PRIORITY

[0001] The present application claims the benefit of following Indian Provisional Patent Application No. 202141034863 filed on 3 August 2021.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds for treating and preventing cardiovascular and neurological diseases. More particularly, it relates a pharmaceutical composition comprises at least two pharmaceutically active agents or compounds which are concomitantly administered to the patient in a fixed dose formulation for the treatment of cardiovascular and neurological diseases and associated complications.

BACKGROUND OF THE INVENTION

[0003] Stroke is the second utmost common source of mortality and third most common cause of disability worldwide. Globally, 68% of all strokes are ischemic and 32% are hemorrhagic, acute coronary syndrome (ACS) in the world and the three most common risk factors for ACS are smoking (40%), high blood pressure (38%), and diabetes (30%).

[0004] High blood pressure is a major risk factor for cardiovascular disease and stroke because it damages the lining of the arteries, making them more susceptible to the buildup of plaque, which narrows the arteries leading to the heart and brain.

[0005] Cardiac manifestations of neurologic diseases are common in clinical practice. There are numerous anatomic and pathophysiologic links between the normal and abnormal function of both systems.

[0006] Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that reduces sulfonylurea receptor 1 (Suri) at nanomolar concentrations. Long used to target KATP (Surl-Kir6.2) channels for the treatment of diabetes mellitus type 2. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings regarding brain swelling (midline shift), MMP-9, functional outcomes and mortality. [0007] Oxidative stress, endothelial dysfunction, and inflammation represent a key triad serving as the foundation for the development and progression of stroke and cardiovascular diseases. The oxidative stress originates mainly in mitochondria from reactive oxygen and reactive nitrogen species (ROS/RNS) and can be identified in most of the key steps in the pathophysiology of atherosclerosis and the consequential clinical manifestations of cardiovascular disease. In addition to the formation of atherosclerosis, it involves lipid metabolism, plaque rupture, thrombosis, myocardial injury, apoptosis, fibrosis and failure. Similarly, Reactive oxygen species (ROS) are recognized as important mediators of brain injury.

[0008] Currently, many preclinical and clinical studies using drug with antioxidant properties are ongoing such as tirilazad mesylate, ebselen, resveratrol and others. While few drugs with antioxidant properties are approved for human use in neurological diseases include edaravone, idebenone, and dimethyl fumarate and many more are under clinical and preclinical development.

[0009] An effective treatment remains to be fully explored owing to the contributions from multiple pathways. A single therapeutic agent which could ameliorate all the pathologies associated with inflammation is clearly desirable.

[0010] The present invention targets various inflammatory conditions that affect the oxidative stress, nitric oxide generation, endothelial dysfunction and vascular damage in order to avoid cardiovascular and neurological disorders.

[0011] Present invention provides a pharmaceutical composition comprising one or more pharmaceutical active agents in combination or alone that enable efficient treatment for cardiovascular and neurological disorders and their respective associated complications without side effects as disclosed in the specification. The present invention provides an optimal liquid formulation which is easy to prepare and physio-chemically stable for pharmaceutical use as a medicament in a particular disease condition.

SUMMARY OF THE INVENTION [0012] The present invention provides novel pharmaceutical compositions comprising these compounds for combinatorial therapies. The pharmaceutical composition comprises one or more pharmaceutical active compounds of the invention.

[0013] In certain embodiments, the present invention relates to the compounds and compositions of formula I

FORMULA I and pharmaceutically acceptable salts, hydrates, solvates, enantiomers, and stereoisomers thereof; wherein,

RH independently represents null, hydrochloric acid, l-hydroxy-2-naphthoic acid, 2,2- dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor- 10- sulfonic acid, caprylic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluene sulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caprilic acid, alpha lipoic acid, R- lipoic acid, myristic acid, myristoleic acid, palmitoleic acid, elaidic acid, linoleic acid, linolenic acid, gamma-linolenic acid, a-linolenic acid, linolelaidic acid eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid or within the proviso, wherein

Ri, R2, R3 independently represents , capric acid (C10:0), lauric acid (C12:0), monoglycerides [MG], monocaprin (MG C10:0), glycerol monolaurate (MG C12:0), oleic acid (C18:l), elaidic acid (trans-C18:l), linoleic acid (C18:2), linolenic acid (C18:3), monocaprylate, monooleate, myristoleic acid, glycerol monocaprylate, C8:0, C10:0, C12:0, C14:0, C16:0, C18:0, C18:l, trans-C18:l, C18:2, C18:3, C6:0, C8:0, C10:0, C12:0, C14:0, C16:0, C18:0, C14:l, C16:l, C18:l, trans-C18:l, C18:2, trans-C18:2, C18:3, C20:4, [MGs] C10:0, C12:0, Cll:0, C12:0,

C13:0, [MGs] Cll:0, C12:0, C13:0, C20:4, C8:0, C10:0, C12:0, C14:0, C16:l, C18:l, [MGs]

C8:0, C10:0, C12:0, C14:0, C16:l, or C18:l; within the proviso,

C x:y is defined such that x is the number of carbons in the primary alkyl chain and y is the number of degrees of unsaturation; and n = 0 to 80.

[0014] The compositions are typically compounds in the forms of salts or hydrates or solvates or prodrugs or derivatives of glyburide and a moiety [RH] containing compound selected [RH] in which the glyburide or glyburide derivative or prodrug is protonated and the moiety [RH] is partially in ionic form as a pharmaceutically acceptable salt. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of glyburide or glyburide derivative, or prodrug and a component represented by [RH] . The invention also provides pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable excipients. [0015] Further, the invention also envisages pharmaceutical compositions comprising compounds of formula I in combination with one or more other pharmaceutically active agents selected from a group comprising of nicorandil, monomethyl fumarate (MMF) or dimethyl fumarate (DMF), anti-coagulants (apixaban, betrixaban, darexaban, edoxaban otamixaban, rivaroxaban), neuroprotective agents (e.g. edaravone, citicoline, minocycline, cerebrolysin), fingolimod, onazimod, antioxidants agents, pyridoxamine or its salt forms, nuclear factor erythroid 2-related factor 2 (NrF2) modulators, mannitol, isotonic solution or saline infusion, (l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), Calcium antagonists, Betablockers, Alpha-blockers or combination thereof. Further, the composition can be combined with one or more other agents and pharmaceutically acceptable excipients thereof.

[0016] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with anti-coagulants along with pharmaceutically acceptable excipients.

[0017] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with neuroprotective agents along with pharmaceutically acceptable excipients.

[0018] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline along with pharmaceutically acceptable excipients.

[0019] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with apixaban and citicoline along with pharmaceutically acceptable excipients.

[0020] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with minocycline and citicoline along with pharmaceutically acceptable excipients.

[0021] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with aspirin and citicoline along with pharmaceutically acceptable excipients. [0022] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with other anti-coagulants and pharmaceutically acceptable excipients.

[0023] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with apixaban and pharmaceutically acceptable excipients.

[0024] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with citicoline and pharmaceutically acceptable excipients.

[0025] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with aspirin and pharmaceutically acceptable excipients.

[0026] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with other anti-coagulants and pharmaceutically acceptable excipients.

[0027] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with apixaban and pharmaceutically acceptable excipients.

[0028] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with citicoline and pharmaceutically acceptable excipients.

[0029] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with aspirin and pharmaceutically acceptable excipients.

[0030] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Calcium antagonists along with pharmaceutically acceptable excipients. [0031] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Beta-blockers along with pharmaceutically acceptable excipients.

[0032] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Alpha-blockers along with pharmaceutically acceptable excipients.

[0033] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with pyridoxamine and pharmaceutically acceptable excipients.

[0034] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, apixaban and pharmaceutically acceptable excipients.

[0035] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, aspirin and pharmaceutically acceptable excipients.

[0036] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant and pharmaceutically acceptable excipients.

[0037] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant in 20% mannitol and pharmaceutically acceptable excipients.

[0038] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant in mannitol and pharmaceutically acceptable excipients.

[0039] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with (l,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid), and pharmaceutically acceptable excipients.

[0040] In an embodiment, the pharmaceutical composition comprising the combination of formula I and an anti-coagulant is used for treating and/or preventing stroke in patients with atrial fibrillation, as well as to the use such combination in treatment and/or prevention of stroke in patients with atrial fibrillation and diabetic conditions.

[0041] In an embodiment, present invention provides a pharmaceutical composition comprising fixed dose combination of compound of formula I and an anticoagulant with at least one pharmaceutically acceptable excipient.

[0042] In an embodiment, present invention provides the composition comprising glyburide; and apixaban. The concentration of glyburide in the composition range about 0.60 mg/ml to about 6.0 mg/mL and that of apixabam range from 2.50 mg/ml to about 5 mg/mL.

[0043] In an embodiment, present invention provides a liquid/aqueous composition suitable for oral administration, preferably an oral suspension.

[0044] In an embodiment, the composition includes one or more pharmaceutically acceptable excipient. In certain aspect the composition includes viscosity modifier/su spending agents, preservative, buffering agent, vehicle, solubilizer and a combination thereof for preparing the oral suspension.

[0045] In an embodiment, the composition includes one or more viscosity modifier such as hydroxyethyl cellulose and xanthan gum. The concentration of viscosity modifier ranges from 1 mg/mL to 8.50 mg/mL or 1 mg/mL to 5 mg/mL or preferable Img/mL to 2.5 mg/mL of the composition. In certain embodiment the concentration of hydroxyethyl cellulose can range from 1 mg/mL to 8.5 mg/mL and that of xanthan gum can range from 1 mg/mL to 5 mg/mL.

[0046] In an embodiment, the composition includes one or more preservative and the concentration of such preservative can range from 0.5-10 mg/mL. In certain embodiment the preservative is sodium benzoate.

[0047] In an embodiment, the composition includes one or more buffering agent such as trisodium citrate anhydrous and lactic acid. The concentration of the buffering agent can range from 1 mg/mL to 25 mg/mL. In certain embodiment the concentration of trisodium citrate anhydrous can range from 1 mg/mL -15 mg/mL and that of lactic acid an range from 1 mg/mL -25mg/mL.

[0048] In an embodiment, the composition includes one or more solubilizer such as sodium lauryl sulphate. The concentration of the solubilizer can range from Img/mL to 10 mg/mL. [0049] In an embodiment, the composition includes one or more one or more antioxidant such as taurine, wherein the concentration of the antioxidant can range from 75 mg/mL to 3000 mg/mL.

[0050] In an embodiment, the composition includes one or more anti-foaming agent, wherein the said anti-foaming agent is simethicone emulsion ranging from 2 mg/mL-20mg/mL.

[0051] In certain embodiment, the pharmaceutical composition comprising glyburide and apixaban is used for treating and/or preventing stroke in patients with atrial fibrillation and diabetic conditions. The glyburide acts both as an insulin sensitizer as well as activation Surl- transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury and apixaban is an anticoagulation agent.

[0052] In an embodiment the composition may further include taurine as antioxidants. The taurine in the composition prevents oxidative stress, vascular stress and endothelial dysfunctions in AF and DM patients.

[0053] In an embodiment, the pharmaceutical composition is formulated for oral administration preferably as an oral suspension.

[0054] The present invention also provides the method of using the pharmaceutically composition of the invention in the treatment of cardiovascular and neurological diseases, which include those triggered by inflammation also. The cardiovascular and neurological diseases include vascular disorders, oxidative stress, stroke, brain/neurological damages, brain edema, subarachnoid hemorrhage, traumatic central nervous system injury, acute spinal cord injury, myotrophic lateral sclerosis, cerebral aneurysm, embolic stroke, syncope, intracerebral bleeding, watershed infarction, brain abscess, meningitis, metastasis, dementia, or aneurysm formation and their associated complications.

[0055] In another aspect, the pharmaceutical composition is a formulation in solid dosage form or a solution or parenteral or a topical which can be administered to the patient by convenient route such as oral, nasal, local, dermal, virginal, rectal, patches (mucosal, buccal, dermal), injections, self-injectable or parenteral administration and other known in the art. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0056] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0057] It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” or “an therapeutic agent” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and the like.

[0058] The term “active agent” or “therapeutic agent”, encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

[0059] The term “combinatorial therapy" or "combined treatment" or "in combination" as used herein denotes any form of concurrent or concomitantly or co-administration of at least two distinct therapeutic agents for treating inflammation, vascular disorders, oxidative stress, stroke, diseases and cardiovascular diseases/disorders and their associated complications [0060] The compounds used in the present pharmaceutical composition can be present in the form of pharmaceutically acceptable salts, esters, (i.e., the methyl and ethyl esters of the acids of compound to be used as prodrugs, solvated, hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound.

[0061] The terms “treating” and “treatment” as used herein refer to reduction in severity and or frequency of symptoms, elimination of symptoms and or underlying cause, and improvement or remediation of damage. [0062] In certain aspects, the terms “treating” and “treatment” as used herein refer to the prevention of the occurrence of symptoms and or their underlying cause. Thus, “treating” a patient as described herein encompasses treating cardiovascular and neurological diseases. This include inflammation, vascular disorders, oxidative stress, endothelaial dysfunctions, stroke, spinal cord injury (SCI), ischemic stroke, brain damages, neurological disorders, brain edema cardiovascular diseases/disorders, cerebrovascular diseases. Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including hypertension, heart failure, myocardial infarction, unstable angina, and peripheral thromboses others and their associated complications.

[0063] Atrial fibrillation (AF) is considered one of the most predominant types of arrhythmias and is a major risk factor for stroke. Patients with diabetes mellitus (DM) are at higher risk of developing this condition compared to other patients. Patients with DM are at higher risk of costly complications due to the nature of their disease and often need combination therapy to manage the disease. The co-existence of DM and AF increases the risk of various critical cardiovascular events, bleeding, and mortality. Moreover, increasing hemoglobin Ale levels and diabetes duration have been reported to raise thromboembolism risk.

[0064] Diabetes is also a stroke independent risk factor, and in contrast with non-diabetic patients, patients with DM have more disabilities and an increased mortality risk. In addition, other stroke risk factors in AF patients are more prevalent in patients with diabetes, such as peripheral vascular disease and renal failure. The probability of the development of thromboembolic events increases by 70% in patients with diabetes. The mechanism of AF is still elusive but studies have indicated that inflammation might play a role in the generation, maintenance, and perpetuation of AF. Glucose and insulin disturbance can directly affect the myocardium in atrium and ventricle, leading to AF. The pharmaceutical composition of the present invention comprising a combination of anticoagulant and compound of formula I is most effective in preventing stoke in patients with co-existence of DM and AF. The patients with diabetes mellitus possess a higher risk for developing AF compared to those without diabetes mellitus. The insulin resistance of diabetes mellitus increases thromboembolic risk through induced hypercoagulability, endothelial dysfunction, and impaired fibrinolysis. Diabetes mellitus and AF are believed to share related mechanistic pathways for thrombosis.

[0065] The pharmaceutical composition of the present invention comprising a combination anticoagulant and compound of formula I prevent stroke by preventing blood clots through directly inhibiting factor Xa, and managing the DM.

[0066] The apixaban an anticoagulant in the pharmaceutical composition of the invention reversible and selective inhibits free and clot-bound FXa, and prothrombinase activity. The apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin by inhibiting FXa, and decreases thrombin generation and thrombus development thus effective in venous and arterial thromboembolism management. While, the compound of formula I in the composition bind to the SURI receptors in the membranes of the beta cells of potassium ATP-dependent channels and by blocking these channels, and insulin is released after the cell becomes depolarized therefore useful in improving insulin secretion rate and DM management. In some embodiment composition may further include taurine as antioxidants, which helps to prevent oxidative stress, vascular stress and endothelial dysfunctions in AF and DM patients.

[0067] The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration as a modified releases dosage form such as immediate release, controlled release, sustained release, extended release formulations thereof.

[0068] The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate. The term “controlled release” as used herein include sustained release, non-immediate release and delayed release formulations.

[0069] The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time.

[0070] The term “pharmaceutically acceptable” means the material incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. “Pharmacologically active” (or simply “active”) as in a “pharmacologically active” derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. The term “pharmaceutically acceptable salts” include acid addition salts, mixtures, which are formed with inorganic and organic acids.

[0071] In an embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one other pharmaceutically active agents. [0072] pharmaceutical compositions comprising compounds of formula I in combination with one or more other pharmaceutically active agents selected from a group comprising of nicorandil, monomethyl fumarate (MMF) or dimethyl fumarate (DMF), anti-coagulants (Apixaban Betrixaban Darexaban, Edoxaban Otamixaban, Rivaroxaban), neuroprotective agents (e.g. edaravone, citicoline minocycline, Cerebrolysin), fingolimod, onazimod, antioxidants agents, pyridoxamine or its salt forms, nuclear factor erythroid 2-related factor 2 (NrF2) modulators, mannitol, isotonic solution or saline infusion, (l,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), Calcium antagonists, Beta-blockers, Alphablockers or combination thereof. Further, the composition can be combined with one or more other agents and pharmaceutically acceptable excipients thereof.

[0073] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with anti-coagulant along with pharmaceutically acceptable excipients.

[0074] In an embodiment the pharmaceutical composition of the present invention comprises compound of formula I and anticoagulant along with a suspending/viscosity modifier, buffering agent, preservative, solubilizer and water. [0075] In an embodiment the pharmaceutical composition of the present invention comprises compound of formula I and anticoagulant along with a suspending/viscosity modifier, buffering agent, preservative and water.

[0076] In an embodiment the pharmaceutical composition of the present invention comprises compound of formula I and antioxidant along with a suspending/viscosity modifier, buffering agent, preservative, solubilizer, anti-forming agent and water.

[0077] In an embodiment, the pharmaceutical composition is an oral suspension comprising: a combination of active agents/drugs glyburide in an amount ranging from 0.60 mg/mL to 6 mg/mL and apixaban in an amount ranging from 2.50 mg/mL -50 mg/mL, wherein the combination of the active agents are suspended in the suspending agents/viscosity modifier such as hydroxyethyl cellulose in an amount ranging from 1- 8.5 mg/mL and xanthan gum in an amount ranging from 1-5 mg/mL. Further the suspension may include one or more preservative such as sodium benzoate in an amount ranging from 5-10 mg/mL, one or more buffering agent such trisodium citrate anhydrous in an amount ranging from 1-15 mg/mL and lactic acid in an amount ranging from 1-25 mg/mL for maintaining the pH of the drug product, a solubilizer such sodium lauryl sulphate in an amount ranging from 1-10 mg/mL, and antiforming agents such as simethicone emulsion in an amount ranging from 2-20 mg/mL and an antioxidant such as taurine in an amount ranging from 75- 3000 mg/mL.

[0078] In an embodiment, the pharmaceutical composition is an oral suspension comprising: a combination of active agents/drugs glyburide and apixaban, wherein the combination of the active agents are suspended hydroxyethyl cellulose and xanthan gum along with sodium benzoate, trisodium citrate anhydrous and lactic acid. In certain embodiment this composition may further include sodium lauryl sulphate.

[0079] In an embodiment, the pharmaceutical composition is an oral suspension comprising glyburide and taurine suspended in hydroxyethyl cellulose and xanthan gum along with sodium benzoate, trisodium citrate anhydrous, lactic acid, sodium lauryl sulphate and simethicone 30% emulsion. [0080] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with neuroprotective agents along with pharmaceutically acceptable excipients.

[0081] In one embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline along with pharmaceutically acceptable excipients.

[0082] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with apixaban and citicoline along with pharmaceutically acceptable excipients.

[0083] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with minocycline and citicoline along with pharmaceutically acceptable excipients.

[0084] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with aspirin and citicoline along with pharmaceutically acceptable excipients.

[0085] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with other anti-coagulants and pharmaceutically acceptable excipients.

[0086] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with apixaban and pharmaceutically acceptable excipients.

[0087] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with citicoline and pharmaceutically acceptable excipients.

[0088] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in mannitol along with aspirin and pharmaceutically acceptable excipients. [0089] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with other anti-coagulants and pharmaceutically acceptable excipients.

[0090] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with apixaban and pharmaceutically acceptable excipients.

[0091] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with citicoline and pharmaceutically acceptable excipients.

[0092] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in isotonic solution along with aspirin and pharmaceutically acceptable excipients.

[0093] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Calcium antagonists along with pharmaceutically acceptable excipients.

[0094] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Beta-blockers along with pharmaceutically acceptable excipients.

[0095] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one Alpha-blockers along with pharmaceutically acceptable excipients.

[0096] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with pyridoxamine and pharmaceutically acceptable excipients.

[0097] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, apixaban and pharmaceutically acceptable excipients. [0098] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, aspirin and pharmaceutically acceptable excipients.

[0099] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant and pharmaceutically acceptable excipients.

[00100] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant in 20% mannitol and pharmaceutically acceptable excipients.

[00101] In certain embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with citicoline, any one selected anticoagulant in mannitol and pharmaceutically acceptable excipients.

[00102] In certain embodiment, the pharmaceutical composition of the present invention comprises compound of formula I in combination with (l,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid), and pharmaceutically acceptable excipients.

[00103] In an embodiment the pharmaceutical composition of the present invention comprises compound of formula I in combination with at least one other pharmaceutically active agents selected from a group consisting of nicorandil, monomethyl fumarate or dimethyl fumarate, mannitol, isotonic solution or saline infusion or agents belong to class of NrF2 modulators, neuroprotective agents, anticoagulants, aspirin, citicoline, antioxidants, pyridoxamine or its salt forms, calcium antagonist, alpha blocker or beta-blocker.

[00104] In an embodiment, the non-limiting examples of neuroprotective agents include polyarginine R18, magnesium sulfate, atorvastatin, mevastatin, rosuvastatin, simvastatin, N- acetyl-L-cysteine (NAC), melatonin, erythropoietin, NXY-059, PEG-SOD, Tempol, hydroxy stilbene oxyresveratrol, cyclosporin A (CsA), FK506 (Tacrolimus), flavocoxid, NS- 398, valdecoxib, celecoxib, curcumin and others.

[00105] In an embodiment, the non-limiting examples of calcium channel blocker (CCB) or calcium antagonists or "-dipine", include amlodipine, aranidipine azelnidipine, barnidipine, benidipine, bepridil, clevidipine, diltiazem, efonidipine, felodipine, flunarizine, fluspirilene, gallopamil, isradipine, lacidipine, levamlodipine, manidipine, miberfradil, nifedipine, nicardipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil, gabapentinoids, ziconotide and others known in the art.

[00106] In an embodiment, the non-limiting examples of beta-blockers include atenolol, acebutolol, betaxolol, bisoprolol/hydrochlorothiazide, bucindolol, butaxamine, carvedilol, carteolol, celiprolol, esmolol, labetalol, metoprolol, nadolol, nebivolol, nebivolol, oxprenolol, propranolol, penbutolol, pindolol, sotalol, sotalol, timolol, ICI-118,55, SR 59230Aand others known in the art.

[00107] In an embodiment, the non-limiting examples of alpha-blockers include alfuzosin, atipamezole, doxazosin, idazoxan, mirtazapine, prazosin, phenoxybenzamine, phentolamine, silodosin, terazosin, tolazoline, trazodone, tamsulosin, yohimbine and others known in the art.

[00108] In embodiment, NrF2 modulators as used here include both activator and inhibitor. The non-limiting examples of NrF2 modulator include NrF2 activators such as Bardoxolone-methyl (CDDO-Me), omaveloxolone, Dimethyl fumarate, ALKS-8700, Oltipraz, Ursodiol, Sulforaphane, Sulforadex, ITH12674, Curcumin, Resveratrol, CXA-10, tBHQ and NrF2 inhibitors include Dexamethasone, Clobetasol propionate, Camptothecin, Emetine, Digoxin, Metformin, All-trans-retinoic acid, Bexarotene, Brusatol (from Brucea javanica), Ochratoxin A, Cryptotanshinone (from Saliva miltiorrhiza), Triptolide, Luteonin, Wogonin, Apigenin, Chrysin, Fibrifugine, Trigonelline, Isoniazid, Ethionamide, Ascorbic acid, ATRA (tretinoin), CBR-031-1, AME1, 4f, Stattic, ML385, AB-ML385 and other known in the art.

[00109] In an embodiment, the Formula I can be combined with additional pharmaceutically active agents. The non-limiting examples of additional pharmaceutical agents are selected from the drug belong to the class of antithrombotic agents, antiplatelet agents, thrombolytic agents, calcium channel blockers, antioxidants, GABA agonists, competitive NMDA Antagonists, noncompetitive NMDA Antagonists, AMPA antagonists, synaptic inhibitor, antiexcito toxic, NMDA ion channel blocker, free radical scavenger, antiinflammatory, antioxidant, mastocyte stabilization, reduction in BBB leakage, antioxidant, HMG-CoA reductase inhibitors, anti-inflammatory, antiexcito toxic, surl-Trpm4 channel inhibitors, NKCC1, aquaporin blockers (aquaporin-4,aquaporin-l), ion channel blockers, cation-Cl- cotransporter inhibitors, Na+/H+ exchanger inhibitors, Na+-Ca2+ exchange inhibitors, VEGF-related drugs, BBB Protective agents and others known in the art.

[00110] In an embodiment, non-limiting examples of additional pharmaceutically active agents include heparin, enoxaparin, cilostazol, aspirin, cilostazol, eptifibatide, abciximab, aspirin, clopidogrel, t-PA, urokinase, nimodipine, NXY-059, ebselen, tirilazad, edaravone, clomethiazole, CGS 19755, aptiganel (CNS-1102), MK-801, ZK 200775, YM872, hypothermia, magnesium sulfate, uric acid, dapsone, cromolyn, ebselen, statin, cyclosporin A. glibenclamide, resveratrol, bumetanide, ZT-la, thyroid hormone (T3), inhaled H2S, acetazolamide, lactosides B, mitochondrial aldehyde dehydrogenase 2, paeoniflorin, astragaloside IV, tongxinluo, fullerenol, bumetanide, HOE-642, compound RU-1355, SEA0400, RB-222, alpha-tocopherol, 8-methoxypsoralen, 3 -aminobenzamide, anti-miR-1 or microRNA-1 antagomir, microRNA-132, microRNA-1906, chemokine-like factors, magnesium sulfate, ulinastatin, ginkgo diterpene lactone meglumine, olaparib, Recombinant human erythropoietin, l-trifuoromethoxyphenyl-3-(l-propionylpiperidin-4-yl) urea and others known in the art.

[00111] In certain embodiments, present invention provides a pharmaceutical composition comprising a combination of compound of formula I and an anticoagulant along with one or more pharmaceutically acceptable excipients or carriers. This composition is administered together in a pharmaceutical dosage form.

[00112] In an embodiment, the pharmaceutical composition comprising a compound of formula I and an anticoagulant as a combination in a fixed dose form along with one or more pharmaceutically acceptable carrier/excipient is a liquid formulation suitable for oral administration for individuals who cannot swallow the oral solid dosage form.

[00113] In an embodiment, the pharmaceutical composition is an oral suspension.

[00114] In an embodiment the oral suspension comprises: a combination of glyburide and apixaban in a fixed dosage formulation. The oral suspension will further include one or more pharmaceutically acceptable excipients selected from viscosity modifier, preservative, buffering agent, vehicle, solubilizer, anti-foaming agent, antioxidant or a combination thereof. [00115] The liquid formulation of the present invention may contain additional ingredients used in the drug industry, herein referred to as additives. Additives include well- known components, but are not limited to sweetening agents, flavors, colorants, chelating agents, surfactants, wetting agents, pH modifiers, acidifiers, cosolvents, and combination thereof.

[00116] The viscosity modifier/suspending agent such as hydroxyethyl cellulose, xantham gum, carageenan, Na CMC/MCC mixers, Avicel and other. The viscosity modifier is soluble in both hot and cold water and do not form gel on heating and improves viscosity and stability of the oral suspension. In certain aspect the suspending agents employed in the present formulation is hydroxyethyl cellulose and xanthan gum besides acting as a suspending agent they also imparts viscosity to the formulation. To address any stability problems all liquid formulation is formulated to an optimum pH. The Rheology, viscosity and other property of the formulation are dependent on the pH of the system.

[00117] The advantages of present oral suspension dosage forms include effective dispensing of hydrophobic drugs; offering resistance to degradation of drugs due to hydrolysis, oxidation or microbial activity; and easy swallowing for young or elderly patients. In addition, when compared to solution dosage forms, relatively higher concentration of drugs can be incorporated into suspension products.

[00118] Challenges faced in the development of the oral suspension include stability, viscosity and sedimentation. As the particle size of two API in the present oral suspension are significantly different i.e. glyburide D90 of less than 10 microns and apixaban D90 of about 60 microns, sedimentation rate for #003 (Table 10) was faster compared to #002 (Table 8). As viscosity increases the sedimentation rate decreases, thus physical stability increases. Thus, for combination drug product of the present invention the suspending agents’ concentrations were increased to minimize the sedimentation rate to avoid the suspended particles in the oral suspension from settling rapidly (refer trial 1-9 provided below).

[00119] In an embodiment the oral suspension is easy to pour yet not watery and no grittiness, and physically, chemically and microbiologic ally stable. [00120] In another embodiment the pharmaceutical composition of the present invention includes one or two buffering agents such as trisodium citrate anhydrous and lactic acid, to stabilize the suspension to a desired PH range (3.5 to 4.5).

[00121] The drug product suspension according to Table A, are prepared and evaluated for sedimentation and viscosity. The observations are provided in Table B.

Table A: Composition

Table B: Observations:

[00122] Based on the above trials, low quantity of suspending agents was not found to be sufficient as sedimentation of solid particles and layer separation was observed. Hence further trials (see Table C) were planned by increasing the concentration of suspending agent to check for sedimentation and viscosity

Table C: Composition

[00123] The drug product suspensions were prepared according to Table C and evaluated for sedimentation and viscosity. The observations is provided in Table D.

Table D: Observation

[00124] Based on the above trials, the viscosity of the suspension was high and caused poor flowability of suspension.

Table E: Composition

[00125] The drug product suspensions were prepared according to table E and evaluated for sedimentation and viscosity. The observations are provided in Table F.

Table F: Observations

[00126] Based on the above trials the concentration of 2.5mg of hydroxyethyl cellulose and 1 mg of xanthan gum were found to exhibit good suspension and flowability. The suspension was physically checked, and no sedimentation was observed when drug product was held for 24hr.

[00127] In another embodiment, the pharmaceutical composition comprising any one of the combinations as disclosed formulated into solid, semi-solid, or liquid form. Non-limiting examples include tablet, capsule, caplet, modified release tablet, oral suspension, oral solution, oral emulsion, suppository, granules, pellets, beads, power, lozenges, spray (oral, nasal, topical or dermal), cream, ointment, lotion, patches, parenteral, pre-filled syringe, pre-filled pen, and gel.

[00128] Further, depending on the intended mode of administration, the pharmaceutical formulation may be a solid, semi-solid or liquid. Non-limiting examples of dosage forms include tablet, lozenge, capsule, caplet, modified release tablets, suspension, solution, emulsion, suppository, granules, pellets, beads, powder, sprays ( oral, nasal, dermal), cream, ointment, lotion, patches, parenteral, pre-filled syringe, pre-filled pen, and gel or the like, preferable unit dosage form suitable for single administration of a precise dosage. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).

[00129] In another embodiment, the pharmaceutical composition comprising any one of the combinations as disclosed are formulated into discrete dosage units each containing a predetermined, ‘unit dosage’ quantity of an one or more active agents in combination calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients.

[00130] The present composition can be in the form of modified release formulation. In certain aspect it may be controlled release oral dosage forms. Generally, the dosage forms provide for sustained release, i.e., gradual, release of the compound of the present invention alone or in combination from the dosage form to the patient's body over an extended time period, typically providing for a substantially constant blood level of the agent over a time period in the range of about 4 to about 12 hours, typically in the range of about 6 to about 10 hours.

[00131] The present formulations may be immediate release oral dosage forms. Generally, the dosage forms provide for immediate release, i.e., fast, release of the compound of the present invention alone or in combination from the dosage form to the patient's body immediately after oral administration time period, typically providing for a substantially constant blood level of the agent within 10, seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds or 60 seconds.

[00132] The present formulations may be a combination of immediate and delayed release oral dosage forms.

[00133] In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion includes the first pharmaceutically active agent, and the second portion includes the second pharmaceutically active agent.

[00134] In an embodiment, pharmaceutical composition comprising any one of the combinations of the present invention as disclosed in the any of the embodiments can be incorporated into any formulations established in the art using the know method of formulation. [00135] In another embodiment, suitable pharmaceutically acceptable excipients examples include one or more fillers and diluents, binders and adhesives, glidants, stability enhancer, lubricants and anti-adherents, disintegrants, coatings changing the dissolution rates of active species, colors, flavors, sweeteners, preservatives, sorbents and others known in the art of formulation.

[00136] In another embodiment, for solid formulation, the non-limiting examples of excipient include plant cellulose, dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate, starches, sugars, cellulose or modified cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, lactose, or sugar alcohols like xylitol, sorbitol or maltitol, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, povidone K25/30/90, starch, sucrose and polyethylene glycol, cellulose, methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol, colloidal silicon dioxide, talc or silica, fats, vegetable stearin, magnesium stearate or stearic acid, PEG 300,400&600, cross linked polyvinyl pyrrolidone, polyvinyl pyrrolidone K90 sodium starch glycolate, cross linked sodium carboxymethyl cellulose (crosscarmellose), crospovidone and sodium glycolate, cross linked cellulose, crosslinked polymer and a crosslinked starch, cellulose film coating, synthetic polymers, shellac, polysaccharides, mint, cherry, peach, liquorice, raspberry, citrus bioflavonoids, neohesperidin or carob powder and vanilla, vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, citric acid, sodium citrate, methyl paraben, propyl paraben.

[00137] In certain embodiment, the pharmaceutical composition may comprise a drugcontaining layer that contains the active ingredient, between a first water- swellable gel-forming layer and a second water-swellable gel-forming layer. The water-swellable gel-forming layers are formed from a composition that contains at least a water-swellable gel-forming agent such as carboxyvinyl polymer, starches and derivatives thereof, agar, alginic acid, arabinogalactan, galactomannan, cellulose and derivatives thereof, carrageen, dextran, tragacanth, gelatin, pectin, hyaluronic acid, gellan gum, collagen, casein, and xanthan gum; a film-forming agent such as polyvinyl alcohol, polyvinyl pyrrolidone (PVP), hydroxyalkyl cellulose, and alkyl celluloses; and a polyvalent metal compound for cross-linking linking gel forming and film forming agent such as aluminum sulfate, aluminum potassium sulfate, iron chloride alum, ammonium solution, ammonium alum, ferric sulfate, aluminum hydroxide, aluminum silicate, aluminum phosphate, calcium chloride, iron citrate, magnesium oxide, calcium oxide or zinc salts.

[00138] In an embodiment, the pharmaceutical composition comprising at least one combination as disclosed is dissolved in a suitable solvent that is incorporated into the liquid formulation. In an embodiment, non-limiting examples of excipients for preparing liquid formulation such as suspension and solution comprises of vehicles/ solvents (such as water, alcohol, glycerin, polysorbate 80, propylene glycol, mannitol, polyethylene glycol 400 and others); co-solvents (such as glycerol, propylene glycol, ethanol, the low molecular weight PEGs and the likes) surfactants (such as anionic (e.g., sodium dodecyl sulfate), cationic (e.g., trialkylammonium), zwitterionic (e.g., glycine and proteins) and nonionic (e.g., polyethylene glycol); preservatives (such as phenol, benzoic acid, boric acid, chlorocresol, 9-phenyl phenol, alkyl esters of para-hydroxybenzoic acid, sorbic acid, and their respective salts such as sodium benzoate, potassium sorbate, methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate , chlorobutanol, benzyl alcohol, and beta-phenylethyl alcohol); viscosity modifiers/ suspending agents (such as cellulose derivatives (e.g., methylcellulose, microcrystalline cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose etc), clays (e.g., hectorite, bentonite, aluminium and/or magnesium silicate), ammonium solution, ammonium hydroxide, natural gums (e.g., acacia, guar gum, tragacanth, xanthan gum, alginates, carrageenan and locust bean gum), synthetic polymers (e.g., carbomers, polyvinyl pyrrolidone, polyvinyl alcohol and poloxamer), and miscellaneous compounds (e.g., colloidal silicon dioxide and silicates). Buffering agents such as trisodium citrate anhydrous, lactic acid. The anti-forming agents such as simethicone (polymethylsiloxane) paraffin oils, organic phosphates and alcohols. In many cases, these excipients are used in combination). Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

[00139] For parenteral administration, fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred. The active ingredient, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the water- soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.

[00140] In an embodiment, the parenteral formulation can be administration through intravenous, intramuscular, subcutaneous, intradermal, intra-cardiac, intracerebral routes. General preferred preparation for neural use is solution, preparation for intramuscular, subcutaneous, intradermal use can be solutions, suspensions or emulsion.

[00141] In an embodiment, pharmaceutically acceptable carrier/excipient/vehicle include aqueous/ non-aqueous examples are water for injection bacteriostatic water for injection sterile water for injection water miscible vehicles, non-aqueous excipient used in combination with water include ethyl alcohol, N-(2-hydroxyethyl)-lactamide, dioxolanes, dimethyl acetamide, butylene glycol, glycerin and others. Examples of water immiscible solvents include fixed oils, ethyl oleate, isopropyl myristate, benzyl benzoate and others [00142] In another embodiment the parenteral formulation can additional include one or more co- solvent; one or more antibacterial agents such as phenol, cresol and others; one or more surfactants such as sorbitol monooleate and others; one or more buffers such as acetate and citrate buffer; one or more anti-oxidants such as ascorbic acid, thiourea, tocopherol and others; one or more tonicity agents such as sodium chloride, potassium chloride, dextrose and others; one or more chelating agents such as EDTA .

[00143] In addition to oral and parenteral administration, the rectal and vaginal routes can be utilized. The combination of active ingredients can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.

[00144] For intranasal instillation, a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.F. water, a dry powder can be formulated when insufflation is the administration of choice.

[00145] For use as aerosols, the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable.

[00146] Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition, Edited by A. H. Kibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0- 917330-96-X, or Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C Rowe - Publisher: Science and Practice.

[00147] In another embodiment the methods of preparing these pharmaceutical compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[00148] The term "unit dosage form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.

[00149] In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used. [00150] In certain embodiments, the pharmaceutical compositions of the instant invention are used as a combinatorial therapy for the treatment of cardio vascular diseases and neurological diseases. Neurological complications of cardiac disease include embolic stroke, syncope, and intracerebral bleeding, watershed infarction, brain abscess, meningitis, metastasis, dementia, and aneurysm formation. Further, heart failure, myocardial infarction, myocardial aneurysm, endocarditis/myocarditis, and noncompaction are also causes of cerebral embolism. Other cardiac cause of neurological complications is systolic dysfunction, arrhythmias, or valve stenosis. Arrhythmias are associated with intra-cardiac thrombus formation and low output failure and watershed infarction, vertigo, fainting, or syncope. Valve abnormalities can be another source of neurological disease.

[00151] Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels which include coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, and deep vein thrombosis and pulmonary embolism.

[00152] The oxidative stress originates mainly in mitochondria from reactive oxygen and reactive nitrogen species (ROS/RNS) and can be identified in most of the key steps in the pathophysiology of atherosclerosis and the consequential clinical manifestations of cardiovascular disease. In addition to the formation of atherosclerosis, it involves lipid metabolism, plaque rupture, thrombosis, myocardial injury, apoptosis, fibrosis and failure. Similarly, Reactive oxygen species (ROS) are recognized as important mediators of brain injury. Another serious conditions brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death.

[00153] Indications: The pharmaceutical composition of the present invention can be used to treat conditions which include inflammation, vascular disorders, oxidative stress, endothelial dysfunctions, stroke, brain edema, brain damage s/injury, subarachnoid hemorrhage, spinal cord injury (SCI), traumatic central nervous system injury, myotrophic lateral sclerosis, ischemic stroke, brain edema, embolic stroke, syncope, intracerebral bleeding, cardiovascular diseases/disorders, cerebrovascular diseases, atherosclerosis, cardiovascular dysfunction, hypertension, heart failure, myocardial infarction, unstable angina, peripheral thromboses, acute spinal cord injury, alzheimer's disease., amyotrophic lateral sclerosis (ALS), cerebral aneurys, watershed infarction, brain abscess, meningitis, metastasis, dementia, and others associated complications.

[00154] Present invention uses combinatorial therapy mainly because the mechanism of action of each therapeutic agents can act on the multiple pathways involved in the development of the diseases thus providing an enhanced/ improved modality of treatment.

[00155] The following example will illustrate the invention in further details. These examples do not intent to limit the scope of the invention but is merely representative of presently preferred embodiments of the invention.

EXAMPLES:

Table 1: Composition comprising glyburide

Table 2: Composition comprising glyburide

Table 3: Composition comprising glyburide

Table 4: HPLC analysis data

Table 5: Composition comprising Glyburide

[00156] Batch Formula for ACG009C0106001B

[00157] Objective: Batch with 0.6 mg/mL of glyburide and with combination of suspending agents to check physical properties and to submit for method development.

Table 7: Composition comprising Glyburide

[00158] Description of the Manufacturing Process 1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of sodium benzoate and trisodium citrate dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then glyburide added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles.

[00159] Batch Formula for ACG009C0106002B

[00160] Objective: Batch similar to #001B to check physical properties and to load for stability.

Table 8: Composition comprising Glyburide

[00161] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed. 3. Weighed quantity of sodium benzoate and trisodium citrate dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then glyburide added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles.

Table 9: Stability data:

[00162] Batch Formula for ACG004C0106003B

[00163] Objective: To take a feasibility batch with combination of 2 API’s (Glyburide and Apixaban) to check physicochemical properties and to submit for method development.

Table 10: Composition comprising Glyburide and Apixaban

[00164] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of sodium benzoate, trisodium citrate and SLS dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then 2 API’s (glyburide and apixaban) (one by one) added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles.

[00165] Batch Formula for ACG004C0102004B

[00166] Objective: Batch similar to #003B with increased concentrations of suspending agent to improve sedimentation rate and to load for stability.

Table 11: Composition comprising Glyburide and Apixaban

[00167] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of sodium benzoate, trisodium citrate and SLS dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then 2 API’s (one by one) added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles

[00168] Batch Formula for ACG004C0102005A

[00169] Objective: Batch similar to #002B with 6 mg/mL concentration to check physical properties and to load for stability.

Table 12: Composition comprising Glyburide

[00170] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring. 2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of sodium benzoate and trisodium citrate dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then glyburide added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles.

Tablel3: Stability data:

[00171] Batch Formula for ACG004C0102006B

[00172] Objective: To take batch similar to #004 with higher concentration of apixaban (5mg/mL) and 0.6 mg/mL of glyburide and with different concentration of suspending agent to check physio-chemical properties and to load for stability.

Table 14: Composition comprising Glyburide and Apixaban

[00173] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of hydroxyethyl cellulose and xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of sodium benzoate and trisodium citrate dissolved in purified water (10%w/w from total qty) and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Then glyburide and apixaban added to above step and mixed well.

6. Volume make up to quantity sufficient using purified water.

7. Above suspension was homogenized until uniform dispersion was observed.

8. Fill the above suspension in 30 mL amber colored glass bottles.

[00174] Batch Formula for ACG009C0106007A

[00175] Objective: To take batch with inclusion of Taurine in the formulating and check for physio-chemical properties.

Table 12: Composition comprising glyburide and an antioxidant

[00176] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of Hydroxyethyl cellulose and Xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of Sodium benzoate, trisodium citrate, sodium lauryl sulfate and simethicone 30% emulsion were added into purified water (10%w/w from total qty) mixed well and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Added Taurine to step 4 and mixed well

6. Then API added to above step and mixed well.

7. Volume make up to quantity sufficient using purified water.

8. Above suspension was homogenized until uniform dispersion was observed.

9. Fill the above suspension in 30 mL amber colored glass bottles

[00177] Batch Formula for ACG009C0106007B

[00178] Objective: To take batch with inclusion of Taurine in the formulating and check for physio-chemical properties.

Table 12: Composition comprising glyburide and an antioxidant

[00179] Description of the Manufacturing Process

1. 70%w/w purified water (70%w/w from total qty) weighed, transferred into a beaker and kept under stirring.

2. Weighed quantity of Hydroxyethyl cellulose and Xanthan gum added to step 1 and stirrer well until uniform dispersion was observed.

3. Weighed quantity of Sodium benzoate, trisodium citrate, sodium lauryl sulfate and simethicone 30% emulsion were added into purified water (10%w/w from total qty) mixed well and added to step-1.

4. Check the pH of step 1 and adjust the pH to 3.5-4.5 using lactic acid.

5. Added Taurine to step 4 and mixed well

6. Then API added to above step and mixed well.

7. Volume make upto quantity sufficient using purified water.

8. Above suspension was homogenized until uniform dispersion was observed.

9. Fill the above suspension in 30 mL amber colored glass bottles

EQUIVALENTS

[00180] The present disclosure provides among other things compositions using combination therapy and methods for treating inflammation, vascular disorders, oxidative stress, brain/neurological damages, stroke, and cardiovascular diseases/disorders and their associated complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE [00181] All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.