Title of Invention

NOVEL STABLE BEADLETS OF LIPOPHILIC NUTRIENTS

Abstract The invention disclosed in this application relates to novel stable beadlets of lipophilic nutrients which comprises an inert core having a coating of a mixture of stabilizing antioxidants and lipophilic nutrients or mixtures thereof. The invention also relates to a process for the preparation of the said novel stable bead lets The bead lets are useful are useful as medicines and dietary supplements to facilitate reduced risk of macular degeneration, cataract and several forms of cancer.
Full Text

NOVEL STABLE BEADLETS OF LIPOPHILIC NUTRIENTS
Technical Field:
The present invention relates to novel beadlets of lipophilic nutrients and a process for their preparation . The present invention, particularly relates to novel and stable beadlets of lipophilic nutrients, materials or substances, particularly nutrients like carotenoids, tocopherols, tocotrienols, plant sterols and stanols, and lecithins, select omega-3 fatty acids and polyunsaturated fatty acids, more particularly novel beadlets of lutein , lutein esters, zeaxanthin, zeaxanthin esters and a process for their preparation .
The novel beadlets of the present invention are useful in the following ways . Beadlets of lipophilic phytochemicals and nutrients such as oil soluble vitamins, omega 3 fatty acids, plant sterols and plant stanols, resinoids such as guggul sterones and the like, are useful as medicines and dietary supplements. Beadlets of lipophilic nutrients like carotenoids lutein, zeaxanthin, beta-carotene, lycopene, astaxanthin, are useful as antioxidants , micronutrients or as dietary supplements. Beadlets of lutein , lutein esters, zeaxanthin, zeaxanthin esters are also useful in formulating powerful antioxidant nutrients to facilitate reduced risk of macular degeneration, cataract and several forms of cancer.
The novel beadlets of the present invention obtained by coating one lipophilic nutrient, or a mixture of such nutrients, on a central inert core to obtain uniform spherical beadlets. The uniform spherical appearance of these beadlet provides excellent free flowing characteristics which are very desirable for manufacturing and formulating operations. These novel spherical beadlets are convenient to use, and have a stronger visual appeal. The novel beadlets of the present invention are further stabilized synergistically with the use of anti-oxidants and with the application of layers of polymeric materials as coatings on the beadlets as barriers to prevent penetration of light, moisture and air. The beadlets of the present invention are well suited for use as directly compressible ingredients in tablets, or in two-piece capsules.
Background Art:
The role of nutrients and phytochemicals in the promotion of good health through nutrition has now been extended to the likely benefits such as prevention of cancer , and protection against

synthesize carotenoids, but many animals-who are unable to synthesize carotenoids- incorporate them from their diet.
These carotenoids are lipophilic molecules which tend to accumulate in lipophilic compartments like membranes or lipoproteins. The lipophilic nature of these compounds also influences their
absorption, transport and excretion in the organism.
i
The unique structure of carotenoids determines not only their colour , but also their potential biological functions and actions. 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. Based on their composition, and structure which is made up at least nine conjugated double bonds responsible for their characteristic colors, carotenoids are divided in two classes, the hydrocarbon class called as carotenes containing only carbon and hydrogen atoms which are non-polar in nature, and oxycarotenoids (or, xanthophylls) which carry at least one oxygen atom in ring structures at the end of their conjugated double bond chain with polar functions like hydroxyl or keto group.
More than 700 different carotenoids have been identified until now, the most common of these being carotenoids like P--carotene, a-carotene, lycopene, and xanthophylls like lutein, zeaxanthin, astaxanthin.
Carotenoids have drawn attention from a health and nutritional support perspective because many epidemiological studies have revealed that an increased consumption of a diet rich in carotenoids is correlated with a diminished risk for several degenerative disorders, including various types of cancer, cardiovascular or ophthalmological diseases. Carotenoids serve as antioxidants in human beings and animals, and the so-called provitamin A carotenoids are used as a source for vitamin A.
Some of the preventive and protective effects that have been associated with carotenoids have been listed below:
□ Antioxidant activity: Carotenoids detected in human serum and tissues, such as P-carotene, lutein zeaxanthin, lycopene and cryptoxanthin are most likely involved in the scavenging of two of the reactive oxygen species, singlet molecular oxygen(102), and

peroxyl radicals. Further, they are effective deactivators of electronically excited sensitizer molecules which are involved in the generation of free radicals and singlet oxygen . The efficacy of carotenoids for physical quenching is related to the number of conjugated double bonds present in the molecule which determines their lowest triplet energy level.
Carotenoids also influence cellular signalling and may trigger redox-sensitive regulatory pathways which have a bio-protective effect. In vitro, carotenoids exert antioxidant functions and inhibit carcinogen-induced neoplastic transformation, inhibit plasma membrane lipid oxidation, and cause upregulated expression of connexin 43. These in vitro results suggest that carotenoids have intrinsic cancer chemo-preventive action in humans.
Protecting cells and tissues from oxidative damage:
Age-related macular degeneration is a major cause for irreversible blindness among the elderly in the Western world and affects the macula lutea (yellow spot) of the retina, the area of maximal visual acuity . Lutein and zeaxanthin are the pigments responsible for coloration of this tissue. The occurrence of lutein and zeaxanthin in the macula has specific functions, namely protection of the cells and tissues from UV light and reduced cataract risk.
When skin is exposed to UV light, erythema is observed as an initial reaction. There is evidence from in vitro and in vivo studies that 3-carotene prevents photo-oxidative damage and protects against sunburn (erythema solare). Such protective effects are also achieved with a dietary intervention using tomato paste, corresponding to a specific dose of lycopene/day. Lycopene and other carotenoids may be used as oral sun protectants and contribute to the maintenance of skin health.
Prostate cancer has become a major public health issue. An important epidemiological finding has been the association between the consumption of tomato products and a lower risk of prostate cancer. Several investigators have proposed that lycopene, a carotenoid consumed largely from tomato products, may be the component responsible for lowering the risk of prostate cancer.

Laboratory and clinical studies have been initiated with the goal of assessing the ability of pure lycopene to serve as a chemo-preventive agent for prostate cancer. Other cardio-protective functions provided by Lycopene and other antioxidant nutrients in tomatoes may include the reduction of low-density lipoprotein (LDL) cholesterol, homocysteine, platelet aggregation, and blood pressure.
Tocopherols and Tocotrienols:
Tocopherols(found as a, p, X' Y tocopherols) and tocotrienoIs(found as a, (3, x, y tocotrienols) comprise eight compounds generically called "vitamin E". Vitamin E is a very active antioxidant acting as a free radical and singlet state oxygen scavenger, playing a crucial role in the protection of the skin from free-radical-generating factors such as ultraviolet radiation. As Vitamin E acts as ; an antioxidant, it plays an important role in the stabilization of oils and fats. Vitamin E is the major fat-soluble antioxidant acting in the cellular membrane. The potential role of vitamin E in providing protection against free-radical-mediated diseases has been the subject of many studies. Tocopherol (a-Tocopherol) is the major vitamin E in vivo and exerts the highest biological activity. Tocopherols are present in polyunsaturated vegetable oils and in the germ of cereal seeds, whereas tocotrienols are found in the aleurone and subaleurone layers of cereal seeds and in palm oils. Chemically, tocopherols and tocotrienols are closely related, however, it has been observed that they have widely varying degrees of biological effectiveness. Although a-tocopherol is known as the most abundant and active form of vitamin E in vivo, the role of y-tocopherol, a major form of vitamin E in many plants and diet, has also received attention.
Studies have shown that dietary supplementation with palm tocotrienols for 6 weeks lowered iipid-associated coronary heart disease risk factors significantly, i.e., total serum cholesterol by 20%, LDL—by cholesterol 28% and apo-lipoprotein by 18%
Vitamin E functions as a chain-breaking antioxidant, inhibiting the propagation of lipid peroxidation, and thus preventing membranes or lipoproteins from oxidative damage. This constitutes an important biological function of vitamin E, since the deterioration of cellular membranes is associated with cellular dysfunction and because oxidative modification of lipoproteins plays a role in the formation of the atherosclerotic plaque. Vitamin E is believed to play a key role in protecting red blood cells , strengthening capillary walls and decreasing

platelet aggregation . Vitamin E plays a role in bringing nourishment to cells, maintaining muscle and nerve function, and promoting a healthy immune system.
In biological sy-stems, vitamin E is thought to be regenerated by other antioxidants such as ascorbate and glutathione. In addition to antioxidant and anti-atherosclerotic activities , vitamin E exhibits a number of other biological activities, including impact on cellular signaling and prevention of infertility in animals .
Plant Stanols and Sterols:
These are structurally related to cholesterol, but are characterized by an extra ethyl (sitosterol) or methyl group (campesterol) in the side chain..
i As they cannot be synthesized by humans, all plant sterols and stanols in the human body therefore originate from the diet. Sitosterol, campesterol and stigmasterol are the most common plant sterols in nature . Sitostanol and campestanol are saturated plant sterols, w^hich are found in nature in much smaller amounts than plant sterols. Because of their cholesterol-lowering effects, these components are incorporated nowadays into a wide variety of food products, referred to as functional foods.
Different mechanisms have been suggested to explain the cholesterol-lowering activity of plant sterols and stanols. Firstly, plant sterols or stanols may displace cholesterol from mixed micelles , because they are more hydrophobic than cholesterol. This replacement causes a reduction of micellar cholesterol concentrations and consequently lowers cholesterol absorption. Furthermore, plant sterols or stanols might reduce the esterification rate of cholesterol in the enterocyte and consequently the amount of cholesterol excreted via the chylomicrons. Plant sterol and stanol esters have comparable effects on serum LDL cholesterol.
Animal studies have been convincing in showing a decreased level of plaque formation in arteries after consumption of plant sterols or stanols. Whether the reduction in LDL cholesterol after consumption of plant sterol and stanol esters lowers cardiovascular risk in humans remains to be fully proven.
Soybeans are, among other potentially bio-active compounds, rich in plant sterols. Populations with high intakes of soybean-based products, such as Seventh-day Adventists and Mexican

Taramuhara Indians, have lower cancer mortality rates, especially of the colon and the prostate. It is therefore tempting to suggest that plant sterols reduce the risk for certain cancers. In vitro cell studies clearly suggested that a possible protective effect of sitosterol on colonic epithelial cell proliferation.
It has also been suggested that sitosterol may beneficially affect prostate cancer. Indeed, it has been reported that men taking 20 mg sitosterol three times a day showed symptomatic improvement of benign prostatic hyperplasia. Clinical improvement was indicated by increased urine flow and decreased residual urinary volume, but no relevant reduction in prostatic volume was observed . Others have found similar beneficial clinical results in men taking 65 mg a day of a sitosterol extract.
Poly-Unsaturated Fatty Acids and Omega-3 Fatty Acids:
Poly-Unsaturated Fatty Acids (PUFAs) are fatty acids with more than one double bond.
Several PUFAs are recognized as 'essential fatty acids' in the normal diet for preventing nutrition-related illnesses. These include linoleic acid(LA), gamma-Iinoleic acid(GLA) and , alpha-linolenic acid( ALA).
Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families of "essential fatty acids" (EFA): pentaene ( composed of arachidonic acid (AA) and eicosapentaenoic acid(EPA)) and hexaene (docosahexaenoic acid(DHA)) acids. Since these fatty acids all have double bonds three carbons from the methyl end of the chain, they are grouped under the term of omega -3 fatty acids ( -3 fatty acids).
LA, GLA, and ALA are typically supplemented in diet through products of plant origin, while AA and DHA are currently supplemented in diet through fish oils. The role of EFA such as linoleic, and y-linolenic acids obtained from plant ingredients in the diet is crucial. Without a source of A A or compounds which can be converted into A A, synthesis of PGs would be compromised, and this would seriously affect many normal metabolic processes.
GLA has been claimed to play a role in development and prevention of some skin diseases, diabetes, reproductive disorders, and others .The cardiovascular health benefits of longchain co-3

polyunsaturated fatty acids such as AA and DHA have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Dietary supplementation with (o-3 PUFA had a beneficial effect in patients with cystic fibrosis , inflammatory bowel diseases , rheumatoid arthritis , and chronic renal diseases.
Linoleic acid(LA) is abundantly found in vegetable oils and meats. The fatty acid y-linolenic acid (GLA, 18:3(1)6) appears in botanical lipids (seed oils) from Oenothera biennis (evening primrose), Borago officinalis (borage) and Ribes nigrum (black currant) . In the body, LA is converted to GLA, and then to dihomo-Gamma-Linolenic Acid(DGLA) -which plays a curcial role in the production of Prostaglandin El-a hormone-like chemical which prevents platelet aggregation, reduces inflammation, lowers blood vessel and has a role in reducing inflammation and boosting immunity.
The role of arachidonic acid(AA) and docasahexaenoic acid(DHA) in the development of nervous system is well supported , and DHA is additionally related to the development of retina. In fact, several health agencies have recommended that infant feed formulae be fortified with DHA and AA . Currently the main commercial source of AA is from animal viscera, and DHA is fish oil.
Ihe role of eicosapentaenoic acid (EPA) in the proper functioning of the circulatory system is well recognized .There is growing interest in the putative involvement of EPA in some cancers and other diseases. The main commercial source of EPA is fish oil.
I^ecithins:
Commercial lecithin is a multifunctional, flexible and versatile surfactant composed of a number of compounds, predominantly phospholipid, which exhibit their own unique physical and chemical properties under their own optimum conditions. Lecithin is typically obtained for commercial purposes from soy-bean , though it can also be obtained from egg, and a number of other vegetable sources.

Physiologically, lecithin is an integral part of all organs and glands. The brain itself contains 25% phospholipids on a dry weight basis. Vital organs such as the liver and reproductive tract, and muscles contain high concentration of phospholipids. Phospholipids are also among the primary building blocks of all cellular membranes. Membrane functions include cellular transport of nutrients and wastes, internal cellular pressure regulation, and ion exchange.
Dietary phospholipids from various origins, particularly polyunsaturated fatty acid phospholipids, such as those of soyabean lecithin, have been reported to have a cholesterol-lowering effect in humans. Commercial soyabean lecithin is a mixture of different lipids in which phosphatidylcholine represents only 25% of the lipid lecithin. The other major lipids are triacylglycerols (20-25%) and phosphatidylethanolamine (20%).
Lecithin contains a nutrient called phosphatidylcholine (PC) that is presumed to be responsible for its health-promoting effects. PC is an important building block and versatile nutrient for cell imembranes. It is crucial to the survival and function of all living cells, especially cells of the liver, one of the body's most vital organs. PC is offered commercially in the form of refined lecithins-typically standardized on PC ranging from around 20% in viscous paste form to over 90% in wax-like form.
When PC is consumed, it is broken down into the nutrient choline rather than being carried directly to cell membranes. Choline acts like folate, TMG (trimethylglycine), and SAMe (S-adenosylmethionine) to promote methylation. It is also used to make acetylcholine, a nerve chemical essential for proper brain function. PC acts as a supplier of choline, which is needed for cell membrane integrity and to facilitate the movement of fats in and out of cells. It is also a component of the neurotransmitter acetylcholine and is needed for normal brain functioning, particularly in infants. Although the human body can synthesize choline, additional amounts from the diet are considered essential under certain circumstances.
A number of products are seen in the international market claiming the role of lecithin in supporting a number of nutritional and metabolic functions such as:
- Improved memory functioning
- Facilitate lipid metabolism and digestion of fats
- Facilitating the elimination of toxins from the liver
- Facilitate a healthy serum hpid profile and thereby protect against atherosclerosis
- Prevention of gallstones.

Other Lipophilic Nutrients in Nutrition:
Lipids are chemically compounds made of fatty acid and fatty acid derivatives. Lipids include products such as vegetable oils, oleoresins, etc. There are numerous applications of lipids in food, nutrition and pharmaceutical industries.
Poly unsaturated fatty acids such as omega-6 linoleic acid and its metabolite gamma-linolenic acid are useful in the treatment of neurodermatitis, eczema and psoriasis. Hemp seed oil is an important industrial product having applications in shaving products, skin care and hair care.
Major vegetable oils of commercial interest are obtained from soya, cotton, copra(coconut), palm-kernel, maize, palm, sunflower, olive, sesame, linseed, hazelnut and walnut oil. Lipophilic substances that have diuretic and cosmetic application include oils of avocado pear, blackcurrant, borage, castor, evening primrose, whea-tgerm and the like.
Issues in Formulating Products With Lipophilic Nutrients:
1. Difficulty in developing dry-delivery form:
Many nutritional formulations in the industry are in the form of tablets, capsules or dry-mixes. It is a major problem for formulators and manufacturers of such supplements to incorporate lipophilic nutrients such as carotenoids, vitamin E sources like tocopherols and tocotrienols, concentrated forms of PC-rich lecithins, phytosterols and plant stanols, various PUFA rich oils and omega-3 fatty acids singly or in combination with other nutrients into dry forms due to the oily, waxy or viscous nature of these products. Some options like spray dried powders , granules or gelatine beadlets work only with select products, and do not necessarily function well under tabletting systems. Some of the challenges in using lipophilic nutrients are explained below:
a. Carotenoids tend to be unstable at room temperature, and prone to degradation on exposure to light, heat, air and acidic environment. Their life needs to be extended by the use of other stabilizing anti-oxidants such as natural tocopherols, ascorbic acid derivatives and citrate.

b. Another option for stabilizing carotenoids is by delivering the same in a oil medium
to provide the protective cover of the oils within naturally present, or added anti
oxidants. Dry delivery forms are considered more difficult to stabilize.
c. Tocopherols and tocotrienols are typically found in an oily medium in the presence
of vegetable oils. Such oily products are difficult to use except in the smallest of
doses in dry delivery forms such as tablets without the use of specialized
technologies to convert them to powders, granules or beadlets.
d. Lecithins rich in the active ingredient PC(20-95%) tend to be viscous pastes or waxy
masses which are not suitable for directly compressible or free-flowing powders.
e. Phytosterols and plant stanols are oily products which have typically been
supplemented through fat based supplements. Incorporating these into free flowing
or directly compressible dry delivery forms would significantly increase the number
of options for formulators and manufacturers of nutritional supplements.
f. PUFAs, GLA and Omega-3 Fatty Acids are currently used sparingly and infrequently
in tablet and capsule based supplements due to their oily nature. Conventional dry
delivery conversion technologies do not provide good solutions for free flowing,
directly compressible beadlets.
2. Difficulties in Stabilizing Lipophilic Nutrients :
By nature , carotenoids are unstable at room temperature. Their stability is affected by light, heat, air (oxygen) and acidic environment. It is known that their stability can be enhanced by the ciddition of certain stabilizing antioxidants such as natural tocopherols, ascorbic acid derivatives and citrate.
Carotenoids and other hpophilic nutrients are typically used as ingredients for nutritional supplement formulations either as dispersions in oil or as powders, granules or beadlets for making tablets or encapsulation in capsule. 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 cold water dispersible powder for use in fruit juices and other aqueous beverages. Out of these three forms , beadlets have the advantage of being suitable for further formulation into compressed tablets or encapsulated in hard gelatin capsules
At present beadlets of carotenoids and other lipophilic nutrients are typically manufactured by spray drying a mixture of said active nutrients and gelatin along with sucrose, and stabilizers. In such beadlets the carotenoid / lipid particles are protected from light and oxygen in the matrix of gelatin and sucrose formed during the spray drying process in which matrix, the carotenoid/ lipoid particles are embedded. The spray dried product is made less cohesive by covering with starch.
A typical process of preparing such beadlets, as described in US patent no. 3998753 involves following main steps:
a. Gelatin, sugar , preservatives and antioxidants are added to water and the gelatin is
solubilised by hydrating overnight at about 50.degree,C.
b. An aqueous solution of ascorbic acid, EDTA, sodium lauryl sulphate is added to the
resulting solution.
c. An oil phase comprising the carotenoid/ lipid , tocopherol, butylated hydroxy anisole in
Chloroform is prepared by heating the above mixture to 80 degree C.
d. The oil phase is cooled to 55 degree C and is slowly added to the aqueous phase of Step
b. The resulting emulsion is homogenized at 55 degree C.
e. After evaporating the solvent at 75 degree C, the emulsion is diluted with water and
spray dried employing a spray drier having a revolving head and a counter rotating
drum .
f. The dried emulsion is forced through the tiny orifices of the revolving spray head of the
sprayer forming the beadlets .
g. The resulting beadlets come into contact with the powdery starch material which is
suspended in air in the rotating drum. The mixture of starch and beadlets is allowed to
stand for about an hour and then dried in an oven.
There are several disadvantages associated with the gelatin based beadlets formed by the above mentioned methods as listed below:
a. The particles of the carotenoids (or the active lipophilic nutrient) at the surface of the beadlets are unprotected and are therefore exposed to the harmful effects of light and air.

Consequently the beadlets undergo degradation resulting in the loss of their biological activities .
b. When compressed into tablets, these beadlets tend to disintegrate and the carotenoid (or the active lipophilic nutrient) gets squeezed out of the gelatin matrix in to the matrix of tablet where it is exposed to the incompatible environment. The carotenoid (or the active lipohilic nutrient) may undergo undesirable chemical reaction with excipients of the tablets, or the other ingredients present therein. Consequently they undergo degradation resulting in the loss of their biological activities ,.
C. During the preparation of the beadlets, the carotenoids (or the active lipophilic nutrient) are suspended in molten gelatin at a temperature above 50 deg C. At this temperature a significant portion of actives such as carotenoids get destabilized thereby resulting in their degradation resulting in the loss of their biological activities .
d. The particles of carotenoids (or the active lipophilic nutrient) are embedded in a highly viscous gelatin-sucrose matrix. Upon oral administration of the beadlets, the carotenoids (or the active lipophihc nutrient) get released in the gastro-intestinal tract from these beadlets , in a slow and erratic fashion. Consequently the bioavailability of the carotenoids (or the active lipohilic nutrient) is significantly reduced and their release is also not uniform.
In addition to gelatin beadlets, lipophilic nutrients like carotenoids have also been reported to be formulated in the form of beadlets using a hydrocolloid such as in US Patent application No. 20030064133 . The carotenoids in such beadlets are affected by similar disadvantages as that of gelatin beadlets.
There are other methods of preparation of the beadlets which have been reported in literature . The important and relevant methods are discussed below -
US patent no. 3998753 describes a process for preparing beadlets of less than 0.1 micron by emulsifying carotenoid solution in an organic solvent with an aqueous solution contaiiung sodium lauryl sulphate, a stabilizer, a preservative, a water soluble carrier composition, by mixing them together at a high speed and high shear. Beadlets are formed upon the removal of solvent, maintaining both the high speed and high shear , forming the emulsion unto droplets ,

collecting them in a powdery starch material, separating the carotenoids from the starch material and drying the former to obtain the beadlets.
The surfaces of the carotenoid beadlets prepared by this process are not protected and therefore they are exposed to light and oxygen due to which the carotenoids may undergo degradation thereby reducing their biological activity .
US patent No. 4254100 discloses a process for the preparation of dry, free flowing beadlets containing microcrystalline vitamin A acetate without containing any antioxidants, by homogenising vitamin A acetate in aqueous solution of gelatin or other water soluble ingredient, (tooling to 15 Deg C and centrifuging the microcrystals formed , isolating and suspending in aqueous solution of gelatin and sugar, warming and mixing with an oil to form fine droplets that are solidified by cooling.
The drawback of this process is the inadequate protection provided to the particles at the surface of crystals that may undergo degradation on their exposure to light and oxygen .
US Patent No. 4670247 describes a method for the preparation of beadlets of vitamin A,D,E, and K in which comprises forming an emulsion of the vitamin in aqueous medium contaiiung gelatin and sugar, converting the droplets of emulsion to dry particulate form and heat treating it to form water insoluble particles are further converted into dry beadlets by cross-linking of gelatin with sugar using heat.
The disadvantage of this process is that the vitamins being sensitive to high temperature undergo significant degradation during beadlet formation and cross-linking.
US Patent No. 4929774 describes a stable mixture of a fat-soluble vitamin and a carotenoid, a triglyceride and a coating substance prepared by mixing the above said components and drying it.
The drawback of this process is that at the surfaces of the beadlets, the carotenoids being not protected, get degraded on exposure to the harmful effects of oxygen, light and moisture.
US Patent No. 5811609 describes a process for the preparation of a powdered water-dispersible carotenoid preparation in the form of discrete carotenoid microparticles by milling a carotenoid

in an aqueous mediuni in the presence of a hydrocolloid to form a suspension, heating the suspension formed by the milling to a temperature sufficiently high to cause a total or partial melting of the carotenoid, subsequently cooling the suspension, and finely dividing and drying the suspension to form a powder.
As the beadlets are prepared at high temperature, there is a possibility of significant degradation of the carotenoid during the beadlet formation .
US Patent no. 6093348 describes a process for the manufacture of a solid carotenoid powder containing carotenoid beadlets, by melting an aqueous suspension containing carotenoid crystals a surfactant, a protective colloid in a heat exchanger wherein the residence time of the Carotenoid crystals in the heat exchanger is less than 60 seconds; homogenising the resulting kqueous suspension to get an emulsion by spray process converting into powders containing tarotenoid beadlets.
The main drawback of this process is that the carotenoid molecules are exposed to high temperature and that the molecule at the surface of the beadlets are unprotected.
US Patent No. 6582721 describes beadlets containing mixture of carotenoids, antioxidants, vegetable oil, sucrose gelatin and corn starch. These beadlets are prepared by blending and granulation of the ingredients and drying . The process steps may vary on the sequence of addition of the components , duration and conditions used the methods used for blending and granulation and drying. An inert atmosphere may be maintained. The main disadvantage of such system is the difficulty in the formulation of tablets. When compressed the carotenoid may get leached into the tablet matrix, resulting in the loss of biological activity.
US Patent No. 5849345 discloses beadlets comprising a mixture of gelatin and carbohydrate having dispersed therein a pharmaceutically acceptable anti oxidant and a carotenoid. In this process also the disadvantage in this process is that the molecules of carotenoid at the surfaces of the beadlets are exposed to harmful effects of oxygen, light and moisture.
US Patent application No. 20030064133 describes a process for the encapsulation of lipophilic compounds using alginate, wherein the micronised lipophilic compound is suspended in alkali metal solution of alginate and then converted to beadlet form by drop-wise addition of the solution into Calcium salt in aqueous medium. The beadlets so formed are washed with acidic

solution and dried. The beadlets are then coated with a polymer to provide additional stability to lipophilic compounds.
The main disadvantage of alginate matrix is its inadequate stability during long period of storage ( such as 36 months). Another drawback of this technology is the use of acidic environment which is detrimental to the stability of many lipophilic compounds such as carotenoids.
Im a recently published US Patent application No. 6663900, a process of preparing microcapsules having high carotenoid content between 10-50% by weight has been described, wherein the crystals of carotenoid suspended in aqueous medium are coated on crystalline sucrose particles in a fluid bed coater at 180 degree F.
The main drawback of this process is that the carotenoid molecules at the surface of the microcapsule are exposed to the harmful effects of light and oxygen. Another significant disadvantage of the afore-mentioned process is that it uses an aqueous coating technique which requires a fluidization temperature as high as 180 deg F. It is well known that carotenoids are less stable in aqueous atmosphere in comparison to an organic medium. Carotenoids are much less Stable at the high fluidization temperature reported herein of 180 deg F when compared to their stability at temperatures of 80-90 deg F commonly employed during coating through an nonaqueous medium. At the high temperatures reported in this process, carotenoids are likely to undergo degradation, or isomerization into other stereo-isomeric forms or degradation products of the original carotenoid material which may not have desired beneficial properties of the original carotenoid.
Yet another drawback of this process is that it employs coating on fine crystals or particles. It is Well known that when crystals are fluidised, they undergo fragmentation with sharp edges and the dust generated thereby chokes the filters used in the coater.
In summing up , the beadlets produced by the hitherto known processes have the following
drawbacks:
i) Since the surfaces of the beadlets are not protected against light, air and moisture , the
actives contained therein undergo degradation .

|ii) The beadlets tend to disintegrate or leach into the matrix of tablet when compressed. Here the active nutrient (such as carotenoids or lipophilic nutrient) is released into an environment where stabilizing antioxidants are absent and where there is a possibility of the active nutrient molecule chemically reacting with other components of tablets.
(iii) The leaching of the active nutrients into the tablet matrix under the force of direct compression reduces the bioavailability of the active nutrients (such as carotenoids) and results in a non-uniform release in the intestines.
(|iv) Leaching of the active nutrient (such as carotenoids or lipids) into tablet matrix causes discoloration of tablets and organoleptic properties such as smell and taste are adversely affected.
timitatioiis of current technology:
From the information given above it is evident and very clear that currently, to prepare the
beadlets of carotenoids, lipophilic nutrients or botanical lipids a complex procedure of
i eembedding the active material in a gelatin matrix and then preparing a beadlet by spray drying
is explained above is being employed . The beadlets obtained by these known processes do not
ensure stability to the active material (such as carotenoids / lipids) either as such, or when
formulated into tablets. In addition, none of the hitherto known methods of making beadlets
provide desirable physical characteristics , such as perfectly spherical, free flowing beadlets
Suitable for tabletting or capsule filling. Further, the beadlets produced by hitherto known
linethods do not prevent leaching of the active nutrients (such as carotenoids) contained in such
beadlets when subjected to compression to form tablets.
Limitation of excipients:
Most of these processes employ gelatin , a protein isolated from the bones and muscles of the animals. In recent times, use of excipients of animal origin in herb-based nutraceuticals is considered undesirable by large section of users. Due to poor digestability, use of gelatin based formulations have a limitation for use among geriatric population. Sometimes, lactose is used as an excipient in the main beadlet matrix due to its compressible nature, but its dairy product (animal) origin makes it unacceptable to many, and is therefore, considered to be undesirable.

At present the nutraceutical industry needs:
a. a solid form of carotenoid and lipids, such as beadlets, suitable for formulation into
tablet.
b. beadlets from which the carotenoid or lipid should not get leached out when compressed
into tablets
c. beadlets which are protected from light or oxygen or moisture with the help of certain
coating.
d. beadlets preferably free from excipients of animal origin or dairy products,
e. beadlets which can be conveniently produced using a simple process and equipments
that are common,
f. beadlets which have an appealing, uniformly spherical appearance.
Therefore in the formulation of oral delivery systems for lipophilic nutrients, particularly Carotenoids, such as lutein, lycopene, beta carotene, avoiding the above mentioned problems present a challenge to the pharmaceutical and food industries, due to the oily nature and iinstability of the carotenoids/lipids.
By nature carotenoids and lipophilic nutrients are unstable in presence of oxygen and light. Therefore, they can be stabilised by the incorporation of certain stabilising antioxidants. To ilurther enhance stability , the active nutrients(eg carotenoids, or lipophilic nutrients such as tocopherols or tocotrienols etc) can be coated with polymer(s) which provide protection against Ijhe harmful effects of oxygen, light and moisture. Carotenoids and other lipophilic nutrients are iliseful as nutritional supplements for the prevention /treatment of diseases, such as , several forms of cancer, immunological disorders, eye disorders, skin manifestations, inflammation, dardio-vascular disease etc. These lipophilic nutrients are typically required to be administered daily through a suitable delivery system. There are several delivery systems such as emulsions 4nd suspensions or oily solutions, that are popularly used currently along with solid delivery fprms such as gelatin beadlets. As the tablet form is considered to be having high user-compliance, carotenoids and other lipophilic nutrients need to be facilitated for such dry delivery forms.
Non-pareil seeds such as sugar spheres or globules, without the active ingredient, on which the active ingredient is coated, are a convenient form for the preparation of oral dosage forms such as tablets or hard gelatin capsule, of the active ingredient . Accordingly , in the pharmaceutical

industry, it is a well-known practice to load sugar spheres of 200 microns to 3 mm with the active ingredient ( drug ) in a suitable solvent using a coating pan or in a Neocota or in a fluidbed system. The beadlets produced by coating the active ingredient on the non- pareil seeds are unifirmly spherical in nature and can be used in size as small as 200 microns. The drug loaded spherical beadlets may further be uniformly coated with a polymeric material to modify the release or mask the bitter taste of the drug.
The major advantage of such coated non-pareil seeds is the possibility of having an uniform coating of the active nutrient. These coated non-pareil seeds (beadlets) are free-flowing and have uniform and controlled release of the active ingredient upon oral administration. Such coated non-pareils seed are more stable . If required , they can be made further stable by applying additional polymeric coating(s) so as to protect them from the harmful effects of Hght, oxygen and moisture.
the above methodology is hitherto well known to be utilized for preparing beadlets of non-Vvaxy, non-oily lipophilic materials or nurients. Fluidisation of such nutrients is smooth and effective, as the active nutrients does not form a cohesive oily mass at the stage of fluidization and coating.
In fluidisation process , the medium of coating can either be aqueous or organic. Attempts have been made in the past to apply fluid bed technology for preparing microcapsules of carotenoids using aqueous coatings process on crystalline sucrose. Such processes suffer from drawbacks such as use of high temperature(180.deg.F) , which are not suitable for many heat ser\sitive products such as carotenoids.
Unfortunately, this method using organic solvent medium is not applicable directly for the formation of beadlets of lipophilic nutrients and carotenoids, in spite of the above said advantages , due to their oily/ waxy nature . Further these nutrients, when subjected to fluidisation, form a cohesive mass which adversely affects the fluidisation . Therefore, a process employing fluid-bed system using a non-aqueous coating medium has hitherto not been Considered possible or demonstrated, for the preparation of beadlets of lipophilic nutrients such as carotenoids. Due to the reason of non-applicability of the non-aqueous fluid-bed system for the formation of beadlets of lipids, hitherto there has been no question of employment of any Core such as non-pareil seeds or other seeds for the preparation of beadlets of lipophilic nutrients.

We undertook scientific investigations in order to overcome the obstacles faced in the preparation of bead lets of various lipophilic nutrients, especially carotenoids, employing the hitherto known spraying processes and to take advantage of employing the coating of an inert core with lipophilic nutrients in organic solvent medium by fluidisation technique, which are successfully employed in pharmaceutical and food industries.
With our sustained efforts we observed , surprisingly , that process of coating an inert core with lipophilic materials or nutrients particularly carotenoids, employing fluidised bed technique in organic solvent medium is possible . This was possible when we found that a solution of lipophilic nutrients, in a non- polar solvent when diluted with a polar solvent forms a colloidal suspension. This colloidal suspension when subjected to fluidisation using a fluid bed system employing an inert core did not form a cohesive mass and does not adversely affect the fluidisation process. On the contrary, the process resulted in the formation of the inert cores uniformly coated with the lipophilic materials or nutrients in the form of uniformly spherical beadlets.
In other words , the fluidisation technique using a non-aqueous solvent which hitherto was not considered as applicable for the formation of beadlets of lipophilic nutrients , has been made possible by the process developed according to the present invention. This invention has resulted in developing a new concept enabling incorporation of oily lipophilic matter into their beadlets..
The formation of stable, uniformly coated free flowing spherical beadlets of oily lipophilic nutrients is a result of synergistic combination of use of spherical inert cores (non-pareil seeds), selected stabilising antioxidants and coating the resulting synergistic combination with oxygen and moisture barrier polymers to provide additional protection.
Spherical nature of beadlets has several advantages such as, free flowing property which is required during tablet compression, enables compression of tablets at as high a compression force as 10 kg/cm^ , superior release property, possibility of site specific controlled release of carotenoids and lipids, and consequently, higher bioavailability. Major advantage of using such technology is that it avoids the use of high temperature (above 50.degree.C) during preparation of beadlets and thus prevents degradation of heat-sensitive bioactive compounds. Another advantage of using spherical cores being flexibility of beadlet size which can range between a wide range of 200 microns to 3 mm. Another advantage of the present invention is that the

invention can be practiced using existing, hitherto well known fluid-bed technology and equipment.
Objectives of the present invention;
Iherefore, the main objective of the present invention is to provide novel stable beadlets of lipophihc nutrients, particularly carotenoids , which are useful as nutritional supplements for the prevention /treatment of diseases, such as , several forms of cancer, immunological disorders, eye disorders, skin manifestations, inflammation, cardio-vascular disease etc.
Another objective of the present invention is to provide novel stable beadlets of xanthophyll crystals standardized on lutein and/or zeaxanthin useful for treatment/prevention of age-related macular degeneration and cataract. Lutein is also found to reduce the risk of breast cancer dind skin disorders.
Another objective of the present invention is to provide novel stable beadlets of xanthophyll esters standardized on lutein and/or zeaxanthin esters useful for treatment/prevention of age-related macular degeneration and cataract. Lutein and zeaxanthin esters are also found to reduce the risk of breast cancer and skin disorders.
Still another objective of the present invention is to provide novel stable beadlets of carotenoids which do not leach when compressed into the form of a tablet and not effected by exposure to light, moisture and air .
Still another objective of the present invention is to provide novel stable lipophilic nutrients particularly carotenoid beadlets, which are preferably spherical in shape so as to ensure free flowing nature.
Yet another objective of the present invention is to provide novel beadlets of lipophilic nutrients particularly carotenoids, in a narrow size range such as 200 microns to 3 mm.
Still another objective of the present invention is to provide novel beadlets of lipophilic nutrients, particularly carotenoids, that facilitate good bio-availability of the nutrient upon oral administration.

Yet another objective of the present invention is to provide novel beadlets of lipophilic materials or nutrients which are free from ingredients of animal origin such as gelatin and lactose.
Another objective of the present invention is to provide novel stable beadlets of lipophilic materials or nutrients which are released in the gastro-intestinal tract in an uniform maimer
Still another objective of this invention is to provide a process for the preparation of novel beadlets of lipophilic materials or nutrients, particularly carotenoids and lipids .
Yet another objective of the present invention is to provide a process for the preparation of novel beadlets of carotenoids like lutein and zeaxanthin and other lipophilic nutrients employing fluid-bed techniques using low temperature thereby ensuring minimum loss of activity during processing.
Accordingly, the present invention provides novel stable beadlets of lipophilic nutrients which comprises an inert core having a coating of a mixture of stabilizing antioxidants and a lipophilic nutrient or mixtures thereof.
Yet another feature of the present invention the lipophilic nutrient used for the coating is either a carotenoid such as lutein or zeaxanthin or mixtures thereof , alpha-carotene, beta-carotene, natural lutein or zeaxanthin esters, astaxanthin, lycopene, or a lipophilic nutrient such as Vitamin A, vitamin D, vitamin E in the form of mixed tocopherols or tocotrienols, vitamin K, lecithin, , medium chain triglycerides , omega-3 fatty acids and the like , or amixture of such lipophilic nutrients .
In an embodiment of the present invention the inert core used may be of any material which does not react with the carotenoid, or lipophilic nutrient employed for coating . It can be selected from non-pareil seeds made of carbohydrates such sugar, mannitol, starch , sago , microcrystalline cellulose . More preferably , the core used may be seeds such as sugar spheres, mannitol spheres and the like.
In another preferred embodiment of the present invention the novel beadlets may have a coating of a layer of a coating of films of an oxygen barrier polymer.

In another preferred embodiment of the present invention the novel beadlets may also have another coating , over the layer of the coating of films of an oxygen barrier polymer , with a film of a moisture barrier polymer .
In a preferred embodiment, the novel beadlets of the present invention may be in the form of spheres, globules and the like . The size of the beadlets of the present invention may range between 200 microns to 3 mm .
The stabilising antioxidants which may be employed to form the mixture of the lipophilic nutrients may include 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 and the like or their combinations thereof. Their amount used may vary from 0.1 % to 20 % by weight of the cjarotenoid, lipophilic nutrient or lipid used
the mixture of stabilising antioxidants and the lipophilic nutrients may also contain other stabilisers which may include sorbic acid, sodium benzoate, sodium salicylate, EDTA, and the like or mixture thereof.
The polymer used for coating for providing protection to the lipophilic nutrients matrix against oixygen may be selected from hydroxy propyl cellulose, hydroxy propyl methyl cellulose, methacrylate copolymers, polyvinyl pyrrolidone, ethyl cellulose, carboxymethyl cellulose and polyvinyl alcohol and the like or their mixtures . Their amount may range from 2 to 20% of the weight of beadlets.
The polymer which is used for providing barrier to the entry of moisture can be selected from carboxy methyl cellulose sodium, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, methacrylate copolymers ,polyvinyl alcohol and the like. Their amount may range from 2 to 20% of the weight of beadlets.
In another embodiment of the present invention there is provided a process for the preparation of the novel beadlets of lipophilic nutrients as defined above which comprises

(i) forming a colloidal suspension of the desired lipophilic nutrients by dissolving the
same in a non-polar solvent and diluting the resulting solution with a polar solvent.
ii) mixing the colloidal suspension obtained with a stabilising antioxidant
(iii) spraying the resulting colloidal suspension on to inert cores present in a fluidbed system provided with bottom spray mechanism, at a temperature in the range of ambient temperature to 45 degree C , at an atomisation pressure in the range of 0 . 5 to 3 Kg / cm ^ and a spray rate in the range of 10 g / hour to 600g / hour and
(iv) drying the beadlets formed at an atomisation pressure of 0.8 to 1.2 kg/ cm 2
In still another embodiment of the present invention there is provided a process for the preparation of the beadlets of lutein or any other carotenoid, which comprises
(i) forming a colloidal suspension of lutein or any other desired carotenoid by dissolving the
material in a non polar solvent and diluting the resulting solution with a polar solvent
(ii) mixing the colloidal suspension obtained with a stabilising antioxidant
(iii) spraying the resulting colloidal suspension on to inert cores present in a fluid-bed system
provided with a bottom-spray mechanism at a temperature in the range of ambient temperature
to 45 degree C , at an atomisation pressure in the range of 0 . 5 to 3 kg / cm 2 and a spray rate
in the range of 10 g/hour to 600g/hour and '
(iv) drying the resulting beadlets at an atomisation pressure of 0.8 to 1.2 Kg/ cm 2
In a preferred embodiment the non-polar solvents which may be used for preparing the colloidal suspension of the hpophilic nutrient include methylene chloride, chloroform, petroleum ether (low boiling), petroleum ether (high boiling) or their mixtures .
In another preferred embodiment, the polar solvents which may be used for preparing the colloidal suspension of the lipophilic nutrient include - isopropyl alcohol, acetone, methanol, ethanol, acetonitrile or their mixtures .
It may be noted that carotenoids or lipophilic nutrients are not completely soluble in polar solvent. This means that thereby that only some part of the carotenoid or liophilic nutrient may form a suspension. This suspension may not be homogeneous due to the presence of large

particles of the undispersed carotenoids or lipophilic nutrients. This suspension can be filtered to remove the solid materials and the resulting colloidal suspension can be used for the fluidisation process .
Although such a process is possible and envisaged within the broad scope of the present invention , the process is not economical and efficient ._When carotenoids are mixed with polar solvent directly, some portion of the carotenoid forms colloidal suspension, where as a large portion remains as a lumpy, un-dispersed solid mass. One can filter such a mixture and use orJy the colloidal dispersion portion for coating. If one follows this procedure, it is not possible to load adequate quantity of carotenoid, and therefore not economical. Therefore it is necessary to dissolve or disperse the carotenoid in non-polar solvent followed by forming a colloidal dispersion by the addition of polar solvent.
The stabilising antioxidants used may include 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 and the like or their combinations thereof. The amount used may vary from 0.1 % to 20 % by weight of the carotenoid, lipophilic nutrient or lipid used The stabilising oxidants may also contain other stabilisers which may include sorbic acid, sodium benzoate, sodium salicylate, EDTA, and the like or mixtures thereof.
Binding agents may be added to along with the stabilising antioxidants for enhancing the efficiency of the coating . The binding agents used may include gum acacia, gum tragacanth, xanthan gum, polyvinyl pyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl Cellulose or their mixtures . Their amount used may range from 0.1 to 10% of the weight of the bead lets.
Disintegrating agents may also be used along with the binding agents . If such agents are used they may be selected from starch, cross-linked polyvinyl pyrrolidone, cross-carmelose sodium and sodium starch glycolate or mixtures thereof. Their amount used may range from 0.1 to 5% of the weight of the beadlets.
In another preferred embodiment of the present invention, the novel beadlets are provided a coating of a layer of films of an oxygen barrier polymer.

In yet another preferred embodiment of the present invention , the novel beadlets are provided with another coating over the layer of the coating of films of an oxygen barrier polymer , with a film of a moisture barrier polymer
The details of the invention are provided in the examples given below which are given for illustrative purposes only and therefore, should not be construed to limit the scope of the
invention
Examples:
p!xample 1
;Preparation of beadlets containing lutein from petals of Marigold Flower
ftep 1 -Preparation of Xanthophvll Crystals as per our Indian Patent Application No. 622/Mas/2002 Dt 26.08.2002, U.S. Applcn Filing Dt 28 Oct 02 Docket No. 14100.2US01. Pet Ptnt No. PCT/IN 002/00219 Dated 13/11/2002
Commercial grade marigold oleoresin (57.98 g) containing 11.54 % xanthophyll content ( by spectrophotometric method) was mixed with potassium isopropyl alcoholate (prepared by dissolving 15 g potassium hydroxide in 175 ml isopropanol.) The saponification mixture was heated and maintained at 70.degree.C for a period of 3 hours. The degree of hydrolysis was monitored by HPLC during the saponification stage. Isopropanol was distilled off under reduced pressure and the sohds obtained were stirred with 230 ml of water at room temperature. The mixture was taken into a separatory funnel and extracted with equal volume of ethyl acetate (3 times). Ethyl acetate layer was collected and washed with distilled water for removing the excess alkali, soapy materials and other water-soluble impurities. The ethyl acetate layer was distilled off under reduced pressure to get saponified crude extract (25.01g)
This resultant crude extract (25.01 g) was subjected to purification by stirring with 100 ml of hexane/acetone mixture (80:20) at room temperature for 30 minutes, followed by filtration. The precipitate of xanthophyll crystals obtained was washed with methanol The resulting orange crystals were vacuum dried at ambient temperature for 72 hrs.

The yield of the xanthophyll crystals was 3.41%(1.98g ). Xanthophyll content was 86.23 % by weight ( as determined by UV/Vis spectrophotometry ) out of which the contents of trans-lutein , zeaxanthin , and other carotenoids were 91.43% , 6.40% and 2.17 % respectively as determined by HPLC analysis.
Step 2- Conversion of Above Xanthophyll Crystals to Beadlets:
Carotenoids in the form of Xanthophyll crystals as described in step 1 a above(92 g, containing 86.23% Xanthophylls by weight (78.84% trans-Iutein ) were suspended in a mixture of 300 g isopropyl alcohol and 800 g methylene chloride. A solution of 10 gm of Hydroxypropylmethyl cellulose (5cps) in 200g isopropyl alcohol and 100 g methylene chloride was added to the above suspension along with 20 g natural tocopherol, 40g ascorbyl palmitate and 15g sodium starch glycolate. The suspension was strained through 100 mesh filter.
300 g of non-pareil seeds made of sugar, were charged into a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The carotenoids suspension as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C . Atomisation pressure of 1.2 kg/cm^ was maintained. 470 g of carotenoid loaded beadlets showing 9.46% trans-lutein were obtained.
$0 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g of hydroxypropyl methyl Cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of methylene chloride. 8 g of polyethylene glycol 600 was added as plasticiser. With this solution the coating was performed on carotenoid loaded non-pareil seeds in UniGlatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/ cm- was maintained. Bed temperature of 38,degree.C was maintained through out the coating process. 540 g of oxygen-barrier coated beadlets showing 8.51% trans-lutein content were obtained.
55 g of polyvinyl alcohol was dissolved in 300 g water , mixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxide and the mixture was sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glatt fluid-bed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^ was maintained. A spray rate of 150 g /hour was used. 580 g of moisture barrier coated carotenoid beadlets showing 6.8% trans-lutein content were obtained.

Example 2
Preparation of beadlets containing Free Lutein in Oil Suspension from petals of Marigold Flower
Lutemax® Free Lutein Oil Suspension( obtained from Marigold flower petals) (110 g free lutein oil suspension in 220 g safflower oil) was suspended in a mixture of 150 g isopropyl alcohol and 800 g chloroform. A solution of 5 gm of hydroxypropylmethyl cellulose (15 cps) in 200g isopropyl alcohol and 100 g methylene chloride was added to the above suspension along with 20 g natural tocopherol 40 g ascorbyl palmitate and 15 g sodium starch glycolate. The suspension was ^trained through 100 mesh filter.
|250 g of non-pareil seeds made of sugar, were charged into a Uni-Glatt fluid bed processor with jbottom-spray, and warmed for 30 minutes at 35.degree.C . The carotenoid suspension as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C . Atomisation pressure of 1.2 kg/cm^ was maintained. 510 g of carotenoid loaded beadlets showing 8.1% trans-lutein were obtained.
80 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of isopropyl alcohol, 8 g of polyethylene glycol 600 was added as plasticiser. With this solution the coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm^ was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 580 g of oxygen-barrier coated beadlets showing 7.2% trans-lutein content were obtained.
60 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated nonpareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature 6f 45 deg C was maintained during coating. Atomisation pressure of 1.5 kg/cm2was maintained. A spray rate of 150 g/ hour was used. 610 g of moisture barrier coated carotenoid beadlets showing 6.5% trans-lutein content were obtained.

Example 3.
Preparation of beadlets containing lutein from petals of Marigold Flower
Lutemax® Free Lutein (92 g, containing 78.84% trans-lutein ) was suspended in a mixture of 100 g isopropyl alcohol and 900 g methylene chloride. A solution of 80 gm of polyvinyl pyrrolidone in 400g isopropyl alcohol and 100 g methylene chloride was added to the above suspension along with 20 g natural tocopherol, 40g ascorbyl palmitate and 15g sodium starch glycolate. The suspension was strained through 100 mesh filter.
300 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The carotenoid suspension as iprepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed ^temperature was maintained at 35.degree.C. Atomisation pressure of 1.2 kg/cm^ was maintained. 550 g of carotenoid loaded beadlets showing 9% trans-lutein were obtained.
80 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of methylene chloride. 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm- was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 600 g of oxygen-barrier coated beadlets showing 7.9% trans-lutein content were obtained.
60 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated nonpareil seeds using Uni-Glatt fluid-bed coater using bottom spray mechanism. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^ was maintained. A spray rate of 150 g/hour was used. 650 g of moisture barrier coated carotenoid beadlets showing 6,6% trans-lutein content were obtained.
Example 4:
Preparation of beadlets containing 25 % trans-lutein from petals of Marigold Flower
Marigold extract (382 g, containing 75% trans-lutein ) was suspended in a mixture of 1200 g
isopropyl alcohol and 2800 g methylene chloride. A solution of 90 gm of hydroxypropylmethyl

cellulose (5cps) in 500g isopropyl alcohol and 200 g methylene chloride was added to the above suspension along with 60 g natural tocopherol, 80 g ascorbyl palmitate and 15 g cross-carmellose. The suspension was strained through 100 mesh filter.
300 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C. The carotenoid suspension as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C. Atomisation pressure of 2 kg/cm^ was maintained. 910 g of carotenoid loaded beadlets showing 29% trans-lutein were obtained.
75 g of polymer mixture comprising 32 g of ethyl cellulose and 48 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of methylene chloride. 8 g of polyethylene glycol 600 was added as plasticiser. With this solution 'the coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 2.2 kg/ cm2 was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 985 g of oxygen-barrier coated beadlets showing 27.1% trans-lutein content were obtained.
65 g of polyvinyl alcohol dissolved in 300 g water, then mixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated non-pareil seeds Using Uni-Glatt fluid-bed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was jmaintained during coating. Atomisation pressure of 2.5 kg/ cm2 was maintained. A spray rate of 150 g/ hour was used. 1040 g of moisture barrier coated carotenoid beadlets showing 25.7% trans-lutein content were obtained.
Example 5.
ftep 1: Preparation Of Xanthophyll Esters Concentrate As Per Our Indian Patent Application No.42Q/Mas/2002 Dtd 5*^ Tune 2002, Us Patent Application U.S.Applcn. Filing Dt: Tuly 30. 02 mocket: 14100.1us01), Pet Ptnt No. Pct/In 02/00218, Dated 13/11/2002
A weighed quantity of marigold oleoresin (150.3 g) with xanthophyll ester content 23.10% and tirans-lutein, cis-lutein and zeaxanthin area percentage by HPLC 67.23, 22.08 and 5.18 respectively was transferred into an Erlenmeyer flask (1000 ml) followed by the addition of 750 ml of 2-propanone. This was stirred using a thermostatically controlled stirrer at 15.degree.C to

25 degree.C for a period of 5-10 hours. After an interval of every 2 hours sample was drawn, filtered and the dried precipitated material was analyzed for the ester content and trans-: cis-ratio by HPLC. Finally when the desired degree of the purity had been achieved the solution containing precipitate was filtered through a Buchner funnel and the precipitate was dried in vacuum drier at ambient temperature.
The yield of the resulting concentrate was 20.10g (13.37 %) and the analysis showed xanthophyll ester content 59.26% assayed by spectrophotometric method, measuring at 474 nm. This xanthophyll esters concentrate contained area percentage by HPLC, trans- lutein 92 .71, cis-lutein 1.40 and zeaxanthin 5.11 respectively. On visual examination, this concentrate showed an improved orange red color as compared to the starting material, which is dark brown in color.
Step 2. Preparation of beadlets containing Xanthophyll Esters and trans-lutein esters from petals of Marigold Flower
Xanthophyll esters concentrate (160 g, containing 59.26% xanthophylls esters by weight-yielding 27.47% trans-lutein on hydrolysis) was suspended in a mixture of 700 g isopropyl alcohol and 600 g methylene chloride. A solution of 80 gm of hydroxypropylmethyl cellulose (IScps) in 400g isopropyl alcohol and 100 g methylene chloride was added to the above suspension along with 20 g natural tocopherol, 40 g ascorbyl palmitate and 20 g sodium starch glycolate. The suspension was strained through 100 mesh filter.
320 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The carotenoid suspension as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C. Atomisation pressure of 1.2 kg/cm^ was maintained. 600 g of carotenoid loaded beadlets showing 10.1% trans-lutein were obtained.
80 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of methylene chloride. 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm2 was maintained. Bed temperature of 38.degree.C was maintained through out the coating

process. 680 g of oxygen-barrier coated beadlets showing 8.67% trans-lutein content were obtained.
150 g of polyvinyl alcohol dissolved in 300 g water , then mixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated non-pareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature of 45.degree. C was maintained during coating. Atomisation pressure of 1.5 kg/cm^ was maintained. A spray rate of 150 g/hour was used. 810 g of moisture barrier coated carotenoid beadlets showing 6.0% trans-lutein content were obtained.
Example 6.
jPreparation of beadlets containing beta-carotene
jBeta-carotene (20% dispersion in palm oil) 160 g, was suspended in a mixture of 900 g isopropyl jalcohol and 800 g chloroform. A solution of 80 gm of polyvinyl pyrrolidone in 400g isopropyl ialcohol and 100 g methylene chloride was added to the above suspension along with 20 g natural tocopherol, 40g ascorbyl palmitate and 12g starch. The suspension was strained through 100 mesh filter.
450 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The carotenoid suspension as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C. Atomisation pressure of 1.2 kg/cm2 was maintained. 650 g of carotenoid loaded beadlets were obtained.
74 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g of hydroxy propyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of methanol. 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the coating Was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm^was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 680 g of oxygen-barrier coated beadlets were obtained.
145 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated non-

pareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^was maintained. A spray rate of 150 g hour was used. 810 g of moisture barrier coated carotenoid beadlets were obtained.
Example 7.
preparation of beadlets containing lecithin
Lecithin (Epikuron 200, made by Degussa Bioactives, containing 95% phophatidylcholine) 120 g, was dissolved in a mixture of 700 g ethanol and 800 g chloroform. A solution of 45 g of hydroxy propyl cellulose in 400 g isopropyl alcohol and 100 g methylene chloride was added to the above Suspension along with 25 g cross-linked polyvinyl pyrrolidone. The suspension was strained through 100 mesh filter.
$00 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The mixture suspension as prepared bove was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degrees.C. Atomisation pressure of 2.9 kg/cm2 was maintained. 680 g of lecithin loaded beadlets were obtained.
60 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of isopropyl alcohol 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the Coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using li>ottom spray technology at a spray rate of 400 g per hour. An atomization speed of 3 kg/cm^was rinaintained. Bed temperature of 45.degree.C was maintained through out the coating process. 740 g of oxygen-barrier coated beadlets were obtained.
120 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated nonpareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^was maintained. A spray rate of 150 g/hour was used. 850 g of moisture barrier coated lecithin beadlets were obtained.

Example 8.
Preparation of beadlets containing Natural Mixed Tocopherol in Vegetable Oil
Natural tocopherols in sunflower oil(Tocoblend L50) 80 g, was suspended in a mixture of 900 g isopropyl alcohol and 800 g chloroform. A solution of 80 g of polyvinyl pyrrolidone in 400 g isopropyl alcohol and 100 g methylene chloride was added to the above suspension along with 40 g ascorbyl palmitate and 12 g starch. The suspension was strained through 100 mesh filter.
400 g of non-pareil seeds made of sugar, were charged into a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C . The mixture as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained iat 35.degree.C. Atomisation pressure of 1.2 kg/cm2 was maintained. 580 g of.natural tocopherol loaded beadlets were obtained.
70 g of polymer mixture comprising 10 g of ethyl cellulose and 70 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g of isopropyl alcohol. 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the coating was performed on carotenoid loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm2 was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 650 g of oxygen-barrier coated beadlets were obtained.
130 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of Polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated Nonpareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^was maintained. A spray rate of 150 g/hour was used. 650 g of moisture barrier coated mixed tocopherol beadlets were obtained.
Example 9.
Preparation of beadlets containing sov bean oil
Soya bean oil, 120 g, was suspended in a mixture of 400 g isopropyl alcohol and 800 g chloroform. A solution of 80 gm of polyvinyl pyrrolidone in 400g isopropyl alcohol and 100 g

niethylene chloride was added to the above suspension along with 12 g of starch. The suspension was strained through 100 mesh filter.
400 g of non-pareil seeds made of sugar, were charged in to a Uni-Glatt fluid bed processor with bottom spray, and warmed for 30 minutes at 35.degree.C , The mixture as prepared above was sprayed on the non-pareil seeds at the rate of 500 g/hour. The bed temperature was maintained at 35.degree.C. Atomisation pressure of 1.2 kg/cm^ was maintained. 590 g of soy oil loaded beadlets were obtained.
70 g of polymer mbcture comprising 10 g of ethyl cellulose and 70 g of hydroxypropyl methyl cellulose was dissolved in solvent mixture comprising 500 g of methylene chloride and 1000 g iisopropyl alcohol, 8 g of polyethylene glycol 600 was added as plasticiser.. With this solution the coating was performed on oil- loaded non-pareil seeds in Uni-Glatt fluid bed coater using bottom spray technology at a spray rate of 400 g per hour. An atomization speed of 1.2 kg/cm^ was maintained. Bed temperature of 38.degree.C was maintained through out the coating process. 650 g of oxygen-barrier coated beadlets were obtained.
130 g of sodium carboxymethyl cellulose dissolved in 300 g water, then mixed with 6 g of (polyethylene glycol 400 and 2 g of titanium dioxide was sprayed on oxygen-barrier coated nonpareil seeds using Uni-Glatt fluidbed coater using bottom spray mechanism.. A bed temperature of 45.degree.C was maintained during coating. Atomisation pressure of 1.5 kg/cm^ was maintained. A spray rate of 150 g/hour was used. 770 g of moisture barrier coated soy oil beadlets were obtained.
Preparation and evaluation of tablet formulation of beadlets:
The beadlets of present invention (Examples 1- 4) 32 g were mixed with di-calcium phosphate 40 g , microcrystalline cellulose 20 g, sodium starch glycolate 2 g, hydroxypropyl cellulose 3 g, aerosil 1 g and talcum Ig. After uniform blending the powder mixture was compressed into tablets of 500 mg weight with hardness of 10 kg/cm-.



The tablets showed disintegration time, as determined by the procedure given in USP23 page No.1790, of less than 2 minutes and friability, as determined by procedure given in USP 23 page no 1981, of less than 1%. The dissolution rate was determined by procedure given in USP 23 page no.l791. The tablets showed dissolution rate of more than 70%. When scored tablets were examined under scanning electron microscopy, the beadlets were found to be spherical and intact. The cross-section beadlets recovered from the tablet when examined under scanning electron microscopy revealed that the polymer coatings could withstand the compression force during tabletting and are in intact condition. No leaching of carotenoid in to the tablet matrix was visible.
Stability Studies:
The beadlet formulations of Example 1-4 were subjected to accelerated stability studies at 40.degree.C and 75% relative humidity. The beadlets were analysed for carotenoid content before and after 6 months. The result of the study is shown in the following Table 2 .
TABLE 2 ; Accelerated Stability ibf beadlets at 40 DEG C 75%RH



Advantages of the present invention:
1. The beadlets of the lipid material is adequately protected against degradation due to oxygen,
light, moisture and acidic envirormient. t- When compressed into tablets, the beadlets do not disintegrate and hence do not allow
leaching of sensitive carotenoid into tablet matrix.
3. When the beadlets are administered their absorption in the body is quick and uniform thereby ensuring maximum bioavailability.
4. The beadlets provide physical attributes such as perfectly spherical shape, narrow particle size range, which are essential during the formulation of tablets and capsules.



We Claim
1.. Novel stable beadlets of lipophilic nutrients which comprises an inert spherical core having a coating of a mixture of stabilizing antioxidants and a lipophilic nutrients or mixtures thereof.
2. Novel stable beadlets as claimed in claim 1 wherein the lipophilic nutrients used are selected
from lutein , lutein esters, alpha-carotene, beta-carotene, zeaxanthin, zeaxanthin esters,
astaxanthin, lycopene.or their mixtures
3. Novel stable beadlets as claimed in claim 1 wherein the lipophilic nutrients used are xanthophyll esters containing lutein and zeaxanthin fatty acid esters in which 90 to 95 % is trans ^ lutein esters , 0 to 5 % is cis - lutein esters and 3.5 to 6 % is zeaxanthin esters
4. Novel stable beadlets as claimed in claim 1 wherein the lipophilic nutrients used are xanthophyll crystals containing at least 85% total xanthophylls in which at least 90 % is trans -lutein and / or zeaxanthin , the remaining being trace amounts of cis - lutein and other carotenoids
5.Novel stable beadlets as claimed in claims 1 to 4 wherein the amount of lipophilic nutrients present in the beadlet ranges from 1-50% of the weight of the beadlet.
6. Novel stable beadlets as claimed in claims 1 to 5 wherein the inert core used is selected from a material which does not react with the lipophilic nutrients employed for coating and is selected from carbohydrates such as sugar, mannitol, starch , sago , microcrystalline cellulose and the like and the lipid is selected from lecithin, mixed tocopherols or tocotrienols , plant stanols or phytosterols, lecithin and the like
7. Novel stable beadlets as claimed in claims 1 to 6 wherein the beadlets are in the form of spheres, globules and the like, the diameter of which ranges between 200 microns to 3 mm.
8. Novel stable beadlets as claimed in claims 1 to 7 wherein the beadlets have a coating of a layer of a film of an oxygen-barrier polymer

9. Novel stable beadlet as claimed in claim 8 wherein the resulting beadlets have a coating of a
layer of a film of a moisture-barrier polymer.
«
10. Novel stable beadlets as claimed in claim 9 wherein the polymer used for coating for
providing protection to the carotenoid or lipophilic nutrient or their mixtures against oxygen is selected from hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, methacrylate coipolymers, polyvinyl pyrrolidone, ethyl cellulose, carboxymethyl cellulose and polyvinyl alcohol and the like or their mixtures
n. Novel stable beadlets as claimed in 9 & 10 wherein the amount of the polymer used for providing a film of oxygen barrier coat is in the range of 2-20% of the weight of beadlets.
IZ- Novel stable beadlet as claimed in claims 9 to 11 wherein the resultant beadlets have a
fijrther coating of a layer of a film of a moisture barrier polymer. v
IS. Novel stable beadlet as claimed in claim 12 wherein the polymer used for coating for providing protection against moisture is selected from carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methacrylate copolymers ,polyvinyl ajlcohol and the like
14. Novel stable beadlets as claimed in claim 13 wherein the amount of the polymer employed for providing the moisture barrier coat is in the range of 2-20 % of the weight of the beadlets.
15. Novel stable beadlets as claimed in claims 1 to 14 wherein the carotenoid or lipophilic nutrient is mixed before coating , with stabilising antioxidants to enhance its stability .
16. Novel stable beadlet as claimed in claim 15 wherein stabilising antioxidants used is selected Irom 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 and the like or combinations thereof.
17. Novel stable beadlet as claimed in claims 15 & 16 wherein the amount of stabilising antioxidants used ranges from 0.1 to 20% of the weight of the beadlet.

18. Novel stable beadlet as claimed in claims 1 to 17 wherein the carotenoid or lipophilic nutrient used contains binding agents and / or disintegrating agents .
19. Novel stable beadlets as claimed in claim 18 wherein the disintegrating agent used is selected from starch, cross-linked polyvinyl pyrrolidone, cross-carmellose sodium and sodium starch glycolate or their mixtures.
20. Novel stable beadlets as claimed in claim 19 , wherein the amount of disintegrating agent used ranges from 0.1 to 5% by weight of the beadlets.
21. Novel stable beadlets as claimed in claims 1 to 20 , wherein the amount of stabilising
antioxidant used ranges from 0.1% to 20 % by weight of the beadlets.
22. A process for the preparation of novel beadlets of lipophilic nutrients as defined in claims
1 to 21 which comprises :
(i) forming a colloidal suspension of the desired lipophilic nutrients by dissolving the lipophilic nutrients in a non-polar solvent and diluting the resulting solution with a polar solvent (ii) spraying the resulting colloidal suspension on to an inert core in a fluid-bed system provided with bottom-spray mechanism at a temperature in the range of ambient temperature to 45 degree C , at an atomisation pressure in the range of 0 . 5 to 3 kg/cm^ and a spray rate in the range of 10 g/hour to 600g/hour and
(iii) drying the resulting beadlets in the fluid-bed system at an atomisation pressure of 0.8 to 1.2 kig/cm2
23. A process as claimed in claim 22 wherein the lipophilic nutrients used are selected from ciarotenoids such as lutein , zeaxanthin, lutein esters , alpha-carotene, beta-carotene, zeaxanthin esters, astaxanthin, lycopene, or lipophilic vitamins such as Vitamin A, Vitamin D, Vitamin E as tocopherols or tocotrienols. Vitamin K, or lipophilic substances like lecithin, plant sterols and stanols, omega 3 fatty acids or polyunsaturated fatty acids or lipids or mixtures thereof..
24. A process as claimed in claims 22 & 23 wherein the amount of lipophilic nutrients used ranges from 1-50% of the weight of the beadlets.

25. A process as claimed in claims 22 to 24 wherein the lipophilic nutrients are mixed with a stabilising antioxidant for enhancing the stability of the beadlets.
26. A process as claimed in claim 25 wherein the stabilising antioxidant used is 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 and the like or combinations thereof.
27. A process as claimed in claims 25 & 26 wherein the amount of stabilising antioxidant used ranges from 0.1 to 20% by weight of the beadlets.
28i. A process as claimed in claims 22 to 27 wherein the inert core used is selected from a material which does not react with the carotenoid or lipophilic nutrients employed for coating arid is selected from carbohydrates such as sugar, mannitol, starch , sago , microcrystalline cejlulose and the like or mixtures thereof, and Upids such as lecithin, mixed tocopherols or tocotrienols, plant stanols or phytosterols, lecithin and the like or mixtures thereof.
29. A process as claimed in claims 22 to 28 wherein the inert core is in the form of spheres, granules and the like and has a diameter in the range of 200 microns-3 mm.
30. A process as claimed in claims 22 to 29 wherein the non-polar solvent employed for forming the suspension of the lipid is selected from methylene chloride, chloroform, petroleum ether (low boiling), petroleum ether (high boiling) or their mixtures
31. A process as claimed in claims 22 to 30 wherein a mixture of methylene chloride and iSopropyl alcohol is used in which their ratio ranges from 1:1 to 0.1:1. , preferably ranging from 0.2:1 to 2:1.
32. A process as claimed in claims 22 to 31 wherein the polar solvent used for preparing the colloidal suspension of the lipid include isopropyl alcohol, acetone, methanol, ethanol, acetonitrile.
33. A process as claimed in claims 22 to 32 wherein the beadlets are provided with a coating of a Uyer of films of an oxygen barrier polymer .

34. A process as claimed in claim 33 wherein the polymer used for providing the coating of a film of oxygen barrier coat is selected from hydroxy propyl cellulose, hydroxy propyl methyl celjlulose, methacrylate copolymers, polyvinyl pyrrolidone, ethyl cellulose, carboxymethyl celjlulose and polyvinyl alcohol and the like or their mixtures
35; A process as claimed in claims 22 to 34 wherein the amount of the polymer employed for providing the coating of the film barrier coat is in the range of 2-20% by weight of the beadlet.
36. A process as claimed in claims 22 to 36 wherein the beadlets are provided with a coating of a layer of a moisture barrier coat barrier polymer
37L A process as claimed in claims 22 to 36 wherein the polymer used a coating for providing the layer of a moisture barrier coat barrier polymer is selected from carboxy methyl cellulose sodium, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, methacrylate copolymers ,polyvinyl alcohol and the like or their mixture
38. A process as claimed in claims 22 to 37 wherein the amount of the polymer used for providing the coating of a moisture barrier coat is in the range of 2-20% of the weight of the beadlets.
39. A process as claimed in claims 22 to 38 wherein the beadlets are in the form of spheres, globules and the like , the size ranging between 200 microns to 3 mm.
40. A process as claimed in claims 22 to 39 wherein stabilizers and / or disintegrating agents is / aite added to the carotenoids or lipophilic nutrients .
41. A process as claimed in claim 40 wherein the stabilisers used is selected from sorbic acid, sodium benzoate, sodium salicylate, EDTA, and the like or mixture thereof.
42. A process as claimed in claim 41 wherein the disintegrating agent used is selected from stjarch, cross-linked polyvinyl pyrrolidone, cross-carmellose and sodium starch glycolate.
43. A process as claimed in claims 22 to 42 , wherein the amount of stabilising and antioxidants used ranges from 0.1% to 20 % by weight of beadlets.

44. A process as claimed in claims 22 to 43 wherein binding agents is mixed with the colloidal suspension before it is used for spraying in the fluidized system include of acacia, tragacanth, polyvinyl pyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose (5 cps) and hydroxypropyl methyl cellulose (15 cps) or mixtures thereof.
#5. A process as claimed in claim 44 wherein the binder used is hydroxypropyl methyl cellulose in a range of 0.1-10 weight% of the beadlet.
46. A process as claimed in claim 45 wherein the disintegrating agents are used along with the
finding agents
i
47. A process as claimed in claim 48 wherein the amount of the disintegrating agent added is in a
ilange of 0.1 to 5 weight percent of the beadlets.
48.A process as claimed in claims 22 to 47 wherein the spraying of the lipid suspension is carried out at a bed temperature'ranging from 25.degree.C to 40.degree.C preferably is in the range of ambient to 32 degree C.
49. A process as claimed in Claims 22 to 48 wherein the atomization pressure during spraying is
in the range of 0.1 kg to 3 kg/cm2 preferably in the range of 1.0 to 2.5 kg/cm2.
50. Novel stable beadlets of carotenoids or lipophilic nutrients, or lipids ,or their mixtures
siibstantially as herein described with reference to the examples
51. A process for the preparation of the beadlets of carotenoids or lipophilic nutrients, or lipids
,ar their mixture substantially as herein described with reference to the examples


Documents:

028-che-2004-abstract.pdf

028-che-2004-assignement.pdf

028-che-2004-claims duplicate.pdf

028-che-2004-claims original.pdf

028-che-2004-correspondnece-others.pdf

028-che-2004-correspondnece-po.pdf

028-che-2004-description(complete) duplicate.pdf

028-che-2004-description(complete) original.pdf

028-che-2004-form 1.pdf

028-che-2004-form 26.pdf

028-che-2004-form 3.pdf

028-che-2004-form 6.pdf

028-che-2004-pct.pdf


Patent Number 209782
Indian Patent Application Number 28/CHE/2004
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 06-Sep-2007
Date of Filing 14-Jan-2004
Name of Patentee M/S. OMNIACTIVE HEALTH TECHNOLOGIES PVT LTD
Applicant Address RAJAN HOUSE, APPASAHEB MARATHE MARG, PRABHADEVI, MUMBAI 400 025,
Inventors:
# Inventor's Name Inventor's Address
1 DR. JAYANT DESHPANDE 201, PRASHANTI NILAYAM, PLOT NO. 17, SECTOR 21, NERUL, NEW BOMBAY 400 706,
PCT International Classification Number A 23 L 1/30
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA