U.S. patent application number 10/970391 was filed with the patent office on 2005-06-02 for rapidly disintegrating films for delivery of pharmaceutical of cosmetic agents.
Invention is credited to Barnhart, Scott D., Full, Andrew P., Moritz, Cathy M..
Application Number | 20050118217 10/970391 |
Document ID | / |
Family ID | 34520112 |
Filed Date | 2005-06-02 |
United States Patent
Application |
20050118217 |
Kind Code |
A1 |
Barnhart, Scott D. ; et
al. |
June 2, 2005 |
Rapidly disintegrating films for delivery of pharmaceutical of
cosmetic agents
Abstract
The invention provides disintegratable films containing a
mixture of high molecular weight and low molecular weight water
soluble components; and a pharmaceutically or cosmetically active
ingredient. Optionally, the films contain a starch component, a
glucose component, a filler, a plasticizer and/or humectant. The
films are preferably in the form of a mucoadhesive monolayer having
a thickness sufficient to rapidly disintegrate in the oral
environment and release the active ingredient without undue
discomfort to the oral mucosa. The monolayer can be cut to any
desired size or shape to provide conveniently useable unit dosage
forms for administration to oral or other mucosal surfaces for
human pharmaceutical, cosmetic, or veterinary applications. The
invention further provides methods of administering the film
compositions by placing the composition into, for example, the oral
cavity for a sufficient period of time to permit the film to
disintegrate and release the active ingredient.
Inventors: |
Barnhart, Scott D.; (Glen
Rock, PA) ; Full, Andrew P.; (Glen Rock, PA) ;
Moritz, Cathy M.; (Glen Rock, PA) |
Correspondence
Address: |
DICKSTEIN SHAPIRO MORIN & OSHINSKY LLP
2101 L Street, NW
Washington
DC
20037
US
|
Family ID: |
34520112 |
Appl. No.: |
10/970391 |
Filed: |
October 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60513547 |
Oct 24, 2003 |
|
|
|
Current U.S.
Class: |
424/401 ;
424/443; 514/282; 514/57; 514/60 |
Current CPC
Class: |
A61K 8/731 20130101;
G01N 33/76 20130101; A61K 8/732 20130101; A61K 9/006 20130101; A61K
47/34 20130101; A61Q 11/00 20130101; A61P 29/00 20180101; A61K
31/485 20130101; A61K 2800/56 20130101; A61K 8/0216 20130101; A61K
47/36 20130101; A61K 47/32 20130101; A61K 47/38 20130101; A61K 8/29
20130101; A61P 11/14 20180101; A61K 47/26 20130101; A61K 9/7007
20130101; G01N 33/543 20130101; A61K 8/86 20130101 |
Class at
Publication: |
424/401 ;
424/443; 514/282; 514/060; 514/057 |
International
Class: |
A61K 031/717; A61K
031/716; A61K 009/70; A61K 007/00 |
Claims
What is claimed as new and desired to be protected by letters
patent of the United States is:
1. A dissolvable film for delivering a pharmaceutical or cosmetic
agent, comprising: a first water soluble polymer having a molecular
weight from about 5,000 daltons to about 60,000 daltons; a second
water soluble polymer having a molecular weight greater than about
60,000 daltons; and a pharmaceutically or cosmetically active
ingredient; wherein the film is in the form of a monolayer of a
thickness sufficient to rapidly disintegrate in the oral
environment to release the active ingredient.
2. The film of claim 1 wherein at least one of the water soluble
polymers comprises a cellulose derivative polymer.
3. The film of claim 1 wherein the concentration of the water
soluble polymers present in the film is about 2% to 35% of the
weight of the film.
4. The film of claim 1 wherein the second water soluble polymer has
a molecular weight of about 60,000 to about 500,000 daltons.
5. The film of claim 1 wherein at least one of the water soluble
polymers comprises hydroxypropyl cellulose.
6. The film of claim 1 wherein at least one of the water soluble
polymers comprises hydroxypropyl methylcellulose.
7. The film of claim 1 further comprising a third water soluble
polymer.
8. The film of claim 1 wherein at least one of the first and second
water soluble polymers comprises a mixture of different
polymers.
9. The film of claim 1 wherein the film is mucoadhesive.
10. The film of claim 1 wherein the film disintegrates within about
20 to about 60 seconds after contact with a mucous membrane.
11. The film of claim 1 wherein the film is in a unit dosage
form.
12. The film of claim 1 wherein the film has a thickness of about
20 microns to about 1200 microns.
13. The film of claim 1 wherein the film is part of a multilayer
device.
14. The film of claim 1 wherein the film is essentially free of
surfactants.
15. The film of claim 1 further comprising a starch component.
16. The film of claim 15 wherein the concentration of the starch
component is about 2% to 50% of the weight of the film.
17. The film of claim 15 wherein the starch component comprises
instant starch.
18. The film of claim 1 further comprising a glucose component.
19. The film of claim 18 wherein the concentration of the glucose
component is about 2% to 20% of the weight of the film.
20. The film of claim 18 wherein the glucose component comprises
maltodextrin.
21. The film of claim 1 further comprising a plasticizer and/or
humectant.
22. The film of claim 21 wherein the concentration of the
plasticizer and/or humectant is about 3% to 30% of the weight of
the film.
23. The film of claim 21 wherein the plasticizer is selected from
the group consisting of sorbitol, polyethylene glycol and
polyethylene oxide.
24. The film of claim 1 further comprising a filler.
25. The film of claim 1 wherein the active ingredient is present as
a dispersed phase.
26. The film of claim 25 wherein the active ingredient is a taste
masked drug.
27. The film of claim 24 wherein the filler comprises titanium
oxide.
28. The film of claim 24 wherein the filler comprises excess active
ingredient beyond the saturation point of the active ingredient in
the film.
29. The film of claim 25 wherein the filler comprises gas.
30. A method of administering the composition of claim 1 wherein
the composition is placed into the oral cavity for a sufficient
period of time to disintegrate and release the active
ingredient.
31. A disintegratable film for delivering a pharmaceutical or
cosmetic agent, comprising: a first water soluble component having
a molecular weight below about 60,000 daltons; a second water
soluble component having a molecular weight greater than about
60,000 daltons; and a pharmaceutically or cosmetically active
ingredient; wherein the film is in the form of a monolayer and
contains substantially no surfactant, and wherein the first and
second water soluble components are present in relative amounts
such that the film rapidly disintegrates in the oral environment to
release the active ingredient.
32. The film of claim 31 wherein at least one of the first and
second water soluble components comprises a cellulose derivative
polymer.
33. The film of claim 31 wherein the second water soluble component
has a molecular weight of about 60,000 to about 500,000
daltons.
34. The film of claim 31 wherein the second water soluble
components comprises hydroxypropyl cellulose.
35. The film of claim 31 wherein at least one of the first and
second water soluble components comprises hydroxypropyl
methylcellulose.
36. The film of claim 31 wherein the first and second water soluble
components are water soluble polymers.
37. The film of claim 36 wherein the second water soluble polymer
comprises cellulose derivative polymers having a molecular weight
in the range of about 60,000 to about 500,000 daltons, and wherein
the first water soluble polymer comprises cellulose derivative
polymers having a molecular weight of about 5,000 to about 60,000
daltons.
38. The film of claim 36 wherein the concentration of the first
water soluble polymer is about 2% to 10% of the weight of the film
and wherein the concentration of the second water soluble polymer
is about 2% to 10% of the weight of the film.
39. The film of claim 31 wherein the film is mucoadhesive.
40. The film of claim 31 wherein the film disintegrates in less
than about 60 seconds after contact with a mucous membrane.
41. The film of claim 31 wherein the film is in a unit dosage
form.
42. The film of claim 31 wherein the film has a thickness of about
20 microns to about 1200 microns.
43. The film of claim 31 wherein the film is part of a multilayer
device.
44. The film of claim 31 further comprising a starch component.
45. The film of claim 44 wherein the concentration of the starch
component is about 2% to 50% of the weight of the film.
46. The film of claim 31 further comprising a glucose
component.
47. The film of claim 46 wherein the concentration of the glucose
component is about 2% to 20% of the weight of the film.
48. The film of claim 46 wherein the glucose component comprises
maltodextrin.
49. The film of claim 31 further comprising a plasticizer and/or
humectant.
50. The film of claim 49 wherein the concentration of the
plasticizer and/or humectant is about 3% to 30% of the weight of
the film.
51. The film of claim 49 wherein the plasticizer is selected from
the group consisting of sorbitol, polyethylene glycol, polyethylene
oxide.
52. The film of claim 31 further comprising a filler.
53. The film of claim 52 wherein the active ingredient is present
as a dispersed phase.
54. The film of claim 53 wherein the active ingredient is a taste
masked drug.
55. The film of claim 54, wherein the active ingredient is selected
from the group consisting of diphenhydramine and
dextromethorphan.
56. The film of claim 54 wherein the filler is a dispersed
particle.
57. The film of claim 56 wherein the filler comprises titanium
oxide.
58. The film of claim 54 wherein the filler comprises excess active
ingredient beyond the saturation point of the active ingredient in
the film.
59. The film of claim 52 wherein the filler comprises
microcrystalline cellulose.
60. The film of claim 52 wherein the filler comprises gas.
61. The film of claim 60 wherein the gas comprises air.
62. A method of administering the composition of claim 31 wherein
the composition is placed into the oral cavity for a sufficient
period of time to disintegrate and release the active
ingredient.
63. A dissolvable film for delivering a pharmaceutical or cosmetic
agent, comprising: a first hydroxypropyl methylcellulose polymer
having a molecular weight of about 30,000 daltons; a second
hydroxypropyl methylcellulose polymer having a molecular weight of
about 90,000 daltons; a hydroxypropyl cellulose having a molecular
weight of about 140,000 daltons; taste masked dextromethorphan;
instant starch; a glucose component; and a plasticizer; the film
being essentially free of surfactants.
64. The film of claim 63 further comprising polyvinyl
pyrrolidone.
65. The film of claim 63 wherein the plasticizer is selected from
the group consisting of polyethylene glycol and polyethylene
oxide.
66. The film of claim 63 wherein the glucose component comprises
maltodextrin.
67. A dissolvable film for delivering a pharmaceutical or cosmetic
agent, comprising: a hydroxypropyl methylcellulose polymer having a
molecular weight of about 90,000 daltons; a hydroxypropyl cellulose
polymer having a molecular weight of about 140,000 daltons;
polyvinyl pyrrolidone; taste masked dextromethorphan; instant
starch; a glucose component; and a plasticizer; the film being
essentially free of surfactants.
68. The film of claim 67 wherein the plasticizer is selected from
the group consisting of polyethylene glycol and polyethylene
oxide.
69. A dissolvable film for delivering a pharmaceutical or cosmetic
agent, comprising: a first hydroxypropyl methylcellulose polymer
having a molecular weight of about 30,000 daltons; a second
hydroxypropyl methylcellulose polymer having a molecular weight of
about 90,000 daltons; a hydroxypropyl cellulose having a molecular
weight of about 140,000 daltons; taste masked diphenhydramine;
instant starch; a glucose component; and a plasticizer; the film
being essentially free of surfactants.
70. The film of claim 69 wherein the plasticizer comprises
polyethyene glycol.
71. The film of claim 69 wherein the glucose component comprises
maltodextrin.
Description
CROSS REFERENCE TO OTHER APPLICATION
[0001] This patent application claims the benefit of U.S.
provisional patent application Ser. No. 60/513,547, filed Oct. 24,
2003, and titled RAPIDLY DISSOLVING FILMS FOR DELIVERY OF
PHARMACEUTICAL OR COSMETIC AGENTS. U.S. provisional patent
application Ser. No. 60/513,547 is hereby incorporated by reference
in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to disintegratable films
and methods for delivering pharmaceutically active or cosmetic
agents. More particularly, the present invention provides in one
embodiment a water soluble mucoadhesive film composition containing
an active pharmaceutical or cosmetic ingredient for administration
to the oral cavity in unit dosage form. Upon administration, the
composition rapidly disintegrates to release the active
ingredient.
BACKGROUND OF THE INVENTION
[0003] Disintegratable films can provide a convenient and effective
delivery vehicle for delivering active ingredients, such as
pharmaceutical compounds and breath freshening or other cosmetic
agents, to the mucosa of humans and animals. Upon placement onto
the mucosa of, for example, the oral cavity, the film disintegrates
and releases the active ingredient. However, the film should have
adequate strength for processing and use as a unit dosage form, and
also ensure appropriate release of the active ingredient while
eliminating or minimizing any undue discomfort to mucosal
surfaces.
[0004] U.S. Pat. Nos. 4,029,757; 4,029,758; and 4,031,200 refer to
pharmaceutical dosage units formed from a multiplicity of edible
webs that are sealed. One layer is fabricated by "fan folding" and
compressing a continuous web structure, and subsequently sealing
the composite into a geometric shape. The films rely on a complex
process of fan folding and sealing to maintain the pharmaceutical
compound internally within the multilayered dosage form.
[0005] U.S. Re 33,093 refers to controlled-release
medicament-containing single or multi-layer thin films for
intra-oral drug delivery. The thin film includes a polymeric matrix
layer of 20-93% by weight of a hydroxypropyl cellulose having a
molecular weight above 100,000; 5-60% of a homopolymer of ethylene
oxide having a molecular weight from 3,000,000-5,000,000; 0-10% of
a water insoluble polymer selected from the group consisting of
ethyl cellulose, propyl cellulose, polyethylene and polypropylene;
2-10% of a plasticizer; and a pharmaceutically effective amount of
medicament. The controlled-release films of U.S. Re. 33,093 are
relatively slow to dissolve/disintegrate in the mouth.
[0006] U.S. Pat. No. 5,984,430 (Reexamination Certificate issued
March 4, 2003); U.S. Pat. Nos. 6,177,096; and 6,284,264 refer to
oral films for the delivery of pharmaceutical and cosmetic
compounds. The compositions referred to in these patents contain a
water-soluble polymer, a polyalcohol, a surfactant, and a
pharmaceutically or cosmetically active ingredient. According to
these patents, inclusion of the surfactant component imparts
"instant wettability" followed by rapid disintegration of the film
when placed into an aqueous environment such as the oral
cavity.
[0007] U.S. Pat. No. 4,136,145 refers to a pharmaceutical unit
dosage composition in which the pharmaceutically active medicament
is uniformly dissolved or suspended in a flexible, water-soluble
film carrier. The compositions include various drug compounds,
water-soluble polymers, surfactants, release agents, parting
compounds, and fillers.
[0008] Each film delivery system can be characterized by its film
strength and its disintegration profile (the speed at which the
film will disintegrate in an aqueous media such as saliva).
Surfactants have been used to affect the disintegration speed and
decrease the time required for complete film disintegration and
thus release of the active ingredient. The present invention
provides disintegratable film compositions that rapidly
disintegrate upon application to mucosal surfaces and which, at the
same time, have sufficient film strength without requiring the use
of any surfactant. While a surfactant is optional in certain
embodiments of the present invention, as described below, other
embodiments are surfactant-free or substantially free of
surfactants.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides disintegratable film
compositions prepared with a combination of ingredients that yield
films of sufficient film strength and rapid disintegration
profiles. Films prepared pursuant to this invention yield similar
or improved disintegration speeds as compared to prior art films,
including the prior art surfactant-containing films.
[0010] The films according to the present invention contain a
mixture of high molecular weight and low molecular weight water
soluble components; and a pharmaceutically or cosmetically active
ingredient. Optionally, the films further contain a starch
component, a glucose component, a plasticizer and/or a humectant.
Also optionally, the films can include a filler, which is a
dispersed phase or particle within the film and which, in certain
embodiments, can cause faster disintegration of the films.
[0011] The films are preferably in the form of a monolayer having a
thickness sufficient to rapidly disintegrate in the oral
environment and release the active ingredient without undue
discomfort to the oral mucosa. The monolayer can be cut to any
desired size or shape to provide conveniently useable unit dosage
forms for administration to oral or other mucosal surfaces for
human pharmaceutical, cosmetic, or veterinary applications. The
films are preferably mucoadhesive, in that upon contact with a
mucosal surface the films adhere to the membrane until
disintegration.
[0012] The invention further provides methods of administering the
mucoadhesive film compositions by placing the composition into, for
example, the oral cavity for a sufficient period of time, typically
a matter of seconds to less than about one minute, to permit the
film to disintegrate and release the active ingredient.
[0013] These and other advantages and features of the invention
will be more readily understood from the following detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
[0014] Reference will now be made in detail to the presently
preferred embodiments of the invention, which, together with the
following examples, serve to explain the principles of the
invention. These embodiments are described in sufficient detail to
enable those skilled in the art to practice the invention, and it
is to be understood that other embodiments may be utilized, and
that various structural, biological, and chemical changes may be
made without departing from the spirit and scope of the present
invention.
[0015] The present invention provides compositions and methods for
the use of film compositions which can be processed into single
layer (monolayer) unit dosage forms or combined with other layers
to prepare multilayer dosage forms comprising a thin film as
described herein containing a pharmaceutically active or cosmetic
ingredient. The thin disintegratable films according to the
invention contain a mixture of high molecular weight and low
molecular weight water soluble components; a pharmaceutically or
cosmetically active ingredient; optionally a starch component, a
glucose component, a plasticizer and/or humectant; and/or other
excipients in suitable amounts as described below, or which may be
determined by one of ordinary skill in the art pursuant to the
guidance provided by the examples and teachings herein. The films
will typically have a thickness in the range of about 10 to about
200 microns, although various other thicknesses are suitable as
desired for particular applications as described in more detail
below.
[0016] According to one embodiment, the disintegratable films
according to the invention achieve their desirable characteristics
of film strength and disintegration profile while requiring no and
containing no or substantially no surfactants, release agents, or
parting compounds, such as those found in U.S. Pat. Nos. 4,136,145
and 5,984,430. The term "essentially free of surfactants" refers to
trace amounts or higher levels of surfactants that are sufficiently
low so as not to substantially increase the disintegration rate of
the film composition following contact with a mucosal surface.
[0017] According to another embodiment, the disintegratable films
according to the invention contain a filler. The filler is a
dispersed phase or particle that in preferred embodiments causes
the films to disintegrate faster upon contact with the targeted
mucosal environment than without the filler. The filler can be an
optional component. Alternatively, in other embodiments, the active
ingredient, when present in the film as a dispersed phase or
particle, can serve the same purposes as a filler.
[0018] In one exemplary embodiment, the water soluble components of
the films according to the present invention include any
pharmaceutically acceptable or food grade water-soluble polymers,
including but not limited to, water-soluble hydroxypropylmethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
polyvinyl pyrrolidone, carboxymethyl cellulose, sodium carboxy
methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium
alginate, polyethylene glycol, xanthan gum, tragacantha, guar gum,
acacia gum, arabic gum, carrageenan, polyacrylic acid,
methylmethacrylate copolymer, carboxyvinyl copolymers, and various
mixtures of the above and other known water-soluble polymers,
cellulose derivatives, and/or gums.
[0019] We have found that particularly beneficial properties are
obtained when the water soluble polymeric component includes a
combination of low molecular weight polymers (e.g., those less than
about 5,000 to about 60,000 daltons) and high molecular weight
polymers (e.g., those of about 60,000 to about 150,00 daltons, and
to about 500,000 daltons or higher). For example, a combination of
hydroxypropyl cellulose (e.g., KluceL grade JF, Hercules Inc.,
Aqualon Division) and hydroxypropyl methylcellulose (e.g.,
Methocel, grades E5, E50, E4M, and SG A16M by Dow Chemical) is
suitable. These water soluble cellulose derivative polymers have
molecular weights of about 140,000; 30,000; 90,000; 400,000; and
greater than about 100,000 daltons, respectively.
[0020] Additional water soluble polymers include polyvinyl
pyrrolidone (PVP), such as Plasdone K-29/32 by ISP Corp., which has
a molecular weight of about 58,000 daltons; and a polyvinyl
alcohol-polyethylene glycol copolymer, such as Kollicoat IR by BASF
Pharma, which has about 75% polyvinyl alcohol units and 25%
polyethylene glycol units and has a molecular weight of about
49,000 daltons. Further, a water soluble polymer may serve the
function of an additional optional component. For example,
polyethylene oxide, specifically Polyox by Dow, having a molecular
weight of about 200,000 daltons, can serve as a high molecular
weight water soluble polymer and a plasticizer, as discussed
below.
[0021] The molecular weights of the water soluble polymers can be
determined as described in Keary, "Characterization of METHOCEL
Cellulose Ethers by Aqueous SEC with Multiple Detectors,"
Carbohydrate Polymers Vol. 45, pp293-303 (2001), which is
incorporated herein by reference.
[0022] Various other polymers can be selected by one of ordinary
skill in the art given the teachings herein, so long as the polymer
is water soluble, and preferably includes a sufficient amount of a
high molecular weight component to impart adequate film strength,
and a sufficient amount of a low molecular weight component to
facilitate the desired film property of rapid disintegration
profile. Various concentrations of each polymer may be utilized.
Such concentrations will typically be in the range of about 2% to
about 35% for each polymer based on the total weight of the dry
film. In one embodiment, the concentration for the high molecular
weight polymer is about 5% to 10% and the concentration of the low
molecular weight polymer is about 5% to 10% of the dry film.
[0023] According to another exemplary embodiment of the invention,
the water soluble low molecular weight component need not be a
water soluble polymer. Instead, the low molecular weight component
may be a low molecular weight monomer or a combination of various
low molecular weight monomers. The low molecular weight component
can also serve the function of an additional optional component.
For example, the low molecular weight component can also serve as
the active ingredient, a glucose component, a plasticizer, starch,
flavoring, colorant, and/or sweetener, and may include any of the
specific compounds listed below or other suitable compounds, which
are water soluble and have a molecular weight less than about
60,000 daltons. The low molecular weight component serves to
promote rapid disintegration, but is present in an amount such that
film strength is adequate for processing and dispensing. Various
concentrations of the low molecular weight component can be
utilized. Such concentrations will typically be in the range of
about 2% to about 80% or more based on the total weight of the dry
film. In one embodiment, the concentration for the high molecular
weight polymer is about 5% to 10% and the concentration of the low
molecular weight component is about 30% to 80% of the dry film.
[0024] Any pharmaceutically or cosmetically active ingredient may
be used in accordance with the principles of this invention,
whether dissolved or dispersed. Examples of pharmaceutically active
compounds include hormones, e.g., cyproterone acetate,
progesterone, estradiol, testosterone, insulin, triiodthyronin,
cortisone, etc.; prostaglandins, e.g., prostaglandin El,
prostaglandin E.sub.2, prostaglandin A.sub.1 and prostaglandin
F.sub.2.alpha.; vitamins, e.g., vitamin A, vitamin D.sub.2, vitamin
D.sub.3, vitamin E, vitamin K.sub.1, vitamin K.sub.2 and
derivatives of vitamin B.sub.1, e.g., thiamine tetrahydrofurfuryl
disulfide or thiamine propyldisulfide; antibiotics, e.g.,
erythromycin and tetracycline; contraceptives, e.g., chlormadinone,
chlormadinone acetate, megestrol acetate, d-norgestrel,
medroxyprogesterone acetate, norethisterone, norethisterone
acetate, etc.; spermicides, e.g.,
p-diisobutylphenoxypolyethoxyethanol, gestagens, estrogens and
mixtures thereof; anxiolytics, sedatives, and hypnotics, such as
bezodiazepines, e.g., diazepam and alprazolam, buspirone HCL,
promethazine HCL, phenobarbital; cerebral stimulants, such as
methylphenidate HCL, pemoline, caffeine; anti-diabetics;
sulfonamides; proton pump inhibitors, such as omeprazole;
trichomonal agents; anesthetics/analgesics, such as benzocaine,
lidocaine, procaine, dyclonine HCi, phenol, aspirin, phenacetin,
acetaminophen, potassium nitrate, etc.; opiate agonists, such as
fentanyl citrate, meperidine HCL, morphine sulphate; anticaries
agents, such as sodium fluoride, sodium monofluorophosphate,
stannous fluoride, etc.; anti-inflammatories, such as
hydrocortisone acetate, triamcinolone acetonide, dipotassium,
glycyrrhizinate, etc.; antihistamines, such as chlorpheniramine
maleate, ephedrine HCl, diphenhydramine HCl, clemastine fumarate,
loratadine, cetirizine, etc.; decongestants, such as
pseudoephedrine; antibacterials, such as chlorhexidine,
cetylpyridinium chloride, benzethonium chloride, dequalinium
chloride, silver sulfadiazene, phenol, thymol, hexedine,
hexetidine, alexidine, etc.; fungistats, such as nystatin,
miconazole, ketoconazole, etc; antitussives, such as
dextromethorphan, codine sulphate, menthol, etc.; anti-diarrheal
agents, such as loperamide; anti-anginals, such as nitroglycerin,
isosorbide mononitrate, isosorbide dinitrate, and other nitric
oxide derivatives; anti-emetics, such as meclazine HCL;
anti-flatulents, such as simethicone; miscellaneous autonomic and
central nervous system agents, such as nicotine and sumatriptan,
respectively; skeletal muscle relaxants, such as baclofen;
antidepressants generally, such as olanzapine, risperidone, and
specifically monoamine oxidase (MAO) inhibitors, e.g., phenelzine,
selegiline, tricyclic antidepressants, e.g., amitriptyline HCL,
clomipramine HCL, imipramine HCL; antipsychotics, such as
phenothiazine derivatives, butyrophenone derivatives, e.g.,
haloperidol; smoking deterrents, such as bupropion; alcohol
deterrents, such as disulfiram, naltrexone; enzymes, such as
papain; cosmetic active ingredients, such as parsley seed oil;
among others.
[0025] The optional glucose component of thin films according to
the invention can be added as a sweetener and/or to promote rapid
disintegration of the film. Preferably, the glucose component
comprises a water soluble polymer or mixture of polymers having
D-glucose units. The dextrose equivalent (DE) of the glucose
component is preferably within the range of about 10 to about 25,
or about 15 to about 20, although various other DE ranges can also
be used. The glucose component can be prepared, for example, by the
partial hydrolysis of starch to yield D-glucose polymer mixtures.
Suitable commercially available glucose components include, for
example, maltodextrin, corn syrup solids, sucrose, and dextrose.
Maltodextrin having a DE of about 16.5 to 19.5, such as that
commercially available from Grain Processing Corp. (GPC) under the
trade name "Maltrin M180," is particularly suitable, although
various other glucose containing polymers and mixtures can be
utilized, including, for example, other grades of "Maltrin,"
"Lycatab DH" (Roquette Freres), and "Star-Dri" (A. E. Staley).
Suitable concentrations as a weight percentage of the dry film
composition will typically be in the range of about 2% to 20%, or
about 3% to about 15%, although other concentrations also may be
used depending on the selection of other components and the desired
film properties.
[0026] The optional starch component of films according to the
present invention can be added to promote rapid disintegration of
the film and/or to aid in film formation. Preferably, the starch
component is a water soluble polysaccharide composition containing
amylose and/or amylopectin. Such compositions may be prepared by,
for example, modifying natural starches, such as corn, wheat, rice,
potato, or tapioca starch, to provide cold water soluble instant
starches. Various water soluble compositions of amylose and/or
amylopectin polysaccharides can be used. Typically, these can be
made by heating a natural starch with steam to modify the natural
starch product so that it is cold water soluble.
[0027] The instant starch commercially available from GPC,
Muscatine IA, as "Instant Pure Cote B792," (IPC B792) is an
exemplary starch component for purposes of the present invention.
Other suitable commercially available instant starches include
"Polartex Instant 12640," available from Cargill, Inc., and various
others may also be utilized. The starch component will typically
have an amylose to amylopectin ratio in the range, for example, of
about 0 to about 2.5. The starch can be incorporated in the wet
film composition in any suitable amount, including, but not limited
to, about 2% to 50%, or about 3% to about 35% by weight based on
the dry film.
[0028] The disintegratable film compositions of the present
invention may also optionally contain a plasticizer or humectant,
for example, polyalcohols, sorbitan esters, and citric acid esters,
to increase the flexibility of the films. The plasticizers can be
added directly to the formulation during manufacture. Suitable
compounds include polyethylene glycol (PEG), such as Lutrol E 400,
by BASF Pharma; polyethylene oxide, such as Polyox by Dow;
polyoxamers, such as Lutrol F by BASF Pharma; polyvinyl alcohol;
polyvinyl methyl ether, such as Lutanol by BASF; or mixtures of
those polymers; triacetin; glycerin; mannitol; xylitol; and various
other polyalcohols and other compounds having plasticizer and/or
humectant properties can be satisfactorily employed. Sorbitol and
PEG 400 are particularly suitable; although compounds having a
higher molecular weight (e.g., Polyox N80) than PEG 400 may be
desirable for certain applications, since they are typically less
volatile than sorbitol and PEG 400. The optional plasticizer and/or
humectant may be present in any suitable range, including, for
example about 3% to 30%, 10% to 20%, or 15% to 18% by weight of the
dry film.
[0029] Additional optional components can.be added to films
according to the invention. For example, flavors and sweeteners can
be added to the film formulations of this invention to make the
film more palatable to the patient or consumer for oral delivery.
Flavors and sweeteners can be added directly to the formulation
during manufacture. Flavors, sweeteners, artificial and natural,
are known to those skilled in the art. The choice of flavor,
sweetener, and/or other optional ingredients is not important for
the practice of this invention.
[0030] Also, any color can be imparted to the film, depending upon
the dye or pigment that is used. The dye or pigment is typically an
FD&C colorant that is approved for oral consumption. Further,
buffers, stabilizers, additives and/or other components can be
added to film formulations according to the invention to provide a
film having desired properties.
[0031] As noted above, according to one embodiment, the films
according to the invention also contain a filler. The filler is a
dispersed phase or particle that, in preferred embodiments, causes
the films to disintegrate faster upon contact with the targeted
mucosal surface. The active ingredient can itself act as a filler
in certain embodiments. For example, a taste masked drug (e.g.,
encapsulated dextromethorphan or diphenhydramine) can act as a
filler and promote rapid disintegration of the film. The
encapsulated or taste masked drug is a dispersed particle. Methods
of taste masking include encapsulation or complexation. For
example, MicroMask.RTM. pseudoephedrine by Particle Dynamics is an
encapsulated form of psuedoephedrine. Additionally, when the active
ingredient is present in the film at a concentration above its
solubility saturation point, the excess active ingredient can act
as a filler. For example, when caffeine is the active ingredient,
the film can be supersaturated with the caffeine such that the
excess caffeine acts as a disintegration-promoting filler.
[0032] The filler can be an optional non-active component. Examples
of such components include titanium oxide and microcrystalline
cellulose, which is available under the name Avicel, among others.
Air or other gasses can also be used as a filler according to the
invention. When air is employed as the filler, a surfactant (e.g.,
sodium lauryl sulfate (SLS), available under the name Stepanol,
Polysorbate 80, or Pluracare F87 Pril) may be included in the film
formulation. The surfactant does not itself serve to significantly
increase the rate of disintegration of the films upon contact with
the targeted mucosal environment. Instead, the surfactant aids in
the processing and formation of the film. Specifically, the
surfactant stabilizes the gaseous bubbles as a dispersed phase
within a solution to allow the solution to be processed, as
described in more detail below, to form the film containing the gas
or air as a dispersed phase filler.
[0033] The film compositions according to the invention may be
prepared by several methods, including, but not limited to, adding
the combination of high and low molecular weight water soluble
components, the optional starch, and optional glucose polymer
ingredients to a solvent that is capable of dissolving them, such
as water or ethanol or a mixture of ethanol and water. Upon forming
a homogeneous solution, the active ingredient and any of the other
optional components, such as plasticizers, flavors, sweeteners,
colorants, and/or other components may be blended into the
active-containing polymer solution. Alternatively, all of the film
components may be added and concurrently blended to form a solution
or dispersion. Also, a dry blend can be compounded by a V-blender.
The dry blend can be subsequently used to form a solution or
dispersion. Additionally, the dry blend can be subsequently
subjected to a melt extrusion to form a film upon cooling. It
should be understood that no particular sequence of steps is
required, except as needed to effectively prepare a desired film
composition. For example, when a particular sequence yields an
undesirable precipitate, an alternative sequence is necessary.
[0034] The active ingredient may be soluble in the solution or it
may be suspended or dispersed in the solution.
[0035] The active ingredient-containing solution or dispersion may
be further processed into a film by any one of many casting,
drawing, or extruding techniques. For example, the solution or
dispersion may be sprayed onto a support such as a release-treated
belt. Alternatively, for example, the solution or dispersion may be
roll coated onto a release treated paper or film substrate.
[0036] After coating of the solution or dispersion onto a support
surface, the solvent may be removed by radiant energy (such as
infra-red), heat, convection, vacuum, or any combination of these
to yield a dry film containing an active ingredient. The resulting
dry film can be wound up into a roll for storage prior to further
processing into unit dose forms. Whether stored for future
processing or immediately following removal of the solvent, the
resulting film can be removed from the support surface and
subsequently processed into unit dose form. Additional ingredients
can be applied to the dried film by, for example, printing,
spraying, dusting, or vapor adsorption processes, among others.
[0037] The dry film can be processed into unit dose form by any
suitable technique, including, for example, by die-cutting or
cutting across the width of a singular narrow roll to prepare unit
dosage forms of any desired geometric size or shape. The unit dose
forms may be subsequently packaged with various suitable materials
known in the art to prevent degradation and protect the active
ingredient from adulteration.
[0038] The preferred films according to the teachings of the
present invention are mucoadhesive monolayers having a thickness in
the range of about 20 microns (.mu.) to about 1200.mu., more
preferably, less than about 250.mu., or equal to or less than about
200.mu.. In another thin film embodiment, the films have a
thickness of less than about 175.mu., or less than about 75.mu..
When placed in the mouth, the films rapidly disintegrate to release
the active ingredient without causing any undue discomfort to the
oral cavity. By "rapid" disintegration, we mean that the active
ingredient, or the taste masked, encapsulated, or complexed form of
the active ingredient, is released from the film matrix in a matter
of a few seconds to less than a minute. Disintegration times can be
determined using the test provided by (USP) 24, Disintegration
<701>. See United States Pharmacopoeia, 24th ed., Ch. 701, p.
1941 (2000), which is incorporated herein by reference.
[0039] Preferably, the composition has already disintegrated in the
oral cavity after less than about 20 to about 30 seconds from
initially placing the composition in the mouth. At the same time,
the films have adequate strength for processing, packaging, and
administration without physical failure (e.g., breakage, fracture,
or otherwise) during processing and normal handling prior to
administration to the intended mucosal surface. The film strength,
specifically, film resilience, springiness and burst strength, can
be determined using the TA.XT2i Texture Analyzer by Texture
Technologies Corp. and the ASTM D3763 "High-Speed Puncture
Properties of Plastics Using Load and Displacement Sensors" test
method. These properties of film strength and rapid disintegration
are the result of the unique combination of the components
described herein.
[0040] The film compositions may be administered to the oral mucosa
or other mucous membranes where they are rapidly disintegrated by
saliva and/or other aqueous materials on the mucosal surface. Upon
disintegration, the films release one or more pharmaceutical or
cosmetic compounds to the mucous membranes. The film compositions
may be administered in such a manner so as to deliver an effective
amount of the active ingredient, which may be present in
pharmaceutically effective trace amounts up to about 60% or more of
the dry film.
[0041] The following illustrative examples provide a number of
specific formulations within the scope of the present invention.
These examples are by way of illustration only and are not intended
to be limiting in any way. Various alternative components,
concentrations, and optional excipients (plasticizers, humectants,
fillers, preservatives, etc.) may be utilized given the teachings
herein to yield thin monolayer films of suitable film strength and
disintegration profile.
[0042] The specific embodiments of examples 1-29 below contain no
surfactants. Surprisingly beneficial film quality can thus be
achieved without any surfactants. The embodiments of examples 11-31
each contain a dispersed phase filler. In examples 11-24, the
active ingredient also serves as a filler; whereas, in examples
25-31 an additional component serves as a filler. The embodiments
of examples 30 and 31 include air as the filler. Accordingly,
examples 30 and 31 also include a surfactant for stabilizing the
air bubbles during processing. The exemplary formulations below are
described in the following manner: 1) the concentrations of the
excipients are expressed in parts in the dry film and/or the wet
solution or dispersion; 2) the weight percent of the excipients in
the dry film and/or the wet solution or dispersion; and/or 3) the
amount of a stock solution (stock soln.) of the excipients
expressed in grams, and the total weight of the wet solution or
dispersion, and the total weight of the dry film expressed in
grams.
1 EXAMPLES Example 1 Dry Film Concentration Parts Methocel E5 10.0
Methocel E50 FG 8.0 IPC B792 27.0 Sucralose 2 Sorbitol 5 Sucrose 10
FD&C Red #40 0.15 Cherry Flavor 29.55 Chlorpheniramine Maleate
8.3 Overall Sum 100 Solids 20% Example 2 Dry Film Concentration Wet
Parts % w/w Methocel E5 6.32 2.59 Methocel E50 15.65 6.42 Klucel JF
2.67 1.10 Maltodextrin M180 3.86 1.58 IPC B792 3.71 1.52 Citric
Acid 1.04 0.43 Sucralose 9.22 3.79 Lemon-Grapefruit Flavor 12.72
5.22 Orange Flavor 12.49 5.13 Pseudoephedrine 16.48 6.76 Sorbitol
13.78 5.66 FD&C Red# 40 1.04 0.43 FD&C Blue# 1 1.04 0.43
Water -- 58.95 Overall Sum 100.02 100.01 Solids 41.05% Example 3 4
Dry Film Dry Film Conc. Wet Conc. Wet Parts % w/w Parts % w/w
Methocel E5 5.84 2.83 8.27 2.71 Methocel E50 14.67 7.10 20.63 6.75
Klucel JF 2.64 1.28 3.49 1.14 Maltodextrin M180 3.33 1.61 4.86 1.59
Instant Starch B792 25.33 12.25 4.86 1.59 Sodium phosphate 1.19
0.58 1.52 0.50 dibasic Sucralose 7.92 3.83 11.07 3.62 PEG 400 6.82
3.30 -- -- Mint Flavor 16.31 7.89 22.80 7.46 Loperamide 3.24 1.57
4.50 1.47 Sorbitol 12.62 6.10 17.90 5.86 FD&C Green Blend 551
0.06 0.05 0.11 0.04 Ethanol -- -- -- -- Water -- 51.63 -- 67.27
Overall Sum 99.97 100.02 100.01 100.00 Solids 48.37% 32.73% Example
5 6 Dry Film Dry Film Conc. Wet Conc. Wet Parts % w/w Parts % w/w
Methocel E5 7.73 2.53 7.37 2.50 Methocel E50 17.74 5.82 16.81 5.71
Klucel JF 3.27 1.07 3.27 1.11 Maltodextrin M180 4.66 1.53 4.32 1.47
IPC B792 4.66 1.53 4.68 1.59 FD&C Red #40 0.01 0.00 -- -- Mint
Green Colorant -- -- 0.08 0.03 Prosweet G 1.87 0.61 1.62 0.55
Sucralose 6.71 2.20 6.43 2.18 PEG 400 3.73 1.22 3.73 1.26
Omeprazole 39.81 13.05 37.74 12.81 Sorbitol 3.69 1.21 3.51 1.19
Spearmint Flavor 6.12 2.01 5.54 1.88 Sodium Hydroxide -- -- 0.74
0.25 Sodium Phosphate -- -- 4.16 1.41 Dibasic Water -- 67.21 --
66.06 Overall Sum 100.00 99.99 100.00 100.00 Solids 32.79% 33.94%
Example 7 Dry Film Concentration Parts Sorbitol 11 Sucrose 11
Vanilla Extract Pure 17 Parsley Seed Oil 4 Verde Green 0.5 Mint
#2684 10 Methocel E50 FG 15 IPC B792 31.4 Sucralose 0.1 Overall Sum
100 Solids 31% Example 8 Dry Film Concentration Parts Methocel E5
9.96 Klucel JF 7.12 Maltodextrin 14.31 Instant Starch 14.31
Sucralose 2.38 Flavor 27.00 Loratadine 10.00 Sorbitol 14.93 Overall
Sum 100.01 Solids 40.89% Example 9 Stock Soln. grams Base: 21.7
10.020 Methocel E5 6.9 0.691 Methocel E50 3.4 0.341 Klucel JF 3.0
0.301 Maltrin M180 4.2 0.421 IPC B792 4.2 0.421 Flavor 100 3.015
Saccharin 100 0.217 Dextromethorphan 100 0.502 Wet Total 13.754
(including water) Dry Total 5.908 Example 10 Dry Film Concentration
Wet Parts % w/w Methocel E5 5.51 2.00 Methocel E50 13.33 4.84
Klucel JF 2.38 0.87 Maltodextrin M180 3.06 1.11 IPC B792 3.66 1.33
Sodium phosphate 0.93 0.34 dibasic Sucralose 7.24 2.63 PEG 400 6.69
2.43 Cherry Flavor 15.21 5.53 Pseudoephedrine 29.47 10.71 Sorbitol
11.86 4.31 FD&C Red# 40 0.66 0.24 Ethanol -- 10.20 Water --
53.46 Overall Sum 100.00 100.00 Solids 36.35% Example Stock 11 12
13 14 Soln. grams grams grams grams Base: 21.7 9.826 9.852 9.967
81.676 Methocel E5 6.9 0.678 0.680 0.688 5.636 Methocel E50 3.4
0.334 0.335 0.339 2.777 Klucel JF 3.0 0.295 0.296 0.299 2.450
Maltrin M180 4.2 0.413 0.414 0.419 3.430 IPC B792 4.2 0.413 0.414
0.419 3.430 Flavor 100 3.019 3.011 3.031 29.313 Saccharin 100 0.201
0.204 Taste Masked 100 1.262 1.227 1.220 11.545 Dextromethorphan
Methocel E50 10 11.661 Sucralose 25 7.858 Sorbitol 70 17.565
FD&C Red #40 10 1.121 Maltrin M180 100 1.909 Wet Total
(including 16.217 17.114 14.218 160.739 water) Dry Total 8.523
6.580 6.414 74.120 Example 15 16 17 Stock Soln. grams grams grams
Base: 14.5 8.935 3.314 6.205 Methocel E50 9.3 0.831 0.308 0.577
Maltrin M180 2.6 0.232 0.086 0.161 IPC B792 2.6 0.232 0.086 0.161
Flavor 100 1.243 0.922 0.902 Taste Masked 100 2.453 1.264 1.239
Dextromethorphan Sucralose 25 0.548 0.280 0.274 FD&C Red #40 1
0.507 0.242 0.238 PEG 400 100 0.608 PVP K29/32 55.19 0.908 2.376
1.664 Polyethyene oxide (about 100 200,000 daltons) Wet Total
15.202 8.398 10.522 Dry Total 6.243 4.050 4.030 Example 18 19 20
Stock Soln. grams grams grams Base: 20.3 81.930 Methocel E5 6.1
4.998 Methocel E50 4.3 3.523 Klucel JF 2.7 2.212 Maltrin M180 3.6
2.949 IPC B792 3.6 2.949 Flavor 100 25.765 0.995 1.102 Taste Masked
100 51.970 1.229 1.226 Dextromethorphan Methocel E50 10 101.579
Sucralose 25 10.397 0.289 0.283 Sorbitol 70 15.388 FD&C Red #40
1 0.269 0.261 FD&C Red #40 10 1.057 PEG 400 100 12.026 PVP
55.19 1.617 1.612 Polyethyene oxide (about 100 0.891 0.909 200,000
daltons) Water 170.08476 Wet Total (including water) 300.112 9.233
8.836 Dry Total 130.027 4.082 4.200 Example 21 Dry film
Concentration Parts Methocel E5 6.14164 Methocel E50 FG 4.34101
Klucel JF 2.71067 Maltrin M180 3.70464 IPC B792 3.70193 Sorbitol
18.5 Sucralose 2 FD&C Red #40 0.15 Flavor 40.0001 Taste Masked
Dextromethorphan 18.75 Overall Sum 100 Solids 53% Example 22 Dry
Film Casting Solution Concentration Concentration % w/w % w/w
Methocel E5 3.96 1.62 Methocel E50 6.71 2.75 Klucel JF 2.07 0.848
Maltrin M180 5.01 2.05 IPC B792 4.73 1.94 Flavor 0.65 0.266 Taste
Masked 60.05 24.60 Diphenhydramine Sucralose 6.74 2.76 Sorbitol
4.40 1.80 FD&C Red #40 0.11 0.0434 PEG 400 5.58 2.29 Ethanol
9.84 Water 49.19 Overall Sum 100 100
[0043] Examples 21 and 22 showed disintegration times of about 0
seconds to about 12 seconds for samples of about 35 grams to about
160 grams and for film thicknesses within the range of about 20
.mu. to about 200 .mu.. Disintegration times were determined using
the test provided by (USP) 24, Disintegration <701>.
2 Example 23 Dry Film Concentration Wet % w/w Parts Methocel E5
28.50 6.49 Methocel E50 13.35 3.04 ProSweet G 4.83 1.1 Aspartame
0.92 0.21 Sucralose 3.95 0.9 Flavor 11.77 2.68 Caffeine 36.67 8.35
Overall Sum 100 22.77 Solids 21.62% Example 24 Dry Film
Concentration Parts Methocel E5 24.20 Methocel E50 11.33 ProSweet G
4.10 Aspartame 0.78 Sucralose 3.36 Flavor 9.99 Caffeine 31.13 PEG
400* 15.10 Overall Sum 100.0001 Solids 26.56% Example 25 26 Dry
Film Dry Film Conc. Wet Conc. Wet Parts % w/w Parts % w/w Methocel
E5 7.55 2.52 7.26 2.45 Methocel E50 20.71 6.92 20.02 6.75 Klucel JF
3.36 1.12 3.22 1.08 Maltodextrin 4.67 1.56 4.56 1.54 M180 IPC B792
4.58 1.53 4.43 1.49 Sucralose 8.92 2.98 12.48 4.21 PEG 400 22.50
7.52 15.15 5.11 Menthol 9.81 3.28 20.42 6.89 Sorbitol 17.92 5.99
12.33 4.16 TiO.sub.2 -- -- 0.15 0.05 Ethanol -- 3.28 -- 6.89 Water
-- 63.30 -- 59.39 Overall Sum 100.02 100.00 100.02 100.01 Solids
33.42% 33.72% Example 27 Dry Film Conc. Wet Parts % w/w Methocel E5
-- -- Methocel E50 28.89 6.73 Klucel JF 3.43 0.80 Maltodextrin 8.58
2.00 M180 IPC B792 8.54 1.99 Sucralose 13.80 3.22 PEG 400 6.40 1.49
Menthol 14.53 3.39 Sorbitol 15.83 3.69 TiO.sub.2 -- -- Ethanol --
3.39 Water -- 73.30 Overall Sum 100.00 100.00 Solids 23.31% Example
28 Dry Film Casting Solution Concentration Concentration % w/w %
w/w Methocel E5 4.51 1.77 Methocel E50 8.66 3.41 Klucel JF 1.84
0.72 Maltodextrin M180 2.85 1.12 IPC B792 2.66 1.05 Sodium
phosphate 1.62 0.638 dibasic Sucralose 9.59 3.78 PEG 400 6.83 2.69
Cherry Flavor 14.47 5.70 Pseudoephedrine 24.39 9.60 Sorbitol 10.49
4.13 FD&C Red# 40 0.107 0.0419 FD&C Blue# 1 0.00128
0.000506 Avicel PH105 11.98 4.72 Ethanol 11.38 Water 49.25 Overall
Sum 100 100 Solids 39.37 Example 29 Dry Film Casting Solution
Concentration Concentration % w/w % w/w Methocel E5 2.49 1.05
Methocel E50 6.93 2.92 Klucel JF 1.48 0.624 Maltodextrin M180 2.12
0.891 IPC B792 2.24 0.944 Sucrose 4.26 1.79 Sucralose 10.06 4.23
PEG 400 1.55 0.652 Crme de Menthe Flavor 17.92 7.54 Pseudoephedrine
19.43 8.17 Sorbitol 8.32 3.50 FD&C Red# 40 0.883 0.371 FD&C
Blue# 1 0.00166 0.000699 Avicel CE15 22.31 9.38 Ethanol 21.12 Water
36.83 Overall Sum 100 100 Solids 42.06% Example 30 Dry Film
Concentration % w/w Methocel E5 8.09 Methocel E4M 3.66 Methocel SG
A16M 4.45 Plasdone K29-32 2.79 Sucralose 1.70 Silica Gel 4.14
Pluracare F87 Prill 20.13 Avicel PH200 31.04 Glycerin 11.49 PEG 400
11.28 Papain 0.408 Sodium Phosphate Monobasic 0.201 Sodium
Phosphate Dibasic 0.215 FD&C Blue #1 0.00206 Cetylpyridium
Chloride 0.402 Overall Sum 100 Solids 20.11% Example 31 Dry Film
Concentration % w/w Methocel E5 12.06 Methocel E4M 5.41 Methocel SG
A16M 6.58 Sorbitol 11.63 Calcium Stearate 10.03 Sodium Saccharin
2.01 Silica Gel 5.03 SLS 0.503 Avicel PH105 36.68 Triacetin 9.06
Papain 0.481 Sodium Phosphate Monobasic 0.251 Sodium Phosphate
Dibasic 0.257 FD&C Blue #1 0.00254 Overall Sum 100 Solids 20%
*The weight % of PEG can range, for example, from between about 15%
to about 52%.
[0044] The formulation of example 31 was aerated prior to casting
and drying. A liquid flavor was applied to the dry film such that
the flavor concentration was approximately 15% w/w of the total
mass of the flavored film.
[0045] The above description is only illustrative of preferred
embodiments which achieve the objects, features and advantages of
the present invention. It is not intended that the present
invention be limited to the illustrated embodiments. Any
modification of the present invention which comes with the spirit
and scope of the following claims is considered part of the present
invention.
* * * * *