Field of Invention
The present invention relates to an oral disintegrating film composition comprising
Methylcobalamin and process for preparation thereof.
Background of the Invention
Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, an equivalent form of
vitamin B12. It differs from cyanocobalamin in that the cyanide is replaced by a methyl group.
Methylcobalamin features an octahedral cobalt (III) centre with metal-alkyl bonds and it is
obtained as bright red crystals. Methylcobalamin can be used to prevent or treat pathology
arising from a lack of vitamin B12 (vitamin B12 deficiency), such as pernicious anaemia.
Methylcobalamin is also used in the treatment of peripheral neuropathy, diabetic neuropathy, and
as a preliminary treatment for amyotrophic lateral sclerosis.
Figure 1: Structure of Methylcobalamin
Several formulations of methylcobalamin have been reported in the literature. Dosage forms
available include capsules, immediate release tablets, sublingual tablets, sprays and injection
formulations. Typically, methylcobalamin is formulated alone or in combination with other B
vitamin as a B-vitamin complex preparation and with folic acid and minerals.
WO 2005/094842 Al discloses a composition that includes one or more Vitamin B12 compounds
with one or more excipients which are said to enhance the solubility of Vitamin B12 compounds.
The excipients include alcohol, in particular ethanol, propylene glycol, polyethylene glycol
(PEG), glycerol, mannitol, sorbitol, Tween 20, or dimethylsulfoxide or a combination thereof.
3
The composition optionally includes one or more therapeutic agents in addition to the Vitamin
B12 compound. The invention also contemplates process by which the composition can be
made; kits containing them (or one or more of the components thereof); and methods of using
the same to treat patients who have a Vitamin B12 deficiency, a proliferative disease, an
inflammatory disease, or a viral disease.
US 5,925,625 is drawn to intranasal hydroxocobalamin. However,US 5,925,625 suggests that
oral, sublingual as well as nasal administration of vitamin B12 appeared to be ineffective routes
of administration especially for headache.
US 6,255,294 discloses modes of delivery to patients of effective allergy-opposing amounts of
Vitamin B12 without the inconvenience and discomfort of subcutaneous and intramuscular
injections. US 6,255,294 discloses enhanced delivery of effective amounts of B12 via the
mucosal membranes of the patient, i.e., mouth, nose, anus and vagina. The delivery is achieved
by instilling vitamin B12 in a carrier matrix, such as controlled release lozenges, chewing gum,
nasal sprays, douches and suppositories, for patient-friendly, self-administration of effective
allergy-opposing amounts of vitamin B12.
US 6,605,646 discloses Vitamin B12 supplement compositions including Vitamin B12 with or
without the addition of folic acid that is essentially free of antioxidants, such as vitamin C, as
well as iron. US 6,605,646 discloses that the supplement may be formulated in a variety of
dosage forms, such as tablets, capsules, oral solutions or suspensions.
Conventional oral dosage forms such as tablets and capsules are difficult to swallow for the
pediatric and geriatric patients. The disintegration time of tablets and capsules is more and which
results in delay in dissolution of drug. Nasal administration of methylcobalamin may result in a
portion of a sprayed dosage either being swallowed, so that the digestive tract destroys its
effectiveness, or a portion may run from the nose, also reducing effectiveness. Methylcobalamin
has a red coloration, which may give the undesirable impression of a bloody nose and therefore
nasal administration is not a preferred dosage form. Lozenge administration of methylcobalamin
may be used, but may be less reliable, given the tendency to chew tablets (especially with
children) and pass a portion of the dose into the digestive tract, which may reduce efficacy.
Injected methylcobalamin, sometimes performed daily, may be an unpleasant experience,
especially for children or adults with psychological or neuro-physiological disorders, such as, for
example, autism spectrum disorders and being a painful delivery form, is not preferred.
4
Therefore, there is a need, for an improved dosage form of methylcobalamin with rapid
disintegration, acceptable taste and easy to administer. An oral disintegrating film of
Methylcobalamin, is a suitable dosage form to fill the existing gap in the medical
armamentarium.
Hence, the present invention is drawn to an oral disintegrating film composition of
Methylcobalam in which is convenient and easy to administer to subjects, disintegrates rapidly,
and improves patient compliance.
Object of the Invention
An object of the present invention is to provide an oral disintegrating film of Methylcobalamin,
capable of rapidly disintegrating in the oral cavity, efficiently masking the bitter taste and a
process for preparation thereof.
Summary of the Invention
The present invention provides an oral disintegrating film composition comprising an aqueous
dispersion of methylcobalamin, film forming polymer and optionally one or more
pharmaceutically acceptable excipients.
The present invention also provides a process of preparing the oral disintegrating film
composition comprises the steps of:
(1) dispersing or dissolving film forming polymer in water to form a dispersion;
(2) dissolving methylcobalamin and optionally one or more pharmaceutically acceptable
excipients in water;
(3) adding the dispersion of step (1) to the solution of step (2), to give a aqueous dispersion; and
(4) drying the aqueous dispersion by spreading on PET film.
Detailed Description of the Invention
In one aspect, the present invention provides an oral disintegrating film composition comprising
an aqueous dispersion of methylcobalamin, a film forming polymer and optionally one or more
pharmaceutically acceptable excipients.
5
The methylcobalamin of the oral disintegrating film composition is present in the range of about
1% w/w to 15 %w/w, more preferably 5% w/w to 15% w/w. Further, overages of the
methylcobalamin are present in the range of about 0-100%.
The film forming polymer of the oral disintegrating film composition is selected from the group
comprising pullulan, hydroxypropylmethyl cellulose of various grades, hydroxyethyl cellulose,
carboxymethyl cellulose, sodium alginate, polyethylene glycol, tragacanth gum, guar gum,
acacia gum, arabic gum, methylmethacrylate copolymer, starch, and combinations thereof.
Preferably, the film forming polymer is hydroxypropylmethyl cellulose-15 cps.The amount of
film forming polymer is present in the range of about 30% w/w to 60% w/w, more preferably is
present in the range of 40% w/w to 50% w/w.
The pharmaceutically acceptable excipient is selected from the group comprising plasticizer,
humectant, preservative, sweetener, flavouring agent, and colouring agent.
The term “plasticizer” as used herein refers to the group of compounds having plasticizing
property and helps in forming film with polymers. The plasticizer is used alone or in
combination with other plasticizer.
The plasticizer is selected from the group comprising glycerine, sorbitol, propylene glycol,
polyethylene glycol, triacetin, triethyl citrate (TEC), acetyl triethyl citrate (ATEC),acetyl tributyl
citrate (ATBC) and other citrate esters or combination thereof.
Preferably, the plasticizer is glycerin.The amount of plasticizer is present in the range of 5% w/w
to 40%w/w, more preferably in the range of about 20%w/w to 30% w/w.
The preservative is present in amounts ranging from about 0.001 wt% to about 5 wt%, preferably
from about 0.01 wt% to about 1 wt% of the film. The preservative is selected from the group
comprising salts of edetate (also known as salts of ethylenediaminetetraacetic acid, or EDTA,
such as disodium EDTA) and parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates,
etc.) or sorbic acid or sodium benzoate and potassium sorbate. Preferably, the preservative is
sodium benzoate.
6
The sweetener is selected from the group comprising Sucralose, Aspartame, Sodium cyclamate,
Sodium saccharin, Acesulfame potassium, Atevia, Sucrose, Advantame, Alitame. Preferably,
the sweetener is sucralose and the amount of the sweetener is present in the range of about 5-
15% w/w of the composition.
The flavouring agent is selected from the group comprising Banana, Cherry, Cinnamon, Tutti
Fruitti, Grape, Orange, Pear, Pineapple, Vanilla, Strawberry, Melon, preferably strawberry and
the flavouring agent is present in the range of 5-15% of the composition.
Other optional additives known in the art for providing various functionalities are included
within the scope of the present invention.
The oral disintegrating film has thickness of about 10-80 μ which provides reduced grittiness and
faster disintegration in the mouth.
The oral disintegrating film size is about 15-25 mm X 25-35 mm and disintegrates rapidly about
in 30-50 seconds.
The oral disintegrating film releases more than 90% of the drug within 30 minutes, preferably
more than 90% within 10 minutes.
The orally disintegrating film dosages form of the present invention may have one or more
favourable properties such as faster disintegration time and most importantly reduced bitterness
of Methylcobalamin.
In another aspect, the present invention provides a process of preparing the oral disintegrating
film composition comprising the steps of:
1. dispersing or dissolving film forming polymer in water to form a dispersion;
2. dissolving methylcobalamin and optionally one or more pharmaceutically acceptable
excipients in water;
3. adding the dispersion of step (1) to the solution of step (2), to give a aqueous dispersion;
and
4. drying the aqueous dispersion by spreading on PET film to obtain the oral disintegrating
film composition.
7
The process step of dissolving the film forming polymer in water to obtain dispersion is selected
from the group comprising heating, stirring, mixing and the similar to obtain dispersion.
The dispersion of step (i) is mixed with solution of step (ii) followed by addition
pharmaceutically acceptable excipients such as plasticizer to obtain aqueous dispersion of step
(iii). This step is achieved by several processes selected from the group comprising stirring,
mixing, heating and the similar.
Aqueous dispersion of step (iii) obtained by adding other pharmaceutical excipients is followed
by sieving and spreading onto the suitable film followed by drying to obtain the oral
disintegrating film composition.
The drying of the polyethylene film is done at a temperature range of about 45ºC to 65ºC, more
preferably the temperature range of about 50ºC to 60ºC.
Without being limited by the theory, the present invention provides a novel oral disintegrating
film composition comprising methylcobalamin, a film forming polymer, plasticizer, sweetener
and optionally flavouring agent, colouring agent and one or more pharmaceutically acceptable
excipients. The optimal use of various components of the present composition renders the
composition synergistic.
By "film" as used herein includes delivery systems of any thickness, including films, sheets,
discs, wafers, and the like, in any shape, including rectangular, square, or other desired shape.
The film is in the form of a continuous roll of film or sized to a desired length and width. The
film described herein is of any desired thickness and size suitable for the intended use. For
example, a film of the present invention is sized such that it is placed into the oral cavity of the
user.
The term "Methylcobalamin" refers to Methylcobalamin, pharmaceutically acceptable salts,
hydrates, solvates, polymorphs, complexes, and pro-drugs thereof. It is envisaged within the
scope of the present invention that the said oral dissolving films of the present invention also
include adenosylcobalamin, cyanocobalamin, methylcobalamin, hydroxocobalamin etc. The
active ingredients are used in different mixtures containing varying effective amounts of each
8
active compound of the invention, which are suitable for the treatment of different types of
vitamin B12 deficiencies.
Herein, “comprising” means the term “comprising” and certain ingredients are defined as
“consisting of” and “consisting essentially of”.
Herein "about" will be understood by persons of ordinary skill in the art and will vary to some
extent on the context in which the term is used, "about" will mean up to plus or minus of the
particular term pharmaceutically acceptable ranges.
By “aqueous dispersion” as used herein includes a liquid system in which very small solid
particles are uniformly dispersed or dissolved in water.
Herein, the terms "disintegrate", "disintegrating", and "disintegrated" includes dissolving,
dispersing, or otherwise breaking apart for release of the drug particles and other components
contained therein, such that they may be swallowed and/or absorbed into the body, including
absorption into the oral cavity and/or the gastrointestinal tract.
ADVANTAGES OF THE INVENTION
1) The oral disintegrating film composition of the present invention disintegrates rapidly in
oral cavity.
2) The oral disintegrating film composition of the present invention efficiently masks the
bitter taste of Methylcobalamin and thus is convenient, easy to administer and has greater
patient compliance.
3) The oral disintegrating film composition of the present invention significantly improves
the treatment of degenerative neurological diseases and other Vitamin B12 deficiency
disorders through significantly enhanced patient compliance because of ease of
administration and reduced frequency of dosing.
The invention is described in detail herein below with respect to the following examples, which
are provided merely for illustration and are not intended to restrict scope of invention in any
manner. Any embodiment that is apparent to a person skilled in the art is deemed to fall within
the scope of present invention.
9
Examples
Example 1: Preparation of Oral Disintegrating film Composition
A film composition is prepared with following components as represented in Table 1:
Table 1:
S. No. Ingredients Qty in %w/w
1 Methylcobalamin 7.5
2 Hydroxy propyl methyl cellulose-15 cps 45.28
3 Xanthan gum 0.93
4 Glycerine 28.55
5 Sucralose 7.5
6 Sodium benzoate 0.25
7 Permitted Flavouring Agent 10
8 Purified Water q.s
Total 100
Process for the preparation of the oral disintegrating film composition of Example 1
The components as set out in Example 1 are accurately weighed.
18.11 mg of HPMC 15 cps &0.37 mg of Xanthan Gum is dispersed in hot purified water under
continuous stirring in a suitable SS vessel using homogenizer.0.1 mg of Sodium Benzoate &3.00
mg of methylcobalamin is dissolved in hot purified water under stirring in a separate suitable SS
vessel. 11.42 mg of Glycerine& 3.00 mg of Sucralose is dissolved respectively in the solution of
sodium benzoate and methylcobalamin under continuous stirring and this solution is added to the
solution of HPMC and Xanthan Gum to obtain the dispersion. To this dispersion 4.00 mg of
flavour is added under stirring. The film is prepared by spreading dispersion on PE film and
dried between50 – 60°C.
Example 2: Preparation of Oral Disintegrating film Composition
A film composition is prepared with following components as represented in Table 2:
Table 2:
S.No. Ingredients Qty/Unit (mg) Qty in %
1 Methylcobalamin 3.000 8.57
2 HPMC 15 cps 16.110 46.03
3 Glycerin 8.790 25.11
4 Sucralose 3.000 8.57
5 Sodium Benzoate 0.100 0.29
6 Strawberry Flavour Dry 4.000 11.43
7 Purified Water q.s. -
Average Weight of film 35 100.00
Process for the preparation of the oral disintegrating film composition of Example 2:
The components as set out in Example 1 are accurately weighed.
10
16.11 mg of HPMC 15 cps & 0.1 mg of Sodium Benzoate are dispersed in hot purified water
under continuous stirring in a suitable SS vessel using homogenizer. 3.00 mg of Sucralose, 8.79
mg of Glycerine & 4.00 mg of flavourare dissolved in hot purified water under continuous
stirring in a separate suitable SS vessel. To this mixture 3.00 mg of methylcobalamin is added
under stirring and this solution is added to the dispersion of HPMC and sodium benzoate to
obtain the aqueous dispersion. The film is prepared by spreading dispersion on PET film and
dried between 50 – 60°C.
Example 2.1: Comparison of effect of quantity of hydroxyl propyl methyl cellulose
(HPMC) on the physical properties of film:
Various experiments are performed to determine the amount of hydroxyl propyl methyl cellulose
and tried with various concentration of hydroxyl propyl methyl cellulose to determine the
physical characteristics of the film like appearance, peelability, elasticity, smoothness and taste.
The results are represented at Table 3 as follows:
Table 3:
Formulation
study
Appearance Peelability Elasticity Smoothness Taste Inference
HPMC 15
cps- 8
mg/film
Red colour
film with
smooth
appearance
Peel off
from base
foil
Not good
elasticity
Smooth
Good
taste
Problem
occur during
cutting
because of
its poor
elasticity.
HPMC 15 cps
-16.11
mg/film
Red colour
film with
smooth
appearance
Smoothly
peel off
from base
foil
Good
elasticity
Smooth
Good
taste
Smooth peel
off and
cutting is
smooth
From Table 3, it is clear that the hydroxyl propyl methyl cellulose (HPMC) in 16.11 mg/film
provides excellent film with respect to appearance, peelability, elasticity, smoothness and taste.
Further, the oral disintegration film composition of the present invention provides optimum
results in various physicochemical parameters as set out below:
Example 2.2: Disintegration time for six units of Example 2
Six films is randomly selected from the batch prepared according to Example 2 are tested for
their disintegration time by suspending each film in 50 ml water at temperature of 37°C. The
disintegration time of the films are set out in Table 4.
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Table 4: Disintegration Time of Oral Disintegrating film
Units Disintegration Time (seconds)
Film 1 36
Film 2 38
Film 3 42
Film 4 38
Film 5 45
Film 6 40
From the table it is seen that the films of the present invention have an optimum disintegration
time of 30 – 50 seconds.
Example 2.3: Thickness of the film
Thickness of the films as set out in example 2 is measured using micrometer and it is seen that
films of the present invention have an average thickness of 30 μm ± 10μm.
Example 2.4: Size of the film
Size of the films as set out in example 2 is measured using micrometer and it is seen that films of
the present invention have an average size of 20 X 30 mm ± 2 mm.
Example 2.5: Taste Masking Test
15 panellists are asked to evaluate the taste by keeping the film in their mouths until dissolved.
Every panellist is given 5 films. Good taste of film is reported by all the 15 panellists as
represented at Table 5.
Table 5:
Panellist 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Film
Taste
good good good good good good good good good good good good good good good
Example 2.6: Dissolution Profile
USP apparatus V (Paddle over Disk) with a stainless steel disk (120 mesh screens) is used at 50
rpms in 900 ml of water at 5, 10, 15, 20 & 30 min to measure the dissolution profile of film. The
dissolution data is presented in Table 6.
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Table 6: Dissolution Profile of Oral Disintegrating film
% of Drug
Released
Time (minutes)
5 minutes 10 minutes 15 minutes 20 minutes 30 minutes
Film 1 102 105 108 108 106
Film2 88 90 88 91 87
Film3 98 98 97 98 94
Film4 84 89 88 90 88
Film5 95 96 96 97 95
Film6 95 96 95 97 92
Example 3: Comparison of effect of different polymers on the physical properties of Oral
Disintegrating film
Various polymers like xanthan gum, polyvinyl alcohol, hydroxyl propyl cellulose, polyvinyl
pyrrolidone K-30 and carbopol are tried for the development of oral disintegrating film
composition of methylcobalamin. The results are represented at Table 7 as follows:
Table 7:
Formulation
study
Appearance Peelability Elasticity Smoothness Taste Inference
HPMC 15 cps
Red colour
smooth
appearance
Smoothly
peel off
from base
foil
Good
elasticity
Smooth Good
taste
Smooth
peel off and
cutting is
smooth.
xanthan gum
Red colour
smooth
appearance
Film does
not peel off
from base
foil
Not good
elasticity
Film is
smooth but
not peel off
Good
taste
Film does
not peel off
Polyvinyl
alcohol
Red colour
smooth
appearance
Smoothly
peel off
from base
foil
Not good
elasticity
Smooth
Bitter
at
end
Problem
occur while
cutting
&bitter taste
Hydroxypropyl
cellulose
Red colour
slight particle
observed
Film does
not peel off
from base
foil
Not good
elasticity
Film is not
peel off
Film does
not peel off
Polyvinyl
pyrrolidone
Red colour
smooth film
Film does
not peel off
from base
foil
Not good
elasticity
Film is
smooth but
not peel off
Good
taste
Film does
not peel off,
film doesn't
have
elasticity.
Carbopol 974
Red colour
slight particle
observed
Film does
not easily
peel off
from base
foil
Not good
elasticity
Film is not
peel off
Good
taste
Film does
not peel off
From Table 7, it is clear that the hydroxypropyl methyl cellulose (HPMC-15) gives films which
have good elasticity, smooth in nature and having good taste.

We Claim:
1. An oral disintegrating film composition comprising an aqueous dispersion of
methylcobalamin, film forming polymer and optionally one or more pharmaceutically
acceptable excipients.
2. The oral disintegrating film composition as claimed in claim 1, wherein film forming
polymer is selected from the group comprising pullulan, hydroxypropylmethyl cellulose
of various grades, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate,
polyethylene glycol, tragacanth gum, guar gum, acacia gum, arabic gum,
methylmethacrylate copolymer, starch, and combinations thereof.
3. The oral disintegrating film composition as claimed in claim 2, wherein film forming
polymer is hydroxypropylmethyl cellulose.
4. The oral disintegrating film composition as claimed in claim 1, wherein the
pharmaceutically acceptable excipient is selected from the group comprising plasticizer,
humectant, preservative, sweetener, flavouring agent, and colouring agent.
5. The oral disintegrating film composition as claimed in claim 4, wherein plasticizer is
selected from the group comprising glycerin, sorbitol, propylene glycol, polyethylene
glycol, triacetin, triethyl citrate (TEC), acetyl triethyl citrate (ATEC),acetyl tributyl
citrate (ATBC) and other citrate esters.
6. The oral disintegrating film composition as claimed in claim 4, wherein preservative is
selected from the group comprising salts of edetate, parabens, sorbic acid, sodium
benzoate and potassium sorbate.
7. The oral disintegrating film composition as claimed in claim 4, wherein sweetener is
selected from the group comprising Sucralose, Aspartame, Sodium cyclamate, Sodium
saccharin, Acesulfame potassium, Atevia, Sucrose, Advantame, Alitame.
8. The oral disintegrating film composition as claimed in claim 1, wherein oral
disintegrating film thickness is 10-80 μm.
14
9. The oral disintegrating film composition as claimed in claim 1, wherein oral
disintegrating film size is 15-25 mm by 25-35 mm.
10. A process of preparing the oral disintegrating film composition as claimed in claim 1
comprising the steps of:
i. dispersing or dissolving film forming polymer in water to form a dispersion;
ii. dissolving methylcobalamin and optionally one or more pharmaceutically
acceptable excipients in water;
iii. adding the dispersion of step (1) to the solution of step (2), to give a aqueous
dispersion; and
iv. drying the aqueous dispersion by spreading on PET film to obtain the oral
disintegrating film composition.