FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
STABLE LERCANIDIPINE FORMULATION
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality : Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention

STABLE LERCANIDIPINE FORMULATION
TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable solid oral dosage form of lercanidipine by using a process of preparation of adsorbates.
The invention further relates to lercanidipine adsorbates that are obtainable by said process, as well as pharmaceutical formulations prepared while employing said lercanidipine adsorbates.
BACKGROUND OF THE INVENTION
Lercanidipine hydrochloride, i.e., (methyl 1,1, N-trimethyl-N-(3, 3-diphenylpropyl)-2-aminoethyl 1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylate), hydrochloride having the formula (I) is disclosed herewith.

\^
O
MeO
H3C N CH3 H
O CH3 CH3

Formula I
Lercanidipine hydrochloride is an antagonist of type-L calcium channels, and has been found to be very active as an antihypertensive and thus useful agent for the treatment of angina and coronary diseases. Its mechanism of antihypertensive activity
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is attributed to a direct relaxant effect on vascular smooth muscle, which lowers total peripheral resistance.
Lercanidipine hydrochloride belongs to dihydropyridine group. The dihydropyridine have been classified into first, second and third generation.
Table 1: Present classification of dihydropyridines

Group First Generation Second Generation Third Generation
Dihydropyridine Nifedipine; Felodipine;Isradipine;Nicardipine;Nimodipine;Nisoldipine;Nitrendipine Amlodipine; Lercanidipine.
Remarks First generation dihydropyridines are the prototype drugs. They have unfavorable pharmacokinetic profiles, unless used as slow release formulations Second generation dihydropyridines exhibit increased tissue selectivity relative to parent prototype, but they require slow release formulations to prevent large fluctuations in plasma levels, and rapid onset of action. Third generation dihydropyridines retains tissue selectivity and its chemistry allows them the favourable pharmacokinetic profile.
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The pharmacokinetics of lercanidipine is unique in comparison to other dihydropyridines. Lercanidipine is an example of a lipophilic and vasoselective dihydropyridine calcium channel blocker, owing to the lipophilic character of such compounds, considerable concentration occurs in lipid-containing membrane depots. The drug thus concentrated is slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of the drug. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensive patients by means of a single daily dose. It is an effective vasodilator / antihypertensive drug, with a slow onset and long duration of action, which is associated with neither reflex tachycardia nor cardio depressant activity. It has a high affinity for and competitively antagonizes the dihyropyridine subunit of the L-type calcium channel.
Lercanidipine hydrochloride is disclosed in US 4,705,797. Lercanidipine has been approved for the treatment of hypertension and has been marketed in several European countries under the under the trade name of Carmen® (Manufacturer : Berlin Chemie) or Corifeo® (Manufacturer : UCB) or Zanidip® (Manufacturer : Recordati).
Lercanidipine and its salts, such as the hydrochloride salt, are practically insoluble in water. Lercanidipine also shows low permeability. Also, when administered to patients, lercanidipine displays high first pass metabolism as a result of its being a substrate for CYP3A4. The combination of low water solubility, low permeability and high first pass metabolism results in low and highly variable bioavailability and thus creating a challenge to develop immediate release composition.
Also, it is known from the prior art like, EP1432683 Al and EP1423367 Bl that Lercanidipine hydrochloride shows polymorphism and available as an amorphous
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form, several crystalline forms and as a mixture of crystalline form with amorphous form.
The polymorph (crystalline form or amorphous form) of the active ingredient in a dosage form may play a significant role in the behavior of the drug in the dosage form, once taken orally, and may in turn influence its therapeutical effect. For example polymorphic state of the drug may modify the dissolution and thus influence absorption and the therapeutic effect of the drug. In such a case it is very important that the polymorphic form of the molecule remains constant during the process of preparing formulation and its shelf life in order to ensure the consistent therapeutical activity of the drug. Any polymorphic form either crystalline or amorphous form of the drug can be used in the present invention.
US 5015479 discloses sustained release capsule or tablet formulation comprising an adsorbate of a mixture of a pharmaceutically useful dihydropyridine and a polyvinylpyrrolidone having an average-molecular weight greater than 55,000 adsorbed on a cross-linked polyvinylpyrrolidone and blended with a polymer or mixture of polymers which gel in the presence of water, the amount of said polymer or polymers being effective to produce the desired sustained release effect. This patent employs specifically the process of adsorbing dihydropyridine with polyvinylpyrrolidone over crosspovidone for preparing sustained release formulation.
WO 2005053689 A2 discloses a controlled release pharmaceutical composition comprising lercanidipine dissolved or dispersed in a solid vehicle at ambient temperature, thus forming a solid dispersion, achieves delayed release of lercanidipine over an extended period of time.
WO 2006037650 Al discloses modified release pharmaceutical composition comprising lercanidipine dissolved or suspended in a waxy substance comprising a
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polyalcohol fatty acid ester, the solution being contained within a pharmaceutical^ acceptable capsule.
US 2006165788 Al discloses a modified release composition containing the low solubility and permeability drug, lercanidipine that provides therapeutically effective plasma concentrations of lercanidipine for 24 hours. The modified release composition releases pulses of lercanidipine based on the pH of the use environment.
US 2006165789 Al discloses modified release composition containing the low permeability and poor solubility drug, lercanidipine that provides therapeutically effective plasma concentrations of lercanidipine for a period of about 20 to about 25 hours.
All the above mention prior art teaches about sustained release, controlled release or modified release formulation of lercanidipine or other dihydropyridines.
US 5266581 discloses rapidly absorbable composition of dihydropyridine selected from nifedipine, nimodipine, nitrendipine, nisoldipine and felodipine, specifically using polyvinylpyrrolidone with an average molecular weight of 15,000 to 50,000 and crosslinked insoluble polyvinylpyrrolidone. This patent employs specifically the process of adsorbing dihydropyridine with polyvinylpyrrolidone over crosspovidone for preparing immediate release formulation.
US 2006134212 Al discloses an immediate release composition for lercanidipine. The immediate release composition comprises a core; a first layer, comprising lercanidipine, a surfactant and a binder, and optionally, a second layer comprising a film coating. The surfactant plays an important role in immediate release composition. The special equipment like fluidized bed coater (GPGC3, Glatt Air Technique, Ramsey, N.J) is required for the manufacturing of the formulation.
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WO 2006089787 Al discloses a substantially pure amorphous lercanidipine hydrochloride having a purity of at least 95% pure, and further provides information about methods of preparing substantially pure amorphous lercanidipine, its immediate release and modified release compositions, as well as methods of providing rapid relief from hypertension by administering the substantially pure amorphous lercanidipine hydrochloride. No detail information is provided in the patent application for manufacturing pharmaceutical composition of the amorphous lercanidipine hydrochloride.
Applicants of the present invention surprisingly found a simple and easy to manufacture, stable solid oral dosage form that provides desired dissolution profile of lercanidipine and additionally retaining the same polymorphic form.
SUMMARY OF THE INVENTION
The present invention relates to stable solid oral dosage form of lercanidipine obtained by process of preparation of adsorbates.
One embodiment of the present invention is immediate release stable solid oral dosage form of lercanidipine obtained by process of preparation of adsorbates of lercanidipine.
Another embodiment of the present invention is immediate release stable solid oral dosage form of lercanidipine obtained by process of preparation of adsorbates of lercanidipine which is free from surfactants.
Another embodiment of the present invention is immediate release stable solid oral uncoated tablet dosage form of lercanidipine obtained by a process of preparation of adsorbates of lercanidipine, which is free from surfactants.
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One embodiment of the present invention is immediate release solid oral dosage form of lercanidipine obtained by a process of preparation of adsorbates of lercanidipine which remains stable with respect to physical, chemical or polymorphic changes.
Another embodiment of the present invention in which the lercanidipine is present in the amount sufficient to provide a therapeutic effect when the composition is administered to a patient, e.g., from about 2 to about 80 mg lercanidipine.
Another embodiment of the present invention is process of preparation of adsorbates of lercanidipine according to which lercanidipine is dissolved in at least one solvent preferably organic solvent, and this solution is adsorbed over adsorbing materials, the solvent is then further removed which can be achieved by drying, immediately after adsorption or at later stages.
Another embodiment of the present invention is lercanidipine adsorbates that are obtainable by said process, and the formulations prepared while employing said lercanidipine adsorbates, which may contain further pharmaceutically acceptable excipients and can be converted into the formulation having desired release profile. Tablets may be produced by direct compression or wet granulation or dry granulation.
These and other aspects of the present invention will be apparent to those of ordinary skill in the art in the light of the present description, claims and figures.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1: Comparative XRPD (X-Ray Powder Diffraction) data of lercanidipine hydrochloride, placebo tablet, initial tablet, tablet at 1 month 40°C-75% relative humidity and tablet at 2 month 40°C-75% relative humidity. Figure-2 shows the comparative dissolution profile in 0.0 IN HC1. Figure-3 shows the comparative dissolution profile in pH 3.0 buffer.
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DETAILED DESCRIPTION OF THE INVENTION
The term "immediate release" as used herein refers to the release of an active ingredient such as a drug from a pharmaceutical composition, formulation or dosage form in which the active ingredient is released according to a desired dissolution profile (Not less than 75% in thirty minutes).
The term "dosage form" or "solid oral dosage form" or "pharmaceutical composition" or "formulation" as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosages, each unit containing a predetermined quantity of active material optionally in association with the required excipients. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units. The dosage form used herein selected from tablets, capsule, sachets, pellets, beads, microspheres, microcapsules, pills, powders, lozenges, or granules.
The term "lercanidipine" or "drug" or "active ingredient" means methyl 1,1,N-
trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl l,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)pyridine-3,5-dicarboxylate, as well its pharmaceutically acceptable salt, or solvates or hydrates. Additionally, lercanidipine may be present in crystalline and / or amorphous forms.
The term "stable" as used herein refers to dosage form which is physically, chemically or polymorphically stable. The dosage form according to present invention may remain physically stable that is there are no substantial change with respect to physical attributes like colour etc. The dosage form according to present invention may remain polymorphically stable that is the polymorph (crystalline or amorphous) in the dosage form does not rearranges into another form upon storage for atleast 2 months at 40°C and 75% relative humidity. The dosage form according to present invention may remain chemically stable that is the total impurities in the
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dosage form is not more than 1.5 % upon storage for atleast 2 months at 40°C and 75% relative humidity, preferably the total impurities in the dosage form is not more than 1.0 % upon storage for atleast 2 months at 40°C and 75% relative humidity, more preferably the total impurities in the dosage form is not more than 0.5 % upon storage for atleast 2 months at 40°C and 75% relative humidity.
The term "adsorbates" or "lercanidipine adsorbates" as used herein refers to particles of lercanidipine that are closely associated with adsorbing materials. However, it is not essential that all the particles of lercanidipine may actually be in contact with adsorbing materials.
The term "Amorphous" as used herein refers to solid-state particles that lack a regular crystalline structure and as a result give a diffuse, i.e., non-distinctive, x-ray powder diffraction pattern.
The term "Crystalline" as used herein refers to solid-state particles having a regular ordered structure, which, in contrast to amorphous material, give a distinctive x-ray powder diffraction pattern with defined peaks.
The present invention discloses a process of preparation of adsorbates of lercanidipine according to which lercanidipine is dissolved in at least one solvent preferably organic solvent, and this solution is adsorbed over adsorbing materials, the solvent is then further removed which can more particularly be achieved by drying, immediately after adsorption or at later stages.
Also, to this organic solution of the active ingredient, a pharmaceutically acceptable ingredient that is insoluble or poorly soluble, can be added as the adsorbing material, well wetted, and the solvent is removed by drying. The drying process can be promoted by temperature, applying a vacuum, sublimation drying for instance, or also by spray drying. Preferably, it is conducted in such a way that appropriate mechanical
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action (e.g., rotating, tumbling, or stirring motion) yields a uniform distribution. Adsorbates prepared by the process described can be employed directly in further processing to drug formulations such as tablets, capsules, pellets, or granules.
The solvent, more preferably organic solvent in which the active ingredient will be dissolved are suitable for the process according to the invention, for the preparation of lercanidipine adsorbates. The organic solvents are selected from the group of lower alkanols with one to four carbon atoms, the group of ethers, the group of esters, the group of aliphatic ketones, and the group of halogenated hydrocarbons, as well as mixtures of said solvents. Methanol, ethanol, isopropanol, n-propanol, acetone and other solvents such as ethyl acetate, methyl ethyl ketone, di-isopropyl ether, MTBE (methyl tert-butyl ether), dichloromethane, petrol ether, acetone, hexane, an acetone/water mixture, an ethyl acetate/hexane mixture, a dichloromethane/ethyl acetate mixture, as well as further mixtures of said solvents thereof.
According to the present invention, those pharmaceutically acceptable excipients are used as adsorbing materials which are appropriate for desired release of the active ingredient, such as celluloses and cellulose derivatives, lactose, maltodextrin, starch and starch derivatives, colloidal silicon dioxide, cyclodextrins, polydextroses or mixtures of said substances. Microcrystalline cellulose, lactose, mannitol and other sugar alcohols are preferred according to the invention. For an improvement of the flow properties, additives containing silica can be used. Also, the desired dissolution profile can be obtained by modifying the surface area of the adsorbing materials.
The ratio of pharmaceutical active ingredient to adsorbing material according to the invention is in the range from 1:0.1 to 1:20, a range from 1:0.5 to 1:10 being particularly preferred.
The excipients present in the pharmaceutical composition according to the invention can be diluents such as microcrystalline cellulose, powdered cellulose, lactose,
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compressible sugar, fructose, dextrates, other sugars such as mannitol, sorbitol, lactitol, sacharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, starches, calcium carbonate, calcium lactate or mixtures thereof and if required, other diluents known to person skilled in the art. Preferably, the excipients include at least one diluent, selected from microcrystalline cellulose and starch.
The pharmaceutical composition according to the invention can also comprise binders, such as polyvinyl pyrrolidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose or other cellulose ethers, starch, pregelatinised starch, or polymethacrylate or mixtures of binders and if required, other binders known to person skilled in the art . It is preferred that the excipients include at least one binder selected from povidone and starch.
Further, disintegrants can also be present, such as starch, e.g. pregelatinised starch, corn starch or other starch derivatives, sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium, polacrilin potassium, low-substituted hydroxypropyl cellulose or mixtures thereof and if required, other disintegrants known to person skilled in the art . It is preferred that the excipients include at least one disintegrant selected form starch, sodium starch glycolate and low-substituted hydroxypropyl cellulose.
The disintegrants can be added to the other excipients according to the process used in the state of the art, either in the process of granulating and/or in the preparation of the compression mixture.
Further, lubricants can also be present as excipients, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, or macrogol or mixtures
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thereof and if required, other lubricants known to person skilled in the art It is preferred that the excipients include at least one lubricant selected from sodium stearyl fumarate, talc and magnesium stearate.
Beyond that, all other excipients known to those skilled in the art, such as lubricants, disintegration aids, wetting agents, agents to improve the flow behavior, other additives, stabilizers, as well as flavors, pigments, and dyes, can be used to prepare the drug formulations according to the invention. The proportions pharmaceutically acceptable excipients can be used, which are known to the person skilled in the art.
According to the invention, a process has now been found which, starting from a solution of lercanidipine in an organic solvent, leads to adsorbates of the active ingredient that can be processed directly to the drug formulation.
The solid oral dosage form of the present invention may be prepared by following steps:
1. Sift the adsorbing materials through 40# mesh and mix thoroughly.
2. Dissolve drug in suitable solvent. Adsorb the drug solution onto the blend of step-1.
3. Optionally dissolve binder in suitable solvent and add over the blend from step-2.
4. Dry the wet granules from step 2 or from step 3 and sift the dried granules through 40# mesh.
5. Sift the lubricants and optionally other pharmaceutically acceptable excipient through suitable mesh and mix this with dried blend of step-4.
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6. Compress the blend from step-5 using suitable punches or fill into the
capsules.
Optionally, the adsorbates or drug formulations thus obtained can be further provided with coatings of pharmaceutical polymethacrylates such as Eudragit®, methyl celluloses, ethyl celluloses, hydroxypropyl methyl celluloses, cellulose acetate phthalates and/or shellac in order to fill a specific application, e.g., controlled release of the active ingredient and/or taste masking or aesthetic purpose or durability purpose. Those skilled in the art of pharmaceutics have sufficient technical possibilities to do this.
EXAMPLES
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various dosage forms and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever:
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Table 2

Ingredients Mg / Tablet
B.No : 001 B.No : 002
Dry mix
Microcrystalline Cellulose (Avicel PH 112) 22.20 -
Maize Starch 15.00 15.20
Sodium Starch Glycolate 15.00 15.00
Colloidal Silicon Dioxide 0.50 5.00
Microcrystalline Cellulose (Avicel PH 113) 33.30 56.30
Drug Solution
Lercanidipine Hydrochloride (Amorphous) 10.00 10.00
Methanol * q.s q.s
Binder Solution
Povidone 2.00 -
Methanol * q.s -
Lubrication
Sodium Stearyl Fumarate 1.50 1.50
Colloidal Silicon Dioxide 0.50 -
Weight of core tablet 100.00 103.00
Coating formula
Hypromellose 6 cps (Pharmacoat 606) 1.50 1.50
Macrogol (PEG 6000) 0.375 0.375
Ferric oxide Yellow 0.05 0.05
Titanium dioxide 0.575 0.575
Purified water * q.s q.s
Weight of coated tablet 102.50 mg 105.50
* Does not remain in finished product except in traces.
Process
1. Sift Microcrystalline cellulose, Maize starch, Sodium starch glycolate, and Colloidal silicon dioxide through 40# mesh and mix thoroughly.
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2. Dissolve Lercanidipine hydrochloride in Methanol. Adsorb the drug solution onto the blend of step-1.
3. Dissolve Povidone in Methanol and add over the blend from step-2 (B.No:001)
4. Dry the wet granules from step 2 (B.No:002) or from step 3 (B.No:001) and sift the dried granules through 40# mesh.
5. Sift Colloidal Silicon Dioxide (B.No:001) and Sodium Stearyl Fumarate through 40# mesh and mix this with dried blend of step-4.
6. Compress the blend from step-5 using suitable punches.
7. Film coat the compressed tablet.
Dissolution profile
The dissolution of the present invention was determined by following method:
Table 3

Instrument USP Apparatus II
RPM 50
Temperature 37°C
Dissolution Medium a) 0.01 NHC1,1000 mLb) 3.0 pH buffer, 1000 mL,
The dissolution profiles of the tablets prepared as per B.No:001, 002 and Carmen® Tablet, market sample of Lercanidipine Tablets (Manufacturer: Berlin Chemie) are given in the table below:
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Table 4

TIME(Minutes) % Cumulative release profile
0.01 N HC1 3.0 pH buffer
001 002 Carmen®TabletB.No:61003 001 002 Carmen®TabletB.No: 61003
10 89.5 92.3 91.0 61.8 73.7 55.4
15 94.5 92.2 93.9 72.4 82.0 65.5
30 96.7 92.3 94.1 83.7 88.6 77.9
45 96.9 92.4 94.2 88.0 90.1 83.5
60 97.2 92.2 94.2 90.1 90.7 86.1
Stability Data:
The stability data of Lercanidipine hydrochloride tablets manufactured as per B.No:001 packed in PVC blister is as below:
Table 5

Condition / Period Assay (%) % drug release in 30 min Related Impurities (%)
Single unknown Total
Initial 103.5 96.7 0.03 0.18
40°C - 75% RH /1 Month 103.8 97.9 0.04 0.31
40°C-75%RH/2Month 104.5 96.8 0.05 0.30
30°C - 65% RH / 2 Month 104.2 96.1 0.04 0.24
Testing the tablets by X-ray diffraction in order to evaluate the polymorphism of the drug is a difficult task. Lercanidipine hydrochloride tablet contains many
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pharmaceutically acceptable excipients. Being crystalline compounds these excipients do have X-ray powder diffraction pattern. This pattern has to be subtracted from the total pattern in order to see the peaks that originate from lercanidipine hydrochloride. The fact that lercanidipine hydrochloride itself is only a small part of the formulation makes it even harder. Moreover, the X-ray powder diffraction patterns of the tablets prepared as per instant invention and the placebo are similar. The absence of extra X-ray powder diffraction peaks in the tablet pattern at initial stage and accelerated stability conditions (1 month and 2 month 40°C -75% relative humidity) indicates that there is no contribution from the lercanidipine hydrochloride in the tablet, showing it remains in amorphous state.
Dated this 05th day of December, 2006

M
Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited, Torrent Research Centre P.O. Bhat-382428, Gandhinagar Gujarat, India.
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ABSTRACT
The present invention relates to stable solid oral dosage form of lercanidipine by using a process of preparation of adsorbates.
The invention further relates to lercanidipine adsorbates that are obtainable by said process, as well as pharmaceutical formulations prepared while employing said lercanidipine adsorbates.