FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"Compositions comprising lipophilic nutrients for eye health benefit"
OMNIACTIVE HEALTH TECHNOLOGIES LIMITED
An Indian Company, registered under the Indian Companies Act, 1956 having its registered
office located at OmniActive Health Technologies Limited, T-8b, 5th Floor, Phoenix House,
A wing, Phoenix Mills Compound, 462, Senapati Bapat Marg, Lower Parel,
Mumbai -400013 Maharashtra, India,
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention:
The invention relates to oil dispersion compositions for oral administration comprising lipophilic nutrient, oil vehicle and at least one pharmaceutically or nutraceutically acceptable excipient for eye health benefit. The composition may be comprised of lipophilic nutrient either partly solubilised or may occur in the form of suspended particles in the oil vehicle comprised of vegetable oil and/or essential oil. The oil vehicle may be comprised of 28-96% of vegetable oils and 0-20% of essential oils by weight of the composition. More particularly, the oral composition described herein may be comprised of 2-50 % by weight of micronized lipophilic nutrient/s dispersed in 28-96% by weight of the oil vehicle and at least one pharmaceutically or nutraceutically acceptable excipient. The invention also relates to solvent free process for preparation of oil dispersion, wherein lipophilic nutrient is dispersed in oil vehicle; and at least one acceptable excipient and it is subjected to particle size reduction by employing suitable milling technique. The oil vehicle may be comprised of vegetable oil alone or optionally may be used in combination with essential oil. Oral oil dispersion as described herein exhibits good stability and improved bioavailability as compared to comparator marketed formulation. The process for preparation is simple and economic for industrial application. The composition is comprised of synergistic combination of lipophilic nutrient and oil vehicle and can be employed for eye health benefits and protection of eye against prolonged exposure to light sources and dry eye syndrome.
Background:
The natural lipophilic nutrients are amply present in and derived from various plant and animal sources. The beneficial health effects of natural lipophilic nutrients and their antioxidant nature are well documented throughout scientific literature. The only hindrance to the effective utilization of these properties by the body is the low bioavalability of these nutrients when consumed in the oral form. Only by understanding the mechanisms of absorption of the nutrients such as fatty acids, fat soluble vitamins, glycerides, carotenoids, curcumin, capsaicin, coenzyme Q 10, can their bioavailability be enhanced and thus the potential for greater health benefits be

realized. Understanding the-bioavailability, helps optimize doses for drugs and set appropriate recommendations for nutrients.
It is well known that lipophilic nutrients especially the fatty acids, fat soluble vitamins, carotenoids, coenzyme Q10 are effective in enhancing eye health, treat eye disorders, retard and ameliorate eye diseases and injuries. Various issues with eye health such as xerophthalmia (dry eyes), age related macular degeneration, cataract, dry eye syndrome due to glandular inflammation, asthenopia, amblyopia, myopia, inflammation and other central nervous system degenerative diseases, photic injury, retinal ischemia,and the like are known to improve on administration of lipophilic nutrients either optically or orally. When given topically the lipophilic nutrients show a local effect on the eye, whereas bioavailability and accumulation into the retina remains a problem in treating topical disorders when given orally.
The oral bioavailability of many lipophilic nutrients is limited due to physicochemical and physiological processes such as low solubility in gastrointestinal fluids; molecular structures, metabolizing enzymes causing chemical transformation within the gastrointestinal tract; low epithelium cell permeability, membrane transporters, interaction with the gut microbiota, and the like. The bioavailability of these agents can be improved by specifically designing the compositions that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract.Various approaches have been used to combat these problems of low bioavalibility of the lipophilic nutrients for their use in the form of nutraceutical products for human or veterinary use. The approaches include use of solvents, solid dispersions, melt granulation, surfactants, solubilisers, chemical modification of lipophilic actives, particle size reduction, colloidal systems (micelles and vesicles), and use of nanosystems (nanoparticles),encapsulation, high temperature among others.
The US granted patent US6844020 discloses concentrated solutions of carotenoids in different essential oils and cosmetic oils like bay oil, cornmint oil, peppermint oil, tea tree oil, spearmint oil, thyme oil and additionally in the presence of antioxidant comprising between 0.8% to about 8% by weight of the carotenoid in oil. For the preparation of the solution, lutein dry cake was dissolved in different oils until visibly saturated and centrifuged at high speed and analyzed for lutein content using UV-VIS and HPLC. The best overall essential oils for lutein were the thyme

oils (red, white, and pure) and had the highest lutein solubility (3-5%). The thyme oil constituent carvacrol had the highest lutein solubility at about 7.8%.
The US granted patent US7435846 indicates the use of diacetate and dipropionate salts of lutein in micromicellar form dissolved in vegetable oil matrix and gives improved bioavailability as compared to crystalline lutein dispersed in oil. The microemulsions composed of a solubilizate of derivatives of carotenoids are prepared by melting the naturally occurring original lipid vegetable matrix in the presence of lipids, phospholipids, fatty acids, emulsifiers and moisture.
EP2403361B1 European patent application discloses a method for producing carotenoid solutions in oil suitable for food. The invention relates to a method for dissolving a carotenoid, in particular astaxanthin, in an oil suitable for food by heating a suspension of the carotenoid, at temperatures below 100 °C, in particular within the range of 30 to 70 °C and then rapidly cooling (quenching) the obtained solution.
The patent application US20160374375 discloses a method of preparing an oil dispersible carotenoid preparation containing 2-14% carotenoid with an average particle size of 0.1 to 1 microns(um).The process involves solubilising the carotenoid in organic solvents like ethanol dicholormethane, chloroform etc and spraying to get an amporphous size reduced form of the carotenoid. This size reduced form is further homogenized and desolventised to obtain a water soluble colloid layer on the carotenoid and termed as microcapsular carotenoid. This microcapsular carotenoid is then mixed with vegetable oils and antioxidants and subjected to grinding in a colloid mill to obtain a uniform oil dispersible carotenoid preparation with an average particle size of 0.1 to 1 µm.
The research publication by Lakshminarayana et al (titled 'phospholipid, oleic acid micelles and dietary olive oil influence the lutein absorption and activity of antioxidant enzymes in rats', Lipids, September 2009, Volume 44, issue 9, 799-806), reports the results of repeated gavages and dietary feeding of lutein dispersed in either phospholipids, fatty acid micelles, or vegetable oils and their effects on lutein bioavalability in rats. For the gavage study rats were intubated with lutein solubilised either in oleic acid, linoleic acid, phosphatidylcholine or lysophosphatidylcholine or no phospholipid micelles for 10 days. The results indicate that

plasma liver and eye lutein levels in oleic acid and lysophosphatidylcholine groups were higher by 23.9, 20.8 and 25.5% and 16.1, 28.5 and 14% than linoleic acid and phosphatidylcholine groups respectively. It thus becomes evident that oleic acid modulate lutein absorption, indicating that the fat source may be vital to enhancing lutein bioavailability.
The research publication by Bhatiwada titled 'Dietary fatty acid determines the intestinal absorption of lutein in lutein deficient mice', Food Research International, Volume 64, October 2014, Pages 256-263, discloses that when lutein (200 µM) was dispersed in dietary lipids such as olive, coconut, groundnut, soybean, sunflower, rice bran, corn, palm, fish oils and administered to lutein deficient mice for a period of 15 days, it was found that lutein accumulation in the liver and the eye was highest in the olive oil (120% and 117%) and coconut oil groups(105% and 109%). It is postulated that this could be due to the influence of oleic acid dominantly present in olive oil and lauric acid dominantly present in coconut oil and their effect on the activity of intestinal lipase, portal absorption, triglycerides, lipoprotein or cholesterol flux between liver and peripheral tissues, which may modulate the uptake and transport of lutein.
Summary:
Even though the prior art deals with various approaches such as use of higher temperatures, organic solvents or emulsification, use of these techniques may affect stability of lipophilic nutrients and also introduce the residual impurities, thus resulting into the product which may not be suitable for human or animal consumption. Further these approaches need specialized and complex industrial equipments which increase overall cost of the process and the product, thus affecting industrial application. Thus there is unmet need for designing a stable oral composition of lipophilic nutrient with improved bioavailability, which can be used for eye health benefits and development of a solvent free process for preparation of oil dispersion compositions which is simple and environment friendly.
The inventors of the present invention have carried out rigorous experiments using various combinations of oil vehicles such as vegetable oils and essential oils and suitable excipients to prepare oral composition of lipophilic nutrients using solvent free process. It was surprisingly

found that when micronized lipophilic nutrient/s were combined with specific amount of oil vehicle comprised of vegetable oil and/or essential oil, using suitable solvent free process, the resulting oil dispersion composition was stable and more bioavailable as compared to comparator marketed formulation. The oil vehicle selected for this composition was comprised of combination of suitable vegetable oil and essential oil which can be used for several eye health benefits. The unique synergistic combination of vegetable oils and essential oils employed in this composition play significant role in conferring stability, more bioavailability and the eye health benefits because of their specific characteristic roles in the composition.
None of the prior art references relate to use of unique combination of vegetable oil and essential oil in specific percentage for preparing stable oil dispersion composition of lipophilic nutrients with improved bioavailability. The solvent free process carried out at ambient temperature employed for the preparation of oil dispersion composition is environment friendly, simple, cost efficient and industrially useful. Because of the synergistic combination of vegetable oil and essential oil, the compositions envisaged here can be used for improving eye health through retinal accumulation of the lipophilic nutrient.
Objectives:
Important objective of the present invention is to provide a stable oil dispersion composition for
oral administration comprising lipophilic nutrients, oil vehicle and at least one pharmaceutically
or nutraceutically acceptable excipient.
One more important objective of the present invention is to provide a solvent free process for
preparation of oil dispersion composition, wherein lipophilic nutrients are dispersed in
combination of vegetable and essential oil in specific percentage amounts at room temperature
and are subjected to particle size reduction by employing suitable milling technique.
Still one more important objective of the present invention is to provide an oil dispersion
comprising a unique synergistic combination of lipophilic nutrient with specific percentage of
vegetable oil and essential oil, which results in a stable composition with improved
bioavailability.

One important objective of the present invention is to provide oil dispersion composition
comprising 2-50% by weight of lipophilic nutrient/s, 28-96% of the oil vehicle and at least one
more pharmaceutically or nutraceutically acceptable excipient.
One more objective of the invention is to provide an oil vehicle comprising about 28-96% of
vegetable oil and 0-20% of essential oil by weight of the oil vehicle.
According to one important objective of the invention, the oil vehicle is selected in such a way,
so that vegetable oil and essential oil will enhance passage of active to retina, enhance retinal
accumulation, promote stability and solubility of the active and also impart benefits such as eye
lubrication, thus providing a unique synergistic combination for deriving eye health benefits
because of administration of this composition.
Still one more objective of the present invention is to provide a solvent free process for
preparation oil dispersion composition, which is carried out at room temperature, wherein oil
vehicle is mixed with at least one pharmaceutically or nutraceutically acceptable excipient under
stirring and weighed amount of micronized lipophilic nutrient is added to this mixture and mixed
well in suitable mill for 3 to 5 hours.
One more essential objective of the present invention is to provide micronized lipophilic nutrient
having particle size in the range of 1 to 10 microns, preferably in the range of 2 to 8 microns,
which is achieved by using suitable equipment for size reduction such as ball mill, jet mill,
colloidal mill, cutter mills, roller mills, pestle and mortars, runner mills, planetary mills,
oscillating mills, low energy wet mills, high pressure homogenizer, high speed stirrer and the
like.
One important objective of the invention is to provide a solvent free process for preparation of
stable oil dispersion composition for oral administration, which is environment friendly, simple,
economically efficient and industrially useful.
One more objective of the present invention is to provide a stable oil dispersion with improved
bioavailability which employs unique combination of vegetable oil and essential oil in specific
percentage with lipophilic nutrient, resulting into improved bioavailability.
One objective of the present invention is to provide a stable oil dispersion having a particle size
in the range 0.1 nanometer to 10 microns, preferably 0.5 nanomerter to 5 microns and most
preferably 0.1 naometer to 4 microns.

One more objective of the present invention is to provide a synergistic combination of lipophilic nutrient and oil vehicle which can offer eye health benefits such as improvement of eye health and protection from over exposure to harsh light and light of variable intensity and dry eye syndrome.
Detailed Description:
The invention relates to oil dispersion compositions for oral administration comprising lipophilic nutrients, oil vehicle and at least one pharmaceutically or nutraceutically acceptable excipient for eye health benefit. The oil vehicle may be comprised of vegetable oil, essential oil or a combination thereof in specific percentage. The lipophilic nutrient may either be partly solubilised in the oil vehicle or may occur in the form of suspended particles. More particularly, the oral composition described herein is comprised of unique synergistic combination of lipophilic nutrients dispersed in suitable oil vehicle, which exhibits desired stability and improved bioavailability.
The invention also relates to solvent free process for preparation of dispersion, wherein lipophilic nutrients are dispersed in oil vehicle and are subjected to particle size reduction by employing suitable milling technique such as ball mill, jet mill, cutter mills, roller mills, pestle and mortars, runner mills, planetary mills, oscillating mills, low energy wet mills and the like. The high cost and energy consuming colloidal mill and high pressure homogenizer is ideally not used in the preparation of the oil dispersion of the present invention.
The term 'oil dispersion' as used herein means a composition in which lipophilic nutrient is either partly solubilised in the oil vehicle or suspended uniformly as micronized particles in the oil vehicle, along with at least one pharmaceutically or nutraceutically acceptable excipient. As the particle size of such oil dispersion is in micron range, the composition appears to be homogeneous to the naked eyes. The oil dispersion is prepared by solvent free process, by mixing lipophilic nutrient and oil vehicle in specific percentage along with the excipient/s by stirring well in suitable milling equipment such as ball mill, colloid mill, jet mill, high speed homogenizer, high speed stirrer and the like for 3 to 5 hours. The particle size of the oil dispersion composition may range from 0.1 nanometer to 10 microns, preferably 0.5 nanomerter to 5 microns and most preferably 0.1 naometer to 4 microns.

The composition is obtained by using unique synergistic combination of lipophilic nutrient and oil vehicle and it exhibits desried stability and improved bioavailability.
As used within the scope of the invention, the term "lipophilic nutrients" refers to nutrients having good solubility in lipids, but very poor solubility in water. The lipophilic nutrients which may be suitable for compositions herein include those which may be sensitive to heat or oxygenating conditions. Such active agents may be vitamins, vitamin like substances, bioengineered pharmaceuticals, nutraceuticals and nutritional supplements. Vitamins particularly that may be delivered using this invention include, and are not limited to the class of, fat soluble vitamins such as thiamin, riboflavin, pyridoxine, pantothenic acid, choline, carnitine, vitamin D and its analogs, vitamin A, vitamin like substance coenzyme Q10, ubiquinol and the carotenoids, retinoic acid, vitamin E and vitamin K. These lipophilic actives may include particularly nutrients like carotenoids, tocopherols, tocotrienols, plant sterols and stanols, and lecithins, select omega-3 fatty acids and poly-unsaturated fatty acids, pungent and odoriferous substances or the combinations thereof. Plant sterols or stanols are naturally occurring lipophilic compounds structurally related to cholesterol found in nuts, vegetable oils, seeds, cereals and beans. Lecithins are complex lipophilic mixtures of glyceride oils and phosphatides (including phosphaptidylcholine, or PC). Polyunsaturated fatty acids (such as linolenic acid, alpha-linolenic acid, and gamma-linolenic acid) and omega-3 fatty acids (such as AA, DHA and EPA) have a significant nutritional role to play with several metabolic processes and healthy body function. Of course, the lipophilic actives can comprise combinations of the above ingredients. In some embodiments, the lipophilic nutrient is selected from at least one from the group, but not limited to, carotenoids (especially alpha-carotene, beta-carotene, 8'-apo-beta-carotenal, 8'-apo-beta-carotenoic acid esters such as the ethyl ester, canthaxanthin, astaxanthin, astaxanthin ester, betacryptoxanthin, lycopene, lutein, lutein (di) ester, zeaxanthin or crocetin, mesozeaxanthin, alpha or beta-zeacarotene or mixtures thereof), Salacia extract, curcumin, vitamins (A, D, E, K, Coenzyme Q10) and derivatives thereof (such as their acetates, e.g. vitamin A acetate or tocopherol acetate, or their longer chain fatty acid esters, e.g. vitamin A palmitate or tocopherol palmitate), polyunsaturated fatty acids (PUFAs) or derivatives thereof, and triglycerides rich in polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or gamma-linolenic acid (GLA), Omega 3, Omega 6 oils and all possible isomers and or

derivatives thereof. Further lipophilic nutrients suitable for formulations and compositions herein may include compounds which have a taste or smell which is required to be masked, such as for example but not limited to bitter tasting vitamins and fish oil. In some preferred embodiments the lipophilic nutrients are selected from the group of, but not restricted to one or more carotenoids such as astaxanthin, P-carotene, canthaxanthin, lutein, zeaxanthin and all isomers used either alone or in the combination thereof.
In one embodiment the lipophilic nutrient is in the form of a micronized cake comprising the active xanthophylls constituents such as free lutein and zeaxanthin obtained from the extract of dried flowers of Marigold (Tagetes Species). The lipophilic nutrient may be micronized using suitable milling technique such as jet mill, colloid mill, ball mill or any other mills commonly used for size reduction processes in pharmaceutical and nutraceutical formulation processes such as homogenizer or high speed stirrer.
In another embodiment the lipophilic nutrient employed in the oil dispersion may be selected from Coenzyme Q10 (also known as CoQ10), curcumin (extract obtained from haldi), free lutein or zeaxanthin. One having ordinary skill in the art would understand that this list of potential lipophilic actives substances is not exhaustive, and there are many other lipophilic actives that offer medicinal, nutritional, pharmaceutical benefit, for eye health which may also be utilized in the current invention.
As per one embodiment, the lipophilic nutrients may be present in the range of 1 to 60% by weight of the oil dispersion, more preferably in the range of 2 to 50% by weight of the oil dispersion. The lipophilic nutrient used in the oil dispersion of the present invention is reduced to a desirable particle size by the process of milling. The desired particle size range of micronized lipophilic nutrient before adding in the oil vehicle is 1- 10 microns. A person of ordinary skill in the art would know the method of determination of particle size by a laser diffraction particle size analyzer. The desired particle size of the lipophilic nutrient in oil dispersion composition is in the range 0.1 nanometer to 10 microns, preferably 0.5 nanomerter to 5 microns and most preferably 0.1 naometer to 4 microns.
The particle size varies from nanaometers to microns depending on the type of size reduction mill used in the invention. The process of size reduction is carried out by well known pharmaceutical milling techniques such as ball mill, jet mill, cutter mills, roller mills, pestle and

mortars, runner mills, planetary mills, oscillating mills, low energy wet mills and the like. The high cost and energy consuming colloidal mill and high pressure homogenizer is ideally not used in the preparation of the oil dispersion of the present invention. The milling process at room temerature and lack of solvent use in the preparation of the oil dispersion of the present invention gives a low cost and better quality product, which was not identified by the prior art formulators.
As used within the scope of the invention, the term 'oil vehicle' refers to the carrier used for dispersion and/or solubilization of lipophilic nutrients. It may be a single oil used for dispersing the active or a combination of oils used in variable amount based on total weight of the composition. It may be only used as carrier for lipophilic active or may have additional function such as solubilization, retinal targeting, even dispersion of the active, or additional synergistic benefit such as eye lubrication, eye protection from prolonged exposure to intense light, improvement of eye function such as blinking, improvement in functioning of optic nerve, improving co-ordination between eye and brain and the like or the combination thereof.
The oil vehicle as used herein includes but is not limited to vegetable oils such as soya oil, partially or fully hydrogenated soya oil, cotton oil, coconut oil, palm-kernel oil, maize oil, palm oil, sunflower oil, sesame oil, linseed oil, hazelnut oil, walnut oils, flaxseed, fish oil, safflower oil, corn oil, medium chain triglyceride oil (MCT oil), peanut oil, corn oil, cotton seed oil, canola oil, olive oil, palm oil, peanut oil, sesame oil, soybean oil, grape seed oil, pumpkin seed oil, argan oil, rice bran oil and other vegetable oils, vegetable oils having an unsaturated long chain fatty acid content of about 30 wt. % to about 90 wt. %, or any blends or fractions of these vegetable oils also come within the scope of the invention. Other essential oils such as bay oil, cornmint oil, peppermint oil, spearmint oil, tea tree oil, and thyme oil castor cerester oil,ajwain oil, oil of wintergreen, clove oil, bay oil, anise oil, eucalyptus, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil; are also included within the scope of the invention. The oil vehicle may be comprised of single oil or combination of oils which may be used in various permutation and combinations. Depending on the properties and concentration of the various oils used they may have various functions to perform in the formulation such as acting as a carrier for the lipophilic nutrient,solubilisation of the lipophilic nutrient, accumulation of the nutrient in retina. Some oils may give synergistic action in eye health benefit along with the lipophilic

nutrient. The oils may be used in the range of 1 to 98 % by weight of the oil dispersion. In a preferred embodiment vegetable oils may be used 28-96% by weight of the oil dispersion composition and 0-20 % by weight of essential oils are added to the vegetable oil to prepare an oil vehicle. In one embodiment the oils used are MCT as a carrier/vehicle for the lipophilic nutrients and other oils. In one preferred embodiment the oils used in the oil dispersion are MCT oil, flaxseed oil, Olive oil and Thyme oil. In one more embodiment of the invention, selection of oil may also depend on type of active used in oil dispersion. Essential oil like thyme oil may be used for macular carotenoids like lutein and zeaxanthin, along with vegetable oil used in the composition.
As is well known to those skilled in the art, excipients such as antioxidants, flavouring agents, surfactant, suspending agents and the combination thereof are routinely incorporated into nutraceutical compositions, dietary supplements, human drug products, veterinary drug products, food products, botanical compositions and the products which are derived using actives from synthetic or natural sources and are meant for administration to mammals. This is done to ease the manufacturing process as well as to improve the performance of the composition in body of subjects.
The antioxidant used in the oil dispersion of the present invention is selected from but not limited to the commonly used antioxidants such as α-Tocopherol, β-Tocopherol, γ-Tocopherol, mix Tocopherol, synthetic d,l a-Tocopherol, citric acid, Rosemary extract, ascorbyl palmitate, sodium ascorbate or the like and the combinations thereof. The antioxidants are used in the range of 1 to 5% preferably 2 to 4% by weight of the oil dispersion.
As used herein, the term "flavorant/flavouring agent" means a natural or artificial compound, or some combination of these, used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Flavors incorporated in the composition may be chosen from natural and synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Such compounds include, by way of example and without limitation, anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, menthol, grape, peppermint oil, citrus oils such as lemon, d-limonene, orange, lime and grapefruit oils; and fruit essences,

including berry, apple, pear, peach, date, blueberry, kiwi, strawberry, raspberry, wildberry, cherry, plum, pineapple, and apricot. All of these flavorants are commercially available. Preferred flavorant include d-limonene. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired.
As used herein the term 'surfactant or emulsifying agent' may be used to relate to agents comprised in the invention to emulsify the oil phase and the actives that may be completely or partly solubilized into said phase, thereby rendering said dispersion proper for application in the field. Thus, addition of surfactants or emulsifiers in the oil dispersion compositions of the present invention may be essential to its final use for oral administration. Among the emulsifiers comprised in the present invention are anionic and non-ionic surfactants, such as the calcium alkyl benzene sulphonates, natural or synthetic ethoxylated fatty alcohols, natural or synthetic, ethoxylated and propoxylated fatty alcohols, ethoxylated and propoxylated short-chain alcohols, EO/PO copolymers, ethoxylated fatty acids, ethoxylated castor oil, ethoxylated sorbitan esters, ethoxylated esterified sorbitols, ethoxylated alkylphenols, ethoxylated tristyrylphenols and ethoxylated fatty amines.
As used herein the term 'suspending or dispersing agents' relates to the agents used for preventing flocculation and agglomeration of a dispersion or suspension formulation. The suspending agent functions to suspend the active uniformly in the oil-based vehicle so that dosages of the active are uniform. Some of the suspending agents for use in the preferred embodiment of the present invention include bentonite, a finely powdered montmorillonite aluminum silicate, a finely powdered sodium calcium alginate and hydrogenated castor oil. Other suspending agents, such as cellulose derivatives, silicates, bentonites, stearates, silicon dioxide and acacia may also be advantageously utilized.
For preparation of the oil dispersion of the present invention, the oil vehicle, antioxidant and flavorant agent are weighed as per batch quantity, the oils in the oil vehicle are mixed one by one under stirring and then antioxidant and flavorant are added to this mixture under constant stirring. This solution mixture is further subjected to stirring for 5 minutes at 1800 rpm. A weighed quantity of lipophilic nutrient is added to the solution mixture which is stirred at 1800 rpm for 5 minutes. After addition of the lipophilic nutrient the mixture, it is subjected to stirring

at 2880 rpm for 15 to 20 minutes. The solution thus obtained is packaged into a suitable packing material preferably high density polyethylene packing and sealed.
Alternatively, the oil dispersion may be prepared by using a suitable milling technique such as technique such as ball mill, jet mill, cutter mills, roller mills, pestle and mortars, runner mills, planetary mills, oscillating mills, low energy wet mills and the like. The high cost and energy consuming colloidal mill and high pressure homogenizer is ideally not used in the preparation of the oil dispersion of the present invention. In this process, the weighed quantities of oils, the antioxidant and flavoring agent were mixed together and subjected to ball and rotated for 5 minutes. A weighed quantity of lipophilic nutrient is added to the solution mixture which is rotated for 5 minutes. This solution is then rotated for 5 hours with a sample collection at every 1 hour interval to check for assay. At the end of 5 hours the solution was packed in appropriate packaging material preferably high density polyethylene packing and sealed.
In some embodiments, physical in vitro evaluations of composition, described herein such as particle size, assay, stability studies at accelerated temperature and humidity conditions were carried out to determine assay content of the lipophilic nutrient and to evaluate the parameters in order to understand the stability traits of the oil dispersion composition.
3 batches of oil dispersion formulation containing lipophilic nutrient were checked for stability under accelerated stability conditions tocheck the drop in active content till 6 months to decide the stability for proposed shelf life.
As oper one important embodiment of the invention, oil dispersion composition comprising oil vehicle is evaluated through single dose oral pharmacokinetics studies in experimental animal models of male Wistar Albino rats. The study was also carried out in two more formulations for comparison purpose- In-house marketed product and comparator makeketed product during this study. In-house developed marketed product was used for comparison purpose to understand effect of use of single oil as the vehicle for dispersing lipophilic nutrient as compared to use of unique synergistic combination of various oils in the composition of instant invention. Fasted animals were divided in groups and were administered with a test item in recommended vehicle by oral route and blood specimens were collected after defined time period for analysis.

The oral bioavailability of the oil dispersion was checked as compared to the comparator marketed product and in-house marketed product.
The lipophilic nutrient oil dispersion composition prepared by solvent free preparation method can exhibit synergistic eye health benefit because of specific combination of lipophilic nutrient with oil vehicle, which may result in enhanced accumulation of lipophilic active in different areas of eye and enhanced bioavailability of the active. The health benefit may be related to improvement, protection, treatment or prevention of eye from certain eye disorders.
This comprehensive action may result from enhanced accumulation of the lipophilic nutrient in the different areas of the eye like lens, cornea, sclera, and choroid. The human eye is an extremely specialized structure and the most important optical instrument. It works by virtue of synchronised individual roles played by the different components. These components may go out of sync or may start underperforming due to various reasons like age, stress, environmental factors (extreme weather; wind; soil erosion), pollution (air water and soil), physical stressors like harsh light exposure to UV light or other lights of the electromagnetic spectrum, chemical stressors like pollution and the like. The lipophilic nutrient dispersion of the present invention has a role to play in attenuating, improving the symptoms and also protecting and treating the eye from these various disorders.
More particularly in one aspect the lipophilic nutrient dispersion of the present invention can be used for decreasing the eye sensitivity on exposure to harsh lights.The term 'harsh lights' includes light from the entire electromagnetic spectrum ie UV radiation (UV-A (315 nm to 400 nm), UV-B (280 nm to 315 nm), and visible light (380 nm to 500 nm), small optical image energy from the visible and infrared portions of the electromagnetic spectrum and other newer sources of light such as Light Emitting Diodes light sources (LEDs) , halogen, metal halide, plasma arc, and diode laser. In a preferred embodiment the lipophilic nutrient can help in decreasing the sensitivity of eyes in harsh light include but is not limited to carotenoids (especially alpha-carotene, beta-carotene, 8'-apo-beta-carotenal, 8'-apo-beta-carotenoic acid esters such as the ethyl ester, canthaxanthin, astaxanthin, astaxanthin ester, betacryptoxanthin,

lycopene, lutein, lutein (di) ester, zeaxanthin or crocetin, mesozeaxanthin, alpha or beta-zeacarotene or mixtures thereof),salacia extract, curcumin, coenzyme Q10.
In another aspect the lipophilic nutrient dispersion of the present invention may help to improve the serum levels of brain derived neurotrophic factors (BDNF) and the ocular BDNF level which further help in ameliorating the damage caused by optic nerve injury and sustain long-term ganglion cell survival and function. In a preferred embodiment the lipophilic nutrient can be used to increase the serum and ocular levels of brain derived neurotrophic factors include but are not limited to carotenoids (especially alpha-carotene, beta-carotene, 8'-apo-beta-carotenal, 8'-apo-beta-carotenoic acid esters such as the ethyl ester, canthaxanthin, astaxanthin, astaxanthin ester, betacryptoxanthin, lycopene, lutein, lutein (di) ester, zeaxanthin or crocetin, mesozeaxanthin, alpha or beta-zeacarotene or mixtures thereof),salacia curcumin, coenzyme Q10 and the combination thereof.
In another aspect the lipophilic nutrient dispersion of the present invention can be used for improving the symptoms of dry eye (xeropthalmia), blinking disorders or tear secretions. More particularly the lipophilic nutrient that helps to improving the symptoms of xerophthalmia include but are not limited to to carotenoids (especially alpha-carotene, beta-carotene, 8'-apo-beta-carotenal, 8'-apo-beta-carotenoic acid esters such as the ethyl ester, canthaxanthin, astaxanthin, astaxanthin ester, betacryptoxanthin, lycopene, lutein, lutein (di) ester, zeaxanthin or crocetin, mesozeaxanthin, alpha or beta-zeacarotene or mixtures thereof),salacia, curcumin, coenzyme Q10 and the combinations thereof.
As per one embodiment of the invention, oil dispersion composition comprising lipophilic nutrient can be used incorporated in suitable forms such as soft gel capsules, liquid filled hard gel capsules or sachets for use in food, nutritional and pharmaceutical products.
The lipophilic nutrients such as lutein and zeaxanthin concentrate incorporated in the oil dispersion can be used in doses ranging from 5 to 40 mg/day which are therapeutically safe and effective for the treatment of different eye disorders, especially dry eye syndrome, eye sensitivity on exposure to harsh lights, and other eye disorders caused by poor retinal health and retinal neuron dysfunction.

The details of the present invention are described in the Examples given below which are provided to illustrate the invention and therefore should not be construed to limit the scope of the present invention.
Experimental Details:
Example 1: Oil dispersion composition (20%) comprising Lutein and Zeaxanthin

S.No. Ingredients Qty (gm)
a. Micronized Lutein and Zeaxanthin concentrate 35.50
b. Mixed Tocopherol 70% 2.00
c. Thyme oil 1.00
d. Olive Oil 5.00
e. MCT Oil 60% 52.50
f. Flax seed Oil 2.00
g- d-Limonene 2.00
Total 100
Process for Preparation:
MCT oil, Olive oil, Flaxseed oil, Thyme oil, d-limonene and Mixed tocopherol were weighed as per batch quantity and mixed well by stirring in a ball mill for 5 to 10 minutes. Weighed quantity of Lutein and Zeaxanthin concentrate was added in above mixture and stirred in ball mill for 3 to 5 hours. The composition was analyzed in -process and also at the end of stirring and it was packed in suitable container. The oil dispersion prepared by above method was reddish orange free flowing homogeneous liquid, which was immiscible with water.
Lutein and zeaxanthin concentrate was micronized by Jet milling to achieve particle size below 10 micron, before adding to the ball mill. The concentrate was manufactured from purified crystals consisting of lutein and zeaxanthin obtained from extract of dried flowers of Marigold (Tagetes erecta). The concentrate is comprised of 20% lutein and 4% zeaxanthin isomers.
The composition was obtained as reddish orange free flowing homogeneous liquid.

Example 2: Oil dispersion composition comprising Coenzyme Q10

S.No. Ingredients gm
1 Coenzyme Q10 25.26
2 Olive Oil 5.0
3 MCT Oil 60% 63.74
4 Flax seed Oil 3.0
5 d-Limonene 2.0
6 Mixed tocopherol-70% 1.0
Batch size 100
Process for Preparation:
MCT oil, Olive oil, Flaxseed oil, d-limonene and Mixed tocopherol were weighed as per batch quantity and mixed well by stirring in a ball mill for 5 minutes. Weighed quantity of micronized Coenzyme Q10 was added in above mixture and stirred in ball mill for 3 to 5 hours. The composition was analyzed in -process and also at the end of stirring and it was packed in suitable container.
Example 3: Oil dispersion composition comprising Curcumin

S.No. Ingredients gm
1 Curcumin extract 25.63
2 Olive Oil 5.0
3 MCT Oil 60% 63.37
4 Flax seed Oil 3.0
5 d-Limonene 2.0
6 Mixed tocopherol-70% 1.0
Batch size 100

Process for Preparation:
MCT oil, Olive oil, Flaxseed oil, d-limonene and Mixed tocopherol were weighed as per batch quantity and mixed well by stirring in a ball mill for 5 minutes. Weighed quantity of micronized Curcumin was added in above mixture and stirred in ball mill for 3 to 5 hours. The composition was analyzed in -process and also at the end of stirring and it was packed in suitable container.
Example 4: Oil dispersion composition comprising Zeaxanthin

S.No. Ingredients gm
1 Micronized Zeaxanthin concentrate 37.5
2 Olive Oil 5.0
3 MCT Oil 60% 51.5
4 Flax seed Oil 3.0
5 d-Limonene 2.0
6 Mixed tocopherol 1.0
Batch size 100
Process for preparation:
MCT oil, Olive oil, Flaxseed oil, d-limonene and Mixed tocopherol were weighed as per batch quantity and mixed well by stirring in a ball mill for 5 minutes. Weighed quantity of micronized zeaxanthin concentrate was added in above mixture and stirred in ball mill for 3 to 5 hours. The composition was analyzed in -process and also at the end of stirring and it was packed in suitable container.
Example 5: Oil dispersion composition comprising Free Lutein

S.No. Ingredients gm
1 Free lutein concentrate 31.3
2 Mixed Tocopherol 70% 2.0
3 Thyme Oil 2.0

4 Olive Oil 5.0
5 MCT Oil 60% 55.7
6 Flax seed Oil 2.0
7 d-Limonene 2.0
Batch size 100
Process for preparation
MCT oil, Olive oil, Thyme oil, Flaxseed oil, d-limonene and Mixed tocopherol were weighed as per batch quantity and mixed well by stirring in a ball mill for 5 minutes. Weighed quantity of micronized Free Lutein concentrate was added in above mixture and stirred in ball mill for 3 to 5 hours. The composition was analyzed in -process and also at the end of stirring and it was packed in suitable container.
Example 6: Characterization of oil dispersion composition prepared in Example 1
a. Particle size: Oil dispersion composition comprising lutein and zeaxanthin prepared in
Example 1 was characterized for Particle size distribution data using Malvern system
Actual value- PSD: d(10)=0.21 Micron d(50)=0.86 Micron d(90)=2.72 Micron
b. Assay: 3 batches of oil dispersion composition prepared as per Example 1 were analyzed for
active content and the result was tabulated in Table 1.
Table 1: Assay of oil dispersion composition comprising Lutein and zeaxanthin

Test Batch I Batch II Batch III
Total Xanthophyll content (TXC) 28.42 27.84 29.59

Lutein Content (tL)
23.29 22.75 24.15
Zeaxanthin Content (tZ) 4.77 4.69 4.98
C. Stability Study for the oil dispersion composition of Example 1
3 batches of oil dispersion prepared as per the process of Example 1 were tested for stability at accelerated conditions of 40C/75% RH for 6 months. The results are tabulated in Table 2.
Table 2: Outcome of Accelerated stability study at 40C/75% RH

Period Initial 1M 2M 3M 6M
Batch No Assay
(%tL) Assay %Loss Assay %Loss Assay %Loss Assay %Loss
I 23.29 22.64 2.79 23.09 0.85 23.02 1.15 22.03 5.41
II 22.75 22.14 2.68 22.16 2.59 22.36 1.71 22.36 1.71
III 24.15 23.61 2.23 23.6 2.27 23.27 3.64 22.56 6.58
Oil dispersion composition comprising lutein and zeaxanthin exhibited maximum 6.58% of drop and lutein content of the composition was above label claim (20%) even after 6 months under accelerated stability conditions. This data confirmed that the product is stable till proposed shelf life of 24 months.
Example 7: Single dose oral pharmacokinetics studies of Lutein and zeaxanthin oil dispersion composition in male Wistar Albino rats
Adult healthy Male Wistar albino rats (species Rattus norvegicus) of age 8 to 10 weeks were used for experimentation after a minimum 3 days of acclimation. Total 40 rats were used for this

study in 4 groups of 10 each. Fasted animals were administered with a test item in recommended vehicle by oral route with a dose of 20 mg/kg body weight at a dose volume of 10 mL/kg body weight. Under mild Isoflurane anesthesia, blood specimens (~250 µL) were collected serially from the retro-orbital plexus into pre-labeled tubes containing anticoagulant (K2EDTA - 2 mg/mL blood) during the next 48 hours of post-dose st definite time intervals. Collected blood samples were centrifuged and plasma was separated and stored at -80°C until analysis by LC-MS/MS.
Composition Details of the samples used for the study:
Sample A- In-house Market sample- Lutein and zeaxnathin 20% concentrate suspended in
Sunflower oil
Sample B- Lutein and zeaxanthin 20% oil dispersion prepared by process of Example 1
(micronized cake dispersed in blend of vegetable oil and essential oil)
Sample C- Comparator Market sample -Lutein and zeaxanthin 20% oil suspension in Safflower
oil
Table 3: Results of single dose oral pharmacokinetics study

Test item PSD for Sample Cmax
(ng/mL) Tmax (h) AUClast
(h* ng/mL) Fold
Increase Vs Sample C
Sample A 11.250 micron 5.437 ± 3.384 12.111 ± 5.11 33.392 ± 37.169 0.92
Sample B 7.055 micron 12.113 ±
7.639 11.111 ± 1.764 90.654 ± 74.308 2.50
Sample C 23.107 micron 6.068 ±3.233 6.6 ± 3.307 36.213 ± 27.847

Conclusion :
• Lutein and zeaxanthin oil dispersion 20% composition prepared by process of Example 1 is 2.5 times more bioavailable than comparator market sample
• Bioavailability of in-house market sample is comparable with comparator market sample.
In-house market sample is comprised of lipophilic nutrient suspended in sunflower oil; while the composition of present invention (Sample B) is comprised of synergistic combination of 3 different vegetable oils combined with 1 essential oil in which the lipophilic nutrient is dispersed. This indicates that oil dispersion composition of Example 1 exhibits improved bioavailability as compared to comparator marketed product as well as in-house marketed product.

Claims:
1. Solvent free oil dispersion composition for oral administration comprising;
2-50% by weight of lipophilic nutrient/s,
an oil vehicle comprised of 0-20% by weight of essential oils and 28-96% by weight of
vegetable oils and; and
at least one pharmaceutically and/or nutraceutically acceptable excipient,
wherein the composition is stable and more bioavailable as compared to the comparator
marketed product and can be used for eye health benefits.
2. The composition as claimed in claim 1, wherein lipophilic nutrient is selected from the group of vitamins, vitamin like substances, bioengineered pharmaceuticals, nutraceuticals and nutritional supplements.
3. The composition as claimed in claim 2, wherein lipophilic nutrient is selected from the group of nutraceuticals such as alpha-carotene, beta-carotene, 8'-apo-beta-carotenal, 8'-apo-beta-carotenoic acid esters, canthaxanthin, astaxanthin, betacryptoxanthin, lycopene, lutein, zeaxanthin, mesozeaxanthin, alpha or beta-zeacarotene and their isomers, salacia extract, curcumin, vitamins A, D, E, K, Coenzyme Q10, polyunsaturated fatty acids (PUFAs), and triglycerides rich in polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or gamma-linolenic acid (GLA), Omega 3, Omega 6 oils and and derivatives and their mixtures thereof.
4. The composition as claimed in claim 1, wherein the vegetable oils may be selected from the group of soya oil, cotton oil, coconut oil, palm-kernel oil, maize oil, palm oil, sunflower oil, sesame oil, linseed oil, hazelnut oil, walnut oils, flaxseed oil, fish oil, safflower oil, corn oil, medium chain triglyceride oil (MCT oil), peanut oil, corn oil, cotton seed oil, canola oil, olive oil, palm oil, peanut oil, sesame oil, soybean oil, grape seed oil, pumpkin seed oil, argan oil, rice bran oil and the combination thereof.
5. The composition as claimed in claim 1, wherein essential oils may be selected from bay oil, cornmint oil, peppermint oil, spearmint oil, tea tree oil, thyme oil, castor cerester oil, ajwain oil, oil of wintergreen, clove oil, anise oil, eucalyptus, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil or the combination thereof.
6. The composition as claimed in claim 1, wherein at least one excipient is selected from the group of antioxidants and flavouring agents.

7. The solvent free process for preparation of oil dispersion composition comprised of
a. mixing the oil vehicle with at least one pharmaceutically or nutraceutically
acceptable excipient under constant stirring.
b. adding weighed quantity of micronized lipophilic nutrient/s to the mixture of step a
and subjecting to stirring in suitable mill for 2 to 5 hours.
c. filling the oil dispersion composition in suitable packaging material.
8. The process as claimed in claim 7, wherein 2-50% by weight of lipophilic nutrient/s is added to the mixture of 0-20% of essential oil and 28-96% by weight of the vegetable oil and at least one pharmaceutically or nutraceutically acceptable excipient such as antioxidant and flavouring agent.
9. The process as claimed in claim 8, wherein the antioxidant is selected from the group of α-Tocopherol, β-Tocopherol, γ-Tocopherol, mix Tocopherol, synthetic d,l α-Tocopherol, citric acid, Rosemary extract, ascorbyl palmitate, sodium ascorbate or the combinations thereof.
10. The process as claimed in claim 8, wherein the flavouring agent is selected from the group of anise oil, cinnamon oil, vanilla, vanillin, cocoa, chocolate, menthol, grape, peppermint oil, citrus oils such as lemon, d-limonene, orange, lime and grapefruit oils; and fruit essences, including berry, apple, pear, peach, date, blueberry, kiwi, strawberry, raspberry, wildberry, cherry, plum, pineapple, apricot or the combinations thereof.
11. The composition as claimed in claim 1, which is prepared for oral administration meant for eye health benefits is more than 2 times bioavailable as compared to the comparator marketed product.