Title of Invention	NOVEL TIMED-RELEASE MULTICAROTENOID COMPOSITION AND A PROCESS FOR ITS PREPARATION
Abstract	The present invention relates to novel timed-release multicarotenoid composition and a process for its preparation . More particularly, the present invention relates to novel timed-release composition of multi carotenoids such as lutein, zeaxanthin, lycopene and betacarotene and process for its preparation . The novel timed-release multicarotenoid composition of the present invention is useful for formulating compressed tablets, two-piece gelatin or vegetarian capsules. More particularly, the novel timed-release system for mixed carotenoids is useful as powerful antioxidant combination that promotes eye, prostrate, and skin health.

Title of Invention

NOVEL TIMED-RELEASE MULTICAROTENOID COMPOSITION AND A PROCESS FOR ITS PREPARATION

Abstract

The present invention relates to novel timed-release multicarotenoid composition and a process for its preparation . More particularly, the present invention relates to novel timed-release composition of multi carotenoids such as lutein, zeaxanthin, lycopene and betacarotene and process for its preparation . The novel timed-release multicarotenoid composition of the present invention is useful for formulating compressed tablets, two-piece gelatin or vegetarian capsules. More particularly, the novel timed-release system for mixed carotenoids is useful as powerful antioxidant combination that promotes eye, prostrate, and skin health.

Full Text	FORM 2 THE PATENTS ACT 70 (Act 39 of 70 ) PROVISIONAL SPECIFICATION (Section 10) NOVEL TIMED-RELEASE MULTICAROTENOID COMPOSITION AND A PROCESS FOR ITS PREPARATION. OMNIACTIVES HEALTH TECHNOLOGIES PVT LTD., an Indian Company , registered under the Indian company'sActl957having its registered office located at Rajan House . Appasaheb Marathe Marg, Prabhadevi, Maharashtra , India 400025 The following specification describes the nature of the invention INTRODUCTION: The present invention relates to novel timed-release multicarotenoid composition and a process for its preparation . More particularly, the present invention relates to novel timed-release composition of multi carotenoids such as lutein, zeaxanthin, lycopene and betacarotene and process for its preparation . The novel timed-release multicarotenoid composition of the present invention is useful for formulating compressed tablets, two-piece gelatin or vegetarian capsules. More particularly, the novel timed-release system for mixed carotenoids is useful as powerful antioxidant combination that promotes eye, prostrate, and skin health. PRIOR ART Carotenoids are yellow, red and orange pigments which are widely distributed in nature Although specific carotenoids have been identified in various fruits and vegetables, bird feathers, egg-yolk, poultry skin, crustaceans and macular eye region, they are especially abundant in marigold petals, corn and leafy vegetables. The correlation between dietary carotenoids and carotenoids found in human serum and plasma indicate that only selected groups of carotenoids make their way into the human blood stream to exert their effect. Carotenoids absorb light in the 400-500 nm region of the visible spectrum. This physical property imparts the characteristic yellow/red color to the pigments. Carotenoids contain a conjugated backbone composed of isoprene units, which are usually inverted at the center of the molecule, imparting symmetry. Changes in geometrical configuration about the double bonds result in the existence of many cis- and trans-isomers. Mammalian species do not synthesize carotenoids and therefore these have to be obtained from dietary sources such as fruits vegetables and egg yolks. In the recent years, carotenoids have been attributed several health benefits, which include prevention and or protection against serious health disorders. Carotenoids are non-polar compounds classified into two sub-classes, namely more polar compounds called xanthophylls or oxy-carotenoids and non-polar hydrocarbon carotenes like .beta.-carotene, lycopene, etc. Both the sub-classes have at least nine conjugated double bonds responsible for the characteristic colors of the carotenoids. Xanthophylls have ring structures at the end of the conjugated double bond chain with polar functions like hydroxyl or keto group. The examples for xanthophylls include lutein, zeaxanthin, capsanthin, canthaxanthin, .beta.-cryptoxanthin, astaxanthin, etc. As natural colorants and also for their role in human health, xanthophylls containing lutein and zeaxanthin have attracted the renewed attention of scientists and researchers in the biomedical, chemical and nutritional field in recent years. Individually, each carotenoid has been shown to provide specific health benefit. For example, lutein and zeaxanthin promote eye health. Beta carotene, being a precursor of Vitamin A, corrects the deficiency of the vitamin A, lycopene promotes prostrate health. There have been attempts to combine these useful carotenoids to have synergistic effect on health benefits. US patent no. 7,090,879 provides a infant formula containing a mixture of lutein, lycopene, and beta carotene in blend of proteins, lipids and carbohydrate. The main drawback of this invention is that all the carotenoids are released together in the body, wherein the carotenoids interact with each other and affect their complete absorption. US patent nos. 7056525, 6509029, and 6261598 describe preparation of different formulations of lutein, lycopene and beta carotene, such as emulsion, solubilizate, dry powder and oil suspension. The main disadvantage of such compositions is that all the three carotenoids are released together in the gastrointestinal tract, where they interact with each other and affect their absorption. US Patent application no.20070082044 teaches us about the synergistic effect of combination of lutein with lycopene and beta carotene. However, the disadvantage of such combination is that the interaction among the carotenoids that renders them less bioavailable. While technologies exist in the pharmaceutical and nutritional industries for providing combination of the carotenoid preparations, there are no techniques available for the prevention of interaction amongst the carotenoids such as lutein, lycopene and betacarotene that drastically affects the absorption of the carotenoids individually. No e prior art references deal with simple admixture of the carotenoids such as lutein, lycopene and beta carotene and delivering them either as emulsions or oil suspensions or powders. When such products are ingested, they compete with each other for micellization, a critical step prior to absorption. For example since beta carotene is absorbed faster, it reduces the absorption of lutein by 40%. Similarly, the absorption of lycopene is affected in the presence of beta carotene and lutein. Such is the position in other carotenoids Carotenoids are important natural products that are useful to the body in promoting eye health, prostrate health and prevention of free radicle damage. When administered individually, these carotenoids are absorbed adequately to provide the health benefits. However, when these carotenoids are administered together in combination, one of them such as beta carotene is absorbed well, whereas other two carotenoids such as lutein and lycopene as not absorbed completely. The carotenoids compete with each other during micellization with the limited quantity of bile salts available in the intestine. Carotenoids undergo a step of micellization before getting in to enterocytes during absorption. The critical step of micellization requires bile salts as an essential component. Since the concentration of bile salts is limited, those carotenoids which have higher affinity for micellization, will form micelles and get absorbed. Whereas the remaining carotenoids will be absorbed to the extent bile salts available in the intestine. The situation is similar when a high dose of any one of the carotenoid is administered. The absorption takes place to the extent of bile salts available in the intestine. OBJECTIVES OF THE PRESENT INVENTION : Therefore, the main objective of the present invention is to provide novel timed-release multi carotenoid composition in which the individual carotenoid is released at different time intervals, such that they do not compete with each other Another objective of the present invention is to provide novel timed-release multi carotenoid composition comprising lutein, lycopene and beta carotene , in which the individual carotenoid is released at different time intervals, such that they do not compete with each other Yet another objective of the present invention is to provide novel timed-release multi carotenoid composition in beadlet form which can be further formulated as compressed tablets or as capsules. Yet another objective of the present invention is to provide novel timed-release carotenoid composition in beadlet form wherein the release of individual carotenoid is such that there is no interaction of the individual carotenoid in the gastrointestinal tract. Still another objective of the present invention is to provide a process for the preparation of novel timed-release multi carotenoid composition in which the individual carotenoid is released at different time intervals, such that they do not compete with each other Yet another objective of the present invention is to provide a process for the preparation of novel timed-release multi carotenoid composition comprising lutein, lycopene and beta carotene , in which the individual carotenoid is released at different time intervals, such that they do not compete with each other The term " timed-release" used refers to a composition in which is the individual carotenoid is released at a specific time interval in the gastrointestinal tract. For example, the multicarotenoid composition of the present invention releases its bioactives only after 2 hrs. Hence it is referred to as a timed release composition . The present invention has been developed based our finding based on continuous R&D efforts, that a multicarotenoid composition can be developed from which the carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption. In other words , the carotenoids present in the composition are absorbed completely separately . Accordingly, the present invention provides a novel timed-release multicarotenoid composition in which the . carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption. The composition of the present invention may be in beadlet form or in tablet form. The composition of the present invention is also useful for the preparation of compressed tablets and for filling in to two-piece capsules. According to the present invention there is provided a process for the preparation of the novel timed-release multicarotenoid composition in which the . carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption, which comprises, (i) granulating the mixture of desired carotenoids with a mixture of a solution of a binder and a stabilizer in an organic solvent, (ii) coating the granules obtained in step (i) with an aqueous enteric coating polymer, (iii) coating product obtained in step (ii) with a bioenhancer in an organic solvent, (iv) coating the granules obtained in step (iii)) with an inert barrier coat and (v) coating the granules obtained in step in step (iv)) with beta carotene suspension , if desired (vi) forming free flowing beadlets of the granules obtained in step (v), (vii) drying the resultant beadlets obtained in step(v)) at temperature not exceeding 45 deg C. The multi carotenoidsn which can be used in the present invention includes lutein and zeaxanthin in both free and esterified form, cis and trans lycopene, alpha and beta carotene, canthaxanthin, astaxanthin and violaxanthin The binder used for granulating may be selected from hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch, methyl cellulose, gum Arabic and gelatin. In another preferred embodiment the solvent employed may be selected from Acetone, Hexane, Ethyl Acetate, Isopropyl Alcohol, Ethanol, Dichloromethane, Methanol, etc, ,more preferably form Acetone, Ethanol, Dichloromethane, Isopropyl alcohol, and more preferably Dichloro Methane and Isopropyl Alcohol and mixtures thereof. The stabilizer used in the process may be selected from ascorbic acid, BHA, BHT, ascorbyl palmitate, mixed natural tocopherols, alpha tocopheryl acetate, sodium ascorbate and mixtures thereof: The enteric coating polymer used may be selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate and polymethacrylic acid ethyl methacrylate, shellac, and shein. The inert barrier coat used in the process may be selected from hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch, methyl cellulose, ethyl cellulose, gum arabic , gelatin, and mixtures thereof: The bioenhancer used in the process may be selected from bile salts, sodium lauryl sulfate, citric acid, polysorbate 20, polysorbate 40, polysorbate 80, and mixtures thereof: The coating process may be performed using fluid bed coater, coating pan, air suspension coating or combination thereof: ADVANTAGES OF THE INVENTION 1. Provides a multicarotenoid composition in a more bioavailable form. 2. Provides free flowing, timed-release multicarotenoid beadlet/tablet preparation such that there is no interaction among the carotenoids during absorption. 3. Provides a multicarotenoid preparation with highest bioavailability for individual carotenoids. 4. Provides amulticarotenoid preparation which is stable in presence of environmental conditions such as light, presence of oxygen and moisture. 5. Provides a multicarotenoid preparation that protects the body against the harmful effects of singlet oxygen. 6. Promotes eye health, skin health and prostrate health.

Full Text

FORM 2
THE PATENTS ACT 70
(Act 39 of 70 )
PROVISIONAL SPECIFICATION
(Section 10)
NOVEL TIMED-RELEASE MULTICAROTENOID COMPOSITION AND A PROCESS FOR ITS PREPARATION.
OMNIACTIVES HEALTH TECHNOLOGIES PVT LTD., an Indian Company , registered under the Indian company'sActl957having its registered office located at Rajan House . Appasaheb Marathe Marg, Prabhadevi, Maharashtra , India 400025
The following specification describes the nature of the invention

INTRODUCTION:
The present invention relates to novel timed-release multicarotenoid composition and a process for its preparation . More particularly, the present invention relates to novel timed-release composition of multi carotenoids such as lutein, zeaxanthin, lycopene and betacarotene and process for its preparation . The novel timed-release multicarotenoid composition of the present invention is useful for formulating compressed tablets, two-piece gelatin or vegetarian capsules. More particularly, the novel timed-release system for mixed carotenoids is useful as powerful antioxidant combination that promotes eye, prostrate, and skin health.
PRIOR ART
Carotenoids are yellow, red and orange pigments which are widely distributed in nature Although specific carotenoids have been identified in various fruits and vegetables, bird feathers, egg-yolk, poultry skin, crustaceans and macular eye region, they are especially abundant in marigold petals, corn and leafy vegetables. The correlation between dietary carotenoids and carotenoids found in human serum and plasma indicate that only selected groups of carotenoids make their way into the human blood stream to exert their effect.
Carotenoids absorb light in the 400-500 nm region of the visible spectrum. This physical
property imparts the characteristic yellow/red color to the pigments. Carotenoids contain
a conjugated backbone composed of isoprene units, which are usually inverted at the
center of the molecule, imparting symmetry. Changes in geometrical configuration about
the double bonds result in the existence of many cis- and trans-isomers. Mammalian
species do not synthesize carotenoids and therefore these have to be obtained from
dietary sources such as fruits vegetables and egg yolks. In the recent years, carotenoids
have been attributed several health benefits, which include prevention and or protection
against serious health disorders.

Carotenoids are non-polar compounds classified into two sub-classes, namely more polar compounds called xanthophylls or oxy-carotenoids and non-polar hydrocarbon carotenes like .beta.-carotene, lycopene, etc. Both the sub-classes have at least nine conjugated double bonds responsible for the characteristic colors of the carotenoids. Xanthophylls have ring structures at the end of the conjugated double bond chain with polar functions like hydroxyl or keto group. The examples for xanthophylls include lutein, zeaxanthin, capsanthin, canthaxanthin, .beta.-cryptoxanthin, astaxanthin, etc. As natural colorants and also for their role in human health, xanthophylls containing lutein and zeaxanthin have attracted the renewed attention of scientists and researchers in the biomedical, chemical and nutritional field in recent years.
Individually, each carotenoid has been shown to provide specific health benefit. For example, lutein and zeaxanthin promote eye health. Beta carotene, being a precursor of Vitamin A, corrects the deficiency of the vitamin A, lycopene promotes prostrate health. There have been attempts to combine these useful carotenoids to have synergistic effect on health benefits.
US patent no. 7,090,879 provides a infant formula containing a mixture of lutein, lycopene, and beta carotene in blend of proteins, lipids and carbohydrate. The main drawback of this invention is that all the carotenoids are released together in the body, wherein the carotenoids interact with each other and affect their complete absorption.
US patent nos. 7056525, 6509029, and 6261598 describe preparation of different formulations of lutein, lycopene and beta carotene, such as emulsion, solubilizate, dry powder and oil suspension. The main disadvantage of such compositions is that all the three carotenoids are released together in the gastrointestinal tract, where they interact with each other and affect their absorption.
US Patent application no.20070082044 teaches us about the synergistic effect of combination of lutein with lycopene and beta carotene. However, the disadvantage of

such combination is that the interaction among the carotenoids that renders them less bioavailable.
While technologies exist in the pharmaceutical and nutritional industries for providing combination of the carotenoid preparations, there are no techniques available for the prevention of interaction amongst the carotenoids such as lutein, lycopene and betacarotene that drastically affects the absorption of the carotenoids individually. No e prior art references deal with simple admixture of the carotenoids such as lutein, lycopene and beta carotene and delivering them either as emulsions or oil suspensions or powders. When such products are ingested, they compete with each other for micellization, a critical step prior to absorption. For example since beta carotene is absorbed faster, it reduces the absorption of lutein by 40%. Similarly, the absorption of lycopene is affected in the presence of beta carotene and lutein. Such is the position in other carotenoids
Carotenoids are important natural products that are useful to the body in promoting eye health, prostrate health and prevention of free radicle damage. When administered individually, these carotenoids are absorbed adequately to provide the health benefits. However, when these carotenoids are administered together in combination, one of them such as beta carotene is absorbed well, whereas other two carotenoids such as lutein and lycopene as not absorbed completely. The carotenoids compete with each other during micellization with the limited quantity of bile salts available in the intestine.
Carotenoids undergo a step of micellization before getting in to enterocytes during absorption. The critical step of micellization requires bile salts as an essential component. Since the concentration of bile salts is limited, those carotenoids which have higher affinity for micellization, will form micelles and get absorbed. Whereas the remaining carotenoids will be absorbed to the extent bile salts available in the intestine. The situation is similar when a high dose of any one of the carotenoid is administered. The absorption takes place to the extent of bile salts available in the intestine.

OBJECTIVES OF THE PRESENT INVENTION :
Therefore, the main objective of the present invention is to provide novel timed-release multi carotenoid composition in which the individual carotenoid is released at different time intervals, such that they do not compete with each other
Another objective of the present invention is to provide novel timed-release multi carotenoid composition comprising lutein, lycopene and beta carotene , in which the individual carotenoid is released at different time intervals, such that they do not compete with each other
Yet another objective of the present invention is to provide novel timed-release multi carotenoid composition in beadlet form which can be further formulated as compressed tablets or as capsules.
Yet another objective of the present invention is to provide novel timed-release carotenoid composition in beadlet form wherein the release of individual carotenoid is such that there is no interaction of the individual carotenoid in the gastrointestinal tract.
Still another objective of the present invention is to provide a process for the preparation of novel timed-release multi carotenoid composition in which the individual carotenoid is released at different time intervals, such that they do not compete with each other
Yet another objective of the present invention is to provide a process for the preparation of novel timed-release multi carotenoid composition comprising lutein, lycopene and beta carotene , in which the individual carotenoid is released at different time intervals, such that they do not compete with each other
The term " timed-release" used refers to a composition in which is the individual carotenoid is released at a specific time interval in the gastrointestinal tract. For example,

the multicarotenoid composition of the present invention releases its bioactives only after 2 hrs. Hence it is referred to as a timed release composition .
The present invention has been developed based our finding based on continuous R&D efforts, that a multicarotenoid composition can be developed from which the carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption. In other words , the carotenoids present in the composition are absorbed completely separately .
Accordingly, the present invention provides a novel timed-release multicarotenoid composition in which the . carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption.
The composition of the present invention may be in beadlet form or in tablet form. The composition of the present invention is also useful for the preparation of compressed tablets and for filling in to two-piece capsules.
According to the present invention there is provided a process for the preparation of the novel timed-release multicarotenoid composition in which the . carotenoids are released in the intestine at different time intervals, thereby avoiding the competion of the carotenoids present in the composition for absorption, which comprises,
(i) granulating the mixture of desired carotenoids with a mixture of a solution
of a binder and a stabilizer in an organic solvent,
(ii) coating the granules obtained in step (i) with an aqueous enteric coating
polymer,
(iii) coating product obtained in step (ii) with a bioenhancer in an organic
solvent,
(iv) coating the granules obtained in step (iii)) with an inert barrier coat and
(v) coating the granules obtained in step in step (iv)) with beta carotene suspension , if desired

(vi) forming free flowing beadlets of the granules obtained in step (v),
(vii) drying the resultant beadlets obtained in step(v)) at temperature not exceeding 45 deg C.
The multi carotenoidsn which can be used in the present invention includes lutein and zeaxanthin in both free and esterified form, cis and trans lycopene, alpha and beta carotene, canthaxanthin, astaxanthin and violaxanthin The binder used for granulating may be selected from hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch, methyl cellulose, gum Arabic and gelatin.
In another preferred embodiment the solvent employed may be selected from Acetone, Hexane, Ethyl Acetate, Isopropyl Alcohol, Ethanol, Dichloromethane, Methanol, etc, ,more preferably form Acetone, Ethanol, Dichloromethane, Isopropyl alcohol, and more preferably Dichloro Methane and Isopropyl Alcohol and mixtures thereof. The stabilizer used in the process may be selected from ascorbic acid, BHA, BHT, ascorbyl palmitate, mixed natural tocopherols, alpha tocopheryl acetate, sodium ascorbate and mixtures thereof:
The enteric coating polymer used may be selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate and polymethacrylic acid ethyl methacrylate, shellac, and shein. The inert barrier coat used in the process may be selected from hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch, methyl cellulose, ethyl cellulose, gum arabic , gelatin, and mixtures thereof:
The bioenhancer used in the process may be selected from bile salts, sodium lauryl sulfate, citric acid, polysorbate 20, polysorbate 40, polysorbate 80, and mixtures thereof:
The coating process may be performed using fluid bed coater, coating pan, air suspension coating or combination thereof:

ADVANTAGES OF THE INVENTION
1. Provides a multicarotenoid composition in a more bioavailable form.
2. Provides free flowing, timed-release multicarotenoid beadlet/tablet preparation such that there is no interaction among the carotenoids during absorption.

3. Provides a multicarotenoid preparation with highest bioavailability for individual carotenoids.
4. Provides amulticarotenoid preparation which is stable in presence of environmental conditions such as light, presence of oxygen and moisture.
5. Provides a multicarotenoid preparation that protects the body against the harmful effects of singlet oxygen.
6. Promotes eye health, skin health and prostrate health.

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Patent Number

272249

Indian Patent Application Number

2181/MUM/2007

PG Journal Number

14/2016

Publication Date

01-Apr-2016

Grant Date

23-Mar-2016

Date of Filing

01-Nov-2007

Name of Patentee

OMNIACTIVE HEALTH TECHNOLOGIES PVT LTD

Applicant Address

RAJAN HOUSE, APPA SAHEB MARATHE MARG, PRABHADEVI, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	JAYANT DESHPANDE	OMNIACTIVE HEALTH TECHNOLOGIES PVT LTD. APPA SAHEB MARATHE MARG, PRABHADEVI, MUMBAI 400025

PCT International Classification Number

A23L1/27

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA