U.S. patent application number 14/195362 was filed with the patent office on 2014-09-04 for film compositions for delivery of actives.
This patent application is currently assigned to MONOSOL RX, LLC. The applicant listed for this patent is MONOSOL RX, LLC. Invention is credited to Richard C. Fuisz, Garry L. Myers.
Application Number | 20140248223 14/195362 |
Document ID | / |
Family ID | 44914708 |
Filed Date | 2014-09-04 |
United States Patent
Application |
20140248223 |
Kind Code |
A1 |
Myers; Garry L. ; et
al. |
September 4, 2014 |
FILM COMPOSITIONS FOR DELIVERY OF ACTIVES
Abstract
The invention relates to the film products and methods of their
preparation that demonstrate a non-self-aggregating uniform
heterogeneity. Desirably, the films disintegrate in water and may
be formed by a controlled drying process, or other process that
maintains the required uniformity of the film. Desirably, the films
contain at least one active agent, which may be administered to a
user topically, transmucosally, vaginally, ocularly, aurally,
nasally, transdermally or orally.
Inventors: |
Myers; Garry L.; (Kingsport,
TN) ; Fuisz; Richard C.; (Beverly Hills, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MONOSOL RX, LLC |
Warren |
NJ |
US |
|
|
Assignee: |
MONOSOL RX, LLC
Warren
NJ
|
Family ID: |
44914708 |
Appl. No.: |
14/195362 |
Filed: |
March 3, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12779316 |
May 13, 2010 |
8663687 |
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14195362 |
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11634280 |
Dec 5, 2006 |
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12779316 |
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10074272 |
Feb 14, 2002 |
7425292 |
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11634280 |
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60742776 |
Dec 6, 2005 |
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60328868 |
Oct 12, 2001 |
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Current U.S.
Class: |
424/59 ;
424/94.1; 514/20.5; 514/460; 514/626; 514/781 |
Current CPC
Class: |
A61Q 15/00 20130101;
A61K 8/0295 20130101; A61K 47/38 20130101; B82Y 5/00 20130101; A61Q
19/00 20130101; A61K 8/0204 20130101; A61K 2800/413 20130101; A61Q
9/02 20130101; A61K 8/0291 20130101; A61Q 19/10 20130101; B29K
2003/00 20130101; A61Q 17/04 20130101; A61K 31/74 20130101; A61K
8/0216 20130101; A61K 8/355 20130101; A61Q 5/12 20130101; B29K
2001/00 20130101; B29C 41/28 20130101; A61K 8/731 20130101; B29K
2005/00 20130101; A61K 47/10 20130101; A61Q 5/06 20130101; A61Q
17/005 20130101; A61K 8/86 20130101; A61K 8/0208 20130101; A61K
9/7007 20130101; A61Q 17/02 20130101; B29K 2001/12 20130101; A61Q
5/02 20130101 |
Class at
Publication: |
424/59 ; 514/781;
514/626; 514/460; 424/94.1; 514/20.5 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 8/73 20060101 A61K008/73; A61K 47/10 20060101
A61K047/10; A61K 8/86 20060101 A61K008/86; A61K 8/02 20060101
A61K008/02; A61K 47/38 20060101 A61K047/38 |
Claims
1. A self-supporting film composition comprising: (i) a water
soluble polymer composition comprising polyethylene oxide and a
saccharide-based polymer; and (ii) a topical agent; wherein said
topical agent is in the form of a small-scale particle selected
from the group consisting of at least one type of nanoparticle, at
least one type of microparticle, and combinations thereof.
2. The composition of claim 1, wherein said topical agent is in the
form of at least one type of liquid crystal.
3. The composition of claim 1, wherein said topical agent is in the
form of at least one type of micelle.
4. The composition of claim 1, wherein said topical agent is bound
to at least one ligand.
5. The composition of claim 1, wherein said film dosage composition
has a substantially uniform distribution of said topical agent.
6. A dosage composition comprising: a. A self-supporting film
comprising: i. At least one polymer; and ii. At least one agent;
wherein said at least one agent is in the form of a small-scale
particle selected from the group consisting of at least one type of
nanoparticle, at least one type of microparticle, and combinations
thereof.
7. The composition of claim 6, wherein said agent is in the form of
at least one type of liquid crystal.
8. The composition of claim 6, wherein said agent is in the form of
at least one type of micelle.
9. The composition of claim 6, wherein said agent is bound to at
least one ligand.
10. The composition of claim 6, wherein said film dosage
composition has a substantially uniform distribution of said at
least one agent.
11. A method of forming a self-supporting film dosage composition,
comprising the steps of: a. Providing a polymeric matrix; b.
Forming a small-scale form of at least one agent; c. Dispersing
said small-scale form of at least one agent throughout said
polymeric matrix; d. Drying said polymeric matrix so as to form a
self-supporting film dosage composition comprising said small-scale
form of at least one agent; wherein said small-scale form of at
least one agent is selected from the group consisting of at least
one type of nanoparticle, at least one type of microparticle, and
combinations thereof.
12. The method of claim 11, wherein said agent is in the form of at
least one type of microdroplet.
13. The method of claim 11, wherein said agent is in the form of at
least one type of micelle.
14. The method of claim 11, wherein said film dosage composition
has a substantially uniform distribution of said at least one
agent.
15. The method of claim 11, wherein said small-scale form of at
least one agent is formed through emulsion processing.
16. The method of claim 11, wherein said small-scale form of at
least one agent is formed through milling.
17. The method of claim 11, wherein said small-scale form of at
least one agent is formed through processing via a microfluidics
pumping apparatus.
18. The method of claim 11, wherein said small-scale form of at
least one agent is bound to at least one ligand.
19. The method of claim 11, wherein said step of drying said
polymeric matrix comprises heating said polymeric matrix so as to
rapidly form a visco-elastic mass to maintain a uniform
distribution of said agent by locking-in or substantially
preventing migration of said agent within said visco-elastic
mass.
20. The method of claim 19, wherein said polymeric matrix
containing said agent varies no more than 10% by weight of said
agent throughout said polymeric matrix.
21. The method of claim 19, wherein said step of drying said
polymeric matrix further comprises further drying said
visco-elastic mass so as to provide a self-supporting film dosage
composition having a solvent content of 10% or less.
22. The method of claim 19, wherein said step of forming a
visco-elastic mass occurs within the first 0.5 to about 10 minutes
of heating to maintain a uniform distribution of said agent by
locking-in or substantially preventing migration of said agent
within said visco-elastic mass.
23. The method of claim 22, wherein said polymeric matrix
containing said agent varies no more than 10% by weight of said
agent throughout said polymeric matrix.
24. The method of claim 22, wherein said step of drying said
polymeric matrix further comprises further drying said
visco-elastic mass so as to provide a self-supporting film dosage
composition having a solvent content of 10% or less.
25. The method of claim 11, wherein said small-scale form of at
least one agent is formed through processing via a high shear
apparatus.
26. The method of claim 11, wherein said small-scale form of said
agent is in the form of at least one liquid crystal.
27. A method of forming a self-supporting film dosage composition,
comprising the steps of: a. Providing a polymeric matrix; b.
Forming a small-scale form of at least one agent; c. Applying said
small-scale form of at least one agent to said polymeric matrix via
deposition; and d. Drying said polymeric matrix so as to form a
self-supporting film dosage composition comprising said small-scale
form of at least one agent.
28. The method of claim 27, wherein said agent is in the form of at
least one type of microdroplet.
29. The method of claim 27, wherein said agent is in the form of at
least one type of micelle.
30. The method of claim 27, wherein said small-scale form of at
least one agent is formed through emulsion processing.
31. The method of claim 27, wherein said small-scale form of at
least one agent is formed through milling.
32. The method of claim 27, wherein said small-scale form of at
least one agent is formed through processing via a microfluidics
pumping apparatus.
33. The method of claim 27, wherein said small-scale form of at
least one agent is bound to at least one ligand.
34. The method of claim 27, wherein said small-scale form of at
least one agent is formed through processing via a high shear
apparatus.
35. The method of claim 27, wherein said small-scale form of said
agent is in the form of at least one liquid crystal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 11/634,280, filed Dec. 5, 2006, which claims
priority to U.S. Provisional Application No. 60/742,776, filed Dec.
6, 2005, which is a continuation-in-part of U.S. application Ser.
No. 10/074,272, filed Feb. 14, 2002, which issued on Sep. 16, 2008
as U.S. Pat. No. 7,425,292, which claims priority to U.S.
Provisional Application No. 60/328,868, filed Oct. 12, 2001.
FIELD OF THE INVENTION
[0002] The invention relates to rapidly dissolving, self-supporting
films and methods of their preparation. The films contain one or
more active agents that are uniformly and evenly distributed
throughout the film such that the final film has uniformity of
content of the active agent(s).
BACKGROUND OF THE RELATED TECHNOLOGY
[0003] Films may be used as a delivery system 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.
[0004] 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 external 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.
[0005] 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 and interparticulate attractive
forces causing crystal growth as the solution gets more saturated
during drying as well as exogenous macro phenomena such as
convection forces, air flow and the like to form such
agglomeration.
[0006] 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 uniformity of active in dosage forms. Currently, as
generally required by various world regulatory authorities, dosage
forms may not vary more than 10-15% in the amount of active
present. When applied to dosage units based on films, this
virtually mandates that uniformity in the film be present.
[0007] 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.
[0008] 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 promotes the aggregation of the active
and other components, notwithstanding the use of viscosity
modifiers. Such processes also run the risk of exposing the active,
i.e., a drug, or vitamin, or other components to prolonged exposure
to moisture and elevated temperatures, which may render it
ineffective or even harmful.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] It is especially useful to incorporate active agents in a
small-scale form into the film. Such small-scale form may include
particles of active agents, in such forms as nanoparticles,
microparticles, micelles, molecular complexes or other minute
forms. As used herein, the term "microparticle" refers to a
composite of nanoparticles, which are joined together to form a
microparticle-sized mass. A small-scale form of the active agent
has a high surface area, allowing the active agent to be more
readily absorbed into the body of the user. However, such
small-scale forms of the active agent may have the tendency to
undesirably agglomerate into larger masses, thereby resulting in
difficulty in achieving a uniform distribution of the active agent
throughout the film.
[0013] Therefore, there is a need for methods and compositions for
film products, which use a minimal number of materials or
components, and which provide a substantially non-self-aggregating
uniform heterogeneity throughout the area of the films. Preferably,
such film products would be suitable for delivery of agents through
a variety of administration routes, including orally,
transmucosally, topically, and other routes of administration,
thereby providing convenience of use to the consumer during
travel.
[0014] Desirably, such films are produced through a selection of a
polymer or combination of polymers that will provide a desired
viscosity. Also, desirably the films are made through a
film-forming process, such as reverse roll coating, or casting and
a controlled, and a desirably rapid, drying process which serves to
maintain the uniform distribution of non-self-aggregated
components. Desirably, the production occurs without the necessary
addition of gel formers or polyhydric alcohols and the like which
appear to be required in the products and for the processes of
prior patents, such as the aforementioned Horstmann and Zerbe
patents. Desirably, the films will also incorporate compositions
and methods of manufacture that substantially reduce or eliminate
air in the film, thereby promoting uniformity in the final film
product. Most desirably, the films incorporate small-scale forms of
an active agent, including nanoparticles or microparticles of the
active agent, while avoiding problems associated with agglomeration
of such small-scale active forms.
SUMMARY OF THE INVENTION
[0015] The present invention provides a film and a method of
forming same. The film can be divided into equally sized units
having substantially equal amounts of each compositional component
present. This advantage is particularly useful because it permits
large area films to be initially formed, and subsequently cut into
individual units without concern for whether each unit is
compositionally equal. For example, the films of the present
invention have particular applicability as delivery systems for
topical active agents because each film unit will contain the
proper amount of the topical active agent. The films of the present
invention also have particular applicability as ingestible films,
which are dissolved in the mouth of the user, either rapidly or
over a controlled period of time. They may also be used for
systemic administration of drugs by applying the films to oral or
vaginal mucosal surfaces.
[0016] In one aspect of the invention, there is provided a
self-supporting film dosage composition including at least one
polymer, at least one active agent, where the active agent is in
the form of a small-scale particle. The small-scale particle may
be, for example, a microparticle or a nanoparticle.
[0017] In another aspect of the present invention, there may be
provided a method of forming a self-supporting film dosage
composition, including the steps of providing a polymeric matrix,
forming a small-scale form of at least one active agent, dispersing
the small-scale form of the active agent throughout the polymeric
matrix, and drying the polymeric matrix so as to form a
self-supporting film dosage composition including the small-scale
form of the active agent. The small-scale form of the active agent
may be in the form of a microparticle or a nanoparticle. The
small-scale form of the active agent may be formed through emulsion
processing, through milling, and/or through a microfluidics pumping
apparatus. In some embodiments, the small-scale form of the active
may be formed via a high shear apparatus. The small-scale form of
the active may be formed in situ, or may be added as a preformed
small-scale form. In cases where the small-scale form of the active
is formed in situ, the process of forming the film may be used to
stabilize the small-scale form of the active and thus prevent
agglomeration. The small-scale form of the active agent may be
bonded to one or more ligands.
[0018] In one aspect of the present invention, there is provided a
self-supporting film. The film includes a water soluble polymer
composition including polyethylene oxide and a saccharide-based
polymer. The film may also include a small scale form of the active
agent. In some aspects, the film may be designed for oral
administration. In other aspects, the film may be designed for
topical administration. As will be described in further detail
below, the film is desirably substantially dissolvable when exposed
to a wetting agent, such as water, alcohol or aqueous mixture of
alcohols. Particularly with a topical film, contacting the film
with the wetting agent permits the agent to be dissolved or
dispersed out of the film. The agent may then be applied to a
particular surface area, such as an area of the skin.
[0019] The present invention also provides a substantially
dissolvable, self-supporting film that includes (i) a water soluble
polymer composition including at least one saccharide-based
polymer; and (ii) one of a hair shampoo, a hair conditioner, a
sunscreen, a hand soap, an insect repellant, a moisturizing cream,
a shaving cream or gel, an antibiotic, and a dish detergent.
[0020] Each of the films of the present invention may be divided
into smaller individual film units which may be sized and packaged
to provide dosage units for consumption.
[0021] In another aspect of the invention, there is a provided a
method of making a self-supporting film unit. The process includes
the steps of combining a polar solvent, an active agent, desirably
in a small-scale form, and a water soluble polymer composition
comprising polyethylene oxide and at least one saccharide-based
polymer to form a material with a uniform distribution of these
components. This material is then formed into a film and fed onto
the top side of a substrate surface having top and bottom sides.
Heat is applied to the bottom side of the substrate surface in
order to dry the film. The dried film is then divided into
individual film units.
[0022] Also, either alternatively, or in addition to the particular
method used to dry the film, the polymer may be selected in order
to provide a viscosity that maintains the non-self-aggregating
uniform heterogeneity. Techniques may also be used to form the
film, including reverse roll coating, deposition, and other
techniques.
[0023] A dispenser is also provided that includes individual film
units of the present invention. The film units may be optionally
stacked in a dispenser or in a roll.
[0024] A further aspect of the present invention provided is a
method of delivering an active agent. This method includes
providing a dry film, which at least partially solubilizes when
wetted, the film comprising (i) a water soluble polymer
composition; and (ii) an active agent. The method may also include
contacting the film with a wetting agent that dissolves out the
active agent; and administering the dissolved agent to the user. In
some embodiments, the water soluble polymer composition may include
polyethylene oxide and a saccharide-based polymer.
[0025] The present invention also provides a system for applying a
topical agent. The system includes a topical agent contained in a
water soluble polymeric film comprising polyethylene oxide and a
saccharide-based polymer. The system also includes a solvent for
dissolving the film. The solvent is provided for direct contact
with the film to cause the topical agent to be dissolved or
dispersed out of the film, whereby the topical agent can be applied
to a surface area in need thereof. Optionally, the system may
further include an applicator for applying the topical agent to the
surface area in need thereof.
[0026] Other aspects of the present invention relate to films for
delivery of emulsion compositions. For example, the present
invention provides a composition including a solid water soluble
polymeric matrix; and a plurality of lipophilic droplets dispersed
within the matrix, the composition forming a liquid/liquid emulsion
when exposed to water.
[0027] Also provided is a self-supporting film for delivery of a
liquid/liquid emulsion. The film includes a solid water soluble
polymeric matrix having dispersed therein a plurality of lipophilic
droplets formed from an emulsion composition.
[0028] The present invention further provides methods of preparing
emulsion compositions.
[0029] One method of preparing an emulsion composition includes
providing an aqueous-based emulsion; and converting the
aqueous-based emulsion into a non-aqueous dry emulsion, wherein the
dry emulsion is in the form of a self-supporting film. The method
further includes dissolving the film with an aqueous solvent,
thereby reforming the aqueous-based emulsion.
[0030] Another method of preparing an emulsion composition includes
providing a solid water soluble polymeric film having dispersed
therein a plurality of lipophilic droplets; and adding water to
dissolve the film, thereby forming an emulsion.
[0031] Moreover, the invention provides a method of preparing a
film for delivery of an active. The method includes preparing a
composition including at least one water soluble polymer; a polar
solvent; and an emulsion composition that includes the active; and
forming a film from the prepared composition. The method further
includes drying the film by a process whereby a plurality of
lipophilic droplets including the active become dispersed within
the film.
[0032] Also provided is a method of preparing a water
reconstitutable emulsion composition. The method includes preparing
a composition including at least one water soluble polymer; a polar
solvent; and an emulsion composition. The method also includes
drying the composition to form a dry emulsion including lipophilic
droplets dispersed within a solid water soluble polymeric
matrix.
[0033] The present invention further provides a method of
delivering an emulsion composition. The method includes providing a
solid water soluble polymeric matrix having dispersed therein a
plurality of lipophilic droplets. The method further includes
exposing the polymeric matrix to a wetting agent to dissolve the
polymeric matrix, thereby forming an emulsion; and applying the
emulsion to a surface area in need thereof.
[0034] Another aspect of the present invention relates to a system
for applying an emulsion. The system includes a dry emulsion
including lipophilic droplets dispersed within a water soluble
polymeric film. The system further includes a solvent for
dissolving the film. The solvent is provided for direct contact
with the dry emulsion to cause the dry emulsion to be
reconstituted, whereby the reconstituted emulsion can be applied to
a surface area in need thereof. Optionally, the system may further
include an applicator for applying the reconstituted emulsion to
the surface area in need thereof.
[0035] A further aspect of the present invention relates to
compositions useful for delivering a dispersion of a eutectic
composition. For example, the invention provides a composition
including a solid water soluble polymeric matrix; and a plurality
of droplets of a eutectic composition dispersed within the matrix,
the composition forming a dispersion of the eutectic composition
when exposed to water.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 shows a side view of a package containing a unit
dosage film of the present invention.
[0037] 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.
[0038] FIG. 3 shows a side view of the adjacently coupled packages
of FIG. 2 arranged in a stacked configuration.
[0039] 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.
[0040] FIG. 5 is a schematic view of a roll of coupled unit dose
packages of the present invention.
[0041] 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.
[0042] FIG. 7 is a schematic view of an apparatus suitable for
drying the films of the present invention.
[0043] FIG. 8 is a sequential representation of the drying process
of the present invention.
[0044] FIG. 9 is a schematic representation of a
continuously-linked zone drying apparatus in accordance with the
present invention.
[0045] FIG. 10 is a schematic representation of a separate zone
drying apparatus in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0046] 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. It is also to be understood
that the terms "agent", "active agent" and "active component" are
interchangeable, and refer generally to any substance or
composition useful for the prevention or treatment of a condition,
including medicaments, bioactive active substances, bioeffective
substances, pharmaceutical compositions, therapeutically active
compositions, or cosmetic components.
[0047] It will be understood that the term "film" includes thin
films and sheets, in any shape, including rectangular, square, or
other desired shape. The films described herein may be any desired
thickness and size suitable for the intended use. For example, a
film of the present invention may be sized such that it may be
placed into the oral cavity of the user. Other films may be sized
for application to the skin of the user, i.e., a topical use. For
example, some films may have a relatively thin thickness of from
about 0.1 to about 10 mils, while others may have a somewhat
thicker thickness of from about 10 to about 30 mils. For some
films, especially those intended for topical use, the thickness may
be even larger, i.e., greater than about 30 mils. In addition, the
term "film" includes single-layer compositions as well as
multi-layer compositions, such as laminated films, coatings on
films and the like. The composition in its dried film form
maintains a uniform distribution of components through the
application of controlled drying of the film.
[0048] The films of the present invention incorporate one or more
agents. An agent may include any substance or composition useful
for the prevention or treatment of a condition, including
medicaments, bioactive active substances, bioeffective substances,
pharmaceutical compositions, therapeutically active compositions,
or cosmetic components, which may be administered to a user in any
desired means. In some embodiments of the invention, the films are
intended for oral administration. In other embodiments, the films
are intended for topical administration. As used herein, the term
"topical agent" is meant to encompass active agents that are
applied to a particular surface area. For example, in one
embodiment, a topical agent is applied to an area of the skin. In
other embodiments, the topical agent may also be applied to mucosal
areas of the body, such as the oral (e.g., buccal, sublingual,
tongue), vaginal, ocular, aural, nasal, and anal areas of the body.
In other embodiments, a topical agent is applied to a hard surface,
such as a particular surface area in need of treatment.
[0049] 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.
[0050] The film products of the present invention are produced by a
combination of a properly selected polymer(s), a polar solvent and
a topical agent, 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 controlled
drying by rapidly forming a visco-elastic mass in about 10 minutes,
and desirably about 4 minutes, such as described in U.S. Pat. Nos.
7,425,292 and 7,357,891, which are herein incorporated by reference
in their entireties. 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).
[0051] 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.
[0052] 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. In some embodiments, the film
is rapidly dried so as to form a visco-elastic structure within the
first ten minutes of drying, and more particularly within the first
four minutes of drying. Desirably, the film is dried at such a
rapid rate that any small-scale forms of an active agent do not
undesirably aggregate together. By rapidly drying the wet matrix, a
substantial number of the small-scale forms of active agent do not
have time to agglomerate.
[0053] If desired, the film, which desirably has a substantially
uniform distribution of components throughout, is formed by first
forming a flowable polymer matrix having a water-soluble polymer
composition, at least 30% solvent and an active component. At this
point, the flowable polymer matrix should preferably have a uniform
distribution of the active component. The flowable polymer matrix
may then be cast into a film, as will be described in more detail
below. After casting into a film, at least a portion of the solvent
may be evaporated from the flowable polymer matrix to form a
viscoelastic film. Desirably, the formation of a viscoelastic film
is completed within about 10 minutes or fewer, more desirably
within about 6 minutes or fewer, and most desirably within about 4
minutes or fewer. This evaporation is useful to maintain the
uniform distribution of the active component by locking-in or
substantially preventing migration of the active component within
the viscoelastic film. Finally, a resulting film from the
viscoelastic film may be formed, where the resulting film has a
water content of 10% or less and the uniform distribution of active
by locking-in or substantially preventing migration of the active
component is maintained.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] 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.
[0061] Stokian analyses have 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.
[0062] 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./.mu..sub.o=1+2.5.phi.+C.sub.1.phi..sup.2+C.sub.2.phi..sup.3+ .
. .
where C is a constant.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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 may be on the order of a microparticle or a
nanoparticle, having a particle size of 150 microns or less, for
example 100 microns or less. Even smaller sized particles may be
used. For example, in especially preferred embodiments, the small
scale particle is 1 micron or less in diameter. 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. In the case of
microparticle-sized actives, the microparticle may include a
composite of nanoparticle-sized actives, which join together to
form a microparticle-sized active.
[0070] In particular, the use of active agents in the form of small
scale particles, such as nanoparticles and/or microparticles, is
especially preferred due to the high surface area of such
small-scale particles. In this form, the active agent has a high
entropy structure, which will require less energy to break down and
be absorbed in the body of the user. This allows for easier
solubility and quicker absorption of the active.
[0071] The present invention desirably incorporates methods of
forming film compositions in which the small-scale agent particles
are maintained in a substantially uniform and non-agglomerated
form. Through controlled and rapid drying of films including
small-scale forms of particles, such as nanoparticles and
microparticles, agglomeration of the particles can be reduced or
altogether avoided. This is especially true when a portion of the
solvent from a wet film matrix incorporating a dispersion of
small-scale forms of the agent is rapidly evaporated to form a
visco-elastic mass in a short time, such as less than about 10
minutes, about 6 minutes, or about 4 minutes or less. The
visco-elastic mass essentially traps the dispersion of active agent
particles in place, reducing or altogether eliminating
agglomeration of particles during the rest of the drying process.
The resulting film, which is formed from the visco-elastic mass,
includes a substantially uniform dispersion of particles, and a
lower solvent content, such as about 10% solvent or less, 6%
solvent or less, or 4% solvent or less.
[0072] 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 or volatile materials. In one
embodiment, the active(s) are combined with 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 of the active agent or other ingredients.
[0073] When the material is formed including the film-forming
polymer and polar solvent in addition to any additives and the
active agent, 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.
[0074] 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
an active agent 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 active or other ingredient 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 active into the pre-mix or master batch
22 is desirable, excessive residence times may result in leaching
or dissolving of the active, especially in the case for a soluble
drug active. 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 active 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.
[0075] 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.
[0076] 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 just 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 source of drying and the top
air flow is the minor source 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.
[0077] Moreover, the films of the present invention may contain
particles that are sensitive to temperature, such as volatile
ingredients, 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.
[0078] During film preparation, it may be desirable to dry films at
high temperatures. High heat drying produces uniform films, and
leads to greater efficiencies in film production. Films containing
sensitive active components, however, may face degradation problems
at high temperatures. Degradation is the "decomposition of a
compound . . . exhibiting well-defined intermediate products." The
American Heritage Dictionary of the English Language (4.sup.th ed.
2000). Degradation of an active component is typically undesirable
as it may cause instability, inactivity, and/or decreased potency
of the active component. For instance, if the active component is a
drug or bioactive material, this may adversely affect the safety or
efficacy of the final pharmaceutical product. Additionally, highly
volatile materials will tend to be quickly released from this film
upon exposure to conventional drying methods.
[0079] Degradation of an active component may occur through a
variety of processes, such as, hydrolysis, oxidation, and light
degradation, depending upon the particular active component.
Moreover, temperature has a significant effect on the rate of such
reactions. The rate of degradation typically doubles for every
10.degree. C. increase in temperature. Therefore, it is commonly
understood that exposing an active component to high temperatures
will initiate and/or accelerate undesirable degradation
reactions.
[0080] Proteins are one category of useful topical, active agents
that may degrade, denature, or otherwise become inactive when they
are exposed to high temperatures for extended periods of time.
Proteins serve a variety of functions in the body such as enzymes,
structural elements, hormones and immunoglobulins. Examples of
proteins include enzymes such as pancreatin, trypsin, pancrelipase,
chymotrypsin, hyaluronidase, sutilains, streptokinaw, urokinase,
altiplase, papain, bromelainsdiastase, structural elements such as
collagen, elastin and albumin, hormones such as thyroliberin,
gonadoliberin, adrenocorticottropin, corticotrophin, cosyntropin,
sometrem, somatropion, prolactin, thyrotropin, somatostatin,
vasopressin, felypressin, lypressin, insulin, glucagons, gastrin,
pentagastrin, secretin, cholecystokinin-pancreozymin, and
immunomodulators which may include polysaccharides in addition to
glycoproteins including cytokines which are useful for the
inhibition and prevention of malignant cell growth such as tumor
growth. A suitable method for the production of some useful
glycoproteins is disclosed in U.S. Pat. No. 6,281,337 to
Cannon-Carlson, et al., which in incorporated herein in its
entirety.
[0081] Peptides are another category of useful active agents that
have the potential to become inactive when exposed to high
temperatures for long periods of time. Peptides may be included in
skin care products, for example.
[0082] Temperatures that approach 100.degree. C. will generally
cause degradation of proteins, certain peptides, as well as nucleic
acids. For example, some glycoproteins will degrade if exposed to a
temperature of 70.degree. C. for thirty minutes. Proteins from
bovine extract are also known to degrade at such low temperatures.
DNA also begins to denature at this temperature.
[0083] Applicants have discovered, however, that the films of the
present invention may be exposed to high temperatures during the
drying process without concern for degradation, loss of activity,
or excessive evaporation due to the inventive process for film
preparation and forming. In particular, the films may be exposed to
temperatures that would typically lead to degradation,
denaturization, or inactivity of the active component, without
causing such problems. According to the present invention, the
manner of drying may be controlled to prevent deleterious levels of
heat from reaching the active component.
[0084] As discussed herein, the flowable mixture is prepared to be
uniform in content in accordance with the teachings of the present
invention. Uniformity must be maintained as the flowable mass was
formed into a film and dried. During the drying process of the
present invention, several factors produce uniformity within the
film while maintaining the active component at a safe temperature,
i.e., below its degradation temperature. First, the films of the
present invention have an extremely short heat history, usually
only on the order of minutes, so that total temperature exposure is
minimized to the extent possible. The films are controllably dried
to prevent aggregation and migration of components, as well as
preventing heat build up within. Desirably, the films are dried
from the bottom. In any drying method, however, it is desirable to
rapidly form a visco-elastic mass of the film within the first ten
minutes of drying, and even more preferably within the first four
minutes of drying. Due to the short heat exposure and evaporative
cooling, the film components such as drug or volatile actives
remain unaffected by high temperatures, and small-scale particles
of active agent are maintained in a non-aggregated fashion. In
contrast, skinning on the top surface traps liquid carrier
molecules of increased energy within the film, thereby causing the
temperature within the film to rise and exposing active components
to high, potentially deleterious temperatures.
[0085] Second, thermal mixing occurs within the film due to bottom
heating and absence of surface skinning. Thermal mixing occurs via
convection currents in the film. As heat is applied to the bottom
of the film, the liquid near the bottom increases in temperature,
expands, and becomes less dense. As such, this hotter liquid rises
and cooler liquid takes its place. While rising, the hotter liquid
mixes with the cooler liquid and shares thermal energy with it,
i.e., transfers heat. As the cycle repeats, thermal energy is
spread throughout the film.
[0086] Robust thermal mixing achieved by the controlled drying
process of the present invention produces uniform heat diffusion
throughout the film. In the absence of such thermal mixing, "hot
spots" may develop. Pockets of heat in the film result in the
formation of particle aggregates or danger areas within the film
and subsequent non-uniformity. The formation of such aggregates or
agglomerations is undesirable because it leads to non-uniform films
in which the active may be randomly distributed. Such uneven
distribution may lead to large differences in the amount of active
per film, which is problematic from a safety and efficacy
perspective.
[0087] Furthermore, thermal mixing helps to maintain a lower
overall temperature inside the film. Although the film surfaces may
be exposed to a temperature above that at which the active
component degrades, the film interior may not reach this
temperature. Due to this temperature differential, the active does
not degrade.
[0088] For instance, the films of the present invention desirably
are dried for 10 minutes or less. Drying the films at 80.degree. C.
for 10 minutes produces a temperature differential of about
5.degree. C. This means that after 10 minutes of drying, the
temperature of the inside of the film is 5.degree. C. less than the
outside exposure temperature. In many cases, however, drying times
of less than 10 minutes are sufficient, such as 4 to 6 minutes.
Drying for 4 minutes may be accompanied by a temperature
differential of about 30.degree. C., and drying for 6 minutes may
be accompanied by a differential of about 25.degree. C. Due to such
large temperature differentials, the films may be dried at
efficient, high temperatures without causing heat sensitive actives
to degrade.
[0089] FIG. 8 is a sequential representation of the drying process
of the present invention. After mechanical mixing, the film may be
placed on a conveyor for continued thermal mixing during the drying
process. At the outset of the drying process, depicted in Section
A, the film 1 preferably is heated from the bottom 10 as it is
travels via conveyor (not shown). Heat may be supplied to the film
by a heating mechanism, such as, but not limited to, the dryer
depicted in FIG. 7. As the film is heated, the liquid carrier, or
volatile ("V"), begins to evaporate, as shown by upward arrow 50.
Thermal mixing also initiates as hotter liquid, depicted by arrow
30, rises and cooler liquid, depicted by arrow 40, takes its place.
Because no skin forms on the top surface 20 of the film 1, as shown
in Section B the volatile liquid continues to evaporate 50 and
thermal mixing 30/40 continues to distribute thermal energy
throughout the film. Once a sufficient amount of the volatile
liquid has evaporated, thermal mixing has produced uniform heat
diffusion throughout the film 1. The resulting dried film 1 is a
visco-elastic solid, as depicted in Section C. The components
desirably are locked into a uniform distribution throughout the
film. It may be desired to form the visco-elastic solid rapidly,
for example within the first 10 minutes or less, desirably within
the first 6 minutes or less, and most desirably within the first 4
minutes or less. Although minor amounts of liquid carrier, i.e.,
water, may remain subsequent to formation of the visco-elastic
film, the film may be dried further without affecting the desired
heterogeneity of the film, if desired.
[0090] Furthermore, particles or particulates may be added to the
film-forming composition or material after the composition or
material 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.
[0091] The particles may be any useful topical agents(s). Useful
topical agents include personal care products and medicinal agents.
In some embodiments, the topical agent may be selected from the
following: soaps, body washing agents, hair shampoos, hair
conditioners, hair styling agents, moisturizing agents, underarm
deodorants and/or antiperspirants, shaving creams or gels,
sunscreens and insect repellants. In some further embodiments, the
topical agent may be selected from antibacterial agents, acne
medications, hormones, agents for preventing motion sickness and
anesthetics, such as prilocaine, lidocaine and combinations
thereof.
[0092] 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.
[0093] 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. Alternatively, the thickness of the film
can also be controlled by manual measurement during the production
process to achieve the desired thickness of the film.
[0094] The film products are generally formed by combining a
properly selected polymer and polar solvent, as well as any topical
agent or filler as desired. Desirably, the solvent content of the
combination is at least about 30% by weight of the total
combination. The material 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.
[0095] 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
[0096] The film units of the present invention include at least one
water soluble polymer. The films may also include water swellable
or water insoluble polymers, if desired.
[0097] In some embodiments, the self-supporting film includes a
saccharide-based polymer, which is water soluble. For example, the
saccharide-based polymer may be cellulose or a cellulose
derivative. Specific examples of useful saccharide-based, water
soluble polymers include, but are not limited to, polydextrose,
pullulan, hydroxypropylmethyl cellulose (HPMC), hydroxyethyl
cellulose (HPC), hydroxypropyl cellulose, carboxymethyl cellulose,
sodium aginate, xanthan gum, tragancanth gum, guar gum, acacia gum,
arabic gum, starch, gelatin, and combinations thereof.
[0098] In some preferred embodiments, the saccharide-based polymer
may be at least one cellulosic polymer, polydextrose, or
combinations thereof. The film may also include
non-saccharide-based, water soluble or water insoluble polymers.
Examples of non-saccharide based, water soluble polymers include
polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol,
polyethylene glycol, polyacrylic acid, methylmethacrylate
copolymer, carboxyvinyl copolymers, and combinations thereof.
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.
[0099] In some further preferred embodiments, the polymer is a
combination of hydroxypropylmethyl cellulose and polyethylene
oxide. In some other preferred embodiments, the polymer is a
combination of polydextrose and polyethylene oxide. In still
further preferred embodiments, the polymer is a combination of
polydextrose, hydroxy propylmethyl cellulose and polyethylene
oxide.
[0100] 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. In some embodiments, the film unit of the
present invention is at least partially dissolvable when exposed to
a wetting agent. In some other embodiments, the inventive film unit
is substantially dissolvable when exposed to a wetting agent.
[0101] 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.
[0102] 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.
[0103] 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 100L, 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 100L, 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.).
[0104] The Biodel materials represent a family of various
polyanhydrides which differ chemically.
[0105] 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 topical agent 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.
[0106] 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 topical agent 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.
[0107] The viscosity may be adjusted based on the selected topical
agent component, 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.
[0108] 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.
[0109] Additionally, polyethylene oxide (PEO), when used alone or
in combination with a hydrophilic cellulosic polymer and/or
polydextrose, achieves flexible, strong films. Additional
plasticizers or polyalcohols are not needed for flexibility.
Non-limiting examples of suitable cellulosic polymers for
combination with PEO include HPC and HPMC. PEO and HPC have
essentially no gelation temperature, while HPMC has a gelation
temperature of 58-64.degree. C. (Methocel EF available from Dow
Chemical Co.). Moreover, these films are sufficiently flexible even
when substantially free of organic solvents, which may be removed
without compromising film properties. As such, if there is no
solvent present, then there is no plasticizer in the films. PEO
based films also exhibit good resistance to tearing, little or no
curling, and fast dissolution rates when the polymer component
contains appropriate levels of PEO.
[0110] To achieve the desired film properties, the level and/or
molecular weight of PEO in the polymer component may be varied.
Modifying the PEO content affects properties such as tear
resistance, dissolution rate, and adhesion tendencies. Thus, one
method for controlling film properties is to modify the PEO
content. For instance, in some embodiments rapid dissolving films
are desirable. By modifying the content of the polymer component,
the desired dissolution characteristics can be achieved.
[0111] In accordance with the present invention, PEO desirably
ranges from about 20% to 100% by weight in the polymer component.
In some embodiments, the amount of PEO desirably ranges from about
1 mg to about 200 mg. The hydrophilic cellulosic polymer and/or
polydextrose ranges from about 0% to about 80% by weight, or in a
ratio of up to about 4:1 with the PEO, and desirably in a ratio of
about 1:1.
[0112] In some embodiments, it may be desirable to vary the PEO
levels to promote certain film properties. To obtain films with
high tear resistance and fast dissolution rates, levels of about
50% or greater of PEO in the polymer component are desirable. To
achieve adhesion prevention, i.e., preventing the film from
adhering to the roof of the mouth, PEO levels of about 20% to 75%
are desirable. In some embodiments, however, adhesion to the roof
of the mouth may be desired, such as for administration to animals
or children. In such cases, higher levels of PEO may be employed.
More specifically, structural integrity and dissolution of the film
can be controlled such that the film can adhere to mucosa and be
readily removed, or adhere more firmly and be difficult to remove,
depending on the intended use.
[0113] The molecular weight of the PEO may also be varied. High
molecular weight PEO, such as about 4 million, may be desired to
increase mucoadhesivity of the film. More desirably, the molecular
weight may range from about 100,000 to 900,000, more desirably from
about 100,000 to 600,000, and most desirably from about 100,000 to
300,000. In some embodiments, it may be desirable to combine high
molecular weight (600,000 to 900,000) with low molecular weight
(100,000 to 300,000) PEOs in the polymer component.
[0114] For instance, certain film properties, such as fast
dissolution rates and high tear resistance, may be attained by
combining small amounts of high molecular weight PEOs with larger
amounts of lower molecular weight PEOs. Desirably, such
compositions contain about 60% or greater levels of the lower
molecular weight PEO in the PEO-blend polymer component.
[0115] To balance the properties of adhesion prevention, fast
dissolution rate, and good tear resistance, desirable film
compositions may include about 50% to 75% low molecular weight PEO,
optionally combined with a small amount of a higher molecular
weight PEO, with the remainder of the polymer component containing
a hydrophilic cellulosic polymer (HPC or HPMC) and/or
polydextrose.
[0116] In some embodiments the film may include polyvinyl alcohol
(PVA), alone or in combination with at least one additional polymer
Examples of an additional polymer include a cellulosic polymer,
starch, polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO), an
alginate, a pectin, or combinations thereof. PVA can be used in the
films to improve film strength and/or to vary and slow dissolution
times. The films are especially useful for the delivery of
cosmetics, nutraceuticals and pharmaceuticals. In a preferred
embodiment, the film includes PVA without any added plasticizers.
For example, the film can include both PVA, which provides strength
to the film and PEO, which provides flexibility to the film and nay
obviate the need for a plasticizer.
[0117] PVA can be used in varying amounts depending upon the
product application and characteristics desired. For example, in
general, a larger amount of PVA will increase film strength and
increase dissolution time. For films that require high active
dosing, PVA can be used effectively at minimum amount of 0.5,
preferably 1%, more preferably 5%, by weight of the film, to
improve film strength. The PVA an be effectively used at a maximum
amount, for example, 80%, preferably 50%, more preferably 25% by
weight of the film. For slowing dissolution time, PVA can be used
at levels as high as 80%. A film containing an active can be coated
on one or both surfaces with a PVA containing layer to modify the
dissolution of the film and the release of an active from the
film.
[0118] High loading of actives can decrease the strength and
flexibility of the film. Including PVA in the film either alone or
in combination with at least one other polymer can increase the
tensile strength of the film. Also, drug particles or taste-masked
or coated or modified release drug particles may have a larger
particle size, which can make loading of these particles into the
film difficult. PVA can increase the viscosity of the film solution
to allow improved drug loading.
Controlled Release Films
[0119] The term "controlled release" is intended to mean the
release of the agent at a pre-selected or desired rate. For
example, in embodiments where the agent is a medicament, it may be
desirable to control its release from the film. 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 releases of the agent
are also contemplated.
[0120] Dissolvable films generally fall into three main classes:
fast dissolving, moderate dissolving and slow dissolving. Films of
the present invention are dissolvable in the presence of liquid,
such as in the oral cavity of the user or when mixed with a liquid,
such as water. Fast dissolving films generally dissolve in about 1
second to about 30 seconds. Moderate dissolving films generally
dissolve in about 1 to about 30 minutes, and slow dissolving films
generally dissolve in more than 30 minutes, e.g., up to about 60
minutes or more. Fast dissolving films may consist of low molecular
weight hydrophilic polymers (i.e., polymers having a molecular
weight between about 1,000 to 200,000). In contrast, slow
dissolving films generally have high molecular weight polymers
(i.e., having a molecular weight in the millions).
[0121] Moderate dissolving films tend to fall in between the fast
and slow dissolving films. Moderate dissolving films dissolve
rather quickly, but also have a good level of mucoadhesion.
Moderate films are also flexible, quickly wettable, and are
typically non-irritating to the user. For oral-dissolving films,
moderate dissolving films are preferred, since such films provide a
quick enough dissolution rate (between about 1 minute and about 5
minutes), while providing an acceptable mucoadhesion level such
that the film is not easily removable once it is placed in the oral
cavity of the user.
[0122] The polymers that are chosen for the films of the present
invention may also be chosen to allow for controlled disintegration
of the agent. This may be achieved by providing a substantially
water insoluble film that incorporates an agent 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 agent particles may be
incorporated into a readily soluble film matrix to achieve the
controlled release property of the agent.
[0123] The convenience of administering a single dose of a
medication which releases 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 levels of medication
delivered to the body over an extended period of time are likewise
recognized.
[0124] The agents 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 a drug may be
coated with polymers, such as ethyl cellulose or polymethacrylate,
which are commercially available under brand names such as Aquacoat
ECD and Eudragit E-100, respectively. Solutions of a drug may also
be absorbed on such polymer materials and incorporated into the
inventive film compositions. Other components may also be employed
in such controlled release compositions.
[0125] When an active agent is introduced to the film, the amount
of agent per unit area is determined by the uniform distribution of
the film. For example, when the films are cut into individual
units, the amount of the agent in the unit can be known with a
great deal of accuracy. This is achieved because the amount of the
agent in a given area is substantially identical to the amount of
agent in an area of the same dimensions in another part of the
film. The accuracy in dosage is particularly advantageous when the
agent is a medicament, i.e. a drug or other pharmaceutical
agent.
[0126] The active agents that may be incorporated into the films of
the present invention include, but are not limited to,
pharmaceutical, cosmetic, cosmeceutical and nutraceutical actives.
As used herein, a cosmeceutical refers to a product, which is a
cosmetic, but which contains biologically active ingredients that
have an effect on the user. A nutraceutical, as used herein, refers
to a product isolated or purified from foods, and sold in medicinal
forms not usually associated with food and demonstrated to have a
physiological benefit or provide protection against disease.
Examples of nutraceuticals include beta-carotene and lycopene.
[0127] As used herein, a topical agent pertains to an agent that
may be applied to a particular surface area, such as, but not
limited to, a certain area of the skin or mucosal tissue. The film
is used as a delivery system to carry the topical active agent to a
particular surface area in need thereof. Also as used herein, an
orally administered agent is an agent that may be ingested by a
user, i.e., through the oral cavity. Such orally administered
agents may be absorbed into the body through one or more mucosal
cavities (i.e., buccal or sublingual) or may be ingested through
the stomach.
[0128] In some embodiments, the polymeric film desirably includes
at least one water soluble polymer. In some other embodiments, the
film includes a combination of both water soluble and water
insoluble polymers. When wetted, the dry film product at least
partially solubilizes. Contacting the film product of the present
invention with a wetting agent permits the topical agent to be
dissolved or dispersed out of the film. Particularly in the case of
topical films, the dissolved or dispersed topical agent may then be
easily applied to a particular surface area, such as a skin area or
mucosal area. The wetting agent may be a polar solvent, such as
water. In orally administered embodiments, for example, the wetting
agent may be saliva.
[0129] The wetting agent may be placed on a substrate surface,
including skin and wounds, and the film placed on the wetted
surface. Alternatively, the film may be placed on the substrate
surface, including skin and wounds, and subsequently hydrated.
[0130] The wetting agent may be dispensed from a container, the
container being separate from or affixed to the film. For example,
the container may be a pump bottle or sealed tube including the
wetting agent.
[0131] Alternatively, the container may be a sealed, rupturable
pouch including the wetting agent. Such a pouch may be separate
from or affixed to the film. When the pouch is ruptured, the
wetting agent may be brought into direct contact with the film to
cause the topical agent to be dissolved out or dispersed out of the
film, whereby the topical agent can be applied to the substrate
surface.
[0132] The film may be interposed between a container including the
solvent and a substrate surface, including skin and wounds.
Alternatively, the film may be interposed between a container
including the solvent and an applicator.
[0133] For example, in some embodiments, a system useful for
applying a topical agent includes a water soluble polymeric film
containing the topical agent, a solvent, which may be present in a
container, and an applicator for applying the topical agent to the
substrate surface. In some embodiments, the applicator is a sponge
applicator. The film may be deposited on top of a wetted sponge
applicator. Alternatively, the film may be deposited on top of a
dry sponge applicator, which is subsequently wetted.
[0134] As further described below, in some embodiments, the method
of making the films of the present invention involves combining a
water soluble, saccharide-based polymer, a polar solvent and the
topical agent to form a wet material or matrix with a
non-self-aggregating uniform heterogeneity. In some embodiments, a
blend of water soluble polymers is used, such as at least one
saccharide-based polymer and polyethylene oxide. The wet material
or matrix is then formed into a film and dried in a controlled
manner. In some embodiments, the topical agent, when combined with
the polymer and the polar solvent, is in the form of a liquid, a
solid or a gel.
[0135] When a topical agent is combined with the water soluble
polymer(s) in the solvent, the type of material that is formed
depends on the solubilities of the topical agent and the
polymer(s). If the agent and/or polymer(s) are soluble in the
selected solvent, this may form a solution. However, if the
components are not soluble, the material that is formed may be
classified as an emulsion, a colloid, or a suspension.
[0136] Examples of suitable topical agents which may be included in
the films of the present invention include, but are not limited to,
body washing agents, hair styling agents, moisturizing agents,
underarm deodorants and/or antiperspirants, shaving creams or gels,
sunscreens, and insect repellants.
[0137] The topical agent may also be a protein and/or peptide. For
example, in some embodiments, the topical agent may be collagen,
elastin or a combination thereof.
[0138] With respect to some preferred medicinal agents for topical
applications, these include, but are not limited to, acne
medications, antibacterial agents (e.g., antibiotics), hormones,
agents for preventing motion sickness, and anesthetics.
[0139] In some embodiments, an active agent in a nanoparticle size,
such as less than about 500 nm, may be combined with a
water-soluble polymer composition to form a self-supporting film in
accordance with the present invention. In some other embodiments, a
medicinal agent in a nanoparticle size, such as preferably less
than about 200 nm, may be combined with a water-soluble polymer
composition to form a self-supporting film in accordance with the
present invention.
[0140] A wide variety of medicaments, bioactive active substances
and pharmaceutical compositions may be included in the dosage forms
of the present invention. Such medicaments, bioactive substances
and pharmaceutical compositions may be useful as
topically-administered dosages or as orally-ingestible dosages.
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, 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.
[0141] 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.
[0142] Analgesics include opiates and opiate derivatives, such as
oxycodone (commercially available as Oxycontin.RTM.); ibuprofen
(commercially available as Motrin.RTM., Advil.RTM., Motrin
Children's.RTM., Motrin IBC), Advil Children's.RTM., Motrin
Infants'.RTM., Motrin Junior.RTM., Ibu-2.RTM., Proprinal.RTM.,
Ibu-200.RTM., Midol Cramp Formula.RTM., Bufen.RTM., Motrin Migraine
Pain.RTM., Addaprin.RTM. and Haltran.RTM.), aspirin (commercially
available as Empirin.RTM., Ecotrin.RTM., Genuine Bayer.RTM., and
Halfprin.RTM.), acetaminophen (commercially available as Silapap
Infant's.RTM., Silapap Children's.RTM., Tylenol.RTM., Tylenol
Children's.RTM., Tylenol Extra Strength.RTM., Tylenol Infants'
Original.RTM., Tylenol Infants'.RTM., Tylenol Arthritis.RTM.,
T-Painol.RTM., Q-Pap.RTM., Cetafen.RTM., Dolono.RTM.,
Tycolene.RTM., APAP.RTM. and Aminofen.RTM.), and combinations
thereof that may optionally include caffeine. Other pain relieving
agents may be used in the present invention, including meperidine
hydrochloride (commercially available as Demerol.RTM.),
hydromorphone hydrochloride (commercially available as
Dilaudid.RTM.), propoxyphene napsylate and acetaminophen
(commercially available as Darvocet-N.RTM.), Fentanyl (commercially
available as Duragesic.RTM. and Fentora.RTM.), sodium hyaluronate
(commercially available as Euflexxa.RTM.), adalimumab (commercially
available as Humira.RTM.), sumatriptan succinate (commercially
available as Imitrex.RTM.), fentanyl iontophoretic (commercially
available as Ionsys.RTM.), orphenadrine citrate (commercially
available as Norgesic.RTM.), magnesium salicylate tetrahydrate
(commercially available as Novasal.RTM.), oxymorphone hydrochloride
(commercially available as Opana ER.RTM.), methocarbamol
(commercially available as Robaxin.RTM.), carisoprodol
(commercially available as Soma.RTM.), tramadol hydrochloride
(commercially available as Ultracet.RTM. and Ultram.RTM.), morphine
sulfate (commercially available as MS Contin.RTM.), metaxalone
(commercially available as Skelaxin.RTM.), oxycodone hydrochloride
(commercially available as OxyContin.RTM.), acetaminophen/oxycodone
hydrochloride (commercially available as Percocet.RTM.),
oxycodone/aspirin (commercially available as Percodan.RTM.),
hydrocodone bitartrate/acetaminophen (commercially available as
Vicodin.RTM.), hydrocodone bitartrate/ibuprofen (commercially
available as Vicoprofen.RTM.), nepafenac (commercially available as
Nevanac.RTM.), and pregabalin (commercially available as
Lyrica.RTM.).
[0143] The present invention may further include agents such as
NSAIDs, including etodolac (commercially available as Lodine.RTM.),
ketorolac tromethamine (commercially available as Acular.RTM.),
naproxen sodium (commercially available as Anaprox.RTM.,
Naprosyn.RTM.), flurbiprofen (commercially available as
Ansaid.RTM.), diclofenac sodium/misoprostol (commercially available
as Arthrotec.RTM.), celecoxib (commercially available as
Celebrex.RTM.), sulindac (commercially available as Clinoril.RTM.),
oxaprozin (commercially available as Daypro.RTM.), piroxicam
(commercially available as Feldene.RTM.), indomethacin
(commercially available as Indocin.RTM.), meloxicam (commercially
available as Mobic.RTM.), mefenamic acid (commercially available as
Ponstel.RTM.), tolmetin sodium (commercially available as
Tolectin.RTM.), choline magnesium trisalicylate (commercially
available as Trilisate.RTM.), diclofenac sodium (commercially
available as Voltaren.RTM.), and misoprostol (commercially
available as Cytotec.RTM.). Opiate agonists and antagonists, such
as buprenorphine and naloxone are further examples of drugs for use
in the present invention.
[0144] Other preferred drugs for other preferred active ingredients
for use in the present invention include anti-diarrheals such as
loperamide (commercially available as Imodium ADC), Imotil.RTM.,
Kaodene.RTM., Imperim.RTM., Diamode.RTM., QC Anti-Diarrheal.RTM.,
Health Care America Anti-Diarrheal.RTM., Leader A-D.RTM., and
Imogen.RTM.), nitazoxanide (commercially available as Alinia.RTM.)
and diphenoxylate hydrochloride/atropine sulfate (commercially
available as Lomotil.RTM.), anti-histamines, anti-tussives,
decongestants, vitamins, and breath fresheners. Common drugs used
alone or in combination for colds, pain, fever, cough, congestion,
runny nose and allergies, such as acetaminophen, ibuprofen,
chlorpheniramine maleate, dextromethorphan, dextromethorphan HBr,
phenylephrine HCl, pseudoephedrine HCl, diphenhydramine and
combinations thereof, such as dextromethophan HBr and phenylephrine
HCl (available as Triaminic.RTM.) may be included in the film
compositions of the present invention.
[0145] Other active agents useful in the present invention include,
but are not limited to alcohol dependence treatment, such as
acamprosate calcium (commercially available as Campral.RTM.);
Allergy treatment medications, such as promethazine hydrochloride
(commercially available as Phenergan.RTM.), hydrocodone
polistirex/chlorpheniramine polistirex (commercially available as
Tussionex.RTM.), cetirizine hydrochloride (commercially available
as Zyrtec.RTM.), cetirizine hydrochloride/pseudoephedrine
hydrochloride (commercially available as Zyrtec-D.RTM.),
promethazine hydrochloride/codeine phosphate (commercially
available as Phenergan.RTM. with Codeine), pemirolast (commercially
available as Alamast.RTM.), fexofenadine hydrochloride
(commercially available as Allegra.RTM.), meclizine hydrochloride
(commercially available as Antivert.RTM.), azelastine hydrochloride
(commercially available as Astelin.RTM.), nizatidine (commercially
available as Axid.RTM.), desloratadine (commercially available as
Clarinex.RTM.), cromolyn sodium (commercially available as
Crolom.RTM.), epinastine hydrochloride (commercially available as
Elestat.RTM.), azelastine hydrochloride (commercially available as
Optivar.RTM.), prednisolone sodium phosphate (commercially
available as Orapred ODT.RTM.), olopatadine hydrochloride
(commercially available as Patanol.RTM.), ketotifen fumarate
(commercially available as Zaditor.RTM.), and montelukast sodium
(commercially available as Singulair.RTM.); and anti-histamines
such as diphenhydramine HCl (available as Benadryl.RTM.),
loratadine (available as Claritin.RTM.), astemizole (available as
Hismanal.RTM.), nabumetone (available as Relafen.RTM.),
diphenydramine HCL (available as TheraFlu.RTM.) and clemastine
(available as Tavist.RTM.).
[0146] Films of the present invention may further include
Alzheimer's treatment medications, such as tacrine hydrochloride
(commercially available as Cognex.RTM.), galantamine (commercially
available as Razadyne.RTM.), donepezil hydrochloride (commercially
available as Aricept.RTM.), rivastigmine tartrate (commercially
available as Exelon.RTM.), and memantine (commercially available as
Namenda.RTM.); anemia medication, such as cyanocobalamin
(commercially available as Nascobal.RTM.); anesthetics, such as
antipyrine with benzocaine (commercially available as
Auralgan.RTM., Aurodex.RTM. and Auroto.RTM.); angina medication,
such as amlodipine besylate (commercially available as
Norvasc.RTM.), nitroglycerin (commercially available as
Nitro-Bid.RTM., Nitro-Dur.RTM., Nitrolingual.RTM., Nitrostat.RTM.,
Transderm-Nitro.RTM.), isosorbide mononitrate (commercially
available as Imdur.RTM.), and isosorbide dinitrate (commercially
available as Isordil.RTM.); anti-tussives such as guaifensin;
anti-Alzheimer's agents, such as nicergoline; and
Ca.sup.H-antagonists such as nifedipine (commercially available as
Procardia.RTM. and Adalat.RTM.).
[0147] Actives useful in the present invention may also include
anti-asthmatics, such as albuterol sulfate (commercially available
as Proventil.RTM.), ipratropium bromide (commercially available as
Atrovent.RTM.), salmeterol xinafoate (commercially available as
Serevent.RTM.), zafirlukast (commercially available as
Accolate.RTM.), flunisolide (commercially available as
AeroBid.RTM.), metaproterenol sulfate (commercially available as
Alupent.RTM.), albuterol inhalation (commercially available as
Ventolin.RTM.), terbutaline sulfate (commercially available as
Brethine.RTM.), formoterol (commercially available as
Foradil.RTM.), cromolyn sodium (commercially available as
Intal.RTM.), levalbuterol hydrochloride (commercially available as
Xopenex.RTM.), zileuton (commercially available as Zyflo.RTM.),
fluticasone propionate/salmeterol (commercially available as
Advair.RTM.), albuterol sulfate/triamcinolone acetonide
(commercially available as Azmacort.RTM.), dimethylxanthine
(commercially available as Theophylline.RTM.), and beclomethasone
(commercially available as Beclovent.RTM., Beconase.RTM.,
Qvar.RTM., Vancenase.RTM., Vanceril.RTM.); and antibacterial
medications, such as trimethoprim/sulfamethoxazole (commercially
available as Bactrim.RTM.), mupirocin (commercially available as
Bactroban.RTM.), metronidazole (commercially available as
Flagyl.RTM.), sulfisoxazole acetyl (commercially available as
Gantrisin.RTM.), bismuth subsalicylate and
metronidazole/tetracycline hydrochloride (commercially available as
Helidac Therapy.RTM.), nitrofurantoin (commercially available as
Macrodantin.RTM.), norfloxacin (commercially available as
Noroxin.RTM.), erythromycin ethylsuccinate/Sulfisoxazole acetyl
(commercially available as Pediazole.RTM.), and levofloxacin
(commercially available as Levaquin.RTM.).
[0148] The present invention may further include one or more
Antibiotics, including amoxicillin (commercially available as
Amoxil.RTM.), ampicillin (commercially available as Omnipen.RTM.,
Polycillin.RTM. and Principen.RTM.), amoxicillin/clavulanate
potassium (commercially available as Augmentin.RTM.), moxifloxacin
hydrochloride (commercially available as Avelox.RTM.),
clarithromycin (commercially available as Biaxin.RTM.), ceftibuten
(commercially available as Cedax.RTM.), cefuroxime axetil
(commercially available as Ceftin.RTM.), cefprozil (commercially
available as Cefzil.RTM.), ciprofloxacin hydrochloride
(commercially available as Ciloxan.RTM. and Cipro.RTM.),
clindamycin phosphate (commercially available as Cleocin T.RTM.),
doxycycline hyclate (commercially available as Doryx.RTM.),
dirithromycin (commercially available as Dynabac.RTM.),
erythromycin (commercially available as E.E.S..RTM., E-Mycin.RTM.,
Eryc.RTM., Ery-Tab.RTM., Erythrocin.RTM., and PCE.RTM.),
erythromycin topical (commercially available as A/T/SO,
Erycette.RTM., T-Stat.RTM.), gemifloxacin (commercially available
as Factive.RTM.), ofloxacin (commercially known as Ocuflox.RTM.,
Floxin.RTM.), telithromycin (commercially available as Ketek.RTM.),
lomefloxacin hydrochloride (commercially available as
Maxaquin.RTM.), minocycline hydrochloride (commercially available
as Minocin.RTM.), fosfomycin tromethamine (commercially available
as Monurol.RTM.), penicillin with potassium (commercially available
as Penicillin VK.RTM., Veetids.RTM.), trimethoprim (commercially
available as Primsol.RTM.), ciprofloxacin hydrochloride
(commercially available as Proquin XR.RTM.), rifampin, isoniazid
and pyrazinamide (commercially available as Rifater.RTM.),
cefditoren (commercially available as Spectracef.RTM.), cefixime
(commercially available as Suprax.RTM.), tetracycline (commercially
available as Achromycin V.RTM. and Sumycin.RTM.), tobramycin
(commercially available as Tobrex.RTM.), rifaximin (commercially
available as Xifaxan.RTM.), azithromycin (commercially available as
Zithromax.RTM.), azithromycin suspension (commercially available as
Zmax.RTM.), linezolid (commercially available as Zyvox.RTM.),
benzoyl peroxide and clindamycin (commercially available as
BenzaClin.RTM.), erythromycin and benzoyl peroxide (commercially
available as Benzamycin.RTM.), ciprofloxacin and dexamethasone
(commercially available as Ciprodex.RTM.), polymyxin B
sulfate/neomycin sulfate/hydrocortisone (commercially available as
Cortisporin.RTM.), colistin sulfate/neomycin sulfate/hydrocortisone
acetate/thonzonium bromide (commercially available as
Cortisporin-TC Otic.RTM.), cephalexin hydrochloride (commercially
available as Keflex.RTM.), cefdinir (commercially available as
Omnicef.RTM.), and gatifloxacin (commercially available as
Zymar.RTM.).
[0149] Other useful actives include cancer treatment medications,
including cyclophosphamide (commercially available as
Cytoxan.RTM.), methotrexate (commercially available as
Rheumatrex.RTM. and Trexal.RTM.), tamoxifen citrate (commercially
available as Nolvadex.RTM.), and anastrozole (commercially
available as Arimidex.RTM.); anti-coagulants, such as aspirin with
extended-release dipyridamole (commercially available as
Aggrenox.RTM.), warfarin sodium (commercially available as
Coumadin.RTM.), dipyridamole (commercially available as
Persantine.RTM.), and clopidogrel bisulfate (commercially available
as Plavix.RTM.); antiemetics, such as granisetron hydrochloride
(commercially available as Kytril.RTM.) and nabilone (commercially
available as Cesamet.RTM.), trimethobenzamide hydrochloride
(commercially available as Tigan.RTM.), and ondansetron
hydrochloride (commercially available as Zofran.RTM.); anti-fungal
treatment, such as ketoconazole (commercially available as
Nizoral.RTM.), posaconazole (commercially available as
Noxafil.RTM.), ciclopirox (commercially available as Penlac.RTM.),
griseofulvin (commercially available as Gris-PEG.RTM.), oxiconazole
nitrate (commercially available as Oxistat.RTM.), fluconazole
(commercially available as Diflucan.RTM.), sertaconazole nitrate
(commercially available as Ertaczo.RTM.), terbinafine hydrochloride
(commercially available as Lamisil.RTM.), ciclopirox (commercially
available as Loprox.RTM.), nystatin/triamcinolone acetonide
(commercially available as Mycolog-II.RTM.), econazole nitrate
(commercially available as Spectazole.RTM.), itraconazole
(commercially available as Sporanox.RTM.), and terconazole
(commercially available as Terazol.RTM.).
[0150] Active agents may further include anti-inflammatory
medications, such as hydroxychloroquine sulfate (commercially
available as Plaquenil.RTM.), fluticasone propionate (commercially
available as Cutivate.RTM.), amcinonide (commercially available as
Cyclocort.RTM.), methylprednisolone (commercially available as
Medrol.RTM.), budesonide (commercially available as Entocort
EC.RTM.), anakinra (commercially available as Kineret.RTM.),
diflorasone diacetate (commercially available as Psorcon.RTM.), and
etanercept (commercially available as Enbrel.RTM.); antispasmodic
medication, such as phenobarbital/hyoscyamine sulfate/atropine
sulfate/scopolamine hydrobromide (commercially available as
Donnatal.RTM.); antiviral treatment, such as oseltamivir phosphate
(commercially available as Tamiflu.RTM.); anti-parasites
medication, including tinidazole (commercially available as
Tindamax.RTM.); appetite treatment mediations, such as megestrol
acetate (commercially available as Megace ESC), phentermine
hydrochloride (commercially available as Adipex-P.RTM.), and
diethylpropion hydrochloride (commercially available as
Tenuate.RTM.); arthritis medications, including leflunomide
(commercially available as Arava.RTM.); bladder control medication,
such as trospium chloride (commercially available as
Sanctura.RTM.), desmopressin acetate (commercially available as
DDAVP.RTM.), tolterodine tartrate (commercially available as
Detrol.RTM.), oxybutynin chloride (commercially available as
Ditropan.RTM.), darifenacin (commercially available as
Enablex.RTM.), and solifenacin succinate (commercially available as
VESIcare.RTM.); blood vessel constrictors, such as methylergonovine
maleate (commercially available as Methergine.RTM.); cholesterol
lowering medication, including paricalcitol (commercially available
as Altocor.RTM.), lovastatin, niacin (commercially available as
Advicor.RTM.), colestipol hydrochloride (commercially available as
Colestid.RTM.), rosuvastatin calcium (commercially available as
Crestor.RTM.), fluvastatin sodium (commercially available as
Lescol.RTM.), atorvastatin calcium (commercially available as
Lipitor.RTM.), lovastatin (commercially available as Mevacor.RTM.),
niacin (commercially available as Niaspan.RTM.), pravastatin sodium
(commercially available as Pravachol.RTM.), pavastatin sodium with
buffered aspirin (commercially available as Pravigard PAC.RTM.),
cholestyramine (commercially available as Questran.RTM.),
simvastatin and niacin (commercially available as Simcor.RTM.),
atenolol, chlorthalidone (commercially available as
Tenoretic.RTM.), atenolol (commercially available as
Tenormin.RTM.), fenofibrate (commercially available as
Tricor.RTM.), fenofibrate (commercially available as
Triglide.RTM.), ezetimibe/simvastatin (commercially available as
Vytorin.RTM.), colesevelam (commercially available as
WelChol.RTM.), bisoprolol fumarate (commercially available as
Zebeta.RTM.), ezetimibe (commercially available as Zetia.RTM.),
bisoprolol fumarate/hydrochlorothiazide (commercially available as
Ziac.RTM.), and simvastatin (commercially available as
Zocor.RTM.).
[0151] The actives included herein may also include chronic kidney
disease medication, such as paricalcitol (commercially available as
Zemplar.RTM.); contraceptive agents, including etonogestrel
(commercially available as Implanon.RTM.), norethindrone acetate,
ethinyl estradiol (commercially available as Loestrin 24 FE.RTM.),
ethinyl estradiol, norelgestromin (commercially available as Ortho
Evra.RTM.), levonorgestrel (commercially available as Plan B.RTM.),
levonorgestrel and ethinyl estradiol (commercially available as
Preven.RTM.), levonorgestrel, ethinyl estradiol (commercially
available as Seasonique.RTM.), and medroxyprogesterone acetate
(commercially available as Depo-Provera.RTM.); COPD medication,
such as arformoterol tartrate (commercially available as
Brovana.RTM.) and ipratropium bromide, albuterol sulfate
(commercially available as Combivent.RTM.); cough suppressants,
including benzonatate (commercially available as Tessalon.RTM.),
guaifenesin, codeine phosphate (commercially available as
Tussi-Organidin NR.RTM.), and acetaminophen, codeine phosphate
(commercially available as Tylenol with Codeine.RTM.); medication
for the treatment of diabetes, including pioglitazone
hydrochloride, metformin hydrochloride (commercially available as
ACTOplus Met.RTM.), pioglitazone hydrochloride (commercially
available as Actos.RTM.), glimepiride (commercially available as
Amaryl.RTM.), rosiglitazone maleate, metformin hydrochloride
(commercially available as Avandamet.RTM.), rosiglitazone maleate
(commercially available as Avandaryl.RTM.), rosiglitazone maleate
(commercially available as Avandia.RTM.), exenatide (commercially
available as Byetta.RTM.), chlorpropamide (commercially available
as Diabinese.RTM.), pioglitazone hydrochloride, glimepiride
(commercially available as Duetact.RTM.), metformin hydrochloride
(commercially available as Glucophage.RTM.), glipizide
(commercially available as Glucotrol.RTM.), glyburide, metformin
(commercially available as Glucovance.RTM.), metformin
hydrochloride (commercially available as Glumetza.RTM.),
sitagliptin (commercially available as Januvia.RTM.), detemir
(commercially available as Levemir.RTM.), glipizide, metformin
hydrochloride (commercially available as Metaglip.RTM.), glyburide
(commercially available as Micronase.RTM.), repaglinide
(commercially available as Prandin.RTM.), acarbose (commercially
available as Precose.RTM.), nateglinide (commercially available as
Starlix.RTM.), pramlintide acetate (commercially available as
Symlin.RTM.), and tolazamide (commercially available as
Tolinase.RTM.).
[0152] Other useful agents of the present invention may include
digestive agents, such as sulfasalazine (commercially available as
Azulfidine.RTM.), rabeprazole sodium (commercially available as
AcipHex.RTM.), lubiprostone (commercially available as
Amitiza.RTM.), dicyclomine hydrochloride (commercially available as
Bentyl.RTM.), sucralfate (commercially available as Carafate.RTM.),
lactulose (commercially available as Chronulac.RTM.), docusate
(commercially available as Colace.RTM.), balsalazide disodium
(commercially available as Colazal.RTM.), losartan potassium
(commercially available as Cozaar.RTM.), olsalazine sodium
(commercially available as Dipentum.RTM.), chlordiazepoxide
hydrochloride, clidinium bromide (commercially available as
Librax.RTM.), esomeprazole magnesium (commercially available as
Nexium.RTM.), famotidine (commercially available as Pepcid.RTM.),
lansoprazole (commercially available as Prevacid.RTM.),
lansoprazole and naproxen (commercially available as Prevacid
NapraPAC.RTM.), amoxicillin/clarithromycin/lansoprazole
(commercially available as Prevpac.RTM.), omeprazole (commercially
available as Prilosec.RTM.), pantoprazole sodium (commercially
available as Protonix.RTM.), metoclopramide hydrochloride
(commercially available as Reglan.RTM.), cimetidine (commercially
available as Tagamet.RTM.), ranitidine hydrochloride (commercially
available as Zantac.RTM.), and omeprazole, sodium bicarbonate
(commercially available as Zegerid.RTM.); diuretics, including
spironolactone, hydrochlorothiazide (commercially available as
Aldactazide.RTM.), spironolactone (commercially available as
Aldactone.RTM.), bumetanide (commercially available as Bumex.RTM.),
torsemide (commercially available as Demadex.RTM.), chlorothiazide
(commercially available as Diuril.RTM.), furosemide (commercially
available as Lasix.RTM.), metolazone (commercially available as
Zaroxolyn.RTM.), and hydrochlorothiazide, triamterene (commercially
available as Dyazide.RTM.).
[0153] Agents useful herein may also include treatment for
emphysema, such as tiotropium bromide (commercially available as
Spiriva.RTM.); enema treatments, including aminosalicylic acid
(commercially available as Mesalamine.RTM. and Rowasa.RTM.);
epilepsy medications, including valproic acid (commercially
available as Depakene.RTM.), felbamate (commercially available as
Felbatol.RTM.), lamotrigine (commercially available as
Lamictal.RTM.), primidone (commercially available as
Mysoline.RTM.), oxcarbazepine (commercially available as
Trileptal.RTM.), zonisamide (commercially available as
Zonegran.RTM.), levetiracetam (commercially available as
Keppra.RTM.), and phenyloin sodium (commercially available as
Dilantin.RTM.).
[0154] Erectile dysfunction therapies useful herein 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 agents for treatment of erectile
dysfunction include, for example, those agents available as
alprostadil (commercially available as Caverject.RTM.), tadalafil
(commercially available as Clalis.RTM.), vardenafil (commercially
available as Levitra.RTM.), apomorphine (commercially available as
Uprima.RTM.), yohimbine hydrochloride (commercially available as
Aphrodyne.RTM., Yocon.RTM.), and sildenafil citrate (commercially
available as Viagra.RTM.).
[0155] Agents useful herein may further include eye medications and
treatment, such as dipivefrin hydrochloride (commercially available
as Propine.RTM.), valganciclovir (commercially available as
Valcyte.RTM.), bromfenac (commercially available as Xibrom.RTM.),
fluorometholone (commercially available as FML.RTM.), pilocarpine
hydrochloride (commercially available as Pilocar.RTM.),
cyclosporine (commercially available as Restasis.RTM.), brimonidine
tartrate (commercially available as Alphagan P.RTM.), dorzolamide
hydrochloride/timolol maleate (commercially available as
Cosopt.RTM.), bimatoprost (commercially available as Lumigan.RTM.),
timolol maleate (available as Timoptic.RTM.), travoprost
(commercially available as Travatan.RTM.), latanoprost
(commercially available as Xalatan.RTM.), echothiophate iodide
(commercially available as Phospholine Iodide.RTM.), and
ranibizumab (commercially available as Lucentis.RTM.); fluid
controllers, such as acetazolamide (commercially available as
Diamox.RTM.); gallstone medications, including ursodiol
(commercially available as Actigall.RTM.); medication for the
treatment of gingivitis, including chlorhexidine gluconate
(commercially available as Peridex.RTM.); headache medications,
including butalbital/codeine phosphate/aspirin/caffeine
(commercially available as Fiornal.RTM. with Codeine), naratriptan
hydrochloride (commercially available as Amerge.RTM.), almotriptan
(commercially available as Axert.RTM.), ergotamine
tartrate/caffeine (commercially available as Cafergot.RTM.),
butalbital/acetaminophen/caffeine (commercially available as
Fioricet.RTM.), butalbital/aspirin/caffeine (commercially available
as Fiorinal.RTM.), frovatriptan succinate (commercially available
as Frova.RTM.), rizatriptan benzoate (commercially available as
Maxalt.RTM.), isometheptene mucate/dichloralphenazone/acetaminophen
(commercially available as Midrin.RTM.), dihydroergotamine mesylate
(commercially available as Migranal.RTM.), eletriptan hydrobromide
(commercially available as Relpax.RTM.), and zolmitriptan
(commercially available as Zomig.RTM.); and heart treatments,
including quinidine sulfate, isosorbide dinitrate/hydralazine
hydrochloride (commercially available as BiDil.RTM.), digoxin
(commercially available as Lanoxin.RTM.), flecamide acetate
(commercially available as Tambocor.RTM.), mexiletine hydrochloride
(commercially available as Mexitil.RTM.), disopyramide phosphate
(commercially available as Norpace.RTM.), procainamide
hydrochloride (commercially available as Procanbid.RTM.), and
propafenone (commercially available as Rythmol.RTM.).
[0156] Other useful agents include hepatitis treatments, including
entecavir (commercially available as Baraclude.RTM.), hepatitis B
immune globulin (commercially available as HepaGam B.RTM.), and
copegus/rebetol/ribasphere/vilona/virazole (commercially available
as Ribavirin.RTM.); herpes treatments, including valacyclovir
hydrochloride (commercially available as Valtrex.RTM.), penciclovir
(commercially available as Denavir.RTM.), acyclovir (commercially
available as Zovirax.RTM.), and famciclovir (commercially available
as Famvir.RTM.); treatment for high blood pressure, including
enalaprilat (available as Vasotec.RTM.), captopril (available as
Capoten.RTM.) and lisinopril (available as Zestril.RTM.), verapamil
hydrochloride (available as Calan.RTM.), ramipril (commercially
available as Altace.RTM.), olmesartan medoxomil (commercially
available as Benicar.RTM.), amlodipine/atorvastatin (commercially
available as Caduet.RTM.), nicardipine hydrochloride (commercially
available as Cardene.RTM.), diltiazem hydrochloride (commercially
available as Cardizem.RTM.), quinapril hydrochloride (commercially
available as Accupril.RTM.), quinapril
hydrochloride/hydrochlorothiazide (commercially available as
Accuretic.RTM.), perindopril erbumine (commercially available as
Aceon.RTM.), candesartan cilexetil (commercially available as
Atacand.RTM.), candesartan cilexetil/hydrochlorothiazide
(commercially available as Atacand HCT.RTM.),
irbesartan/hydrochlorothiazide (commercially available as
Avalide.RTM.), irbesartan (commercially available as Avapro.RTM.),
amlodipine besylate/olmesartan medoxomil (commercially available as
Azor.RTM.), levobunolol hydrochloride (commercially available as
Betagan.RTM.), betaxolol hydrochloride (commercially available as
Betoptic.RTM.), nebivolol (commercially available as
Bystolic.RTM.), captopril/hydrochlorothiazide (commercially
available as Capozide.RTM.), doxazosin mesylate (commercially
available as Cardura.RTM.), clonidine hydrochloride (commercially
available as Catapres.RTM.), carvedilol (commercially available as
Coreg.RTM.), nadolol (commercially available as Corgard.RTM.),
nadolol/bendroflumethiazide (commercially available as
Corzide.RTM.), valsartan (commercially available as Diovan.RTM.),
isradipine (commercially available as DynaCirc.RTM.), wytensin.
(commercially available as Guanabenz Acetate.RTM.), tenex
(commercially available as Guanfacine Hydrochloride.RTM.), losartan
potassium/hydrochlorothiazide (commercially available as
Hyzaar.RTM.), propranolol hydrochloride (commercially available as
Indera.RTM.), propranolol hydrochloride/hydrochlorothiazide
(commercially available as Inderide.RTM.), eplerenone (commercially
available as Inspra.RTM.), ambrisentan (commercially available as
Letairis.RTM.), enalapril maleate/felodipine (commercially
available as Lexxel.RTM.), metoprolol tartrate (commercially
available as Lopressor.RTM.), benazepril hydrochloride
(commercially available as Lotensin.RTM.), benazepril
hydrochloride/hydrochlorothiazide (commercially available as
Lotensin HCT.RTM.), amlodipine/benazepril hydrochloride
(commercially available as Lotrel.RTM.), indapamide (commercially
available as Lozol.RTM.), trandolapril (commercially available as
Mavik.RTM.), telmisartan (commercially available as Micardis.RTM.),
telmisartan/hydrochlorothiazide (commercially available as Micardis
HCT.RTM.), prazosin hydrochloride (commercially available as
Minipress.RTM.), amiloride, hydrochlorothiazide (commercially
available as Moduretic.RTM.), fosinopril sodium (commercially
available as ZZXT Monopril.RTM.), fosinopril
sodium/hydrochlorothiazide (commercially available as
Monopril-HCT.RTM.), pindolol (commercially available as
Visken.RTM.), felodipine (commercially available as Plendil.RTM.),
sildenafil citrate (commercially available as Revatio.RTM.),
Nisoldipine (commercially available as Sular.RTM.),
trandolapril/verapamil hydrochloride (commercially available as
Tarka.RTM.), aliskiren (commercially available as Tekturna.RTM.),
eprosartan mesylate (commercially available as Teveten.RTM.),
eprosartan mesylate/hydrochlorothiazide (commercially available as
Teveten HCT.RTM.), moexipril hydrochloride/hydrochlorothiazide
(commercially available as Uniretic.RTM.), moexipril hydrochloride
(commercially available as Univasc.RTM.), enalapril
maleate/hydrochlorothiazide (commercially available as
Vaseretic.RTM.), and lisinopril/hydrochlorothiazide (commercially
available as Zestoretic.RTM.).
[0157] The present invention may include agents useful in the
medication for the treatment of HIV/AIDS, such as amprenavir
(commercially available as Agenerase.RTM.), tipranavir
(commercially available as Aptivus.RTM.),
efavirenz/emtricitabine/tenofovir (commercially available as
Atripla.RTM.), lamivudine/zidovudine (commercially available as
Combivir.RTM.), indinavir sulfate (commercially available as
Crixivan.RTM.), lamivudine (commercially available as Epivir.RTM.),
saquinavir (commercially available as Fortovase.RTM.), zalcitabine
(commercially available as Hivid.RTM.), lopinavir/ritonavir
(commercially available as Kaletra.RTM.), fosamprenavir calcium
(commercially available as Lexiva.RTM.), ritonavir (commercially
available as Norvir.RTM.), zidovudine (commercially available as
Retrovir.RTM.), atazanavir sulfate (commercially available as
Reyataz.RTM.), efavirenz (commercially available as Sustiva.RTM.),
abacavir/lamivudine/zidovudine (commercially available as
Trizivir.RTM.), didanosine (commercially available as Videx.RTM.),
nelfinavir mesylate (commercially available as Viracept.RTM.),
nevirapine (commercially available as Viramune.RTM.), tenofovir
disoproxil fumarate (commercially available as Viread.RTM.),
stavudine (commercially available as Zerit.RTM.), and abacavir
sulfate (commercially available as Ziagen.RTM.); homocysteiene
removers, including betaine anhydrous (commercially available as
Cystadane.RTM.); medications, such as insulin (commercially
available as Apidra.RTM., Humalog.RTM., Humulin.RTM., Iletin.RTM.,
and Novolin.RTM.); and HPV treatment, such as Human papillomavirus
vaccine (commercially available as Gardasil.RTM.);
immunosuppressants, including cyclosporine (commercially available
asgENGRAF.RTM., Neoral.RTM., Sandimmune.RTM., and
Apo-Cyclosporine.RTM.).
[0158] Agents useful in the present invention may further include
prolactin inhibitors, such as bromocriptine mesylate (commercially
available as Parlodel.RTM.); medications for aiding in stress
tests, such as regadenoson (commercially available as
Lexiscan.RTM.); baldness medication, including finasteride
(commercially available as Propecia.RTM. and Proscar.RTM.);
pancreatitis treatment, such as gemfibrozil (commercially available
as Lopid.RTM.); hormone medications, such as norethindrone
acetate/ethinyl estradiol (commercially available as femHRT.RTM.),
goserelin acetate (commercially available as Zoladex.RTM.),
progesterone gel (commercially available as Prochieve.RTM.),
progesterone (commercially available as Prometrium.RTM.),
calcitonin-salmon (commercially available as Miacalcin.RTM.),
calcitriol (commercially available as Rocaltrol.RTM.), Synthroid
(commercially available as Levothroid.RTM., Levoxyl.RTM.,
Unithroid.RTM.), testosterone (commercially available as
Testopel.RTM., Androderm.RTM., Testoderm.RTM., and AndroGel.RTM.);
menopause medication, such as estradiol/norethindrone acetate
(commercially available as Activella.RTM.), drospirenone/estradiol
(commercially available as Angeliq.RTM.), estradiol/levonorgestrel
(commercially available as Climara Pro.RTM.),
estradiol/norethindrone acetate (commercially available as
CombiPatch.RTM.), estradiol (commercially available as
Estrasorb.RTM., Vagifem.RTM. and EstroGel.RTM.), esterified
estrogens and methyltestosterone (commercially available as
Estratest.RTM.), estrogen (commercially available as Alora.RTM.,
Climara.RTM., Esclim.RTM., Estraderm.RTM., Vivelle.RTM.,
Vivelle-Dot.RTM.), estropipate (commercially available as
Ogen.RTM.), conjugated estrogens (commercially available as
Premarin.RTM.), and medroxyprogesterone acetate (commercially
available as Provera.RTM.); menstrual medications, including
leuprolide acetate (commercially available as Lupron Depot), and
norethindrone acetate (commercially available as Aygestin); and
muscle relaxants, including cyclobenzaprine hydrochloride
(commercially available as Flexeril.RTM.), tizanidine (commercially
available as Zanaflex.RTM.), and hyoscyamine sulfate (commercially
available as Levsin.RTM.).
[0159] Agents useful herein may also include osteoporosis
medications, including ibrandronate sodium (commercially available
as Boniva.RTM.), risedronate (commercially available as
Actonel.RTM.), raloxifene hydrochloride (commercially available as
Evista.RTM., Fortical.RTM.), and alendronate sodium (commercially
available as Fosamax.RTM.); ovulation enhancers, including
clomiphene citrate (commercially available as Serophene.RTM.,
Clomid.RTM., Serophene.RTM.); Paget's disease treatment, such as
etidronate disodium (commercially available as Didronel.RTM.);
pancreatic enzyme deficiency medications, such as pancrelipase
(commercially available as Pancrease.RTM.); medication for the
treatment of Parkinson's disease, such as pramipexole
dihydrochloride (commercially available as Mirapex.RTM.),
ropinirole hydrochloride (commercially available as Requip.RTM.),
carbidopa/levodopa (commercially available as Sinemet CR.RTM.),
carbidopa/levodopa/entacapone (commercially available as
Stalevo.RTM.), selegiline hydrochloride (commercially available as
Zelapar.RTM.), rasagiline (commercially available as Azilect.RTM.),
entacapone (commercially available as Comtan.RTM.), and selegiline
hydrochloride (commercially available as Eldepryl.RTM.); prostate
medication, including flutamide (commercially available as
Eulexin.RTM.), nilutamide (commercially available as
Nilandron.RTM.), dutasteride (commercially available as
Avodart.RTM.), tamsulosin hydrochloride (commercially available as
Flomax.RTM.), terazosin hydrochloride (commercially available as
Hytrin.RTM.), and alfuzosin hydrochloride (commercially available
as UroXatral.RTM.).
[0160] Films of the present invention may further include
psychiatric medications, including alprazolam (available as
Niravam.RTM., Xanax.RTM.), clozopin (available as Clozaril.RTM.),
haloperidol (available as Haldol.RTM.), fluoxetine hydrochloride
(available as Prozac.RTM.), sertraline hydrochloride (available as
Zoloft.RTM.), and paroxtine hydrochloride (available as
Paxil.RTM.), aripiprazole (commercially aavialbe as Abilify.RTM.),
Amphetamines and methamphetamines (commercially available as
Adderall.RTM. and Desoxyn.RTM.), clomipramine hydrochloride
(commercially available as Anafranil.RTM.), Buspirone hydrochloride
(commercially available as BuSpar.RTM.), citalopram hydrobromide
(commercially available as Celexa.RTM.), duloxetine hydrochloride
(commercially available as Cymbalta.RTM.), methylphenidate
(commercially available as Ritalin, Daytrana.RTM.), divalproex
sodium (Valproic acid) (commercially available as Depakote.RTM.),
dextroamphetamine sulfate (commercially available as
Dexedrine.RTM.), venlafaxine hydrochloride (commercially available
as Effexor.RTM.), selegiline (commercially available as
Emsam.RTM.), carbamazepine (commercially available as
Equetro.RTM.), lithium carbonate (commercially available as
Eskalith.RTM.), fluvoxamine maleate/dexmethylphenidate
hydrochloride (commercially available as Focalin.RTM.), ziprasidone
hydrochloride (commercially available as Geodon.RTM.), ergoloid
mesylates (commercially available as Hydergine.RTM.), escitalopram
oxalate (commercially available as Lexapro.RTM.), chlordiazepoxide
(commercially available as Librium.RTM.), molindone hydrochloride
(commercially available as Moban.RTM.), phenelzine sulfate
(commercially available as Nardil.RTM.), thiothixene (commercially
available as Navane.RTM.), desipramine hydrochloride (commercially
available as Norpramin.RTM.), benzodiazepines (such as those
available as Oxazepam.RTM.), nortriptyline hydrochloride
(commercially available as Pamelor.RTM.), tranylcypromine sulfate
(commercially available as Parnate.RTM.), prochlorperazine,
mirtazapine (commercially available as Remeron.RTM.), risperidone
(commercially available as Risperdal.RTM.), quetiapine fumarate
(commercially available as Seroquel.RTM.), doxepin hydrochloride
(commercially available as Sinequan.RTM.), atomoxetine
hydrochloride (commercially available as Strattera.RTM.),
trimipramine maleate (commercially available as Surmontil.RTM.),
olanzapine/fluoxetine hydrochloride (commercially available as
Symbyax.RTM.), imipramine hydrochloride (commercially available as
Tofranil.RTM.), protriptyline hydrochloride (commercially available
as Vivactil.RTM.), bupropion hydrochloride (commercially available
as Wellbutrin.RTM., Wellbutrin SR.RTM., and Wellbutrin XR.RTM.),
and olanzapine (commercially available as Zyprexa.RTM.).
[0161] Agents useful herein may also include uric acid reduction
treatment, including allopurinol (commercially available as
Zyloprim.RTM.); seizure medications, including gabapentin
(commercially available as Neurontin.RTM.), ethotoin (commercially
available as Peganone.RTM.), and topiramate (commercially available
as Topamax.RTM.); treatment for shingles, such as zoster vaccine
live (commercially available as Zostavax.RTM.); skin care
medications, including calcipotriene (commercially available as
Dovonex.RTM.), isotretinoin (commercially available as
Accutane.RTM.), hydrocortisone/iodoquinol (commercially available
as Alcortin.RTM.), sulfacetamide sodium/sulfur (commercially
available as Avar.RTM.), azelaic acid (commercially available as
Azelex.RTM., Finacea.RTM.), benzoyl peroxide (commercially
available as Desquam-E.RTM.), adapalene (commercially available as
Differin.RTM.), fluorouracil (commercially available as
Efudex.RTM.), pimecrolimus (commercially available as Elidel.RTM.),
topical erythromycin (commercially available as A/T/SO,
Erycette.RTM., T-Stat.RTM.), hydrocortisone (commercially available
as Cetacort.RTM., Hytone.RTM., Nutracort.RTM.), metronidazole
(commercially available as MetroGel.RTM.), doxycycline
(commercially available as Oracea.RTM.), tretinoin (commercially
available as Retin-A.RTM. and Renova.RTM.), mequinol/tretinoin
(commercially available as Solage.RTM.), acitretin (commercially
available as Soriatane.RTM.), calcipotriene hydrate/betamethasone
dipropionate (commercially available as Taclonex.RTM.), tazarotene
(commercially available as Tazorac.RTM.), fluocinonide
(commercially available as Vanos.RTM.), desonide (commercially
available as Verdeso.RTM.), miconazole nitrate/Zinc oxide
(commercially available as Vusion.RTM.), ketoconazole (commercially
available as Xolegel.RTM.), and efalizumab (commercially available
as Raptiva.RTM.).
[0162] Other agents useful herein may include Sleep disorder
medications, including zaleplon (available as Sonata.RTM.) and
eszopiclone (available as Lunesta.RTM.), zolpidem tartrate
(commercially available as Ambient, Ambien CR.RTM.), lorazepam
(commercially available as Ativan.RTM.), flurazepam hydrochloride
(commercially available as Dalmane.RTM.), triazolam (commercially
available as Halcion.RTM.), clonazepam (commercially available as
Klonopin.RTM.), barbituates, such as Phenobarbital.RTM.), Modafinil
(commercially available as Provigil.RTM.), temazepam (commercially
available as Restoril.RTM.), ramelteon (commercially available as
Rozerem.RTM.), clorazepate dipotassium (commercially available as
Tranxene.RTM.), diazepam (commercially available as Valium.RTM.),
quazepam (commercially available as Doral.RTM.), and estazolam
(commercially available as ProSom.RTM.); smoking cessation
medications, such as varenicline (commercially available as
Chantix.RTM.), nicotine, such as Nicotrol.RTM., and bupropion
hydrochloride (commercially available as Zyban.RTM.); and steroids,
including alclometasone dipropionate (commercially available as
Aclovate.RTM.), betamethasone dipropionate (commercially available
as Diprolene.RTM.), mometasone furoate (commercially available as
Elocon.RTM.), fluticasone (commercially available as Flonase.RTM.,
Flovent.RTM., Flovent Diskus.RTM., Flovent Rotadisk.RTM.),
fluocinonide (commercially available as Lidex.RTM.), mometasone
furoate monohydrate (commercially available as Nasonex.RTM.),
desoximetasone (commercially available as Topicort.RTM.),
clotrimazole/betamethasone dipropionate (commercially available as
Lotrisone.RTM.), prednisolone acetate (commercially available as
Pred Forte.RTM., Prednisone.RTM., Budesonide Pulmicort.RTM.,
Rhinocort Aqua.RTM.), prednisolone sodium phosphate (commercially
available as Pediapred.RTM.), desonide (commercially available as
Tridesilon.RTM.), and halobetasol propionate (commercially
available as Ultravate.RTM.).
[0163] Films of the present invention may further include agents
useful for thyroid disease treatment, such as hormones TC and TD
(commercially available as Armour Thyroid.RTM.); potassium
deficiency treatment, including potassium chloride (commercially
available as Micro-K.RTM.); triglycerides regulators, including
omega-3-acid ethyl esters (commercially available as Omacor.RTM.);
urinary medication, such as phenazopyridine hydrochloride
(commercially available as Pyridium.RTM.) and methenamine,
methylene blue/phenyl salicylate/benzoic acid/atropine
sulfate/hyoscyamine (commercially available as Urised.RTM.);
prenatal vitamins (commercially available as Advanced
Natalcare.RTM., Materna.RTM., Natalins.RTM., Prenate Advance.RTM.);
weight control medication, including orlistat (commercially
available as Xenical.RTM.) and sibutramine hydrochloride
(commercially available as Meridia.RTM.).
[0164] One particularly useful active for use in the present
invention includes cyclosporine, which is an immunosuppressive
agent, typically used in organ transplant patients. Cyclosporine is
known to be quite insoluble in water. For this reason, it is
currently known to prepare cyclosporine in an emulsified form, so
as to increase its bioavailability. The present invention provides
a dosage form including actives, such as cyclosporine, in a
small-scale form, so as to increase its bioavailability. In one
embodiment, the active may be stabilized in a small-scale form in
combination with an additive, such as vitamin E TPGS, an
amphiphilic additive. In addition to vitamin E TPGS, any other
amphiphilic additives may be used, including but not limited to
sodium dodecyl sulfate, benzalkonium chloride, cocamido propyl
betaine, saponins, fatty acids, bile acids, and combinations
thereof. The present invention is not limited to amphiphilic
additives, and may include any solvent with the addition of a
surface active agent.
[0165] Such small-scale particles may reduce the size of the active
to as low as 1% its size in an unencumbered state (referred to
herein as the "raw state"). In some embodiments, the small-scale
particle may be about 5% the size of the active in its raw state,
about 10% the size of the active in its raw state, about 15% the
size of the active in its raw state, about 25% the size of the
active in its raw state, or about 50% the size of the active in its
raw state.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] An anti-oxidant may also be added to the film to prevent the
degradation of an active, especially where the active is
photosensitive.
[0170] 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.
[0171] 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.
[0172] Moreover, fragrances can be included in the films. These may
include extracts derived from plants, leaves, flowers, fruits and
combinations thereof, for example.
Films for Delivery of Small-Scale Actives
[0173] Films of the present invention may include small-scale forms
of the active component to be delivered. As used herein, the term
"small scale actives" includes actives in a small form, such as
droplets and particles. One particularly useful form of the
small-scale active is a small particle, such as a microparticle or
nanoparticle as further defined herein. Other small-scale forms
include microdroplets and nanodroplets. Such small-scale forms of
actives may be formed through any desired means, including via
emulsion technology, evaporation, precipitation, milling or any
other desired means. In some embodiments, the small-scale active
may be formed into a complex with another component, such as a
ligand, for the purpose of maintaining the small size of the active
during mixing with the polymeric matrix. The small-scale active may
be chemically bound to another component or may be physically bound
to the component.
[0174] Some of the aforementioned agents may be classified as
emulsion compositions. An emulsion is typically a fluid consisting
of a heterogeneous mixture of two normally immiscible liquid
phases, in which one liquid forms droplets suspended in the other
liquid. Emulsion compositions may include, but are not limited to,
skin care creams, sunscreens, insect repellants, hair conditioners,
hair styling agents (e.g., hair thickening agents), certain
shampoos, and pharmaceutical ointments. Emulsions may additionally
be used in orally-administered dosages. Such products are
traditionally sold as liquids or semi-solids (e.g., ointments).
[0175] It has been discovered that liquid/liquid emulsions may be
captured in a flowable film matrix, which when dried transforms the
liquid/liquid emulsion into a liquid/solid emulsion. At least a
portion of the water from the captured emulsion may be evaporated
during the drying of the film. The resultant dried film product may
be a solid film matrix having a plurality of discrete lipophilic
droplets dispersed therein, the droplets being deposited from the
liquid/liquid emulsion. The dried film, however, is readily
rehydrated to dissolve the water soluble matrix and reform the
emulsion by contacting the film with water. As used herein, the
term "lipophilic" means having an affinity or attraction for
lipids.
[0176] In some embodiments, the lipophilic droplets captured within
the film during drying of the film may include therewithin drugs.
When the dried film is rehydrated with water, a drug emulsion is
formed, which may be topically applied.
[0177] In some embodiments, a method of preparing an emulsion
composition in accordance with the present invention includes
providing an aqueous-based emulsion; and converting the
aqueous-based emulsion into a non-aqueous dry emulsion, wherein the
dry emulsion is in the form of a self-supporting film. The method
further includes dissolving the film with an aqueous solvent,
thereby reforming the aqueous-based emulsion.
[0178] Where typical emulsions require a substantial amount of
kinetic energy to "emulsify" the constituents, e.g., heavy mixing
or shearing to form oil droplets in an aqueous medium, the
invention provides a product which readily forms an emulsion upon
contact with water, with very low energy input. Since the
lipophilic droplets are already formed and suspended in the water
soluble matrix, once the matrix is solubilized by contact with
water, the liquid droplets readily become suspended in the
surrounding water.
[0179] The lipophilic droplets are preferably microscopically
discrete and distinct droplets that have an affinity for lipids.
For example, the lipophilic droplets may be fat droplets, oil
droplets, wax droplets, sterol droplets, glyceride droplets, or
combinations thereof.
[0180] A film of the present invention may be formed by preparing a
composition including at least one water soluble polymer, a polar
solvent (e.g., water), and an emulsion composition. A film is then
formed from the prepared composition, and the film is dried by a
process whereby a plurality of lipophilic droplets become dispersed
within the film. Suitable water soluble polymers for forming the
film are the same as those described above. The emulsion
composition employed to prepare the film may include an active,
such that, during the drying process, a plurality of lipophilic
droplets including the active become dispersed in the film. The
emulsion, in effect, remains stable and intact during drying, and
can be reconstituted when water is added back to dissolve the film.
The reconsituted emulsion may then be administered to a user.
[0181] The small-scale form of the active agent may take one of
many various forms. As will be described in more detail below, the
small scale form may be in the form of a nanoparticle.
Alternatively, the small scale form of the active may include
liposomes, dendrimers, polymer nanoparticles and coated
polymer-based nanoparticles, micelles, fullerenes, nanotubes,
chitosan/lecithin nanoparticles, nanostructured biomaterials,
stealth liposomes, nanocrystals, particles produced by
homogenization and/or precipitation, nanoparticles with
phospholipid-cation precipitates, calcium phosphate-based
particles, albumin-bound particles, water/oil emulsions, and
combinations thereof.
[0182] The films of the present invention are particularly well
suited for delivery of small drug particles, such as nanoparticles.
Nanoparticles are generally understood to be particles which have
an average size of less than one micron. Typically this is an
average diameter size. In some embodiments, the emulsions of the
present invention include the drug particles, for example
nanoparticles, to be captured within the lipophilic droplets which
themselves are captured within the film and which when
reconstituted with appropriate solvent, such as aqueous media, can
be released. The presence of the active need not be limited,
however, to the lipophilic droplets but can also be included in the
matrix of the film. Additionally, one or more actives can be
present and different actives may be included in a lipophilic
droplet and concurrently in the film matrix.
[0183] In another aspect of the invention, liquid crystal
structures, such those used in U.S. Pat. No. 5,891,845, which is
herein incorporated in its entirety by reference, may be employed
to deliver and/or control the release of drugs. These liquid
crystal structures may be included in the films. Liquid crystal
structures may include solid solutions of the drug and film. For
example, such liquid crystal structures may include, for example,
actives such as cyclosporine, nifedipine, diltiazem hydrochloride,
and other related compounds. These actives form a solid solution
when mixed with a surfactant, such as Vitamin E TPGS. The
active/Vitamin E TPGS complex may be formed via any means,
including heat-melting the components together to form a liquid
crystal structure. The resulting composition is a small-scale,
liquid crystal form of the active, which may be dispersed through a
polymeric matrix as will be described in more detail below.
[0184] The small-scale active may be formed via any other desired
means. For example, the small-scale form may be formed through
microfluidics processing. In such processes, the small-scale active
may include a nano-emulsion (or micro-emulsion). The microfluidic
process may include the use of a high-energy device, such as a
microfluidic pump. The pump is capable of colliding two streams of
fluid into each other at high energy levels, forming an emulsion of
the two fluids while also creating extremely small, fine droplet
size. For example, the pump may generate a stream of solvent, such
as water or other polar solvent, which is collided with a second
stream, which may include an oil-based solvent with the active
dissolved therein. The streams of fluid are desirably collided at
high pressures, for example from about 3,000 to about 5,000 psi.
Alternatively, the streams of fluid may be collided at pressures of
at least 3,000 psi. The resultant fine droplets may be dispersed
throughout a polymeric matrix as will be described in more detail
below, and formed into a film for administration.
[0185] In another embodiment, the small-scale active may be formed
through physical manipulation, such as milling or grinding. In such
embodiments, the active may be formed into a powder, slurry, or any
other form. The active may then be dispersed into water or other
fluid. The suspended active agent may then be subjected to a
physical manipulation, such as milling or grinding or other similar
process, until a suspension of small-scale particles of the active
agent remains. The small-scale active may then be collected and
dispersed throughout a polymeric matrix as will be described in
more detail below, and formed into a film for administration. In
some embodiments, the small-scale active may be added to the
polymeric matrix via deposition. That is, the small-scale active
may be deposited onto one or more surfaces of the polymeric matrix.
Optionally, the small-scale active may be dispersed throughout a
polymeric matrix in addition to being deposited onto one or more
surfaces of the polymeric matrix.
[0186] In still other embodiments of forming the small-scale
active, the active may be heated to the point of melting and
subjected to evaporation. Such methods of heating to melt the
active may be found in Applicant's co-pending U.S. application
Publication No. 2009/0104270, the contents of which are
incorporated by reference herein in their entirety. The active may
be dispersed into a heated solvent to the point of melting, and the
solvent evaporated to leave a residue of small-scale form of
active. The small-scale form of active may be collected and
dispersed throughout a polymeric matrix as will be described in
more detail below, and formed into a film for administration.
[0187] Once the small-scale form of the agent has been formed,
through any desired process, the small-scale form of the agent may
optionally be bound to one or more ligands prior to dispersion into
the polymeric matrix. Any ligand material may be used, including
metals such as gold, polymers such as polyethylene glycol, and the
like. The agent may be chemically bound to the ligand or it may be
physically bound to the ligand (such as through electrostatic
binding). Associating the small-scale form of the agent with a
ligand aids in sustaining the small-scale form of the agent during
preparation and formation of the film dosage. The ligand is bound
to the agent during the formation of the film, which restricts the
ability of the particles of the agent to agglomerate and therefore
become non-uniform. Once the film has been ingested or absorbed by
the user, the ligand is released from the agent, allowing the
small-scale form of the agent to be absorbed into the body.
[0188] The ligand may be exposed to any body cavity, so long as
there is sufficient moisture present to release the ligand. For
example, the ligand may be placed in the oral cavity of the user,
using saliva to release the agent. The delivery may be buccal,
sublingual, peroral, topical, or any other delivery means
desired.
[0189] The small-scale form of the agent, whether bound to a ligand
or free, may be dispensed into a film forming polymeric matrix.
Desirably, the agent is dispensed into the matrix in such a fashion
that the agent is substantially uniform in distribution throughout
the polymeric matrix. The polymeric matrix may then be subjected to
heat so as to rapidly form a visco-elastic mass, as explained
above. One particularly desirable drying process is described
herein. By rapidly forming the visco-elastic mass, the particles of
the agent are effectively trapped in place, so as to avoid
undesirable agglomeration and/or migration of particles, which
would result in non-uniformity of content in the unit dosage film.
The resulting film product has a substantially uniform distribution
of a small-scale form of the agent and has a predictable uniformity
of content per unit dosage, i.e., the film formed can be cut into
individual doses and will have substantially the same active
content per unit dose.
[0190] While not wishing to be bound by any one theory, it is
believed that, in the present invention, the film rheology changes
so quickly during drying that the emulsion, which typically will
break when heated and water is evaporated, is in fact still intact.
The emulsion characteristics are substantially maintained, even
when all of the water is evaporated away during the film drying
process. When water is added back to the film, the emulsion
reforms, and can be delivered topically or orally.
[0191] In some embodiments, the drying process includes heating the
film at a temperature above the phase inversion temperature of the
emulsion composition. A phase inversion temperature for an emulsion
is the temperature at which an emulsion will go from either a
water/oil emulsion to an oil/water emulsion or vice versa.
Typically, if one were to try to remove the water phase from an
aqueous-based emulsion by drying, then one would expect the
emulsion to turn into one phase (i.e., oil). However, by heating
the film in accordance with the methods provided herein, the oil
droplets are captured in the film before coalescence of the oil
droplets can occur, thereby permitting the system to be stabilized
at a higher energy state relative to that if the emulsion converted
to just one phase in the absence of water. For example, in some
embodiments, the film is heated at a temperature above the phase
inversion temperature for the emulsion in order to capture a
plurality of oil droplets in the film. In some other embodiments,
the drying is performed for about 10 to about 15 minutes.
[0192] In the present invention, an emulsion may be prepared by
providing a solid water soluble polymeric film having dispersed
therein a plurality of the lipophilic droplets; and adding water to
dissolve the film, thereby forming an emulsion. The emulsion may be
applied to surface in need thereof, such as a body surface.
[0193] A further aspect of the present invention relates to a
method of preparing a water reconsitutable emulsion composition.
The method includes preparing a composition including at least one
water soluble polymer; a polar solvent; and an emulsion
composition. The method further includes drying the composition to
form a dry emulsion including lipophilic droplets dispersed within
a solid water soluble polymeric matrix. As described above, the
drying process may include heating at a temperature above the
critical inversion temperature of the emulsion. In some
embodiments, the dry emulsion is formed by drying for about 10 to
about 15 minutes.
[0194] In some embodiments, a system useful for applying an
emulsion includes a dry emulsion including lipophilic droplets
dispersed with a water soluble polymeric film; and a solvent for
dissolving the polymeric film. The solvent is provided for direct
contact with the dry emulsion to cause the dry emulsion to be
reconstituted, whereby the reconstituted emulsion can be applied to
the substrate surface, including skin and wounds. The solvent may
be present in a container separate from or affixed to the film.
Suitable containers include, but are not limited to, pump bottles,
sealed tubes and sealed, rupturable pouches.
[0195] The system may optionally include an applicator for applying
the reconstituted emulsion to the substrate surface. The applicator
may, for example, be a sponge. In some embodiments, the film is
deposited on top of a wetted sponge applicator. In some other
embodiments, the film is deposited on top of a dry sponge
applicator, which when subsequently wetted with the solvent, is
used to apply the reconstituted emulsion.
[0196] The film may be interposed between a container including the
solvent and an area of skin. Alternatively, the film may be
interposed between a container including the solvent and an
applicator, such as a sponge applicator.
[0197] In some embodiments, the films of the present invention are
useful for delivering any biologically active compound, including,
for example, a pharmaceutical, cosmetic, cosmeceutical or
nutraceutical active. For example, the lipophilic droplets
deposited from a liquid/liquid emulsion may contain any of the
actives described herein, such as drugs, vitamins, minerals,
medicinal agents, herbals, botanicals, animal extracts or products,
cosmetic ingredients, cosmeceuticals or nutraceuticals. In some
embodiments, the active is solubilized in the lipophilic droplets.
In some other embodiments, the active is suspended in the
lipophilic droplets.
Films for Delivery of Eutectic Compositions
[0198] The present invention also provides film compositions, which
are useful for delivering a dispersion of a eutectic composition.
The film composition includes a solid water soluble polymeric
matrix; and a plurality of droplets of a eutectic composition
dispersed within the matrix. The film composition forms a
dispersion of the eutectic composition when exposed to water. As
defined herein, a eutectic composition is a mixture of two or more
components which has a lower melting point than any of its
constituents.
[0199] In some embodiments, the eutectic composition is a mixture
of prilocaine and lidocaine. It has been discovered that a eutectic
composition can be formed in situ from lidocaine and the HCl salt
of prilocaine, as shown in the examples below. In particular, the
HCl salt of prilocaine was neutralized with sodium hydroxide in
situ in order to obtain the prilocaine base needed to form the
eutectic composition with lidocaine. The prilocaine/lidocaine
eutectic was combined with a blend of polymers in the presence of
water to produce a film containing a dispersion of the eutectic oil
as observed under a microscope. When wetted, the film dissolved,
and turned opaque, indicating that the eutectic oil was being
released as small emulsion-type droplets.
Dosages
[0200] The film products of the present invention are capable of
accommodating a wide range of amounts of the agent. The films are
capable of providing an accurate dosage amount (determined by the
size of the film and concentration of the agent in the original
polymer/water combination) regardless of whether the required
dosage is high or extremely low. Therefore, depending on the type
of agent that is incorporated into the film, the agent 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.
[0201] The film products and methods of the present invention are
well suited for high potency, low dosage active agents. 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-Foaming and De-Foaming Compositions
[0202] 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.
[0203] 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.
[0204] 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.
[0205] 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.
[0206] 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
[0207] 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.
[0208] 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, 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).
[0209] 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
methylcelluose, 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.
[0210] 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.
[0211] Further additives may be glidants and opacifiers, 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.
[0212] 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.
[0213] There may further be added compounds to improve the texture
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.
[0214] 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
[0215] 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
opacifiers and flow agents.
[0216] 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.
[0217] 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.
[0218] 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.
[0219] 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.
[0220] Films of the present invention, particularly films useful
for oral ingestion by a user, may further include one or more
taste-enhancing agents, such as flavors and/or sweeteners. Suitable
flavors and sweeteners include those set forth in U.S. Pat. No.
7,425,292, the entire contents of which are incorporated by
reference herein.
[0221] Further potential additives include solubility enhancing
agents, such as substances that form inclusion compounds with
active components. Such agents may be useful in improving the
properties of very insoluble and/or unstable actives. In general,
these substances are doughnut-shaped molecules with hydrophobic
internal cavities and hydrophilic exteriors. Insoluble and/or
instable actives may fit within the hydrophobic cavity, thereby
producing an inclusion complex, which is soluble in water.
Accordingly, the formation of the inclusion complex permits very
insoluble and/or instable actives to be dissolved in water. A
particularly desirable example of such agents are cyclodextrins,
which are cyclic carbohydrates derived from starch. Other similar
substances, however, are considered well within the scope of the
present invention.
Forming the Film
[0222] 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 component as desired, the combination is formed
into a sheet or film, by any method known in the art such as
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.
[0223] 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.
Casting the Film Composition
[0224] The invention uses processes for making self-supporting
films having a substantially uniform distribution of components.
The self supporting film is particularly useful for delivery of
actives as discussed herein. The processes for making the film are
designed to maintain the compositional uniformity of components
distributed throughout the film, which is particularly necessary
when actives, such as pharmaceutical actives, are incorporated into
the film. In the pharmaceutical context, it is essential that the
film is compositionally uniform so that it can be divided into
individual film dosage units, each dosage unit having the
appropriate amount of active when administered, such that
regulatory approval can be secured.
[0225] One process used to make the films is described in U.S.
application Ser. No. 10/074,272, which is incorporated in its
entirety herein by reference. In this process, the films are
prepared by rapidly forming a visco-elastic film by applying hot
air currents to the film to prevent flow migration and
intermolecular forces from creating aggregates or conglomerates
thereby maintaining compositional uniform distribution of
components in the film; and further drying the visco-elastic film
to form a self-supporting film.
[0226] Desirably, the hot air currents are applied to the bottom of
the film, with substantially no top air flow. This allows the depth
of the film to be dried prior to forming a polymer skin on the top
surface of the film, which would disrupt the surface of the film,
leading to non-uniformity. The dried, self-supporting film is
uniform in the distribution of the components contained therein,
weight and thickness.
[0227] The film first may be fed onto the top side of a surface
prior to the application of hot air currents. The wet film is
desirably formed from a deaerated matrix within a time period
before the active contained therein degrades. The hot air currents
may then be applied to the bottom side of the surface with
substantially no top air flow. The process may further include a
step of dividing the dried film into individual dosage units of
equal dimensions and compositional make-up. The hot air currents
may be applied to the bottom surface of the film at a higher
velocity than to the top surface of the film during drying. Hot air
currents applied to dry the top of the films are less than that
which would cause surface rippling or skinning. This permits the
film to sufficiently thicken in viscosity to lock-in volumetric
uniformity while permitting evaporation of water through the
non-skinned surface.
[0228] The process may further include the preliminary steps of
forming a masterbatch premix of an edible water-soluble polymer and
water; deaerating the premix by mixing; feeding a predetermining
amount of the deaerated premix to at least one mixer; adding an
active component to the mixer; and mixing the components to achieve
a uniform distribution thereof. Thereafter, the wet film is formed
and dried.
[0229] 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.
[0230] 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.
[0231] 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.
[0232] Offset Gravure is common, where the coating is deposited on
an intermediate roller before transfer to the substrate.
[0233] 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.
[0234] 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.
[0235] 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.
[0236] 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.
[0237] 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.
[0238] 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
[0239] 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
unite.
[0240] 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.
[0241] 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.
[0242] 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.
[0243] In some embodiments, the weight of the polar solvent is at
least about 30% of the film before drying. In some other
embodiments, the drying of the film reduces the weight percent of
the polar solvent to about 10% or less. Preferably, the drying
occurs within about 10 minutes or fewer.
[0244] 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.
[0245] 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.
[0246] 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.
[0247] 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.
[0248] Another method of controlling the drying process involves a
zone drying procedure. A zone drying apparatus may include a
continuous belt drying tunnel having one or more drying zones
located within. The conditions of each drying zone may vary, for
example, temperature and humidity may be selectively chosen. It may
be desirable to sequentially order the zones to provide a stepped
up drying effect.
[0249] The speed of the zone drying conveyor desirably is
continuous. Alternatively, the speed may be altered at a particular
stage of the drying procedure to increase or decrease exposure of
the film to the conditions of the desired zone. Whether continuous
or modified, the zone drying dries the film without surface
skinning
[0250] According to an embodiment of the zone drying apparatus 100,
shown in FIG. 9, the film 110 may be fed onto the continuous belt
120, which carries the film through the different drying zones. The
first drying zone that the film travels through 101 may be a warm
and humid zone. The second zone 102 may be hotter and drier, and
the third zone 103 may also be hot and dry. These different zones
may be continuous, or alternatively, they may be separated, as
depicted by the zone drying apparatus 200 in FIG. 10, where the
first drying zone 201, second drying zone 202 and third drying zone
203 are shown. The zone drying apparatus, in accordance with the
present invention, is not limited to three drying zones. The film
may travel through lesser or additional drying zones of varying
heat and humidity levels, if desired, to produce the controlled
drying effect of the present invention.
[0251] To further control temperature and humidity, the drying
zones may include additional atmospheric conditions, such as inert
gases. The zone drying apparatus further may be adapted to include
additional processes during the zone drying procedure, such as, for
example, spraying and laminating processes, so long as controlled
drying is maintained in accordance with the invention.
[0252] 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. In some embodiments, the film
product has a thickness of greater than 0.1 mils. In some other
embodiments, the film product has a thickness of about 10 mils or
fewer. In some further embodiments, the film product has a
thickness of about 0.5 mils to about 5 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.
Testing Films for Uniformity
[0253] It may be desirable to test the films of the present
invention for chemical and physical uniformity during the film
manufacturing process. In particular, samples of the film may be
removed and tested for uniformity in film components between
various samples. Film thickness and over all appearance may also be
checked for uniformity. Uniform films are desired, particularly for
films containing pharmaceutical active components for safety and
efficacy reasons.
[0254] A method for testing uniformity in accordance with the
present invention includes conveying a film through a manufacturing
process. This process may include subjecting the film to drying
processes, dividing the film into individual dosage units, and/or
packaging the dosages, among others. As the film is conveyed
through the manufacturing process, for example on a conveyor belt
apparatus, it is cut widthwise into at least one portion. The at
least one portion has opposing ends that are separate from any
other film portion. For instance, if the film is a roll, it may be
cut into separate sub-rolls. Cutting the film may be accomplished
by a variety of methods, such as with a knife, razor, laser, or any
other suitable means for cutting a film.
[0255] The cut film then may be sampled by removing small pieces
from each of the opposed ends of the portion(s), without disrupting
the middle of the portion(s). Leaving the middle section intact
permits the predominant portion of the film to proceed through the
manufacturing process without interrupting the conformity of the
film and creating sample-inducted gaps in the film. Accordingly,
the concern of missing doses is alleviated as the film is further
processed, e.g., packaged. Moreover, maintaining the completeness
of cut portions or sub-rolls throughout the process will help to
alleviate the possibility of interruptions in further film
processing or packaging due to guilty control issues, for example,
alarm stoppage due to notice of missing pieces.
[0256] After the end pieces, or sampling sections, are removed from
the film portion(s), they may be tested for uniformity in the
content of components between samples. Any conventional means for
examining and testing the film pieces may be employed, such as, for
example, visual inspection, use of analytical equipment, and any
other suitable means known to those skilled in the art. If the
testing results show non-uniformity between film samples, the
manufacturing process may be altered. This can save time and
expense because the process may be altered prior to completing an
entire manufacturing run. For example, the drying conditions,
mixing conditions, compositional components and/or film viscosity
may be changed. Altering the drying conditions may involve changing
the temperature, drying time, moisture level, and dryer
positioning, among others.
[0257] Moreover, it may be desirable to repeat the steps of
sampling and testing throughout the manufacturing process. Testing
at multiple intervals may ensure that uniform film dosages are
continuously produced. Alterations to the process can be
implemented at any stage to minimize non-uniformity between
samples.
Uses of Thin Films
[0258] 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 skin and other body surfaces,
including those with mucous membranes.
[0259] The films may be used to topically administer an active
agent or may be used to orally administer the active agent. Topical
administration may be accomplished by preparing the film as
described above, introducing the film to a skin surface of a
mammal, and wetting the film if necessary, for example. If desired,
this film may be prepared and adhered to a second or support layer
from which it is removed prior to use, i.e. application to the
skin. 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 an adhesive that does not alter the properties of the
active. Mucoadhesive compositions are also useful. The film
compositions in many cases serve as mucoadhesives themselves.
[0260] The films of the present invention take advantage of the
films' tendency to dissolve quickly when wetted, i.e., through
contact with a wetting agent such as water or saliva. 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 to prepare a liquid dosage form of an
active, which may then be administered to the user.
[0261] A specific film shape or size may be preferred. Therefore,
the film may be cut to any desired shape or size.
[0262] 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, such as a medicinal agent, is shown.
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.
[0263] The films of the present invention dissolve instantly with a
wetting agent, such as water, or by contact with mucosal membrane
areas, such as found in the oral, anal or vaginal cavities. A
wetting agent permits an active agent contained within the film to
be dissolved or dispersed out of the film. In instances where the
active agent is a topical agent, wetting the topical agent allows
the topical agent to be easily applied to the skin or other
particular surface area.
[0264] 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.
[0265] 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
Example 1
Incorporation of a Skin Care Cream into a Film Base
[0266] The present example is directed to the incorporation of a
skin care cream into a polyethylene oxide/hydroxypropylmethyl
cellulose (70/30) film base. The skin care cream used in this
example is an emulsion composition. The resulting film was found to
be useful as a dissolvable skin lotion film (22.38% solids, by
weight). The components are shown below in Table A.
TABLE-US-00001 TABLE A Components Wt (g) Polyethylene oxide WSR-N80
4.73 Hydroxypropylmethyl cellulose E15 2.03 Skin care cream.sup.1
3.35 Sorbitan monooleate NF (Span 80).sup.2 0.04 .sup.1Available
from Stockhausen, and containing 2.15 g of three ingredients and
1.2 g water. .sup.2Available from Farma International, Coral
Gables, Florida.
[0267] The skin care cream and sorbitan monooleate from Table A
were combined with 29.85 g of distilled water, and added to a
Degussa 1100 bowl. Then, a blend of the polyethylene oxide and
hydroxypropylmethyl cellulose (Table A) was added to the bowl. The
combination of components was mixed using the Degussa Dental
Multivac Compact. In particular, a solution was prepared by mixing
the components at 125 rpm for preset time intervals under
increasing vacuum as set forth in Table B below.
TABLE-US-00002 TABLE B Time (min) Mixing Speed (rpm) Vacuum (Hg) 20
125 17 20 125 24 12 125 26.5 8 125 28
[0268] The solution was cast into film using the K-Control Coater
with the micrometer adjustable wedge bar set at 450 microns onto
the HDP side of 6330, coated side of 6330 and 55 # PS/1/5 "IN"
release paper (tariff, Fallsington, Pa.). The film was dried 15
minutes in an 80.degree. C. air oven to about 3.50% moisture (HR 73
Moisture Analyzer). The film released readily from all
substrates.
[0269] The resulting film had a thickness of 2.8 mils, had good
tear resistance, had sufficient strength when pulled, was not
sticky, and passed the 180.degree. bend test out of the moisture
analyzer.
[0270] A piece of the film, when wetted in the hand with water,
dissolved readily, leaving the skin care cream which spread on the
skin easily. The emulsion reformed when the film was contacted with
water.
[0271] The present example demonstrates the feasibility of
preparing a dissolvable skin lotion film. The film was cut into
11/2 inch by 21/2 inch strips, which each weighed 148 mg,
demonstrating the uniformity of the composition of the film.
Example 2
Incorporation of a Sunscreen into a Film Base
[0272] The present example is directed to the incorporation of a
sunscreen into a polyethylene oxide/hydroxypropylmethyl cellulose
(70/30) film base. The sunscreen used in this example is an
emulsion composition. The resulting film was found to be useful as
a dissolvable sunscreen lotion film (22% solids, by weight). The
components of the film are shown below in Table C.
TABLE-US-00003 TABLE C Components Wt (g) Polyethylene oxide WSR-N80
4.90 Hydroxypropylmethyl cellulose 2.10 Sunscreen.sup.3 1.92
Sorbitan monooleate NF (Span 80) 0.044 .sup.3Blue Lizard sunscreen
containing: 1.76 g (20%) active and other ingredients; and 0.16 g
water.
[0273] The sunscreen and sorbitan monooleate from Table C were
combined with 31.04 g of distilled water and added to a Degussa
1100 bowl. Then, a blend of the polyethylene oxide and
hydroxypropylmethyl cellulose was added to the bowl. The
combination of components was mixed using the Degussa Dental
Multivac Compact under the same conditions as described in Table B
of Example 1.
[0274] The resulting solution was cast into film using the
K-Control Coater with the micrometer adjustable wedge bar set at
450 microns onto the HDP side of 6330. The film was dried 15
minutes in an 80.degree. C. air oven. The film had 2.94% of
moisture (HR73 Moisture Analyzer).
[0275] The resulting film had a thickness of 3 mil, showed some
mottling on surface, showed curling, had good tear resistance and
had a film adhesion rating of 5 from the HDP side of 6330. It also
had sufficient strength when pulled, was not sticky and passed the
180.degree. bend test out of the moisture analyzer. The film was
cut into 11/2 inch by 21/2 inch pieces, each weighting 152 mg.
[0276] A piece of the film, when wetted in the hand, dissolved
readily and left the sunscreen, which spread on the skin easily. In
particular, the sunscreen emulsion reformed when the film was
dissolved with water.
Example 3
Incorporation of an Antibacterial Hand Soap into a Film Base
[0277] The present example is directed to the incorporation of an
antibacterial soap (Equate brand) into a polyethylene
oxide/hydroxypropylmethyl cellulose (70/30) film base for use as a
dissolvable soap film (22% solids, by weight). The components of
the film are shown below in Table D.
TABLE-US-00004 TABLE D Components Wt (g) Polyethylene oxide WSR-N80
5.21 Hydroxypropylmethyl cellulose E15 2.23 Liquid antibacterial
soap.sup.4 9.62 Sorbitan monooleate NF (Span 80) 0.044 .sup.4Equate
brand containing: 1.32 g (15%) active and other ingredients; and
8.3 g water.
[0278] The antibacterial soap and sorbitan monooleate were combined
with 22.9 g distilled water in a Degussa 1100 bowl. Then, a blend
of the polyethylene oxide and hydroxypropylmethyl cellulose was
added to the bowl. The combination of components was mixed using
the Degussa Dental Multivac Compact under the conditions set forth
in Table E below.
TABLE-US-00005 TABLE E Time (min) Mixing Speed (rpm) Vacuum (Hg) 20
100 17 20 100 19.75 12 100 22 8 100 25
[0279] The resulting solution was cast into film using the
K-Control Coater with micrometer adjustable wedge bar set at 450
microns onto the HDP side of 6330, coated side of 6330, and 55
#PS/1/5 "IN" release paper (Griff). The film was dried 15 minutes
in an 80.degree. C. air oven to about 1.60% moisture (HR73 Moisture
Analyzer).
[0280] The resulting film had a thickness of 4.5 mils, had a film
adhesion rating of 6 from HDP side of 6330 and came loose from all
substrates. It also had moderate tear resistance, had adequate
strength when pulled, was not sticky, and passed the 180.degree.
bend test out of the moisture analyzer. A 11/2 inch.times.21/2 inch
piece of film weighed 150 mg.
[0281] A piece of film, when wetted in the hand, dissolved fairly
well, and left the soap which lathered on the skin.
Example 4
Incorporation of a Further Antibacterial Hand Soap into a Film
Base
[0282] The present example is directed to incorporation of an
antibacterial hand soap into a polyethylene
oxide/hydroxypropylmethyl cellulose (70/30) film base. The film is
to be used as a dissolvable hand soap film (22% solids, by weight).
The components of the film are shown below in Table F.
TABLE-US-00006 TABLE F Components Wt (g) Polyethylene oxide WSR-N80
4.87 Hydroxypropylmethyl cellulose E15 2.08 Antibacterial Hand
Soap.sup.8 2.86 Menthol .09 .sup.7Ultra Dawn Antibacterial Hand
Soap containing: 1.76 g (20%) of active and other ingredients; and
1.1 g water.
[0283] The menthol and 30.1 g of distilled water were placed in a
Degussa 1100 bowl. Then, a blend of the polyethylene oxide and
hydroxypropylmethyl cellulose was added to the bowl.
[0284] A solution was prepared as described in Table G using the
Degussa Dental Multivac Compact.
TABLE-US-00007 TABLE G Time (min) Mixing Speed (rpm) Vacuum (Hg) 20
125 17 20 100 24 12 100 26.5 4 100 28
[0285] After 4 minute mixing interval shown in Table G, the
antibacterial hand soap was added, and mixing continued for an
additional four minutes at 100 rpm under vacuum at 28 Hg.
[0286] The resulting solution was cast into film using the
K-Control Coater with the micrometer adjustable wedge bar set at
450 microns onto the HDP side of 6330, and coated side of 6330. The
film was dried for 15 minutes in an 80.degree. C. air oven. The
percent moisture of the film was 2.6% (HR73 Moisture Analyzer).
[0287] The film had a thickness of 3 mils, came loose from both
substrates, had a film adhesion rating of 5 from HDP side of 6330
and had moderate tear resistance. It also had good strength when
pulled, was not sticky, and passed the 180.degree. bend test out of
the moisture analyzer. A 11/2 inch.times.21/2 inch strip weighed
153 mg.
[0288] When wetted in the hands, the film lumped up, indicating
that a different film base would be needed for hand soap.
Example 5
Incorporation of an Anesthetic into a Film Base
[0289] The present example is directed to the incorporation of a
prilocaine/lidocaine (50/50) eutectic into a
PEO/hydroxypropylmethyl cellulose/polydextrose (70/10/20) film base
at the 50 mg dose level in a 110 mg strip. Droplets of eutectic oil
are captured in the film base during the drying of the film. The
film base, when wetted, is useful as a dispersion of a
prilocaine/lidocaine eutectic. The prilocaine/lidocaine eutectic is
an oil at room temperature and therefore permits better skin
penetration than the corresponding salt forms.
[0290] The components of the film are shown below in Table H:
TABLE-US-00008 TABLE H Components Wt (g) Polyethylene oxide WSR-N80
5.82 Hydroxypropylmethyl cellulose E15 0.83 Polydextrose 1.66
Lidocaine/Prilocaine (50/50) Eutectic Mixture 7.95 Sodium chloride
1.056 Menthol 0.17
[0291] In order to obtain the prilocaine base needed to form a
eutectic with lidocaine, the HCl salt of prilocaine was neutralized
with NaOH according to the following reaction, which was performed
in situ, as described in further detail below:
Prilocalne HCl+NaOH.fwdarw.Prilocalne+NaCL+H.sub.2O
[0292] The procedure used to make the film product will now be
described. Distilled water (29.29 g) was first added to a Degussa
1100 bowl. Then, 4.636 g of prilocaine HCl, 3.61 g of a 20% NaOH
solution (containing 0.722 g NaOH and 2.88 g water) and 3.977 g of
lidocaine were added to the bowl, in the order mentioned.
Subsequently, 0.17 g of menthol and a blend of polyethylene oxide,
hydroxypropylmethyl cellulose and polydextrose were added to the
bowl. The combination of components was mixed using the Degussa
Dental Multivac Compact under the conditions set forth in Table I
below.
TABLE-US-00009 TABLE I Time (min) Mixing Speed (rpm) Vacuum (Hg) 20
125 17 20 125 24 12 125 26.5 8 125 28
[0293] The resulting solution was cast into film using the
K-Control Coater with the micrometer adjustable wedge bar set at
550 microns onto the HDP side of 6330. The film was dried 17
minutes in an 80.degree. C. oven to about 2.83% moisture. The film
was cut into 11/4.times.1 inch strips, which weighed 107 mg.
[0294] The resulting film was a dry film which contained a
dispersion of the eutectic oil, as observed under the microscope.
This observation was made when water was added to the film, as
further described below.
[0295] The dry film had excellent tear resistance, was only
slightly sticky and had adequate strength when pulled. It also had
a film adhesion rating of 6 from the HDP side of 6330, and cut
satisfactorily with die.
[0296] When skin was wetted, and the film was placed on the wetted
skin, the film began to dissolve and turn opaque, indicating that
the eutectic oil was being released as small emulsion-type
droplets. The released oil was absorbed into the skin over time, as
indicated by a decrease in the opaqueness of the film.
Example 6
Preparation of Nanometer Size Simvastatin Slurry
[0297] Ten grams of simvastatin (Biogal), having a particle size of
from 10 to 100 microns is combined with 100 ml of distilled water
and 2 grams of Cremophor RH 40. The combination is added to a micro
lab sized micromill. The micromill is operated for about 1 hour,
and the slurry is then examined under a microscope. The resulting
particles are all smaller than 1 micron, indicating submicron
nanometer-sized particles.
Example 7
Preparation of Film Using Nanometer Size Simvastatin Slurry
[0298] Forty two grams of nanometer sized simvastatin slurry are
prepared using the method of Example 6. The resulting slurry
contains 8.929% simvastatin. The slurry is added to a glass bowl
and mixed with additives to create a polymeric matrix. The
polymeric matrix includes the components set forth in Table J
below.
TABLE-US-00010 TABLE J Components Wt (g) Simvastatin 3.75 Cremophor
RH 40 0.75 Water 37.5 HPMC 3.437 Polyethylene Oxide 1.719 Xylitol
1.719 Sucralose 0.375 Menthol flavor 0.125
[0299] The combination is stirred for about 40 minutes at 125 rpm
under a vacuum of 60% (16 in Hg); then stirred for another about 40
minutes at 125 rpm under a vacuum of 90% (25 in Hg); then stirred
for about 20 minutes at 125 rpm under a vacuum of 95% (26 in Hg);
and stirred for about 8 minutes at 125 rpm under a vacuum of 98%
(27 in Hg). To the mixture is added 0.625 g peppermint flavor, and
the resulting mixture is stirred for about 8 minutes at 100 rpm
under a vacuum of 100% (28 in Hg). The solution is then cast into a
film using a coating mechanism onto the HDP side of a polymeric or
paper substrate. The film is dried for 25 minutes in an 80.degree.
C. convection air oven. The film is then cut into 0.875.times.1.25
inch strips which each weigh 66.67 mg. Film strips are then
observed under a microscope, where no particles greater than 1
micron are observed. This indicates that all particles in the film
are submicron in size, and there has been no agglomeration of
particles.
Example 8
Preparation of Nanometer Size CoQ10 Emulsion
[0300] Ten grams of CoQ10 (Spectrum), having an average particle
size of 20 to 150 microns is mixed with 3 grams of Cremophor EL
(BASF) and 5 grams of Sesame oil. The mixture is heated to a
temperature of 80.degree. C. until the CoQ10 is dissolved in the
Cremophor/Sesame oil mixture. The resulting mixture is added drop
wise to 200 ml of distilled water, as it is pumped through a
microfluidics high pressure pump. Pressure was set at 10,000 psi
and 120 ml/min flow rate. The resulting emulsion is collected and
cooled with an in-line cooler. The resulting emulsion is recycled
three times through the apparatus. The resulting droplet is viewed
through a microscope, and no droplets are seen to be larger than 1
micron. This indicates that the resulting droplets are submicron in
size, and there has been no agglomeration of particles.
Example 9
Preparation of Film Using Nanometer Size CoQ10 Emulsion
[0301] 90.83 grams of the nanometer size CoQ10 emulsion containing
4.587% CoQ10 are prepared as set forth in Example 8 above. The
emulsion is used to prepare a wet matrix of 108.33 grams, including
25 grams of solids and 83.33 grams of water. The wet matrix
contains the components set forth in Table K below.
TABLE-US-00011 TABLE K Components Wt (g) CoQ10 4.1665 Cremophor EL
1.250 Sesame oil 2.084 Water 83.33 HPMC E15 7.625 Polyethylene
oxide 3.813 Xylitol 3.813 Sucralose 0.75 Menthol flavor 0.25
[0302] The combination is stirred for about 40 minutes at 125 rpm
under a vacuum of 60% (16 in Hg); then stirred for another about 40
minutes at 125 rpm under a vacuum of 90% (25 in Hg); then stirred
for about 20 minutes at 125 rpm under a vacuum of 95% (26 in Hg);
and stirred for about 8 minutes at 125 rpm under a vacuum of 98%
(27 in Hg). To the mixture is added 1.250 g peppermint flavor, and
the resulting mixture is stirred for about 8 minutes at 100 rpm
under a vacuum of 100% (28 in Hg). The solution is then cast into a
film using a coating mechanism onto the HDP side of a paper
substrate. The film is dried for 25 minutes in an 80.degree. C.
convection air oven. The film is then cut into 0.875.times.1.25
inch strips which each weigh 66.67 mg. Film strips are then
observed under a microscope, where no oil droplets greater than 1
micron are observed. This indicates that all droplets in the film
are submicron in size, and there has been no agglomeration of
droplets.
Example 10
Preparation of Nanometer Size Cyclosporine Slurry
[0303] 0.5 grams of cyclosporine and 4.5 grams of Vitamin E (TPGS)
were placed in a vial and heated in an 80.degree. C. air oven until
melted. The solution was taken out of the oven and allowed to cool.
The sample was submitted for microscopy evaluation. It was
determined that the cyclosporine was maintained in a small,
nanoparticle size.
Example 11
Preparation of Film Incorporating Small-Scale Cyclosporine
[0304] The goal was to incorporate cyclosporine in an oral film
strip at the 2 mg dosage level as a small-scale active
(particularly in the size of a nanoparticle or in a nanosolution).
The film composition included the components set forth in Table L
below:
TABLE-US-00012 TABLE L Components Wt (g) Polyethylene Oxide (WSR
N80) 5.831 g HPMC 3.334 g Cyclosporine slurry 3.334 g Simethicone
0.001 g Distilled water 37.5 g
[0305] The cyclosporine slurry was prepared as in Example 8 above,
using 0.334 g of cyclosporine and 3.0 g of Vitamin E (TPGS). The
cyclosporine slurry, simethicone, and distilled water were added to
a fabricated glass bowl. The solution was prepared as described
below.
[0306] First, the solution was mixed for 4 minutes while stirring
at 150 rpm at 0% vacuum. The bowl was then equipped with a heating
mantel and the heat was turned on. The solution was stirred for 12
minutes, stirring at 150 rpm at a temperature of 30.degree. C. and
0% vacuum. The solution was then stirred for 8 minutes, stirring at
200 rpm, in a 0% vacuum at a temperature of 40.degree. C. The heat
was then turned off, and the blend of polyethylene oxide and HPMC
were added to the bowl.
[0307] The solution was then stirred for 4 minutes at 125 rpm in a
60% vacuum (16 in Hg). Distilled water was then added to the
mixture to reduce the solids to about 20%. The solution was then
stirred for 4 minutes at 100 rpm in a vacuum of 60% (16 in Hg). One
drop of simethicone and water were added to reduce the solids to
about 18%. The solution was then stirred for 12 minutes at 100 rpm
in a 60% vacuum (16 in Hg). The solution was then stirred for 20
minutes at 100 rpm in a 90% vacuum (25 in Hg), and then stirred for
8 minutes at 100 rpm in a 95% vacuum (26 in Hg). The solution was
then stirred for 12 minutes at 100 rpm in a 98% vacuum (27 in Hg),
and finally stirred for 8 minutes at 100 rpm in a 100% vacuum (28
in Hg).
[0308] The solution was then cast into films using a K-Control
Coater with the micrometer adjustable wedge bar set at 770 microns.
The film was dried for 28 minutes in an 80.degree. C. air oven. The
film was then cut into 3/8.times.1.25 inch strips. The moisture
content of the strips was found to be 0.00%. Each strip weighed
about 70 mg. The film strips had good tear resistance and had
adequate strength when pulled. The strips were sealed in foil and
submitted for evaluation.
* * * * *