Description:TECHNICAL FIELD OF INVENTION:
The present invention relates to compositions of Cholecalciferol (Vitamin D3) and method of preparation thereof. The stable compositions of the present invention are obtained by spray drying of Vitamin D3 emulsion.

BACKGROUND OF THE INVENTION:
Nutrition is the prime factor for a healthy and sound body. The skeletal system functions as the basic framework of a body and the entire body are built around the hard framework of Skeleton which is a combination of all the bones and tissues associated with cartilages and joints. The health and strength of our bones rely on a balanced diet comprising nutrients. Many nutrients play a role in bone health, such as calcium, vitamin D, protein, magnesium, phosphorous, and potassium.
Cholecalciferol or Vitamin D3 is one such nutrient which is of utmost importance right from the conception to the infinitude for all form of life. Cholecalciferol is needed by the body for healthy bones, muscles, nerves, and to support the immune system. It works by helping the body to use more of the calcium found in foods or supplement. Vitamin D3 (cholecalciferol) is a fat-soluble vitamin that helps the body absorb calcium and phosphorus and facilitates immune system function. Deficiency of Vitamin D3 can lead to weak bones and skeletal abnormalities. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. Thus, Deficiency of Vitamin D is almost considered as a pandemic and is a world-wide concern.
Cholecalciferol or Vitamin D3 is required by our body for bone mineralisation. Foods like fish, liver, egg, milk, and fortified products are a good source of vitamin D3.
Further considering the sources of Vitamin D3, Vitamin D3 it is also considered of prime importance for the poultry animals and birds which provide the sources of Vitamin D3. Studies have proven that Vitamin D3 affects the Calcium and Phosphorus utilization, egg quality, and bone mineralization of laying hens. Enriching laying hen diets with specific vitamins has a direct impact on vitamin content in the egg yolk and meat.
Thus, Cholecalciferol, also known as vitamin D3, is a prohormone indicated for use as a dietary supplement for all forms of life with vitamin D insufficiency or deficiency as well as for enriching the life forms with Vitamin D3.
To be used by the body, vitamin D3 must be metabolised following ingestion into 25-Hydroxycholecalciferol (25(OH)D3) in the liver and subsequently into its active metabolite 1,25-dihydroxycholecalciferol (1,25(OH)2D3) in the kidneys. Hence the from in which Vitamin D3 id made available to the body is of utmost importance.
Prior reveals several compositions of Vitamin D3 comprising other added excipients and having varying potency of Vitamin D3 prepared by different processing technologies.
WO2003059358 discloses oil composition containing 25-hydroxy Vitamin D3 including oils, emulsions, microencapsulated oils and feed premixes and methods of making and using such compositions.
WO2004062382 provides a process for the manufacture of water dispersible preparations of fat-soluble substances.
US5668183 discloses novel, stable, cold water-dispersible preparations of fat-soluble substances contain a water-soluble or water-dispersible lignin derivative as the matrix component.
US5804573 provides pharmaceutically active derivatives of vitamin D2 and vitamin D3 in a solid-state composition stabilized by the presence of effective amounts of pharmaceutically acceptable antioxidant and polyoxy alkyl stabilizer.
US20160030356 relates to stable solid formulations of vitamin D3 and to processes for preparation of the same. The inventio provides stabilized compositions comprising vitamin D3 at least one lipophilic dispersant, one or more antioxidants, at least one adsorbent and one or more pharmaceutically acceptable excipients and further coated with a barrier coating.

Considering the stability aspect of Cholecalciferol, it is of utmost importance that the compositions fulfil the stability criteria failing which the compositions would be vulnerable to oxidation. Oxygen is abundantly present in nature and hence liquid compositions or those involving oxidising agents would affect the stability of the final composition which is an undesirable aspect.
Further considering the prior art scenario the compositions as exemplified fail to meet the stability conditions of high temperature and humidity. Compositions in the oil phase are susceptible to rancidity and further would raise stability and storage concerns. Similarly liquid preparations would be prone to oxidation which would affect the final content and form of Cholecalciferol or Vitamin D3.
Thus, identifying the necessity and importance of this Vitamin D3 for all life forms and in consideration with the stability aspect of Vitamin D3 the inventors of the present invention have provided compositions comprising vitamin D3 with enhanced stability of vitamin D3. The inventors of the present invention have also identified that process for preparation the present invention would also play a vital role and would affect the stability of the final product Accordingly the inventors of the present invention have also provided a process for these compositions which is cost effective and economic. The compositions comprising Vitamin D3 and process for preparing them involve a technological advance over the existing prior art and are economically significant.
OBJECT OF THE INVENTION:
It is an object of the present invention to provide stable compositions comprising Cholecalciferol or Vitamin D3.
Another object of the invention is to provide a process for preparing stable compositions comprising Cholecalciferol or Vitamin D3.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides composition comprising Cholecalciferol or Vitamin D3 SD100.
In an aspect the present invention provides a stable composition comprising Cholecalciferol or Vitamin D3 along with pharmaceutically acceptable ingredients.
In a further aspect the provides a stable composition comprising Cholecalciferol or Vitamin D3, medium chain triglyceride oil, encapsulating agent diluent, antioxidant, preservative and flow promotors or glidant.
In another aspect the present invention provides a process for preparation of stable compositions comprising Cholecalciferol or Vitamin D3.
In an aspect the stable composition of the present invention is obtained by spray drying of Vitamin D3 emulsion.
In yet another aspect the process for preparation of the stable composition of the present composition comprises:
i) Preparation of the Oil Phase;
ii) Preparation of the Water/Aqueous Phase;
iii) Homogenisation of the oil phase and water phase of step (i) and (ii) to form a uniform emulsion;
iv) Spray drying the Homogenised emulsion formed in step (iii); and
v) Adding the flow promoter to the spray dried powder of step (iv) to yield the final product.
In a yet further aspect, the oil phase for processing the present invention is prepared by dissolving Vitamin D3 or Cholecalciferol in medium chain Triglyceride oil along with antioxidant Dl alpha tocopherol.
In a yet further aspect, the Aqueous /water phase for processing the present invention is prepared by dissolving encapsulating agent Modified Corn Starch, Sucrose, preservative Sodium ascorbate in water.
In an aspect the composition of Vitamin D3 or Cholecalciferol is used as a dietary supplement to treat deficient levels of Vitamin D3.
In another aspect the composition of Vitamin D3 or Cholecalciferol is used for calcium and phosphorus absorption.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: Manufacturing Process flow chart (Vitamin D3 100SD)

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides spray dried stable compositions comprising Cholecalciferol or Vitamin D3 along with pharmaceutically acceptable excipients. The invention relates to a spray dried Vitamin D3 powder suitable for supplementation to treat deficient levels of Vitamin D and for calcium and phosphorous absorption.
The term Vitamin D3 and Cholecalciferol may be used interchangeably and would refer to the same active ingredient of the present invention.
‘Vitamin D3 100’ as referred to in the present invention means Vitamin D3 having a potency of 100000 IU/g.
‘SD’ refers to Spray dried or ‘Spray drying’.
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. As used herein, the following terms and phrases shall have the meaning set forth below.
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention.
Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.
In an embodiment of the present invention there is provided a composition comprising Cholecalciferol or Vitamin D3.
In another embodiment the present invention provides a stable composition comprising Cholecalciferol or Vitamin D3 along with pharmaceutically acceptable ingredients.
In a further embodiment the stable composition of the present invention comprises Cholecalciferol or Vitamin D3, medium chain triglyceride oil, encapsulating agent, diluent, antioxidant, preservative and flow promotors or glidant.
In an embodiment the composition of the present invention comprises about 0.15% to 0.35% of Vitamin D3.
In a preferred embodiment the per gram of the composition of the present invention comprises 100000 IU of Vitamin D3.
In yet another preferred embodiment the composition of the present invention is obtained by spray drying of Vitamin D3 emulsion.
In a further embodiment of the present invention the process for preparation of stable compositions of the present invention comprises:
i) Preparation of the Oil Phase;
ii) Preparation of the Aqueous/ Water Phase;
iii) Homogenisation of the oil phase and water phase of step (i) and (ii) to form a uniform emulsion;
iv) Spray drying of the Homogenised emulsion formed in step (iii); and
v) Adding the flow promoter to the spray dried powder of step (iv) to yield the final product.
vi) Packing the product under Nitrogen to avoid degradation.
The medium chain triglyceride oil aids as a medium in the composition and ensures the uniform distribution of Cholecalciferol in the oil phase and present in a concentration ranging from 2.0% to 6.0% of the total solid contents in the emulsion.
In an embodiment medium chain triglyceride oil is MCT oil and present in a concentration ranging from 2.7% to 3.3% of the total solid contents in the emulsion.
The encapsulating agent for the present invention is selected from but not limited to the group consisting of starch, corn starch, modified corn starch, microcrystalline cellulose, dicalcium phosphate dihydrate or a mixture thereof.
The encapsulating agent serves as a protective covering over Vitamin D3 and is present in a concentration ranging from 65% to 85% of the total solid contents in the emulsion.
In an embodiment encapsulating agent is Modified Corn starch and present in a concentration ranging from 66% to 80% of the total solid contents in the emulsion.
The diluents of the present invention are selected from but not limited to the group consisting of lactose, Maltodextrin, fructose , Sucrose or combination thereof present in a concentration of 10 to 30 % of the total solid contents in the emulsion.
In an embodiment diluent/sweetener is Sucrose present in a concentration of 16 to 19 % of the total solid contents in the emulsion.
The Antioxidant for the composition of the present invention is selected from but not limited to propyl gallate, butylated hydroxyanisole, ascorbic acid, sodium ascorbate, calcium ascorbate, tocopherol, tocopherol acetate, tocopherol acid succinate or mixtures thereof and are present in a concentration of 0.5 5 to 1.5 % of the total solid contents in the emulsion
In an embodiment the antioxidant is Dl -alpha Tocopherol present in a concentration of 0.9 % to 1.1 % of the total solid contents in the emulsion
The composition further comprises of preservatives selected from but not limited to the group consisting of Sorbic acid , Benzoic acid , sodium benzoate, sodium ascorbate or mixtures thereof and present in a concentration ranging from 3.0% to 8.0% of the total solid contents in the emulsion
In an embodiment the preservative is Sodium Ascorbate present in a concentration of 3.0 % to 5.0% of the total solid contents in the emulsion
The oil phase for processing the present invention is prepared by dissolving Vitamin D3 or Cholecalciferol in medium chain Triglyceride oil along with antioxidant Dl alpha tocopherol.
Accordingly in an embodiment the oil phase prepared by dissolving the solid content in the oil comprises Vitamin D3 100SD equivalent to 100000 IU/g +/- 20% Medium Chain Triglyceride Oil (2.7% to 3.3%) and antioxidant Dl alpha tocopherol (0.9% to 1.1%) based on the total solid contents in emulsion.
The water /Aqueous phase for processing the present invention is prepared by dissolving encapsulating agent Modified Corn Starch, Sucrose, preservative Sodium ascorbate in water.
Purified water is used as a preferred vehicle for preparation of the Aqueous or Water phase.
Accordingly in an embodiment the Water/Aqueous phase is prepared by dissolving encapsulating agents like Modified Corn Starch (65.745% to 80.311%), Sucrose (15.75% to 19.25%), along with preservative sodium ascorbate in water.
In another embodiment the oil and water phases are homogenised to uniform emulsion having a viscosity of 30 cp to 150cp.
In yet further embodiment the emulsion having a viscosity of 30 cp to 150cp is spray dried through a nozzle equivalent to 1.0 /1.2/1.5/2.0/2.5 mm size using a peristaltic pump or pressure pump with an inlet temperature of 130 ? to 230 ? and an outlet temperature of 70 ? to 120 ?.
The composition of the present invention further includes flow promotors or glidants or lubricants selected from but not limited to the group consisting of colloidal silica , silicon dioxide, precipitated silica or mixtures thereof present in a concentration ranging from 1.0 % to 5.0 % of the total composition.
In an embodiment the flow promoter or glidant is Silicon dioxide present in a concentration of 1.0 % to 2.0 % of the total composition.
In an embodiment the process for preparation of the composition of the present invention comprises:
i) Preparation of Oil phase
Vitamin D3 antioxidant Dl- alpha -tocopherol and oil (Medium Chain Triglyceride Oil) are taken in a Stainless steel or Glass container and stirred for 30 to 150 minutes at temperature 30? to 60 ? to form a uniform Oil phase.
ii) Preparation of Water phase
Modified Starch, Sucrose and Sodium Ascorbate are dissolved in water in a stainless-steel container and stirred at 30? to 90? for 30-120 minutes.
iii) Emulsion preparation
The Oil phase prepared in Step (i) and Water /Aqueous phase prepared in step (ii) are homogenised together with a high-speed homogeniser forming a uniform emulsion for a period of 15 to 90 minutes. Viscosity of the Emulsion is checked which should be around 30 centipoise to 120 centipoise. Addition of purified water is done to bring the viscosity in range if required.
iv) Spray drying
Homogenised Emulsion of step (iii) is spray dried through a nozzle equivalent to 1.0 /1.2/1.5/2.0/2.5 mm size using a peristaltic pump or pressure pump with an inlet temperature of 130 ? to 230 ? and an outlet temperature of 70 ? to 120 ?.
The high temperature range in the present process has resulted in lower moisture content and higher stability of the product.
Spray dried encapsulated Vitamin D3 100SD powder is collected in product receivers of spray drier.
v) The spray dried encapsulated Vitamin D3 100SD powder obtained in step (iv) is blended with the flow promoter Silicon Dioxide sifted through a 30 mesh or 40 mesh or 80 mesh to ensure proper flow of the product.
vi) The spray dried encapsulated Vitamin D3 100SD powder blended with Silicon Dioxide is packed under nitrogen/vacuum blanketing to avoid degradation.
The manufacturing process flow chart of the above process has been shown in Figure 1.
The spray dried encapsulated Vitamin D3 100SD powder may be further processed to unit dosage forms such as but not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles.
These spray dried compositions may find wide use for all forms of life and may be used as food fortifiers or food supplement which may be administered along with food, beverages such as water, juices, soups, milk and other liquids, poultry feeds or may be further processed into compliant dosage forms for administration to the respectable recipient.

The spray dried encapsulated Vitamin D3 100SD powder is further subjected to Accelerated and Long-term stability to ensure the long-term stability of the composition.
Accordingly, the composition of the present invention was subjected to storage conditions of 25° C./60% RH, , and 40° ±2ºC./75±5%RH.
In an embodiment of the present invention the spray dried Vitamin D3 or Cholecalciferol spray dried powder is used as a dietary supplement to treat deficient levels of Vitamin D3.
In another embodiment the spray dried Vitamin D3 or Cholecalciferol spray dried powder is used for calcium and phosphorus absorption.
The following examples are set forth below to illustrate the composition and methods according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter and embodiments disclosed herein, but rather to illustrate representative compositions, methods /processes and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.
EXAMPLES
Example 1
Composition of Vitamin D3 100SD Spray Dried Powder:
Sr. No. Ingredients % Function
1. Vitamin D3 0.25% Active ingredient
2. Modified Starch 73.05% Encapsulating agent
3. Sucrose 17.50% Diluent/Sweetener
4. Sodium Ascorbate 4.00% Antioxidant
5. Dl- alpha -tocopherol 1.00% Preservative
6. Medium Chain Triglyceride Oil 3.00% Medium
7. Silicon dioxide 1.50% Glidant

Purified water is used to make an emulsion with 20 to 50% solids.
Procedure:
i) Preparation of Oil phase
Take Vitamin D3 antioxidant Dl- alpha -tocopherol and oil (Medium Chain Triglyceride Oil) in a Stainless steel or Glass container and stir for 30 to 150 minutes at temperature 30? to 60 ? to form a uniform Oil phase.
ii) Preparation of Water phase
Dissolve Modified Starch, Sucrose and Sodium Ascorbate in water in a stainless-steel container and stir at 30? to 90? for 30-120 minutes.
iii) Emulsion preparation
Homogenise the Oil phase prepared in Step (i) and Water /Aqueous phase prepared in step (ii) together with a high-speed homogeniser for a period of 15 to 90 minutes to form a uniform emulsion.
Check the Viscosity of the Emulsion.
Add purified water to achieve a viscosity around 30 centipose to 120 centipose.
iv) Spray drying
Spray dry the Homogenised Emulsion of step (iii) through a nozzle equivalent to 1.0 /1.2/1.5/2.0/2.5 mm size using a peristaltic pump or pressure pump with an inlet temperature of 130 ? to 230 ? and an outlet temperature of 70 ? to 120 ?.
Collect the Spray dried encapsulated Vitamin D3 100SD powder in product receivers of spray drier.
v) Blend the spray dried encapsulated Vitamin D3 100SD powder obtained in step (iv) with the flow promoter Silicon Dioxide sifted through a 30 mesh or 40 mesh or 80 mesh to ensure proper flow of the product.
vi) Pack the spray dried encapsulated Vitamin D3 100SD powder blended with Silicon Dioxide under nitrogen/vacuum blanketing to avoid degradation.

Example 2:
Stability study of the Composition: Lab trial Data
Vitamin D3 100 SD -Stability Data
Batch No.: Lab#007
TEST LIMITS Stability Condition? 25± 2°C and 60 ± 5 % RH
Long Term
Initial 6 Months 18 Months
Assay (Vit.D3 content) NLT 100000 IU/gm 117353 122152 109000
Loss on drying (LOD) NMT 5% 1.87 1.8 2.1
Appearance White to off white powder White to off white powder

White to off white powder White to off white powder

Example 3:
Stability study of the Composition: Stability Batches
i)
Vitamin D3 100 SD -Stability Data
Batch No.: VDSD0124002
TEST LIMITS Stability Condition? 25± 2°C and 60 ± 5 % RH
Long Term 40± 2°C and 75 ± 5 % RH Accelerated
Initial 1 Month 1 Month
Assay (Vit.D3 content) (90 – 110) % 108.0% 106.2% 103.8%
Appearance White to off white powder
White to off white powder White to off white powder White to off white powder

ii)
Vitamin D3 100 SD -Stability Data
Batch No.: VDSD0124003
TEST LIMITS Stability Condition? 25± 2°C and 60 ± 5 % RH
Long Term 40± 2°C and 75 ± 5 % RH Accelerated
Initial 1 Month 1 Month
Assay (Vit.D3 content) (90 – 110) % 108.0% 108.0% 105.0%
Appearance White to off white powder White to off white powder
White to off white powder White to off white powder

iii)
Vitamin D3 100 SD -Stability Data
Batch No.: VDSD0124004
TEST LIMITS Stability Condition? 25± 2°C and 60 ± 5 % RH
Long Term 40± 2°C and 75 ± 5 % RH Accelerated
Initial 1 Month 1 Month
Assay (Vit.D3 content) (90 – 110) % 108.0% 106.0% 103.6%
Appearance White to off white powder
White to off white powder White to off white powder White to off white powder

, Claims:
1. A stable Cholecalciferol composition comprising 100000 IU /g of Vitamin D3 encapsulated in Modified corn starch.
2. The stable composition as claimed in Claim 1, wherein the said composition comprises pharmaceutically acceptable excipients selected from medium chain triglyceride oil, antioxidants, diluents, preservatives and flow promotors or glidants.
3. The stable composition as claimed in claim 1, comprising Vitamin D3, Modified Corn Starch, Sucrose, Sodium Ascorbate, Medium chain Triglyceride oil, Dl-alpha tocopherol and Silicon dioxide.
4. The stable composition as claimed in claim 1, comprising 100000 IU /g of Vitamin D3, Medium Chain Triglyceride Oil in an amount ranging from 2.7% to 3.3% , Dl -alpha Tocopherol in an amount ranging from 0.9 % to 1.1 % , Modified corn Starch in an amount ranging from 66% to 80%, Sucrose in an amount ranging from 16 % to 19% and sodium ascorbate in an amount ranging from 3% to 5% and Silicon dioxide in an amount ranging from 1.0 % to 2.0 %.
5. The stable composition as claimed in claim 1, wherein the composition is spray dried.
6. A process for preparation of the stable Cholecalciferol composition comprising 100000 IU /g of Vitamin D3 comprising:
i) Preparation of the Oil Phase;
ii) Preparation of the Aqueous/ Water Phase;
iii) Homogenisation of the oil phase and water phase of step (i) and (ii) to form a uniform emulsion;
iv) Spray drying of the Homogenised emulsion formed in step (iii); and
v) Adding the flow promoter to the spray dried powder of step (iv) to yield the final product.
vi) Packing the product under Nitrogen to avoid degradation.
7. The process as claimed in claim 6, wherein the Oil phase comprises 100000 IU /g of Vitamin D3, Medium Chain Triglyceride Oil in an amount ranging from 2.7% to 3.3% and Dl -alpha Tocopherol in an amount ranging from 0.9 % to 1.1 %.
8. The process as claimed in claim 6, wherein the Aqueous/Water phase comprises of Modified corn Starch in an amount ranging from 66% to 80%, Sucrose in an amount ranging from 16 % to 19% and sodium ascorbate in an amount ranging from 3% to 5% and purified water.
9. The process as claimed in claim 6, wherein the inlet temperature of the Homogenizing peristaltic pump or pressure pump is between 130 ? to 230 ? and an outlet temperature of the Homogenizing peristaltic pump or pressure pump is between of 70 ? to 120 ?.
10. The process as claimed in claim 6, wherein the viscosity of the emulsion is between 30 centipoise to 120 centipoise.
11. Use of the stable composition as claimed in any of the preceding claims as a dietary supplement to treat deficient levels of Vitamin D3.
12. Use of the stable composition as claimed in any of the preceding claims for calcium and phosphorus absorption.