FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A NOVEL CONTROLLED POROSITY OSMOTIC RELEASE (CPOR)
DELIVERY SYSTEM"
2. APPLICANT (S):
(a) NAME: Lyka Labs Limited
(b) NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road, Andheri (East), Mumbai 400 059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner
in which it is to be performed !
i

TECHNICAL FIELD
The present invention relates to a novel Controlled Porosity Osmotic Release (CPOR) delivery system for controlled release of highly water soluble drugs wherein the controlled porosity of the membrane is accomplished by the use of different channeling agents in varying proportions in the coating solution.
More particularly, the present invention relates to a CPOR based novel osmotic drug delivery system for Citicoline Sodium.
BACKGROUND AND PRIOR ART
While oral dosage forms of Immediate Release (IR) composition of highly water soluble drugs do not offer any problem during formulation, Controlled Release (CR) dosage forms of highly water soluble drugs offer serious challenges in developing and formulating oral dosage forms.
There are techniques available to formulate CR systems such as matrix reservoir and others. It is well known that matrix systems using hydrophilic polymeric materials is the most preferred method in the prior art. However, it is difficult to control the release rate in case of highly water soluble active ingredients using matrix system. Further, the need for large quantity of polymer, increases the size of the tablet or capsule in the matrix based CR systems.
With specific reference to highly water soluble drugs, PCT Publication No. WO/1999/47128 describes a biphasic controlled release delivery system for metformin hydrochloride. This formulation is very bulky and hence, inconvenient for human consumption.
US 6340475 describes a monolithic controlled release formulation of metformin hydrochloride, which is a highly water soluble drug, by incorporating hydrophilic polymers which forms a swellable and erodible matrix.

WO/1996/26718 similarly describes polymeric matrix to form a tablet. WO/2002/36100 describes a once a day formulation of metformin hydrochloride, which is a controlled release composition.
WO/2006/080029 discloses an extended release pharmaceutical composition of Levetiracetam with once a day dosage regime and the process of preparing it. The extended release tablet of Levetiracetam with the core comprising of Levetiracetam and water dispersible rate controlling polymer, and the tablet core optionally functional coated comprising a combination of water non-dispersible and/or water dispersible polymer. According to the examples disclosed in the patent application, at least 45% release controlling polymer is required with respect the active substance to achieve the desired dissolution profile; which results in unacceptable size of the dosage form.
WO/2006/123357 describes oral controlled release pharmaceutical composition comprising a highly water soluble high dose active ingredient consisting essentially of therapeutically effective amount of Levetiracetam and a rate controlling means comprising a rate-controlling agent and optionally coating selected form (i) an active ingredient permeable coating surrounding the unit dosage form, and (ii) an active ingredient impermeable coating covering one or more surfaces but not all the surfaces of the unit dosage form. The problem associated with the technology discussed in this patent application is non-uniform release of active ingredient from one side in coated tablet. This technique is very critical with respect to uniform breaking or opening of tablet coating under all physiological conditions.
A controlled release pharmaceutical composition in the form of a tablet comprising, Levetiracetam and, as excipient within the core of the tablet, 5.0 to 59.0 % per weight of at least one hydrophilic matrix agent, with respect to the total weight of the core of the tablet is described in WO/2008/006528.
WO/2008/062446 discloses an extended release composition of Levetiracetam, which exhibits no adverse food effect, comprising from about 30% w/w to about 85% w/w of Levetiracetam and about 1 % w/w to about 50% w/w of the composition of a water dispersible rate controlling polymer.

Citicoline which is also known as cytidine diphosphate-choline (CDP-Choline) is a psychostimulant/nootropic. It has putative activity as a cognition enhancer and in cell-membrane repair. Citicoline is also an intermediate metabolite in the major pathway for the synthesis of the membrane phospholipid, phosphatidylcholine. Phosphatidylcholine is crucial for the maintenance of cell-membrane fluidity and cellular integrity. Citicoline, hypothetically, may aid in cell-membrane repair, particularly neuronal cell membrane that have been damaged by trauma, ischemic events, toxins, infections and during the course of aging.
Citicoline may further be described as a delivery form of choline and cytidine. Choline is a precursor of acetylcholine and betaine. Acetylcholine is a neurotransmitter whose deficiency in certain regions of the brain is delivered to be an etiological factor in certain dementia, syndromes, including Alzheimer's disease. Betaine is involved in the conversion of the amino acid homocysteine to the essential amino acid L-methionine. L-methionine is a protein amino acid. Cytidine, following conversion to cytidine triphosphate, participates in a few reactions, including the formation of Citicoline and nucleic acids.
Citicoline being a highly water soluble drug, has continued to be a multi-dose oral medication, while there existed a need for a controlled release high dose medication for patient convenience. The prior art documents employing matrix system as well as polymers, fail to handle large dosage with effective and uniform release of highly water soluble drugs such as Citicoline Sodium. WO/2010/026467 describes a controlled release dosage form of highly water soluble active ingredients such as Levetiracetam or Citicoline wherein a single step granulation process using at least one hydrophobic controlling agent and compressed tablet thereof is coated with at least one hydrophobic release controlling agent devoid of diluent. This PCT publication has an Indian Priority Application No. 1868/MUM/2008.
Further, Citicoline dosage forms reported in CN1628690 are l00mg, 200mg, 300mg of Citicoline, while the recommended dose is 500mg to lgm daily. CN1628690 discloses a Citicoline sustained and controlled release preparation prepared by matrix system using

HPMC as release controlling agent and other conventional adjuvant and process for making the same. However, since the amount of polymer required is almost more than 100% of the amount of Citicoline it results in unacceptably and large size of the dosage form.
Consequently, there is an unmet need for providing controlled release dosage form of drugs of high aqueous solubility, such as Citicoline Sodium, without compromising on the size and shape of the tablet, which has been met by the inventors of the present invention.
OBJECTIVE OF THE INVENTION
The primary objective of the present invention is to formulate and optimize a controlled release delivery system for highly water soluble drug using Controlled Porosity Osmotic Release (CPOR) based drug delivery system.
More particularly, the object of the present invention is to design a controlled porosity osmotic release (CPOR) based drug delivery system for controlled release of highly water soluble drug, such as, Citicoline Sodium.
Another objective of the present invention is to keep the weight and size of the formulated tablet in desired range to make it acceptable and suitable for human use.
SUMMARY OF THE INVENTION
In accordance with the objective, the present invention discloses novel Controlled Porosity Osmotic Release (CPOR) delivery system for controlled release of highly water soluble drugs wherein the controlled porosity of the membrane is accomplished by the use of different channeling agents in varying proportions in the coating solution.
In an aspect, the present invention relates to a CPOR based novel osmotic drug delivery system for Citicoline Sodium comprising a core consisting of Citicoline sodium as active and osmogen or mixture of osmogens preferably in the ratio in the range of 1:0.027 to 1: 0.064, which exhibits an osmotic pressure gradient across the wall against external fluid,

coated with a rate controlling membrane consisting of cellulose acetate as water-insoluble polymer and PEG as pore former as well as plasticizer along with other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
The present invention is described herein after in more details substantiating various embodiments and conditions of reaction for better understanding/appreciation of the invention.
A controlled release dosage form of highly water soluble drug such as Citicoline Sodium is described herein. The technique employed is Controlled Porosity Osmotic Release (CPOR) system wherein controlled release (CR) of the membrane is accomplished by the use of different channeling agents in varying proportions in the coating solution.
The inventors have focused on the effect of concentration of pore former, Polyethylene Glycol 400 (Here after mentioned as PEG400). Controlled porosity osmotic release (CPOR), contain water-soluble additives along with water insoluble additives in the coating membrane, water soluble actives after coming in contact with water, dissolve resulting in an in situ formation of channels in the membrane. The resulting membrane is substantially permeable to both water and dissolved solutes and the mechanism of drug release from these systems was found to be primarily osmotic, with simple diffusion playing a minor role. The mechanisms by which drug release is controlled in CPOR are dependent on many variables. One of the principles of drug release employed is the selection of the range of osmogens/mixture of osmogens of different osmotic pressure and the concentration of channeling agent used. It is possible that one can modulate the release profile of the water soluble, sparingly soluble and poorly soluble active agents.
The dosage form developed was designed as a tablet core coated with a rate controlling membrane. Tablet core consists of drug along with osmogen selected from the group of mannitol, sodium chloride, potassium chloride, fructose and the like;, and other conventional excipients to form the core compartment. The core compartment is surrounded by a membrane consisting of a semipermeable membrane-forming polymer,

water-soluble pore forming additives, and at least one plasticizer capable of improving film-forming properties of the polymers. The semipermeable membrane-forming polymer is permeable to aqueous fluids but substantially impermeable to the components of the core. In operation, the core compartment imbibes aqueous fluids from the surrounding environment across the membrane and dissolves the drug. The dissolved drug is released through the pores created after leaching of water-soluble additive(s) in the membrane. In the present invention, Cellulose acetate is used as water-insoluble polymer and PEG400, is used as water-soluble additive that acts both as pore former as well as plasticizer.
To optimize the amount of osmogen to be used in the formulation and to study the effect of drug to osmogen ratio, core formulations were prepared with varying amount of drug to osmogen ratio. The ratio of drug to osmogen used is preferably in the range of 1: 0.027 to 1: 0.064, most preferably the ratio is 1: 0.045 that exhibits an osmotic pressure gradient across the wall against external fluid. All the core formulations were coated with similar coating composition containing CA and PEG400. Osmogen enhances the release of drug and had a direct effect on drug release. This is evidenced from a formulation, which was devoid of any osmogen in the core, showed very slow drug release in first hr. However, the use of osmogen enhanced the release depending on the amount of osmogen present in the core formulation which might be due to the increased water uptake and hence, increased driving force for drug release.
Effect of level of pore former (PEG400), core tablets were coated with coating composition containing varying percent of PEG400. It was found that the drug release increases with the level of PEG400. As the level of pore former increases, the membrane becomes more porous after coming in contact with the aqueous environment, resulting in faster drug release.
Accordingly, in an embodiment, the present invention disclose a controlled release solid dosage form for highly water soluble citicoline sodium, using controlled Porosity Osmotic Release (CPOR) based drug delivery system, along with other pharmaceutically acceptable excipients; characterized in the following;

a core consisting of citicoline sodium and osmogen or mixture of osmogens in the ratio in the range of 1:0.027 to 1: 0.064, which exhibits an osmotic pressure gradient across the wall against external fluid, coated with a rate controlling membrane consisting of (i) cellulose acetate in the range of 1-4% w/v; (ii) PEG as pore former as well as plasticizer in concentration of 22.5% to 25% of total solid content of coating material.
As the pore former level increases, the membrane becomes porous after coming in contact with the water (when the pore former leaches out of the membrane). At levels up to low percent (w/w) of pore former, number of pores are not sufficient to contribute to significant drug release. On the other hand, membranes that initially contained high percent (w/w) of pore former, the membrane becomes more porous after coming in contact with water. The explainable reason for the sudden change in the release profile is that the threshold might not have reached in formulations containing higher and lesser percentage of pore former. Therefore, it has been found that drug release is directly proportional to the level of pore former in the membrane and this parameter can be varied to control the drug release.
In addition to release, type of pore former also affected the burst strength of the exhausted shells and this parameter should also be taken into consideration while selecting the pore former. The drug release and the burst strength were satisfactory with the formulations containing PEG400 as the pore former. This formulation was selected as the "optimized" formulation and used for further evaluation.
It was found that with an increase in the level of pore former, porosity of the membrane would increase because of leaching of pore former from the membrane. This was confirmed from the release studies, wherein the release increased with the increase in level of pore former.
In case of membrane containing 0 % level of PEG400 as pore former, there were no pores in the membrane. It was concluded that the membrane did not develop significant porosity after coming in contact with the aqueous environment. In case of low % of

PEG400, formation of significantly fewer pores in the membrane and high % of PEG400 . led to the increased number of pores in the membrane than later. The drug release was found to be optimum when PEG 400 was used in concentration of 22.5% to 25% of total solid content of coating material. This was confirmed with the drug release studies given in Table 1. The weight gain of tablets was about 3% core weight during coating.
The process of preparing the composition of the present invention is given below in example 2.
Further details of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Example 1: Composition
Each Film coated controlled released tablet contains:-
Citicoline Sodium
equivalent to Citicoline 1000 mg
Excipients q.s.
Formula

Sr. No. Ingredients Role of Ingredients Concentration range
CORE TABLET
1. Citicoline Sodium Active Pharmaceutical Ingredient 1088 mg
2. Microcrystalline Cellulose (Avicel pH 102) Filler/Diluent 80mg-120mg
3. Lactose Filler/Diluent 10mg-30mg
4. Mannitol (Perlitol 200-SD) Osmogen 30mg-70mg
5. Polyvinyl Pyrolidone (PVP-K30) Binder 5mg-25mg
6. Magnesium Stearate Lubricant 3mg-9mg
7. Talc Lubricant 3mg-9mg

8.
Colloidal silicon dioxide Glidant lmg-8mg
9. Isopropyl alcohol Vehicle q.s.
COATING LAYER
10. Cellulose acetate Semipermeable membrane 1%-4%W/V
11. Polyethylene Glycol 400 Pore former/Channeling agent 10%-40%w/w*
12. Talc Anti-adherent 0.1%-2%w/v
13. Titanium dioxide Opacifier 0.1%-2%w/v
14. Acetone Vehicle 60%-90% v/v
15. Isopropyl Alcohol Vehicle 10%-40%v/v
*NOTE: - Ingredient no.11 is calculated as % of Total Solid Content (TSC) (TSC: - It is calculated as sum of Ingredient no. 10, 12 and 13)
The quantities indicated hereinabove as concentration range is indicative. A person skilled in the art should appreciate that the range can be altered suitably to meet specific standards of stability, uniformity and release pattern.
The stability study of the composition of present invention is carried out as per ICH guideline for six months at accelerated condition of 40°C and 75% RH and real time condition at 30°C and 65% RH. The composition was found to be stable.
Example 2: PROCEDURE
A) CORE TABLET
1. Citicoline Sodium, MCC, Lactose & mannitol was weighed, passed through sieve 40# & mixed for 5 mins.
2. PVPK-30 was dissolved in sufficient amount of IPA to prepare granulating solution.
3. Step 1 blend was granulated with step 2 granulating solution.
4. The wet mass was then passed through sieve 12#.
5. The granules were dried in dryer at 50°C for sufficient time.
6. The dried granules were passed through sieve 16#.
7. Talc and Aerosil were sifted through sieve 40# and mixed with granules for 5-10 mins.

8. The granules were lubricated using Magnesium stearate which was previously passed through sieve 40# for 5- 10 mins.
9. The lubricated granules were compressed using suitable capsule shape punch plain on both sides.
B) COATING OF CORE TABLET
1. Cellulose acetate was weighed and dissolved in acetone under stirring.
2. To this was added Polyethylene Glycol 400 under stirring.
3. In another beaker isopropyl alcohol was taken and to this was added talc and Titanium dioxide and homogenized through colloidal mill for about 5mins.
4. Solution obtained in step 3 was added to step 2 solution under stirring.
5. The core tablet was coated using the coating solution prepared to achieve 2-5% weight gain over the core.
Example 3: DESIRED DRUG RELEASE PROFILE:
In vitro drug release of the formulation as described herein above was carried out using USP type II dissolution apparatus with sinkers. The drug release at different time intervals was analyzed by UV.

Parameters Citicoline Sodium CR Tablet
Dissolution media Water
USP Type II (Paddle) with Sinkers
Volume 900 ml
RPM 75
Temperature 37 °C
Analytical method UV
The desired drug release profile of the Controlled release Citicoline tablets is given in
Table 1:
Time Limit
For 1st hour 18 to 35%
For 4th hour 35 to 65%
For 8th hour NLT 70%
For 12th hour NLT 85%

We claim;
1. A controlled release solid dosage form for highly water soluble citicoline sodium,
using controlled Porosity Osmotic Release (CPOR) based drug delivery system,
along with other pharmaceutically acceptable excipients; characterized in the
following;
a core consisting of citicoline sodium and osmogen or mixture of osmogens in ratio in the range of 1:0.027 to 1: 0.064 which exhibits an osmotic pressure gradient across the wall against external fluid, coated with a rate controlling membrane consisting of (i) cellulose acetate in the range of 1-4% w/v; (ii) PEG as pore former as well as plasticizer in concentration of 22.5% to 25% of total solid content of coating material.
2. The controlled release solid dosage form according to claim 1, wherein the ratio of citicoline sodium and osmogen or mixture of osmogens in the core is 1:0.045.
3. The controlled release solid dosage form according to claim 1, wherein the osmogen selected from mannitol, sodium chloride, potassium chloride, fructose and the like.
4. The controlled release solid dosage form according to claim 1, wherein the semipermeable membrane-forming polymer is permeable to aqueous fluids but substantially impermeable to the components of the core.