U.S. patent application number 14/892731 was filed with the patent office on 2016-04-28 for methods of treating biofilms.
The applicant listed for this patent is BIOMIMETIX J.V., LLC, NATIONAL JEWISH HEALTH. Invention is credited to James D. Crapo, Sarah Lindsay, Elizabeth Regan.
Application Number | 20160113940 14/892731 |
Document ID | / |
Family ID | 51541338 |
Filed Date | 2016-04-28 |
United States Patent
Application |
20160113940 |
Kind Code |
A1 |
Crapo; James D. ; et
al. |
April 28, 2016 |
METHODS OF TREATING BIOFILMS
Abstract
A method of treating or preventing a condition caused by a
biofilm in a subject is carried out by: providing a subject having,
or susceptible to, a condition mediated by a biofilm produced by a
microorganism, where the biofilm comprises a matrix and the
microorganism on a surface and administering to the subject an
active agent under conditions effective for the condition caused by
a biofilm in the subject to be treated or prevented, where the
active agent is a compound of general Formula (I): or a
pharmaceutically acceptable salt thereof. ##STR00001##
Inventors: |
Crapo; James D.; (Englewood,
CO) ; Regan; Elizabeth; (Golden, CO) ;
Lindsay; Sarah; (Greenwood Village, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOMIMETIX J.V., LLC
NATIONAL JEWISH HEALTH |
Englewood
Denver |
CO
CO |
US
US |
|
|
Family ID: |
51541338 |
Appl. No.: |
14/892731 |
Filed: |
August 29, 2014 |
PCT Filed: |
August 29, 2014 |
PCT NO: |
PCT/US2014/053436 |
371 Date: |
November 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61872991 |
Sep 3, 2013 |
|
|
|
Current U.S.
Class: |
424/49 ;
514/185 |
Current CPC
Class: |
C02F 2307/14 20130101;
C02F 5/12 20130101; A61Q 11/00 20130101; C02F 2103/42 20130101;
A61P 31/00 20180101; A01N 59/16 20130101; C09K 8/035 20130101; A61P
13/10 20180101; A61P 15/10 20180101; A61K 8/58 20130101; A61K 8/19
20130101; A61K 8/494 20130101; C02F 2103/026 20130101; A61K 31/555
20130101; A01N 59/20 20130101; C11D 3/0078 20130101; C02F 1/30
20130101; Y02A 50/30 20180101; A61P 13/02 20180101; A61P 43/00
20180101; A61K 45/06 20130101; C02F 2303/20 20130101; C02F 2305/04
20130101; C09K 8/524 20130101; A61K 2800/58 20130101; A01N 55/02
20130101; C02F 1/50 20130101; C02F 2303/04 20130101; Y02A 50/473
20180101; C02F 1/32 20130101; A61P 31/04 20180101; A61K 31/555
20130101; A61K 2300/00 20130101; A01N 59/20 20130101; A01N 43/713
20130101; A01N 2300/00 20130101; A01N 59/16 20130101; A01N 43/713
20130101; A01N 2300/00 20130101 |
International
Class: |
A61K 31/555 20060101
A61K031/555; A61Q 11/00 20060101 A61Q011/00; A61K 8/58 20060101
A61K008/58; A61K 45/06 20060101 A61K045/06; A01N 55/02 20060101
A01N055/02 |
Claims
1. A method of treating or preventing a condition caused by a
biofilm in a subject, said method comprising: providing a subject
having, or susceptible to, a condition mediated by a biofilm
produced by a microorganism, where the biofilm comprises a matrix
and the microorganism on a surface and administering to the subject
an active agent under conditions effective for the condition caused
by a biofilm in the subject to be treated or prevented; wherein
said active agent is a compound of Formula I: ##STR00011## wherein:
each R is independently selected substituted or unsubstituted aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl; each A is an
independently selected hydrogen, an electron-withdrawing group, or
electron donating group; M is a metal; and Z.sup.- is a counterion;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 further comprising: administering to the
subject, in conjunction with said administering the active agent,
an antimicrobial treatment selected from the group consisting of
one or more of biocides, surfactants, antibiotics, antiseptics,
detergents, chelating agents, virulence factor inhibitors,
ultrasonic treatment, radiation treatment, thermal treatment, and
mechanical treatment.
3. The method of claim 1, wherein a subject with a bone fracture is
treated (e.g., an open or compound bone fracture).
4. The method of claim 1, wherein a subject with a burn (e.g.,
second or third degree burns, including chemical and thermal burns
to the skin, eye, etc.) is treated, or other acute or chronic wound
(e.g., incision, laceration, ulceration such as a bed sore,
etc.)
5. The method of claim 1, wherein a subject with dental plaque,
dental caries, gingival disease, and/or oral infection is
treated.
6. The method of claim 5, wherein said administering is carried out
with a dentifrice, mouthwash, dental floss, gum, strip, or
brush.
7. The method of claim 1, wherein a subject with acne or other
biofilm-associated skin infections on the skin is treated.
8. The method of claim 1, wherein a subject with a chronic
biofilm-associated disease is treated.
9. The method of claim 8, wherein the chronic biofilm-associated
disease is selected from the group consisting of middle ear
infection, osteomyelitis, prostatitis, cystic fibrosis, colitis,
vaginitis, urethritis, gastric or duodenal ulcer,
ventilation-associated pneumonia, endocarditis, necrotizing
fasciitis, biliary tract infection, and infectious kidney
stones.
10. The method of claim 1, wherein a subject with a Staphylococcus
aureus (e.g., methicillin-resistant Staphylococcus aureus (MRSA)),
Haemophllus influenza, Pseudomonas aeruginosa Burkholderea cepacia
Escherichla coil, or Actinomyces israelli infection is treated.
11. A method of treating or inhibiting formation of a biofilm on a
surface, said method comprising: providing a surface having or
being susceptible to formation of a biofilm produced by a
microorganism, where the biofilm comprises a matrix and the
microorganism on the surface, and administering to the surface an
active agent under conditions effective for formation of the
biofilm on the surface to be treated or inhibited; wherein said
active agent is a compound of Formula I: ##STR00012## wherein: each
R is independently selected substituted or unsubstituted aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl; each A is an
independently selected hydrogen, an electron-withdrawing group, or
electron donating group; M is a metal; and Z.sup.- is a counterion;
or a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the surface is a contact
lens.
13. The method of claim 11, wherein the surface is an indwelling
medical device selected from the group consisting of catheters
(e.g., urinary tract catheters), respirators, ventilators, and
intrauterine devices (IUDs).
14. The method of claim 11, wherein the surface is an implanted
medical device selected from the group consisting of stents,
artificial valves, joints, sutures, staples, pacemakers, bone
implants, pins, vascular grafts, mechanical heart valves,
arteriovenous shunts, cerebral spinal fluid shunts, endovascular
catheters, penile prostheses, surgical mesh, and orthopedic
fixation devices (e.g., plates, rods, screws, etc.).
15. The method of claim 11, wherein the surface is selected from
the group consisting of drains, tubs, kitchen appliances,
countertops, shower curtains, grout, toilets, industrial food and
beverage production facilities, flooring, and food processing
equipment.
16. The method of claim 11, wherein the surface is a heat exchanger
surface or a filter surface.
17. The method of claim 11, wherein the surface is a marine
structure selected from the group consisting of boats, piers, oil
platforms, water intake ports, sieves, and viewing ports.
18. The method of claim 11, wherein the surface is associated with
a system for water treatment and/or distribution.
19. The method of claim 18, wherein the system for water treatment
and/or distribution is selected from the group consisting of a
system for drinking water treatment and/or distribution, a system
for pool and spa water treatment, a system for treatment and/or
distribution of water in manufacturing operations, and a system for
dental water treatment and/or distribution.
20. The method of claim 11, wherein the surface is associated with
a system for petroleum drilling, storage, separation, refining,
distribution, and/or porous medium from which the petroleum is
extracted.
21. The method claim 20, wherein the system for petroleum drilling,
storage, separation, and/or distribution is selected from the group
consisting of a petroleum separation train, a petroleum container,
petroleum distributing pipes, and petroleum drilling equipment.
22. The method of claim 11 further comprising: administering to the
surface, in conjunction with said administering the active agent,
at least one antimicrobial treatment selected from the group
consisting of biocides, surfactants, antibiotics, antiseptics,
detergents, chelating agents, virulence factor inhibitors,
ultrasonic treatment, radiation treatment, thermal treatment, and
mechanical treatment.
23. The method of claim 22, wherein the active agent and the
antimicrobial treatment are administered simultaneously.
24. The method of claim 22, wherein the active agent and
antimicrobial treatment are administered separately.
25. The method of claim 22, wherein the active agent is impregnated
in the surface.
26. The method of claim 22, wherein the active agent is
administered in a copolymer or a gel coating over the surface.
27. The method of claim 1, wherein said active compound has a
structure of Formula A1: ##STR00013## wherein: each R is C1-12
alkyl; each A is, independently, hydrogen or an electron
withdrawing group; M is metal selected from the group consisting of
manganese, iron, copper, cobalt, nickel and zinc, and Z.sup.- is a
counterion.
28. The method of claim 1, wherein said active compound has the
formula: ##STR00014## wherein Z-- is a counterion.
29. The method of claim 1, wherein said active compound has a
structure of Formula B1: ##STR00015## wherein: each R is C1-12
alkyl; each A is, independently, hydrogen or an electron
withdrawing group; M is metal selected from the group consisting of
manganese, iron, copper, cobalt, nickel and zinc, and Z-- is a
counterion.
30. The method of claim 1, wherein said active compound has the
structure: ##STR00016## wherein Z.sup.- is a counterion.
31. The method of claim 1, wherein said active compound has a
structure of Formula C1: ##STR00017## wherein: each R is
--(CH2)mCH2OX; m is 1 or 2; X is C1-12 alkyl; each A is,
independently, hydrogen or an electron withdrawing group; M is
metal selected from the group consisting of manganese, iron,
copper, cobalt, nickel and zinc, and Z-- is a counterion.
32. The method of claim 1, wherein said active compound has the
structure: ##STR00018## wherein Z.sup.- is a counterion.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/872,911, filed Sep. 3, 2013, the
disclosure of which is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] Microbial biofilms in infections and in industrial systems
present significant problems due to their recalcitrance to
effective treatment. See, e.g., U.S. Pat. No. 8,513,305 to Davies
et al. Accordingly, there is a need for new ways to combat or
disrupt biofilm formation, both in vivo and ex vivo.
SUMMARY OF THE INVENTION
[0003] Described herein is a method of treating, inhibiting or
preventing a condition caused by a biofilm in a subject, the method
comprising: providing a subject having, or susceptible to, a
condition mediated by a biofilm produced by a microorganism, where
the biofilm comprises a matrix and the microorganism on a surface
and administering to the subject an active agent as described
herein under conditions effective for the condition caused by a
biofilm in the subject to be treated, inhibited or prevented.
[0004] Also described herein is a method of treating or inhibiting
formation of a biofilm on a surface, the method comprising:
providing a surface having or being susceptible to formation of a
biofilm produced by a microorganism, where the biofilm comprises a
matrix and the microorganism on the surface, and administering to
the surface an active agent as described herein under conditions
effective for formation of the biofilm on the surface to be treated
or inhibited.
[0005] A still further aspect of the present invention is an active
agent as described herein for use in a method of treatment as
described herein, or for use in the preparation of a medicament for
carrying out a method of treatment as described herein.
[0006] The present invention is explained in greater detail in the
specification set forth below. The disclosures of all United States
Patents cited herein are incorporated herein by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1. In vitro biofilm intensity with and without
treatment with of the SOD mimetic MnTE-2-PyP.
[0008] FIG. 2. Bacterial Counts from femur tissues. Keflex with
MnTE compared to Keflex alone showed significant decrease in
bacteria counts (p=0.007).
[0009] FIG. 3. Fracture Healing in Infected Fracture Model of
Blofilm forming Staphylococcus Aureus. Little or no fracture
healing was seen in the group of animals with no treatment.
Antibiotic and Antibiotic plus SOD mimetic showed significantly
improved fracture healing compared to no treatment. Antibiotic with
mimetic was significantly better than antibiotic alone (p=0.001)
for fracture healing at 2 wks.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0010] The present invention is primarily concerned with the
treatment of human subjects, but the invention may also be carried
out on animal subjects, particularly mammalian subjects such as
dogs, cats, livestock and horses for veterinary purposes. While
subjects may be of any suitable age, the subjects are in some
embodiments neonatal, infant, juvenile, adolescent, adult, or
geriatric subjects.
[0011] "Treat" as used herein refers to any type of treatment that
imparts a benefit to a patient or subject matter as described
herein, particularly delaying or retarding the onset or progression
of the conditions described herein, or reducing the severity of
symptoms, or speeding or improving recovery therefrom.
[0012] "Pharmaceutically acceptable" as used herein means that the
compound or composition is suitable for administration to a subject
to achieve the treatments described herein, without unduly
deleterious side effects in light of the severity of the disease
and necessity of the treatment.
[0013] "Combination" as used herein with respect to a method of
administration (e.g., an active compound and an antibiotic
administered in combination) includes administering the the two or
more compounds simultaneously, or sequentially, sufficiently close
in time to produce a combined therapeutic or treatment effect.
[0014] "Alkyl" as used herein alone or as part of another group,
refers to a straight or branched chain hydrocarbon containing from
1 to 10 carbon atoms. Representative examples of alkyl include, but
are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,
n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. "Lower alkyl" as
used herein, is a subset of alkyl, in some embodiments preferred,
and refers to a straight or branched chain hydrocarbon group
containing from 1 to 4 carbon atoms. Representative examples of
lower alkyl include, but are not limited to, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term "akyl" or "loweralkyl" is intended to include both
substituted and unsubstituted alkyl or loweralkyl unless otherwise
indicated and these groups may be substituted with groups selected
from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,
heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy
such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy,
cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy,
heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O).sub.m,
haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m
cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m,
arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m,
heterocycloalkyl-S(O).sub.m, amino, carboxy, alkylamino,
alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,
cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,
heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy,
ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy,
nitro or cyano where m=0, 1, 2 or 3.
[0015] "Alkenyl" as used herein alone or as part of another group,
refers to a straight or branched chain hydrocarbon containing from
1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which
include 1 to 4 double bonds in the normal chain. Representative
examples of alkenyl include, but are not limited to, vinyl,
2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,
2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. The term
"alkenyl" or "loweralkenyl" is intended to include both substituted
and unsubstituted alkenyl or loweralkenyl unless otherwise
indicated and these groups may be substituted with groups as
described in connection with alkyl and loweralkyl above.
[0016] "Alkynyl" as used herein alone or as part of another group,
refers to a straight or branched chain hydrocarbon containing from
1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which
include 1 triple bond in the normal chain. Representative examples
of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl,
2-butynyl, 4-pentynyl, 3-pentynyl, and the like. The term "alkynyl"
or "loweralkynyl" is intended to include both substituted and
unsubstituted alkynyl or loweralknynyl unless otherwise indicated
and these groups may be substituted with the same groups as set
forth in connection with alkyl and loweralkyl above.
[0017] "Cycloalkyl" as used herein alone or as part of another
group, refers to a saturated or partially unsaturated cyclic
hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons
(which carbons may be replaced in a heterocyclic group as discussed
below). Representative examples of cycloalkyl include, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
These rings may be optionally substituted with additional
substituents as described herein such as halo or loweralkyl. The
term "cycloalkyl" is generic and intended to include heterocyclic
groups as discussed below unless specified otherwise.
[0018] "Heterocyclic group" or "heterocyclo" as used herein alone
or as part of another group, refers to an aliphatic (e.g., fully or
partially saturated heterocyclo) or aromatic (e.g., heteroaryl)
monocyclic- or a bicyclic-ring system. Monocyclic ring systems are
exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4
heteroatoms independently selected from oxygen, nitrogen and
sulfur. The 5 membered ring has from 0-2 double bonds and the 6
membered ring has from 0-3 double bonds. Representative examples of
monocyclic ring systems include, but are not limited to, azetidine,
azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane,
furan, imidazole, imidazoline, imidazolidine, isothiazole,
isothiazoline, isothiazolidine, isoxazole, isoxazoline,
isoxazolidine, morpholine, oxadiazole, oxadiazoline,
oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine,
piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine,
pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine,
tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole,
thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline,
thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone,
thiopyran, triazine, triazole, trithiane, and the like. Bicyclic
ring systems are exemplified by any of the above monocyclic ring
systems fused to an aryl group as defined herein, a cycloalkyl
group as defined herein, or another monocyclic ring system as
defined herein. Representative examples of bicyclic ring systems
include but are not limited to, for example, benzimidazole,
benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole,
benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine,
1,3-benzodioxole, cinnoline, indazole, indole, indoline,
indolizine, naphthyridine, isobenzofuran, isobenzothiophene,
isoindole, isoindoline, isoquinoline, phthalazine, purine,
pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline,
tetrhydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and
the like. These rings include quaternized derivatives thereof and
may be optionally substituted with groups selected from halo,
alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy,
alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy,
cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy,
heterocyclolalkyloxy, mercapto, alkyl-S(O).sub.m,
haloalkyl-S(O).sub.m, alkenyl-S(O).sub.m, alkynyl-S(O).sub.m,
cycloalkyl-S(O).sub.m, cycloalkylalkyl-S(O).sub.m, aryl-S(O).sub.m,
arylalkyl-S(O).sub.m, heterocyclo-S(O).sub.m,
heterocycloalkyl-S(O).sub.m, amino, alkylamino, alkenylamino,
alkynylamino, haloalkylamino, cycloalkylamino,
cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,
heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy,
ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy,
nitro or cyano where m=0, 1, 2 or 3.
[0019] "Aryl" as used herein alone or as part of another group,
refers to a monocyclic carbocyclic ring system or a bicyclic
carbocyclic fused ring system having one or more aromatic rings.
Representative examples of aryl include, azulenyl, indanyl,
indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The
term "aryl" is intended to include both substituted and
unsubstituted aryl unless otherwise indicated and these groups may
be substituted with the same groups as set forth in connection with
alkyl and loweralkyl above.
[0020] "Arylalkyl" as used herein alone or as part of another
group, refers to an aryl group, as defined herein, appended to the
parent molecular moiety through an alkyl group, as defined herein.
Representative examples of arylalkyl include, but are not limited
to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and
the like.
[0021] "Heteroaryl" as used herein is as described in connection
with heterocyclo above.
[0022] "Alkoxy" as used herein alone or as part of another group,
refers to an alkyl or loweralkyl group, as defined herein (and thus
including substituted versions such as polyalkoxy), appended to the
parent molecular moiety through an oxy group, --O--. Representative
examples of alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy,
hexyloxy and the like.
[0023] "Halo" as used herein refers to any suitable halogen,
including --F, --Cl, --Br, and --I.
[0024] "Mercapto" as used herein refers to an --SH group.
[0025] "Azido" as used herein refers to an --N.sub.3 group.
[0026] "Cyano" as used herein refers to a --CN group.
[0027] "Formyl" as used herein refers to a --C(O)H group.
[0028] "Carboxylic acid" as used herein refers to a --C(O)OH
group.
[0029] "Hydroxyl" as used herein refers to an --OH group.
[0030] "Nitro" as used herein refers to an --NO.sub.2 group.
[0031] "Acyl" as used herein alone or as part of another group
refers to a --C(O)R radical, where R is any suitable substituent
such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable
substituent as described herein.
[0032] "Alkylthio" as used herein alone or as part of another
group, refers to an alkyl group, as defined herein, appended to the
parent molecular moiety through a thio moiety, as defined herein.
Representative examples of alkylthio include, but are not limited,
methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
[0033] "Amino" as used herein means the radical --NH.sub.2.
[0034] "Alkylamino" as used herein alone or as part of another
group means the radical --NHR, where R is an alkyl group.
[0035] "Arylalkylamino" as used herein alone or as part of another
group means the radical --NHR, where R is an arylalkyl group.
[0036] "Disubstituted-amino" as used herein alone or as part of
another group means the radical --NR.sub.aR.sub.b, where R.sub.a
and R.sub.b are independently selected from the groups alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclo, heterocycloalkyl.
[0037] "Acylamino" as used herein alone or as part of another group
means the radical --NR.sub.aR.sub.b, where R.sub.a is an acyl group
as defined herein and R.sub.b is selected from the groups hydrogen,
alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heterocyclo, heterocycloalkyl.
[0038] "Acyloxy" as used herein alone or as part of another group
means the radical --OR, where R is an acyl group as defined
herein.
[0039] "Ester" as used herein alone or as part of another group
refers to a --C(O)OR radical, where R is any suitable substituent
such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
[0040] "Amide" as used herein alone or as part of another group
refers to a --C(O)NR.sub.aR.sub.b radical, where R.sub.a and
R.sub.b are any suitable substituent such as alkyl, cycloalkyl,
alkenyl, alkynyl or aryl.
[0041] "Sulfoxyl" as used herein refers to a compound of the
formula --S(O)R, where R is any suitable substituent such as alkyl,
cycloalkyl, alkenyl, alkynyl or aryl.
[0042] "Sulfonyl" as used herein refers to a compound of the
formula --S(OXO)R, where R is any suitable substituent such as
alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
[0043] "Sulfonate" as used herein refers to a compound of the
formula --S(OXO)OR, where R is any suitable substituent such as
alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
[0044] "Sulfonic acid" as used herein refers to a compound of the
formula --S(OXO)OH.
[0045] "Sulfonamide" as used herein alone or as part of another
group refers to a --S(O).sub.2NR.sub.aR.sub.b radical, where
R.sub.a and R.sub.b are any suitable substituent such as H, alkyl,
cycloalkyl, alkenyl, alkynyl or aryl.
[0046] "Urea" as used herein alone or as part of another group
refers to an --N(R.sub.c)C(O)NR.sub.aR.sub.b radical, where
R.sub.a, R.sub.b and R.sub.c are any suitable substituent such as
H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
[0047] "Alkoxyacylamino" as used herein alone or as part of another
group refers to an --N(R.sub.a)C(O)OR.sub.b radical, where R.sub.a,
R.sub.b are any suitable substituent such as H, alkyl, cycloalkyl,
alkenyl, alkynyl or aryl.
[0048] "Aminoacyloxy" as used herein alone or as part of another
group refers to an --OC(O)NR.sub.aR.sub.b radical, where R.sub.a
and R.sub.b are any suitable substituent such as H, alkyl,
cycloalkyl, alkenyl, alkynyl or aryl.
1. Active Compounds/Active Agents.
[0049] Active compounds or active agents of the present invention
are, in general, porphyrin compounds. The active compounds include
superoxide dismutase (SOD) mimetic prophryin compounds, and/or
redox active porphyrin compounds.
[0050] Examples of porphyrin active compounds, and methods of
making the same, include but are not limited to those set forth in
U.S. Pat. No. 8,470,808 to Piganelli et al.; U.S. Pat. No.
8,183,364 to Batinic-Haberle et al., U.S. Pat. No. 6,916,799 to
Fridovich et al.; U.S. Pat. No. 6,479,477 to Crapo et al.; U.S.
Pat. No. 6,583,132 to Crapo et al. and in US Patent Application
Pub. No. US 2012/0065181 to Warner et al.; the disclosures of which
are incorporated by reference herein in their entirety.
[0051] Examples of active compounds include but are not limited to
compounds of Formula I:
##STR00002##
wherein:
[0052] each R is independently substituted or unsubstituted aryl,
heteroaryl, cycloalkyl, or heterocycloalkyl;
[0053] each A is an independently selected hydrogen, or an
electron-withdrawing or electron donating group (e.g., e.g., is
halogen, NO.sub.2 or CHO),
[0054] M is a metal, e.g., selected from the group consisting of
manganese, iron, copper, cobalt, nickel and zinc, or is absent (in
which case a hydrogen is added to each of the two nitrogens
required to correct valency), and
[0055] Z.sup.- is a counterion.
[0056] In some embodiments of Formula I above, each R is preferably
heteroaryl or heterocycloalkyl, particularly those containing at
least one or two nitrogen atoms in the heterocyclic ring (e.g.,
pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, triazinyl,
oxazolyl, thiazolyl, oxazinyl, thiazinyl, oxathiazinyl, etc.), in
some embodiments wherein at least one of which nitrogen atoms (or
in some embodiments at least two of which nitrogen atoms) are
optionally but preferably substituted (e.g., quaternized) with a
substituent such as described in connection with heterocyclic
groups above (e.g., substituted with alkyl, alkoxyalkyl, etc.).
[0057] Still more particular examples of the foregoing active
compounds include but are not limited to those set forth below.
[0058] A. Alkyl Substituted Imidazole Porphyrins.
[0059] In some embodiments the active compound has a structure of
Formula A1 or A2:
##STR00003##
wherein:
[0060] each R is C.sub.1-12 alkyl (straight chain or branched),
more preferably C.sub.2-6 alkyl, and most preferably ethyl, propyl,
butyl, or pentyl (straight chain or branched);
[0061] each A is, independently, hydrogen or an electron
withdrawing group (e.g., halogen, NO.sub.2 or CHO),
[0062] M is metal selected from the group consisting of manganese,
iron, copper, cobalt, nickel and zinc, and
[0063] Z.sup.- is a counterion.
[0064] In some embodiments the active compound has the formula:
##STR00004##
wherein Z.sup.- is a counterion.
[0065] B. Alkyl Substituted Pyridyl Porphyrins
[0066] In some embodiments the active compound has a structure of
Formula B1 or B2:
##STR00005##
wherein:
[0067] each R is C.sub.1-12 alkyl (straight chain or branched),
more preferably C.sub.2-6 alkyl, and most preferably ethyl, propyl,
butyl, or pentyl (straight chain or branched);
[0068] each A is, independently, hydrogen or an electron
withdrawing group (e.g., halogen, NO.sub.2 or CHO),
[0069] M is metal selected from the group consisting of manganese,
iron, copper, cobalt, nickel and zinc, and
[0070] Z.sup.- is a counterion.
[0071] In some embodiments the compound has a structure of the
Formula V:
##STR00006##
wherein each R, A, M and Z is as given in connection with Formula
B1 and B2 above.
[0072] In some embodiments the compound has the structure:
##STR00007##
wherein Z.sup.- is a counterion.
[0073] C. Alkoxyalkyl Substituted Pyridyl Porphyrins.
[0074] In some embodiments the active compound has a structure of
Formula C1 or C2:
##STR00008##
wherein:
[0075] each R is --(CH.sub.2).sub.mCH.sub.2OX;
[0076] m is 1 or 2, preferably 1;
[0077] X is C.sub.1-12 alkyl (straight chain or branched), more
preferably C.sub.2-6 alkyl, and most preferably ethyl, propyl,
butyl, or pentyl (straight chain or branched).
[0078] each A is, independently, hydrogen or an electron
withdrawing group (e.g., halogen, NO.sub.2 or CHO),
[0079] M is metal selected from the group consisting of manganese,
iron, copper, cobalt, nickel and zinc, and
[0080] Z.sup.- is a counterion.
[0081] In some embodiments the compound has a structure of the
Formula V:
##STR00009##
wherein each R, A, M and Z is as given in connection with Formula
C1 and C2 above.
[0082] In some embodiments the compound has the structure:
##STR00010##
wherein Z.sup.- is a counterion.
[0083] D. Salts.
[0084] The active compounds disclosed herein can, as noted above,
be prepared in the form of their salts or pharmaceutically
acceptable salts, e.g., to provide a compound or composition
including a counterion as noted above. Pharmaceutically acceptable
salts are salts that retain the desired biological activity of the
parent compound and do not impart undesired toxicological effects.
Examples of such salts are (a) acid addition salts formed with
inorganic acids, for example hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, nitric acid and the like; and salts
formed with organic acids such as, for example, acetic acid, oxalic
acid, tartaric acid, succinic acid, maleic acid, fumaric acid,
gluconic acid, citric acid, malic acid, ascorbic acid, benzoic
acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid,
naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic
acid, naphthalenedisulfonic acid, polygalacturonic acid, and the
like; (b) salts formed from elemental anions such as chlorine,
bromine, and iodine, and (c) salts derived from bases, such as
ammonium salts, alkali metal salts such as those of sodium and
potassium, alkaline earth metal salts such as those of calcium and
magnesium, and salts with organic bases such as dicyclohexylamine
and N-methyl-D-glucamine.
2. Pharmaceutical Formulations.
[0085] The active compounds described above may be formulated for
administration in a pharmaceutical carrier in accordance with known
techniques. See, e.g., Remington, The Science And Practice of
Pharmacy (9.sup.th Ed. 1995). In the manufacture of a
pharmaceutical formulation according to the invention, the active
compound (including the physiologically acceptable salts thereof)
is typically admixed with, inter alia, an acceptable carrier. The
carrier must, of course, be acceptable in the sense of being
compatible with any other ingredients in the formulation and must
not be deleterious to the patient. The carrier may be a solid or a
liquid, or both, and is preferably formulated with the compound as
a unit-dose formulation, for example, a tablet, which may contain
from 0.01 or 0.5% to 95% or 99% by weight of the active compound.
One or more active compounds may be incorporated in the
formulations of the invention, which may be prepared by any of the
well known techniques of pharmacy comprising admixing the
components, optionally including one or more accessory
ingredients.
[0086] The formulations of the invention include those suitable for
oral, rectal, topical, buccal (e.g., sub-lingual), vaginal,
parenteral (e.g., subcutaneous, intramuscular, intradermal, or
intravenous), topical (i.e., both skin and mucosal surfaces,
including airway surfaces) and transdermal administration, although
the most suitable route in any given case will depend on the nature
and severity of the condition being treated and on the nature of
the particular active compound which is being used.
[0087] Formulations suitable for oral administration may be
presented in discrete units, such as capsules, cachets, lozenges,
or tablets, each containing a predetermined amount of the active
compound; as a powder or granules; as a solution or a suspension in
an aqueous or non-aqueous liquid; or as an oil-in-water or
water-in-oil emulsion. Such formulations may be prepared by any
suitable method of pharmacy which includes the step of bringing
into association the active compound and a suitable carrier (which
may contain one or more accessory ingredients as noted above). In
general, the formulations of the invention are prepared by
uniformly and intimately admixing the active compound with a liquid
or finely divided solid carrier, or both, and then, if necessary,
shaping the resulting mixture. For example, a tablet may be
prepared by compressing or molding a powder or granules containing
the active compound, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing, in
a suitable machine, the compound in a free-flowing form, such as a
powder or granules optionally mixed with a binder, lubricant, inert
diluent, and/or surface active/dispersing agent(s). Molded tablets
may be made by molding, in a suitable machine, the powdered
compound moistened with an inert liquid binder.
[0088] Formulations suitable for buccal (sub-lingual)
administration include lozenges comprising the active compound in a
flavoured base, usually sucrose and acacia or tragacanth; and
pastilles comprising the compound in an inert base such as gelatin
and glycerin or sucrose and acacia.
[0089] Formulations of the present invention suitable for
parenteral administration comprise sterile aqueous and non-aqueous
injection solutions of the active compound(s), which preparations
are preferably isotonic with the blood of the intended recipient.
These preparations may contain anti-oxidants, buffers,
bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient. Aqueous and non-aqueous
sterile suspensions may include suspending agents and thickening
agents. The formulations may be presented in unit\dose or
multi-dose containers, for example sealed ampoules and vials, and
may be stored in a freeze-dried (lyophilized) condition requiring
only the addition of the sterile liquid carrier, for example,
saline or water-for-injection immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared
from sterile powders, granules and tablets of the kind previously
described. For example, in one aspect of the present invention,
there is provided an injectable, stable, sterile composition
comprising an active compound(s), or a salt thereof, in a unit
dosage form in a sealed container. The compound or salt is provided
in the form of a lyophilizate which is capable of being
reconstituted with a suitable pharmaceutically acceptable carrier
to form a liquid composition suitable for injection thereof into a
subject. The unit dosage form typically comprises from about 10 mg
to about 10 grams of the compound or salt. When the compound or
salt is substantially water-insoluble, a sufficient amount of
emulsifying agent which is physiologically acceptable may be
employed in sufficient quantity to emulsify the compound or salt in
an aqueous carrier. One such useful emulsifying agent is
phosphatidyl choline.
[0090] Formulations suitable for rectal administration are
preferably presented as unit dose suppositories. These may be
prepared by admixing the active compound with one or more
conventional solid carriers, for example, cocoa butter, and then
shaping the resulting mixture.
[0091] Formulations suitable for topical application to the skin
preferably take the form of an ointment, cream, lotion, paste, gel,
spray, aerosol, or oil. Carriers which may be used include
petroleum jelly, lanoline, polyethylene glycols, alcohols,
transdermal enhancers, and combinations of two or more thereof.
[0092] Formulations suitable for transdermal administration may be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Formulations suitable for transdermal administration may also be
delivered by iontophoresis (see, for example, Pharmaceutical
Research 3 (6):318 (1986)) and typically take the form of an
optionally buffered aqueous solution of the active compound.
Suitable formulations comprise citrate or bis\ris buffer (pH 6) or
ethanol/water and contain from 0.1 to 0.2M active ingredient.
[0093] Further, the present invention provides liposomal
formulations of the compounds disclosed herein and salts thereof.
The technology for forming liposomal suspensions is well known in
the art. When the compound or salt thereof is an aqueous-soluble
salt, using conventional liposome technology, the same may be
incorporated into lipid vesicles. In such an instance, due to the
water solubility of the compound or salt, the compound or salt will
be substantially entrained within the hydrophilic center or core of
the liposomes. The lipid layer employed may be of any conventional
composition and may either contain cholesterol or may be
cholesterol-free. When the compound or salt of interest is
water-insoluble, again employing conventional liposome formation
technology, the salt may be substantially entrained within the
hydrophobic lipid bilayer which forms the structure of the
liposome. In either instance, the liposomes which are produced may
be reduced in size, as through the use of standard sonication and
homogenization techniques.
[0094] Of course, the liposomal formulations containing the
compounds disclosed herein or salts thereof, may be lyophilized to
produce a lyophilizate which may be reconstituted with a
pharmaceutically acceptable carrier, such as water, to regenerate a
liposomal suspension.
[0095] Other pharmaceutical compositions may be prepared from the
water-insoluble compounds disclosed herein, or salts thereof, such
as aqueous base emulsions. In such an instance, the composition
will contain a sufficient amount of pharmaceutically acceptable
emulsifying agent to emulsify the desired amount of the compound or
salt thereof. Particularly useful emulsifying agents include
phosphatidyl cholines, and lecithin.
[0096] In addition to active compound(s), the pharmaceutical
compositions may contain other additives, such as pH-adjusting
additives. In particular, useful pH-adjusting agents include acids,
such as hydrochloric acid, bases or buffers, such as sodium
lactate, sodium acetate, sodium phosphate, sodium citrate, sodium
borate, or sodium gluconate. Further, the compositions may contain
microbial preservatives. Useful microbial preservatives include
methylparaben, propylparaben, and benzyl alcohol. The microbial
preservative is typically employed when the formulation is placed
in a vial designed for multidose use. Of course, as indicated, the
pharmaceutical compositions of the present invention may be
lyophilized using techniques well known in the art.
3. Dosage and Routes of Administration.
[0097] As noted above, the present invention provides
pharmaceutical formulations comprising the active compounds
(including the pharmaceutically acceptable salts thereof), in
pharmaceutically acceptable carriers for oral, rectal, topical,
buccal, parenteral, intramuscular, intradermal, or intravenous, and
transdermal administration.
[0098] The effective amount (e.g., therapeutically effective or
treatment effective amount) or dosage of any specific active
compound as described herein, for use in any specific method as
described herein, will vary depending on factors such as the
condition being treated, the route of administration, the general
condition of the subject (e.g., age, gender, weight, etc.), etc. In
general (e.g., for oral or parenteral administration), the dosage
may be from about 0.01, 0.05, or 0.1 milligram per kilogram subject
body weight (mg/kg), up to about 1, 5, or 10 mg/kg. For topical
administration, the active agent may be included in a
pharmaceutically acceptable composition to be applied in any
suitable amount, typically from 0.01, 0.1, or 1 percent by weight,
up to 10, 20, or 40 percent by weight, or more, of the weight of
the composition, again depending on factors such as the condition
being treated, condition of the subject, etc.
[0099] The active agents described herein may be administered
directly or through the administration to the subject of a
pharmaceutically acceptable prodrug which is in turn converted to
the active agent in vivo. The term "prodrug" refers to compounds
that are rapidly transformed in vivo to yield the parent compound
of the above formulae, for example, by hydrolysis in blood. A
thorough discussion is provided in T. Higuchi and V. Stella,
Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium
Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug
Design, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated by reference herein. See also
U.S. Pat. No. 6,680,299 Examples include a prodrug that is
metabolized in vivo by a subject to an active drug having an
activity of active compounds as described herein, wherein the
prodrug is an ester of an alcohol or carboxylic acid group, if such
a group is present in the compound; an acetal or ketal of an
alcohol group, if such a group is present in the compound; an
N-Mannich base or an imine of an amine group, if such a group is
present in the compound; or a Schiff base, oxime, acetal, enol
ester, oxazolidine, or thiazolidine of a carbonyl group, if such a
group is present in the compound, such as described in U.S. Pat.
No. 6,680,324 and U.S. Pat. No. 6,680,322.
4. Biofilm Treatment.
[0100] Active agents as described herein can be used to treat,
control, inhibit or disrupt biofilm formation in vivo or in vitro
in like manner as described in connection with other biofilm
dispersing or disrupting agents, including but not limited to those
described in U.S. Pat. No. 8,513,305 to Davies, the disclosure of
which is incorporated herein by reference in its entirety.
[0101] Biofilms formed from any film-forming microorganism (e.g.,
fungal or bacterial, including gram negative and gram positive
bacteria) can be treated by the methods of the present invention.
Examples of such film-forming microorganisms include, but are not
limited to, Staphylococcus aureus (e.g., methicillin-resistant
Staphylococcus aureus (MRSA)), Haemophilus influenza, Pseudomonas
aeruginosa, Burkholdereia cepacla, Escherichia coli, Actinomyces
israelii, etc.
[0102] Thus an aspect of the present invention relates to a method
of treating or preventing a condition mediated by a biofilm in a
subject. The method comprises providing a subject having, or
susceptible to, a condition mediated by a biofilm produced by a
microorganism, whereby the biofilm comprises a matrix and the
micro-organism on a surface. Administered to the subject is an
active agent as described herein, under conditions effective for
the active agent to selectively act on the microorganism and have a
suitable biological response without a required direct effect on
the matrix. As a result, the condition mediated by a biofilm in the
subject is treated, inhibited or prevented. The method of
dispersing the biofilm may further include administering to the
biofilm, in conjunction with administering the active agent, an
antimicrobial treatment. The treatment can be the administration of
biocides (e.g., hydrogen peroxide), surfactants, antibiotics,
antiseptics, detergents, chelating agents, virulence factor
inhibitors, gels, polymers, pastes, edible products, chewable
products, ultrasonic treatment, radiation treatment, thermal
treatment, and/or mechanical treatment.
[0103] An additional aspect of the present invention relates to a
method of treating or inhibiting formation of a biofilm on a
surface. This method involves providing a surface having or being
susceptible to formation of a biofilm produced by a microorganism,
where the biofilm comprises a matrix and the micro-organism on the
surface. Administered to the surface is a active agent as described
herein under conditions effective for the formation of the biofilm
on the surface is treated or inhibited.
[0104] In one embodiment, the surface to be treated includes
indwelling medical devices, such as catheters (e.g., urinary tract
catheters), respirators, ventilators, and intrauterine devices
(IUDs). In addition, the surface can be in implanted medical
devices, such as stents, artificial valves, joints, sutures,
staples, pacemakers, bone implants, pins, vascular grafts,
mechanical heart valves, arteriovenous shunts, cerebral spinal
fluid shunts, endovascular catheters, penile prostheses, surgical
mesh, and orthopedic fixation devices (e.g., plates, rods, screws,
etc.). The active agent of the present invention can also be
included in surgical glue.
[0105] In another embodiment, the surface to be treated includes
drains, tubs, kitchen appliances, countertops, shower curtains,
grout, toilets, industrial food and beverage production facilities,
flooring, and food processing equipment.
[0106] In a further embodiment, the surface to be treated is a heat
exchanger surface or a filter surface. Thus, treatment provides a
means for reducing the degree of biofouling of the heat exchanger
or filter.
[0107] In a further embodiment, the surface to be treated is a
marine structure which includes boats, piers, oil platforms, water
intake ports, sieves, and viewing ports. The surface can
alternatively be associated with a system for water treatment
and/or distribution (e.g., a system for drinking water treatment
and/or distributing, a system for pool and spa water treatment, a
system for treatment and/or distribution of water in manufacturing
operations, and a system for dental water treatment and/or
distribution). The surface can also be associated with a system for
petroleum drilling, storage, separation, refining and/or
distribution (e.g., a petroleum separation train, a petroleum
container, petroleum distributing pipes, and petroleum drilling
equipment). The active agent can also be included in formulations
directed at reducing or eliminating biofilm deposits or biofouling
in porous medium, such as with oil and gas bearing geological
formations. The treatment may be accomplished by applying a coating
containing the active agent, such as paint, to the surface.
[0108] The method of inhibiting formation of a biofilm on a surface
may further involve administering to the surface, in conjunction
with administering the active agent, an antimicrobial treatment.
The treatment can be administration of biocides, surfactants,
antibiotics, antiseptics, disinfectants, medicines, detergents,
chelating agents, virulence factor inhibitors, ultrasonic
treatment, radiation treatment, thermal treatment, and mechanical
treatment. In one embodiment, the active agent and the
antimicrobial treatment are administered simultaneously. In another
embodiment, the active agent and antimicrobial treatment are
administered separately.
[0109] The active agent can be impregnated in a surface in order to
inhibit formation of a biofilm on the surface. Alternatively, the
active agent can be in a copolymer or a gel coating over the
surface.
[0110] The present invention also relates to a method of treating
subjects with burns. The method involves administering the active
agent according to the present invention, under conditions
effective to treat burns in the subject. A specific application of
the invention provides a topical dressing for burn patients
comprising dispersion inducing molecules or their natural or
synthetic analogs to prevent the development of infectious biofilms
or to disperse the cells of existing infectious biofilms.
[0111] The present invention further relates to a method of
treating and/or preventing dental plaque, dental carries, gingival
disease, periodontal disease, and oral infection in a subject. The
method involves treating the oral cavity of the subject with the
active agent according to the present invention. Treating can be
carried out with a dentifrice, mouthwash, dental floss, gum, strip,
toothpaste, a toothbrush containing the active agent, and other
preparations containing the active agent. The composition may also
contain other compounds known in the dental arts that are typically
added to dental compositions. For example, the active agent
composition may also include fluoride, desensitizing agents,
anti-tartar agents, anti-bacterial agents, remineralization agents,
whitening agents, and anti-caries agents.
[0112] The amount of active agent present will vary dependent on
the dental composition that contains the active agent. It has been
found that the active agent is active over a wide range of
concentrations against oral bacteria. For instance, the active
agent may be present in an amount ranging from 0.1 nM to 10 mM.
However, lower and higher concentrations may be used depending on
the dental composition, the other components present in the active
agent composition, and various other factors appreciated by those
of skill in the art. The known properties of the active agent, such
as its fatty acid characteristics and its hydrophobicity, will
assist a skilled artisan in determining how much of the active
agent should be used, determining how the compound will chemically
interact with other components, and providing other useful
information about the compound.
[0113] Specific dental applications and dental compositions are
contemplated in this invention. In this regard, the invention
relates to a toothbrush containing a active agent composition.
Toothbrushes, as is well known in the art, contain a plurality of
bristles and a solid support on which the bristles are mounted,
where the solid support includes a brush head having a plurality of
tuft holes that receive the bristles. Variations and modifications
of the basic toothbrush are well known in the art. See, for
example, U.S. Pat. No. 7,251,849, herein incorporated by reference
in its entirety.
[0114] The active agent of this invention has a chemical formula as
set forth above. Additional components that may be included in the
active agent compositions are also set forth above. The active
agent composition may be incorporated in the various parts of the
toothbrush by means known in the art. For instance, the active
agent composition may be contained in the tuft holes of the
toothbrush. See U.S. Pat. No. 5,141,290, herein incorporated by
reference in its entirety, for an example of how a composition can
be contained within the tuft holes of a toothbrush. Alternatively,
the active agent composition may be coated or embedded in the
bristles of the toothbrush.
[0115] Other parts of the toothbrush may also be coating or
embedded with the active agent composition, including any parts of
the toothbrush that supplement the bristles and are designed to be
contacted with the oral cavity. For example, it is common for
toothbrushes to contain rubber paddles, tongue cleaners, or other
pieces extended from the head for the purposes of being contacted
with the tooth, tongue, gums, or other areas of the oral cavity.
These parts may be embedded with the active agent composition and,
optionally, a surfactant, biocide, and/or other additive discussed
above.
[0116] To assist in controlling the release of the active agent
from the toothbrush, the active agent composition may contain an
agent that interacts with the active agent to assist in the
controlled release. The agent may interact with the active agent in
a manner that the release is either accelerated or prolonged,
depending on the desired use. The level of controlled release can
also depend on how easily or difficult the active agent adheres to
the portion of the toothbrush that it is applied to. In a preferred
embodiment, the active agent is slowly released from the toothbrush
over repeated brushings. Agents that enable the slow release of an
active ingredient are well known to those of skill in the art.
[0117] The controlled release may also be effectuated by
encapsulating the active agent in an encapsulated system that
allows a controlled release. In this embodiment, the active agent
composition is preferably in the form of a plurality of small
microspheres that encapsulate the active agent. The microspheres
can have an outer coating of dissolvable material that enables the
active agent to slowly release over repeated brushings. Suitable
microspheres include those disclosed in U.S. Pat. No. 5,061,106,
herein incorporated by reference in its entirety.
[0118] This invention also relates to a toothpaste composition that
contains (a) fluoride and/or a remineralization agent; (b) an
orally-accepted vehicle; and (c) a active agent composition. The
active agent of this invention has a chemical formula as set forth
above. Additional components that may be included in the active
agent compositions are also set forth above. Often, toothpastes
also contain sodium lauryl sulfate or other sulfates.
[0119] Fluoride in its various forms is a common active ingredient
in toothpaste to prevent cavities and promote the formation of
dental enamel and bones. Any fluoride source, such as fluoride
salts may be used in the toothpaste of this invention. Preferably,
the fluoride is sodium fluoride (NaF) or sodium
monofluorophosphate. Typically, the amount of fluoride present in
the toothpaste ranges from 100 to 5000 parts per million fluoride
ion, preferably 1000 to 1100 parts per million.
[0120] In certain instances, it is preferable to replace or
supplement the fluoride with a remineralization agent.
Remineralization, in the context of dental usage, generally refers
to treating the teeth so as to prevent dental caries, or decrease
their chance of occurring, and otherwise enhance the teeth so that
they can return to their original, healthy state. While fluoride
can be considered a remineralization agent, other agents often take
the place of fluoride or supplement fluoride to provide the
toothpaste with a stronger cleansing or remineralization
properties. Common remineralization agents are calcium salts, such
as calcium phosphate, calcium sulfate, anhydrous calcium sulfate,
calcium sulfate hemihydrate, calcium sulfate dihydrate, calcium
malate, calcium tartrate, calcium malonate, and calcium succinate.
Hydroxyapitate nanocrystals and zinc compounds have also been shown
to be effective remineralization agents.
[0121] The orally-accepted vehicle may be any vehicle known in the
art that can be used to deliver the fluoride and/or
remineralization agent, and active agent to the teeth of a patient.
The orally-accepted vehicle may also be glycerin, propylene glycol,
polyethylene glycol, triglyceride, diglyceride, mineral oil,
organic oils, essential oils, fatty vegetable oils, and
combinations thereof. Often these vehicles are used in combination
with water or a water-based solvent.
[0122] The toothpaste composition may contain other components of
toothpastes well known in the art. For instance, the toothpaste
composition may contain baking soda, enzymes, vitamins, herbs,
calcium compounds such as calcium sodium phosphosilicate, coloring
agents, and/or flavoring agents. Desensitizing agents may also be
added. As known in the art, desensitizing agents can reduce
sensitivity in teeth by treating sensitivities caused by
demineralization or suppressing the sensitivity symptoms by
desensitizing the nerves. The composition may also contain an
antibacterial or an antiplaque agent. Antibacterial agents are
preferable included in the composition to prevent gingivitis,
periodontitis, and other oral diseases. Suitable antibacterial
agents include triclosan, zinc chloride, chlorhexidine,
benzethonium chloride, and cetyl pyridinium chloride.
[0123] This invention also relates to an oral composition for
treating and/or preventing dental plaque, gingival diseases,
periodontal diseases, and/or oral infection. The oral composition
contains an orally-accepted vehicle and a active agent composition.
The active agent of this invention has a chemical formula as set
forth above. Additional components that may be included in the
active agent compositions are also set forth above.
[0124] The oral composition can be various compositions in the
field of dental hygiene known to those in the art. For instance,
the oral composition may be a mouthwash, breath spray, dentifrice,
tooth powder, whitening strips, or prophylaxis paste. As is well
known in the art, mouthwashes are commonly used to help remove
mucous and food particles in the oral cavity or throat. Mouthwashes
typically contain antiseptic and/or anti-plaque components to kill
the bacterial plaque that causes caries, gingivitis, and bad
breath. They can also contain anti-cavity components, such as
fluoride, to protect against tooth decay. Suitable mouthwash
components may be found in U.S. Pat. No. 5,968,480, herein
incorporated by reference in its entirety.
[0125] Likewise, the same or similar antiseptic, anti-plaque, and
anti-cavity components can be used in breath sprays, dentifrices,
including gel dentifrices, tooth powders, whitening strips, and
prophylaxis pastes. Suitable breath spray compositions are
disclosed in U.S. Pat. No. 7,297,327; suitable tooth powder
compositions, such as those used in tooth bleaching compositions,
are disclosed in U.S. Pat. No. 5,989,526; suitable whitening strips
are disclosed in U.S. Pat. No. 6,514,483; and suitable dentifrices
and prophylaxis paste compositions, including dental abrasives, are
disclosed in U.S. Pat. No. 5,939,051, all of which are herein
incorporated by reference in their entirety.
[0126] The ingredients of orally-accepted vehicle are similar to
those discussed above. However, the orally-accepted vehicle will
vary depending on the desired consistency and desired end product
of the oral composition. For instance, a mouthwash is in a liquid
form, so liquid carriers, typically carriers having a high
percentage of water, should be used. On the other hand, a gel
dentifrice should be in the form of a gel and would utilize gelling
agents or other carriers that enable the final product to be in the
form of a gel. The orally-accepted vehicle should have properties
that both allow the active agent composition to be delivered while
also providing the final product with the desired consistency.
[0127] The oral composition may also be in the form of chewing gum,
a breath strip, a lozenge, or a breath mint. Chewing gum is
typically a combination of a water-insoluble phase, or gum base,
and a water-soluble phase of sweeteners, flavoring and/or food
coloring. Other components may also be added to the gum, including
breath-freshening additives such as zinc and phosphate salts,
teeth-whitening additives such as silica, and plaque-reducing
additives to moderate dental plaque. Suitable gum compositions may
be found in U.S. Pat. Nos. 6,416,744 and 6,592,849, both of which
are herein incorporated by reference in their entirety.
[0128] Breath strips are similar to chewing gum, except that the
strips are designed to dissolve in the mouth, often absorbed
through the tongue. The strips can deliver bioactive ingredients to
freshen the mouth as well functional bioactive ingredients, such as
vitamins, minerals, supplements, pharmaceuticals, and vaccines.
[0129] Lozenges and breath mints are typically discoid-shaped
solids that contain a therapeutic agent in a flavored base. The
base may be a hard sugar candy, glycerinated gelatin or combination
of sugar with sufficient mucilage to give the composition requisite
form. The active agent may represent the therapeutic agent, or it
may be added in addition to therapeutic agents known in the art.
Suitable lozenge and breath mint compositions are disclosed in U.S.
Pat. No. 7,025,950, herein incorporated by reference in its
entirety.
[0130] The oral composition may also be in the form of a cleaning
preparation for a dental apparatus that is placed in the oral
cavity. Dental apparatuses such as dentures, dental dams, and
certain types of orthodontic braces are placed in the oral cavity
for a period of time, and then periodically removed for cleaning.
The cleaning composition used to clean the dental apparatuses
should function in its customary manner of cleaning the apparatus,
but may also contain therapeutic agents that can assist in treating
or preventing dental plaque, gingival diseases, periodontal
diseases, and oral infection when the dental apparatuses are in
contact with the oral cavity. Cleaning compositions such as
effervescent cleansers made with alkaline mixtures containing a
chlorine compounds and the like are known in the art. Suitable
cleaning compositions for dental apparatuses are disclosed in U.S.
Pat. No. 3,936,385, herein incorporated by reference in its
entirety. The active agent may be added to the cleaning
compositions in a manner than enables it to coat the dental
apparatus upon contact. After the dental apparatus has been
introduced into the oral cavity, the active agent can interact with
the teeth and other elements of the oral cavity in a
therapeutically effective manner, i.e. to prevent dental plaque,
gingival diseases, periodontal diseases, and/or oral infection.
[0131] This invention also relates to an article for oral use
comprising a dental article and a active agent. The active agent
has the chemical formula set forth above, and is coated on,
encapsulated in, or impregnated in the dental article. Additional
components that may be included in the active agent compositions
are also set forth above.
[0132] Various dental articles known in the art may used in this
embodiment of the invention. In one embodiment, the dental article
is a dental floss. Any fiber known in the art may be used in the
dental floss. Suitable fibers include polyamides (such as nylon),
polyesters, polypropylenes, polytetrafluoroethylenes, cellulose,
and cotton. Nylon and polytetrafluoroethylene fibers are the most
common fibers used in dental floss and represent preferred fibers.
Suitable dental flosses are disclosed in U.S. Pat. Nos. 6,270,890
and 6,289,904, both of which are herein incorporated by reference
in their entirety. The active agent composition may be impregnated
into the fiber, coated on the fiber, or otherwise incorporated into
the dental floss.
[0133] The dental floss may be coated or impregnated with a wax or
other hydrophobic substance for ease of use during the flossing
process. Suitable waxes include microcrystalline waxes, beeswax,
paraffin waxes, carnauba waxes, and polyethylene waxes. The active
agent composition may be coated onto the dental floss as part of
the wax layer, as a second or additional layer in conjunction with
the wax layer, or applied to the fiber as discussed above.
[0134] The dental article may be a toothpick that is impregnated
with or coated with the active agent composition. Toothpicks may be
made from natural products, such as wood, or artificial components,
including various plastics. Suitable toothpicks are disclosed in
U.S. Pat. No. 7,264,005, herein incorporated by reference in its
entirety.
[0135] The dental article may also be a dental appliance such as a
dental aspirator, bite block, dental dam, tongue stabilizer, tongue
deflector, or any other piece of dental equipment that a dentist or
dental assistant may use in the mouth of a patient. A discussion of
dental appliances may be found in U.S. Pat. Nos. 4,865,545 and
5,152,686, both of which are herein incorporated by reference. The
portion of the dental appliance that comes into contact with the
oral cavity of a patient may be coated with the active agent
composition.
[0136] The dental article may also be a dental construct, such as a
veneers, crowns, inlays, onlays, or bridges that are placed on the
teeth. Dental constructs are typically made of metal alloys,
porcelain, ceramic, amalgam, acrylate polymers, or a combination of
these materials. Suitable dental constructs are disclosed in U.S.
Pat. No. 7,229,286, herein incorporated by reference in its
entirety. The active agent composition may be embedded in the
composition used to make the dental construct. Alternatively, the
active agent composition may be coated on the dental construct
after it has been prepared.
[0137] This invention also relates to an aqueous composition
applied to the oral cavity with the use of a dental article,
comprising water and a active agent composition. Various dental
articles are attached to or designed to be used with a water line
so that water can be distributed through the dental article, and
then routed from the dental article to the oral cavity of a
subject. Suitable dental articles include dental water lines,
dental water picks, and the like.
[0138] While tap water or purified water may be used in these type
of dental devices, the water source may also be supplemented with
additives so that the water delivers the additives to the oral
cavity of the subject when used with the dental article. In this
case, the additive supplemented to the water is a active agent
composition.
[0139] Dental water lines and dental water picks are known in the
art and commonly used by dentists and dental assistants. A
discussion of different types of dental water lines and their
different applications may be found in U.S. Pat. No. 5,785,523,
herein incorporated by reference in its entirety. Suitable water
picks are disclosed in U.S. Pat. No. 4,257,433, herein incorporated
by reference in its entirety.
[0140] The present invention also relates to a method of cleaning
and/or disinfecting contact lenses. The method involves treating
contact lenses with a cleaning and/or disinfecting solution
containing the active agent according to the present invention. The
contact lens may be treated in this manner while being stored in
solution or while being used in vivo. Alternatively, the active
agent can be used in eye drops.
[0141] The present invention further relates to a method of
treating and/or preventing acne or other biofilm-associated skin
infections on the skin of a subject. The method involves treating
the skin of the subject with the active agent according to the
present invention under conditions effective to treat and/or
prevent the acne or biofilm-associated skin infections. The active
agent may be present in an ointment, cream, liniment, salves,
shaving lotion, or aftershave. It may also be present in a powder,
cosmetic, ointment, cream, liquid, soap, gel, cosmetic applicator,
and/or solid, woven or non-woven material intended to contact or be
proximate with the skin.
[0142] The present invention also relates to a method of treating
and/or preventing a chronic biofilm-associated disease in a
subject. The method involves administering to the subject the
active agent according to the present invention under conditions
effective to treat and/or prevent the chronic biofilm-associated
disease. The chronic biofilm-associated diseases to be treated
and/or prevented include, but are not limited to, middle ear
infections, osteomyelitis, prostatitis, colitis, vaginitis,
urethritis, arterial plaques, sinovial infections, infections along
tissue fascia, respiratory tract infections (e.g., infections
associated with lung infections of cystic fibrosis patients,
pneumonia, pleurisy, pericardial infections), genito-urinary
infections, and gastric or duodenal ulcer infections. For gastric
or duodenal ulcers caused by Helicobacter pylori, the active agent
will need to function at a pH of below 5.5. The active agent may be
administered in combination with an antimicrobial agent, such as
biocides, surfactants, antibiotics, antiseptics, detergents,
chelating agents, or virulence factor inhibitors. In the case of
gastric therapies, acid reducing therapies, such as antacids,
proton pump inhibitors, antihistamines, and the like may also be
employed.
[0143] The present invention also relates to a composition
comprising one or more active agents and one or more additive
components. These additive components are selected from the group
consisting of biocides, surfactants, antibiotics, antiseptics,
detergents, chelating agents, virulence factor inhibitors, gels,
polymers, pastes, edible products, and chewable products. The
composition is formulated so that when it is contacted with a
biofilm produced by a microorganism, where the biofilm comprises a
matrix and microorganism on a surface, the active agent selectively
acts on the microorganism and has a suitable biological response
without a required direct effect to disrupt the matrix.
[0144] Another aspect of the present invention relates to a method
of treating or preventing a condition mediated by a biofilm in a
subject. This method involves providing a subject having, or
susceptible to, a condition mediated by a biofilm produced by a
microorganism, whereby the biofilm comprises a matrix and the
micro-organism on a surface. An active agent is administered to the
subject under conditions effective for the active agent to
selectively act on the microorganism and have a suitable biological
response without a required direct effect on the matrix, whereby
the condition mediated by a biofilm in the subject is treated or
prevented.
[0145] A further embodiment of the present application is directed
to a method of treating or inhibiting formation of a biofilm on a
surface. This involves providing a surface having or being
susceptible to formation of a biofilm produced by a microorganism,
whereby the biofilm comprises a matrix and the micro-organism on
the surface. An active agent is administered to the surface under
conditions effective for the active agent to selectively act on the
microorganism and have a suitable biological response without a
required direct effect on the matrix, whereby formation of the
biofilm on the surface is treated or inhibited.
[0146] When the active agents described herein are used in
combination with an antibiotic, any suitable antibiotic may be used
(alone, or in combination with other antibiotics). Examples
include, but are not limited to, at least one of aminoglycoside;
amikacin; gentamicin; kanamycin; neomycin; netilmicin; steptomycin;
tobramycin; ansamycin; geldanamycin; herbimycin; carbacephem;
loracarbef; carbacepenem; ertapenem; doripenem;
imipenem/cilastatin; meropenem; cephalosporin; cefadroxil;
cefazolin; cefalotin or cefalothin; cefalexin; cefaclor;
cefamandole; cefoxitin; cefprozil; cefuroxime; cefixime; cefdinir;
cefditoren; cefoperazone; cefotaxime; cefpodoxime; ceftazidime;
ceftibuten; ceftizoxime; ceftriaxone; cefepime; ceftobiprole;
glycopeptide; teicoplanin; vancomycin; macrolide; azithromycin;
clarithromycin; dirithromycin; erythromicin; roxithromycin;
troleandomycin; telithromycin; spectinomycin; monobactam;
aztreonam; penicillin; amoxicillin; ampicillin; azlocillin;
carbenicillin; cloxacillin; dicloxacillin; flucloxacillin;
mezlocillin; meticillin; nafcillin; oxacillin; penicillin,
piperacillin, ticarcillin; bacitracin; colistin; polymyxin B;
quinolones; ciprofloxacin; enoxacin; gatifloxacin; levofloxacin;
lomefloxacin; moxifloxacin; norfloxacin; ofloxacin; trovafloxacin;
sulfonamide; mafenide; prontosil (archaic); sulfacetamide;
sulfamethizole; sufanilimide (archaic); sulfasalazine;
sulfisoxazole; trimethoprim; trimethoprim-sulfamethoxazole
(co-trimoxazole) (TMP-SMX); tetracycline; demeclocycline;
doxycycline; minocycline; oxytetracycline; tetracycline;
arsphenamine; chloramphenicol; clindamycin; lincomycin; ethambutol;
fosfomycin; fusidic acid; furazolidone; isoniazid; linezolid;
metronidazole; mupirocin; nitrofuantoin; platensimycin;
purazinamide; quinupristin/dalfopristin; rifampin or rifampicin; or
tinidazole. See, e.g., U.S. Pat. No. 8,211,656.
[0147] The present invention is explained in greater detail in the
following non-limiting Examples.
Example 1
Inhibition of Staphylococcus Aureus Biofilm Formation In Vitro
[0148] Biofilm forming S. aureus was grown in 96 well plates for 24
hours to allow a biofilm to form. Wells were allowed to grow an
additional 24 hours after being treated with either PBS or SOD
mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin, or
"MnTE-PyP"). Biofilm intensity was measured using absorbance at 600
nm. Results are shown in FIG. 1. These results showed that MnTE
disrupts established S. aureus biofilms in culture.
(p<0.0001)
Example 2
Biofilm Disruption In Vivo in a Mouse Infected Fracture Model
[0149] A total of 20 C57B5 male mice were randomly divided into
four treatment groups after surgery to create an infected femur
fracture (midshaft femur fracture fixed with intramedullary 23 g
needle and with 10.sup.4 S. aureus added to the fracture site):
[0150] 1. Control (no active treatment),
[0151] 2. Antibiotic (Keflex) starting 24 hours post-surgery,
[0152] 3. SOD mimetic MnTE-2-PyP (starting 24 hours
post-surgery,
[0153] 4. Antibiotic plus MnTE-2-PyP (starting 24 hours
post-surgery).
(Though not felt to be related to the compound, it is noted that
one mouse died in the initial post-operative period from the
mimetic only group.)
[0154] The mice were followed for 2 weeks and received daily access
to Keflex in drinking water at 250 m/ml dose for the antibiotic
treated groups and MnTE three time per week (loading dose day 1=5.0
mg/kg SQ, followed by 2.5 mg/kg SQ three times weekly). Mice
resumed weight-bearing on post operative day 1 and were weighed
three times per week and monitored for complications. Mice were
harvested after 2 weeks and femurs were homogenized in PBS,
supernatants were serially diluted and plated to determine cell
counts. Results are given in FIGS. 2-3.
[0155] The foregoing is illustrative of the present invention, and
is not to be construed as limiting thereof. The invention is
defined by the following claims, with equivalents of the claims to
be included therein.
* * * * *