Extended-release formulations for cilnidipine and their manufacturing processes

Abstract

The present invention provides various extended-release formulations of Cilnidipine, particularly extended release oral formulations of Cilnidipine such as granules, powder for oral suspension, capsules and tablets and method of manufacturing the same. More particularly, monolithic matrix and OROS formulations are provided to address issues mainly inability or failure to sustain plasma levels beyond couple of hrs. The extended-release formulations exhibit sustained in vitro release in phosphate buffer of pH 6.8 with 1% sodium lauryl sulphate. The present invention also provides simple processes to prepare various extended-release formulations of Cilnidipine including monolithic matrix and osmotic drug delivery system. Consistent plasma levels improve safety and efficacy, provide consistent therapeutic benefits while minimizing adverse effects, and thus achieve better patient compliance.

Description

[0001] Title: Extended-Release Formulations for Cilni dipine and their Manufacturing

[0002] Processes

[0003] FIELD OF THE INVENTION:

[0004] The present invention provides various extended-release formulations of Cilnidipine, particularly extended release oral formulations of Cilnidipine such as granules, powder for oral suspension, capsules and tablets and method of manufacturing the same. The formulations of the present invention address issues with conventional formulations, mainly inability or failure to sustain plasma levels beyond couple of hrs. The extended-release formulations of the present invention exhibit sustained in vitro release in phosphate buffer of pH 6.8 with 1% sodium lauryl sulphate meeting at least one, preferably at least two and more preferably, all three criteria as follows, not more than 35 % Cilnidipne is released over two hrs., not more than 75 %, preferably, not more than 70 % Cilnidipine is released over 6 hrs. and at least 80 % Cilnidipine is released over 16 hrs.

[0005] The present invention also provides a process to prepare various extended-release formulations of Cilnidipine including osmotic drug delivery system. Consistent plasma levels improve safety and efficacy, provide consistent therapeutic benefits while minimizing adverse effects and thus achieves better patient compliance.

[0006] Objects of the invention

[0007] A first object of the invention is to arrive at an extended release formulations of Cilnidipine which can address issues with an immediate release formulations, particularly addressing rapid drop in the plasma levels within a few hrs of administration.

[0008] Second object of the invention is to cause extended release of Cilnidipine such that at least 50 % is not released in two hrs (Tmax is 2 - 2.5 hrs) when tested in vitro. For in vitro release, the specification sets a limit of not more than 35 % over two hours. Third object of the invention is to provide a simple and robust manufacturing process for preparing extended-release formulations of Cilnidipine.

[0009] Background of invention:

[0010] The global burden of hypertension is substantial, affecting a significant portion of the population, with approximately 972 million individuals experiencing high blood pressure. Despite advancements in antihypertensive medications, cardiovascular and cerebrovascular diseases resulting from hypertension remain a leading cause of mortality worldwide. This is particularly concerning considering the projected increase in age-related ailments, including hypertension, stroke, and coronary heart disease, due to the growing aging population. Consequently, there is an urgent and compelling need for improved antihypertensive drugs that can effectively address these health challenges.

[0011] Cilnidipine, belonging to the lipophilic dihydropyridine-type calcium antagonist class, demonstrates hypotensive effects by specifically targeting L-type calcium channels in vascular smooth muscle cells, inhibiting the flow of calcium ions.

[0012] Cilnidipine, a dihydropyridine calcium antagonist, is utilized for treating hypertension and hypertension-associated vascular disorders. It falls under BCS Class II category due to its low aqueous solubility and inadequate dissolution rate. With a log P value of 4.7, it exhibits high lipophilicity, resulting in favorable intestinal permeability. However, its oral bioavailability in humans is significantly low, approximately 13%. The primary factors contributing to this limited oral bioavailability are its low aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism in the liver. Despite these challenges in oral absorption, Cilnidipine is considered relatively more effective and safer than other calcium antagonists for managing hypertension.

[0013] Cilnidipine tablets are administered once a day. Cilnidipine is very rapidly absorbed and peak plasma concentration is achieved in 2 - 2.5 hrs. Elimination half-life is 7.5 hrs. If a tablet is administered at 8 am, peak plasma concentrations are achieved by or before 11 am. Although elimination half-life is 7.5 hrs, it is observed that more than half of the dose is eliminated within couple of hrs after achieving Cmax. Thus from 2 pm to next day morning, plasma levels of Cilnidipine are low.

[0014] In a study conducted by Jieon Lee et al (2014), it was noted that when Cilnidipine 10 mg is administered alone, peak plasma concentration which is more than 6 ng / ml is achieved at 2 - 2.5 hrs with reported Cmax at 8.9 + 4.2 ng / ml. But it rapidly drops to less than 2 ng / ml at or after 6 hrs. This is a 66 - 77 % decrease. Also, it further continues to drop because the elimination half-life is also at 7.5 hrs and hence half of the administered dose is already eliminated.

[0015] The plasma concentration versus time curve of Jieon’ s study is provided in figure 1A. Further, in that study, Cilnidipine was administered with Valsartan 160 mg. However, there was no impact of this combined administration on plasma levels of either medicine. This effect is provided in figure IB.

[0016] In order to sustain Cilnidipine levels beyond 2.5 hrs and preferably beyond its elimination half- life was thought desirable. Therefore, extended release formulations of the present invention are developed.

[0017] W02009140527A1 provides an extended release tablet composition of dihydropyridine compound or a prodrug or salt thereof for oral administration containing a first release control agent and a second release control agent and a third release control agent. The dihydropyridine compound exemplified is Nifedipine. No formulation of Cilnidipine is provided.

[0018] US patent US 8,865,213 B2 discloses a multiparticulate modified release pharmaceutical composition comprising a first portion and a second portion wherein both the portions contain a calcium channel blocker and both portions have different release profiles and wherein active from the first portion is released in pH dependent manner.

[0019] Some mucoadhesive films of Cilnidipine are reported in the literature to cause sustained release of Cilnidipine. The mucoadhesive buccal films make the patients extremely uncomfortable to retain for 24 hrs. A patient may spit out the film. Such films are good for immediate-release formulations where patients need not hold them for long in the oral cavity.

[0020] There is a need of time to provide oral, swallowable Cilnidipine formulations that which can produce sustained plasma levels which shall be evident by testing in vitro release of such formulations. In testing in vitro release, the crucial time points will be 2 hrs, where peak plasma concentration is observed, and 6 hrs, where the major drop in plasma concentration is observed.

[0021] In a 24 hrs cycle after delivering Cilnidipine dose, it is also crucial to ensure that at least at 16 hrs. 80 %, preferably 85 % and most preferably, 90 % of Cilnidipine is released so that this maximum amount is sustained over its elimination half-life of 7.5 hrs starting from 16 hrs. (16 hrs. + 7.5 hrs.= 23.5 hrs.)

[0022] Further aim is to ensure that certain amount of Cilnidipine remains unreleased at 2 hrs. and 6 hrs. and not more than 20 % is unreleased at 16 hrs.

[0023] Summary of the Invention:

[0024] The present invention aims to develop oral swallowable extended-release Cilnidipine compositions which can significantly sustain plasma levels beyond 6 hrs, which shall be evident by testing the in vitro release of such formulations.

[0025] Therefore, in vitro release is a crucial factor. In the present invention, it is ensured that Cilnidipine is released continuously. It is further ensured that not more than 35 %, preferably not more than 30 %, and more preferably, not more than 25 % is released within the first two hrs.

[0026] The release is controlled by a polymer, preferably a swellable polymer. The swellable polymer can be hydrophilic or hydrophobic. The present invention does not employ a pH-dependent or an enteric polymer even when it is desirable to control release for the first two hrs. This is because once an enteric or pH-dependent polymer breaks open, it results in a burst release which is undesired. Release is controlled for at least 6 hrs. so that not more than 75 %, preferably, not more than 70 % and most preferably, not more than 60 % Cilnidipine is released in the first 6 hrs.

[0027] Under the first aspect, the present invention provides extended-release formulations of Cilnidipine which can address issues with immediate-release formulations, particularly addressing rapid drop / reduction in the plasma levels within a few hrs of administration of an immediate release formulation. The formulations can sustain plasma levels of Cilnidipine for longer period causing its effect to sustain over 24 hrs. The Tmax can be extended from 2 hrs to one of the 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12hrs. by using different types of formulations incorporating different concentration and different grades of polymers.

[0028] Under the second aspect, the invention provides extended-release formulations of Cilnidipine such that not more than 35 % is released in the first two hrs. Preferably, not more than 30 % and more preferably, not more than 25 % is released in first two hrs. Also, since a major drop in the plasma levels is observed at and after 6 hrs., it is ensured that not more than 75 %, preferably not more than 70 %, and most preferably, not more than 60 % of Cilnidipine is released in 6 hrs.

[0029] Further for in vitro release, the specification sets a limit of not more than 35 % should be released over two hours. Further, the specification sets a limit that preferably not more than 75 % of Cilnidipine is released in 6 hrs.

[0030] To achieve the sustained release, two types of extended-release formulations are developed. First, a matrix type and second, an osmotic controlled release oral delivery system (OROS system). Both employed a polymer, preferably, a swellable polymer. The swellable polymer is one or more hydrophilic polymers, or one or more hydrophobic polymers or a combination of a hydrophilic and hydrophobic polymers, or

[0031] The matrix system employed a matrix of polymer in which the Cilnidipine is dispersed. The polymers are preferably either hydrophilic or hydrophobic polymer or in combination, and more preferably a swellable polymer. The matrix system is preferably a monolithic system. The "monolithic matrix" refers to a drug- containing matrix formed by uniformly dispersing the drug within a suitable polymer, preferably within suitable highly swellable polymer.

[0032] When two polymers are used, one can be incorporated during granulation and the other is mixed after the granules are formed.

[0033] Cilnidipine, filler, and swellable polymer are blended and granulated to produce granules of Cilnidipine containing Cilnidipine, fillers and swellable polymer. The granules are further processed and filled into sachet, capsules, bottles or further processed into monolayer tablets or bilayer tablets and the tablets are further coated. Suitable polymers include hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol, polyethylene oxide, polyvinyl acetate, a mixture of polyvinyl acetate and povidone (Kollidon SR) carbomer, sodium alginate etc. are preferably selected.

[0034] The OROS system with an Osmotic drug delivery technology is also termed as a Push-pull osmotic drug delivery (OROS) system. It consists of a semipermeable membrane surrounding an osmotically active drug core, preferably a tablet. The core (tablet) itself is divided into two layers: an “active” layer containing the drug which is Cilnidipine and osmotic layer which is a “push” layer containing pharmacologically inert but osmotically active components known as osmogen or osmagent which is an osmotic driving agent.

[0035] As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer.

[0036] The extended-release drug delivery system when based upon the Osmotic drug delivery technology, contains Cilnidipine dispersed / embeded in the low viscosity hydrophilic polymer which is preferably a low viscosity polyethylene oxide. The other layer, the push layer, contains high viscosity polymer such as high viscosity polyethylene oxide and an osmotic agent. An osmotic agent is a compound having an osmotic activity and high water solubility. The osmotic agent can be organic or inorganic. The bilayer tablets are then coated with semipermeable membrane of another polymer. Preferably, polymer is cellulose acetate.

[0037] This controlled rate of drug delivery from this system into the gastrointestinal lumen is independent of pH or gastrointestinal motility.

[0038] Under the third aspect, the invention provides a simple and robust process to prepare extended release formulations of Cilnidipine that can release Cilnidipine in a sustained manner and the release is independent of pH of the medium.

[0039] For a matrix system, the process preferably employs wet granulation method to produce granules of Cilnidipine containing Cilnidipine, fillers and swellable polymer. Wet granulation method employs a binder solution employing a suitable binder to granulate mixture of Cilnidipine, fillers and swellable polymer.

[0040] These granules are further processed and filled into sachet, capsules, bottles or further processed into monolayer tablets or bilayer tablets and the tablets are further coated.

[0041] Preparing an OROS system involves preparation of two separate layers, an active layer or a drug-containing layer and push layer containing an osmotically active compound known as osmogen or osmagent.

[0042] First, Cilnidipine layer is prepared by granulating blend of Cilnidipine, filler and polymer with a binder solution to produce granulate which is dried and optionally subjected to sizing.

[0043] Preferably, binder is employed in the form of its solution in water or alcohol or a combination of water and alcohol.

[0044] The granules / sized granules are mixed with one or more of a glidant and a lubricant to produce a lubricated blend.

[0045] The second push layer is prepared by blending polymer preferably of higher viscosity than the polymer in the drug layer, osmogen, and optionally a glidant and a suitable colorant if required. On a bilayer production machine, the two layers are compressed into a bilayer tablet. The tablet is coated with a semipermeable membrane such as cellulose acetate or other suitable polymer. The coated tablets are then drilled on the drug layer- 1 side / Cilnidipine layer side using laser drilling machine.

[0046] Both the processes are simple and economical involving economically viable ingredients and machines.

[0047] Brief Description of the Drawings

[0048] Figure 1 provides Mean plasma concentration-time profiles of cilnidipine (A) alone and with valsartan (B) in a study conducted by Jieon Lee et al (2014).

[0049] Figure 2 provides Dissolution profile study as specified in the specification conducted on tablets of examples 1- 4 providing % Cumulative release of Cilnidipine over 24 hrs.

[0050] Figures 3(a) provides a pictorial depiction of a typical OROS system and Figures 3(b) and 3(c) provide a pictorial depiction of a typical OROS system before activation and upon activation wherein before activation push layer is not expanded but upon activation, expansion of push layer is seen pushing the drug through a laser drilled orifice on the drug layer side.

[0051] Figure 4 provides Dissolution profile study as specified in the specification conducted on tablets of examples 5 - 8 providing % Cumulative release of Cilnidipine over 24 hrs.

[0052] Detailed description of the invention

[0053] The present invention provides an oral swallowable extended-release formulations of Cilnidipine and a method for manufacturing the same.

[0054] The extended-release formulations of the present invention address the issues of rapid fall of plasma levels of Cilnidipine as discussed in the background section.

[0055] Using Cilnidipine immediate-release tablets, the peak plasma levels are achieved in 2 - 2.5 hrs. The peak plasma concentration which is more than 6 ng / ml is achieved at 2 - 2.5 hrs with reported Cmax at 8.9 + 4.2 ng / ml. But it rapidly drops to less than 2 ng / ml at or after 6 hrs. This is a 66 - 77 % decrease. Also, it further continues to drop because the elimination half-life is also at 7.5 hrs and hence half of the administered dose is already eliminated.

[0056] Accordingly, under the first aspect, the invention provides extended-release formulations of Cilnidipine which can provide sustained plasma levels of Cilnidipine.

[0057] The present invention provides oral swallowable formulations that can sustain plasma levels of Cilnidipine for longer period such as beyond 6 hrs, beyond 7.5 hrs. This will be particularly beneficial for patients who exhibit rise in blood pressure in the evening or during the night when the effect of immediate-release formulation fades away.

[0058] The Tmax can be extended from 2 hrs. to one of the 3,4, 5, 6, 7, 8, 9, 10, 11 or 12hrs. by using different types of formulations incorporating different concentration and different grades of polymers.

[0059] Preferably, the Tmax is extended from 2 hrs. to 3 - 10 hrs’, or from 3 - 8 hrs. or from 4 - 7 hrs.

[0060] Under the second aspect, the invention provides an oral swalloable extended release formulations of Cilnidipine such that not more than 35 % is released in the first two hrs. Preferably, not more than 30 % and more preferably, not more than 25 % is released in first two hrs. Also, since a major drop / reduction in the plasma levels is observed at and after 6 hrs., it is ensured that not more than 75 %, preferably not more than 70 % and most preferably, not more than 60 % of Cilnidipine is released in 6 hrs. Further for in vitro release, the specification sets a limit of not more than 35 % should be released over two hours. Further, the specification sets a limit that preferably not more than 75 % of Cilnidipine should be released in 6 hrs.

[0061] To achieve the above release, two types of extended release formulations are developed. First, a matrix type and second, an osmotic controlled release oral delivery system (OROS system). Both employed a polymer, preferably, a hydrophilic or hydrophobic polymer, single or in combination.

[0062] The matrix system employed a matrix of polymer in which the Cilnidipine is dispersed. The polymer is preferably highly swellable. The matrix system is preferably monolithic. The "monolithic matrix" refers to a drug-containing matrix formed by uniformly dispersing the drug within a suitable polymer, preferably within suitable swellable polymer.

[0063] Cilnidipine, filler, and swellable polymer are blended and granulated to produce granules of Cilnidipine containing Cilnidipine, fillers, and swellable polymer. The granules are further processed and filled into sachets, capsules, bottles or further processed into monolayer tablets or bilayer tablets and the tablets are further coated.

[0064] Suitable polymers include hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol, polyethylene oxide, polyvinyl acetate, a mixture of polyvinyl acetate and povidone (Kollidon SR) carbomer, sodium alginate are preferably selected.

[0065] The amount of polymer to sustain release in a monolithic matrix system is from 10 - 50 % w / w, preferably from 15 - 40 % w / w, and most preferably from 15 - 35 % w / w of the coated tablet.

[0066] In an embodiment, the polymer is 25 %. In another embodiment, it is 35 %. In one more embodiment, it is 30 %. The OROS system with an Osmotic drug delivery technology is also termed as a Push-pull osmotic drug delivery (OROS) system. It consists of a semipermeable membrane surrounding an osmotically active drug core, preferably a tablet. The core (tablet) itself is divided into two layers: an “active” layer containing the drug which is Cilnidipine and osmotic layer which is a “push” layer containing pharmacologically inert but osmotically active components known as osmogen or osmagent which is an osmotic driving agent.

[0067] After ingesting an OROS tablet of the present invention, as water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer.

[0068] The extended-release drug delivery system when based upon the Osmotic drug delivery technology, contains Cilnidipine dispersed / embeded in the low viscosity hydrophilic polymer. A preferred polymer is a low viscosity polyethylene oxide. The other layer, the push layer, contains high viscosity polymer such as high viscosity polyethylene oxide and an osmotic agent. An osmotic agent is a compound having an osmotic activity and high water solubility. The osmotic agent can be organic or inorganic. Inorganic osmotic agent includes one or more of magnesium sulfate, sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate etc. Preferably, the inorganic osmotic agent is sodium chloride. Organic osmotic agent includes one or more of sorbitol, mannitol, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and hydroxy ethyl methyl cellulose etc. Preferably, the organic osmotic agent is mannitol.

[0069] The bilayer tablets are then coated with semipermeable membrane of another polymer including but not limited to cellulose acetate, ethyl cellulose, agar acetate, amylose triacetate, beta glucan acetate, poly acetals, poly (glycolic acid) derivatives and poly (lactic acid) derivatives etc.

[0070] The amount of polymer employed in the semipermeable coating is preferably from 6 - 25 % w / w, more preferably from 8 - 20 % w / w , and most preferably from 10 - 15 % w / w of the coated tablet. In an embodiment, it is 11.5 %w / w. In another embodiment, it is 13 %w / w. In one more embodiment, it is 14 %w / w.

[0071] A plasticizer from 5 - 20 % w / w of the weight of the polymer is also present. Optionally, a small amount of glidant can be added.

[0072] The amount of polymer to sustain release in an OROS system is from 40 - 90 % w / w, more preferably from 45 - 85 % w / w, and most preferably from 50 - 80 % w / w of the coated tablet. This polymer amount includes an amount of polymer in the drug layer, push layer, and release control coating.

[0073] In an embodiment, it is 63 % w / w. In another embodiment, it is 74.5 % w / w. In yet another embodiment, it is 72.5 % w / w.

[0074] This controlled release rate of drug from this system into the gastrointestinal lumen is independent of pH or gastrointestinal motility. The release rate through such systems depends for its action on the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the gastrointestinal tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

[0075] Thus, under the second aspect, the present invention provides extended release formulations of Cilnidipine which exhibit following in vitro release profile when tested in phosphate buffer of pH 6.8 having 1 % sodium lauryl sulphate, Not more than 35 % Cilnidipine is released in 2 hrs;

[0076] Not more than 75 % Cilnidipine is released in 6 hrs; and

[0077] Not less than 80 % of Cilnidipine is released in 16 hrs.

[0078] These formulations exhibit release of Cilnidipine over 16 hrs when tested in phosphate buffer of pH 6.8 having 1 % sodium lauryl sulphate. The formulations release not more than 35 % Cilnidipine in first two hrs. This may allow at least half of the dose to be not available to get eliminated in the initial few hrs. such as initial 3 - 4 hrs.

[0079] The release is controlled by using polymers. Preferably polymers are hydrophilic or hydrophobic in nature. The present invention does not employ a pH dependent polymer even to control release in the first two hrs. This is because a burst release after two hrs. is not desired. In fact, release is controlled for at least 6 hrs. so that not more than 75 %, preferably, not more than 70 % and most preferably, not more than 60 % Cilnidipine is released in first 6 hrs.

[0080] Suitable polymers include hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol, polyethylene oxide, polyvinyl acetate, a mixture of polyvinyl acetate and povidone (Kollidon SR) carbomer, sodium alginate are preferably selected.

[0081] The oral swallowable extended release formulations of the present invention comprise a formulation prepared from or a formulation containing granules comprising Cilnidipine, one or more fillers, binder and a water swellable polymer. It is observed that in vitro release of Cilnidipine is more sustained when swellable polymer is present within or inside the granules as well as outside the granules. Cilnidipine to polymer ratio is preferably from 1:2. to 1: 12, more preferably from 1:2 to 1: 10 and most preferably from 1:2 to 1:8.

[0082] Release of Cilnidipine from Systems with Cilnidipine to swellable polymer ratio of 1:< 2 is faster and may not provide sustained effect.

[0083] Example 1 provides an extended release tablet composition having swellable polymer within granules from which tablet is prepared. Further these granules are lubricated. These granules can be filled in sachet or bottle or in capsules. Further these lubricated granules can be compressed into tablets.

[0084] Preferably, the swellable polymers includes water swellable cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxy methylcellulose, and hydroxy ethylcellulose. Swellable and gelling polymer such as polyethyle oxide can be used in various grades depending upon the molecular weight and viscosity of the polymer. Alginic acid derivatives, including alginic acid and its physiologically acceptable salts, hydrophobic polymer polyvinyl acetate or a mixture of polyvinyl acetate and povidone (Kollidon SR) may also be used. Furthermore, cationic polymers like methacrylic acid derivatives with dimethylaminoethyl ammonium groups are suitable.

[0085] The extended release formulations of the present invention comprise from 1 to 20 % w / w , preferably from 1-10 % w / w of Cilnidipine, 0.5 - 10 % w / w, preferably from 0.5 - 8 % w / w , more preferably, from 1 - 6 % w / w of a binder and from 10 % to 90 % w / w, preferably from 15 -85 % w / w and more preferably from 15 - 80 % w / w of a swellable polymer. Additionally, a filler from 1 % w / w to 80 % w / w is present. Also, lubricants, glidants are present in amount of up to 3 %.

[0086] The binder may consist of starch, polyvidone, polyvinylpyrrolidone, cellulose derivatives such as carboxymethyl cellulose sodium, hydroxypropyl cellulose etc. Preferably, binder is employed in the form of its solution in water or alcohol.

[0087] Osmotic agents are well known to those skilled in the art. Osmotic agents suitable for the present invention are simple sugars such as sucrose, xylitol, glucose, lactose; salts such as sodium chloride, potassium chloride; low molecular weight hydrophilic polymers such as cellulose ethers and maltodextrins. Osmotic agents can be incorporated in the formulation of this invention in the amount of from 1% by weight to 30% by weight, preferably from 5% to 20% and most preferably from 5% to 15% by weight. Osmotic agents are typically incorporated in the layer-2 known as “Push-Layer”.

[0088] Lubricating agents or flow aids, such as colloidal silicon dioxide, magnesium stearate and Talc, are employed in the formulation.

[0089] The core tablet is typically coated with a semi-permeable membrane containing at least one plasticizer. The coating polymer is dissolved with at least one plasticizer in an appropriate solvent or a mixture of solvents and sprayed on the tablets for coating. The coating polymers include, but are not limited, to cellulose acetate. The coating membrane preferably also contains at least one plasticizer to improve flexibility and durability of the coat. Such plasticizers include, but are not limited to, triethyl citrate (TEC), propylene glycol (PG), polyethylene glycols (PEGs) or mixtures thereof ; other polyoxyethylene sorbitan esters, triacetin, diethyl phthalate, mineral oil, tributyl sebacate, and glycerol. The coating level can vary from 6 % to 25%, preferably from 8% to 20%, and most preferably from 8 % to 16% by weight.

[0090] The semi-permeable wall also includes at least one opening to provide for the osmotic delivery of the drug(s). In general the at least one opening has a diameter of from 50 pm to 1000 pm, preferably from 100 pm to 800 pm. The opening is formed by drilling using a laser or any other appropriate hole drilling system. The opening can be of any shape. The various shapes contemplated for this invention include, but are not limited to round, cross-shaped, rectangular, diamond, star, and square shapes. As the dosage unit (osmotic tablet) imbibes water, the releaseenhancing agents go into solution providing an environment for the drug to dissolve. The osmotic agent(s) in the core tablet draws water into the core tablet creating an osmotic gradient across the semi-permeable membrane. The osmotic gradient pushes the drug in the solution out through the laser-drilled hole.

[0091] Various fillers that are employed include one or more from lactose, microcrystalline cellulose, calcium hydrogen phosphate, starch, mannitol, and dextrin, can be used.

[0092] By utilizing these specific raw materials, the inventive formulation achieves the desired extended-release properties for cilnidipine, allowing for improved therapeutic outcomes.

[0093] The swellable polymer, including water swellable cellulose derivatives and polyethylene oxide, provides controlled drug release characteristics. The binder promotes cohesion and maintains the integrity of the formulation. Lubricating agents or flow aids facilitate the manufacturing process and aid in tablet formation. Filling adjuvants assist in achieving the desired tablet size and stability. In both monolithic matrix system and OROS system, Cilnidipine to polymer ratio is preferably from 1:2 to 1: 12, more preferably from 1:2 to 1: 10.

[0094] In OROS system, the ratio of Cilnidipine to polymer is more preferably from 1:5 to 1: 12 and most preferably from 1:6 to 1: 10.

[0095] Release of Cilnidipine from Systems with Cilnidipine to swellable polymer ratio of 1:< 2 is faster and may not provide sustained effect.

[0096] The novel extended-release formulation and manufacturing process for cilnidipine tablets offer improved therapeutic efficacy, reduced plasma fluctuations.

[0097] Under the third aspect, there is provided a process to manufacture an extended release formulations of the present invention.

[0098] The process for producing extended-release formulations of Cilnedipine employing monolithic matrix comprises

[0099] 1. Sieving cilnidipine through a mesh size of 20 - 40 microns and mixing it with one or more fillers and water swellable polymer in a mixer to prepare a mixture;

[0100] 2. Granulating the mixture in a rapid mixer granulator or fluidized bed processor using a solution of binder in water or isopropyl alcohol or mixture of water and isopropyl alcohol;

[0101] 3. drying granulate in a dryer and sizing if required;

[0102] 4. optionally pre-lubricating the dried granules with a water swellable polymer;

[0103] 4. Lubricating the granules with lubricants and glidants selected from colloidal silicon dioxide, magnesium stearate and Talc.

[0104] 5. Filling the lubricated granules in sachet or bottles or in a capsule or compressing the lubricated blend to form tablets and optionally coat tablets using a coating material based on Hypromellose or polyvinyl alcohol.

[0105] Example 1 provides preparation of tablets without pre-lubrication. These tablets exhibit slightly faster release than tablets of examples 2, 3 and 4 which are prepared by the same process but including a step of pre-lubrication. Use of monolithic system which can be developed by employing a swellable polymer are preferred. Monolithic systems, which consist of a hydrophilic polymer or hydrophobic polymer and various excipients, offer convenience and costeffectiveness for extended-release dosage forms. In this context, the term "monolithic matrix" refers to a drug -containing matrix formed by uniformly dispersing the drug within a suitable polymer, preferably within suitable swellable polymer. The preparation of a monolithic matrix can be accomplished through methods such as direct compression, wet granulation, or dry granulation. Preferred process in the present invention is wet granulation employing binder solution. The primary objective of such dosage forms is to control the release rate of the drug by enabling diffusion through the matrix to serve as the rate-limiting step.

[0106] The general process for osmotic based extended release drug delivery system comprises-

[0107] Manufacturing process for Layer- 1 / drug layer

[0108] 1. Sifting Cilnidipine and a water swellable polymer through a sieve of a mesh size of 20 - 40 and mixing in a mixer with one or more fillers to prepare a mixture of Cilnidipine, water swellable polymer and filler;

[0109] 2. Granulating the mixture of step 1 in a rapid mixer granulator or fluidized bed processor using a solution of a binder in water or in isopropyl alcohol or in a mixture of water and isopropyl alcohol;

[0110] 3. Drying granulate in a dryer and subjecting dried granulate to sizing if required i.e. upon observation of lumps;

[0111] 4. Lubricating dried granules with lubricants and glidants selected from one or more of colloidal silicon dioxide, magnesium stearate, and talc.

[0112] Manufacturing process for Layer-2 / Push layer

[0113] 1. Sifting swellable polymer through a sieve of mesh size of 20 - 40 and sifting an osmotic agent through a sieve of mesh size of 80 - 100;

[0114] 2. Mixing swellable polymer, osmotic agent and filler in a mixer to prepare a mixture; 3. Lubricating mixture with one or more lubricants and glidants selected from colloidal silicon dioxide, magnesium stearate, and Talc;

[0115] 4. Compressing both drug layer and push layer into bilayer tablets on a bilayer tablet manufacturing machine;

[0116] 5. Coating bilayer tablets with a semipermeable membrane;

[0117] 6. Drilling coated tablets to form an orifice on drug layer side using a laser drilling machine;

[0118] 7. Coating laser drilled tablets with a film coating polymer.

[0119] The tablets based on Push-pull osmotic drug delivery (OROS) Technology are similar in appearance to a conventional tablet. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an “active” layer containing the drug and a “push” layer containing pharmacologically inert (but osmotically active) components.

[0120] As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer.

[0121] The Cilnidipine extended release tablet is designed to provide Cilnidipine at an approximately constant rate over 16 hours. This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. The system depends for its action on the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the gastrointestinal tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

[0122] OROS based drug delivery systems are not affected by the gastric pH, food intake, GI motility, and differing intestinal environments. Drug release through OROS systems follows Zero-order release kinetics and provides precise control over drug release rate.

[0123] Following examples illustrate the invention without limiting its scope in any way. Example 1

[0124] In accordance with the general procedure outlined above, tablets were prepared using the following composition:

[0125] Table 1: Extended release formulation of Cilnidipine using monolithic matrix with drug to polymer ratio of 1:8.33

[0126] Process

[0127] 1. Cilnidipine is sifted through a sieve of mesh size of 20 - 40 and mixed with fillers Lactose Monohydrate and Microcrystalline Cellulose, and water- swellable polymer Hypromellose K4M in a mixer to prepare a mixture; 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder prepared in water or in isopropyl alcohol or in a mixture of water and isopropyl alcohol; 3. The granulate is dried in a dryer and subjected to sizing if required;

[0128] 4. The dried granules are lubricated with lubricant magnesium stearate;

[0129] 5. Lubricated granules are filled in sachet or bottle or capsules of suitable size or compressed using suitable tooling to form tablets; and

[0130] 6. Tablets are coated using a coating material based on Hypromellose or polyvinyl alcohol.

[0131] In vitro dissolution tests - To evaluate the dissolution characteristics of the tablets, in vitro dissolution tests were performed using a paddle apparatus with a sinker. The dissolution medium employed was a 6.8 phosphate buffer containing 1% SLS (sodium lauryl sulfate) with a total volume of 900 mL. The paddle apparatus was set to rotate at 75 rpm.

[0132] The release rate of Cilnidipine from the tablets of example 1 in the given dissolution medium was analyzed and in vitro release is provided under table A and graph of % Cumulative release vs. time is plotted and provided in Figure 2.

[0133] Example 2

[0134] Using the general procedure outlined above, tablets were prepared with the following composition for each tablet containing 20 mg strength:

[0135] Table 2: Extended release formulation of Cilnidipine using monolithic matrix with drug to polymer ratio of 1:2.5 intragranularly and having an additional polymer extragranularly making overall drug to polymer ratio of 1:3.125

[0136] Process:

[0137] 1. Cilnidipine is sifted through a sieve of mesh size of 20 - 40 and mixed with fillers Lactose Monohydrate and Microcrystalline Cellulose and water swellable polymer Hypromellose K100M in a mixer to prepare a mixture;

[0138] 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in water or isopropyl alcohol or mixture of water and isopropyl alcohol;

[0139] 3. The granulate is dried in a dryer and subjected to sizing if required;

[0140] 4. The dried granules are first pre-lubricated with swellable polymer Hypromellose K100M and further lubricated with lubricant magnesium stearate;

[0141] 5. Lubricated granules are filled in sachet or bottle or capsules of suitable size or compressed using suitable tooling to form tablets; and

[0142] 6. Tablets are coated using a coating material based on Hypromellose or polyvinyl alcohol.

[0143] The release rate of Cilnidipine from the tablets of example 2 in the given dissolution medium was analyzed and in vitro release is provided under table A and graph of % Cumulative release vs. time is plotted and provided in Figure 2.

[0144] Example 3

[0145] Using the general procedure detailed in above were prepared each having following composition Table 3: Extended release formulation of Cilnidipine using monolithic matrix with drug to polymer ratio of 1:3.33 intragranularly and having an additional polymer of larger viscosity extragranularly (drug to extragranular polymer ratio is 1:1.66) making overall drug to polymer ratio of 1:5

[0146] Process:

[0147] 1. Cilnidipine is sifted through a sieve of mesh size of 20 - 40 and mixed with fillers Lactose Monohydrate and Microcrystalline Cellulose and water swellable polymer Hypromellose K4M in a mixer to prepare a mixture;

[0148] 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in water or isopropyl alcohol or mixture of water and isopropyl alcohol;

[0149] 3. The granulate is dried in a dryer and subjected to sizing if required;

[0150] 4. The dried granules are first pre-lubricated with swellable polymer Hypromellose K100M and further lubricated with lubricant magnesium stearate;

[0151] 5. Lubricated granules are filled in sachet or bottle or capsules of suitable size or compressed using suitable tooling to form tablets; and

[0152] 6. Tablets are coated using a coating material based on Hypromellose or polyvinyl alcohol. The release rate of Cilnidipine from the tablets of example 3 in the given dissolution medium was analyzed and in vitro release is provided under table A and graph of % Cumulative release vs. time is plotted and provided in Figure 2. Example 4

[0153] Using the general procedure detailed in above were prepared each having following composition. The hydrophobic, swellable polymer was selected to control the drug release.

[0154] Table 4: Extended release formulation of Cilnidipine using monolithic matrix with drug to polymer ratio of 1:1,25 intragranularly and having an additional hydrophobic polymer extragranularly (drug to extragranular polymer ratio is 1:2.5) making overall drug to polymer ratio of 1:3.75 Process:

[0155] 1. Cilnidipine is sifted through a sieve of mesh size of 20 - 40 and mixed with fillers Lactose Monohydrate and Microcrystalline Cellulose and water swellable hydrophobic polymer Kollidon SR in a mixer to prepare a mixture; 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in water or isopropyl alcohol or mixture of water and isopropyl alcohol;

[0156] 3. The granulate is dried in a dryer and subjected to sizing if required;

[0157] 4. The dried granules are first pre-lubricated with swellable hydrophobic polymer Kollidon SR and further lubricated with lubricant magnesium stearate;

[0158] 5. Lubricated granules are filled in sachet or bottle or capsules of suitable size or compressed using suitable tooling to form tablets; and

[0159] 6. Tablets are coated using a coating material based on Hypromellose or polyvinyl alcohol.

[0160] The release rate of Cilnidipine from the tablets of example 4 in the given dissolution medium was analyzed and in vitro release is provided under table A and graph of % Cumulative release vs. time is plotted and provided in Figure 2.

[0161] Table A: In vitro release of tablets of examples 1-4 in phosphate buffer of pH

[0162] 6.8 with 1% SLS

[0163] Following examples illustrate the extended release tablets of Cilnidipine prepared using OROS technology and do not limit the scope of the invention in any way. Example 5

[0164] In accordance with the general procedure outlined above, tablets were prepared using the following composition:

[0165] Table 5: Extended release formulation of Cilnidipine using OROS technology having drug layer with drug to polymer ratio of 1:4.125 and having a push layer with an additional polymer of larger viscosity making overall drug to polymer ratio in the formulation of 1:6.25

[0166] Process:

[0167] Manufacturing process for Layer- 1

[0168] 1. Cilnidipine and water swellable polymer like polyethyle oxide are sifted through a sieve of mesh size of 20 - 40 and mixed with filler like lactose in a mixer to prepare a mixture;

[0169] 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in isopropyl alcohol;

[0170] 3. The granulate is dried in a dryer and subjected to sizing when required to produce granules;

[0171] 4. The granules are lubricated with lubricant such as magnesium stearate.

[0172] Manufacturing process for Layer-2

[0173] 5. Polyethylene oxide (WSR 303) and colloidal silicon dioxide are sifted through a sieve of mesh size of 20 - 40, and sodium chloride and red ferric oxide are sifted through a sieve of mesh size of 80 - 100, and mixed in a mixer to prepare a mixture;

[0174] 6. The mixture is lubricated with a lubricant such as magnesium stearate.

[0175] Compression & coating

[0176] 7. On a bilayer tablet machine, both the layers are compressed into bilayer tablets and coated by a semipermeable membrane of cellulose acetate.

[0177] 8. The coated tablets are then drilled on the drug layer- 1 side using laser drilling machine.

[0178] 9. The laser drilled tablets are then subsequently coated with film coating polymer based on Hypromellose or polyvinyl alcohol.

[0179] In vitro dissolution tests - To evaluate the dissolution characteristics of the tablets, in vitro dissolution tests were performed using a paddle apparatus with a sinker. The dissolution medium employed was a 6.8 phosphate buffer containing 1% SLS (sodium lauryl sulfate) with a total volume of 900 mL. The paddle apparatus was set to rotate at 75 rpm. The release rate of Cilnidipine from the tablets of example 5 in the given dissolution medium was analyzed and in vitro release is provided under table B and graph of % Cumulative release vs. time is plotted and provided in Figure 4.

[0180] Example 6 Using the general procedure detailed in above were prepared each having following composition

[0181] Table 6: Extended release formulation of Cilnidipine using OROS technology having drug layer with drug to polymer ratio of 1:5.25 and having a push layer with an additional polymer of larger viscosity making overall drug to polymer ratio in the formulation of 1:7.875

[0182] Process:

[0183] Manufacturing process for Layer- 1

[0184] 1. Cilnidipine and water swellable polymer like polyethyle oxide are sifted through a sieve of mesh size of 20 - 40 and mixed with filler like lactose in a mixer to prepare a mixture;

[0185] 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in isopropyl alcohol;

[0186] 3. The granulate is dried in a dryer and subjected to sizing when required to produce granules;

[0187] 4. The granules are lubricated with lubricant such as magnesium stearate.

[0188] Manufacturing process for Layer-2

[0189] 5. Polyethylene oxide (WSR 303) and colloidal silicon dioxide are sifted through a sieve of mesh size of 20 - 40, and sodium chloride and red ferric oxide are sifted through a sieve of mesh size of 80 - 100, and mixed in a mixer to prepare a mixture;

[0190] 6. The mixture is lubricated with a lubricant such as magnesium stearate.

[0191] Compression & coating

[0192] 7. On a bilayer tablet machine, both the layers are compressed into bilayer tablets and coated by a semipermeable membrane of cellulose acetate. 8. The coated tablets are then drilled on the drug layer- 1 side using laser drilling machine.

[0193] 9. The laser drilled tablets are then subsequently coated with film coating polymer based on Hypromellose or polyvinyl alcohol.

[0194] In vitro dissolution tests - To evaluate the dissolution characteristics of the tablets, in vitro dissolution tests were performed using a paddle apparatus with a sinker. The dissolution medium employed was a 6.8 phosphate buffer containing 1% SLS (sodium lauryl sulfate) with a total volume of 900 mL. The paddle apparatus was set to rotate at 75 rpm.

[0195] The release rate of Cilnidipine from the tablets of example 6 in the given dissolution medium was analyzed and in vitro release is provided under table B and graph of % Cumulative release vs. time is plotted and provided in Figure 4.

[0196] Example 7

[0197] In accordance with the general procedure outlined above, tablets were prepared using the following composition:

[0198] Table 7 : Extended release formulation of CilnidipineCilnedipine using OROS technology having drug layer with drug to polymer ratio of 1:5.25 and having a push layer with an additional polymer of larger viscosity making overall drug to polymer ratio in the formulation of 1:7.875

[0199] Process:

[0200] Manufacturing process for Layer- 1

[0201] 1. Cilnidipine and water swellable polymer like polyethyle oxide are sifted through a sieve of mesh size of 20 - 40 and mixed with filler like lactose in a mixer to prepare a mixture;

[0202] 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in isopropyl alcohol;

[0203] 3. The granulate is dried in a dryer and subjected to sizing when required to produce granules;

[0204] 4. The granules are lubricated with lubricant such as magnesium stearate.

[0205] Manufacturing process for Layer-2 5. Polyethylene oxide and colloidal silicon dioxide are sifted through a sieve of mesh size of 20 - 40, and sodium chloride and red ferric oxide are sifted through a sieve of mesh size of 80 - 100, and mixed in a mixer to prepare a mixture;

[0206] 6. The mixture is lubricated with a lubricant such as magnesium stearate.

[0207] Compression & coating

[0208] 7. On a bilayer tablet machine, both the layers are compressed into bilayer tablets and coated by a semipermeable membrane of cellulose acetate.

[0209] 8. The coated tablets are then drilled on the drug layer- 1 side using laser drilling machine.

[0210] 9. The laser drilled tablets are then subsequently coated with film coating polymer based on Hypromellose or polyvinyl alcohol.

[0211] In vitro dissolution tests - To evaluate the dissolution characteristics of the tablets, in vitro dissolution tests were performed using a paddle apparatus with a sinker. The dissolution medium employed was a 6.8 phosphate buffer containing 1% SLS (sodium lauryl sulfate) with a total volume of 900 mL. The paddle apparatus was set to rotate at 75 rpm.

[0212] The release rate of Cilnidipine from the tablets of example 7 in the given dissolution medium was analyzed and in vitro release is provided under table B and graph of % Cumulative release vs. time is plotted and provided in Figure 4.

[0213] Example 8

[0214] In accordance with the general procedure outlined above, tablets were prepared using the following composition:

[0215] Table 8 : Extended release formulation of Cilnidipine using OROS technology having drug layer with drug to polymer ratio of 1:5 and having a push layer with an additional polymer of larger viscosity making overall drug to polymer ratio in the formulation of 1:7.625

[0216] Process:

[0217] Manufacturing process for Layer- 1 1. Cilnidipine and water swellable polymer like polyethyle oxide are sifted through a sieve of mesh size of 20 - 40 and mixed with filler like lactose in a mixer to prepare a mixture; 2. The mixture is granulated in a rapid mixer granulator or fluidized bed processor using a solution of binder in isopropyl alcohol;

[0218] 3. The granulate is dried in a dryer and subjected to sizing when required to produce granules;

[0219] 4. The granules are lubricated with lubricant such as magnesium stearate.

[0220] Manufacturing process for Layer-2

[0221] 5. Polyethylene oxide and colloidal silicon dioxide are sifted through a sieve of mesh size of 20 - 40, and sodium chloride and red ferric oxide are sifted through a sieve of mesh size of 80 - 100, and mixed in a mixer to prepare a mixture;

[0222] 6. The mixture is lubricated with a lubricant such as magnesium stearate.

[0223] Compression & coating

[0224] 7. On a bilayer tablet machine, both the layers are compressed into bilayer tablets and coated by a semipermeable membrane of cellulose acetate.

[0225] 8. The coated tablets are then drilled on the drug layer- 1 side using laser drilling machine.

[0226] 9. The laser drilled tablets are then subsequently coated with film coating polymer based on Hypromellose or polyvinyl alcohol.

[0227] In vitro dissolution tests - To evaluate the dissolution characteristics of the tablets, in vitro dissolution tests were performed using a paddle apparatus with a Japanese sinker. The dissolution medium employed was a 6.8 phosphate buffer containing 1% SLS (sodium lauryl sulfate) with a total volume of 900 mL. The paddle apparatus was set to rotate at 75 rpm.

[0228] The release rate of Cilnidipine from the tablets of example 8 in the given dissolution medium was analyzed and in vitro release is provided under table B and graph of % Cumulative release vs. time is plotted and provided in Figure 4. Table B: In vitro release of tablets of examples 5 - 8 in phosphate buffer of pH

[0229] 6.8 with 1% SLS

Claims

ClaimsWe claim1. An extended-release oral and swallowable formulation comprising Cilnidipine and a hydrophilic and / or hydrophobic water-swellable polymer.

2. The extended-release formulation of Cilnidipine as claimed in claim 1 comprising Cilnidipine in granulated form or within granules.

3. The extended-release formulation of Cilnidipine as claimed in claim 1 comprising granules of Cilnidipine prepared using binder selected from one or more of starch, polyvidone, polyvinylpyrrolidone, cellulose derivatives such as carboxymethyl cellulose sodium, hydroxypropyl cellulose.

4. The extended-release formulation of Cilnidipine as claimed in claim 1 devoid of any pH dependent or enteric polymer.

5. The extended-release formulation of Cilnidipine as claimed in claim 1 exhibiting an in vitro release of not more than 35 % in first two hrs. when tested in a dissolution medium of phosphate buffer of pH 6.8 having 1 % sodium lauryl sulfate.

6. The extended-release formulation of Cilnidipine as claimed in claim 1 exhibiting an in vitro release of i) not more than 35 % in first two hrs.; ii) not more than 75 % in 6 hrs.; iii) not less than 80 % in 16 hrs; when tested in a dissolution medium of phosphate buffer of pH 6.8 having 1 % sodium lauryl sulfate.

7. The extended-release formulation of Cilnidipine as claimed in claim 1 of monolithic matrix type comprising Cilnidipine dispersed in a matrix of a polymer.

8. The extended-release formulation of Cilnidipine as claimed in claim 7 wherein the polymer is selected from the group consisting of hydroxy propyl cellulose, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl methyl cellulose, polyethylene glycol,polyethylene oxide, polyvinyl acetate, a mixture of polyvinyl acetate and povidone (Kollidon SR), carbomer, and sodium alginate.

9. The extended-release formulation of Cilnidipine as claimed in claim 7 wherein Cilnidipine to polymer ratio is from 1 :2 to 1 : 12, preferably from 1 :2 to 1 : 10 and more preferably from 1 :2 to 1 :8.

10. The extended-release formulation of Cilnidipine as claimed in claim 7 wherein the amount of polymer to sustain release is from 10 - 50 % w / w, preferably from 15 - 40 % w / w and more preferably from 15 - 35% w / w of the coated tablet.

11. The extended-release formulation of Cilnidipine as claimed in claim 7 wherein polymer is present within granules / intragranularly.

12. The extended-release formulation of Cilnidipine as claimed in claim 7 wherein polymer is present within granules / intragranularly as well as outside granules / extra-granularly.

13. The extended-release formulation of Cilnidipine as claimed in claim 1 of osmotic controlled release oral delivery system type having a core and a semipermeable membrane coating the core.

14. The extended-release formulation of Cilnidipine as claimed in claim 13 having a core in the form of a bilayer tablet.

15. The extended-release formulation of Cilnidipine in the form of a bilayer tablet as claimed in claim 14 having a Cilnidipine layer and a push layer wherein Cilnidipine layer comprises granules of Cilnidipine, water swellable polymer and a binder and push layer comprises water swellable polymer and osmogen or osmagent.

16. The extended-release formulation of Cilnidipine as claimed in claim 15 wherein osmogen or osmagent is selected from one or more of magnesium sulfate, sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate, sorbitol, mannitol, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and hydroxy ethyl methyl cellulose.

17. The extended-release formulation of Cilnidipine as claimed in claim 13 wherein semipermeable membrane contains a polymer selected from agroup consisting of cellulose acetate, agar acetate, amylose triacetate, beta glucan acetate, poly acetals, poly (glycolic acid) derivatives and poly (lactic acid) derivatives.

18. The extended-release formulation of Cilnidipine as claimed in claim 15 wherein the water swellable polymer is selected from the group consisting of hydroxy propyl cellulose, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl methyl cellulose, polyethylene glycol, polyethylene oxide, carbomer, and sodium alginate.

19. The extended-release formulation of Cilnidipine as claimed in claim 15 wherein Cilnidipine to polymer ratio is from 1:2 to 1 : 12, preferably from 1 :5 to 1 : 12, and more preferably from 1 :6 - 1 : 10.

20. A process for producing extended-release formulations in the form of a monolithic matrix comprising i) Sieving Cilnidipine through a mesh size of 20 - 40 and mixing it with one or more fillers and water swellable polymer in a mixer to prepare a mixture; ii) Granulating the mixture in a rapid mixer granulator or fluidized bed processor using a solution of binder in water or isopropyl alcohol or mixture of water and isopropyl alcohol; iii) Drying granulate in a dryer and sizing if required; iv) optionally pre-lubricating the dried granules with a water swellable polymer; v) Lubricating the granules with lubricants and glidants selected from colloidal silicon dioxide, magnesium stearate and Talc. vi) Filling the lubricated granules in sachet or bottles or in a capsule or compressing the lubricated blend to form tablets and optionally coat tablets using a coating material based on Hypromellose or polyvinyl alcohol.

21. The process for producing extended-release formulations as claimed in claim 20 comprising pre-lubricating the dried granules with a water swellable polymer.

22. A process for producing extended-release formulations in the form of an osmotic controlled release oral delivery system comprising i) Preparing Cilnidipine layer; ii) Preparing a push layer; iii) Compressing the Cilnidipine layer and the push layer into a bilayer tablet; iv) Coating bilayer tablet with a semipermeable membrane; v) Drilling coated tablets to form an orifice on drug layer side using a laser drilling machine; vi) Coating laser drilled tablets with a film coating polymer.

23. The process for producing an osmotic controlled release oral delivery system of Cilnidipine as claimed in claim 22 wherein preparing the Cilnidipine layer comprises i) Sifting Cilnidipine and a water swellable polymer through a sieve of a mesh size of 20 - 40 and mixing in a mixer with one or more fillers to prepare a mixture of Cilnidipine, water swellable polymer and filler; ii) Granulating the mixture of step 1 in a rapid mixer granulator or fluidized bed processor using a solution of a binder in water or in isopropyl alcohol or in a mixture of water and isopropyl alcohol; iii) Drying granulate in a dryer and subjecting dried granulate to sizing if required i.e. upon observation of lumps; iv) Lubricating dried granules with lubricants and glidants selected from one or more of colloidal silicon dioxide, magnesium stearate, and talc.

24. The process for producing an osmotic controlled release oral delivery system of Cilnidipine as claimed in claim 22 wherein preparing the push layer comprises i) Sifting swellable polymer through a sieve of mesh size of 20 - 40 and sifting an osmotic agent through a sieve of mesh size of 80 - 100; ii) Mixing swellable polymer, osmotic agent and filler in a mixer to prepare a mixture;iii) Lubricating mixture with one or more lubricants and glidants selected from colloidal silicon dioxide, magnesium stearate, and Talc.

25. The process for producing extended-release formulations of Cilni dipine as claimed in any of the preceding claims wherein i) the water swellable polymer is selected from the group consisting of hydroxy propyl cellulose, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl methyl cellulose, polyethylene glycol, polyethylene oxide, mixture of polyvinyl acetate and povidone (Kollidon SR) , carbomer, and sodium alginate; ii) Binder is selected from one or more of starch, polyvidone, polyvinylpyrrolidone, cellulose derivatives such as carboxymethyl cellulose sodium, hydroxypropyl cellulose; iii) Filler is selected from one or more of lactose, microcrystalline cellulose, calcium hydrogen phosphate, starch, mannitol, and dextrin iv) Osmotic agent or osmogen or osmagent is selected from one or more of magnesium sulfate, sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate, sucrose, xylitol, glucose, lactose, sorbitol, mannitol, maltodextrin, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose and hydroxy ethyl methyl cellulose; and v) glidant and lubricant is selected from one or more of colloidal silicon dioxide, magnesium stearate and talc.

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