Note: Descriptions are shown in the official language in which they were submitted.
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TOPICAL MEDICATED BIOADHESIVE COMPOSITIONS
AND METHODS OF USE AND PREPARATION THEREOF
The Field of the Invention
This invention relates to topical medicated
bioadhesive compositions.
More particularly, the invention concerns such
compositions which are specially adapted to use in
applying topical medications to human tissue.
In a further aspect, the invention relates to
methods for preparation of such bioadhesive compositions.
Background of the Invention
For many years prior to the mid-1980s, medical and
dental clinicians had long sought a topical carrier that
would adhere tenaciously to human tissue, especially
mucosal tissues, that would be chemically compatible with
a wide variety of medications and from which such
medications would be bioavailable to the underlying
tissue. For example, see Stoughton, Ann..Pharmacol.
Toxiaol, 1989, 29:55-69).
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The Prior Art
In the mid-1980s, a line of topical medicated
bioadhesive products became commercially available and
was distributed under the trademark "ZILACTIN~". These
compositions, which were disclosed in United States
Patents 5,081,157 and 5,081,158 to Pomera,ntz, formed
medicated films on body tissue, which tenaciously adhered
to even wet mucosal tissues for up to several hours. The
components of these film forming compositions were
chemically compatible with a wide variety of medications,
which were readily bioavailable from the in situ
deposited film.
The compositions disclosed by the Pomerantz patents
comprised a medicinal component, hydroxypropyl cellulose
(HPC), an esterification agent (e. g., salicylic and/or
tannic acid) which reacted with the HPC to form a
reaction product which was insoluble in body fluids
(saliva, etc.), and a volatile non-toxic solvent for the
HPC and the reaction product.
Commercial products such as the ZILACTIN~ products
and a product marketed under the trademark "ORABASE GEL"
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(as it was formulated during 1994-1996), which employed
the Pomerantz technology and which contained active
medications such as topical analgesics (e. g., benzocaine)
and topical canker sore medications (e. g., benzyl
alcohol) were widely and quickly accepted in the "over
the counter" pharmaceutical market.
More recently, a similar product, has appeared, in
which ethyl cellulose is used as the film-former instead
of the esterified HPC of the Pomerantz formulations.
However, this product still contains compounds such as
salicylic acid and tannic acid. It is not known whether
there is any reaction between the salicylic and tahnic
acids of these~more recent products and the ethyl
cellulose. See, e.g., United States Patent 5,885,611 to
Church, et al., in which the salicylic acid is alleged to
be a "keratolytic agent" and the tannic acid is alleged
to be an "astringent."
Still more recently a topical medicated film forming
composition has been disclosed in United States Patent
5,955,097 to Tapolsky et al., in which the combination of
ethyl cellulose and a bioadhesive polymer is combined in
a formulation with an alcoholic solvent and a medicinal
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component. It is not. known whether such formulations
have tissue adhesion properties equal to the Pomerantz
formulations, whether these carrier formulations are
chemically compatible ~niith a wide variety of medications
or whether the medications contained in these
formulations are readily topically bioavailable.
Topical carriers known in the art include gels,
pastes, tablets, and films. These products, however, may
lack one or several of the preferred characteristics for
an efficient and commercially acceptable pharmaceutical
delivery device. Some characteristics which are desired
for topical carriers include water-solubility, ease of
handling and application to the treatment site minimal
foreign body sensation. Other desired characteristics
for an effective, user-friendly product for the treatment
of mucosal surfaces include the use of pharmaceutically
approved components or materials, initial adhesion to
mucosal surface upon application, increased residence
time for the protection of the affected tissue or the
delivery of the pharmaceutical component, and ease of
removal from the affected tissue or natural dissolution'
of the delivery device. at the delivery site.
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Gels for application to mucosal tissues and
especially the oral cavity are known in the art. For
example, U.S. Pat. No. 5,192,802 describes a teething gel
made from a blend of sodium carboxymethyl cellulose and
xanthan gum. The gel may also have potential use in the
treatment of canker sores, fever blisters, and
hemorrhoids. However, this type of pharmaceutical
carrier has a very limited residence time, given that
body fluids such as saliva quickly wash it away from the
treatment site. Topical gels are also described in U.S.
Pat. Nos. 5,314,914; 5,298,258; and 5,642,749. The gels
described in those patents use no aqueous or oily medium
and different types of gelling agents.
Denture "adhesive" pastes are also known in the art.
However, these preparations are used primarily for their
adhesive properties, to adhere dentures to the gums,
rather than for the protection of tissue or for the
topical delivery of pharmaceuticals, although drugs such
as local anesthetics may be used in the paste for the
relief of sore gums. U.S. Pat. Nos. 4,894,232 and
4,518,721 describe denture adhesive pastes. The '721
Patent describes a combination of sodium carboxymethyl
cellulose and polyethylene oxide in polyethylene glycol.
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Pastes have also been used as protectants~and as
drug delivery systems. One such paste is the product
commercialized under the name,Orabase~-B, which is a
thick paste containing benzocaine for the relief of mouth
sores. Ingredients include guar gum, sodium
carboxymethyl cellulose, tragacanth gum, and pectin.
Even though it does provide numbing to the area of
appl~.cation, the paste is easily displaced from that area
and has limited residence time.
Adhesive tablets are described in U.S. Pat. No.
4,915,948. The water-soluble adhesive material used in
this device is a xanthan gum or a pectin combined with an
adhesion enhancing material .such as a polyol. Although
residence time is improved with the use of bioadhesive
tablets, they are not user friendly, especially for use
in the oral cavity, given the unpleasant feelings
associated with their solidity, bulkiness, and slow
dissolution time. Adhesive tablets are also described
iri U.S. Pat. Nos. 4,226,848; 4,292,299; and 4,250,163,
and are single layer or bilayer devices having an average
thickness of 0.2 to 2.5 mm. The adhesive tablets
described in these patents utilize.a non-.adhesive
component such as cellulose ether, a bioadhesive
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component such as polyacrylic acid, sodium
carboxymethylcellulose, or polyvinylpyrrolidone, and a
binder for tableting purposes. The cellulose derivatives
may or may not be water-soluble. The claimed cellulosic
materials in the '299 patent are methyl cellulose,
hydroxypropyl cellulose, and hydroxypropylmethyl
cellulose.
The use of laminated film "bandages", which are
thinner and flexible and therefore give a decreased
foreign body sensation, is described in U.S. Patent N.
3,996,934 and 4,286,592. These products are used to
deliver drugs through the skin or mucosa. The laminated
films, which are thinner and flexible and therefore have
a decreased foreign body sensation, is described in U.S.
Pat. Nos. 3,996,934 and 4,286,592. The laminated films
usually include an adhesive layer, a reservoir layer, and
a backing layers These devices, designed to release drug
through the skin at a given rate and over a period of
time, are usually not water soluble and are not dissolved
or washed away by bodily fluids.
In addition to film systems for the delivery of drug
through the skin, film delivery systems for use on
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mucosal surfaces are, also known. These types of systems,
which are~water-insoluble and usually in the form of
preformed laminated, extruded or composite films, are
described in U.S. Pat. Nos. 4,517,173; 4,572,832;
4,713,243; 4,900,554; and 5,137,729. The '173 Patent
describes and claims a membrane-adhering film consisting
of at least three layers, including a pharmaceutical
layer, a layer of low water solubility is made by the
combination of one or more cellulose derivatives with a
soluble fatty acid of low water solubility, and the
intermediate layer is made of cellulose derivatives. The
'832 Patent relates to a soft film for buccal delivery,
made by the combined use of a water-soluble protein, a
polyol, and a polyhydric alcohol such as cellulose and
other polysaccharides, and also teaches the use of
coloring or flavoring agents. The '243 Patent describes
a single or multi-layered thin film made from 40-95~
water soluble hydroxypropyl cellulo e, 5-60~ water-
insoluble ethylene oxide, 0-10~ water-insoluble ethyl
cellulose, propyl cellulose, polyethylene, or
polypropylene, and a medicament. The films~are three-
layered laminates and include an adhesive layer, a
reservoir layer, and a water-insoluble outer protective
layer.
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The '729 Patent teaches a soft adhesive film
applicable to the oral mucosa containing a systemic drug
and comprising a mixture of a vinyl acetate, water-
insoluble homopolymer, an acrylic acid polymer, and a
cellulose derivative. Finally, the '554 Patent describes
a device for use in the oral cavity having an adhesive
layer including a mixture of an acrylic acid polymer, a
water-insoluble cellulose derivative, and a
pharmaceutical preparation, and a water-insoluble or
sparingly soluble backing layer. The adhesive layer
contains the pharmaceutical, and upon application to the
mucosalsurface, delivers the drug to the underlying
tissue.
U.S. Patents Nos. 5,081,157 and 5,081,158 describe
compositions made of hydroxypropyl cellulose, a non-toxic
volatile solvent, an esterification agent which reacts
with the hydroxypropyl cellulose to form a reaction
product which is soluble in the solvent but not soluble
in body fluids at body temperature, and a medicinal
component. A crosslinking agent may be used. Following
application and air drying, an in situ film forms. As
stated in the '158 Patent, ~~alkyl or hydroxyalkyl
substituted cellulose are not suitable substitutes for
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hydroxypropyl cellulose" (column 2, lines 28-31) for
forming adherent films on body tissues.
Although the 158 Patent admonishes that an
esterification agent be included in the composition to
effect film formation, the present invention provides a
pharmaceutical preparation for application to mucosal
surfaces and body tissues, which forms a film upon
application to the treatment site without the use of an
esterification agent, and, thus provides effective drug
delivery to the treatment site, surrounding tissues, and
other bodily fluids. The film forming components are a
water soluble cellulosic polymer, preferably
hydroxypropyl cellulose, and a bioadhesive polymer.
SUMMARY OF THE INVENTION
The present invent~~~on relates to a mucoadhesive gel
for application to mucosal surface and other body
tissues, utilizing volatile or diffusing solvents, a
water-soluble polymer plus a bioadhesive polymer and a
pharmaceutically effective amount of an active
pharmaceutical component. Typically, the composition
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will have. at least one water-soluble hydroxyalkyl
cellulose, a bioadhesive polymer, a volatile non-aqueous
solvent, and at least one active pharmaceutical. Upon
application, the gel forms an adherent, substantive and
cohesive film, providing protection to the treatment
site. The carrier composition is. chemically compatible
with a wide variety of pharmaceutical agents from which
the agents are bioavailable for delivery of the
pharmaceutical to the underlying treatment site,
surrounding body tissues, and body fluids. Methods for
the protection and localized delivery of pharmaceutical
to mucosal surfaces or body tissues are also provided.
The gel provides a film having an effective residence
time and is easy to apply and use.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, a novel gel carrier
composition is formed from hydroxypropyl cellulose and a
bioadhesive polymer which adheres to moist body tissue,
which serves as a pharmaceutical carrier and which
adheres to mucosal surfaces and body tissues. One or
,more biologically active pharmaceutical compounds are
incorporated in the gel.
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The present invention finds particular use in the
localized treatment of mucosal surfaces and body tissues
such as the skin. Upon application to the mucosal
surface or skin, the volatile ox nonaqueous solvent
evaporates,. diffuses, or penetrates the surrounding
tissues, and a film is formed. The film offers
protection to the treatment site, while also providing
effective drug delivery to the treatment site,
surrounding body tissues, and bodily fluids. Over time,
the film slowly erodes away.
The desired properties of the present invention are
achieved in the combination of hydroxypropyl cellulose or
another pharmacologically acceptable water-soluble
polymer, a pharmacologically acceptable bioadhesive
polymer, a volatile pharmacologically acceptable solvent
and an active pharmaceutical agent. Thickening, coloring,
flavoring, or plasticizing agents may also be used. Upon
application, the solvent evaporates, diffuses, or
penetrates,the surrounding tissues, and a film is formed.
Unlike certain gels and pastes known in the art,
which have a very limited~residence time, given the
tendency of bodily fluids such as saliva to wash away the
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gel from the treatment site, the present invention offers
an increased residence time because of its film
persistency and adhesion and its nonaqueous composition.
For example, the Orabase~ gel is an aqueous based system,
and as a result, the film formed upon application is
quickly washed away, in a matter of seconds. Unlike the
compositions of the Pomerantz '158 patent, which depends
on chemical reactions of the components used, the present
invention relies on a specific combination of water-
soluble and bioadhesive polymers chosen for their desired
adhesion. and/or film-forming qualities in an appropriate
solvent. Importantly, the Pomerantz '157 and '158
Patents teach away from the use of hydroxypropyl
cellulose unless it is esterified, teaching that the
mechanism of film formation is specific to hydroxypropyl
cellulose plus and esterification agent. Despite this
teaching, the present invention indeed utilizes soluble
alkyl cellulose derivatives such as hydroxypropyl
cellulose along with a bioadhesive polymer as the film-
forming components in a non-toxic volatile solvent,
without the need for an esterification agent.
Also, unlike the mucoadhesive tablets which are
known in the art, which offer effective residence time
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but also have the disadvantages of discomfort to the use
and a foreign body sensation in the oral cavity due to
their solidity., bulkiness, and slow dissolution time, the
present invention is a gel which offers a very limited
and almost nonexistent foreign body sensation.
The residence time of the film formed upon
dissipation of the solvent depends on several factors,
including the amount of get applied, as well as the
components used to make the composition and their
relative percentages. Use of polymers with different
molecular weights or of different chemical reactivity,
for example, may affect the dissolution kinetics of the
film. Residence times of up to several hours have been
achieved with this invention, depending on the particular
formulation. A preferred residence time for effective
drug delivery depends on the characteristics of the
particular drug, but is at least 1-2 hours. The kinetics
of drug release~depend on the characteristics of the
carrier gel and relative percentages of its components,
the total amount of pharmaceutical incorporates into the
gel, the particular application site, and the physical
and chemical characteristics of the particular drug or
combination of drugs.
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The pharmaceutical component of the present
invention may comprise a single pharmaceutical or a
combination of pharmaceuticals, Pharmaceuticals which may
be~used, either alone or in combination, include anti-
inflammatory analgesic agents, steroidal anti-
inflammatory agents, antihistamines, local anesthetics,
bactericides and disinfectants, vasoconstrictors,
hemostatics, chemotherapeutic drugs, antibiotics
keratolytics, cauterizing agents and antiviral drugs.
Examples of anti-inflammatory analgesic agents
include acetaminopen, methyl salicylate, monoglycol
salicylate, aspirin, mefanamic acid, flufenamic acid, .
indomethacin, dielofenac, alcolofenac, diclofenac sodium,
ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen,
sulindac, fenclofenac, slidanac, flurbiprofen, fentizac,
bufexomac, piroxicam, phenylbutazone, oxyphenbutazone,
clofezone, pentazocine, mepirizole, tiaramide
hydrochloride, etc.
Examples of antihistamines include diphenhydramine
hydrochloride, diphenhydramine salicylate,
diphenhydramine, chlorpheniramine hydrochloride,
chlorpheniramine maleate, tripelennamine hydrochloride,
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promethazine hydrochloride, methdilazine hydrochloride,
etc.
Examples of local anesthetics include dibucain
hydrochloride, dibucaine, lidocaine hydrochloride,
lidocaine benzocaine, p-huthylaminobenzoic acid 2-die-
ethylamino) ethyl ester hydrochloride; procain
hydrochloride, tetracaine, tetracain hydrochloride,
chloroprocaine hydrochloride, oxyprocaine hydrochloride,
mepivacaine, cocaine hydrochloride, piperocain
dydrochloride, dyclonine, dyclonine dydrochloride, etc.
Examples of bactericides and~disinfectants include
thimerosal, phenol, thymol, benzalko.nium chloride,
benzethonium chloride, chlorbesidine, povidone,
cetylpyridinium chloride, eugenol, trimethylammonium
bromide, etc.
Examples of vasoconstrictors include naphazonile
nitrate, tetrabydrozoline hydrochloride, oxymetazoline
hydrochloride, phenylephrine hydrochloride, tramazoline
hydrochlroide, etc.
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Examples, of hemostatics include thrombin,
phylonadione, protamine.sulfate, aminocaprioc acid,
tranexamic acid, carbazochrome, charboxochrome,. sodium
sulfonate, rutin, hesperidin, etc.
Examples of chemotherapeutic drugs include
sulfamine, sulfathiazole, sulfadizine, homosulfamine,
sulfaaoxazone, sulfaomidine, sulfamethizole,
nitrofurazone, etc. Examples of antibiotics include
penicillin, meticillin, oxacillin, cefalotin, cefalordin,
erythromcycin, lincomycin, tetracycline,
chlortetracyline, oxytetracycline, metacyline,
chloramphenicaol, kanamycin, streptomycin, gentamicin,
bacitracin, cycloserine, etc.
Examples of keratolytics include salicylic acid,
podophyllum resin, podolifox, and cantharidin.
Examples of cauterizing agents include the
chloroacetic acids and silver nitrate.
Examples of antiviral drugs include protease
inhibitors, thymadine kinase inhibitors, sugar or
glycoprotein synthesis inhibitors, structural protec~.n
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cynthesis inhibitors, attachment and adsorption
inhibitors, and nucleoside analogues such as acyclovir,
penciclovir, valacyclovir, and ganciclovir.
Various suitable polymers known in the art for
bioadhesive properties are incorporated into the
compositions of the present invention. The polymers
should be pharmacologically acceptable. Some polymers
having bioadhesive properties for use in this invention
include polyacrylic acid, cross linked or not,
polyvinylpyrrolidone, and sodium carboxymethyl cellulose,
alone or in combination.
Permeation enhancers may also be used to improve
absorption of the drug at the treatment site. Permeation
enhancers for use in this invention include sodium lauryl
sulfate, sodium glycopholate, atone, EDTA, sodium
cholate, sodium 5-methoxysalicylate, and others known in
the art.
The relative percentages of the components materials
of the present invention may vary, depending on the type
of drug or combination of drugs, the particular target
treatment site, the solvent, and the particular polymers
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used. Preferably, the solvent or combination of solvents
comprise between 50 and 80~ by weight of the composition.
More preferably, the solvent comprises between 60 and 70~
by weight. The active pharmaceutical or combination of
pharmaceuticals comprises between 0.1 and 25~ by weight,
more preferably between 0.2 and 20~ by weight. The
film-forming gel components should comprise between about
la and 25~ by weight, more preferably between l~.and 100
by weight. The optional flavoring, coloring, or
thickening agentsand/or permeation enhancer should
comprise between 0 and 3~ by weight, more preferably
between 0.5 and 2.5~ by weight.
The characteristics of~the film which is formed upon
application of the gel, such as thickness, tensile
strength, and erosion kinetics, may vary greatly
depending on the properties of the tissue to which the
gel is applied, the amount of get applied, the amount of
saliva or other bodily fluid at the treatment site or
surrounding areas, the contact surface, and other
physiological factors. However, the properties of the
film obtained in v.ivo may be adjusted via the formulation
of the gel, as well as by the addition of plasticizers,
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the use of cross linking agents, or the amount of solvent
residual.
To make the gel of the present invention, the
various.components are dissolved in the chosen solvent.
Because of the possibility that one or more of the
components might not.be in solution, a suspension may
also be formed.. The gelling step may take place at any
moment and may be induced by the addition of a special
component, a change in pH, a change in temperature, or
over time. The solutions and gels may be prepared by w
various methods known in the art. The gel may be applied
to the treatment site by spraying, dipping, by direct
application from a suitable dispenser or by finger or
swab.
Methods for the treatment of mucosal surfaces and
body tissues using the pharmaceutical carrier of the
present invention are also provided. In one embodiment,
a method for the protection and localized delivery of
pharmaceutical to mucosal surfaces or body tissues
comprises the steps of preparing the above described
film-forming pharmaceutical carrier having at least one
water-soluble cellulosic polymer, e.g., hydroxypropyl
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cellulose, a bioadhesive polymer, a volatile,°~nonaqueous
solvent, and at least one active pharmaceutical
component, and applying the pharmaceutical carrier to the
mucosal surface or body tissue by spraying, dipping, or
direct application. In the preferred embodiment, the
method further comprises the use of hydroxypropyl
cellulose, polyacrylic acid, a 95~ ethanol and water
mixture; and a local anesthetic.
EXAMPLE 1
An ethyl alcohol based gel is prepared using the
following components: 65~ by weight 95~ ethyl. alcohol;
0.8~ by weight mint flavor; 8~ by weight bydroxypropyl
cellulose; 2.2~ by weight polyacrylic acid; 5~ water USP;
15~ benzocaine USP; and 4~ by weight menthol USP. A
clear, yellowish gel with film-forming capabilities is
formed.
EXAMPLE 2
An ethyl alcohol/ethoxydiglycol based gel is
prepared using the following components: 55~ by weight of
95~ ethyl alcohol; 1~ by weight mint flavor; 8~ by weight
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hydroxypropyl cellulose; 2~ by weight polyacrylic acid;
15~ by weight ethoxydiglycol; 15~ by weight benzocaine
USP; and 4~ by weight menthol USP. Here, the mixture of
two compatible solvents impacts the time for the film to
form. Compared to Example 1, which is a mixture of 950
ethyl alcohol and water as the solvent, the film-forming
kinetics of this gel are slower.
EXAMPLE 3
An ethyl alcohol based gel is prepared using the
following components: 75~ by weight ethyl alcohol, 1~ by
eight mint flavor, 4~ by weight hydroxypropyl cellulose,
3~ polyacrylic acid, 9~ by weight ethoxydiglycol; and 4~
by weight dyclonine. This results in a gel having a
stiffer and thicker consistency, which slightly increases
the foreign body sensation.
EXAMPLE 4
An ethyl alcohol/1-methyl-2-pyrrolidone based gel is
prepared using the following components: 55~ by weight of
95~ ethyl alcohol; 1.5~ by weight mint flavor; 26~ by
weight 1-methyl-2-pyrrolidone; 6~ by weight hydroxypropyl
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cellulose; 2.5~ by weight polyacrylic acid; 5$ by weight
water; and 4~ by weight menthol USP. Because methyl
pyrrolidone has undesirable taste, a higher percentage of
flavoring agent is used to mask the taste. The kinetics
of diffusion of this gel are appropriate and allows for
the formation of an effective film.
EXAMPLE 5
An ethyl alcohol based gel is prepared, using
polyvinyl pyrrolidone as a bioadhesive polymer. The
components are as follows: 65~ by weight 95~ ethyl
alcohol, 0.8~ by weight mint flavor, 6.2~ by weight
hydroxypropyl cellulose, 4~ by weight polyvinyl
pyrrolidone, 5~ by weight water USP, 15~ by weight
benzocaine USP, and 4~ by weight menthol USP. The use of
polyvinyl pyrrolidone instead of polyacrylic acid as the
bioadhesive polymer results in the formation of an
effective film, but adhesion is weaker than that achieved
with the use of polyacrylic acid.
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EXAMPLE 6
An ethyl alcohol based gel is prepared, using sodium
carboxymethyl cellulose as a bioadhesive polymer. The
components are as follows: 75~ by weight of 95~ ethyl
alcohol, l~ by weight mint flavor, 8~ by weight
hydroxypropyl cellulose, 4~ by weight sodium
carboxymethyl cellulose, 8~ by weight water USP, and 4~
by weight menthol USP. The use of sodium carboxymethyl
cellulose instead of polyacrylic acid results in a weaker
adhesion.
EXAMPLE 7 -
An ethyl alcohol based gel is prepared using the
following components: 78~ by weight of 95~ ethyl alcohol,
1~ by, weight mint flavor, 8~ by weight hydroxypropyl
cellulose, 3~ by weight polyacrylic acid, 6~ by weight
water USP, 0.1~ by weight sodium lauryl sulfate, and 3.9~
by weight dyclonine USP. The gel formed is comparable to
that of Example 1. However, the use of a different
anesthetic, dyclonine instead of benzocaine, results in a
less intense numbing effect.
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EXAMPLE 8
A gel according to the formulation of Example 1 is
prepared and is administered to eight healthy volunteers.
Participants are directed to apply a very small quantity
of the gel to the tip on one finger and then to place and
quickly spread/rub the gel at one location in the oral
cavity. The volunteers are asked to describe, on a scale
of 0 to 3 (with 3 being very good, 2 good, 1 fair, and 0
poor), the ease of handling of the gel, and its numbing
effect. The volunteers are also asked to describe the
time necessary for the formation of a film at the site of
application, as well as its residence time, and whether
or not they experienced a foreign body sensation.
Additionally, the volunteers are asked to describe as
positive (+) or negative (-) their impressions of the
taste and overall efficiency of the gel, as well as their
overall impression of the gel. The results are provided
in Table 1 below.
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26
O
+ + I I +, + I +
O
H
'~ >~
O
W .O ~-I N ~-I O O ~I
-~ ~ -~ ~ ~ Dy ~ ~~ ,
N O
O
W
U
N
U
+ + I I + I + I
.,
4-I
4-1
W
ri N
a
U7 + I I I + ~- I +
H
H
U
ri
N
M N N M N N M N
,~ 4~
z W
U
x x
N N M v-IN N
N
t t t t 1 t 1 1
N
.~ O
H 4-I ~ ~ o ,~ o ~ ,-i o .-m-t
~.-I M M M
v v v v v v v v
is
a
.r.,
M N M M M N N M
cd
x
- O ~ N M C~ Ln ~ (~
Op
z
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The formulation of Example 1 will be easy to apply
and will rapidly forms film, while providing only a
minimal foreign body sensation to the user. The film
will stay in place long enough to provide effective drug
delivery, while also providing effective numbing to the
treatment site and surrounding tissues.
Having described my invention is such terms as to
enable those skilled in the art to understand and
practice it and, having identified the presently
preferred embodiments thereof, I CZAIM:
