Note: Descriptions are shown in the official language in which they were submitted.
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TITLE
WATER SOLUBLE PHARMACEUTICAL FILM WITH ENHANCED
STABILITY
TECHNICAL FIELD
The present invention relates to orally disintegrating stable film type dosage
forms
for delivering active pharmaceutical agents, neutraceuticals, diagnostic aids
and
dietary additives.
BACKGROUND OF THE INVENTION
Oral thin film is a dosage form that is used for delivering various active
pharmaceutical active agents, nutraceuticals, diagnostic aids and dietary
additives.
The mouth dissolving films have been reported for various applications
including,
without limitation, altering the delivery profile of given pharmaceutical
agents, by
increasing its rate of dissolution or absorption, or bypassing metabolic
processes that
increased the bioavailability of the drug. Few illustrative examples are oral
thin films
disclosed in U.S. patent no. 6709671, U.S. patent application number
2008053466,
U.S. patent no. 4900552, and U.S. patent no.5166233.
However, the oral thin films (OTF) available in the market, when exposed to
atmospheric conditions for short periods during course of routine use to
consume
them, undergo curving. The curved edges of OTF pose difficulty in dispensing
of
these films from multi-dose (Multiple dose) container. These curved edges also
pose
difficulty in packaging of these films into single or multi-dose packages.
These
curved edges can lead to dispensing of more than one unit dosage, which is a
serious
adverse issue related to dose dispensing. Curving of these thin films affects
aesthetic
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appeal and raise doubt about the stability of these films. Hence it is
important that
films should retain flatness during casting, packaging and throughout their
shelf life
and should not be deformed during course of conditions of use on account of
exposures to variable environmental conditions. Moreover, films prepared by
prior
methods, have a disadvantage of sticking to each other or to the surface of
package
because of their smooth surfaces and hygroscopic nature. This leads to limited
suitability for the further processing e.g. film cutting, stacking, packaging,
dispensing and use and may also lead to microbial contamination, loss in
potency
and error in dosing.
Further, prior art films involve the use of hydrophilic polymers and use of
water in
the process of casting the film. Because of these factors, moisture sensitive
Active
Pharmaceutical Ingredients are not stable during the conventional process of
casting
these films and during storage.
Thus, OTFs have long unsolved problem of stickiness, curving of the film and
instability of moisture sensitive Active Pharmaceutical Ingredients that
needed to be
solved.
GB927963 achieved prevention of adhering and achievement of non-sticky Water-
Soluble Films of Polyvinyl Alcohol Derivatives by making the film from a
composition comprising a water-soluble polyvinyl alcohol derivative and not
more
than 30% by weight of an aliphatic dicarboxylic acid based on the polyvinyl
alcohol
derivative, the solubility of the said acid being less than 3.0% at 20 C, and
more
than 0.3% at 100 C. GB927963 also claims a non-sticky film nade from a water
soluble polyvinyl alcohol derivative together with less than 30% by weight of
an
aliphatic di-carboxylic acid, said acid having a solubility in water less than
3.0% at
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20 C. and more than 0.3% at 1000 C. This method is restricted to the films
made
specifically from polyvinyl alcohols derivatives and to which an aliphatic
dicarboxylic acid has been added, and does not cover within its scope other
water
soluble polymers and other additives that would result into an a water soluble
anti-
tacking, non-curving film
US3316190 achieved a cold water soluble polyvinyl alcohol film, which is non-
sticky at high humidity comprising either a surface active alone or with water
soluble
starch as defined in one of the following groups of essential elements: (a)
from 0.2%
to 20% by weight of a surface active agent having an HLB in the range of 8 to
20,
based on the weight of polyvinyl alcohol, (b) from 2% to 50% by weight of a
water-
soluble starch, based on the weight of polyvinyl alcohol, and from 0.2% to 20%
by
= weight of a surface active agent having an HLB value in the range of 8 to
20%,
based on the weight of polyvinyl alcohol, (c) from 2% to 50% by weight of a
water-
soluble starch, based on the weight of polyvinyl alcohol, and from 0.2% to 20%
by
weight of an anionic surface active agent having an HLB value in the range of
8 to
= 20%, based on the weight of polyvinyl alcohol, (d) from 2% to 50% by
weight of a
water-soluble starch, based on the weight of polyvinyl alcohol, and from 0.2%
to
20% by weight of a non-ionic surface active agent having an HLB value in the
range
of 8 to 20%, based on the weight of polyvinyl alcohol selected from the group
consisting of ethylene oxide adducts of fatty acids, fatty alcohols and
alkylphenols.
Anionic surface active agent used was dialkylsulfosuccinate; and processes of
preparing of above embodiments of the films. This patent also describes method
of
preparation of non sticky films limited to polyvinyl alcohol as film forming
polymer
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and either surface active agent alone or with a surface active agent and water
soluble
starch.
W02007030754 discloses films having one of the following groups of essential
features/elements of an edible film: (1) at least one anti-tacking agent
selected from
the group consisting of lubricants, antiadherants, glidants and combinations
thereof.
(2) an edible, water-soluble polymer component comprising at least one polymer
selected from the group consisting of hydroxypropyl cellulose,
hydroxypropylmethyl
cellulose, polyethylene oxide and combinations thereof and an anti-tacking
agent
comprising Vitamin E TPGS present in amounts of about 0.01% to about 20% by
weight of said film, (3) an edible, water-soluble polymer component comprising
polyethylene oxide in combination with a polymer selected from the group
consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose and
combinations thereof; and Vitamin E TPGS present in amounts sufficient to
provide
anti-tacking and therapeutic properties, wherein said film is self-supporting,
(4)
an edible, water-soluble polymer comprising polyethylene oxide and
hydroxypropyl
cellulose; polydextrose, wherein said polyethylene oxide, hydroxypropyl
cellulose
and polydextrose are present in a ratio of about 45:45: 10; and at least one
anti-
tacking agent, (5) an edible, water-soluble polymer; and a coating on said at
least
one surface of said self-supporting film, said coating comprising at least one
anti-
tacking agent, (6) a multi-layer film for delivery of an active comprising:
(a) at least one first film layer comprising: (i) an edible, water-soluble
polymer; and
(ii) an anti-tacking agent; and (b) a second film layer comprising: (i) an
edible,
water-soluble polymer; and (ii) an active component selected from the group
consisting of cosmetic agents, pharmaceutical agents, vitamins, bioactive
agents and
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combinations thereof, wherein said first film layer is substantially in
contact with
said second film layer.
W02007030754 also discloses a process for making a self-supporting film having
a
substantially uniform distribution of components comprising following
essential
features: at least one anti-tacking agent to form a matrix with a uniform
distribution
of said components; providing a surface having top and bottom sides; (d)
feeding
said film onto said top side of said surface; and (e) drying said film by
applying heat
to said bottom side of said surface.
A granted patent from above application W02007030754, represented by
US8765167, has claims narrowed down wherein it claims an oral film for
delivery of
a desired amount of an active component comprising: an ingestible, water-
soluble,
polymer matrix, the films having a substantially uniform distribution of said
desired
amount of said active component within said polymer matrix, which is "
measured
by substantially equally sized individual unit doses which do not vary by more
than
10% of said desired amount of said active component", the film is self-
supporting
and the active component is substantially uniformly distributed, said film
being
formed by a controlled drying process which rapidly forms a viscoelastic
matrix to
lock-in said active in place within said matrix and maintain said
substantially
uniform distribution; wherein said film is self-supporting and the active
component
is substantially uniformly distributed. In addition to these elements which
are
common to all claims, following are some selective essential elements in the
claims.
In one embodiment (claim 1) the anti-tacking agent to the group is limited to
consist
of stearates; stearic acid; vegetable oil; waxes; a blend of magnesium
stearate and
sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium
acetate;
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sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate; sodium lauryl
sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon
dioxide;
syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations
thereof. In another embodiment (claim 13), the polymers comprise at least one
polymer selected from the group consisting of hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl
cellulose,
polyethylene oxide and combinations thereof and an anti-tacking agent is
limited to
be selected from the group consisting of Vitamin E, Vitamin E TPGS, and sodium
benzoate, wherein said anti-tacking agent is present in amounts of about 0.01%
to
about 20% by weight of said film. In a further embodiment (claim 14),
essential
elements comprise: an ingestible, water-soluble polymer matrix comprising
polyethylene oxide in combination with a polymer selected from the group
consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxyethyl
cellulose, carboxymethyl cellulose, and combinations thereof; and an anti-
tacking
agent selected from the group consisting of Vitamin E, Vitamin E TPGS, and
sodium
benzoate, wherein said anti-tacking agent is present in amounts sufficient to
provide
anti-tacking and therapeutic properties. In a still further embodiment (claim
15),
essential elements comprise: water-soluble polymer matrix comprising
polyethylene
oxide and a polymer selected from the group consisting of hydroxypropyl
cellulose,
hydroxyethyl cellulose, and carboxymethyl cellulose; and polydextrose, wherein
said
polyethylene oxide, said polymer selected from the group consisting of
hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose,
and
said polydextrose are present in a ratio of about 45:45:10 by weight; at least
one anti-
tacking agent selected from the group consisting of stearates; stearic acid;
vegetable
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oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; boric
acid;
surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-Leucine;
polyethylene glycol; sodium oleate; sodium lauryl sulfate; magnesium lauryl
sulfate;
talc; corn starch; amorphous silicon dioxide; syloid; metallic stearates,
Vitamin E,
Vitamin E TPGS, silica and combinations thereof. In yet another embodiment
(claim
16), essential elements are: at least one anti-tacking agent selected from the
group
consisting of stearates; stearic acid; vegetable oil; waxes; a blend of
magnesium
stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate;
sodium
acetate; sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate;
sodium
lauryl sulfate; magnesium lauryl sulfate; talc; cornstarch; amorphous silicon
dioxide;
syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations
thereof. Embodiment represented by Claim 17 discloses a multilayer film
comprising: (a) at least one first film layer comprising: (i) an ingestible,
water-
soluble polymer matrix; and (ii) at least one anti-tacking agent selected from
the
group consisting of stearates; stearic acid; vegetable oil; waxes; a blend of
magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium
benzoate; sodium acetate; sodium chloride; DL-Leucine; polyethylene glycol;
sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn
starch;
amorphous silicon dioxide; syloid; metallic stearates, Vitamin E, Vitamin E
TPGS,
silica and combinations thereof; and (b) a second film layer comprising: (i)
an
ingestible, water-soluble polymer matrix; and (ii) a substantially uniform
distribution
of said desired amount of said active component within said polymer matrix,
wherein
said active component is selected from the group consisting of cosmetic
agents,
pharmaceutical agents, vitamins, bioactive agents and combinations thereof,
wherein
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said first film layer is substantially in contact with said second film layer;
said film
being formed by a controlled drying process which rapidly forms a viscoelastic
matrix to lock-in said active in place within said matrix and maintain said
substantially uniform distribution. Embodiment of Claim 19 discloses following
essential features of a process for making a self-supporting. film comprising:
providing a surface having top and bottom sides; feeding the film onto said
top side
of said surface; and drying said film by applying heat to said bottom side of
said
surface. Claim 109 essentially claims an embodiment, wherein, in addition to
water
soluble polymers, use of at least one anti-tacking agent comprising sodium
benzoate,
an active component selected from the group consisting of an opiate, opiate
derivative, an analgesic and combinations thereof; said film being formed by a
controlled drying process to maintain a substantially uniform distribution
thereof.
Claim 110 has disclosed following essential elements: a multi-layer film
comprising:
(a) a first film layer comprising: (i) an ingestible, water-soluble or water-
swellable
polymer matrix; and (b) at least a second film layer comprising: (i) an
ingestible,
water-soluble or water-swellable polymer matrix comprising a water-soluble or
swellable polymer; wherein the first and/or second layers further comprise: a
desired
amount of a substantially uniformly distributed active component, a component
selected from the group consisting of an anti-tacking agent, a sweetener, a
flavor, an
acidulent, an oxide filler, propylene glycol, vitamin E acetate, polyacrylic
acid, a
preservative, a buffer, a coloring agent and combinations thereof; and wherein
said
first film layer is substantially in contact with said second film layer; said
film being
formed by a controlled drying process to maintain substantially uniform
distribution
of the component.
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In the context of above patent, Vitamin E is an oily liquid. Its presence in
the film
beyond a certain concentration will make the film appear oily and hamper with
its
aesthetic appeal. Moreover, all the film formulations require addition of
suitable
plasticizers which at many instances are liquids. Addition of vitamin E along
with
liquid plasticizers will result) into films that are oily to touch. That means
using
vitamin E and other liquid excipients to make film non sticky will pose a
restriction
to the use= of other liquid or oily excipients that are used for other
functions like,
plasticizers, flavors, surfactants, emulsifiers, sweetener, etc.
However, use of vegetable oils and waxes including strearic acid impart
unacceptable taste to the film when it is meant to get dissolved in oral
cavity. Being
liquid at higher ambient temperatures the waxes alter the appearance of films
by
making them appear waxy. Vegetable oils have problems of oxidation and
rancidity
and thus will require the incorporation of antioxidants. Further some of the
excipients mentioned as anti-tacking agents belong to the class of lubricants
but
when used in the films give sticky films because of their oily and waxy nature
like
strearic acid, vitamin E, oils and waxes. Similarly amongst the mentioned
excipients
some are hygroscopic in nature e.g. polyethylene glycols, boric acid etc.
Films made
using these hygroscopic excipients will be sensitive to atmospheric conditions
and
will not be stable for a sufficiently long time.
.. Further, the above mentioned application does not describe details of the
controlled
heating process. During the casting of such films, the films are always casted
on a
support material which may be made up of PVC or similar materials, stainless
steel
belt or some other metal bets. While heating is being done from the bottom
side the
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heat will be first transferred to the support material which in turn will pass
to the
film. The way a film gets dried will be affected by the nature of the support
material.
It is desired to achieve non-sticky films by methods other than used so far so
that a
wider choice of methods is available to make non-sticky films, which may
require
different methods for different requirements of actives that are added to the
film.
Further, despite non-sticky nature, the methods disclosed in the prior art do
not make
films that are free from problem of curving.
Accordingly, it is an object of present invention to provide orally
disintegrating
stable film dosage form for delivering active pharmaceutical agents,
neutraceuticals,
dietary additives, diagnostic aids and cosmaceuticals by alternative newer
methods.
Another objective of present invention is to solve the problem of curving in
the film,
from the edges when exposed to atmospheric conditions of varying humidity and
temperature. Prior art talks only about the stability of films and is silent
on the
curving problem of the film. But the films available in the market have this
problem.
Yet another objective of present invention is to provide instant wettability,
adequate
tensile strength and fast disintegration while achieving stable films that are
non-
curving and non sticky or non tacky by newer methods.
Yet another objective of present invention is to provide manufacturing
techniques
and methodologies for manufacturing of non-curving, and non-sticky films.
For the purpose of this specification, the term "stable film" means and
includes
"non-curving film" and "non-sticky or non-tacky film".
SUMMARY OF THE INVENTION
This invention comprises an Oral Thin Film that is instantly wettable, rapid
dissolving, non-sticky, non-tacky and non-curving, the said Film capable of
carrying
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an active ingredient for oral delivery being a moisture stabilized film that
remains
non-sticky and non-curving when exposed to 70-15 % RH (Relative Humidity) at
25 C for at least 2 minutes up to 2 hours in open conditions without
packaging.
This invention also comprises processes/methods to make the said Oral Thin
Film
.. that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-
curving.
In one embodiment, the process/method of preparation of the said rapidly
dissolving
oral water soluble film for oral delivery of an active ingredient comprises
steps of
casting a film comprising water soluble polymer/s, optional additives; and
drying the
same by application of heat; wherein the drying of the film after casting is
done by
.. increasing temperature of drying in two or more stages. In one embodiment
of this
process/method in the first stage the temperature of drying is kept in a range
of 45 C
to 60 C and drying is done until the moisture content of the film reaches in
the range
of 50% to 20%, in the second stage, temperature is kept in the range of 60 C
to
110 C and drying is done until the moisture content of the film reaches in the
range
of 30 % to 10 %, and in the third stage, temperature is kept in the range of
80 C to
130 C and drying is done until the moisture content of the film reaches to in
the
range of 10% to 2% at the end of drying process. The process of this
embodiment
also comprises addition of additives, which comprise an active ingredient and
excipients. The active ingredient may comprise, without limitation, an active
pharmaceutical, nutraceutical or cosmaceutical ingredient.
In another embodiment, this invention comprises a process/method of
preparation of
the said rapidly dissolving oral water soluble film for oral delivery of an
active
ingredient, the process comprising steps of casting a film comprising water
soluble
polymer/s, optional additives; and drying the same by application of heat;
wherein
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the drying of the film after casting is done alternately on both the sides
wherein: (a)
in the first stage, drying is done on top side of the casted film at 70 C to
120 C until
moisture content of the film reaches in the range of 50% to 20%, (b) the
resulting
film is then removed from the support and dried in second stage from other
side at 70
to 120 C until the moisture content reaches in the range of 20% to 2%.
Preferably,
the first stage drying is preferably done in the range 35% to 25% and the
second
stage drying is done in the range of 10% to 2%, and the film contains an
active
ingredient. This process/method 'may comprising following steps: (a) casting a
solution comprising a rapidly water soluble polymer as a film on a support,
(b)
drying the casted film at 100 C to a semi-dried condition to a moisture
content in the
range of 20% to 50%, (c) coating the semi-dried film with moisture resistant
or
moisture repellent solution, (d) drying at 80 C, (e) removing the double
layer film
from the support, (f) flipping the removed double layer film and further
casting with
moisture resistant or moisture repellant solution, and (g) drying at 80 C.
The
thickness of the thin film of the moisture resistant or moisture repellent
polymer may
be in the range of 1-5 gm, the thickness of the entire single layer or
multilayer film
may range from 40 gm to 150 gm, and moisture of the entire film may range from
10% to 2%.
In yet another embodiment, this invention comprises a process/method of
preparation
of a said rapidly dissolving oral water soluble film for oral delivery of an
active
ingredient comprising steps of casting a film comprising water soluble
polymer/s,
optional additives; and drying the same by application of heat, coating the
dried film
with synthetic water insoluble moisture resistant/moisture repellant
hydrophobic
polymers that does not melt at high temperature; wherein the thickness of the
coating
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being such that it prevents uptake of moisture from ambient humidity, but
dissolves
rapidly when contacted with water.
In yet another embodiment, this invention comprises a process/method of
preparation
of the said rapidly dissolving oral water soluble film for oral delivery of an
active
ingredient comprising steps of casting a film comprising water soluble
polymer/s,
optional synthetic water insoluble moisture resistant/moisture repellant
additives and
one or more of a synthetic water insoluble moisture resistant/moisture
repellant
hydrophobic polymer that does not melt at high temperature, wherein the said
polymer is added in a range that shall permit instant wettability and rapid
dissolution
when the film comes in contact with water. The synthetic water insoluble
moisture
resistant/moisture repellant hydrophobic polymer used in the film is in a
concentration range from 1.5% to 7.5% of the dry weight of the dry film. The
water
insoluble polymer, preferably, is polymethacrylate. This process/method may
further
comprise, in addition to water insoluble polymer, addition of one or more of
moisture absorbents also to make the film.
DETAILED DESCRIPTION
Brief description of figures and legends
Figure 1: The diagram of machine used to manufacture the stabilized film (1)
denotes casting solution/dispersion (2) Roller, (3) First stage drying, (4)
Casted Film
, (5) Support roller, (6) Second stage drying.
Figure 2: - Depicts the diagram of machine used to manufacture the moisture
repellent/ moisture resistant film. (1) denotes casting solution/dispersion,
(2) Roller,
(3) film casting, (4) Heater, (5) Moisture resistant polymeric solution, (6)
Heater, (7)
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Flipping of film, (8) Moisture resistant polymeric solution, (9) Heater, (10)
dried
film.
Figure 3: depicts (1) a Multiple dose container, (2) films stacked in the
multiple dose
container, and (3) dispensing of one film from the stack, which exposes the
films to
ambient humidity in the course of handling and makes dispensing difficult if
the
films are sticky or/and curved.
The present invention comprises a method of manufacturing of instantly
wettable,
non-sticky and non-curving OTF by using means of improving moisture
stabilization
' of the OTF at an ambient humidity at or below 70 5 % RH; wherein moisture
stabilization is defined as retention of flatness of the thin film during
casting,
packaging and storage such that the OTF remains non-sticky and non-curving
when
exposed to 70 5 % RH (Relative Humidity) at 25 C for at least 2 minutes up to
2
hours in open conditions without packaging..
The invention also provides an instantly wettable, oral dissolving, non-sticky
and
non-curving Oral Thin Film capable of carrying an active ingredient for oral
delivery
and a method of manufacturing of the same.
In first embodiment of the means of improving moisture stabilization of the
OTF, a
casted film is dried at gradually increasing temperature. In an illustrative
embodiment, the temperature is increased in three stages. In the first stage
the
temperature is kept in a range of 45 C to 60 C and drying is done until the
moisture
content of the film reaches in the range of 50% to 20%; in the second stage,
temperature is kept in the range of 60 C to 110 C and drying is done until the
moisture content of the film reaches in the range of 30 % to la %; and in
third stage,
temperature is kept in the range of 80 C to 130 C and drying is done until the
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moisture content of the film reaches to in the range of 10% to 2% at the end
of
drying process (Example 1).
In second embodiment of this invention, moisture stabilization of the OTF is
achieved by drying of a casted film alternately on both the sides in two
stages. In the
first stage, drying is done on top side of the casted film at 100 C until
moisture
content of the film reaches in the range of 50% to 20%, more preferably in the
range
=
35% to 25%. The resulting film is then removed from the support and dried from
other side at 100 C until the moisture content reaches in the range of 20% to
2%,
more preferable in the range of 10% to 2%. Figure 1 depicts the diagram of
machine
used to manufacture the stabilized film (Example 2).
The First and Second embodiment of this invention described above are
improvement over prior art methods of drying of casted films. The prior art
methods
comprise drying of casted films on one side of the films by exposing to heat,
which
leads to migration of all water soluble constituents from one side along with
water
molecules, this is one of the reasons for defects in the film like curving of
edges,
sticking etc. or to make a uniform film, they are required to make rapid
heating, but
they do not result into a non-curving film because the heating/drying is
uneven at
two surfaces. In the instant invention, (a) the heating, when dome on one side
only, is
done in more than two stages giving reasonable time for the moisture to get
readjusted, come to an equilibrium across the cross section of the film and
then
further drying is done in further stage; or (b) it is done in two stages, in
first stage on
one side upto a certain temperature. and then it is flipped and further drying
at higher
temperature is done on the other side; these two approaches result in a film
that not
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only results in a uniform molecular distribution but also results in a
uniformly dried
film that is non-curving also.
Figure 2 depicts the diagram of machine used to manufacture the moisture
repellent/
moisture resistant film.
In third illustrative embodiment, this invention comprises moisture
stabilization of an
OTF made from water soluble polymers by coating them with water insoluble
moisture resistant/moisture repellant, hydrophobic polymers that does not melt
at
high temperature and alter/s the ability of films to absorb moisture and make
them
resistant to changing ambient humidity conditions to overcome stickiness and
curving of the film during storage and usage; wherein the thickness of the
coating
being such that it prevents uptake of moisture from ambient humidity, but
dissolves
rapidly when contacted with water. The said moisture resistant/ repellent
polymers
are used as a thin layer on the already casted oral thin film coating or
enveloping the
film from both the sides using thin layer of moisture resistant/ moisture
repellent
agents. This results in enveloping of film for its protection from moisture.
The
resulting film remains flat and flexible. A preferred range of thickness of
coated
layer is in the range of 5-1 gm. In this embodiment, in the first stage,
solution casting
and drying is done at 100 C, the semidried film possesses moisture in the
range of
20% to 5%. The resulting film is then coated/ casted with moisture resistant/
moisture repellent polymeric solution and dried at 80 C. The resulting double
layered film is removed from the support; flipped and further casting is done
with
moisture resistant/ moisture repellent solution and dried at 80 C. The
resulting
tripled layered/ laminated film contains moisture in the range of 10% to 2%.
This
invention is illustrated by Examples 3, 3.1 and 3.2.
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The said moisture resistant/ repellent polymers are used as a thin layer on
the already
casted oral thin film may be polyacrylates.
In fourth embodiment of this invention moisture stabilization was achieved by
adding, to the water soluble polymer containing solution prepared for casting
the
film, a synthetic water insoluble hydrophobic polymer that does not melt at
even
extreme temperature conditions such as 55 to 60 C., the said synthetic
polymer
being added in a range that shall not adversely affect the dissolution
property of the
film, shall permit instant wettability and rapid dissolution when the film
comes in
contact with water but shall impart non folding, non curving and non sticky
characteristic to the films. Such water insoluble polymers include, without
limitation,
Acrylic/methacrylic acid copolymers including pH dependent polymers such as
acrylic acid/methacrylic acid copolymers, pH independent polymers including
acrylic/methacrylate copolymers and carbomer. polymers. Presence of
hydrophobic/water-insoluble polymer in concentration range from 1.5 to 7.5 %
in the
conventional composition of films will impart non curving
and non sticky
characteristic to the films (Example 4).
In a fifth embodiment of means of improving moisture stabilization of the OTF,
moisture adsorbants and hydrophobic polymers can be added in combination in
the
range of 1 to 10 %.
Other components like emulsifying agents, preservatives, buffering agents,
antioxidants, plasticizers, super-disintegrants, absorbents, sweeteners, taste
modifiers, flavorants, colorants, water insoluble polymers, pH modifiers,
buffering
agents, surfactants and stabilizers may also be added while making an Oral
Thin
Film.
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The film forming polymer that can be used for making films of this invention
comprise one or more or a combination of hydrocolloids, natural or semi
synthetical,
and comprising, without limitation, hydroxypropyl methyl cellulose, hydroxy
ethyl
cellulose, carboxy methyl cellulose, pullulan, polyvinyl alcohol, polyethylene
glycol
graft polymer, soluble cellulosic polymers, guar gum, xanthan gum, locust bean
gum, carrageenan, gum tragacanth, pectin, Carboxy methyl guar gum, and Carboxy
methyl locust bean gum. The Polyoxyethylene polymers are selected according to
the viscosity and the molecular weight.
The preferred ranges in which various ingredients, used are indicated below in
percentages of dry weight of the final film comprising, without limitation:
active
agents0.01-80%, emulsifying agent/s 0.1%-10%, preservative/s 0.01-10%,
buffering
agent/s 0.01-10%, antioxidant/s 0.001-10%, plasticizer/s 0.5-40%, super dis-
integrant/s 0.01 to 5%, absorbent/s 0.01 to 10 %, flavoring agent/s 0.001-10%,
coloring agent/s 0.001-5%, water-insoluble/hydrophobic polymer/s 1.5 to 7.5 %,
pH
modifier/s 0.01-10%, buffering agent/s 0.01 to 5 %, stabilizer/s 0.01-5% and
water
soluble polymer/s 25 - 85%.
Moisture resistant polymers used in this invention comprise, without
limitation,
polymethacrylate/s. The polymethcryalte used may be selected form the group
comprising, without limitation: Poly(butyl methacrylate, (2-
dimethylaminoethyl)
methacrylate, methyl methacrylate), Poly(ethyl acrylate, methyl methacrylate),
Poly(methacrylic acid, methyl methacrylate), Poly(methacrylic acid, ethyl
acrylate),
Poly(methacrylic acid, methyl methacrylate), Poly(methyl acrylate, methyl
methacrylate, methacrylic acid), Poly(ethyl acrylate, methyl methacrylate,
trimethyl ammoni ethyl methacrylate chloride) Poly(ethyl acrylate, methyl
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methacrylate, trimethylammonioethyl methacrylate chloride) ethyl cellulose,
phthalate derivatives and shellac.
Thickness of the single or multi-layer films may vary widely in the range of
40 gm
to 150 gm, more preferably from about 50 gm to about 120 gm and has the
moisture
content in the range of 10% to 2%.
The above list is illustrative only and does not have any limiting effect; the
illustrated ingredients can be replaced by alternative substances having
equivalent
function and properties which are known to those skilled in the art.
The active compound/ingredient may, for example, be medicinal, neutraceutical,
dietary additive, cosmaceutical, colorant and a dignostic.
This invention is especially suitable for pharmaceutical, neutraceutical and
dietary
additives that have ability to absorb moisture or those that degrade in the
presence of
moisture.
Besides above mentioned embodiments, there may be several other embodiments
that achieve moisture stabilization, including the ones which are obvious
variants of
above or equivalents of above, and all of them are included within the scope
of
disclosure of this specification. The non-limiting examples given below are
only
illustrative and do not limit the scope of means used for moisture
stabilization nor
the conditions used for moisture stabilization. ,
Example 1
Drying a casted film at gradually increasing temperature
Name of excipients Amount (in
%)
19
Maltodextrin 15.6
Polyvinyl alcohol 1.8
Sorbic Acid 0.2
Sucralose 0.4
Polysorbate 80 2
Water 80
Maltodextrin, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80 were
added
in order as they appeared in table 1 in 400 ml of water. The resulting
solution was
then stirred at room temperature until homogeneous solution was formed. It was
then
coated onto a belt of support material using conventional coating
equipment.
Support material could be TeflonTm coated PVC, simple PVC or Stainless steel
belt.
Wet film thickness was adjusted to achieve dry thickness between 20 to 50 um.
Resulting film was then dried in first heating chamber at 60 C, the film was
then
allowed to cool to room temperature and then re-dry at 90 C in second drying
chamber, resulting film was again allowed to cool to room temperature and
again
this procedure was repeated for drying of film in third heating chamber at 120
C.
The resulting film was then removed from support and cut into pieces of
desired size
and shape. The formed films were uniform in appearance and dissolved rapidly.
Moisture stability test: These films were then packed in multi-dose
containers that
were not air tight and exposed to 70+5%, 50+5% and 30+5% RH (relative
humidity) at a temperature of 25 2 C and were observed for 15, 30 and 45 min
for
their stability in exposed and packed conditions. Films were stable for 10, 12
and
15 minutes respectively in exposed conditions and in a condition when a multi-
dose
container in which these films are placed, after they are exposed in course of
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handling for use to ambient humidity for a multiple number of times for a
total of 45
minutes of exposure.
Example 1.1:
Drying a casted film containing pharmaceutical agent at gradually increasing
temperature
Name of Ingredients Quantity (In
%)
Phenylephrine 1.17
Maltodextrin 14.68
Polyvinyl alcohol 1.69
Sorbic Acid 0.188
Sucralose 0.37
Polysorbate 80 1.88
Water 80
Phenylephrine, maltodextrin, polyvinyl alcohol, bronopol, sucralose and
Polysorbate
80 were added in order as they appeared in table 1 in 400 ml of water. The
resulting
solution was then stirred at room temperature until homogeneous solution was
formed.
It was then coated onto a belt of support material using conventional coating
equipment. Support material could be Teflon coated PVC, simple PVC or
Stainless
steel belt. Wet film thickness was adjusted to achieve dry thickness between
20 to 50
1_1M. Resulting film was then dried in first heating chamber at 60 C, the film
was then
allowed to cool to room temperature and then re-dry at 90 C in second drying
chamber, resulting film was again allowed to cool to room temperature and
again this
procedure was repeated for drying of film in third heating chamber at 120 C.
The
resulting film was then removed from support and cut into pieces of desired
size and
21
shape. The formed films were uniform in appearance and dissolved rapidly.
These
films were then packed in multi-dose containers and exposed to 70 5%, 50 5%
and 30 5% RH (relative humidity) at a temperature of 25 2 C and were observed
for 15, 30 and 45 min for their stability in exposed and packed conditions.
Films
were stable for at least 10, 12 and 15 minutes respectively in exposed
conditions
and in multi-dose container in which these films are placed, after they are
exposed
in course of handling in course of use to ambient humidity for a multiple
number
of times for a total of 45 minutes of exposure.
Example 1.2:
Formulating stable film containing pharmaceutical active agent dried using
gradually increasing temperature.
Name of Quantity in
Ingredients percentage
Phenylephrine 2.5
HPMC 5 cps 20
PEG 4000 8
Bronopol 0.1
TweenTM 80 0.5
Sucralose 0.1
Water 68.8
HPMC was dissolved in fixed quantity of water and PEG 4000 was added to HPMC
solution. Remaining ingredients including phenylephrine were added to
polymeric
solution. The resulting solution was then stirred at room temperature until
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homogeneous solution was formed. It was then coated onto a belt of support
material
using conventional coating equipment. Support material could be Teflon coated
PVC,
simple PVC or Stainless steel belt. Wet film thickness was adjusted to achieve
dry
thickness between 20 to 50 1AM. Resulting film _was then dried in first
heating chamber
at 60 C, the film was then allowed to cool to room temperature and then re-dry
at
90 C in second drying chamber, resulting film was again allowed to cool to
room
temperature and again this procedure was repeated for drying of film in third
heating
chamber at 120 C. The resulting film was then removed from support and cut
into
pieces of desired size and shape. These films were then packed in multi-dose
containers and exposed to different humidity conditionsas described in example
1 and
were observed for 15, 30 and 45 mm for their stability in exposed and packed
conditions. Films were stable for at least 10, 12 and 15 minutes respectively
in
exposed conditions and in multi-dose container in which these films are
placed, after
they are exposed in course of handling in course of use to ambient humidity
for a
multiple number of times for a total of 45 minutes of exposure.
Example 2
Drying the film in two stages
Name of excipients Amount (In %)
Pullulan 14.54
Polyvinyl alcohol 1.79
Bronopol 0.20
Sucralose 0.40
Polysorbate 80 , 1.99
Polyethylene Glycol 1.40
Water 79.68
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Pullulan, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80, talcum
and
titanium dioxide were added in 400 ml water in the fashion presented in the
Examplel. The resulting solution was then stirred at room temperature until
homogeneous solution was formed. It was then coated onto a belt of support
material
Support material could be Teflon coated PVC, simple PVC or Stainless steel
belt
using conventional film casting equipment. Wet film thickness was adjusted to
achieve dry thickness between 20 to 50 p.m. In first stage, drying was done
from top at
100 C. The resulting film was then removed from support and dried from other
side at
100 C. The resulting films was then removed from support and cut into pieces
of
desired size and shape. The so prepared films were then subjected to the test
described
in example 1 and it was found that all the films retained their flatness for
at least up to
10 minutes in exposed conditions and throughout the observation period in
packed
conditions.
Example 2.1: , .
Name of Ingredients Quantity (In %)
Simethicone 5.8
Neusilin 2.3
Pullulan 8.47
Polyvinyl alcohol 1.04
Bronopol 0.11
Sucralose 0.23
Polysorbate 80 1.15
Polyethylene Glycol 0.81
Water 80
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Simethicone and Neusilin were mixed intimately and were added to the solution
of
Pullulan, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80, in fixed
quantity
of water. The resulting solution was then stirred at room temperature until
homogeneous solution was formed. It was then coated onto a belt of support
material.
Support material could be Teflon coated PVC, simple PVC or Stainless steel
belt
using conventional film casting equipment. Wet film thickness was adjusted to
achieve dry thickness between 20 to 801.1,M. In first stage, drying was done
from top at
100 C. The resulting film was then removed from support and dried from other
side at
100 C. The resulting films were then removed from support and cut into pieces
of
desired size and shape.
The so prepared films were then subjected to the test described in example 1
and it
was found that all the films retained their flatness for at least upto 10
minutes in
exposed conditions and throughout the observation period in packed conditions.
Example 2.2: Drying of film containing pharmaceutical agent in two stages.
Name of Ingredients Quantity in
percentage
= Simethicone 20
Neusilin 8
HPMC 5 cps 20
PVA 5
= Polyethylene Glycol 3.5
Tween 80 = 1.45
Sucralose 0.05
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Water 42
Simethicone and Neusilin were mixed- intimately and were added to the solution
of
1-IPMC, polyvinyl alcohol, Polyethylene Glycol, sucralose and Tween 80 in
fixed
quantity of water. The resulting solution was then stirred at room temperature
until
homogeneous solution was formed. It was then coated onto a belt of support
material
Support material could be Teflon coated PVC, simple PVC or Stainless steel
belt
using conventional film casting equipment. Wet film thickness was adjusted to
- achieve dry thickness between 20 to 80 um. In first stage, drying was
done from top at
100 C. The resulting film was then removed from support and dried from other
side at
100 C. The resulting films were then removed from support and cut into pieces
of
desired size and shape.
The so prepared films were then subjected to the test described in example 1
and it
was found that all the films retained their flatness for at least upto 12
minutes in
exposed conditions and throughout the observation period in packed conditions.
Example 3
Method of making non-sticky oral thin films by using coating or enveloping the
film
Name of excipients Amount (In %)
Solution A
Pullulan 13. 44
Polyvinyl alcohol 1.99
Bronopol 0.20
Sucralose 0.40
Polysorbate 80 1.99
Water 67.00
Solution B
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Methycrylic acid 2.3
copolymer
Ethanol 12.68
Solution A; Pullulan, Polyvinyl alcohol,Bronopol, Sucralose and Polysorbate 80
were
added in water.
Solution B; methycrylic acid copolymer was dissolved in ethanol.
Solution A was stirred at room temperature until homogeneous solution was
formed.
Wet film thickness was adjusted to achieve dry thickness between 20 to 50 gm.
Drying was done at 100 C. Then solution B was coated on moisture resistant/
moisture
repellent polymeric solution and dried at 80 C. The resulting double layered
film is
removed from the support; flipped and further casting is done with moisture
resistant/
moisture repellent solution and dried at 80 C. The resulting tripled layered/
laminated
film contains moisture in the range of 10% to 2%.
The so prepared films were then subjected to the test described in example 1
and it
was found that all the films retained their flatness for at least upto 10
minutes in
exposed conditions and throughout the observation period in packed conditions.
Example 3.1
Method of making stable films by coating both sides of films
Name of Ingredients Quantity in
percentage
Donepezil 1.16
Pullulan 12.56
Polyvinyl alcohol 1.86
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I Bronopol 0.189
Polysorbate 80 0.37
Sucralose 1.86
Water ' 82
Solution A: Donepezil, Pullulan, Polyvinyl alcohol, Bronopol, Sucralose and
Polysorbate 80 were added in water.
Solution B: As described in example 3
Solution A was stirred at room temperature until homogeneous solution was
formed.
Wet film thickness was adjusted to achieve dry thickness between 20 to 50 rim.
Drying
was done at 100 C. Then solution B was coated on moisture resistant/ moisture
repellent polymeric solution and dried at 80 C. The resulting double layered
film is
removed from the support; flipped and further casting is done with moisture
resistant/
moisture repellent solution and dried at 80 C. The resulting tripled layered/
laminated
film contains moisture in the range of 10% to 2%.
The so prepared films were then subjected to the test described in example 1
and it was
found that all the films retained their flatness for at least upto 10 minutes
in exposed
conditions and throughout the observation period in packed conditions.
Example 4
Coating moisture sensitive ingredient particles with moisture resistant
polymers
Name of Ingredients Quantity (In %)
Montelukast Sodium 2
Methacrylate acid copolymer 2
Pullulan 14.54
Polyvinyl alcohol 1.79
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Glycerin 4.20
Sucralose 0.40
Polysorbate 80 1.99
Talcum 0.20
Titanium dioxide 0.20
Water 72.68
Particles of Montelukast sodium were coated with methacrylate acid copolymer
using
fluidized bed coater. Pullulan, polyvinyl alcohol, bronopol, sucralose and
Polysorbate
80, talcum and titanium dioxide were added in 400 ml water in the order
presented in
the Example 1. The resulting solution was then stirred at room temperature
until
homogeneous solution was formed. Resulting solution was then coated onto a
belt of
support material using conventional film casting equipment Support material
could be
Teflon coated PVC, simple PVC or Stainless steel belt. Coating thickness was
adjusted
to achieve dry thickness between 20 to 50 um. Resulting film was then dried in
heating
chamber at 120 C. The resulting film was then removed from support and cut
into
pieces of desired size and shape.
The so prepared films were then subjected to the test described in example 1
and it was
found that all the films retained their flatness for at least upto 10 minutes
in exposed
conditions and throughout the observation period in packed conditions.
Example 5:
Formulation of stable films using hydrophobic polymers
Name of Ingredients Quantity in
percent
Ondansetron 4.4
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Methacrylate acid copolymer 3.3
HPMC 22.2
Polyvinyl alcohol 2.77
Glycerin 5.55
Sucralose 0.55
Polysorbate 80 1.11
Water 60
Polymeric solution was prepared by adding HPMC to the fixed quantity of water
and
remaining ingredients were added to this solution. The solution was mixed to
obtain the
homogenous dispersion and casted on a support to obtain a dry film with
thickness in
the range of 50 to 100 pm. The film was dried at 70 C to obtain moisture
content in the
range of 4% to 10%. The resulting film was then removed from support and cut
into
pieces of desired size and shape.
The so prepared films were then subjected to the test described in example 1
and it was
found that all the films retained their flatness for at least upto 10 minutes
in exposed
conditions and throughout the observation period in packed conditions.
Example 6:
Name of Ingredients Quantity (In %)
Ondansetron 3.69
Methacrylate acid 2.77
copolymer
HPMC 18.66
Polyvinyl alcohol 2.32
Glycerin 4.66
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Sucralose 0.46
Polysorbate 80 0.93
Talcum 3.69
Titanium dioxide 2.77
Water 60
Polymeric solution was prepared by adding HPMC to the fixed quantity of water
and
remaining ingredients were added to this solution. The solution was mixed to
obtain
the homogenous dispersion and casted on a support to obtain a dry film with
thickness
in the range of 50 to 100 [m-i. The film was dried to obtain moisture content
in the
range of 4% to 10%. The resulting film was then removed from support and cut
into
pieces of desired size and shape.
The so prepared films were then subjected to the test described in example 1
and it
was found that all the films retained their flatness for at least upto 15
minutes in
exposed conditions and throughout the observation period in packed conditions.
31
