FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "EFONIDIPINE COMBINATION COMPOSITIONS"
Zuventus Healthcare Limited,
an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE
INVENTION

FIELD OF THE INVENTION
The present invention relates to an oral pharmaceutical composition in the form of bilayer tablet comprising combination of efonidipine in one layer and one or more active ingredients in the second layer along with one or more pharmaceutically acceptable excipients. The invention also relates to the method of preparing the said combination composition.
BACKGROUND OF THE INVENTION
High blood pressure (hypertension) is a common condition in which the long-term force of the blood against the artery walls is high enough such that it may eventually cause health problems, such as heart disease.
Fortunately, there are many medications available to help control hypertension and include diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, vasodilators, calcium channel blockers etc.
Dihydropyridines (DHPs), a type of calcium channel blocker, are commonly prescribed for the treatment of hypertension and angina pectoris. Efonidipine is a calcium channel blocker of the dihydropyridine class and inhibits both L-type and T-type calcium channels. Efonidipine acts by regulating the blood pressure by relaxing the blood vessels and reducing the pressure on them, thus making it easier for the heart to pump more blood throughout the body. In this way, it normalizes the blood pressure in patients with high blood pressure.
Chemically, efonidipine is 2-(N-benzylanilino)ethyl 5-(5,5-dimethyl-2-oxo-l,3,2?c5-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3-carboxylate and have the following structure (I).


Beta blockers, also known as beta-adrenergic blocking agents, are medications that are also routinely used to control hypertension. Beta blockers work by blocking the effects of the hormone epinephrine, also known as adrenaline. The main mechanism behind which beta blockers exert their effect is by the reduction of cardiac output through lowering, of the heart rate.
Metoprolol is a beta 1-selective (cardio-selective) adrenoceptor blocking agent. It is commercially available in two different salt forms viz. metoprolol succinate and metoprolol tartrate.
Chemically, metoprolol succinate is known as s (±)l-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt) and have the following chemical structure (II).

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.
Telmisartan is an orally active and specific angiotensin II receptor (type ATI) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the ATI receptor subtype, which is responsible for the known actions of angiotensin II.
Telmisartan is chemically described as 4'-[(l,4'-dimethyl-2'-propyl [2,6'-bi-lH-benzimidazol]-l'-yl)methyl]-[l,r-biphenyl]-2-carboxylic acid of formula III.


When hypertensive patients do not achieve adequate control of their blood pressure, the options to try and achieve required treatment goals are to increase the dose of monotherapy (which increases the risk of side effects) or to use drug combinations with minimum side effects.
By combining two drugs with different mechanisms of action, an antihypertensive effect of two to five times greater than that obtained by monotherapy is possible. Fixed-dose combinations (both drugs in one tablet) offer additional advantages, such as improved adherence, easier indications and potentially reduced cost. In summary, combination therapy looks like a better option than increasing the dose.
US patent no. 4885284 discloses efonidipine. European Patent no 502314 discloses telmisartan.
US patent no. 4942040 discloses a pharmaceutical preparation giving a controlled and extended release of both a dihydropyridine, e.g. felodipine and a p-adrenoreceptor antagonist, e.g. metoprolol.
International patent application no. WO2009125987 discloses a pharmaceutical formulation containing an extended-release compartment having a dihydropyridine calcium channel blocker and an immediate-release compartment having an angiotensin-2 receptor blocker.
International patent application no. WO2007001066 discloses a pharmaceutical preparation comprising an angiotensin II receptor antagonist, a calcium channel blocker and at least one substance selected from a hydrophilic polymer, an acidic substance and a fluidizing agent.

International patent application no. WO2013030725 discloses once-a-day therapeutically synergistic pharmaceutical dosage form for treatment of cardiovascular disorders, wherein the dosage form comprises a fixed dose combination of metoprolol in extended release form and one or more calcium channel blocker, angiotensin II receptor blocker or angiotensin converting enzyme inhibitor along with one or more rate controlling excipient.
International patent application no. WO1999018957 discloses a pharmaceutical combination of atenolol with amiodipine besylate.
Indian patent application 2523/CHE/2007 discloses a solid dosage form comprising an angiotensin II receptor antagonist drug and calcium channel blocker drug along with non-polymeric, water-soluble pharmaceutically acceptable excipients.
Otsuka et al (Eur J Pharm Biopharm. 2016 Nov; 108:25-31) discloses solid dispersions of efonidipine hydrochloride ethanolate prepared with microwave treatment.
Efonidipine hydrochloride ethanolate has a very low solubility in water. It is classified as a poorly soluble drug, and improvements in its solubility and higher bioavailability with oral administration are needed. Solid dispersion has been widely used to improve the dissolution rate, solubility, and oral absorption of poor water-soluble drugs.
Metoprolol has been classified as a class I substance according to the Biopharmaceutics Classification Scheme (BCS), meaning that it is highly soluble and highly permeable. The drug is readily and completely absorbed throughout the whole intestinal tract but is subject to extensive first pass metabolism resulting in incomplete bioavailability (about 50%).
Telmisartan belongs to class II drug in BCS classification and it has good permeability. But, it is poorly water soluble. Biological half-life of telmisartan is 24 hours and also shows very low bioavailability (only 42~58%). The absorption of a drug is often limited by dissolution rate.
Considering these physicochemical parameters, there is an ongoing need for the development of improved dosage forms comprising an extended release metoprolol or telmisartan with

calcium channel blocker i.e efonidipine, which is safe and has an enhanced therapeutic effect over the existing individual drug therapy.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising efonidipine in one layer and one or more active ingredients in the second layer along with one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a pharmaceutical composition comprising efonidipine wherein efonidipine is present in the form of solid dispersion.
In another embodiment, the present invention provides a pharmaceutical composition wherein one or more active ingredients comprise beta blockers and angiotensin II receptor blockers.
In another embodiment, the present invention provides a pharmaceutical composition wherein the beta blocker comprises one or more of metoprolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol and nebivolol.
In another embodiment, the present invention provides a pharmaceutical composition wherein the angiotensin II receptor blocker comprises one or more of telmisartan, valsartan, losartan, irbesartan, azilsartan, candesartan, eprosartan, and olmesartan.
In another embodiment, the present invention provides a pharmaceutical composition wherein the composition comprises about 2.5mg to about 80mg of efonidipine, about 25 mg to about 200 mg of beta blocker and about 20 mg to about 800 mg of angiotensin II receptor blocker.
In another embodiment, the present invention provides a pharmaceutical composition, wherein one or more pharmaceutically acceptable excipients comprise fillers, binders, disintegrants, lubricants, rate controlling polymers, coloring agents and flavoring agents.
In another embodiment, the present invention provides a process for preparing pharmaceutical composition in the form of a bilayer tablet comprising:

i. Preparing the granules of efonidipine;
ii. Preparing the granules of beta-blocker or angiotensin II receptor blockers;
iii. Lubricating the individual granules with suitable lubricating agent;
iv. Compressing the individual granules of step iii) into a bilayer tablet.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition in the form of a bilayer tablet comprising efonidipine in one layer and one or more active ingredients in the second layer along with one or more pharmaceutically acceptable excipients.
The present inventors while working on the development of pharmaceutical composition comprising a fixed dose combination of efonidipine with beta blockers or angiotensin II receptor blockers, found that the pharmaceutical composition of the present invention provides a therapeutically effective release of the actives over a period of about 24 hours.
The term bilayer tablet refers to the double-layer tablet and consist of two same or different drugs combined in a single dose for effective treatment of the disease.
Efonidipine is a slightly-soluble medication and has a poor absorbability. There are various methods that are used to increase the absorbability of slightly soluble medication. One such method is formation of a solid dispersion. The solid dispersion is a substance obtained by dispersing a medication into a carrier in a monomolecular state. In solid dispersion, the medication is retained in a completely amorphous state. In general, an amorphous form is expected to have a high absorbability. Thus, forming a solid dispersion of efonidipine would help to increase the absorbability of efonidipine when present in the solid dosage form.
The term beta blockers as used herein, refers to beta blocker base, or any pharmaceutically acceptable salt or ester thereof.
Beta blockers may be selected from, but not limited to one or more of metoprolol, acebutolol, . atenolol, betaxolol, bisoprolol, celiprolol, esmolol and nebivolol.

In a preferred embodiment, beta blocker is metoprolol.
In another embodiment, metoprolol is present in an extended release form.
The present invention provides an extended release composition comprising metoprolol together with one or more rate controlling polymers and other suitable pharmaceutically acceptable excipients.
Extended release formulations may be useful to reduce the frequency of drug administration, improve patient compliance, reduce drug toxicity, reduce drug level fluctuation in blood, stabilize medical condition with more uniform drug levels, reduce drug accumulation with chronic therapy, improve bioavailability of some drugs because of spatial control, and reduce total drug usage when compared with immediate release drugs.
The term angiotensin II receptor blockers as used herein, refers to angiotensin II receptor blocker base, or any pharmaceutically acceptable sail or ester thereof.
The angiotensin II receptor blockers may be selected from, but not limited to one or more of telmisartan, valsartan, losartan, irbesartan, azilsartan, candesartan, eprosartan, and olmesartan.
In a preferred embodiment, the angiotensin II receptor blocker is telmisartan.
The pharmaceutical dosage form of the present invention further comprises other pharmaceutically acceptable excipients selected from the group consisting of diluent, filler, binder, glidant, lubricants, disintegrants, rate controlling polymers, cushioning agents and flavoring agent.
Examples of suitable diluents include, but not limited to one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, powdered cellulose, silicified cellulose, cellulose acetate and celluloses, starch, calcium phosphate, dibasic calcium phosphate or metal carbonate.

Examples of suitable binders include, but not limited to, starch, gums, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
Suitable lubricants include, but are not limited to, one or more talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, talc, colloidal silicon dioxide and sodium benzoate.
Compositions of the present invention may include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
Suitable disintegrant may include, but not limited to, one or more of starch, croscarmellose sodium, crospovidone, and sodium starch glycolate.
Suitable rate controlling polymers may include, but not limited to cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof.
Cellulose derivatives include, but not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethyl methyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.
Polyhydric alcohols include, but are not limited to, polyethylene glycol (PEG) or polypropylene glycol; or any combinations thereof.

Saccharides, gums and their derivatives include, but not limited to, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan gum, karaya gum, tragacanth, carrageenan, acacia gum, arabic gum or gellan gum or the like; or any combinations thereof.
Vinyl derivatives, polymers, copolymers or mixtures thereof include, but not limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations thereof.
Polyalkylene oxides or copolymers thereof include, but not limited to, polyethylene oxide, polypropylene oxide, poly (oxyethylene)-poly (oxypropylene) block copolymers (poloxamers) or combinations thereof.
Acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol. Pharmaceutically acceptable acrylic polymer may be include one or more, but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethaerylale, poly(methyl methacrylate), poly(mcthyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate.
The examples given below serve to illustrate embodiments of the present invention. However, they do not intend to limit the scope of present invention.
EXAMPLES
Example 1:

Composition Qty/Tab (mg)

Efonidipine layer
Efonidipine hydrochloride ethanolate 20-60
Methanol q.s.
Methylene chloride q.s.
Hydroxypropyl methyl cellulose acetate succinate 100-140
Dibasic calcium phosphate 20-60
Microcrystalline cellulose 330-370
Crospovidone 5-40
Colloidal silicon dioxide 5-30
Crospovidone 5-30
Magnesium stearate 1-5
S (-) Metoprolol succinate ER layer
S (-) Metoprolol succinate eq to S (-) Metoprolol tartrate 20-60
Hypromellose 160-220
Dibasic calcium phosphate 45-85
Lactose monohydrate 420-460
Isopropyl alcohol q.s.
Purified water q.s.
Povidone IP 30-70
Carbomer 15-55
Colloidal silicon dioxide 1-7
Magnesium stearate 1-7
Procedure:
Efonidipine drug solution was prepared by mixing efonidipine, methanol, methylene chloride and hydroxypropyl methylcellulose acetate succinate under continuous stirring. Iron Oxide yellow, dibasic calcium phosphate, microcrystalline cellulose and crospovidone were mixed together and charged into fluidized bed dryer. Granules were prepared by spraying the drug solution onto the above dry mixture by top spray method followed by drying. Dried granules

were lubricated in a blender by using colloidal silicon dioxide, crospovidone and magnesium stearate.
For preparing metoprolol granules, S (-) metoprolol succinate, hypromcllosc and dibasic calcium phosphate and lactose monohydrate were mixed together in a rapid mixer granulator. Binder solution was prepared by mixing isopropyl alcohol, purified water and povidone until clear solution is formed. This binder solution was mixed slowly into dry mix until wet mass is formed. Metoprolol granules were prepared by milling this wet mass through multimill followed by drying. Dried granules were lubricated using carbomer, colloidal silicon dioxide and magnesium stearate.
Bilayer tablet was prepared from lubricated efonidipine and metoprolol granules by using compression machine.
Example 2

Composition Qty/Tab (mg)
Efonidipine layer
Efonidipine hydrochloride ethanolate 20-60
Methanol q.s.
Methylene chloride q.s.
Hydroxypropyl methyl cellulose acetate succinate 100-140
Dibasic calcium phosphate 20-60
Microcrystalline cellulose 330-370
Crospovidone 5-40
Colloidal silicon dioxide 5-30
Crospovidone 5-30
Magnesium stearate 1-5
Telmisartan layer
Telmisartan 20-80
Sodium hydroxide 80-120
Meglumine 45-85
Povidone 380-420

Purified water q.s.
Meglumine q.s.
Mannitol 30-70
Talc 15-45
Magnesium stearate 1-8
The formulation was prepared by the procedure as described above and is evaluated for various parameters.

WE CLAIM:
1. A pharmaceutical composition in the form of a bilayer tablet comprising efonidipine in one layer and one or more active ingredients in the second layer along with one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1, wherein one or more active ingredients comprise beta blockers and angiotensin II receptor blockers.
3. The pharmaceutical composition of claim 2, wherein the beta blocker comprises one or more of metoprolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol and nebivolol.
4. The pharmaceutical composition of claim 2, wherein the angiotensin II receptor blocker comprises one or more of valsartan, telmisartan, losartan, irbesartan, azilsartan, candesartan, eprosartan, and olmesartan.
5. The pharmaceutical composition of claim 1, wherein the composition comprises about 20mg to about 60mg of efonidipine.
6. The pharmaceutical composition of claim 2, wherein the composition comprises about 20 mg to about 60 mg of beta blocker.
7. The pharmaceutical composition of claim 2, wherein the composition comprises about 20 mg to about 80 mg of angiotensin II receptor blocker.
8. The pharmaceutical composition of claim 1, wherein one or more pharmaceutically acceptable excipients comprise fillers, binders, disintegrants, lubricants, rate controlling polymers, coloring agents and flavoring agents.

9. The process for preparing pharmaceutical composition in the form of a bilayer tablet comprising:
i. Preparing the granules of efonidipine;
ii. Preparing the granules of beta-blocker or angiotensin II receptor blockers;
iii. Lubricating the individual granules with suitable lubricating agent; iv. Compressing the individual granules of step iii) into a bilayer tablet.