DESC:A COMBINATION FOR CARDIOVASCULAR DISEASES AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to a combination of anthelmintic drug and antifungal agent used for the treatment of cardiovascular diseases such as heart attack (myocardial infarction) or heart failure. Additionally, the present invention also relates to the process of preparing such composition.

BACKGROUND OF THE INVENTION

A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck or jaw. Often it occurs in the center or left side of the chest and lasts for more than a few minutes. The discomfort may occasionally feel like heartburn. Other symptoms may include shortness of breath, nausea, feeling faint, a cold sweat or feeling tired. About 30% of people have atypical symptoms. Women more often present without chest pain and instead have neck pain, arm pain or feel tired. Among those over 75 years old, about 5% have had an MI with little or no history of symptoms. An MI may cause heart failure, an irregular heartbeat, cardiogenic shock or cardiac arrest.

Myocardial infarction (MI) is the most severe and fatal manifestation of coronary heart disease, globally characterized by extremely high rates of disability and mortality. Its pathophysiology is linked to increase infract size, hypertrophy, inflammation, apoptosis, and reduced left ventricular ejection volume. Growing evidence indicates that inflammation and fibrosis are major contributors to heart failure. Therefore, there is an urgent need to identify new agents to mitigate the cardiac inflammation and fibrosis caused by MI.

Recently, levamisole has been reported as a potassium channel agonist, enhancing cardiac function by reducing calcium overload, inflammation, and hypertrophy, while improving left ventricular ejection volume in preclinical studies. Meanwhile, ciclopirox has shown the ability to inhibit deoxyhypusine hydroxylase (DOHH), decreasing hypusination of elongation factor 5A (e1F5A), which in turn reduces infarct size and inflammation in animal models. Together, these findings suggest that a combination of Levamisole and Ciclopirox may have a synergistic effect, particularly in the treatment of MI in animal models

Levamisole is a medication that has been used to treat parasitic worm infections in humans and animals. It was previously used as an adjuvant therapy for certain types of cancer, but its used in cancer treatments has significantly decreased due to safety concerns. Levamisole, although primarily known as an anthelmintic medication used to combat parasitic worm infections in both humans and animals, had been employed in the past as an adjuvant therapy for specific types of cancer.

Levamisole is a synthetic imidazothiazole derivative which is used widely in the treatment of worm infestations in both humans and animals. As it is an anthelmintic, it works by targeting the nematode nicotinaergic acetylcholine receptor. As an immunomodulator, it appears that Levamisole is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjunctly along with 5FU for Stage III colon cancer. Levamisole has been reported as potassium channel agonist and improved the cardiac activity by decreasing calcium overloading, inflammation and hypertrophy of heart as well as improved the ejection volume of left ventricle.

Ciclopirox is a broad-spectrum antifungal medication, belongs to hydroxypyridone derivatives, which is also having antibacterial and anti-inflammatory properties. Its main mode of action is thought to be its high affinity for trivalent cations, which inhibit essential co-factors in enzymes. Ciclopirox exhibits either fungistatic or fungicidal activity in vitro against a broad spectrum of fungal organisms, such as dermatophytes, yeasts, dimorphic fungi, eumycetes, and actinomycetes. In addition to its broad spectrum of action, ciclopirox also exerts antibacterial activity against many Gram-positive and Gram-negative bacteria. Furthermore, the anti-inflammatory effects of ciclopirox have been demonstrated in human polymorphonuclear cells, where ciclopirox has inhibited the synthesis of prostaglandin and leukotriene. Ciclopirox can also exhibit its anti-inflammatory effects by inhibiting the formation of 5-lipoxygenase and cyclooxygenase. Several reports suggest that Ciclopirox inhibits deoxyhypusine hydroxylase (DOHH) and decreases the hypusination of elongation factor 5A (elF5A) and that results in decrease in infarct size as well as inflammation in animal studies.

The combination of an anthelmintic agent, and antifungal agent along with one or more pharmaceutically acceptable excipients has advantageous properties which makes these combinations suitable for treating & preventing cardiovascular diseases including heart attack (myocardial infarction) or heart failure.

OBJECTIVES OF THE INVENTION

The principal objective of the present invention is to provide a pharmaceutical combination comprising an anthelmintic agent or pharmaceutically acceptable salts thereof and antifungal agent or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a pharmaceutical combination comprising anthelmintic agent or pharmaceutically acceptable salts thereof and antifungal agent or pharmaceutically acceptable salts thereof, wherein the anthelmintic agent and synthetic antifungal agent includes its ester(s) metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters, solvate.

Another objective of the present invention is to provide a pharmaceutical composition comprising anthelmintic agent and antifungal agent along with one or more pharmaceutically acceptable excipients, wherein the anthelmintic agent is levamisole and the antifungal agent is ciclopirox.

Another objective of the present invention is to provide a combination comprising about 1-200mg of an anthelmintic agent or pharmaceutically acceptable salts thereof and about 1-300mg of antifungal agent or pharmaceutically acceptable salts thereof, wherein the said anthelmintic agent is levamisole and the said antifungal agent is ciclopirox.

Another objective of the present invention is to provide a combination in the form of co-crystal using about 1-200mg of an anthelmintic agent or pharmaceutically acceptable salts thereof and about 1-300mg of antifungal agent or pharmaceutically acceptable salts thereof, wherein the said anthelmintic agent is levamisole and the said antifungal agent is ciclopirox.

Another objective of the present invention is to chemically conjugate an anthelmintic agent or pharmaceutically acceptable salts thereof, preferably Levamisole and an antifungal agent or pharmaceutically acceptable salts thereof, preferably Ciclopirox, through cleavable linkers sensitive to pH for cleavage.

Further objective of the present invention is to provide a pharmaceutical composition comprising:
a) an anthelmintic agent in the range of 1-200mg;
b) an antifungal agent in the range of 1-300mg; and
c) one or more pharmaceutical excipients.
wherein the said composition is used for the treatment of cardiovascular diseases including heart attack, myocardial infarction and/or heart failure by administering the said composition.

Another objective of the present invention is to provide a pharmaceutical composition comprising anthelmintic agent and antifungal agent along with one or more pharmaceutical excipients, wherein the one or more pharmaceutical excipients are selected from a group comprising diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a pharmaceutical combination comprising an anthelmintic agent or pharmaceutically acceptable salts thereof and antifungal agent or pharmaceutically acceptable salts thereof along with one or more pharmaceutically acceptable excipients.

The present invention relates to a pharmaceutical composition comprising levamisole and ciclopirox along with one or more pharmaceutically acceptable excipients.

In another aspect of the present invention relates to a pharmaceutical composition comprising about 1mg to 200mg of levamisole and about 1mg to 300mg of ciclopirox along with one or more pharmaceutically acceptable excipients.

In another aspects of the present invention provides a combination comprising:
(a) therapeutically effective amount of anthelmintic agent or pharmaceutically acceptable salts thereof;
(b) therapeutically effective amount of antifungal agent or pharmaceutically acceptable salts thereof.

In another aspects of the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of anthelmintic agent or pharmaceutically acceptable salts thereof;
(b) therapeutically effective amount of antifungal agent or pharmaceutically acceptable salts thereof, Wherein the said anthelmintic agent is in the range of 1-200 mg and the said antifungal agent is in the range of 1-300mg.
wherein the said combination is used for the treatment of cardiovascular diseases, including heart attack, myocardial infarction and/or heart failure.

In another aspects of the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of anthelmintic agent or pharmaceutically acceptable salts thereof;
(b) therapeutically effective amount of antifungal agent or pharmaceutically acceptable salts thereof; and
(c) one or more pharmaceutical excipients.
wherein the said anthelmintic agent is levamisole 50 mg and the said antifungal agent is ciclopirox in the range of 50mg-100mg. and the said composition is used for the treatment of cardiovascular diseases, including heart attack, myocardial infarction and/or heart failure.

In another aspect of the present invention is to provides the use of the combination of anthelmintic agent and synthetic antifungal agent in the preparation of medicines for the prevention and/or treatment of cardiovascular diseases including heart attack (myocardial infarction), heart failure, abnormal heart rhythms or arrhythmias, aorta diseases, congenital heart disease, deep vein thrombosis, heart muscle diseases and other related disorders.

In another aspect of the present invention it provides a process for the preparation of the pharmaceutical composition, wherein the said pharmaceutical composition comprising:
a) therapeutically effective amount of anthelmintic agent or pharmaceutically acceptable salts thereof;
b) therapeutically effective amount of antifungal agent or pharmaceutically acceptable salts thereof; and
c) one or more pharmaceutical excipients.
wherein the said pharmaceutical composition is used for the treatment of cardiovascular diseases including heart attack (myocardial infarction) and/or heart failure.

In another aspect of the present invention it provides a process for preparation of pharmaceutical composition comprising:
a) therapeutically effective amount of anthelmintic agent;
b) therapeutically effective amount of antifungal agent; and
c) one or more pharmaceutical excipients, wherein the said anthelmintic agent is administered in an amount of about 1-200 mg and the said antifungal agent is administered in 1-300mg.
wherein the said composition is used for the treatment of cardiovascular diseases including heart attack, myocardial infarction and heart failure.

In one more aspect, the present invention provides a kit comprising:
a) composition comprising therapeutically effective amount of Levamisole and one or more pharmaceutically acceptable excipients;
b) composition comprising therapeutically effective amount of ciclopirox and one or more pharmaceutically acceptable excipients.

According to another aspect, the present invention provides a method of treating or prevention of cardiovascular diseases including heart attack (myocardial infarction), heart failure, abnormal heart rhythms or arrhythmias, Aorta diseases, congenital heart disease, deep vein thrombosis, heart muscle diseases and other related disorders by administering therapeutically effective amount of anthelmintic agent and therapeutically effective amount of antifungal agent either simultaneously, concurrently, alternately or sequentially.

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

DETAIL DESCRIPTION OF THE INVENTION

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

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

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

Accordingly, the present invention relates to a combination comprising anthelmintic agent and antifungal agent used for the treatment of cardiovascular diseases.

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

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

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to organic acids and inorganic acid salts.

The term “cardiovascular disease” is used in the context of present invention refer to heart attack (myocardial infarction), heart failure, abnormal heart rhythms or arrhythmias, Aorta diseases, congenital heart disease, deep vein thrombosis, heart muscle diseases and other related disorders.

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

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

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

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

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

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

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

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

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

Coloring agents include any FDA approved color for pharmaceutical use.

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

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

Solid form preparations for oral administration may include capsules, tablets, pills, powders, granules, and suppositories. For solid-form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filter an extender.

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

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

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

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

Accordingly, in an embodiment, the present invention provides a composition comprising of:
(a) therapeutically effective amount of anthelmintic agent;
(b) therapeutically effective amount of antifungal agent; and
(c) one or more pharmaceutically acceptable excipients.

In another embodiment of the present it provides a pharmaceutical composition comprising co-crystal of levamisole or their pharmaceutically acceptable salts, derivative, metabolite, isomers or polymorphs thereof and ciclopirox or their pharmaceutically acceptable salts, derivative, metabolite, isomers or polymorphs thereof.

In another embodiment of the present it provides a pharmaceutical composition comprising co-crystal of levamisole and ciclopirox along with one or more pharmaceutically acceptable excipients.

In another embodiment of the present it provides a pharmaceutical composition comprising complex of levamisole and ciclopirox, wherein the said composition further comprising one or more pharmaceutically acceptable excipients.

In another embodiment of the present it provides a pharmaceutical composition comprising complex of levamisole and ciclopirox, wherein the said composition further comprising one or more pharmaceutically acceptable excipients, wherein the said composition is used for the treatment or prevention of cardiovascular diseases including heart attack (myocardial infarction), heart failure, abnormal heart rhythms or arrhythmias, Aorta diseases, congenital heart disease, deep vein thrombosis, heart muscle diseases and other related disorders.

In another embodiment of the present it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of anthelmintic agent;
(b) therapeutically effective amount of antifungal agent;
(c) less than 20% w/w/ of binders;
(d) about 10% w/w to about 80% w/w of diluents;
(e) less than 20% w/w of disintegrant;
(f) one or more pharmaceutically acceptable excipients.

In another embodiment of the present it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of anthelmintic agent;
(b) therapeutically effective amount of antifungal agent;
(c) less than 20% w/w/ of binders;
(d) about 10% w/w to about 80% w/w of diluents;
(e) less than 20% w/w of disintegrant;
(f) about 0.01% w/w to about 10% w/w of lubricants;
(g) one or more pharmaceutically acceptable excipients.

In another embodiments of the present invention provides a pharmaceutical composition comprising about 10mg to about 100mg of Levamisole; about 10mg to about 500mg of Ciclopirox; about 75mg of lactose; about 10mg of hydroxypropyl methyl cellulose; about 10.5mg of colloidal silicon dioxide; about 4mg of maize starch; about 2.5 mg of magnesium stearate and optionally one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention the said anthelmintic agent or pharmaceutically acceptable salts thereof is in the range of 1mg – 200mg.

In another embodiment of the present invention the said anthelmintic agent or pharmaceutically acceptable salts thereof is selected from the group comprising levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine, pyrantel or combination thereof.

In another embodiment of the present invention, the said anthelmintic agent or pharmaceutically acceptable salts thereof is Levamisole is 25- 100 mg.

In another embodiment of the present invention, the said antifungal agent or pharmaceutically acceptable salts thereof is in the range of 1-300mg.

In another embodiment of the present invention the said antifungal agent or pharmaceutically acceptable salts thereof is selected from the group comprising hydroxypyridone derivatives.

In another embodiment of the present invention, the said antifungal agent or pharmaceutically acceptable salts thereof is ciclopirox is in the range of 50mg-200mg.

In another embodiment of the present invention provides a pharmaceutical composition comprising levamisole, and ciclopirox, wherein the said composition is prepared by dry granulation, wet granulation, direct compression or compaction method.

In another embodiment of the present invention provides a pharmaceutical composition comprising levamisole, wherein the levamisole is in the form of crystalline or amorphous polymorphic form.

In another embodiment of the present invention provides a pharmaceutical composition comprising ciclopirox, wherein ciclopirox is in the form of crystalline or amorphous polymorphic form.

In another embodiment of the present invention provides a pharmaceutical composition comprising combination of anthelmintic agent and antifungal agents along with one or more pharmaceutically acceptable excipients, wherein the anthelmintic agent is levamisole and antifungal agent is ciclopirox.

In another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is in the form of immediate release, delayed release, sustained release, extended release, controlled release or modified release form.

In another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition can be formulated by any suitable granulation methods are known in the art such as wet granulation, direct compression, dry granulation/compaction or melt granulation. More preferably, composition is prepared by direct compression method.

In another embodiment of the present invention provides a pharmaceutical composition comprising combination of about 1-200mg of levamisole and about 1-300mg of ciclopirox along with one or more pharmaceutical excipients.

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

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

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

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

Another embodiment of the present invention it provides a pharmaceutical composition, wherein the composition is encapsulated in to soft gel Capsules filled with liquid.

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

Another embodiment of the present invention it provides a pharmaceutical composition, wherein the composition is encapsulated in to Capsules filled with granules.

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

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

Another embodiment of the present invention provides a pharmaceutical composition comprising levamisole and ciclopirox, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising of levamisole in the form of soft gelatin capsule and ciclopirox is in the form of pellet, mini-pellet, mini-tablet, granule or powders.

Another embodiment of the present invention provides a pharmaceutical composition comprising levamisole, and ciclopirox, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising ciclopirox in the form of soft gelatin capsule and levamisole is in the form of pellet, mini-tablet, granule or powders.

In another embodiment of the present invention provides a combination of about 1-200mg of levamisole and about 1-300mg of ciclopirox, wherein the combination is used for the treatment of cardiovascular diseases like myocardial infarction or heart attack.

In another embodiment of the present invention provides a combination levamisole and ciclopirox, wherein the levamisole is having particle size of D90 less than 500 µm

In another embodiment of the present invention provides a combination levamisole and ciclopirox, wherein the ciclopirox is having particle size of D90 less than 500 µm

Another embodiment of the present invention provides a kit comprising:
(a) composition comprising therapeutically effective amount of levamisole and one or more pharmaceutically acceptable excipient;
(b) composition comprising therapeutically effective amount of ciclopirox and one or more pharmaceutically acceptable excipients;

wherein the composition of levamisole and composition of ciclopirox are administered either simultaneously, concurrently, alternately and/or sequentially.

Another embodiment of the present invention provides pharmaceutical kit comprising two parts divided with a perforation or a punch or other suitable means to place two medicaments separately, wherein medicaments are selected from levamisole and antifungal agent respectively.

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

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

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

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

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

Example 1:

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

Examples 2:

Ingredients Amount (mg/tablet)
Levamisole 50.00
Ciclopirox 100.00
Lactose Monohydrate 75.50
Hypermellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10% of tablet weight

Preparation:
Levamisole, Ciclopirox, lactose monohydrate, Hypromellose, colloidal silicon dioxide, maize starch and magnesium stearate are mixed together. The blend was compressed into tablets and subsequently subjected to a film coating process.

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

1. A pharmaceutical composition comprising an anthelmintic agent or its salts thereof, and antifungal agent or its salts thereof along with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the anthelmintic agent is selected from the group comprising levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine, pyrantel or combination thereof.

3. The pharmaceutical composition as claimed in claim 1, wherein the antifungal agent is selected from the group comprising of hydroxypyridone derivatives.

4. The pharmaceutical composition as claimed in claim 2, wherein the particle size of the anthelmintic agent is D90 less than 500 µm.

5. The pharmaceutical composition as claimed in claim 3, wherein the particle size of the antifungal agent is D90 less than 500 µm.

6. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising binders, disintegrates, lubricants, plasticizers, opacifiers and/or diluents.

7. The pharmaceutical composition as claimed in claim 1, wherein the said pharmaceutical composition comprising:
a. less than 20% w/w/ of binders;
b. about 10% w/w to about 80% w/w of diluents;
c. less than 20% w/w of disintegrant;
d. one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition as claimed in claim 1, wherein the said pharmaceutical composition comprising:
a. less than 20% w/w/ of binders;
b. about 10% w/w to about 80% w/w of diluents;
c. less than 20% w/w of disintegrant;
d. about 0.01% w/w to about 10% w/w of lubricants;
e. one or more pharmaceutically acceptable excipients.

9. A kit comprising:
(a) Composition comprising therapeutically effective amount of levamisole and one or more pharmaceutically acceptable excipients;
(b) Composition comprising therapeutically effective amount of ciclopirox and one or more pharmaceutically acceptable excipients;
Wherein the composition of levamisole and composition of ciclopirox are administered either simultaneously, concurrently, alternately and/or sequentially.

10. The kit as claimed in claim 10, wherein the kit comprises of two parts divided with a perforation or a punch or other suitable means to place two medicaments separately.

Dated this the 27th day of September 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer