U.S. patent application number 14/466637 was filed with the patent office on 2014-12-11 for highly penetrating compositions and methods for treating disordered tissues.
The applicant listed for this patent is QUADEX PHARMACEUTICALS, LLC. Invention is credited to B. Ron Johnson, James P. McCarthy.
Application Number | 20140364496 14/466637 |
Document ID | / |
Family ID | 45563563 |
Filed Date | 2014-12-11 |
United States Patent
Application |
20140364496 |
Kind Code |
A1 |
Johnson; B. Ron ; et
al. |
December 11, 2014 |
HIGHLY PENETRATING COMPOSITIONS AND METHODS FOR TREATING DISORDERED
TISSUES
Abstract
Compositions and methods for treating disordered tissues, such
as caused by pathogens and/or by toxins. The treatment compositions
include an anti-infective active agent, a liquid carrier, and
benzocaine in an amount so that the treatment composition
penetrates more quickly into disordered tissue compared to the
treatment composition in the absence of the benzocaine. In
addition, the benzocaine can increase residence time of the
anti-infective active in the treatment area. The preferred
anti-infective active agent can be an organohalide, such as a
quaternary ammonium halide compound, an example of which is
benzalkonium chloride. The treatment compositions and methods may
employ the use of an applicator adapted for use in promoting
penetration of the treatment composition and/or agitation of the
disordered tissue to further enhance penetration.
Inventors: |
Johnson; B. Ron; (Sandy,
UT) ; McCarthy; James P.; (Sandy, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
QUADEX PHARMACEUTICALS, LLC |
Midvale |
UT |
US |
|
|
Family ID: |
45563563 |
Appl. No.: |
14/466637 |
Filed: |
August 22, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13012719 |
Jan 24, 2011 |
8846725 |
|
|
14466637 |
|
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Current U.S.
Class: |
514/536 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 31/04 20180101; A61K 9/0014 20130101; A61K 47/18 20130101;
A61K 31/4425 20130101; A61P 31/00 20180101; A61K 31/14 20130101;
A61P 31/10 20180101; A61K 31/4425 20130101; A61P 23/00 20180101;
A61K 2300/00 20130101; A61K 31/245 20130101; A61K 2300/00 20130101;
A61K 31/245 20130101; A61K 31/14 20130101; A61K 31/155 20130101;
A61K 45/06 20130101; A61K 9/08 20130101; A61P 31/12 20180101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 31/155 20130101; A61P
17/02 20180101; A61K 47/10 20130101 |
Class at
Publication: |
514/536 |
International
Class: |
A61K 31/245 20060101
A61K031/245; A61K 31/14 20060101 A61K031/14 |
Claims
1. A method for the treatment of disordered tissue caused by a
virus, bacteria, or fungus by administering a treatment composition
to a subject in need thereof, comprising: at least one benzalkonium
chloride compound: ##STR00002## where R=C.sub.8H.sub.17 to
C.sub.18H.sub.37; a liquid carrier comprising a tissue penetrating
component for penetrating disordered tissue in a rapid manner
without rapidly diffusing beyond the skin; and benzocaine present
in an amount ranging from 3.5% to about 20% by weight of the
treatment composition.
2. The method of treatment as recited in claim 1, wherein the at
least one benzalkonium chloride compound is present in an amount
ranging from about 0.01% to about 0.5% by weight of the treatment
composition.
3. The method of treatment as recited in claim 1, wherein the at
least one benzalkonium chloride compound is present in an amount
ranging from about 0.05% to about 0.3% by weight of the treatment
composition.
4. The method of treatment as recited in claim 1, wherein the at
least one benzalkonium chloride compound is present in an amount
ranging from about 0.1% to about 0.2% by weight of the treatment
composition.
5. The method of treatment as recited in claim 1, wherein the
benzocaine increases residence time of the benzalkonium chloride
compound in a treatment area by at least about 10% compared to the
treatment composition in the absence of the benzocaine.
6. The method of treatment as recited in claim 1, wherein the
benzocaine increases residence time of the benzalkonium chloride
compound in a treatment area by about 20% to about 100% compared to
the treatment composition in the absence of the benzocaine.
7. The method of treatment as recited in claim 1, wherein the
liquid carrier comprises isopropyl alcohol and water, the isopropyl
alcohol comprising from about 50% to about 80% by volume of the
liquid carrier.
8. The method of treatment as recited in claim 1, wherein the
benzocaine is present in a range of about 4% to about 15% by weight
of the treatment composition.
9. The method of treatment as recited in claim 1, wherein the
benzocaine is present in a range of about 4.5% to about 10% by
weight of the treatment composition.
10. The method of treatment as recited in claim 1, wherein the
benzocaine is present in a range of about 5% to about 7.5% by
weight of the treatment composition.
11. The method of treatment as recited in claim 1, the liquid
carrier penetrating the disordered tissue more rapidly than a
liquid carrier consisting of 80% by volume isopropyl alcohol and
20% by volume water.
12. The method of treatment as recited in claim 1, wherein the
treatment composition is void of penetration inhibiting oils.
13. A method for the treatment of disordered tissue caused by a
toxin or inflammatory agent by administering a treatment
composition in a subject in need thereof and eliminating or
neutralizing the toxin, inflammatory agent, or its source, the
treatment composition comprising: at least one benzalkonium
chloride compound: ##STR00003## where R=C.sub.8H.sub.17 to
C.sub.18H.sub.37; a tissue penetrating liquid carrier comprising
isopropyl alcohol and water, the isopropyl alcohol comprising from
about 50% to about 80% by volume of the liquid carrier; and
benzocaine present in an amount ranging from 3.5% to about 20% by
weight of the treatment composition.
14. The method of treatment as recited in claim 13, wherein the
toxin or inflammatory agent is caused or produced by a
pathogen.
15. The method of treatment as recited in claim 14, wherein
pathogen is a virus, bacteria, or fungus.
16. The method of treatment as recited in claim 13, wherein the
toxin or inflammatory agent is caused or produced by venom.
17. The method of treatment as recited in claim 13, wherein the
benzocaine is included in a concentration in a range of about 4% to
about 15% by weight of the treatment composition.
18. The method of treatment as recited in claim 13, wherein the
treatment composition is void of penetration inhibiting oils.
19. A method for treatment of disordered tissue caused by a
pathogen, psoriasis, eczema, seborrhea, or dermatitis, comprising:
at least one benzalkonium chloride compound: ##STR00004## where
R=C.sub.8H.sub.17 to C.sub.18H.sub.37; a tissue penetrating liquid
carrier comprising isopropyl alcohol and water, the isopropyl
alcohol comprising from about 50% to about 80% by volume of the
liquid carrier; and benzocaine present in an amount ranging from
3.5% to about 20% by weight of the treatment composition.
20. The method of treatment as recited in claim 19, wherein the
benzocaine is included in a concentration in a range of about 4% to
about 15% by weight of the treatment composition.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This Application is a continuation of U.S. patent
application Ser. No. 13/012,719, filed Jan. 24, 2011, the
disclosure of which is incorporated herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. The Field of the Invention
[0003] The invention relates to treatment compositions and methods
for treatment of disordered tissues, such as those caused by a
virus, fungus, or bacteria.
[0004] 2. The Relevant Technology
[0005] Tissue disorders caused by pathogens, particularly those
which impact epithelial tissue and are caused by the Herpes virus,
such as Herpes Simplex Types I and II and Herpes Zoster (shingles),
cold sores, genital herpes, or, candida albicans, chicken pox,
acne, psoriasis, eczema, seborrhea, and dermatitis, are common but
often difficult to treat. Herpes simplex virus (HSV-I and HSV-II)
and Herpes Varicella-Zoster (chicken pox, shingles), commonly
referred to as herpes virus or herpes, is an infectious disease
which has reached crisis proportions nationally with estimated
numbers of infected people at 70%-80% of U.S. population as
reported by the American Social Health Association (ASHA). Other
literature sources put the number of infected Americans at 85%-90%
of the adult population.
[0006] Herpes virus enters the human body through minuscule breaks
in the epidermal tissue, usually by contact with an infected host,
and is marked by eruption of one or more vesicles, usually in
groups, following an incubation period of approximately two to ten
days. Typically, the course of the infectious outbreak initiates
with the prodromal stage, advancing to vesicular eruption, followed
by ulceration, coalescing, resolution by formation of scab, and the
latency period. The outbreak can last for several weeks and, on
average, lasts one to three weeks. In some immune compromised
individuals, the outbreak can last for months. The vesicles can
appear anywhere on epithelial tissues including the skin or mucosa,
typically appearing on the lips as cold sores, glands, and oral
mucosa. More severe cases may involve the conjunctiva and cornea.
Genital herpes may involve the genitalia, anal mucosa and peri-anal
tissue.
[0007] Herpes symptoms include inguinal swelling, pain, fever,
malaise, headaches, muscle aches, and swollen glands. During
latency, the virus lies dormant in the trigeminal nerve ganglia.
Some individuals with oral herpes have excruciating facial pain,
difficulty swallowing, eating and facial swelling. Individuals with
the herpes that impacts the sacral nerve (genital herpes) have pain
in the genital area, upper leg pain, swelling, and on occasion
great difficulty walking.
[0008] Herpes simplex virus (HSV) infection, whether oral or
genital, is recurring, residing in the nerve ganglia, then
recurring due to some, as yet unknown, mechanism. Recurrent
herpetic infections can be precipitated by numerous stimuli,
including exposure to sunlight, nutritional deficiencies, stress,
menstruation, immunosuppression, certain foods, drugs, and febrile
illness.
[0009] Herpes infections can pose serious health threats, often
causing blindness if the virus infects the cornea, increased cancer
risk of the cervix, aseptic meningitis and encephalitis, neonatal
deaths, viremia, the spread of the human immunodeficiency virus
(HIV), etc. The devastating effects of this disease go well beyond
the medical scope of human suffering. HSV can be responsible for
serious psychological and emotional distress as well as substantial
economic loss. Individuals with Auto Immune Deficiency Syndrome
(AIDS) are seriously immune-compromised and can suffer especially
debilitating outbreaks of HSV.
[0010] Various treatments for herpes have been proposed and include
topical application of such agents as povidone-iodine, idoxuridine,
trifluorothyidine, or acyclovir and its analogs. Such treatments
have met with varying degrees of success. Most treatments have
proven disappointing. Acyclovir and similar analogs, acyclic
nucleosides, are taken orally for systemic treatment of HSV or they
are applied topically. Acyclovir is somewhat effective in
inhibiting the activity of several herpes viruses. However,
acyclovir is only successful in interrupting the replication of the
virus and is used to treat infectious outbreak systemically.
Denavir is the topical version of an acyclovir analog. Few topical
treatments have proven to be effective and all nucleoside
treatments must be applied at first signs and symptoms of disease
to achieve maximum effectiveness.
[0011] Biologically active antiviral and antimicrobial compositions
have been met with marginal success when administered topically for
tissue disorders. Such compositions have been applied as gels,
creams, lotions, oils, ointments, pastes, tinctures, emulsions, and
colloidal suspensions. Most of the compositions are oil-based to
ensure the composition has sufficient viscosity and/or tackiness to
remain on the surface of the skin without being rubbed off. In
fact, such compositions are often absorbed into clothing more than
into the skin due to a relatively slow epidermal penetration rate.
Even when sufficient time is allowed for the compositions to
penetrate, they are often not sufficiently effective in treating
the disordered tissue and must generally be applied repeatedly over
a period of days or even weeks.
[0012] Many efforts have been undertaken to remedy the inadequacies
of topically administered compositions. The therapeutic effects of
such compositions depend upon the specific active agent and the
method of application. Many compositions contain ingredients that
may provide symptomatic relief of pain and itching but are not
claimed to be effective against Herpes infection except drugs based
on acyclovir technology, which are purported to have some topical
efficacy. Most compositions intended to treat such disorders do not
effectively treat the discomfort and the disease symptoms, let
alone cure the disorder or put it into a significant remission.
[0013] One useful treatment composition, sold under the name
Viroxyn.RTM., has been effective in providing relief for cold
sores. Viroxyn.RTM. is covered by one or more of the following U.S.
Pat. Nos. 6,759,434; 6,423,750; 6,420,431; 6,414,032; 6,410,599;
and 6,211,243, the disclosures of which are incorporated herein by
reference. When used as instructed, which includes using a
specifically designed applicator to vigorously rub or burnish the
composition into the cold sore, Viroxyn can be effective in
reducing the healing time of a cold sore. Vigorous rubbing is
required to force the composition to penetrate into the cold sore
to a depth sufficient to kill the viruses causing the
infection.
[0014] An example of a less useful composition and treatment method
is provided in U.S. Pat. No. 5,753,270 to Beauchamp et al. This
patent discloses a composition that includes: (a) an antiseptic
and/or anesthetic compound which is (i) a terpene, such as menthol
or eucalyptol or (ii) a phenolic compound, such as thymol; (b) a
quaternary ammonium antiseptic compound, such as benzethonium
chloride; and (c) an antiseptic compound containing iodine, salts
thereof and/or complexes thereof dissolved in an organic solvent,
such as a mixture of water and acetone. The composition requires
application to the afflicted area in a sequence that includes 3 to
4 applications over a one minute period, which is then repeated
every 3 minutes over a 10 minute period. The entire procedure is
then repeated every 1/2 to 1 hour for 2 to 3 hours or until
activity is stopped and healing is evident. The composition must
therefore be applied many times over an extended period of time to
be effective, which greatly diminishes compliance and
effectiveness.
SUMMARY OF DISCLOSED EMBODIMENTS
[0015] The disclosure relates to the treatment of disordered
tissues caused by pathogens (e.g., viruses, bacteria or fungi). An
applicator may be used to apply a treatment composition comprising
an anti-infective active agent in a carrier. The method includes
applying the treatment composition to the disordered tissue
treatment site with the applicator under conditions that enable the
active agent to rapidly penetrate the disordered tissue. Gentle
rubbing may assist penetration but may not be required in all cases
due to enhanced penetration of the treatment composition.
[0016] An important issue when applying the treatment composition
to a painful cold sore or other disordered tissue is proper
compliance by the user. Solvent carriers, such as isopropyl
alcohol, ethanol, acetone, and the like, can cause excruciating
pain when applied to sensitive disordered tissues such as cold
sores, genital herpes, and shingles. Such pain can discourage
compliance by the user and undermine the effectiveness of an
otherwise effective treatment composition.
[0017] It has now been discovered that adding benzocaine in
specific amounts to a treatment composition that includes an
organic solvent carrier, such as isopropyl alcohol, greatly
increases the effectiveness in treating disordered tissues.
Unexpectedly, benzocaine, when included in specific amounts, can
increase the ability of such treatment compositions to penetrate
into the disordered tissue in order for the active agent to more
quickly contact and kill viruses or other pathogens within the
disordered tissue. In addition, benzocaine also enhances efficacy
by increasing kill time by at least 10% and typically by about
20-100%. It does this blocking influx of interstitial fluid into
the disordered tissue, which helps to retain the active agent in
the treatment area rather than being displaced by interstitial
fluid. Benzocaine can also increase patient compliance by reducing
the pain associated with application of the anti-infective
composition to painful disordered tissue, particularly with open
sores. However, beyond merely reducing pain, benzocaine has been
found to increase efficacy of treatment because it promotes faster
penetration of the treatment composition into disordered tissue,
which reduces the amount of rubbing or agitation that would
otherwise be required for the composition to be effective. It also
increases residence time of the active agent in the treatment
site.
[0018] The amount of benzocaine within the treatment composition
must be high enough to enhance penetration, and preferably increase
kill time and help alleviate pain. However, the amount of
benzocaine is advantageously not so high as to leave a residue on
the surface of the skin and/or cause loss of sensation in
surrounding tissue and/or for a prolonged period of time (e.g.,
greater than about 15 minutes). For example, if included in
excessive amounts, benzocaine can cause numbing of a substantial
portion of a person's lips for an extended period of time, which
can inhibit normal activities such as drinking and talking (e.g.,
as can occur after a person leaves a dental office after receiving
an injection of novocaine).
[0019] The amount of benzocaine is most effective when numbing is
temporary and goes away once the treatment composition has
effectively penetrated into the disordered tissue and resided long
enough in the disordered tissue to kill the pathogens and
neutralize inflammatory agents in the tissue causing the pain.
According to one embodiment, the amount of benzocaine is selected
to provide a numbing effect for a time period of about 1 minute to
about 20 minutes, preferably about 2 minutes to about 15 minutes,
more preferably about 3 minuets to about 10 minutes, and most
preferably about 4 minutes to about 8 minutes after numbing first
occurs. It is desirable to include an amount of benzocaine so that
numbing begins in about 10 seconds or less after application of the
treatment composition, preferably in about 8 seconds or less, more
preferable in about 6 seconds or less, and most preferably in about
4 seconds or less.
[0020] The highly penetrating compositions are formulated, as a
result of including benzocaine in combination with a penetrating
carrier, so as to penetrate quickly so that the treatment
composition is no longer detected on the skin surface after less
than about 1 minute, preferably less than about 40 seconds, more
preferably less than about 20 seconds, and most preferably less
than about 10 seconds. Pathogens are killed and inflammatory agents
are destroyed within minutes or seconds after effective penetration
such that it is desirable for the numbing effect of benzocaine to
subside within about 10 minutes of application, preferably within
about 8 minutes, more preferably within about 6 minutes, and most
preferably within about 5 minutes.
[0021] After extensive comparative survey testing supervised by
learned health care intermediates (i.e., doctors and dentists),
which included obtaining feedback from patients (to whom the
benzocaine-containing treatment compositions were administered by
the learned health care intermediates), who in this case suffered
from painful and highly infective cold sores, it was determined
that the most effective amount of benzocaine within treatment
compositions that also included a liquid carrier comprised of 70%
by volume isopropyl alcohol in water and 0.13% by weight
benzalkonium chloride was between about 2.5% and about 7.5% by
weight. Above 7.5%, a benzocaine residue was sometimes detected.
Below about 2%, benzocaine did not significantly enhance
penetration. Between about 2.5% to about 7.5%, however, benzocaine
enhanced penetration, increased kill time, and caused temporary,
but not excessive, numbing when using the treatment compositions
that were tested. A more optimal range for this anti-infective
composition is about 2.75% to about 6% benzocaine by weight, and
the most optimal range was found to be about 3% to about 5%
benzocaine by weight.
[0022] Nevertheless, depending on the type of carrier that is used,
particularly if it is less penetrating than a mixture of about 70%
by volume isopropyl alcohol and 30% water (e.g., about 10-50%, or
about 15-40%, or about 20-30% by volume isopropyl alcohol with the
balance comprising mostly water), the amount of benzocaine can be
increased in order to promote enhanced penetration and enhance kill
time, and can be as high as 20% by weight, although this amount may
cause prolonged numbing (e.g., 1-3 hours). When using a liquid
carrier that is significantly less penetrating than a 70/30 v/v
mixture of isopropyl alcohol and water, the amount of benzocaine
can be included in a range of about 3.5% to about 20% by weight,
preferably in a range of about 4% to about 15%, more preferably in
a range of about 4.5% to about 10%, and most preferably in a range
of about 5% to about 7.5% by weight (e.g., about 6%).
[0023] Alternatively, when a composition consists essentially of
70% v/v isopropyl alcohol and 30% v/v water, organohalide, and
benzocaine so as to not include any components that inhibit
penetration, or where when liquid carriers are used that are more
penetrating than a mixture of 70% v/v isopropyl alcohol and 30% v/v
water (e.g., that include more than 70%, more than about 75%, more
than about 80%, more than about 85%, or more than more than about
90% by volume isopropyl alcohol), it may be possible to use smaller
quantities of benzocaine while still obtaining a penetration
enhancing and kill time increasing effect, such as from about 1% to
about 6.5%, preferably between about 1.5% to about 5.5%, and most
preferably between 2.1% and about 5% by weight.
[0024] In general, the amount of benzocaine should be limited to
that amount that increases penetration so as to provide enhanced
effectiveness but beyond which increasing amounts of benzocaine do
not further enhance penetration and effectiveness but merely
prolong the numbing effect. The amount of benzocaine should
therefore be less than about 20% by weight, preferably less than
about 15%, more preferably less than about 10%, and most preferably
less than about 7.5%.
[0025] Although less preferred and not as effective as benzocaine
in enhancing penetration of penetrating treatment compositions
and/or reducing pain without causing undue numbing of a user's lip,
other topical anesthetics may be useful in enhancing patient
compliance by reducing pain associated with applying penetrating
treatment compositions to disordered tissue. Examples of other
topical anesthetics include butamben, dibucaine, lidocaine,
oxybuprocaine, pramoxine, proparacaine, proxymetacaine, and
tetracaine. Of the foregoing, butamben may perform most similar to
benzocaine given the similarity in the two chemical structures. In
general, such other topical anesthetics can be used in amounts
similar to those of benzocaine.
[0026] Based on the comparative survey testing that was performed,
and in view of the similarity between a wide range of disordered
tissues caused by the Herpes virus, it would reasonably be expected
that treatment compositions that provided enhanced penetration and
treatment of cold sores would also be more effective in treating
other disordered tissues caused by the Herpes virus and related
viruses, as well as painful disordered tissues caused by bacteria
and fungi. Examples include genital herpes, shingles, chicken pox,
and forms of Zoster. Other forms of disordered tissue may benefit
from this invention as well including cow pox, vaccinia virus,
smallpox, and anthrax, candida albicans, acne, psoriasis, eczema,
seborrhea, dermatitis, and other viral, fungal, and bacteriological
tissue disorders. The treatment compositions with enhanced
penetration provided by benzocaine are also effective in treating
various viral, microbial and fungal disordered tissues.
Additionally, disordered tissue caused by non-pathogenic toxins,
such as spider venom, as results from spider bites, e.g., venom
infections from Brown Recluse spiders and Black Widow spiders,
respond well to treatment with the disclosed enhanced penetration
treatment compositions.
[0027] These and other advantages and features of the present
invention will become more fully apparent from the following
description and appended claims, or may be learned by the practice
of the invention as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] In order that the manner in which the above-recited and
other advantages and objects of the invention are obtained, a more
particular description of the invention briefly described above
will be rendered by reference to specific embodiments thereof which
are illustrated in the appended drawings. Understanding that these
drawings depict only typical embodiments of the invention and are
not therefore to be considered to be limiting of its scope, the
invention will be described and explained with additional
specificity and detail through the use of the accompanying drawings
in which:
[0029] FIG. 1 is a vertical cross-section of the epidermis and the
papillae of the dermis;
[0030] FIG. 2A is an exploded perspective view of an example
applicator that contains the treatment composition;
[0031] FIG. 2B is a perspective view of the example applicator
depicted in FIG. 2A as it appears assembled prior to use;
[0032] FIG. 2C is a perspective view of the example applicator
depicted in FIG. 2B after the glass reservoir is crushed and the
treatment composition is allowed to permeate the agitation pad;
[0033] FIG. 2D is a perspective view of an individual applying the
treatment composition according to the present invention;
[0034] FIG. 2E is a detail taken along the section line 5-5 that
depicts a close-up view of the inventive method;
[0035] FIG. 2F shows a sheet of material before it is folded or
collapsed to form an application pad;
[0036] FIG. 3 is an elevational cross section view of an applicator
that has a finger loop for vigorous topical irritation of the
treatment site;
[0037] FIG. 4 is an elevational side view of an alternative
applicator used in the present invention;
[0038] FIG. 5 is an elevational side view of an alternative example
applicator that is fixed to a digit for vigorous topical irritation
of the treatment site;
[0039] FIG. 6 is a cross-sectional plan view of an alternative
example applicator that is placed over a digit and that is
contained in a pre-wetted state before use;
[0040] FIG. 7 is a perspective view with a partial break-away view
of an alternative example applicator that is used to apply the
treatment composition to large surface areas of the body;
[0041] FIG. 8 is a perspective view of the example alternative
applicator in FIG. 7 being used to apply the treatment composition
to sores from shingles on the chest area;
[0042] FIG. 9 is a perspective view of an example towelette used to
apply the treatment composition to a cold sore;
[0043] FIG. 10 is a perspective view of an example towelette used
to apply the treatment composition to a sore on male genitalia;
and
[0044] FIG. 11 is a perspective view of an example towelette used
to apply the treatment composition to sores from shingles on the
chest area.
DETAILED DESCRIPTION OF DISCLOSED EMBODIMENTS
[0045] Embodiments of the disclosure relate to treatment
compositions formulated so as to have enhanced penetration and
methods for treating disordered tissue using such compositions. The
treatment compositions are rapidly absorbed into the disordered
tissue, wherein penetration is enhanced as a result of including
benzocaine in an amount so as to increase penetration beyond
penetration of the treatment composition in the absence of
benzocaine. Benzocaine has also been found to increase the
residence time of the active agent in the treatment area, which
increases kill time.
[0046] As a result of enhanced penetration of the treatment
composition, coupled with increased kill time and a numbing effect
from the benzocaine, effective relief from the pain and discomfort
of disordered tissues can most often be achieved after only a
single application to the disordered tissue and, at most, 2 or 3
applications. Moreover, the pain associated with the disordered
tissue can usually be permanently resolved without recurrence in
less than about 10 minutes, 5 minutes, 3 minutes, 2 minutes or even
1 minute after initial application of the composition. The fact
that pain is usually resolved and does not recur even after the
numbing effect of benzocaine has subsided further emphasizes the
increased efficacy of treatment compositions that include
benzocaine in specific amounts based on the particular liquid
carriers being used. Finally, the fact that the disclosed treatment
compositions can effectively penetrate into and reliably treat
disordered tissue with less rubbing or agitation than would
otherwise be required if the treatment compositions were devoid of
benzocaine is further proof that benzocaine provides a therapeutic
benefit beyond simply temporarily numbing pain.
[0047] The treatment composition is preferably absorbed into the
disordered tissue to such an extent that in less than 1 minute
after application the composition can no longer be seen or felt
(i.e., the treatment area looks dry and feels dry to the touch).
More preferably, the treatment composition is essentially
completely absorbed into the disordered tissue in less than about
40 seconds, more preferably less than about 20 seconds, and most
preferably less than about 10 seconds. In the case where a dry
white residue of benzocaine is present but the surface is otherwise
dry, the treatment composition is considered to be essentially
completely absorbed into the disordered tissue.
[0048] The treatment composition preferably penetrates through the
skin to a nerve ending and may cause a penetration sensation at the
nerve ending, which is a positive indication that the treatment
composition is effectively treating the disordered tissue. The
pathway for this penetration is discussed in greater detail below
with reference to FIG. 1. After the treatment composition is
delivered, optionally with some level of agitation, although
agitation may be less than is normally required due the unexpected
penetration-enhancing effect of benzocaine, penetration or the
sensation of penetration can occur within seconds, e.g., in less
than about 5 seconds, 4 seconds, 3 seconds, or even 2 seconds.
[0049] FIG. 1 is a vertical cross-section of the epidermis and the
papillae of the dermis. FIG. 1 illustrates the stratum corneum 28
disposed upon the fatty layer or stratum lucidum 30. The stratum
lucidum is disposed over the stratum granulosum 32. Below the
stratum granulosum 32 is the stratum spinosum 34. Typically, the
stratum spinosum 34 has a lipid film disposed around each
individual cell. Below the stratum spinosum 34 is the stratum
basale 38 that overlies vascularized tissue. Within the
vascularized tissue the nervous papilla of the corium 36 is located
along with blood vessels and nerves 40. FIG. 1 shows a treatment
composition being delivered to the stratum corneum 28 in order to
allow enhanced penetrating treatment composition 22 to penetrate
therethrough. The treatment composition is shown being delivered
from an impregnated application pad 12.
[0050] The arrows illustrate directions of optional movement of the
application pad 12 by way of example. FIG. 1 does not depict
application of pressure as the objective is to show the particular
layers involved in their natural positions, and once pressure is
applied the layers are moved from their natural positions.
Treatment composition 22 can penetrate to the nervous papilla of
the corium 36 by the penetrating nature of the composition
including a liquid carrier and benzocaine to enhance penetration,
optionally in combination with agitation. The penetrating
activities of the liquid carrier and benzocaine are often
sufficient to cause the anti-infective active agent to penetrate
through the disordered tissue to a nerve ending, such as the
nervous papilla of the corium 36, with much less agitation than
would otherwise be needed.
[0051] Application of pressure may further increase the ability of
the treatment composition to penetrate, as pressure may flatten or
compress the layers and assist in forcing the treatment composition
downward through the tissue. In any event, penetration to the nerve
ending is rapidly accomplished, preferably in several seconds,
mainly as a result of the enhanced tissue penetrating effects of
benzocaine in combination with a liquid carrier system having
penetration properties, such a mixture of water and one or more of
isopropyl alcohol, ethanol, acetone, and the like.
[0052] While the treatment composition 22 rapidly penetrates to the
nerve endings, it is also postulated that the treatment composition
resides in reservoir amounts within the stratum spinosum 34 and may
continue to diffuse across the stratum basale 38 to the nerve
endings over an extended period of time. Pressure may assist in
displacing interstitial fluid held within the stratum spinosum,
which is then replaced with the treatment composition. When the
stratum spinosum 34 is filled with the treatment composition, the
treatment composition is available as a bath that continues to kill
viruses and destroy inflammatory agents as it slowly diffuses. On
this basis, it is desirable to deliver a large quantity of
treatment composition into the disordered tissue such that the
stratum spinosum 34 is saturated in the region of the cold sore or
other disordered tissue for a period that enables the treatment
composition to achieve its purpose before it diffuses into the
body. For example, the volume applied to a typical cold sore may be
in range from about 0.2 ml to about 1 ml, preferably in range from
about 0.4 ml to about 0.8 ml and is most preferably about 0.6 ml.
Low volumes, such as about 0.2 ml, can work for a single cold sore,
especially if the applicator does not retain a significant portion
of the treatment composition.
[0053] The rate at which the bath diffuses into the surrounding
tissue and is replaced by interstitial fluid can be reduced by
including benzocaine. Because active agents such as benzalkonium
chloride are water soluble, they can be flushed out and displaced
by the influx of interstitial fluid back into the treatment area
(e.g., stratum spinosum) over time. Benzocaine is soluble within a
carrier that includes a tissue penetrating component, such as
isopropyl alcohol, but is relative insoluble in water. To the
extent that the tissue penetrating component is volatile and
selectively evaporates, the relatively insoluble benzocaine is left
behind, which can form a barrier that slows down the influx of
interstitial fluid, which is aqueous, and thereby slow down the
diffusion of active agent out of the treatment area (e.g., stratum
spinosum) over time. Thus, benzocaine can enhance initial
penetration of the treatment composition in the treatment area and
then help maintain the active agent in the treatment area in order
to increase the residence time and hence the kill time of the
active agent.
[0054] Benzocaine, when included in the amounts disclosed herein,
can increase residence time of the active agent by at least 5%
compared to the treatment composition in the absence of benzocaine,
preferably by at least 10%, more preferably by at lease about 20%,
and most preferably by at least about 50%. In many cases, the
increase in residence time of the active agent is increased by
about 20% to about 100% compared to the treatment composition in
the absence of benzocaine.
[0055] The treatment compositions include at least a biologically
active agent, a liquid carrier, and benzocaine in an amount so as
to enhance penetration of the treatment composition into disordered
tissue. The biologically active agent is selected so as to be
effective in treating disordered tissue caused by pathogens (e.g.,
viruses, fungi or bacteria) or toxins (e.g., spider venom). The
liquid carrier is selected to optimally enable the treatment
composition to penetrate into the disordered tissue, including
through the cell walls of infected and/or infectious cells. The
biologically active agents suitable for use in the treatment
compositions are set forth hereinbelow and the liquid carriers are
described thereafter. Effective amounts of benzocaine are described
thereafter, and optional components are also described.
[0056] The biologically active agents included in the treatment
compositions are preferably anti-infective quaternary ammonium
halides and organic compounds that contain at least one
carbon-halogen bond. These anti-infective compounds are referred to
herein collectively as organohalides, even though some of the
anti-infective compounds of this invention do not contain a
carbon-halogen bond. Biologically active agents included in
anti-infective treatment compositions according to this invention
comprise anti-viral organohalides. Benzalkonium chloride is a
preferred organohalide. However, other organohalides or quaternary
ammonium halide compounds may be used as the active agents in the
compositions. Other active agents that are organohalides may
include organo-bromides and organo-iodides. Preferably, the
organohalides have an alkyl group attached thereto such as a simple
C.sub.nH.sub.2n+1 chain, where n is in a range from 1 to about
50.
[0057] The generic chemical structure of benzalkonium chloride is
shown below:
##STR00001## [0058] where R=C.sub.8H.sub.17 to
C.sub.18H.sub.37.
[0059] As shown, benzalkonium chloride includes a benzene ring and
a nitrogen constituent (i.e., a quaternary ammonium group) near the
ring. A carbon atom is disposed between the nitrogen constituent
and the benzene ring. Two methyl groups and an R group of varying
size extend from the nitrogen atom. Suitable benzalkonium chloride
may be obtained from many suppliers for example, Spectrum of
Gardena, Calif.; Stepan of Northfield, Ill.; Sanofit
Pharmaceuticals, Inc. of New York, N.Y. and Mason Chemical of
Arlington Heights, Ill.
[0060] The term "benzalkonium chloride" as used herein includes
compounds in which the alkyl group chain length is within a wide
range. A preferred embodiment involves a mixture of compounds with
an alkyl chain length distribution that is about 40% C.sub.12,
about 50% C.sub.14, and about 10% C.sub.16 (CAS Reg. No.
68424-85-1). Examples of such products include Maquat MC-1412-50%,
Mason Chemical Company, 50% activity; Maquat MC-1412-80%, Mason
Chemical Company, 80% activity; and BTC-835, Stepan Company, 50%
activity. While the foregoing examples satisfy the US Pharmacopoeia
requirements for alkyl chain distribution, other alkyl chain
distributions are effective against the target lipid coated viruses
and other target pathogens. These embodiments are also contemplated
within the scope of this invention. These ranges include about
1%-99% C.sub.12, about 1%-99% C.sub.14, and about 1%-99% C.sub.16.
and optionally about 1%-99% C.sub.18. Each manufacturer publishes
methods to analyze the bulk substance. Notwithstanding the fact
that benzalkonium chloride often refers to mixtures of compounds of
varying alkyl chain length, it should be understood that it is
within the scope of the invention to utilize a singular
benzalkonium chloride compound comprising only one alkyl chain of a
particular length.
[0061] These anti-infective agents, particularly benzalkonium
chloride, are highly effective in killing pathogens (e.g., viruses,
bacteria or fungi) or otherwise limiting the source of infections
and other complications related to disordered tissue. Also, these
anti-infective agents can neutralize or eliminate toxins and
inflammatory agents caused by pathogens such as viruses, bacteria
or fungi. Rapidly eliminating or neutralizing toxins, inflammatory
agents, and their sources results in prompt pain relief.
[0062] Benzalkonium bromide and benzalkonium iodide are also
examples of suitable organohalides. Benzalkonium bromide has the
structure of benzalkonium chloride with the difference being that
the chlorine is substituted with a bromine constituent. Analogous
considerations apply to benzalkonium iodide. Another example of a
suitable organohalide is cetyl trimethylammonium bromide.
[0063] Examples of other organochlorides which have anti-infective
properties and are suitable for use as the anti-infective
organochloride in the treatment composition include benzethonium
chloride, methyl benzethonium chloride, cetyl pyridinium chloride,
chloroxylenol, hexachlorophene, triclosan, and chlorhexidine. Note
that some of the above organochlorides are not suitable for all
purposes. For example, benzethonium chloride, chloroxylenol, and
chlorhexidine should not be used in a manner which would enable
them to be ingested in a toxic quantity.
[0064] Additional examples of other organohalides which may be
suitable, more particularly quaternary ammonium halides having an
alkyl with 6-18 carbons, include: alkyl benzyl dimethyl ammonium
halide, alkyl dimethyl ethyl benzyl ammonium halide, n-alkyl
dimethyl benzyl ammonium halide, diisobutyl phenoxy ethoxy ethyl
dimethyl benzyl ammonium halide, n-(C.sub.12C.sub.14C.sub.16) alkyl
dimethyl benzyl ammonium halide, dodecyl dimethyl ammonium halide,
dioctyl dimethyl ammonium halide, dialkyl dimethyl ammonium halide,
dialkyl methyl benzyl ammonium halide, octyl decyl dimethyl
ammonium halide, lauryl dimethyl benzyl ammonium halide,
o-benzyl-p-chlorophenol, dideryl dimethyl ammonium halide, dioctyl
dimethyl ammonium halide, and alkyl (C.sub.14C.sub.12C.sub.16)
dimethyl benzyl ammonium halide. In addition, other known
antimicrobial agents may also be used as the active agent or in
combination with the active agents provided above, for example,
chemicals which are known to act as an antiviral, antibacterial or
antifungal agents, such as antifungal agents disclosed by Chodosh
in U.S. Pat. No. 5,661,170 and U.S. Pat. No. 5,827,870. Additional
examples of effective organohalides include dual quaternary
ammonium compounds comprising at least two quaternary ammonium
compounds.
[0065] One of such embodiments comprises a mixture of n-alkyl
dimethyl benzyl ammonium halide and n-dialkyl methyl benzyl
ammonium halide. One example of such embodiments is distributed by
Stepan as BTC7 776, with a chain length distribution for the
n-alkyl of about 60% C.sub.14, about 30% C.sub.16, about 5%
C.sub.12, and about 5% C.sub.18 (CAS Reg. No. 683991-10-5), and a
chain length distribution for the n-dialkyl of about 60% C.sub.14,
about 30% C.sub.16, about 5% C.sub.12, and about 5% C.sub.18 (CAS
Reg. No. 68391-05-9). Another of such embodiments comprises a
mixture of n-alkyl dimethyl benzyl ammonium halide (I) and n-alkyl
dimethyl ethyl benzyl ammonium halide (II). One example of such
embodiments is distributed by Stepan as BTC 21257M series with a
chain length distribution for the n-alkyl in entity (I) of about
60% C.sub.14, about 30% C.sub.16, about 5% C.sub.12, and about 5%
C.sub.18 (CAS Reg. No. 683991-10-5), and a chain length
distribution in entity (II) of about 68% C.sub.12, and about 32%
C.sub.14 (CAS Reg. No. 68956-79-6).
[0066] A preferred method of preparing an example treatment
composition involves taking 70% isopropyl rubbing alcohol USP (70%
isopropanol, v/v, specific gravity 0.877 at 20 C, see 24 USP, p.
927) and then admixing the benzalkonium halide, NF and benzocaine.
Isopropyl alcohol USP (IPA) is available from any number of US
sources, including Union Carbide, Aldrich Chemical, Texaco, and
Shell. Purified water USP is available from a variety of laboratory
supply houses, such as Aldrich Chemical, Fisher Scientific, and VWR
Scientific. Purified water USP can also be obtained by means of a
commercially available water purification system designed to meet
the requirements of Purified Water USP.
[0067] Embodiments of the present invention include preparations
with organohalide concentrations in the range from about 0.001% to
about 2% by weight of the treatment composition. These
concentration values also refer to preparations that include
benzalkonium chloride and where the active ingredient is not
benzalkonium chloride, but one of the other substances herein
disclosed as active ingredients and equivalents thereof.
Furthermore, these concentration values also refer to the combined
amounts of active ingredients when more than one active ingredient
is present in other embodiments according to this invention, such
as when the composition comprises dual quaternary ammonium
compounds.
[0068] When the anti-infective agent is benzalkonium chloride or
other aromatic quaternary ammonium halide compound, the
concentration within a topical composition is preferably in a range
from about 0.01% and to about 0.5% by weight of the treatment
composition, more preferably in a range from about 0.05% to about
0.3% by weight of the treatment composition, and even more
preferably in a range from about 0.1% to about 0.2% by weight of
the treatment composition. To avoid toxicity, the concentration is
less than 0.26% by weight and is more preferably about 0.13% by
weight of the treatment composition. Depending on the particular
organohalide or quaternary ammonium chloride that is used as the
active agent and its toxicity and activity level, the concentration
may vary. For example, the concentration may range from about
0.001% to about 2% by weight of the treatment composition.
[0069] In one embodiment, the treatment composition consists of
only the active agent, such as benzalkonium chloride, the liquid
carrier, and benzocaine in a tissue penetration enhancing amount.
In other embodiments, the treatment composition consists
essentially of the active agent, liquid carrier, and benzocaine,
together with other components as described hereinbelow. In any
event, the liquid carrier is preferably sufficiently inert with
respect to the active agent and any other component present to
enable the treatment composition to be stored for long periods of
time without deactivating the anti-infective agent, such as at
least 1 year and preferably at least 2 or more years.
[0070] The liquid carrier preferably has properties that enhance
the ability of the treatment composition to penetrate into the
disordered epithelial tissue, particularly when used in combination
with benzocaine to further enhance penetration beyond the amount of
penetration provided by the liquid carrier by itself. The carrier
may have a viscosity and/or density which is not significantly
greater than that of water in order to optimally enable the
treatment composition to penetrate into the disordered tissue.
Using a carrier composition having a viscosity which is not
significantly greater than water is in contrast to compositions
that are coated onto afflicted tissue. Accordingly, the treatment
compositions preferably exclude formulations which may be
considered to be primarily or essentially gels, creams, lotions,
oils, ointments, pastes, emulsions, and viscous colloidal
suspensions. It will be appreciated that the liquid carrier may
include substances which have either a viscosity or density which
is greater than water as long as other substances are also included
in the carrier such that the mixture has either a viscosity or
density which is not significantly greater than that of water.
[0071] The carrier preferably has a tissue penetrating component,
such as isopropyl alcohol, that is capable of penetrating the skin
and cells in a rapid manner without rapidly diffusing beyond the
skin into the body. Benzocaine is included in an amount so as to
further enhance penetration of the liquid carrier beyond the
ability of the carrier to penetrate in the absence of benzocaine.
The treatment composition enables the stratum spinosum 34
illustrated in FIG. 1 to be saturated in the region of the cold
sore or other disordered tissue for a period that enables the
treatment composition to achieve its purpose before it diffuses
into the body. In this way, the treatment composition forms a
temporary reservoir (or bath) in the region where it is needed
most. In this way, the treatment composition can maximize its
effect of killing pathogens and/or destroying toxins within the
disordered tissue while minimizing possible damage to surrounding
healthy tissues or the organism as a whole.
[0072] While isopropyl alcohol is a preferred carrier, other
alcohols may also be used. In addition to isopropyl alcohol,
ethanol and methanol are also suitable carriers. Benzyl alcohol can
be used as a carrier or as an additive as it also acts as a
bacteriostat and an anesthetic. Acetone can also be used. Mixtures
of the above-mentioned solvents may also be used as desired
depending upon the application. As indicated above, however,
isopropyl alcohol or ethyl alcohol is preferably used in
combination with other carrier constituents. For example, as
mentioned above, water may be added to isopropyl alcohol to reduce
the pain which may be felt when only isopropyl alcohol is used.
Similarly, isopropyl alcohol may be utilized with cetyl alcohol or
a combination of cetyl, stearyl, myristyl, or lauryl alcohol and
water to reduce the sensation.
[0073] Carriers that include isopropyl alcohol and water can have
varying ratios depending on the intended use. However, for treating
colds sores, the water is preferably included in a range from about
10% to about 50% by volume of the carrier with the remainder being
isopropyl alcohol. The water content is more preferably in a range
from about 20% to about 40% by volume of the carrier, and most
preferably about 30% by volume of the carrier and wherein the
isopropyl alcohol is included in an amount of about 70%.
Embodiments of preparations according to the present invention may
include a carrier that comprises an alcohol, preferably isopropyl
alcohol, at a concentration in a range from about 20% to about 90%
by volume, preferably in a range from about 40% to about 85% by
volume, and more preferably in a range from about 50% to about 80%
by volume. The carrier may also include other solvents such as
acetone, and the like.
[0074] An important issue when applying the treatment composition
to a painful cold sore or other disordered tissue is proper
compliance by the user. Solvent carriers, such as isopropyl
alcohol, ethanol, methanol, acetone, and the like, can cause
excruciating pain when applied to sensitive disordered tissues such
as cold sores and shingles. Such pain can discourage compliance by
the user and undermine the effectiveness of an otherwise effective
treatment composition.
[0075] It has now been discovered that adding benzocaine in
specific amounts to a treatment composition that includes an
organic solvent carrier, such as isopropyl alcohol, greatly
increases the effectiveness in treating disordered tissues.
Unexpectedly, benzocaine, when included in specific amounts, can
increase the ability of such treatment compositions to penetrate
into the disordered tissue in order for the active agent to more
quickly contact and kill viruses or other pathogens within the
disordered tissue. Benzocaine can also increase patient compliance
by reducing the pain associated with application of the
anti-infective composition to painful disordered tissue,
particularly with open sores. However, beyond merely reducing pain,
benzocaine has been found to increase efficacy of treatment because
it promotes faster penetration of the treatment composition into
disordered tissue, which reduces the amount of rubbing or agitation
that would otherwise be required for the composition to be
effective.
[0076] The amount of benzocaine within the treatment composition
must be high enough to enhance penetration, and preferably help
alleviate pain. However, the amount of benzocaine is advantageously
not so high as to leave a residue on the surface of the skin and/or
cause loss of sensation in surrounding tissue and/or for a
prolonged period of time (e.g., greater than about 15 minutes). For
example, if included in excessive amounts, benzocaine can cause
numbing of a substantial portion of a person's lips for an extended
period of time, which can inhibit normal activities such as
drinking and talking (e.g., as can occur after a person leaves a
dental office after receiving an injection of novocaine).
[0077] The amount of benzocaine is most effective when numbing is
temporary and goes away once the treatment composition has
effectively penetrated into the disordered tissue and resided long
enough in the disordered tissue to kill the pathogens and
neutralize inflammatory agents in the tissue causing the pain.
According to one embodiment, the amount of benzocaine is selected
to provide a numbing effect for a time period of about 1 minute to
about 20 minutes, preferably about 2 minutes to about 15 minutes,
more preferable about 3 minutes to about 10 minutes, and most
preferably about 4 minutes to about 8 minutes after numbing first
occurs. It is desirable to include an amount of benzocaine so that
numbing begins in about 10 seconds or less after application of the
treatment composition, preferably in about 8 seconds or less, more
preferably in about 6 seconds or less, and most preferably in about
4 seconds or less.
[0078] The highly penetrating compositions are formulated, as a
result of including benzocaine in combination with a penetrating
carrier, so as to penetrate quickly so that the treatment
composition is no longer detected on the skin surface after less
than about 1 minute, preferably less than about 40 seconds, more
preferably less than about 20 seconds, and most preferably less
than about 10 seconds. Pathogens are killed and inflammatory agents
are neutralized within minutes or seconds after effective
penetration such that it is desirable for the numbing effect of
benzocaine to subside in less than about 10 minutes after
application, preferably less than about 8 minutes, more preferably
less than about 6 minutes, and most preferably less than about 5
minutes.
[0079] After extensive comparative survey testing supervised by
learned health care intermediates, which included obtaining
feedback from patients (to whom the benzocaine-containing treatment
compositions were administered by the learned health care
intermediates), who in this case suffered from painful and highly
infective cold sores, it was determined that the most effective
amount of benzocaine within treatment compositions that also
included a liquid carrier comprised of 70% by volume isopropyl
alcohol in water and 0.13% by weight benzalkonium chloride was
between about 2.5% and about 7.5% by weight. Above 7.5%, a
benzocaine residue was sometimes detected. Below about 2%,
benzocaine did not significantly enhance penetration. Between about
2.5% to about 7.5%, however, benzocaine enhanced penetration and
caused temporary, but not excessive, numbing when using the
treatment compositions that were tested. A more optimal range for
this anti-infective composition is about 2.75% to about 6%
benzocaine by weight, and the most optimal range was found to be
about 3% to about 5% benzocaine by weight.
[0080] Nevertheless, depending on the type of carrier that is used,
particularly if it is less penetrating than a mixture of about 70%
by volume isopropyl alcohol and 30% water (e.g., that includes a
less penetrating organic solvent than isopropyl alcohol and/or less
than about 50%, or less than about 40%, or less than about 30% by
volume isopropyl alcohol), the amount of benzocaine can be
increased in order to promote enhanced penetration, and can be as
high as 20% by weight, although this amount may cause prolonged
numbing (e.g., 1-3 hours). When using a liquid carrier that is
significantly less penetrating than a 70/30 v/v mixture of
isopropyl alcohol and water, the amount of benzocaine can be
included in a range of about 3.5% to about 20% by weight,
preferably in a range of about 4% to about 15%, more preferably in
a range of about 4.5% to about 10%, and most preferably in a range
of about 5% to about 7.5% by weight (e.g., about 6%).
[0081] Alternatively, when a composition consists essentially of
70% v/v isopropyl alcohol and 30% v/v water, organohalide, and
benzocaine so as to not include any components that inhibit
penetration, or where when carriers are used that are more
penetrating than a mixture of 70% v/v isopropyl alcohol and 30% v/v
water (e.g., that include an organic solvent that is more
penetrating into disordered tissue than isopropyl alcohol and/or
that include more than 70%, more than about 75%, more than about
80%, more than about 85%, or more than more than about 90% by
volume isopropyl alcohol and/or a quantity of DMSO), it may be
possible to use smaller quantities of benzocaine while still
obtaining a penetration enhancing effect, such as from about 1% to
about 6.5%, preferably between about 1.5% to about 5.5%, and most
preferably between 2.1% and about 5% by weight.
[0082] In general, the amount of benzocaine should be limited to
that amount that increases penetration so as to provide enhanced
effectiveness but beyond which increased amounts of benzocaine do
not further enhance penetration and effectiveness but merely
prolong the numbing effect and/or leave a residue. The amount of
benzocaine should therefore be less than about 20% by weight (e.g.,
2.1% to about 20%), preferably less than about 15% (e.g., 2.2% to
about 15%), more preferably less than about 10% (e.g., about 2.25%
to about 10%), and most preferably less than about 7.5% by weight
(e.g., about 2.5% to about 7.5%).
[0083] Although less preferred and not as effective as benzocaine
in enhancing penetration of penetrating treatment compositions
and/or reducing pain without causing undue numbing of a user's lip,
other topical anesthetics may be useful in enhancing patient
compliance by reducing pain associated with applying penetrating
treatment compositions to disordered tissue. Examples of other
topical anesthetics that may be used in addition to or instead of
include butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine,
proparacaine, proxymetacaine, tetracaine, and mixtures thereof. Of
the foregoing, butamben may perform most similar to benzocaine
given the similarity in the two chemical structures. Such other
topical anesthetics can be included in amounts similar to those of
benzocaine. Alternatively, they can be included in an amount
between 2.1% and about 15% by weight of the treatment composition,
or between about 2.2% and about 10% by weight, or between about
2.3% to about 8% by weight, or between about 2.5% to about 6% by
weight. Such other topical anesthetic, either alone or if combined
with another topical anesthetic, such as benzocaine, may be
included in an amount so as to numb the treatment area for a time
period of about 1 minute to about 20 minutes, preferably about 2
minutes to about 15 minutes, more preferably about 3 minutes to
about 10 minutes, and most preferably about 4 minutes to about 8
minutes after numbing first occurs. It is desirable to include an
amount of topical anesthetic so that numbing begins in about 10
seconds or less after application of the treatment composition,
preferably in about 8 seconds or less, more preferable in about 6
seconds or less, and most preferably in about 4 seconds or
less.
[0084] The carrier may also include other components that, by
themselves, may be too viscous to act as tissue penetrating agents,
but which, in combination with water, isopropyl alcohol, and other
solvents identified herein or known to those of skill in the art,
can penetrate tissue. Such components include ethoxylated alcohols
(e.g., lauryl alcohol ethoxylates), ethoxylated nonylphenols (e.g.,
Nonoxynol-9), low molecular weight glycols (e.g., ranging from
ethylene glycol to PEG-400, propylene glycol, propanediol, and the
like), ethoxylated amines, and their quaternaries. Certain
essential oils and emollients, which are normally water insoluble,
can be made soluble in water by ethoxylation (e.g., ethoxylated
lanolin).
[0085] Penetration inhibiting components include chemicals which
are petrolatum based substances, materials conventionally utilized
as thickeners, naturally occurring oils, substances derived from
naturally occurring oils, or any other substance which is added
primarily to increase the tendency of a treatment composition to
remain on the surface of disordered tissue such as a cold sore.
Note that while substances such as petrolatum or thickeners may not
be added individually, a component may be added which includes
minute amounts of naturally occurring oils or substances derived
from oils obtained from natural sources. So, the inventive
composition is preferably substantially oil-free, the term
"substantially oil-free" means that oil substances are preferably
not individually added but may be present due to the natural
content of a substance added to the inventive composition. As such,
oil may be incidentally present in an amount of less than about 2%
by volume, preferably incidentally present in an amount of less
than about 1%, more preferably incidentally present in an amount
less than about 0.05%, and most preferably in an amount less than
about 0.01%.
[0086] Treatment compositions may include other components that
achieve a particular result and do not substantially reduce the
ability of the treatment composition to penetrate into the
disordered tissue or the ability of the treatment composition to be
anti-infective. Examples of such components include pH adjusters,
substances having anesthetic qualities, vasodilators, analgesics
and defoamers. Example pH adjustors may include organic acids,
mineral acids in minute amounts, organic bases or mineral bases
also in minute amounts. Preservatives may be added to the
anti-infective composition, including parabens, preferably methyl
and propyl parabens. Preservatives, if present, are included in the
composition in a range from about 0.0001% to about 0.01% by volume
of the treatment composition.
[0087] Applicators may form part of a method and system for
applying the treatment compositions. As such, applicators may be
preconfigured with particular mixtures to treat specific disorders,
such as cold sores, chickenpox, herpes zoster (shingles), genital
herpes, eczema, and the like. Examples of applicators include those
taught in U.S. Pat. No. 5,709,866 (Booras et al.), U.S. Pat. No.
5,704,906 (Fox), U.S. Pat. No. 5,527,534 (Mythling), U.S. Pat. No.
5,016,651 (Stalcup et al.), U.S. Pat. No. 4,887,994 (Bedford), and
U.S. Pat. No. 4,952,204 (Korteweg), the disclosures of which are
incorporated herein by reference. Example applicators include
prepackaged applicators with agitation pads impregnated with the
treatment composition. An applicator may be provided as a unitary
structure such as a sealed container that is frangible and
configured for a single use.
[0088] FIGS. 2A-2E depict an example applicator 10. The details of
applicator 10 are best seen in FIG. 2A, which is an exploded
perspective view, FIG. 2B, which is a perspective view of the
assembled applicator, and FIG. 2C as it appears when ready for
application. Applicator 10 includes an absorbent pad 12 abutted
against a frangible ampule or reservoir 14 via open delivery end 17
of the flexible container 16. Frangible reservoir 14 is housed in a
container 16 that forms a holder for pad 12. Frangible reservoir is
enclosed by pad 12, the sidewalls of container 16, and the closed
end 19 of container 16. Frangible reservoir 14 is preferably a thin
glass ampule, while container 16 is preferably formed from a
flexible plastic. A protective sleeve 18 is provided, which is
designed to keep pad 12 free from contamination until applicator 10
is ready for use on the disordered tissue. A cap 20 is provided to
fit into sleeve 18. The treatment composition 22 is held in
frangible reservoir 14 until such time as frangible reservoir 14 is
broken. One source for applicators having a frangible reservoir and
various pad configurations is James Alexander Corporation of
Blairtown, N.J.
[0089] FIG. 2C is a perspective view of the applicator depicted in
FIG. 2B after frangible reservoir 14 has been ruptured. Treatment
composition 22 is allowed to permeate pad 12 in preparation for
application to disordered tissue. In FIG. 2C, sleeve 18 has been
removed to expose an impregnated pad 12. After impregnated pad 12
is sufficiently wetted, application to the disordered tissue
treatment site commences.
[0090] FIG. 2D is a perspective view of an individual 26 applying
treatment composition 22 to a cold sore at or near the lip
according to the present invention. FIG. 2D illustrates that
sufficient pressure is being applied against a non-puckered lip as
the lip is pressed against the patient's teeth and/or gums in order
to direct focused pressure into the disordered tissue while the
active compounds are expressed from impregnated agitation pad 12
and into the disordered tissue. The combined effect of vigorous
irritation of the disordered tissue and the administration of
treatment composition 22 has the result of surprising therapeutic
effects.
[0091] FIG. 2E is a detail taken along the section line 2E-2E in
FIG. 2D that depicts a close-up view of an example method of
treatment. The detail view more clearly illustrates agitation of
the disordered tissue site where impregnated pad 12 is being
pressed into the lip in order to be firmly felt at the gums or
teeth opposite the disordered tissue. The arrows illustrate
directions of movement by way of example.
[0092] Once frangible reservoir 14 is ruptured the treatment
composition is delivered to pad 12 as gravity enables it to flow
into pad 12; however, rupturing frangible reservoir 14 creates
shards of glass. Pad 12 prevents shards from passing and causing
injury during delivery of the composition to the disordered tissue.
Another purpose of pad 12 is delivery of treatment composition. As
discussed above, as pad 12 delivers the treatment composition it
may be useful to also agitate and/or compress the disordered
tissue. Many configurations are available for pad 12, such as those
disclosed in U.S. Pat. No. 1,822,566 and France Patent No.
2,700,698.
[0093] Pad 12 is a folded sheet formed from a web of fibers. FIG.
2F depicts sheet 12' before it has been folded or collapsed to form
pad 12. As shown in FIG. 2F, the sheet has a fluted appearance in
order to provide an alignment such that when the sheet is gathered
together in a bundle, it has longitudinal flutes. These
longitudinal flutes provide a flow path for treatment composition
22 while the interlocked web of fibers can prevent shards of glass
from passing out of container 16. Pad 12 has a configuration
similar or identical to that of a cigarette filter. Examples of
cigarette filters configurations that may be utilized are disclosed
in U.S. Pat. No. 5,465,739 and U.S. Pat. No. 5,998,500, which are
hereby incorporated by reference.
[0094] Pad 12 is preferably made of synthetic fibers that have a
mesh which enables it to hold treatment composition 22 while having
sufficient roughness to allow agitation of the disordered tissue to
enhance penetration by treatment composition 22. The fibers forming
pad 12 are relatively densely positioned and can be relatively
rigid. Pad 12 has a retention portion 13 positioned within flexible
container 16. Retention portion 16 is can be attached to flexible
container 16 through use of an appropriate adhesive that remains
inert in the presence of the treatment composition or through heat
fusing retention portion 13 with flexible container 16. Pad 12 also
has a delivery portion 14 opposite from retention portion 16 that
extends beyond open delivery end 17 of the flexible container 16.
Regardless of the configuration of pad 12 or the material from
which it is formed, the delivery portion is adapted to deliver the
treatment composition to the disordered tissue such that the
treatment composition is no longer visibly detectable on the
disordered tissue in less than about 1 minute after delivery of the
treatment composition onto the disordered tissue, preferably less
than about 40 seconds, more preferably less than about 20 seconds,
and most preferably less than about 10 seconds.
[0095] Delivery portion 17 terminates at an application surface 15
that is relatively flat such that the disordered tissue is
uniformly contacted. Uniformly contacting the disordered tissue
with the flat application surface 15 reduces the risk of injuring
the disordered tissue as the disordered tissue is contacted and
agitated.
[0096] The retention portion of pad has a length that is sufficient
for the pad to be securely anchored in the open delivery end of the
container. The delivery portion has a length and sufficient
rigidity to enable the application surface to optionally scrub the
disordered tissue. When the pad is formed by folding or compressing
together a sheet that is a polyester fiber web as shown in FIG. 2F
at 12', the retention portion preferably has a length ranging from
about 5 mm to about 7 mm and the delivery portion can have a length
ranging from about 1 mm to about 5 mm. The length of the retention
portion is more preferably about 6 mm and the length of the
delivery portion is more preferably 4 mm. The diameter of the pad
is preferably about 7 mm to about 1 cm, and is most preferably
about 8 mm. This diameter is sufficiently large to enable large
amounts of treatment composition to be delivered and provides
sufficient surface area to contact a cold sore or other disordered
tissue as needed. More particularly, a pad diameter that roughly
corresponds with the diameter of a cold sore in its various stages
of development is ideally configured to agitate the cold sore
treatment site.
[0097] In addition to a pad that is a folded sheet formed from a
web of fibers, the pad may also be formed from a cluster of aligned
bristles. Use of bristles having relatively small diameters is
preferred to enable the cluster to scrub while minimizing potential
injury to the disordered tissue. For example, if the bristles are
formed from nylon and are about 1 cm long so that the retention
portion and the delivery portion are each about 5 mm long, the
diameter may range from about 0.1 mm to about 0.2 mm, and is more
preferably 0.15 mm.
[0098] An advantage of applicator 10 is that frangible reservoir 14
holds a relatively large volume of the treatment composition so
that the treatment composition is delivered in an amount that is
relatively large compared with the surface area to be treated.
Further, the delivery is rapidly achieved due to the design of
applicator 10 without requiring rewetting of pad 12 as the
treatment composition is continually delivered to pad 12 until it
is all used. For example, frangible reservoir 14 may deliver about
0.2 ml to about 1 ml to an area that is no greater than about 1
cm.sup.2. Accordingly, the volume to surface area ratio is
preferably in a range from about 0.2 ml/cm.sup.2 to about 1
ml/cm.sup.2. Such quantities are ideally sufficient to saturate the
stratum spinosum 34 in the region of the cold sore or other
disordered tissue so that it is available as a protective bath
around the nerve.
[0099] A suggested application procedure using applicator 10 is to
apply the 0.6 ml of the treatment composition for 30 seconds or
longer, preferably while agitating the skin. Typical pain relief is
within 5 minutes or less. It may also be advantageous, especially
during the prodromal stage, to deliver half of the treatment
composition to the cold sore or other disordered tissue for about
30 seconds, wait about 1 minute, and then deliver the remainder for
about 30 seconds again. Typically a single application, or at most
2 or 3 applications, are all that is required per outbreak.
[0100] Another example applicator is illustrated in FIG. 3, which
is a cross-sectional elevational view of an applicator 210
including an absorbent pad 212 that may be typical of a sterile
adhesive bandage. Applicator 210 also includes adhesive wings 214
that may have adhesive typical of a sterile adhesive bandage. A
separate strip acts as a container 216 in order to cause treatment
composition 22 to remain in pad 212 until container 216 is stripped
away from adhesive wings 214 of applicator 210. In addition
thereto, a finger loop 228 that may include finger loop folds 230,
and a finger loop tab 232 is attached to applicator 210 immediately
above pad 212. Finger loop 228 is configured to lie flat against
adhesive wings 214 and can be opened by lifting on finger loop tab
232 and hinge open at finger loop folds 230. Applicator 210 may be
applied to a treatment site as typical of a sterile adhesive
bandage and left in place indefinitely. Additionally, after a
selected time period of having applicator 210 on a treatment site,
the medical professional or the patient may grasp the adhesive wing
tabs 234 and gently them away from the skin. Meanwhile, the medical
professional or the patient may insert a finger into finger loop
228, draw adhesive wings 214 toward finger loop 228, and commence
agitating the disordered tissue.
[0101] Where it is desired to agitate the cold sore, applicator 210
may be applied at the point of pad 212 onto the disordered tissue
and then agitated against the disordered tissue. Thereafter,
applicator 210 may be discarded or adhesive wings 214 may be
applied to the patient's skin to allow applicator 210 to remain
over the disordered tissue. This alternative may be preferable
where bleeding is incidental to the inventive method. As such,
applicator 210 doubles as an adhesive sterile bandage.
[0102] In summary, applicator 210 may be used for agitation of the
disordered tissue or merely as a relatively passive delivery
applicator. It may be used initially for application of the
anti-infective active agent without agitation of the disordered
tissue, followed by agitation of the disordered tissue. Agitation
by applicator 210 of the disordered tissue may be alternatively
followed by leaving applicator 210 in place like a sterile adhesive
bandage.
[0103] FIG. 4 is an elevational side view of an alternative
applicator 310, which includes a swab agitation pad 312 upon a stem
314. Stem 314 may be formed from any suitable material; however, it
is preferably relatively rigid to enable agitation pad 312 to be
pushed and/or moved in the desired manner. Pad 312 is preferably
used such that the side thereof is pushed against the disordered
tissue and not the bulbous tip. The side is used so that sufficient
pressure can be applied.
[0104] It is preferable that swab agitation pad 312 be used under
substantially sterile conditions so as to not introduce pathogenic
elements into the treatment site of the disordered tissue. The
sterile agitation pad of the swab may be dipped into the treatment
composition and used to gently abrade the skin. More preferably,
the swab is held in a bag as shown at 330, which also holds a burst
pouch as shown at 340. Burst pouch 340 holds the treatment
composition and is sized and/or positioned within the bag such that
upon bursting it can saturate the cotton swab. An example of a bag
holding a swab and a burst pouch designed to be frangible is
disclosed in U.S. Pat. No. 5,709,866 to Booras, previously
referenced.
[0105] The swab agitation pad may be replaced with a sponge to
gently agitate disordered tissue. An example of a foam pad or
sponge mounted on a stick such as stem 314 is disclosed in U.S.
Pat. No. 4,887,994 to Bedford, previously referenced. Reference is
made to Bedford, col. 2, ln. 44-46, to coarse foam pads. Coarse
foam pads enable disordered tissue to be more easily agitated
through combined rubbing and application of an appropriate amount
of pressure than softer foam pads.
[0106] FIG. 5 is an elevational perspective view of a fingertip
applicator 410, which includes an absorbent pad 412 held on an
adhesive surface 414, which can be applied to a fingertip. Pad 412
may include an absorbent material for retaining the treatment
composition and it may alternatively contain fixed abrasive
elements to assist in agitating disordered tissue.
[0107] FIG. 6 is an elevational cross-section view of a finger- or
digit-container applicator 510, which includes an absorbent pad 512
with a first side 512 and a second side 514 that acts as a support.
The user may rupture the container 516 such as by tearing a slit
518 and inserting a finger into applicator 510 against second side
514. Container 516 is a bag like that shown at 330 and may be
referred to as what is commonly called a pillow pouch or package.
Container 516 may also contain a burst pouch. Applicator 510 is
preferably pre-moistened by treatment composition 522 within
container 516. Applicator may also be held in a container 516 in a
dry sterile condition for dipping into a separate reservoir of the
treatment composition. First side 512 is made of an absorbent and
mildly abrasive material that is substantially uniform in relation
to the size of a disordered tissue site. First side 512 can
approximate the roughness of a conventional gauze bandage or terry
cloth and can be seamless and devoid of fabric folds. Additionally,
where second side 514 is used to interface with a finger, it is a
support for first side 512 as the delivery portion of applicator
510.
[0108] Applicator 510 can have varying sizes depending on its
intended use. For example, if applicator 510 is used to deliver the
treatment composition to a cold sore it is large enough to permit
entry of at least one fingertip into it. However, if applicator 510
is used to treat sores caused by shingles on, for example, an
individual's back or large surface, it may be useful for applicator
510 to be large enough so that several fingers or even the entire
hand can fit inside it like a mit. A mit-sized applicator enables
the treatment composition to be rapidly delivered to large surface
areas.
[0109] FIG. 7 depicts another embodiment of a delivery system. Like
the mit sized version of applicator 510, applicator 610 is useful
for treating large surfaces such as a patient's back. Applicator
610 comprises a treatment composition in a large frangible ampule
614 or reservoir, a container 616, and a pad 612. Container 616 has
thin walls at recess 618, the closed end opposite from open
delivery end 617, into which frangible ampule 614 is
positioned.
[0110] When applicator 610 is ready for use, handle wings 620 are
squeezed until they compress the thin sidewalls of container 616
inward at recess 618 such that pressure is applied to frangible
ampule 614 and ampule 614 ruptures. The treatment composition is
then released and flows into pad 612. Frangible ampule 614 can
contain a volume of treatment composition ranging from about 0.5 ml
to about 4 ml, preferably from about 1.5 ml to about 3 ml, and more
preferably from about 2 ml to about 3 ml.
[0111] Pad 612 is adhered to the rim of open delivery end 617 of
container 616 by suitable means, such as an adhesive, heat fusion,
or a mechanically interlocked configuration. Pad 612 prevents
shards from the rupture ampule from passing through and causing
injury. Once pad 612 is adequately moistened, it can be used to
rapidly apply treatment composition to large surface areas as shown
in FIG. 8, which depicts the use of applicator 610 to apply the
treatment composition to a patient's chest afflicted with sores
from shingles. Applicator 610 can be used to merely deliver the
treatment composition or it can be used to apply pressure and/or
scrub the treatment area.
[0112] FIGS. 9-11 depict a towelette being used as an applicator to
treat various disordered tissue. The towelette depicted at 710 may
be relatively smooth or relatively abrasive and can have varying
thickness. The towelette can be repeatedly dipped to rewet it. For
example, FIG. 9 depicts a user with a finger wrapped in a towelette
used to deliver the treatment composition to a cold sore on the
user's lip. The towelette may be formed from fibers such as those
discussed above in reference to applicator 10 or any of the other
applicators. The towelette may be selected from existing stock
formed from treated natural fibers, synthetic fibers, and untreated
natural fibers. One example of an abrasive towelette is a rough
paper towel used in the paper towel industry or the like. One of
ordinary skill in the art may select a towelette that has the
preferred abrasive qualities while maintaining a preferred
absorbability in order to convey the anti-infective active agent to
the disordered tissue treatment site.
[0113] FIG. 10 depicts towelette 710 being used in the genital
area. An advantage of using a towelette for delivering the
treatment composition in the genital area is that the towelette is
able to conform to the various surface features and it enables the
user to deliver the composition with sensitivity to the more
sensitive parts in the genital area of the body. As with the other
applicators, the towelette is disposed of after a single use to
prevent the spread of substances contained in the disordered
tissue.
[0114] FIG. 11 depicts towelette 710 being used to deliver the
treatment composition to a patient that has sores from shingles on
his chest. Towelettes are ideal for areas of the body that have
surfaces areas that are not primarily flat or that have irregular
surfaces such as the genital area. The towelette is ideal for these
areas as it can access all areas without causing pain.
[0115] The towelette may be held in a bag such as the bag shown at
330 which also holds a burst pouch as shown at 340. Burst pouch 340
holds the treatment composition and is sized and/or positioned
within the bag such that upon bursting it saturates the towelette.
The bag may hold the towelette and the burst pouch in a similar
fashion to the designs disclosed in U.S. Pat. No. 5,709,866 to
Booras, previously referenced. Towelette 710 may be dipped into a
separate reservoir and then used to deliver the treatment
composition.
[0116] An example method of treating disordered tissue includes
impregnating an applicator with the treatment composition and
contacting the treatment site with the applicator. Though rigorous
agitation is not required, moderate to gentle agitation of the
disordered tissue may be useful as the induced physical trauma can
cause awakening of the body's immune response local to the
irritation. As such, the immune response and the penetration of the
inventive composition into the disordered tissue has the concerted
effect of a rapid decline of the infection. Nevertheless, the
enhanced penetration of treatment compositions that include
benzocaine reduces or eliminates the need to agitate the disordered
tissue to obtain effective treatment.
[0117] Chemotaxis, the migration of phagocytes such as granular
leucocytes and human leucocyte associated (HLA) antigens to an area
of a tissue disorder, may be enhanced and assisted by agitation of
disordered tissue with the enhanced penetration treatment
composition. The combination of the anti-infective active agent,
preferably benzalkonium chloride, with the chemotaxis phenomenon
caused by agitation of the disordered tissue, has the unexpected
effect of rapid decline of infectant such as a virus or a microbe
in the disordered tissue. One type of granular leucocyte, the
neutrophil, has the ability to activate defenses which are amino
acids that exhibit a broad range of antibiotic activity against
bacteria, fungi, and viruses. Consequently, the synergistic effect
of agitation is rapid delivery and awakening of immune response.
The neutrophil, if activated, is useful to treat disordered tissue
according to the present invention where bacteria, fungi, or virus
infections occur. Further, agitation causes fluids to concentrate
in the area of the disordered tissue, which further enables the
active agent to penetrate effectively.
EXAMPLES
[0118] The following examples are provided in order show how
including benzocaine in various amounts can enhances penetration of
treatment compositions comprising an organohalide anti-infective
agent and a liquid carrier. It should be understood that the
following examples are given by way of example only and not by
limitation. Given the effects and trends shown the examples, one of
ordinary skill in the art will readily understand that virtually
any treatment composition within the scope of the disclosure can
have enhanced penetration when combined with an appropriate amount
of benzocaine as described above, which is selected for use in
combination with a given liquid carrier having a particular native
propensity to penetrate a targeted disordered tissue.
Comparative Study
[0119] A comparative study was performed by retrospective written
survey by participants comparing the efficacy of original formula
Viroxyn.RTM. (isopropyl alcohol tincture of benzalkonium chloride,
0.13%) versus Viroxyn.RTM. professional with benzocaine (isopropyl
alcohol tincture of benzalkonium chloride, 0.13% and 5% benzocaine)
in the treatment of herpes labialis outbreaks in consumers with
naturally occurring classical cold sores who have experience in the
use of both products and using participant reported outcomes of
untreated cold sore lesion outbreaks as the control.
[0120] The study examined the primary outcome variables of
time-to-healing (loss of hard scab and return to intact skin) and
time to loss of discomfort (a persistent report of mild or none).
The hypothesis of "No Difference" was used to test for differences
in study drug outcomes.
[0121] A retrospective written survey was conducted using
participants who were experienced in the use of both products
(n=118). While the retrospective survey design employed in this
study may have limitations, the potential for both investigator and
patient bias, and subsequent study confounding, have been
identified as being impossible to manage in a prospective clinical
study. Thus, a retrospective study may be the only credible way to
study these two drugs in a head-to-head manner. Simple descriptive
statistics (mean, median, standard deviation) were employed.
Differences between cohorts were measured using T-test.
[0122] The results of this study show a dramatic difference in
outcome versus untreated cold sores with both drugs performing well
against untreated cold sores (Control). Further examination shows a
better outcome using Viroxyn.RTM. Professional with 5% benzocaine
(n=118), than using original formula Viroxyn.RTM. (n=118) with no
benzocaine. The differences in time to healing are dramatic,
statistically significant, and clinically relevant, with the
Viroxyn.RTM. Professional with 5% benzocaine cohort showing a
median 6.0 day reduction in time-to-healing versus the Control
(p<0.01) and the original formula Viroxyn.RTM. cohort showing a
median 5.0 day reduction in time-to-healing versus the Control
(p<0.01). A direct comparison of the time to healing outcomes of
the two drugs shows Viroxyn.RTM. Professional with Benzocaine
median time to healing of 4.0 days versus the original formula
Viroxyn.RTM. median time to healing outcome of 5.0 days (p=0.02). A
similar result was seen in time to loss of discomfort with the
Treatment cohort (Viroxyn.RTM. Professional with benzocaine)
reporting loss of symptoms in a median 2 minutes and the Comparator
cohort (original formula Viroxyn.RTM.) showing loss of symptoms in
a median 10 minutes versus a median 5.0 days (7200 minutes) of
discomfort in the Control group (p<0.01). This is significant
given that the loss of discomfort must remain persistent and the
effect of the benzocaine component in the treatment drug is short
lived. A direct comparison of the Viroxyn.RTM. Professional group
versus the Viroxyn.RTM. group was significant as well (p=0.05).
[0123] Both Viroxyn.RTM. and Viroxyn.RTM. Professional with
benzocaine have been well received in the dental healthcare
profession. Initially, the decision to reformulate Viroxyn.RTM. to
contain benzocaine was intended to alleviate consumer complaints of
extreme discomfort in applying the medication. Upon reformulation,
the incidence of discomfort did abate. However, there were nearly
immediate reports of increased overall satisfaction with
Viroxyn.RTM. Professional with benzocaine and reports of increased
efficacy versus the original formula Viroxyn.RTM.. Consumers noted
that the numbing effect of the benzocaine took place very quickly
and, unexpectedly, they experienced increased efficacy with less
rubbing and/or less intense rubbing compared to original formula
Viroxyn.RTM..
[0124] The purpose of this study was to compare these two products
designed for OTC usage relative to time of the healing process to
learn if one is superior to the other both in terms of time to
healing and in time to participant loss of discomfort. Due to the
design of the study, and the importance of measuring any such
differences using sufficient numbers to be convincing, sufficient
time in the marketplace with Viroxyn.RTM. Professional with
benzocaine was needed so that a larger study population of persons
experienced in using both drugs, more typical of scientifically
sound human clinical studies, would be available.
[0125] The "Gold Standard" for a drug study typically includes
multiple study sites, randomization, double blinding, and placebo
control. However, for OTC products that have become familiar to the
public, keeping study participants from becoming aware of which OTC
drug they have been assigned may not be possible. Newly issued FDA
Guidance documents (December 2009 & March 2010) provided the
basis for the study design. Clinical trials based on patient
reported outcomes are now being accepted by FDA as pivotal trials.
There are several key provisions of such clinical trials. First,
the study participant must directly report the outcome metrics on a
suitable instrument without input or filtering from any healthcare
professional. This means that paper or electronic surveys, diary
cards, etc. are sent directly to the investigators. Second, there
is a reasonable expectation that the participant has a good memory
of the outcome, i.e., the patient was not under anesthesia, does
not suffer from a disease or condition that affects the
participant's memory, etc. Third, the measurements under study are
clinically relevant to the disease, and can be self-evaluated by
the layman. The Comparative Study used a design that is in
accordance with the new FDA Guidance Documents.
[0126] The primary outcome objectives that were studied were: 1)
time to persistent resolution of discomfort (pain, itching, and
burning) and 2) time-to-healing (loss of hard scab and return to
intact skin). These outcomes were studied for both drugs versus
Control (untreated lesions) and head-to-head against each other.
Participants were selected from a list of persons who had used both
Viroxyn.RTM. (Comparator) and Viroxyn.RTM. Professional with
benzocaine (Treatment). It was anticipated that some participants
would have more than one member of a household that used
Comparator, Treatment, or both, and would submit a separate survey.
All surveys were returned directly to the investigators and data
entries were made by one person and verified by a second person. In
accordance with the study protocol, surveys that included data for
one drug, but no data for the other, were not analyzed in that
"intent to treat" was not triggered. Surveys returned with some
data present for each drug, but missing other data, triggered the
protocol imputation rule of "assign all missing data the median
value".
[0127] Participant natural history was gathered for use as the
Control. A 4-point discomfort scale was provided as was used in
similar studies. Time to healing was given as whole days. If
participants entered a range (e.g., 10-12 days), the lower number
was used in the study. The survey asked the following: [0128]
Initials, Age, Gender, Race [0129] How many cold sore do you get
per year?______ [0130] How much discomfort (pain, itching, or
burning) without treatment when the cold sore is at its worst?
[0131] ______ None [0132] ______ Mild (I hardly notice it) [0133]
______ Moderate (I am very aware of the discomfort) [0134] ______
Severe (I find it hard to concentrate, work, or sleep) [0135] How
long until the scab falls off without treatment? ______ days [0136]
How long until the pain is down to mild or none? ______ days
[0137] Page two of the survey asked the patient to indicate the
time to persistent loss of discomfort when using Treatment and when
using Comparator to treat a cold sore. The time intervals were
presented as multiple-choice to standardize responses. Potential
selections included 1 minute or less, 2-10 minutes, 10-30 minutes,
30-60 minutes, 1-2 hours, 2-4 hours, 5-10 hours, and 11+ hours.
Page two of the survey also asked the patient to indicate the
time-to-healing (loss of hard scab and return to intact skin) when
using Treatment and when using Comparator drug to treat a cold
sore. The time intervals were presented as multiple-choice from 1
day to "13 days or more" in one day increments to standardize
responses.
[0138] All participants who returned a survey with at least one
data point showing outcome data for each drug were treated as
"intent-to-treat" and the data submitted was included in the
analysis. Simple summary statistics (mean & standard deviation)
were provided for demographical information. Differences in age
between male and female participants were analyzed using t-test,
2-tailed, equal variance. Time-to-healing and time to loss of
discomfort were compared to Control and subsequently head-to-head
for the two study drugs using t-test, 2-tailed, equal variance. The
hypothesis of "No Difference" was used to analyze potential
differences in primary outcomes for both groups. With regard to
simple descriptive statistics, most scholarly papers describing
time-to-healing outcomes observed in clinical studies of herpes
labialis rely on the median value for time-to-healing as this tends
to negate the effects of out-lying data and often because the data
are not normally distributed.
[0139] In the comparative study, the outcome data is presented as
median value and as mean value+standard deviation (Std. dev.).
Statistical significance is expressed as "p". A p-value of >0.05
confirms the null hypothesis of no difference between groups. A
p-value of <0.05 invalidates the null hypothesis of no
difference and confirms a statistically significant difference
between the two groups being measured.
[0140] The participant reported outcome results were as follows.
All surveys returned with at least one data entry were analyzed as
"intent-to-treat". The survey sample was n=137 and the distribution
of responses strongly favoring those who had experience with the
use of both products were as follows, wherein each number was
sufficiently large enough to "power" the respective portions of the
study. [0141] Supplied data for both Viroxyn & Viroxyn
Professional: n=118 (86.2%) [0142] No data for Viroxyn: n=4 (2.9%)
[0143] No data of Viroxyn Professional: n=15 (10.9%).
[0144] It will be noted that a significant number of participants
did not trigger "intent to treat" for at least one treatment group.
It is easily seen that total censoring of the data for these
individuals is more appropriate than assigning all the median
value. Using that imputation rule would unfairly introduce bias in
favor of the Viroxyn.RTM. Professional with benzocaine group given
the dissimilarities in median outcome for the two groups. The
demographics of the group with experience using both products
favored women over men, and Caucasians over other races, but the
differences in ages of the groups were not statistically
significant. No conclusions can be drawn from the skew toward women
and Caucasians. The demographics for n=118 were as follows: [0145]
Male: n=44 (37.3%); Mean Age+std. dev.: 44.2.+-.13.2 years [0146]
Females: n=74 (62.7%); Mean Age+std. dev.: 44.2+11.1 years [0147]
Age; Male vs Female p=0.99* [0148] Caucasian: n=114 (96.6%) [0149]
Black: n=1 (0.9%) [0150] Hispanic/Latino: n=1 (0.9%) [0151]
Asian/Other: n=1 (0.9%) [0152] Native American n=1 (0.9%)
[0153] The time to healing is defined as loss of hard scab and
return to intact skin. The number of cold sores per year shown
below is consistent with the literature values from other placebo
controlled human clinical trials. Participants reported that both
Comparator and Treatment demonstrated a time-to-healing advantage
over Control and the differences are statistically significant
(p<0.01). This finding was expected for Viroxyn.RTM. or
Viroxyn.RTM. Professional with benzocaine. However, the "Null
Hypothesis of No Difference" is not valid when participant reported
time-to-healing using Viroxyn.RTM. Professional with benzocaine is
compared to that using original formula Viroxyn.RTM.. The
differences are both statistically significant and clinically
significant and strongly favor Viroxyn.RTM. Professional with
benzocaine.
[0154] Participants reported a median 5.0 and mean 5.1+2.7 days
time-to-healing using original formula Viroxyn.RTM. versus a median
4.0 days and a mean 4.3+2.4 days time-to-healing using Viroxyn
Professional with Benzocaine (p=0.02) and versus a median 10.0 and
mean 11.3+4.3 days time-to-healing of Control (p<0.01 for both
treatments). The Control outcome data compares favorably to other
studies.
[0155] The participant reported outcomes (time to healing in days)
for n=118 (loss of hard scab and return to intact skin) were as
follows:
TABLE-US-00001 median mean .+-. std. dev. Number of Cold Sores per
year: 4.0 4.6 .+-. 4.0 .sup. Participant Reported Time-to-healing:
Control: 10.0 days 11.3 .+-. 4.3 days Viroxyn .RTM. 5.0 days 5.1
.+-. 2.7 days Viroxyn .RTM. Professional with Benzocaine 4.0 days
4.3 .+-. 2.4 days 1. p < 0.01 for a comparison of Control vs.
Viroxyn .RTM. 2. p < 0.01 for a comparison of Control vs.
Viroxyn .RTM. Professional with benzocaine 3. p = 0.02 for a
comparison of Viroxyn .RTM. vs. Viroxyn .RTM. Professional with
benzocaine
[0156] The additional 1 day advantage of Viroxyn.RTM. Professional
with benzocaine versus Viroxyn.RTM. is statistically significant
(p=0.02) and clinically significant. Other herpes treatment drugs
have been approved by FDA for showing less than one day improvement
versus control (e.g., Abreva). Thus, the median 1.0 day advantage
in time to healing is indeed clinically significant.
[0157] The time to loss of discomfort is a persistent report of
none or mild on the 4-point pain scale. Participants reported that
both Treatment and Comparator demonstrated a time to loss of
discomfort advantage over Control and the differences are
statistically significant (p<0.01) and clinically significant.
This finding again was expected. However, the "Null Hypothesis of
No Difference" is not valid when participant reported time to loss
of discomfort using Viroxyn.RTM. Professional with benzocaine is
compared to that using the original formula Viroxyn.RTM..
Viroxyn.RTM. Professional with benzocaine demonstrated a median 2
minute time to loss of discomfort versus a median 10 minute time to
loss of discomfort using Viroxyn.RTM.. When the mean values are
taken into account, the differences are more dramatic with
Viroxyn.RTM. Professional demonstrating a 30 minute time to loss of
discomfort and the original formula Viroxyn demonstrating a 60
minute time to loss of discomfort. These differences are both
statistically significant (p=0.05) and clinically significant.
[0158] The participant reported time to loss of discomfort
(persistent report of mild or none) for n=118 were as follows:
TABLE-US-00002 median mean .+-. std. dev. Control .sup. 5.0 days
.sup. 6.3 .+-. 3.4 days Viroxyn .RTM. 0.167 hours 1.0 hour .+-. 2.3
hours .sup. (10 minutes) (60 minutes) Viroxyn .RTM. Professional
0.033 hours 0.5 .+-. 1.7 hours.sub.3 with benzocaine .sup. (2
minutes) (30 minutes) 1. p < 0.01 for a comparison of Control
vs. Viroxyn .RTM. 2. p < 0.01 for a comparison of Control vs.
Viroxyn .RTM. Professional with benzocaine .sub.3p = 0.05 for a
comparison of Viroxyn .RTM. vs. Viroxyn .RTM. Professional with
benzocaine.
[0159] It should be understood that the study design-induced bias
favors original formula viroxyn. The maximum reportable time to
healing value of "13 days or more" was assigned a value of 13. That
means the time to healing outcomes of more than 13 days were
effectively censored at 13 days. Four (4) times as many
participants reported this value when reporting their
time-to-healing when using original formula Viroxyn.RTM. (n=4 or
3.4% of respondents) versus Viroxyn.RTM. Professional with
benzocaine (n=1 or 0.85% of respondents). It is reasonable to
assume this bias is real and had a significant effect that favored
the original formula Viroxyn.RTM. by cutting short the 4 reports of
13 days or more. The further beyond 13 days the report may have
been, the more the bias favors original formula Viroxyn.RTM. and
thus the observed differences are the more credible.
[0160] A similar study design-induced bias is seen in participant
reported time to loss of discomfort. The designation "more than 11
hours" was assigned the value of 11 hours, effectively censoring
all data of outcomes lasting more than 11 hours. Like the study
design-induced bias demonstrated above, the original formula
Viroxyn.RTM. drug group had a larger number of respondents
reporting "more than 11 hours" (n=3 or 2.5% of respondents) versus
the Viroxyn.RTM. Professional with benzocaine group (n=1 or 0.85%
of respondents). Like the time to healing values, the further
beyond 11 hours the reported data may have been, the more the bias
favors original formula Viroxyn.RTM. and thus any observed
difference become all the more credible.
[0161] With respect to memory bias in reporting untreated cold sore
data, any tendency to overstate the severity and/or duration of an
untreated cold sore event will favor the less effective drug, which
in this study was the Comparator drug (original formula
Viroxyn.RTM.). However, as previously mentioned, the fact that the
Control group time to healing value corresponded so favorably to
the placebo time to healing values in other cold sore studies found
in the peer-reviewed literature offers reassurance that memory
bias, if any, was nil.
[0162] With respect to bias conclusions, all bias favors the
Comparator drug (original formula Viroxyn.RTM.) over the Treatment
drug (Viroxyn.RTM. Professional with benzocaine). Both drugs are
labeled to treat cold sores, and both have the same anti-viral
ingredient at identical concentrations. Thus, for Viroxyn.RTM.
Professional with benzocaine to show superiority to the Comparator
drug (original formula Viroxyn.RTM.) in clinically relevant
endpoints is indeed remarkable since the expected effect of the
benzocaine is limited to an anesthetic action of extremely short
duration and was intended to relieve user discomfort during
application. For this outcome to be observed despite identified
bias favoring original formula Viroxyn.RTM. makes the outcome for
Viroxyn.RTM. Professional with benzocaine all the more dramatic and
credible.
[0163] With respect to time to healing metric, even though all bias
favored the Comparator cohort (original formula Viroxyn.RTM.), the
Treatment cohort (Viroxyn.RTM. Professional) demonstrated dramatic
and clinically relevant differences in time-to-healing when
compared to original formula Viroxyn.RTM. (p=0.02) and Control
(p<0.01) cohorts. As expected, original formula Viroxyn.RTM.
also demonstrated an advantage in time-to-healing versus Control
(p<0.01).
[0164] With respect to time to loss of discomfort metric, even
though all bias favored the Comparator (Viroxyn.RTM.) cohort, the
Treatment cohort (Viroxyn.RTM. Professional with benzocaine)
demonstrated statistically significant and clinically relevant
differences in time to persistent loss of pain versus Comparator
(p=0.05) and Control (p<0.01). As expected, Comparator (original
formula Viroxyn.RTM.) also demonstrated an advantage in time to
loss of discomfort versus Control. (p<0.01).
[0165] In summary, while both drugs demonstrated clinically
relevant advantages versus the untreated cold sores that served as
the Control, the advantage clearly favors Treatment (Viroxyn.RTM.
Professional with benzocaine) versus Comparator (original formula
Viroxyn.RTM.). The fact that all identified biases favored
Comparator adds credibility to the study outcome. Further
credibility is suggested in that the Control value compares
favorably with placebo outcome values published in other cold sore
studies. The study conclusions strongly suggest that, given that
both drugs have the same anti-viral active ingredient (benzalkonium
chloride) and that the anti-viral ingredient is present in the same
concentration (0.13%) in both drugs, a previously unexpected
increase in overall efficacy has been created by the addition of
the benzocaine that goes well beyond what a person skilled in the
study of herpes labialis, would reasonably expect. The anesthetic
effect of benzocaine is fast acting, but very short lived, and
would not alone explain the observed results.
COMPARATIVE EXAMPLES
[0166] The following comparative examples are provided in order to
compare how well compositions that do not contain benzocaine do
that penetrate disordered tissue as well and therefore require
rigorous agitation in order to promote good penetration into the
disordered tissue.
Comparative Example 1
[0167] A cold sore treatment composition sold through dentists
under the name Viroxin.RTM. has the following composition:
TABLE-US-00003 Benzalkonium Chloride 0.13% by weight Liquid Carrier
(IPA + H2O) 99.87% by weight Isopropyl Alcohol 70% v/v Water 30%
v/v
[0168] This treatment composition was shown to work well in
treating cold sores using an applicator such as the one illustrated
in FIGS. 2A-2F together with applying the composition to the cold
sore area using an applicator with vigorous rubbing to promote
penetration of the composition into the cold sore. In many cases,
the cold sore was so painful that users could not simply apply the
composition all at once but often applied a first amount, which
caused initial pain, and then a second amount once the pain was
reduced to an acceptable level. The main impediment to effective
treatment was lack of compliance by the user as a result of the
intense pain caused by the composition combined with vigorous
rubbing.
Comparative Example 2
[0169] The treatment composition of Comparative Example 1 was
applied but only with slight rubbing. Soap was used on the cold
sore treatment site that evening. Although the cold sore formed a
scab after about two days, a new cold sore erupted at that time
above the existing scab and spread itself into the scab.
WORKING EXAMPLES
[0170] In an attempt to ameliorate the pain associated with the
treatment composition of Example 1, particularly when applied to an
open sore, various amounts of benzocaine were added in an attempt
to ensure better compliance by the user. Unexpectedly, benzocaine
not only reduced the pain associated with application of the
treatment composition, it also significantly enhanced penetration
of the treatment composition beyond the amount of penetration of
the composition in the absence of the benzocaine. This was
demonstrated by the fact that effective treatment of cold sores was
obtained with less rubbing and damage to the cold sore.
[0171] In the previous patents by the inventor, it was explicitly
taught that vigorous rubbing, even to the point of causing tissue
damage, was desirable and necessary in order for the treatment
composition of Example 1 to properly penetrate into the cold sore
and provide the desired killing of the cold sore viruses and
neutralization of toxins released by the viruses.
[0172] In contrast, including benzocaine together with the other
components significantly decreased the amount of rubbing that was
required by the user in order to feel the sensation of penetration
by the treatment composition down the nerves. Numbing can only
occur when the composition penetrates deeply enough to reach the
nerves. Such numbing was often felt simply by applying the
composition with little or no rubbing, which objectively
demonstrated that treatment compositions augmented with benzocaine
have enhanced tissue penetration properties. While numbing of the
cold sore site substantially decreased the pain and discomfort
associated with application of the treatment composition and
lessened the fear and reticence associated with rubbing the cold
sore with the applicator (i.e., the same applicator used to apply
the treatment composition of Example 1), it was surprisingly and
unexpectedly found that significantly less, or even no, rubbing was
typically required to obtain the same level of treatment as
compared to treating cold sores with the composition of Example
1.
[0173] Following are various treatment compositions that were
prepared, which are modifications of the composition of Example
1.
Example 3
TABLE-US-00004 [0174] Benzocaine 5% by weight Benzalkonium Chloride
0.13% by weight Liquid Carrier (IPA + H2O) 94.87% by weight
Isopropyl Alcohol 70% v/v Water 30% v/v
[0175] The composition of this Example provided enhanced
penetration of cold sores as described herein and resulted in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1. In fact,
effective treatment of cold sores occurred in many cases with
little or no rubbing, or only very gentle rubbing. Numbing
typically occurred within a few seconds (e.g., 2-5 seconds) and
persisted for a few minutes (e.g., 2-5 minutes) and then subsided
and restored use of the person's mouth. Such enhanced penetration
compared to the composition of Example 1 was even more unexpected
considering the fact that Example 3 included only 94.87% by weight
of tissue penetrating liquid carrier while Example 1 included
99.87%.
[0176] While penetration into the cold sore was enhanced, there
was, in a small number of cases, a slight amount of white
benzocaine residue on the cold sore depending on the amount of
treatment composition applied to the cold sore. It is postulated
that, once the cold sore was fully saturated with the treatment
composition, further penetration of the composition was inhibited.
Because benzocaine is not volatile like the liquid carrier, it
could not evaporate away and therefore remained on the surface. In
most cases, however, no benzocaine residue was reported.
Example 4
TABLE-US-00005 [0177] Benzocaine 2.5% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 97.37% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0178] The composition of this Example provided enhanced
penetration of cold sores as described herein and resulted in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1.
Effective treatment of cold sores occurred in many cases with
little or no rubbing, or very gentle rubbing. The treatment
composition of this Example enhanced penetration virtually the same
degree as the composition of Example 3 and also resulted in initial
numbing in a few seconds and subsidence of numbing after a few
minutes but did not leave behind any residue.
[0179] The fact that the composition of Example 4 worked about as
well as the composition of Example 3 is a surprising and unexpected
result in view of the FDA Cold Sore Analgesic Monograph that
requires a composition to include 5-20% benzocaine to be considered
safe and effective. Including 2.5% by weight benzocaine was found
to be virtually as effective as including 5% in reducing the
sensation of pain.
Example 5
TABLE-US-00006 [0180] Benzocaine 10% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 89.87% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0181] The composition of this Example provided enhanced
penetration of cold sores as described herein and resulted in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1. The
treatment composition of this Example caused initial numbing within
a few seconds but numbing persisted longer than in Examples 3 and
4. In addition, the composition left behind a significant amount of
white benzocaine residue. Nevertheless, the treatment composition
of this Example was superior to the composition of Example 1 in
terms of patient compliance and efficacy.
Example 6
TABLE-US-00007 [0182] Benzocaine 20% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 79.87% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0183] The composition of this Example provided enhanced
penetration of cold sores as described herein and resulted in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1. The
treatment composition of this Example caused initial numbing within
a few seconds but numbing persisted for over 1 hour in many cases,
which many patients found objectionable due to the loss of normal
use of their lips and mouth. In addition, the composition left
behind an even greater amount of white benzocaine residue than in
Example 5. Nevertheless, the treatment composition of this Example
was superior to the composition of Example 1 in terms of patient
compliance and efficacy.
Example 7
TABLE-US-00008 [0184] Benzocaine 1.25% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 98.62% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0185] The composition of this Example provided effective treatment
of the cold sores but did not penetrate as rapidly and did not numb
the pain as quickly or as completely as when larger amounts of
benzocaine were included. In the case of cold sores that were not
open, the composition of this Example could not completely numb the
disordered tissue.
HYPOTHETICAL EXAMPLES
[0186] The following are hypothetical and are given by way of
example in order to show other compositions within the scope of the
invention and how they would be expected to perform based on test
data obtained relative to working Examples 3-7 and Comparative
Examples 1-2.
Example 8
TABLE-US-00009 [0187] Benzocaine 4% by weight Benzalkonium Chloride
0.13% by weight Liquid Carrier (IPA + H2O) 95.87% by weight
Isopropyl Alcohol 70% v/v Water 30% v/v
[0188] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1. The
treatment composition of this Example enhances penetration
virtually the same degree as the composition of Example 3 but does
not leave behind any significant or noticeable benzocaine
residue.
Example 9
TABLE-US-00010 [0189] Benzocaine 3% by weight Benzalkonium Chloride
0.13% by weight Liquid Carrier (IPA + H2O) 96.87% by weight
Isopropyl Alcohol 70% v/v Water 30% v/v
[0190] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1. The
treatment composition of this Example enhances penetration
virtually the same as the composition that included 2.5%
benzocaine. It is possible that this composition is able to numb
disordered tissue slightly faster and/or more completely than when
2.5% benzocaine is used.
Example 10
TABLE-US-00011 [0191] Benzocaine 2% by weight Benzalkonium Chloride
0.13% by weight Liquid Carrier (IPA + H2O) 97.87% by weight
Isopropyl Alcohol 70% v/v Water 30% v/v
[0192] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with somewhat less rubbing
and pain compared to the composition of Example 1. The treatment
composition of this Example enhances penetration and does not leave
behind any benzocaine residue but does not work quite as well at
rapidly reducing pain as compared to when larger amounts of
benzocaine are used. The penetration enhancing effect of benzocaine
is less than when greater amounts of benzocaine are used.
Accordingly, when using a liquid carrier consisting of 70% by
volume isopropyl alcohol in water, including more than 2%
benzocaine is more effective in reducing pain and enhancing
penetration when treating cold sores or other disordered
tissue.
Example 11
TABLE-US-00012 [0193] Benzocaine 6% by weight Benzalkonium Chloride
0.13% by weight Liquid Carrier (IPA + H2O) 93.87% by weight
Isopropyl Alcohol 70% v/v Water 30% v/v
[0194] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1.
Penetration is enhanced about the same as when 5% benzocaine is
used but there is slightly more benzocaine residue depending on the
amount of treatment composition applied to the cold sore. As
discussed above, it is possible that once a cold sore is fully
saturated with the treatment composition, further penetration of
the composition is inhibited. Because benzocaine is not volatile
like the liquid carrier, it cannot evaporate away and can leave a
residue once the cold sore becomes saturated and further
penetration is inhibited.
Example 12
TABLE-US-00013 [0195] Benzocaine 7.5% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 92.37% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0196] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1.
Penetration is enhanced as when 5% benzocaine is used but there is
more benzocaine residue depending on the amount of treatment
composition applied to the cold sore.
Example 13
TABLE-US-00014 [0197] Benzocaine 15% by weight Benzalkonium
Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 84.87% by
weight Isopropyl Alcohol 70% v/v Water 30% v/v
[0198] The composition of this Example provides enhanced
penetration of cold sores as described herein and results in
effective treatment of the cold sores with significantly less
rubbing and pain compared to the composition of Example 1.
Penetration is enhanced as when smaller quantities of benzocaine
are used but there is substantially more benzocaine residue
depending on the amount of treatment composition applied to the
cold sore. In addition, the disordered tissue remains numb for a
longer amount of time than when smaller quantities of benzocaine
are used.
Example 14
[0199] Any of the foregoing examples is modified by substituting
the identified liquid carrier with a liquid carrier comprised of
80%, 90% or 100% by volume isopropyl alcohol and/or an organic
solvent that is more penetrating than isopropyl alcohol. The
treatment compositions have even further enhanced penetration and
can provide adequate penetration into cold sores or other
disordered tissue using the same or smaller quantities of
benzocaine.
Example 15
[0200] Any of the foregoing examples is modified by substituting
the liquid carrier with a liquid carrier comprised of 60%, 50%,
40%, 30% or 20% by volume isopropyl alcohol and/or an organic
solvent that is less penetrating than isopropyl alcohol. The
treatment compositions provide enhanced penetration into cold sores
or other disordered tissue compared to the same compositions in the
absence of benzocaine but benefit from including larger quantities
of benzocaine.
Example 16
[0201] Any of the foregoing examples is modified so that the amount
of benzalkonium chloride is included in an amount of 0.01%, 0.05%,
0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5% by weight. The
treatment compositions provide enhanced penetration into cold sores
or other disordered tissue compared to the same compositions in the
absence of benzocaine. Less composition is required to provide a
desired treatment level and/or may benefit from using a less
penetrating liquid system to offset the greater toxicity when
including more than 0.13% benzalkonium chloride. Conversely, more
composition is required to provide a desired treatment level and/or
may benefit from using a more penetrating liquid system when
including less than 0.13% benzalkonium chloride.
Example 17
[0202] Any of the foregoing examples is modified by combining or
substituting benzalkonium chloride with one or more of the
following organohalides: benzethonium chloride, methyl benzethonium
chloride, cetyl pyridinium chloride, chloroxylenol,
hexachlorophene, triclosan, or chlorhexidine. Depending on the
level of toxicity or anti-pathogenic activity of a given
organohalide, it may be beneficial adjust the concentration of
anti-infective agent to provide a desired level of anti-infective
activity in view of the penetrating qualities of the overall
treatment composition. The treatment compositions are useful in
treating a wide variety of disordered tissues caused by viruses,
bacteria, fungi or non-pathogenic toxins.
Example 18
[0203] Any of the foregoing examples is modified by combining or
substituting benzalkonium chloride with one or more of the
following organohalides: quaternary ammonium halide having an alkyl
group with 6-18 carbons including mixtures of varied alkyl chains,
ethoxylated quaternary ammonium halides including mixtures of alkyl
chains, alkyl benzyl dimethyl ammonium halide, alkyl dimethyl ethyl
benzyl ammonium halide, n-alkyl dimethyl benzyl ammonium halide,
diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium halide,
n-(C.sub.12C.sub.14C.sub.16) alkyl dimethyl benzyl ammonium halide,
dodecyl dimethyl ammonium halide, dioctyl dimethyl ammonium halide,
dialkyl dimethyl ammonium halide, dialkyl methyl benzyl ammonium
halide, octyl decyl dimethyl ammonium halide, lauryl dimethyl
benzyl ammonium halide, o-benzyl-p-chlorophenol, dideryl dimethyl
ammonium halide, dioctyl dimethyl ammonium halide, or alkyl
(C.sub.14C.sub.12C.sub.16) dimethyl benzyl ammonium halide.
Depending on the level of toxicity or anti-pathogenic activity of a
given organohalide, it may be beneficial adjust the concentration
of anti-infective agent to provide a desired level of
anti-infective activity in view of the penetrating qualities of the
overall treatment composition. The treatment compositions are
useful in treating a wide variety of disordered tissues caused by
viruses, bacteria, fungi or non-pathogenic toxins.
[0204] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects only as illustrated and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. All changes which come
within the meaning and range of equivalency of the claims are to be
embraced within their scope.
* * * * *