Complete specification

NOVEL PRODUCTION PROCESS OF HIGH STABILITY BEADLETS AND

EMULSION FOR LIPOPHILIC COMPOUNDS.

FIELD OF INVENTION:

The invention relates to a process of preparing highly stable formulations such as coated beadlets and emulsions containing fat soluble substances .The invention particularly deals with stable formulations of carotenoids in the form of beadlets /emulsions and a method of making such formulations

BACKGROUND OF THE INVENTION:

Lipophilic actives such as vitamins and carotenoids play a significant role in both human and animal nutrition. Carotenoids have attracted the interest of researchers from diverse fields including chemistry, biochemistry, biology, food science and technology, medicine and nutrition for more than a century. Carotenoids are widely distributed natural pigments and are extracted from vegetal products and microbes such as algae and fungi -using different methods of extraction and purification. For long time the nutrition industry faces difficulties in handling these active substances in their highly pure form for the reason that they are sensitive substances to different conditions. The major challenge is to stabilize these lipophilic active ingredients from the exposure to oxidation, heat, and light sensitivity and to moisture. The stability of the lipophilic substances can be achieved through encapsulation, trapping the actives in a blanket of protecting materials.

Encapsulation is a process in which minor particles of size or droplets are surrounded by a coating to give small capsules these encapsulated substance can be in dry or liquid forms. Beadlets are one such form of dry encapsulated materials, to be defining beadlets in simpler term; a beadlet is a small sphere having a uniform wall around it. The material
inside the beadlet is referred to as the core substance, inner phase, or fill, whereas the wall is referred to a shell, coating, or membrane. These beadlets are generally less than about a millimeter in diameter.

There are various techniques know and used in the past for making beadlets including physical process such pan coating, centrifugal extrusion, spray drying, air suspension coating etc , there are also physio-chemical process such as isotropic gelatin, Coacervation, Poly condensation, Cross-linking, Polymerization etc have been used in the industry to make the beadlets.

U.S. Pat. No. 4,670,247 describes a process for preparing fat-soluble vitamin active beadlets which includes forming an aqueous emulsion of a fat-soluble vitamin-active material, gelatin, and a sugar converting the emulsion to dry particulate form containing the non-aqueous constituents of the emulsion and heat treating the resulting product to form water insoluble beadlets.

U.S. Pat. No. 4,389,419, Describes vitamin encapsulation process which comprises the steps of making an emulsion with alkali metal alginate, polar polysaccharide, and vitamin dispersed in oil. A droplet of this emulsion is then allowed to immerse in an alcoholic cations solution, finally giving a spherical alginate matrix containing polysaccharide and oil droplets. Thus the vitamins are protected from oxidation.

U.S.Pat.No. 5,492,701 Describes a process for the preparation of spherules by passing an oil-in-water emulsion through a nozzle forming spherules are recovered using cross linking agent under cold air blow.

U.S. Pat. No. 6,146,671 discloses a method for protecting a heat and/or oxygen-labile compound by encapsulation in a protective matrix of alginate and an additional polymeric material such as gelatin which is a non vegetal source.

U.S. Pat. No. 7,097,868 Teaches a process to make Stable coated microcapsules containing lipophilic compounds by combining a first solution made out of a surface active agent to a second solution of alkali metal alginate then adding the combined third
solution in drops to a fourth solution containing calcium ion which forms beadlets, finally these beadlets are washed in acid solution and coating is given.

U.S.PatNo 7,691,297 teaches a method for powderous preparations of fat-soluble substances by mixing an aqueous emulsion of the fat-soluble substance and a matrix component which are sprayed in a vertical spray tower and then by separate inlets, powderous starch and a stream of hot air are also fed in the upper section similarly a stream of cold air is fed in the lower section of the spray tower to form a fluidized bed of starch-covered beadlets comprising the matrix component as well as the fat-soluble substances. The beadlets are then dried.

U.S.Pat.Application 20100112188 discloses a method for Novel stable beadlets of lipophilic nutrients comprising a inner core consisting of a stabilizing antioxidants, lipophilic nutrients, or mixtures thereof further the beadlets are coated with one or more can be used to protect against moisture and/or oxygen.

Obtaining high purity product, developing cost effective process and establishing a stable formulation- are still major issues, in the field of carotenoids. A simple, highly stable encapsulation method with only natural ingredients is the need of the hour

OBJECTIVE OF THE INVENTION

The main object of the invention is to provide a stable composition of fat soluble substances like carotenoids in the form of beadlets.

Another object of the invention is to provide a cost effective method of making such beadlets using the natural ingredients.

Yet another object of the invention is to produce a water soluble emulsion of the lipophilic compounds like carotenoids using natural emulsifying agents.

The invention describes a process for preparing beadlety containing fat soluble substances having the steps of: (1) forming beadlets of lipophilic compounds such as carotenoids, xanthophylls and vitamins with natural ingredients using extrusion-spherodization method; (2) coating the beadlets with a mixture comprising of a natural
antioxidant, polymer and a solvent mixture to give a highly stable coated beadlets; Another aspect of this invention is to make natural water soluble emulsion for the lipophilic compounds by using natural emulsifiers

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a production of Carotenoid formulations such as beadlets or pellets and emulsions with better stability and other functional properties like better compressibility, dispersibility, stability, flowability for beadlets or pellets and better emulsion stability, despersibily, suspendability for the emulsion formulation.

The bare beads of both water dispersible grade and directly compressible grades are produced by extrusion - spheroidization technology, are stabilized with a novel coat mixture as a primary coat using fluid bed technology bottom spray technology. The primary coat is named as stability coat. As a result of stability coat the stability of the beads are increased to more than 90% of stability in an accelerated stability study.

The emulsions of carotenoids are manufactured using 100% vegetarian based ingredients with better properties like dispersibility, emulsion stability, active stability. The carotenoids are complexed with natural based emulsifier with HLB more than 12 for better emulsification.

The process of the invention comprises the following steps:

(a) The stable beadlets with better stability, compressibility and flowabailiy is produced by extrusion and spheroidization technology. The carotenoids are mixed with dilution, solid emulsifier, antioxidant, filler, and anti-caking agent of natural origin to form a semi wet mass along with De-mineralized water of required consistency. The semi wet mixture is extruded and spheroidized to form beads of 200 to 600 micron sizes.

(b) The produced beads are dried in fluid bed dryer at a temperature of 30°C to 60°C, more preferably 35°C to 55°C and most preferably 40°C to 50°C till a moisture level of 2% to 8% in the bare bead level, more preferably 2.5% to 7% level and most preferably 3 % to 6%.

(c) The dried beads are coated with novel antioxidant polymer solvent mixture in a bottom spray fluid bed processor. The polymer used for the coating is of 2% to 10% of the bare bead, more preferably 2.5% to 8 % and most preferably 3% to 5%. The polymer is mixed with a solvent for coating. The antioxidant used for in the antioxidant coating is of 0.5% to 3% of the bare beads, more preferably 0.7% to 2.8% and most preferably 1% to 2%.

(d) The beads were also coated with different ratio of polymer - antioxidant mixture based on the particle size distribution using surface area calculation.

(e) The produced bead of the process has better stability and better recovery. The stability of the beads is at least 90% and recovery is at least 95% from the process.

(f) The emulsions are produced by mixing the carotenoids with natural emulsifiers with Hydrophilic Lipophilic balance (HLB) of more than 12, natural diluents, water, and natural antioxidant for both actives and emulsion. And mixed under high shear condition to produce emulsions of less than 20 micron size. The emulsions produced have very good stability on storage and also after its application as a coloring agent or antioxidant in food application.

Example 1:

The beadlets are produced by extrusion - spheroidization technique. Clean all equipment used in the process with DM water and dry it proper. The active ingredient Free Lutein powder with 82.393 mg/g of carotenoids content [lutein is about 76.62 mg/ g

and zeaxanthin is about 7.62 mg/g] of about 70 gms is mixed with 10 gms of silicon dioxide, 80 gms of starch, 315 gms of MCC and 12.5 gms starch ester. The above mixture is blended properly in a planetary mixture and sieved through 35 mesh to make Mixture I. Mixture II is prepared by adding 2.5 gms of starch ester, 5 gms of natural
mixed tocopherol and 5 gm of vitamin C in 500ml DM water, Mixture II is mixed with mixture I, Blend it thoroughly till it is homogeneous. Once homogenous mixture is prepared, the mixture is then extruded in a extruder with a mesh size of 0.6 mm. After extrusion, the extrudes are loaded into spheroidizer with 2 mm pitch plate on a lot wise to produce beads, the extrudes are loaded into spheroidizer at low RPM [700 - 800], once the addition is complete and beads are formed after 10-15 min process at high RPM [1300 - 1400], once spheroidization is completed, the material is dried in fluid bed processor [FBP] for a period of 2 hrs till the LOD of the product is less than 5%, the material is dried at inlet temp ( 60 degree) and outlet temp (45 degree) in FBP. Once drying is complete, the dried beads are sieved through 25 mesh to remove the lumps. The sieved beadlets are further sieved using different sieve size as required to produce narrow particle size beads for coating on batches. The sieve analysis results in 95 gms of 25#(+) and 230 gms of 30#(+) and 100 gms of 35#(+) and 75 gms of 35#(-). The bare beadlets of mesh size 25#(+) and 30#(+) were mixed together and coated with 3% of hydroxylpropyl methylcellulose (HPMC) and 1.2% of Mixed tocopherol mixture in methylene dichloride. And the bare beads of 35#(+) and 35#(-) were mixed together and coated with 4% of HPMC and 1.6% of Mixed tocopherol mixture in methylene dichloride. The coating is done in fluid bed processor at 35 deg C with a slow flow rate for uniform coating. Once coating is done, the coated beads are dried in FBP to remove the traces of methylene dichloride. The coated beads have a stability of more than 90%. Figure 1 shows the stability of the coated beadlets.

The present invention has made it possible to achieve a process which can be very easy to implement in terms of industrial application. All of the ingredients utilized in the process are both edible and safe for consumption without any animal or fish origin. Thus one is able to use the process of the present invention to obtain a highly stable carotenoids beadlets.

Various modifications and use of substances with similar properties are possible and have to be considered within the scope of the invention.

FIGURE1

Example 2:

The emulsion of Lycopene is prepared by the following process, Lasemul [ Ethoxylated castor oil derivative] of about 21 gms is homogenized with 15 gms of purity gum [ Modified food starch]. This mixture is homogenized at room temperature. The above mixture is mixture I, Mixture II is prepared by homogenizing 3 gm of vitamin E oil and 70 gms of 10% tomato lycopene oleoresin and 20gms of MCT [ Medium Chain triglyceride]. Both the mixture I and Mixture II is homogenized in a high shear homogenizer for 20 min to produce Microemulsion of Lycopene. The emulsion has a very good water dispersibility and emulsion stability once dispersed. The product is also highly stable, has a stability of more than 90%.

CLAIMS:

We claim:

1. A stable formulation of lipophilic compounds comprising of beadlets obtained by extrusion-spherodization using at least one natural ingredient and an antioxidant and the beadlets having a coating comprising of at least one natural antioxidant, polymer and a solvent mixture.

2. The stable formulation of lipophilic compounds as per claim 1 wherein the lipophilic compound is selected from carotenoids, xanthophylls and vitamins.

3. The stable formulation of lipophilic compounds as per claim 1 or claim 2 wherein the carotenoids are selected from the group consisting of singly or mixed together including, but not limited to: Alpha-carotene, Apocarotinal, Beta-carotene, Gama-Carotene, Lycopene, Neurosporene, Phytoene and Phytofluene.

4.The stable formulation of lipophilic compounds as per claim 1 or claim 2 wherein the xanthophylls are selected from the group consisting of singly or mixed together including, but not limited to :Astaxanthin, Canthaxanthin, Citranaxanthin , Cryptoxanthin, Fucoxanthin, Lutein, Neoxanthin, Rhodoxanthin, Rubixanthin, Violaxanthin, Zeaxanthin.

5. The stable formulation of lipophilic compounds as per claim 1 or claim 2 wherein the vitamins are selected from the group consisting of singly or mixed together including, but not limited to; tocopherol, tocopherol acetate, tocopherol succinate, vitamins A, Vitamin D, Vitamin E, and Vitamin K.

6. The stable formulation of lipophilic compounds as per claim 1 or claim2 wherein the natural ingredient is selected from the group: silicon dioxide, starch, microcrystalline cellulose, and starch ester.

7. The stable formulation of lipophilic compounds as per claim 1 or claim 2 wherein the anti-oxidant is from the group consisting of singly or mixed together including, but not limited to: Vitamins such as Vitamin E, tocotrienols, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, epsilon-tocopherol, Vitamin C, ascorbyl palmitate, and natural oils. Polyphenols compounds extracted from Tea, Rosemary, Coffee, Turmeric, Cinnamon, Grapes, Pomegranate, Berries, and Apples.,

8. The stable formulation of lipophilic compounds as per claim 1 wherein the polymer is from the group consisting of singly or mixed together including, but not limited to methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxylpropyl methylcellulose, methylethyle cellulose, carboxymethyl cellulose, xanthan gum, gum arabica, guar gum, gum acacia, gum tragacanth, gum karaya, gellan gum, carob gum, and tara gum.,

9. The stable formulation of lipophilic compounds as per claim 1 wherein the solvent mixture is from the group consisting of singly or mixed together including but not limited to methylene chloride, chloroform, petroleum ether, ethanol, methanol, isopropyl alcohol, acetonitrile, and acetone.,

10. A method for obtaining stable formulation of lipophilic compounds comprising the steps of:

a) forming the beadlets of lipophilic substance using extrusion-spherodization method using a natural ingredient such as silicon dioxide, starch, microcrystalline cellulose, starch ester and antioxidants.

b) coating the beadlets with a mixture comprising of at least one natural antioxidant, polymer and a solvent mixture

11. The method as per claim 10 wherein the lipophilic compounds are selected from: carotenoids, xanthophylls and vitamins

12. The method as per claim 10 wherein the lipophilic compounds are carotenoids.

13. The method as per claim 10 wherein the natural antioxidant is selected from the group consisting of singly or mixed together including but not limited to:

a) Vitamins such as Vitamin E, tocotrienols, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, epsilon-tocopherol, Vitamin C, ascorbyl palmitate, and natural oils,

b) Polyphenols compounds extracted from Tea, Rosemary, Coffee,Turmeric, Cinnamon, Grapes, Pomegranate, Berries, and Apples.

14. The method as per any of the preceding claim 10 wherein the polymer is hydroxylpropyl methylcellulose.

15. The method as per any of the preceding claims 10 wherein the solvent mixture is methylene dichloride

16. A method of preparing a stable formulation of carotenoids comprising steps of:

a) forming the beadlets of carotenoids using extrusion-spherodization method using
silicon dioxide , starch, microcrystalline cellulose, starch ester, mixed tocopherol and
vitamin C

b) coating the beadlets with a mixture comprising of hydroxylpropyl methylcellulose;
mixed tocopherol and methylene dichloride.

17. The method of preparing a stable a stable emulsion of carotenoids comprising the step of mixing the carotenoids with natural emulsifiers with Hydrophilic Lipophilic balance (HLB) of more than 12, natural diluents, water, and natural antioxidant wherein the mixing is done under high shear condition to produce emulsions of less than 20 micron size.

18. A method for obtaining stable formulation of lipophilic compounds comprising the steps of:

a) mixing the lipophilic substances with silicon dioxide, starch, microcrystalline cellulose, starch ester ,mixed tocopherol and vitamin C to form a semi wet mixture.

b) extruding and spherodizing the mixture obtained from the above step to form beads of approximately 200-600microns.

c) drying the beads at a temperature of 30°C to 60°C, more preferably 35°C to 55°C and most preferably 40°C to 50°C preferably in fluid bed dryer till a moisture level of 2% to 8% in the bare bead level, more preferably 2.5% to 7% level and most preferably 3 % to 6%.

d) coating the dried beads with natural antioxidant ,polymer, solvent mixture in a bottom spray fluid bed processor.

19. The method as per claim 18 wherein the polymer used is hydroxypropyl methyl cellulose.

20. The method as per claim 18 wherein the concentration of hydroxypropyl methyl cellulose used for the coating is of 2% to 10% of the bare bead, more preferably 2.5% to 8 % and most preferably 3% to 5%.

21. The method as per claim 18 wherein the antioxidant used is mixed tocopherol mixture

22. The method as per claim 18 wherein the concentration of mixed tocopherol mixture used for coating is of 0.5%to 3% of the bare beads, more preferably 0.7% to 2.8% and most preferably 1% to 2%

23. A method of preparing stable micro-emulsion of lycopene comprising the steps of;

i) homogenizing Lasemul [ Ethoxylated castor oil derivative] of about 21 gms with 15 gms of purity gum [ Modified food starch]

ii) homogenizing appox. 3gm of vitamin E, around 70gms of 10% tomato lycopene oleoresin and 20gms of Medium chain triglyceride

iii) homogenizing the mixtures obtained step i) and mixture obtained from step ii) in high shear homogenizer for approx. 20 minutes to produce micro-emulsion of lycopene.