U.S. patent application number 13/292590 was filed with the patent office on 2012-05-10 for water soluble film for oral administration with instant wettability.
Invention is credited to Jian-Hwa Guo, Anthony Serino, Horst Georg ZERBE.
Application Number | 20120114705 13/292590 |
Document ID | / |
Family ID | 7811214 |
Filed Date | 2012-05-10 |
United States Patent
Application |
20120114705 |
Kind Code |
A1 |
ZERBE; Horst Georg ; et
al. |
May 10, 2012 |
WATER SOLUBLE FILM FOR ORAL ADMINISTRATION WITH INSTANT
WETTABILITY
Abstract
A composition containing therapeutic agents and/or breath
freshening agents for use in the oral cavity is disclosed. The
carrier comprises water-soluble polymers in combination with
certain ingredients and provides a therapeutic and/or cosmetic
effect. The film is coated and dried utilizing existing coating
technology and exhibits instant wettability followed by rapid
dissolution/disintegration upon administration in the oral
cavity.
Inventors: |
ZERBE; Horst Georg; (Green
Pond, NJ) ; Guo; Jian-Hwa; (Sparta, NJ) ;
Serino; Anthony; (Boonton, NJ) |
Family ID: |
7811214 |
Appl. No.: |
13/292590 |
Filed: |
November 9, 2011 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10771388 |
Feb 5, 2004 |
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13292590 |
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10143962 |
May 14, 2002 |
6709671 |
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10771388 |
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09927327 |
Aug 13, 2001 |
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10143962 |
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09630562 |
Aug 2, 2000 |
6284264 |
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09927327 |
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09287181 |
Apr 6, 1999 |
6177096 |
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09630562 |
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08904607 |
Aug 1, 1997 |
5948430 |
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09287181 |
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Current U.S.
Class: |
424/400 ;
514/772; 514/772.2; 514/772.5; 514/781; 514/784; 514/786 |
Current CPC
Class: |
A61K 8/8176 20130101;
A61K 8/4926 20130101; A61P 1/02 20180101; A61K 8/90 20130101; A61K
8/731 20130101; A61K 8/922 20130101; A61K 9/006 20130101; A61K
8/0208 20130101; A61K 8/39 20130101; A61Q 11/00 20130101; A61P
11/00 20180101; A61P 29/00 20180101; A61P 25/26 20180101 |
Class at
Publication: |
424/400 ;
514/772; 514/786; 514/784; 514/781; 514/772.5; 514/772.2 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/44 20060101 A61K047/44; A61K 47/32 20060101
A61K047/32; A61K 47/38 20060101 A61K047/38; A61P 29/00 20060101
A61P029/00; A61K 47/10 20060101 A61K047/10; A61K 47/12 20060101
A61K047/12 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 11, 1996 |
DE |
196 46 392.0 |
Claims
1-9. (canceled)
10. A film comprising: i. at least one water-soluble polymer, ii.
at least one polyalcohol, and iii. at least one pharmaceutically
active ingredient.
11. A film according to claim 10 wherein the at least one
polyalcohol is selected from the group consisting of glycerol,
propylene glycol, glycerol esters with fatty acids and other
pharmaceutically used polyalcohols.
12. A film according to claim 11 wherein the concentration of the
at least one water-soluble polymer is between 20 and 75% (w/w).
13. A film according to claim 11 wherein the concentration of the
at least one polyalcohol is between 0.1 and 5% (w/w).
14. A film according to claim 10 wherein the concentration of at
least one pharmaceutically active ingredient is between 0.01 and
20% (w/w).
15. A film according to claim 10 wherein at least one
pharmaceutically active ingredient is selected from the group of
narcotics.
16. A film according to claim 10 wherein the film has a thickness
between 5 and 200 .mu.m.
17. A film according to claim 16 wherein the film has a thickness
between 5 and 70 .mu.m.
18. A film according to claim 10 further comprising at least one
member of the group consisting of colorants, sweetening agents,
flavours, and flavour enhancers.
19. A film according to claim 10 further comprising tartaric
acid.
20. A film according to claim 10 further comprising citric
acid.
21. A film according to claim 10 further comprising vanillin.
22. A film according to claim 10 wherein i. a first water-soluble
polymer is a water-soluble cellulose derivative and ii. a second
water-soluble polymer is selected from the group consisting of
polyvinyl pyrrolidone, polyvinyl alcohol and polyethylene
glycol.
23. A film according to claim 22 wherein the water-soluble
cellulose derivative is selected from the group consisting of
hydroxypropylmethyl cellulose, hydroxyethyl cellulose and
hydroxypropyl cellulose.
24. A film according to claim 10 wherein a first water-soluble
polymer is hydroxypropylmethyl cellulose and a second water-soluble
polymer is polyethylene glycol.
25. A film according to claim 10 wherein the film is capable to
release at least one pharmaceutically active ingredient to the oral
cavity.
26. A film according to claim 10 wherein the film is rapidly
dissolving.
27. A film according to claim 10 wherein the film is
mucoadhesive.
28. A film comprising i. a first water-soluble polymer which is a
water-soluble cellulose derivative selected from the group
consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose
and hydroxypropyl cellulose, ii. a second water-soluble polymer
which is selected from the group consisting of polyvinyl
pyrrolidone, polyvinyl alcohol and polyethylene glycol, and iii. at
least one pharmaceutically active ingredient.
29. A film according to claim 28 wherein at least one
pharmaceutically active ingredient is selected from the group of
narcotics.
30. A film according to claim 28 wherein a first water-soluble
polymer is hydroxypropylmethyl cellulose and a second water-soluble
polymer is polyethylene glycol.
31. A film according to claim 28 wherein the concentration of at
least one water-soluble polymer is between 20 and 75% (w/w).
32. A film according to claim 28 wherein the concentration of
polyethylene glycol is between 20 and 75% (w/w).
33. A film according to claim 28 further comprising at least one
polyalcohol.
34. A film according to claim 28 wherein the concentration of the
at least one pharmaceutically active ingredient is between 0.01 and
20% (w/w).
35. A film according to claim 28 wherein the concentration of at
least one pharmaceutically active ingredient selected from the
group of narcotics is between 0.01 and 20% (w/w).
36. A film according to claim 28 wherein the film has a thickness
between 5 and 200 .mu.m.
37. A film according to claim 36 wherein the film has a thickness
of between 5 and 70 .mu.m.
38. A film according to claim 28 further comprising at least one
member of the group consisting of colorants, sweetening agents,
flavours, and flavour enhancers.
39. A film according to claim 28 further comprising tartaric
acid.
40. A film according to claim 28 further comprising citric
acid.
41. A film according to claim 28 further comprising vanillin.
42. A film according to claim 28 wherein the film is capable to
release the at least one pharmaceutically active ingredient to the
oral cavity.
43. A film according to claim 28 wherein the film is rapidly
dissolving.
44. A film according to claim 28 wherein the film is
mucoadhesive.
45. A film comprising: i. at least one water-soluble
hydroxypropylmethyl cellulose, ii. at least one water-soluble
polyethylene glycol in a concentration of between 20 and 75% (w/w),
iii. and at least one pharmaceutically active ingredient selected
from the group of narcotics in a concentration of between 0.01 and
20% (w/w).
46. A film according to claim 45 further comprising at least one
polyalcohol, at least one colorant, at least one sweetening agent,
and citric acid.
Description
[0001] A composition containing therapeutic agents and/or breath
freshening agents for use in the oral cavity is disclosed. The
carrier comprises water-soluble polymers in combination with
certain ingredients and provides a therapeutic and/or cosmetic
effect. The film is coated and dried utilizing existing coating
technology and exhibits instant wettability followed by rapid
dissolution/disintegration upon administration in the oral
cavity.
[0002] Mucoadhesive dosage forms for application to the oral cavity
which are designed to deliver therapeutic and/or cosmetic agents to
the oral mucosa are known in the art. U.S. Pat. No. 5,047,244
describes a mucoadhesive carrier allowing the controlled release of
a therapeutic agent via the mucosal tissue comprising an anhydrous
but hydratable polymer matrix and amorphous fumed silica. An
optional water-insoluble film can be added to provide a
non-adhering surface. In WO 91/06270, the same authors disclose a
trilaminate film suitable for prolonged delivery of an active
ingredient in the oral cavity.
[0003] In a similar way, U.S. Pat. No. 4,876,092 discloses a
sheet-shaped adhesive preparation comprising an adhesive layer
containing certain water-soluble and water-insoluble polymers and a
water-insoluble carrier which can adhere to the oral mucosa thereby
releasing an active agent to the oral cavity. All the devices so
far cited are not completely water soluble and will stay in the
oral cavity even after the therapeutic goal has been achieved
leaving the patient with a certain discomfort in the mouth
resulting mainly from the support layer which leaves an insoluble
residue in the mouth.
[0004] A number of attempts have been made to reduce the adverse
feeling in the oral cavity caused by the rigidity and inflexibility
of the support layer by introducing soft film supports. EP 0 200
508 B1 and EP 0 381 194 B1 disclose the use of polyethylene films,
polyvinyl acetate, ethylene-vinyl acetate copolymers, metal foils,
laminates of cloth or paper and a plastic film, and similar
materials as soft film supports, whereby synthetic resins like
polyethylene, vinyl acetate homopolymers, and ethylene-vinyl
acetate are the preferred materials. In a similar way, CA 1 263 312
discloses the use of polyolefines such as polyethylene,
polypropylene, polyesters, PVC, and non-woven fabrics as soft
support materials.
[0005] However, these devices still leave the patient with a
considerable amount of residue from the water-insoluble support
film thereby still causing a feeling of discomfort. The obvious
solution to overcome this problem was to develop mucoadhesive films
which completely disintegrate, or even completely dissolve in the
saliva. Fuchs and Hilmann (DE 24 49 865.5) prepared homogeneous,
water-soluble films intended for buccal administration of hormones.
They proposed the use of water-soluble cellulose-derivatives, like
hydroxyethyl cellulose, hydroxypropyl cellulose, or methyl
hydroxypropyl cellulose, as film forming agents.
[0006] Both DE 36 30 603 and EP 0 219 762 disclose the use of
swellable polymers such as gelatine or corn starch as film forming
agents, which upon application to the oral cavity slowly
disintegrate, thereby releasing an active ingredient incorporated
in the film. The same polymers can also be used to prepare films
which are intended for dental cleansing, as described in EP 0 452
446 B1.
[0007] These preparations still create an adverse feeling in the
mouth which is mainly caused by their initial rigidity and delayed
softening. Thus, there has still been a demand for a composition
for use in the oral cavity which meets the requirement of providing
a pleasant feeling in the mouth.
[0008] The present invention discloses methods and compositions
that are capable of avoiding an adverse feeling by providing the
film which is intended for application to the oral mucosa with
instant wettability, while achieving adequate tensile strength in
the free film to allow for easy coating, converting, and packaging
of a consumer-friendly product.
[0009] The present invention contemplates a rapidly dissolving film
which can be adhered to the oral cavity thereby releasing a
pharmaceutically or cosmetically active agent, said film comprising
water-soluble polymers, one or more polyalcohols, and one or more
pharmaceutically or cosmetically active ingredients. Optionally,
the formulation may contain a combination of certain plasticizers
or surfactants, colorants, sweetening agents, flavors, flavor
enhancers, or other excipients commonly used to modify the taste of
formulations intended for application to the oral cavity. The
resulting film is characterized by an instant wettability which
causes the film to soften immediately after application to the
mucosal tissue thus preventing the patient from experiencing any
prolonged adverse feeling in the mouth, and a tensile strength
suitable for normal coating, cutting, slitting, and packaging
operations.
[0010] The mucoadhesive film of the present invention contains as
essential components a water-soluble polymer or a combination of
water-soluble polymers, one or more plasticizers or surfactants,
one or more polyalcohols, and a pharmaceutically or cosmetically
active ingredient.
[0011] The polymers used for the mucoadhesive film include polymers
which are hydrophilic and/or water-dispersible. Preferred polymers
are water-soluble cellulose-derivatives. Hydroxypropylmethyl
cellulose, hydroxyethyl cellulose, or hydroxypropyl cellulose,
either alone, or mixtures thereof, are particularly preferred.
Other optional polymers, without limiting the invention, include
polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol,
sodium alginate, polyethylene glycol, natural gums like xanthane
gum, tragacantha, guar gum, acacia gum, arabic gum,
water-dispersible polyacrylates like polyacrylic acid,
methylmethacrylate copolymer, carboxyvinyl copolymers. The
concentration of the water-soluble polymer in the final film can
vary between 20 and 75% (w/w), preferably between 50 and 75%
(w/w).
[0012] The surfactants used for the mucoadhesive film may be one or
more nonionic surfactants. When a combination of surfactants is
used, the first component may be a polyoxyethylene sorbitan fatty
acid ester or a .alpha.-hydro-.omega.-hydroxypoly(oxyethylene)
poly(oxypropylene)poly(oxyethylene) block copolymer, while the
second component may be a polyoxyethylene alkyl ether or a
polyoxyethylene castor oil derivative. Preferably, the HLB value of
the polyoxyethylene sorbitan fatty acid ester should be between 10
and 20, whereby a range of 13 to 17 is particularly preferred. The
.alpha.-hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)
poly(oxyethylene) block copolymer should contain at least 35
oxypropylene-units, preferably not less than 50
oxypropylene-units.
[0013] The polyoxyethylene alkyl ether should have an HLB value
between 10 and 20, whereby an HLB value of not less than 15 is
preferred. The polyoxyethylene castor oil derivative has to have an
HLB value of 14-16.
[0014] In order to achieve the desired instant wettability, the
ratio between the first and second component of the binary
surfactant mixture should be kept within 1:10 and 1:1, more
preferably between 1:5 and 1:3.
[0015] The total concentration of surfactants in the final film
depends on the properties of the other ingredients, but usually has
to stay between 0.1 and 5% (w/w).
[0016] The polyalcohol is used to achieve the desired level of
softness of the film. Examples of polyalcohols include glycerol,
polyethylene glycol, propylene glycol, glycerol monoesters with
fatty acids or other pharmaceutically used polyalcohols. The
concentration of the polyalcohol in the dry film usually ranges
between 0.1 and 5% (w/w).
[0017] The film is well suited for the delivery of a wide range of
pharmaceutically active ingredients via the mucous membranes of a
patient, particularly the buccal mucosa. Therapeutic agents which
exhibit absorption problems due to solubility limitations,
degradation in the gastro-intestinal tract, or extensive
metabolism, are particularly well suited. Without limiting the
invention, examples of the therapeutic agents include hypnotics,
sedatives, antiepileptics, awakening agents, psychoneurotropic
agents, neuromuscular blocking agents, antispasmodic agents,
antihistaminics, antiallergics, cardiotonics, antiarrhythmics,
diuretics, hypotensives, vasopressors, antitussive expectorants,
thyroid hormones, sexual hormones, antidiabetics, antitumor agents,
antibiotics and chemotherapeutics, and narcotics.
[0018] The amount of drug to be incorporated into the film depends
on the kind of drug and is usually between 0.01 and 20% (w/w), but
it can be higher if necessary to achieve the desired effect.
[0019] Cosmetically active agents may include breath freshening
compounds like menthol, other flavors or fragrances commonly used
for oral hygiene, and/or actives used for dental and/or oral
cleansing like quarternary ammonium bases. The effect of flavors
may be enhanced using flavor enhancers like tartaric acid, citric
acid, vanillin, or the like. Colorants which may optionally be
mixed in the film must be safe in terms of toxicity and should be
accepted by the Food and Drug Administration for use in
cosmetics.
[0020] The mucoadhesive film according to the present invention can
be prepared as follows: The polyalcohol, surfactants, plasticizers,
and possible other ingredients except the water-soluble or
water-dispersible polymer(s) are dissolved in a sufficient amount
of a solvent which is compatible with them. Examples of compatible
solvents include water, alcohols or mixtures thereof. After a clear
solution has been formed, the water-dispersible polymer or mixture
of the water-dispersible polymers is slowly added with stirring,
and heat if necessary, until a clear and homogeneous solution has
been formed, followed by the addition of active ingredients and
flavors. The solution is coated onto a suitable carrier material
and dried to form a film. The carrier material must have a surface
tension which allows the polymer solution to spread evenly across
the intended coating width without soaking in to form a destructive
bond between the two. Examples of suitable materials include
non-siliconized polyethylene terephthalate film, non-siliconized
kraft paper, polyethylene-impregnated kraft paper, or
non-siliconized polyethylene film.
[0021] The coating of the solution onto the carrier material can be
performed using any conventional coating equipment. A more
preferred coating technique would involve a knife-over-roll coating
head.
[0022] The thickness of the resulting film depends on the
concentration of solids in the coating solution and on the gap of
the coating head and can vary between 5 and 200 .mu.m. Drying of
the film is carried out in a high-temperature air-bath using a
drying oven, drying tunnel, vacuum drier, or any other suitable
drying equipment, which does not adversely affect the active
ingredient(s) or flavor of the film. In order to reliably avoid an
adverse feeling in the mouth, a dry film thickness of 70 .mu.m
should not be exceeded.
[0023] For better ease of use, the dry film can be cut into pieces
of suitable size and shape and packed into a suitable
container.
[0024] The invention will now be explained more specifically with
reference to the following examples, which are given for
illustration of this invention and are not intended to be limiting
thereof.
EXAMPLE 1
[0025] 15 g of sorbitol, 6 g of glycerol, 0.5 g of polysorbate 80
(Tween 80), 2 g of Brij 35, 25 g of lemon mint flavor, 3 g of
aspartame, 15 g of 1-menthol, and 3 g of citrc acid are stirred at
60.degree. C. in a mixture of 250 g water and 250 g ethanol until a
clear solution has been formed. To the solution, 30 g of
hydroxypropylmethyl cellulose are added slowly under stirring until
a clear and homogeneous solution has been formed. The resulting
solution is allowed to cool to room temperature and coated onto a
suitable carrier material, for example non-siliconized,
polyethylene-coated kraft paper using conventional coating/drying
equipment. Coating gap and web speed have to be adjustable to
achieve a dry film thickness between 20 and 50 .mu.m. The drying
temperature depends on the length of the drying oven and the web
speed and has to be adjusted to remove the solvents completely, or
almost completely, from the film. The resulting film is peeled off
the carrier web and cut into pieces of a shape and size suitable
for the intended use.
EXAMPLE 2
[0026] 3 g sorbitol, 1.5 g Kollidon 30 (supplier: BASF), 5 g
glycerol, 5 g propylene glycol, 5 g polyethylene glycol, 4 g
polysorbate 80 (Tween 80), 8 g Brij 35, 12 g peppermint flavor, and
0.8 g aspartame are dissolved in a mixture containing 400 g water
and 400 g ethanol at 60.degree. C. under stirring. To the clear
solution, 28 g hydroxypropylmethyl cellulose are added slowly under
stirring. After the polymer is completely dissolved, the solution
is cooled to room temperature and coated onto a suitable carrier
web using the coating and drying conditions as described in the
previous example. The dry film is again cut into pieces of suitable
size and shape.
EXAMPLE 3
[0027] 15 g sorbitol, 22.5 g glycerol, 2.5 g propylene glycol, 2.5
g Brij 35, 2.5 g polyoxamer 407, 3.5 g Cremophor RH 40, 9 g herb
mint flavor, and 0.5 g aspartame are dissolved under stirring at
60.degree. C. in a mixture containing 250 g water and 250 g
ethanol. To the clear solution, 75 g hydroxypropyl cellulose are
added slowly under continuous stirring. The clear solution is again
coated and dried under the conditions as described in EXAMPLE 1 and
the dry film is cut into pieces of a shape and size suitable for
the intended use.
EXAMPLE 4
[0028] 3.6 g Tween 80, 3.6 g glycerol, 39 g menthol, and 171 g
Kollidon 30 are dissolved in a solution of 600 ml water and 2800 ml
ethanol at ambient temperature with stirring. 247.5 g
hydroxypropylmethyl cellulose is then added slowly and portionwise
at 50-55.degree. C. and stirred until completely dissolved. The
mixture is then allowed to cool and added in succession are 90 g
lemon mint flavor followed by a solution/suspension of 27.13 g
aspartame, 18 g citric acid, and 0.17 g FD&C yellow #5 in 120
ml water with stirring. The clear solution is coated and dried
under the conditions as described in EXAMPLE and the dry film is
cut into pieces of a shape and size suitable for the intended
use.
EXAMPLE 5
[0029] 165.4 g Kollidon 30 are dissolved in a solution of 720 ml
water and 2660 ml ethanol at ambient temperature with stirring.
220.5 g hydroxypropylmethyl cellulose is then added at
55-60.degree. C. and stirred vigorously until clear and
homogeneous. The mixture is then allowed to cool and added in
succession are 78.75 g flavor followed by a mixture of 28.88 g
nicotine salicylate and 31.5 g caramel liquid in 120 ml water with
stirring. The clear, tan-colored solution is coated an dried under
the conditions as described in EXAMPLE 1 and the dry film is cut
into pieces of a shape and size suitable for the intended use so as
to deliver a nicotine dose between 1-2 mg per piece.
* * * * *