FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
THE PATENTS RULES, 2010 COMPLETE SPECIFICATION
(See section 10; rule 13)

"PHARMACEUTICAL COMPOSITIONS OF LACIDIPINE"
CADILA PHARMACEUTICALS LIMITED
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210, Gujarat,
India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention is related to solid oral pharmaceutical compositions of lacidipine.
BACKGROUND OF THE INVENTION:
Lacidipine is a BCS class IV drug with low solubility and low permeability. Low solubility results in low dissolution rate of an active ingredient from solid pharmaceutical dosage form, leading to an incomplete absorption and poor bioavailability.
US4801599 discloses lacidipine and its composition comprising lacidipine, polyvinylpyrrolidone (PVP), lactose and magnesium stearate. It further discloses the method of preparation of tablet wherein drug is granulated by a solution of PVP in ethanof, blended with the excipients and compressed using punches to suit. However, the tablets prepared by above method did not show desired dissolution of lacidipine.
W01995/08987 discloses compositions comprising one or more 1, 4 dihydropyridine derivatives such as nitrendipine, nimodipine, lacidipine; a carrier such as water-soluble derivatives of mono-, di-, oligo- or poly- saccharides; a disintegrant selected from polacrilin potassium, sodium starch glycolate and/or cross-linked carboxy methylcellulose and surfactants selected from sodium lauryl sulfate, poloxamers and/or higher fatty acids polyoxyethylene sorbitan esters.
WO2006/113309 discloses the preparation of agglomerate free particles of lacidipine having smaller particle size with a higher surface area using ultrasound technique. In addition, the said patent discloses premix composition prepared by dispersing a solution comprising lacidipine onto a solid substrate material and then drying the granules in fluid bed drier till the loss on drying is less than 3.5% w/w. The obtained premix is further mixed with disintegrant and other pharmaceutical excipients(s) to prepare the tablet.
All the above mentioned prior art disclose pharmaceutical composition comprising of lacidipine by using surfactant(s) and/or disintegrant(s) or micronized lacidipine. It would thus be significant improvement in the art to provide pharmaceutical dosage

form of lacidipine without the use of surfactant(s) and/or disintegrant(s) or without micronization of Lacidipine.
SUMMARY OF THE INVENTION:
The main object of the invention is to provide pharmaceutical dosage form of lacidipine with desired dissolution rate.
Another object of the invention is to provide said pharmaceutical dosage form with at least 80% drug release within 45 min.
Another object of the invention is to provide said pharmaceutical dosage form without the use of surfactant(s) and/or disintegrant(s).
Another object of the invention is to provide said pharmaceutical dosage form without micronization of the active ingredient.
"Yet another object of the Invention is to provide a process 'for the preparation of said pharmaceutical dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 represents comparative dissolution profiles of the lacidipine tablet prepared
according to composition and process of examples 2-6.
Figure 2 represents dissolution profiles of the lacidipine tablet prepared according to the present invention wherein the drug to PVP ratio is in the range of 1:11 to 1:20, prepared by fluid bed granulation method.
DETAILED DESCRIPTION OF THE INVENTION:
In accordance with the invention, solid oral pharmaceutical compositions with desired dissolution rate comprises of lacidipine, carrier, diluent and lubricant wherein the weight ratio of lacidipine to carrier is not less than 1:11
Further the said pharmaceutical composition with desired dissolution rate is prepared without micronization and use of surfactant(s) and/or disintegrant(s).
The process for the preparation of a solid oral pharmaceutical composition of lacidipine comprising the steps of

a) dissolving an active ingredient and a carrier in solvent or mixture of solvents to get a solution;
b) spraying the solution of step a) onto diluent(s) in fluid bed granulator to get granules and drying the same;
c) mixing of dried granules of step b) with lubricant;
d) optionally adding one or more pharmaceutical exeipient to step c), to prepare a tablet or a capsule dosage form.
For the purpose of the invention the term "desired dissolution rate" as used herein refers to at least 80% drug release within 45 min as per the British Pharmacopoeia dissolution specification for a conventional-release dosage form.
For the purpose of invention the term "dissolution medium" as used herein refers to 500 ml of purified water having 1% polysorbate 20(Tween 20)
Carrier is selected from the group of polyvinylpyrrolidone (PVP), polyethylene glycol; preferably high molecular weight polyethylene glycol (PEG), urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof and the preferred carrier is polyvinylpyrrolidone (PVP). The weight ratio of the drug to carrier is preferably in the range of 1:11 to 1:20 and more preferably 1:13 to 1:15.
Solvent is selected from the group of lower alcohols such as methanol, isopropyl alcohol and ethanol or mixtures thereof. The preferred solvent is isopropyl alcohol or ethanol.
The pharmaceutical compositions contain one or more diluent selected from the group of microcrystalline cellulose, cellulose derivatives, lactose, starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin and mannitol. The preferred diluent is lactose.
The lubricant is selected from stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica,

cornstarch, calcium silicate, magnesium silicate, silicon hydrogel or mixture thereof. The preferred lubricant is magnesium stearate.
The one or more pharmaceutical excipients are selected from glidant, coloring agent and optionally flavoring agent.
The pharmaceutical composition is in the form of a tablet or a capsule.
Comparative Examples
Comparative examples 1 to 4 disclose the preparation of lacidipine tablets using processes (wet granulation, solvent removal and melting method) other than the present invention. Comparative examples 5 & 6 disclose the preparation of lacidipine tablets using process as per the present invention i.e. fluid bed granulation method wherein the lacidipine' to PVP ratio is 1:10 and 1:7, respectively.
Example 1: Wet granulation method: Lacidipine tablets prepared according to composition disclosed in US4801599, wherein the weight ratio of lacidipine to PVP is 1:20.
Table 1: Composition of Example 1

Sr. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 80.00
3 Lactose 213.00
4 Magnesium Stearate 3.00
5 Isopropyl alcohol (IPA) q.s
Process description:
a) Lacidipine and PVP were dissolved in IPA;
b) lactose was granulated with the solution of step (a) in a rapid mixer granulator. The mass obtained from step (b) was sticky thus the batch was discarded due to processing problems.
The result indicates that when lacidipine tablet prepared according to method and composition disclosed in US 4801599 produce sticky mass that results in processing problems.

Example 2: Wet granulation method.
Table 2: Composition of Example2

S. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 20.00
3 Lactose 273.00
4 Magnesium Stearate 3.00
5 IPA q.s
Process description:
a) Lacidipine and PVP were dissolved in IPA;
b) lactose was granulated with the solution of step (a) in a rapid mixer granulator;
c) the wet mass obtained from step (b) was dried till loss on drying (LOD) was not more than 1.0% w/w;
d) the dry mass obtained from step (c) was sifted through 20# and lubricated with magnesium stearate and finally compressed into tablet.
The drug release was 24% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 1.
Example 3: Solvent removal method.
Table 3: Composition of Example 3

S. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 40.00
3 Lactose 253.00
4 Magnesium Stearate 3.00
5 IPA q.s
Process description:
a) Lacidipine and PVP were dissolved in IPA;
b) lactose was granulated with the solution of step (a);
c) the wet mass of step (b) was dried and LOD was kept below 1% w/w;
d) the dry mass of step (c) was sifted through 20# and lubricated with magnesium stearate and compressed into tablet.

The drug release was 63% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 1.
Example 4: Melting method
Table 4: Composition of Example 4

S. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 40.00
3 Lactose 253.00
4 Magnesium Stearate 3.00
Process description:
a) Lacidipine and PVP were melted in a container and a yellow colored mass was obtained;
b) the mass of step (a) was cooled at room temperature (RT) and sifted through 20# sieve;
c) lactose was granulated with water and LOD was maintained below 2.0% w/w;
d) dry mass of step (c) was sifted through 20# sieve;
e) sifted mass of step (b) and (c) were mixed and lubricated with magnesium stearate and compressed into tablet.
The drug release was 35% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 1.
Example 5 and 6: Fluid bed granulation method.
Table 5: Composition of Example 5 and 6

S. No. Ingredients Example 5 Example 6

mg / Tablet mg / Tablet
1 Lacidipine 4.00 4.00
2 PVP 40.00 30.00
3 Lactose 253.00 263.00
4 Magnesium Stearate 3.00 3.00
5 IPA q.s q.s
Process Description:
a) Lacidipine and PVP were dissolved in IPA;
b) the solution of step (a) was sprayed onto lactose in fluid bed granulator;
c) the granules of step (b) were further dried in fluid bed granulator;

d) the dried mass of step (c) was lubricated with magnesium stearate and compressed into tablet at an average weight of 300 mg.
in the case of examples 5 & 6 the drug release was 76% and 63% respectively, in 45 min in dissolution medium at 37 °C using dissolution apparatus II at 50 rpm.
As shown in Figure 1 dissolution profile of lacidipine tablets prepared according to composition and process of examples 2 to 6 is less than 80% within 45 min.
The pharmaceutical composition prepared according to these examples indicates that the ratio of lacidipine to PVP and method of preparation of composition ha^e significant effect on dissolution of lacidipine.
The invention is farther illustrated by the following non-limiting examples:
Example 7: Fluid bed granulation method
Table 6: Composition of Example 7

Sr. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 80.00
3 Lactose 213.00
4 Magnesium Stearate 3.00
5 IPA q.s
Process Description:
a) Lacidipine and PVP were dissolved in IPA;
b) the solution of step (a) was sprayed onto lactose in fluid bed granulator;
c) the granules of step (b) were dried in fluid bed granulator;
d) the dried mass of step (c) was lubricated with magnesium stearate and compressed into tablet at an average weight of 300 mg.
The drug release was 83% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 2.

Example 8: Fluid bed granulation method
Table 7: Composition of Example 8

Sr. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 70.00
3 Lactose 223.00
4 Magnesium Stearate 3.00
5 IPA q.s
Process Description;
a) Lacidipine and PVP were dissolved in IPA;
b) the solution of step (a) was sprayed onto lactose in fluid bed granulator;
c) the granules of step (b) were dried in fluid bed granulator;
d) the dried mass of step (c) was lubricated with magnesium stearate and compressed into tablet at an average weight of 300 mg.
The drug release was 85% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 2.
Example 9: Fluid bed granulation method
Table 8: Composition of Example 9

Sr. No. Ingredients mg / Tablet
1 Lacidipine 4.00
2 PVP 60.00
3 Lactose 233.00
4 Magnesium Stearate 3.00
5 IPA q.s
Process Description;
a) Lacidipine and PVP were dissolved in IPA;
b) the solution of step (a) was sprayed onto lactose in fluid bed granulator;
c) the granules of step (b) were dried in fluid bed granulator;
d) the dried mass of step (c) was lubricated with magnesium stearate and compressed at an average weight of 300 mg:
The drug release was 87% in 45 min in dissolution medium at 37°C using dissolution apparatus I! at 50 rpm as shown in Figure 2.

Example 10: Fluid bed granulation method
Table 9: Composition of Example 10

Sr. No. Ingredients mg / Tablet
1 Lacidipine 6.00
2 PVP 80.00
3 Lactose 359.50
4 Magnesium Stearate 4.50
5 Absolute Alcohol q.s
Process Description:
a) Lacidipine and PVP were dissolved in absolute alcohol;
b) the solution of step (a) was sprayed onto lactose in fluid bed granulator;
c) the granules of step (b) was further dried in fluid bed granulator;
d) the dried mass of step (c) was lubricated with magnesium stearate and compressed at an average weight of 450 mg.
The drug release was 107% in 45 min in dissolution medium at 37°C using dissolution apparatus II at 50 rpm as shown in Figure 2.
It was concluded that pharmaceutical composition prepared by fluid bed granulation technique showed rapid dissolution of lacidipine when the lacidipine to PVP ratio is in the range of 1:11 to 1:20 as shown in Figure 2.

We claim
1. A solid oral pharmaceutical composition comprising lacidipine,
polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG), diluent and lubricant; wherein weight ratio of lacidipine to PVP or PEG is not less than 1:11; prepared by fluid bed granulation technique; showing at least 80% drug release within 45 min,
2. The solid oral pharmaceutical composition as claimed in claim 1 wherein the said composition is prepared without micronization of lacidipine and the use of surfactant(s) and/or disintegrant(s).
3. The solid oral pharmaceutical composition as claimed in claim 1, wherein the weight ratio of lacidipine to PVP or PEG is preferably in the range of 1:11 to 1:20, more preferably 1:13 to 1:15..
4. The solid oral pharmaceutical composition as claimed in claim 1, wherein the polyethylene glycol is preferably high molecular weight polyethylene glycol.
5. A process for the preparation of the solid oral pharmaceutical composition comprising the steps of;

a) dissolving an active ingredient and carrier in solvent to get a solution;
b) spraying the solution of step (a) onto diluent(s) in fluid bed granulator to get granules and drying the granules;
c) mixing of dried granules of step (b) with lubricant; and
d) optionally, adding one or more pharmaceutical excipient to step (c).

6. The solid oral pharmaceutical composition as claimed in claim 1, wherein the diluent(s) is selected from microcrystalline cellulose, cellulose derivatives, lactose, starch, dextrose, mannitol, preferably lactose.
7. The solid oral pharmaceutical composition as claimed in claim 1, wherein the lubricant is selected from stearic acid, polyethylene glycol, magnesium

stearate, calcium stearate, talc, zinc stearate, silica, colloidal silica or mixture thereof.
8. The solid oral pharmaceutical composition as claimed in claim 1 is further comprises of one or more pharmaceutical excipient.
9. The solid oral pharmaceutical composition as claimed in claim 1 is in the form of a tablet or a capsule.