FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
RAPIDLY DISPERSIBLE XANTHOPHYLL FORMULATIONS AND PROCESS THEREOF
OMNIACTIVE HEALTH TECHNOLOGIES LTD., an Indian Company,
registered under the Indian Companies Act, 1956 having its registered office
located at Rajan House, Appasaheb Marathe Marg, Prabhadevi, Maharashtra,
India 400025
The following specification particularly describes the invention and the manner in
which it is to be performed

Field of the invention:
The present invention generally relates to a rapidly dispersible and stable xanthophylls
formulation and a process for its preparation. More particularly, the present invention
provides rapidly dispersible and stable vegetarian xanthophyll formulations,
standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-
cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients,
which are resistant to oxidation and are highly soluble in hydrophilic media. The
formulations are suitable for direct application as colorants/additives in the i
pharmaceutical, food and cosmetics fields and as dietary supplements for the wellbeing of healthy population in significantly cost-effective manner.
Background of the invention
Xanthophylls are yellow pigments that form one of the two major divisions of the carotenoid group. Their molecular structure is similar to carotenes, which form another major group of carotenoids. Xanthophylls contain oxygen atoms, while carotenes are purely hydrocarbons with no oxygen atom. Xanthophylls contain their oxygen either as hydroxyl groups and/or as pairs of hydrogen atoms that are substituted by oxygen atoms acting as a bridge (epoxide). For these reasons, they are more polar than the hydrocarbon carotenes. Typically, xanthophylls are less orange in color than carotenes (Ison JA. Vitamin A. In: Machlin L J (Ed.), Handbook of vitamins (1st ed.) pp. 1-43. New York: Dekker, 1984). The xanthophylls, viz: lutein, zeaxanthin, astaxanthin, canthaxanthin, neoxanthin, violaxanthin, and , α- and β-cryptoxanthin are water insoluble and waxy in nature compounds. To prepare composition of these ingredients, organic solvents and/or oils such as vegetable oils are used to dissolve the waxy materials during processing.

Xanthophylls are powerful antioxidants which protects body cells from free radicals. Free radicals are harmful substances that get released into the body cells during oxygen based reactions. Research data suggests that they can cause cancer, diabetes, premature ageing and a weak immune system. By consuming plenty of xanthophylls one can keep body cells safe from free radicals. Cryptoxanthin can be used by the body to create vitamin A which helps in maintaining healthy vision and much more (Anumihardjo SA, Binkley N. Carotenoids and bone health. In: Carotenoids and Human Health, Chapter 14, Tanumihardjo SA Ed., 2012).
Xanthophylls nutrients are typically used as ingredients for nutritional supplement formulations either as dispersion in oil or as powders, granules or beadlets for making tablets or hard gelatin capsules. In the form of oil dispersion, these nutrients are generally encapsulated in soft gelatin capsules. Some of these, such as carotenoids are also manufactured as beadlets for use in fruit juices and other aqueous beverages. Many nutritional formulations in the industry are in the form of tablets, capsules and/or blend of dry nutrients. At present there are a few compositions of xanthophylls in the market in the form of beadlets or powder. These beadlets or powders are generally manufactured by using either organic solvents and/or vegetable oils.
Some of the major challenges in preparing xanthophylls and/or lipophilic nutrients compositions and the available marketed products are explained below:
a. Xanthophylls tend to be unstable at room temperature, and are prone to degradation on exposure to light, heat, air and acidic environment. Their life needs to be extended by the use of stabilizing anti-oxidants.
Another option of stabilizing xanthophylls is by delivering the same in an oily medium to provide a protective coating of the oils. But the dry delivery forms of such oil protected xanthophylls are more difficult to stabilize.

b. Xanthophylls such as free lutein, lutein ester, zeaxanthin, astaxanthin,
canthaxanthin, neoxanthin, violaxanthin, and , α- and β-cryptoxanthin contain at
least 15% waxy materials in the form of fatty acids. These waxy xanthophylls
are not readily dispersible in aqueous media. To overcome this difficulty,
manufacturers of water dispersible formulations prepare a colloidal emulsion
by either dissolving these waxy xanthophylls in organic solvents such as
ethanol, isopropyl alcohol, acetone, ethyl acetate etc. or in vegetable oils.
Dissolving xanthophylls in oily medium is a very expensive and complicated process. Also, the vegetable oils used in dissolving such waxy xanthophylls are associated with unpleasant odour due to its susceptible to rancidification during shelf-life.
c. A sports person is required to have a nutritional drink during the exercise or
competition. Stick packs are the perfect solution for single serve packaging of
energy drink mix. The currently marketed products cannot be rapidly dispersed
homogeneously within a minute without stirring or turbulence causing
inconvenience to the sports person who is required to have a nutritional drink
before he goes for the competition.
Prior Art:
In view of the increasing research interest in the various health benefits of xanthophylls as can be seen above, there have been several approaches to commercially produce the xanthophylls formulation. The important and relevant methods are discussed below:
At present the beadlets/pellets of xanthophylls and other lipophilic nutrients are typically manufactured by fluid bed coating or spray drying a mixture of said active nutrients and gelatin along with sucrose, and stabilizers. In such developed formulations the xanthophylls are embedded in the matrix formed by gelatin and sucrose and are thus

protected from the light and oxygen. The spray dried product is made less cohesive by covering with starch.
Some of the disadvantages associated with the gelatin/starch based formulations are listed below:
a. The particles of xanthophylls at the surface of the said beadlets/pellets are unprotected
and are therefore exposed to the harmful effects of light and air. Consequently it leads
to degradation resulting in the loss of their biological activity.
b. When such beadlets/pellets are compressed into tablets, the particles tend to disintegrate
and the xanthophylls are squeezed out of the polymer matrix into the matrix of tablets
where these xanthophylls get exposed to the incompatible environment. The
carotenoids/xanthophylls may undergo undesirable chemical reaction with excipients of
tablets or the other ingredients present therein. Consequently they undergo degradation
resulting in the loss of their biological activity.
c. During the preparation of these formulations, the xanthophylls are suspended in molten
mass of polymers (i.e. gelatin) at a temperature above 50°C. At this temperature a
significant portion of active may get destabilized thereby resulting in loss of their
biological activity.
d. The particles of xanthophylls are embedded in highly viscous gelatin-sucrose matrix.
Upon oral administration of the developed formulation, the xanthophylls get released in
the gastro-intestinal-tract from these formulations, in a slow and erratic fashion.
Consequently, the bioavailability of the xanthophylls is significantly reduced.
Under the above mentioned circumstances, there is a need to prepare waxy xanthophylls formulation which is free of organic solvents as well as vegetable oils and is resistant to oxidation for prolonged periods during storage and at the same time, it is rapidly dispersible in hydrophilic media, permitting its use into conventional compressed tablets, oro-dispersible tablets, hard gelatin capsules or/and dry blend/premix for beverage applications. Also, there is a need to prepare xanthophylls formulation without

using any animal-derived ingredients such as gelatin and hence free of the safety concerns surrounding animal derived ingredients.
Numerous mechanisms have been employed to prepare water dispersible xanthophylls formulation some of which are listed below:
One of the main difficulties in using the carotenoids as colorants is their very low solubility in water. US3998753 demonstrates solubilization of carotenoids by preparing solutions of carotenoids in volatile organic solvents, such as halogenated hydrocarbons, and further emulsifying them with an aqueous solution of sodium lauryl sulfate. The main disadvantage of this process is that it makes use of harsh organic solvents, which has effect on healthy human beings in the long term use.
US5364563 describes a method of producing colloid-dispersed carotenoids in powder form, which involves forming a suspension of carotenoids in high boiling point oil. The suspension is superheated with steam for a maximum period of 30 seconds to form a solution of carotenoids in oil Further, this solution is emulsified with an aqueous solution of colloid and then the emulsion is spray dried. The disadvantage of this process is the use of high boiling point vegetable oils which give unpleasant odour during shelf life due to rancidification of the oil in presence of oxygen.
Various processes for the manufacture of water-dispersible carotenoid compositions are already known from the literature, but these are all associated with certain disadvantages. Thus, for example, DE1211911 describes manufacturing carotenoid compositions by dissolving a carotenoid, emulsifying the resulting solution into an aqueous solution of a protective colloid and subsequently removing the solvent from this emulsion. The disadvantage of this process resides in the fact that chlorinated hydrocarbons are preferably used as the solvent and their removal creates an environmental burden which makes the process extremely expensive from a commercial point of view.

EP65193 describes a method of manufacturing carotenoid compositions by dissolving a carotenoid in a non-chlorinated volatile water-miscible organic solvent at temperatures between 50°C and 200°C within a period of less than 10 seconds, precipitating the carotenoid in colloid-dispersed form from the solution obtained by mixing with a solution of a colloid and subsequently removing the solvent. Here also an organic solvent must therefore be removed, which again is expensive on an industrial scale.
Alternatives to the use of organic solvents are well known. For example, US5460823 describes a process for milling of the carotenoid crystal in an aqueous medium. However, while the stability of the resultant powders are good, their tinctorial power in aqueous solutions and thus their bioavailability, are poor due to the coarse size of the carotenoid particle relative to that obtained with sub-micron-emulsion techniques. Other methods, for example US2861891 include the use of solubilizing oils to effect the desired particle size reduction. The use of the solubilizing oils is limited where, for example, there are concerns about the healthiness of the various oils, and where the manufacture of higher potency powders is desired, due to the limited solubility of the carotenoids, even when the oils are rendered supersaturated with carotenoid at elevated temperature.
EP0807431 describes a process for the manufacture of colloid-dispersed carotenoid compositions. In the disclosed method, an aqueous suspension of the carotenoid is heated to melt at higher temperature, and then homogenized under pressure to form an emulsion, and the resulting emulsion is dried to obtain the carotenoid powder. The said process preferably makes use of compounds of animal origin (i.e. Gelatin) for matrixing. Also, the product contains synthetic preservatives. Moreover this process of drug dispersion is complicated and costly, which involves several steps.
Broadly, state-of-the-art does not disclose vegetarian xanthophylls formulation without using harsh organic solvents and/or vegetable oils and which are resistant to oxidation

for prolonged periods during storage. Also, none of the prior art provides a rapidly dispersible formulation which is dispersed in hydrophilic media within a minute without any stirring or turbulence required, permitting their use for subsequent formulation into conventional compressed tablets, oro-dispersible tablets, hard gelatin capsules or/and dry blend/premix for beverage applications.
Based on the above needs and during experimentation it was surprisingly found that when xanthophylls along with other food grade excipients like hydrophilic carriers, surfactant and antioxidants are dispersed in the aqueous media in specific concentration, forms a colloidal dispersion. Xanthophylls alone are devoid of wettability in aqueous media. During experimentation it was found that by using specific surfactant system the solubility/dispersibility of xanthophylls can be increased in the aqueous media. Moreover, the hydrophilic carrier used in the present invention is solubilized as soon as it comes in contact with the aqueous media forming pores and channels in the granules or powder allowing water to easily penetrate and disperse the formulation, rapidly within a minute.
By using conventional homogenizer a homogeneous colloidal dispersion is formed which is spray dried to get uniform size, free flowing granules and/or powder. Optionally, the said colloidal dispersion containing xanthophylls is sprayed on the inert carriers by using fluid bed system with top/tangential or bottom spray technique to form uniform size, free flowing granules. The inert carriers can also be granulated using homogenous colloidal dispersion by high shear granulator.
The granules and/or powders prepared by using above mentioned processes were found to be rapidly dispersible in cold water by forming a homogeneous dispersion within a minute without the aid of stirring or turbulence. The said granules and/or powder were also found to be stable when subjected to accelerated stability studies as per 1CH conditions of 40°C/75% RH. The said processes make use of temperature in the range

of 30-70°C, thereby ensuring prevention of degradation of nutrients due to high processing temperature.
Objectives of the present invention
The main objective of the present invention is to provide rapidly dispersible and stable vegetarian formulation of xanthophylls nutrients by using aqueous media as processing aid in combination with other excipients.
Another objective of the present invention is to provide rapidly dispersible and stable composition of waxy xanthophylls nutrients, standardized in the form of free Lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients.
Yet another objective of the present invention is to provide stable vegetarian xanthophylls formulation which is homogenously dispersed in water within a minute without the aid of stirring or turbulence.
Yet another objective of the present invention is to provide rapidly dispersible and stable vegetarian formulation of xanthophylls nutrients having the particle size in the range of 10-300 microns for powder and 300-1200 microns for granules.
Still another objective of the present invention is to provide rapidly dispersible and stable vegetarian granules and/or powder of xanthophylls nutrients which are sufficiently free flowing for compression into conventional and oro-dispersible tablets, can be filled into hard gelatin capsules or blend as dry premix for beverage applications.

Still another objective of the present invention is to provide rapidly dispersible and stable vegetarian formulation of xanthophylls nutrients which are free from ingredients of animal origin such as gelatin or lactose.
Yet another objective of the present invention is to provide a process for the preparation of said rapidly dispersible and stable vegetarian granules and/or powder of xanthophylls nutrients by employing fluid bed system with top/tangential or bottom spray technique or by spray drying using low temperature in the range of 30-70°C, thereby ensuring prevention of degradation of nutrients due to high processing temperature.
Further object of the present invention is to provide a stable, cheaper and cost-effective formulation of xanthophylls using excipients having E-number/ generally recognized as safe (GRAS) status that ensures safety of human beings for long term administration.
Another objective of the present invention is to provide rapidly dispersible and stable vegetarian formulation of xanthophylls which is adequately protected from degradation by oxygen, light, moisture and acidic environment.
Further objects and advantages of the invention will become apparent from a consideration of the ensuing description.
Summary of the invention
The product and the process of the present invention is described herein below which is illustrative as shown in the examples and should not be construed to limit the scope of the present invention in any manner whatsoever.
Accordingly, the present invention provides rapidly dispersible and stable vegetarian xanthophylls formulations standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or β-cryptoxanthin or in combination

with other lipophilic nutrients by using aqueous media as a processing aid in combination with other excipients. The said xanthophylls formulations are resistant to oxidation and rapidly disperse in hydrophilic media within a minute by forming a homogenous dispersion. The free flowing nature of the granules and/or powder allows it to be compressed into conventional and oro-dispersible tablets, to be filled into hard gelatin capsules or blend as dry premix for beverage applications.
The present invention also provides a process for the preparation of the said rapidly dispersible and stable vegetarian xanthophylls formulations by employing fluid bed system with top/tangential or bottom spray technique or by spray drying using low temperature in the range of 30-70°C, thereby ensuring prevention of degradation of nutrients due to high processing temperature.
Detailed description of the invention:
According to the present invention, rapidly dispersible and stable vegetarian xanthophylls formulations are prepared which are suitable for further formulation to conventional as well as oro-dispersible tablets, to be filled into hard gelatin capsules and/or blend/dry premix for beverage applications.
The details of the invention are as set forth.
The present invention provides rapidly dispersible and stable vegetarian xanthophylls formulation which comprises:
a. xanthophylls;
b. surfactant and/or emulsifier;
c. at least one antioxidant;
d. at least one hydrophilic carrier; and
e. optionally an inert carrier.

The said formulation is in the form of free flowing granules and/or powder and can be compressed into conventional and oro-dispersible tablets, or filled into hard gelatin capsules or blend as dry premix for beverage applications.
The xanthophylls are standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or (3-cryptoxanthin, preferably lutein or in combination with other lipophilic nutrients.
Xanthophylls used are in the range of 5-11% w/w of the formulation.
The surfactants and/or emulsifiers used are selected from sodium lauryl sulfate, tween 80, docusate sodium or mixture thereof
The said surfactants and/or emulsifiers are used in the range of 4-9% by weight of the formulation.
The antioxidants used are selected from vitamin E acetate, natural tocopherols, ascorbyl palmitate, ascorbic acid, sodium ascorbate, citric acid, rosemary extract or rosemary oil, curcuminoids, green tea extract, ginger extract, carnosic acid, butylated hydroxy anisole, butylated hydroxy toluene, sorbic acid, sodium benzoate, sodium salicylate, EDTA or mixture thereof.
The said antioxidants used are in the range of 2-10% by weight of the formulation.
The hydrophilic carriers used are selected from hydroxy propyl cellulose, hydroxy propyl methyl cellulose, polyvinyl pyrollidone, carboxymethyl cellulose or mixture thereof.

The said hydrophilic carriers used are in the range of 20-60% by weight of the formulation.
The inert carriers used for loading colloidal dispersion of xanthophylls are selected from monosaccharide, polysaccharides, starches, modified starches, sorbitol, mannitol, maltodextrin or mixture thereof.
The said inert carriers used are in the range of 40-60% by weight of the formulation.
The present invention also provides a process for the preparation of rapidly dispersible and stable vegetarian xanthophylls formulations which comprises:
a. preparing a colloidal dispersion by dissolving in aqueous system hydrophilic
carriers, surfactants and/or emulsifier and xanthophylls in a continuous manner;
b. mixing the stabilizing antioxidants with the colloidal dispersion of step (a);
c. passing the said colloidal dispersion of step (b) through colloid mill to get a
homogenous colloidal dispersion;
d. spray drying the homogenous colloidal dispersion prepared in step (c) at the
temperature of 30-70°C, preferably 45-60DC, at an atomization pressure in the
range of 1.0-3.0 kg/cm2 to form powder of 10-300 microns particle size.
e. optionally, spraying the homogenous colloidal dispersion of step (c) on the inert
carrier by using fluid bed system with top/tangential or bottom spray technique, at
the temperature in the range of 30-70°C and an atomization pressure in the range of
0.5-2.0 kg/cm to obtain granules of 300-1200 microns particle size.
f. further, passing the granules obtained in step (e) through the vibro-sifter fitted
with 30 mesh ASTM and the same procedure is repeated by using vibro-sifter fitted
with 60 mesh ASTM to remove the fines and collect the 30/60 fraction.
g. optionally, granulating inert carriers using the homogenous colloidal dispersion
of step (c) by high shear granulator.

The following examples are given by the way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.
I) Method of manufacturing powder by Spray drying technique:
A colloidal dispersion of xanthophylls was formed by dissolving required quantities of tween 80, docusate sodium, disodium EDTA, and sodium ascorbate in required quantity of water. Polyvinylpyrrolidone K-30 followed by Sodium lauryl sulphate was added and dissolved under stirring. Xanthophylls, standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients were dispersed under stirring. Further, mixed tocopherol (70%w/w), rosemary oil extract (10%w/w) were added under stirring. Cross povidone (Kollidon CL-SF) and sodium starch glycolate were dispersed in the colloidal dispersion. The said colloidal dispersion was homogenized using colloidal mill and was passed through sieve #80 ASTM. The homogenized colloidal dispersion of xanthophylls was spray dried under optimized parameters using advance spray-dryer Lab-Ultima Model LU 227. The powder was sifted through sieve #60 ASTM. The sifted powder was further blended with aerosil 200.
Following tables represent different compositions of rapidly dispersible xanthophylls formulation prepared by the above given process.
Example 1

Sr.No. Ingredient Composition 1 Composition 2 Composition 3
1 High Purity Marigold Extract (Lutein 72%w/w) 9.31 9.31 9.31
2 Mixed Tocopherol
(70%w/w) 3.40 3.40 3.40
3 Sodium Ascorbate 1.14 1.14 1.14
4 Di sodium EDTA 0.10 0.10 0.10

5
Rosemary extract (10%w/w) 0.10 0.10 0.10
6 Tween-80 1.64 1.64 -
7 Polyvinylpyrrolidone K-30 65.61 65.61 67,25
8 Cross povidone (Kollidon CL-SF) 6.00 6.00 6.00
9 Sodium Starch Glycolate 7.50 9.00 7.50
10 Sodium Lauryl Sulphate 3.00 1.50 2.00
11 Docusate sodium 1.50 1.50 2.50
12 Aerosil 200 0.20 0.20 0.20
13 Water 250 250 250
Example 2

Sr. No. Ingredient Composition 4 Composition 5 Composition 6
1 High Purity Marigold
Extract (Lutein Ester
66%w/w) 9.31 9.31 9.31
2 Mixed Tocopherol
(70%w/w) 3.40 3.40 3.40
3 Sodium Ascorbate 1.14 1.14 1.14
4 Di sodium EDTA 0.10 0.10 0.10
5 Rosemary extract (10%vv/w) 0.10 0.10 0.10
6 Tween-80 1.64 1.64 -
7 Polyvinyl pyroliidone
K-30 65.61 65.61 67.25
8 Crosspovidone (Kollidon 6.00 6.00 6.00

CL-SF)
9 Sodium Starch Glycolate 7.50 9.00 7.50
10 Sodium Lauryl Sulphate 3.00 1.50 2.00
11 Docusate sodium 1.50 1.50 2.50
12 Aerosil 200 0.20 0.20 0.20
13 Water 250 250 250
Example 3

Sr. No. Ingredient Composition 7 Composition 8 Composition 9
1 High Purity Marigold
Extract (Lutein
63%:Zeaxanthin
13%w/w) 9.31 9.31 9.31
2 Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
3 Sodium Ascorbate 1.14 1.14 1.14
4 Di sodium EDTA 0.10 0.10 0.10
5 Rosemary extract (10%w/w) 0.10 0.10 0.10
6 Tween-80 1.64 1.64 -
7 Polyvinyl pyrollidone K-30 65.61 65.61 67.25
8 Crosspovidone (Kollidon CL-SF) 6.00 6.00 6.00
9 Sodium Starch Glycolate 7.50 9.00 7.50
10 Sodium Lauryl Sulphate 3.00 1.50 2.00
11 Docusate sodium 1.50 1.50 2.50

12
Aerosil 200 0.20 0.20 0.20
13 Water 250 250 250
II) Method of loading active dispersion on inert carrier by fluid bed processor
A colloidal dispersion of xanthophylls was formed by dissolving required quantities of tween 80, docusate sodium, disodium EDTA, and sodium ascorbate in required quantity of water. Polyvinylpyrrolidone K-30 followed by Sodium lauryl sulphate was added and dissolved under stirring. Xanthophylls, standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or α-cryptoxanthin and/or β-cryptoxanthin or in combination with other lipophilic nutrients were dispersed under stirring. Further, mixed tocopherol (70%w/w), rosemary oil extract (10%w/w) were added under stirring in the colloidal dispersion. The said colloidal dispersion was homogenized using colloidal mill and was passed through sieve #80 ASTM. The homogenized colloidal dispersion was loaded on Pearlitol SD 200® using Pam Glatt's GPCG 1.1 with top/tangential spray provision and/or bottom spray provision. The dried granules were sifted through sieve #30 ASTM and then, fines were separated using sieve #60 ASTM to obtain required size granules (i.e. #30-60). Sifted granules were further blended with Aerosil 200.
Following tables represent different compositions of rapidly dispersible xanthophylls formulation prepared by the above given process.
Example 4

Sr. No. Ingredient Composition 10 Composition 11 Composition 12
1 High Purity Marigold Extract (Lutein 72%) 10 10 10
2 Mannitol (Pearlitol SD 200) 50 50 50

3
Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 , 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract (10%w/w) 0.10 0.10 0.10
7 Tween-80 1.64 1.64 -
10 Polyvinylpyrrolidone K-30 29.12 30.62 31.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00
12 Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 100 100 100
Example 5

Sr. No. Ingredient Composition 13 Composition 14 Composition 15
1 High Purity Marigold
Extract (Lutein Ester
66%) 10 10 10
2 Mannitol (Pearlitol SD 200) 50 50 50
3 Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract 0.10 0.10 0.10

(10%w/w)
7 Tween-80 1.64 1.64 -
10 PolyvinylpyrrolidoneK-30 29.12 30.62 31.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00
12 Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 100 100 100
Example 6

Sr. No. Ingredient Composition 16 Composition 17 Composition 18
1 High Purity Marigold Extract (Lutein 63%:Zeaxanthin
13%w/w) 10 10 10
2 Mannitol (Pearlitol SD 200) 50 50 50
3 Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract (10%w/w) 0.10 0.10 0.10
7 Tween-80 1.64 1.64 -
10 Polyvinylpyrrolidone K-30 29.12 30.62 31.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00

12
Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 100 100 100
III) Conventional granulation method by high shear granulator
A colloidal dispersion of xanthophylls was formed by dissolving required quantities of tween 80, docusate sodium, disodium EDTA, and sodium ascorbate in required quantity of water. Polyvinylpyrrolidone K-30 followed by Sodium lauryl sulphate was added and dissolved under stirring. Xanthophylls, standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or α-cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients were dispersed under stirring. Further, mixed tocopherol (70%w/w), rosemary oil extract (10%w/w) were added under stirring in the colloidal dispersion. The said colloidal dispersion was homogenized using colloidal mill and was passed through sieve #80 ASTM. Pearlitol SD 200® was loaded in high shear granulator (Kalweka HD-410AC) and granulated with said homogenous colloidal dispersion. The wet mass was sifted through sieve #10 ASTM and then dried for 5-10 minutes in hot air oven. Semi dried granules were sieved through #30 ASTM. Further, fines were separated below sieve #60 to obtain required size granules. The sifted granules (fraction #30-60) were blended with aerosil 200.
Following tables represent different compositions of rapidly dispersible xanthophylls formulation prepared by the above given process.
Example 7

Sr. No. Ingredient Composition 19 Composition 20 Composition 21
] High Purity Marigold Extract (Lutein 72%) 10 10 10
2 Mannitol(PearlitolSD200) 70 70 70

3
Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract (10%w/w) 0.10 0.10 0.10
7 Tween-80 1.64 1.64 -
10 Polyvinylpyrrolidone K30 9.12 9.12 11.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00
12 Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 50 50 50
Example 8

Sr.
No. Ingredient Composition 22 Composition 23 Composition 24
1 High Purity Marigold
Extract (Lutein Ester
66%) 10 10 10
2 Mannitol (Pearlitol SD 200) 70 70 70
3 Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract
(10%w/w) 0.10 0.10 0.10

7
Tween-80 1.64 1.64 -
10 Polyvinylpyrrolidone K-30 9.12 9.12 11.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00
12 Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 50 50 50
Example 9

Sr. No. Ingredient Composition 25 Composition 26 Composition 27
1 High Purity Marigold
Extract (Lutein
63%:Zeaxanthin
13%w/w) 10 10 10
2 Mannitol (Pearlitol SD 200) 70 70 70
3 Mixed Tocopherol (70%w/w) 3.40 3.40 3.40
4 Sodium Ascorbate 1.14 1.14 1.14
5 Di sodium EDTA 0.10 0.10 0.10
6 Rosemary extract (10%w/w) 0.10 0.10 0.10
7 Tween-80 1.64 1.64 -
10 Polyvinylpyrrolidone K-30 9.12 9.12 11.62
11 Sodium Lauryl Sulphate 3.00 1.50 2.00

12
Docusate sodium 1.50 1.50 -
13 Aerosil 200 0.20 0.20 0.20
14 Water 50 50 50
Manufacturing procedure of oro-dispersible tablets:
The oro-dispersible tablets were prepared by following procedure:
a) cold water dispersible granules and/or powder of xanthophylls nutrients, standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients was prepared by one of the above mentioned three methods.
b) further diluents, disintegrants, flavoring agent and sweetener were homogeneously mixed together in powder form. Lubricants were added to the said mixture.
c) the said powder mixture was then fed to the die of a tablet press (Rimek Minipress-II MT) and sufficient pressure was applied to form the solid tablet. The pressure used can vary, and typically ranges about 20-60N, preferably 30-50N.
The oro-dispersible tablets comprise at least 50% by weight of diluents, selected from the group of saccharide such as monosaccharide, oligosaccharides or polysaccharides, and/or their oxidized and/or reduced forms; ribose, lactose in its various forms, anhydrous, monohydrate, agglomerated forms or atomized forms; sugar alcohols such as mannitol, maltol, sorbitol, maltitol etc.
The disintegrants used are in the range of 10-20% by weight of the formulation and are selected from the group of natural starches, such as maize starch and/or potato starch; directly compressible starch such as starch 1500; modified or pregelatinized starch, such as carboxymethyl starch and sodium starch glycolate; natural or chemically-modified cellulose, especially cross linked sodium carboxymethyl cellulose (croscarmellose sodium) or low substituted hydroxypropyl cellulose; microcrystalline cellulose; gum,

especially agar gum, and guar gum; alginic acid or salts thereof; acetates and citrates: sugars (especially lactose, mannitol and sorbitol); aluminum oxide; synthetic polymers such as cross-linked polyvinylpyrrolidone, preferably cross povidone.
The sweetener used is in the range of 0.5 to 3% by weight of the formulation and is selected from the group of aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, sucrose, fructose, monoarnmoniurn glycyrrhizinate, and mixtures thereof.
The flavoring agents used are in the range of 0.5 to 2% by weight of the formulation and are selected from the group of strawberry, cherry, orange, peppermint, black currant, banana, raspberry, red fruits, wild berries and caramel flavor.
The lubricant used is in the range of 0.2 to 2% by weight of the formulation and is selected from the group of sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid and glyceryl monostearate, preferably sodium stearyl fumarate or magnesium stearate or mixture thereof.
Following tables represent different compositions of oro-dispersible tablets prepared by the above given process.
Example 10

Sr. No. Ingredient % (w/w)

Composition 28 Composition 29 Composition 30
1 Lutein 5%w/w CWD powder or Granules 20 20 20
2 Mannitol (Pearlitol SD 200) 55 40 55
3 Cross povidone 5 10 7.5

4 Sodium starch glycolate 10 5 7.5
5 Microcrystalline cellulose (ComprecelPH 102) 7.4 7.4 7.4
6 Aspartame 1 1 1
7 Mint flavor 0.8 0.8 0.8
8 Magnesium stearate 0.8 0.8 0.8
Total weight of tablet (mg) 120 120 120
Hardness (N) 45 42 40
Thickness (mm) 2.1 2.0 2.0
Friability (%) 0.24 0.29 0.15
Disintegration Time (Seconds) 21 24 22
Example 11

Sr. No. Ingredient % (w/w)

Composition 31 Composition 32 Composition 33
1 Lutein Ester 5% w/w CWD powder or granules 20 20 20
2 Mannitol (Pearlitol SD 200) 55 40 55
3 Crosspovidone 5 10 7.5
4 Sodium starch glycolate 10 5 7.5
5 Microcrystalline cellulose (ComprecelPH 102) 7.4 7.4 7.4
6 Aspartame 1 1 1
7 Mint flavor 0.8 0.8 0.8
8 Magnesium stearate 0.8 0.8 0.8

Total weight of tablet (mg)
120 120 120
Hardness (N) 45 42 40
Thickness (mm) 2.1 2.0 2.0
Friability (%) 0.35 0.29 0.25
Disintegration Time (Seconds) 31 33 32
Example 12

Sr. No. Ingredient % (w/w)

Composition 34 Composition 35 Composition 36
1 Lutein & Zeaxanthin (5:1) 5% w/w CWD powder or granules 20 20 20
2 Mannitol(PaerlitolSD200) 55 40 55
3 Crosspovidone 5 10 7.5
4 Sodium starch glycolate 10 5 7.5
5 Microcrystalline cellulose (ComprecelPH102) 7.4 7.4 7.4
6 Aspartame 1 1 1
7 Mint flavor 0.8 0.8 0.8
8 Magnesium stearate 0.8 0.8 0.8
Total weight of tablet (mg) 120 120 120
Hardness (N) 46 42 43
Thickness (mm) 2.1 2.0 2,1
Friability (%) 0.42 0.49 0.36
Disintegration Time (Seconds) 21 25 24

Stability data
Accelerated stability studies were performed to establish the intrinsic stability of rapidly dispersible vegetarian granules and/or powder of xanthophylls nutrients and to help predict what can be expected during the long term stability study at controlled room temperature. Rapidly dispersible vegetarian granules and/or powder of xanthophylls nutrients and the oro-dispersible tablets of the said granules and/or powder were charged for stability studies at 40 ±2°C /75±5% RH for 3 months period. In this study the composition was analyzed at the period of 1, 2, and 3 months for various parameters, such as assay, disintegration time and physical appearance/observation of the composition. Stability data for some of the above given compositions is given below:
Tablel: Stability data of vegetarian granules and/or powder of Xanthophylls nutrients

Batch Initial 1 Month
(40±2°C/75±5%RH) 2 Month
(40 ±2°C /75±5%RH) 3 Month
(40 ±2°C /75±5%RH)
Assay
(%) Physical
appeara
nee Assay
(%) Physical
appeara
nee Assay
(%) Physical
appearan
ce Assay (%) Physical appearance
Composition 1 99.98 * 99.32 * 96.54 * 96.12 *
Composition 4 99.68 * 99.10 * 98.23 * 98.00 *
Composition 8 99.85 * 98.09 * 96.98 * 95.24 ;£
Composition 10 99.97 * 99.22 * 98.56 * 98.04

Composition 13 101.02 * 99.56 * 98.28 * 98.21 *
Composition 16 99.36 * 98.95 * 96.84 * 96.12 *
Composition 19 100.68 * 100 * 98.29 * 98.06 *
Composition 22 99.98 * 99.52 * 96.75 * 96.16 *
Composition 26 99.25 * 98.88 * 97.24 * 95.01 *
* Free flowing, reddish orange powder/granules Table 2: Stability data for oro-dispersible tablets of xanthophylls nutrients

Batch Initial 1 Month 2 Month 3 Month
Assay DT
(Seconds) Physical appearance Assay
(%) DT
(Seconds) Physical
appeara
nee Assay (%)' DT
(Seconds) Physical
appeara
nee Assay
(%) DT (Seconds) Physic
al appeal
Composition 28 99.89 21 ** 99.01 21 ** 98.67 22 ** 98.55 23 **
Composition 29 99.70 24 ** 98.32 24 ** 98.25 25 ** 98.14 25 **
Composition 31 99.87 31 ** 99.23 31 ** 99.14 31 ** 99.00 32 **
Composition 34 99.65 21 ** 98.46 22 ** 97.28 23 ** 97.05 24 **
Composition
35 99.28 25 ** 99.17 23 ** 99.09 23 ** 99.04 23 **
*Reddish orange colored round biconcave tablet plain on both sides.
Results of stability studies:
There was no significant change in the assay and the physical appearance during the 3 months accelerated stability study of the vegetarian granules and/or powder of

xanthophylls nutrients. This indicates that the formulation will have shelf-life of at least 18 months. Overages can be added in the formulation to compensate the reduction in the assay during the shelf-life.
There is no significant change in the assay and disintegration time (DT) during the 3 months accelerated stability study of the oro-dispersible tablets. This indicates that the formulation will have shelf-life of at least 18 months.
Dispersibility data
Rapidly dispersible vegetarian granules and/or powder of xanthophylls nutrients were studied for dispersibility. In this study 4mg of the composition was dispersed in 240ml of water. Dispersibility data for the above given compositions in the form of granules and powder is given below:

Composition Dispersibility Time (seconds) Bulk density (g/cc)
Composition 1 36 0.4
Composition 2 29 0.4
Composition 3 42 0.38
Composition 4 38 0.39
Composition 5 39 0.4
Composition 6 44 0.41
Composition 7 40 0.37
Composition 8 44 0.33
Composition 9 48 0.38
Composition 10 39 0.39
Composition 11 42 0.41
Composition 12 44 0.39
Composition 13 40 0.38
Composition 14 40 0.36
Composition 15 42 0.35
Composition 16 39 0.35
Composition 17 44 0.35
Composition 18 42 0.3
Composition 19 45 0.42
Composition 20 44 0.41

Composition 21 38 0.44
Composition 22 35 0.39
Composition 23 33 0.44
Composition 24 39 0.4
Composition 25 41 0.38
Composition 26 46 0.39
Composition 27 45 0.39
Comparative dispersibility data:
The dispersibility of the instant rapidly dispersible and stable vegetarian xanthophylls nutrients formulation was compared with one of the marketed product. It was observed that the vegetarian granules and/or powder of the present invention rapidly dispersed within a minute without the aid of stirring or turbulence. Whereas, the marketed lutein beadlets settled down and required stirring to disperse homogeneously in water. Thus, the formulation of the present invention has an advantage over the products available in the market.
Advantages of the present invention
The present invention provides rapidly dispersible and stable vegetarian formulations of xanthophylls nutrients without using organic solvents or vegetable oils in the process.
The xanthophylls nutrients are standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or p-cryptoxanthin or in combination with other lipophilic nutrients.
The present invention provides stable vegetarian xanthophylls formulations which are homogenously dispersed in water within a minute without the aid of stirring or turbulence.
The powder and granules obtained in the present invention have the particle size in the range of 10-300 microns and 300-1200 microns, respectively.

The said formulations are sufficiently free flowing for compression into conventional and oro-dispersible tablets, can be filled into hard gelatin capsules or blend as dry premix for beverage applications.
The present invention also provides rapidly dispersible and stable xanthophylls formulations which are free from ingredients of animal origin such as gelatin or lactose.
The present invention also provides a process for the preparation of said rapidly dispersible and stable vegetarian granules and/or powder of xanthophylls nutrients, by employing fluid bed system with top/tangential or bottom spray technique or by spray drying using low temperature in the range of 30-70°C, thereby ensuring prevention of degradation of nutrients due to high processing temperature.
The present invention provides a stable, cheaper and cost-effective formulation of xanthophylls using excipients having E-number/ GRAS status that ensures safety of human beings for long term administration.
The said rapidly dispersible xanthophylls formulation is adequately protected from degradation by oxygen, light, moisture and acidic environment.

We claim
1. A rapidly dispersible and stable vegetarian xanthophylls formulation which comprises:
a. xanthophylls;
b. surfactant and/or emulsifier;
c. at least one antioxidant;
d. at least one hydrophilic carrier; and
e. optionally an inert carrier.
2. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1,
wherein the said formulation is in the form of free flowing granules and/or powder and
can be compressed into conventional and oro-dispersible tablets, or filled into hard
gelatin capsules or blend as dry premix for beverage applications.
3. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim \, wherein the said xanthophylls are standardized in the form of free lutein and/or zeaxanthin and/or neoxanthin and/or a-cryptoxanthin and/or p-cryptoxanthin, preferably lutein or in combination with other lipophilic nutrients.
4. The rapidly dispersible and stable vegetarian xanthophylls formulation of claims 1 or 3, wherein the said xanthophylls are used in the range of 5-11% w/w of the formulation.
5. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1, wherein the surfactants and/or emulsifiers used are selected from sodium lauryl sulfate, tween 80, docusate sodium or mixture thereof.
6. The rapidly dispersible and stable vegetarian xanthophylls formulation of claims 1 or 5, wherein the said surfactants and/or emulsifiers are used in the range of 4-9% by weight of the formulation.

7. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1, wherein the antioxidants used are selected from vitamin E acetate, natural tocopherols, ascorbyl palrnitate, ascorbic acid, sodium ascorbate, citric acid, rosemary extract or rosemary oil, curcuminoids, green tea extract, ginger extract, carnosic acid, butylated hydroxy anisole, butylated hydroxy toluene, sorbic acid, sodium benzoate, sodium salicylate, EDTA or mixture thereof.
8. The rapidly dispersible and stable vegetarian xanthophylls formulation of claims 1 or 7, wherein the said antioxidants are used in the range of 2-10% by weight of the formulation.
9.The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1, wherein the hydrophilic carriers used are selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, starch, starch derivatives or mixture thereof.
10. The rapidly dispersible and stable vegetarian xanthophylls formulation of claims 1 or 9, wherein the said hydrophilic carriers are used in the range of 20-60% by weight of the formulation.
11. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1, wherein the inert carriers used are selected from monosaccharide, polysaccharides, starches, modified starches, sorbitol, mannitol, maltodextrin or mixture thereof.
12. The rapidly dispersible and stable vegetarian xanthophylls formulation of claims 1 or 11. wherein the said inert carriers are used in the range of 40-60% by weight of the formulation.

13. The rapidly dispersible and stable vegetarian xanthophylls formulation of claim 1, wherein the said formulation is homogenously dispersible in water in less than 60 seconds.
14. A process for the preparation of rapidly dispersible and stable vegetarian xanthophylls formulation which comprises:
a. preparing a colloidal dispersion by dissolving in aqueous system hydrophilic
carriers, surfactants and/or emulsifiers and xanthophylls in a continuous manner in
the aqueous system;
b. mixing the stabilizing antioxidants with the colloidal dispersion of step (a);
c. passing the said colloidal dispersion of step (b) through colloid mill to get a
homogenous colloidal dispersion;
d. spray drying the homogenous colloidal dispersion prepared in step (c) to obtain
powder;
e. optionally, spraying the homogenous colloidal dispersion of step (c) on the inert
carrier by using fluid bed system with top/tangential or bottom spray technique to
obtain granules;
f. further, passing the granules obtained in step (e) through the vibro-sifter fitted
with #30 mesh ASTM and the same procedure is repeated by using vibro-sifter
fitted with #60 mesh ASTM to remove the fines and collect the #30/60 fraction.
g. optionally, granulating inert carriers using the homogenous colloidal dispersion
of step (c) by high shear granulator.
15. The process for the preparation of rapidly dispersible and stable vegetarian xanthophylls
formulation as claimed in claim 13, wherein the xanthophylls, surfactants and/or
emulsifiers, antioxidants, hydrophilic carriers and inert carriers are as defined in the
preceding claims.

16. The process for the preparation of rapidly dispersible and stable vegetarian xanthophylls formulation as claimed in claim 13, wherein the particle size of the powder is in the range of 10-300 microns.
17. The process for the preparation of rapidly dispersible and stable vegetarian xanthophylls formulation as claimed in claim 13, wherein the particle size of the granules is in the range of 300-1200 microns.