FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMPOSITION COMPRISING CITICOLINE AND
VINPOCETINE"
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 - 400059, 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 INVENTION:
The present invention relates to an oral pharmaceutical composition comprising a combination of psychostimulant/ nootropic drug such as Citicoline and memory enhancer drug such as Vinpocetine, in a solid dosage form, preferably a tablet, useful for the treatment of variety of CNS disorders such as stroke and brain injury. It decreases fatality and dependency in ischemic stroke. Also useful in treating cognitive impairment in Alzheimer's disease, age associated memory impairment and some non-Alzheimer's dementias. The invention further relates to process for preparation thereof.
BACKGROUND OF THE INVENTION:
Citicoline or CDP-coline is a naturally occurring substance found in most life forms. It is an intermediate metabolite in major pathway for the synthesis of Phosphatidylcholine. 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-membrane repair. It is an intermediate metabolite in the major pathway for the synthesis of the membrane phospholipids, phosphatidylcholine. Phosphatidylcholine is crucial for maintenance of cell-membrane fluidity and cellular integrity. CITI-choline, hypothetically, may aid in celt-membrane repair, particularly neuronal cell membrane that have been damaged by trauma, ischemic events, toxins, infections or 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 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 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 tow 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 oedema.
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.
Citicoline is also known as cytidine diphosphate-choline (CDP-Choline) and cytidine 5'-diphosphocholine. Chemically, Citicoline is 5'-0-[hydroxyl({hydroxy[2(trimethyl ammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine. It has the following structural formula:


Vinpocetine is a semisynthetic derivative alkaloid of vincamine (sometimes described as "a synthetic ethyl ester of apovincamine"), an extract from the periwinkle plant Vinca minor. It is marketed worldwide as a neutraceutical as well as a pharmaceutical agent for the treatment of cerebrovascular and cognitive disorders.
Vinpocetine is reported to increase blood flow; cerebral vasodilation produces an immediate increase in the cerebral oxygenation and this result finally in the activation of the cerebral metabolism, the increase of glucose and the improvement of certain neurotransmitters utilization. It is used as a drug in Eastern Europe for the treatment of cerebrovascular disorders and age-related memory impairment. Another benefit that has been observed by using vinpocetine is its neuronal protection effects which increase resistance of the brain to hypoxia and ischemia, reduce platelet aggregation, and improve red blood cells deformability allowing oxygen to feed neurons through microcapillaries.
Vinpocetine is a cerebral metabolic activator and a neuronal protector. It facilitates cerebral metabolism by improving blood flow to the brain, boosting brain cell ATP production, and increasing utilization of glucose and oxygen by neurons. It also increases the production of Noradrenaline and Dopamine, contributing, in this way, to the release of Serotonin and the concentration of Acetylcholine. Research has shown that the effects of this compound go beyond mere prevention and turn it into a Powerful Memory Enhancer.
Vinpocetine is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory. In other words, Vinpocetine helps support brain function such as enhancing concentration and memory by activating cerebral metabolism.

Chemically, Vinpocetine is (3a, 16a)-Eburnamenine-14-carboxylic acid ethyl ester. It has the following structural formula:

Several mechanisms of action have been proposed for vinpocetine. It is believed to have calcium-channel blocking activity, as well as voltage gated sodium blocking activity. It has also been reported to inhibit acetylcholine release evoked by excitatory amino acids and to protect neurons against excitotoxicity. In addition, vinpocetine has been shown to inhibit a cyclic GMP phosphodiesterase, and it is speculated that this inhibition enhances cyclic GMP levels in the vascular smooth muscle, leading to reduced resistance of the cerebral vessels and increase cerebral flow. In some studies, vinpocetine has demonstrated antioxidant activity equivalent to that of vitamin E.
US5827832 discloses the use of citicoline (cytidine-5'-diphosphocholine or CDP-choline) and aspirin or dipyridamole in a novel treatment regimen to reduce cerebral infarct volume and improve the chances for complete or substantial recovery.
EP2018868 relates to the use of a combination of citicoline, Ginkgo biloba extract and dimeric flavones of Ginkgo biloba for the preparation of a formulation for the treatment and prevention of vertigo and tinnitus.
WO2005041952 relates to a vinpocetine and Piracetam pharmaceutical composition which is embodied in the form of a solid dosage form and exhibits a cerebral vasodilatation and nootropic activity.

EP0689844 relates to pharmaceutical compositions, useful in the treatment of cerebrovascular disorders, containing an inclusion complex of vinpocetine (eburnamenine-14-carboxylic acid ethyl ester) formed with any kind of cyclodextrin, preferably alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and hydroxypropy1-beta-cyclodextrin, and a process for preparing said composition.
Citicoline and Vinpocetine - A Therapeutic Need:
Considering the actions of CDP-choline and vinpocetine, it would be prudent to assume that the combination would have profound effects on various parameters of cerebral functioning. In this combination, CDP-choline ensures neuronal cell membrane integrity as well as optimal levels of acetylcholine. Vinpocetine further contributes to cerebral function due to its cerebral vasodilating property and antioxidant potential. Thus, the properties of both CDP-choline and vinpocetine would ensure that enhanced cognitive activity rn the presence of pathological insults to cerebral function such as ischemia, oxidative damage and disease processes such as Alzheimer's disease.
In light of the above therapeutic need, the present inventors have come up with an oral pharmaceutical composition comprising a combination of Citicoline with Vinpocetine in a solid dosage form, useful for the treatment of variety of CNS disorders such as stroke and brain injury. It decreases fatality and dependency in ischemic stroke. Also useful in treating cognitive impairment in Alzheimer's disease, age associated memory impairment and some non-Alzheimer's dementias.
SUMMARY OF THE INVENTION:
Accordingly, present invention discloses a pharmaceutical composition comprising a combination of Citicoline and Vinpocetine, in the form of tablet, useful for the treatment of variety of CNS disorders such as stroke and brain injury. The invention further discloses the process for preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention describes a pharmaceutical composition comprising a combination of Citicoline with Vinpocetine in a solid dosage form, preferably a tablet and the process for preparation thereof.
Pharmacokinetics:
Pharmacokinetics of Citicoline with Vinpocetine is based on animal studies of CDP-choline and human studies of vinpocetine.
Following oral intake of CDP-choline in animals, it is hydrolysed in the small intestine to choline and cytidine. They are absorbed and transported to the liver via the portal circulation. In the liver, choline may enter various metabolic pathways, resulting in the biosynthesis of various substances, including CDP-choline, betaine and phosphatidyl choline. Cytidine enters the cytidine nucleotide pool and may be incorporated into nucleic acids. Choline and cytidine are not metabolized in the liver and are distributed to various tissues in the body, where they undergo further metabolism. The uptake of CDP-choline by the brain is low. However, choline and cytidine may be taken up by the brain. Within the brain, choline and cytidine may be metabolised via a few steps to CDP-choline, which can serve as a substrate for phosphatidylcholine synthesis.
Vinpocetine is absorbed from the small intestine, from where it is transported to the liver via the portal circulation. From the liver, via the systemic circulation, it is distributed to various tissues in the body, including the brain. Absorption of vinpocetine is significantly higher when given with food and can be upto 60% of the ingested dose. On an empty stomach, absorption of an ingested dose may be as low as 7%. Peak plasma levels are obtained 1-1.5 hours after ingestion. Extensive metabolism to the inactive apovincaminic acid occurs in the liver. Only small amounts of unmetabolised vinpocetine are excreted

in the urine, the major route of excretion of apovincamininc acid. Most of a dose is excreted within 24 hours as this metabolite. The elimination half-life of vinpocetine following ingestion is 1-2 hours.
Indications:
Citicoline with Vinpocetine is a nutritional supplement that has been found to be useful in a variety of CNS disorders. It is useful in the treatment of stroke and brain injury. It decreases fatality and dependency in ischemic stroke. It is also useful in treating cognitive impairment in Alzheimer's disease, age associated memory impairment and some non-Alzheimer's dementias.
Accordingly in a preferred embodiment, the present invention describes pharmaceutical composition comprising Citicoline with Vinpocetine in a solid dosage form preferably a tablet along with the pharmaceutically acceptable excipients selected from the group comprising diluents, binders, disintegrant and lubricants.
According to the another embodiment, the pharmaceutical composition comprising Citicoline in the range of 200 to 1100 mg with Vinpocetine in the range of 5.0 to 5.50 mg in a tablet form is prepared by wet granulation method where both Citicoline and Vinpocetine are mixed with other suitable diluents, granulated by appropriate binding agent, dried, lubricated and compressed into tablets and coat with pharmaceutically accepted excipients having coating material.
According to the present invention, depending upon the strength of the dosage form the recommended dose of Citicoline and Vinpocetine tablet is 1 to 3 tablets/capsules daily.
According to the present invention, the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is prepared using diluents selected from microcrystalline cellulose, lactose, maize starch, dibasic calcium phosphate, and can be used individually or in combination to give desired product parameters.

According to the present invention, the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is prepared using binders such as purified water along with maize starch, Hydroxy propyl methyl cellulose, Povidone K-30 or purified water alone or isopropyl alcohol alone or mixture of purified water and isopropyl alcohol may be used in optimum concentrations.
According to the present invention, the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is prepared using disintegrants such as croscarmellose sodium, crosslinked povidone, sodium starch glycolate, maize starch, pregelatinized starch alone or in combination may be added.
According to the present invention, the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is prepared using lubricants such as magnesium stearate, colloidal silicon dioxide, talc alone or in combination may be used.
According to the present invention, the tablets are film coated using coating polymer along with plasticizer, opacifies colouring pigment and suitable solvents
In a most preferred embodiment, the process for manufacturing the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is as follows:
1) weighing and sifting Citicoline sodium, Vinpocetine, microcrystalline cellulose, maize starch and croscarmellose sodium through 40 # sieve;
2) mixing the sifted ingredients of step 1 for sufficient time to get uniform blend;
3) preparing starch paste using maize starch and purified water; or mixture of purified water and isopropyl alcohol in the ratio of 1:4 is used as binding solution;
4) granulating the blend of step 2 with starch paste or purified water and isopropyl alcohol mixture of step 3 to obtain wet mass of suitable consistency;
5) passing the wet mass through 12 # sieve;
6) drying the granules in tray dryer 55°C - 60°C for sufficient time;
7) passing dried granules through 18 # sieve to obtain a particular size;

8) weighing and sifting colloidal silicon dioxide, croscarmellose sodium and maize starch through 40 # sieve;
9) mixing dried granules of step 7 and sifting lubricants of step 8 for sufficient time to get uniform blend;

10) weighing and sifting magnesium stearate through 40 # sieve. Mixing with blend of step 9 for 5 minutes to get uniform blend;
11) compressing the lubricated granules with the following average weight

• 360.0 mg for Citicoline and Vinpocetine tablets (200+5) mg strength,
• 940.0 mg for Citicoline and Vinpocetine tablets (500+5) mg strength,
• 960.0 mg for Citicoline and Vinpocetine tablets (750+5) mg strength,
• 1365.0 mg for Citicoline and Vinpocetine tablets (1000+5) mg strength.
12) preparing film coating solution by using ready to use coating material or In-House
prepared coating material with either aqueous or non aqueous solvents.
The process for preparation of film coated tablets further comprises film coating using Non-aqueous or Aqueous or In-house prepared Non-aqueous coating solutions as mentioned below, wherein said coating process further comprises:
a) Coating the compressed tablets obtained in step 7 with a non-aqueous coating
solution, prepared by Opadry ready mix coating powder manufactured by colorcon
mix with Isopropyl alcohol and Methylene chloride
Non-aqueous coating comprises:
i. Opadry 6%
ii. Isopropyl alcohol 40%
iii. Methylene Chloride 52%
b) Coating the compressed tablets obtained in step 7 with an aqueous coating solution
prepared by Opadry ready mix coating powder manufactured by colorcon, mix with
distilled water.

Aqueous coating comprises:
i. Opadry 8%
ii. Distilled water 92%
c) Coating the compressed tablets obtained in step 7 with in-house prepared non aqueous coating solution prepared by dispersing Hypromellose (E5), Diethylphthalate, Polyethylene Glycol 4000, Titanium dioxide, Talc and color, Quinoline yellow lake in Isopropyl alcohol & Methylene Chloride mixture and homogenised in colloidal mill.
In-house prepared Non-aqueous coating solution comprises:
i. Hypromelllose (E5) 3%
ii. Diethylphalate 0.45%
iii. Polyethylene Glycol 4000 0.45%
iv. Titanium dioxide 1.1%
v. Talc 0.7%
vi. Color: Quinoline yellow lake 0.1%
vii. Isopropyl alcohol 40%
viii. Methylene chloride 54.2%
13) Film coating the tablets using coating solution of step 12 till a weight gain of 2-3% over core weight is obtained.
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLE:
1) For Citicoline and Vinpocetine Tablets (200+5) mg Each film coated tablet contains:
Citicoline sodium equivalent to Citicoline 200 mg
Vinpocetine 5 mg

Excipients q.s.
Colour: Titanium Dioxide I.P.

S.NO. INGREDIENTS QTY/TABLET RANGE
1. Citicoline Sodium equivalent to Citicoline 200.0 mg 200 to 220 mg
2. Vinpocetine 5.0 mg 5.0 to 5.50 mg
3. Microcrystalline Cellulose 78.0 mg 75.0 to 90.00 mg
4. Maize Starch 36.0 mg 35.0 to 42.0 mg
5. Croscarmellose Sodium 13.0 mg 10.0 to 15.0 mg
6. Colloidal silicon dioxide 3.20 mg 3.0 to 4.50 mg
7. Magnesium Stearate 5.60 mg 5.0 to 8.0 mg
8. Purified water Q.s Q.s
2) For Citicoline and Vinpocetine Tablets (500+5) mg Each film coated tablet contains:
Citicoline sodium equivalent to Citicoline 500 mg
Vinpocetine 5 mg
Excipients q.s.
Colour: Titanium Dioxide LP.

S.NO. INGREDIENTS QTY/TABLET RANGE
1. Citicoline Sodium equivalent to Citicoline 500.0 mg 500 mg to550 mg
2. Vinpocetine 5.0 mg 5.0 to 5.50 mg
3. Microcrystalline Cellulose 195.00 mg 180.0 mg to 225.0 mg
4. Maize Starch 92.00 mg 85.0 to 100.0 mg
5. Croscarmellose Sodium 32.00 mg 25.0 to 40.0 mg
6. Colloidal silicon dioxide 8.0 mg 5.0 to 12.0 mg
7. Magnesium Stearate 14.0 mg 10.0 to 18.0 mg
8. Purified water Q.s Q.s
3) For Citicoline and Vinpocetine Tablets (750+5) mg Each film coated tablet contains:

Citicoline sodium equivalent to Citicoline 750 mg
Vinpocetine 5 mg
Excipients q.s.
Colour: Titanium Dioxide I.P.

S.NO. INGREDIENTS QTY/T ABLET RANGE
1. Citicoline Sodium equivalent to Citicoline 750.0 mg 750 mg to 825 mg
2. Vinpocetine 5.0 mg 5.0 to 5.50 mg
3. Microcrystalline Cellulose 13.0 mg 10.0 mg to 18.0mg
4. Maize Starch 10.0 mg 7.0 mg to 15.0 mg
5. Croscarmellose Sodium 32.00 mg 25.0 to 40.0 mg
6. Colloidal silicon dioxide 8.0 mg 5.0 to 12.0 mg
7. Magnesium Stearate 14.0 mg 10.0 to 18.0 mg
8. Purified water Q.s Q.s
9. Isopropyl alcohol Q.s Q.s
4) For Citicoline and Vinpocetine Tablets (1000+5) mg Each film coated tablet contains:
Citicoline sodium equivalent to Citicoline 1000 mg
Vinpocetine 5 mg
Excipients q.s.
Colour: Titanium Dioxide LP.

S.NO. INGREDIENTS QTY/TABLET RANGE
1. Citicoline Sodium equivalent to Citicoline 1000.0 mg 1000 mgto 1100 mg
2. Vinpocetine 5.0 mg 5.0 to 5.50 mg
3. Microcrystalline Cellulose 38.00 mg 25.0 mg to 45.0 mg
4. Maize Starch 90.0 mg 80.0 mg to 100.0 mg
5. Croscarmellose Sodium 45.0 mg 35.0 mgto 50.0mg
6. Colloidal silicon dioxide 10.0 mg 7.50mgto 13.0 mg
7. Magnesium Stearate 18.00 mg 14.0 mgto22.0 mg
8. Purified water Q.s Q.s

Overages of Citicoline and Vinpocetine can be added for the long term stability purpose. STABILITY DATA:
Stability study of the product is carried out as per ICH guideline for 6 months at accelerated condition of 40°c / 75% RH and real time condition of 30°c / 65%RH. Product is stable.

We Claim,
1. An oral pharmaceutical composition comprising Citicoline and Vinpocetine in a therapeutically effective amount along with pharmaceutical!}/ acceptable excipients; useful for the treatment of variety of CNS disorders such as stroke and brain injury, cognitive impairment in Alzheimer's disease, age associated memory impairment and some non-Alzheimer's dementias.
2. The oral pharmaceutical composition as claimed in claim 1, wherein the Citicoline is present in an amount of 200 to 1100 mg.
3. The oral pharmaceutical composition as claimed in claim 1, wherein the Vinpocetine is present in an amount of 5.0 to 5.50 mg.
4. The oral pharmaceutical composition as claimed m claim 1, -wherein the composition is in the form of film coated tablet.
5. The oral pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, disintegrant and lubricants.
6. The oral pharmaceutical composition as claimed in claim 5, wherein the diluents are selected from microcrystalline cellulose, lactose, maize starch, dibasic calcium phosphate, alone or in combination.
7. The oral pharmaceutical composition as claimed in claim 5, wherein the binders are selected from purified water along with maize starch, Hydroxy propyl methyl cellulose, Povidone K-30 or purified water alone or isopropyl alcohol alone or mixture of purified water and isopropyl alcohol in optimum concentrations.
8. The oral pharmaceutical composition as claimed in claim 5, wherein the disintegrants are selected from croscarmellose sodium, croslinked povidone,

sodium Starch glycolate, maize starch, pregelatinised starch, alone or in combination.
9. The oral pharmaceutical composition as claimed in claim 5, wherein the lubricants are selected from magnesium stearate, colloidal silicon dioxide, talc, alone or in combination.
10. The oral pharmaceutical composition as claimed in claim 1 and 4, wherein the tablet is coated with coating polymer along with plasticizer, opacifier, colouring pigment and suitable solvents.
11. The oral pharmaceutical composition as claimed in claim 1, wherein the process for manufacturing the pharmaceutical composition comprising Citicoline with Vinpocetine in a tablet form is as follows:
i) weighing and sifting Citicoline sodium, Vinpocetine, microcrystalline
cellulose, maize starch and croscarmellose sodium through 40 # sieve;
ii) mixing the sifted ingredients of step 1 for sufficient time to get uniform
blend;
iii) preparing starch paste using maize starch and purified water; or mixture of
purified water and isopropyl alcohol in the ratio of 1:4 is used as binding solution;
iv) granulating the blend of step 2 with starch paste or purified water and
isopropyl alcohol mixture of step 3 to obtain wet mass of suitable consistency;
v) passing the wet mass through 12 # sieve;
vi) drying the granules in tray dryer 550c-600c for sufficient time;
vii) passing dried granules through 18 # sieve to obtain a particular size;
viii) weighing and sifting colloidal silicon dioxide, croscarmellose sodium and
maize starch through 40 # sieve;
ix) mixing dried granules of step 7 and sifting lubricants of step 8 for
sufficient time to get uniform blend;
x) weighing and sifting magnesium stearate through 40 # sieve. Mixing with
blend of step 9 for 5 minutes to get uniform blend;
xi) compressing the lubricated granules with the following average weight
(a) 360.0 mg for Citicoline and Vinpocetine tablets (200+5) mg strength,

(b) 940.0 mg for Citicoline and Vinpocetine tablets (500+5) mg strength,
(c) 960.0 mg for Citicoline and Vinpocetine tablets (750+5) mg strength,
(d) 1365.0 mg for Citicoline and Vinpocetine tablets (1000+5) mg strength;
xii) preparing film coating solution by using ready to use coating material or In-House prepared coating material with either aqueous or non-aqueous solvents; xiii) Film coat the tablets using coating solution of step (xii) till a weight gain of 2-3% over core weight is obtained.