U.S. patent application number 11/348127 was filed with the patent office on 2006-06-22 for anti-infective compositions, methods and systems for treating pathogen-induced disordered tissues.
Invention is credited to B. Ron Johnson.
Application Number | 20060135464 11/348127 |
Document ID | / |
Family ID | 46301124 |
Filed Date | 2006-06-22 |
United States Patent
Application |
20060135464 |
Kind Code |
A1 |
Johnson; B. Ron |
June 22, 2006 |
Anti-infective compositions, methods and systems for treating
pathogen-induced disordered tissues
Abstract
Compositions, methods and systems for treating disordered
epithelial tissues, such as is caused by pathogens and/or by toxins
produced thereby. The invention relates to the use of an
anti-infective and/or antimicrobial active agent in a carrier, with
vigorous agitation of the disordered epithelial tissue for topical
treatment thereof under such conditions sufficient to achieve
clinically discernable improvement of the disordered epithelial
tissue. The preferred anti-infective and/or antimicrobial active
agent comprises a nucleoside, such as acyclovir, valcyclovir,
penciclovir, famciclovir, ganciclovir, cidofovir, adefovir, and
tenofovir, and derivatives, analogs, or metabolites thereof, or a
mixture thereof, or 1-docosanol, optionally in combination with an
organohalide. The inventive compositions and methods may employ the
use of an applicator adapted for use in promoting the penetration
of the treatment composition and/or the vigorous agitation of the
disordered tissue.
Inventors: |
Johnson; B. Ron; (Sandy,
UT) |
Correspondence
Address: |
WORKMAN NYDEGGER;(F/K/A WORKMAN NYDEGGER & SEELEY)
60 EAST SOUTH TEMPLE
1000 EAGLE GATE TOWER
SALT LAKE CITY
UT
84111
US
|
Family ID: |
46301124 |
Appl. No.: |
11/348127 |
Filed: |
February 6, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10816571 |
Apr 1, 2004 |
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11348127 |
Feb 6, 2006 |
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10200897 |
Jul 22, 2002 |
6759434 |
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11348127 |
Feb 6, 2006 |
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09668953 |
Sep 22, 2000 |
6423750 |
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11348127 |
Feb 6, 2006 |
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09401076 |
Sep 22, 1999 |
6211243 |
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11348127 |
Feb 6, 2006 |
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Current U.S.
Class: |
514/45 ;
514/263.35; 514/263.36; 514/269; 514/49; 514/81; 514/85 |
Current CPC
Class: |
A61K 31/522 20130101;
A61K 31/7076 20130101; A61K 31/155 20130101; A61K 45/06 20130101;
A61K 47/08 20130101; Y10S 514/931 20130101; A61M 35/003 20130101;
A61K 47/10 20130101; A61K 31/205 20130101; A61K 31/055 20130101;
A61K 31/53 20130101; A61K 31/7072 20130101; A61K 31/675 20130101;
Y10S 514/934 20130101; A61K 31/4425 20130101; A61K 9/0014
20130101 |
Class at
Publication: |
514/045 ;
514/049; 514/263.35; 514/263.36; 514/081; 514/085; 514/269 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61K 31/7072 20060101 A61K031/7072; A61K 31/675
20060101 A61K031/675; A61K 31/522 20060101 A61K031/522; A61K 31/53
20060101 A61K031/53 |
Claims
1. An anti-viral composition for treating disordered tissue caused
by a virus, comprising: a nucleoside; and a liquid carrier
comprising a tissue penetrating component for penetrating skin in a
rapid manner without rapidly diffusing beyond the skin.
2. An anti-viral composition as recited in claim 1, wherein the
nucleoside is in the form of a salt, phosphate ester, acyl
derivative, or other derivative.
3. An anti-viral composition as recited in claim 1, wherein the
nucleoside comprises an acyclic nucleoside.
4. An anti-viral composition as recited in claim 3, wherein the
acyclic nucleoside is selected from the group comprising acyclovir,
penciclovir, and famciclovir.
5. An anti-viral composition as recited in claim 3, wherein the
acyclic nucleoside is selected from the group comprising analogs of
acyclovir, analogs of penciclovir, and analogs of famciclovir.
6. An anti-viral composition as recited in claim 5, wherein the
analogs of acyclovir, penciclovir, and famciclovir comprise at
least one of salts, phosphate esters, acyl derivatives, or
metabolites thereof.
7. An anti-viral composition as recited in claim 1, wherein the
nucleoside is selected from the group comprising valcyclovir,
ganciclovir, cidofovir, adefovir, tenofovir, and analogs of the
foregoing.
8. An anti-viral composition as recited in claim 7, wherein the
analogs of valcyclovir, ganciclovir, cidofovir, adefovir, and
tenofovir comprise at least one of salts, phosphate esters, acyl
derivatives, or metabolites thereof.
9. An anti-viral composition as recited in claim 1, further
comprising an organohalide.
10. An anti-viral composition as recited in claim 1, further
comprising 1-docosonal.
11. An anti-viral composition as recited in claim 10, wherein said
at least one benzalkonium chloride compound comprises benzalkonium
chloride having an n-alkyl chain length that is at least one of
C.sub.12, C.sub.14, C.sub.16, or C.sub.18.
12. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises isopropyl alcohol.
13. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises isopropyl alcohol and water.
14. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises isopropyl alcohol and water, the water
being in an amount ranging form about 20% to about 40% by volume of
the carrier.
15. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises an aqueous solution of isopropyl alcohol
at a concentration in a range of about 20% to about 90% of
isopropyl alcohol by volume of the carrier.
16. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises an aqueous solution of isopropyl alcohol
at a concentration in a range of about 30% to about 85% of
isopropyl alcohol by volume of the carrier.
17. An anti-viral composition as recited in claim 1, wherein the
liquid carrier comprises an aqueous solution of isopropyl alcohol
at a concentration in a range of about 40% to about 80% of
isopropyl alcohol by volume of the carrier.
18. An anti-viral composition as recited in claim 1, wherein the
carrier comprises at least one of acetone, acetic acid, or acetic
anhydride, ethanol, methanol, cetyl alcohol, or benzyl alcohol.
19. An anti-viral composition as recited in claim 1, wherein the
treatment composition is substantially free of tissue penetration
inhibiting components.
20. An anti-viral composition as recited in claim 1, wherein the
treatment composition penetrates into disordered tissue such that
the treatment composition is no longer visibly detectable on the
disordered tissue within about two minutes after application of the
treatment composition onto the disordered tissue.
21. An anti-viral composition as recited in claim 1, wherein the
nucleoside has a concentration in a range from about 0.01% to about
50% by weight of the treatment composition.
22. An anti-viral composition as recited in claim 1, wherein the
nucleoside has a concentration in a range from about 0.075% to
about 20% by weight of the treatment composition.
23. An anti-viral composition as recited in claim 1, wherein the
nucleoside has a concentration in a range from about 0.2% to about
15% by weight of the treatment composition.
24. An anti-viral composition as recited in claim 1, wherein the
nucleoside has a concentration in a range from about 0.5% to about
10% by weight of the treatment composition.
25. An anti-viral composition for treating disordered tissue caused
by a virus, comprising: at least one of a nucleoside or
1-docosonal; and a liquid carrier comprising a tissue penetrating
component for penetrating skin in a rapid manner without rapidly
diffusing beyond the skin.
26. A method for treating viral-induced disordered tissue,
comprising: identifying disordered tissue that comprises one or
more lesions caused by a virus; and applying an effective amount of
the treatment composition of claim 25 to a surface of the
disordered tissue and causing and/or allowing the treatment
composition to penetrate into the disordered tissue.
27. A method for treating viral-induced disordered tissue,
comprising: identifying disordered tissue that comprises one or
more lesions caused by a virus; and applying an effective amount of
a treatment composition to a surface of the disordered tissue and
causing and/or allowing the treatment composition to penetrate into
the disordered tissue, the treatment composition comprising a
nucleoside in a liquid carrier comprising a tissue penetrating
agent for penetrating skin in a rapid manner.
28. The method as recited in claim 27, further comprising
delivering the treatment composition to the disordered tissue using
an applicator and by vigorously agitating the disordered tissue
with the applicator.
29. The method as recited in claim 28, wherein said applicator is
frictionally rubbed across the skin surface.
30. The method as recited in claim 28, wherein said applicator is
non-frictional moved so that the skin surface moves substantially
in concert with the applicator.
31. The method as recited in claim 28, wherein said applicator is
pressed against the disordered tissue with sufficient pressure in
order to firmly compress the disordered tissue against underlying
tissue.
32. A method for treating viral-induced disordered tissue,
comprising: identifying disordered tissue that comprises one or
more lesions caused by a virus; and applying an effective amount of
a treatment composition to a surface of the disordered tissue, the
treatment composition comprising at least one of a nucleoside or
1-decosanol in a liquid carrier, the treatment composition being
applied while applying sufficient pressure to the disordered tissue
so as to firmly compress the disordered tissue against bone, tooth,
gum, or other tissue underlying the disordered tissue in order to
assist penetration of the treatment composition into the disordered
tissue.
33. A method as recited in claim 32, wherein the carrier comprises
an aqueous solution of water and at least one organic solvent.
34. A method as recited in claim 32, wherein the carrier comprises
water and isopropyl alcohol.
35. A method as recited in claim 32, wherein the treatment
composition is applied to the disordered tissue using an
applicator.
36. A method as recited in claim 32, wherein the treatment
composition is applied to the disordered tissue using a finger.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of copending U.S.
application Ser. No. 10/816,571, filed Apr. 1, 2004, which is a
continuation-in-part of copending U.S. application Ser. No.
10/200,897, filed Jul. 22, 2002, now U.S. Pat. No. 6,759,434, which
is a continuation-in-part of U.S. application Ser. No. 09/668,953,
filed on Sep. 22, 2000, now U.S. Pat. No. 6,423,750, which is a
continuation-in-part of U.S. application Ser. No. 09/401,076, filed
Sep. 22, 1999, now U.S. Pat. No. 6,211,243. For purposes of
disclosure, the foregoing patents and applications are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. The Field of the Invention
[0003] The present invention relates to the treatment of disordered
tissue with anti-viral compositions. Such treatment compositions
include a tissue-penetrating substance and at least one anti-viral
agent, such as a nucleoside, docosanol, and/or a quaternary amine
compound having at least one carbon-halogen bond.
[0004] 2. The Relevant Technology
[0005] Tissue disorders, particularly those which impact epithelial
tissue caused by all types of Herpes, such as Herpes Simplex types
I and II and Herpes Zoster (shingles), candida albicans, chicken
pox, acne, psoriasis, eczema, seborrhea, dermatitis, and pink eye
are common but often difficult to treat. Such disorders are more
likely to develop in people living with compromised sanitary
conditions, the elderly, and the chronically ill. Others
susceptible to such disorders include workers in health care,
agricultural workers, chemical industry workers, individuals
working with industrial cleaners, and painters, where chronic
exposure to chemicals, pathogens, and unsanitary conditions tend to
weaken and irritate epithelial tissue.
[0006] 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) and growing annually by
500,000 people or more.
[0007] Herpes 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, 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, oral mucosa, conjunctiva it and cornea,
and genitalia, anal mucosa and peri-anal tissue as herpes
genitalis.
[0008] Herpes symptoms include inguinal swelling, pain, fever,
malaise, headaches, muscle aches, and swollen glands. Some
individuals with oral herpes that impacts the trigeminal nerve have
excruciating facial pain, difficulty swallowing, eating and facial
swelling. Individuals with the herpes that impacts the sacral nerve
have pain in the genital area, upper leg pain, swelling, and on
occasion great difficulty walking.
[0009] Herpes simplex virus (HSV) infection is recurring, residing
in the nerve ganglia, then recurring due to some, as yet unknown,
stimulus. Recurrent herpetic infections can be precipitated by
almost anything, including exposure to sunlight, nutritional
deficiencies, stress, menstruation, immunosuppression, certain
foods, drugs, febrile illness, etc.
[0010] Herpes infections pose very serious health threats, often
causing blindness, 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 is responsible for serious psychological and
emotional distress as well as substantial economic loss.
[0011] Various treatments for herpes have been proposed and have
included topical application of such agents as povidone-iodine,
idoxuridine, or trifluorothyidine. Such treatments have met with
varying degrees of success. Most prior treatments have proven
disappointing. Acyclovir and similar analogs, acyclic nucleosides,
are taken orally for systemic treatment of HSV. 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 currently only used to treat
infectious outbreak systemically. Denavir is a topical version of
an acyclovir analog. To date, not a single nucleoside has proven to
be effective in significantly reducing discomfort (e.g., by more
than a trivial amount) caused by disordered tissue when
administered topically. This is likely because nucleosides work by
interfering with virus replication but such replication occurs
subcutaneously, not on the skin surface. Strains resistant to
systemically administered acyclovir and acyclovir analogs have been
reported.
[0012] Individuals with Auto Immune Deficiency Syndrome (AIDS) are
seriously immune-compromised and can suffer especially debilitating
outbreaks of HSV. Additionally, AIDS individuals may carry
acyclovir resistant strains of HSV, which can make acyclovir
ineffective for these individuals. It would therefore be an
improvement in the art to develop a safe and successful medical
treatment to overcome the very serious problems caused by the
herpes virus.
[0013] Biologically active antiviral and microbial 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, including those
that contain acyclovir, are oil-based to ensure that the
composition has sufficient viscosity and/or tackiness to remain on
the surface of the skin. In fact, such compositions are generally
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.
[0014] Many efforts have been undertaken to remedy the inadequate
results of topically administered compositions having antiviral and
antimicrobial qualities. The therapeutic effects of such
compositions depend upon the specific active agent and the method
of application. Many compositions of the prior art contain
ingredients that may provide symptomatic relief of pain and
itching, but are not claimed to be effective against Herpes
infection except the drugs based on acyclovir technology, which are
purported to have some topical efficacy. Additionally, 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.
[0015] Examples of conventional application methods and
compositions are provided in WO 98/42188 and in WO 98/11778 by
Squires, both of which are hereby incorporated by reference. In WO
98/42188 at page 9, lines 12-18 and in WO 98/11778 at page 5, lines
22-30, it is stated that the composition is applied by "spraying,
dabbing, dusting, swabbing, sponging, brushing, pouring,
dispensing, covering or heavily coating." The stated objective of
these techniques for applying the composition is to insure that the
composition remains on the infected area. Like other conventional
treatment compositions, the composition has a viscosity and/or
tackiness which enables it to remain on the surface of the infected
area. A portion of such compositions may eventually penetrate
beyond the surface of the disordered tissue such as the outer
surface of skin or a lip; however, the viscosity of the
composition, combined with the application technique, prevents such
compositions from achieving effective penetration.
[0016] Another example of conventional application methods and
compositions is provided in U.S. Pat. No. 5,753,270 to Beauchamp et
al., which is also incorporated by reference. U.S. Pat. No.
5,732,270 discloses a composition which 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 skin
penetrating solvent, such as a mixture of water and acetone. The
methodology is described in the examples provided at columns 5-7 as
involving the liberal application of the composition to the
afflicted area in a sequence such as 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 after
approximately 1/2 to 1 hour for 2 to 3 hours or until activity is
stopped in healing is evident. The use of a cotton swab is
mentioned at column 6, lines 10-11 for applying the
composition.
[0017] Although it is mentioned in U.S. Pat. No. 5,753,270 at
column 3, lines 44-49 that the formulations may be prepared as a
gel, cream, a lotion, an ointment, or a paste, the preferred
embodiment appears to be a solution having an aqueous solvent
system. It is noted at column 3, lines 6-9 that although use of
water and acetone as a solvent is preferred, such a solvent is not
considered essential to the overall synergistic action of the
formulation. In any event, the formulation appears not to rely on
either its viscosity or tackiness to ensure that the formation is
maintained on the surface of the afflicted area as do most
conventional compositions. Rather the methodology involves the very
frequent reapplication of the formulation to the afflicted area.
Some of the formulation may be absorbed into the skin; however, a
significant portion is likely rapidly evaporated due to the high
content of water and acetone.
[0018] The active agents disclosed in U.S. Pat. No. 5,753,270 that
are discussed above include at least one compound which is an
antiseptic and/or an anesthetic. The primary examples of such
compounds--menthol, eucalyptol, and thymol--are either obtained
from natural sources, such as naturally occurring oils, or are
derived from such oils. Eucalyptol is described as being an
essential oil and a terpene ether. Thymol is derived from thyme oil
or other oils. Menthol is obtained from peppermint oil or other
oils. Other suitable compounds are also recited in the claims as
including eugenol, camphor, hexetidine, or anethol. While the basis
for inclusion of hexetidine in this grouping is not clear, the
other chemicals are also obtained from natural sources or are
derived therefrom. Eugenol is obtained by extraction of clove oil
and then chemical modification. Camphor is a ketone which occurs
naturally in the wood of the camphor tree. Anethol is derived from
anise or fennel oils. While these compounds are useful,
particularly as antifungal agents, it is doubtful that they assist
in penetrating the afflicted tissue and may in fact retard
penetration or enhance the skin's natural resistance to
penetration. The FDA does not consider these compounds as useful in
the treatment of herpes, rather they are used for their softening
effects.
[0019] In conclusion, significant medical research in this field of
endeavor has been focused on developing compositions used for
treating affected tissues and yet compositions which provide rapid
relief to these ailments are still needed. It would therefore be an
improvement in the art to provide compositions, systems and methods
for treating tissue disorders (such as epithelial tissue disorders)
that overcome the problems of the prior art.
[0020] Such compositions, methods and systems of application are
taught and claimed herein.
SUMMARY OF THE INVENTION
[0021] The present invention relates to the treatment of disordered
tissues. An applicator may be used to apply a treatment composition
comprising an anti-infective active agent in a carrier. The method
may include vigorously agitating the disordered tissue treatment
site with the applicator under conditions that enable the
anti-infective active agent to rapidly penetrate the disordered
tissue.
[0022] The present invention relates to the treatment of tissue
disorders such as infections, particularly herpes related cold
sores or other herpes disordered tissue. Throughout this
disclosure, the terms "disordered tissue" or "afflicted tissue" are
understood to represent all tissue which has been affected by
disorders such as all herpes, including, but not restricted to,
cold sores, genital herpes and shingles, and chicken pox, forms of
Zoraster, also disorders such as cow pox-vaccinia virus, smallpox
and anthrax, candida albicans, acne, psoriasis, eczema, seborrhea,
dermatitis, pink eye, and other predominantly viral disorders.
Thus, various viral, microbial and fungal infections are examples
of disordered tissues. Additionally, disordered tissue includes
tissue which has been infected by toxins, such as snake or spider
venom, as results from snake and spider bites, e.g., venom
infections from Brown Recluse spiders and Black Widow spiders.
[0023] It has been found that the therapeutic irritation of
disordered tissue with a preferred treatment composition and the
optional use of an applicator, stimulates rapid immunological
attack and makes the composition and therapeutic irritation
synergistically more effective. After the therapeutic irritation of
the disordered tissue through vigorous rubbing and/or pressure, the
treatment composition penetrates into the disordered tissue to
enable the anti-infective active agent or agents to become
chemically active much more deeply within the disordered tissue as
compared to conventional application techniques.
[0024] In addition to the anti-infective active agent or agents,
the composition also includes a carrier such as an alcohol. Oil and
fatty carrier substances are preferably not added to the
composition to the extent they inhibit penetration of the treatment
composition into the skin. Although various compositions have been
applied to disordered tissue, the inventive methods and systems of
vigorous agitation of the disordered tissue in connection with a
preferred composition has an extraordinary therapeutic effect.
Consequently, the inventive compositions as well as the methods of
application with vigorous agitation of disordered tissue provide
effective methods of treatment.
[0025] The inventive systems utilize an applicator to deliver the
treatment composition and most of the applicators can also be
utilized to vigorously agitation disordered tissue to convey the
inventive composition into the disordered tissue. The applicators
allow the patient or a health professional to vigorously agitate
the disordered tissue without cross-contamination from a dirty
finger or the like. A finger may be used, of course; however, it
lacks the advantages of a sterile applicator, the absorbability of
an applicator tip, and the ability to agitate or massage the skin
surface in the same manner as an applicator tip. The applicator has
the added advantage of directing focused pressure into the
disordered tissue while the active compounds are expressed from the
applicator into the disordered tissue. The combined effect of
vigorous agitation of the disordered tissue and the administration
of the inventive treatment compositions has the remarkable result
of surprising therapeutic effects.
[0026] A preferred composition contains a tissue penetrating
component, such as aqueous isopropyl alcohol, and at least one
anti-viral agent selected from the group comprising nucleosides,
1-docosanol (also called behenyl alcohol, a primary alcohol
comprising a linear alkyl chain having 22 carbon atoms), and
quaternary ammonium organo-halide anti-infective compounds.
Exemplary nucleosides include acyclic nucleosides, including but
not limited to, acyclovir, valcyclovir, penciclovir, famciclovir,
ganciclovir, cidofovir, adefovir, and tenofovir, and derivatives,
analogs, or metabolites thereof, or a mixture thereof. An exemplary
quaternary ammonium organo-halide is benzalkonium chloride.
[0027] It is therefore an object of the present invention to
provide a method for treating disordered tissues, such as
disordered portions of skin and mucous membranes. It is an object
of one embodiment of the present invention to provide a system for
the treatment of epithelial tissue disorders that includes a
preferred biologically anti-infective active composition and an
applicator in connection with delivering the treatment composition
and also preferably vigorously agitating the disordered tissue
site.
[0028] 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
[0029] 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:
[0030] FIG. 1 is a vertical cross-section of the epidermis and the
papillae of the dermis;
[0031] FIG. 2A is an exploded perspective view of a preferred
applicator that contains the treatment composition;
[0032] FIG. 2B is a perspective view of the preferred applicator
depicted in FIG. 2A as it appears assembled prior to use;
[0033] FIG. 2C is a perspective view of the preferred applicator
depicted in FIG. 2B after the glass reservoir is crushed and the
treatment composition is allowed to permeate the agitation pad;
[0034] FIG. 2D is a perspective view of an individual applying the
treatment composition according to the present invention;
[0035] FIG. 2E is a detail taken along the section line 5-5 that
depicts a close-up view of the inventive method;
[0036] FIG. 2F shows a sheet of material before it is folded or
collapsed to form an application pad;
[0037] FIG. 3 is an elevational cross section view of an applicator
that has a finger loop for vigorous topical irritation of the
treatment site;
[0038] FIG. 4 is an elevational side view of an alternative
applicator used in the present invention;
[0039] FIG. 5 is an elevational side view of an alternative
applicator that is fixed to a digit for vigorous topical irritation
of the treatment site;
[0040] FIG. 6 is a cross-sectional plan view of an alternative
applicator that is placed over a digit and that is contained in a
pre-wetted state before use;
[0041] FIG. 7 is a perspective view with a partial break-away view
of an alternative applicator that is used to apply the treatment
composition to large surface areas of the body;
[0042] FIG. 8 is a perspective view of the alternative applicator
in FIG. 7 being used to apply the treatment composition to sores
from shingles on the chest area;
[0043] FIG. 9 is a perspective view of a towelette being used to
apply the treatment composition to a cold sore;
[0044] FIG. 10 is a perspective view of a towelette being used to
apply the treatment composition to a sore on male genitalia;
and
[0045] FIG. 11 is a perspective view of a towelette being used to
apply the treatment composition to sores from shingles on the chest
area.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0046] The present invention relates to the treatment of disordered
tissue with compositions that are at least one of antiviral,
antimicrobial, antifungal, and antivenomous. The compositions
include an active agent that exhibits antiviral, antimicrobial,
antifungal, and/or antivenomous properties. As described more fully
below, the active agent can be a nucleoside, docosanol, or a
quaternary organo-halide compound. The anti-viral agent is
preferably dispersed in a liquid carrier which allows the topical
composition to be applied to and rapidly absorbed into the
disordered tissue. The efficacy of the compositions in penetrating
the disordered tissue and initiating the restoration of the
disordered tissue is enhanced by vigorously irritating the
disordered tissue site. The disordered tissue is preferably
vigorously agitated with an applicator. This is remarkably
efficacious in causing the compositions to penetrate into
disordered tissue and/or to stimulate the immune responses. Whether
the anti-infective compositions are rubbed onto the disordered
tissue or delivered with vigorous agitation of the disordered
tissue, the results are surprisingly advantageous in the treatment
of epithelial tissue disorders.
[0047] Hereinbelow is a discussion of what is meant by vigorous
irritation of disordered tissue, followed by a detailed description
of the treatment composition. The description of the treatment
composition is followed by a detailed description of several
embodiments of applicators. FIGS. 2A-2F depict a preferred
applicator. Other embodiments of applicators are shown in FIGS.
3-8. FIGS. 9-11 depict towelettes being used. FIG. 1 depicts a
cross-sectional view of skin.
[0048] The phrase "vigorous agitation" means that the skin is
irritated (e.g., by vigorous rubbing) in a manner that allows the
inventive compositions to penetrate below the surface of the skin,
preferably to a nerve ending in the case where the pathogenic agent
and/or toxin is located in the nerve region (e.g., HSV). As
described in more detail hereinbelow, such vigorous agitation is
achieved through either applying an appropriate amount of pressure
for an adequate period of time and/or appropriate rubbing for an
adequate period of time. Vigorous agitation is preferably a
combination of both adequate pressure and rubbing. The term
"rubbing" includes moving the tissue back and forth without
necessarily brushing the applicator across the skin.
[0049] A suggested theory for the effectiveness which results from
vigorously agitating the disordered tissue is set forth below.
However, it should be understood that the objective in vigorously
agitating the disordered tissue includes altering the tissue to
better enable the treatment composition to physically move through
the layers of the disordered tissue by moving the cells and fluids
in the disordered tissue. Also, another objective of vigorous
agitation is to stimulate the immune responses.
[0050] Vigorous agitation achieved through applying appropriate
pressure may be understood to be an amount of pressure such that,
where tissue overlies bone, the tissue is depressed to be firmly
against the bone. Similarly, if the disordered portion of the
tissue is adjacent to teeth or gums such as the skin around the
mouth, then the disordered tissue is sufficiently compressed due to
the pressure that the pressure is felt on the opposing surfaces
within the mouth. Additionally, if disordered tissue located around
a patient's lip is also opposite the patient's gums then pressure
applied to the disordered tissue would also be felt at the portion
of the patient's gums opposite the disordered tissue through the
lip or cheek.
[0051] Vigorous agitation achieved through rubbing involves
repeated movement of the applicator (e.g., in either a frictional
or non-frictional manner relative to the disordered tissue). For
example, the applicator may be moved in a steady back and forth
motion on the disordered tissue or rotated as the treatment
composition is applied or after delivery of the composition. As
described in greater detail in reference to the applicator, the
applicator may be configured to provide a relatively uniform
abrasive action in the case of frictional movement. In the case of
non-frictional movement (i.e., where the underlying tissue is moved
back and forth in concert with the applicator but the applicator
does not brush or scrape across the skin surface), the applicator
need not apply abrasive action, although sufficient friction may be
advantageous to ensure the skin moves in concert with the movement
of the applicator. The oscillation rate of the back and forth
motion depends on several factors such as the amount of pressure
being simultaneously applied and the condition of the disordered
tissue. So in some instances the oscillation rate may be only 1
stroke every few seconds while in other circumstances the
oscillation rate may range from about 1 strokes per second to about
10 strokes per second. More typically, however, the oscillation
rate is in a range from about 2 strokes per second to about 6
strokes per second and is most typically in a range from about 3
strokes per second to about 4 strokes per second. Note that the
portion of the applicator used to agitate the disordered tissue
preferably has a size in a range from about 50% to about 200% the
size of the disordered tissue treatment site. For example, it has
been found that a contact surface that is about 8 mm in diameter is
useful for agitating most cold sore treatment sites.
[0052] The length of time that vigorous agitation of this type may
be sustained upon a disordered tissue treatment site may vary
according to the individual, the size of the applicator surface in
relation to the size of the disordered tissue to be agitated, the
amount of pressure applied as defined above and the oscillation
rate of the rubbing. As the length of time increases in which the
applicator delivery surface is maintained in contact with the
disordered tissue, the required pressure decreases for achieving
the desired penetration of the treatment composition into the
disordered tissue. Typically, the vigorous agitation is maintained
for at least 1 second and is more typically maintained for a few
seconds. However, the period of time may range from about 3 seconds
to about 1 minute depending on the condition of the disordered
tissue, the amount of pressure being applied and/or the movement of
the applicator. Vigorous agitation is most typically maintained for
a period of time in a range from about 5 seconds to about 15
seconds.
[0053] The intensity of the vigorous agitation is adjusted
depending on the thickness of the skin. For example, the tissue on
a lip that must be penetrated is much thinner than that of the skin
on the arms, legs, and chest. The thickness is even greater for the
skin on the palms of hands and feet and is still greater for other
body parts such as backs. So it may be necessary to vigorously
agitate the disordered tissue with greater intensity when treating
sores on a patient's chest or back caused by shingles than the
vigorous agitation required to treat a cold sore on one's lip.
[0054] It is counterintuitive to vigorously agitate disordered
tissue such as a cold sore as the disordered tissue already hurts
so one inherently desires to avoid even contacting such sensitive
disordered tissue. However, patients are likely to be more tolerant
of any pain which may result from vigorous agitation when bolstered
by knowledge that vigorous agitation significantly enhances the
ability of the treatment compositions disclosed herein to
effectively penetrate and cure disordered tissue.
[0055] Vigorous agitation need not necessarily be painful, although
vigorous agitation may also be understood to mean that discomfort
is felt by the patient beyond nominal dabbing of the disordered
tissue as with other treatments that call for gentle application to
the disordered tissue. Before a cold sore has erupted, and is in
the prodromal stage or vesicular stage such that at most there is
merely a vistule, it may not be painful to vigorously agitate the
disordered tissue. However, when vigorously agitating disordered
tissue which is in an erupted stage, the agitation may be
sufficient to cause sharp pain and bleeding.
[0056] Obviously, however, disordered tissue such as cold sores
cannot always be agitated to the same extent. As indicated above,
when a cold sore is in the prodormal stage it can be vigorously
agitated without significant sensitivity. However, when the cold
sore has become an open sore less pressure may be utilized so as to
minimize the potential for causing pain. Also, if the cold sore has
coalesced then it is best not to vigorously agitate the treatment
site as such action is likely to disturb the coalesced tissue,
scab, etc. Also, when treating sensitive areas such as inside the
mouth, mucous coated tissues, the eyes, genitalia, etc., the
treatment composition should be applied without vigorous
agitation.
[0057] As indicated above, the vigorous agitation can also be
defined by contrasting it with nominal dabbing of the disordered
tissue which involves the mere application of a treatment
composition. The same is likewise true for other application
techniques such as swabbing, sponging, and brushing merely to
ensure that a treatment composition is applied or delivered.
Dabbing and other application techniques do not involve pressing
hard enough such that the disordered tissue is compressed against a
bone, tooth, gum or other underlying tissue such that pressure is
felt as a surface in the mouth opposite the disordered tissue is
pressed against the underlying tissue.
[0058] Despite a patient's desire to enable disordered tissue to
return to normal, some patients are also likely to adjust the
amount of pressure applied or the rate of rubbing in order to
minimize pain. However, as indicated above, it is not necessary for
a patient to feel pain in order for the treatment composition to be
delivered with vigorous agitation. The objective is to move the
tissue somehow either through compressing the tissue through the
application of an appropriate amount of pressure as discussed above
for an adequate period of time, preferably while moving the
underlying tissue with a back and forth motion, and/or by rubbing
the applicator across the tissue in manner such that tissue is
agitated for an adequate period of time for the treatment
composition to penetrate such that it does not remain on the
surface.
[0059] The treatment composition is preferably absorbed into the
disordered tissue to such an extent that within several minutes
after application the composition can no longer be seen. This is
absorption or penetration rate is achieved either with or without
vigorous agitation. More preferably, the composition is not visibly
detectable within 2 minutes after being applied and is most
preferably not visibly detectable within 1 minute after being
applied. Note that the content of the composition has different
formulations; however, in the preferred embodiment there is no
significant residue remaining after the composition has been
applied and absorbed that is visibly detectable.
[0060] As indicated above, the treatment composition preferably
penetrates through the skin to a nerve ending or causes a
penetration sensation at the nerve ending. The pathway for this
penetration is discussed in greater detail below with reference to
FIG. 1. After the composition is delivered with simultaneous
agitation, the penetration or the penetration sensation preferably
occurs within about one minute. The penetration or penetration
sensation to a nerve ending is more preferably achieved in about 30
seconds, and most preferably in less than about 10 seconds. In more
serious cases when the disordered tissue represents an extensive
problem and/or involves a life threatening pathogen (e.g., smallpox
or anthrax), several treatments may be used instead of a single,
primary treatment. Note that when several treatments are used
instead of a single, primary treatment, it is preferable to use a
clean and sterile applicator for each repeated treatment.
[0061] 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 the treatment
composition being delivered to the stratum corneum 28 in order to
allow treatment composition 22 to penetrate therethrough. The
treatment composition is shown being delivered from an impregnated
agitation pad 12 accompanied by vigorously rubbing.
[0062] The arrows illustrate directions of agitation movement by
way of non-limiting example. Note, however, that FIG. 1 does not
depict the application of pressure as the objective in FIG. 1 is to
show the particular layers involved in their natural positions and
once pressure is applied the layers are moved from their natural
positions. Although the inventor does not wish to be bound to a
single theory, it is postulated that treatment composition 22 may
move through the stratum corneum 28 without significant rupture
thereof due to the vigorous agitation by impregnated agitation pad
12. Treatment composition 22 can penetrate to the nervous papilla
of the corium 36 by the combination of vigorous agitation and the
penetrating nature of the carrier. Preferably, vigorous agitation
and the combination of the penetrating quality of the carrier are
sufficient conditions to cause the anti-infective active agent to
penetrate the disordered tissue to a nerve ending such as the
nervous papilla of the corium 36.
[0063] Note that the application of pressure further increases the
ability of the treatment composition to penetrate as the pressure
may flatten or compress the layers and may assist in forcing the
treatment composition downward. In any event, under the inventive
conditions, penetration to the nerve ending is rapidly
accomplished, preferably in several seconds.
[0064] 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. Vigorous agitation may
assist in displacing 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 then the
treatment composition is available as a bath that continues to
provide protection as it slowly diffuses. On this basis, it is
preferred to deliver a large quantity of the treatment composition
on 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 amounts of volume, such as
about 0.2 ml, work for a single cold sore especially if the
applicator does not retain a significant portion of the volume
however the volume is preferably greater. In order for all of the
volume to be delivered, half of the total volume in the applicator
may be delivered and then the remainder may be delivered. Delivery
of such large volumes is discussed below in reference to the
applicators used to deliver the treatment composition.
[0065] For lesions that cover substantially larger portions of a
person's body (e.g., smallpox, anthrax, chicken pox, shingles,
etc.), it will be desirable to apply whatever quantity of the
treatment composition as may be necessary to cover and penetrate
the disordered tissue being treated.
[0066] The treatment compositions include at least a biologically
active agent and a carrier. The biologically active agent is
selected so as to be effective in treating tissue disorders caused
by pathogens (e.g., viruses, fungi or bacteria) or toxins (e.g.,
snake or spider venom), and the 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
carriers are described thereafter. Other optional components are
also described.
[0067] According to one embodiment, the biologically active agents
or anti-infective agents included in the anti-infective treatment
compositions include 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". 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.
[0068] The generic chemical structure of benzalkonium chloride is
shown below: ##STR1## wherein R=C.sub.8H.sub.17 to
C.sub.18H.sub.37. 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.
[0069] Benzalkonium chloride according to the present invention
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.10 (CAS Reg. No.
68424-85-1). Examples of such products include, but are not limited
to, 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 and they are used in other embodiments of the same. These
ranges include about 1%-99% C.sub.12, about 1%-99% C.sub.14, and
about 1%-99% C.sub.16. Each manufacturer publishes methods to
analyze the supplied 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.
[0070] 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 destroy or eliminate toxins caused by
pathogens such as viruses, bacteria or fungi. Rapidly eliminating
toxins and their sources results in prompt pain relief. Moreover,
clinical evidence strongly suggests that benzalkonium chloride and
aqueous isopropyl alcohol provide a synergistic effect (i.e., the
level of the anti-viral activity of the mixture is significantly
greater than the sum of the individual effects of benzalkonium
chloride and aqueous isopropyl alcohol).
[0071] While the active agents broadly include organohalides, most
suitable organohalides are organochlorides. Benzalkonium bromide
and benzalkonium iodide are examples of suitable organohalides in
the context of this invention which are not organochlorides.
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 which is not an
organochloride is cetyl trimethylammonium bromide.
[0072] 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 should not be used in
a manner which would enable it to be ingested in a toxic quantity.
Similarly, the concentration of benzalkonium chloride must not be
excessively high.
[0073] Additional examples of other organochlorides which may be
suitable, more particularly quaternary ammonium chlorides having an
alkyl with 6-18 carbons, include: alkylbenzyldimethylammonium
chloride, alkyldimethyl/ethylbenzyl-ammonium chloride,
n-alkyldimethylbenzylammonium chloride,
diisobutylphenoxy-ethoxyethyldimethylbenzylammonium chloride,
n-(C.sub.12C.sub.14C.sub.16) alkyl dimethylbenzyl-ammonium
chloride, didecyldimethylammonium chloride, dioctyldimethylammonium
chloride, dialkyldimethylammonium chloride,
dialkylmethylbenzylammonium chloride, octyldecyldimethylammonium
chloride, lauryldimethylbenzylammonium chloride,
o-benzyl-p-chlorophenol, dideryldimethylammonium chloride,
dioctyldimethyl-ammonium chloride, alkyl (C.sub.14C.sub.12C.sub.16)
dimethylbenzylammonium chloride. In addition to these
organochlorides, 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
antiviral, antibacterial or antifungal agents, such as the
antifungal agents disclosed by Chodosh in U.S. Pat. No. 5,661,170
and U.S. Pat. No. 5,827,870, which are hereby incorporated by
reference. Additional examples of effective organochloride that are
comprised in additional embodiments of the present invention
include dual quaternary ammonium compounds. These embodiments
comprise at least two quaternary ammonium compounds.
[0074] It is also possible that a chemical such as acyclovir may be
effective as an anti-infective agent when delivered with the
carriers as disclosed herein combined with vigorous agitation. So
in contrast to the conventional understanding that acyclovir is
marginally effective when topically applied, it may be useful as an
anti-infective agent when used as taught herein. Note, however,
that acyclovir is not an organohalide and so may not be as easily
absorbed into the skin or penetrate as readily. However, to the
extent that acyclovir or related substances and analogs such as
denavir, or any other suitable nucleoside, can be delivered in the
inventive compositions or in accordance with inventive
methodologies and systems, it is also within the scope of the
present invention.
[0075] One of such embodiments comprises a mixture of n-alkyl
dimethyl benzyl ammonium chloride and n-dialkyl methyl benzyl
ammonium chloride. One example of such embodiments is distributed
by Stepan as BTC.RTM. 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).
[0076] Another of such embodiments comprises a mixture of n-alkyl
dimethyl benzyl ammonium chloride (I) and n-alkyl dimethyl
ethylbenzyl ammonium chloride (II). One example of such embodiments
is distributed by Stepan as BTC 2125.RTM. M 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).
[0077] Embodiments of the present invention are effective for
treating disorders of human tissue that are caused by germs such as
lipid coated viruses and skin pathogens. Reference to the U.S.
Pharmacopoeia (USP) is made herein to describe constituents of
embodiments of the present invention. Persons skilled in the art
will recognize that other grades of constituents are possible,
provided that they are validated against the USP quality standards
where such validation is to be performed for their use in the
treatment of human beings.
[0078] A preferred method of preparation involves taking 70%
isopropyl rubbing alcohol USP (70% isopropanol, v/v, specific
gravity 0.877 at 20.degree. C., see 24 USP, p. 927) and then
admixing the benzalkonium chloride, NF. Isopropyl alcohol USP (IPA)
is available from any number of US sources including, but not
limited to, 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.
[0079] As an example, the preparation of what is herein termed 70%
IPA is described below. This concentration is given by volume, and
it is understood to be interpreted as follows. About 70 ml of
isopropyl alcohol USP, specific gravity 0.785, are mixed with about
30 ml of purified water USP, resulting in about 84.95 g, or 96.86
ml, of a product that has a specific gravity in the range from
about 0.872 to about 0.883 at 20.degree. C., with a target specific
gravity of about 0.877 at 20.degree. C. The corresponding
concentration range by volume is from about 68% to about 72%, with
a target of 70% by volume in accordance with the requirements at 24
USP, p. 927.
[0080] Testing the ratio in the admixture is done preferably
according to the methods found at 24 USP p. 927. Those of ordinary
skill in the art will recognize that other tests are possible, such
as gas-liquid chromatography, provided proper validation is
performed when the intended use is as a drug for human beings where
such validation is required.
[0081] The preparation of a benzalkonium chloride solution with a
concentration of about 0.13% is preferably made by adding to
isopropyl alcohol that is about 70% by volume an amount of
benzalkonium chloride according to this product's activity, so that
a solution of about 0.13% by weight of benzalkonium chloride is
obtained. As indicated above, benzalkonium chloride is available
from several primary manufacturers, such as Stepan Company, Mason
Chemical Company, Lonza, and Huntington Labs., or from several
distributors and suppliers, such as Aldrich Chemical, Van Waters
& Rogers, and Fisher Scientific. The bulk ingredients are
typically sold as about 50% active or 80% active.
[0082] 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.
[0083] The amount of benzalkonium chloride by weight to be
dissolved in 70% v/v isopropyl alcohol is calculated by multiplying
the weight of 70% v/v isopropyl alcohol that is used by the weight
concentration of benzalkonium chloride referred to one (this is,
for example, 0.0013 in the case of a 0.13% by weight benzalkonium
chloride solution), and further multiplied by the benzalkonium
chloride activity referred to one (this is, for example, 0.5 for a
benzalkonium chloride activity of 50%). By way, of example, the
amount of benzalkonium chloride (activity of 50%) by weight that
must be added to 84.95 g of isopropyl alcohol (70% v/v in water) to
yield a solution that contains 0.13% by weight benzalkonium
chloride is calculated by multiplying together 84.95 g and 0.0013
and dividing the result by 0.5, which yields 0.22087 g benzalkonium
chloride (50% activity) (i.e., 84.95 g.times.0.0013/0.5=0.22087 g).
The constituents are mixed well until the mixture is uniform.
[0084] A plurality of qualitative and quantitative analytic methods
is known for the analysis of the resulting benzalkonium chloride
solution. Reference to 24 USP, pp. 2419-20 is usually made in the
context of drugs for human beings. Those of ordinary skill in the
art will recognize that other methods are possible, such as those
indicated by the manufacturers referred to above, nuclear magnetic
resonance (NMR), and high performance liquid chromatography
(HPLC).
[0085] 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 volume of the treatment
composition, more preferably in a range from about 0.05% to about
0.3% by volume of the treatment composition, and even more
preferably in a range from about 0.1% to about 0.2% by volume of
the treatment composition. To avoid toxicity, the concentration is
less than 0.26% and is more preferably about 0.13% by volume of the
treatment composition. Depending on the particular organohalide or
quaternary ammonium chloride that is used as the active agent, the
concentration may vary. For example, the concentration may range
from about 0.001% to about 2% by volume of the treatment
composition.
[0086] For the specialized treatment of the eyes, an eyewash
composition having the active agent is made into a composition with
an active agent concentration in the volume range from about 0.001%
to about 0.05%. Preferably, the active agent concentration for an
eyewash composition is in-the range from about 0.005% to about
0.03%. Higher concentrations may be administered by a medical
professional. The specialized treatment of the eyes may also
require several treatments instead of a single, primary treatment.
Where eye drops are used, according to the inventive method, the
composition is deposited onto the eye and the patient closes the
eye after the eye has been contacted with the composition, and the
patient may opt to rub the eyeball through the eyelid to assist in
the delivery of the treatment composition and the penetration into
the eye tissue. If the disordered tissue is in a corner of the eye,
it may even be vigorously agitated. A subsequent treatment and a
series of subsequent treatments may also be carried out on the
eyes.
[0087] As discussed above, while nucleosides are generally only
effective when taken internally, while generally ineffective when
applied topically, it is within the scope of the invention to
administer a nucleoside in a carrier comprising a tissue
penetrating component, preferably with vigorous agitation. A
nucleoside resembles one of the nucleotides (e.g., adenosine,
guanosine, cytidine and thymidine) and is incorporated into the
viral DNA instead of the correct nucleotide. This results in a
virus having faulty DNA which impairs, disrupts or limits the
ability of the virus to reproduce.
[0088] In one embodiment, the nucleoside is an acyclic nucleoside
or analog thereof. Acyclic nucleosides have been widely studied for
their anti-viral properties. Acyclic nucleoside analogs include,
but are not limited to, acyclovir, valcyclovir (sold under the
trademark Valtrex.RTM.), penciclovir (sold under the trademark
Denavir.RTM.), famciclovir (sold under the trademark Famvir.RTM.,
erroneously spelled "femiver" in parent U.S. application Ser. No.
09/401,076, filed Sep. 22, 1999, now U.S. Pat. No. 6,211,243),
ganciclovir (sold under the trademark Cytovene.RTM.), cidofovir
(sold under the trademark Vistide.RTM.); adefovir (sold under the
trademark Hepsera.RTM.), and tenofovir (sold under the trademark
Viread.RTM.). While only some of these nucleosides will be
discussed in detail, it will be appreciated that these, as well as
other nucleosides listed below, can be effective in a topical
composition.
[0089] In one embodiment, the composition includes acyclovir,
either alone or in combination with any other anti-pathogenic agent
disclosed herein. The chemical formulation of acyclovir is
9-(2-hydroxyethoxymethyl)guanine, which has the structure:
##STR2##
[0090] Acyclovir phosphate derivatives can also be used as active
agents. Acyclovir phosphate derivatives can include:
[0091] acyclovir monophosphate (ACV-MP);
[0092] acyclovir diphosphate (ACV-DP);
[0093] acyclovir monophosphate glycerol (ACV-MP-G);
[0094] acyclovir diphosphate glycerol (ACV-DP-G);
[0095] acyclovir monophosphate morpholidate
(ACV-MP-morpholine);
[0096] acyclovir monophosphate isopropylidene glycerol
(ACV-MP-isoP-G); and
[0097] acyclovir diphosphate isopropylidene glycerol
(ACV-DP-isoP-G).
[0098] Methods for making the above acyclovir phosphate derivatives
are taught in U.S. Pat. No. 5,580,571, herein incorporated by
reference. These phosphate esters of acyclovir can be used to
successfully treat strains of DNA or RNA virus that are resistant
to acyclovir.
[0099] Other acyclovir derivatives can be formed from purinyl and
pyrimidinyl tetrahydrofurans to enhance anti-viral activity. These
derivatives can include: [0100]
[3R-(3.alpha.,4.beta.,5.alpha.)]-2-Amino-1,9-dihydro-9-tetrahydro-4-hydro-
xy-5-(hydroxymethyl)-3-furanyl]-6H-purin-6-one; [0101]
[2R-[2.alpha.(S*),3.alpha.,4.beta.]]-Tetrahydro-.beta.,3,4-trihydroxy-2-f-
uranethanol; [0102]
[2S-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-3,4-dihydroxy-2-furancarboxal-
dehyde; [0103]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-3,4-dihydroxy-2-furanmethanol-
; [0104]
[4aR-(4a.alpha.,7.alpha.,7a.alpha.)]-Tetrahydro-2,2-dimethyl-4H-
-furo[3,2-d]-1,3-dioxin-7-ol; [0105]
[4aR-(4a.alpha.,7.alpha.,7a.alpha.)]-Tetrahydro-2,2-dimethyl-4H--
furo [3,2-d]-1,3-dioxin-7-ol, acetate ester; [0106]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-3,4-dihydroxy-2-furanmethanol-
, 4-acetate ester; [0107]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-2-[[(4-methoxyphenyl)diphenyl-
methoxy]methyl]-3,4-furandiol, 4-acetate ester; [0108]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-2-[[(4-methoxyphenyl)diphenyl-
methoxy]methyl]-3,4-furandiol, 4-acetate, 3-methanesulfonate ester;
[0109]
[2R-(2.alpha.,3.beta.,4.beta.)]-3,4-Epoxytetrahydro-2-[[(4-methox-
yphenyl)diphenylmethoxy]methyl]furan; [0110]
3R-(3.alpha.,4.beta.,5.beta.]-6-(phenylmethoxy)-9-tetrahydro-4-hydroxy-5--
[[(4-methoxyphenyl)diphenylmethoxy]methyl]-3-furanyl]-9H-purin-2-amine;
[0111]
[3R-(3.alpha.,4.beta.,5.alpha.)]-2-Amino-1,9-dihydro-9-tetrahydro-
-4-hydroxy-5-(hydroxymethyl)-3-furanyl]-6H-purin-6-one; [0112]
[3R-(3.alpha.,4.beta.,5.alpha.)]-5-Methyl-1-[tetrahydro-4-hydroxy-5-(hydr-
oxymethyl)-3-furanyl]2,4(1H,3H)pyrididinedione; [0113]
[2R-[2.alpha.(S*),3.alpha.,4.beta.]]-Tetrahydro-.beta.,3,4-trihydroxy-2-f-
uranethanol; [0114]
[4aR(4a.alpha.,7.alpha.,7a.alpha.)]-Tetrahydro-2,2-dimethyl-4H-furo[3,2-d-
]-1,3-dioxin-7-ol; [0115]
[4aR-(4a.alpha.,7.alpha.,7a.alpha.)]-Tetrahydro-2,2-dimethyl-4H-furo[3,2--
d]-1,3-dioxin-7-ol, acetate ester; [0116]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-3,4-dihydroxy-2-ftiranmethano-
l, 4-acetate ester; [0117]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-2-[(4-methoxyphenyl)diphenylm-
ethoxy]methyl]-3,4-furandiol, 4-acetate ester; [0118]
[2R-(2.alpha.,3.alpha.,4.beta.)]-Tetrahydro-2-[[(4-methoxyphenyl)diphenyl-
methoxy]methyl]-3,4-furandiol, 4-acetate, 3-methanesulfonate ester;
[0119]
[2R-(2.alpha.,3.beta.,4.beta.)]-3,4-Epoxytetrahydro-2-[[(4-methox-
yphenyl)diphenylmethoxy]-methyl]furan; [0120]
[3R-(3.alpha.,4.beta.,5.alpha.)]-5-Methyl-1-[tetrahydro-4-hydroxy-5-[[(4--
methoxyphenyl)diphenylmethoxy]methyl]-3-furanyl]-2,4(1H,3H)pyrimidinedione-
; [0121]
[3R-(3.alpha.,4.beta.,5.alpha.)]-5-Methyl-1[tetrahydro-4-hydrox-
y-5-(hydroxymethyl)-3-furanyl]-2,4-(1H,3H)pyrimidinedione; [0122]
[3R-(3.alpha.,4.beta.,5.alpha.)]-4-Amino-1-[tetrahydro-4-hydroxy-5-(hydro-
xymethyl)-3-furanyl]-2(1H)-pyrimidinone; [0123]
[3R-(3.alpha.,4.beta.,5.alpha.)]-4-Amino-1-[tetrahydro-4-hydroxy-5-[[(4-m-
ethoxyphenyl)diphenylmethoxy]methyl]-3-furanyl]-2(1H)-pyrimidinone;
[0124]
3R-(3.alpha.,4.beta.,5.alpha.)]-4-Amino-1-[tetrahydro-4-hydroxy-5-
-(hydroxymethyl)-3-furanyl]-2(1H)-pyrimidinone; [0125]
[3R-(3.alpha.,4.beta.,5.alpha.)]-1-[Tetrahydro-4-hydroxy-5-(hydroxymethyl-
)-3-furanyl]-2,4(1H,3H)pyrimidinedione; [0126]
[2R-(2.alpha.,3.beta.,4.beta.)]Tetrahydro-2-[(triphenylmethoxy)methyl]-3,-
4-furandiol; [0127]
[3aR-(3a.alpha.,4.alpha.,6a.alpha.)]-Tetrahydro-4-[(triphenylmethoxy)meth-
yl]furo[3,4-d]-1,3,2-dioxathiole, 2,2-dioxide; [0128]
[3R-(3.alpha.,4.beta.,5.alpha.)]-1-[Tetrahydro-4-hydroxy-5-[(triphenylmet-
hoxy)methyl]-3-furanyl]-2,4(1H,3H)-pyrimidinedione; and [0129]
[3R-(3.alpha.,4.beta.,5.alpha.)]-1-Tetrahydro-4-hydroxy-5-(hydroxymethyl)-
-3-furanyl]2,4(1H,3H)pyrimidinedione. Methods for producing
pharmaceutically acceptable formulations of the above acyclovir
derivatives are taught in U.S. Pat. No. 5,272,152, herein
incorporated by reference.
[0130] In one embodiment, the active agent is an amino acid ester
of acyclovir. Amino acid esters of acyclovir include glycine,
alanine, valine esters. For example, the valine ester of acyclovir,
also referred to as valcyclovir (also called valacyclovir), has
been shown in U.S. Pat. No. 4,957,924, herein incorporated by
reference, to have improved bioavailability in oral administration.
Valcyclovir can be converted to acyclovir and are thus analogs of
each other. Further, acyclovir is a metabolite of valcyclovir. The
chemical formula of valcyclovir is
2-(2-amino-1,6-dihydro-6-oxo-(H(purin-9-yl)methyxy)ethyl
L-valinate, which has the structure: ##STR3## where R.sub.1
represents a group of formula --CH[CH.sub.3].sub.2 and
pharmaceutically acceptable salts thereof. Suitable valcyclovir
derivatives include: [0131]
2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
N-[(benzyloxy) carbonyl] L-valinate; [0132]
2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl
L-valinate; [0133]
2-(2-Amino-1,6-dihydro-6-oxo-9H(purin-9-yl)methoxy)ethyl L-valinate
hydrochloride monohydrate; [0134]
2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
N-[(benzyloxy)carbonyl] L-valinate; and [0135]
2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl
L-valinate hydrochloride monohydrate. Methods for producing
pharmaceutically acceptable formulations of valcyclovir or a
suitable salt thereof is described in further detail in U.S. Pat.
No. 4,957,924, herein incorporated by reference.
[0136] In another embodiment, the active agent is penciclovir,
which is another derivative of acyclovir which can be useful for
its anti-viral properties. The chemical formula of penciclovir is
9-[4-Hydroxy-3-(hydroxymethyl)butyl]guanine, which has the chemical
structure: ##STR4## or a salt, phosphate ester or acyl derivative
thereof, where X represents chlorine, straight or branched chain
C.sub.1-6 alkoxy, preferably methoxy, phenoxy, phenyl C.sub.1-6
alkoxy, --NH.sub.2, --OH or --SH with the proviso that when X is
--OH, the compound of penciclovir is in a purity state of greater
than 50% by weight of pure compound. Suitable derivatives of
penciclovir include: [0137]
2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]-6H-pu-
rine; [0138] 5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxan; [0139]
5-(2-Bromoethyl)-2,2-dimethyl-1,3-dioxan; [0140]
2-Amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-purine;
[0141] 9-(4-Hydroxy-3-hydroxymethylbut-1-yl)guanine; [0142] Ethyl
4-benzyloxy-2-ethoxycarbonylbutanoate; [0143]
4-Benzyloxy-2-hydroxymethylbutan-1-ol; [0144]
2-Acetoxymethyl-4-benzyloxybut-1-yl acetate; [0145]
2-Acetoxymethyl-4-hydroxybut-1-yl acetate; [0146]
2-Acetoxymethyl-4-bromobut-1-yl acetate; [0147]
9-(4-Acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine;
[0148]
7-(4-Acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine;
[0149] 9-(4-Hydroxy-3-hydroxymethylbut-1-yl)guanine, sodium salt;
[0150] 9-(4-Hydroxy-3-hydroxymethylbut-1-yl)guanine, potassium
salt; [0151]
2-Amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine
hydrochloride; [0152]
2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-methoxypurine;
[0153]
2-Amino-6-ethoxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine;
[0154] 2-Amino-6-benzyloxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)
purine; [0155]
2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-thiopurine; [0156]
2-Amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-purine;
[0157] 2,6-Diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine;
[0158] 2,6-Diamino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine;
[0159] 9-(4-Acetoxy-3-acetoxymethylbut-1-yl)guanine; [0160]
9-(4-Propionyloxy-3-propionyloxymethylbut-1-yl)guanine; [0161]
N2-Propionyl-9-(4-propionyloxy-3-propionyloxymethyl-but-1-yl)guanine;
[0162] 9-(4-Hexanoyloxy-3-hexanoyloxymethylbut-1-yl)guanine; [0163]
9-(4-Formyloxy-3-formyloxymethylbut-1-yl)guanine; [0164]
9-[4-(N-Imidazolylcarbonyloxy)-3-(N-imidazolylcarbonyloxymethyl)-but-1-yl-
]guanine; [0165]
N2-Monomethoxytrityl-9-(4-monomethoxytrityloxy-3-hydroxymethylbut-1-yl)gu-
anine; [0166]
N2-Monomethoxytrityl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-guanine;
[0167] 9-(4-Pivalyloxy-3-pivalyloxymethylbut-1-yl)guanine; [0168]
9-(4-Acetoxy-3-hydroxymethylbut-1-yl)guanine; [0169]
9-(4-Benzoyloxy-3-hydroxymethylbut-1-yl)guanine; [0170]
9-(4-Hexanoyloxy-3-hydroxymethylbut-1-yl)guanine; [0171]
9-(4-Hexadecanoyloxy-3-hydroxymethylbut-1-yl)guanine; [0172]
9-(4-Hydroxy-3-hydroxymethylbut-1-yl)guanine 4'-phosphate
diammonium salt; [0173]
N2-Acetyl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; [0174]
N2-Hexanoyl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; [0175]
2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine;
and [0176]
2-Amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-phenoxypurine.
Methods for producing pharmaceutically acceptable formulations of
penciclovir are described in detail in U.S. Pat. No. 5,075,445,
herein incorporated by reference.
[0177] In still another embodiment, the active agent is
famciclovir, which is another derivative of acyclovir that can be
used for its anti-viral properties. Famciclovir can be converted to
penciclovir. The chemical formula for famciclovir is
9-(4-hydroxy-3-hydroxymethylbutyl) guanine, which has the chemical
structure: ##STR5## or a pharmaceutically acceptable salt thereof,
where R.sub.1 and R.sub.2 are each independently hydrogen, acyl or
phosphate, provided that when one of R.sub.1 or R.sub.2 is
phosphate, the other is hydrogen; or R.sub.1 and R.sub.2 are joined
together to form a cyclic acetal group, a cyclic carbonate group or
a cyclic phosphate group. Suitable derivatives of famciclovir
include: [0178]
2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine; [0179]
2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine; [0180]
2-amino-9-(4-acetoxy-3-hydroxymethylbut-1-yl)purine; [0181]
2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine;
[0182] 2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine;
[0183]
2-amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine;
[0184] 2-amino-9-(4-butyryloxy-3-hydroxyinethylbut-1-yl)purine;
[0185] 2-amino-9-(4-benzoyloxy-3-hydroxymethylbut-1-yl)purine;
[0186] 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine
4'-phosphate; and [0187]
2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine
4':4''phosphate. Methods for producing pharmaceutically acceptable
formulations of famciclovir are described in detail in U.S. Pat.
No. 5,246,937, herein incorporated by reference.
[0188] In addition, U.S. Pat. No. 5,580,571, incorporated by
reference, teaches that the following nucleosides exhibit enhanced
anti-viral activity as phosphate esters and can be used as active
agents: [0189] 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil
[broavir; BV-araU]; [0190] 2'-fluorocarbocyclic-2'-deoxyguanosine;
[0191] 6'-fluorocarbocyclic-2'-deoxyguanosine; [0192]
1-(beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil; [0193] SQ
34,514; [0194] HOE 602; [0195] triflurothymidine; [0196]
9-[(1,3-dihydroxy-2-propoxy)methyl]guanine; [0197]
5-ethyl-2'-deoxyuridine; [0198] E-5-(2-bromovinyl)-2'-deoxyuridine;
[0199] 5-(2-chloroethyl)-2'-deoxyuridine; [0200]
1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);
[0201] 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouridine
(FIAU); [0202] buciclovir; [0203] 6-deoxyacyclovir; [0204]
9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; [0205]
E-5-(2-iodovinyl)-2'-deoxyuridine; [0206]
5-vinyl-1-beta-D-arabinofuranosyluracil (V-araU); [0207]
1-beta-D-arabinofuranosulthymine (Ara-T); [0208]
2'-nor-2'deoxyguanosine (2'NDG); [0209]
9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir, BRL
3912); and [0210] 1-beta-D-arabinofuranosyladenine (Ara-A;
vidarabine).
[0211] It will be appreciated that each of these nucleosides can be
an active agent in a topical composition. In addition, analogs or
derivatives of the nucleosides discussed herein may be used as the
active agent. The nucleoside is preferably delivered in an active
form when used in a topical composition. The active agent may thus
be any of the above-cited nucleosides, an analog, derivative, or
metabolite thereof in order to provide an active form of the active
agent.
[0212] In addition, the active agent is preferably in a state which
is able to be mixed with a suitable carrier. A pharmaceutically
acceptable salt, phosphate ester or acyl derivative of the
nucleoside can be formulated for use as a topical treatment
optionally with a carrier (discussed below). In one embodiment, the
nucleoside can be provided in a salt form which allows it to be
more easily soluble in water or other carrier. A pharmaceutically
acceptable salt form of the nucleoside can thus be prepared using
sodium, potassium, ammonium, or hydrogen. In addition, salt forms
of nucleosides can be formed using hydrochloric, sulphuric,
phosphoric, maleic, fumaric, citric, tartaric, lactic, acetic or
p-toluenesulphonic acid.
[0213] Topical formulations incorporating nucleosides as the active
agent, including analogs, metabolites, or derivatives thereof, can
include the active agent in an amount of, for example, about 0.01%
to about 50% w/w; preferably from about 0.1% to 30% w/w; most
preferably from about 1% to about 15% w/w. Other topical
formulations incorporating nucleosides may include the active agent
in an amount of, for example, about 0.075 to about 20% w/w,
preferably about 0.2 to about 15% w/w, and most preferably about
0.5 to about 10% w/w.
[0214] Topical formulations containing nucleosides may contain
0.075% to about 20% w/w nucleoside or a salt or an ester thereof,
from about 20% to about 90% w/w of an alcohol, and from about 10%
to about 80% w/w water. In a preferred embodiment, a topical
formulation comprises about 0.2% to about 15% w/w nucleoside, from
about 30% to about 85% w/w of an alcohol, and from about 15% to
about 70% w/w water, whilst another preferred formulation comprises
from about 0.5% to about 10% w/w nucleoside, from about 40% to
about 80% w/w of an alcohol, and from about 20% to about 50% w/w
water.
[0215] The active agent could also be a non-nucleoside that acts to
reduce or inhibit DNA or RNA viral replication other than by
substituting as a nucleotide. In one embodiment, a non-nucleoside
includes 1-docosanol, or behenyl alcohol (sold under the trademark
Abreva.TM.). Docosanol is a 22 carbon straight chain-saturated
alcohol. 1-docosanol inhibits fusion between the plasma membrane
and the viral envelope. This prevents viral entry into the cell
and, as a result, reduces or disrupts viral replication. When
present in a topical formulation, docosonal can be present in a
range from about 1% to about 50% by volume, more preferably in a
range from about 2% to about 30% by volume, and most preferably in
a range from about 3% to about 15% by volume.
[0216] As indicated above, the carrier is a vehicle for the
biologically active agent, more particularly the anti-infective
active agent. The carrier causes effective wetting and penetration
of the tissue to be treated and then enables the anti-infective
agent to move within this carrier into the disordered tissue.
[0217] In one embodiment, the treatment composition consists of
only one type of active agent such as benzalkonium chloride,
nucleoside, or docosanol and the carrier. In still other
embodiments, the treatment composition may include a combination of
active agents, such as a combination of a nucleoside and
benzalkonium chloride and/or 1-decosanol and a carrier. In other
embodiments, the treatment composition consists essentially of the
active agent and the carrier, together with other components as
described hereinbelow. In any event, the 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 years.
[0218] The carrier preferably has properties which enhance the
ability of the treatment composition to penetrate into the
disordered epithelial tissue. More particularly, the carrier has 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 that of water is in sharp contrast to conventional
compositions which enable the composition to be 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. Note,
however, that small amounts of inert abrasive material may be
present in the treatment compositions as discussed hereinbelow. It
will be appreciated that the carrier may include substances which
have either a viscosity or density which is more than slightly
greater than that of 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.
[0219] 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. More particularly, the carrier preferably
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.
[0220] The carrier may be formed from a single liquid constituent
such as isopropyl alcohol or water as described hereinbelow, or
from more than one constituent. Although water alone may be used as
the carrier, it is not preferred because other compounds, such as
some alcohols, have a tissue penetrating capability that is
superior to water. The carrier in the treatment composition is also
preferably not formed entirely from an alcohol such as isopropyl
alcohol or ethyl alcohol, since their use may be more painful in
some circumstances. More particularly, when an open sore is part of
the disordered tissue, the amount of alcohol or other composition
that has a significant tissue penetrating ability may be modified
by adding water so as to moderate the amount of discomfort that the
patient experiences by the application of the composition to the
open sore. Additionally, the evaporation rate of a carrier that
includes alcohols such as isopropyl alcohol can be reduced by
including water. Further, it may be preferred to use alcohols such
as isopropyl alcohol with other constituents such as water due to
regulatory issues. Also some substances, such as benzylkonium
chloride, dissolve best in a carrier that includes water.
[0221] While isopropyl alcohol is a preferred carrier due to its
ability to effectively penetrate tissue, 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.
Mixtures of the above-mentioned alcohols 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
with a combination of both cetyl alcohol and water to reduce the
sensation.
[0222] As noted above, the carrier preferably has a
tissue-penetrating constituent such as isopropyl alcohol. It has
been noted that the ability of the treatment composition to
penetrate disordered tissue is significantly enhanced when at least
a portion of the carrier is isopropyl alcohol. While not being
limited by any particular theory, it is suggested that isopropyl
alcohol opens cells and is not blocked by lipids or lipid layers in
the disordered tissue. Accordingly, it is believed that isopropyl
alcohol penetrates so effectively due to its ability to penetrate
the lipid structure and cell wall of the tissue. The penetration
ability of a carrier comprising isopropyl alcohol may be further
enhanced by including a very small amount of ethyl alcohol such
that the carrier is less than about 1% ethyl alcohol.
[0223] As indicated above, the preferred carrier includes isopropyl
alcohol and water. As also discussed above, isopropyl alcohol is
included in the carrier for its ability to rapidly penetrate
disordered tissue while the water is included primarily to minimize
the sensation which may be felt as the isopropyl alcohol penetrates
the skin. While substances like lidocaine and other substances that
have anesthetic qualities can be used instead of water to reduce
the sensation caused by isopropyl alcohol, the carrier preferably
includes water with the isopropyl alcohol as benzalkonium chloride
dissolves more easily in such a combination than in isopropyl
alcohol alone. It is also simpler to use a carrier that includes
both isopropyl alcohol and water than it is to pretreat the
disordered tissue with an anesthetic composition. However,
pretreating the disordered tissue with an anesthetic composition is
also within the scope of the present invention.
[0224] Carriers that include isopropyl alcohol and water have
varying ratios depending on the intended use. However, for treating
cold 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. The most
preferred carrier for treating cold sores is a carrier in which
water is included in an amount of about 30% by volume of the
carrier and wherein the isopropyl alcohol is included in an amount
of about 70%. Although, these ranges of water content are provided
based on the volume of water in the carrier, essentially the same
water contents apply to the overall treatment composition since the
other active agent and any other optional component are typically
included in such small amounts. Embodiments of preparations
according to the present invention include a carrier that comprises
an alcohol, preferably isopropyl alcohol, at a concentration by
volume in the range from about 20% to about 90%.
[0225] When treating sensitive parts of the body such as the
genitalia and adjacent areas, the carrier may include isopropyl
alcohol in an amount of about 10 to about 15% by volume of the
carrier and water in an amount of about 85% to about 90%. However,
as noted above, higher concentrations can still be used even in
sensitive areas, particularly when pretreated with an anesthetic
composition.
[0226] While rapid penetration is desired, it should be understood
that the objective is rapid penetration through the skin so as to
form a subcutaneous reservoir (or bath) of the treatment
composition in the spiked or homed cells shown as element 34 in
FIG. 1. In the case of herpes or other viruses that reside in the
nerves, it may be desirable for the treatment composition to
penetrate through the subcutaneous layers to the infected nerve
without thereafter rapidly passing into the blood stream.
Accordingly, the carrier preferably does not include substances, or
at least not large quantities of substances, such as dimethyl
sulfoxide (DMSO) that immediately penetrate far beyond the skin and
subcutaneous layers and enter the blood stream. In general, it is
desirable for the treatment composition to reside for a length of
time sufficient to maintain the desired activity until it slowly
reacts with surrounding bodily fluids and tissues.
[0227] The carrier may also include other solvents such as acetone,
acetic acid, acetic anhydride, and the like. However, if acetone
and the like are used they are preferably used in smaller
quantities and not as the sole constituent as they may evaporate
too rapidly and do not penetrate the skin and cells as well as
isopropyl alcohol. While such solvents may not be as effective as
certain alcohols, particularly isopropyl alcohol, acetone does
exhibit some ability to penetrate tissue. So although solvents such
as acetone may be used alone, it is preferably used in combination
with other substances. One preferred carrier combination is ethanol
and acetone in a ratio of about 70% ethanol by volume of the
carrier, preferably 80% ethanol and most preferably about 90%
ethanol with 10% acetone by volume of the carrier. As mentioned
above with respect to the water content for carriers formed from
water and alcohol, the ratios provided for combinations of ethanol
and acetone based on the volume of the carrier a apply also to the
volume of the treatment composition.
[0228] The above carriers may also be combined across class lines.
As such, the carriers such as water, alcohols, and other solvent
compounds may be combined. One example is water, alcohol, and
acetone in respective amounts of 30%, 60%, and 10%, by volume of
the carrier. Generally speaking, the constituents may be combined
in any suitable ratio such as: 1:1:0, 1:2:0, 1:10:0, 1:1:1, 1:2:1,
1:10:1, 1:10:10, and 1:2:10.
[0229] As indicated above, the carrier is preferably a liquid that
includes alcohol as it is believed that alcohols included in
sufficient quantity to act as the carrier may have the quality of
removing lipids from the tissue and thereby enabling the active
agent to move within the disordered tissue. It is also believed
that the ability of the treatment composition to penetrate the
disordered tissue is hindered by including components in the
composition such as oils or materials which have traditionally been
included to enable the composition to be coated onto the surface of
the disordered tissue. Examples of such materials include
petrolatum which is used in various cold sore treatment
compositions. For example, the popular over-the-counter lip
ointment sold under the trademark BLISTEX by Blistex Incorporated
of Oakbrook, Il. 60521. The BLISTEX ointment contains allantoin
(1%), camphor (0.5%) and phenol (0.5%) in an emollient base with
petrolatum, lanolin, menthol, methyl salicylate, and other
ingredients. Other widely used ingredients that are included to
increase the viscosity or to increase the tackiness include
polyethylene glycol and polypropylene glycol. An example of a
product which utilizes polyethylene glycol and polypropylene glycol
is a gel sold under the trademark ORAGEL MOUTH AID by Del
Laboratories Incorporated of Farmingdale, N.Y. 11735. Other
thickeners are taught in U.S. Pat. No. 5,661,170, which was
previously incorporated by reference, as including cellulosic
materials and waxes. In addition to petrolatum based materials and
thickeners, it is also believed that materials which are either
obtained from natural sources such as naturally occurring oils
present in trees, bushes, plants, etc. or substances which are
derived from such oils may also reduce the ability of the treatment
composition to penetrate the disordered tissue. Such materials are
referred to herein as penetration inhibiting components.
[0230] 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 above, can actually enhance penetration. Such
components may be classified as "auxiliary penetrating components",
examples of which include, but are not limited to, 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), and ethoxylated amines (e.g., amine
quaternaries). Certain essential oils and emollients, which are
normally water insoluble, can be made soluble in water by
ethoxylation (e.g., ethoxylated lanolin). In quantities less than
about 10% by volume, the foregoing do not increase the viscosity of
the carrier and can assist in penetrating the tissue, though they
are not as efficient as alcohols such as isopropyl alcohol and
ethanol.
[0231] As indicated above, penetration inhibiting components
includes 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 are not 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
although, the inventive composition is preferably substantially oil
free, the term "substantially oil free," is meant 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, and is preferably
incidentally present in an amount of less than about 1%, and is
most preferably incidentally present in an amount less than about
0.05% and even more so at an amount less than about 0.01%.
Additionally, in some instances it may be desirable to add very
small quantities of naturally occurring oils or substances;
however, the concentration is no more than the incidental amounts
discussed above.
[0232] Note that penetration inhibiting components are believed to
act as a barrier which seals in toxic irritating by-products of
viral growth. They prevent the natural weeping process of the
disordered tissue which flows to remove toxins, etc. Accordingly,
use of such penetration inhibiting components may actually cause
more damage to the disordered tissue despite the temporary
advantages achieved though using such substances.
[0233] As indicated above, the treatment composition may consist of
only the active agent and the carrier. Treatment compositions
consisting essentially of the active agent and the carrier do not
include penetration inhibiting substances but may include other
components added for specific purposes. These components or
additives are added to achieve a particular result and do not have
a substantial impact on 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 are additives which are conventionally used as
preservatives, pH adjusters, substances having anesthetic
qualities, vasodilators, analgesics and defoamers. These components
or additives are used in concentrations which correspond with
amounts conventionally utilized.
[0234] Generally, preservatives may be added to the anti-infective
composition. Examples of preferred preservatives include parabens,
preferably methyl and propyl parabens. Preferably the
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.
[0235] Additives such as those set forth above can be blended with
other ingredients to make up the inventive composition including pH
adjustors. Such pH adjustors may include organic acids, mineral
acids in minute amounts, organic bases or mineral bases also in
minute amounts. Preferred organic acids include acetic acid,
caproic acid, and the like, and combinations thereof. When other
organic acids do not cause undesirable effects, such as chelation,
on the active ingredients of embodiments according to this
invention, they can also be used as such pH adjustors, and such
acids include citric acid, ascorbic acid, sorbic acid, malic acid,
succinic acid, and combinations thereof. Other preferred acids
include hydrochloric acid, nitric acid, hydroiodic acid, and the
like in minute amounts. Preferred bases include methyl and
ethylamines such as triethanolamine, and the like. Other preferred
bases include, ammonium hydroxide, potassium hydroxide, sodium
hydroxide, and the like.
[0236] The inventive compositions may include compounds with
anesthetic qualities. Depending upon the application site, whether
on dermal layers or on mucous membranes, different anesthetics may
be preferred. One particularly preferred anesthetic is benzocaine.
Benzocaine is especially useful in the areas of open sores such as
cold sores, eczema sores, and the like. Of the amides, such
compounds as bupivocaine, carbocaine, and ropivocaine may be
preferred. Of the esters, such compounds as procaine, cocaine,
novocaine, tetracaine, and benzocaine may be preferred. Other
preferred anesthetics include alkaloids such as cocaine, caffeine,
nicotine, xylocalne, and the like. Another preferred anesthetic
includes a combination of lidocaine HCl and prilocalne. With these
two compounds, an eutectic mixture is achieved with a melting point
below room temperature. A preferred composition of the lidocaine
and prilocalne is about 2.5% each in a 1:1 mixture. Other preferred
anesthetics include oil of cloves, tea tree oil (melaleuca
altemifolia, which also acts as a disinfectant) and the like. Other
preferred anesthetics include lidocaine hydrochloride, dibucaine,
dibucaine hydrochloride, tetracaine hydrochloride, tronothane,
dyclonine, dyclonine hydrochloride, pramoxine hydrochloride,
diperodon, butamben picrate, cyclomethycaine sulfate,
cyclomethycaine hydrochloride, and dimethisoquin hydrochloride.
Where an anesthetic is present, it is included in an amount in a
range from about 0.001% to about 2% by volume of the treatment
composition.
[0237] Other preferred components for the inventive composition
include vasodilators, such as nitroglycerine and the like.
Vasodilators are useful for causing penetration of the active agent
or agents into the disordered tissue to its base in the skin or
mucous membranes an beyond. Care must be taken to balance the
effect of localized vasodilation against the systemic toxicity of
the inventive composition such that penetration into the disordered
tissue is clinically significant, but that the active agent or
agents remain substantially local to the disordered tissue for
maximum efficacy. Where a vasodilator is supplied to make up the
inventive composition, it may be provided in a preferred range from
about 0.001% to about 0.05% by volume of the treatment
composition.
[0238] Other preferred components for the inventive composition
include analgesics such as methyl salicylate, aspirin, and other
salicylate salts. Other preferred components for their analgesic
effects include N,N-dimethyl aspartic acid; N-N-dimethyl glutamic
acid, trolamine salicylate, antipyrine, and salicylamide. Where an
analgesic is present, it may be included in a preferred range of
about 0.001% to about 2% by volume of the treatment
composition.
[0239] Many of the active agents disclosed above are considered to
be cationic surfactants so it is generally unnecessary to include
any surfactants. It is also generally unnecessary to include
surfactants as the treatment composition is substantially oil free.
Additionally, the active agent can be used with various carriers so
the carrier can be modified to achieve optimal solubility as
needed. To the extent that a surfactant is included, for example,
to assist in tissue wetting properties, the surfactants may be
cationic, nonionic, and combinations thereof. In some circumstances
it may be useful to use other surfactants such as another cationic
surfactant. U.S. Pat. No. 5,661,170, referenced above, may be
referred to for a disclosure of suitable surfactants. Anionic
surfactants are generally less desirable because they tend to
deactivate benzalkonium chloride, rendering it bio-unavailable.
Amphoteric surfactants, which contain both cationic and anionic
functionality, can work so long as the pH is controlled so that the
anionic functionality does not deactivate the benzalkonium
chloride. To the extent that an anionic surfactant can be made to
work without deactivating benzalkonium chloride, however, such as
by controlling the pH, it is certainly within the scope of the
invention to use such surfactants.
[0240] Abrasives are generally not necessary as a component of the
composition as the applicators are configured for abrasion.
Additionally, when irritating an open sore it is generally
undesirable for abrasives to be deposited into the open sore. Nor
is it generally necessary to include abrasives on the applicators,
which also risks the abrasives being dislodged from the applicator
and placed into an open sore. However, this does not exclude the
use of abrasives as free-floating inert components in a treatment
composition nor their surface attachment to or impregnation in an
applicator. If used, suitable abrasives may include pumice and the
like as well as oxides such as alumina, silica, mica, zirconia,
titania (both anatase and rutile), and the like.
[0241] In making a mixture of any of the preceding carriers and
additives, it is understood that the recitation of compounds as
mixtures includes the solution and reaction products thereof. A
preferred method for preparing the inventive composition is to
dissolve the anti-infective active agent into the carrier, such as
to dissolve benzalkonium chloride in isopropyl alcohol. In general,
it is only necessary to mix the agent, such as benzalkonium
chloride, into the carrier. In some instances, it may be helpful to
first lower the pH of the solution into a range preferred to assist
the dissolution of selected components. Note that benzalkonium
chloride are generally acidic but can be made alkaline by adding pH
adjusters. Following dissolution of the selected components that
are assisted in their dissolution by a lower pH, the solution may
be either warmed or the pH increased, or both, and other components
may be added, preceding or following the warming and/or the pH
increase.
[0242] The use of soap is preferably avoided in the inventive
method as it tends to significantly reduce the efficacy of the
methodology. However, the inventive method may include a
precleaning step that comprises washing the disordered tissue
treatment site. The precleaning step may include the use of a
pre-moistened, organohalide impregnated towelette. Commercially
available towelettes are preferably not used as these towelettes
contain components which are generally considered undesirable in
combination with the present invention. Accordingly, when a
precleaning towelette is used, it is preferred that the towelette
be moistened with a composition which does not contain any
penetration inhibiting components such as lanolin. An example of a
commercially available towelette is the PDI.RTM. towelette made by
Professional Disposables, Inc. of Orangeburg, N.Y. which is
impregnated with benzalkonium chloride. Another example is the WET
ONES.RTM. towelette made by Playtex Products, Inc. of Dover, Del.
which is pre-moistened, benzethonium chloride impregnated
towelette.
[0243] In one method of the present invention, a topical anesthetic
may be applied to the treatment site and enough time may be allowed
to elapse in order to substantially anesthetize the nerve endings
for disordered tissue and surrounding tissue at and near the
treatment site. For example, towelettes may also be used that are
impregnated with anesthetics to reduce the sensitivity of an area
that is to be treated with vigorous agitation. After sufficient
anesthetization of the treatment site, the inventive method
continues by providing the inventive composition that contains the
anti-infective agent followed by impregnating an applicator with
the composition, or using a pre-impregnated applicator. Finally,
the disordered tissue at the treatment site is vigorously agitated
with the applicator while contacting the disordered tissue with the
composition. According to this alternative inventive method, where
a patient may have a low threshold of pain tolerance, the
preliminary anesthetization of disordered tissue at and near the
treatment site allows for the vigorous irritation of the disordered
tissue without the accompanying discomfort.
[0244] Another alternative includes the application of a substance
in liquid form in order to provide both sterile and cosmetic
covering of the disordered tissue after the inventive vigorous
agitation treatment. One example of a suitable liquid is
NEW-SKIN.RTM. Liquid Bandage made by Medtech Laboratories, Inc. of
Jackson, Wyo.
[0245] Applicators are preferably part of the inventive method and
system. As such, applicators may be preconfigured with particular
mixtures to treat specific disorders such as cold sores, eczema,
and the like. Applicators are well known in the art. Examples
thereof include those taught by Booras et al. in U.S. Pat. No.
5,709,866; by Fox in U.S. Pat. No. 5,704,906; by Mythling in U.S.
Pat. No. 5,527,534; by Stalcup et al. in U.S. Pat. No. 5,016,651;
by Bedford in U.S. Pat. No. 4,887,994; and by Korteweg in U.S. Pat.
No. 4,952,204; the disclosures of which are incorporated herein by
specific reference. Preferred applicators include prepackaged
applicators that have agitation pads impregnated with the inventive
composition. An applicator may be provided as a unitary structure
such as a sealed container that is frangible and configured for a
single use.
[0246] Applicators are preferably configured to enable the
treatment composition to be either delivered with vigorous
agitation or to be merely delivered onto the disordered tissue.
Such flexibility is useful since tissue disorders such as cold
sores typically progresses in stages that have varying pain
thresholds. Whether the applicator is designed to vigorously
agitate the disordered tissue or not, the applicator is preferably
able to deliver large volumes of the treatment composition onto the
disordered tissue. The delivery of large volumes of the treatment
composition may be achieved in several different ways. Applicators
are also disclosed, however, that can only hold relatively small
quantities of the treatment composition.
[0247] FIGS. 2A-2E depict a preferred applicator 10. The details of
applicator 10 are best seen in FIG. 2A which is an exploded
perspective view, FIG. 2B a perspective view of the assembled
applicator and FIG. 2C as it appears when ready for
application.
[0248] Applicator 10 includes an absorbent, agitation pad 12, that
is 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 agitation
pad 12. Frangible reservoir is enclosed by agitation 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 that is designed to keep agitation
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 to be broken. One
source for applicators having a frangible reservoir and various pad
configurations is James Alexander Corporation of Blairtown,
N.J.
[0249] FIG. 2C is a perspective view of the preferred applicator
depicted in FIG. 2B after frangible reservoir 14 has been ruptured.
Treatment composition 22 is allowed to permeate agitation pad 12 in
preparation for vigorous application to a disordered tissue
treatment site. In FIG. 2C, sleeve 18 has been removed to expose an
impregnated agitation pad 12. After impregnated agitation pad 12 is
sufficiently wetted, application to the disordered tissue treatment
site may commence.
[0250] 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.
[0251] FIG. 2E is a detail taken along the section line 2E-2E in
FIG. 2D that depicts a close-up view of the inventive method. The
detail view more clearly illustrates vigorous agitation of the
disordered tissue site where impregnated agitation 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 agitation movement by way of non-limiting
example.
[0252] Pad 12 has several purposes. 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
these shards from passing and causing injury as the pad is used to
deliver the composition to the disordered tissue. Another purpose
of pad 12 is obviously the delivery of the treatment composition so
the pad has a certain mesh or configuration that enables it to hold
and deliver the treatment composition due to porosity, capillary
action, etc. As discussed above in reference to FIG. 2D, as pad 12
delivers the treatment composition it is also preferably used to
vigorously agitate the disordered tissue.
[0253] Many configurations are available for a pad such as those
disclosed in U.S. Pat. No. 1,822,566 and French Patent No.
2,700,698. The pad must of course be configured to prevent the
passage of shards of glass out of container 16 and to enable
treatment composition 22 to be held and delivered. The pad also
preferably is configured for vigorously agitating the disordered
tissue. Features that enable pad 12 to be used in vigorously
agitating the disordered tissue are discussed below.
[0254] 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 prevents the shards of glass
from passing out of container 16. Pad 12 has a configuration that
is 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, both of
which are hereby incorporated by reference.
[0255] 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 vigorous or continual agitation of
the disordered tissue to enhance penetration by treatment
composition 22. The fibers forming pad 12 are relatively densely
positioned and are also relatively rigid. The dense positioning and
the rigid nature of the fibers enables applicator 10 to be used to
vigorously agitate the disordered tissue. Note that applicator 10
is not used like a brush to merely apply the treatment composition
like conventional methodologies which involve coating the afflicted
tissue. If the fibers are relatively soft such that they flex
significantly when pushed against the disordered tissue then it is
necessary to also push relatively hard against the disordered
tissue in order to insure that the disordered tissue has been
adequately agitated. Accordingly, the fibers are preferably
relatively rigid through either proper selection of the fiber
material, the length of the fibers and/or the positioning of the
fibers.
[0256] Pad 12 has a retention portion 13 positioned within flexible
container 16. Retention portion 16 is preferably 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 and flexible container 16
together. 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 while vigorously agitating the disordered tissue to enhance
penetration of the treatment composition into the disordered tissue
such that the treatment composition is no longer visibly detectable
on the disordered tissue within several minutes after delivery of
the treatment composition onto the disordered tissue.
[0257] Delivery portion 17 terminates at an agitation surface 15
that is relatively flat such that the disordered tissue is
uniformly contacted. Uniformly contacting the disordered tissue
with the flat surface reduces the risk of injuring the disordered
tissue as the disordered tissue is vigorously agitated. Use of such
a pad is to be contrasted with the use of a pad having a delivery
portion that is bulbous such as a swab used in some applicators
having a frangible ampule as disclosed in U.S. Pat. No. 1,822,566
and French Patent No. 2,700,698. A bulbous swab may tend to provide
either insufficient contact when lightly pressed or uneven pressure
when pushed hard enough to vigorously agitate the disordered
tissue. Although use of such a bulbous swab in place of a pad such
as pad 12 may result in these disadvantages, such swabs may be used
in certain circumstances.
[0258] The fibers used in pad 12 are preferably formed from
polyester as such polyester fibers provide adequate stiffiness at
the desired length. Pad 12 may also be formed from polyolefin,
porous polyethylene or laminated polyester foam. As used in the
specification and the appended claims, the term "fibers" includes
both synthetic fibers, inorganic fibers, naturally occurring
organic fibers and treated organic fibers. As indicated above,
synthetic fibers such polyester fibers are preferred. Another
example of synthetic fibers includes polyethylene fibers.
Polyethylene fibers having the same length and diameter as
polyester fibers are not as preferred as they tend be softer. Of
course the abrasiveness of fibers can be increased by increasing
the diameter of the fiber; however, it is preferred not to increase
the diameter of the fibers as this results in a decrease in surface
area for the treatment composition to move downward on the fibers.
Examples of inorganic fibers include glass, silica, ceramic,
graphite, metal fibers, and mixtures thereof. Any fiber which has
the preferred physical qualities such as strength, roughness,
ability to hold liquids, and/or proper flexibility is also within
the scope of the present invention. The only limiting criterion is
that the fibers be able to be configured in a manner that enables
them to hold the treatment composition and agitate the afflicted
tissue without adversely reacting with the chemical constituents of
treatment composition 22. Examples of naturally occurring fibers,
include cellulosic fibers extracted from abaca, bagasse, hemp,
cotton, plant leaves, wood or stems. The wood fibers may be both
hard wood or soft wood, such as southern pine. While pad 12 may be
made of such organic or naturally occurring fibers, it may be
necessary to treat some naturally occurring fibers as discussed
hereinbelow. Since fibers such as cotton react with benzalkonium
chloride, a sacrificial amount of benzalkonium chloride in addition
to the desired dosage may applied to an applicator made from cotton
fibers.
[0259] 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 agitation surface to 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 preferably has a length
ranging from about 3 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. However, these lengths
depend on the particular material so the delivery portion may
merely range in length from about 1 mm to about 3 mm.
[0260] 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 need. 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
vigorously agitate the cold sore treatment site.
[0261] 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. Factors related to selecting appropriate bristles include
the rigidity and flexibility of the bristles based on the
properties of the material used to form the bristles, the length of
the bristles especially the delivery portion, and the diameter of
the bristles. Another factor is the diameter of the cluster. All of
these factors are balanced so that the cluster of aligned bristles
enables the treatment composition to be delivered while preventing
passage of glass shards and so that the cluster of aligned bristles
may be used in a scrubbing action. So while the cluster of aligned
bristles may be held in place much like a brush and may be
configured to brush the composition onto the disordered tissue, the
bristles are preferably sufficiently rigid for scrubbing the
disordered tissue as the treatment composition is delivered. Such
rigidity is preferably achieved through selecting a material, such
as nylon, that is relatively rigid even when the bristle formed
from the material has a relatively small diameter. Use of bristles
having relatively small diameters is preferred to enable the
cluster to scrub while minimizing any potential for injuring 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 then the diameter may
range from about 0.1 mm to about 0.2 mm, and is more preferably
0.15 mm.
[0262] Note that the treatment composition flows more easily
through a pad that is a cluster of bristles than it does through a
compressed sheet formed from a web of fibers. Also, less treatment
composition is retained by a cluster of bristles. Accordingly, the
frangible ampule need not contain as much treatment composition
when the pad is a cluster of bristles.
[0263] 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. In any event, the treatment composition is
preferably delivered in sufficiently large quantities that the
disordered tissue at least appears moist and preferably such that
the treatment composition pools initially on the surface of the
disordered tissue. As indicated above, the penetrating capabilities
of the treatment composition enables it to be no longer visibly
detectable on the disordered tissue within several minutes after
delivery of the treatment composition onto the disordered
tissue.
[0264] 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 vigorously agitating the skin. Typical
pain relief is within minutes. It may also be advantageous,
especially during the prodromal stage, to deliver half of the
treatment composition while rubbing the cold sore or other
disordered tissue for about 30 seconds, wait about 1 minute and
then deliver the remainder while rubbing for about 30 seconds
again. Typically a single application is all that is required per
outbreak, if the pain is not gone, or healing started in 24 hours
then the treatment composition should be reapplied.
[0265] Another preferred applicator is illustrated in FIG. 3. FIG.
3 is a cross-sectional elevational view of an applicator 210 that
may be part of the inventive system and method. Applicator 210
includes an absorbent agitation 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 agitation 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 agitation 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, particularly agitation pad 212, upon a treatment
site, the medical professional or the patient may grab the adhesive
wing tabs 234, and gently pull adhesive wings 214 away from the
skin. Meanwhile, the medical professional or the patient may insert
a finger into finger loop 228, draw adhesive wings 214 also toward
finger loop 228 and commence to vigorously agitate the disordered
tissue.
[0266] Where it is preferable to immediately agitate the cold sore,
applicator 210 may be applied at the point of agitation pad 212
onto the disordered tissue and then vigorously 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.
[0267] In summary, applicator 210 may be used for vigorous
irritation of the disordered tissue or merely as a delivery
applicator. It may be used initially for application of the
(anti-infective active agent without vigorous irritation of the
disordered tissue which is then followed by vigorous irritation of
the disordered tissue. Vigorous irritation by applicator 210 of the
disordered tissue may be alternatively followed by leaving
applicator 210 in place like a sterile adhesive bandage.
[0268] FIG. 4 depicts another applicator at 310 in an elevational
side view which may be used in an alternative embodiment of the
present invention. The applicator or cotton swab depicted at 310
has a swab agitation pad 312 upon a stem 314. Stem 314 may be
formed from any suitable material, however, hed against the
disordered tissue and not the bulbous tip. The side is used so that
sufficient pressure can be applied while using the tip presents
certain difficulties. More particularly, when significant pressure
is applied, the bulbous tip is likely to dig into the disordered
tissue while the surrounding area receives less pressure.
Additionally, use of the bulbous tip results in a smaller surface
area being contacted which may require agitating different portions
sequentially.
[0269] It is preferable that the use of 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 inventive composition and then used to 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 saturates 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, which was
previously referenced.
[0270] An applicator and a burst pouch may also be held in separate
compartments of a bag such as bag 330 with a perforated divider.
Similarly, an applicator and a frangible reservoir such as
frangible reservoir 14 may be held in separate compartments. The
advantage of this arrangement is that the burst pouch or frangible
reservoir can be ruptured to enable the treatment composition to
flow into contact with applicator. When a frangible glass reservoir
is used, the perforation prevents glass from contacting the
applicator.
[0271] Fibers such as cotton are not preferred for holding the
treatment composition while agitating the disordered tissue as
extended exposure to cotton appears to reduce the efficacy of the
methodology. Accordingly, when swab agitation pad 312 is formed
from cotton, it is preferred that the pad not be stored in contact
with the treatment composition. The use of a container such as
burst pouch 340 when swab agitation pad 312 is formed from cotton
achieves this objective. Applicators such as a swab may be stored
in the same container as the treatment composition when swab
agitation pad 312 is formed from synthetic materials, naturally
occurring fibers which do not reduce the efficacy of the
methodology, or fibers such as cotton which have been appropriately
treated. Examples of suitable fibers include those discussed above
in reference to applicator 10. Examples of a single bag or
container for holding a swab are disclosed in U.S. Pat. No.
5,704,906 to Fox and U.S. Pat. No. 4,952,204 to Korteweg which were
both previously referenced. Note that bag 330 and burst pouch 340
may be formed from any suitable materials and in any suitable
manner.
[0272] Due to the relatively smooth texture of the cotton portion
of most conventional swabs, when such swabs are used it is
typically necessary to apply much more pressure than when an
applicator such as applicator 10 or 210 is utilized. Increased
pressure and tissue agitation occurs by using the side, rather than
the tip, of the swab. Additionally, an applicator such as
applicator 10 is further preferred as applicator 10 enables the
treatment composition to be continuously delivered without
requiring rewetting as a swab may. Further, swab agitation pad 312
holds only small quantities of the treatment composition so it is
necessary to rewet it in order to deliver large volumes of the
treatment composition. This prevents swab agitation pad 312 from
rapidly delivering large quantities of the treatment
composition.
[0273] The swab agitation pad 312 may be replaced with a sponge to
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 which was previously incorporated. Reference
is made in U.S. Pat. No. 4,887,994 at col. 2, lines 44-46 to coarse
foam pads, such coarse foam pads are preferred for use as an
agitation pad in accordance with the present invention. Coarse foam
pads enable the disordered tissue to be more easily agitated
through combined rubbing and application of an appropriate amount
of pressure than softer foam pads. The coarse foam pad may also be
utilized with a stick or stem.
[0274] Like the swab shown at 310, the other embodiments discussed
above may be stored and used in a similar manner. More
particularly, the coarse foam pad on a stick, the coarse foam pad
alone, or a towelette may be held in a bag or other sterile
container such as is shown at 330 along with a burst pouch as shown
at 340. Additionally, these applicators may be held in a bag such
as bag 330 without a burst pouch 340 in a dry sterile condition for
dipping into a separate reservoir of the treatment composition or
the treatment composition may be held in the bag along with the
applicator.
[0275] FIG. 5 is an elevational perspective view of an alternative
applicator that includes a fingertip applicator 410. Fingertip
applicator 410 includes an absorbent, agitation pad 412 held on an
adhesive surface 414 that the individual being treated or the
medical professional applies to the fingertip. Agitation pad 412
may include an absorbent material for retaining the treatment
composition and it may alternatively contain fixed abrasive
elements to assist in the vigorous irritating of the disordered
tissue at the treatment site.
[0276] FIG. 6 is an elevational cross-section view of an
alternative applicator that includes a finger- or digit-container
applicator 510. Digit-container applicator 510 includes an
absorbent, agitation pad 512 with a first side 512 that acts as the
agitation pad 516, and a second side 514 that acts at the support
514. 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 such as burst pouch
340. Applicator 510 is, however, preferably pre-moistened by the
presence of 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.
[0277] First side 512 is made of an absorbent and abrasive material
that is substantially uniform in relation to the size of a
disordered tissue site. First side 512 preferably has the
approximate roughness of a conventional gauze bandage or terry
cloth. However, first side 512 and/or second side 512 are not
necessarily formed from cotton. In fact, as discussed above, cotton
is preferably not used unless it has been appropriately treated not
to absorb the treatment composition, particularly the benzalkonium
chloride.
[0278] Preferably, first side 512 is seamless and devoid of fabric
folds etc. Additionally, where second side 514 is used to interface
with a finger, it is a support for first side 512 as the agitation
pad and delivery portion of applicator 510. As a structural
explanation of applicator 510, if applicator were to be turned
inside-out, first side 512 would be under compressive stress and
second side would be under tensile stress.
[0279] Like the other applicators, 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 then it
is large enough to enable at least one fingertip into it. However,
if applicator 510 is used to treat the sores caused by shingles on,
for example, an individual's back or other large surface of the
body then 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. Such a mit-sized applicator enables the treatment
composition to be rapidly delivered to large surface areas.
[0280] FIG. 7 depicts another embodiment of a system for delivering
a treatment composition to disordered tissue. Like the mit sized
version of applicator 510, applicator 610 is very useful for
treating large surfaces of the body such as a patient's back.
Applicator 610 comprises only four main components: the treatment
composition that is contained in a large frangible ampule 614 or
reservoir, the container 616 and pad 612 hold frangible ampule 614
in place.
[0281] Container 616 has thin-walls at recess 618, the closed end
opposite from open delivery end 617, into which frangible ampule
614 is positioned. 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 such that ampule 614 ruptures. The treatment
composition is then released and flows into pad 612.
[0282] Frangible ampule 614 preferably contains a volume of the
treatment composition ranging from about 0.5 ml to about 4 ml. The
volume preferably ranges from about 1.5 ml to about 3 ml and more
preferably about 2 ml to about 3 ml.
[0283] Pad 612 is adhered to the rim of open delivery end 617 of
container 616 through any 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 then it can be
used to rapidly apply the treatment composition to large surface
areas as shown in FIG. 8. FIG. 8 depicts the use of applicator 610
to apply the treatment composition to a patient's chest afflicted
with sores from shingles.
[0284] Applicator 610 can be used to merely deliver the treatment
composition without any vigorous agitation. Applicator 610 can also
be used to apply pressure and/or scrub the surface area to which
the treatment composition is being or has been delivered. Note that
abrasiveness of pad 612 can be varied significantly to achieve
varying degrees of ability to vigorously agitate the disordered
tissue. Another example of an applicator that has a container that
also acts as a handle, a glass ampoule positioned in the handle and
a porous pad is disclosed in U.S. Pat. No. 4,183,684. U.S. Pat. No.
4,183,684 is hereby incorporated by reference. Not only are such
applicators are able to deliver the treatment composition to large
surface areas of the body, it is delivered rapidly in large
quantities without requiring rewetting.
[0285] FIGS. 9-11 depict a towelette being used as an applicator to
treat various disordered tissue. The towelettes depicted at 710 may
be a relatively smooth towelette or a relatively abrasive
towelette, the towelettes can also have varying thicknesses.
Towelettes are generally not as useful as other applicators in
treating disordered tissue as they require a large quantity of the
treatment composition in order to be wetted and yet deliver only a
small quantity of the treatment composition to the disordered
tissue. However, the ability to hold a greater volume of the
treatment composition can be increased by increasing the thickness
of the towelette. Additionally, the towelette can be repeatedly
dipped to rewet it. For example, FIG. 9 depicts a user with a
finger wrapped in a towelette that is being used to deliver the
treatment composition to a cold sore on the user's lip. The user
can then rewet only the portion of towelette 710 being used to
apply pressure to the cold sore.
[0286] Note that while it is less effective to use a towelette as
compared with an applicator such as applicator 10 since the
towelette cannot be used to rapidly deliver a large volume of the
treatment composition it can still serve several functions. As
discussed above, a towelette may be used to preclean the disordered
tissue or to deliver an anesthetic. Precleaning disordered tissue
with a towelette, especially an abrasive towelette, may be useful
to awaken the immune response for a synergistic effect once the
disordered tissue is vigorously agitated. The abrasive surface
towelette also has the advantage of removing tissue that is in the
process of sloughing off from the disordered tissue site. Such
tissue may provide a hindrance to the inventive method because it
restricts penetration of the anti-infective active agent to living
disordered tissue.
[0287] The towelette may be used to deliver the treatment
composition even if it is not as effective as applicators used to
rapidly delivering a large quantity of the treatment composition. A
smooth towelette is generally ineffective in rubbing the disordered
tissue as it has inadequate roughness to agitate the disordered
tissue by rubbing it, however, it can be used to push against the
disordered tissue. For example, if towelette 710 is relatively
smooth then the user shown in FIG. 9 may dab the cold sore with the
treatment composition soaked towelette or the user may apply
pressure to the cold sore. Use of a towelette that has a thickness
and smoothness that is comparable to that of ordinary handwipes may
be scrunched in order to better hold the towelette while dabbing
the disordered tissue and to concentrate the moisture held in the
towelette. Such a scrunched smooth towelette may result in folds,
so it should not be rubbed against the disordered tissue as it may
dig into the disordered tissue, particularly if it is an open sore.
In any event, folds resulting from drawing the towelette together
prevent the towelette from being used to uniformly agitate
disordered tissue through rubbing. If a towelette is be rubbed
against the disordered tissue, then it is preferable to use an
abrasive towelette.
[0288] As indicated above, the abrasive towelettes are
distinguished from conventional towelettes used for cleaning hands,
etc. In addition to being too smooth, conventional towelettes are
sometimes too thin to hold adequate amounts of moisture while an
abrasive towelette preferably has sufficient thickness to hold
adequate amounts of the treatment composition. Of course, smooth
towelettes with increased thickness can also be used. The abrasive
towelettes can also have increased thickness to hold more treatment
composition.
[0289] The towelette fiber 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.
[0290] 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.
[0291] FIG. 11 depicts towelette 710 being used to deliver the
treatment composition to a patient that has sores from shingles on
his chest. Since the skin on body parts such as the chest, arms,
the back, etc. are thicker than it is on the lips, use of a
towelette is especially less effective than use of an applicator
such as applicator 610. It may however be useful to preclean the
disordered tissue in this manner. Essentially, towelettes are
primarily 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.
[0292] 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, which was previously referenced. The towelette and a burst
pouch may also be held in separate compartments of a bag such as
bag 330 with a perforated divider. Depending on the material used
to form the towelette, it may be advantageous to either separately
store the towelette and the treatment composition, as discussed
above, or to store them together in the same container, especially
when the towelette is formed from synthetic materials. As discussed
above, examples of a single bag or container for holding a
towelette are disclosed in U.S. Pat. No. 5,704,906 to Fox and U.S.
Pat. No. 4,952,204 to Korteweg which were both previously
referenced. Towelette 710 may be dipped into a separate reservoir
and then used to deliver the treatment composition.
[0293] The above embodiments comprise examples of an inventive
method and system of treating disordered tissue. It is preferred
not to dip a bare finger into a container of the treatment
composition because oils or other materials contained on the finger
may be of sufficient amount to cause the treatment composition to
be rendered ineffective and spread infection if disordered tissue
is infective. Additionally, back contamination of composition in
the container may occur as well as auto-innoculation. The agitation
pads 12, 212, 312 412, 612 as well as first side 512 are examples
of a delivery and agitation means for delivering the treatment
composition and for agitating the disordered tissue of the patient.
Note that other examples include an abrasive towelette and a coarse
foam pad. Though not most preferred, a conventional smooth
towelette is an example of a delivery and agitation means capable
of being used to rub the disordered tissue.
[0294] The container 16 of applicator 10, the finger loop 228 of
applicator 210, the stem 314 of applicator 310 or similar
applicators, the adhesive surface 414, the second side 514 of
applicator 510 and the container 616 of applicator 610 are examples
of a means for supporting the delivery means.
[0295] A coarse foam pad, pad 212, pad 412, first side 512, pad 612
and abrasive towelette 710 are all examples of delivery and
agitation means capable of conforming to the surface features of
the disordered tissue as the corresponding supporting means also
conforms to the surface features. Stated otherwise, the applicator
is flexible such that both the delivery and agitation means as well
as the supporting means flex in conformance with the surface
anatomy of the disordered tissue. First side 512 is particularly
useful for adapting to the surface anatomy of the disordered
tissue. Pad 612 can also be thick enough to conform to various
surfaces features of the body area being treated.
[0296] The frangible reservoir 14, container 216, container 516 and
frangible ampule 614 are examples of a reservoir means for
containing the composition. Additionally, a bottle or the like that
contains treatment composition 22 for use with applicator 310 is
another example of a reservoir means for containing the
composition. Note that reservoir 14, container 216, container 516,
and ampule 614 however, are configured to be in fluid communication
with the delivery and agitation means. Frangible reservoir 14,
burst pouch 340 and frangible ampule 614 are configured to be in
fluid communication with the delivery and agitation means once
ruptured. Frangible reservoir 14 and frangible ampule 614 are
further configured to continually deliver the treatment composition
to the delivery and agitation means while the delivery and
agitation means is agitating the disordered tissue until all of the
treatment composition has been delivered. Note that one of the
primary distinctions between frangible reservoir 14 as compared
with burst pouch 340 is that the frangible reservoir 14 is located
within the container 16. Similarly, frangible ampule 614 is located
within container 616.
[0297] Container 516 and bag 330 are examples of container means
for holding the applicator. This configuration, as discussed above,
enables the applicator to be held in a dry sterile condition for
dipping into a separate reservoir of the treatment composition. As
also indicated above, container 516 and bag 330 can also hold the
treatment composition along with the applicator such that the
applicator is premoistened. Accordingly, container 516 and bag 330
are also examples of container means for holding the applicator and
the treatment composition. As further indicated above, container
516 and bag 330 can also hold the treatment composition in a pouch
along with the applicator. On this basis, container 516 and bag 330
are also examples of container means for holding the applicator and
a reservoir means.
[0298] The inventive method of treating disordered tissue and the
like includes impregnating an applicator with the inventive
anti-infective composition and contacting the treatment site with
the applicator. Vigorous agitation of the disordered tissue is
particularly useful as the induced physical trauma causes the
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.
[0299] Chemotaxis, the migration of phagocytes such as granular
leucocytes and human leucocyte associated (HLA) antigens to an area
of a tissue disorder, is enhanced and assisted in the present
invention by the vigorous agitation of the disordered tissue with
the anti-infective active agent or agents. The combination of the
anti-infective active agent, preferably benzalkonium chloride, with
the chemotaxis phenomenon caused by the vigorous agitation of the
disordered tissue, has the surprising effect of a rapid decline of
the infectant such as a virus or a microbe in the disordered
tissue. Note that 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 vigorous
agitation is rapid delivery and the awakening of the immune
response. The neutrophil, if activated is therefore 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 move as needed in order
to penetrate effectively.
[0300] Other immune responses may occur with the vigorous agitation
of the disordered tissue site by the inventive method, and the
inventors do not wish to be bound to any single theory that may
explain the surprising efficacy of the inventive method and
system.
TESTS AND EXAMPLES
[0301] The following tests and examples are provided as
illustrative of the inventive method and system. These tests and
examples are not intended to be limiting of the invention. The
tests and examples produce clinically discernable improvement of
disordered tissue. By "clinically discernable improvement of
disordered tissue," it is understood that various testing methods
may be used to quantify improvement of disordered tissue. One
example of clinically discernable improvement of disordered tissue
include arresting the normal progression of a tissue disorder such
as a cold sore. Another example of clinically discernable
improvement of disordered tissue is healing of a tissue disorder at
a faster rate than was observed before in a recurrent disorder such
as a cold sore. Another example of clinically discernable
improvement of disordered tissue is an arrest of pain usually
associated with the progression of a tissue disorder such as a cold
sore. Another example of clinically discernable improvement of
disordered tissue is the permanent deactivation of a recurrent
tissue disorder site after the inventive method is applied to a
disordered tissue site.
[0302] Other ways to evaluate the progression of the cold sore
healing process include measuring the size of the cold sore and
also the degree of inflammation thereof. One such method of
evaluation is colorimetry of inflamed tissue that creates a color
scale that has apparently healthy tissue of the patient as the
baseline, and ranks the inflamed color with some external standard
or that nominalizes the inflamed tissue such as being at a nominal
red scale of 10. A "nominal red scale" is defined as assigning the
tissue color a nominal 10; a nominal zero being undisordered tissue
of the same type for the specific patient. Clinically discernable
improvement of inflamed tissue is defined as reducing in the
nominal red scale within about 24 hours by as much as about two or
more on the nominal red scale of 10. With a disordered tissue
having substantially no clinically discernable improvement of
disordered tissue, a red scale decrease of below about one or less
within 24 hours is observed.
[0303] Another method is the assay of eosinophils and other immune
response substances in the inflamed area before and after the
inventive method of treatment. Where the presence of eosinophils
and the like increases by more than about 10% within about one hour
of the inventive method of treatment, as opposed to less than about
10% increase in eosinophils and the like with a control cold sore,
a clinically discernable improvement has occurred.
[0304] The clinical tests provided hereinbelow were performed with
a treatment composition which included benzalkonium chloride. The
carrier was aqueous isopropyl alcohol (70% by volume isopropyl
alcohol). The treatment composition was prepared with about one
part benzalkonium chloride to about 750 parts carrier. More
particularly, 5 drops of benzalkonium chloride having a
concentration of about 17% in isopropyl alcohol were added for each
ounce of the carrier. The result was a treatment composition
containing about 0.133% benzalkonium chloride by weight of the
treatment composition. Although additives and other constituents
may be combined with the mixture as set forth above these
particular test treatment compositions did not include any
additives.
[0305] As discussed above, the methodology in the examples includes
vigorously applying the composition to the disordered tissue and
removing the superficial lipids by the carrier. The carrier also is
useful for the penetration of the disordered cells at the tissue
disorder site. Either following or simultaneously with the
penetration of disordered cells with the composition at the tissue
disorder site, vigorous agitation of the tissue with the
composition is carried out under conditions to increase the flow of
intercellular fluid to the tissue at the tissue disorder site. This
enables the active agent greater ease of transportation at the site
to better penetrate.
Clinical Testing in Humans
[0306] Clinical Test 1
[0307] A male was diagnosed with several vesicles beginning to
coalesce on the lip. Treatment was initiated immediately. After
about 1 day, it was observed that the vesicles had not coalesced
further and that progression of the cold sore through its normal
stages was arrested. After about two days, scab tissue was observed
to be sloughing off. After about seven days, no sign was left of
the disordered tissue. The patient observed that for previous
eruptions the complete healing of this cold sore at this site took
from about two to three weeks.
[0308] Clinical Test 2
[0309] A male was diagnosed with a cold sore erupting below the
corner of the mouth. The usual tingling and tightening sensation
that occurs with a cold sore onset was observed by the patient. The
inventive composition and method was applied to the patient
according to the inventive method. Immediately upon application,
the usual tingling and tightening sensation was not noticed. After
about two days, no visible sign of a cold sore was observable.
[0310] Clinical Test 3
[0311] A male with a history of cold sores ranging in a size from
about 1.5 cm to about 2.5 cm in diameter was treated immediately
upon sensing the tingling and tightening of an oncoming cold sore.
A numbing sensation was immediately noticed and the pain was gone.
After about 3 days, the cold sore had begun to heal.
[0312] Clinical Test 4
[0313] A female was diagnosed with pustules and vistules upon the
lower lip. The inventive composition was applied to the patient
according to the inventive method, and pain was gone as soon as the
application of the inventive composition was done. Instead of the
normal weeping and scabbing the patient was used to, the cold sore
healed without weeping, and pain was minimal in comparison to
previous experiences.
[0314] Clinical Test 5
[0315] A female had a disordered tissue eruption upon a digit with
about 7 vistules in the pre-eruption stage. The blistering typical
of this type of tissue disorder began to fade immediately after
application of the inventive composition. A small amount of scaling
was observed after about 2 weeks. The patient observed that the
normal course of an eruption and healing at this cold sore site was
shortened by the inventive composition and method.
[0316] Clinical Test 6
[0317] A female was diagnosed with a cold sore taking up about
one-half of the area of the lower lip. The cold sore had multiple
lesions. The inventive composition was vigorously applied to the
cold sore. Pain was immediately relieved and weeping was
immediately arrested from the cold sore.
[0318] Clinical Test 7
[0319] A female observed tingling and tightening upon the inside of
her lip in the evening and observed one small pustule and three to
four vistules at the time of treatment the next morning. The
inventive composition was applied by vigorous rubbing with a cotton
swab. A second treatment was carried out that evening, and a third
treatment was carried out the following morning. The pain was
observed to be relieved fairly quickly upon the first treatment.
The patient observed that the inventive composition and method
worked at least as well as her usual Zovirax.RTM. prescription,
manufactured by Glaxo Wellcome Inc. of Research Triangle Park, N.C.
The following advantages of the inventive composition and method
were observed in comparison. One advantage was that fewer
applications were required. Additionally, no unpleasant tasting
ointment remains upon the lip during the treatment time.
[0320] Clinical Test 8
[0321] A female with a cold sore history including at least one
eruption per month was diagnosed with some yellow scabbing present
upon a cold sore site. After vigorous irritation of the disordered
tissue with the inventive composition, the patient observed that
pain was completely gone after about seven hours.
[0322] Clinical Test 9
[0323] A male was diagnosed with a cold sore upon the lower lip.
The inventive composition was applied by rubbing. The cold sore was
observed to be healed after two days.
[0324] Clinical Test 10
[0325] A male was diagnosed with a number of cold sores at the
corner of the mouth and above the lip. Prior to vesicular eruption,
the usual pain that precedes the eruption of a cold sore was
observed about 24 hours previously. The inventive composition was
applied by rubbing. Growth of the disordered tissue was immediately
arrested and the tissue appeared to have cleared in three days
following the treatment.
[0326] Clinical Test 11
[0327] A female diagnosed with a cold sore upon the chin about half
way between the base of the chin and the lower lip. The inventive
composition was applied with rubbing. The cold sore was observed to
have healed within about two days.
[0328] Clinical Test 12
[0329] A six year old female was diagnosed with an open cold sore
upon the lower lip. The inventive composition was applied by
vigorous rubbing. The cold sore was barely observable in about
three days.
[0330] Clinical Test 13
[0331] A male was diagnosed with a cold sore upon the lower lip.
The inventive composition was applied by vigorous rubbing. The
progression of the cold sore was arrested and pain was stopped
within a few minutes.
[0332] Clinical Test 14
[0333] A female was diagnosed with a cold sore at the corner of the
mouth that would crack when the mouth was opened. The inventive
composition was applied by vigorous rubbing. Within about two days,
the cold sore was observed to be completely healed. The patient
observed that cold sores in the corner of the mouth of this type
usually took at least 7 to 10 days to heal.
[0334] Clinical Test 15
[0335] A three-year old male was diagnosed with a cold sore upon
the lip. The inventive composition was applied by vigorous rubbing.
It was observed that progression of the cold sore was immediately
arrested and that the cold sore did not form at that site again.
The patient had about six sites that erupted upon the lips
frequently, and no treated site re-erupted after treatment.
[0336] Clinical Test 17
[0337] A male was diagnosed with a cold sore below the corner of
the lower lip. The inventive composition was applied by vigorous
rubbing. Immediately upon application, the tingling sensation that
accompanied the cold sore was gone. The next morning the cold sore
had closed and was scabbed and healing. Within two days of the
application, the cold sore was completely healed. The patient
observed that normal healing time, before the inventive treatment,
took about two weeks.
[0338] Clinical Test 18
[0339] A male was diagnosed with a cold sore in the vistial stage
upon the lower lip. The inventive composition was applied by
vigorous rubbing. The cold sore was observed not to progress beyond
the vistial stage. Healing occurred without pain and throbbing. The
cold sore was totally healed within seven days.
[0340] Clinical Test 19
[0341] A female was diagnosed with two cold sores upon the lower
lip. The inventive composition was applied by vigorous rubbing
between about 30 and about 60 seconds. No pain was felt after the
vigorous rubbing. Two days later, one of the cold sores was gone
and the other one had a slight scab that was also gone after three
more days.
[0342] Clinical Test 20
[0343] A female was diagnosed with a cold sore that was about 2 cm
across and generally round in shape, below one corner of the lower
lip. The inventive composition was applied by vigorous rubbing. The
patient described the cold sore to be burning and weeping. Within
about one minute of treatment, the burning had stopped. Within
hours, the weeping stopped and a normal or non-cold sore scab
appeared. Within days, the cold sore was gone and healed. No
re-occurrence of the cold sore was observed.
[0344] Clinical Test 21
[0345] A male was diagnosed with an extremely swollen, red and
weeping cold sore above one eye. The inventive composition was
applied by vigorous rubbing to the cold sore. The swelling and
redness were reduced within minutes of the treatment. By the next
morning, the cold sore appeared to be a normal or non-cold sore
scab. Complete healing was observed after about four days.
[0346] Clinical Test 22
[0347] A female was diagnosed with a canker or ulcer. The inventive
composition was applied by vigorous rubbing until blood was seen on
the cotton swab. The patient observed that the canker was gone
after only about two or three days. When the patient was
re-examined one week after the treatment, there was no sign of the
canker.
[0348] Clinical Test 23
[0349] A male was diagnosed with shingles in two eruptions; one
upon the face over the cheekbone and the other upon the back of the
neck. The inventive composition was applied by vigorous rubbing to
the eruption upon the face. Immediate reduction in discomfort was
observed. The redness also immediately began to fade. The patient
used shaving soap the same day following treatment and observed
that the eruption on the face was returning. A second treatment was
repeated in the same manner and progress was again arrested. The
treatment site was not contacted the second time with any soap. The
eruption on the face healed completely while the eruption on the
back of the neck remained even after about four weeks. Treatment
was carried out on the eruption on the back of the neck and the
eruption was healed in a few days.
[0350] Clinical Test 24
[0351] A female was diagnosed with a rash of shingles across the
midsection above and at the naval. The inventive composition was
applied by extensive and vigorous rubbing for about 20 minutes. The
progression of the rash was immediately arrested and no new
outbreaks were observed. The rash had been growing from small spots
into large sores.
[0352] Clinical Test 25
[0353] A number of patients with primary eruption cases were
treated by the inventive method. It was observed that in each
patient, there was no reoccurrence of cold sores, as is typical
with untreated primary occurrences.
[0354] Clinical Test 26
[0355] An individual was diagnosed with what appeared to be a
spider bite upon the lower calf area of the leg from a Brown
Recluse. A "bullseye" discoloration was observed at the bite
location with a brown-red middle region and a red circumferential
region. The entire area affected by the venom appeared to be about
eight to about nine centimeters in diameter. The inventive
composition was applied by vigorous rubbing. After an overnight
wait following treatment, the discoloration was not observable. A
scab that formed at the center of the bite, fell off after about
three days.
[0356] Herpes types I and II infect all areas of the body because
of life style changes. Genital herpes is known to be caused by any
one of herpes 1 and 2. Herpes type 1 was previously localized on
the lips whereas herpes type 2 was found in the genital area.
Herpes types 1 and 2 infect nowadays the lip and genital areas and
they also infect the skin through scratches or other injuries.
These infected areas include the eyes, nose, any mucous membranes,
anal tissue, mouth and throat tissues, pubic area tissue, anal
area, and portions of skin that are scratched, pricked or otherwise
injured. Treatment according to the present invention for any
herpes skin lesion in any area has shown the same surprising
reduction of pain, the stopping of the infection and quick healing.
Surprisingly another herpes infection, chicken pox sores respond to
treatment according to the present invention by stopping the
intense itching, which in turn stops the scratching with its sores
and scaring. The progression of the pox stopped and healing was
surprisingly rapid with this treatment.
[0357] The number and severity of any of the Herpes types I and II
outbreaks that are treated quickly and aggressively according to
the present invention are reduced or stopped. It is believed that
the nerve pathways that enable the re-infection are affected in
such a way that the re-infection no longer occurs.
[0358] Clinical Test 27
[0359] Young woman presented with Herpes in the genital area,
apparently infected by non-sexual means. The infection occurred
when this individual was 20, it was diagnosed as herpes by a
physician and treated with acyclovir. Normal recurrence presented
and it was treated aggressively according to the present invention,
resulting in surprising healing of the infection. The recurrence
lesions surprisingly stopped and this individual has been lesion
free for one and a half years after the aggressive treatment of the
lesions that had appeared.
[0360] Clinical Test 28
[0361] A woman of about 45 had a history of herpetic lesions in the
genital area that recurred almost every month at menstruation time.
This individual experienced pain relief and quick healing after
aggressive treatment according to the present invention. The time
between recurrences has surprisingly decreased and this individual
has been lesion-free for over three months. The lesion sites are
being eliminated and no return of such lesions is being
observed.
[0362] Clinical Test 29
[0363] A male diagnosed with a cold sore in the corner of the eye
lid, a lesion that subsequently progressed onto the white of the
eye. Careful treatment according to the present invention stopped
the progression of the lesion, and healed it without scaring.
Lesions of this type that extend to the cornea can lead to
blindness.
[0364] Clinical Test 30
[0365] A female under treatment with interferon for leukemia had
constant recurrence of cold sores on her lips and inside her mouth;
she was constantly afflicted by lesions in progress. At the time of
treatment according to this invention, she had one cold sore lesion
healing on her lip and a count of about 30 vesicles forming inside
her lip and mouth. Treatment according to the present invention
stopped the pain and all the vesicles healed without producing
lesions. No new lesion developed for a nine-month period after the
treatment according to this invention.
[0366] Clinical Test 31
[0367] A male had a history of cold sores developing about six
times a year. The lesions would break out at one of five places on
the lips. Treatment according to the present invention lead to the
reduction of lesions and also to an increase in the time between
lesion recurrence. It was observed that the more quickly the
lesions were treated upon noticing their onset, the more effective
was the reduction of both the lesions and the number of affected
sites. All the lesion sites have been free of cold sores for over
one year, and some sites have not had lesions for more than two
years.
[0368] Clinical Test 32
[0369] A 56 year old woman underwent a bone marrow transplant
resulting in an immunosuppressed condition. She subsequently
contracted chicken pox and experienced classic chicken pox lesions
over approximately 60% of her body from just above the genital area
and covering her trunk, arms, and head. There were multiple pox
manifestations of which 2 were scratched open. There was intense
itching and pain associated with the pox. The condition was
diagnosed as chicken pox (Herpes Varicella-Zoster Virus) by a
physician. A treatment according to this invention was applied by
using the rubbing action described herein on each pox or lesion for
approximately 10 seconds per lesion. The pox manifestations were
too numerous to count, but were estimated to exceed one hundred.
Treatment of such extensive manifestations took approximately one
hour. Following treatment, pain and itching symptomatically abated
in about 10 minutes. There was no further progression of any of the
treated sores. The condition fully abated with a return to intact
skin with normal appearance and with no pain or itching within two
days. There have been no recurrences since the time the treatment
according to the present invention was administered.
[0370] Clinical Test 33
[0371] A female, age 45, with clinical history of recurrent Herpes
Zoster (HZV), commonly known as shingles, experienced a recurrent
outbreak after a stressful week at work and a weekend in the sun.
This subject had her first episode with HZV about one year prior to
the presently described outbreak. She was diagnosed by her
physician and given a prescription for Zovirax. She has had three
episodes of HZV outbreaks since then that were not treated with
Zovirax. The lesions included all the classic stages for this
disease, including weeping, but the outbreaks caused small lesions
in rather small numbers, such as three or four in each episode.
Each of these recurring episodes lasted at least three or four
weeks. Treatment according to this invention was applied to a
recurrence that was in the beginning of the third day and had
progressed from prodromal "tingle", through papule (raised bump) to
vesicle, and to ulcerated vesicles. Ulceration may have been
exacerbated by inadvertent scratching of the lesions. This is a
tendency that is often experienced by individuals with this type of
lesions, despite their best efforts not to scratch the itching
areas of their bodies. This individual reported that the pain was
localized at each lesion site, but that the experienced overall
discomfort had made it difficult to sleep the night before.
Approximately 35 distinct lesions were displayed by this individual
at the time of this treatment, and these lesions were located in
the chest area and covered approximately one fourth of the upper
chest area, spreading up onto her shoulders. The lesions varied in
size from about 3 mm.times.5 mm to the largest, which was a series
of lesions that had joined together to form a lesion area of about
18 mm.times.25 mm. The subject reported that this was the worst
episode of HZV that she had ever experienced in all aspects: It was
the most painful, covered the largest area, and it was the most
bothersome.
[0372] Prior to treatment according to the present invention at 10
am, the lesions were consistent with herpes lesions, but epithelial
damage was still limited, probably due to the early stage of the
disease progression. A solution according to the present invention
was rubbed onto each sore site in accordance with the rubbing
action described herein. Following treatment, the area was rubbed
using bulk solution. This subject reported a gradual loss of pain,
itching, and burning during the day of treatment, and her sleep
that night was trouble-free. All the pain, itching and burning had
subsided the next day, and the lesions were beginning to scab. Four
days following the treatment according to the present invention,
all but a few small scabs had fallen off. No other symptoms were
present about 102 hours following the treatment. Furthermore, no
adverse events were experienced.
[0373] Comparative Clinical Test 1
[0374] A female was diagnosed with a cold sore above the upper
corner of the upper lip. The inventive composition was applied but
only slight rubbing occurred. 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.
HYPOTHETICAL EXAMPLES
[0375] The following are hypothetical examples. These hypothetical
examples include treatment compositions utilizing organochlorides
other than benzalkonium chloride, docosanol, or nucleosides.
Example 1
[0376] In a first example, disordered tissue that has a redness of
10 of a nominal red scale is subjected to the inventive method by
impregnating an applicator with about 0.02% benzalkonium chloride
in isopropyl alcohol composition. The impregnated applicator is
then vigorously applied to a labial disordered tissue for a time
period of about 30 seconds. During the application time period,
about 0.2 ml of the inventive composition is absorbed into the
patient's disordered tissue. The patient's disordered tissue is
estimated to have an area of about 0.5 cm.sup.2. The patient's
disordered tissue is then examined and is found to have a decreased
nominal red scale to about 6 after about 24 hours and an increased
eosinophil assay of about 40% before about one hour.
Comparative Example 1
[0377] In a first comparative example, an applicator with about
0.02% benzalkonium chloride in isopropyl alcohol is gently applied
to a disordered tissue by dabbing such that substantially no
pressure is applied sufficient to depress the tissue against hard
tissue that lies underneath. The impregnated applicator is applied
to a labial disordered tissue for a time period of about 30
seconds. During the application time period, about 0.1 ml of the
inventive composition is absorbed into the patient's disordered
tissue. The patient's disordered tissue is estimated to have an
area of about 0.5 cm.sup.2. The patient's disordered tissue is then
examined and is found to have a decreased nominal red scale from 10
to about 9 after about 24 hours and an increased eosinophil assay
of about 5% before about one hour.
Comparative Example 2
[0378] In another example comparative to the first example, a
disordered tissue is treated substantially the same as in the first
example with the exception that only isopropyl alcohol is
impregnated in the applicator. The patient's disordered tissue is
examined after the treatment and is found to have an unchanged
nominal red scale score and a negligibly increased eosinophil
assay. However, note that some reduction of redness occurs when
just alcohol is used, especially when the disordered tissue is an
open sore, as the alcohol tends to wash away toxic material. The
redness returns as does the pain as toxins continue to build up
since the source of the infection has not been eliminated. Note
also that in the United States, alcohol cannot be listed as an
active agent in the treatment of cold sores caused by herpes.
Example 2
[0379] In a second example, all conditions are the same as in the
first example with the following variations. An embodiment of the
inventive composition is applied to a typical sterile bandage and
left over the patient's disordered tissue for about one hour. The
sterile bandage may double as part of the applicator. The
composition contains, in addition to about 0.02% benzalkonium
chloride in isopropyl alcohol, about 5% of a composition of
lidocaine and prilocalne in about a 1:1 mixture. After the one hour
time period, the patient's skin is substantially numbed, and the
applicator is vigorously rubbed into the disordered tissue for
about 30 seconds. The patient experiences significantly less pain
than that experienced in the first example. The patient's
disordered tissue is then examined and is found to have a decreased
nominal red scale to about 3 from a beginning of eight after about
24 hours and an increased eosinophil assay of about 50% before
about one hour.
Comparative Example 3
[0380] In a second comparative example, all conditions are the same
as in the second example except that no agitation of the disordered
tissue occurs. The patient again experiences a numbing sensation
after contact of the inventive composition with the cold sore, but
is found to have a decreased nominal red scale to about nine and an
increased eosinophil assay of about 10% before one hour.
Comparative Example 4
[0381] In another example comparative to the second example, the
applicator is impregnated with the lidocaine: prilocaine mixture in
isopropyl alcohol but no benzalkonium chloride or any other active
agent is included. The patient's disordered tissue is then examined
and is found to have a nominal red scale of about nine and a
negligibly increased eosinophil assay before one hour.
Example 3
[0382] In a third example, a patient with pink eye is administered
the inventive composition containing about 0.01% benzalkonium
chloride in a carrier that is substantially nonirritating to the
sclera and supporting eye tissue. The patient, with washed and
disinfected hands, then rubs the closed eyelid with the hand or
fingers for about 30 seconds. The patient's eye is then examined
and is found to have a decreased nominal red scale to about 1 after
about 24 hours.
Comparative Example 5
[0383] In a third comparative example, a patient is treated exactly
as in the third example except that no rubbing through the closed
eyelid is carried out. The patient's eye is then examined and is
found to have a decreased nominal red scale only to about 7 after
about 24 hours.
Comparative Example 6
[0384] In another comparative example to the third example, the
patient with pink eye is administered with a carrier but with no
active agent therein. The patient's eye is then examined and is
found to have a decreased nominal red scale to about 8 after about
24 hours.
Example 4
[0385] In this example, a treatment composition is formed with
benzethonium chloride as the active agent. The treatment
composition is applied to disordered tissue like that in Example 1
which has a redness of 10 or a nominal red scale. The disordered
tissue was on the patient's back. Note that when the treatment
composition is applied to thicker sections of skin such as occur on
the back it is more difficult to penetrate than on thinner sections
such as the lip or cheek. Accordingly when treating such thick skin
portions, it is necessary to increase the active agent
concentration, rub and/or press harder, or agitate more frequently.
The treatment composition includes about 0.01% benzethonium
chloride in isopropyl alcohol. An applicator impregnated with the
treatment composition is then vigorously applied to a labial
disordered tissue for a time period of about 30 seconds. During the
application time period, about 0.2 ml of the inventive composition
is absorbed into the patient's disordered tissue. The patient's
disordered tissue is estimated to have an area of about 0.5
cm.sup.2. The patient's disordered tissue is then examined after
about one hour and is found to have reduced redness, which is
however not as reduced compared to that achieved in Example 1.
Similarly, the eosinophil assay is increased but not to the extent
of that in Example 1 which used benzalkonium chloride.
Example 5
[0386] In this example, a treatment composition is formed with
methyl benzethonium chloride as the active agent. The treatment
composition is applied to disordered tissue like that in Example 1
which has a redness of 10 or a nominal red scale. The treatment
composition includes about 0.02% methyl benzethonium chloride in a
carrier comprising about 70% isopropyl alcohol by volume of the
carrier and about 30% water. An applicator impregnated with the
treatment composition is then vigorously applied to a labial
disordered tissue for a time period of about 30 seconds. During the
application time period, about 0.2 ml of the inventive composition
is absorbed into the patient's disordered tissue. The patient's
disordered tissue is estimated to have an area of about 0.5
cm.sup.2. The patient's disordered tissue is then examined after
about one hour and is found to have reduced redness, which is
however not as reduced compared to that achieved in Example 1.
Similarly, the eosinophil assay is increased but not to the extent
of that in Example 1 which used benzalkonium chloride.
Example 6
[0387] In this example, a treatment composition is formed with
cetyl pyridinium chloride as the active agent. The treatment
composition is applied to disordered tissue like that in Example 1
on a patient's arm which has a redness of 10 or a nominal red
scale. The treatment composition includes about 2.0% cetyl
pyridinium chloride iii a carrier comprising about 60% isopropyl
alcohol by volume of the carrier, about 30% water and 10% acetone.
An applicator impregnated with the treatment composition is then
vigorously applied to a labial disordered tissue for a time period
of about 30 seconds. During the application time period, about 0.2
ml of the inventive composition is absorbed into the patient's
disordered tissue. The patient's disordered tissue is estimated to
have an area of about 0.5 cm.sup.2. The patient's disordered tissue
is then examined after about one hour and is found to have reduced
redness, which is however not as reduced compared to that achieved
in Example 1. Similarly, the eosinophil assay is increased but not
to the extent of that in Example 1 which used benzalkonium
chloride.
Example 7
[0388] In this example, a treatment composition is formed with
chloroxylenol as the active agent. Hereinbelow is the chemical
structure of chloroxylenol. ##STR6##
[0389] The treatment composition is applied to disordered tissue
like that in Example 1 which has a redness of 10 or a nominal red
scale. The treatment composition includes about 0.5% chloroxylenol
in acetone. An applicator impregnated with the treatment
composition is then vigorously applied to a labial disordered
tissue for a time period of about 30 seconds. During the
application time period, about 0.2 ml of the inventive composition
is absorbed into the patient's disordered tissue. The patient's
disordered tissue is estimated to have an area of about 0.5
cm.sup.2. The patient's disordered tissue is then examined after
about one hour and is found to have reduced redness, which is
however not as reduced compared to that achieved in Example 1.
Similarly, the eosinophil assay is increased but not to the extent
of that in Example 1 which used benzalkonium chloride.
Example 8
[0390] In this example, a treatment composition is formed with
hexachlorophene as the active agent. Hereinbelow is the chemical
structure of hexachlorophene. ##STR7##
[0391] The treatment composition is applied to disordered tissue
like that in Example 1 which has a redness of 10 or a nominal red
scale. The treatment composition includes about 0.04%
hexachlorophene in a carrier comprising about 80% isopropyl alcohol
by volume of the carrier, about 15% water and 5% cetyl alcohol. An
applicator impregnated with the treatment composition is then
vigorously applied to a labial disordered tissue for a time period
of about 30 seconds. During the application time period, about 0.2
ml of the inventive composition is absorbed into the patient's
disordered tissue. The patient's disordered tissue is estimated to
have an area of about 0.5 cm.sup.2. The patient's disordered tissue
is then examined after about one hour and is found to have reduced
redness, which is however not as reduced compared to that achieved
in Example 1. Similarly, the eosinophil assay is increased but not
to the extent of that in Example 1 which used benzalkonium
chloride.
Example 9
[0392] In this example, a treatment composition is formed with
triclosan as the active agent. Hereinbelow is the chemical
structure of triclosan. ##STR8##
[0393] The treatment composition is applied to disordered tissue
like that in Example 1 which has a redness of 10 or a nominal red
scale. The treatment composition includes about 0.01% triclosan in
a carrier comprising about 60% methyl alcohol by volume of the
carrier, about 30% water and 10% acetone. An applicator impregnated
with the treatment composition is then vigorously applied to a
labial disordered tissue for a time period of about 30 seconds.
During the application time period, about 0.2 ml of the inventive
composition is absorbed into the patient's disordered tissue. The
patient's disordered tissue is estimated to have an area of about
0.5 cm.sup.2. The patient's disordered tissue is then examined
after about one hour and is found to have reduced redness, which is
however not as reduced compared to that achieved in Example 1.
Similarly, the eosinophil assay is increased but not to the extent
of that in Example 1 which used benzalkonium chloride.
Example 10
[0394] In this example, a treatment composition is formed with
chlorhexidine as the active agent. Hereinbelow is the chemical
structure of chlorhexidine. ##STR9##
[0395] The treatment composition is applied to disordered tissue
like that in Example 1 which has a redness of 10 or a nominal red
scale. The treatment composition includes about 0.03% chlorhexidine
in methyl alcohol. An applicator impregnated with the treatment
composition is then vigorously applied to a labial disordered
tissue for a time period of about 30 seconds. During the
application time period, about 0.2 ml of the inventive composition
is absorbed into the patient's disordered tissue. The patient's
disordered tissue is estimated to have an area of about 0.5
cm.sup.2. The patient's disordered tissue is then examined after
about one hour and is found to have reduced redness, which is
however not as reduced compared to that achieved in Example 1.
Similarly, the eosinophil assay is increased but not to the extent
of that in Example 1 which used benzalkonium chloride.
Example 11
[0396] A treatment composition similar to the composition used in
the Clinical Examples is applied to the smallpox lesions of a
person suffering from smallpox. Based on the results set forth in
the Clinical Examples, particularly those that showed an
improvement when the composition was used to treat chicken pox,
cold sores and shingles, it would be expected that the treatment
composition would be effective in lessening the effects of
smallpox, both in terms of the duration and extent of the small pox
lesions as well as the ability to arrest the disease prior to
death. The isopropyl alcohol carrier will break through and
penetrate the cell walls of any infected cells and carry with it
the benzalkonium chloride molecules, which will then kill the
infected cells and prevent further advancement of the infection.
The treatment composition will also act to breakdown any toxins
released by the infected cells located in the skin area. It will
also directly attack and denature any free viruses within the
subcutaneous reservoir or bath of treatment composition. Based on
the incubation period of smallpox virus, the treatment composition
should be applied and then reapplied periodically until the disease
is eradicated, such as 2-4 treatments a day for 1-3 weeks.
Example 12
[0397] A treatment composition similar to the composition used in
the Clinical Examples is applied to the skin of a person infected
with anthrax. Based on the results set forth in the Clinical
Examples, particularly those that showed an improvement when the
composition was used to treat chicken pox, cold sores and shingles,
as well as the knowledge that 70% isopropyl alcohol is effective in
breaking through and penetrating cell walls, it would be expected
that the treatment composition would be effective in lessening the
effects of anthrax. The isopropyl alcohol carrier will break
through and penetrate the anthrax bacteria's cell walls and carry
with it the benzalkonium chloride molecules, which will then kill
the anthrax cell and prevent further advancement of the infection.
The treatment composition will also act to breakdown any toxins
released by the anthrax cells located in the skin area. Based on
the incubation period of the anthrax bacteria, the treatment
composition should be applied and then reapplied periodically until
the disease is eradicated, such as 2-4 treatments a day for 1-3
weeks.
Example 13
[0398] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight acyclovir. Although acyclovir has only been proven
to be effective in treating disordered tissue caused by a herpes
virus when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the acyclovir beneath the skin surface and into the
subcutaneous "bath" where it is available for disruption of viral
replication.
Example 14
[0399] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of an acyclovir derivative. Although acyclovir
derivatives have only been proven to be effective in treating
disordered tissue caused by a herpes virus when administered
systemically, rather than topically, this exemplary composition
works to inhibit viral replication because the tissue penetrating
component (i.e., aqueous isopropyl alcohol) carries the acyclovir
derivative beneath the skin surface and into the subcutaneous
"bath" where it is available for disruption of viral
replication.
Example 15
[0400] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of valcyclovir or a derivative thereof. Although
valcyclovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the valcyclovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 16
[0401] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of penciclovir or a derivative thereof. Although
penciclovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the penciclovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 17
[0402] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of famciclovir or a derivative thereof. Although
famciclovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the famciclovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 18
[0403] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of ganciclovir or a derivative thereof. Although
ganciclovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the ganciclovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 19
[0404] An anti-viral composition is formed from a mixture
containing 99% by weight aqueous isopropyl alcohol (70% by volume)
and 1% by weight of cidofovir or a derivative thereof. Although
cidofovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the cidofovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 20
[0405] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of adefovir or a derivative thereof. Although
adefovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the adefovir or derivative thereof beneath the skin surface
and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 21
[0406] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5%-by weight of tenofovir or a derivative thereof. Although
tenofovir and derivatives thereof have only been proven to be
effective in treating disordered tissue caused by a herpes virus
when administered systemically, rather than topically, this
exemplary composition works to inhibit viral replication because
the tissue penetrating component (i.e., aqueous isopropyl alcohol)
carries the tenofovir or derivative thereof beneath the skin
surface and into the subcutaneous "bath" where it is available for
disruption of viral replication.
Example 22
[0407] An anti-viral composition is formed from a mixture
containing 95% by weight aqueous isopropyl alcohol (70% by volume)
and 5% by weight of 1-docosanol. Although docosanol has been used
topically to treat disordered tissue caused by a herpes virus, this
exemplary composition is a vast improvement because of the tissue
penetrating effect of the aqueous isopropyl alcohol, which carries
the 1-docosanol beneath the skin surface and into the subcutaneous
"bath" where it is available for anti-viral treatment.
[0408] 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.
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