharmaceutical composition comprising about 20mg to about 180mg of dasatinib, and about 100mg to about 400mg of quinacrine.

According to another aspect, the present invention provides a pharmaceutical composition/combination, wherein the composition/combination is used for the treatment of cancer such as breast cancer, melanoma, colorectal cancer, non-small cell lung cancer.

According to another aspect, the present invention provides a pharmaceutical composition along with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group comprising of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.

BRIEF DESCRIPTION OF DRAWINGS/FIGURES

Figure 1 illustrates the Effect of Dasatinib and its combination to Simvastatin on mean tumor volume (mm3) in A375 cell line-based Melanoma xenograft mice model.

Figure 2 illustrates the Effect of Dasatinib and its combination with Quinacrine on mean tumor volume (mm3) in A375 cell line-based Melanoma xenograft mice model.

DETAIL DESCRIPTION OF THE INVENTION

The present invention as embodied by “A Pharmaceutical anti-cancer combination and process for preparation thereof” succinctly fulfils the above-mentioned need[s] in the art. The present invention has objective[s] arising as a result of the above-mentioned need[s], said objective[s] having been enumerated hereinabove.

The following description is directed to a Pharmaceutical anti-cancer combination and the process for preparation thereof as much as the objective(s) of the present invention is enumerated, it will be obvious to a person skilled in the art that, the enumerated objective(s) is not exhaustive of the present invention in its entirety, and is enclosed solely for the purpose of illustration. Further, the present invention encloses within its scope and purview, any structural alternative(s) and/or any functional equivalent(s) even though, such structural alternative(s) and/or any functional equivalent(s) are not mentioned explicitly herein or elsewhere, in the present disclosure. The present invention therefore encompasses also, any improvisation[s]/modification[s] applied to the structural alternative[s]/functional alternative[s] within its scope and purview. The present invention may be embodied in other specific form[s] without departing from the essential attributes thereof.

Furthermore, the terms and phrases used herein is not intended to be limiting, but rather is to provide an understandable description. Throughout this specification, the use of the word "comprise" and variations such as "comprises" and "comprising" may imply the inclusion of an element or elements not specifically recited.

The term Tyrosine kinase inhibitor are used as anticancer agents, include Dasatinib, Imatinib, Nilotinib, Ponatinib, Bosutinib, Bosutinib1, Bafetinib or its ester, metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters solvate thereof.

The term “Dasatinib” includes its ester, metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters solvate thereof.

The “HMG-CoA reductase inhibitor” are the lipid lowering medications used in the primary & secondary prevention of coronary heart diseases, includes Simvastatin, Atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastin or its ester, metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters solvate thereof.

The “antiprotozoal drug are those that is used to treat protozoal infections includes Quinacrine, metronidazole, nifurtimox, atovaquone, pentamidine, benznidazole, dehydroemetine, sodium stibogluconate or its ester, metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters solvate thereof.

The ‘extended release’ as used herein refers to release of drug over an extended period of time i.e. from about 2 hours to about 24 hours. The extended release includes but is not limited to sustained release, controlled release, delayed release, or modified release form or combination thereof. The term “therapeutically effective amount” or “effective amount” used interchangeably, is defined to mean the amount or quantity of the active drug, which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The “composition” or “dosage form” or “pharmaceutical composition” as used herein synonymously include oral, parenteral, topical, transdermal, mucosal, nasal, buccal, or sublingual administration to a patient. Further, the oral dosage form of administration includes tablets such as mono-layered tablets, bilayer tablets, trilayered tablet, multilayer tablet, caplets, minitablets, micro tablets, capsules, tablet in tablet, tablets in a capsule, micro tablets in a capsule, minitablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, extrudes, pellets, beads or spheroids, suspension or any other suitable dosage form.

The “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids and inorganic salts may further include alkali metal and alkaline earth metal salts.

The “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent, disintegrant, carrier, and the like, of a pharmaceutical product. The excipients that are useful in preparing a dosages form are generally safe, non-toxic, and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient. The pharmaceutically acceptable excipients may include one or more pharmaceutically acceptable excipients are selected from the group comprising of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

Suitable fillers/ diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and/or combinations thereof.

Suitable binders include, without limitation, microcrystalline cellulose, polyvinylpyrrolidone (PVP), such as e.g., PVP K 30 or PVP90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, pregelatinized starch, copovidone, gelatin, sugars and/or combinations thereof.

Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, aluminium or calcium silicate, stearic acid, PEG, talc and/or combinations thereof.

Suitable disintegrants include, without limitation, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (pirimojel and explotab), sodium starch glycolate, low-substituted hydroxypropyl cellulose, polacrillin and/or combinations thereof.

Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and/or combinations thereof.

The surfactants include but are not limited to anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Suitable surface active are poloxamer, polysorbate, cremophore, soluplus, lecithin and sodium lauryl sulfate and/or combinations thereof.

The pharmaceutical combination of the present invention may be further film coated. Film coating may be an immediate release or an extended release coating. The extended release coating comprises at least one or more extended release polymer and one or more pharmaceutically acceptable excipients.

Suitable film forming agents include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers. Examples of cellulosic polymers include, but are not limited to, polyvinyl alcohol, hydroxypropyl methyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") or salts thereof, hydroxypropyl cellulose ("HPC"), methylcellulose ("MC"), hydroxyethyl cellulose ("HEC"), ethylcellulose, acrylates, Eudragits, and the like. Further, commercially available coating materials are available marketed under the brand name Opadry®. The polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate can be used as a film forming agent.

Coloring agents include any FDA approved color for pharmaceutical use.

Suitable plasticizers are selected from the group comprising of triethylcitrate, dibutyl sebacate, acetylated triacetin, tributylcitrate, glycerlotributyrate, monoglyceride, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate and/or combinations thereof.

Suitable opacifiers is selected from the group comprising of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide and/or combinations thereof.

According to an embodiment of the present invention, the above-mentioned pharmaceutical combination may be any dosage form suitable for oral administration. When administered orally, the pharmaceutical dosage form of the present invention using the pharmaceutical combination/composition as the active ingredient includes, but is not limited to, tablets, sublingual tablets, effervescent tablets, coated tablets, sugar-coated tablets, dispersible tablets, enteric-coated tablets, granules, gelatin capsules, soft gelatin capsules, enteric-coated capsules, sustained-release capsules, controlled-release capsules, oral liquids, preferably tablets or capsules.

Accordingly, in an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of Tyrosine kinase inhibitor and HMG-CoA reductase inhibitor.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dasatinib and simvastatin.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of tyrosine kinase inhibitor and antiprotozoal drug.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dasatinib and quinacrine.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dasatinib, simvastatin and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dasatinib, quinacrine and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising antiprotozoal drug, wherein the antiprotozoal drug having the particle size in the range of D90 less than 200 microns (µ), preferably in the range of D90 less than 100 microns (µ).

In an embodiment, the present invention provides a pharmaceutical composition comprising HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor having the particle size in the range of D90 less than 200 microns (µ), preferably in the range of D90 less than 100 microns(µ).

In an embodiment, the present invention provides a pharmaceutical composition comprising Dasatinib, wherein the dasatinib having the particle size in the range of D90 less than 200 microns (µ), preferably in the range of D90 less than 100 microns(µ).

In an embodiment, the present invention provides a pharmaceutical composition comprising Tyrosine kinase inhibitor, wherein the said Tyrosine kinase inhibitor is selected from the group of Dasatinib, Imatinib, Nilotinib, Ponatinib, Bosutinib, Bafetinib, present in the range of 20-800 mg.

In an embodiment, the present invention provides a pharmaceutical composition comprising HMG-CoA reductase inhibitor, wherein the said HMG-CoA reductase inhibitor is selected from the group of Simvastatin, atorvastatin, Fluvastatin, Pitavastatin, Pravastatin, Rosuvastin, present in the range of 2-80 mg.

In an embodiment, the present invention provides a pharmaceutical composition comprising antiprotozoal drug, wherein the said antiprotozoal drug is selected from the group of Quinacrine, metronidazole, nifurtimox, atovaquone, pentamidine, benznidazole, dehydroemetine, sodium stibogluconate present in the range of 30-400 mg.

Accordingly, in an embodiment of the present invention it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Tyrosine kinase inhibitor or its salt, ester (s), polymorph or metabolites thereof;
(b) therapeutically effective amount of HMG-CoA reductase inhibitors or its salt, ester (s), polymorph or metabolites thereof;
(c) one or more pharmaceutically acceptable excipients selected from binders, disintegrates, lubricants, plasticizers, opacifiers and/or diluents.

In another embodiment of the present invention it provides a pharmaceutical composition comprising
(a) therapeutically effective amount of Tyrosine kinase inhibitor or its salt, ester (s), polymorph or metabolites thereof;
(b) therapeutically effective amount of HMG-CoA reductase inhibitors or its salt, ester (s), polymorph or metabolites thereof;
(c) less than 20% w/w of binders;
(d) about 10% w/w to about 80% w/w diluents;
(e) about 0.001% w/w to about 10% w/w of lubricants;
(f) less than 20% w/w of disintegrants;
(g) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug along with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug along with one binder and disintegrant, wherein the ratio of binder to disintegrant is about 1: 10 to about 10:1.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug along with one diluent and disintegrant, wherein the ratio of diluent to disintegrant is about 1: 90 to about 90:1.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug along with one diluent and binder, wherein the ratio of diluent to binder is about 1: 90 to about 90:1.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug, wherein the said composition is free of stearate.

In another embodiment of the present invention it provides a pharmaceutical composition comprises of Tyrosine kinase inhibitor, HMG-CoA reductase inhibitor, or the antiprotozoal drug, wherein the said composition comprises stearate and fumarate derivative of stearic acid.

Solid form preparations for oral administration may include capsules, tablets, pills, powders, granules and suppositories. For solid-form preparations, the active compound is mixed with at least one inert, pharmaceutical excipient or carrier binders; disintegrating agents; wetting agents; lubricants and mixtures thereof.

In case of capsules, tablets, or pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared with coatings and shells, such as enteric coating and other coatings well known in the pharmaceutical formulating art.

Liquid-form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid-form preparations, the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers.

Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.

Another embodiment of the present invention it provides a pharmaceutical composition, wherein the composition is in the form of a bilayer tablet.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of Tablets in Tablets.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of capsule filled with granules.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of capsule filled with pellets.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of tablet coatings.

The combinations and the composition as per the present invention can be given in single dose or as divided dose administered at appropriate intervals i.e. two, three, four or more sub-doses per patient per day, with or without food.

In another embodiment of the present invention provides a pharmaceutical composition comprising tyrosine kinase inhibitor, HMG CoA reductase inhibitor, or antiprotozoal drug along with one or more pharmaceutical acceptable excipients, wherein the said composition is prepared by dry granulation, wet granulation, direct compression or compaction method.

In another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib, simvastatin or Quinacrine, wherein the dasatinib, simvastatin or Quinacrine is present in the composition either in crystalline form or amorphous polymorphic form.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib, and simvastatin, wherein the pharmaceutical composition is in the form of a bilayer tablet, wherein Dasatinib is present in one layer and simvastatin in another layer to facilitate optimized drug release and therapeutic effect.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib and quinacrine, wherein the pharmaceutical composition is in the form of a bilayer tablet, wherein Dasatinib is present in one layer and quinacrine is present in another layer to facilitate optimized drug release and therapeutic effect.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib and simvastatin, wherein the pharmaceutical composition is in the form of tablets in tablets, wherein Dasatinib is present in the tablet core and simvastatin is in the tablet shell or vice-versa.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib and quinacrine, wherein the pharmaceutical composition is in the form of tablets in tablets, wherein Dasatinib is present in the tablet core and quinacrine is in the tablet shell or vice-versa.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib and simvastatin, wherein the pharmaceutical composition is encapsulated in to soft gel capsules filled with active ingredients for improved bioavailability and ease of administration.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib and quinacrine, wherein the pharmaceutical composition is encapsulated in to soft gel capsules filled with active ingredients for improved bioavailability and ease of administration.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib, simvastatin or quinacrine, wherein the pharmaceutical composition is in the form of capsules with pellets or granules or powder.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib, simvastatin or quinacrine, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising Dasatinib in the form of soft gelatin capsule and simvastatin or quinacrine is in the form of pellets, mini-tablet, granules or powders.

Another embodiment of the present invention provides a pharmaceutical composition comprising Dasatinib, simvastatin or quinacrine, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising simvastatin or quinacrine in the form of soft gelatin capsule and Dasatinib is in the form of pellets, mini-tablet, granules or powders.

Another embodiment of the present invention provides a kit comprising:
(a) composition comprising therapeutically effective amount of Dasatinib and one or more pharmaceutically acceptable excipients;
(b) composition comprising therapeutically effective amount of simvastatin and one or more pharmaceutically acceptable excipients;
wherein the composition of Dasatinib and composition of simvastatin are administered either simultaneously, concurrently, alternately and/or sequentially.

Another embodiment of the present invention provides a kit comprising:
(a) composition comprising therapeutically effective amount of Dasatinib and one or more pharmaceutically acceptable excipients;
(b) composition comprising therapeutically effective amount of quinacrine and one or more pharmaceutically acceptable excipients;
wherein the composition of Dasatinib, composition of quinacrine are administered either simultaneously, concurrently, alternately and/or sequentially.

Another embodiment of the present invention provides pharmaceutical kit comprising two parts divided with a perforation or punch or other suitable means to place three medicaments separately, wherein medicaments are selected from Dasatinib, HMG-CoA reductase inhibitor or antiprotozoal drug respectively.

Another embodiment of the present invention provides pharmaceutical kit, wherein the pharmaceutical kit is made up of primary packaging material selected from aluminum blister, clear PVC blister or PVdC blister, opaque PVC/PVdC blister or amber PVC/PVdC blister and cavities of the blister are sealed with aluminum foil and this aluminum foil is printed with necessary information related to doses of medication.

Another embodiment of the present invention provides pharmaceutical kit comprising three parts wherein three parts are divided with perforation or punch or suitable means; wherein one part containing single cavity for one class or medicament and second or third part containing one or more than one cavity for other class of medicament.

Various modifications of these embodiments will readily apparent to those skilled in the art in view of present disclosure, and generic method defined herein may be applied to other embodiments.

EXAMPLES
The examples used herein for such illustration are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the following examples should not be construed as limiting the scope of the embodiments herein.

Examples 1:
Ingredients Quantity (%w/w of total formulation)
Dasatinib 1-75%
Simvastatin 1-75%
Diluent 10-80%
Binder 0-20%
Disintegrant 0-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20% weight gain

Example 2:
Ingredients Amount (mg/tablet)
Dasatinib 100.00
Simvastatin 10
Lactose Monohydrate 75.50
Hypromellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10% of tablet weight

Process:
1. lifting all the ingredients through appropriate sieves (100% should pass through sieve);
2. pre-sifted Dasatinib, Simvastatin, hypromellose, lactose monohydrate, Maize starch and dry mixing silicon dioxide in a suitable blender;
3. lubricating the dry mixed ingredients as obtained in step 2 in the blender using magnesium stearate;
4. passing the blend as obtained in step 3 through roller compactor to obtain compacted mass/ribbons;
5. passing the compacted mass/ribbons through appropriate mesh screen and then passing the blend through the required sieve to obtain granules;
6. blending the granules as obtained in step 5 in a suitable blender and lubricated using sodium stearyl fumarate;
7. compressing the blend of step 6 into tablets;
8. film coating the tablets of step 7.

Example 3:
Ingredients Quantity (%w/w of total formulation)
Dasatinib 1-75%
Quinacrine 1-90%
Diluent 10-80%
Binder 0-20%
Disintegrant 0-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20% weight gain

Example 4:
Ingredients Amount (mg/tablet)
Dasatinib 100
Quinacrine 100
Lactose Monohydrate 75.50
Hypromellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10% of tablet weight

Process:
1. Sifting all the ingredients through appropriate sieves (100% should pass through sieve);
2. pre-sifted Dasatinib, Quinacrine, hypromellose, lactose monohydrate, Maize starch and dry mixing silicon dioxide in a suitable blender;
3. Lubricating the dry mixed ingredients as obtained in step 2 in the blender using magnesium stearate;
4. Passing The blend through roller compactor to obtain compacted mass/ribbons;
5. Passing the compacted mass/ribbons through appropriate mesh screen and passing the blend through the required sieve to obtain granules;
6. Blending the granules as obtained in step 5 in a suitable blender, followed by lubrication using sodium stearyl fumarate;
7. Compressing the blend as obtained in step 6 into tablets;
8. Film coating the tablets as obtained in step 7.

Example 5
In the present invention, a novel combination of simvastatin and Dasatinib is been tested in A375 cell line-based melanoma Xenograft model. Simvastatin, 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase inhibitor, is a cholesterol-lowering drug and used in the prevention of cardiovascular disease. It has been reported that simvastatin can induce apoptosis and inhibit proliferation alone or synergistically. It has been reported that simvastatin caused a dose-dependent increase in S-phase cell cycle and induced significant apoptosis, which was associated with inhibition of Chk 1 expression, downregulation of Cdc25S, cyclin A and CDK2 expression, whereas, Dasatinib, a multi-target tyrosine kinase inhibitor identified as a potential Wee 1 kinase inhibitor in a recent in-silico study. Wee1 is a kinase involved in checkpoint regulation, that can halt cell cycle progression in response to DNA damage or replication stress, and is often over expressed in various cancers.

In the present invention, inventors tested Simvastatin and Dasatinib combinations in an A375 melanoma xenograft model, and significant reduction in tumor growth is observed in comparison to vehicle control.

Example 6: In-vivo Evaluation of Anti-Cancer Potential of Simvastatin and Dasatinib in A375 cell line-based Melanoma xenograft mice model.
Protocol: In this study Nude mice (NCr-Foxn1nu) are used as the test system and A375 melanoma cell line is used to develop xenograft model. Cells in serum free media is mixed with Matrigel in a ratio of 1:1 so as to achieve a cell population of 7x106 in 200 µl of volume and injected subcutaneously on right flank of mice. All the animals are monitored for tumor growth and randomized into different groups (n=8) once the tumor volume reached around 100 mm3. All animals are treated from Day-1 to Day-21 as per dosing regimen mentioned below with dose volume of 10ml/kg. All test items are formulated as suspension in 0.5% tween-80 and 99.5% methylcellulose as per recommended dose on daily basis.
Groups and dosing regimen:
• Group 1: n=8, Vehicle control (10 ml/kg), QD, PO
• Group 2: n=8, Dasatinib (5 mg/kg), QD, PO
• Group 3: n=8, Dasatinib (10 mg/kg), QD, PO
• Group 4: n=8, Dasatinib (5 mg/kg) + Simvastatin (5 mg/kg), QD, PO
• Group 5: n=8, Dasatinib (10 mg/kg) + Simvastatin (5 mg/kg), QD, PO
The body weight is recorded daily as compounds and vehicle is administered orally in respective groups with dose volume of 10ml/kg for 21 days. Tumor volume for all animals is recorded twice a week. After completion of the study, blood is collected in EDTA vials from four animals of each group under mild isoflurane anaesthesia through retro-orbital technique to separate plasma. All animals are humanly sacrificed by CO2 asphyxiation.

Results: Tumor volume is significantly increased in vehicle or disease control group. Significant decrease in tumor volume is observed in all treatment groups as compared to vehicle/disease control following 21-days of treatments. Dasatinib alone and in combination to Simvastatin showed similar efficacy in A375 cell line-based melanoma xenograft mice model as represented in Fig. 1.

Example 7
Combination of Quinacrine and Dasatinib has been tested. Quinacrine is an antiprotozoal drug commonly used against Malaria and Giardiasis. Quinacrine has been demonstrated the anticancer effect via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by Quinacrine induced cell death via cell cycle arrest. Whereas, Dasatinib, a multi-target tyrosine kinase inhibitor, is identified as a potential Wee 1 kinase inhibitor in a recent in-silico study. Wee 1 is a kinase involved in checkpoint regulation, that can halt cell cycle progression in response to DNA damage or replication stress, and is often overexpressed in various cancers.

In the present invention, the inventors have tested Quinacrine and Dasatinib combinations in an A375 melanoma xenograft model, and significant reduction in tumor growth is observed in comparison to vehicle control.

Example 8: In-vivo Evaluation of Anti-Cancer Potential of Quinacrine and Dasatinib in A375 cell line-based Melanoma xenograft mice model.

Protocol: Nude mice (NCr-Foxn1nu) are used as the test system and A375 melanoma cell line is used to develop xenograft model. Cells in serum free media is mixed with matrigel in a ratio of 1:1 so as to achieve a cell population of 7x106 in 200 µl of volume and injected subcutaneously on right flank of mice. All the animals are monitored for tumor growth and randomized into different groups (n=8) once the tumor volume reached around 100 mm3. All animals are treated from Day-1 to Day-21 as per dosing regimen mentioned below with dose volume of 10ml/kg. All test items are formulated as suspension in 0.5% tween-80 and 99.5% methylcellulose as per recommended dose on daily basis.
Groups and dosing regimen:
• Group 1: n=8, Vehicle control (10 ml/kg), QD, PO
• Group 2: n=8, Dasatinib (5 mg/kg), QD, PO
• Group 3: n=8, Dasatinib (10 mg/kg), QD, PO
• Group 4: n=8, Quinacrine (30 mg/kg), QD, PO
• Group 5: n=8, Dasatinib (5 mg/kg) + Quinacrine (30 mg/kg), QD, PO
• Group 6: n=8, Dasatinib (10 mg/kg) + Quinacrine (30 mg/kg), QD, PO
The body weight is recorded daily as compounds and vehicle are administered orally in respective groups with dose volume of 10ml/kg for 21 days. Tumor volume for all animals is recorded twice a week. After completion of study, on day 21, before sacrifice, blood is collected in EDTA vials from four animals of each group under influence of mild isoflurane anesthesia through retro-orbital technique to separate plasma.

Results: Tumor volume is significantly increased in vehicle or disease control group. Significant decrease in tumor volume is observed in dasatinib (5mg/kg), dasatinib (10mg/kg) and dasatinib (10mg/kg) + quinacrine (30mg/kg) groups as compared to vehicle/disease control following 21-days treatments. However, marked reduction in tumor volume is not observed with quinacrine alone (30mg/kg), and dasatinib (5mg/kg) + quinacrine (30mg/kg) combination. Dasatinib (10 mg/kg), and dasatinib (10mg/kg) + quinacrine (30mg/kg) combination showed similar efficacy in A375 cell line-based Melanoma xenograft mice model as represented in Fig. 2.

It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements without deviating from the spirit and the scope of the invention may be made by a person skilled in the art.
,CLAIMS:We Claim:

1. A pharmaceutical composition comprising therapeutically effective amount of Tyrosine kinase inhibitor and HMG-CoA reductase inhibitor or antiprotozoal drugs optionally along with one or more pharmaceutically acceptable excipients.

2. A pharmaceutical combination for cancer comprising of therapeutically effective amount of dasatinib, simvastatin or Quinacrine.

3. The pharmaceutical composition as claimed in claim 1, wherein the tyrosine kinase inhibitor is selected from the group comprising dasatinib, imatinib, nilotinib, ponatinib, bosutinib or bafetinib.

4. The pharmaceutical composition as claimed in claim 1, wherein the tyrosine kinase inhibitor is present in the range of about 20mg to about 800mg.

5. The pharmaceutical composition as claimed in claim 1, wherein the HMG-CoA reductase inhibitor is selected from the group comprising simvastatin, atorvastatin, fluvastatin, pitavastatin, pravastatin or rosuvastatin.

6. The pharmaceutical composition as claimed in claim 1, wherein the HMG-CoA reductase inhibitor is present in the range of about 2mg to about 80 mg.

7. The pharmaceutical composition as claimed in claim 1, wherein the antiprotozoal drug is selected from the group of quinacrine, metronidazole, nifurtimox, atovaquone, pentamidine, benznidazole, dehydroemetine or sodium stibogluconate.

8. The pharmaceutical composition as claimed in claim 1, wherein the antiprotozoal drug is present in the range of 30mg to 400mg.

9. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition further comprising:
(a) less than 20% w/w of binders;
(b) about 10% w/w to about 80% w/w diluents;
(c) about 0.001% w/w to about 10% w/w of lubricants;
(d) less than 20% w/w of disintegrants;
(e) optionally with one or more pharmaceutically acceptable excipients.

10. A kit comprising:
(a) composition comprising therapeutically effective amount of Dasatinib and one or more pharmaceutically acceptable excipients;
(b) composition comprising therapeutically effective amount of quinacrine or simvastatin and one or more pharmaceutically acceptable excipients;
wherein the composition of Dasatinib, composition of quinacrine or simvastatin are administered either simultaneously, concurrently, alternately and/or sequentially.

Dated this the 25th day of September 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer