DESC:TECHNICAL FIELD
The present invention relates to cholecalciferol oral formulations, for use in the
treatment of vitamin D deficiencies. The invention particularly relates to formulation
of softgel capsule encapsulating Vitamin D3.
BACKGROUND
Vitamin D belongs to group of fat soluble steroid prohormones which regulates the
calcium absorption in the gut and maintains adequate serum calcium and phosphate
concentrations. It has other beneficial effects such as immunomodulatory,
neuroprotective, reduction of inflammation and glucose metabolism and many more.
In food and dietary supplements, Vitamin D has two main forms, D2 (ergocalciferol)
and D3 (cholecalciferol).
Vitamin D3 also known as cholecalciferol produced in skin when exposed to sun light
and also present in certain foods. Nowadays most people works indoor and wear
sunscreen to avoid damages from harmful UV rays of sun therefore getting enough
vitamin from this source is tough therefore many doctors recommend dietary
supplements for optimal musculoskeletal health. The labeled indication for
cholecalciferol is dietary supplementation. The off-label indications for cholecalciferol
include hypothyroidism, prevention of osteoporosis, and Vitamin D insufficiency/
deficiency in both healthy patients or those with chronic kidney disease [Brandi ML.
Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes.
Clin Cases Miner Bone Metab. 2010 Sep.7(3):243-50]. Research have shown that low
3
blood levels of the vitamin with higher risks of everything from heart disease, diabetes,
and cancer to mood disorders and dementia. Thus it is necessary to maintain the level
of cholecalciferol in blood.
Pharmaceutical formulations as well as nutraceuticals, aimed at addressing deficiencies
of Vitamin D in both humans and animal are well-known. Oral dosage forms such as
liquid oral, oil-filled capsules, sachet and tablets are popular and well known in the art
and typically contain 400 IU to 5,000 IU of Vitamin D3.
There are several prior arts which discloses the formulation comprising vitamin D3,
for example, US20060019933A1 discloses a process for preparing a stabilized form of
vitamin D which comprises the steps of: a) dissolving vitamin D in a solution that
contains water and at least one surfactant to produce a mixture; b) spraying the mixture
onto an inert carrier to produce a wet mass; and c) drying the wet mass obtain the
stabilized form of vitamin D.
WO2012117236A1 teaches high dosage vitamin D formulations, in particular vitamin
D3 that can be used for the treatment of vitamin D deficiency and insufficiency. The
formulation further comprises a lipid based carrier excipient that stabilizes vitamin D
wherein aid lipid based carrier excipient comprises an oil or a mixture of oils.
US20160030356A1 discloses a stable solid formulations of vitamin D3 and to
processes for preparation of the same. The present invention provides stabilized
compositions comprising vitamin D3 at least one lipophilic dispersant, one or more
4
antioxidants, at least one adsorbent and one or more pharmaceutically acceptable
excipients and further coated with a barrier coating.
WO2019175830A1 discloses stable oral nanoemulsion formulation and methods for
producing same. The nanoemulsion formulation comprises a stabilizer and one or more
pharmaceutically acceptable excipients wherein the process involves solubilizing the
stabilizing agent in double distilled water with continuous stirring.
WO2022195016A1 discloses a formulation adapted for oral administration, wherein
the pharmaceutical formulation comprises at least 1000 IU, preferably of from 5000 to
400000 IU of a Vitamin D, per dosage form, and wherein the pharmaceutical
formulation comprises, or consists of, an aqueous dispersion of micelles encapsulating
said Vitamin D, and wherein the micelles are formed of, and essentially consist of, a
tocopherol polyalkylene glycol such as D-a-tocopherol polyethylene glycol succinate.
The process involves combining Vitamin D3 in molten state and D-a-tocopherol
polyethylene glycol succinate in molten state forming an aqueous dispersion of
micelles encapsulating the Vitamin D. However this process of preparing the
composition have limitation. The inventor of the present invention found that when
tocophersolan is used for encapsulating the Vitamin D3, the softgel obtained were
unable to disintegrate and dissolve.
The above mentioned prior art are mainly water or oil based Vitamin D3 formulations.
However, its instability in water and oil remains a challenge for manufacturers to
formulate an appropriate dosage form. Vitamin D3 is sensitive to moisture, oxygen,
5
temperature, pH and light more particularly to moisture. This observation was reported
by Žane Temova Rakuša et. al., in study titled “Comprehensive Stability Study of
Vitamin D3 in Aqueous Solutions and Liquid Commercial Products” the authors of the
study had conducted an experiment on stability of Vitamin D3 in aqueous solutions.
Three different medicines and six food supplements (FSs), commercially available on
the European market, all in the form of oral drops were analyzed where the products
were stored in different climatic conditions i.e. at 25 and 40°C, and in a refrigerator at
4°C and perform stability study on them. It was observed that Vitamin D3 was very
unstable in aqueous media as compared with oil based formulation. But it was observed
that oil-based formulation show degradation at an elevated temperature after 6 months
of storage. Still the market is flooded with many water and oil based formulations
which may impact the quality and efficacy of the product.
Thus there remain a need in an art to formulate a stable formulation of Vitamin D3
from existing pharmaceutical or nutraceutical preparations, especially when
administered in high doses which remains stable for longer period of time.
Since Vitamin D3 is a fat soluble steroid it is generally available as emulsion to enhance
the rate and extend and improve the solubility of Vitamin, thus it become an obstacle
to formulate a stable dosage form without water and oil, however the inventors of the
present inventions have been able overcome the problems associated with use of water
by developing a stable formulation without using water.
6
The inventors of the present invention were able to prepare a formulation wherein
Vitamin D is solubilized in tocophersolan and/or adjuvant such as water-free nonionic
surfactant which is then encapsulated in a soft gel capsule. The use of
Tocophersolan as a solubilizer and encapsulating the same in gelatin also solved the
issue of disintegration or dissolution associated with the use of Tocophersolan as a
gelling agent. Thus the present invention provides a formulation which have been able
to overcome the issues faced in the prior art and provide a stable oral formulation
comprising cholecalciferol which is free from water and oil.
SUMMARY
It is an object of the present invention to provide an oral formulation wherein the
pharmaceutical formulation comprises at least 1000 IU, preferably from 10000 to
400000 IU of Vitamin D3, per dosage form, and wherein the pharmaceutical
formulation comprises, or consists primarily of tocophersolan.
It is equally an object of the present invention to provide process for producing a
pharmaceutical formulation adapted for oral administration according to the above,
said process comprising of solubilizing cholecalciferol in tocophersolan alone or with
an adjuvant water-free non-ionic surfactant, and an oil soluble antioxidant, without the
need for water and oil in the composition.
The adjuvant or auxiliary non-ionic surfactants are chosen from those that have HLB
value from 8 to 40. Preferably, the surfactants are o/w emulsifiers and includes
7
polysorbates, Poloxamer, polyoxyethylene alkyl ethers, polyoxyl castor oil derivatives,
polyoxyethylene stearates, sucrose stearate, and mixtures thereof.
Antioxidants that are preferably added include ascorbyl palmitate, butylated hydroxy
anisole, butylated hydroxyl toluene, monothioglycerol, propyl gallate, sodium
metabisulfite, etc.
The pharmaceutical formulation according to the present invention is water-soluble and
may be in solid or semisolid form. More preferably, the homogeneous solution of
cholecalciferol in tocophersolan and/or adjuvant o/w emulsifier is encapsulated in a
gelatin or veg softgel or filled in hard capsule or hypromellose capsule shell.
The present invention provides softgel capsule comprising:
i. A fill material comprising effective amount of Vitamin D and one or more
excipients and;
ii. An outer shell of gelatin wherein gelatin encapsulate the fill material.
DETAILED DESCRIPTION OF THE INVENTION
The following paragraphs detail various embodiments of the present invention. For the
avoidance of doubt, it is specifically intended that any particular feature(s) described
individually in any one of these paragraphs (or part thereof) may be combined with one
or more other features described in one or more of the remaining paragraphs (or part
thereof). In other words, it is explicitly intended that the features described below
individually in each paragraph (or part thereof) represent important aspects of the
8
invention that may be taken in isolation and combined with other important aspects of
the invention described elsewhere within this specification as a whole, and including
the examples. The skilled person will appreciate that the invention extends to such
combinations of features and that these have not been recited in detail here in the
interests of brevity.
The use of the terms "a" and "an" and "the" and similar referents in the context of
describing the invention (especially in the context of the following claims) are to be
construed to cover both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context.
The term “cholecalciferol” and Vitamin D3 are interchangeable words used to describe
active agent used for the treatment of Vitamin D3 deficiency.
The term “antioxidants” refers to the compounds which can be natural or synthetic that
prevent or delay the oxidative or free radical or photo-induced deterioration of a
compound, and combinations thereof.
The term “nano capsule” means cholecalciferol is in nanoform and the fill liquid obtain
is in nanosize.
The present invention discloses a pharmaceutical composition comprising an active
ingredient and one or more pharmaceutically acceptable excipients wherein active
ingredient is cholecalciferol.
9
The present invention provides an oral composition comprising cholecalciferol with
improved stability and doesn’t contain water or oil and therefore prevent the
degradation of the formulation from moisture or water thus having more extended
storage shelf-life as compared to marketed water-based or oil-based composition.
In an embodiment the present invention is an oral pharmaceutical composition
comprising cholecalciferol in the range of 5000 to 400000 IU per dosage form more
preferably 60000 IU.
In an embodiment oral composition comprises cholecalciferol and one more excipients
wherein the composition is essentially free from water and oil.
In another embodiment the present invention provides oral composition comprising
60000 IU cholecalciferol and one or more pharmaceutically acceptable excipients.
In yet another embodiment the pharmaceutically acceptable excipients are selected
from group consisting of but not limited to solubilizing agent, surfactants and
antioxidants.
In an embodiment the solubilizing agent are selected from but not limited to
Poloxamer, polysorbate 80, polysorbate 20, tocophersolan, PEG-40 hydrogenated
castor oil (Cremophor RH40), PEG-35 castor oil (Cremophor EL), PEG-8-glyceryl
capylate/caprate (Labrasol), PEG-32-glyceryl laurate (Gelucire 44/14), PEG-32-
glyceryl palmitostearate (Gelucire 50/13); polysorbate 85, polyglyceryl-6-dioleate
(Caprol MPGO) or combinations thereof.
10
In an another embodiment the solubilizing agent is tocophersolan also known as
Vitamin E TPGS, present in an amount ranging from 10-100 mg.
In another embodiment the non-ionic surfactants are chosen from those that have HLB
value from 8 to 40. Preferably, the surfactants are o/w emulsifiers and includes
polysorbates, Poloxamer, Caprylocaproyl Polyoxyl-8 glycerides, polyoxyethylene
alkyl ethers, polyoxyl castor oil derivatives, polyoxyethylene stearates, macrogol 15
hydroxystearate, sucrose stearate, and mixtures thereof.
In a preferred embodiment the non-ionic surfactant is macrogol 15 hydroxystearate.
In an another embodiment the preferred non-ionic surfactant is Caprylocaproyl
Polyoxyl-8 glycerides.
In an embodiment the antioxidants that are preferably added include ascorbyl
palmitate, butylated hydroxy anisole, butylated hydroxyl toluene, monothioglycerol,
propyl gallate, sodium metabisulfite, etc.
In a preferred embodiment the antioxidant is butylated hydroxytoluene present in an
amount ranging from 0.05-0.5 mg more preferably 0.2 mg.
In an embodiment the oral pharmaceutical composition comprises:
a. an effective amount of cholecalciferol and;
b. an effective amount of one or more excipients and;
wherein the composition may comprise non-ionic surfactant and antioxidants.
11
In an another embodiment the oral composition is in form of may be in solid or semisolid form more preferably solid dosage form that contain drug in solid, liquid or semisolid enclosed in a shell wherein the solid dosage form is a capsule.
In another embodiment capsule is present as hard gelatin capsule, soft gelatin capsule
or HPMC capsules (veg capsule).
In an another embodiment Cholecalciferol is present in nano-sized and the fill material
is a nano solution encapsulated into gelatin mass.
In an another embodiment the oral pharmaceutical composition is a softgel capsule
comprising:
a) a fill material; and
b) a shell composition
wherein fill material comprises atleast 60000 IU Cholecalciferol and one or more
excipients and;
wherein the shell composition comprises gelatin and wherein shell encapsulated fill
material.
In an another embodiment the fill material is a liquid solution wherein liquid solution
can be aqueous or non-aqueous solution.
In a preferred embodiment fill material is non aqueous solution comprising
Cholecalciferol and one or more excipients.
12
In an another embodiment non aqueous solution comprises 60000 IU Cholecalciferol,
tocophersolan and one or more excipients In an another embodiment one or more
excipients are selected from solubilizer, anti-oxidants and non-ionic surfactant.
In an another embodiment solubilizer is tocophersolan present in an amount ranging
from 5 to 10 mg.
In an another embodiment anti-oxidant is Butylated hydroxytoluene present in an
amount ranging from 0.05 to 1 mg.
In an another embodiment non-ionic surfactant is Caprylocaproyl Polyoxyl-8
glycerides present in an amount ranging from 50 to 100 mg.
In an another embodiment the softgel capsule comprises:
i. a fill material comprising 60,000 IU Cholecalciferol; 10 mg Tocophersolan; 0.2
mg Butylated hydroxyl toluene and 87.86 mg Caprylocaproyl Polyoxyl-8
glycerides and;
ii. a shell composition comprising Gelatin encapsulating the fill material
In an another embodiment the softgel capsule is formulated as nano capsule.
The present invention provides a pharmaceutical soft or hard capsule oral formulation,
wherein the formulation comprises 60000 IU of cholecalciferol wherein vitamin D3
dissolved in tocophersolan and is essentially free from water and oil.
In an embodiment the present invention optionally comprises an adjuvant nonionic
surfactant wherein non-ionic surfactant is macrogol 15 hydroxystearate.
13
In an another embodiment the present invention the softgel capsule is nano capsule
comprising
i. a fill material comprising 60,000 IU Cholecalciferol; 10 mg Tocophersolan; 0.2
mg Butylated hydroxyl toluene and 87.86 mg Caprylocaproyl Polyoxyl-8
glycerides and;
ii. a shell composition comprising Gelatin encapsulating the fill material
In an another embodiment the fill material is free of water and oil.
In another embodiment the present invention optionally comprises an oil soluble
antioxidant.
In another embodiment the present invention can be used a medicament for the
treatment of a Vitamin D deficiency.
In another embodiment the present invention provides process for preparation of stable
oral composition comprising steps of:
a) Melting tocophersolan at about 40 to 45°C and; adding non-ionic surfactant
b) Add butylated hydroxyl toluene into above solution
c) Let the solution of step (b) to cool down to 45°C
d) Admixing cholecalciferol into liquefied tocophersolan solution obtained from
step (c) and;
e) Optionally adding one or more antioxidants into liquefied solution obtain from
step (b) to obtain a clear solution and;
14
f) Encapsulating the clear solution blend into soft or hard capsule.
In an another embodiment the present invention provides a process of preparing softgel
capsule comprising following process:
i. Preparation of fill material:
Take Caprylocaproyl Polyoxyl-8 glycerides and vitamin E TPGS and heat
the mixture upto 50-60° C with continuous stirring and dissolve butylated
toluene into the mixture with continuous stirring till clear solution obtained.
After cooling the solution, dissolve Cholecalciferol into the solution with
continuous stirring until clear solution observed. Deaerated the solution
obtained
ii. Preparation of Gelatin mass:
Add glycerin with methyl paraben & propyl paraben and heat upto 50-60°
C with continuous stirring to obtain homogenous clear solution. Take
purified water, glycerin & sorbitol solution in clean vessel mix it well &
transfer gelatin in gelatin melter.
Start the gelatin melter for 15 minutes and cook the gelatin mass for 45-60
minutes. Supply vaccum in the melter for 30-40 minutes and stop the
vacuum pump. Open the outlet valve to release vacuum from the gelatin
melter.
iii. Encapsulating the fill material in gelatin mass in encapsulation machine and
dry the obtained softgel capsule for 24-48 hours.
15
The following examples are provided to illustrate particular features and/or
implementations. These examples should not be construed to limit the disclosure
to the particular features or implementations described.
EXAMPLES
A pharmaceutical formulation according to the present invention was prepared as
presented in the examples outlined below.
Example 1
Ingredients Amount Role
Cholecalciferol 1.5 mg (equivalent to 60000 IU) Active agent
Tocophersolan 98.5 mg Solubilizing agent
Melt tocophersolan at about 40 to 45°C, admix cholecalciferol into liquefied
tocophersolan to obtain a clear solution and encapsulate the blend into soft capsule or
hard capsule.
Example 2
Ingredients Amount Role
Cholecalciferol 1.5 mg (equivalent to 60000 IU) Active agent
Tocophersolan 10.0 mg Solubilizing agent
Butylated hydroxytoluene 0.2 mg Antioxidant
16
Kolliphor HS (macrogol 15
hydroxystearate
100.0 mg Non-ionic surfactant
Melt tocophersolan and Kolliphor HS 15 at about 40 to 45°C, admix cholecalciferol
and butylated hydroxyl toluene into liquefied surfactant mixture to obtain a clear
solution and encapsulate the blend into soft capsule or hard capsule.
Example 3
Ingredients Amount Role
Cholecalciferol 1.93 mg (equivalent to 60000 IU) Active agent
Tocophersolan 10.0 mg Solubilizing agent
Butylated hydroxytoluene 0.2 mg Antioxidant
Caprylocaproyl Polyoxyl-8
glycerides
87.86 mg Non-ionic surfactant
Example 4: Stability study report
The composition of Example 3 was subjected to stability studies. The results are
tabulated in below table:
Test Acceptance
criteria
Initial testing 3 month
Description Light yellow
coloured, soft
gelatin capsule
contain clear
solution.
Light yellow
coloured, soft
gelatin capsule
contain clear
solution.
Light yellow
coloured, soft
gelatin capsule
contain clear
solution.
17
Average fill weight 100.0 mg± 10.0% 99.78 mg 96.62 mg
Dissolution: (by HPLC) As below
For 60 minutes Not less than 75%
at 60 minutes
Avg= 92.01% Avg.= 86.73%
Microbial contamination As below
Total viable count As below
Total aerobic bacterial count Not more than
1000 cfu/gm
<20 cfu/gm
Total combined yeast & mould
count
Not more than 100
cfu/gm
<10 cfu/gm
Test for specified
microorganism
As below
Escherichia coli Should be
absent/gm
Salmonella Should be
absent/10 gm
Pseudomonas aeruginosa Should be
absent/gm
Staphylococcus aureus Should be
absent/gm
Shigella Should be
absent/10 gm
Bile-tolerant Gram Negative
Bacteria
(Enterobacteria)
Should be
absent/gm
Absent/gm
Assay (by HPLC) Each soft
Gelatin capsule contains:
Shelf life limit
Cholecalciferol
(60000 IU in nano form)
Not less than
54,000.00 mg
(not less than
90.00% of label
claimed)
58,644.00 IU
97.74%
56879.84 IU
94.80%
From above table, it is evident that the nano capsule is stable when stored at 25°C±
2°C & RH 60% ± 5% for 3 months. ,CLAIMS:A softgel capsule comprising:
a) a fill material; and
b) a gelatin shell
wherein fill material is a non-aqueous solution comprising of 60000 IU Cholecalciferol
and Tocophersolan
wherein the fill material is encapsulated by the gelatin shell
2. The fill material as claimed in claim 1 further comprises one or more excipients
selected from anti-oxidants and non-ionic surfactant.
3. The fill material as claimed in claim 1 comprises Tocophersolan present in an
amount ranging from 5 to 10 mg
4. The fill material as claimed in claim 2 further comprises anti-oxidant wherein
anti-oxidant is Butylated hydroxytoluene present in an amount ranging from
0.05 to 1 mg
5. The fill material as claimed in claim 2 further comprises non-ionic surfactant
wherein non-ionic surfactant is Caprylocaproyl Polyoxyl-8 glycerides present
in an amount ranging from 50 to 100 mg.
6. The fill material as claimed claim 2-5 comprises
a) 10 mg of Tocophersolan as solubilizer
b) 0.2 mg of Butylated hydroxy toluene as antioxidant
19
c) 87.86 mg of Caprylocaproyl Polyoxyl-8 glycerides as non-ionic
surfactant
7. The softgel capsule as claimed in previous claims comprises:
I. A fill material comprising
a) 60,000 IU of Cholecalciferol and;
b) 10 mg of Tocophersolan as solubilizer and;
c) 0.2 mg of Butylated hydroxy toluene as antioxidant and;
d) 87.86 mg of Caprylocaproyl Polyoxyl-8 glycerides as non-ionic
surfactant
II. An outer shell comprising of gelatin
Wherein the outer shell encapsulates the fill material.
8. The softgel as claimed in claim 1-7 is a nano capsule comprising:
I. A fill material comprising
a) 60,000 IU of Cholecalciferol and;
b) 10 mg of Tocophersolan as solubilizer and;
c) 0.2 mg of Butylated hydroxy toluene as antioxidant and;
d) 87.86 mg of Caprylocaproyl Polyoxyl-8 glycerides as non-ionic
surfactant
II. An outer shell comprising of gelatin
Wherein the outer shell encapsulates the fill material
9. The process of preparing softgel as claimed in claim 8 comprises:
20
a. Melting 10 mg of tocophersolan at about 40 to 45°C and; adding nonionic surfactant
b. Adding 0.2 mg of butylated hydroxyl toluene into above solution
c. Let the solution of step (b) to cool down to 45°C
d. Admixing 60,000 IU cholecalciferol into liquefied tocophersolan
solution obtained from step (c) and;
e. Optionally adding one or more antioxidants into liquefied solution
obtain from step (b) to obtain a clear solution and;
f. Encapsulating the clear solution blend into gelatin outer shell.
10. The fill material as claimed in claim 1-9 is free from water and oil.