FIELD OF INVENTION
[OJ] The present invention relates generally to a vitamin supplement and method
of preparing thereof. Preferably, the present invention relates to a liquid dosage form
of vitamin 0 and method of preparing thereof. More specifically, the invention
5 discloses an emulsion formulation where vitamin D is dispersed as nano-sized oil
droplets in the dispersant. The invention also discloses a sugar free vitamin 0
preparation.
BACKGROUND OF INVENTION
10 [02] Vitamins are organic compounds and vital nutrients. They are responsible for
carrying out different vital biological activities and to maintain different
physiological activities. Vitamins cannot be synthesized in human body and therelore
must be obtained through the diet. Deficiency of eli fl"erent vitamins is linked to
different physical disorders. Vitamins are categorized into two groups e.g. vvater
15 soluble vitamins and fat soluble vitamins. There are four fat soluble vitamins -
· vitamin A, vitamin 0 (group of vitamins), vitamin E and vitamin K.
[03] Vitamin 0 is a fat-soluble vitamin that is naturally present in very few foods,
added to others, and available as a dietary supplement. It. is also produced
endogenous! y when ultraviolet rays from sun I ight strike the skin and trigger vi tam in
20 0 synthesis. Vitamin D promotes calcium absorption in the gut and maintains
adequate serum calcium and phosphate concentrations to enable normal
mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone
growth and bone remodeling by osteoblasts and osteoclasis. \Vithout sufficient
vitamin 0, bones can become thin, brittle, or misshaperi. Vitamin D sufficiency
25 prevents rickets in children and osteomalacia in adults. Together with calcium,
vitamin 0 also helps protect older adults from osteoporosis.
[04] Vitamin 0 deficiency has emerged as a significant public health problem
throughout the world. Even in the Indian context, it has been reported to be present in
IPO DELH~ B~-a4~2015 11"19
majority of children in spite of wide availability of sunlight. The manifestations of
deficiency may vary ft'om hypocalcemic seizures, tetany in infancy and adolescence
to florid rickets in toddlers. Treatment is necessary for all individuals \.vith deficiency
whether symptomatic or not and consists of vitamin D su pp Iemen tat ion as cia i I y or
5 weekly oral regimens combined with calcium supplements. ·rhe recommended
vitamin D intake is 400 IU/clay in infants less than year and 600 IU/clay in children
more than I year of age as suggested by US 10M.
[05] The vitamin D supplements available in market are; Vitamin 03 - as oral
drops 400 IU/mL; Syrup 400 IU/5mL; and Tablets as 1000 and 2000 IU in blister
10 packing and also as sachet in powder form with each sachet containing 60000 IU of
vitamin 03. These supplements are available in market with or \·Vithout calcium
supplements.
[06] Dosage forms such as tablet, drops and syrups are preferably used clue to their
palatability as compared to powder dosage form. These palatable dosage forms
15 require dosage regimen on daily basis which consists drawbacks related to
conventional dosage torm. Vitamin D is !'at soluble vitamin and therefore itS
bioavailability is always doubtful from liquid dosage forms such as syrups and drops.
Moreover, these preferred dosage forms specially drops and syrups also require taste
enhancing agents such as sugar or sugar conl<:lining sweeteners. ·rhe use of sugars or
20 sugar containing sweeteners may make these dosage forms unfit for administration to
diabetic patients. Therefore, there is an urgent need of palatable dosage form vvhich
can eliminate the dravibacks related to dosage· regimen, poor bioavailability and
which can also be administered to diabetic patients.
25 SUMMARY OF THE INVENTION
[07] . One object of the present invention is to provide a vitamin D supplement in
palatable form which also doesn't need dosage regimen on daily basis.
2
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[08] One another object of this invention to provide a vitamin D supplement with
increased bioavailability of vitamin D.
[09] One another object of this invention is to provide a vitamin D supplement in
palatable form containing sugarfree sweeteners so that, the supplement can be used
5 by diabetic patients also.
[10] In one aspect, the invention discloses a palatable vitamin 03 dosage form
containing 60000 IU/SmL of vitamin 03.
[II] In another aspect, the invention discloses an emulsion dosage form of vitamin
03 vvhere the vitamin D3 is dispersed in nano-sized oil droplets in dispersant.
10 [12] In one another aspect, the invention discloses a sugarfree liquid dosage form
ofvitamin 03.
[13] In yet another aspect, the invention discloses method or preparing liquid
dosage form of vitamin 03.
15 DETAILED DESCRIPTION
[14] The following description· is full and informative description of the best
method and embodiments presently contemplated for carrying out the present
invention which is known to the inventors at the time of liling the patent application.
Of course, many modifications and adaptations will be apparent to those sh:illed in the
20 relevant arts in view of the following description and the appended claims. While the
composition and method described herein are provided with a certain degree or
specificity, the present invention may be implemented with either greater or lesser
specificity, depending on the needs of the user. Further, some of the features of the
present invention may be used to advantage without the corresponding use of other
25 · features described in the following paragraphs. As such, the present description
should be considered as merely illustrative of the principles of the present invention
and not in limitation thereof, since the pre'sent invention is defined solely by the
claims.
3
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[ 15] The foregoing description of the embodiments of the invention has been
presented for the purposes of illustration and description. It is not intended to be
exhaustive or to limit the invention to the precise form disclosed. Many
modifications and variations are possible in light of the above teaching. It is intended
5 that the scope of the invention be limited not by this detailed description, but rather
by the claims appended hereto.
[16] While, the following description is presented to enable a person or ordinary
skill in the art to make and use the invention and is provided in the context of the
requirement for a obtaining a patent. The present description is the best presently-
10 contemplated method for carrying out the present invention. Various modifications
to the preferred embodiment will be readily apparent to those skilled in the art and the
generic principles of the present invention may be applied to other embodiments, and
some features of the present invention may be used without the corresponding use of
other features. Accordingly, the present invention is not intended to be limited to the
15 embodiment shown but is to be accorded the widest cope consistent with the
principles and features described herein.
[17] The present invention relates to a liquid dosage lorm of vitamin D and method
for preparing thereof. The invention discloses liquid dosage fc1rm or vitamin· D3,
specifically an o/vv emulsion wherein the vitamin D3 is dispersed in nano-sized oil
20 droplets in dispet'sant. Size reduction has always been a preferred option to increase
bioavailability of therapeutic agents. In present invention, the vitamin 1)3 is provided
in liquid dosage form. The liquid dosage form is an emulsion formulation where the
vitamin 03 is dispersed as nano-sized oil droplets in a dispersant to increase
bioavailability ofthe vitamin D3.
25 [18] In one embodiment, the liquid dosage form comprises vitamin D and nne or
more pharmaceutical acceptable excipients.
[ 19] In one embodiment, the vitamin D is preferably vitamin D2 ~mel vitamin D3
but not limited thereto.
4
[20] In one prefen'ed embodiment, the vitamin 0 is vitamin 03.
[21] In one embodiment, the liquid dosage form is selected !'rom solution,
emulsion and suspension but also includes other liquid dosage forms and not limited
thereto.
5 [22] In one embodirnent, the acceptable pharmaceutical excipients may be selected
from the group of solubilizers·, fat soluble anti-oxidants, preservatives, stabilizers,
emulsifiers/surfactants, dispersants, navoring agents, sweetening agents and coloring
agents.
[23] In one preferred embodiment, the solubilizers are selected preferably l'rom
10 hydrogenated castor oil and vitamin E acetate but not limited thereto and can inclutk
other oils also.
[24] lri one preferred embodiment, the fat soluble anti-oxidants is vitamin E acetate
but not limited thereto.
[25] In one preferred embodiment, the preservatives are selected from methyl
15 paraben and propylparaben but not limited thereto.
[26] In one preferred embodiment, the emulsifier is polysorbate 80 but not limited
thereto.
[27] In one preferred embodiment, sweetening agent is sugarfree and preferably
selected from aspartame and sorbitol but not limited thereto and can include other
20 sugarfree sweeteners.
[28] In one preferred embodiment, the coloring agent IS Ponceau 4R but not
limited thereto.
[29] In one preferred embodiment, the dispersant is purified water and glycerin,
but not limited thereto.
25 [30] The present invention also discloses a method of preparing liquid dosage form
of vitamin 03 where the vitamin 03 is present as nano-sized droplets in the
dispersant. Four batches or oil phase of emulsion were prepared by general method I
5
5
given below. The composition of such four batches is provided in table- I. All four
batches consist of similar quantity of active constituent vitamin 03 and
pharmaceutical excipients. These batches are prepared applying eli ITerent
homogenization parameters e.g. time and speed.
Table- I Compos1 Ion for oil phase l'ormu a 1011
Ingredients
Example 1 Example 2 Example 3
Homogenization
20 minutes,
Parameters
10000 RPM
(Time & Speed)
0/o w/w
20 minutes,
10000 RPM
20 minutes,
20000 RPM
Example 4
35 minutes,
10000 RPM
Vitamin 03 0.06 0.06 0.06 0.06 j
Vitamin E 0.05 0.05 ---j--0-.0-)--------- 0.05 -----~
Acetate i I
1---------1-------t------------------------~--------------·--· .. !
Hydrogenated 0.4 0.4 0.4 j 0.4 j
rC_a_st_o_r_O_i_l __ 1 ______ 4----------j-----------1 ____ !
Polysorbate 80 0.8 0.8 O.R 1 0.8 i
Solvent* Not Used q.s ----· q.s --=-~~:=--~~~:i~~!=~-- -----~=]
r---------1--------r---------- r·
Particle Size
Distribution
Larger
Particles (D9o
> 300 nm)
and wide PSD
observed
Smaller (Dqo No
< I 00 nm)
and uniform
PSD
significant
change in
PSD
No Signilicant
change in PSD
* Solvent evaporates during process (if solvent is organic); only traces appear 111 final
formulation.
1311 Method of preparation of oil phase
10 General Method-/
Preparation of Oil Phase:
The required quantity of fat soluble anti-oxidant, oil, surl~1ctants and Vitamin D3
were weighed. Heated the Oil up to 55° C to from first clear solution and allowed it to
cool down to 45° C. To this first clear solution were added surfactants and fat soluble
6
anti-oxidants under slovv stirring speed. Other side, minimum quantity of solvent was
taken and the vitamin 03 was dissolved in it to form second clear soluti011. Now, the
second clear solution was added into first clear solution with continuous
homogenization (High Speed; Polytron 3100 0/Uitra Tun·ex T25) and allowed
5 homogenizing the mixture for specified time at specified speed (rpm).
1321 Particle size distribution of oil phase form
Method: Particle size distribution of the prepared nann-emulsion is carried out using
Malvern Zetasizer.
10 Procedure: All four above mentioned batches were checked for particle s1ze
distribution over Malvern Zetasizer.
Results: For example 2 the particle size distribution was found to be (090 < I 00 nm).
1331 Preparation of liquid dosage form
15 General method II provides method of preparing. liquid dosage form ol· vitamin D3
using oil phase prepared by general method I.
General Method-If:
Preparation of liquid dosage form:
Required amount of purified water was taken in suitabie vessel and allowed it to heat
20 at 95°C. To this was added and dissolved preservatives and sweeteners to get clear
solution. To this clear solution was transferred other vehicle or excipients and
Glycerin under continuous stirring and mixed for 15 minutes. To this prepared
dispersant was added, oil phase prepared by general method I under continuous
stirring at slow speed (300 - 500 RPM) and mixed for 30 minutes. Added required
25 quantity of Coloring agent and Flavoring agent and made-up the linctl volume to
required volume with Purified Water. Allowed to mix this linal emulsion for 20
7
' . I .
minutes. Filtered the emulsion through sieve // 400 and fill in bottles and evaluated
for Paiticle Size Analysis and Chemical Analysis.
(34] Example-lA
Table-2: Composition for emulsion formulation (Example- I A)
Ingredients
Qty. o;., \v/v Inferred FUJiction
(for 10 Lt)
Vitamin D3 6.00 g 0.06 Active
Vitamin E Acetate 5.00 g 0.05 Oil soluble anti-oxidant
Hydrogenated Castor Oil 40.00 g 0.40 Surfactant/emu lsi lier
..
Polysorbate 80 80.00 g (HO Sur facta n t/e 111 uls i lie r
'
Ethanol q.s NA Solvent - --·-------·------------- -·-
Methyl Paraben 20.00 g 0.20
Propyl Paraben 2.00 g 0.02 I
Preservative
Sorbitol Solution 70% I 000.00 g 10.00
Glycerin 500.00 g 5.00 Dispersant
Propylene Glycol 250.00 g 2.50
Aspartame 15.00 g 0.15 Sweetening Agent
Flavor 30.00 mL 0.30 Flavoring Agent
Ponceau 4R 0.007 g 0.7 mg% Coloring Agent
Purified Water q.s. to I 0.0 L q.s. to I 00 Dispersant
%
- ·- 5 *Solvent evaporates durtng process (tfsolvent ts organtc); only traces appear 111 ltnal
formulation.
Preparation of Oil Phase:
The required quantity of Vitamin E Acetate, Hydrogenated Castor Oil, Polysorbate
10 80 and Vitamin D3 were weighed. Heated the Hydrogenated Castor Oil up to 55°C to
from first clear solution and allowed it to cool down to 45° C. To this first clear
solution was added polysorbate 80 and Vitamin E Acetate under slow stirring speed.
Other side, minimum quantity of Ethanol was taken and the vitamin D3 was
dissolved in it to form second clear solution. Now, the second clear solution was
8
added into first clear solution with continuous homogenization (High Speed; Polytron
3100 0/Uitra Turrex T25) and allowed homogenizing the mixture for 20 minutes at
20000 rpm speed.
5 Preparation of liquid dosage form:
Required amount of purified water was taken in suitable vessel and allowed it to heat
at 95°C. To this, dissolve Methyl Paraben, Propyl Paraben and Aspartcp11e in to get
clear solution. To this transferred Sorbitol Solution 70%, Propylene Glycol and
Glycerin under continuous stirring and mixed for 15 minutes. To this was added, oil
.10 phase prepared by general method I under continuoLfs stirring at slow speed (300-
500 RPM) and mixed for 30 minutes. Added required quantity of Coloring agent and
Flavoring agent; and made-up the final volume to required volume .with Purified
Water. Allowed to mix final solution for 20 minutes. Filtered the solution through
sieve# 400 and fill in bottles and evaluated for Particle Size Analvsis and Chemical
15 Analysis.
[351 Stability studies of liquid dosage form of vitamin D3
Stability studies for the prepared liquid dosage form were carried out for 6 months on
different conditions. The iII ustrative exam p'les of such studies were carried out at
20 30±2° C, 75±5% RH.
Procedure: I 00 1111 of pharmaceutical composition of example-! A was packed in
amber colored container and kept at 30±2° C, 75:1:5'Yo Rl-1. The stability study was
carried out 30±2° C, 75:!:5%) Rl-1. The stability studies were carried out r·or 6 months.
For the said 6 months period samples were taken from such container and the
25 formulation were tested for physical, chemical and microbial stability.
Results: The emulsion was found stable in all the stability studies. Results are
provided in table-3.
9
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6.
Tahlc-3: Stability Summary Report of Vitamin 03 Oral Solution at 30±2" C, 75±5'Yo Rll
Parameter Specification Initial 3 Months 6 Months
Description Pink coloured clc3r flavored solution Complies Complies Complies
Identification Principle peak in the chromatogram of test Complies Complies Complies
solution should correspond to that in the
chromatogram of the rclcrencc solution.
Weight/ml 1.0 ±0.2 g/ml 1.035 g/ml 1.031 g/ml 1.035 g/ml
pH 4.0 to 7.0 5.31 5.20 5.15
Particle Size (0,.,) I NMT 100 nm 24.76 nm Complies Complies
Assay NLT 90% of label claim 193.54% 190.07% 182.78%
Microbial limit test
I) Total bacterial count I) NMT 100 cfu/ml I) I Ocfu/ml I) IOcfu/ml I) 15 cfu/ml
2) Total fungal count 2) NMT 10 cfu/ml 2) <10 cfu/rnl 2) <10 ct"u/ml 2) <10 cfu/ml
3) Pathogens 3) 3) 3) 3)
a) E. Coli a) Abscntfml a) Abscntfml a) Abscntfml a) 1\bsentfml

WE CLAIM:
1. A liquid dosage form comprises Vitamin D and one or more pharmaceutically
acceptable excipients.
2. The liquid dosage form claimed in claim 1, wherein vitamin D is selected from
5 vitamin D2 and vitamin D3.
3. The liquid dosage form claimed in claims 1 to 2, wherein the liquid dosage form
is selected from solution, suspension and emulsion ..
4. The liquid dosage form claimed in claims 1 to 3, wherein the liquid dosage form
is emulsion.
10 5. The liquid dosage form claimed in claims 1 to 4, wherein more than 90 percent of·
oil droplets in the emulsion are less than 1 OOnm of diameter.
6. The liquid dosage form claimed in claims 1 to 5, wherein more than 90 percent of
oil droplets in the emulsion are less than 50nm of diameter.
7. The liquid dosage form claimed in claims 1 to 6, wherein one or more
15 pharmaceutically acceptable excipients are selected from solubilizers, oil soluble
anti-oxidants, preservatives, stabilizers, emulsifiers/stirfactants, vehicles,
dispersants! coloring agent, flavoring agents and sweetening agents.
8. The liquid dosage form claimed in claim 7, wherein sweetening agent is sugar
free.
20 9. The liquid dosage form claimed in claims 7 to 8, wherein sweetening agent are
selected from aspartame and sorbitol.
I 0. The liquid dosage form claimed in ciaims 1 tQ 9, wherein the liquid dosage form
comprises vitamin D 0.03-0.10% w/v, fat soluble anti-oxidant 0.05-0.10% w/v,
solubilizer 0.04-0.10% w/v, surfactant 0.08-0.20% w/v, preservative 0.10-0.50%
25 w/v and dispersants 90-99.90% v/v.
II
IPO DELHI 91-04-2015. 17"19
i 1. The liquid dosage form claimed in claims 1 to 10, wherein the liquid dosage form
comprises vitamin D3 0.06% w/v, vitamin E acetate 0.0~% w/v, hydrogenated
castor oil 0.04% w/v, polysorbate 80 0.08% w/v, methyl paraben 0.20% w/v,
propyl paraben 0.02% w/v, sorbitol solution (70%) 10% w/v, glycerin 5% w!v,
5 propylene glycol2.50% w/v, aspartame 0.15% w/v and purified water 5-85% v/v.
10
15
20
25
12. A methqd of preparing a liquid dosage form ofvitamin D, the method comprises
a. preparing a oil phase, the method comprises
1. preparing a first clear solution of hydrogenated castor oil, tween 80 and
vitamin E acetate,
ii. preparing a second clear solution of vitamin D in minimum quantity of a
so\ vent,
111. preparing the oil phase by adding the second clear solution to the first
clear solution under homogenization;
b. preparin-g the liquid d_osage form of vitamin D, the method comprises
1. preparing a third solution of methyl paraben, propyl paraben · and
·aspartame in required quantity ofwater,
11. preparing a fourth solution by adding required quantity of sorbitol solution
(70%), propylene glycol and glycerin to the third solution,
iii. preparing the liquid dosage form by adding the oil phase to the fourth
solution under mixing.