U.S. patent application number 10/925548 was filed with the patent office on 2005-01-27 for bioadhesive antibacterial wound healing composition.
Invention is credited to Leone, Robert S., Leung, Sau-Spence, Martin, Alain.
Application Number | 20050020537 10/925548 |
Document ID | / |
Family ID | 22398769 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020537 |
Kind Code |
A1 |
Leung, Sau-Spence ; et
al. |
January 27, 2005 |
Bioadhesive antibacterial wound healing composition
Abstract
A bioadhesive wound-healing composition includes pullulan,
pyruvate, an antioxidant, and a mixture of saturated and
unsaturated fatty acids. The composition can be provided in the
form of a film that does not self-adhere. The composition can
include additional medicinal agents, such as polymyxin B sulfate,
bacitracin zinc, and neomycin sulfate. Methods for producing the
composition and methods for treating wounds with the composition
are also disclosed.
Inventors: |
Leung, Sau-Spence;
(Parsippany, NJ) ; Martin, Alain; (Ringoes,
NJ) ; Leone, Robert S.; (Fanwood, NJ) |
Correspondence
Address: |
Warner-Lambert Company LLC
201 Tabor Rd
Morris Plains
NJ
07950
US
|
Family ID: |
22398769 |
Appl. No.: |
10/925548 |
Filed: |
August 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10925548 |
Aug 25, 2004 |
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09978152 |
Oct 16, 2001 |
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09978152 |
Oct 16, 2001 |
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09511869 |
Feb 25, 2000 |
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6329343 |
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60121784 |
Feb 26, 1999 |
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Current U.S.
Class: |
514/54 ; 514/458;
514/474; 514/557; 514/725; 514/763 |
Current CPC
Class: |
A61L 15/225 20130101;
A61L 26/0023 20130101; Y10S 514/904 20130101; A61P 17/00 20180101;
C08L 5/00 20130101; A61L 26/0023 20130101; Y10S 514/886 20130101;
A61L 15/28 20130101; A61L 15/28 20130101; A61K 45/06 20130101; C08L
5/00 20130101; A61L 26/0052 20130101; Y10S 514/887 20130101 |
Class at
Publication: |
514/054 ;
514/557; 514/458; 514/725; 514/474; 514/763 |
International
Class: |
A61K 031/715; A61K
031/355; A61K 031/015; A61K 031/07 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 27, 2000 |
WO |
PCT/US00/02079 |
Claims
1-25. (cancelled)
26. A bioadhesive film composition wherein said film is a solid
film comprising pyruvate, an antioxidant, and a mixture of
saturated and unsaturated fatty acids that resuscitate injured
mammalian cells.
27. The composition according to claim 26, wherein said film
comprises an agent selected from the group consisting from
pullulan, polyvinyl alcohol, methylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcell- ulose and
carboxymethylcellulose and salts thereof and combinations
thereof.
28. The composition according to claim 26 further comprising a
anesthetic agent.
29. The composition according to claim 28, wherein said anesthetic
agent comprises pramoxine hydrochloride.
30. The composition according to claim 28, wherein said anesthetic
agent comprises lidocaine.
31. The composition according to claim 28, wherein said anesthetic
agent comprises benzocaine.
32. The composition according to claim 26, further comprising an
anti-microbial agent.
33. The composition according to claim 32, wherein said
anti-microbial agent comprises neomycin sulfate.
34. The composition according to claim 32, wherein said
anti-microbial agent comprises bacitracin zinc.
35. The composition according to claim 32, wherein said
anti-microbial agent comprises polymyxin B sulfate.
36. The composition according to claim 32, wherein said
anti-microbial agent comprises triclosan.
37. The composition according to claim 26, further comprising a
scar reducing agent.
38. The composition according to claim 37, wherein said scar
reducing agent comprises all forms of vitamin E.
39. The composition according to claim 26, further comprising a
pharmaceutically active agent.
40. The composition according to claim 39, wherein said
pharmaceutically active is selected from the groups consisting of
immunostimulating agents, antiviral agents antikeratolytic agents,
anti-inflammatory agent, antifungal agents, tretinoin, sunscreen
agents, dermatological agents, topical antihistamine agents,
antibacterial agents, other bioadhesive agents, respiratory
bursting inhibitors, inhibitors of prostaglandin synthesis,
steroidal anti-inflammatory agents, burn relief medications, sun
burn medications, acne preparations, insect bite and sting
medications, wound cleansers, wound dressings and combinations
thereof.
41. The composition according to claim 26, wherein said film is a
standalone film.
42. The composition according to claim 26, wherein said film is a
solid dried film.
43. The composition according to claim 26, wherein said film is a
single layer film.
Description
FIELD OF THE INVENTION
[0001] This invention pertains to therapeutic bioadhesive
wound-healing compositions useful for treating wounds. More
particularly, the bioadhesive wound-healing compositions comprise
pullulan and wound-healing agents and/or metabolites thereof. This
invention also pertains to methods for preparing and using the
bioadhesive wound-healing compositions and the pharmaceutical
products in which the therapeutic compositions may be used.
BACKGROUND OF THE INVENTION
[0002] Wounds are internal or external bodily injuries or lesions
caused by physical means, such as mechanical, chemical, viral,
bacterial, or thermal means, which disrupt the normal continuity of
structures. Such bodily injuries include, e.g., contusions, wounds
in which the skin is unbroken, incisions, wounds in which the skin
is broken by a cutting instrument, and lacerations, wounds in which
the skin is broken by a dull or blunt instrument.
[0003] A wide variety of products have been developed that enhance
the body's ability to heal itself when wounded. These products
typically function by medicating the wound, isolating the wound
from infectious agents, and/or by binding the wound to prevent
wound growth and to minimize the gap that the body's natural repair
mechanisms must bridge to heal the wound.
[0004] For example, U.S. Pat. No. 5,856,364 to Martin discloses a
therapeutic antiviral wound-healing composition comprising an
antiviral agent and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin E
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0005] U.S. Pat. No. 5,692,302 to Martin et al. discloses a razor
cartridge comprising a wound-healing composition delivery system
fixed to the cartridge. The wound-healing composition comprises
effective amounts of pyruvate; an antioxidant, preferably Vitamin B
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0006] U.S. Pat. No. 5,674,912 to Martin discloses a sunscreen
wound-healing composition comprising a sunscreen agent, an
anti-inflammatory agent and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin B
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0007] U.S. Pat. No. 5,663,208 to Martin discloses an anti-fungal
wound-healing composition comprising an anti-fungal agent and a
wound-healing composition effective amounts of pyruvate; an
antioxidant, preferably Vitamin B acetate; and a mixture of
saturated and unsaturated fatty acids.
[0008] U.S. Pat. No.5,658,957 to Martin discloses an
immunostimulating wound-healing composition comprising an
immunostimulating agent and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin E
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0009] U.S. Pat. No. 5,658,956 to Leung and Martin discloses a
bioadhesive wound-healing composition comprising a bioadhesive
agent and a wound-healing composition comprising effective amounts
of pyruvate; an antioxidant, preferably Vitamin B acetate; and a
mixture of saturated and unsaturated fatty acids.
[0010] U.S. Pat. No. 5,652,274 to Martin discloses a therapeutic
wound-healing composition comprising effective amounts of pyruvate;
an antioxidant, preferably Vitamin E acetate; and a mixture of
saturated and unsaturated fatty acids.
[0011] U.S. Pat. No. 5,648,380 to Martin discloses an
anti-inflammatory wound-healing composition comprising an
anti-inflammatory agent and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin E
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0012] U.S. Pat. No. 5,646,190 to Martin discloses an acne treating
wound-healing composition useful for the topical treatment of acne
vulgaris tretinoin and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin E
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0013] U.S. Pat. No. 5,641,814 to Martin discloses an
antikeratolytic wound-healing composition comprising an
antikeratolytic agent and a wound-healing composition comprising
effective amounts of pyruvate; an antioxidant, preferably Vitamin B
acetate; and a mixture of saturated and unsaturated fatty
acids.
[0014] U.S. Pat. No. 5,633,285 to Martin discloses a cytoprotective
wound-healing composition comprising a cytotoxic agent and a
wound-healing composition comprising effective amounts of pyruvate;
an antioxidant, preferably Vitamin B acetate; and a mixture of
saturated and unsaturated fatty acids.
[0015] U.S. Pat. No. 5,614,561 to Martin discloses an antihistamine
wound-healing composition comprising an antihistamine and a
wound-healing composition comprising effective amounts of pyruvate;
an antioxidant, preferably Vitamin E acetate; and a mixture of
saturated and unsaturated fatty acids.
[0016] U.S. Pat. No. 5,602,183 to Martin et al; discloses a
dermatological wound-healing composition useful to minimize and
treat diaper comprising a therapeutically effective amount of a
buffering agent to maintain the pH of the composition and a
wound-healing composition comprising effective amounts of pyruvate;
an antioxidant, preferably Vitamin B acetate; and a mixture of
saturated and unsaturated fatty acids.
[0017] The foregoing Martin patents do not disclose wound-healing
compositions comprising pullulan, unlike the following patents.
[0018] U.S. Pat. No. 5,722,942 to Tanaka et al. discloses wound
covering materials suitable for protection and treatment of wounds.
The materials comprise: (a) 1 part by weight of glucomannan; (b)
0.20-0.99 part by weight of a solubility modifier comprising
pullulan or carrageenan; (c) 0.10-12 parts by weight of a
physiologically acceptable adhesive polymer base; and (d) 0.20-20
parts by weight of at least one plasticizer selected from the group
consisting of polyhydric alcohols, sugar alcohols, monosaccharides,
disaccharides and oligosaccharides. The materials are provided in
the form of a film or a laminate of a film and another sheet
material.
[0019] U.S. Pat. No. 5,618,799 to Inagi et al. discloses a powder
preparation for healing damaged skin, which comprises: (a) 50-90
wt.% sucrose; (b) 0.5-10 wt.% povidone-iodine; and (c) a
water-soluble polymer selected from the group consisting of
polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid and
salts thereof, pullulan, carboxyvinyl polymers, methylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellulose, and
carboxymethylcellulose and salts thereof.
[0020] U.S. Pat. No. 4,844,898 to Komori et al. discloses a
wound-healing preparation which comprises 50-90 wt.% of a sugar,
0.5-10 wt.% of povidone-iodine, 1-20 wt.% of water, 0.1-5 wt.% of
an agent for imparting an appropriate consistency and stability
selected from polysaccharides and derivatives thereof, and a buffer
in an amount sufficient to adjust the pH of the preparation to
3.5-6. The polysaccharide can be, e.g., dextrin, gum arabic,
pullulan, chondroitin sulfate, methylcellulose, sodium
carboxymethylcellulose and the like.
[0021] U.S. Pat. No. 5,518,902 to Ozaki et al. discloses high
pullulan content products, such as ointments and cosmetic packs.
The products can include a variety of ingredients in addition to
pullulan, such as other polysaccharides, polyhydric alcohols, and
antiseptics.
[0022] U.S. Pat. No. 5,411,945 to Ozaki et al. discloses a pullulan
binder and products produced therewith, including a facial pack.
The products can include a variety of ingredients in addition to
pullulan, such as other polysaccharides, antibacterial agents,
pharmaceutically active substances and biologically active
substances.
[0023] Despite the existence in the prior art of wound-healing
compositions containing pullulan, there is still room for
improvement in such compositions, and in processes for making
them.
[0024] All references cited herein are incorporated herein by
reference in their entireties.
SUMMARY OF THE INVENTION
[0025] The invention provides a bioadhesive composition comprising
pullulan, pyruvate, an antioxidant, and a mixture of saturated and
unsaturated fatty acids adapted to resuscitate injured mammalian
cells. Also provided is a method for treating a wound, wherein a
bioadhesive composition of the invention is applied to the
wound.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0026] The bioadhesive composition of the invention comprises
pullulan, pyruvate, an antioxidant, and a mixture of saturated and
unsaturated fatty acids. Although the Martin patents teach the
wound-healing effectiveness of a combination of pyruvate,
antioxidant and a mixture of fatty acids, the inventors have
discovered that pullulan acts as a surprisingly effective vehicle
for topically administering the active ingredients.
[0027] Compositions of the invention preferably comprise pullulan
in an amount of about 0.1 to about 80 wt.%, preferably about 40 to
about 80 wt.% of the total weight of the composition.
[0028] A variety of pyruvate forms are suitable for use in the
invention. The pyruvate is preferably selected from the group
consisting of pyruvic acid, lithium pyruvate, sodium pyruvate,
potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc
pyruvate, manganese pyruvate, methyl pyruvate, .alpha.-ketoglutaric
acid, pharmaceutically acceptable salts of pyruvic acid, prodrugs
of pyruvic acid, and mixtures thereof. More preferably, the
pyruvate is sodium pyruvate. Pyruvate is preferably present in the
composition in an amount of about 10 to about 50 wt.% of the total
weight of the composition.
[0029] A suitable antioxidant is preferably selected from the group
consisting of all, forms of Vitamin A; all forms of carotene; all
forms of Vitamin C; all forms of Vitamin E; Vitamin E esters which
readily undergo hydrolysis to Vitamin E; prodrugs of Vitamin A,
carotene Vitamin C, and Vitamin E; pharmaceutically acceptable
salts of Vitamin A, carotene, Vitamin C, and Vitamin E; and
mixtures thereof. More preferably, the antioxidant is Vitamin E
acetate. The antioxidant is preferably present in an amount of
about 0.1 to about 40 wt.% of the total weight of the
composition.
[0030] The mixture of saturated and unsaturated fatty acids
preferably comprises animal and vegetable fats and waxes. More
preferably, the fatty acid mixture includes fats selected from the
group consisting of human fat, chicken fat, cow fat, sheep fat,
horse fat, pig fat, and whale fat. The fatty acid mixture
preferably comprises lauric acid, myristic acid, myristoleic acid,
pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid,
margaroleic acid, stearic acid, oleic acid, linoleic acid,
linolenic acid, arachidic acid, and gadoleic acid. The mixture of
saturated and unsaturated fatty acids is preferably present in an
amount of about 10 to about 50 wt.% of the total weight of the
composition..
[0031] The composition of the invention can further comprise water,
pharmaceutically active agents, additional film-forming agents,
plasticizing agents, additional flavoring agents, cooling agents,
surfactants, stabilizing agents, emulsifying agents, thickening
agents, binding agents, coloring agents, sweeteners, fragrances and
the like. The composition is preferably in the form of a film,
which can be employed as a physiologically acceptable vehicle for
administering pharmaceutically active agents through the skin or
open wounds of a patient as it adheres thereto.
[0032] The expression "physiologically acceptable" as used herein
is intended to encompass compounds, which upon administration to a
patient, are adequately tolerated without causing undue negative
side-effects.
[0033] The expression "pharmaceutically active agents" as used
herein is intended to encompass agents that promote a structural
and/or functional change in and/or on bodies to which they have
been administered. These agents are not particularly limited;
however, they should be physiologically acceptable and compatible
with the film. Suitable pharmaceutically active agents include, but
are not limited to: immunostimulating agents (Betafectin.TM.),
antiviral agents, antikeratolytic agents, anti-inflammatory agents,
antifungal agents, tretinoin, sunscreen agents, dermatological
agents, topical antihistamine agents, antibacterial agents, other
bioadhesive agents, respiratory bursting inhibitors (lactic acid,
adenosine), inhibitors of prostaglandin synthesis (ibuprofen,
aspirin, indomethacin, meclofenomic acid, retinoic acid, padimate
O, meclomen, oxybenzone), steroidal anti-inflammatory agents
(corticosteroids including synthetic analogs), antimicrobial agents
(Neosporin.RTM. ointment, silvadine, triclosan), antiseptic agents,
anesthetic agents (pramoxine hydrochloride, lidocaine, benzocaine),
cell nutrient media, burn relief medications, sun burn medications,
acne preparations, insect bite and sting medications, wound
cleansers, wound dressings, scar reducing agents (vitamin E), and
the like, and mixtures thereof, to further enhance the
proliferation and resuscitation rate of mammalian cells.
[0034] Preferred antimicrobial agents include the essential oils
(i.e., thymol, methyl salicylate, menthol and eucalyptol), copper
gluconate, triclosan, polymyxin B sulfate, bacitracin zinc, and
neomycin sulfate.
[0035] A particularly preferred wound-healing composition of the
invention includes pullulan, pyruvate, an antioxidant, a mixture of
saturated and unsaturated fatty acids, polymyxin B sulfate,
bacitracin zinc, and neomycin sulfate. Preferably, the polymyxin B
sulfate is present in an amount of about 1000 to about 15,000
units/gm, the bacitracin zinc is present in an amount of about 100
to about 1,500 units/gm, and the neomycin sulfate is present in an
amount of about 1 to about 15 mg/gm.
[0036] The composition of the invention is preferably provided in
the form of a film that adheres on contact to moist skin. Due to
the relatively high oil content in the film, it is preferable to
avoid substantial amounts of humectant in the film (and more
preferable to have no humectant in the film), so as to avoid
producing an overly moist, self-adhering film. In particular, it is
preferred to formulate the film with a plasticizing agent other
than glycerin, which is also a humectant. If the film includes a
sweetener, it is preferable to use a sweetener other than sorbitol,
which is a mild humectant.
[0037] Preferred plasticizing agents include triacetin in amounts
ranging from about 0 to about 20 wt.%, preferably about 0 to about
2 wt.%. Other suitable plasticizing agents include monoacetin and
diacetin.
[0038] Preferred cooling agents include physcool, in amounts
ranging from about 0.001 to about 2.0 wt.%, preferably about 0.2 to
about 0.4 wt.%. Other suitable cooling agents include WS3 and the
like.
[0039] Preferred surfactants include Polysorbate 80 and Atlas 3000
(Atmos 300) in amounts ranging from about 0.5 to about 15 wt.%,
preferably about 2 to about 5 wt.%. Other suitable surfactants
include pluronic acid, sodium lauryl sulfate, and the like.
[0040] Preferred stabilizing agents include xanthan gum, locust
bean gum and carrageenan, in amounts ranging from about 0 to about
10 wt.%, preferably about 0.01 to about 2 wt.%. Other suitable
stabilizing agents include guar gum and the like.
[0041] Preferred emulsifying agents include triethanolamine
stearate, quaternary ammonium compounds, acacia, gelatin, lecithin,
bentonite, veegum, and the like, in amounts ranging from about 0 to
about 5 wt.%, preferably about 0.01 to about 0.7 wt.%.
[0042] Preferred thickening agents include methylcellulose,
carboxyl methylcellulose, and the like, in amounts ranging from
about 0 to about 20 wt.%, preferably about 0.01 to about 5wt.%.
[0043] Preferred binding agents include starch, in amounts ranging
from about 0 to about 10 wt.%, preferably about 0.01 to about 2
wt.%.
[0044] Preferred film formers include pullulan, in amounts ranging
from about 0.1 to about 80 wt.%, preferably about 30 to about 70
wt.%. Other suitable film formers include polyvinyl alcohol,
suitable cellulose, and the like.
[0045] Suitable sweeteners that can be included are those
well-known in the art, including both natural and artificial
sweeteners. Suitable sweeteners include, e.g.:
[0046] A. water-soluble sweetening agents such as monosaccharides,
disaccharides and polysaccharides such as xylose, ribose, glucose
(dextrose), mannose, galactose, fructose (levulose), sucrose
(sugar), maltose, invert sugar (a mixture of fructose and glucose
derived from sucrose), partially hydrolyzed starch, corn syrup
solids, dihydrochalcones, monellin, steviosides, and
glycyrrhizin;
[0047] B. water-soluble artificial sweeteners such as the soluble
saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate
salts, the sodium, ammonium or calcium salt of
3,4-dihydro-6-methyl-1,2,3- -oxathiazine-4-one-2, 2-dioxide, the
potassium salt of
3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide
(acesulfame-K), the free acid form of saccharin, and the like;
[0048] C. dipeptide based sweeteners, such as L-aspartic acid
derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester
(aspartame) and materials described in U.S. Pat. No. 3,492, 131,
L-alpha
-aspartyl-N-(2,2,4,4,-tetramethyl-3-thietanyl)-D-alaninamide
hydrate, methyl esters of L-aspartyl-L-phenylglycerin and
L-aspartyl-L-2,5,dihydro- phenyl-glycine,
L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1
-cyclohexyen)-alanine, and the like;
[0049] D. water-soluble sweeteners derived from naturally occurring
water-soluble sweeteners, such as a chlorinated derivative of
ordinary sugar (sucrose), known, for example, under the product
description of sucralose; and
[0050] E. protein based sweeteners such as thaumatoccous danielli
(Thaumatin I and II).
[0051] In general, an effective amount of auxiliary sweetener is
utilized to provide the level of sweetness desired for a particular
composition, and this amount will vary with the sweetener selected.
This amount will normally be 0.1% to about 10% by weight of the
composition when using an easily extractable sweetener. The
water-soluble sweeteners described in category A above, are usually
used in amounts of about 0.1 to about 10 wt. %, and preferably in
amounts of about 2 to about 5 wt. %. Some of the sweeteners in
category A (e.g., glycyrrhizin) can be used in amounts set forth
for categories B-E below due to the sweeteners' known sweetening
ability. In contrast, the sweeteners described in categories B-E
are generally used in amounts of about 0.1 to about 10 wt.%, with
about 2 to about 8 wt.% being preferred and about 3 to about 6 wt.%
being most preferred. These amounts may be used to achieve a
desired level of sweetness independent from the flavor level
achieved from any optional flavor oils used. Of course, sweeteners
need not be added to films intended for non-oral
administration.
[0052] The flavorings that can be used include those known to the
skilled artisan, such as, natural and artificial flavors. These
flavorings may be chosen from synthetic flavor oils and flavoring
aromatics, and/or oils, oleo resins and extracts derived from
plants, leaves, flowers, fruits and so forth, and combinations
thereof. Representative flavor oils include: spearmint oil,
cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar
leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds.
Also useful are artificial, natural or synthetic fruit flavors such
as vanilla, and citrus oil, including lemon, orange, grape, lime
and grapefruit and fruit essences including apple, pear, peach,
strawberry, raspberry, cherry, plum, pineapple, apricot and so
forth. These flavorings can be used individually or in admixture.
Commonly used flavors include mints such as peppermint, artificial
vanilla, cinnamon derivatives, and various fruit flavors, whether
employed individually or in admixture. Flavorings such as aldehydes
and esters including cinnamyl acetate, cinnamaldehyde, citral,
diethylacetal, dihydrocarvyl acetate, eugenyl formate,
p-methylanisole, and so forth may also be used. Generally, any
flavoring or food additive, such as those described in Chemicals
Used in Food Processing, publication 1274 by the National Academy
of Sciences, pages 63-258, may be used. Further examples of
aldehyde flavorings include, but are not limited to acetaldehyde
(apple); benzaldehyde (cherry, almond); cinnamic aldehyde
(cinnamon); citral i.e., alpha citral (lemon, lime), neral, i.e.
beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin
(vanilla, cream); heliotropine, i.e., piperonal (vanilla, cream);
vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruity
flavors); butyraldehyde (butter, cheese); valeraldehyde (butter,
cheese); citronellal (modifies, many types); decanal (citrus
fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus
fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde
(berry fruits); hexenal, i.e. trans-2 (berry fruits); tolyl
aldehyde (cherry, almond); veratraldehyde (vanilla);
2,6-dimethyl-5-heptenal, i.e. melonal (melon); 2-6-dimethyloctanal
(green fruit); and 2-dodecenal (citrus, mandarin); cherry; grape;
mixtures thereof; and the like.
[0053] The amount of flavoring employed is normally a matter of
preference subject to such factors as flavor type, individual
flavor, and strength desired. Thus, the amount may be varied in
order to obtain the result desired in the final product. Such
variations are within the capabilities of those skilled in the art
without the need for undue experimentation. In general, amounts of
about 0.1 to about 30 wt.% are useable with amounts of about 10 to
about 25 wt.% being preferred.
[0054] The compositions of this invention can also contain coloring
agents or colorants. The coloring agents are used in amounts
effective to produce the desired color. The coloring agents useful
in the present invention, include pigments such as titanium
dioxide, which may be incorporated in amounts of up to about 5
wt.%, and preferably less than about 1 wt.%. Colorants can also
include natural food colors and dyes suitable for food, drug and
cosmetic applications. These colorants are known as FD&C dyes
and lakes. The materials acceptable for the foregoing spectrum of
use are preferably water soluble, and include FD&C Blue No. 2,
which is the disodium salt of 5,5-indigotindisulfonic acid.
Similarly, the dye known as Green No. 1 comprises a
triphenylmethane dye and is the monosodium salt of
4-[4-N-ethyl-p-sulfobenzylamino)diphenyl-methylene]-[1-
-N-ethyl-N-p-sulfonium
benzyl)-.DELTA..sup.2,5-cyclo-hexadienimine]. Additional examples
include the yellow dye, known as D&C Yellow No. 10, and the dye
known as FD&C Green No. 3, which comprises a triphenylmethane
dye. A full recitation of all FD&C and D&C dyes and their
corresponding chemical structures may be found in the Kirk-Othmer
Encyclopedia of Chemical Technology, Volume 5, Pages 857-884, which
text is accordingly incorporated herein by reference.
[0055] Methods for preparing films according to the invention are
capable of encapsulating the oil ingredients within the
film-forming matrix and maintaining the integrity of the film, even
when the film contains oils in amounts of 10 wt.% or more.
[0056] In certain methods for preparing films according to the
invention, the film-forming ingredients are mixed and hydrated with
water separately from the water-soluble ingredients, which are
mixed in aqueous solution separately from the organic ingredients
(i.e., oils) and surfactants. In these methods, the final
formulation is preferably produced by mixing the film-forming phase
with the aqueous phase, then mixing in the organic phase, which
includes surfactants, such as Polysorbate 80 and Atmos 300 (i.e.,
Atlas 3000).
[0057] The resulting formulation is cast on a suitable substrate
and dried to form a film. The film is preferably air-dried or dried
under warm air and cut to a desired dimension, packaged and stored.
The film preferably contains about 3% to about 8% moisture after
drying.
[0058] The film-forming phase can include pullulan and stabilizing
agents such as xanthan gum, locust bean gum and carrageenan. These
ingredients are mixed and then hydrated in water for about 2 to
about 48 hours to form a gel. The water is heated to a temperature
of about 25 to about 45.degree. C. to promote hydration. The amount
of water is about 40 to 80% of the gel. The resulting hydrated gel
is then chilled to a temperature of about 20 to about 30.degree. C.
for about 2 to about 48 hours. The water is preferably
deionized.
[0059] The aqueous phase can include ingredients such as coloring
agent(s), copper gluconate and sweetener. The water is preferably
deionized and the amount of water used is about 5 to about 80 wt.%
of the final gel mixture.
[0060] If sodium saccharine and copper gluconate are both
ingredients in the formulation, it is preferable to dissolve them
separately in solution to avoid precipitation.
[0061] In a preferred method of producing films according to the
invention, it is possible to hydrate the film-forming ingredients
and combine all of the ingredients without heating. The preferred
method of producing films comprises: (a) dissolving the
water-soluble ingredients in water to form an aqueous mixture; (b)
mixing the film-forming ingredients together in powder form to form
a powder mixture; (c) adding the powder mixture to the aqueous
mixture to form a hydrated polymer gel; (d) stirring the hydrated
polymer at room temperature for about 1 to about 48 hours; (e)
mixing the hydrophobic ingredients and surfactants to form an oil
phase; (f) adding the oil phase to the hydrated polymer gel and
mixing until uniform; (g) casting the uniform mixture on a suitable
substrate; and (h) drying the cast mixture to form a film.
[0062] The preferred method can be conducted without hydrating the
film-forming ingredients in hot water. Heating the ingredients
increases energy costs in the manufacturing process. Moreover,
heating results in undesirable losses of volatile ingredients to
evaporation, which also affects the composition of the formulation.
Further, mixing the oils in two steps minimizes the amount of
flavor lost.
[0063] While not wishing to be bound by any theories, it is
believed that the film-forming ingredients can be hydrated and
mixed without heating due to an ionic effect known as the Donnan
equilibrium. Hydrating the film-forming agents in the presence of
electrolytes in solution effectively lowers the viscosity of the
polymer gel being formed, thus increasing the efficiency of the
hydrating process. The electrolytes are provided by the
water-soluble ingredients of the formulation, which are dissolved
in the hydration solution prior to addition of the film-forming
ingredients.
[0064] It is preferable to avoid adding both copper gluconate and
saccharin to the aqueous solution, as a precipitate will form.
Thus, it is preferred to combine sweeteners other than saccharin
with copper gluconate.
[0065] The invention will be illustrated in more detail with
reference to the following Examples, but it should be understood
that the present invention is not deemed to be limited thereto.
EXAMPLE 1
Antimicrobial/Wound-Healing Film
[0066]
1EXAMPLE 1 NUMBER INGREDIENT WEIGHT (grams) 1 Xanthan Gum 0.0385 2
Locust Bean Gum 0.0770 3 Carrageenan 0.3850 4 Pullulan 18.5000 5
Deionized Water 84.2500 6 Mineral Oil 3.000 7 Sodium Pyruvate
0.2200 8 Vitamin E 0.2200 9 Rendered Chicken Fat 0.2200 10
Polysorbate 80 0.4000 11 Atlas 3000/Atmos 300 0.4000 12 Triclosan
0.0500
[0067] Ingredients 1-4 were dry mixed together and then added to
ingredient 5 with further mixing to provide a gel phase.
Ingredients 6-12 were mixed to uniformity in a separate container
to provide an oil phase. The oil phase was then added to the gel
phase with mixing and stored overnight.
[0068] The next day, the mixture was further mixed, poured on a
mold and cast to form a film of a desired thickness at room
temperature. The film was dried under warm air and cut to a desired
dimension for testing.
[0069] The resulting film was slightly opaque and adhered to wet
skin.
EXAMPLE 2
Antimicrobial/Wound-Healing Film
[0070]
2 NUMBER INGREDIENT WEIGHT (grams) 1 Xanthan Gum 0.035 2 Locust
Bean Gum 0.070 3 Carrageenan 0.350 4 Pullulan 18.000 5 Deionized
Water 75.755 6 Tween 80 0.400 7 Atlas 3000/Atmos 300 0.400 8
Polymyxin B Sulfate 0.0035 9 Bacitracin Zinc 0.0319 10 Neomycin
Sulfate 0.030 11 Petrolatum, White 4.135 12 Vitamin E 0.100 13
Cocoa Butter 0.120 14 Olive Oil 0.180 15 Cottonseed Oil 0.300 16
Sodium Pyruvate 0.100
[0071] Ingredients 1-4 were dry mixed together and then added to
ingredient 5 with further mixing to provide a gel phase.
Ingredients 8-16 were added to the gel phase in the form of 5.0
grams of Neosporin.TM. (Warner-Lambert Company, Morris Plains,
N.J.) along with ingredients 6-7. The ingredients were mixed,
poured on a mold and cast to form a film of a desired thickness at
room temperature. The film was dried under warm air and cut to a
desired dimension for testing.
[0072] The resulting film was not difficult to remove from the
backing, but adhered to wet skin well. The film dried to a clear
and shiny protective film on the skin.
EXAMPLE 3
Anesthetic Film
[0073]
3 NUMBER INGREDIENT WEIGHT (grams) 1 Xanthan Gum 0.0385 2 Locust
Bean Gum 0.077 3 Carrageenan 0.385 4 Pullulan 18.5 5 Deionized
Water 54.25 6 Deionized Water 30 7 BHT (hydroxybutyl toluene) 0.03
8 Mineral Oil 3.0 9 Lidocaine 1.2 10 Polysorbate 80 0.4 11 Atlas
3000/Atmos 300 0.4
[0074] Ingredients 1-4 were dry mixed together and then added to
ingredient 5 with further mixing to provide a gel phase.
Ingredients 6-7 were mixed together in a separate container to
provide an aqueous phase. Ingredients 8-11 were mixed to uniformity
in a separate container to provide an oil phase. The aqueous phase
was added to the gel phase, and then the oil phase was added to the
gel/aqueous phase mixture with mixing.
[0075] The mixture was further mixed, poured on a mold and cast to
form a film of a desired thickness at room temperature. The film
was dried under warm air and cut to a desired dimension.
EXAMPLE 4
Antimicrobial/Wound-Healing Film
[0076]
4 NUMBER INGREDIENT WEIGHT (grams) 1 Xanthan Gum 0.0385 2 Locust
Bean Gum 0.077 3 Carrageenan 0.385 4 Pullulan 18.5 5 Deionized
Water 54.25 6 Copper Gluconate 0.4 7 Deionized Water 30 8 Mineral
Oil 3.0 9 Sodium Pyruvate 0.22 10 Vitamin E 0.22 11 Rendered
Chicken Fat 0.22 12 Polysorbate 80 0.4 13 Atlas 3000/Atmos 300
0.4
[0077] Ingredients 1-4 were dry mixed together and then added to
ingredient 5 with further mixing to provide a gel phase.
Ingredients 6-7 were mixed together in a separate container to
provide an aqueous phase. Ingredients 8-13 were mixed to uniformity
in a separate container to provide an oil phase. The aqueous phase
was added to the gel phase, and then the oil phase was added to the
gel/aqueous phase mixture with mixing.
[0078] The mixture was further mixed, poured on a mold and cast to
form a film of a desired thickness at room temperature. The film
was dried under warm air and cut to a desired dimension.
[0079] While the invention has been described in detail and with
reference to specific examples thereof, it will be apparent to one
skilled in the art that various changes and modifications can be
made therein without departing from the spirit and scope
thereof.
* * * * *