FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Liquid pharmaceutical composition of Citicoline"
2. APPLICANT (S)
(a) NAME: LYKA LABS LIMITED.
(b)NATIONALITY: Indian Company incorporated under the Companies Act 1956
(c) ADDRESS: 77, Nehru Road, Vile Parle (East) Mumbai - 400 099, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to pharmaceutical composition for the treatment of stroke and brain injury. More particularly the present invention relates to liquid pharmaceutical composition comprising Citicoline (cytidine-5'-diphosphocholine or CDP-choline) or it's pharmaceutically acceptable salts in the form of palatable syrup which may benefit patients suffering from Cerebrovascular conditions such as Alzheimer's disease, Parkinson's disease and Ischamia due to stroke as well as in Glaucoma of varying severity and for the management of memory loss.
Background and prior art:
Citicoline is a naturally occurring substance found in most life forms. Citicoline is a pyrimidine 5-nucleotide which serves as an essential precursor in the synthesis of lecithin (phosphatidylcholine) and other phospholipids. Phosphatidylcholine is a phospholipid that is a major component of cell membranes. Phosphatidylcholine is necessary for the structure and function of all cells and is crucial for sustaining life.
Citicoline is synthesized in cells by the reaction of the nucleotide cytidine triphosphate or CTP with phosphocholine. The enzyme catalyzing the reaction is called CTP: phosphocholine cytidyltransferase. This reaction is the rate-limiting step in the synthesis of phosphatidyl choline.
Phosphocholine is synthesized from choline, and for the synthesis of phosphatidylcholine, CITI-choline reacts with diacylglyceride, catalyzed by the enzyme Citicoline: 1,2-diacylglycerol cholinephosphotransferase.
Citicoline has putative activity as a cognition enhancer and in cell-membrance repair.
Citicoline is an intermediate metabolite in the major pathway for the synthesis of the membrance phospholipids, phosphatidylcholine. Phosphatidylcholine is crucial for maintenance of cell-membrance fluidity and cellular integrity. Citicoline, hypothetically,
2

may aid in cell-membrance repair, particularly neuronal cell membranes that have been damaged by trauma, ischemic events, toxins, infections and during the course of aging. Citicoline is also 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 beleived 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 is useful in the treatment of stroke and brain injury. It may be helpful in some with tardive dyskinesia, Parkinson's disease, Alzheimer's disease and other conditions characterized by impaired cognitive function, including memory loss. An indication may emerge for it to help visual acuity in those with amblyopia. Citicoline is more effective and have a number of advantages over other agents being developed for the reduction of infarct volume subsequent to an ischemic event. Being an endogenous compound, Citicoline is inherently safe. Citicoline has a very low toxicity and an extremely broad therapeutic index.
In numerous studies of Citicoline, favorable results have been obtained in cerebral ischemia and traumatic head injury. Its efficacy in these studies has been attributed to its apparent ability to increase phosphatidylcholine synthesis in the brain. In animal studies, it has been shown to enhance cell-membrane formation and repair, to restore intracellular enzyme function, to limit nerve damage and decrease edema.
The same mechanism, generally are said to account for favorable effects reported for it in the treatment of Parkinson's disease, Alzheimer's disease and a variety of cognitive disorders, including impaired memory associated with aging.
US 5,827,832 describes the use of Citicoline in combination with second therapeutic agent such as aspirin or dipyridamole for the treatment of stroke and severe head trauma patients. US 5872108 patent relates to the use of Citicoline for the preparation of a pharmaceutical medicament for the reduction of infarct volume.
3

Citicoline or its salt as an active ingredient is normally administered parenterally in the form of injectables or orally in the form of tablets, capsules. But, patients suffering from Alzheimer's disease, Parkinson's disease, cognitive disorder find difficult to swallow Citicoline tablets. The palatable syrup will facilate administration of Citicoline to elderly patients and improve compliance.
Object of the invention:
The object of the invention is to provide a pharmaceutical composition comprising Citicoline or pharmaceutical acceptable salts thereof in the form of palatable syrup for the treatment of patients with cerebral injuries of vascular or traumatic origin, memory loss, chronic cerebral vascular insufficiency and degenerative changes in senile dementia.
Summary of the invention
The present invention discloses the pharmaceutical composition comprising Citicoline (cytidine-5'-diphosphocholine or CDP-choline) in the form of palatable syrup and method of preparation thereof.
Detailed Description
The present invention describes pharmaceutical liquid composition for the treatment of patients with cerebral injuries of vascular or traumatic origin, memory loss, chronic cerebral vascular insufficiency and degenerative changes in senile dementia which comprises Citicoline in the form of palatable syrup and can be easily administered to geriatric patient population.
In accordance with the above object of the invention the composition comprises citicoline or pharmaceutically acceptable salts thereof as an active ingredient and other pharmaceutically acceptable excipients selected from flavours, colours, chelating agent, preservatives and sweeteners or combinations thereof.
4

Citicoline or pharmaceutical^ acceptable salts thereof used in the pharmaceutical composition is in the range of 2 - 17 % w/v.
Disodium edetate is used as chelating agent in an amount of 0.01-0.1 % w/v preferably 0.05 % w/v.
The preservatives are selected from methyl paraben, propyl paraben and sodium benzoate or their combination wherein methyl paraben is present in an amount of 0.05-0.2 % w/v preferably 0.072 % w/v and propyl paraben is present in an amount of 0.0025-0.02 % w/v preferably 0.0072 % w/v
The sweetener used is particularly sugar and is present in an amount of 30-80% preferably 70 % w/v.
Additionally, flavours such as pineapple flavour, orange flavour, lemon flavour can be added to the liquid composition of the present invention to enhance the taste. The flavour used is preferably pineapple sweet flavour in the range of 0.25-2 % v/v preferably
1 % v/v.
The Colour used in the liquid composition is selected from Ponceau 4R, quinoline yellow, Sunset yellow and Erythrosine supra to enhance the appearance.
The colour used is preferably Ponceau 4R in the range of 0.001-0.01 % w/v preferably 0.002 % w/v
A process for manufacture of pharmaceutical liquid composition comprises the following
steps:
i) adding sugar to purified water, heating to boiling point for dissolving sugar, adding
disodium edetate, methyl paraben and propyl paraben in syrup followed by cooling the
syrup to room temperature and filtering through muslin cloth; ii) dissolving Citicoline sodium in purified water and adding to the syrup solution of
step i) and mixing well; iii) dissolving Ponceau 4 R supra in purified water and transferring to the syrup of step ii);
5

iv) adding flavour (Pineapple sweet) to the obtained bulk under stirring and mix well; v) making up the volume of the syrup with purified water and mixing well; vi) checking pH of the syrup and record (pH limit 5.0-7.0).
The pharmaceutical composition is in the oral dosage form preferably in the form of palatable syrup which can be easily administered by elderly patients for the treatment of cerebral injuries of vascular or traumatic origin, memory loss, chronic cerebral vascular insufficiency and degenerative changes in senile dementia.
Hence, a composition is provided for the treatment of a subject who has experienced an ischemic event or brain injury comprising an effective amount of Citicoline or its pharmaceutically acceptable salt in a pharmaceutically acceptable carrier. The effective amount of active ingredients may vary according to the particular need. However, it may be present in the range of about 100 mg to about 750 mg preferably about 500 mg to about 550 mg.
The present invention is illustrated by the examples that follow, it being understood, however, that the invention is not limited to the specific details of these Examples.
Example 1
Formulation:

Sr. No. Ingredients Ingredient Specification Qty/Batch 1.0 litre
1. Citicoline sodium eq. to Citicoline I.H.S. 107.9 gm
2. Sugar IP 700.0 gm
3. Disodium edetate IP 0.5 gm
4. Methyl paraben IP 0.72 gm
5. Propyl paraben IP 0.072 gm
6. Colour: Ponceau 4R Supra HIS 0.020 gm
7. Pineapple sweet flavour HIS 10.0 ml
8. Purified water IP q.s.tol.Oltr.
6

The method of manufacture of the formulation is as follows:
Step 1
Heat 350 ml of Purified water to boiling, dissolve 700 gm sugar. Add and dissolve 0.5 gm
Disodium edetate with mixing. Add and dissolve 0.72 gm Methyl Paraben and 0.072 gm
Propyl Paraben in syrup by mixing. Cool the syrup to room temperature and filter through
muslin cloth.
Step 2
Dissolve 107.9 gm Citicoline sodium in about 200ml water and add under stirring to the
contents of step 1.
Step 3
Dissolve 20 mg colour Ponceau 4R in Purified water and add to the main bulk under
stirring.
Step 4
Add 10 ml pineapple essence under stirring to the main bulk. Mix well. Take pH.
Step 5
Make up the volume with purified water and stir for 30 minutes with stirrer.
Example 2
Formulation:

Sr.No. Ingredients Ingredient Specification Qty/Batch 1.0 litre
1. Citicoline sodium eq. to Citicoline I.H.S. 107.9 gm
2. Sugar IP 700.0 gm
3. Disodium edetate IP 0.5 gm
4. Methyl paraben IP 0.72 gm
5. Propyl paraben IP 0.072 gm
6. Colour:Quinoline Yellow Supra HIS 0.020 gm
7. Pineapple sweet flavour HIS 10.0 ml
8. Purified water IP q.s.to 1.0 ltr.
7

The method of manufacture of the formulation is as follows:
Step l
Heat 350 ml of Purified water to boiling, dissolve 700 gm sugar. Add and dissolve 0.5 gm
Disodium Edetate with mixing. Add and dissolve 0.72 gm Methyl Paraben and 0.072 gm
Propyl Paraben in syrup by mixing. Cool the syrup to room temperature and filter through
muslin cloth.
Step 2
Dissolve 107.9 gm Citicoline sodium in about 200 ml water and add under stirring to the
contents of step 1.
Step 3
Dissolve 20 mg colour Quinoline yellow supra in purified water and add to the main bulk
under stirring.
Step 4
Add 10 ml pineapple essence under stirring to the main bulk. Mix well. Take pH.
Step 5
Make up the volume with purified water and stir for 30 minutes with stirrer.
8

We claim,
1. A liquid pharmaceutical composition in the form of palatable syrup comprises Citicoline or it's pharmaceutically acceptable salts and other pharmaceutically acceptable excipients useful for the treatment of cerebral injuries of vascular or traumatic origin, memory loss, chronic cerebral vascular insufficiency and degenerative changes in senile dementia.
2. The pharmaceutical composition as claimed in claim 1, wherein pharmaceutically acceptable salt of Citicoline is Citicoline sodium and is present in an amount of 2 - 17 % w/v.
3. The pharmaceutical composition as claimed in claim 1, where in said pharmaceutically acceptable excipients are selected from chelating agent, preservatives, sweeteners, colours and flavours or combination thereof.
4. The pharmaceutical composition as claimed in claim 3, wherein said chelating agent is disodium edetate in an amount of 0.01-0.1 % w/v, preferably 0.05 %w/v.
5. The pharmaceutical composition as claimed in claim 3, wherein said preservatives are selected from methyl paraben, propyl paraben or combination thereof.
6. The pharmaceutical composition as claimed in claim 3, wherein said methyl paraben is present in an amount of 0.05 - 0.2 % w/v, preferably 0.072 % w/v.
7. The pharmaceutical composition as claimed in claim 3, wherein said propyl paraben is present in an amount of 0.0025 - 0.02 % w/v, preferably 0.0072 %w/v The pharmaceutical composition as claimed in claim 3, wherein said sweetener is particularly sugar in the range of 30-80 % w/v, preferably 70 % w/v.
8. The pharmaceutical composition as claimed in claim 3, wherein said flavour is pineapple sweet flavour in the range of 0.25-2 % v/v, preferably 1 % v/v.
9. The pharmaceutical composition as claimed in claim 3, wherein said colour used is preferably Ponceau 4R in the range of 0.001-0.01 % w/v preferably 0.002 % w/v.
10. The pharmaceutical composition as claimed in claim 1, wherein the pH is about 5-7.
11. The process of preparation of pharmaceutical composition as claimed in claim 1 comprises following steps,
9

i. heating purified water to boiling for dissolving sugar, adding disodium edetate
with mixing and adding methyl paraben and propyl paraben in syrup by
mixing followed by cooling the syrup to room temperature and filtering
through muslin cloth;
ii. dissolving Citicoline sodium in purified water and adding to the contents of
step i. under stirring;
iii. dissolving colour Ponceau 4R in purified water and adding to the main bulk
under stirring;
iv. adding pineapple essence under stirring to the main bulk followed by mixing
and check the pH and
v. making up the volume with purified water and stir for 30 minutes with stirrer
to get the syrup.
12. A liquid pharmaceutical composition in the form of palatable syrup and the process for preparation thereof as substantially described herein with reference to the orgoing examples 1 to 2.
Dated this 27th day of April, 2007
Dr. Gopakumar G. Nair Gopakumar Nair Associates
10

Abstract
The present invention relates to liquid pharmaceutical composition in the form of palatable syrup for the treatment patients with cerebral injuries of vascular or traumatic origin, memory loss, chronic cerebral vascular insufficiency and degenerative changes in senile dementia. The liquid pharmaceutical composition comprises Citicoline (cytidine-5'-diphosphocholine or CDP-choline) or it's pharmaceutically acceptable salts and pharmaceutically acceptable excipients.
11