FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATIONS (See section 10, rule 13)
"CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION"
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 INVENTION:
The present invention relates to a controlled release pharmaceutical composition comprises of highly soluble drug and hydrogenated oil and process for preparation of the said composition by hot melt granulation
BACKGROUND OF INVENTION:
Controlled release dosage forms are well known in the art to release drug gradually over an extended period of time after the drug makes contact with an aqueous solution or gastrointestinal fluid. These dosage forms are desirable in treating various diseases because the desired drug concentration is maintained in-vivo for longer period of time as compared to immediate release dosage forms and allowing less frequent dosing.
In pharmaceutical science, for an oral solid dosage formulation a drug must first become soluble in the aqueous media of the stomach or small intestine to absorb in the systemic circulation to produce desired pharmacological effects. Products which are rapidly dissolved in water are also rapidly absorbed into the body. For such products, controlling their rate of dissolution after ingestion also influences their rate of absorption and the drugs which are highly or moderately water soluble needs particular thought during formulation development.
For the preparation of controlled release dosage form, different technologies are well known in the art among them the melt granulation process offers several advantages over other pharmaceutical convectional granulation methods. The said process does not require the use of solvents thus eliminating the drying step. Because there is no drying step, the overall process is less time consuming and requires few processing steps. Hence, the entire process is simple, continuous and efficient.
US 20080248107 discloses controlled release formulation comprising high water soluble active ingredient and rate retarding polymer Lubritab (hydrogenated vegetable oil, Type I, USPNF) to prepare extended release tablets of metopropol succinate by melt granulation technique, but additional retarding polymer like kollidone SR, kollidone VA 64 is used to control the release of active substance from formulation.
US 6290990 discloses the use of hydrogenated castor oil to prepare slow release pellets of Gallopamil HCI or Theophylline by melt extrusion method and additional retardant polymer like ethyl cellulose and gel forming polymer is used to prepare the said pellets.
US 20060013876 discloses the pharmaceutical composition of floating dosage form preferably bilayer tablets for controlled delivery of active ingredient in upper parts of

gastrointestinal tract, wherein the first layer comprises of ethyl cellulose and hydrogenated oil in ratio 95:5 to 30:70 prepared by hot melt granulation method to retain the dosage form in stomach and second layer comprises of controlled release matrix polymer such as synthetic or semi synthetic cellulose derivatives thereof, natural polymer, gum, acrylic acid derivatives thereof.
US 20030195249 discloses extended release composition of venlafaxine besylate preferably hydrogel tablets prepared by hot melt granulation method. US 20030195249 disclose the use of one or more retardant material like glyceryl behenate with hydrogenated castor oil to prepare extended release tablets of poorly soluble active ingredient.
WO 2011107750 discloses a press coated tablet formulation for a delayed, followed by a prolonged release of verapamil. In WO 2011107750 the prolonged release of verapamil is achieved by preparing the core using wax such as beeswax, carnauba wax, microcrystalline wax and hydrogenated castor oil. WO 2011107750 further discloses that said core is press coated by mixture of wax and low substituted hydroxypropyl cellulose to achieve delayed release. WO 2011107750 only discloses the use of glycerol behenate in example to prepare said dosage form.
US 4461759 discloses the controlled release dosage form of verapamil comprising acid retardant or hydrophobic cellulose derivative, hydrogenated vegetable oil, acrylic acid polymer, fumed silicon dioxide but the process used is by wet granulation method.
US20110217373A1 discloses the preparation of controlled release composition of Guanfacine Hydrochloride using hydrogenated castor oil by melting of hydrogenated castor oil and incorporating drug into the oil but additional Hydroxypropyl methyl cellulose is used to control the drug release.
US5043167A discloses the preparation of controlled release granules of Naproxen Sodium using Hydrogenated castor oil but additional ethyl cellulose is used to retard the drug release by wet granulation method.
WO2011128914A2 discloses the composition of Pramipexole consisting of Hydrogenated castor oil but the manufacturing process is by wet granulation method
US20110218216A1 discloses the preparation of controlled release formulation of Donepezil using Hydrogenated castor oil but additional Eudragit is used to retard the drug release
US20110123610A1 discloses the preparation of controlled release composition of Tolterodine using Hydrogenated castor oil but additional ethyl cellulose is used to retard the drug release by wet granulation method.

US4942040A discloses the composition of Metoprolol sing Hydrogenated castor oil but additional Hydroxy propyl methyl cellulose is used to retard the drug release by wet granulation method.
In wet granulation method many process variables such as fluid uptake, rate of addition of binder, granulation time, and impeller and chopper torque are critical and drug molecules which are not entrapped in matrix may produce burst effects.
We have prepared controlled release tablet of verapamil hydrochloride in (Example 1) using a combination of Hydrophilic rate retarding polymer HPMC (Hydroxy propylmethyl cellulose) and celluloses derivatives which is substantially similar to composition disclosed in US 6,368,628 B1. In vitro dissolution shows the initial burst release of drug wherein 29% drug is released in one hour.
None of the above cited prior art suggest the use of combination of plant derived product like hydrogenated oils as sole controlled release matrix forming excipient coupled with hot melt granulation technique to provide a controlled release pharmaceutical composition of highly soluble drug through simple, less time consuming process with minimum process variable which reduces or eliminates the initial burst effect would represent a significant advancement as describes in the present invention.
OBJECT OF INVENTION:
An object of the present invention is to provide a controlled release pharmaceutical composition comprises of highly soluble drug and plant derived product like hydrogenated oils as sole controlled release matrix forming excipient which reduces or eliminates the initial burst effect and release the highly soluble drug over an extended period of time in controlled manner from suitable dosage form,
An another object of the invention is to provide a said composition, which further comprises of one or more pharmaceutically acceptable excipients which does not produce any significant effect on controlled release of highly soluble actives.
An another object of the invention is to provide simple, cost effective, less time consuming hot melt granulation process involving minimum process variables to prepared said dosage form.
DETAILED DESCRIPTION OF INVENTION:
The present invention provides a controlled release pharmaceutical composition comprises of highly soluble drug and plant derived product like hydrogenated oils as sole

controlled release matrix forming excipient, which reduces or eliminates the initial burst effect and release the highly soluble drug over extended period of time in controlled manner from suitable dosage form, wherein said composition is prepared by hot melt granulation technique.
The present invention further provides a controlled release pharmaceutical composition comprises of highly soluble drug and plant derived product like hydrogenated oils as sole controlled release matrix forming excipient, wherein the ratio of the highly soluble drug to hydrogenated oil is 1:1 to 1:3.
The present invention provides a controlled release pharmaceutical composition which is further comprises of one or more pharmaceutically acceptable excipient which does not significantly contribute to control the release of highly soluble drug.
The present invention further provides a controlled release pharmaceutical composition wherein one or more pharmaceutically acceptable excipients are selected from group of non release retarding excipients, which does not significantly contribute to control the release of highly soluble drug.
The present invention further provides a controlled release pharmaceutical composition wherein non release retarding excipient used are selected form diluent, lubricant and glidant.
The present invention further provides a controlled release pharmaceutical composition wherein the ratio of drug to non release retarding excipient is 1:1 to 1:5.
For the purpose of the invention a drug is therapeutically active compounds for which oral administration is desired. However, the selected therapeutically active compound should be compatible with the selected material and any excipients. Drug includes therapeutically active compounds or pharmaceutically acceptable salts or esters or amides or pro-drugs thereof.
For the purpose of the invention the highly soluble drug is selected from valsartan, Olmesartan, nifedipine, Nicardipine, Felodipine, Nisoldipine, Nicardipine, Bepridil, Felodipine, verapamil and Diltiazem or pharmaceutically acceptable salt thereof and preferably Verapamil or pharmaceutically acceptable salt thereof.
For the purpose of the invention the hydrogenated oils are selected from castor oil, linseed oil, cottonseed oil, soybean oil, corn oil, peanut oil, palm oil, sunflower seed oil or mixtures thereof and preferably hydrogenated cottonseed oil.
For the purpose of the invention the term "diluent" refers to an excipient which fills out the size of a tablet or capsule, making it practical to produce and convenient for the

consumer to use. Suitable diluents include e.g. pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate sugar, sugar alcohols, corn starch, sucrose, silicic anhydride, polysaccharides, N-methyl pyrrolidone and mixtures thereof. The term sugar and sugar alcohols comprises mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and mixtures thereof.
For the purpose of the invention the term "lubricant" refers to an excipent which improve the flowability of the powder by reducing interparticle friction and cohesion are selected from colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate and silica gel.
For the purpose of the invention glidant is selected from silica colloidal anhydrous, magnesium trisilicate, talc, and functional equivalents thereof.
A controlled release pharmaceutical composition comprises of highly soluble drug and plant derived product like hydrogenated oils as sole controlled release matrix forming excipient comprising the steps of:
a) mixing highly soluble drug and one or more pharmaceutically acceptable excipients;
b) melting the hydrogenated oil;
c) adding melted hydrogenated oil of step (b) to the dry mixture of step (a) under continuous mixing in order to form granules; and
d) Sifting the granules of step (c) in order to obtain homogenous uniform sized granules.
The pharmaceutical composition of highly soluble drug is presented in the form of tablet or capsule.
The present invention provides a controlled release pharmaceutical composition comprises highly soluble drug and hydrogenated oils as sole controlled release matrix forming excipient which reduces or eliminates the initial burst effect and a much greater percentage of the active agent would remain in the dosage form for controlled release. Further, the efficacy of such systems would also be improved.
The inert nature of hydrogenated oil used in the present invention helps in establishing good stability at varying pH and moisture level. The stability study result of Example 3 is shown in table 2
Additionally the present invention also provides simple, continuous and efficient process to prepare said composition.

The invention is further illustrated by following non-limiting examples which does not limit the scope of the invention.
EXAMPLE 1: Substantially similar to composition disclosed in US 6,368,628 B1

Sr. No Ingredients w/w%
1 Verapamil HCI 67
2 3 Macrocrystalline Cellulose
(AvicelpH101)
Hydroxy propyl methyl cellulose
(100cpsand 15,000 cps) 7 15
4 Plasdone K30 6
5 Silicon dioxide 0.4
6 Magnesium stearate 1
7 Coating:
(Eudragit L30D55 , Syloid 244 FP
and Polyethylene glycol 1450) 3.6
Total 100.0
a) Verapamil HCI and Hydroxy propyl methyl cellulose are mixed together with Microcrystalline cellulose (Avicel pH 101)
b) Binder solution was prepared by mixing Povidone in ethanol under stirring;
c) Binder solution of step (b) was added to step (a) until appropriate granules are formed
d) Wet mass of step (c) was dried until desired LOD is reached
e) Sifted granules of step (d) is passed through appropriate sieving screen and lubricated with Aerosil and magnesium stearate to form lubricated granule
f) Lubricated granule was compressed into tablets
g) The tablet core were then coated with the said coating composition disclosed in the said patent
The formulation of Example 1 showed a burst effect of 29 % in 1 hour when compared to the formulation of Example 5 which releases only 18 % of drug without any burst effect in 1 hour (Table 1). Hydroxy propyl cellulose due to hydrophilic nature rapidly takes up the water molecules leading to swelling and release the drug. It is thus concluded that Hydroxy propyl methyl cellulose is unable to control the initial burst release of highly soluble drug.

EXAMPLE 2: Composition with Hydrogenated oil and additional polymer Hydroxy propyl methyl cellulose

Sr. No Ingredients w/w %
1 Verapamil HCI 22.0
2 Microcrystalline Cellulose (Avicel pH 101) 27.6
3 Hydrogenated cottonseed oil 37.7
4 Hydroxy propyl methyl cellulose (100cpsand 15,000 cps) 5.5
5 Magnesium stearate 1.8
6 Silicon dioxide 1.8
7 Coating :
(Eudragit L30D55 , Syloid 244 FP
and Polyethylene glycol 1450) 3.6
Total 100.0
a) Verapamil HCI and Microcrystalline cellulose (Avicel pH101) are mixed together
b) Hydrogenated cottonseed oil was melted at a temperature between 60-70 °C to form a clear liquid
c) Hydrogenated cotton seed oil of step (b) was added to the dry mix of step (a) under continuous mixing in order to form granules
d) Granules of step (c) was passed through appropriate sieving screen in order to obtain homogenous uniform sized granules
e) Sifted granules of step (d) was mixed extra-granular with Hydroxy propyl methyl cellulose and finally lubricated with Aerosil and magnesium stearate to form lubricated granule
f) Lubricated granule was compressed into core tablet
g) The tablet core were coated with the said coating composition
The formulation of Example 2 gives a burst effect of 30 % when compared to the formulation of Example 5 which releases only 18 % of drug without any burst effect in 1 hour (Table 1).A combination of Hydrophilic and Hydrophobic polymer were unable to control the initial burst effect. The probable reason for the burst release of drug is due to the different mechanism of two polymers used. Hydroxy propyl methyl cellulose due to hydrophilic nature rapidly takes up the water molecules leading to swell-ing, while on the other side Hydrogenated Castor Oil due to hydrophobic nature repels the water molecules, re-sulting in separation of the formulation components and leading to the burst affect in initial time. From the dissolution data (Table 1) one can conclude that the combination of hydrophilic and

hydrophobic polymer matrices is not suitable in the development of a con-trolled-release dosage form for highly soluble drugs
EXAMPLE 3

Sr. No Ingredients w/w %
1 2 3 4 6 7 Verapamil HCI Microcrystalline Cellulose HypromelloseKIOOMCR Povidone K 30 Magnesium stearate Silicon dioxide 26.8
40.3
29.8
1.9
0.6
0.6
Total 100
h) Mixing verapamil HCI, microcrystalline cellulose and hypromellose; i) preparing binder solution by mixing povidone in water under stirring; j) adding binder solution of step (b) to step (a) until appropriate granules are
formed; k) drying wet mass step (c) is dried until LOD reaches below 3.5 % w/w; and I) sifting granules of step (d) and lubricated with Aerosil and magnesium stearate to
form lubricated granule to compress to form tablets.
The formulation of Example 3 gives a burst effect of 29 % when compared to the formulation of Example 6 which gives the 18 % of burst effect in 1 hour.
EXAMPLE 4

Sr.No Ingredients w/w %
1 Verapamil HCI 22.0
2 Microcrystalline Cellulose 27.5
3 hydrogenated cottonseed oil 41.3
4 Hypromellose K 100 MCR 5.5
5 Magnesium stearate 1.8
6 Silicon dioxide 1.8
Total 100
h) Mixing verapamil HCI and microcrystalline cellulose;
i) melting hydrogenated cottonseed oil at a temperature between 60-70 °C to form a clear liquid ;

j) adding melted hydrogenated oil of step (b) to the dry mix of step (a) under
continuous mixing in order to form granules; k) sifting the granules of step (c) in order to obtain homogenous uniform sized
granules;
I) mixing sifted granules of step (d) with Hypromeltose and lubricated with Aerosil and magnesium stearate to form lubricated granule to compress into tablets.
The formulation of Example 4 gives a burst effect of 30 % when compared to the formulation of Example 1 which gives the 18 % of burst effect in 6 hour.
EXAMPLE 5: As per the present invention

Sr. No Ingredients w/w %
Ratio of Verapamil: Hydrogenated Cotton seed Oil 1:1 1:2 1:3 1:4
1 Verapamil HCI 15 15 15 15
2 Microcrystalline Cellulose (Avicel pH 101) 65 50 35 20
3 Hydrogenated cottonseed oil 15 30 45 60
4 Magnesium Stearate 2 2 2 2
5 Silicon Di-oxide 1 1 1 1
6 Coating:
Titanium dioxide,Triacetin, Pregelatinized Modified Starch 2 2 2 2
Total 100 100 100 100
a) Verapamil HCI and microcrystalline cellulose (Avicel pH 101) were mixed together
b) Hydrogenated cottonseed oil is melted at a temperature between 60-70 °C to form a clear liquid
c) Hydrogenated oil of step (b) is added to the dry mixture of step (a) under continuous mixing in order to form granules
d) Granules of step (c) is passed through appropriate sieving screen in order to obtain homogenous uniform sized granules
e) uniform sized granules of step (d) was further mixed with one or more pharmaceutical excipient to compress into tablet
f) Sifted granules of step (d) is passed through appropriate sieving screen and lubricated with Aerosil and magnesium stearate to form lubricated granule
g) Lubricated granule is compressed into tablets
h) The tablet core were then coated with the said coating composition mentioned in Table 3

EXAMPLE 6: As per the present invention

Sr. No Ingredients w/w %
1 Verapamil HCI 26.8
2 Microcrystalline Cellulose 40.3
3 hydrogenated cottonseed oil 29.8
4 Magnesium Stearate 1.6
5 Silicon Di-oxide 1.6
Total 100
i) Mixing verapamil HCI and microcrystalline cellulose;
j) melting hydrogenated cottonseed oil at a temperature between 60-70 °C to form
a clear liquid; k) adding melted hydrogenated oil of step (b) to the dry mixture of step (a) under
continuous mixing in order to form granules; I) sifting the granules of step (c) in order to obtain homogenous uniform sized
granules; m) uniform sized granules of step (d) further mixed with one or more pharmaceutical
excipient to compress into tablet.
In-vitro dissolution study:
In-vitro drug release study for the prepared tablets as per Example 1 to 6 is conducted for period of 8 hours using a USP XXVII type 2 (Paddle) apparatus at 37°C ± 0.5 °C and 50 rpm speed. The dissolution studies are carried out in 900 ml acid buffer pH 1.2 for one hour and in phosphate buffer pH 6.8 for further seven hours under sink condition. At one hour and then 2, 3.5, 5 and 8 hours interval samples of 10 ml are withdrawn from dissolution medium and replaced with fresh medium to sink condition. After filtration the sample solution is analyzed for verapamil CL.Since Verapamil Hydrochloride Extended release tablet is official in United state Pharmacoepia (USP); the dissolution profile of different batches were compared with the desired release profile as per USP

Table 1: Comparative Dissolution Profile of Verapamil HCI

% Drug Released
USP Time Desired Example Example Example Example
(Hr.) limit 12 3 4 Example 5 Example 6

Ratio of Drug: Polymer

1:1 1:2 1:3 1:4 1:1.5
0.1 N HCI, Paddle , 50 rpm ,37+0.5 °C,900 ml
1 18 15 12 8 30 18 15 12 8 18
pH 6.8 Phosphate buffer, Paddle , 50 rpm ,37±0.5 °C,900 ml
2 18-33% 44 42 44 42 28 25 21 19 28
3.5 35-60 % 55 53 50 45 42 39 36 32 42
5 50-82 % 87 84 52 56 73 68 60 55 63
8 NLT85% 94 91 69 87 97 95 94 89 97
Tablets formulated according to the invention (Example 5 & 6) allow controlled release active agent as per USP (United State Pharmacopeia) desired limits and reduces the initial burst effect in the ratio of drug is to polymer from 1:1 to 1:3.It was observed that when drug and polymer is used in ratio is 1:4 then it produce retardant effect and slowed down the drug release which does not meet the USP desired limit. The batch in Example 5 with drug to polymer ratio in 1:3 is charged in stability accelerated condition at 40 °C/75% RH up to 3 months and the results is tabulated below in Table 2
Table 2: Stability Results of Verapamil HCI:

Verapamil ER tablet : Example 5 Drug is to polymer ratio : 1:3 Parameters: Assay , Impurities profile and i _oss on Drying
Parameters Unknown Max % Total Imp % Assay LOD % w/w
ICH limit 0.5 1.0 90-110 NMT 8.0%*
Initial ND 0.08 97 5.5
1 Month 0.03 0.03 99 6.1
2 Month 0.03 0.04 98 6.5
3 Month 0.03 0.05 98 7.2
* In house Limit

Verapamil ER tablet : Example 3
Drug to polymer ratio : 1:3
Parameters: Dissolution in 0.1 N HCI followed by 6.8 phosphate buffer in
900 ml using Paddle, 50 rpm.
Time points: 1 Hr 2Hr 3.5 Hr 5Hr 8Hr
Acidic Media Basic Media
USP Limit (%) 10-21 18-33 35-60 50-82 NLT85%
Initial 11 22 46 70 96
1 Month 13 25 43 62 98
2 Month 13 25 43 61 95
3 Month 13 24 43 60 95
From the result it can be concluded that the results are satisfactory and are within the desired limit.

We Claim:
1. A controlled release pharmaceutical composition comprising Verapamil or pharmaceutically acceptable salt thereof and hydrogenated oil as sole controlled release matrix forming excipient wherein said composition is prepared by hot melt granulation technique.
2. The controlled release pharmaceutical composition as claimed in claim 1, wherein the ratio of Verapamil or pharmaceutically acceptable salt thereof to hydrogenated oil is 1:1 to 1:3.
3. The controlled release pharmaceutical composition as claimed in claim 1, wherein hydrogenated oil is selected from castor oil, linseed oil, cottonseed oil, soybean oil, corn oil, peanut oil, palm oil, sunflower seed oil or mixtures thereof and preferably hydrogenated cottonseed oil.
4. The controlled release pharmaceutical composition as claimed in claim 1 is further comprises of one or more pharmaceutically acceptable excipients selected from group of non release retarding excipients such as diluent, lubricant and glidant.
5. The controlled release pharmaceutical composition as claimed in claim 4, wherein the ratio of Verapamil or pharmaceutically acceptable salt thereof to non release retarding excipient is 1:1 to 1:5.
6. A process for preparation of the controlled release pharmaceutical composition as claimed in claim 1 comprising the step of:

a) mixing highly soluble drug and one or more pharmaceutically acceptable excipients;
b) melting the hydrogenated oil;
c) adding melted hydrogenated oil of step b) to the dry mix of step a) under continuous stirring in order to form granules; and
d) Sifting the granules of step c) in order to obtained homogenous uniform sized granules.
7. The controlled release pharmaceutical composition as claimed in any proceeding
claims is in the form of a tablet or a capsule.