U.S. patent application number 14/844810 was filed with the patent office on 2015-12-31 for uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions.
This patent application is currently assigned to MonoSol Rx, LLC. The applicant listed for this patent is MonoSol Rx, LLC. Invention is credited to Vimala Francis, Laura Moss, Garry L. Myers, Pradeep Sanghvi, Andrew Philip Verrall.
Application Number | 20150374640 14/844810 |
Document ID | / |
Family ID | 38087822 |
Filed Date | 2015-12-31 |
United States Patent
Application |
20150374640 |
Kind Code |
A1 |
Myers; Garry L. ; et
al. |
December 31, 2015 |
UNIFORM FILMS FOR RAPID-DISSOLVE DOSAGE FORM INCORPORATING
ANTI-TACKING COMPOSITIONS
Abstract
The present invention relates to water-soluble films
incorporating anti-tacking agents and methods of their preparation.
Anti-tacking agents may improve the flow characteristics of the
compositions and thereby reduce the problem of film adhering to a
user's mouth or to other units of film. In particular, the present
invention relates to edible water-soluble delivery systems in the
form of a film composition including a water-soluble polymer, an
active component selected from cosmetic agents, pharmaceutical
agents, vitamins, bioactive agents and combinations thereof and at
least one anti-tacking agent.
Inventors: |
Myers; Garry L.; (Kingsport,
TN) ; Sanghvi; Pradeep; (Schererville, IN) ;
Verrall; Andrew Philip; (Crown Point, IN) ; Francis;
Vimala; (Fremont, CA) ; Moss; Laura;
(Schererville, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MonoSol Rx, LLC |
Warren |
NJ |
US |
|
|
Assignee: |
MonoSol Rx, LLC
Warren
NJ
|
Family ID: |
38087822 |
Appl. No.: |
14/844810 |
Filed: |
September 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14284019 |
May 21, 2014 |
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14844810 |
|
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11517982 |
Sep 8, 2006 |
8765167 |
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14284019 |
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10074272 |
Feb 14, 2002 |
7425292 |
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11517982 |
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60715528 |
Sep 9, 2005 |
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60328868 |
Oct 12, 2001 |
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Current U.S.
Class: |
424/443 ;
427/2.31; 514/286; 514/458 |
Current CPC
Class: |
A61K 47/38 20130101;
A23P 20/20 20160801; A23V 2002/00 20130101; A61K 9/7007 20130101;
A23L 33/10 20160801; A61K 47/14 20130101; A61K 9/006 20130101; A23L
33/16 20160801; A61K 47/12 20130101; A61K 47/02 20130101; A61K
47/22 20130101; A61K 9/0056 20130101; A23L 33/15 20160801; A23L
33/105 20160801; A61K 47/36 20130101; A23P 30/10 20160801; A61K
47/34 20130101; A61K 31/355 20130101; A23V 2002/00 20130101; A23V
2200/324 20130101; A61K 31/485 20130101; A23V 2250/21 20130101;
A23V 2250/156 20130101; A23V 2250/70 20130101; A23V 2200/30
20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/355 20060101 A61K031/355; A61K 47/22 20060101
A61K047/22; A61K 9/00 20060101 A61K009/00; A61K 47/02 20060101
A61K047/02; A61K 47/34 20060101 A61K047/34; A61K 47/38 20060101
A61K047/38; A61K 31/485 20060101 A61K031/485; A61K 47/12 20060101
A61K047/12 |
Claims
1. An edible film for delivery of an active comprising: an edible,
water-soluble polymer; at least one anti-tacking agent selected
from the group consisting of lubricants, antiadherants, glidants
and combinations thereof; and an active component selected from the
group consisting of cosmetic agents, pharmaceutical agents,
vitamins, bioactive agents and combinations thereof, wherein said
film is self-supporting.
2. The film of claim 1, wherein said anti-tacking agent comprises
Vitamin E TPGS.
3. The film of claim 1, wherein said anti-tacking agent comprises
magnesium stearate.
4. The film of claim 3, wherein said anti-tacking agent further
comprises silica.
5. The film of claim 1, wherein said anti-tacking agent is present
in amounts of about 0.01% to about 20% by weight of said delivery
system.
6. The film of claim 1, wherein said anti-tacking agent comprises:
magnesium stearate present in amounts of about 0.1% to about 2.5%
by weight of said delivery system; and silica present in amounts of
about 0.1% to about 1.5% by weight of said delivery system.
7. The film of claim 1, wherein said water-soluble polymer
comprises polyethylene oxide and a cellulosic polymer.
8. The film of claim 7, wherein said cellulosic polymer comprises
hydroxypropyl cellulose.
9. The film of claim 7, wherein said cellulosic polymer comprises
hydroxypropylmethyl cellulose.
10. The film of claim 1, wherein said active component comprises
dextromethorphan.
11. The film of claim 1, further comprising polydextrose.
12. The film of claim 1, wherein said film is applied to an oral
cavity of a mammal.
13. The film of claim 13, wherein said film adheres to the tongue
of the mammal.
14. An edible film for delivery of an active comprising: 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; an active component selected from the group consisting of
cosmetic agents, pharmaceutical agents, vitamins, bioactive agents
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.
15. An edible film for delivery of an active comprising: 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.
16. An edible film for delivery of an active comprising: 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; an active component selected from the
group consisting of cosmetic agents, pharmaceutical agents,
vitamins, bioactive agents and combinations thereof; and at least
one anti-tacking agent.
17. An edible film for delivery of an active comprising: (a) a
self-supporting film having at least one surface, said film
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
combinations thereof; and (b) a coating on said at least one
surface of said self-supporting film, said coating comprising at
least one anti-tacking agent.
18. A multi-layer film for delivery of an active comprising: (a) at
least one first film layer comprising: an edible, water-soluble
polymer; and (ii) an anti-tacking agent; and (b) a second film
layer comprising: an edible, water-soluble polymer; and (ii) an
active component selected from the group consisting of cosmetic
agents, pharmaceutical agents, vitamins, bioactive agents and
combinations thereof, wherein said first film layer is
substantially in contact with said second film layer.
19. The multi-layer film of claim 18, wherein said first film layer
is laminated to said second film layer.
20. A process for making a self-supporting film having a
substantially uniform distribution of components comprising: (a)
combining an edible, water-soluble polymer, a solvent, an active
component selected from the group consisting of cosmetic agents,
pharmaceutical agents, vitamins, bioactive agents and combinations
thereof and at least one anti-tacking agent to form a matrix with a
uniform distribution of said components; (b) forming a
self-supporting film from said matrix; (c) 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.
21. The process of claim 20, wherein said anti-tacking agent
comprises Vitamin E TPGS.
22. The process of claim 20, wherein said anti-tacking agent
comprises magnesium stearate and silica.
23. The process of claim 20, wherein said matrix further comprises
polydextrose.
24. The process of claim 20, wherein said film is ingestible.
25. The process of claim 20, wherein said film is flexible when
dried.
26. The process of claim 20, wherein step (e) comprises applying
hot air currents to said bottom side of said surface with
substantially no top air flow.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/715,528, filed Sep. 9, 2005, and is
a continuation-in-part of U.S. application Ser. No. 10/074,272,
filed Feb. 14, 2002, which claims the benefit of U.S. Provisional
Application No. 60/328,868, filed Oct. 12, 2001, the contents all
of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to rapidly dissolving films
incorporating anti-tacking agents and methods of their preparation.
The films also may contain an active ingredient that is evenly
distributed throughout the film.
BACKGROUND OF THE RELATED TECHNOLOGY
[0003] Active ingredients, such as drugs or pharmaceuticals, may be
prepared in a tablet form to allow for accurate and consistent
dosing. However, this form of preparing and dispensing medications
has many disadvantages including that a large proportion of
adjuvants that must be added to obtain a size able to be handled,
that a larger medication form requires additional storage space,
and that dispensing includes counting the tablets which has a
tendency for inaccuracy. In addition, many persons, estimated to be
as much as 28% of the population, have difficulty swallowing
tablets. While tablets may be broken into smaller pieces or even
crushed as a means of overcoming swallowing difficulties, this is
not a suitable solution for many tablet or pill forms. For example,
crushing or destroying the tablet or pill form to facilitate
ingestion, alone or in admixture with food, may also destroy the
controlled release properties.
[0004] As an alternative to tablets and pills, films may be used to
carry active ingredients such as drugs, pharmaceuticals, and the
like. However, historically films and the process of making drug
delivery systems therefrom have suffered from a number of
unfavorable characteristics that have not allowed them to be used
in practice.
[0005] Films that incorporate a pharmaceutically active ingredient
are disclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al.
("Fuchs"). These films may be formed into a sheet, dried and then
cut into individual doses. The Fuchs disclosure alleges the
fabrication of a uniform film, which includes the combination of
water-soluble polymers, surfactants, flavors, sweeteners,
plasticizers and drugs. These allegedly flexible films are
disclosed as being useful for oral, topical or enteral use.
Examples of specific uses disclosed by Fuchs include application of
the films to mucosal membrane areas of the body, including the
mouth, rectal, vaginal, nasal and ear areas.
[0006] Examination of films made in accordance with the process
disclosed in Fuchs, however, reveals that such films suffer from
the aggregation or conglomeration of particles, i.e.,
self-aggregation, making them inherently non-uniform. This result
can be attributed to Fuchs' process parameters, which although not
disclosed likely include the use of relatively long drying times,
thereby facilitating intermolecular attractive forces, convection
forces, air flow and the like to form such agglomeration.
[0007] The formation of agglomerates randomly distributes the film
components and any active present as well. When large dosages are
involved, a small change in the dimensions of the film would lead
to a large difference in the amount of active per film. If such
films were to include low dosages of active, it is possible that
portions of the film may be substantially devoid of any active.
Since sheets of film are usually cut into unit doses, certain doses
may therefore be devoid of or contain an insufficient amount of
active for the recommended treatment. Failure to achieve a high
degree of accuracy with respect to the amount of active ingredient
in the cut film can be harmful to the patient. For this reason,
dosage forms formed by processes such as Fuchs, would not likely
meet the stringent standards of governmental or regulatory
agencies, such as the U.S. Federal Drug Administration ("FDA"),
relating to the variation of active in dosage forms. Currently, as
required by various world regulatory authorities, dosage forms may
not vary more than 10% in the amount of active present. When
applied to dosage units based on films, this virtually mandates
that uniformity in the film be present.
[0008] The problems of self-aggregation leading to non-uniformity
of a film were addressed in U.S. Pat. No. 4,849,246 to Schmidt
("Schmidt"). Schmidt specifically pointed out that the methods
disclosed by Fuchs did not provide a uniform film and recognized
that that the creation of a non-uniform film necessarily prevents
accurate dosing, which as discussed above is especially important
in the pharmaceutical area. Schmidt abandoned the idea that a
mono-layer film, such as described by Fuchs, may provide an
accurate dosage form and instead attempted to solve this problem by
forming a multi-layered film. Moreover, his process is a multi-step
process that adds expense and complexity and is not practical for
commercial use.
[0009] Other U.S. Patents directly addressed the problems of
particle self-aggregation and non-uniformity inherent in
conventional film forming techniques. In one attempt to overcome
non-uniformity, U.S. Pat. No. 5,629,003 to Horstmann et al. and
U.S. Pat. No. 5,948,430 to Zerbe et al. incorporated additional
ingredients, i.e. gel formers and polyhydric alcohols respectively,
to increase the viscosity of the film prior to drying in an effort
to reduce aggregation of the components in the film. These methods
have the disadvantage of requiring additional components, which
translates to additional cost and manufacturing steps. Furthermore,
both methods employ the use the conventional time-consuming drying
methods such as a high-temperature air-bath using a drying oven,
drying tunnel, vacuum drier, or other such drying equipment. The
long length of drying time aids in promoting the aggregation of the
active and other adjuvant, notwithstanding the use of viscosity
modifiers. Such processes also run the risk of exposing the active,
i.e., a drug, or vitamin C, or other components to prolonged
exposure to moisture and elevated temperatures, which may render it
ineffective or even harmful.
[0010] In addition to the concerns associated with degradation of
an active during extended exposure to moisture, the conventional
drying methods themselves are unable to provide uniform films. The
length of heat exposure during conventional processing, often
referred to as the "heat history", and the manner in which such
heat is applied, have a direct effect on the formation and
morphology of the resultant film product. Uniformity is
particularly difficult to achieve via conventional drying methods
where a relatively thicker film, which is well-suited for the
incorporation of a drug active, is desired. Thicker uniform films
are more difficult to achieve because the surfaces of the film and
the inner portions of the film do not experience the same external
conditions simultaneously during drying. Thus, observation of
relatively thick films made from such conventional processing shows
a non-uniform structure caused by convection and intermolecular
forces and requires greater than 10% moisture to remain flexible.
The amount of free moisture can often interfere over time with the
drug leading to potency issues and therefore inconsistency in the
final product.
[0011] Conventional drying methods generally include the use of
forced hot air using a drying oven, drying tunnel, and the like.
The difficulty in achieving a uniform film is directly related to
the rheological properties and the process of water evaporation in
the film-forming composition. When the surface of an aqueous
polymer solution is contacted with a high temperature air current,
such as a film-forming composition passing through a hot air oven,
the surface water is immediately evaporated forming a polymer film
or skin on the surface. This seals the remainder of the aqueous
film-forming composition beneath the surface, forming a barrier
through which the remaining water must force itself as it is
evaporated in order to achieve a dried film. As the temperature
outside the film continues to increase, water vapor pressure builds
up under the surface of the film, stretching the surface of the
film, and ultimately ripping the film surface open allowing the
water vapor to escape. As soon as the water vapor has escaped, the
polymer film surface reforms, and this process is repeated, until
the film is completely dried. The result of the repeated
destruction and reformation of the film surface is observed as a
"ripple effect" which produces an uneven, and therefore non-uniform
film. Frequently, depending on the polymer, a surface will seal so
tightly that the remaining water is difficult to remove, leading to
very long drying times, higher temperatures, and higher energy
costs.
[0012] Other factors, such as mixing techniques, also play a role
in the manufacture of a pharmaceutical film suitable for
commercialization and regulatory approval. Air can be trapped in
the composition during the mixing process or later during the film
making process, which can leave voids in the film product as the
moisture evaporates during the drying stage. The film frequently
collapse around the voids resulting in an uneven film surface and
therefore, non-uniformity of the final film product. Uniformity is
still affected even if the voids in the film caused by air bubbles
do not collapse. This situation also provides a non-uniform film in
that the spaces, which are not uniformly distributed, are occupying
area that would otherwise be occupied by the film composition. None
of the above-mentioned patents either addresses or proposes a
solution to the problems caused by air that has been introduced to
the film.
[0013] Moreover, films go through numerous processing steps prior
to primary packaging, e.g., in canisters, and secondary packaging,
e.g., in pouches or blister packs. The processing steps present
significant challenges for the development of quality films that
possess optimal film surface properties such as low coefficient of
friction or high slip. Throughout this process, it is important to
maintain the integrity of the film from initial manufacture to
final packaging. It is desirable, therefore, to prevent or
alleviate problems that diminish the integrity of the film, such as
films that soften, get tacky, adhere, dry up, or become brittle
over time.
[0014] More specifically, over-the-counter film products, such as
candy and breath films, typically are packaged in canisters
containing 16 film units, also referred to as strips, or higher (up
to 24 or even 32 film strips per canister). The number of film
strips per canister varies based on product type, active dose and
packaging configuration among other considerations. When packaging
multiple film strips in a canister, however, problems such as
strips sticking to one another often arise.
[0015] Adherence between film strips is a common problem
encountered in edible film products and may arise due to a variety
of reasons. For instance, in some cases, adherence between film
strips may be caused by the components used in film manufacture.
Components such as flavors, plasticizers, and actives in the film
can sometimes soften the film and have a detrimental effect on film
quality. For example, in films having high acidulent content, the
acids may exert an excessive plasticizing effect on the film. Such
effect may be intensified by the hygroscopicity of some acids or
other components in the film.
[0016] In some cases, adherence between film strips may be caused
by changes in film properties due to temperature and/or humidity
changes. Some films may become tacky over time when exposed to
non-optimal temperature and/or humidity conditions. This problem
may be amplified for products that have a very narrow optimal
temperature and/or humidity range for storage.
[0017] Overall, films that exhibit tackiness or become tacky over
time may present numerous problems. First, conversion of master
rolls to daughter rolls, and further conversion to film strips
becomes substantially more difficult when film is tacky. In
addition, tacky film strips tend to adhere to one another when
stacked in packaging, e.g., a canister. Accordingly, it becomes
difficult for a user to remove a single film strip at a time from
the film packaging. Overall, such adherence within the packaging
decreases the aesthetics of the film strips as well as an
individual consumer's ease of use.
[0018] Therefore, there is a need for compositions that enable
films to slide against one another, thereby providing ease of
conversion, maximum storage stability and ease of consumer use,
among other benefits. Further, there is a need for methods of
preparing such films, which maintain the uniform distribution of
components therein, thereby preventing undesired aggregations and
promoting uniformity in the final film product.
SUMMARY OF THE INVENTION
[0019] In one aspect of the present invention, there is provided an
edible film for delivery of an active including: an edible,
water-soluble polymer; at least one anti-tacking agent selected
from the group consisting of lubricants, antiadherants, glidants
and combinations thereof; and an active component selected from the
group consisting of cosmetic agents, pharmaceutical agents,
vitamins, bioactive agents and combinations thereof, wherein the
film is self-supporting.
[0020] In another aspect of the present invention, there is
provided an edible film for delivery of an active including: an
edible, water-soluble polymer component which includes at least one
polymer selected from hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, polyethylene oxide and combinations thereof; an active
component selected from cosmetic agents, pharmaceutical agents,
vitamins, bioactive agents and combinations thereof; and an
anti-tacking agent containing Vitamin E TPGS present in amounts of
about 0.01% to about 20% by weight of the film.
[0021] In another aspect of the present invention, there is
provided an edible film for delivery of an active including: an
edible, water-soluble polymer component which includes polyethylene
oxide in combination with a polymer selected from hydroxypropyl
cellulose, hydroxypropylmethyl cellulose and combinations thereof;
and Vitamin E TPGS present in amounts sufficient to provide
anti-tacking and therapeutic properties, wherein the film is
self-supporting.
[0022] In some embodiments, there is provided an edible film for
delivery of an active which includes: an edible, water-soluble
polymer including polyethylene oxide and hydroxypropyl cellulose;
polydextrose, wherein the polyethylene oxide, hydroxypropyl
cellulose and polydextrose are present in a ratio of about
45:45:10; an active component selected from cosmetic agents,
pharmaceutical agents, vitamins, bioactive agents and combinations
thereof; and at least one anti-tacking agent.
[0023] In another aspect, there is provided an edible film for
delivery of an active including: (a) a self-supporting film having
at least one surface, the film including: (i) an edible,
water-soluble polymer; and (ii) an active component selected from
cosmetic agents, pharmaceutical agents, vitamins, bioactive agents
and combinations thereof; and (b) a coating on the at least one
surface of the self-supporting film, the coating including at least
one anti-tacking agent.
[0024] Some embodiments provide a multi-layer film for delivery of
an active including: (a) at least one first film layer containing:
(i) an edible, water-soluble polymer; and (ii) an anti-tacking
agent; and (b) a second film layer including: (i) an edible,
water-soluble polymer; and (ii) an active component selected from
cosmetic agents, pharmaceutical agents, vitamins, bioactive agents
and combinations thereof. The first film layer is substantially in
contact with the second film layer.
[0025] The present invention also provides a process for making a
self-supporting film having a substantially uniform distribution of
components including the steps of: combining an edible,
water-soluble polymer, a solvent, an active component selected from
cosmetic agents, pharmaceutical agents, vitamins, bioactive agents
and combinations thereof and at least one anti-tacking agent to
form a matrix with a uniform distribution of the components;
forming a self-supporting film from the matrix; providing a surface
having top and bottom sides; feeding the film onto the top side of
the surface; and drying the film by applying heat to the bottom
side of the surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 shows a side view of a package containing a unit
dosage film of the present invention.
[0027] FIG. 2 shows a top view of two adjacently coupled packages
containing individual unit dosage forms of the present invention,
separated by a tearable perforation.
[0028] FIG. 3 shows a side view of the adjacently coupled packages
of FIG. 2 arranged in a stacked configuration.
[0029] FIG. 4 shows a perspective view of a dispenser for
dispensing the packaged unit dosage forms, dispenser containing the
packaged unit dosage forms in a stacked configuration.
[0030] FIG. 5 is a schematic view of a roll of coupled unit dose
packages of the present invention.
[0031] FIG. 6 is a schematic view of an apparatus suitable for
preparation of a pre-mix, addition of an active, and subsequent
formation of the film.
[0032] FIG. 7 is a schematic view of an apparatus suitable for
drying the films of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0033] For the purposes of the present invention the term
non-self-aggregating uniform heterogeneity refers to the ability of
the films of the present invention, which are formed from one or
more components in addition to a polar solvent, to provide a
substantially reduced occurrence of, i.e. little or no, aggregation
or conglomeration of components within the film as is normally
experienced when films are formed by conventional drying methods
such as a high-temperature air-bath using a drying oven, drying
tunnel, vacuum drier, or other such drying equipment. The term
heterogeneity, as used in the present invention, includes films
that will incorporate a single component, such as a polymer, as
well as combinations of components, such as a polymer and an
active. Uniform heterogeneity includes the substantial absence of
aggregates or conglomerates as is common in conventional mixing and
heat drying methods used to form films.
[0034] Furthermore, the films of the present invention have a
substantially uniform thickness, which is also not provided by the
use of conventional drying methods used for drying water-based
polymer systems. The absence of a uniform thickness detrimentally
affects uniformity of component distribution throughout the area of
a given film.
[0035] The film products of the present invention are produced by a
combination of a properly selected polymer and a polar solvent,
optionally including an active ingredient as well as other fillers
known in the art. These films provide a non-self-aggregating
uniform heterogeneity of the components within them by utilizing a
selected casting or deposition method and a controlled drying
process. Examples of controlled drying processes include, but are
not limited to, the use of the apparatus disclosed in U.S. Pat. No.
4,631,837 to Magoon ("Magoon"), herein incorporated by reference,
as well as hot air impingement across the bottom substrate and
bottom heating plates. Another drying technique for obtaining the
films of the present invention is controlled radiation drying, in
the absence of uncontrolled air currents, such as infrared and
radio frequency radiation (i.e. microwaves).
[0036] The objective of the drying process is to provide a method
of drying the films that avoids complications, such as the noted
"rippling" effect, that are associated with conventional drying
methods and which initially dry the upper surface of the film,
trapping moisture inside. In conventional oven drying methods, as
the moisture trapped inside subsequently evaporates, the top
surface is altered by being ripped open and then reformed. These
complications are avoided by the present invention, and a uniform
film is provided by drying the bottom surface of the film first or
otherwise preventing the formation of polymer film formation (skin)
on the top surface of the film prior to drying the depth of the
film. This may be achieved by applying heat to the bottom surface
of the film with substantially no top air flow, or alternatively by
the introduction of controlled microwaves to evaporate the water or
other polar solvent within the film, again with substantially no
top air flow. Yet alternatively, drying may be achieved by using
balanced fluid flow, such as balanced air flow, where the bottom
and top air flows are controlled to provide a uniform film. In such
a case, the air flow directed at the top of the film should not
create a condition which would cause movement of particles present
in the wet film, due to forces generated by the air currents.
Additionally, air currents directed at the bottom of the film
should desirably be controlled such that the film does not lift up
due to forces from the air. Uncontrolled air currents, either above
or below the film, can create non-uniformity in the final film
products. The humidity level of the area surrounding the top
surface may also be appropriately adjusted to prevent premature
closure or skinning of the polymer surface.
[0037] This manner of drying the films provides several advantages.
Among these are the faster drying times and a more uniform surface
of the film, as well as uniform distribution of components for any
given area in the film. In addition, the faster drying time allows
viscosity to quickly build within the film, further encouraging a
uniform distribution of components and decrease in aggregation of
components in the final film product. Desirably, the drying of the
film will occur within about ten minutes or fewer, or more
desirably within about five minutes or fewer.
[0038] The present invention yields exceptionally uniform film
products when attention is paid to reducing the aggregation of the
compositional components. By avoiding the introduction of and
eliminating excessive air in the mixing process, selecting polymers
and solvents to provide a controllable viscosity and by drying the
film in a rapid manner from the bottom up, such films result.
[0039] The products and processes of the present invention rely on
the interaction among various steps of the production of the films
in order to provide films that substantially reduce the
self-aggregation of the components within the films. Specifically,
these steps include the particular method used to form the film,
making the composition mixture to prevent air bubble inclusions,
controlling the viscosity of the film forming composition and the
method of drying the film. More particularly, a greater viscosity
of components in the mixture is particularly useful when the active
is not soluble in the selected polar solvent in order to prevent
the active from settling out. However, the viscosity must not be
too great as to hinder or prevent the chosen method of casting,
which desirably includes reverse roll coating due to its ability to
provide a film of substantially consistent thickness.
[0040] In addition to the viscosity of the film or film-forming
components or matrix, there are other considerations taken into
account by the present invention for achieving desirable film
uniformity. For example, stable suspensions are achieved which
prevent solid (such as drug particles) sedimentation in
non-colloidal applications. One approach provided by the present
invention is to balance the density of the particulate
(.rho..sub.p) and the liquid phase (.rho..sub.l) and increase the
viscosity of the liquid phase (.mu.). For an isolated particle,
Stokes law relates the terminal settling velocity (Vo) of a rigid
spherical body of radius (r) in a viscous fluid, as follows:
V.sub.o=(2gr.sup.r)(.rho..sub.p-.rho..sub.l)/9.mu..
[0041] At high particle concentrations, however, the local particle
concentration will affect the local viscosity and density. The
viscosity of the suspension is a strong function of solids volume
fraction, and particle-particle and particle-liquid interactions
will further hinder settling velocity.
[0042] Stokian analyses has shown that the incorporation of a third
phase, dispersed air or nitrogen, for example, promotes suspension
stability. Further, increasing the number of particles leads to a
hindered settling effect based on the solids volume fraction. In
dilute particle suspensions, the rate of sedimentation, v, can be
expressed as:
v/V.sub.o=1/(1+.kappa..phi.)
where .kappa.=a constant, and .phi. is the volume fraction of the
dispersed phase. More particles suspended in the liquid phase
results in decreased velocity. Particle geometry is also an
important factor since the particle dimensions will affect
particle-particle flow interactions.
[0043] Similarly, the viscosity of the suspension is dependent on
the volume fraction of dispersed solids. For dilute suspensions of
non-interaction spherical particles, an expression for the
suspension viscosity can be expressed as:
.mu./.mu..sub.o=1+2.5.phi.
where .mu..sub.o is the viscosity of the continuous phase and .phi.
is the solids volume fraction. At higher volume fractions, the
viscosity of the dispersion can be expressed as
.mu./82 .sub.o=1+2.5.phi.+C.sub.1.phi..sup.2+C.sub.2.phi..sup.3+ .
. .
where C is a constant.
[0044] The viscosity of the liquid phase is critical and is
desirably modified by customizing the liquid composition to a
viscoelastic non-Newtonian fluid with low yield stress values. This
is the equivalent of producing a high viscosity continuous phase at
rest. Formation of a viscoelastic or a highly structured fluid
phase provides additional resistive forces to particle
sedimentation. Further, flocculation or aggregation can be
controlled minimizing particle-particle interactions. The net
effect would be the preservation of a homogeneous dispersed
phase.
[0045] The addition of hydrocolloids to the aqueous phase of the
suspension increases viscosity, may produce viscoelasticity and can
impart stability depending on the type of hydrocolloid, its
concentration and the particle composition, geometry, size, and
volume fraction. The particle size distribution of the dispersed
phase needs to be controlled by selecting the smallest realistic
particle size in the high viscosity medium, i.e., <500 .mu.m.
The presence of a slight yield stress or elastic body at low shear
rates may also induce permanent stability regardless of the
apparent viscosity. The critical particle diameter can be
calculated from the yield stress values. In the case of isolated
spherical particles, the maximum shear stress developed in settling
through a medium of given viscosity can be given as
.tau..sub.max=3V.mu./2r.
For pseudoplastic fluids, the viscosity in this shear stress regime
may well be the zero shear rate viscosity at the Newtonian
plateau.
[0046] A stable suspension is an important characteristic for the
manufacture of a pre-mix composition which is to be fed into the
film casting machinery film, as well as the maintenance of this
stability in the wet film stage until sufficient drying has
occurred to lock-in the particles and matrix into a sufficiently
solid form such that uniformity is maintained. For viscoelastic
fluid systems, a rheology that yields stable suspensions for
extended time period, such as 24 hours, must be balanced with the
requirements of high-speed film casting operations. A desirable
property for the films is shear thinning or pseudoplasticity,
whereby the viscosity decreases with increasing shear rate. Time
dependent shear effects such as thixotropy are also advantageous.
Structural recovery and shear thinning behavior are important
properties, as is the ability for the film to self-level as it is
formed.
[0047] The rheology requirements for the inventive compositions and
films are quite severe. This is due to the need to produce a stable
suspension of particles, for example 30-60 wt %, in a viscoelastic
fluid matrix with acceptable viscosity values throughout a broad
shear rate range. During mixing, pumping, and film casting, shear
rates in the range of 10-10.sup.5 sec..sup.-1 may be experienced
and pseudoplasticity is the preferred embodiment.
[0048] In film casting or coating, rheology is also a defining
factor with respect to the ability to form films with the desired
uniformity. Shear viscosity, extensional viscosity,
viscoelasticity, structural recovery will influence the quality of
the film. As an illustrative example, the leveling of
shear-thinning pseudoplastic fluids has been derived as
.alpha..sup.(n-1/n)=.alpha..sub.o.sup.(n-1/n)-((n-1)/(2n-1))(.tau./K).su-
p.1/n(2.pi./.lamda.).sup.(3+n)/nh.sup.(2n+1/nt
where .alpha. is the surface wave amplitude, .alpha..sub.o is the
initial amplitude, .lamda. is the wavelength of the surface
roughness, and both "n" and "K" are viscosity power law indices. In
this example, leveling behavior is related to viscosity, increasing
as n decreases, and decreasing with increasing K.
[0049] Desirably, the films or film-forming compositions of the
present invention have a very rapid structural recovery, i.e. as
the film is formed during processing, it doesn't fall apart or
become discontinuous in its structure and compositional uniformity.
Such very rapid structural recovery retards particle settling and
sedimentation. Moreover, the films or film-forming compositions of
the present invention are desirably shear-thinning pseudoplastic
fluids. Such fluids with consideration of properties, such as
viscosity and elasticity, promote thin film formation and
uniformity.
[0050] Thus, uniformity in the mixture of components depends upon
numerous variables. As described herein, viscosity of the
components, the mixing techniques and the rheological properties of
the resultant mixed composition and wet casted film are important
aspects of the present invention. Additionally, control of particle
size and particle shape are further considerations. Desirably, the
size of the particulate a particle size of 150 microns or less, for
example 100 microns or less. Moreover, such particles may be
spherical, substantially spherical, or non-spherical, such as
irregularly shaped particles or ellipsoidally shaped particles.
Ellipsoidally shaped particles or ellipsoids are desirable because
of their ability to maintain uniformity in the film forming matrix
as they tend to settle to a lesser degree as compared to spherical
particles.
[0051] A number of techniques may be employed in the mixing stage
to prevent bubble inclusions in the final film. To provide a
composition mixture with substantially no air bubble formation in
the final product, anti-foaming or surface-tension reducing agents
are employed. Additionally, the speed of the mixture is desirably
controlled to prevent cavitation of the mixture in a manner which
pulls air into the mix. Finally, air bubble reduction can further
be achieved by allowing the mix to stand for a sufficient time for
bubbles to escape prior to drying the film. Desirably, the
inventive process first forms a masterbatch of film-forming
components without active ingredients such as drug particles or
volatile materials such as flavor oils. The actives are added to
smaller mixes of the masterbatch just prior to casting. Thus, the
masterbatch pre-mix can be allowed to stand for a longer time
without concern for instability in drug or other ingredients.
[0052] When the matrix is formed including the film-forming polymer
and polar solvent in addition to any additives and the active
ingredient, this may be done in a number of steps. For example, the
ingredients may all be added together or a pre-mix may be prepared.
The advantage of a pre-mix is that all ingredients except for the
active may be combined in advance, with the active added just prior
to formation of the film. This is especially important for actives
that may degrade with prolonged exposure to water, air or another
polar solvent.
[0053] FIG. 6 shows an apparatus 20 suitable for the preparation of
a pre-mix, addition of an active and subsequent formation of a
film. The pre-mix or master batch 22, which includes the
film-forming polymer, polar solvent, and any other additives except
a drug active is added to the master batch feed tank 24. The
components for pre-mix or master batch 22 are desirably formed in a
mixer (not shown) prior to their addition into the master batch
feed tank 24. Then a pre-determined amount of the master batch is
controllably fed via a first metering pump 26 and control valve 28
to either or both of the first and second mixers, 30, 30'. The
present invention, however, is not limited to the use of two
mixers, 30, 30', and any number of mixers may suitably be used.
Moreover, the present invention is not limited to any particular
sequencing of the mixers 30, 30', such as parallel sequencing as
depicted in FIG. 6, and other sequencing or arrangements of mixers,
such as series or combination of parallel and series, may suitably
be used. The required amount of the drug or other ingredient, such
as a flavor, is added to the desired mixer through an opening, 32,
32', in each of the mixers, 30, 30'. Desirably, the residence time
of the pre-mix or master batch 22 is minimized in the mixers 30,
30'. While complete dispersion of the drug into the pre-mix or
master batch 22 is desirable, excessive residence times may result
in leaching or dissolving of the drug, especially in the case for a
soluble drug. Thus, the mixers 30, 30' are often smaller, i.e.
lower residence times, as compared to the primary mixers (not
shown) used in forming the pre-mix or master batch 22. After the
drug has been blended with the master batch pre-mix for a
sufficient time to provide a uniform matrix, a specific amount of
the uniform matrix is then fed to the pan 36 through the second
metering pumps, 34, 34'. The metering roller 38 determines the
thickness of the film 42 and applies it to the application roller.
The film 42 is finally formed on the substrate 44 and carried away
via the support roller 46.
[0054] While the proper viscosity uniformity in mixture and stable
suspension of particles, and casting method are important in the
initial steps of forming the composition and film to promote
uniformity, the method of drying the wet film is also important.
Although these parameters and properties assist uniformity
initially, a controlled rapid drying process ensures that the
uniformity will be maintained until the film is dry.
[0055] The wet film is then dried using controlled bottom drying or
controlled microwave drying, desirably in the absence of external
air currents or heat on the top (exposed) surface of the film 48 as
described herein. Controlled bottom drying or controlled microwave
drying advantageously allows for vapor release from the film
without the disadvantages of the prior art. Conventional convection
air drying from the top is not employed because it initiates drying
at the top uppermost portion of the film, thereby forming a barrier
against fluid flow, such as the evaporative vapors, and thermal
flow, such as the thermal energy for drying. Such dried upper
portions serve as a barrier to further vapor release as the
portions beneath are dried, which results in non-uniform films. As
previously mentioned some top air flow can be used to aid the
drying of the films of the present invention, but it must not
create a condition that would cause particle movement or a rippling
effect in the film, both of which would result in non-uniformity.
If top air is employed, it is balanced with the bottom air drying
to avoid non-uniformity and prevent film lift-up on the carrier
belt. A balance top and bottom air flow may be suitable where the
bottom air flow functions as the major SOURSce of drying and the
top air flow is the minor SOURSce of drying. The advantage of some
top air flow is to move the exiting vapors away from the film
thereby aiding in the overall drying process. The use of any top
air flow or top drying, however, must be balanced by a number of
factors including, but not limited, to rheological properties of
the composition and mechanical aspects of the processing. Any top
fluid flow, such as air, also must not overcome the inherent
viscosity of the film-forming composition. In other words, the top
air flow cannot break, distort or otherwise physically disturb the
surface of the composition. Moreover, air velocities are desirably
below the yield values of the film, i.e., below any force level
that can move the liquids in the film-forming compositions. For
thin or low viscosity compositions, low air velocity must be used.
For thick or high viscosity compositions, higher air. velocities
may be used. Furthermore, air velocities are desirable low so as to
avoid any lifting or other movement of the film formed from the
compositions.
[0056] Moreover, the films of the present invention may contain
particles that are sensitive to temperature, such as flavors, which
may be volatile, or drugs, which may have a low degradation
temperature. In such cases, the drying temperature may be decreased
while increasing the drying time to adequately dry the uniform
films of the present invention. Furthermore, bottom drying also
tends to result in a lower internal film temperature as compared to
top drying. In bottom drying, the evaporating vapors more readily
carry heat away from the film as compared to top drying which
lowers the internal film temperature. Such lower internal film
temperatures often result in decreased drug degradation and
decreased loss of certain volatiles, such as flavors.
[0057] Furthermore, particles or particulates may be added to the
film-forming composition or matrix after the composition or matrix
is cast into a film. For example, particles may be added to the
film 42 prior to the drying of the film 42. Particles may be
controllably metered to the film and disposed onto the film through
a suitable technique, such as through the use of a doctor blade
(not shown) which is a device which marginally or softly touches
the surface of the film and controllably disposes the particles
onto the film surface. Other suitable, but non-limiting, techniques
include the use of an additional roller to place the particles on
the film surface, spraying the particles onto the film surface, and
the like. The particles may be placed on either or both of the
opposed film surfaces, i.e., the top and/or bottom film surfaces.
Desirably, the particles are securably disposed onto the film, such
as being embedded into the film. Moreover, such particles are
desirably not fully encased or fully embedded into the film, but
remain exposed to the surface of the film, such as in the case
where the particles are partially embedded or partially
encased.
[0058] The particles may be any useful organoleptic agent, cosmetic
agent, pharmaceutical agent, or combinations thereof. Desirably,
the pharmaceutical agent is a taste-masked or a controlled-release
pharmaceutical agent. Useful organoleptic agents include flavors
and sweeteners. Useful cosmetic agents include breath freshening or
decongestant agents, such as menthol, including menthol
crystals.
[0059] Although the inventive process is not limited to any
particular apparatus for the above-described desirable drying, one
particular useful drying apparatus 50 is depicted in FIG. 7. Drying
apparatus 50 is a nozzle arrangement for directing hot fluid, such
as but not limited to hot air, towards the bottom of the film 42
which is disposed on substrate 44. Hot air enters the entrance end
52 of the drying apparatus and travels vertically upward, as
depicted by vectors 54, towards air deflector 56. The air deflector
56 redirects the air movement to minimize upward force on the film
42. As depicted in FIG. 7, the air is tangentially directed, as
indicated by vectors 60 and 60', as the air passes by air deflector
56 and enters and travels through chamber portions 58 and 58' of
the drying apparatus 50. With the hot air flow being substantially
tangential to the film 42, lifting of the film as it is being dried
is thereby minimized. While the air deflector 56 is depicted as a
roller, other devices and geometries for deflecting air or hot
fluid may suitable be used. Furthermore, the exit ends 62 and 62'
of the drying apparatus 50 are flared downwardly. Such downward
flaring provides a downward force or downward velocity vector, as
indicated by vectors 64 and 64', which tend to provide a pulling or
drag effect of the film 42 to prevent lifting of the film 42.
Lifting of the film 42 may not only result in non-uniformity in the
film or otherwise, but may also result in non-controlled processing
of the film 42 as the film 42 and/or substrate 44 lift away from
the processing equipment.
[0060] Monitoring and control of the thickness of the film also
contributes to the production of a uniform film by providing a film
of uniform thickness. The thickness of the film may be monitored
with gauges such as Beta Gauges. A gauge may be coupled to another
gauge at the end of the drying apparatus, i.e. drying oven or
tunnel, to communicate through feedback loops to control and adjust
the opening in the coating apparatus, resulting in control of
uniform film thickness.
[0061] The film products are generally formed by combining a
properly selected polymer and polar solvent, as well as any active
ingredient or filler as desired. Desirably, the solvent content of
the combination is at least about 30% by weight of the total
combination. The matrix formed by this combination is formed into a
film, desirably by roll coating, and then dried, desirably by a
rapid and controlled drying process to maintain the uniformity of
the film, more specifically, a non-self-aggregating uniform
heterogeneity. The resulting film will desirably contain less than
about 10% by weight solvent, more desirably less than about 8% by
weight solvent, even more desirably less than about 6% by weight
solvent and most desirably less than about 2%. The solvent may be
water, a polar organic solvent including, but not limited to,
ethanol, isopropanol, acetone, methylene chloride, or any
combination thereof.
[0062] Consideration of the above discussed parameters, such as but
not limited to rheology properties, viscosity, mixing method,
casting method and drying method, also impact material selection
for the different components of the present invention. Furthermore,
such consideration with proper material selection provides the
compositions of the present invention, including a pharmaceutical
and/or cosmetic dosage form or film product having no more than a
10% variance of a pharmaceutical and/or cosmetic active per unit
area. In other words, the uniformity of the present invention is
determined by the presence of no more than a 10% by weight of
pharmaceutical and/or cosmetic variance throughout the matrix.
Desirably, the variance is less than 5% by weight, less than 2% by
weight, less than 1% by weight, or less than 0.5% by weight.
Film-Forming Polymers
[0063] The polymer may be water soluble, water swellable, water
insoluble, or a combination of one or more either water soluble,
water swellable or water insoluble polymers. The polymer may
include cellulose or a cellulose derivative. Specific examples of
useful water soluble polymers include, but are not limited to,
polyethylene oxide (PEO), pullulan, hydroxypropylmethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl
pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium
aginate, polyethylene glycol, xanthan gum, tragancanth gum, guar
gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate
copolymer, carboxyvinyl copolymers, starch, gelatin, and
combinations thereof. In some embodiments, combinations of PEO and
a cellulosic polymer, such as hydroxypropyl cellulose, are
employed. Specific examples of useful water insoluble polymers
include, but are not limited to, ethyl cellulose, hydroxypropyl
ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl
cellulose phthalate and combinations thereof.
[0064] As used herein the phrase "water soluble polymer" and
variants thereof refer to a polymer that is at least partially
soluble in water, and desirably fully or predominantly soluble in
water, or absorbs water. Polymers that absorb water are often
referred to as being water swellable polymers. The materials useful
with the present invention may be water soluble or water swellable
at room temperature and other temperatures, such as temperatures
exceeding room temperature. Moreover, the materials may be water
soluble or water swellable at pressures less than atmospheric
pressure. Desirably, the water soluble polymers are water soluble
or water swellable having at least 20 percent by weight water
uptake. Water swellable polymers having a 25 or greater percent by
weight water uptake are also useful. Films or dosage forms of the
present invention formed from such water soluble polymers are
desirably sufficiently water soluble to be dissolvable upon contact
with bodily fluids.
[0065] Other polymers useful for incorporation into the films of
the present invention include biodegradable polymers, copolymers,
block polymers and combinations thereof. Among the known useful
polymers or polymer classes which meet the above criteria are:
poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanoes,
polyoxalates, poly(.alpha.-esters), polyanhydrides, polyacetates,
polycaprolactones, poly(orthoesters), polyamino acids,
polyaminocarbonates, polyurethanes, polycarbonates, polyamides,
poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.
Additional useful polymers include, stereopolymers of L-and
D-lactic acid, copolymers of bis(p-carboxyphenoxy) propane acid and
sebacic acid, sebacic acid copolymers, copolymers of caprolactone,
poly(lactic acid)/poly(glycolic acid)/polyethyleneglycol
copolymers, copolymers of polyurethane and (poly(lactic acid),
copolymers of polyurethane and poly(lactic acid), copolymers of
.alpha.-amino acids, copolymers of .alpha.-amino acids and caproic
acid, copolymers of .alpha.-benzyl glutamate and polyethylene
glycol, copolymers of succinate and poly(glycols), polyphosphazene,
polyhydroxy-alkanoates and mixtures thereof. Binary and ternary
systems are contemplated.
[0066] Other specific polymers useful include those marketed under
the Medisorb and Biodel trademarks. The Medisorb materials are
marketed by the Dupont Company of Wilmington, Del. and are
generically identified as a "lactide/glycolide co-polymer"
containing "propanoic acid, 2-hydroxy-polymer with hydroxy-polymer
with hydroxyacetic acid." Four such polymers include
lactide/glycolide 100 L, believed to be 100% lactide having a
melting point within the range of 338.degree.-347.degree. F.
(170.degree.-175.degree. C.); lactide/glycolide 100 L, believed to
be 100% glycolide having a melting point within the range of
437.degree.-455.degree. F. (225.degree.-235.degree. C.);
lactide/glycolide 85/15, believed to be 85% lactide and 15%
glycolide with a melting point within the range of
338.degree.-347.degree. F. (170.degree.-175.degree. C.); and
lactide/glycolide 50/50, believed to be a copolymer of 50% lactide
and 50% glycolide with a melting point within the range of
338.degree.-347.degree. F. (170.degree.-175.degree. C.).
[0067] The Biodel materials represent a family of various
polyanhydrides which differ chemically.
[0068] Although a variety of different polymers may be used, it is
desired to select polymers to provide a desired viscosity of the
mixture prior to drying. For example, if the active or other
components are not soluble in the selected solvent, a polymer that
will provide a greater viscosity is desired to assist in
maintaining uniformity. On the other hand, if the components are
soluble in the solvent, a polymer that provides a lower viscosity
may be preferred.
[0069] The polymer plays an important role in affecting the
viscosity of the film. Viscosity is one property of a liquid that
controls the stability of the active in an emulsion, a colloid or a
suspension. Generally the viscosity of the matrix will vary from
about 400 cps to about 100,000 cps, preferably from about 800 cps
to about 60,000 cps, and most preferably from about 1,000 cps to
about 40,000 cps. Desirably, the viscosity of the film-forming
matrix will rapidly increase upon initiation of the drying
process.
[0070] The viscosity may be adjusted based on the selected active
depending on the other components within the matrix. For example,
if the component is not soluble within the selected solvent, a
proper viscosity may be selected to prevent the component from
settling which would adversely affect the uniformity of the
resulting film. The viscosity may be adjusted in different ways. To
increase viscosity of the film matrix, the polymer may be chosen of
a higher molecular weight or crosslinkers may be added, such as
salts of calcium, sodium and potassium. The viscosity may also be
adjusted by adjusting the temperature or by adding a viscosity
increasing component. Components that will increase the viscosity
or stabilize the emulsion/suspension include higher molecular
weight polymers and polysaccharides and gums, which include without
limitation, alginate, carrageenan, hydroxypropyl methyl cellulose,
locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan
gum and combinations thereof.
[0071] It has also been observed that certain polymers which when
used alone would ordinarily require a plasticizer to achieve a
flexible film, can be combined without a plasticizer and yet
achieve flexible films. For example, HPMC and HPC when used in
combination provide a flexible, strong film with the appropriate
plasticity and elasticity for manufacturing and storage. No
additional plasticizer or polyalcohol is needed for
flexibility.
Controlled Release Films
[0072] The term "controlled release" is intended to mean the
release of active at a pre-selected or desired rate. This rate will
vary depending upon the application. Desirable rates include fast
or immediate release profiles as well as delayed, sustained or
sequential release. Combinations of release patterns, such as
initial spiked release followed by lower levels of sustained
release of active are contemplated. Pulsed drug releases are also
contemplated.
[0073] The polymers that are chosen for the films of the present
invention may also be chosen to allow for controlled disintegration
of the active. This may be achieved by providing a substantially
water insoluble film that incorporates an active that will be
released from the film over time. This may be accomplished by
incorporating a variety of different soluble or insoluble polymers
and may also include biodegradable polymers in combination.
Alternatively, coated controlled release active particles may be
incorporated into a readily soluble film matrix to achieve the
controlled release property of the active inside the digestive
system upon consumption.
[0074] Films that provide a controlled release of the active are
particularly useful for buccal, gingival, sublingual and vaginal
applications. The films of the present invention are particularly
useful where mucosal membranes or mucosal fluid is present due to
their ability to readily wet and adhere to these areas.
[0075] The convenience of administering a single dose of a
medication which releases active ingredients in a controlled
fashion over an extended period of time as opposed to the
administration of a number of single doses at regular intervals has
long been recognized in the pharmaceutical arts. The advantage to
the patient and clinician in having consistent and uniform blood
levels of medication over an extended period of time are likewise
recognized. The advantages of a variety of sustained release dosage
forms are well known. However, the preparation of a film that
provides the controlled release of an active has advantages in
addition to those well-known for controlled release tablets. For
example, thin films are difficult to inadvertently aspirate and
provide an increased patient compliance because they need not be
swallowed like a tablet. Moreover, certain embodiments of the
inventive films are designed to adhere to the buccal cavity and
tongue, where they controllably dissolve. Furthermore, thin films
may not be crushed in the manner of controlled release tablets
which is a problem leading to abuse of drugs such as Oxycontin.
[0076] The actives employed in the present invention may be
incorporated into the film compositions of the present invention in
a controlled release form. For example, particles of drug may be
coated with polymers such as ethyl cellulose or polymethacrylate,
commercially available under brand names such as Aquacoat ECD and
Eudragit E-100, respectively. Solutions of drug may also be
absorbed on such polymer materials and incorporated into the
inventive film compositions. Other components such as fats and
waxes, as well as sweeteners and/or flavors may also be employed in
such controlled release compositions.
[0077] The actives may be taste-masked prior to incorporation into
the film composition, as set forth in co-pending PCT application
titled, Uniform Films For Rapid Dissolve Dosage Form Incorporating
Taste-Masking Compositions, (based on U.S. Provisional Application
No. Express Mail Label No.: EU552991605 US of the same title, filed
Sep. 27, 2003, attorney docket No. 1199-15P) the entire subject
matter of which is incorporated by reference herein.
Actives
[0078] When an active is introduced to the film, the amount of
active per unit area is determined by the uniform distribution of
the film. For example, when the films are cut into individual
dosage forms, the amount of the active in the dosage form can be
known with a great deal of accuracy. This is achieved because the
amount of the active in a given area is substantially identical to
the amount of active in an area of the same dimensions in another
part of the film. The accuracy in dosage is particularly
advantageous when the active is a medicament, i.e. a drug.
[0079] The active components that may be incorporated into the
films of the present invention include, without limitation
pharmaceutical and cosmetic actives, drugs, medicaments, antigens
or allergens such as ragweed pollen, spores, microorganisms
including bacteria, seeds, mouthwash components such as chlorates
or chlorites, flavors, fragrances, enzymes, preservatives,
sweetening agents, colorants, spices, vitamins and combinations
thereof.
[0080] A wide variety of medicaments, bioactive active substances
and pharmaceutical compositions may be included in the dosage forms
of the present invention. Examples of useful drugs include
ace-inhibitors, antianginal drugs, anti-arrhythmias,
anti-asthmatics, anti-cholesterolemics, analgesics, anesthetics,
anti-convulsants, anti-depressants, anti-diabetic agents,
anti-diarrhea preparations, antidotes, anti-histamines,
anti-hypertensive drugs, anti-inflammatory agents, anti-lipid
agents, anti-manics, anti-nauseants, anti-stroke agents,
anti-thyroid preparations, anti-tumor drugs, anti-viral agents,
acne drugs, alkaloids, amino acid preparations, anti-tussives,
anti-uricemic drugs, anti-viral drugs, anabolic preparations,
systemic and non-systemic anti-infective agents, anti-neoplastics,
anti-parkinsonian agents, anti-rheumatic agents, appetite
stimulants, biological response modifiers, blood modifiers, bone
metabolism regulators, cardiovascular agents, central nervous
system stimulates, cholinesterase inhibitors, contraceptives,
decongestants, dietary supplements, dopamine receptor agonists,
endometriosis management agents, enzymes, erectile dysfunction
therapies, fertility agents, gastrointestinal agents, homeopathic
remedies, hormones, hypercalcemia and hypocalcemia management
agents, immunomodulators, immunosuppressives, migraine
preparations, motion sickness treatments, muscle relaxants, obesity
management agents, osteoporosis preparations, oxytocics,
parasympatholytics, parasympathomimetics, prostaglandins,
psychotherapeutic agents, respiratory agents, sedatives, smoking
cessation aids such as bromocryptine and nicotine, sympatholytics,
tremor preparations, urinary tract agents, vasodilators, laxatives,
antacids, ion exchange resins, anti-pyretics, appetite
suppressants, expectorants, anti-anxiety agents, anti-ulcer agents,
anti-inflammatory substances, coronary dilators, cerebral dilators,
peripheral vasodilators, psycho-tropics, stimulants,
anti-hypertensive drugs, vasoconstrictors, migraine treatments,
antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs,
anti-coagulants, anti-thrombotic drugs, hypnotics, anti-emetics,
anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and
hypo-glycemic agents, thyroid and anti-thyroid preparations,
diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs,
erythropoietic drugs, anti-asthmatics, cough suppressants,
mucolytics, DNA and genetic modifying drugs, and combinations
thereof.
[0081] Examples of medicating active ingredients contemplated for
use in the present invention include antacids, H.sub.2-antagonists,
and analgesics. For example, antacid dosages can be prepared using
the ingredients calcium carbonate alone or in combination with
magnesium hydroxide, and/or aluminum hydroxide. Moreover, antacids
can be used in combination with H.sub.2-antagonists.
[0082] Analgesics include opiates and opiate derivatives, such as
oxycodone (available as Oxycontin.RTM.), ibuprofen, aspirin,
acetaminophen, and combinations thereof that may optionally include
caffeine.
[0083] Other preferred drugs for other preferred active ingredients
for use in the present invention include anti-diarrheals such as
immodium AD, anti-histamines, anti-tussives, decongestants,
vitamins, and breath fresheners. Suitable vitamins contemplated for
use herein include any conventionally known vitamins, such as, but
not limited to, Vitamins A, B, C and E. Common drugs used alone or
in combination for colds, pain, fever, cough, congestion, runny
nose and allergies, such as acetaminophen, chlorpheniramine
maleate, dextromethorphan, pseudoephedrine HCl and diphenhydramine
may be included in the film compositions of the present
invention.
[0084] Also contemplated for use herein are anxiolytics such as
alprazolam (available as Xanax.RTM.); anti-psychotics such as
clozopin (available as Clozaril.RTM.) and haloperidol (available as
Haldol.RTM.); non-steroidal anti-inflammatories (NSAID's) such as
dicyclofenacs (available as Voltaren.RTM.) and etodolac (available
as Lodine.RTM.), anti-histamines such as loratadine (available as
Claritin.RTM.), astemizole (available as Hismanal.TM.), nabumetone
(available as Relafen.RTM.), and Clemastine (available as
Tavist.RTM.); anti-emetics such as granisetron hydrochloride
(available as Kytril.RTM.) and nabilone (available as Cesamet.TM.);
bronchodilators such as Bentolin.RTM., albuterol sulfate (available
as Proventil.RTM.); anti-depressants such as fluoxetine
hydrochloride (available as Prozac.RTM.), sertraline hydrochloride
(available as Zoloft.RTM.), and paroxtine hydrochloride (available
as Paxil.RTM.); anti-migraines such as Imigra.RTM., ACE-inhibitors
such as enalaprilat (available as Vasotec.RTM.), captopril
(available as Capoten.RTM.) and lisinopril (available as
Zestril.RTM.); anti-Alzheimer's agents, such as nicergoline; and
Ca.sup.H-antagonists such as nifedipine (available as
Procardia.RTM. and Adalat.RTM.), and verapamil hydrochloride
(available as Calan.RTM.).
[0085] Erectile dysfunction therapies include, but are not limited
to, drugs for facilitating blood flow to the penis, and for
effecting autonomic nervous activities, such as increasing
parasympathetic (cholinergic) and decreasing sympathetic
(adrenersic) activities. Useful non-limiting drugs include
sildenafils, such as Viagra.RTM., tadalafils, such as Cialis.RTM.,
vardenafils, apomorphines, such as Uprima.RTM., yohimbine
hydrochlorides such as Aphrodyne.RTM., and alprostadils such as
Caverject.RTM..
[0086] The popular H.sub.2-antagonists which are contemplated for
use in the present invention include cimetidine, ranitidine
hydrochloride, famotidine, nizatidien, ebrotidine, mifentidine,
roxatidine, pisatidine and aceroxatidine.
[0087] Active antacid ingredients include, but are not limited to,
the following: aluminum hydroxide, dihydroxyaluminum aminoacetate,
aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium
carbonate, bicarbonate, bismuth aluminate, bismuth carbonate,
bismuth subcarbonate, bismuth subgallate, bismuth subnitrate,
bismuth subsilysilate, calcium carbonate, calcium phosphate,
citrate ion (acid or salt), amino acetic acid, hydrate magnesium
aluminate sulfate, magaldrate, magnesium aluminosilicate, magnesium
carbonate, magnesium glycinate, magnesium hydroxide, magnesium
oxide, magnesium trisilicate, milk solids, aluminum mono-ordibasic
calcium phosphate, tricalcium phosphate, potassium bicarbonate,
sodium tartrate, sodium bicarbonate, magnesium aluminosilicates,
tartaric acids and salts.
[0088] The pharmaceutically active agents employed in the present
invention may include allergens or antigens, such as, but not
limited to, plant pollens from grasses, trees, or ragweed; animal
danders, which are tiny scales shed from the skin and hair of cats
and other furred animals; insects, such as house dust mites, bees,
and wasps; and drugs, such as penicillin.
[0089] Botanicals, herbals and minerals also may be added to the
film. Examples of botanicals include, without limitation: roots;
barks; leaves; stems; flowers; fruits; tobacco; sunflower seeds;
snuff; and combinations thereof.
[0090] An anti-oxidant may also be added to the film to prevent the
degradation of an active, especially where the active is
photosensitive.
[0091] The bioactive active substances employed in the present
invention may include beneficial bacteria. More specifically,
certain bacteria normally exist on the surface of the tongue and in
the back of the throat. Such bacteria assist in the digestion of
food by breaking down proteins found in the food. It may be
desirable, therefore, to incorporate these bacteria into the oral
film products of the present invention.
[0092] It also may be desirable to include actives for treating
breath malodor and related oral care conditions, such as actives
which are effective in suppressing microorganisms. Because breath
malodor can be caused by the presence of anaerobic bacteria in the
oral cavity, which generate volatile sulfur compounds, components
that suppress such microorganisms may be desirable. Examples of
such components include antimicrobials such as triclosan, chlorine
dioxide, chlorates, and chlorites, among others. The use of
chlorites, particularly sodium chlorite, in oral care compositions
such as mouthrinses and toothpastes is taught in U.S. Pat. Nos.
6,251,372, 6,132,702, 6,077,502, and U.S. Publication No.
2003/0129144, all of which are incorporated herein by reference.
Such components are incorporated in amounts effective to treat
malodor and related oral conditions.
[0093] Cosmetic active agents may include breath freshening
compounds like menthol, other flavors or fragrances, especially
those used for oral hygiene, as well as actives used in dental and
oral cleansing such as quaternary ammonium bases. The effect of
flavors may be enhanced using flavor enhancers like tartaric acid,
citric acid, vanillin, or the like.
[0094] Also color additives can be used in preparing the films.
Such color additives include food, drug and cosmetic colors
(FD&C), drug and cosmetic colors (D&C), or external drug
and cosmetic colors (Ext. D&C). These colors are dyes, their
corresponding lakes, and certain natural and derived colorants.
Lakes are dyes absorbed on aluminum hydroxide.
[0095] Other examples of coloring agents include known azo dyes,
organic or inorganic pigments, or coloring agents of natural
origin. Inorganic pigments are preferred, such as the oxides or
iron or titanium, these oxides, being added in concentrations
ranging from about 0.001 to about 10%, and preferably about 0.5 to
about 3%, based on the weight of all the components.
[0096] Flavors may be chosen from natural and synthetic flavoring
liquids. An illustrative list of such agents includes volatile
oils, synthetic flavor oils, flavoring aromatics, oils, liquids,
oleoresins or extracts derived from plants, leaves, flowers,
fruits, stems and combinations thereof. A non-limiting
representative list of examples includes mint oils, cocoa, and
citrus oils such as lemon, orange, grape, lime and grapefruit and
fruit essences including apple, pear, peach, grape, strawberry,
raspberry, cherry, plum, pineapple, apricot or other fruit
flavors.
[0097] The films containing flavorings may be added to provide a
hot or cold flavored drink or soup. These flavorings include,
without limitation, tea and soup flavorings such as beef and
chicken.
[0098] Other useful flavorings include aldehydes and esters such as
benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon,
lime), neral, i.e., beta-citral (lemon, lime), decanal (orange,
lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits),
aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond),
2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus,
mandarin), combinations thereof and the like.
[0099] The sweeteners may be chosen from the following non-limiting
list: glucose (corn syrup), dextrose, invert sugar, fructose, and
combinations thereof; saccharin and its various salts such as the
sodium salt; dipeptide sweeteners such as aspartame;
dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana
(Stevioside); chloro derivatives of sucrose such as sucralose;
sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
Also contemplated are hydrogenated starch hydrolysates and the
synthetic sweetener
3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,
particularly the potassium salt (acesulfame-K), and sodium and
calcium salts thereof, and natural intensive sweeteners, such as Lo
Han Kuo. Other sweeteners may also be used.
[0100] When the active is combined with the polymer in the solvent,
the type of matrix that is formed depends on the solubilities of
the active and the polymer. If the active and/or polymer are
soluble in the selected solvent, this may form a solution. However,
if the components are not soluble, the matrix may be classified as
an emulsion, a colloid, or a suspension.
Dosages
[0101] The film products of the present invention are capable of
accommodating a wide range of amounts of the active ingredient. The
films are capable of providing an accurate dosage amount
(determined by the size of the film and concentration of the active
in the original polymer/water combination) regardless of whether
the required dosage is high or extremely low. Therefore, depending
on the type of active or pharmaceutical composition that is
incorporated into the film, the active amount may be as high as
about 300 mg, desirably up to about 150 mg or as low as the
microgram range, or any amount therebetween.
[0102] The film products and methods of the present invention are
well suited for high potency, low dosage drugs. This is
accomplished through the high degree of uniformity of the films.
Therefore, low dosage drugs, particularly more potent racemic
mixtures of actives are desirable.
Anti-Tacking Compositions
[0103] It is useful to add anti-tacking agents, such as lubricants,
antiadherants and glidants to the film compositions of the present
invention. Anti-tacking agents assist in the flow characteristics
of the material, for example, by reducing sticking to the die in
extrusion processes and reducing sticking to the roof of the mouth
during administration of the dosage form.
[0104] During consumption of films, particles tend to adhere to the
roof of the mouth. This is undesirable for films containing bitter
drugs, such as, for example, dextromethorphan, because the adhered
particles elude drug, which increases the amount of bitterness
detected by the user. Addition of an anti-tacking agent to the
films reduces adherence to the roof of the mouth, thereby
effectively reducing the bitterness that may be detected by a user
during consumption.
[0105] Anti-taking agents also may impart reduced film-to-film
coefficient of friction, thereby reducing the problem of film
dosage units, i.e., strips, adhering to one another. More
specifically, in many types of film packaging, strips are stacked
against one another. The incorporation of anti-tacking agents may
permit the individual strips to slide smoothly against one another
as each unit is removed from the packaging.
[0106] Examples of suitable lubricants for use as anti-tacking
agents include, but are not limited to: stearates, such as
magnesium stearate, calcium stearate, and sodium stearate; stearic
acid; sterotex; talc; waxes; stearowet; boric acid; sodium
benzoate; sodium acetate; sodium chloride; DL-Leucine; Carbowax
4000; Carbowax 6000; sodium oleate; sodium lauryl sulfate;
magnesium lauryl sulfate; and combinations thereof.
[0107] Examples of suitable antiadherants include, but are not
limited to: talc; cornstarch; Cab-O-Sil; syloid; DL-Leucine; sodium
lauryl sulfate; metallic stearates; and combinations thereof.
Examples of suitable glidants include, but are not limited to:
talc; cornstarch; Cab-O-Sil; syloid; aerosol; and combinations
thereof.
[0108] Some embodiments of the present invention include fats
and/or waxes as anti-tacking agents.
[0109] Vitamin E is another suitable anti-tacking agent for use in
some embodiments of the present invention. Vitamin E may serve as
both an anti-tacking agent and an active component in the film.
Desirably, Vitamin E TPGS (d-alpha tocopheryl polyethylene glycol
1000 succinate) is employed. Vitamin E TPGS is a water-soluble form
of Vitamin E derived from natural sources. As compared to other
forms, Vitamin E TPGS is easily absorbed. Further, Vitamin E TPGS
imparts practically no taste to film. Vitamin E TPGS may be
employed in solution, such as, for example 10% or 20% solution with
water. Vitamin E TPGS is particularly useful in reducing the
stickiness of the films and the tendency to adhere to the roof of
the user's mouth. Vitamin E may be present in amounts of about
0.01% to about 20% by weight of the composition.
[0110] Anti-tacking agents generally are present in amounts of
about 0.01% to about 20% by weight of the film composition. More
specifically, anti-tacking agents may be present in amounts of
about 0.01% to about 10% by weight of the film composition, and
even more specifically, about 0.25% to about 5% by weight of the
film composition.
[0111] Combinations of anti-tacking agents also may be employed.
For instance, in some embodiments of the present invention, a
combination of a stearate, such as magnesium stearate, and silica
may be used. SIPERNAT 500LS, which is a silica product having a 4.5
.mu.m mean particle size, is suitable for use herein (commercially
available from Degussa). Combinations of magnesium stearate and
silica may provide improved glidant properties, i.e., assist film
strips in sliding smoothly against one another in packaging.
Accordingly, in some embodiments, magnesium stearate may be present
in amounts of about 0.1% to about 2.5% by weight of the film
composition and silica may be present in amounts of about 0.1% to
about 1.5% by weight of the film composition. Such combination of
anti-tacking agents may be useful in a variety of films containing
different flavors and/or actives.
[0112] In some embodiments, anti-tacking agents may be included in
the film composition itself. For example, single or multi-layer
films including anti-tacking agents may be formed. Multi-layer
films, for example, may include two, three or more layers of film
substantially in contact with one another. In some embodiments, the
film layers may be laminated to one another. Anti-tacking agents
may be present in one or more of the layers of the multi-layer
film. For example, some embodiments may include a bi-layer film in
which anti-tacking agents are present in one of the two film
layers. Some embodiments may include a three-layer film in which
anti-tacking agents are present in each of the outer layers but not
in the inner, or middle, layer of the three-layer film. In
accordance therewith, a variety of different combinations of layers
may be formed.
[0113] Alternatively, in some embodiments, anti-tacking agents may
be included in a composition that is used to coat the external
surfaces of the film. For instance, anti-tacking agents may be
applied to the film in the form of a wet or dry coating, such as,
for example, a sugared or sugar-free coating. The film may be
coated with the anti-tacking agents in any conventional manner,
such as, but not limited to, dip coating, spray coating, dusting,
or fluidized bed. One or more film surfaces may be coated. In some
embodiments, the anti-tacking coating may be applied to a
substrate, such as a backing for the film, rather than directly to
the film itself. When the film is removed from the backing, the
anti-tacking coating may adhere to the film.
Anti-Foaming and De-Foaming Compositions
[0114] Anti-foaming and/or de-foaming components may also be used
with the films of the present invention. These components aid in
the removal of air, such as entrapped air, from the film-forming
compositions. As described above, such entrapped air may lead to
non-uniform films. Simethicone is one particularly useful
anti-foaming and/or de-foaming agent. The present invention,
however, is not so limited and other anti-foam and/or de-foaming
agents may suitable be used.
[0115] Simethicone is generally used in the medical field as a
treatment for gas or colic in babies. Simethicone is a mixture of
fully methylated linear siloxane polymers containing repeating
units of polydimethylsiloxane which is stabilized with
trimethylsiloxy end-blocking unites, and silicon dioxide. It
usually contains 90.5-99% polymethylsiloxane and 4-7% silicon
dioxide. The mixture is a gray, translucent, viscous fluid which is
insoluble in water.
[0116] When dispersed in water, simethicone will spread across the
surface, forming a thin film of low surface tension. In this way,
simethicone reduces the surface tension of bubbles air located in
the solution, such as foam bubbles, causing their collapse. The
function of simethicone mimics the dual action of oil and alcohol
in water. For example, in an oily solution any trapped air bubbles
will ascend to the surface and dissipate more quickly and easily,
because an oily liquid has a lighter density compared to a water
solution. On the other hand, an alcohol/water mixture is known to
lower water density as well as lower the water's surface tension.
So, any air bubbles trapped inside this mixture solution will also
be easily dissipated. Simethicone solution provides both of these
advantages. It lowers the surface energy of any air bubbles that
trapped inside the aqueous solution, as well as lowering the
surface tension of the aqueous solution. As the result of this
unique functionality, simethicone has an excellent anti-foaming
property that can be used for physiological processes (anti-gas in
stomach) as well as any for external processes that require the
removal of air bubbles from a product.
[0117] In order to prevent the formation of air bubbles in the
films of the present invention, the mixing step can be performed
under vacuum. However, as soon as the mixing step is completed, and
the film solution is returned to the normal atmosphere condition,
air will be re-introduced into or contacted with the mixture. In
many cases, tiny air bubbles will be again trapped inside this
polymeric viscous solution. The incorporation of simethicone into
the film-forming composition either substantially reduces or
eliminates the formation of air bubbles.
[0118] Simethicone may be added to the film-forming mixture as an
anti-foaming agent in an amount from about 0.01 weight percent to
about 5.0 weight percent, more desirably from about 0.05 weight
percent to about 2.5 weight percent, and most desirably from about
0.1 weight percent to about 1.0 weight percent.
Optional Components
[0119] A variety of other components and fillers may also be added
to the films of the present invention. These may include, without
limitation, surfactants; plasticizers which assist in
compatibilizing the components within the mixture; polyalcohols;
anti-foaming agents, such as silicone-containing compounds, which
promote a smoother film surface by releasing oxygen from the film;
and thermo-setting gels such as pectin, carageenan, and gelatin,
which help in maintaining the dispersion of components.
[0120] The variety of additives that can be incorporated into the
inventive compositions may provide a variety of different
functions. Examples of classes of additives include excipients,
lubricants, buffering agents, stabilizers, blowing agents,
pigments, coloring agents, fillers, bulking agents, sweetening
agents, flavoring agents, fragrances, release modifiers, adjuvants,
plasticizers, flow accelerators, mold release agents, polyols,
granulating agents, diluents, binders, buffers, absorbents,
glidants, adhesives, anti-adherents, acidulants, softeners, resins,
demulcents, solvents, surfactants, emulsifiers, elastomers and
mixtures thereof. These additives may be added with the active
ingredient(s).
[0121] Useful additives include, for example, gelatin, vegetable
proteins such as sunflower protein, soybean proteins, cotton seed
proteins, peanut proteins, grape seed proteins, whey proteins, whey
protein isolates, blood proteins, egg proteins, acrylated proteins,
water-soluble polysaccharides such as alginates, carrageenans, guar
gum, agar-agar, xanthan gum, gellan gum, gum arabic and related
gums (gum ghatti, gum karaya, gum tragancanth), pectin,
water-soluble derivatives of cellulose: alkylcelluloses
hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as
methylcelulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxyethylmethylcellulose,
hydroxypropylmethylcellulose, hydroxybutylmethylcellulose,
cellulose esters and hydroxyalkylcellulose esters such as cellulose
acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC);
carboxyalkylcelluloses, carboxyalkylalkylcelluloses,
carboxyalkylcellulose esters such as carboxymethylcellulose and
their alkali metal salts; water-soluble synthetic polymers such as
polyacrylic acids and polyacrylic acid esters, polymethacrylic
acids and polymethacrylic acid esters, polyvinylacetates,
polyvinylalcohols, polyvinylacetatephthalates (PVAP),
polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, and
polycrotonic acids; also suitable are phthalated gelatin, gelatin
succinate, crosslinked gelatin, shellac, water soluble chemical
derivatives of starch, cationically modified acrylates and
methacrylates possessing, for example, a tertiary or quaternary
amino group, such as the diethylaminoethyl group, which may be
quaternized if desired; and other similar polymers.
[0122] Such extenders may optionally be added in any desired amount
desirably within the range of up to about 80%, desirably about 3%
to 50% and more desirably within the range of 3% to 20% based on
the weight of all components.
[0123] Further additives may be inorganic fillers, such as the
oxides of magnesium aluminum, silicon, titanium, etc. desirably in
a concentration range of about 0.02% to about 3% by weight and
desirably about 0.02% to about 1% based on the weight of all
components.
[0124] Further examples of additives are plasticizers which include
polyalkylene oxides, such as polyethylene glycols, polypropylene
glycols, polyethylene-propylene glycols, organic plasticizers with
low molecular weights, such as glycerol, glycerol monoacetate,
diacetate or triacetate, triacetin, polysorbate, cetyl alcohol,
propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl
citrate, tributyl citrate, and the like, added in concentrations
ranging from about 0.5% to about 30%, and desirably ranging from
about 0.5% to about 20% based on the weight of the polymer.
[0125] There may further be added compounds to improve the flow
properties of the starch material such as animal or vegetable fats,
desirably in their hydrogenated form, especially those which are
solid at room temperature. These fats desirably have a melting
point of 50.degree. C. or higher. Preferred are tri-glycerides with
C.sub.12-, C.sub.14-, C.sub.16-, C.sub.18-, C.sub.20- and
C.sub.22-fatty acids. These fats can be added alone without adding
extenders or plasticizers and can be advantageously added alone or
together with mono- and/or di-glycerides or phosphatides,
especially lecithin. The mono and di-glycerides are desirably
derived from the types of fats described above, i.e. with
C.sub.12-, C.sub.14-, C.sub.16-, C.sub.18-, C.sub.20- and
C.sub.22-fatty acids.
[0126] The total amounts used of the fats, mono-, di-glycerides
and/or lecithins are up to about 5% and preferably within the range
of about 0.5% to about 2% by weight of the total composition
[0127] It is further useful to add silicon dioxide, calcium
silicate, or titanium dioxide in a concentration of about 0.02% to
about 1% by weight of the total composition. These compounds act as
texturizing agents.
[0128] These additives are to be used in amounts sufficient to
achieve their intended purpose. Generally, the combination of
certain of these additives will alter the overall release profile
of the active ingredient and can be used to modify, i.e. impede or
accelerate the release.
[0129] Lecithin is one surface active agent for use in the present
invention. Lecithin can be included in the feedstock in an amount
of from about 0.25% to about 2.00% by weight. Other surface active
agents, i.e. surfactants, include, but are not limited to, cetyl
alcohol, sodium lauryl sulfate, the Spans.TM. and Tweens.TM. which
are commercially available from ICI Americas, Inc. Ethoxylated
oils, including ethoxylated castor oils, such as Cremophor.RTM. EL
which is commercially available from BASF, are also useful.
Carbowax.TM. is yet another modifier which is very useful in the
present invention. Tweens.TM. or combinations of surface active
agents may be used to achieve the desired hydrophilic-lipophilic
balance ("HLB") The present invention, however, does not require
the use of a surfactant and films or film-forming compositions of
the present invention may be essentially free of a surfactant while
still providing the desirable uniformity features of the present
invention.
[0130] It may be further useful to add polydextrose to the films of
the present invention. Polydextrose serves as a filler and
solubility enhancer, i.e., it increases the dissolution time of the
films in the oral cavity.
[0131] As additional modifiers which enhance the procedure and
product of the present invention are identified, Applicants intend
to include all such additional modifiers within the scope of the
invention claimed herein.
[0132] Other ingredients include binders which contribute to the
ease of formation and general quality of the films. Non-limiting
examples of binders include starches, pregelatinize starches,
gelatin, polyvinylpyrrolidone, methylcellulose, sodium
carboxymethylcellulose, ethylcellulose, polyacrylamides,
polyvinyloxoazolidone, and polyvinylalcohols.
Forming the Film
[0133] The films of the present invention must be formed into a
sheet prior to drying. After the desired components are combined to
form a multi-component matrix, including the polymer, water, and an
active or other components as desired, the combination is formed
into a sheet or film, by any method known in the art such as
extrusion, coating, spreading, casting or drawing the
multi-component matrix. If a multi-layered film is desired, this
may be accomplished by co-extruding more than one combination of
components which may be of the same or different composition. A
multi-layered film may also be achieved by coating, spreading, or
casting a combination onto an already formed film layer.
[0134] Although a variety of different film-forming techniques may
be used, it is desirable to select a method that will provide a
flexible film, such as reverse roll coating. The flexibility of the
film allows for the sheets of film to be rolled and transported for
storage or prior to being cut into individual dosage forms.
Desirably, the films will also be self-supporting or in other words
able to maintain their integrity and structure in the absence of a
separate support. Furthermore, the films of the present invention
may be selected of materials that are edible or ingestible.
[0135] Coating or casting methods are particularly useful for the
purpose of forming the films of the present invention. Specific
examples include reverse roll coating, gravure coating, immersion
or dip coating, metering rod or meyer bar coating, slot die or
extrusion coating, gap or knife over roll coating, air knife
coating, curtain coating, or combinations thereof, especially when
a multi-layered film is desired.
[0136] Roll coating, or more specifically reverse roll coating, is
particularly desired when forming films in accordance with the
present invention. This procedure provides excellent control and
uniformity of the resulting films, which is desired in the present
invention. In this procedure, the coating material is measured onto
the applicator roller by the precision setting of the gap between
the upper metering roller and the application roller below it. The
coating is transferred from the application roller to the substrate
as it passes around the support roller adjacent to the application
roller. Both three roll and four roll processes are common.
[0137] The gravure coating process relies on an engraved roller
running in a coating bath, which fills the engraved dots or lines
of the roller with the coating material. The excess coating on the
roller is wiped off by a doctor blade and the coating is then
deposited onto the substrate as it passes between the engraved
roller and a pressure roller.
[0138] Offset Gravure is common, where the coating is deposited on
an intermediate roller before transfer to the substrate.
[0139] In the simple process of immersion or dip coating, the
substrate is dipped into a bath of the coating, which is normally
of a low viscosity to enable the coating to run back into the bath
as the substrate emerges.
[0140] In the metering rod coating process, an excess of the
coating is deposited onto the substrate as it passes over the bath
roller. The wire-wound metering rod, sometimes known as a Meyer
Bar, allows the desired quantity of the coating to remain on the
substrate. The quantity is determined by the diameter of the wire
used on the rod.
[0141] In the slot die process, the coating is squeezed out by
gravity or under pressure through a slot and onto the substrate. If
the coating is 100% solids, the process is termed "Extrusion" and
in this case, the line speed is frequently much faster than the
speed of the extrusion. This enables coatings to be considerably
thinner than the width of the slot.
[0142] The gap or knife over roll process relies on a coating being
applied to the substrate which then passes through a "gap" between
a "knife" and a support roller. As the coating and substrate pass
through, the excess is scraped off.
[0143] Air knife coating is where the coating is applied to the
substrate and the excess is "blown off" by a powerful jet from the
air knife. This procedure is useful for aqueous coatings.
[0144] In the curtain coating process, a bath with a slot in the
base allows a continuous curtain of the coating to fall into the
gap between two conveyors. The object to be coated is passed along
the conveyor at a controlled speed and so receives the coating on
its upper face.
Drying the Film
[0145] The drying step is also a contributing factor with regard to
maintaining the uniformity of the film composition. A controlled
drying process is particularly important when, in the absence of a
viscosity increasing composition or a composition in which the
viscosity is controlled, for example by the selection of the
polymer, the components within the film may have an increased
tendency to aggregate or conglomerate. An alternative method of
forming a film with an accurate dosage, that would not necessitate
the controlled drying process, would be to cast the films on a
predetermined well. With this method, although the components may
aggregate, this will not result in the migration of the active to
an adjacent dosage form, since each well may define the dosage unit
per se.
[0146] When a controlled or rapid drying process is desired, this
may be through a variety of methods. A variety of methods may be
used including those that require the application of heat. The
liquid carriers are removed from the film in a manner such that the
uniformity, or more specifically, the non-self-aggregating uniform
heterogeneity, that is obtained in the wet film is maintained.
[0147] Desirably, the film is dried from the bottom of the film to
the top of the film. Desirably, substantially no air flow is
present across the top of the film during its initial setting
period, during which a solid, visco-elastic structure is formed.
This can take place within the first few minutes, e.g. about the
first 0.5 to about 4.0 minutes of the drying process. Controlling
the drying in this manner, prevents the destruction and reformation
of the film's top surface, which results from conventional drying
methods. This is accomplished by forming the film and placing it on
the top side of a surface having top and bottom sides. Then, heat
is initially applied to the bottom side of the film to provide the
necessary energy to evaporate or otherwise remove the liquid
carrier. The films dried in this manner dry more quickly and evenly
as compared to air-dried films, or those dried by conventional
drying means. In contrast to an air-dried film that dries first at
the top and edges, the films dried by applying heat to the bottom
dry simultaneously at the center as well as at the edges. This also
prevents settling of ingredients that occurs with films dried by
conventional means.
[0148] The temperature at which the films are dried is about
100.degree. C. or less, desirably about 90.degree. C. or less, and
most desirably about 80.degree. C. or less.
[0149] Another method of controlling the drying process, which may
be used alone or in combination with other controlled methods as
disclosed above includes controlling and modifying the humidity
within the drying apparatus where the film is being dried. In this
manner, the premature drying of the top surface of the film is
avoided.
[0150] Additionally, it has also been discovered that the length of
drying time can be properly controlled, i.e. balanced with the heat
sensitivity and volatility of the components, and particularly the
flavor oils and drugs. The amount of energy, temperature and length
and speed of the conveyor can be balanced to accommodate such
actives and to minimize loss, degradation or ineffectiveness in the
final film.
[0151] A specific example of an appropriate drying method is that
disclosed by Magoon. Magoon is specifically directed toward a
method of drying fruit pulp. However, the present inventors have
adapted this process toward the preparation of thin films.
[0152] The method and apparatus of Magoon are based on an
interesting property of water. Although water transmits energy by
conduction and convection both within and to its surroundings,
water only radiates energy within and to water. Therefore, the
apparatus of Magoon includes a surface onto which the fruit pulp is
placed that is transparent to infrared radiation. The underside of
the surface is in contact with a temperature controlled water bath.
The water bath temperature is desirably controlled at a temperature
slightly below the boiling temperature of water. When the wet fruit
pulp is placed on the surface of the apparatus, this creates a
"refractance window." This means that infrared energy is permitted
to radiate through the surface only to the area on the surface
occupied by the fruit pulp, and only until the fruit pulp is dry.
The apparatus of Magoon provides the films of the present invention
with an efficient drying time reducing the instance of aggregation
of the components of the film.
[0153] The films may initially have a thickness of about 500 .mu.m
to about 1,500 .mu.m, or about 20 mils to about 60 mils, and when
dried have a thickness from about 3 .mu.m to about 250 .mu.m, or
about 0.1 mils to about 10 mils. Desirably, the dried films will
have a thickness of about 2 mils to about 8 mils, and more
desirably, from about 3 mils to about 6 mils.
Uses of Thin Films
[0154] The thin films of the present invention are well suited for
many uses. The high degree of uniformity of the components of the
film makes them particularly well suited for incorporating
pharmaceuticals. Furthermore, the polymers used in construction of
the films may be chosen to allow for a range of disintegration
times for the films. A variation or extension in the time over
which a film will disintegrate may achieve control over the rate
that the active is released, which may allow for a sustained
release delivery system. In addition, the films may be used for the
administration of an active to any of several body surfaces,
especially those including mucous membranes, such as oral, anal,
vaginal, ophthalmological, the surface of a wound, either on a skin
surface or within a body such as during surgery, and similar
surfaces.
[0155] The films may be used to orally administer an active. This
is accomplished by preparing the films as described above and
introducing them to the oral cavity of a mammal. This film may be
prepared and adhered to a second or support layer from which it is
removed prior to use, i.e. introduction to the oral cavity. An
adhesive may be used to attach the film to the support or backing
material which may be any of those known in the art, and is
preferably not water soluble. If an adhesive is used, it will
desirably be a food grade adhesive that is ingestible and does not
alter the properties of the active. Mucoadhesive compositions are
particularly useful. The film compositions in many cases serve as
mucoadhesives themselves.
[0156] The films may be applied under or to the tongue of the
mammal. When this is desired, a specific film shape, corresponding
to the shape of the tongue may be preferred. Therefore the film may
be cut to a shape where the side of the film corresponding to the
back of the tongue will be longer than the side corresponding to
the front of the tongue. Specifically, the desired shape may be
that of a triangle or trapezoid. Desirably, the film will adhere to
the oral cavity preventing it from being ejected from the oral
cavity and permitting more of the active to be introduced to the
oral cavity as the film dissolves.
[0157] Another use for the films of the present invention takes
advantage of the films' tendency to dissolve quickly when introduce
to a liquid. An active may be introduced to a liquid by preparing a
film in accordance with the present invention, introducing it to a
liquid, and allowing it to dissolve. This may be used either to
prepare a liquid dosage form of an active, or to flavor a
beverage.
[0158] The films of the present invention are desirably packaged in
sealed, air and moisture resistant packages to protect the active
from exposure oxidation, hydrolysis, volatilization and interaction
with the environment. Referring to FIG. 1, a packaged
pharmaceutical dosage unit 10, includes each film 12 individually
wrapped in a pouch or between foil and/or plastic laminate sheets
14. As depicted in FIG. 2, the pouches 10, 10' can be linked
together with tearable or perforated joints 16. The pouches 10,
10'may be packaged in a roll as depicted in FIG. 5 or stacked as
shown in FIG. 3 and sold in a dispenser 18 as shown in FIG. 4. The
dispenser may contain a full supply of the medication typically
prescribed for the intended therapy, but due to the thinness of the
film and package, is smaller and more convenient than traditional
bottles used for tablets, capsules and liquids. Moreover, the films
of the present invention dissolve instantly upon contact with
saliva or mucosal membrane areas, eliminating the need to wash the
dose down with water.
[0159] Desirably, a series of such unit doses are packaged together
in accordance with the prescribed regimen or treatment, e.g., a
10-90 day supply, depending on the particular therapy. The
individual films can be packaged on a backing and peeled off for
use.
[0160] The features and advantages of the present invention are
more fully shown by the following examples which are provided for
purposes of illustration, and are not to be construed as limiting
the invention in any way.
EXAMPLES
Examples 1-2
[0161] Water-soluble thin film compositions were prepared using the
amounts described in Table 1. In particular, composition 1
incorporated Vitamin E as an anti-tacking agent along with various
other components. Composition 2 contained similar components to
composition 1, but absent Vitamin E.
TABLE-US-00001 TABLE 1 Weight (g unless otherwise indicated)
Component 1 2 Polyethylene oxide 2.8 3.5 Hydroxypropyl cellulose
2.8 3.5 Polydextrose 0.69 0.79 Sucralose 0.35 0.75 Taste-Masking
flavor.sup.1 0.07 0 Titanium dioxide 0.07 0.18 Coated
dextromethorphan 5.56 6.94 (45% w/w) Mint flavor 1.26 1.71 Vitamin
E.sup.2 3.9 0 WS-3.sup.3 0.035 0.044 Simethicone emulsion.sup.4
0.035 0.09 Water 19.49 32.5 Blue food color 4 drops 5 drops
.sup.1Magna Sweet, available from Mafco Worldwide Corp. .sup.210%
solution containing 0.39 g Vitamin E and 3.51 g water
.sup.3N-Ethyl-p-menthane-3-carboxamide cooling agent, available
from Millennium Chemicals .sup.4Available from Sentry
[0162] The above components for each composition were combined by
mixing until a uniform mixture was achieved, and then cast into
films. In particular, the solutions were cast onto release paper
(available from Gruff Paper & Film) using a K Control Coater
with a 350 micron smooth bar. The films were then dried at about
80.degree. C. for about 10 minutes. Composition 1 was dried to a
moisture level of about 2.68%, and composition 2 was dried to a
moisture level of about 3.35%.
[0163] The dried films were tested for various properties,
including dissolution testing to determine how long it will take
the film to dissolve in the mouth and bend testing to determine
flexibility of the film. In addition, a panel observed the tendency
of the films to exhibit stickiness in the mouth and the tendency to
adhere to the roof of the user's mouth.
[0164] To test dissolution rate, an approximately 20 mm by 100 mm
piece of film, having a 2.85 g weight attached, was lowered into a
32.5.degree. C. water bath to a depth of about 50 mm. The time
required for the film to dissolve and separate into two pieces was
determined (in seconds).
[0165] The films also were subject to bend testing, i.e.,
180.degree. bend test. The dried films were placed in a moisture
analyzer (HR73 Moisture Analyzer from Mettler Toledo) to obtain
percent moisture and to remove any solvent (e.g. water) remaining
in the films after drying at 80.degree. C. in accordance with the
present invention. The films then were creased to about 180.degree.
and observed for break. Films that broke during creasing were
considered a failure. If the film did not break during creasing, a
200 g weight was dropped onto the creased film from a height of
about 8.5 mm. Films that broke were considered a failure, and those
that did not break were considered a pass. It should be noted,
however, that this flexibility test is an extreme test. Films that
failed this test are still considered operable within the scope of
the present invention. More specifically, there may be certain
applications that do not require such extreme flexibility
properties.
[0166] Both films of compositions 1 and 2 exhibited adequate
strength, good tear resistance, passed the 180.degree. bend test
both prior and subsequent to placement in the moisture analyzer and
dissolved on the tongue at a moderate to fast rate. Composition 1,
which contained Vitamin E, exhibited no stickiness in the mouth and
did not exhibit a tendency to adhere to the roof of the user's
mouth. Composition 2, in contrast, did not contain Vitamin E.
Composition 2 exhibited stickiness and tendency to adhere to the
roof of the mouth.
Examples 3-243
[0167] Water-soluble thin films were prepared incorporating silica
and magnesium stearate as anti-tacking agents in the amounts
described in Table 2. More specifically, various combinations of
silica and magnesium stearate were incorporated into a variety of
different film compositions as shown in the table below.
TABLE-US-00002 TABLE 2 Magnesium Silica.sup.1 stearate Example Film
description (weight %) (weight %) 3 SOURS 1.5 2.0 4 SOURS 1.5 2.0 5
SOURS 1.5 2.0 6 SOURS 1.5 2.0 7 SOURS 1.5 2.0 8 SOURS 1.5 2.0 9
SOURS 1.5 2.0 10 SOURS 1.5 2.0 11 SOURS 1.5 2.0 12 SOURS 1.5 2.0 13
SOURS 1.5 2.0 14 SOURS 1.5 2.0 15 BENZOCAINE/MENTHOL 1.5 1.5 16
BENZOCAINE/MENTHOL 1.5 1.5 17 BENZOCAINE/MENTHOL 1.5 1.5 18
BENZOCAINE/MENTHOL 1.5 1.5 19 BENZOCAINE/MENTHOL 1.5 1.5 20 SOURS 2
2.5 21 SOURS 1.5 2 22 SOURS 1.5 2 23 SOURS 1.5 2 24 SOURS 1.5 2 25
SOURS 1.5 2 26 SOURS 1.5 2 27 SOURS 1.5 2.5 28 SOURS 1.5 2.5 29
SOURS 1.5 2.5 30 SOURS 1.5 2.5 31 SOURS 1.5 2 32 SOURS 1.5 2 33
SOURS 1.5 2.5 34 SOURS 1.5 2.5 35 SOURS 1.5 2.5 36 SOURS 1.5 2.5 37
SOURS 1.5 2.5 38 SOURS 1.5 2.5 39 SOURS 1.5 2.5 40 SOURS 1.5 2.5 41
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 2 42 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 2 43 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.9 1 44
ENERGY/WELLNESS SUPPLEMENT.sup.2 1.15 1 45 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 46 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1 47
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5 48 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 49 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1 50
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 51 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 52 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 53
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 54 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 55 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 56
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 57 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 58 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 59
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 60 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 61 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5 62
ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 1.5 63 ORAL ANALGESIC 0.54 0.5
64 ORAL ANALGESIC 1.54 1 65 ORAL ANALGESIC 0.5 0.54 66 ORAL
ANALGESIC 1.54 1 67 ORAL ANALGESIC 1.04 1 68 ORAL ANALGESIC 1.24
1.5 69 ORAL ANALGESIC 1.24 1.5 70 ORAL ANALGESIC 1.24 1.5 71 ORAL
ANALGESIC 1.24 1.5 72 ORAL ANALGESIC 1.24 1.5 73 ORAL ANALGESIC
1.24 1.5 74 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 1.5 75 MELATONIN 1
2 76 MELATONIN 1 2 77 MELATONIN 1 2 78 MELATONIN 1 1.5 79 MELATONIN
1.1 1.3 80 MELATONIN 1.2 1.3 81 CHLORINE DIOXIDE 1.5 1.5 82
MULTIVITAMIN 1 1 83 MULTIVITAMIN 1 1 84 ZINC/ELDERBERRY 0.5 1 85
ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1 86 ENERGY/WELLNESS
SUPPLEMENT.sup.2 0.75 1 87 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1
88 MELATONIN 1.1 1.3 89 MULTIVITAMIN 1 1 90 B-COMPLEX VITAMIN 1 1
91 MULTIVITAMIN 1 1 92 B-COMPLEX VITAMIN 1 1 93 MULTIVITAMIN 1 1 94
MULTIVITAMIN 1 1 95 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1 96
MULTIVITAMIN 1 1 97 MELATONIN 1 1 98 ENERGY/WELLNESS
SUPPLEMENT.sup.2 0.75 1 99 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1
100 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.75 1 101 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1.5 102 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5
103 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 2 104 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1.5 1 105 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 2 106
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 2 107 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1.5 108 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 2 109
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5 110 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1.5 111 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5
112 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5 113 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1.5 114 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1.5
115 MULTIVITAMIN 1 1.5 116 MULTIVITAMIN 1 1.5 117 IMMUNE BOOSTER 1
1 118 MELATONIN 1.1 1.3 119 MELATONIN 1.1 1.3 120 MELATONIN 1.1 1.3
121 MELATONIN 1.1 1.3 122 MELATONIN 0.5 0.75 123 COLD & COUGH 1
1 124 COLD & COUGH 1 1 125 MULTIVITAMIN 1 1 126 MULTIVITAMIN 1
1 127 MULTIVITAMIN 1 1.5 128 MULTIVITAMIN 1 1 129 MULTIVITAMIN 1 1
130 MULTIVITAMIN 1 1.5 131 MULTIVITAMIN 1 1 132 MULTIVITAMIN 1 1
133 B-COMPLEX VITAMIN 1 1 134 B-COMPLEX VITAMIN 1 1 135 B-COMPLEX
VITAMIN 1 1 136 B-COMPLEX VITAMIN 1 1 137 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1.5 1.5 138 ENERGY/WELLNESS SUPPLEMENT.sup.2 1.5
1.5 139 ENERGY/WELLNESS SUPPLEMENT.sup.2 1.5 1.5 140 MULTIVITAMIN 1
1 141 B-COMPLEX VITAMIN 1 1 142 B-COMPLEX VITAMIN 1 1 143
MULTIVITAMIN 1 1 144 B-COMPLEX VITAMIN 1 1 145 MULTIVITAMIN 1 1 146
MULTIVITAMIN 1 1 147 MULTIVITAMIN 1 1 148 MULTIVITAMIN 1 1 149
B-COMPLEX VITAMIN 1 1 150 B-COMPLEX VITAMIN 1 1 151 MULTIVITAMIN 1
1 152 MULTIVITAMIN 1 1 153 MULTIVITAMIN 1 1 154 MULTIVITAMIN 1.5
0.3 155 ENERGY/WELLNESS SUPPLEMENT.sup.2 1.5 1 156 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 1 157 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 1 158
MULTIVITAMIN 1 1 159 MULTIVITAMIN 1 1 160 MULTIVITAMIN 1.5 0.3 161
MULTIVITAMIN 1 1 162 B-COMPLEX VITAMIN 1 1 163 B-COMPLEX VITAMIN 1
1 164 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 0.5 165 ENERGY/WELLNESS
SUPPLEMENT.sup.2 0.5 0.5 166 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5
0.5 167 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 0.5 168
ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 0.5 169 ENERGY/WELLNESS
SUPPLEMENT.sup.2 0.5 0.5 170 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5
0.5 171 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 172 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 0.5 173 MULTIVITAMIN 1 1 174 MULTIVITAMIN 1 1
175 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 0.5 176 MULTIVITAMIN 1 1
177 ENERGY/WELLNESS SUPPLEMENT.sup.2 0.5 0.5 178 ENERGY/WELLNESS
SUPPLEMENT.sup.2 0.5 0.5 179 MULTIVITAMIN 1 1 180 MULTIVITAMIN 1 1
181 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 182 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 0.5 183 MULTIVITAMIN 1 1 184 MULTIVITAMIN 1 1
185 MULTIVITAMIN 1 1 186 MULTIVITAMIN 1 1 187 MULTIVITAMIN 1 1 188
ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 189 MULTIVITAMIN 1 1 190
MULTIVITAMIN 1 1 191 MULTIVITAMIN 1 1 192 MULTIVITAMIN 1 1 193
MULTIVITAMIN 1.37 2.05 194 MULTIVITAMIN 1 1 195 MULTIVITAMIN 1 1
196 MULTIVITAMIN 1 1 197 B-COMPLEX VITAMIN 1 1 198 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 0.5 199 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5
200 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 201 B-COMPLEX VITAMIN 1
1 202 MULTIVITAMIN 1 1 203 MULTIVITAMIN 1 1 204 MELATONIN 1.1 1.3
205 MULTIVITAMIN 1.5 0.3 206 MULTIVITAMIN 1 1 207 STRESS RELIEF 1
0.3 208 MULTIVITAMIN 1 1 209 MULTIVITAMIN 1 1 210 MULTIVITAMIN 1 1
211 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 212 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 0.5 213 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5
214 ENERGY/WELLNESS SUPPLEMENT.sup.2 1 0.5 215 ENERGY/WELLNESS
SUPPLEMENT.sup.2 1 0.5 216 MULTIVITAMIN 1.5 0.3 217 MELATONIN 1 0.5
218 MELATONIN 1 0.5 219 STRESS RELIEF 1 0.3 220 MULTIVITAMIN 1 1
221 MELATONIN 1 0.5 222 MULTIVITAMIN 1.5 0.3 223 MULTIVITAMIN 1 1
224 MULTIVITAMIN 1 1 225 CINNAMINT 1 1 226 MELATONIN 1 0.5 227
MELATONIN 1 0.5 228 B-COMPLEX VITAMIN 1 1 229 MULTIVITAMIN 1 1 230
MULTIVITAMIN 1 1 231 MULTIVITAMIN 1 1 232 MULTIVITAMIN 1 1 233
MULTIVITAMIN 1 1 234 MULTIVITAMIN 1 1 235 MULTIVITAMIN 1 1 236
MULTIVITAMIN 1 1 237 MULTIVITAMIN 1 1 238 MULTIVITAMIN 1 1 239
MULTIVITAMIN 1 1 240 MULTIVITAMIN 1 1 241 BENZOCAINE/MENTHOL 1.5
1.5 242 MULTIVITAMIN 1 1 243 DEXTROMETHORPHAN HYDROBROMIDE 0.5 1.82
.sup.1Sipernat 500LS, available from Degussa
.sup.2Energy/Wellness Supplement may contain any/all of the
following actives or combinations thereof: Green Tea, Guarana,
Chromium Picolinate, Caffeine, Yohimbie HCl, Taurine, Vitamin B3,
Vitamin B6, Vitamin B12
[0168] In addition to silica and magnesium stearate, each of the
films listed above contains a variety of components, such as
polymers and flavors, among others. The remainder of the components
are provided below for each film description used in Table 2.
[0169] Films identified in Table 2 above as "SOURS" contain the
following components listed in Table 3:
TABLE-US-00003 TABLE 3 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-60% CITRIC ACID 0.01%-40% NATURAL
&ARTIFICIAL FLAVORS 0.01%-25% GUM ARABIC 0.01%-10% MAGNESIUM
STEARATE 0.01%-10% SODIUM HEXAMETAPHOSPHATE 0.01%-5% SILICA
0.01%-2% POLYSORBATE 80 0%-5% MALIC ACID 0.01%-10% ASPARTAME
0.01%-3.5% POTASSIUM ACESULFAME 0.01%-0.5% DYE 0.01%-1% POTASSIUM
SORBATE 0.01%-0.1% SODIUM BENZOATE 0.01%-0.1%
[0170] Films identified in Table 2 above as "Benzocaine/Menthol"
contain the following components listed in Table 4:
TABLE-US-00004 TABLE 4 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% NATURAL &ARTIFICIAL FLAVORS 0.01%-25%
POLYETHYLENE OXIDE 0.01%-50% MENTHOL CRYSTALS 0.01%-30% CORN STARCH
0.01%-30% BENZOCAINE 0.01%-10% SUCRALOSE 0.01%-5% MALIC ACID
0.01%-5% MAGNESIUM STEARATE 0.01%-10% SILICA 0.01%-2% TITANIUM
DIOXIDE 0.01%-5% BUTYLATED HYDROXYTOLUENE 0.01%-1% DYE 0.01%-1%
[0171] Films identified in Table 2 above as "Energy/Wellness
Supplement" contain the following components listed in Table 5:
TABLE-US-00005 TABLE 5 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0%-70%% HYDROXYPROPYL CELLULOSE 0%-40% PECTIN
0%-40% NATURAL &ARTIFICIAL FLAVORS/FLAVOR 0%-30% ADJUVANTS
POLYDEXTROSE 0.01%-30% SODIUM CARBOXYMETHYLCELLULOSE 0%-10%
ENERGY/WELLNESS ACTIVES.sup.2 0.01%-50% ERYTHRITOL 0%-20% SUCRALOSE
0.01%-5% CITRIC ACID 0%-10% MAGNESIUM STEARATE 0.01%-10% GLYCERYL
MONOOLEATE 0%-1% SILICA 0.01%-2% POLYSORBATE 80 0%-1% SORBITAN
MONOOLEATE 0%-1% POTASSIUM SORBATE 0%-0.1% SODIUM BENZOATE 0%-0.1%
SODIUM HEXAMETAPHOSPHATE 0%-10% PROPYLENE GLYCOL 0%-25% GUM ARABIC
0%-10% DYE 0.01%-1%
[0172] Films identified in Table 2 above as "ORAL ANALGESIC"
contain the following components listed in Table 6:
TABLE-US-00006 TABLE 6 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% CHOLINE SALICYLATE 0.01%-60% NATURAL
&ARTIFICIAL FLAVORS 0.01%-10% MAGNESIUM STEARATE 0.01-5% SILICA
0.01-2% CETALKONIUM CHLORIDE 0.01%-5% METHYL PARABEN 0.01%-0.1%
DIMETHYLPOLYSILOXANE 0.01%-0.05%
[0173] Films identified in Table 2 above as "Melatonin" contain the
following components listed in Table 7:
TABLE-US-00007 TABLE 7 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% NATURAL &ARTIFICIAL FLAVORS/FLAVOR
0.01%-20% ADJUVANTS POLYETHYLENE OXIDE 0.01%-30% MELATONIN
0.01%-20% PECTIN 0.01%-10% POLYDEXTROSE 0.01%-20% SUCRALOSE
0.01%-5% MAGNESIUM STEARATE 0.01%-10% SILICA 0.01%-2% GLYCERYL
MONOOLEATE 0.01%-1% TITANIUM DIOXIDE 0.01%-5% MONOAMMONIUM
GLYCYRRHIZINATE 0.01%-2% BUTYLATED HYDROXYTOLUENE 0.01%-1% DYE
0.01%-1%
[0174] Films identified in Table 2 above as "Chlorine Dioxide"
contain the following components listed in Table 8:
TABLE-US-00008 TABLE 8 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% POLYETHYLENE OXIDE 0.01%-50% POLYDEXTROSE
0.01%-20% NATURAL &ARTIFICIAL FLAVORS/FLAVOR 0.01%-30%
ADJUVANTS MAGNESIUM STEARATE 0.01%-5% SILICA 0.01%-2% SUCRALOSE
0.01%-5% ZINC GLUCONATE DIHYDRATE 0.01%-5% CITRIC ACID 0.01%-2%
GLYCERYL MONOOLEATE 0.01%-1% SODIUM HYDROXIDE 0.01%-5% SODIUM
BICARBONATE 0.01%-5% CHLORINE DIOXIDE 2% SOLUTION 0.01%-10%
BUTYLATED HYDROXYTOLUENE 0.01%-1% DYE 0.01%-1% SODIUM BENZOATE
0.01%-0.1%
[0175] Films identified in Table 2 above as "Multivitamin" contain
the following components listed in Table 9:
TABLE-US-00009 TABLE 9 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-50% NATURAL &ARTIFICIAL FLAVORS 0.01%-20%
NIACINAMIDE -100% (Vitamin B3) 0.01%-30% POLYETHYLENE OXIDE
0.01%-30% POLYDEXTROSE 0.01%-20% ASCORBIC ACID -100% (Vitamin C)
0.01%-20% 50% VITAMIN E ACETATE -91.2% 0.01%-10% CALCIUM
d-PANTOTHENATE -92% (Vitamin 0.01%-10% B5) SUCRALOSE 0.01%-5%
VITAMIN A PALMITATE -15% 0.01%-10% PYRIDOXINE HYDROCHLORIDE -82.3%
0.01%-10% (VITAMIN B6) RIBOFLAVIN -100% (Vitamin B2) 0.01%-10%
THIAMINE HYDROCHLORIDE -89.2% 0.01%-10% (Vitamin B1) MAGNESIUM
STEARATE 0.01%-2% SILICA 0.01%-2% GLYCERYL MONOOLEATE 0.01%-1% 5%
VITAMIN K -100% 0.01%-5% 2.5% VITAMIN D3 LIQUID -100% 0.01%-5%
BUTYLATED HYDROXYTOLUENE 0.01%-1% CYANOCOBALAMIN -100% (Vitamin
B12) 0.001%-1%
[0176] Films identified in Table 2 above as "Zinc/Elderberry"
contain the following components listed in Table 10:
TABLE-US-00010 TABLE 10 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-60% ZINC GLUCONATE 0.01%-20% ELDERBERRY
EXTRACT 0.01%-20% FRUCTOSE 0.01%-20% NATURAL &ARTIFICIAL
FLAVORS 0.01%-30% POLYETHYLENE OXIDE 0.01%-20% POLYDEXTROSE
0.01%-20% ASCORBIC ACID -100% (Vitamin C) 0.01%-20% SUCRALOSE
0.01%-5% GLYCERYL MONOOLEATE 0.01%-1% MAGNESIUM STEARATE 0.01%-5%
TITANIUM DIOXIDE 0.01%-2% SILICA 0.01%-2% BUTYLATED HYDROXYTOLUENE
0.01%-1%
[0177] Films identified in Table 2 above as "B-Complex Vitamin"
contain the following component listed in Table 11:
TABLE-US-00011 TABLE 11 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-60% POLYETHYLENE OXIDE 0.01%-50% CALCIUM
d-PANTOTHENATE - 92% (Vitamin B5) 0.01%-20% POLYDEXTROSE 0.01%-30%
NATURAL &ARTIFICIAL FLAVORS/FLAVOR 0.01%-25% ADJUVANTS
PYRIDOXINE HYDROCHLORIDE - 82.3% 0.01%-20% (VITAMIN B6) RIBOFLAVIN
-100% (Vitamin B2) 0.01%-20% THIAMINE HYDROCHLORIDE -89.2%
0.01%-20% (Vitamin B1) SUCRALOSE 0.01%-5% PROPYLENE GLYCOL 0.01%-5%
MAGNESIUM STEARATE 0.01%-10% SILICA 0.01%-2% GLYCERYL MONOOLEATE
0.01%-1% BUTYLATED HYDROXYTOLUENE 0.01%-1% DYE 0.01%-1%
CYANOCOBALAMIN -100% (Vitamin B12) 0.001%-1%
[0178] Films identified in Table 2 above as "Immune Booster"
contain the following components listed in Table 12:
TABLE-US-00012 TABLE 12 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% POLYDEXTROSE 0.01%-50% POLYETHYLENE OXIDE
0.01%-50% ZINC CITRATE TRIHYDRATE 0.01%-40% SUCRALOSE 0.01%-5%
NATURAL FLAVORS 0.01%-20% CITRIC ACID 0.01%-20% MAGNESIUM STEARATE
0.01%-10% SILICA 0.01%-2% SODIUM CITRATE 0.01%-5% GLYCERYL
MONOOLEATE 0.01%-1% BUTYLATED HYDROXYTOLUENE 0.01%-2% MONOAMMONIUM
GLYCYRRHIZINATE 0.01%-1% DYE 0.01%-1%
[0179] Films identified in Table 2 above as "Cold & Cough"
contain the following components listed in Table 13:
TABLE-US-00013 TABLE 13 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-60% POLYDEXTROSE 0.01%-30% NATURAL
&ARTIFICIAL FLAVORS 0.01%-25% POLYETHYLENE OXIDE 0.01%-50%
ASCORBIC ACID -100% (Vitamin C) 0.01%-30% ZINC CITRATE DIHYDRATE
0.01%-20% ECHINACEA PURPUREA 0.01%-20% SUCRALOSE 0.01%-10% PECTIN
0.01%-20% CITRIC ACID 0.01%-10% SODIUM CITRATE 0.01%-5% MAGNESIUM
STEARATE 0.01%-10% SILICA 0.01%-2% GLYCERYL MONOOLEATE 0.01%-1% DYE
0.01%-1% BUTYLATED HYDROXYTOLUENE 0.01%-1% MONOAMMONIUM
GLYCYRRHIZINATE 0.01%-1%
[0180] Films identified in Table 2 above as "Stress Relief" contain
the following components listed in Table 14:
TABLE-US-00014 TABLE 14 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-60% CHAMOMILE 0.01%-40% PASSION FLOWER
0.01%-40% PECTIN 0.01%-20% NATURAL &ARTIFICIAL FLAVORS
0.01%-25% GLYCERIN 0.01%-10% POLYSORBATE 80 0%-2% SUCRALOSE
0.01%-5% POLYDIMETHYLSILOXANE EMULSION 0.01%-2% ASPARTAME 0.01%-5%
POTASIUM ACESULFAME 0.01%-3% POTASSIUM SORBATE 0.01%-1%
[0181] Films identified in Table 2 above as "Cinnamint" contain the
following components listed in Table 15:
TABLE-US-00015 TABLE 15 Component Weight % HYDROXYPROPYL
METHYLCELLULOSE 0.01%-70% POLYETHYLENE OXIDE 0.01%-50% POLYDEXTROSE
0.01%-30% BUTYLATED HYDROXYTOLUENE 0.01%-1% GLYCERYL MONOOLEATE
0.01%-1% MAGNESIUM STEARATE 0.01%-10% SILICA 0.01%-2% POTASSIUM
SORBATE 0.01%-0.1% SODIUM BENZOATE 0.01%-0.1% NATURAL
&ARTIFICIAL FLAVORS 0.01%-30% SUCRALOSE 0.01%-5% XYLITOL
0.01%-10% DYE 0.01%-1%
[0182] Films identified in Table 2 above as "Dextromethorphan
Hydrobromide" contain the following components listed in Table
16:
TABLE-US-00016 TABLE 16 Component Weight % Dextromethorphan
Hydrobromide 60% 0.01%-60% POLYETHYLENE OXIDE 0.01%-70%
POLYDEXTROSE 0.01%-30% HYDROXYPROPYL METHYLCELLULOSE 0.01%-70%
NATURAL &ARTIFICIAL FLAVORS 0.01%-30% SUCRALOSE 0.01%-5%
MAGNESIUM STEARATE 0.01%-10% SILICA 0%-2% SODIUM BICARBONATE
0.01%-5% XANTHAN GUM 0.01%-10% TITANIUM DIOXIDE 0.01%-5% BUTYLATED
HYDROXYTOLUENE 0.01%-1% DYE 0.01%-1%
[0183] The films prepared in these Examples exhibited improved
glidant properties, particularly the ability to slide against one
another without sticking together.
Examples 244-300
[0184] Water-soluble thin films were prepared incorporating silica
and magnesium stearate as anti-tacking agents in the amounts
described in Table 17. More specifically, various combinations of
silica and magnesium stearate were incorporated into a variety of
different film compositions as shown in the table below.
TABLE-US-00017 TABLE 17 Magnesium Silica.sup.1 stearate (weight
Example Film description (weight %) %) 244 SOURS 1.5 2.5 245
ENERGY/WELLNESS 0.75 1 SUPPLEMENT.sup.2 246 ENERGY/WELLNESS 0.75 1
SUPPLEMENT.sup.2 247 MELATONIN 1 2 248 MELATONIN 1.5 1.5 249
CHLORINE DIOXIDE 1.5 1.5 250 MELATONIN 1.5 1.5 251 MELATONIN 1.5
1.5 252 MELATONIN 1.5 1.5 253 MELATONIN 1.5 1.5 254 CHLORINE
DIOXIDE 1.5 1.5 255 MELATONIN 1.1 1.3 256 MULTIVITAMIN 1 1 257
MULTIVITAMIN 1 1 258 B COMPLEX VITAMIN 1 1 259 MULTIVITAMIN 1 1 260
B COMPLEX VITAMIN 1 1 261 COLD & COUGH 1 1 262 MULTIVITAMIN 1 1
263 MULTIVITAMIN 1 1 264 MULTIVITAMIN 1 1 265 MULTIVITAMIN 266
MULTIVITAMIN 267 MULTIVITAMIN 268 MULTIVITAMIN 1 1.5 269 IMMUNE
BOOSTER 1.16 1.16 270 MULTIVITAMIN 1 1 271 ENERGY/WELLNESS 1 1.5
SUPPLEMENT.sup.2 272 MULTIVITAMIN 1 1.5 273 MULTIVITAMIN 1 1.5 274
MELATONIN 1.1 1.3 275 MULTIVITAMIN 1 1 276 MULTIVITAMIN 1 1 277
MULTIVITAMIN 1 1 278 MULTIVITAMIN 1 1 279 MULTIVITAMIN 1 1 280
ENERGY/WELLNESS 1.5 1.5 SUPPLEMENT.sup.2 281 MULTIVITAMIN 1 1.5 282
MULTIVITAMIN 1 1.5 283 MULTIVITAMIN 1.5 0.3 284 MULTIVITAMIN 1 1
285 B-COMPLEX VITAMIN 1 1 286 ENERGY/WELLNESS 1 0.5
SUPPLEMENT.sup.2 287 MULTIVITAMIN 1 1 288 MELATONIN 1.1 1.3 289
B-COMPLEX VITAMIN 1 1 290 B-COMPLEX VITAMIN 1 1 291 ENERGY/WELLNESS
1 0.5 SUPPLEMENT.sup.2 292 ENERGY/WELLNESS 1 0.5 SUPPLEMENT.sup.2
293 B-COMPLEX VITAMIN 1 1 294 MULTIVITAMIN 1 1 295 CHLORINE DIOXIDE
1.5 1.5 296 MULTIVITAMIN 1 1.5 297 MULTIVITAMIN 1 1 298
MULTIVITAMIN 1 1 299 MULTIVITAMIN 1 1 300 BENZOCAINE/MENTHOL 1.5
1.5 .sup.1Sipernat 500LS, available from Degussa
.sup.2Energy/Wellness Supplement may contain any/all of the
following actives or combinations thereof: Green Tea, Guarana,
Chromium Picolinate, Caffeine, Yohimbie HCl, Taurine, Vitamin B3,
Vitamin B6, Vitamin B12
[0185] Besides silica and magnesium stearate, the remainder of the
components contained in the films listed in Table 17 are provided
in connection with Table 2 above. The film descriptions used in
Tables 2 and 17 are the same.
[0186] The films prepared in these Examples exhibited improved
glidant properties, particularly the ability to slide against one
another without sticking together.
[0187] While there have been described what are presently believed
to be the preferred embodiments of the invention, those skilled in
the art will realize that changes and modifications may be made
thereto without departing from the spirit of the invention, and it
is intended to include all such changes and modifications as fall
within the true scope of the invention.
* * * * *