[0001] The present disclosure generally relates to the field of pharmaceuticals. Specifically, it relates to pharmaceutical formulations and compositions comprising a P2Y12 inhibitor and aspirin and processes of preparing the same.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] The human heart is connected by a number of vessels responsible for the to and fro motion of blood from the heart. Arteries are blood vessels responsible for the transport of blood rich in oxygen from the heart to the cells, while the veins are responsible for the transport of deoxygenated blood from the cells to the heart for purification. Any disturbance in these vessels can trigger a dysfunction in the normal working of the cardiovascular system and may lead to diseases.
[0004] Blood constitutes solids particles like red blood cells, white blood cells and platelets. When a person gets injured, platelets are rushed to the site of damage to form a clot to stop bleeding. In case of an injury or wound this is a boon, as it prevents a further loss of blood. However, sometimes these platelets may trigger coagulation or clustering within the blood vessels. This is a dangerous situation as it blocks the normal flow of blood in the cardiovascular system triggering conditions like ischemia, angina, stroke, myocardial infarction etc. Anti-platelets are administered to patients suffering from such conditions which de-coagulate the platelets and lead to normal flow of blood through the vessels. Cardiovascular diseases like stroke, myocardial infarctions affect millions across the globe each year, making it a major health concern and thus, pharmaceuticals in this field are of extreme importance.
[0005] Aspirin or acetylsalicylic acid is an anti-pyretic, anti-inflammatory and mildly analgesic drug. It is a Non-Steroidal Anti-Inflammatory drug (NSAID). Aspirin is also commonly used as an anti-platelet. It has the following structure:

Formula I
[0006] P2Y12 is a chemoreceptor for Adenosine Diphosphate (ADP) that plays a major role in platelet activation. P2Y12 on binding with ADP decreases the cAMP levels, leading to activation of glycoprotein IIb/IIIa receptor that consequently, results in platelet aggregation.
[0007] In the presence of a P2Y12 inhibitor, the P2Y12 receptors are reversibly or irreversibly bound by the pharmaceutical active, thereby preventing the ADP from binding the receptor. This results in a decrease in the tendency of the platelets to stick to one another thereby decreasing blood clots.
[0008] Ticagrelor is a P2Y12 inhibitor used in patients with acute coronary syndrome or to prevent clots post heart surgery making it easier for blood to flow through the veins. It has the following structure:

Formula II
[0009] There is a continuing need for development of formulations and compositions that provide an improved efficacy in the treatment of cardiovascular conditions and diseases.
[0010] To reduce the incidence of thrombotic cardiovascular events such as myocardial infarction or stroke induced by acute thrombosis, there is a need for administration of ticagrelor in combination with aspirin as a single capsule.
OBJECTS OF THE INVENTION
[0011] An object of the present invention is to provide a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0012] An object of the present invention is to provide a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and ticagrelor or pharmaceutically active salts thereof.
[0013] An object of the present invention is to provide a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and ticagrelor or pharmaceutically active salts thereof, wherein the composition is formulated as capsule.
[0014] An object of the present invention is to provide a pharmaceutical composition comprising Ticagrelor or pharmaceutically active salts thereof; Acrypol 912G; microcrystalline cellulose; P.V.P. K-30 (polyvinyl pyrrolidone K-30); Isopropyl alcohol; Magnesium Stearate; Colloidal Silicon Dioxide; optional additives selected from but not limited to Methocel K4M. Methocel K100M; Metolose 90SH 100000; and Lactose.
[0015] An object of the present invention is to provide a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof; Starch 1500; microcrystalline cellulose 112; Isopropyl alcohol; glyceryl mono stearate; and Colloidal Silicon Dioxide.
[0016] An object of the present invention is to provide a method of preparing a pharmaceutical formulation comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0017] An object of the present invention is to provide a method of preparing pharmaceutical composition comprising Ticagrelor or pharmaceutically active salts thereof; aspirin or pharmaceutically active salts thereof.
[0018] Yet another object of the invention was to a method of treatment, amelioration or prevention of a cardiovascular condition by administering the pharmaceutically effective amount of the formulation or the composition comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
SUMMARY OF THE INVENTION
[0019] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0020] In an aspect, the present disclosure relates to pharmaceutical formulations comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0021] In an aspect, the present disclosure relates to pharmaceutical formulations comprising aspirin or pharmaceutically active salts thereof and one or more P2Y12 inhibitor selected from the group comprising of ticagrelor, clopidogrel, prasugrel, cangrelor, ticlopidine, elinogrel, their pharmaceutically active salts or combinations thereof.
[0022] In an aspect, the present disclosure provides pharmaceutical compositions comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0023] In an aspect, the present disclosure relates to pharmaceutical compositions comprising aspirin or pharmaceutically active salts thereof and one or more P2Y12 inhibitor selected from the group comprising of ticagrelor, clopidogrel, prasugrel, cangrelor, ticlopidine, elinogrel, their pharmaceutically active salts and combinations thereof.
[0024] In an aspect, the present disclosure relates to a method of preparing a pharmaceutical formulation comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0025] In an aspect, the present disclosure relates to a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and ticagrelor.
[0026] In an aspect, the present disclosure relates to a method of preparing a pharmaceutical formulation comprising aspirin or pharmaceutically active salts thereof and ticagrelor.
[0027] In an aspect, the present disclosure relates to a method of preparing a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0028] In an aspect, the present disclosure relates to a method of preparing a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and ticagrelor.
[0029] In an aspect, the present disclosure relates to a method of treatment, amelioration or prevention of a cardiovascular condition by administering the pharmaceutically effective amount of the formulation or the composition comprising aspirin or pharmaceutically active salts thereof and a P2Y12 inhibitor.
[0030] In an aspect, the present disclosure relates to a granule comprising Ticagrelor or pharmaceutically active salts thereof; Acrypol 912G; microcrystalline cellulose; P.V.P. K-30; Isopropyl alcohol; Magnesium Stearate; Colloidal Silicon Dioxide; optional additives selected from but not limited to Methocel K4M. Methocel K100M; Metolose 90SH 100000; and Lactose.
[0031] In yet another aspect, the present disclosure relates to a sustained release coating of the granules comprising Ticagrelor or pharmaceutically active salts thereof using supercoat white F; yellow oxide of iron; isopropyl alcohol; and methylene dichloride.
[0032] In an aspect, the present disclosure relates to a granule comprising aspirin or pharmaceutically active salts thereof; Starch 1500; microcrystalline cellulose 112; Isopropyl alcohol; glyceryl monostearate; and Colloidal Silicon Dioxide.
[0033] In yet another aspect, the present disclosure relates to an enteric coating of the granules comprising aspirin or pharmaceutically active salts thereof using Seal Opadry Clear 03K19229; yellow oxide of iron; isopropyl alcohol; and methylene dichloride.
[0034] In yet another aspect, the present disclosure relates to an enteric coating of the granules comprising aspirin or pharmaceutically active salts thereof using Opadry Enteric White 940580000; talcum; titanium dioxide; isopropyl alcohol; and purified water.
[0035] In an aspect, the present disclosure relates to a pharmaceutical composition comprising aspirin or pharmaceutically active salts thereof and ticagrelor or pharmaceutically active salts thereof, wherein the composition is formulated as capsule
[0036] In an aspect, the present disclosure relates to a hard or soft gelatin capsule formulation comprising the granules of Ticagrelor or pharmaceutically active salts thereof; and the granules of aspirin or pharmaceutically active salts thereof.
[0037] In an aspect, the present disclosure relates to a method of preparing pharmaceutical compositions comprising Ticagrelor or pharmaceutically active salts thereof; Acrypol 912G; microcrystalline cellulose; P.V.P. K-30; Isopropyl alcohol; Magnesium Stearate; Colloidal Silicon Dioxide; optional additives selected from but not limited to Methocel K4M. Methocel K100M; Metolose 90SH 100000; and Lactose.
[0038] In an aspect, the present disclosure relates to a method of preparing pharmaceutical compositions comprising aspirin or pharmaceutically active salts thereof; Starch 1500; microcrystalline cellulose 112; Isopropyl alcohol; glyceryl monostearate; and Colloidal Silicon Dioxide.
[0039] In an aspect, the present disclosure relates to a method of treatment, amelioration or prevention of a cardiovascular condition by administering the pharmaceutically effective amount of the formulation or the composition comprising Ticagrelor or pharmaceutically active salts thereof; aspirin or pharmaceutically active salts thereof.
[0040] In a preferred embodiment, the formulation provided in the present invention comprises a sustained release component, wherein the sustained release component comprises ticagrelor or a pharmaceutically acceptable salt thereof; aspirin or pharmaceutically active salts thereof; and a sustained release matrix material.
[0041] Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.
DETAILED DESCRIPTION
[0042] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0043] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0044] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0045] In some embodiments, numbers have been used for quantifying weight percentages, angles, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0046] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0047] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0048] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0049] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0050] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0051] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0052] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0053] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0054] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0055] As described herein, the term “active ingredient” has the meaning known in the state of the art. The term denotes a pharmaceutical drug or compound that produces a desired biological activity in the body.
[0056] As described herein, the term “matrix material” has the meaning present in the state of the art. The term denotes a homogeneous phase in which the pharmaceutical actives are present.
[0057] While a particular form of the invention has been illustrated and described, it will be apparent that various modifications can be made without departing from the spirit and scope of the invention.
[0058] The present disclosure generally relates to pharmaceutical formulations and compositions and processes of preparing these formulations and compositions for cardiovascular conditions.
[0059] In an embodiment, the present disclosure relates to pharmaceutical compositions comprising ticagrelor or a pharmaceutically acceptable salt thereof and aspirin or pharmaceutically active salts thereof.
[0060] In an embodiment, the present disclosure relates to pharmaceutical compositions comprising aspirin in a weight of at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 97 mg, at least 100 mg, at least 150 mg, at least 200 mg. More preferably at least 75 g.
[0061] In an embodiment, the present disclosure relates to pharmaceutical compositions comprising aspirin in weights ranging from at least 0-2.5 g, 2.5-5 g, 5-10 g, 10-15 g, 15-20 g, 20-25 g, 25-30 g, 30-35 g, 35-40 g, 40-45 g, 45-50 g, 45-55 g, 45-65 g, 46-65 g, 47-65 g, 48-65 g, 49-65 g, 50-65 g, 51-65 g, 52-65 g, 53-65 g, 54-65 g, 55-65 g, 50-55 g, 55-60 g, 60-65 g, 65-70 g, 70-75 g, 75-80 g, 80-85 g, 85-90 g, 90-95 g, or 95-97 g. More preferably 75-80 g.
[0062] In an embodiment, the P2Y12 inhibitor may be selected from the group comprising of ticagrelor, copidogrel, prasugrel, cangrelor, ticlopidine, elinogrel, their pharmaceutically active salts and combinations thereof. Most preferably ticagrelor.
[0063] In an embodiment, the present disclosure relates to pharmaceutical compositions comprising P2Y12 inhibitor in a weight of at least 60 g, at least 70 g, at least 80 g, at least 90 g, at least 100 g, at least 110 g, at least 120 g, at least 140 g, at least 160 g, at least 180 g, at least 200 g. More preferably 120 g or 180 g.
[0064] In an embodiment, the present disclosure relates to pharmaceutical compositions comprising P2Y12 inhibitor in weights ranging from at least 60 – 70 g, 70 – 80 g, 80 – 90 g, 90 – 100 g, 100 – 110 g, 110 – 120 g, 120 – 130 g, 130 – 140 g, 140 – 150 g, 150 – 160 g, 160 – 170 g, 170 – 180 g, 180 – 190 g, 190 – 200 g. Most preferably 120 – 200 g.
[0065] In an embodiment, the pharmaceutical composition may be formulated as an oral dosage form, selected from the group comprising tablet, pellets, capsule, granules, sachets, lozenges, liquids, suspension, gel, microparticles, nanoparticles and the like.
[0066] In an embodiment, the pharmaceutical composition may be formulated as tablets (including delayed capsules, and controlled release tablets), capsules (including delayed, and controlled release capsules), granules and the like.
[0067] In a preferred embodiment, the pharmaceutical formulation comprising aspirin or pharmaceutically active salts thereof and ticagrelor or pharmaceutically active salts thereof, wherein the composition is formulated as capsule.
[0068] In a preferred embodiment, the pharmaceutical formulation is a hard or soft gelatin capsule formulation
[0069] In an embodiment, the pharmaceutical composition may be formulated as a tablet with a coating.
[0070] In a preferred embodiment, the pharmaceutical formulation is an enteric coated formulation.
[0071] In a preferred embodiment, the pharmaceutical formulation is sustained-release coated formulation.
[0072] In an embodiment, the pharmaceutical formulation may be a sustained release formulation. The pharmaceutical formulation may further comprise at least one sustained release matrix.
[0073] In an embodiment of the present disclosure, the sustained release matrix material may be a hydrophilic (water soluble) polymer having polar groups such as hydroxy, amino, carboxy, carbonyl, ether, ester and sulfate.
[0074] In an embodiment of the present disclosure, the sustained release matrix material may be selected from the group comprising of methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably as sodium or calcium salt, hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), copolymers of polyvinylpyrrolidone, polyoxyethylenalkyl ether, polyethylenglycol, co-block-polymers of ethylenoxide and propyleneoxide (poloxamer, pluronic), polymethacrylate derivatives, polyvinyl alcohol, polyvinyl alcohol derivatives and polyethylenglycol derivatives, and the like. The hydrophilic polymer can be selected from known polymers having polar groups. Most preferably cellulose ethers e.g. Methocel K100M or Methocel K4M or combinations thereof.
[0075] In an embodiment of the present disclosure, the pharmaceutical compositions further comprise at least one pharmaceutically acceptable excipient.
[0076] In an embodiment of the present disclosure, the pharmaceutically acceptable excipients include but are not limited to, binders, diluents, thickeners, flow agents, absorbents, disintegrants, superdisintegrants, preservatives, emulsifiers, taste makers, stabilizers, sugars, anti-foaming agents, anti-caking agents, lubricants, coloring agents, coating materials, and combinations thereof. The excipients may be selected from those well known in the art.
[0077] In an embodiment of the present disclosure, the pharmaceutical composition may further comprise sugars selected from the group comprising of sucrose, glucose, dextrose, lactose, fructose, maltose, galactose, maltodextrin and the like.
[0078] In an embodiment of the present disclosure, the pharmaceutical excipients may be selected from magnesium stearate, calcium stearate, glyceryl monostearate, carboxylic acids, croscarmellose, cellulose derivatives, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose, microcrystalline cellulose, talc, lactose, isopropyl alcohol, ethyl alcohol, polyethylene glycols, water, dichloro methane, a povidone (for example, crospovidone, polyvinyl pyrrolidone, copovidone), polyacrylic acid, starch, modified starch, silicon dioxides, silicates, titanium dioxide, red oxide of iron, and combinations thereof.
[0079] In an embodiment of the present disclosure, the pharmaceutical composition may further comprise additional active ingredient(s) selected from one or more of group consisting of: ace-inhibitors, anti-Alzheimer's agents, antianginal drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents, anti-diarrhea preparations, antidotes, anti-emetics, anti-histamines, anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents, anti-manics, anti-migraines, anti-nauseants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs, alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic preparations, systemic and non-systemic anti-infective agents, anti-neoplastics, anti-parkinsonian agents, anti-rheumatic agents, anxiolytics, anti-psychotics, appetite stimulants, biological response modifiers, blood modifiers, bone metabolism regulators, bronchodilators, cardiovascular agents, central nervous system stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary supplements, dopamine receptor agonists, endometriosis management agents, enzymes, erectile dysfunction agents, fertility agents, gastrointestinal agents, H2-antagonists, homeopathic remedies, hormones, hypercalcemia and hypocalcemia management agents, immunomodulators, immunosuppressives, migraine preparations, motion sickness treatments, muscle relaxants, non-steroidal anti-inflammatories (NSAID's), obesity management agents, osteoporosis preparations, oxytocics, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sedatives, serotonin 5-HT3 receptor antagonists, smoking cessation aids, sympatholytics, tremor preparations, urinary tract agents, vasodilators, laxatives, antacids, ion exchange resins, anti-pyretics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, anti-obesity drugs, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs, and combinations thereof.
[0080] In an embodiment of the present disclosure, the pharmaceutical composition may be formulated in a solid oral dosage form, selected from the group comprising tablet, pellets, capsule, granules, sachets, lozenges, micro-particles, suppositories, re-constitutable powders, powder, nano- particles and the like.
[0081] In an embodiment of the present disclosure, may also be formulated in other dosage forms, including, liquids, suspensions, semi-solids, solutions, syrups, gels, emulsions and the like.
[0082] In an embodiment of the present disclosure, the pharmaceutical composition is a granule comprising Ticagrelor or pharmaceutically active salts thereof; Acrypol 912G; microcrystalline cellulose; P.V.P. K-30; Isopropyl alcohol; Magnesium Stearate; Colloidal Silicon Dioxide; optional additives selected from but not limited to Methocel K4M. Methocel K100M; Metolose 90SH 100000; and Lactose.
[0083] In an embodiment of the present disclosure, the granules comprising Ticagrelor or pharmaceutically active salts thereof is coated with sustained release coat comprising supercoat white F; yellow oxide of iron; isopropyl alcohol; and methylene dichloride.
[0084] In an embodiment of the present disclosure, the pharmaceutical composition is a granule comprising aspirin or pharmaceutically active salts thereof; Starch 1500; microcrystalline cellulose 112; Isopropyl alcohol; glyceryl mono stearate; and Colloidal Silicon Dioxide.
[0085] In an embodiment of the present disclosure, the granule comprising aspirin or pharmaceutically active salts thereof is coated with enteric coating comprising Seal Opadry Clear 03K19229; yellow oxide of iron; isopropyl alcohol; and methylene dichloride.
[0086] In an embodiment of the present disclosure, the granule comprising aspirin or pharmaceutically active salts thereof is coated with enteric coating comprising Opadry Enteric White 940580000; talcum; titanium dioxide; isopropyl alcohol; and purified water.
[0087] In an embodiment of the present disclosure, the pharmaceutical formulation is a hard or soft gelatin capsule formulation comprising the granules of Ticagrelor or pharmaceutically active salts thereof; and the granules of aspirin or pharmaceutically active salts thereof.
[0088] In another embodiment, the present disclosure relates to a method of preparing pharmaceutical compositions comprising Ticagrelor or pharmaceutically active salts thereof; aspirin or pharmaceutically active salts thereof.
[0089] In another embodiment, the present disclosure relates to a method of treatment, amelioration or prevention of a cardiovascular condition by administering the pharmaceutically effective amount of the formulation or the composition comprising Ticagrelor or pharmaceutically active salts thereof; aspirin or pharmaceutically active salts thereof.
[0090] In an embodiment of the present disclosure, the present disclosure relates to a method of treatment, amelioration or prevention of a cardiovascular condition by administering a pharmaceutically effective amount of the formulation or the composition.
[0091] In an embodiment of the present disclosure, the pharmaceutical composition may be used for the effective treatment, prevention or amelioration of cardiovascular diseases associated to obesity, surgery, or diabetes.
[0092] In an embodiment of the present disclosure, the pharmaceutical composition may be used for the effective treatment, prevention or amelioration of thrombotic events in patients with acute coronary syndrome (ACS) including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).
[0093] In an embodiment of the present disclosure, the pharmaceutical composition may be used for the effective treatment, prevention or amelioration of thrombus or embolus, for example, diseases induced by platelet aggregation, including stable or unstable angina pectoris and so forth; cardiovascular or cerebrovascular disorders, such as thromboembolism, associated with atherosclerosis or diabetes mellitus, such as unstable angina pectoris, cerebral ischemic insult or restenosis due to angioplasty, endarterectomy or stent therapy; or thromboembolism caused by thromboembolization such as recurrent embolism after degradation of the original thrombus, embolism, ischemia-induced dementia, peripheral arteriopathy, thromboembolization associated with hemodialysis or atrial fibrillation, or thromboembolization in the vascular prosthesis, or in the bypass between the aorta and the coronary artery.
[0094] In an embodiment of the present disclosure, the pharmaceutical composition of the present invention may be administered for enhancing anti-platelet activity.
[0095] In an embodiment, the present disclosure relates to processes of preparing a pharmaceutical composition comprising ticagrelor or a pharmaceutically acceptable salt thereof and aspirin or pharmaceutically active salts thereof.
[0096] In an embodiment, the present disclosure relates to a method for preparing the hard gelatin formulation comprising ticagrelor and aspirin comprise the steps of:
a. Preparing ticagrelor granules by dry mixing ticagrelor or a pharmaceutically acceptable salt thereof with Acrypol 912 G and microcrystalline cellulose;
b. Adding the clear binder solution comprising P.V.P. K-30 and isopropyl alcohol to the dry mix from step a;
c. Air and heat drying of the wet mix from step b;
d. Lubricating the granules from step c using colloidal silicon dioxide and magnesium stearate.
e. Preparing aspirin granules by dry mixing aspirin or a pharmaceutically acceptable salt thereof with starch 1500 and microcrystalline cellulose 112;
f. Lubricating the granules from step e using colloidal silicon dioxide and glyceryl monostearate.
g. tableting the granules obtained from step d and step f into a pharmaceutically acceptable hard gelatin tablet container.
[0097] In an embodiment of the present disclosure, the processes of preparing the pharmaceutical composition may involve the steps of milling (wet or dry), weighing, packaging, binder preparation, binding, mixing, lubricating, granulating, melt granulation, blending, sifting, sieving, sizing, direct compression, freeze drying, compaction, refining, and the like well-known in the art.
[0098] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0099] In an embodiment, the pharmaceutical composition of the present invention maybe used in any manner known to a person skilled in the art.
EXAMPLES
[00100] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
[00101] Example 1: Preparation of Ticagrelor granules
Step 1: 1.2 kg or 1.8 kg of ticagrelor is dry mixed with 0.480 kg of Acrypol 912 G and 0.552 kg of microcrystalline cellulose at a slow impeller speed for 10 min.
Step 2: Binder is prepared by adding 0.060 kg of P.V.P. K-30 to 0.627 kg of isopropyl alcohol in a clean container followed by continuous stirring till a clear solution is obtained.
Step 3: Wet mixing: binder solution from step 2 is added to dry mix from step 1 in a rapid mixer granulator and mixed at a slow speed for 9 min. to get optimum dough consistency.
Step 4: The wet mass from step 3 is milled after sieving.
Step 5: The wet material from step 4 is heat and air dried for 10 min.
Step 6: The material from step 5 is fully dried till desired moisture content is obtained.
Step 7: The granules obtained from step 6 is sized through a desired sieve.
Step 8: The sized granules mixed with lubricant except magnesium stearate and blended for 10 min in an octagonal blender, followed by the addition of magnesium stearate and mixed for 5 min.
Step 9: The granules are coated with sustained release coat comprising supercoat white F; yellow oxide of iron; isopropyl alcohol; and methylene dichloride
[00102] Example 2: Preparation of aspirin granules
Step 1: 0.750 kg of aspirin is dry mixed with 0.315 kg of starch 1500 and 0.280 kg of microcrystalline cellulose 112 at a slow impeller speed.
Step 2: The dry granules from step 1 is mixed with lubricant except glyceryl monostearate for 25 min in an octagonal blender, followed by the addition of glyceryl monostearate and mixed for 5 min.
Step 3: The granules are coated with enteric coating comprising Seal Opadry Clear 03K19229, yellow oxide of iron, isopropyl alcohol, and methylene dichloride; or enteric coating comprising Opadry Enteric White 940580000; talcum; titanium dioxide; isopropyl alcohol; and purified water.
[00103] Example 3: Hard gelatin capsule comprising Ticagrelor and aspirin
Ticagrelor granules as prepared from Example 1 and aspirin granules from Example 2 are mixed and filled in hard gelatin capsule containers.

WE CLAIM

A pharmaceutical composition for treating cardiovascular condition, wherein the composition comprises ticagrelor or a pharmaceutically acceptable salt thereof and aspirin or pharmaceutically active salts thereof,
characterized in that:
- the composition is formulated as capsule;
- ticagrelor is formulated as sustained-release coated granules of ticagrelor or a pharmaceutically acceptable salt thereof; and
- aspirin is formulated as enteric-coated granules of aspirin or pharmaceutically active salts thereof.
2. The composition as claimed in claim 1, wherein ticagrelor is present in an amount ranging from about 10 mg to about 200 mg.
3. The composition as claimed in claim 1, wherein aspirin is present in an amount ranging from about 50 mg to about 200 mg.
4. The composition as claimed in claim 1, wherein the composition is formulated as hard or soft gelatin capsule.
5. The composition as claimed in claim 1, wherein the composition comprises pharmaceutically acceptable excipients.
6. The composition as claimed in claim 1, wherein the ticagrelor granule comprises ticagrelor or pharmaceutically active salts thereof; Acrypol 912G; microcrystalline cellulose; P.V.P. K-30; Isopropyl alcohol; Magnesium Stearate; Colloidal Silicon Dioxide.
7. The composition as claimed in claim 1, wherein the aspirin granule comprises aspirin or pharmaceutically active salts thereof; Starch 1500; microcrystalline cellulose 112; Isopropyl alcohol; glyceryl mono stearate; and Colloidal Silicon Dioxide.
8. The composition as claimed in claim 6, wherein the composition comprises,
a. ticagrelor or a pharmaceutically acceptable salt thereof in an amount ranging from about 10 mg to about 200 mg;
b. Acrypol 912G in an amount ranging from about 10 mg to about 100 mg;
c. microcrystalline cellulose in an amount ranging from about 5 mg to about 50 mg;
d. P.V.P. K-30 in an amount ranging from about 1 mg to about 10 mg;
e. Isopropyl alcohol in an amount ranging from about 50 mg to about 200 mg;
f. Magnesium Stearate in an amount ranging from about 1 mg to about 10 mg; and
g. Colloidal Silicon Dioxide in an amount ranging from about 0.5 mg to about 5 mg.
9. The composition as claimed in claim 7, wherein the composition comprises,
a. aspirin or pharmaceutically active salts thereof in an amount ranging from about 50 mg to about 200 mg;
b. Starch 1500 in an amount ranging from about 10 mg to about 50 mg;
c. microcrystalline cellulose 112 in an amount ranging from about 5 mg to about 50 mg;
d. Isopropyl alcohol in an amount ranging from about 50 mg to about 200 mg;
e. Glyceryl monostearate in an amount ranging from about 1 mg to about 10 mg; and
f. Colloidal Silicon Dioxide in an amount ranging from 0.5 mg to about 5 mg;
10. A method for preparing the hard gelatin formulation comprising ticagrelor and aspirin comprise the steps of:
a. preparing ticagrelor granules by dry mixing ticagrelor or a pharmaceutically acceptable salt thereof with Acrypol 912 G and microcrystalline cellulose;
b. adding the clear binder solution comprising P.V.P. K-30 and isopropyl alcohol to the dry mix from step a;
c. air and heat drying of the wet mix from step b;
d. lubricating the granules from step c using colloidal silicon dioxide and magnesium stearate.
e. preparing aspirin granules by dry mixing aspirin or a pharmaceutically acceptable salt thereof with starch 1500 and microcrystalline cellulose 112;
f. lubricating the granules from step e using colloidal silicon dioxide and glyceryl monostearate.
g. tableting the granules obtained from step d and step f into a pharmaceutically acceptable hard gelatin tablet container.