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:
"ESSENTIAL PHOSPHOLIPID STABLE, FREE FLOWING GRANULES ENCAPSULATED IN HARD GELATIN CAPSULES"
2. APPLICANT:
(a) NAME: NEON LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 140, Damji Shamji Industrial Complex, Mahakali Caves
Road, Andheri (East), Mumbai - 400093, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner
in which it is to be performed:

RELATED APPLICATION:
This application relates to our earlier Application No. 2423/ MUM/2011 titled "A stable solid oral free flowable essential phospholipid formulation" filed on 29/08/2011
TECHNICAL FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition containing non sticky, free flowable essential phospholipid as active ingredient along with pharmaceutical^ acceptable excipients encapsulated in hard gelatin capsule. The present invention further relates to a process for preparation of said pharmaceutical composition thereof,
BACKGROUND AND PRIOR ART:
Essentiale (polyenylphosphatidylcholine or PPC) is a preparation of essential phospholipids. The body can synthesize some phospholipid compounds but others must be supplied by the diet. Phospholipids that can only be obtained through dietary intake are called "essential phospholipids." Essentiale normalizes the metabolism of lipids and proteins, improves the detoxification function of the liver, restores the cellular structure of the liver and retards the producing of conjunctive tissue. Phospholipids are essential structural components of all cellular membranes. One of the most important and prominent phospholipids in cell membranes is called phosphatidylcholine (PC). At birth up to 90% of cellular membranes are made up of PC. As humans age, the percentage of PC in their cellular membranes can decrease to about 10%. Hence consistent supplementation with this essential phospholipid is required to satisfy the body's need for PC.
Essential phospholipids (substance EPL) are the complex substances of natural origin (ethers of cholinephosphoric acid (phosphatidylcholine) and unsaturated fatty acids (linoleic, linolenic, olein). Essentiale medications possess the membranotropic properties, metabolic and hepatoprotective action; regulates lipid and carbohydrate metabolism. Essential phospholipids increase functional status of the liver,
Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline. The structure of the phospholipid molecule generally consists

of hydrophobic tails and a hydrophilic head. When placed in water, phospholipids form a variety of structures depending on the specific properties of the phospholipid.
Essentiale medications are manufactured in the form of capsules, intravenous injection, high compressed tablets, either alone or in combination with vitamins and pharmaceutically acceptable excipients.
CN1511516 relates to protein and protein/phospholipid microcapsule and the emulsifying preparation process thereof.
CN 1371735 discloses the composition of phospholipid capsule as health-care and contains (by weight portion) 40-50 portions of soya lecithin, 10-15 portions of ethyl linoleate, 37-48 portions of refined soybean oil and 2-3 portions of span 80. It is mainly used for regulating blood-lipid and raising immunity of human body.
CN1194141 discloses phospholipid hard capsule which include soya bean powder phospholipid 80%, and vitamin E and C and other component 20% as tonic food.
JP 62263119 discloses a gelatin capsule composition consisting of 15-60wt% concentrated phospholipid containing about 65wt% phosphatidylcholine, 35-80wt% fats and oils (e.g. evening primrose oil, wheat germ oil or safflower oil) and 5-40wt% oil-soluble physiologically active component (e.g. vitamin E, vitamin A, vitamin D, etc). The concentrated phospholipid is obtained by de-fatting natural lecithin such as soybean lecithin, egg yolk lecithin, etc., with acetone, etc., for 4-5 times to remove neutral lipids and further treating the lecithin with hydrous ethanol, etc., to obtain about 65% phosphatidylcholine concentration.
JP55115820 discloses phospholipid capsule formation comprising adding to pure phospholipid fat oil, an nonionic surfactant of a fatty acid glycerol ester and a fatty acid sorbitol ester or propylene glycol fatty acid ester and an unsaturated fatty acid of 18 carbon atoms, 180 or more iodine value and -9 deg C or lower melting point or its ester, e.g. linolic acid, linoleic acid or their ethyl ester to obtain said phospholipid capsules.
Several commercials products of essential phospholipids are available in the market under the trade name ESSENTIALE, ESSENTIALE FORTE N, ESSENTIALE N, ESSENTIALE FORTE thereof.

The available products in the market are in the form of injectable (Intravenous) and oral formulations like capsules, high compressed tablets. The capsules contain semisolid sticky mass of EPL.. Due to stickiness of lipids it is difficult to fill into capsule and requires specially designed machine. This makes the process of capsule filling quite costly. Further, the lipids are water insoluble and have poor dissolution properties thus resulting in poor bioavailability. Moreover, due to physicochemical nature of the lipoid it is difficult to compress high dose of active pharmaceutical ingredient in dry form.
There therefore remains a need to provide essential phospholipids as non-sticky, free flowable, solid granules that can be used for manufacturing hard gelatin capsules having improved therapeutic efficacy, pharmacokinetic effects and bioavailability. There is also a need to provide a manufacturing process for the preparation of said formulation which is simple, economical and time saving.
SUMMARY OF THE INVENTION:
In an aspect, the present invention provides highly stabilized solid oral formulation consisting of non-sticky, free flowing granules of water insoluble active agent compared to the semisolid sticky composition filled into capsules of marketed products.
In a preferred aspect, the present invention provides solid, oral pharmaceutical composition of essential phospholipid (EPL), where sticky essential phospholipid (active agent) is converted into free flowing, solid granules, having high stability and bioavailability, are encapsulated into hard gelatin capsules.
Accordingly, the present invention provides stable hard gelatin capsules consisting of non-sticky, free flowing, essential phospholipid (EPL) granules as active agent along with pharmaceutically acceptable excipients.
In yet another aspect, the present invention provides simple, cost effective, time saving manufacturing process for the preparation of hard gelatin capsules of essential phospholipid.
Yet another aspect of the invention relates to a method for treating or preventing fatty degeneration of the liver, hepatitis, cirrhosis of the liver, disturbances in liver function associated with different illnesses, in a subject comprising administering a therapeutically

effective amount of the pharmaceutical formulation of the current invention to a subject in need 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 fully understood and appreciated.
The present invention relates to solid, oral pharmaceutical composition of essential phospholipids (EPL) as active ingredient, where sticky and water insoluble active agent converted into non-sticky, free flowing, dried granules, having high stability and bioavailability, are filled into hard gelatin capsules.
The pharmaceutical composition of the instant invention comprising of free flowing solid granules of essential phospholipids as active ingredient provide specific advantages over the known marketed formulation of semi-solid sticky mass content of EPL with respect to dissolution, bioavailability, stability, dosage forms and patient compliance.
The protective barrier (membrane) around every cell in human body is made from phospholipids. Many of the structures inside each cell are also made from phospholipids. The body can synthesize some phospholipid compounds but others must be supplied by the diet. Phospholipids that can only be obtained through dietary intake are called "essential phospholipids." The term essential phospholipid is derived from soya lecithin containing (3-sn-phosphatidylcholine).
Hard gelatin capsules are a modern dosage form for medicinal use, stemming from the increased emphasis on pharmacokinetics found in drug development today. Due to the simplicity of hard gelatin capsule formulation and manufacturing as well as the versatility of this dosage form, considerable emphasis is laid on the formulation of drugs utilizing hard gelatin capsules as a simple dosage form for oral drug delivery.
The present invention is directed to a pharmaceutical composition comprising of non-sticky, free flowing, dried granules of essential phospholipids (EPL) as active ingredient along with pharmaceuticalIy acceptable excipients encapsulated into hard gelatin capsules.

Accordingly, the present invention relates to a pharmaceutical composition consisting of non-sticky, free flowing solid granules of essential phospholipids (EPL) as active ingredient in an amount of 42.85% to 46.52% weight of the total composition along with the pharmaceutically acceptable excipients such as Adsorbent, Binder, Solubilizer, and Disintegrant encapsulated into hard gelatin capsules.
The phospholipid may be any natural or synthetic phospholipid, for example
phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted, hydrogenated or partially or fully hydrogenated natural, semi synthetic or synthetic. Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl), Lipoid E80 (Lipoid); and hydrogenated soy phospholipids Phospholipon 90H and 100H (Natterman) and 99% pure soy or egg phosphatidyl choline (Avanti Polar Lipids). The essential phospholipid is present in amount of 42.85% to 46.52% weight of the total composition.
The adsorbent for the lipid is selected from silicon dioxide and is present in an amount of 28-38%, more preferably in an amount of 33%.
Binder is added to the formulations to add cohesiveness to powders thereby providing the necessary bonding to form granules. The binders are selected from the group consisting of corn starch, carnuba wax, pregelatinized microcrystalline cellulose, polyvinylpyrrolidone preferably povidone K-30 in amount of 2-4%, more preferably in an amount of 3%.
The solubilizer improves the solubility and dissolution of essential phospholipid. It is used to increase water solubility. The solubilizer is selected from propylene glycol, tween 80, sodium lauryl sulfate etc. preferably sodium lauryl sulfate in an amount of 1-5%, more preferably in 4%.
Disintegrants are agents added to capsule formulations to promote the breakup of the capsule "slugs' into smaller fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance. The disintegrants are selected from croscarmellose sodium, crospovidone, and sodium starch

glycolate etc. The disintegrants are preferably selected from croscarmellose sodium and crospovidone.
The purpose of use of Crosscaramellose sodium is to aid disintegration and dissolution of capsule in the gastro intestinal tract at the required location. Crosscaramellose sodium is used in the amount of 5-10%, preferably in 7%. Crospovidone as a dismtegrant is used in an amount of 5-10% more preferably in 7%.
The solvent is used in the present invention to dissolve essential phospholipid to form solution which is easy to adsorb on inert absorbent like Colloidal silicon dioxide. The solvents are selected from ethanol, isopropyl alcohol, methylene dichloride etc. Preferably the solvent used is ethanol 99%.
The medication of the invention contains essential phospholipids (EPL -substance) specially derived from soya lecithin which represent a highly purified fraction of phosphatidylcholine. Essential phospholipids work by regulating permeability of cellular wall, improve membranous function and the process of intracellular perspiration and biological oxidation. Essentiale phospholipids eliminates fatty infiltration of hepatocytes, stabilizes physicochemical bile properties, activates RNA synthesis and normalizes protein metabolism.
In another embodiment, the present invention provides a process for the preparation of hard gelatin capsules of essential phospholipid, where sticky and water insoluble active agent is converted into non-sticky, free flowable, dried granules, having high stability and bioavailability.
In yet another embodiment, the present invention provides a process for the preparation of hard gelatin capsules of essential phospholipid consisting of non-sticky, free flowing, dried granules comprising the following steps;
i. dissolving Povidone K.-30 in 99% ethanol to form a clear solution;
ii. dissolving Essential phospholipid into the solution of step (i) under stirring;

iii. adding a slurry in the form of dispersion of Sodium Lauryl sulphate in 99% ethanol to solution of essential phospholipid of step (ii) with constant stirring;
iv. adding a blend of Colloidal Silicon Dioxide, intragranular croscaramellose sodium and crospovidone to the solution of step (iii) with continuous shear mixing to form viscous semisolid mass;
v. adding manually remaining quantity of Colloidal silicon dioxide to the viscous semisolid mass of step (iv) with continuous shear mixing to form free flowing granules and sifting;
vi. evaporating the excess solvent from the granules of step (v) in dehumidified area and sifting;
vii. lubricating the sifted granules of step (vi) and step (v) with croscarmellose sodium and Crospovidone; and
viii. filling the lubricated granules of step (vii) in to size '00' empty hard gelatin capsule by hand filling capsule machine.
The process for the preparation of hard gelatin capsules is carried out in the temperature range of 20-34°C and atmospheric pressure.
The formulation of the current invention exhibited excellent stability at room temperature and intermediate condition (30°C/65% RH) throughout three months. The dissolution rate is in the range of 80-90%. The stability data is given below in example 5,
In an embodiment, the composition of the present invention is taken in capsule form. The initial dose is 2 capsules (600mg) three times per day without exceeding 6 capsules (1800mg) per day. The maintenance therapy is I capsule (300mg) three times per day.
The dosage forms prepared by the process of the present invention may be administered to a mammal in need for the treatment of fatty degeneration of the liver, hepatitis (including toxic hepatitis, liver damage caused by medicines or alcohol abuse), cirrhosis of the liver, disturbances in liver function associated with different illnesses. It can be useful in the treatment of various diseases, for example fatty degeneration of the liver of various etiologies (including diabetes), Acute and chronic hepatitis, Liver cirrhosis ,

Necrosis of liver cells, Hepatic coma and precoma. Toxic liver damage, Gestational toxicosis pre-and postoperative care, especially during surgeries on hepatobiliary system, Psoriasis (in complex treatment) and Radiation Syndrome.
The hard gelatin capsule formulation consisting of essential phospholipid also finds use in the treatment of the following diseases:
1. Diseases of the cardiovascular system: coronary heart disease, stable stenocardia , post-infarction condition, disturbance of the cerebral and peripheral circulation, Hypertension, thrombembolia prophylaxis, atherosclerosis, diabetic angiopathy, thrombembolia prophylaxis and fat em bo I ism (solution for injection);
2. Digestive system diseases (chronic pancreatitis, gastric and duodenum ulcer;
3. Toxicosis of pregnancy(edema, proteinuria H and blood pressure disorders);
4. Radiation sickness (radiation syndrome);
5. Psoriasis, atomic dermatitis, eczema;
6. Pyelonephritis; and
7. Prophylaxis of micromegaly.
The most important advantages of the present invention can be summarized as follows:
1. Easy, Economical, time saving, non -sticky hard gelatin capsule manufacturing process.
2. The process according to the invention can be continuously carried out, and allows the conversion of sticky essential phospholipid (active agent) into free flowable solid granules that can be tilled in the capsules.
3. The hard gelatin capsule formulation exhibited excellent stability and dissolution with optimal bioavailability.
4. The hard gelatin capsule composition of the present invention is superior than marketed capsule with relevance to process, stability and bioavailability. The comparative analysis is given in example 6 below.

The following are working examples demonstrating the production and use of solid essential phospholipid compositions of the present invention.
EXAMPLE 1
A hard gelatin capsule composition for free flowable, non-sticky granules of essential phospholipid is prepared as per the process described above. The composition comprises essential phospholipid-322mg; colloidal silicon dioxide (Aerosil-200) -261mg; povidone K-30-45mg; sodium lauryl sulphate-20mg; ethanol (99%)-q.s solvent for adsorption of essential phospholipid. This is followed by addition of croscarmellose sodium-26mg; crospovidone -26 mg for dry mixing and formulating.
The test results for the above described hard gelatin capsule composition for the essential phospholipid is found to be satisfactory.
EXAMPLE 2
A hard gelatin capsule composition for free flowable, non-sticky granules of essential phospholipid is prepared as per the process described above. The composition comprises essential phospholipid -322mg; colloidal silicon dioxide (Aerosil-200)-230mg; povidone K-30-30mg; sodium lauryl sulphate-30mg; ethanol (99%)-q.s solvent for adsorption of essential phospholipid. This is followed by addition of croscarmellose sodium-44mg; crospovidone -44 mg for dry mixing and formulating.
The test results for the above described hard gelatin capsule composition for the essential phospholipid is found to be satisfactory.
EXAMPLE 3
A hard gelatin capsule composition for free flowable, non-sticky granules of essential phospholipid is prepared as per the process described above. The composition comprises essential phospholipid -322mg; colloidal silicon dioxide (Aerosil-200)-230mg; povidone K-30-20mg; sodium lauryl sulphate-30mg; ethanol (99%)-q.s solvent for adsorption of essential phospholipid. This is followed by addition of croscarmellose sodium-49mg; crospovidone -49 mg for dry mixing and formulating.

The test results for the above described hard gelatin capsules composition for the essential phospholipid is found to be satisfactory.
EXAMPLE 4
A hard gelatin capsule composition for free flowable, non-sticky granules of essential phospholipid is prepared as per the process described above. The composition comprises essential phospholipid -322mg; colloidal silicon dioxide (Aerosii-200)-230mg; povidone K-30-20mg; sodium lauryl sulphate-30mg; ethanol (99%)-q.s solvent; croscarmellose sodium-25mg; crospovidone -25mg for adsorption of essential phospholipid. This is followed by addition of croscarmellose sodium-24mg; crospovidone -24 mg for dry mixing and formulating.
The test results for the above described hard gelatin capsules composition for the essential phospholipid is found to be satisfactory.
Example 5: Stability data of essential phospholipid capsule

Sr. Parameters STD Initial 1M 3M
No Limit

RT 30°C RT 30°C
l. Description Dark
brown
colored
size'OO'
capsule
contains
off white
to
yellowish
granular
powder same@ same@ same@ same@ same@
2 Net content inmg 700 710 709 706 703 700

4 Dissolution NLT 70% 89.15% 82.95% 80.55% 88.24% 84.18%
5 Disintegration NMT 30 Min 5.26 min 6.30 min 5.40 min 4.20 min 7.28 min
7 Weight Variation To comply Complies Complies Complies Complies Complies
Example 6: Comparative Analysis between Invention and Market product

TEST PRODUCT (INVENTION ) MARKET PRODUCT
Sr. No Parameters STD Limit Initial 1M 3M

RT 30°C RT 30°C Initial
1. Description Dark brown
colored
size'O'
capsule
contains ofl
white to
yellowish
granular
powder same@ same@ same@ same@ Light brown
colored
size "0" hard
gelatin
capsule contains
semi solid
sticky mass.
2 Net content in mg 700 710 709 706 700 415
3 Assay 90 to 110% 105.07% 102.52% 100.35% 102.06% 100.97% 70-75%
4 Dissolution NLT 70% 89.15% 82.95% 80.55% 88.24% 84.18% 0.00%, Fails
5 Disintegrati on NMT 30 Min 5.26 min 6.30 min 5.40 min 4.20 min 7.28 min Fails
6 Weight Variation To comply Complies Complies Complie s Complie s Complies —

same@: Dark brown colored size'OO' capsule contains off white to yellowish granular powder
Conclusion:
Comparative dissolution of this water insoluble lipid proved to be bioavailable for oral route as remarkable in vitro dissolution results are obtained in the current invention than the market product. The novel composition of essential phospholipid capsule of the present invention is found superior than marketed capsule with relevance to process, stability and bioavailability.

WE CLAIM,
1. A pharmaceutical composition comprising non-sticky, free flowable, dried granules of essential phospholipid as active ingredient in an amount of 42.85% to 46.52% by weight of the total composition along with adsorbent in an amount of 28-38%; binder in an amount of 2-4%; solubilizer in an amount of 1-5%; disintegrants in an amount 5-10% encapsulated into hard gelatin capsules.
2. The pharmaceutical composition according to claim 1, wherein, the active agent essential phospholipid selected from natural or synthetic phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatide acid, lysophospholipids, egg or soybean phospholipid either alone or in combination thereof.
3. The pharmaceutical composition according to claim 1, wherein, the adsorbent is silicon dioxide.
4. The pharmaceutical composition according to claim I, wherein, the binder is povidone K-30.
5. The pharmaceutical composition according to claim I, wherein, the solubilizer selected from tween 80, sodium lauryl sulfate etc. preferably sodium lauryl sulfate.
6. The pharmaceutical composition according to claim 1, wherein, the disintegrants selected from croscarmellose sodium, crospovidone, and sodium starch glycolate.
7. The pharmaceutical composition according to claim 7, wherein the disintegrant is croscarmellose sodium.
8. The pharmaceutical composition according to claim 8, wherein the disintegrant is crospovidone.
9. The process for the preparation of pharmaceutical composition according to claim 1, wherein, said pharmaceutical composition is prepared by a process comprising the steps of:

i. dissolving Povidone K-30 in 99% ethanol to form a clear solution;
ii. dissolving Essential phospholipid into the solution of step (i) under stirring;
iii. adding a slurry in the form of dispersion of Sodium Lauryl sulphate in 99% ethanol to solution of essential phospholipid of step (ii) with constant stirring;
iv. adding a blend of Colloidal Silicon Dioxide, intragranular croscaramellose sodium and crospovidone to the solution of step (iii) with continuous shear mixing to form viscous semisolid mass;
v. adding manually remaining quantity of Colloidal silicon dioxide to the viscous semisolid mass of step (iv) with continuous shear mixing to form free flowing granules and sifting;
vi. evaporating the excess solvent from the granules of step (v) in dehumidified area and sifting;
vii. lubricating the sifted granules of step (vi) and step (v) with croscarmellose sodium and Crospovidone; and
viii. filling the lubricated granules of step (vii) in to size '00' empty hard gelatin capsule by hand filling capsule machine.