U.S. patent application number 17/745058 was filed with the patent office on 2022-09-22 for biophotonic compositions for treating skin and soft tissue wounds having either or both non-resistant and resistant infections.
The applicant listed for this patent is VETOQUINOL S.A.. Invention is credited to Francesco BELLINI, Lise HEBERT, Nikolaos LOUPIS, David OHAYON, Angela PALUMBO PICCIONELLO, Remigio PIERGALLINI, Alberto SALVAGGIO, Andrea SPATERNA, Cecilia VULLO.
Application Number | 20220296713 17/745058 |
Document ID | / |
Family ID | 1000006344788 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220296713 |
Kind Code |
A1 |
BELLINI; Francesco ; et
al. |
September 22, 2022 |
BIOPHOTONIC COMPOSITIONS FOR TREATING SKIN AND SOFT TISSUE WOUNDS
HAVING EITHER OR BOTH NON-RESISTANT AND RESISTANT INFECTIONS
Abstract
The present document describes methods and uses of biophotonic
compositions which comprise at least one oxidant and at least one
chromophore capable of activating the oxidant, in association with
a pharmacologically acceptable carrier for use in the treatment of
skin and soft tissue wounds that have either or both non-resistant
and resistant infections.
Inventors: |
BELLINI; Francesco;
(Calgary, CA) ; SALVAGGIO; Alberto; (Matelica,
IT) ; PALUMBO PICCIONELLO; Angela; (Matelica, IT)
; SPATERNA; Andrea; (Matelica, IT) ; LOUPIS;
Nikolaos; (Athens, GR) ; HEBERT; Lise;
(Montreal, CA) ; OHAYON; David;
(Dollard-des-Ormeaux, CA) ; PIERGALLINI; Remigio;
(Grottammare, IT) ; VULLO; Cecilia;
(Castelraimondo, IT) |
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Applicant: |
Name |
City |
State |
Country |
Type |
VETOQUINOL S.A. |
Lure |
|
FR |
|
|
Family ID: |
1000006344788 |
Appl. No.: |
17/745058 |
Filed: |
May 16, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16068714 |
Jul 9, 2018 |
11382977 |
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PCT/CA2017/050036 |
Jan 11, 2017 |
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17745058 |
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62277286 |
Jan 11, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/04 20180101;
A61N 2005/0663 20130101; A61K 31/728 20130101; A61K 31/352
20130101; A61K 31/7008 20130101; A61K 33/40 20130101; A61K 41/0057
20130101; A61K 31/4166 20130101; A61N 2005/0651 20130101; A61K
31/17 20130101; A61P 1/02 20180101; A61P 17/02 20180101; A61N
2005/0662 20130101; A61N 5/062 20130101; A61K 31/327 20130101 |
International
Class: |
A61K 41/00 20060101
A61K041/00; A61K 31/17 20060101 A61K031/17; A61K 31/352 20060101
A61K031/352; A61P 31/04 20060101 A61P031/04; A61P 1/02 20060101
A61P001/02; A61P 17/02 20060101 A61P017/02; A61K 31/327 20060101
A61K031/327; A61K 31/4166 20060101 A61K031/4166; A61K 31/7008
20060101 A61K031/7008; A61K 31/728 20060101 A61K031/728; A61K 33/40
20060101 A61K033/40; A61N 5/06 20060101 A61N005/06 |
Claims
1. A method of treating a skin or soft tissue wound having a
non-resistant or a resistant infection, or both categories of
infection, comprising: a) applying a biophotonic composition to a
patient in need thereof, wherein the biophotonic composition
comprises at least one oxidant and at least one chromophore capable
of activating the oxidant; and b) exposing said biophotonic
composition to actinic light for a time sufficient for said
chromophore to cause activation of said oxidant.
2. The method according to claim 1, wherein the infection is a
bacterial infection.
3. The method according to claim 2, wherein the bacterial infection
is resistant to antibiotics.
4.-8. (canceled)
9. The method according to claim 1, wherein the infection is an
antibiotic resistant infection.
10. The method according to claim 1, wherein the wound is a skin
wound.
11. The method according to claim 1, wherein the method promotes
the healing of wound.
12. The method according to claim 1, wherein the soft tissue wound
comprises an oral disease.
13. The method according to claim 1, wherein said biophotonic
composition is exposed to actinic light for a period of less than
about 5 minutes.
14.-16. (canceled)
17. The method according to claim 1, wherein the source of actinic
light is positioned over an area to be treated.
18. The method according to claim 1, wherein said actinic light is
visible light having a peak wavelength from about 400 nm to about
700 nm.
19. The method according to claim 1, wherein the oxidant is chosen
from hydrogen peroxide, carbamide peroxide and benzoyl
peroxide.
20. (canceled)
21. The method according to claim 1, wherein the composition
further comprises at least one healing factor chosen from
hyaluronic acid, glucosamine and allantoin.
22. The method according to claim 1, wherein the composition
further comprises at least one gelling agent.
23. The method according to claim 22, wherein the gelling agent is
chosen from glucose, modified starch, methyl cellulose,
carboxymethyl cellulose, propyl cellulose, hydroxypropyl cellulose,
a carbomer, alginic acid, sodium alginate, potassium alginate,
ammonium alginate, calcium alginate, agar, carrageenan, locust bean
gum, pectin, and gelatin.
24. The method according to claim 1, wherein the chromophore is
chosen from a xanthene derivative dye, an azo dye, a biological
stain, and a carotenoid.
25. The method according to claim 24, wherein said xanthene
derivative dye is chosen from a fluorene dye, a fluorone dye, and a
rhodole dye.
26.-28. (canceled)
29. The method according to claim 25, wherein said fluorone dye is
chosen from fluorescein and fluorescein derivatives.
30. The method according to claim 29, wherein said fluorescein
derivative is chosen from phloxine B, rose bengal, and
merbromine.
31. The method according to claim 29, wherein said fluorescein
derivative is chosen from Eosin Y, Eosin B and Erythrosine B.
32. The method according to claim 31, wherein said fluorescein
derivative is Eosin Y.
33.-68. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims priority to and benefit from U.S.
Provisional Patent Application No. 62/277,286, filed Jan. 11, 2016,
the disclosure of which is incorporated herein by reference in its
entirety.
TECHNICAL FIELD
[0002] This disclosure relates to the field of biophotonic
compositions, methods, and uses for treating skin and soft tissue
wounds that have either or both non-resistant and resistant
infections.
BACKGROUND
[0003] Treatment of skin and soft tissue wounds in mammals such as
humans, horses, cats, or dogs can be challenging, especially due to
infection of the wound, and moreover if the infection becomes a
resistant infection. A resistant infection is an infection caused
by a microorganism that is resistant to an antimicrobial or
anti-infective agent that was originally effective for treatment of
infections caused by it. Resistant microorganisms (including
bacteria, fungi, viruses and parasites) are able to withstand
treatment by antimicrobial or anti-infective agents, such as
antibacterial agents (e.g., antibiotics), antifungals, antivirals,
and antiprotozoals, so that standard treatments become ineffective
and infections persist. As resistant infections fail to respond to
standard treatments, they result in prolonged healing, reduced
effectiveness of treatment, higher care expenditures, and a greater
risk of death.
[0004] Effective treatments for the treatment of skin and soft
tissue wounds having non-resistant infections or resistant
infections or both categories of infections, are needed.
SUMMARY OF THE DISCLOSURE
[0005] In some aspects, this disclosure provides new methods of
treatment of a skin or soft tissue wound having a non-resistant or
a resistant infection or both categories of infections, and makes
the management of these infections less frustrating and
economically challenging. The compositions, methods, and uses
disclosed herein reduce healing time compared to conventional
treatments, therefore result in less stress and discomfort to the
patient. The compositions, methods, and uses disclosed herein are
also easier to use than unconventional treatments, such as
platelet-rich plasma therapy and stem cell therapy. Additionally,
the compositions, methods, and uses disclosed herein can reduce the
microbial load of wounds and are useful in maintaining asepsis
during surgeries. The compositions, methods, and uses of the
disclosure can be used to treat resistant infections, and even
non-resistant infections, of skin and soft tissue wounds without or
with reduced use of antibiotics or antimicrobial agents.
[0006] In some aspects, this disclosure provides a method of
treating a skin or soft tissue wound having a non-resistant or a
resistant infection, or both categories of infection, comprising:
applying a biophotonic composition to a patient in need thereof,
wherein the biophotonic composition comprises at least one oxidant
and at least one chromophore capable of activating the oxidant; and
exposing said biophotonic composition to actinic light for a time
sufficient for said chromophore to cause activation of said
oxidant. In certain such aspects, the soft tissue wound comprises
an oral disease. In certain such aspects, the wound is a skin
wound. In certain aspect, the method promotes the healing of wound.
In certain such aspects, either or both the non-resistant and the
resistant infection is a bacterial infection. In certain such
aspects, the bacterial infection is resistant to antibiotics. In
certain such aspects, the patient is a mammal, such as a human, an
equine, a feline, or a canine. In certain such aspects, the
infection is a resistant infection. In certain aspects, the
infection is an antibiotic resistant infection.
[0007] In some embodiments, said biophotonic composition is exposed
to actinic light for a period of less than about 5 minutes, e.g.,
for a period of from about 1 second to about 5 minutes. In certain
such embodiments, said biophotonic composition is exposed to
actinic light for a period of less than about 5 minutes per
cm.sup.2 of an area to be treated, e.g., for a period of about 1
second to about 5 minutes per cm.sup.2.
[0008] In some embodiments, the source of actinic light is
positioned over an area to be treated. In some embodiments, said
actinic light is visible light having a wavelength between about
400 nm and about 700 nm.
[0009] In some embodiments, the oxidant present in the biophotonic
composition is chosen from hydrogen peroxide, carbamide peroxide,
and benzoyl peroxide. In other embodiments, the oxidant is chosen
from a peroxy acid and an alkali metal percarbonate.
[0010] In some embodiments, the biophotonic composition further
comprises at least one healing factor chosen from hyaluronic acid,
glucosamine, and allantoin.
[0011] In some embodiments, the biophotonic composition further
comprises at least one gelling agent, such as glucose, modified
starch, methyl cellulose, carboxymethyl cellulose, propyl
cellulose, hydroxypropyl cellulose, a carbomer, alginic acid,
sodium alginate, potassium alginate, ammonium alginate, calcium
alginate, agar, carrageenan, locust bean gum, pectin, or
gelatin.
[0012] In some embodiments, the chromophore of the biophotonic
composition is chosen from a xanthene derivative dye, an azo dye, a
biological stain, and a carotenoid. In certain such embodiments,
said xanthene derivative dye is chosen from a fluorene dye (e.g., a
pyronine dye, such as pyronine Y or pyronine B, or a rhodamine dye,
such as rhodamine B, rhodamine G, or rhodamine WT), a fluorone dye
(e.g., fluorescein, or fluorescein derivatives, such as phloxine B,
rose bengal, merbromine, Eosin Y, Eosin B, or Erythrosine B, i.e.,
Eosin Y), or a rhodole dye. In certain such embodiments, said azo
dye is chosen from methyl violet, neutral red, para red, amaranth,
carmoisine, allura red AC, tartrazine, orange G, ponceau 4R, methyl
red, and murexide-ammonium purpurate. In certain such embodiments,
said biological stain is chosen from saffranin 0, basic fuchsin,
acid fuschin, 3,3' dihexylocarbocyanine iodide, carminic acid, and
indocyanine green. In certain such embodiments, said carotenoid is
chosen from crocetin, .alpha.-crocin (S,S-diapo-S,S-carotenoic
acid), zeaxanthine, lycopene, .alpha.-carotene, .beta.-carotene,
bixin, and fucoxanthine. In certain such embodiments, said
carotenoid is present in the composition as a mixture chosen from
saffron red powder, annatto extract, and brown algae extract.
[0013] In certain embodiments, said biophotonic composition further
comprises at least one chelating agent chosen from
ethylenediaminetetraacetic acid (EDTA) and ethylene glycol
tetraacetic acid (EGTA).
[0014] In some aspects, the disclosure provides for use of a
biophotonic composition for the manufacture of a medicament for
treating a patient afflicted with a skin or soft tissue wound
having a non-resistant infection or a resistant infection or both
categories of infection, wherein said composition comprises: at
least one oxidant, and at least one chromophore capable of
activating the oxidant; in association with a pharmacologically
acceptable carrier. In certain such aspects, the soft tissue wound
comprises an oral disease. In certain such aspects, the wound is a
skin wound. In certain such aspects, either or both the
non-resistant and the resistant infection is a bacterial infection.
In certain such aspects, the bacterial infection is resistant to
antibiotics. In certain such aspects, the patient is a mammal, such
as a human, an equine, a feline or a canine. In certain such
aspects, the infection is a resistant infection.
[0015] In some aspects, the disclosure provides for use of a
biophotonic composition for the treatment of a patient afflicted
with a skin or soft tissue wound having a non-resistant or a
resistant infection or both categories of infection, wherein said
composition comprises: at least one oxidant; and at least one
chromophore capable of activating the oxidant; in association with
a pharmacologically acceptable carrier. In certain such aspects,
the soft tissue wound comprises an oral disease. In certain such
aspects, the wound is a skin wound. In certain such aspects, either
or both the non-resistant and the resistant infection is a
bacterial infection. In certain such aspects, the bacterial
infection is resistant to antibiotics. In certain such aspects, the
patient is a mammal, such as a human, an equine, a feline or a
canine. In certain such aspects, the infection is a resistant
infection.
Definitions
[0016] Before continuing to describe the present disclosure in
further detail, it is to be understood that this disclosure is not
limited to specific compositions or process steps, as such may
vary. It must be noted that, as used in this specification and the
appended embodiments, the singular form "a", "an" and "the" include
plural referents unless the context clearly dictates otherwise.
[0017] It is understood that, whether the term "about" is used
explicitly or not, every quantity given herein is meant to refer to
the actual given value, and it is also meant to refer to the
approximation to such given value that would reasonably be inferred
based on the ordinary skill in the art, including equivalents and
approximations due to the experimental and/or measurement
conditions for such given value.
[0018] It is convenient to point out here that "and/or" where used
herein is to be taken as specific disclosure of each of the two
specified features or components with or without the other. For
example "A and/or B" is to be taken as specific disclosure of each
of (i) A, (ii) B and (iii) A and B, just as if each is set out
individually herein.
[0019] "Biophotonic" means the generation, manipulation, detection
and application of photons in a biologically relevant context. In
other words, biophotonic compositions exert their physiological
effects primarily due to the generation and manipulation of
photons. "Biophotonic composition" is a composition as described
herein that may be activated by light to produce photons for
biologically relevant applications.
[0020] "Topical" means as applied to body surfaces, such as the
skin, mucous membranes, vagina, oral cavity, internal surgical
wound sites, and the like.
[0021] Terms "chromophore", "photoactivating agent" and
"photoactivator" are used herein interchangeably. A chromophore
means a compound, when contacted by light irradiation, is capable
of absorbing the light. The chromophore readily undergoes
photoexcitation and can then transfer its energy to other molecules
or emit it as light.
[0022] The term "oxidant" is intended to mean either a compound
that readily transfers oxygen atoms to, and thus, oxidizes other
compounds, or a substance that gains electrons in a redox chemical
reaction.
[0023] The term "chelating agent" is intended to mean a compound
that binds metal ions, such as iron, cobalt, copper, manganese, and
chromium ions, and facilitates their solvation in solution.
[0024] The term "healing factor" is intended to mean a compound
that promotes or enhances the healing or regenerative process of a
tissue.
[0025] The term "active oxygen species" is intended to mean
chemically-reactive molecules containing oxygen. Examples include,
but are not limited to, oxygen ions and peroxides. They can be
either inorganic or organic. Active oxygen species are highly
reactive due to the presence of unpaired valence shell electrons.
They are also referred to as "reactive oxygen", "active oxygen", or
"reactive oxygen species".
[0026] "Wound" means an injury to any tissue, including, for
example but are not limited to, acute, subacute, delayed or
difficult to heal wounds, and chronic wounds. Examples of wounds
include both open and closed wounds. Wounds include, for example,
but are not limited to, burns, incisions, excisions, lesions,
lacerations, abrasions, puncture or penetrating wounds, gunshot
wounds, surgical wounds, contusions, hematomas, crushing injuries,
ulcers (such as for example pressure, venous, pressure or
diabetic), wounds caused by periodontitis (inflammation of the
periodontium), or other soft tissue disorders.
[0027] A "resistant infection" is an infection caused by a
microorganism that is resistant to treatment with an antimicrobial
or anti-infective agent that was originally effective in treating
such an infection. Resistant microorganisms (including bacteria,
fungi, viruses and parasites) are able to withstand treatment by
antimicrobial or anti-infective agents, such as antibacterial
agents (e.g., antibiotics), antifungals, antivirals, and
antiprotozoals, so that standard treatments become ineffective and
infections persist.
[0028] An "anti-infective agent" or an "antimicrobial agent" is an
agent that can ameliorate any symptom caused by an infectious agent
and may reduce the spread of the infection. Anti-infective or
antimicrobial agents include antibiotics and antibacterials,
antifungals, antivirals and antiprotozoals.
[0029] Features and advantages of the subject matter hereof will
become more apparent in light of the following detailed description
of selected embodiments, as illustrated in the accompanying
figures. As will be realized, the subject matter disclosed is
capable of modifications in various respects, all without departing
from the scope of the disclosed embodiments. Accordingly, the
figures and the description are to be regarded as illustrative in
nature, and not as restrictive and the full scope of the subject
matter is set forth in the disclosed embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Further features and advantages of the present disclosure
will become apparent from the following detailed description, taken
in combination with the appended drawings, in which:
[0031] FIG. 1 illustrates the Stokes' shift.
[0032] FIG. 2 illustrates the absorption and emission spectra of
donor and acceptor chromophores. The spectral overlap between the
absorption spectrum of the acceptor chromophore and the emission
spectrum of the donor chromophore is also shown.
[0033] FIG. 3 is a schematic of a Jablonski diagram that
illustrates the coupled transitions involved between a donor
emission and acceptor absorbance.
[0034] FIG. 4 presents photographs of healing of a traumatic wound
for a canine patient (patient 6). The patient was treated five
times with a biophotonic composition comprising 6% by weight urea
peroxide. During each treatment, the biophotonic composition was
exposed to actinic light for five minutes.
[0035] FIG. 5 presents photographs of healing of a tail surgery
wound dehiscence for a canine patient (patient 7). The patient was
treated seven times with a biophotonic composition comprising 6% by
weight urea peroxide. During each treatment, the biophotonic
composition was exposed to actinic light for five minutes.
[0036] FIG. 6 presents photographs of healing of a surgical wound
for a canine patient (patient 11). The patient was treated four
times with a biophotonic composition comprising 3% by weight urea
peroxide. During each treatment, the biophotonic composition was
exposed to actinic light for two minutes. The first treatment with
the biophotonic composition was performed during surgery.
[0037] FIG. 7 presents photographs of healing of a surgical wound
for a canine patient (patient 17). The patient was treated three
times with a biophotonic composition comprising 3% by weight urea
peroxide. During each treatment, the biophotonic composition was
exposed to actinic light for two minutes. The first treatment with
the biophotonic composition was performed during surgery.
[0038] FIGS. 8A and 8B present tissue analysis of healing of a
surgical wound for a canine patient (patient 17). FIG. 8A shows
tissues treated three times with a biophotonic composition
comprising 3% by weight urea peroxide. During each treatment, the
biophotonic composition was exposed to actinic light for two
minutes. The first treatment with the biophotonic composition was
performed during surgery. FIG. 8B shows tissues not treated with
biophotonic therapy (a control sample).
[0039] FIGS. 9A-9G presents photographs of biophotonic therapy of a
dehisced wound for a canine patent (patient 12). The patient was
treated five times with a biophotonic composition comprising 6% by
weight urea peroxide. During each treatment, the biophotonic
composition was exposed to actinic light for 3.3 minutes. FIG. 9A
shows photographs of the wound before treatment (T0) and after the
first and second treatments (T1 and T2). FIG. 9B shows photographs
of the wound after the third, fourth, and fifth treatments (T3, T4,
and T5). FIG. 9C shows measure of the wound at T0, T1, T2, T3, T4,
and T5. FIGS. 9D and 9E illustrate the decrease in the size of the
wound during the course of treatment. FIG. 9F shows a comparison in
the size of the wound before treatment and after 15 days of
treatment. FIG. 9G is a graph with the size of the wound on the
y-axis and the days of treatment on the x-axis. The graph
illustrates a decrease in the size of the wound during biophotonic
therapy treatment.
[0040] FIG. 10 presents photographs of healing of a surgical wound
for a canine patient (patient 10). The patient was treated five
times with a biophotonic composition comprising 3% by weight urea
peroxide. During each treatment, the biophotonic composition was
exposed to actinic light for two minutes. The first treatment with
the biophotonic composition was performed during surgery.
[0041] FIGS. 11A and 11B present photographs of healing of a
traumatic injury (shearing injury) in a control canine patient
(FIG. 11A) and patient 16 (FIG. 11B). The control patient was given
eight months of conventional treatment, whereas the patient 16 was
treated seven times over 30 days with a biophotonic composition
comprising 6% by weight urea peroxide. During each treatment, the
biophotonic composition was exposed to actinic light for 3.3
minutes. The first treatment with the biophotonic composition was
performed during surgery.
[0042] FIGS. 12A and 12B present photographs of a tolerability
study for the biophotonic compositions on a six year old healthy
gelding Trotter horse. As shown in FIG. 12A, three zones of
treatment where selected, the left flank, the right flank, and the
breast. The zones were treated with a biophotonic composition with
0%, 3%, 6%, or 12% urea peroxide (UP) two times per week for a
total of 4 weeks. FIG. 12B shows treatment of the zones with blue
light.
[0043] FIGS. 13A-13D present photographs of treatment of a 12 year
old female, mixed breed horse with post-traumatic subcutaneous
collection of purulent material. FIG. 13A illustrates swelling to
the left carpal region and two wounds draining purulent material.
It also illustrates a fistula located on the palmar surface of the
region. FIG. 13B illustrates treatment of the large wound with a
biophotonic composition comprising 12% UP and treatment of the
small wound with a biophotonic composition comprising 3% UP. FIG.
13C illustrates treatment of the wounds with blue light. FIG. 13D
illustrates treatment of the wounds over the course of six
weeks.
[0044] FIGS. 14A-14E present photographs of treatment of a 14 year
old female, mixed breed horse with an old wound on the lateral
surface of the chest. FIG. 14A shows treatment of the wound with
lavage, disinfection, wound suture, drainage, and systemic
antibiotic (conventional treatment). FIG. 14B shows dehiscence of
the wound after conventional treatment. FIG. 14C shows treatment of
the dehisced wound with a 12% UP biophotonic composition and blue
light. FIG. 14D shows healing of the wound after one week of
treatment and before application of another round of biophotonic
therapy. FIG. 14E shows healing of the wound after two applications
of biophotonic therapy (two weeks of treatment).
[0045] FIG. 15 presents photographs of measuring of probing pocket
depth (PPD, in mm) of a canine patient.
[0046] FIG. 16 presents a photograph of measuring of bleeding on
probing (BOP) of a canine patient.
[0047] FIG. 17 present photographs of measuring of plaque
index/calculus index (PI/CI) and plaque thickness/calculus
thickness (PT/CT) of a canine patient.
[0048] FIG. 18 present photographs of measuring of clinical
attachment level (CAL, in mm) of a canine patient.
[0049] FIGS. 19A-19C present photographs of the first application
of a biophotonic composition of the disclosure to a canine patient.
FIG. 19A shows application of the biophotonic composition. FIG. 19B
shows photoactivation of the biophotonic composition. FIG. 19C
shows scaling and root planing (SRP) of the canine patient.
[0050] FIGS. 20A-20B present photographs of the second application
of a biophotonic composition of the disclosure to a canine patient.
The second application was applied once the SRP was completed. FIG.
20A shows application of the biophotonic composition. FIG. 20B
shows photoactivation of the biophotonic composition.
[0051] FIG. 21 presents a photograph of showing that the first
application of biophotonic therapy considerably facilitated the
performing of SRP and reduced the time required.
[0052] FIG. 22 present photographs of healing of a traumatic wound
for a cat patient (case 29) treated with the biophotonic
composition of this disclosure.
DETAILED DESCRIPTION
[0053] In some aspects, the disclosure provides a method of
treating a skin or soft tissue wound having a non-resistant or a
resistant infection or both categories of infection, comprising:
applying a biophotonic composition to a patient in need thereof,
wherein the biophotonic composition comprises at least one oxidant
and at least one chromophore capable of activating the oxidant; and
exposing said biophotonic composition to actinic light for a time
sufficient for said chromophore to cause activation of said
oxidant. In certain such aspects, the soft tissue wound comprises
an oral disease. In certain such aspects, the wound is a skin
wound. In certain such aspects, either or both the non-resistant
and the resistant infection is a bacterial infection. In certain
such aspects, the bacterial infection is resistant to antibiotics.
In certain such aspects, the patient is a mammal, such as a human,
an equine, a feline or a canine. In certain such aspects, the
infection is a resistant infection.
[0054] In other aspects, the disclosure provides for use of a
biophotonic composition for the manufacture of a medicament for
treating a patient afflicted with a skin or soft tissue wound
having a non-resistant or a resistant infection or both categories
of infection, wherein said composition comprises: at least one
oxidant, and at least one chromophore capable of activating the
oxidant; in association with a pharmacologically acceptable
carrier. In certain such aspects, the soft tissue wound comprises
an oral disease. In certain such aspects, the wound is a skin
wound. In certain such aspects, either or both the non-resistant
and the resistant infection is a bacterial infection. In certain
such aspects, the bacterial infection is resistant to antibiotics.
In certain such aspects, the patient is a mammal, such as a human,
an equine, a feline or a canine. In certain such aspects, the
infection is a resistant infection. In some aspects, the
biophotonic compositions of this disclosure are for topical
use.
[0055] In some other aspects, the disclosure provides for use of a
biophotonic composition for the treatment of a patient afflicted
with a skin or soft tissue wound having a non-resistant or a
resistant infection or both categories of infection, wherein said
composition comprises: at least one oxidant; and at least one
chromophore capable of activating the oxidant; in association with
a pharmacologically acceptable carrier. In certain such aspects,
the soft tissue wound comprises an oral disease. In certain such
aspects, the wound is a skin wound. In certain such aspects, either
or both the non-resistant and the resistant infection is a
bacterial infection. In certain such aspects, the bacterial
infection is resistant to antibiotics. In certain such aspects, the
patient is a mammal, such as a human, an equine, a feline or a
canine. In certain such aspects, the infection is a resistant
infection.
Biophotonic Compositions
[0056] The present disclosure provides methods and uses comprising
biophotonic compositions for treating a skin or soft tissue wound
having a non-resistant or a resistant infection or both categories
of infection. Biophotonic compositions are compositions that are,
in a broad sense, activated by light (e.g., photons) of specific
wavelength. These compositions contain at least one exogenous
chromophore which is activated by light and accelerates the
dispersion of light energy, which leads to light carrying on a
therapeutic effect on its own, and/or to the photochemical
activation of other agents contained in the composition. The
composition may comprise an agent which, when mixed with a
chromophore or combination of chromophores and subsequently
activated by light, can be photochemically activated which may lead
to the formation of oxygen radicals, such as singlet oxygen. In
some aspects, the disclosure provides a method of treating a
resistant infection comprising: applying a biophotonic composition
to a patient in need thereof, wherein the biophotonic composition
comprises at least one oxidant and at least one chromophore capable
of activating the oxidant; and exposing said biophotonic
composition to actinic light for a time sufficient for said
chromophore to cause activation of said oxidant.
[0057] When a chromophore absorbs a photon of a certain wavelength,
it becomes excited. This is an unstable condition and the molecule
tries to return to the ground state, giving away the excess energy.
For some chromophores, it is favorable to emit the excess energy as
light when transforming back to the ground state. This process is
called fluorescence. The peak wavelength of the emitted
fluorescence is shifted towards longer wavelengths compared to the
absorption wavelengths (`Stokes` shift`). The emitted fluorescent
energy can then be transferred to the other components of the
composition or to a treatment site on to which the biophotonic
composition is topically applied. Differing wavelengths of light
may have different and complementary therapeutic effects on tissue.
Stokes' shift is illustrated in FIG. 1.
[0058] Without being bound to theory, it is thought that
fluorescent light emitted by photoactivated chromophores may have
therapeutic properties due to its femto-, pico- or nano-second
emission properties which may be recognized by biological cells and
tissues, leading to favorable biomodulation. Furthermore, the
emitted fluorescent light has a longer wavelength and hence a
deeper penetration into the tissue than the activating light.
Irradiating tissue with such a broad range of wavelengths,
including in some embodiments the activating light which passes
through the composition, may have different and complementary
effects on the cells and tissues.
[0059] Moreover, in some embodiments of the composition containing
oxidants, micro-bubbling within the composition has been observed
which may be associated with the generation of oxygen species by
the photoactivated chromophores. This may have a physical impact on
the tissue to which it is applied, for example by dislodging
biofilm and debridement of necrotic tissue or providing a pressure
stimulation. The biofilm can also be pre-treated with an
oxygen-releasing agent to weaken the biofilm before treating with
the composition of the present disclosure.
[0060] In certain embodiments, the biophotonic compositions of the
present disclosure are substantially transparent/translucent and/or
have high light transmittance in order to permit light dissipation
into and through the composition. In this way, the area of tissue
under the composition can be treated both with the fluorescent
light emitted by the composition and the light irradiating the
composition to activate it, which may benefit from the different
therapeutic effects of light having different wavelengths.
[0061] The percentage (%) transmittance of the biophotonic
composition can be measured in the range of wavelengths from 250 nm
to 800 nm using, for example, a Perkin-Elmer Lambda.TM. 9500 series
UV-visible spectrophotometer. Alternatively, a Synergy.TM. HT
spectrophotometer (BioTek Instrument, Inc.) can be used in the
range of wavelengths from 380 nm to 900 nm.
[0062] Transmittance is calculated according to the following
equation:
A .lamda. = log 10 .times. I 0 I = log 1 .times. 0 .times. 1 T .
##EQU00001##
where A is absorbance, T is transmittance, I.sub.0 is intensity of
radiation before passing through material, and I is intensity of
light passing through material.
[0063] The values can be normalized for thickness. As stated
herein, % transmittance (translucency) is as measured for a 2 mm
thick sample at a wavelength of 526 nm. It will be clear that other
wavelengths can be used.
[0064] Embodiments of the biophotonic compositions of the present
disclosure are for topical uses. The biophotonic composition can be
in the form of a semi-solid or viscous liquid, such as a gel, or
are gel-like, and which have a spreadable consistency at room
temperature (e.g., about 20-25.degree. C.), prior to illumination.
By spreadable is meant that the composition can be topically
applied to a treatment site at a thickness of less than about 0.5
mm, or from about 0.5 mm to about 3 mm, about 0.5 mm to about 2.5
mm, or about 1 mm to about 2 mm. In some embodiments, the
composition can be topically applied to a treatment site at a
thickness of about 2 mm or about 1 mm. Spreadable compositions can
conform to a topography of a treatment site. This can have
advantages over a non-conforming material in that a better and/or
more complete illumination of the treatment site can be achieved
and the compositions are easy to apply and remove.
[0065] These compositions may be described based on the components
making up the composition. Additionally or alternatively, the
compositions of the present disclosure have functional and
structural properties and these properties may also be used to
define and describe the compositions. Individual components of the
composition of the present disclosure are detailed below.
Oxidants
[0066] In some embodiments, the biophotonic compositions of the
present disclosure further comprise oxidants as a source of oxygen
radicals. For instance, peroxide compounds are oxidants that
contain the peroxy group (R--O--O--R), which is a chainlike
structure containing two oxygen atoms, each of which is bonded to
the other and a radical or some element. In some embodiments, the
biophotonic compositions of this disclosure comprises an oxidant
selected from, but not limited to, hydrogen peroxide, carbamide
peroxide, benzoyl peroxide, peroxy acids, or alkali metal
percarbonates.
[0067] Hydrogen peroxide (H.sub.2O.sub.2) is the starting material
to prepare organic peroxides. H.sub.2O.sub.2 is a powerful
oxidizing agent, and the unique property of hydrogen peroxide is
that it breaks down into water and oxygen and does not form any
persistent, toxic residual compound. Hydrogen peroxide for use in
this composition can be used in a gel, for example with 6% hydrogen
peroxide by weight of the composition. A suitable range of
concentration over which hydrogen peroxide can be used in a
composition of the present disclosure is less than about 12% by
weight of the total compositions. In some embodiments, hydrogen
peroxide is present in an amount from about 0.1% to about 12%, from
about 1% to about 12%, from about 3.5% to about 12%, from about
3.5% to about 6% or from about 0.1% to about 6% by weight of the
total composition.
[0068] Urea hydrogen peroxide (also known as urea peroxide,
carbamide peroxide or percarbamide) is soluble in water and
contains about 36% hydrogen peroxide. Carbamide peroxide for use in
this composition can be used as a gel, for example with about 16%
carbamide peroxide that represents about 5.6% hydrogen peroxide. A
suitable range of concentration over which urea peroxide can be
used in the present composition is less than about 36% by weight of
the total composition. In some embodiments, urea peroxide is
present in an amount from about 0.3% to about 36%, such as from
about 3% to about 36%, from about 10% to about 36%, from about 3%
to about 16%, from about 3% to about 9%, or from about 0.3% to
about 16% by weight of the total composition. In some embodiments,
urea peroxide is present in an amount of about 2% by weight of the
total composition. In some embodiments, urea peroxide is present in
an amount of about 3% by weight of the total composition. In some
embodiments, urea peroxide is present in an amount of about 6% by
weight of the total composition. In some embodiments, urea peroxide
is present in an amount of about 8% by weight of the total
composition. In some embodiments, urea peroxide is present in an
amount of about 9% by weight of the total composition. In some
embodiments, urea peroxide is present in an amount of about 12% by
weight of the total composition. Urea peroxide breaks down to urea
and hydrogen peroxide in a slow-release fashion that can be
accelerated with heat or photochemical reactions. The released urea
(i.e., carbamide, (NH.sub.2).sub.2CO), is highly soluble in water
and is a powerful protein denaturant. It increases solubility of
some proteins and enhances rehydration of the skin and/or
mucosa.
[0069] Benzoyl peroxide consists of two benzoyl groups (benzoic
acid with the H of the carboxylic acid removed) joined by a
peroxide group. The released peroxide groups are effective as
antibacterial agents. Benzoyl peroxide also promotes skin turnover
and clearing of pores. Benzoyl peroxide breaks down to benzoic acid
and oxygen upon contact with skin, neither of which is toxic. A
suitable range of concentration over which benzoyl peroxide can be
used in the present composition is less than about 10% by weight of
the total composition. In some embodiments, benzoyl peroxide is
present in an amount from about 1% to about 10%, or from about 1%
to about 8%, or from about 2.5% to about 5% by weight of the total
composition.
[0070] Suitable oxidants may also include peroxy acids and alkali
metal percarbonates, but the inclusion of any other forms of
peroxides (e.g., organic or inorganic peroxides) should be avoided
due to their increased toxicity and their unpredictable reaction
with the photodynamic energy transfer.
Chromophores/Photoactivators
[0071] In some embodiments, the biophotonic compositions of the
present disclosure further comprise one or more chromophores, which
can be considered exogenous, e.g., a chromophore that is not
naturally present in skin or tissue. When a biophotonic composition
of the present disclosure is illuminated with light, the
chromophore(s) are excited to a higher energy state. When the
chromophore(s)' electrons return to a lower energy state, they emit
photons with a lower energy level, thus causing the emission of
light of a longer wavelength (Stokes' shift). In the proper
environment, some of this energy release is transferred to oxygen
and causes the formation of oxygen radicals, such as singlet
oxygen.
[0072] Suitable chromophores for the biophotonic compositions of
the disclosure can be fluorescent dyes (or stains), although other
dye groups or dyes (biological and histological dyes, food
colorings, carotenoids, naturally occurring fluorescent and other
dyes) can also be used.
[0073] In some embodiments, the biophotonic topical composition of
the present disclosure comprises a chromophore which undergoes
partial or complete photobleaching upon application of light. By
photobleaching is meant a photochemical destruction of the
chromophore which can generally be characterized as a loss of
visual color or loss of fluorescence.
[0074] In some embodiments, the chromophore absorbs at a wavelength
in the range of the visible spectrum, such as at a wavelength of
about 380-800 nm, about 380-700 nm, or about 380-600 nm. In some
embodiments, the chromophore absorbs at a wavelength of about
200-800 nm, about 200-700 nm, about 200-600 nm or about 200-500 nm.
In some embodiments, the chromophore absorbs at a wavelength of
about 200-600 nm. In some embodiments, the chromophore absorbs
light at a wavelength of about 200-300 nm, about 250-350 nm, about
300-400 nm, about 350-450 nm, about 400-500 nm, about 400-600 nm,
about 450-650 nm, about 600-700 nm, about 650-750 nm or about
700-800 nm.
[0075] In some embodiments, the chromophore or combination of
chromophores is present in an amount of about 0.001-40% by weight
of the total composition. In some embodiments, the chromophore or
combination of chromophores is present in an amount of about
0.005-2%, about 0.01-1%, about 0.01-2%, about 0.05-1%, about
0.05-2%, about 0.1-1%, about 0.1-2%, about 1-5%, about 2.5-7.5%,
about 5-10%, about 7.5-12.5%, about 10-15%, about 12.5-17.5%, about
15-20%, about 17.5-22.5%, about 20-25%, about 22.5-27.5%, about
25-30%, about 27.5-32.5%, about 30-35%, about 32.5-37.5%, or about
35-40% by weight of the total composition. In some embodiments, the
chromophore or combination of chromophores is present in an amount
of at least about 0.2% by weight of the total composition.
[0076] In some embodiments, the chromophore or combination of
chromophores is present in an amount of 0.001-40% by weight of the
composition. In some embodiments, the chromophore or combination of
chromophores is present in an amount of 0.005-2%, 0.01-1%, 0.01-2%,
0.05-1%, 0.05-2%, 0.1-1%, 0.1-2%, 1-5%, 2.5-7.5%, 5-10%, 7.5-12.5%,
10-15%, 12.5-17.5%, 15-20%, 17.5-22.5%, 20-25%, 22.5-27.5%, 25-30%,
27.5-32.5%, 30-35%, 32.5-37.5%, or 35-40% by weight of the total
composition. In some embodiments, the chromophore or combination of
chromophores is present in an amount of at least 0.2% by weight of
the total composition.
[0077] It will be appreciated to those skilled in the art that
optical properties of a particular chromophore may vary depending
on the chromophore's surrounding medium. Therefore, as used herein,
a particular chromophore's absorption and/or emission wavelength
(or spectrum) corresponds to the wavelengths (or spectra) measured
in a biophotonic composition of the present disclosure.
[0078] In some embodiments, the biophotonic compositions disclosed
herein may include at least one additional chromophore. Combining
chromophores may increase photo-absorption by the combined dye
molecules and enhance absorption and photo-biomodulation
selectivity. This creates multiple possibilities of generating new
photosensitive, and/or selective chromophores mixtures.
[0079] When such multi-chromophore compositions are illuminated
with light, energy transfer can occur between the chromophores.
This process, known as resonance energy transfer, is a
photophysical process through which an excited `donor` chromophore
(also referred to herein as first chromophore) transfers its
excitation energy to an `acceptor` chromophore (also referred to
herein as second chromophore). The efficiency and directedness of
resonance energy transfer depends on the spectral features of donor
and acceptor chromophores. In particular, the flow of energy
between chromophores is dependent on a spectral overlap reflecting
the relative positioning and shapes of the absorption and emission
spectra. For energy transfer to occur the emission spectrum of the
donor chromophore overlap with the absorption spectrum of the
acceptor chromophore (FIG. 2).
[0080] Energy transfer manifests itself through decrease or
quenching of the donor emission and a reduction of excited state
lifetime accompanied also by an increase in acceptor emission
intensity. FIG. 3 is a Jablonski diagram that illustrates the
coupled transitions involved between a donor emission and acceptor
absorbance.
[0081] To enhance the energy transfer efficiency, the donor
chromophore should have good abilities to absorb photons and emit
photons. Furthermore, it is thought that the more overlap there is
between the donor chromophore's emission spectra and the acceptor
chromophore's absorption spectra, the better a donor chromophore
can transfer energy to the acceptor chromophore.
[0082] In some embodiments, the biophotonic topical composition of
the present disclosure further comprises an acceptor, or a second,
chromophore. In some embodiments, the donor, or first, chromophore
has an emission spectrum that overlaps at least about 80%, about
70%, about 60%, about 50%, about 40%, about 30%, about 20%, or
about 10% with an absorption spectrum of the second chromophore. In
some embodiments, the first chromophore has an emission spectrum
that overlaps at least about 20% with an absorption spectrum of the
second chromophore. In some embodiments, the first chromophore has
an emission spectrum that overlaps at least 1-10%, 5-15%, 10-20%,
15-25%, 20-30%, 25-35%, 30-40%, 35-45%, 50-60%, 55-65% or 60-70%
with an absorption spectrum of the second chromophore.
[0083] Percentage (%) spectral overlap, as used herein, means the %
overlap of a donor chromophore's emission wavelength range with an
acceptor chromophore's absorption wavelength range, measured at
spectral full width quarter maximum (FWQM). For example, FIG. 2
shows the normalized absorption and emission spectra of donor and
acceptor chromophores. The spectral FWQM of the acceptor
chromophore's absorption spectrum is from about 60 nm (about 515 nm
to about 575 nm). The overlap of the donor chromophore's spectrum
with the absorption spectrum of the acceptor chromophore is about
40 nm (from 515 nm to about 555 nm). Thus, the % overlap can be
calculated as 40 nm/60 nm.times.100=66.6%.
[0084] In some embodiments, the second chromophore absorbs at a
wavelength in the range of the visible spectrum. In some
embodiments, the second chromophore has an absorption wavelength
that is relatively longer than that of the first chromophore within
the range of about 50-250 nm, about 25-150 nm or about 10-100
nm.
[0085] As discussed above, the application of light to the
compositions of the present disclosure can result in a cascade of
energy transfer between the chromophores. In some embodiments, such
a cascade of energy transfer provides photons that penetrate the
epidermis, dermis and/or mucosa of the target tissue, including,
such as, a site of wound.
[0086] In some embodiments, the chromophore or chromophores are
selected such that their emitted fluorescent light, on
photoactivation, is within one or more of the green, yellow,
orange, red and infrared portions of the electromagnetic spectrum,
for example having a peak wavelength within the range of about 490
nm to about 800 nm. In some embodiments, the emitted fluorescent
light has a power density of between 0.005 to about 10 mW/cm.sup.2,
about 0.5 to about 5 mW/cm.sup.2.
[0087] Suitable chromophores useful in the biophotonic topical
compositions, methods, and uses of the present disclosure include,
but are not limited to the following:
Xanthene Derivatives
[0088] The xanthene derivative dyes have been used and tested for a
long time worldwide. They display low toxicity and increased
fluorescence. The xanthene group consists of three sub-groups: a)
the fluorenes; b) fluorones; and c) the rhodoles, any of which may
be suitable for the biophotonic compositions, methods, and uses of
the present disclosure.
[0089] The fluorenes group comprises the pyronines (e.g., pyronine
Y and B) and the rhodamines (e.g., rhodamine B, G and WT).
Depending on the concentration used, both pyronines and rhodamines
may be toxic and their interaction with light may lead to increased
toxicity. Similar effects are known to occur for the rhodole dye
group.
[0090] The fluorone group comprises the fluorescein dye and the
fluorescein derivatives.
[0091] Fluorescein is a fluorophore commonly used in microscopy
with an absorption maximum of about 494 nm and an emission maximum
of about 521 nm. The disodium salt of fluorescein is known as
D&C Yellow 8. It has very high fluorescence but photodegrades
quickly. In the present composition, mixtures of fluorescein with
other photoactivators such as indocyanin green and/or saffron red
powder will confer increased photoabsorption to these other
compounds.
[0092] The eosins group comprises Eosin Y (tetrabromofluorescein,
acid red 87, D&C Red 22), a chromophore with an absorption
maximum of about 514-518 nm that stains the cytoplasm of cells,
collagen, muscle fibers and red blood cells intensely red; and
Eosin B (acid red 91, eosin scarlet, dibromo-dinitrofluorescein),
with the same staining characteristics as Eosin Y. Eosin Y and
Eosin B are collectively referred to as "Eosin", and use of the
term "Eosin" refers to either Eosin Y, Eosin B or a mixture of
both. Eosin Y, Eosin B, or a mixture of both can be used because of
their sensitivity to the light spectra used: broad spectrum blue
light, blue to green light and green light. In some embodiments,
the composition includes in the range of less than about 12% by
weight of the total composition of at least one of Eosin B or Eosin
Y or a combination thereof. In some embodiments, at least one of
Eosin B or Eosin Y or a combination thereof is present from about
0.001% to about 12%, or between about 0.01% and about 1.2%, or from
about 0.01% to about 0.5%, or from about 0.01% to about 0.05%, or
from about 0.1% to about 0.5%, or from about 0.5% to about 0.8% by
weight of the total composition. In some embodiments, at least one
of Eosin B or Eosin Y or a combination thereof is present is an
amount of at about 0.005% by weight of the total composition. In
some embodiments, at least one of Eosin B or Eosin Y or a
combination thereof is present is an amount of at about 0.01% by
weight of the total composition.
[0093] In some embodiments, at least one of Eosin B or Eosin Y or a
combination thereof is present is an amount of about 0.02% by
weight of the total composition. In some embodiments, at least one
of Eosin B or Eosin Y or a combination thereof is present is an
amount of about 0.05% by weight of the total composition. In some
embodiments, at least one of Eosin B or Eosin Y or a combination
thereof is present is an amount of about 0.1% by weight of the
total composition. In some embodiments, at least one of Eosin B or
Eosin Y or a combination thereof is present is an amount of at
about 0.2% by weight of the total composition. In some embodiments,
at least one of Eosin B or Eosin Y or a combination thereof is
present is an amount of at least about 0.2% by weight of the total
composition but less than about 1.2% by weight of the total
composition. In some embodiments, at least one of Eosin B or Eosin
Y or a combination thereof is present is an amount of at least
about 0.01% by weight of the total composition but less than about
12% by weight of the total composition.
[0094] In some embodiments, the composition includes in the range
of less than 12% by weight of the total composition of at least one
of Eosin B or Eosin Y or a combination thereof. In some
embodiments, at least one of Eosin B or Eosin Y or a combination
thereof is present from 0.001% to 12%, or between 0.01% and 1.2%,
or from 0.01% to 0.5%, or from 0.1% to 0.5%, or from 0.5% to 0.8%,
or from 0.01% to 0.05%, by weight of the total composition. In some
embodiments, at least one of Eosin B or Eosin Y or a combination
thereof is present is an amount of 0.005% by weight of the total
composition. In some embodiments, at least one of Eosin B or Eosin
Y or a combination thereof is present is an amount of 0.01% by
weight of the total composition. In some embodiments, at least one
of Eosin B or Eosin Y or a combination thereof is present is an
amount of 0.02% by weight of the total composition. In some
embodiments, at least one of Eosin B or Eosin Y or a combination
thereof is present is an amount of 0.05% by weight of the total
composition. In some embodiments, at least one of Eosin B or Eosin
Y or a combination thereof is present is an amount of 0.1% by
weight of the total composition. In some embodiments, at least one
of Eosin B or Eosin Y or a combination thereof is present is an
amount of 0.2% by weight of the total composition. In some
embodiments, at least one of Eosin B or Eosin Y or a combination
thereof is present is an amount of at least 0.2% by weight of the
total composition but less than 1.2% by weight of the total
composition. In some embodiments, at least one of Eosin B or Eosin
Y or a combination thereof is present is an amount of at least
0.01% by weight of the total composition but less than 12% by
weight of the total composition.
[0095] Phloxine B (2,4,5,7 tetrabromo
4,5,6,7,tetrachlorofluorescein, D&C Red 28, acid red 92) is a
red dye derivative of fluorescein which is used for disinfection
and detoxification of waste water through photooxidation. It has an
absorption maximum of 535-548 nm. It is also used as an
intermediate for making photosensitive dyes and drugs.
[0096] Erythrosine B, or simply Erythrosine or Erythrosin (acid red
51, tetraiodofluorescein) is a cherry-pink, coal-based fluorine
food dye used as a biological stain, and a biofilm and dental
plaque disclosing agent, with a maximum absorbance of 524-530 nm in
aqueous solution. It is subject to photodegradation. Erythrosine is
also used in some embodiments due to its photosensitivity to the
light spectra used and its ability to stain biofilms. In
embodiments, the composition includes in the range of less than
about 2% by weight Erythrosine B. In some embodiments, Erythrosine
B is present in an amount from about 0.005 to about 2%, or from
about 0.005% to about 1%, or about 0.01% to about 1% by weight of
the total composition. In some embodiments, Erythrosine B is
present in an amount of about 0.005% and about 0.15% by weight of
the total composition.
[0097] Rose Bengal (4,5,6,7 tetrachloro 2,4,5,7
tetraiodofluorescein, acid red 94) is a bright bluish-pink
fluorescein derivative with an absorption maximum of 544-549 nm,
that has been used as a dye, biological stain and diagnostic aid.
Rose Bengal is also used in synthetic chemistry to generate singlet
oxygen from triplet oxygen.
[0098] Merbromine (mercurochrome) is an organo-mercuric disodium
salt of fluorescein with an absorption maximum of 508 nm. It is
used as an antiseptic.
Azo Dyes
[0099] The azo (or diazo-) dyes share the N--N group, called azo
the group. They are used mainly in analytical chemistry or as food
colorings and are not fluorescent. Suitable azo dyes for the
compositions, methods, and uses of the disclosure include: Methyl
violet, neutral red, para red (pigment red 1), amaranth (Azorubine
S), Carmoisine (azorubine, food red 3, acid red 14), allura red AC
(FD&C 40), tartrazine (FD&C Yellow 5), orange G (acid
orange 10), Ponceau 4R (food red 7), methyl red (acid red 2), and
murexide-ammonium purpurate.
Biological Stains
[0100] Dye molecules commonly used in staining protocols for
biological materials can also be used as photoactivators for the
compositions, methods, and uses of the disclosure. Suitable
biological stains include, but not limited to, saffranin, fuchsin,
3,3'-dihexylocarbocyanine iodide, carminic acid, and indocyanin
green.
[0101] Saffranin (Saffranin 0, basic red 2) is an azo-dye and is
used in histology and cytology. It is a classic counter stain in a
Gram stain protocol.
[0102] Fuchsin (basic or acid) (rosaniline hydrochloride) is a
magenta biological dye that can stain bacteria and has been used as
an antiseptic. It has an absorption maximum of 540-555 nm.
[0103] 3,3'-dihexylocarbocyanine iodide (DiOC6) is a fluorescent
dye used for staining the endoplasmic reticulum, vesicle membranes
and mitochondria of cells. It shows photodynamic toxicity; when
exposed to blue light, has a green fluorescence.
[0104] Carminic acid (acid red 4, natural red 4) is a red
glucosidal hydroxyanthrapurin naturally obtained from cochineal
insects.
[0105] Indocyanin green (ICG) is used as a diagnostic aid for blood
volume determination, cardiac output, or hepatic function. ICG
binds strongly to red blood cells and when used in mixture with
fluorescein, it increases the absorption of blue to green
light.
Carotenoids
[0106] Carotenoid dyes are also photoactivators that are useful in
the compositions, methods, and uses of the disclosure.
[0107] Saffron red powder is a natural carotenoid-containing
compound. Saffron is a spice derived from crocus sativus. It is
characterized by a bitter taste and iodoform or hay-like fragrance;
these are caused by the compounds picrocrocin and saffranal. It
also contains the carotenoid dye crocin that gives its
characteristic yellow-red color.
[0108] Saffron contains more than 150 different compounds, many of
which are carotenoids: mangicrocin, reaxanthine, lycopene, and
various a and .beta.-carotenes, which show good absorption of light
and beneficial biological activity. Also saffron can act as both a
photon-transfer agent and a healing factor. Saffron color is
primarily the result of .alpha.-crocin (8,8 diapo-8,8-carotenoid
acid). Dry saffron red powder is highly sensitive to fluctuating pH
levels and rapidly breaks down chemically in the presence of light
and oxidizing agents. It is more resistant to heat. Data show that
saffron has anticarcinogenic, immunomodulating and antioxidant
properties. For absorbance, the crocin specific photon wavelength
is 440 nm (blue light). It has a deep red colour and forms crystals
with a melting point of 186.degree. C. When dissolved in water, it
forms an orange solution.
[0109] Crocetin, another compound of saffron, was found to express
an antilipidemic action and promote oxygen penetration in different
tissues. More specifically, an increased oxygenation of the
endothelial cells of the capillaries was observed. Additionally, an
increase of the oxygenation of muscles and cerebral cortex was
observed and led to an improved survival rate in laboratory animals
with induced hemorrhagic shock or emphysema.
[0110] Anatto, a spice, contains as main constituent (70-80%) the
carotenoid bixin which displays relevant antioxidative properties.
.beta.-carotene, also displays suitable characteristics.
[0111] Fucoxanthine is a constituent of brown algae with a
pronounced ability for photosensitization of redox reactions.
Chlorophyll Dyes
[0112] Exemplary chlorophyll dyes that are useful in the
compositions, methods, and uses of the disclosure, include, but are
not limited to, chlorophyll a, chlorophyll b, oil soluble
chlorophyll, bacteriochlorophyll a, bacteriochlorophyll b,
bacteriochlorophyll c, bacteriochlorophyll d, protochlorophyll,
protochlorophyll a, amphiphilic chlorophyll derivative 1, and
amphiphilic chlorophyll derivative 2.
[0113] In some aspects of the disclosure, the one or more
chromophores of the biophotonic composition disclosed herein can be
independently selected from any of Acid black 1, Acid blue 22, Acid
blue 93, Acid fuchsin, Acid green, Acid green 1, Acid green 5, Acid
magenta, Acid orange 10, Acid red 26, Acid red 29, Acid red 44,
Acid red 51, Acid red 66, Acid red 87, Acid red 91, Acid red 92,
Acid red 94, Acid red 101, Acid red 103, Acid roseine, Acid rubin,
Acid violet 19, Acid yellow 1, Acid yellow 9, Acid yellow 23, Acid
yellow 24, Acid yellow 36, Acid yellow 73, Acid yellow S, Acridine
orange, Acriflavine, Alcian blue, Alcian yellow, Alcohol soluble
eosin, Alizarin, Alizarin blue 2RC, Alizarin carmine, Alizarin
cyanin BBS, Alizarol cyanin R, Alizarin red S, Alizarin purpurin,
Aluminon, Amido black 10B, Amidoschwarz, Aniline blue WS,
Anthracene blue SWR, Auramine O, Azocannine B, Azocarmine G, Azoic
diazo 5, Azoic diazo 48, Azure A, Azure B, Azure C, Basic blue 8,
Basic blue 9, Basic blue 12, Basic blue 15, Basic blue 17, Basic
blue 20, Basic blue 26, Basic brown 1, Basic fuchsin, Basic green
4, Basic orange 14, Basic red 2 (Saffranin 0), Basic red 5, Basic
red 9, Basic violet 2, Basic violet 3, Basic violet 4, Basic violet
10, Basic violet 14, Basic yellow 1, Basic yellow 2, Biebrich
scarlet, Bismarck brown Y, Brilliant crystal scarlet 6R, Calcium
red, Carmine, Carminic acid (acid red 4), Celestine blue B, China
blue, Cochineal, Celestine blue, Chrome violet CG, Chromotrope 2R,
Chromoxane cyanin R, Congo corinth, Congo red, Cotton blue, Cotton
red, Croceine scarlet, Crocin, Crystal ponceau 6R, Crystal violet,
Dahlia, Diamond green B, DiOC6, Direct blue 14, Direct blue 58,
Direct red, Direct red 10, Direct red 28, Direct red 80, Direct
yellow 7, Eosin B, Eosin Bluish, Eosin, Eosin Y, Eosin yellowish,
Eosinol, Erie garnet B, Eriochrome cyanin R, Erythrosin B, Ethyl
eosin, Ethyl green, Ethyl violet, Evans blue, Fast blue B, Fast
green FCF, Fast red B, Fast yellow, Fluorescein, Food green 3,
Gallein, Gallamine blue, Gallocyanin, Gentian violet, Haematein,
Haematine, Haematoxylin, Helio fast rubin BBL, Helvetia blue,
Hematein, Hematine, Hematoxylin, Hoffman's violet, Imperial red,
Indocyanin green, Ingrain blue, Ingrain blue 1, Ingrain yellow 1,
INT, Kermes, Kermesic acid, Kemechtrot, Lac, Laccaic acid, Lauth's
violet, Light green, Lissamine green SF, Luxol fast blue, Magenta
0, Magenta I, Magenta II, Magenta III, Malachite green, Manchester
brown, Martius yellow, Merbromin, Mercurochrome, Metanil yellow,
Methylene azure A, Methylene azure B, Methylene azure C, Methylene
blue, Methyl blue, Methyl green, Methyl violet, Methyl violet 2B,
Methyl violet 10B, Mordant blue 3, Mordant blue 10, Mordant blue
14, Mordant blue 23, Mordant blue 32, Mordant blue 45, Mordant red
3, Mordant red 11, Mordant violet 25, Mordant violet 39 Naphthol
blue black, Naphthol green B, Naphthol yellow S, Natural black 1,
Natural red, Natural red 3, Natural red 4, Natural red 8, Natural
red 16, Natural red 25, Natural red 28, Natural yellow 6, NBT,
Neutral red, New fuchsin, Niagara blue 3B, Night blue, Nile blue,
Nile blue A, Nile blue oxazone, Nile blue sulphate, Nile red, Nitro
BT, Nitro blue tetrazolium, Nuclear fast red, Oil red 0, Orange G,
Orcein, Pararosanilin, Phloxine B, phycobilins, Phycocyanins,
Phycoerythrins. Phycoerythrincyanin (PEC), Phthalocyanines, Picric
acid, Ponceau 2R, Ponceau 6R, Ponceau B, Ponceau de Xylidine,
Ponceau S, Primula, Purpurin, Pyronin B, Pyronin G, Pyronin Y,
Rhodamine B, Rosanilin, Rose bengal, Saffron, Safranin 0, Scarlet
R, Scarlet red, Scharlach R, Shellac, Sirius red F3B, Solochrome
cyanin R, Soluble blue, Solvent black 3, Solvent blue 38, Solvent
red 23, Solvent red 24, Solvent red 27, Solvent red 45, Solvent
yellow 94, Spirit soluble eosin, Sudan III, Sudan IV, Sudan black
B, Sulfur yellow S, Swiss blue, Tartrazine, Thioflavine S,
Thioflavine T, Thionin, Toluidine blue, Toluyline red, Tropaeolin
G, Trypaflavine, Trypan blue, Uranin, Victoria blue 4R, Victoria
blue B, Victoria green B, Water blue I, Water soluble eosin,
Xylidine ponceau, or Yellowish eosin.
[0114] Chromophores can be selected, for example, based on their
emission wavelength properties in the case of fluorophores, on the
basis of their energy transfer potential, their ability to generate
reactive oxygen species, or their antimicrobial effect.
[0115] In some embodiments, the biophotonic compositions of the
present disclosure comprise Eosin Y as a first chromophore. In some
embodiments, the composition comprises Eosin Y as a first
chromophore and any one or more of Rose Bengal, Erythrosin,
Phloxine B as a second chromophore. It is believed that these
combinations have a synergistic effect as Eosin Y can transfer
energy to Rose Bengal, Erythrosin or Phloxine B when activated.
This transferred energy is then emitted as fluorescence or by
production of reactive oxygen species. This absorbed and re-emitted
light is thought to be transmitted throughout the composition, and
also to be transmitted into the site of treatment.
[0116] In some embodiments, the biophotonic compositions of this
disclosure comprise the following synergistic combinations: Eosin Y
and Fluorescein; Fluorescein and Rose Bengal; Erythrosine in
combination with one or more of Eosin Y, Rose Bengal or
Fluorescein; or Phloxine B in combination with one or more of Eosin
Y, Rose Bengal, Fluorescein and Erythrosine. Other synergistic
chromophore combinations may also be suitable for the biophotonic
compositions of this disclosure.
[0117] By means of synergistic effects of the chromophore
combinations in the composition, chromophores which cannot normally
be activated by an activating light (such as a blue light from an
LED) can be activated through energy transfer from chromophores
which are activated by the activating light. In this way, the
different properties of photoactivated chromophores can be
harnessed and tailored according to the cosmetic or the medical
therapy required.
[0118] For example, Rose Bengal can generate a high yield of
singlet oxygen when photoactivated in the presence of molecular
oxygen, however it has a low quantum yield in terms of emitted
fluorescent light. Rose Bengal has a peak absorption at around 540
nm; so it is normally activated by green light. Eosin Y has a high
quantum yield and can be activated by blue light. By combining Rose
Bengal with Eosin Y, one obtains a composition which can emit
therapeutic fluorescent light and generate singlet oxygen when
activated by blue light. In this case, the blue light
photoactivates Eosin Y which transfers some of its energy to Rose
Bengal and emits some energy as fluorescence.
[0119] Chromophore combinations can also have a synergistic effect
in terms of their photoactivated state. For example, two
chromophores may be used, one of which emits fluorescent light when
activated in the blue and green range, and the other which emits
fluorescent light in the red, orange and yellow range, thereby
complementing each other and irradiating the target tissue with a
broad wavelength of light having different depths of penetration
into target tissue and different therapeutic effects.
Healing Factors
[0120] According to some embodiments, the biophotonic compositions
of the present disclosure may further comprise one or more healing
factors. Healing factors include compounds that promote or enhance
the healing or regenerative process of the tissues on the
application site of the composition. During the photoactivation of
the composition, there is an increase of the absorption of
molecules at the treatment site. An augmentation in the blood flow
at the site of treatment is observed for an extended period of
time. An increase in the lymphatic drainage and a possible change
in the osmotic equilibrium due to the dynamic interaction of the
free radical cascades can be enhanced or even fortified with the
inclusion of healing factors. In some embodiments, the biophotonic
compositions of this disclosure comprises one or more healing
factors selected from, but not limited to, hyaluronic acid,
glucosamine, allantoin, or saffron.
[0121] Hyaluronic acid (hyaluronan or hyaluronate) is a
non-sulfated glycosaminoglycan, distributed widely throughout
connective, epithelial and neural tissues. It is one of the primary
components of the extracellular matrix, and contributes
significantly to cell proliferation and migration. Hyaluronan is a
major component of the skin, where it is involved in tissue repair.
While it is abundant in extracellular matrices, it contributes to
tissue hydrodynamics, movement and proliferation of cells and
participates in a wide number of cell surface receptor
interactions, notably those including primary receptor CD44. The
hyaluronidase enzymes degrade hyaluronan, and there are at least
seven types of hyaluronidase-like enzymes in humans, several of
which are tumor suppressors. The degradation products of hyaluronic
acid, the oligosaccharides and the very-low molecular weight
hyaluronic acid, exhibit pro-angiogenic properties. In addition,
recent studies show that hyaluronan fragments, but not the native
high molecular mass of hyaluronan, can induce inflammatory
responses in macrophages and dendritic cells in tissue injury.
Hyaluronic acid is well suited to biological applications targeting
the skin. Due to its high biocompatibility, it is used to stimulate
tissue regeneration. Current studies evidenced hyaluronic acid
appearing in the early stages of healing to physically create room
for white blood cells that mediate the immune response. It is used
in the synthesis of biological scaffolds for wound healing
applications and in wrinkle treatment. In certain embodiments, the
composition includes hyaluronic acid in the range of less than
about 2% by weight of the total composition hyaluronic acid. In
some embodiments, hyaluronic acid is present in an amount from
about 0.001% to about 2%, or from about 0.002% to about 2%, or from
about 0.002% to about 1% by weight of the total composition.
[0122] Glucosamine is one of the most abundant monosaccharides in
human tissues and a precursor in the biological synthesis of
glycosylated proteins and lipids. It is commonly used in the
treatment of osteoarthritis. The common form of glucosamine used is
its sulfate salt. Glucosamine shows a number of effects, including
anti-inflammatory activity, stimulation of the synthesis of
proteoglycans and the synthesis of proteolytic enzymes. A suitable
range of concentration over which glucosamine can be used in the
present composition is from less than about 5% by weight of the
total composition. In some embodiments, glucosamine is present in
an amount from about 0.0001% to about 5%, or from about 0.0001% to
about 3%, or from about 0.001% to about 3%, or from about 0.001% to
about 1%, or from about 0.01% to about 1%, or from about 1% to
about 3% by weight of the total composition.
[0123] Allantoin is a diureide of glyosilic acid. It has
keratolytic effect, increases the water content of the
extracellular matrix, enhances the desquamation of the upper layers
of dead (apoptotic) skin cells, and promotes skin proliferation and
wound healing. In certain embodiments, the composition includes in
the range of less than about 1% by weight of the total composition
allantoin. In some embodiments, allantoin is present in an amount
of from about 0.001% to about 1%, or from about 0.002% to about 1%,
or from about 0.02% to about 1%, or from about 0.02% to about 0.5%
by weight of the total composition.
[0124] Saffron can act as both a photon-transfer agent and a
healing factor.
Chelating Agents
[0125] According to some embodiments, the biophotonic compositions
of the present disclosure may further comprise one or more
chelating agents. Chelating agents can be included to promote smear
layer removal in closed pockets and difficult to reach lesions.
Chelating agents act as a metal ion quencher and as a buffer. In
some embodiments, the biophotonic compositions of this disclosure
comprise a chelating agent selected from, but not limited to,
ethylenediaminotetraacetic acid or ethylene glycol tetraacetic
acid.
[0126] Ethylenediaminotetraacetic acid (EDTA) is an amino acid and
is used to sequester di- and trivalent metal ions. EDTA binds to
metals via four carboxylate and two amine groups. EDTA forms
especially strong complexes with Mn(III), Fe(III), Cu(III),
Co(III). It is used to buffer solutions.
[0127] Ethylene glycol tetraacetic acid (EGTA) is related to EDTA,
but with a much higher affinity for calcium than magnesium ions. It
is useful for making buffer solutions that resemble the environment
inside living cells.
Gelling Agents
[0128] According to some embodiments, the biophotonic compositions
of the present disclosure may further comprise one or more gelling
agents. The gelling agent may be an agent capable of forming a
cross-linked matrix, including physical and/or chemical
cross-links. The gelling agent can be biocompatible, and may be
biodegradable. In some embodiments, the gelling agent is able to
form a hydrogel or a hydrocolloid. An appropriate gelling agent is
one that can form a viscous liquid or a semisolid. In some
embodiments, the gelling agent and/or the composition has
appropriate light transmission properties. It is also important to
select a gelling agent which will allow biophotonic activity of the
chromophore(s). For example, some chromophores require a hydrated
environment in order to fluoresce. The gelling agent may be able to
form a gel by itself or in combination with other ingredients such
as water or another gelling agent, or when applied to a treatment
site, or when illuminated with light.
[0129] The gelling agent according to various embodiments of the
present disclosure may include, but not be limited to, polyalkylene
oxides, particularly polyethylene glycol and poly(ethylene
oxide)-poly(propylene oxide) copolymers, including block and random
copolymers; polyols such as glycerol, polyglycerol (particularly
highly branched polyglycerol), propylene glycol and trimethylene
glycol substituted with one or more polyalkylene oxides, e.g.,
mono-, di- and tri-polyoxyethylated glycerol, mono- and
di-polyoxy-ethylated propylene glycol, and mono- and
di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol,
polyoxyethylated glucose; acrylic acid polymers and analogs and
copolymers thereof, such as polyacrylic acid per se,
polymethacrylic acid, poly(hydroxyethylmethacrylate),
poly(hydroxyethylacrylate), poly(methylalkylsulfoxide
methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers
of any of the foregoing, and/or with additional acrylate species
such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate;
polymaleic acid; poly(acrylamides) such as polyacrylamide per se,
poly(methacrylamide), poly(dimethylacrylamide), and
poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as
poly(vinyl alcohol); poly(N-vinyl lactams) such as poly(vinyl
pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof,
polyoxazolines, including poly(methyloxazoline) and
poly(ethyloxazoline); silicones, polyvinyl silicates,
tetramethoxyorthosilicates, methyltrimethoxyorthosilicates,
tetraalkoxyorthosilicates, trialkoxyorthosilicates, pressure
sensitive silicone adhesives (such as BioPSA from Dow-Corning), and
polyvinylamines.
[0130] The gelling agent according to some embodiments of the
present disclosure may include a polymer selected from any of
synthetic or semi-synthetic polymeric materials, polyacrylate
copolymers, cellulose derivatives and polymethyl vinyl ether/maleic
anhydride copolymers. In some embodiments, the hydrophilic polymer
comprises a polymer that is a high molecular weight (i.e., molar
masses of more than about 5,000, and in some instances, more than
about 10,000, or about 100,000, or about 1,000,000) and/or
cross-linked polyacrylic acid polymer.
[0131] In some embodiments, the gelling agent comprises a carbomer.
Carbomers are synthetic high molecular weight polymer of acrylic
acid that are cross-linked with either allylsucrose or allylethers
of pentaerythritol having a molecular weight of about
3.times.10.sup.6. The gelation mechanism depends on neutralization
of the carboxylic acid moiety to form a soluble salt. The polymer
is hydrophilic and produces sparkling clear gels when neutralized.
Carbomer gels possess good thermal stability in that gel viscosity
and yield value are essentially unaffected by temperature. As a
topical product, carbomer gels possess optimum rheological
properties. The inherent pseudoplastic flow permits immediate
recovery of viscosity when shear is terminated and the high yield
value and quick break make it ideal for dispensing. Aqueous
solution of Carbopol.RTM. is acidic in nature due to the presence
of free carboxylic acid residues. Neutralization of this solution
cross-links and gelatinizes the polymer to form a viscous integral
structure of desired viscosity.
[0132] Carbomers are available as fine white powders which disperse
in water to form acidic colloidal suspensions (a 1% dispersion has
a pH of approximately 3) of low viscosity. Neutralization of these
suspensions using a base, for example sodium, potassium or ammonium
hydroxides, low molecular weight amines and alkanolamines, results
in the formation of translucent gels. Nicotine salts such as
nicotine chloride form stable water-soluble complexes with
carbomers at about pH 3.5 and are stabilized at an optimal pH of
about 5.6.
[0133] In some embodiments of the disclosure, the carbomer is
Carbopol.RTM.. Such polymers are commercially available from B.F.
Goodrich or Lubrizol under the designation Carbopol.RTM. 71G NF,
420, 430, 475, 488, 493, 910, 934, 934P, 940, 971PNF, 974P NF, 980
NF, 981 NF and the like. Carbopols are versatile controlled-release
polymers, as described by Brock (Pharmacotherapy, 14:430-7 (1994),
incorporated herein by reference) and Durrani (Pharmaceutical Res.
(Supp.) 8:S-135 (1991), incorporated herein by reference), and
belong to a family of carbomers which are synthetic, high molecular
weight, non-linear polymers of acrylic acid, crosslinked with
polyalkenyl polyether. In some embodiments, the carbomer is
Carbopol.RTM. 974P NF, 980 NF, 5984 EP, ETD 2020NF, Ultrez 10 NF,
934 NF, 934P NF or 940 NF. In some embodiments, the carbomer is
Carbopol.RTM. 980 NF, ETD 2020 NF, Ultrez 10 NF, Ultrez 21 or 1382
Polymer, 1342 NF, 940 NF. In some embodiments, from about 0.05% to
about 10%, about 0.5% to about 5%, or about 1% to about 3% by
weight of the total composition of a high molecular weight carbopol
can be present as the gelling agent. In some embodiments, the
biophotonic composition of the disclosure comprises from about
0.05% to about 10%, about 0.5% to about 5%, or from about 1% to
about 3% by weight of the total composition of a high molecular
weight carbopol.
[0134] In some embodiments, the gelling agent comprises a
hygroscopic and/or a hydrophilic material useful for their water
attracting properties. The hygroscopic or hydrophilic material may
include, but is not limited to, glucosamine, glucosamine sulfate,
polysaccharides, cellulose derivatives (hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
methylcellulose and the like), noncellulose polysaccharides
(galactomannans, guar gum, carob gum, gum arabic, sterculia gum,
agar, alginates and the like), glycosaminoglycan, poly(vinyl
alcohol), poly(2-hydroxyethylmethylacrylate), polyethylene oxide,
collagen, chitosan, alginate, a poly(acrylonitrile)-based hydrogel,
poly(ethylene glycol)/poly(acrylic acid) interpenetrating polymer
network hydrogel, polyethylene oxide-polybutylene terephthalate,
hyaluronic acid, high-molecular-weight polyacrylic acid,
poly(hydroxy ethylmethacrylate), poly(ethylene glycol),
tetraethylene glycol diacrylate, polyethylene glycol methacrylate,
and poly(methyl acrylate-co-hydroxyethyl acrylate). In some
embodiments, the hydrophilic gelling agent is selected from
glucose, modified starch, methyl cellulose, carboxymethyl
cellulose, propyl cellulose, hydroxypropyl cellulose, carbomers,
alginic acid, sodium alginate, potassium alginate, ammonium
alginate, calcium alginate, agar, carrageenan, locust bean gum,
pectin, and gelatin.
[0135] The gelling agent may be protein-based/naturally derived
material such as sodium hyaluronate, gelatin or collagen, lipids,
or the like. The gelling agent may be a polysaccharide such as
starch, chitosan, chitin, agarose, agar, locust bean gum,
carrageenan, gellan gum, pectin, alginate, xanthan, guar gum, and
the like.
[0136] In some embodiments, the composition can include up to about
2% by weight of the final composition of sodium hyaluronate as the
single gelling agent. In some embodiments, the composition can
include more than about 4% or more than about 5% by weight of the
total composition of gelatin as the single gelling agent. In some
embodiments, the composition can include up to about 10% or up to
about 8% starch as the single gelling agent. In some embodiments,
the composition can include more than about 5% or more than about
10% by weight of the total composition of collagen as the gelling
agent. In some embodiments, about 0.1% to about 10% or about 0.5%
to about 3% by weight of the total composition of chitin can be
used as the gelling agent. In some embodiments, about 0.5% to about
5% by weight of the final composition of corn starch or about 5% to
about 10% by weight of the total composition of corn starch can be
used as the gelling agent. In some embodiments, more than about
2.5% by weight of the total composition of alginate can be used in
the composition as the gelling agent. In some embodiments, the
percentages by weight percent of the final composition of the
gelling agents can be as follows: cellulose gel (from about 0.3% to
about 2.0%), konjac gum (from about 0.5% to about 0.7%),
carrageenan gum (from about 0.02% to about 2.0%), xanthan gum (from
about 0.01% to about 2.0%), acacia gum (from about 3% to about
30%), agar (from about 0.04% to about 1.2%), guar gum (from about
0.1% to about 1%), locust bean gum (from about 0.15% to about
0.75%), pectin (from about 0.1% to about 0.6%), tara gum (from
about 0.1% to about 1.0%), polyvinylypyrrolidone (from about 1% to
about 5%), sodium polyacrylate (from about 1% to about 10%). Other
gelling agents can be used in amounts sufficient to gel the
composition or to sufficiently thicken the composition. It will be
appreciated that lower amounts of the above gelling agents may be
used in the presence of another gelling agent or a thickener.
[0137] In some embodiments, the biophotonic compositions of the
present disclosure may be further encapsulated, e.g., in a
membrane. Such a membrane may be transparent, and/or substantially,
or fully impermeable. The membrane may be impermeable to liquid but
permeable to gases such as air. In some embodiments, the
composition may form a membrane that encapsulates the
chromophore(s) of the biophotonic topical composition, where the
membrane may be substantially impermeable to liquid and/or gas. The
membrane may be formed of one or more lipidic agents, polymers,
gelatin, cellulose or cyclodextrins, or the like. In some
embodiments, the membrane is translucent or transparent to allow
light to infiltrate to and from the chromophore(s). In some
embodiments, the composition is a dendrimer with an outer membrane
comprising poly(propylene amine). In some embodiments, the outer
membrane comprises gelatin.
Polyols
[0138] According to some embodiments, the biophotonic compositions
of the present disclosure may optionally further comprise one or
more polyols. Suitable polyols that may be included in the
composition include, but are not limited to a diol, a triol, a
saccharide, glycerine, butane- 1,2,3-triol, butane-1,2,4-triol,
hexane-1,2,6-triol, propylene glycol, butanediol, butenediol,
butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol,
2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,
tetraethylene glycol, dipropylene glycol and dibutylene glycol. In
some embodiments when the biophotonic composition of the disclosure
includes one or more polyols, the polyol is glycerine. In some
embodiments when the biophotonic composition of the disclosure
includes one or more polyols, the polyol is propylene glycol. In
some embodiments when the biophotonic composition of the disclosure
includes one or more polyols, the polyol is a combination of
glycerine and propylene glycol.
[0139] In some embodiments, one or more polyols are present in an
amount of about 5-75% by weight of the total composition, such as
5-75% by weight of the total composition. In some embodiments, one
or more polyols are present in an amount of about 10-75% by weight
of the total composition, such as 10-75% by weight of the total
composition. In some embodiments, one or more polyols are present
in an amount of about 15-75% by weight of the total composition,
such as 15-75% by weight of the total composition. In some
embodiments, one or more polyols are present in an amount of about
20-75% by weight of the total composition, such as 20-75% by weight
of the total composition.
Antimicrobials
[0140] According to some embodiments, the biophotonic compositions
of the present disclosure may optionally further comprise one or
more antimicrobials. Antimicrobials are useful in reducing
microbial growth or accumulation. Exemplary antimicrobials (or
antimicrobial agent) are recited in U.S. Patent Application
Publication Nos. 20040009227 and 20110081530. Suitable
antimicrobials for use in the methods of the present disclosure
include, but not limited to, phenolic and chlorinated phenolic and
chlorinated phenolic compounds, resorcinol and its derivatives,
bisphenolic compounds, benzoic esters (parabens), halogenated
carbonilides, polymeric antimicrobial agents, thazolines,
trichloromethylthioimides, natural antimicrobial agents (also
referred to as "natural essential oils"), metal salts, and
broad-spectrum antibiotics.
[0141] Specific phenolic and chlorinated phenolic antimicrobial
agents that can be used in the disclosure include, but are not
limited to: phenol; 2-methyl phenol; 3-methyl phenol; 4-methyl
phenol; 4-ethyl phenol; 2,4-dimethyl phenol; 2,5-dimethyl phenol;
3,4-dimethyl phenol; 2,6-dimethyl phenol; 4-n-propyl phenol;
4-n-butyl phenol; 4-n-amyl phenol; 4-tert-amyl phenol; 4-n-hexyl
phenol; 4-n-heptyl phenol; mono- and poly-alkyl and aromatic
halophenols; p-chlorophenyl; methyl p-chlorophenol; ethyl
p-chlorophenol; n-propyl p-chlorophenol; n-butyl p-chlorophenol;
n-amyl p-chlorophenol; sec-amyl p-chlorophenol; n-hexyl
p-chlorophenol; cyclohexyl p-chlorophenol; n-heptyl p-chlorophenol;
n-octyl; p-chlorophenol; o-chlorophenol; methyl o-chlorophenol;
ethyl o-chlorophenol; n-propyl o-chlorophenol; n-butyl
o-chlorophenol; n-amyl o-chlorophenol; tert-amyl o-chlorophenol;
n-hexyl o-chlorophenol; n-heptyl o-chlorophenol; o-benzyl
p-chlorophenol; o-benxyl-m-methyl p-chlorophenol;
o-benzyl-m,m-dimethyl p-chlorophenol; o-phenyl ethyl
p-chlorophenol; o-phenylethyl-m-methyl p-chlorophenol; 3-methyl
p-chlorophenol 3,5-dimethyl p-chlorophenol, 6-ethyl-3-methyl
p-chlorophenol, 6-n-propyl-3-methyl p-chlorophenol;
6-iso-propyl-3-methyl p-chlorophenol; 2-ethyl-3,5-dimethyl
p-chlorophenol; 6-sec-butyl-3-methyl p-chlorophenol;
2-iso-propyl-3,5-dimethyl p-chlorophenol; 6-diethylmethyl-3-methyl
p-chlorophenol; 6-iso-propyl-2-ethyl-3-methyl p-chlorophenol;
2-sec-amyl-3,5-dimethyl p-chlorophenol;
2-diethylmethyl-3,5-dimethyl p-chlorophenol; 6-sec-octyl-3-methyl
p-chlorophenol; p-chloro-m-cresol p-bromophenol; methyl
p-bromophenol; ethyl p-bromophenol; n-propyl p-bromophenol; n-butyl
p-bromophenol; n-amyl p-bromophenol; sec-amyl p-bromophenol;
n-hexyl p-bromophenol; cyclohexyl p-bromophenol; o-bromophenol;
tert-amyl o-bromophenol; n-hexyl o-bromophenol;
n-propyl-m,m-dimethyl o-bromophenol; 2-phenyl phenol;
4-chloro-2-methyl phenol; 4-chloro-3-methyl phenol;
4-chloro-3,5-dimethyl phenol; 2,4-dichloro-3,5-dimethylphenol;
3,4,5,6-tetabromo-2-methylphenol; 5-methyl-2-pentylphenol;
4-isopropyl-3-methylphenol; para-chloro-metaxylenol (PCMX);
chlorothymol; phenoxyethanol; phenoxyisopropanol; and
5-chloro-2-hydroxydiphenylmethane.
[0142] Resorcinol and its derivatives can also be used as
antimicrobial agents. Specific resorcinol derivatives include, but
are not limited to: methyl resorcinol; ethyl resorcinol; n-propyl
resorcinol; n-butyl resorcinol; n-amyl resorcinol; n-hexyl
resorcinol; n-heptyl resorcinol; n-octyl resorcinol; n-nonyl
resorcinol; phenyl resorcinol; benzyl resorcinol; phenylethyl
resorcinol; phenylpropyl resorcinol; p-chlorobenzyl resorcinol;
5-chloro-2,4-dihydroxydiphenyl methane;
4'-chloro-2,4-dihydroxydiphenyl methane;
5-bromo-2,4-dihydroxydiphenyl methane; and
4'-bromo-2,4-dihydroxydiphenyl methane.
[0143] Specific bisphenolic antimicrobial agents that can be used
in the disclosure include, but are not limited to: 2,2'-methylene
bis-(4-chlorophenol); 2,4,4'trichloro-2'-hydroxy-diphenyl ether,
which is sold by Ciba Geigy, Florham Park, N.J. under the trade
name Triclosan.RTM.; 2,2'-methylene bis-(3,4,6-trichlorophenol);
2,2'-methylene bis-(4-chloro-6-bromophenol);
bis-(2-hydroxy-3,5-dichlorophenyl)sulphide; and
bis-(2-hydroxy-5-chlorobenzyl)sulphide.
[0144] Specific benzoic esters (parabens) that can be used in the
disclosure include, but are not limited to: methylparaben;
propylparaben; butylparaben; ethylparaben; isopropylparaben;
isobutylparaben; benzylparaben; sodium methylparaben; and sodium
propylparaben.
[0145] Specific halogenated carbanilides that can be used in the
disclosure include, but are not limited to:
3,4,4'-trichlorocarbanilides, such as
3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea sold under the
tradename Triclocarban.RTM. by Ciba-Geigy, Florham Park, N.J.;
3-trifluoromethyl-4,4'-dichlorocarbanilide; and
3,3',4-trichlorocarbanilide.
[0146] Specific polymeric antimicrobial agents that can be used in
the disclosure include, but are not limited to: polyhexamethylene
biguanide hydrochloride; and poly(iminoimidocarbonyl
iminoimidocarbonyl iminohexamethylene hydrochloride), which is sold
under the tradename Vantocil.RTM. IB.
[0147] Specific thazolines that can be used in the disclosure
include, but are not limited to that sold under the tradename
Micro-Check.RTM.; and 2-n-octyl-4-isothiazolin-3-one, which is sold
under the tradename Vinyzene.RTM. IT-3000 DIDP.
[0148] Specific trichloromethylthioimides that can be used in the
disclosure include, but are not limited to:
N-(trichloromethylthio)phthalimide, which is sold under the
tradename Fungitrol.RTM.; and
N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide, which is
sold under the tradename Vancide.RTM..
[0149] Specific natural antimicrobial agents that can be used in
the disclosure include, but are not limited to, oils of: anise,
lemon, orange, rosemary, wintergreen, thyme, lavender, cloves,
hops, tea tree, citronella, wheat, barley, lemongrass, cedar leaf,
cedarwood, cinnamon, fleagrass, geranium, sandalwood, violet,
cranberry, eucalyptus, vervain, peppermint, gum benzoin, basil,
honey, fennel, fir, balsam, menthol, ocmea origanuin, hydastis,
carradensis, Berberidaceac daceae, Ratanhiae longa, and Curcuma
longa. Also included in this class of natural antimicrobial agents
are the key chemical components of the plant oils which have been
found to provide antimicrobial benefit. These chemicals include,
but are not limited to: anethol, catechole, camphene, thymol,
eugenol, eucalyptol, ferulic acid, farnesol, hinokitiol, tropolone,
limonene, menthol, methyl salicylate, carvacol, terpineol,
verbenone, berberine, ratanhiae extract, caryophellene oxide,
citronellic acid, curcumin, nerolidol, and geraniol.
[0150] Specific metal salts that can be used in the disclosure
include, but are not limited to, salts of metals in Groups 3a-5a,
3b-7b, and 8 of the periodic table. Specific examples of metal
salts include, but are not limited to, salts of: aluminum,
zirconium, zinc, silver, gold, copper, lanthanum, tin, mercury,
bismuth, selenium, strontium, scandium, yttrium, cerium,
praseodymiun, neodymium, promethum, samarium, europium, gadolinium,
terbium, dysprosium, holmium, erbium, thalium, ytterbium, lutetium,
and mixtures thereof. An example of the metal-ion based
antimicrobial agent is sold under the tradename HealthShield.RTM.,
and is manufactured by HealthShield Technology, Wakefield,
Mass.
[0151] Specific broad-spectrum antimicrobial agents that can be
used in the disclosure include, but are not limited to, those that
are recited in other categories of antimicrobial agents herein.
[0152] Additional antimicrobial agents that can be used in the
methods of the disclosure include, but are not limited to:
pyrithiones, and in particular pyrithione-including zinc complexes
such as these sold under the tradename Octopirox.RTM.;
dimethyidimethylol hydantoin, which is sold under the tradename
Glydant.RTM.; methylchloroisothiazolinone/methylisothiazolinone,
which is sold under the tradename Kathon CG.RTM.; sodium sulfite;
sodium bisulfite; imidazolidinyl urea, which is sold under the
tradename Germall 115.RTM.; diazolidinyl urea, which is sold under
the tradename Germall 11.RTM.; benzyl alcohol
v2-bromo-2-nitropropane-1,3-diol, which is sold under the tradename
Bronopol.RTM.; formalin or formaldehyde; iodopropenyl
butylcarbamate, which is sold under the tradename Polyphase
P100.RTM.; chloroacetamide; methanamine; methyldibromonitrile
glutaronitrile (1,2-dibromo-2,4-dicyanobutane), which is sold under
the tradename Tektamer.RTM.; glutaraldehyde;
5-bromo-5-nitro-1,3-dioxane, which is sold under the tradename
Bronidox.RTM.; phenethyl alcohol; o-phenylphenol/sodium
o-phenylphenol sodium hydroxymethylglycinate, which is sold under
the tradename Suttocide A.RTM.; polymethoxy bicyclic oxazolidine;
which is sold under the tradename Nuosept C.RTM.; dimethoxane;
thimersal; dichlorobenzyl alcohol; captan; chlorphenenesin;
dichlorophene; chlorbutanol; glyceryl laurate; halogenated diphenyl
ethers; 2,4,4'-trichloro-2'-hydroxy-diphenyl ether, which is sold
under the tradename Triclosan.RTM. and is available from
Ciba-Geigy, Florham Park, N.J.; and
2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.
[0153] Additional antimicrobial agents that can be used in the
methods of the disclosure include those disclosed by U.S. Pat. Nos.
3,141,321; 4,402,959; 4,430,381; 4,533,435; 4,625,026; 4,736,467;
4,855,139; 5,069,907; 5,091,102; 5,639,464; 5,853,883; 5,854,147;
5,894,042; and 5,919,554, and U.S. Pat. Appl. Publ. Nos.
20040009227 and 20110081530, the contents of all of which are
incorporated herein by reference.
Collagens and Agents that Promote Collagen Synthesis
[0154] According to some embodiments, the biophotonic compositions
of the present disclosure may optionally further comprise one or
more collagens and/or agents that promote collagen synthesis.
Collagen is a fibrous protein produced in dermal fibroblast cells
and forming 70% of the dermis and benefits all stages of the wound
healing process. Thus, collagens and agents that promote collagen
synthesis may also be useful in the present disclosure. Agents that
promote collagen synthesis (i.e., pro-collagen synthesis agents)
include amino acids, peptides, proteins, lipids, small chemical
molecules, natural products and extracts from natural products.
[0155] For instance, it was discovered that intake of vitamin C,
iron, and collagen can effectively increase the amount of collagen
in skin or bone. See, e.g., U.S. Patent Application Publication
20090069217, the contents of which are all incorporated herein by
reference. Examples of the vitamin C include an ascorbic acid
derivative such as L-ascorbic acid or sodium L-ascorbate, an
ascorbic acid preparation obtained by coating ascorbic acid with an
emulsifier or the like, and a mixture containing two or more of
those vitamin Cs at an arbitrary rate. In addition, natural
products containing vitamin C such as acerola and lemon may also be
used. Examples of the iron preparation include: an inorganic iron
such as ferrous sulfate, sodium ferrous citrate, or ferric
pyrophosphate; an organic iron such as heme iron, ferritin iron, or
lactoferrin iron; and a mixture containing two or more of those
irons at an arbitrary rate. In addition, natural products
containing iron such as spinach or liver may also be used.
Moreover, examples of the collagen include: an extract obtained by
treating bone, skin, or the like of a mammal such as bovine or
swine with an acid or alkaline; a peptide obtained by hydrolyzing
the extract with a protease such as pepsin, trypsin, or
chymotrypsin; and a mixture containing two or more of those
collagens at an arbitrary rate. Collagens extracted from plant
sources may also be used.
[0156] Additional pro-collagen synthesis agents are described, for
example, in U.S. Patent Patents 7598291, 7722904, 6203805, 5529769,
etc, and U.S. Patent Application Publications 20060247313,
20080108681, 20110130459, 20090325885, and 20110086060, the
contents of all of which are incorporated herein by reference.
Additional Components
[0157] In some embodiments, the compositions of the disclosure can
also include other ingredients such as humectants (e.g., glycerine,
ethylene glycol, and propylene glycol), preservatives such as
parabens, and pH adjusters such as sodium hydroxide, sodium
bicarbonate, and HCl. In some embodiments, the pH of the
composition is in or adjusted to the range of about 4 to about 10.
In some embodiments, the pH of the composition is in or adjusted to
the range of about 4 to about 9. In some embodiments, the pH of the
composition is in or adjusted to the range of from about 4 to about
8. In some embodiments, the pH of the composition is within the
range of from about 4 to about 7. In some embodiments, the pH of
the composition is within the range of from about 4 to about 6.5.
In some embodiments, the pH of the composition is within the range
of from about 4 to about 6. In some embodiments, the pH of the
composition is within the range of from about 4 to about 5.5. In
some embodiments, the pH of the composition is within the range of
from about 4 to about 5. In some embodiments, the pH of the
composition is within the range of from about 5.0 to about 8.0. In
some embodiments, the pH of the composition is within the range of
from about 6.0 to about 8.0. In some embodiments, the pH of the
composition is within the range of from about 6.5 to about 7.5. In
some embodiments, the pH of the composition is within the range of
from about 5.5 to about 7.5.
[0158] In some embodiments, the pH of the composition is in or
adjusted to the range of 4 to 10. In some embodiments, the pH of
the composition is in or adjusted to the range of 4 to 9. In some
embodiments, the pH of the composition is in or adjusted to the
range of 4 to 8. In some embodiments, the pH of the composition is
within the range of 4 to 7. In some embodiments, the pH of the
composition is within the range of 4 to 6.5. In some embodiments,
the pH of the composition is within the range of 4 to 6. In some
embodiments, the pH of the composition is within the range of 4 to
5.5. In some embodiments, the pH of the composition is within the
range of 4 to 5. In some embodiments, the pH of the composition is
within the range of 5.0 to 8.0. In some embodiments, the pH of the
composition is within the range of 6.0 to 8.0. In some embodiments,
the pH of the composition is within the range of 6.5 to 7.5. In
some embodiments, the pH of the composition is within the range of
5.5 to 7.5.
[0159] In some embodiments, the biophotonic compositions of the
disclosure also include an aqueous substance (such as water) or an
alcohol. Alcohols include, but are not limited to, ethanol,
propanol, isopropanol, butanol, iso-butanol, t-butanol or pentanol.
In some embodiments, the chromophore or combination of chromophores
is in solution in a medium of the biophotonic composition. In some
embodiments, the chromophore or combination of chromophores is in
solution in a medium of the biophotonic composition, wherein the
medium is an aqueous substance.
METHODS OF USE AND TREATMENT
Photoactivation
[0160] The biophotonic compositions suitable for use in the methods
of the present disclosure may be selected from any of the
embodiments of the biophotonic compositions described above. For
instance, the biophotonic compositions useful in the method of the
present disclosure may comprise a chromophore that undergoes at
least partial photobleaching upon application of light. The
chromophore may absorb at a wavelength of about from 200 nm to
about 800 nm, such as from about 200 nm to about 700 nm, from about
200 nm to about 600 nm or from about 200 nm to about 500 nm. In
some embodiments, the chromophore absorbs at a wavelength of about
from 200 nm to about 600 nm. In some embodiments, the chromophore
absorbs light at a wavelength of from about 200 nm to about 300 nm,
from about 250 nm to about 350 nm, from about 300 nm to about 400
nm, from about 350 nm to about 450 nm, from about 400 nm to about
500 nm, from about 450 nm to about 650 nm, from about 600 nm to
about 700 nm, from about 650 nm to about 750 nm or from about 700
nm to about 800 nm. In some embodiments, suitable biophotonic
compositions for the methods of the present disclosure may further
comprise at least one additional chromophore (e.g., a second
chromophore). The absorption spectrum of the second chromophore
overlaps at least about 80%, about 70%, about 60%, about 50%, about
40%, about 30%, or about 20% with the emission spectrum of the
first chromophore. In some embodiments, the first chromophore has
an emission spectrum that overlaps at least about 1-10%, about
5-15%, about 10-20%, about 15-25%, about 20-30%, about 25-35%,
about 30-40%, about 35-45%, about 50-60%, about 55-65% or about
60-70% with an absorption spectrum of the second chromophore.
[0161] In the methods of the present disclosure, any source of
actinic light can be used to illuminate the biophotonic
compositions. Any type of halogen, LED or plasma arc lamp or laser
may be suitable. The primary characteristic of suitable sources of
actinic light will be that they emit light in a wavelength (or
wavelengths) appropriate for activating the one or more
photoactivators present in the composition. In some embodiments, an
argon laser is used. In some embodiments, a potassium-titanyl
phosphate (KTP) laser (e.g., a GreenLight.TM. laser) is used. In
another embodiment, sunlight may be used. In some embodiments, a
LED photocuring device is the source of the actinic light. In some
embodiments, the source of the actinic light is a source of light
having a wavelength between about 200 nm and about 800 nm. In some
embodiments, the source of the actinic light is a source of visible
light having a wavelength between about 400 nm and about 700 nm. In
some embodiments, the source of the actinic light is a source of
visible light having a wavelength between about 400 nm and about
600 nm. In some embodiments, the source of the actinic light is a
source of visible light having a wavelength between about 400 nm
and about 550 nm. In some embodiments, the source of the actinic
light is a source of visible light having a wavelength between
about 380 nm and about 700 nm. In some embodiments, the source of
the actinic light is a source of visible light having a wavelength
between about 380 nm and about 600 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between about 380 nm and about 550 nm. In some
embodiments, the source of the actinic light is a source of light
having a wavelength between 200 nm to 800 nm. In some embodiments,
the source of the actinic light is a source of visible light having
a wavelength between 400 nm and 700 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between 400 nm and 600 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between 400 nm and 550 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between 380 nm and 700 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between 380 nm and 600 nm. In some embodiments, the
source of the actinic light is a source of visible light having a
wavelength between 380 nm and 550 nm. In some embodiments, the
biophotonic composition of the disclosure is illuminated with
violet and/or blue light. Furthermore, the source of actinic light
should have a suitable power density. Suitable power density for
non-collimated light sources (LED, halogen or plasma lamps) are in
the range from about 1 mW/cm.sup.2 to about 1200 mW/cm.sup.2, such
as from about 20 mW/cm.sup.2 to about 1000 mW/cm.sup.2 from about
100 mW/cm.sup.2 to about 900 mW/cm.sup.2 from about 200 mW/cm.sup.2
to about 800 mW/cm.sup.2, or from about 1 mW/cm.sup.2 to about 200
mW/cm.sup.2. In some embodiments, the power density for
non-collimated light sources (LED, halogen or plasma lamps) are in
the range from about 1 mW/cm.sup.2 to about 200 mW/cm.sup.2
Suitable power density for laser light sources is in the range from
about 0.5 mW/cm.sup.2 to about 0.8 mW/cm.sup.2.
[0162] In some embodiments of the methods of the present
disclosure, the light has an energy at the patient's skin of from
about 1 mW/cm.sup.2 to about 500 mW/cm.sup.2, or about 1
mW/cm.sup.2 to about 300 mW/cm.sup.2, or about 1 mW/cm.sup.2 to
about 200 mW/cm.sup.2, wherein the energy applied depends at least
on the condition being treated, the wavelength of the light, the
distance of the patient's skin from the light source, and the
thickness of the biophotonic composition. In some embodiments, the
light at the patient's skin is from about 1 mW/cm.sup.2 to about 40
mW/cm.sup.2, or about 20 mW/cm.sup.2 to about 60 mW/cm.sup.2, or
about 40 mW/cm.sup.2 to about 80 mW/cm.sup.2, or about 60
mW/cm.sup.2 to about 100 mW/cm.sup.2, or about 80 mW/cm.sup.2 to
about 120 mW/cm.sup.2, or about 100 mW/cm.sup.2 to about 140
mW/cm.sup.2, or about 120 mW/cm.sup.2 to about 160 mW/cm.sup.2, or
about 140 mW/cm.sup.2 to about 180 mW/cm.sup.2, or about 160
mW/cm.sup.2 to about 200 mW/cm.sup.2, or about 110 mW/cm.sup.2 to
about 240 mW/cm.sup.2, or about 110 mW/cm.sup.2 to about 150
mW/cm.sup.2, or about 190 mW/cm.sup.2 to about 240 mW/cm.sup.2.
[0163] In some embodiments, a mobile device can be used to activate
embodiments of the biophotonic composition of the present
disclosure, wherein the mobile device can emit light having an
emission spectrum which overlaps an absorption spectrum of the
chromophore in the biophotonic composition. The mobile device can
have a display screen through which the light is emitted and/or the
mobile device can emit light from a flashlight which photoactivates
the biophotonic composition.
[0164] In some embodiments, a display screen on a television or a
computer monitor can be used to activate the biophotonic
composition, wherein the display screen can emit light having an
emission spectrum which overlaps an absorption spectrum of a
photoactive agent in the photoactivatable composition.
[0165] In some embodiments, the chromophore or combination of
chromophores can be photoactivated by ambient light which may
originate from the sun or other light sources. Ambient light can be
considered to be a general illumination that comes from all
directions in a room that has no visible source. In some
embodiments, the chromophore or combination of chromophores can be
photoactivated by light in the visible range of the electromagnetic
spectrum. Exposure times to ambient light may be longer than that
to direct light.
[0166] In some embodiments, different sources of light can be used
to activate the biophotonic compositions, such as a combination of
ambient light and direct LED light.
[0167] The duration of the exposure to actinic light required will
be dependent on the surface of the treated area, the severity of
the condition that is being treated, the power density, wavelength
and bandwidth of the light source, the thickness of the biophotonic
composition, and the treatment distance from the light source. The
illumination of the treated area by fluorescence may take place
within seconds or even fragment of seconds, but a prolonged
exposure period is beneficial to exploit the synergistic effects of
the absorbed, reflected and reemitted light on the composition of
the present disclosure and its interaction with the tissue being
treated. In some embodiments, the time of exposure to actinic light
of the tissue or skin or wound on which the biophotonic composition
has been applied is a period from about 1 second to about 30
minutes. In some embodiments, the time of exposure to actinic light
of the tissue or skin or wound on which the biophotonic composition
has been applied is a period from about 1 minute to about 30
minutes. In some embodiments, the time of exposure to actinic light
of the tissue, skin or wound on which the biophotonic composition
has been applied is a period from about 1 minute to about 5
minutes. In some embodiments, the time of exposure to actinic light
of the tissue, skin or wound on which the biophotonic composition
has been applied is a period between 1 minute to about 5 minutes.
In another embodiment, the time of exposure is from about 20
seconds to about 5 minutes, or from about 60 seconds to about 5
minutes. In another embodiment, the time of exposure to actinic
light of the tissue on which the biophotonic composition has been
applied is a period of less than about 5 minutes. In another
embodiment, the time of exposure is between about 20 seconds to
about 5 minutes, or from about 60 seconds to about 5 minutes per
cm.sup.2 of the area to be treated, so that the total time of
exposure of a 10 cm.sup.2 area would be from about 10 minutes to
about 50 minutes.
[0168] In some embodiments, the biophotonic composition is
illuminated for a period from about 1 minute and 3 minutes. In some
embodiments, light is applied for a period of from about 1 to about
30 seconds, from about 1 second to about 60 seconds, from about 15
seconds to about 45 seconds, from about 30 seconds to about 60
seconds, from about 0.75 minute to about 1.5 minutes, from about 1
minute to about 2 minutes, from about 1.5 minutes to about 2.5
minutes, from about 2 minutes to about 3 minutes, from about 2.5
minutes to about 3.5 minutes, from about 3 minutes to about 4
minutes, from about 3.5 minutes to about 4.5 minutes, from about 4
minutes to about 5 minutes, from about 5 minutes to about 10
minutes, from about 10 minutes to about 15 minutes, from about 15
minutes to about 20 minutes, from about 20 minutes to about 25
minutes, or from about 20 minutes to about 30 minutes. In some
embodiments, light is applied for a period of 1 second. In some
embodiments, light is applied for a period of about 5 seconds. In
some embodiments, light is applied for a period of about 10
seconds. In some embodiments, light is applied for a period of
about 20 seconds. In some embodiments, light is applied for a
period of about 30 seconds. In some embodiments, the biophotonic
composition is illuminated for a period less than about 30 minutes.
In some embodiments, the biophotonic composition is illuminated for
a period less than about 20 minutes. In some embodiments, the
biophotonic composition is illuminated for a period less than about
15 minutes. In some embodiments, the biophotonic composition is
illuminated for a period less than about 10 minutes. In some
embodiments, the biophotonic composition is illuminated for a
period less than about 5 minutes. In some embodiments, the
biophotonic composition is illuminated for a period less than about
1 minute. In some embodiments, the biophotonic composition is
illuminated for a period less than about 30 seconds. In some
embodiments, the biophotonic composition is illuminated for a
period less than about 20 seconds. In some embodiments, the
biophotonic composition is illuminated for a period less than 10
seconds. In some embodiments, the biophotonic composition is
illuminated for a period less than 5 seconds. In some embodiments,
the biophotonic composition is illuminated for a period less than 1
second. In some embodiments, the source of actinic light is in
continuous motion over the treated area for the appropriate time of
exposure. In some embodiments, multiple applications of the
biophotonic composition and actinic light are performed. In some
embodiments, the tissue, skin or wound is exposed to actinic light
at least two, three, four, five or six times. In some embodiments,
the tissue, skin or wound is exposed to actinic light at least two,
three, four, five or six times with a resting period in between
each exposure. In certain such embodiments, the resting period is
less than about 1 minute, less than about 5 minutes, less than
about 10 minutes, less than about 20 minutes, less about 40
minutes, less than about 60 minutes, less than about 2 hours, less
than about 4 hours, less than about 6 hours, or less than 12 hours.
In some embodiments, the entire treatment may be repeated in its
entirety as may be required by the patient. In some embodiments, a
fresh application of the biophotonic composition is applied before
another exposure to actinic light.
[0169] In the methods of the present disclosure, the biophotonic
composition may be optionally removed from the site of treatment
following application of light. In some embodiments, the
biophotonic composition is left on the treatment site for more than
about 30 minutes, more than one hour, more than about 2 hours, or
more than about 3 hours. It can be illuminated with ambient light.
To prevent drying, the composition can be covered with a
transparent or translucent cover such as a polymer film, or an
opaque cover which can be removed before illumination.
[0170] The biophotonic compositions of the disclosure may be
applied at regular intervals such as once a week, or at an interval
deemed appropriate by the physician or veterinarian. In some
embodiments, the biophotonic compositions of the disclosure are
applied once per week for one or more weeks, such as once per week
for one week. In some embodiments, the biophotonic compositions of
the disclosure are applied once per week for two weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied once per week for three weeks. In some embodiments, the
biophotonic compositions of the disclosure are applied once per
week for four weeks. In some embodiments, the biophotonic
compositions of the disclosure are applied once per week for five
weeks. In some embodiments, the biophotonic compositions of the
disclosure are applied once per week for six weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied once per week for seven weeks. In some embodiments, the
biophotonic compositions of the disclosure are applied once per
week for eight or more weeks.
[0171] In some embodiments, the biophotonic compositions of the
disclosure are applied twice per week for one or more weeks, such
as twice per week for one week. In some embodiments, the
biophotonic compositions of the disclosure are applied twice per
week for two weeks. In some embodiments, the biophotonic
compositions of the disclosure are applied twice per week for three
weeks. In some embodiments, the biophotonic compositions of the
disclosure are applied twice per week for four weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied twice per week for five weeks. In some embodiments, the
biophotonic compositions of the disclosure are applied twice per
week for six weeks. In some embodiments, the biophotonic
compositions of the disclosure are applied twice per week for seven
weeks. In some embodiments, the biophotonic compositions of the
disclosure are applied twice per week for eight or more weeks.
[0172] In some embodiments, the biophotonic compositions of the
disclosure are applied three times or more per week for one or more
weeks, such as three times or more for one week. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for two weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for three weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for four weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for five weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for six weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for seven weeks. In some
embodiments, the biophotonic compositions of the disclosure are
applied three times or more per week for eight or more weeks.
[0173] For any of the methods described herein, the embodiments of
this disclosure contemplate the use of any of the compositions, or
mixtures of them, described throughout the application. In
addition, in various embodiments of any of the methods described
herein, combinations of any step or steps of one method with any
step or steps from another method may be employed.
Resistant Infections
[0174] The biophotonic compositions of the present disclosure have
numerous uses. In some embodiments, the biophotonic compositions of
the present disclosure are useful in the treatment of resistant
infections. A resistant infection is an infection caused by a
microorganism that is resistant to an antimicrobial or
anti-infective agent that was originally effective for treatment of
infections caused by it. Resistant microorganisms (including
bacteria, fungi, viruses and parasites) are able to withstand
treatment by antimicrobial or anti-infective agents, such as
antibacterial agents (e.g., antibiotics), antifungals, antivirals,
and antiprotozoals, so that standard treatments become ineffective
and infections persist. As resistant infections fail to respond to
standard treatments, they result in prolonged illness and/or
healing, reduced effectiveness of treatment, higher health care
expenditures, and a greater risk of death. In some embodiments
wherein the present disclosure provides biophotonic compositions
and methods for treating and/or preventing resistant infections,
the resistant infection is a bacterial infection. In certain such
embodiments wherein the resistant infection is a bacterial
infection, the bacterial infection is resistant to antibiotics.
[0175] The present disclosure provides biophotonic compositions and
methods for treating a resistant infection, wherein the resistant
infection is present on a mammal. In certain such embodiments, the
mammal is a human, an equine, a feline, or a canine. In some
embodiments, the resistant infection is present on and/or in a
wound or as part of an oral disease.
[0176] In some embodiments, the biophotonic compositions and
methods of the present disclosure are useful in treating resistant
infections, for example, by maintaining asepsis. In some
embodiments, the biophotonic compositions and methods of the
present disclosure are useful in treating resistant infections, for
example, by ameliorating any symptom caused by an infectious agent
or inhibiting it from spreading. In some embodiments, the
biophotonic compositions and methods of the present disclosure are
useful in treating resistant infections, for example, by treating
or preventing infection. In some embodiments, the biophotonic
compositions and methods of the present disclosure are useful in
treating resistant infections, for example, by treating or
preventing bacterial infection. In some embodiments, the
biophotonic compositions and methods of the present disclosure are
useful in treating resistant infections, for example, by treating
or preventing resistant bacterial infections. In some embodiments,
the biophotonic compositions and methods of the present disclosure
are useful in treating resistant infection without or with reduced
use of antibiotics.
Wounds and Wound Healing
[0177] In some embodiments, the biophotonic compositions of the
present disclosure are useful in the treatment of wounds of the
skin or soft tissues that have a non-resistant or resistant
infection, or that are infected by both a non-resistant and a
resistant bacteria population, or other pathological agents (e.g.
fungi). In certain embodiments, the resistant infection has
developed from an infection that was originally a non-resistant
infection. In certain such embodiments, the wounds may comprise a
non-resistant or resistant infection. In certain such embodiments,
the non-resistant or resistant infection is a bacterial infection.
In certain such embodiments wherein the resistant infection is a
bacterial infection, the bacterial infection is resistant to
antibiotics. In certain such embodiments, the wound is present on a
patient and the patient is a mammal, such as a human, an equine, a
feline, or a canine.
[0178] Therefore, it is an objective of the present disclosure to
provide a method of providing biophotonic therapy to a wound of the
skin or soft tissues that has a non-resistant or resistant
infection or a combination of such infections. In certain such
embodiments, the wounds comprise a resistant infection. In certain
such embodiments, the non-resistant or resistant infection is a
bacterial infection. In certain such embodiments wherein the
resistant infection is a bacterial infection, the bacterial
infection is resistant to antibiotics. In certain such embodiments,
the wound is present on a patient and the patient is a mammal, such
as a human, an equine, a feline, or a canine.
[0179] Wounds that may be treated by the biophotonic compositions
and methods of the present disclosure include, for example,
injuries to the skin and subcutaneous tissue initiated in different
ways (e.g., pressure ulcers from extended bed rest, wounds induced
by trauma, wounds induced by conditions such as periodontitis and
periodontal disease) and with varying characteristics. In some
embodiments, the present disclosure provides biophotonic
compositions and methods for treating and/or promoting the healing
of, for example, burns, incisions, excisions, lacerations,
abrasions, puncture or penetrating wounds, chronic wounds, acute
wounds, surgical wounds, contusions, hematomas, crushing injuries,
sores and ulcers. Wounds that may be treated by the biophotonic
compositions and methods of the present disclosure also include
wounds of the skin and soft tissues.
[0180] Biophotonic compositions and methods of the present
disclosure are useful to treat and/or promote the healing of
chronic cutaneous ulcers or wounds, which are wounds that have
failed to proceed through an orderly and timely series of events to
produce a durable structural, functional, and cosmetic closure.
[0181] The present disclosure provides biophotonic compositions and
methods for treating and/or promoting healing in Grade I-IV ulcers.
In some embodiments, the application provides compositions suitable
for use with Grade II ulcers in particular. Ulcers may be
classified into one of four grades depending on the depth of the
wound: i) Grade I: wounds limited to the epithelium; ii) Grade II:
wounds extending into the dermis; iii) Grade III: wounds extending
into the subcutaneous tissue; and iv) Grade IV (or full-thickness
wounds): wounds wherein bones are exposed (e.g., a bony pressure
point such as the greater trochanter or the sacrum).
[0182] In some embodiments, the present disclosure provides
biophotonic compositions and methods for treating and/or promoting
healing of a pressure ulcer. Pressure ulcer includes bed or
pressure sores, decubitus ulcers and ischial tuberosity ulcers and
can cause considerable pain and discomfort to a patient. A pressure
ulcer can occur as a result of a prolonged pressure applied to the
skin. Thus, pressure can be exerted on the skin of a patient due to
the weight or mass of the patient or due to the presence of any
type of apparatus on the skin or soft tissue for a prolonged period
of time and which may have, periodically, additional weight added
to the apparatus, for example a horse saddle or other load-bearing
apparatus. A pressure ulcer can develop when blood supply to an
area of the skin is obstructed or cut off for more than two or
three hours. The affected skin area can turn red, becomes painful
and can become necrotic. If untreated, the skin breaks open and can
become infected. An ulcer sore is therefore a skin ulcer that
occurs in an area of the skin that is under pressure from e.g.,
lying, sitting, and/or wearing a cast or other apparatus for a
prolonged period of time. Pressure ulcer can occur when a patent is
bedridden, unconscious, unable to sense pain, or immobile. Pressure
ulcer often occur in honey prominences of the body such as the
buttocks area (on the sacrum or iliac crest), or on the hips or
elbows.
[0183] In some embodiments, the present disclosure provides
biophotonic compositions and methods for treating and/or promoting
healing of traumatic ulcers.
[0184] In some embodiments, the present disclosure provides
biophotonic compositions and methods for treating and/or promoting
healing of acute wounds. An acute wound is an injury to the skin
that occurs suddenly rather than over time. Acute wounds can happen
anywhere on the body and vary from superficial scratches to deep
wounds damaging blood vessels, nerves, muscles or other body
parts.
[0185] In some embodiments, the present disclosure provides
biophotonic compositions and methods for treating and/or promoting
healing of chronic wounds. A chronic wound develops when any acute
wound fails to heal in the expected time frame for that type of
wound, which might be a couple of weeks or up to six weeks in some
cases. Failure of any wound to heal can be due to a lack of one or
more of the main requirements of healing, including a good supply
of blood, oxygen and nutrients, and a clean and infection-free
environment.
[0186] In some embodiments, the present disclosure provides
biophotonic compositions and methods for treating and/or promoting
healing of surgical wounds. In certain such embodiments,
administration of post-operative antibiotics is not part of the
method of treatment. In some embodiments, the present disclosure
provides biophotonic compositions and methods for treating and/or
promoting healing of surgical dehisced wounds. Wound dehiscence is
one of the most common complications of surgical wounds, involving
the breaking open of the surgical incision along the suture. When
wound dehiscence occurs, the edges starts to separate and the wound
reopens instead of healing closed as planned.
[0187] Additional types of wounds that can be treated by the
biophotonic compositions and methods of the present disclosure
include those disclosed by U.S. Pat. Appl. Publ. No. 20090220450,
which is incorporated herein by reference.
[0188] Any of the types of wounds described herein are susceptible
to microbial infection, and in some cases, these infections become
resistant infections. In some embodiments, the present disclosure
provides biophotonic compositions and methods for treating and/or
preventing wounds comprising resistant infections, wherein the
wounds are selected from any of the types of wounds described
herein.
[0189] The present disclosure provides biophotonic compositions and
methods for treating any one of the types of wounds described
herein, wherein the wound is present on a mammal. In certain such
embodiments, the mammal is a human, an equine, a feline, or a
canine. Treatment of wounds in mammals such as horses, cats, or
dogs can be challenging. Management of the wounds, regardless of
size, is frequently laborious and frustrating, as animals tend to
lick, chew, or scratch at their wounds. Maintaining asepsis is
difficult, and complications, such as infection, can lead to
physical pain, emotional distress, and longer healing time.
[0190] Wound healing in mammalian tissues is a complicated
reparative process. For example, the healing process for skin
involves the recruitment of a variety of specialized cells to the
site of the wound, extracellular matrix and basement membrane
deposition, angiogenesis, selective protease activity and
re-epithelialization.
[0191] There are three distinct phases in the wound healing
process. First, in the inflammatory phase, which typically occurs
from the moment a wound occurs until the first two to five days,
platelets aggregate to deposit granules, promoting the deposit of
fibrin and stimulating the release of growth factors. Leukocytes
migrate to the wound site and begin to digest and transport debris
away from the wound. During this inflammatory phase, monocytes are
also converted to macrophages, which release growth factors for
stimulating angiogenesis and the production of fibroblasts.
[0192] Second, in the proliferative phase, which typically occurs
from two days to three weeks, granulation tissue forms, and
epithelialization and contraction begin. Fibroblasts, which are key
cell types in this phase, proliferate and synthesize collagen to
fill the wound and provide a strong matrix on which epithelial
cells grow. As fibroblasts produce collagen, vascularization
extends from nearby vessels, resulting in granulation tissue.
Granulation tissue typically grows from the base of the wound.
Epithelialization involves the migration of epithelial cells from
the wound surfaces to seal the wound. Epithelial cells are driven
by the need to contact cells of like type and are guided by a
network of fibrin strands that function as a grid over which these
cells migrate. Contractile cells called myofibroblasts appear in
wounds, and aid in wound closure. These cells exhibit collagen
synthesis and contractility, and are common in granulating
wounds.
[0193] Third, in the remodeling phase, the final phase of wound
healing which can take place from three weeks up to several years,
collagen in the scar undergoes repeated degradation and
re-synthesis. During this phase, the tensile strength of the newly
formed skin increases.
[0194] However, as the rate of wound healing increases, there is
often an associated increase in scar formation. Scarring is a
consequence of the healing process in most adult animal and human
tissues. Scar tissue is not identical to the tissue which it
replaces, as it is usually of inferior functional quality. The
types of scars include, but are not limited to, atrophic,
hypertrophic and keloidal scars, as well as scar contractures.
Atrophic scars are flat and depressed below the surrounding skin as
a valley or hole. Hypertrophic scars are elevated scars that remain
within the boundaries of the original lesion, and often contain
excessive collagen arranged in an abnormal pattern. Keloidal scars
are elevated scars that spread beyond the margins of the original
wound and invade the surrounding normal skin in a way that is site
specific, and often contain whorls of collagen arranged in an
abnormal fashion.
[0195] In contrast, normal skin consists, in humans, of collagen
fibers arranged in a basket-weave pattern, which contributes to
both the strength and elasticity of the dermis. Thus, to achieve a
smoother wound healing process, an approach is needed that not only
stimulates collagen production, but also does so in a way that
reduces scar formation.
[0196] The biophotonic compositions and methods of the present
disclosure promote the wound healing by promoting the formation of
substantially uniform epithelialization; promoting collagen
synthesis; promoting controlled contraction; and/or by reducing the
formation of scar tissue. In some embodiments, the biophotonic
compositions and methods of the present disclosure are useful in
promoting wound healing by promoting the formation of substantially
uniform epithelialization. In some embodiments, the biophotonic
compositions and methods of the present disclosure promote collagen
synthesis. In some embodiments, the biophotonic compositions and
methods of the present disclosure promote controlled contraction.
In some embodiments, the biophotonic compositions and methods of
the present disclosure promote wound healing, for example, by
reducing the formation of scar tissue or by speeding up the wound
closure process. In some embodiments, the biophotonic compositions
and methods of the present disclosure promote wound healing, for
example, by reducing inflammation. In some embodiments, the
biophotonic composition can be used following wound closure to
optimize scar revision.
[0197] In some embodiments, the biophotonic compositions and
methods of the present disclosure promote wound healing, for
example, by maintaining asepsis. In some embodiments, the
biophotonic compositions and methods of the present disclosure
promote wound healing, for example, by ameliorating any symptom
caused by an infectious agent or inhibiting it from spreading. In
some embodiments, the biophotonic compositions and methods of the
present disclosure promote wound healing, for example, by treating
or preventing infection. In some embodiments, the biophotonic
compositions and methods of the present disclosure promote wound
healing, for example, by treating or preventing bacterial or fungal
infection. In some embodiments, the biophotonic compositions and
methods of the present disclosure promote wound healing, for
example, by treating or preventing resistant infections or
infections that have a population of non-resistant and resistant
bacteria or other microorganisms. In some embodiments, the
biophotonic compositions and methods of the present disclosure
promote wound healing, for example, by treating or preventing
resistant bacterial infections. In some embodiments, the
biophotonic compositions and methods of the present disclosure
promote wound healing, for example, by preventing reinfection of
the wound. In some embodiments, the biophotonic compositions and
methods of the present disclosure promote wound healing without the
use of antibiotics. The biophotonic compositions of the disclosure
may be applied at regular intervals such as once a week for one or
more weeks, or at an interval deemed appropriate by the physician
or veterinarian.
[0198] The biophotonic composition may be soaked into a woven or
non-woven material or a sponge and applied as a wound dressing. A
light source, such as LEDs or waveguides, may be provided within or
adjacent the wound dressing or the composition to illuminate the
composition. The waveguides can be optical fibers which can
transmit light, not only from their ends, but also from their body.
In some embodiments, the waveguides are made of polycarbonate or
polymethylmethacrylate.
[0199] Adjunct therapies which may be topical or systemic such as
antibiotic treatment may also be used. Negative pressure assisted
wound closure can also be used to assist wound closure and/or to
remove the composition.
Oral Diseases
[0200] The biophotonic compositions and methods of the present
disclosure are useful to treat oral diseases. In certain such
embodiments, the oral diseases comprise a non-resistant infection
or a resistant infection or a combination of a non-resistant and a
resistant infection. In certain embodiments, the resistant
infection has developed from a non-resistant infection that was
treated by a method not comprising a biophotonic composition of the
present description. In certain such embodiments, the non-resistant
or the resistant infection, or both, is a bacterial infection. In
certain such embodiments wherein the resistant infection is a
bacterial infection, the bacterial infection is resistant to
antibiotics. In certain such embodiments, the oral disease is
present in a patient and the patient is a mammal, such as a human,
an equine, a feline, or a canine. The biophotonic compositions of
the disclosure may be applied at regular intervals such as once a
week, or at an interval deemed appropriate by the physician, dental
professional, or veterinarian.
[0201] Therefore, it is an objective of the present disclosure to
provide a method of providing biophotonic therapy to an oral
disease. In certain such embodiments, the oral disease comprises a
non-resistant infection or a resistant infection or a combination
of a non-resistant and a resistant infection. In certain such
embodiments, either or both of the non-resistant and the resistant
infections are a bacterial infection. In certain such embodiments
wherein the resistant infection is a bacterial infection, the
bacterial infection is resistant to antibiotics. In certain such
embodiments, the oral disease is present on a patient and the
patient is a mammal, such as a human, an equine, a feline, or a
canine. The oral disease may be chosen from, but is not limited to,
gingivitis, periodontitis, periodontal disease, and oral
lesions.
Gingivitis
[0202] Gingivitis is a disorder that is defined by the inflammation
of the gums, and is characterized as a periodontal disease, which
is characterized by the destruction of the gums, tissue, tooth
sockets, and ligaments which create the structure that holds the
teeth in place. Gingivitis is one of the first stages of serious
periodontal disease.
[0203] The symptoms of gingivitis include swollen gums, mouth
sores, a bright red or purple appearance to the gums, shiny gums,
gums that are painless except when touched, and bleeding gums.
Often the first signs of gingivitis have no symptoms except for
visual symptoms and are likely only to be diagnosed by a dental
professional or veterinarian specializing in the treatment of oral
diseases in animals.
Periodontal Disease
[0204] Periodontal disease (PD) is more prevalent in developing
nations and in most cases, a professional cleaning and antibiotics
can clear up most cases of periodontal disease in humans.
Periodontal diseases are also prevalent in non-human mammals, and
as per the situation with human periodontal disease, if left
untreated the infection can spread throughout the body and can lead
to serious health complications. In many instances, treatment of
the periodontal disease in an afflicted non-human mammal entails an
extraction of the entire tooth.
[0205] PD consists of an infection of the periodontium and can
result in serious local consequences (oro nasal fistulas, class 11
perio-endo lesions, pathologic fractures, ocularproblems,
osteomyelitis, and increased incidence of oral cancer) and systemic
complications (renal, hepatic, pulmonary, and cardiac diseases;
osteoporosis, adverse pregnancy effects, and diabetes mellitus). PD
has a multifactorial etiology although, at the onset, bacterial
plaque plays a role of prime importance. Plaque is a biofilm, which
is made up almost entirely of oral bacteria, contained in a matrix
composed of salivary glycoproteins and extracellular
polysaccharides. Calculus (or tartar) is basically plaque which has
secondarily become calcified by the minerals in saliva. In some
embodiments, the present disclosure provides biophotonic
compositions and methods for treating and/or promoting healing of
wounds associated with PD1, gingivitis only without attachment
loss; PD2, early periodontitis with <25% of attachment loss;
PD3, moderate periodontitis with 25-50% attachment loss; or PD4,
advanced periodontitis with >50% attachment loss.
[0206] Symptoms of periodontal disease include painful gums, bad
breath, a foul taste to the mouth, fever, gums that bleed with only
mild amounts of pressure, crater sized canker sores between the
teeth and gums, swollen lymph nodes around the head, neck, or jaw,
a gray film on the gums, red gums, swollen gums, and pain when
eating and swallowing.
Periodontitis
[0207] Periodontitis or Pyorrhea alveolaris is the inflammation of
the periodontium which comprises tissues supporting the teeth in
the oral cavity. Parts included in the periodontium are the gingiva
(gum tissue), the alveolar bone which are sockets where teeth are
attached, the cementum or outer layer of teeth roots and the
periodontal ligaments or PDL composed of connective tissue fibers
linking the gingival and cementum to the alveolar bone. The
condition is described as the progressive loss of bone around teeth
leading to loose teeth or loss of teeth if left unattended. There
are different causes for the disease in which bacteria is the most
common. Periodontitis is considered as an advanced phase of gum
disease since it already involves bone loss in the area. It is the
effect of mild gingivitis being left untreated. Due to the presence
of bacterial infection, the body can also respond negatively to it
leading to further complications. The condition is one of the
leading causes of tooth loss among human adults, affecting around
50% of everyone over the age of 30.
[0208] Signs and symptoms arise due to the unstable anchoring of
teeth as well as the presence of microorganisms. Gums occasionally
or frequently bleed or turn red while brushing teeth, using dental
floss, biting into food, chewing or touching with fingers. Gums
swell or develop pus occasionally as well. The affected individual
likely has halitosis or bad breath and, in humans, have a lingering
metallic or tinny taste inside the mouth. Teeth, in afflicted
humans, seem longer and sharper due to gingival recession which
partly may also be caused by hard brushing. If enzymes called
collagenases have begun destroying collagen, the person will have
deep pockets between the teeth and gums. In some embodiments,
biophotonic compositions of the present disclosure are applied to
the periodontal pockets of a subject.
[0209] During the early stages of periodontal disease, only a few
signs and symptoms may be noticeable. Aggressive periodontitis may
affect younger individuals and can occur in episodes. Some episodes
may present very mild symptoms while others may be very severe. The
signs and symptoms especially in the case of chronic periodontitis
are usually progressive in nature.
Other Oral Inflammatory Lesions
[0210] The present disclosure may be used to treat other types of
oral inflammation, including but not limited to oral mucositis,
oral ulcers caused by viral, bacterial, fungal or protozoan
infections. Included is glossitis, an inflammation or infection of
the tongue. It causes the tongue to swell and change color.
[0211] Any of the types of oral diseases described herein are
susceptible to microbial infection, and in some cases, these
infections become resistant infections. In some embodiments, the
present disclosure provides biophotonic compositions and methods
for treating and/or preventing oral disease comprising a
non-resistant or resistant infection or both non-resistant and
resistant infections, wherein the oral diseases are selected from
any of the types of oral diseases described herein.
[0212] In some embodiments, the biophotonic compositions and
methods of the present disclosure are useful in treating oral
diseases, for example, by maintaining asepsis. In some embodiments,
the biophotonic compositions and methods of the present disclosure
are useful in treating oral diseases, for example, by ameliorating
any symptom caused by an infectious agent or inhibiting it from
spreading. In some embodiments, the biophotonic compositions and
methods of the present disclosure are useful in treating oral
diseases, for example, by treating or preventing infection. In some
embodiments, the biophotonic compositions and methods of the
present disclosure are useful in treating oral diseases, for
example, by treating or preventing bacterial infection. In some
embodiments, the biophotonic compositions and methods of the
present disclosure are useful in treating oral diseases, for
example, by treating or preventing a non-resistant or a resistant
infection or a combination of a non-resistant and resistant
infection. In some embodiments, the biophotonic compositions and
methods of the present disclosure are useful in treating oral
diseases, for example, by treating or preventing resistant
bacterial infections. In some embodiments, the biophotonic
compositions and methods of the present disclosure are useful in
treating oral diseases, for example, by preventing reoccurrence of
the oral disease or for preventing a non-resistant infection from
evolving into a resistant infection. In some embodiments, the
biophotonic compositions and methods of the present disclosure are
useful in treating oral diseases without or with reduced use of
antibiotics.
[0213] In some aspects, there is provided a method of treating a
skin or soft tissue wound having a non-resistant or a resistant
infection, or both categories of infection, comprising: applying a
biophotonic composition to a patient in need thereof, wherein the
biophotonic composition comprises at least one oxidant and at least
one chromophore capable of activating the oxidant; and exposing
said biophotonic composition to actinic light for a time sufficient
for said chromophore to cause activation of said oxidant. In
certain such aspects, the soft tissue wound comprises an oral
disease. In certain such aspects, the wound is a skin wound. In
certain such aspects, either or both the non-resistant and the
resistant infection is a bacterial infection. In certain such
aspects, the bacterial infection is resistant to antibiotics. In
certain such aspects, the patient is a mammal, such as a human, an
equine, a feline or a canine. In certain such aspects, the
infection is a resistant infection. In certain such aspects, the
method is performed once per week for one or more weeks, such as
for one week, two weeks, three weeks, four weeks, five weeks, or
six weeks. In certain such aspects, the method is performed twice
per week for one or more weeks, such as twice per week for one
week, two weeks, three weeks, four weeks, five weeks, or six
weeks.
[0214] In other aspects, the disclosure provides for use of a
biophotonic composition for the manufacture of a medicament for
treating a patient afflicted with a skin or soft tissue wound
having a non-resistant infection or a resistant infection or both
categories of infection, wherein said composition comprises: at
least one oxidant, and at least one chromophore capable of
activating the oxidant; in association with a pharmacologically
acceptable carrier. In certain such aspects, the soft tissue wound
comprises an oral disease. In certain such aspects, the wound is a
skin wound. In certain such aspects, either or both the
non-resistant and the resistant infection is a bacterial infection.
In certain such aspects, the bacterial infection is resistant to
antibiotics. In certain such aspects, the patient is a mammal, such
as a human, an equine, a feline or a canine. In certain such
aspects, the infection is a resistant infection.
[0215] In some other aspects, the disclosure provides for use of a
biophotonic composition for the treatment of a patient afflicted
with a skin or soft tissue wound having a non-resistant or a
resistant infection or both categories of infection, wherein said
composition comprises: at least one oxidant; and at least one
chromophore capable of activating the oxidant; in association with
a pharmacologically acceptable carrier. In certain such aspects,
the soft tissue wound comprises an oral disease. In certain such
aspects, the wound is a skin wound. In certain such aspects, either
or both the non-resistant and the resistant infection is a
bacterial infection. In certain such aspects, the bacterial
infection is resistant to antibiotics. In certain such aspects, the
patient is a mammal, such as a human, an equine, a feline or a
canine. In certain such aspects, the infection is a resistant
infection.
Combination Therapies
[0216] Any of the biophotonic compositions, methods, or uses of
this disclosure may be useful in combination with other
therapeutics.
[0217] In some embodiments, the phrase "combination therapy"
embraces the administration of any of the compositions described
herein, and an additional therapeutic agent, or mixtures of them,
as part of a specific treatment regimen intended to provide a
beneficial effect from the co-action of these therapeutic agents.
Administration of these therapeutic agents in combination typically
is carried out over a defined time period (usually minutes, hours,
days or weeks depending upon the combination selected).
"Combination therapy" is intended to embrace administration of
these therapeutic agents in a sequential manner, that is, wherein
each therapeutic agent is administered at a different time, as well
as administration of these therapeutic agents, or at least two of
the therapeutic agents, in a substantially simultaneous manner. The
therapeutic agents can be administered by the same route or by
different routes. For example, a first therapeutic agent of the
combination selected may be administered by intravenous injection
or orally while the biophotonic composition of the disclosure is
administered topically. Alternatively, for example, all therapeutic
agents may be administered topically. The sequence in which the
therapeutic agents are administered is not narrowly critical.
"Combination therapy" also embraces the administration of the
compositions as described herein in further combination with other
biologically active ingredients (such as, but not limited to, a
second and different therapeutic agent) and/or non-drug therapies
(such as, but not limited to, surgery or radiation).
[0218] In some embodiments, the therapeutic agents administered in
combination therapy simultaneously, separately, or sequentially
with any of the compounds and compositions of this disclosure, or
mixtures thereof, can comprise, but are not limited to: a
non-steroidal anti-inflammatory drug (NSAID), an anti-inflammatory
agent, a corticosteroid, an anti-allergic agent, a steroid drug,
one or more of the antimicrobial agents described above, one or
more collagens and/or agents that promote collagen synthesis
described above, or mixtures thereof.
[0219] In some embodiments, any of the compositions described
herein can allow the combination therapeutic agents and/or
compositions described herein or mixtures thereof to be
administered at a low dose, that is, at a dose lower than has been
conventionally used in clinical situations.
[0220] Alternatively, the methods and combinations of this
disclosure maximize the therapeutic effect at higher doses.
[0221] In some embodiments, when administered as a combination, the
therapeutic agents can be formulated as separate compositions which
are given at the same time or different times, or the therapeutic
agents can be given as a single composition.
Kits
[0222] The present disclosure also provides kits for preparing
and/or applying any of the compositions of the present disclosure
for the treatment of a skin or soft tissue wound having a resistant
or non-resistant infection. The kit may include a biophotonic
composition (e.g., a topical biophotonic composition), as described
herein, and may also include an apparatus for applying or removing
the composition, and instructions of use for the composition and/or
a light source. In some embodiments, the biophotonic composition
comprises at least one oxidant and at least one chromophore capable
of activating the oxidant.
[0223] In some embodiments, the kit includes more than one
composition, for example, a first and a second composition. The
first composition may include at least one chromophore capable of
activating the oxidant and the second composition may include at
least one oxidant. In certain such embodiments, the oxidant is
chosen from hydrogen peroxide, carbamide peroxide and benzoyl
peroxide. In certain such embodiments, the first and/or second
composition further comprises one or more gelling agents.
[0224] In some embodiments, the first composition may comprise at
least one chromophore capable of activating the oxidant in a liquid
or as a powder, and the second composition may comprise at least
one oxidant. In certain such embodiments, the oxidant is chosen
from hydrogen peroxide, carbamide peroxide and benzoyl peroxide. In
certain such embodiments, the first and/or second composition
further comprises one or more gelling agents.
[0225] In some embodiments, the kit includes containers comprising
the compositions of the present disclosure. In some embodiments,
the kit includes a first container comprising the at least one
chromophore capable of activating the oxidant, and a second
container comprising at least one oxidant. In certain such
embodiments, the oxidant is chosen from hydrogen peroxide,
carbamide peroxide and benzoyl peroxide. In certain such
embodiments, the first and/or second composition further comprises
one or more gelling agents.
[0226] The containers may be light impermeable, air-tight and/or
leak resistant. Exemplary containers include, but are not limited
to, syringes, vials, or pouches. The first and second compositions
may be included within the same container but separated from one
another until a user mixes the compositions. In some embodiments,
the container may be a dual-chamber syringe where the contents of
the chambers mix on expulsion of the compositions from the
chambers. In some embodiments, the pouch may include two chambers
separated by a frangible membrane. In some embodiments, one
component may be contained in a syringe and injectable into a
container comprising the second component.
[0227] The biophotonic composition may also be provided in a
container comprising one or more chambers for holding one or more
components of the biophotonic composition, and an outlet in
communication with the one or more chambers for discharging the
biophotonic composition from the container.
[0228] In some embodiments, the kit comprises a systemic or topical
drug for augmenting the treatment of the composition. For example,
in certain such embodiments, the kit may include a systemic or
topical antibiotic or hormone treatment for a non-resistant or
resistant infection or both.
[0229] Written instructions on how to use the biophotonic
composition in accordance with the present disclosure may be
included in the kit, or may be included on or associated with the
containers comprising the compositions of the present
disclosure.
[0230] In some embodiments, the kit may comprise a further
component which is a dressing. The dressing may be a porous or
semi-porous structure for receiving the biophotonic composition.
The dressing may comprise woven or non-woven fibrous materials.
[0231] In some embodiments of the kit, the kit may further comprise
a light source such as a portable light with a wavelength
appropriate to activate the chromophore in the biophotonic
composition. The portable light may be battery operated or
re-chargeable.
[0232] In some embodiments, the kit may further comprise one or
more waveguides.
[0233] Identification of equivalent compositions, methods and kits
are well within the skill of the ordinary practitioner and would
require no more than routine experimentation, in light of the
teachings of the present disclosure. Practice of the disclosure
will be still more fully understood from the following examples,
which are presented herein for illustration only and should not be
construed as limiting the disclosure in any way.
Examples
[0234] The examples below are given so as to illustrate the
practice of various embodiments of the present disclosure. They are
not intended to limit or define the entire scope of this
disclosure.
[0235] It should be appreciated that the disclosure is not limited
to the particular embodiments described and illustrated herein but
includes all modifications and variations falling within the scope
of the disclosure as defined in the appended embodiments.
1. Use of Biophotonic Compositions for the Treatment of Wounds
(e.g., Surgical or Traumatic Wounds) in Canines and Felines
[0236] The biophotonic compositions and methods of the disclosure
were tested to analyze significant acceleration of wound healing in
canines and/or felines for the areas treated with biophotonic
therapy compared to those treated in the classical/conventional
way.
[0237] The study was conducted on three groups of patients (dogs or
cats) each composed of at least 50 patients: [0238] The first group
consisted of patients that have simple surgical wounds from
orthopedic (joint) or neurological surgeries. From the first day
after operation (T0) and then every other day, 50% of the length of
the surgical wound was treated with biophotonic therapy using a
biophotonic composition comprising a carrier gel comprising
peroxide (in the form of urea peroxide) and a
chromophore-containing gel (final chromophore concentration of
0.01% w/w), while 50% was treated with sterile saline. In cases
where patients exhibited two surgical wounds (common in joint
diseases often congenital and bilateral), one was treated with the
biophotonic composition and the other treated daily with sterile
saline. This procedure was conducted for 14 days.
[0239] The second group consisted of patients suffering from:
[0240] Delayed healing of surgical dehiscent and ulcerated wounds,
[0241] Protracted decubital ulcers, [0242] Traumatic ulcers, and
[0243] Burns.
[0244] The subjects included in this study were treated with the
biophotonic therapy, for 5 minutes every 3 days until healing
occurred. Every three days, the treatment area was cleaned with
sterile isotonic saline and then treated with the biophotonic
therapy. After treatment, the wound was covered with a three-layer
bandage. The therapy was suspended after complete healing of the
wound.
[0245] The third group, namely the control group of group two,
consisted of patients that, as in the second group, were affected
by: [0246] Delayed healing of surgical dehiscent and ulcerated
wounds, [0247] Protracted decubital ulcers, [0248] Traumatic
ulcers, and [0249] Burns.
[0250] They were treated according to a traditional technique that
consists of cleaning the injured area with sterile isotonic saline,
followed by application of sterile paraffin-impregnated gauzes and
covering with a three-layer bandage. This procedure was applied
every 3 days until wound healing was complete.
[0251] All wounds were clinically evaluated at the beginning of
treatment (T0) and then monitored during the treatment.
[0252] The lesion area, for each treatment was calculated using a
planimetric dedicated software. In each phase of treatment (every
other day for group one and every three days for groups two and
three) the lesion was photographed and its area was calculated to
objectively monitor the progression of healing.
[0253] To track the possible presence of infectious complications
(bacterial), samples were collected by swabbing at T0, and then,
subsequently every 3 days for the duration of the treatment, for
bacteriological culture.
[0254] All patients in the study were hospitalized and underwent
clinical, laboratory and instrumental exams to verify general good
health. Any patients with moderate or severe systemic diseases of
any nature were excluded from the study.
[0255] An Elizabethan collar was applied to all patients for the
duration of the study.
[0256] Data from the study are summarized in the table 1 below:
TABLE-US-00001 TABLE 1 Intra- No. of Exposure Time/ Patient Wound
No. of surgical Treated % Treatment Figure Number Type Treatments
Application.sup.(a) Layers.sup.(b) UP.sup.(c) (minutes).sup.(d)
with data 1 Surgical 4 No 1 (s) 12 2 N/A 2 Surgical 6 Yes 2 (s, sb)
6 Not reported N/A 3 Surgical 4 Yes 2 (s, sb) 6 5 N/A 4 Surgical 4
Yes 3 (s, sb, m) 6 5 N/A 5 Surgical 3 Yes 2 (s, sb) 6 Not reported
N/A 6 Traumatic 5 No 3 (s, sb, m) 6 5 FIG. 4 7 Dehisced 7 No 3 (s,
sb, m) 6 5 FIG. 5 8 Dehisced 6 No 2 (s, sb) 6 Not reported N/A 9
Ulcer 6 No 3 (s, sb, m) 6 Not reported N/A 10 Surgical 5 Yes 3 (s,
sb, m) 3-6 2 FIG. 10 11 Surgical 4 Yes 3 (s, sb, m) 3-6 2 FIG. 6 12
Dehisced 5 No 3 (s, sb, m) 6 3.3 FIGS. 9A-9G 13 Surgical 4 Yes 3
(s, sb, m) 3 Not reported N/A 14 Dehisced 9 No 3 (s, sb, m) 6 Not
reported N/A 15 Dehisced 11 No 4 (s, sb, m, b) 3 Not reported N/A
16 Traumatic 7 Yes 4 (s, sb, m, b) 6 3.3 FIG. 11B.sup.(e) 17
Surgical 3 Yes 3 (s, sb, m) 3 2 FIGS. 7, 8A-8B 18 Traumatic 3 No 2
(s, sb) 6 Not reported N/A 19 caustic 5 No 2 (s, sb) 6 Not reported
N/A 20 Insect bite 11 No 3 (s, sb, b) 6 Not reported N/A 21
Surgical 3 Yes 3 (s, sb, m) 3 Not reported N/A 22 Traumatic 3 No 4
(s, sb, m, b) 6 Not reported N/A 23 Flemmone 28 No 3 (s, sb, m) 6
Not reported N/A (Phlegmon) 24 Flemmone 6 No 3 (s, sb, m) 6 Not
reported N/A (Phlegmon) 25 Traumatic 8 No 3 (s, sb, m) 6 2 N/A 26
Flemmone 3 No 3 (s, sb, m) 6 Not reported N/A (Phlegmon) 27
Traumatic 4 No 3 (s, sb, m) 6 Not reported N/A 28 Traumatic 19 Yes
5 (s, sb, m, b, t) 6 Not reported N/A 29 Infection 11 No 2 (s, sb)
6 2 FIG. 22 Skin 30 Traumatic 6 Yes 3 (s, sb, m) 6 Not reported N/A
31 Traumatic 7 No 5 (s, sb, m, b, t) 6 Not reported N/A 32
Traumatic 2 No 2 (s, sb) 6 Not reported N/A 33 Traumatic 2 No 2 (s,
sb) 6 Not reported N/A .sup.(a)Intra-surgical application refers to
whether or not the first treatment with the biophotonic composition
was applied during surgery, .sup.(b)The treated wound layers are as
follows: s = surface, sb = sub-surface, m = middle; and b = bone,
.sup.(c)% UP is the % of urea peroxide by weight of the total
composition, .sup.(d)Exposure time was the time the biophotonic
composition on the wound was exposed to actinic (e.g., blue) light,
.sup.(e)FIG. 11A shows a control subject with a similar injury as
patient 16, but the control subject was not treated with
biophotonic therapy.
[0257] Tissue analysis of healing of a surgical wound for a canine
patient (patient 17) is shown in FIGS. 8A and 8B. FIG. 8A shows
tissues (surface, subsurface, and middle) which were treated three
times with a biophotonic composition comprising 3% by weight urea
peroxide. During each treatment, the biophotonic composition was
exposed to blue light for two minutes. The first treatment with the
biophotonic composition was performed during surgery. FIG. 8B shows
tissues not treated with biophotonic therapy (a control
sample).
[0258] Comparing the time course of healing as presented in panels
1 to 4 of FIG. 8A versus those of FIG. 8B, it is evident that the
wound that received the application of the biophotonic composition
treatment healed, to complete closure, at a faster rate than the
wound that did not receive the application of the biophotonic
composition treatment. Furthermore, as can be seen in panel 4 of
FIG. 8A versus FIG. 8B, both the epithelial and underlying cell
layers in the treated wound appear organized in a fashion that
would be close to that of unwounded canine skin tissue, while the
wound that did not receive the biophotonic composition treatment
had a thinner epidermal layer and the underlying cell layers had a
pronounced degree of disorganization even though the wound had
closed.
[0259] Tests were also conducted to analyze healing of a traumatic
injury (shearing injury) in a control canine patient (FIG. 11A) and
patient 16 (FIG. 11B). The tissues treated were surface,
sub-surface, middle, and bone. The control patient was given eight
months of conventional treatment, whereas the patient 16 was
treated seven times over 30 days with a biophotonic composition
comprising 6% by weight urea peroxide. During each treatment, the
biophotonic composition was exposed to blue light for 3.3 minutes.
The first treatment with the biophotonic composition was performed
during surgery. Without wishing to be bound by theory, biophotonic
therapy appeared to shorten the healing time required for the
shearing injury.
[0260] The studies also examined whether antibiotics were needed in
the treatment of the wounds. Patient 12 received treatment of a
dehisced wound with biophotonic therapy and no antibiotic treatment
(FIGS. 9A-9G). Patient 10 (FIG. 10) received treatment of a
surgical wound with biophotonic therapy and no post-operative
antibiotic treatment (only pre-operative antibiotic treatment). The
tissues treated in Patients 10 and 12 surface, sub-surface, and
middle. In patient 16 (FIG. 11B), antibiotic resistant Pseudomonas
was observed at T0, but after treatment with biophotonic therapy in
the absence of antibiotics, a reduced number of colony forming
units (CFUs) was observed during bacteriological assessment.
Without wishing to be bound by theory, the data illustrate that the
compositions, methods, and uses disclosed herein can reduce the
microbial load of wounds and are useful in maintaining asepsis
during surgeries. Additionally, the compositions, methods, and uses
of the disclosure are useful for treating wounds without the use of
antibiotics or antimicrobial agents and are useful in the treatment
of resistant infections, such as antibiotic resistant
infections.
2. Use of Biophotonic Compositions for the Treatment of Wounds in
Equines
[0261] Natural reactions of horses to danger predispose them to
traumatic injuries which can be further complicated by additional
trauma, tissue loss, or infection. For horses, injuries are often
localized on lower limbs, such as the distal legs, where soft
tissue and circulation are poor and joint movement make management
and healing difficult. Injury sites on a horse may also occur in
other parts of the horse, for example the barrel or the shoulder of
the horse as examples. The desirable treatment for horse wounds
(traumatic, infective, or surgical) should be cost effective,
non-invasive, restorative of function, and also providing
satisfactory cosmetic results. Classical wound management in
equines includes surgical debridement and lavage, coupled with
topical medication and wound dressings. This study evaluated the
safety and effect of biophotonic therapy comprising application of
a biophotonic composition, as described above, however, comprising
6% urea peroxide (UP), on equine wound healing.
[0262] All patients (horses or donkeys) were hospitalized for the
duration of the study in the facilities of Veterinary Teaching
Hospital, School of Biosciences and Veterinary Medicine, Veterinary
Medicine Department, Camerino University.
[0263] Horses were divided in two groups named A and B. Group A
consisted of horses with surgical wounds (resulting from any
surgery) and Group B consisted of horses with naturally occurring
wounds, ulcers and sores.
[0264] The in vivo efficacy was assessed by evaluating
hypersensitivity reactions and swelling after the application of
biophotonic therapy. The frequency of application in each group
depended on the severity of the wound, but, when possible, it
followed the following scheme: weekly, twice a week, or three times
a week. The treatment was prolonged for one week after the
resolution of the disease. Different protocols were compared for
side effects or differences in effectiveness.
[0265] Various wound-healing parameters (granulation tissue, crust
formation, scar formation, grade of contamination) were visually
evaluated daily, and the time points of tissue/wound appearance
were documented until no more progress could be noticed for at
least 3 weeks. Images of the wound area were obtained using a
digital camera, and the dimensions of the wound area and/or length
were measured using image analysis software.
[0266] Sampling of tissue for histological (when necessary),
cytological and microbiological evaluation are performed before,
during (at least two times) and after the end of the therapy. A
monthly follow-up is performed until six months after the end of
the therapy.
[0267] Data were analyzed by the Student t-test for group
comparisons of normally distributed variables, and p<0.05 is
considered significant.
[0268] The results of tolerability study for the biophotonic
compositions on a six year old healthy gelding Trotter horse are
shown in FIGS. 12A and 12B and in the table below. As shown in FIG.
12A, three zones of treatment where selected, the left flank, the
right flank, and the breast. In each zone, two rectangular areas of
different sizes, one small and one large, were clipped. On all
small rectangular areas, the chromophore gel with 0% urea peroxide
(UP) was applied. On the large rectangular area of the right flank,
a 3% UP chromophore gel was applied. On the large rectangular area
of the left flank, a 6% UP chromophore gel was applied. On the
large rectangular area of the breast, a 12% UP chromophore gel was
applied. FIG. 12B shows treatment of the zones with blue light. The
areas were treated at a distance of 5 cm with an exposure time of
five minutes. Each area was treated two times per week for a total
of four weeks (eight treatments per area in total). As shown in the
table 2 below, no relevant changes were observed during the course
of treatment and there were no negative effects. There were no
significant variations in the appearance of the patient's skin or
on skin thickness. The data indicated the treatment was
well-tolerated at each of the UP concentrations.
TABLE-US-00002 TABLE 2 Schedule and results of different activities
SCHEDULE AND RESULTS OF DIFFERENT ACTIVITIES Time of study T0 T1 T2
T3 T4 T5 T6 T7 Action B A B A B A B A B A B A B A B A Right
Clinical nr nr nr nr nr nr nr nr nr nr nr nr nr nr nr nr flank Skin
0.71 0.71 0.73 0.73 0.73 0.73 0.73 thickness ( ) Left nr nr nr nr
nr nr nr nr nr nr nr nr nr nr nr nr flank (inspection) Skin 0.73
0.73 0.74 0.74 0.74 0.72 0.73 0.72 073 0.73 thickness ( ) Breast nr
nr nr nr nr nr nr nr nr nr nr nr nr nr nr nr (inspection) | Skin
0.73 0.73 0.74 0.74 0.72 0.74 0.72 0.73 0.73 0.73 0.74 0.73 0.73
0.73 thickness ( ) Pictures X X X X X X LEGEND: NR--NOTHING
RELEVANT B = BEFORE A = AFTER indicates data missing or illegible
when filed
[0269] As shown in FIGS. 13A-13D, a 12 year old female, mixed breed
horse with post-traumatic subcutaneous collection of purulent
material was treated with biophotonic therapy. FIG. 13A illustrates
swelling to the left carpal region and two wounds draining purulent
material. It also illustrates a fistula located on the palmar
surface of the region. FIG. 13B illustrates treatment of the large
wound with a biophotonic composition comprising 12% UP and
treatment of the small wound with a biophotonic composition
comprising 3% UP. FIG. 13C illustrates treatment of the wounds with
blue light applied at a distance of 5 cm for five minutes. FIG. 13D
illustrates treatment of the wounds over the course of six weeks.
The wounds were treated once a week over the course of the six
weeks, and healing time appeared to be reduced compared to that
observed with conventional treatment.
[0270] As shown in FIGS. 14A-14E, a 14 year old female, mixed breed
horse with an old wound on the lateral surface of the chest was
treated with biophotonic therapy. FIG. 14A shows treatment of the
wound with lavage, disinfection, wound suture, drainage, and
systemic antibiotic (conventional treatment). FIG. 14B shows
dehiscence of the wound after conventional treatment. FIG. 14C
shows treatment of the dehisced wound with a 12% UP biophotonic
composition and blue light applied at a distance of 5 cm for five
minutes. FIG. 14D shows healing of the wound after one week of
treatment and before application of another round of biophotonic
therapy. FIG. 14E shows healing of the wound after two applications
of biophotonic therapy (two weeks of treatment). Healing time
appeared to be reduced compared to that observed with conventional
treatment. Additionally, antibiotic therapy was not required when
biophotonic therapy was applied.
3. Use of Biophotonic Compositions for the Treatment of Periodontal
Disease
[0271] The goal of this study was to evaluate the effects of
biophotonic therapy on the treatment of moderate to advanced
periodontal disease in dogs, such as in dogs with a periodontal
disease at PD3 stage (moderate periodontitis with 25-50% attachment
loss as measured either by the probing of the clinical attachment
level, radiographic determination of the distance of the alveolar
margin from cement-enamel junction relative to the length of the
root, or a stage 2 furcation involvement in multi-rooted teeth) to
PD4 stage (advanced periodontitis with >50% attachment loss as
measured either by the probing of the clinical attachment level, or
radiographic determination of the distance of the alveolar margin
from the cement-enamel junction relative to the length of the root,
or a stage 3 furcation involvement in multirooted teeth)
[0272] The impact of biophotonic therapy on the following
parameters was assessed: [0273] 1. Impact on tissues (visual
evaluation) [0274] 2. Ease of performing scaling and root planing
[0275] 3. Probing pocket depth (PPD): mm [0276] 4. Bleeding on
probing (BOP): +/- [0277] 5. Plaque index/Calculus index (PI/CI):
0-4 [0278] 6. Plaque thickness/Calculus thickness (PT/CT): 1-3
[0279] 7. Gingival index (GI): 0-3 [0280] 8. Clinical attachment
level (CAL): mm [0281] 9. Adverse events
[0282] Twelve (12) dogs were evaluated. In each patient (dog), only
the right half of the mouth was treated with a biophotonic
composition followed by exposure of the treated area to blue light.
The composition had 6% or 12% urea peroxide (UP), with six dogs
treated with the 6% UP composition and 6 dogs treated with the 12%
UP composition. The patients had to have a least two sites in each
quadrant with a periodontal pocket (PP).gtoreq.4 mm or .ltoreq.10
mm. The PP is an extension of the normal gingival sulcus.
[0283] On the first treatment day (T0), a thin layer of the
biophotonic composition of the disclosure (approximately 1 mm
thick) was applied using a sterile dental syringe above the
calculus and around the PP to be treated. The composition was then
photoactivated by inserting into the PP the probe-like tip of the
LED curing lamp (Bluephase.RTM. lamp (Ivoclar Vivadent AG, FL-9494
Schaan, Liechtenstein)) set at high power mode for two periods of
20 seconds (before and following scaling and root planing (SRP)).
The first application was administered immediately prior to
performing SRP (FIGS. 19A, 19B, and 19C), whereas the second
application was applied once the SRP was completed (FIGS. 20A and
20B) and without any other co-procedures.
[0284] The following parameters were assessed at T0: [0285] 1.
Impact on tissues (visual evaluation) [0286] 2. Ease of performing
scaling and root planing [0287] 3. Probing pocket depth (PPD): mm
(FIG. 15) [0288] 4. Bleeding on probing (BOP): +/-(FIG. 16) [0289]
5. Plaque index/Calculus index (PI/CI): 0-4 (FIG. 17) [0290] 6.
Plaque thickness/Calculus thickness (PT/CT): 1-3 (FIG. 17) [0291]
7. Gingival index (GI): 0-3 [0292] 8. Clinical attachment level
(CAL): mm (FIG. 18) [0293] 9. Adverse events
[0294] After 20 days (T1), the following parameters were assessed:
[0295] 1. Probing pocket depth (PPD): mm [0296] 2. Bleeding on
probing (BOP): +/- [0297] 3. Plaque index/Calculus index (PI/CI):
0-4 [0298] 4. Plaque thickness/Calculus thickness (PT/CT): 1-3
[0299] 5. Gingival index (GI): 0-3 [0300] 6. Clinical attachment
level (CAL): mm
[0301] No adverse effects were found. The first application of
biophotonic therapy considerably facilitated the performing of SRP
and reduced the time required (FIG. 21).
INCORPORATION BY REFERENCE
[0302] All references cited in this specification, and their
references, are incorporated by reference herein in their entirety
where appropriate for teachings of additional or alternative
details, features, and/or technical background.
EQUIVALENTS
[0303] While the disclosure has been particularly shown and
described with reference to particular embodiments, it will be
appreciated that variations of the above-disclosed and other
features and functions, or alternatives thereof, may be desirably
combined into many other different systems or applications. Also,
that various presently unforeseen or unanticipated alternatives,
modifications, variations or improvements therein may be
subsequently made by those skilled in the art which are also
intended to be encompassed by the following claims.
* * * * *