FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"CITICOLINE READYMIX GRANULES"
2. APPLICANT:
(a) NAME: LYKA LABS LIMITED.
(b)NATIONALITY: Indian Company incorporated under the Indian
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 describes the invention.

Technical Field of Invention:
The present invention relates to a granular pharmaceutical formulation comprising Citicholine, also known as CDP-choline or cytidine diphosphate choline and a physiologically acceptable acidic ingredient. In particular it relates to a granular pharmaceutical composition comprising Citicholine and a physiologically acceptable acidic ingredient formulated for dispersion in water prior to administration.
Background Of The Invention:
Citicoline is a naturally occurring substance. It is a precursor of the synthesis of phosphatidylcholine, a type of phospholipids, a component of cell membranes. Phosphatidylcholine is necessary for the structure and function of all cells and is crucial for sustaining life.
Phosphatidylcholine is crucial for the maintenance of cell membrane fluidity and cellular integrity. Citicoline is believed to stabilize the neuronal cell membranes that have been damaged by trauma, ischemic events, toxins, infections or during the course of aging.
Citicoline when absorbed by the body, breaks down into choline and cytidine. Choline is a precursor of acetylcholine and betaine. Acetylcholine, a neurotransmitter, whose deficiency in certain regions of the brain is believed 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 L-methionine. Cytidine participates in formation of citicoline and nucleic acids.
For pharmaceutical applications, citicoline has been formulated in solution, suitable for parenteral administration, usually intravenous administration. However, currently available solid forms of citicoline suffer from a number of drawbacks. Conventional solid forms of citicoline are unstable on exposure to atmospheric humidity due to the hygroscopic nature of the molecule. Citicoline also has a health care drink features in

addition to nourishing and medical functions making it attractive as a main raw material for the health care drink products.
Medicines for internal use are generally taken orally with water or tea. However, patients, especially aged persons or the like have difficulty in swallowing such medicines with water or tea. Sometimes there is a possibility of getting medicine choked or remaining in their mouth when taking medicines in solid dosage forms such as tablets or the like. Therefore, a sufficient therapeutic effect was not obtained, and further the patient had discomfort.
Thus pharmaceutical formulations, which are stable and suitable for administrations for patients having swallowing difficulties, are highly desirable.
Single dose powders for reconstitution in sachet form offer the advantages of suspensions without the problems of instability and measuring inaccuracy. It has been found that pharmaceutical granules can enable very rapid formation (10-30 seconds) of suspension in small volume of water, without use of additional disintegrating agents. The resultant suspension is found to be highly palatable and can consequently easily swallow by a patient.
Such sachet presentations are thus well-accepted by patients of all groups, who may otherwise find the medicine difficult to take and who might otherwise refuse treatment. In addition there are commercial advantages of such a presentation. For example, product reduces raw material costs, enables more unit doses per batch and simplifies the manufacturing and packaging processes.
The present invention provides solution to above problems by providing a pharmaceutical formulation, being a unit dose sachet comprising granules of granular product containing citicoline of 1 to 20% by weight and a physiologically acceptable an acidic ingredient.

Object of the Invention:
Object of the present invention is to provide a granular pharmaceutical composition comprising Citicholine and a physiologically acceptable acidic ingredient and its use as raw material for a health care drink.
Another object of the present invention is to provide a granular pharmaceutical composition comprising Citicholine and a physiologically acceptable acidic ingredient; wherein the said formulation is stable and suitable for patients who have difficulty in swallowing.
Yet another object of the present invention is to provide a granular pharmaceutical formulation comprising citichloine and a physiologically acceptable acidic ingredient; wherein the said formulation has goof flow characteristics leading to an improved sachet filling performance.
Detailed Description Of The Invention:
The present invention relates to a granular pharmaceutical formulation comprising Citicholine, also known as CDP-choline or cytidine diphosphate choline and a physiologically acceptable acidic ingredient.
The said pharmaceutical composition is formulated for dispersion in water prior to administration.
In a preferred embodiment, the present invention relates to pharmaceutical compositions for oral administration of health care drink containing Citicoline as main raw material and other materials including citric acid, sodium citrate, sugar, salt etc.
The said acidic ingredient used in pharmaceutical composition is selected from the group consisting of citric acid, sodium hydrogen citrate, tartaric acid, adipic acid, fumaric acid and malic acid.

This invention typically comprises citric acid, tartaric acid, adipic acid, fumaric acid or malic acids; sodium citrate, edible salt etc.
The weight of the acidic ingredient may be in the range of 0.5% to 20%, preferably 1.0% to 15%, especially 1.5% to 12% of the weight of the formulation.
The granular formulation may contain any of the conventional excipients such as bulking agents for example Lactose, sucrose, maltose, dextrose alone or in combination example making up 10% to 98%, typically 40% to 95% by weight of the formulation. Other conventional excipients may include edible salt making up 0.1% to 2%, typically 0.25% to 1.5% by weight of the formulation; sweetener, typically making up 0.08% to 0.6%; flavour example orange, lemon, pineapple, mango; typically making up 0.5% to 12% by weight of the formulation and colour.
The formulation made by the present inventive process comprising different average weights example 6.0g, 7.0g, 10.0g, 15.0g and 19.0g.
The granular product of the invention also has good flow characteristics which results in improved sachet filling performance.
The present invention is illustrated by the following non-limiting examples:
EXAMPLES:
Example 1:

S. No. Ingredients Qty/sachet
Example I Example II Example III Example IV
1. Citicoline Sodium 0.217g 0.217 g 0.217 g 0.217 g
2. Sucrose 17.533 g 4.85 g 2.95g -
3. Dextrose - - 5.3 g 8.24 g

4. Saccharine - 0.08 g 0.07 g 0.09 g
5. Citric Acid 0.40 g 0.90 g 0.60 g 0.60 g
6. Sodium Citrate 0.02 g 0.02 g 0.02 g 0.02 g
7. Sodium Chloride 0.15 g 0.15 g 0.15 g 0.15 g
8 Orange flavour 0.67 g 0.77g 0.67 g 0.67 g
9. Colour 0.015 g 0.015 g 0.015 g 0.015 g
10. Purified Water Volatile Volatile Volatile Volatile
Average weight 19g 7g 10g 10g
The above mentioned formulation depicts 200mg citicoline and the same composition has been used for higher strengths example 500mg, 750mg, l000mg.
The invention also provides a process for the preparation of such a pharmaceutical formulation, comprising admixing the medicament and the excipients.
Typically the manufacturing process involves the following stages:
1) sifting the medicament and bulking agent through 40 mesh screen.
2) sifting the color through 100 mesh screen.
3) mixing the component of step 1 and step 2 for 10 minutes.
4) granulating the blend of step 3 with water.
5) sifting the wet mass of step 4 through 20 mesh sieve and dry for sufficient time.
6) sifting the dried granules through 40 mesh sieve.
7) sifting the acid ingredients, edible salt, and flavours through 40 mesh sieve and mixing with granules of step 6 for 10 minutes.
8) filling the granules in sachet under low humidity.

Preferably the entire process step 1 to step 8 was carried out under a low humidity between 30% to 40% RH and a low temperature 20°C to 25°C.
Accelerated stability was carried out as per the ICH guideline and formulation was found stable in chemical as well as physical form.
The granules were preferably packed in conventional unit dose sachets example composed of a laminate of polyester, aluminium foil and polyester. A common granular formulation may be used at a range of different fill weights to provide a range of unit doses example 200mg, 500mg, 750mg and 1000mg of Citicoline per sachet.