U.S. patent application number 10/659571 was filed with the patent office on 2005-03-17 for antimicrobial compositions and methods.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Andrews, Jeffrey F., Capecchi, John T., Gibbs, Dianne L., Scholz, Matthew T..
Application Number | 20050058673 10/659571 |
Document ID | / |
Family ID | 34273521 |
Filed Date | 2005-03-17 |
United States Patent
Application |
20050058673 |
Kind Code |
A1 |
Scholz, Matthew T. ; et
al. |
March 17, 2005 |
Antimicrobial compositions and methods
Abstract
Antimicrobial compositions, especially those useful when applied
topically, particularly to mucosal tissues (i.e., mucous
membranes), including a fatty acid ester, fatty ether, or alkoxide
derivative thereof. The compositions can also include an enhancer
component, a surfactant, a hydrophobic component, and/or a
hydrophilic component. Such compositions provide effective topical
antimicrobial activity and are accordingly useful in the treatment
and/or prevention of conditions that are caused, or aggravated by,
microorganisms (including viruses).
Inventors: |
Scholz, Matthew T.;
(Woodbury, MN) ; Gibbs, Dianne L.; (St. Paul,
MN) ; Capecchi, John T.; (Oakdale, MN) ;
Andrews, Jeffrey F.; (Stillwater, MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
34273521 |
Appl. No.: |
10/659571 |
Filed: |
September 9, 2003 |
Current U.S.
Class: |
424/401 ;
514/557 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 9/0046 20130101; A61P 31/12 20180101; A61P 11/00 20180101;
A61K 9/007 20130101; A61K 9/0014 20130101; A61P 1/00 20180101; A61P
31/10 20180101; A61P 31/04 20180101; A61K 47/10 20130101; A61K
9/0053 20130101; Y02A 50/473 20180101; A61K 47/14 20130101; A61K
45/06 20130101; Y02A 50/30 20180101; A61K 31/25 20130101; A61K
31/19 20130101; A61K 31/23 20130101; A61K 47/20 20130101; A61P
17/02 20180101; A61K 47/06 20130101; A61P 31/00 20180101; A61P
27/16 20180101; A61K 9/0043 20130101; A61K 47/44 20130101; A61K
31/231 20130101; A61P 17/00 20180101; A61K 31/19 20130101; A61K
2300/00 20130101; A61K 31/23 20130101; A61K 2300/00 20130101; A61K
31/231 20130101; A61K 2300/00 20130101; A61K 31/25 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/401 ;
514/557 |
International
Class: |
A61K 031/19; A61K
007/00 |
Claims
What is claimed is:
1. An antimicrobial composition comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; a surfactant; a hydrophilic
component; and a hydrophobic component which forms the greatest
portion of the composition.
2. The composition of claim 1 wherein water is present in less than
10 wt-%.
3. The composition of claim 1 wherein the antimicrobial lipid
component is present in an amount of at least 0.1 wt-%.
4. The composition of claim 3 wherein the antimicrobial lipid
component comprises a monoester of a polyhydric alcohol, a
monoester of a polyhydric alcohol, or an alkoxylated derivative
thereof, and the antimicrobial lipid component further includes 0
to 15 wt-%, based on the total weight of the antimicrobial lipid
component, of a di- or tri-ester, a di- or tri-ether, alkoxylated
derivative thereof, or combinations thereof.
5. The composition of claim 1 wherein the total concentration of
the enhancer component relative to the total concentration of lipid
component is within a range of 10:1 to 1:300, on a weight
basis.
6. The composition of claim 1 wherein the total concentration of
the surfactant to the total concentration of antimicrobial lipid
component is within a range of 5:1 to 1:100, on a weight basis.
7. The composition of claim 1 wherein the hydrophilic component is
present in an amount of 1 wt-% to 40 wt-%.
8. The composition of claim 1 wherein the hydrophobic component is
present in an amount of 50 wt-% to 99 wt-%.
9. The composition of claim 1 wherein the antimicrobial lipid
component comprises glycerol monolaurate, glycerol monocaprate,
glycerol monocaprylate, propylene glycol monolaurate, propylene
glycol monocaprate, propylene glycol monocaprylate, or combinations
thereof.
10. The composition of claim 1 wherein the enhancer component
comprises a carboxylic acid.
11. The composition of claim 1 wherein the enhancer component
comprises an alpha-hydroxy acid.
12. The composition of claim 1 wherein the surfactant comprises a
sulfonate, a sulfate, a phosphonate, a phosphate, a poloxamer, a
cationic surfactant, or mixtures thereof.
13. The composition of claim 12 wherein the surfactant is selected
from the group consisting of a sulfonate, a sulfate, a phosphate,
and mixtures thereof.
14. The composition of claim 1 wherein the hydrophilic component
comprises a glycol, a lower alcohol ether, a short chain ester, or
combinations thereof, wherein the hydrophilic component is soluble
in water in an amount of at least 20 wt-% at 23.degree. C.
15. The composition of claim 1 wherein the hydrophobic component is
an organic compound that is liquid, gelatinous, semisolid, or solid
at 23.degree. C. and has a solubility in water of less than 5 wt-%
at 23.degree. C.
16. The composition of claim 1 having at least 4 log reduction in
test bacteria in 10 minutes.
17. An antimicrobial composition comprising: 0.01 wt-% to 20 wt-%
of an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, and
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; 0.01 wt-% to 20 wt-% of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; 0.1 wt-% to 10 wt-% of a
surfactant; 1 wt-% to 40 wt-% of a hydrophilic component; 50 wt-%
to 95 wt-% of a hydrophobic component; and less than 10 wt-%
water.
18. An antimicrobial composition comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; a surfactant; and a
hydrophilic component; wherein the viscosity of the composition is
at least 500 cps.
19. An antimicrobial composition comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; a surfactant; a hydrophilic
component; a hydrophobic component; and less than 10 wt-% water;
wherein the hydrophilic component forms the greatest portion of the
composition by weight.
20. An antimicrobial composition comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty
ether of a polyhydric alcohol, an alkoxylated derivative thereof,
and combinations thereof, wherein the alkoxylated derivative has
less than 5 moles of alkoxide per mole of polyhydric alcohol; with
the proviso that for polyhydric alcohols other than sucrose, the
ethers comprise monoethers, and for sucrose the ethers comprise
monoethers, diethers, or combinations thereof; an effective amount
of an enhancer component comprising an alpha-hydroxy acid, a
beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic
acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic
acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
and a hydrophobic component which forms the greatest portion of the
composition by weight.
21. An antimicrobial composition comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty
ether of a polyhydric alcohol, an alkoxylated derivative thereof,
and combinations thereof, wherein the alkoxylated derivative has
less than 5 moles of alkoxide per mole of polyhydric alcohol; with
the proviso that for polyhydric alcohols other than sucrose, the
ethers comprise monoethers, and for sucrose the ethers comprise
monoethers, diethers, or combinations thereof; an effective amount
of an enhancer component comprising an alpha-hydroxy acid, a
beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic
acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic
acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
and a hydrophilic component which forms the greatest portion of the
composition; wherein the viscosity of the composition is at least
500 cps.
22. A method of preventing and/or treating an affliction caused, or
aggravated by, a microbial organism on skin and/or a mucous
membrane, the method comprising contacting the skin and/or mucous
membrane with the antimicrobial composition of claim 1.
23. A method of preventing and/or treating an affliction caused, or
aggravated by, a microorganism on skin and/or a mucous membrane,
the method comprising contacting the skin and/or mucous membrane
with the antimicrobial composition of claim 17.
24. A method of preventing and/or treating an affliction caused, or
aggravated by, a microorganism on skin and/or a mucous membrane,
the method comprising contacting the skin and/or mucous membrane
with the antimicrobial composition of claim 18.
25. A method of preventing and/or treating an affliction caused, or
aggravated by, a microorganism on skin and/or a mucous membrane,
the method comprising contacting the skin and/or mucous membrane
with the antimicrobial composition of claim 19.
26. A method of preventing and/or treating an affliction caused, or
aggravated by, a microorganism on skin and/or a mucous membrane,
the method comprising contacting the skin and/or mucous membrane
with the antimicrobial composition of claim 20.
27. A method of preventing and/or treating an affliction caused, or
aggravated by, a microorganism on skin and/or a mucous membrane,
the method comprising contacting the skin and/or mucous membrane
with the antimicrobial composition of claim 21.
28. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 1 in an amount effective to kill one or more
microorganisms.
29. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 17 in an amount effective to kill one or more
microorganisms.
30. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 18 in an amount effective to kill one or more
microorganisms.
31. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 19 in an amount effective to kill one or more
microorganisms.
32. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 20 in an amount effective to kill one or more
microorganisms.
33. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with the antimicrobial
composition of claim 21 in an amount effective to kill one or more
microorganisms.
34. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 1 in an amount effective to kill or inactivate
one or more microorganisms.
35. The method of claim 34 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
36. The method of claim 35 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
37. The method of claim 36 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
38. The method of claim 34 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
39. The method of claim 34 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
40. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 17 in an amount effective to kill or
inactivate one or more microorganisms.
41. The method of claim 40 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
42. The method of claim 41 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
43. The method of claim 42 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
44. The method of claim 40 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
45. The method of claim 40 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
46. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 18 in an amount effective to kill or
inactivate one or more microorganisms.
47. The method of claim 46 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
48. The method of claim 47 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
49. The method of claim 48 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
50. The method of claim 46 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
51. The method of claim 46 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
52. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 19 in an amount effective to kill or
inactivate one or more microorganisms.
53. The method of claim 52 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
54. The method of claim 53 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
55. The method of claim 54 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidennidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
56. The method of claim 52 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
57. The method of claim 52 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
58. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 20 in an amount effective to kill or
inactivate one or more microorganisms.
59. The method of claim 58 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
60. The method of claim 59 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
61. The method of claim 60 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidennidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
62. The method of claim 58 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
63. The method of claim 58 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
64. A method of killing or inactivating microorganisms, the method
comprising contacting the microorganisms with the antimicrobial
composition of claim 21 in an amount effective to kill or
inactivate one or more microorganisms.
65. The method of claim 64 wherein the microorganisms comprise
bacteria and the antimicrobial composition is used in an amount
effective to kill one or more bacteria.
66. The method of claim 65 wherein the bacteria comprise
Staphylococcus spp., Streptococcus spp., Escherichia spp.,
Enterococcus spp., or Pseudamonas spp.
67. The method of claim 66 wherein the bacteria comprise
Staphylococcus aureus, Staphylococcus epidermidis, Escherichia
coli, Pseudomonas aeruginosa, or Streptococcus pyogenes.
68. The method of claim 64 wherein the microorganisms comprise one
or more viruses and the antimicrobial composition is used in an
amount effective to inactivate one or more viruses.
69. The method of claim 64 wherein the microorganisms comprise one
or more fungi and the antimicrobial composition is used in an
amount effective to kill one or more fungi.
70. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 1.
71. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 17.
72. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 18.
73. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 19.
74. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 20.
75. A method of providing residual antimicrobial efficacy on a
surface, the method comprising contacting the surface with the
composition of claim 21.
76. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 1 in at least a portion of the subject's respiratory
system in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
77. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 17 in at least a portion of the subject's respiratory
system in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
78. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 18 in at least a portion of the subject's respiratory
system in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
79. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 19 in at least a portion of the subject's respiratory
system in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
80. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 20 in at least a portion of the subject's respiratory
system in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
81. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting the subject with the composition
of claim 21 in at least a portion of the subject's respiratory
system in an amount effective to kill inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction.
82. A method of decolonizing at least a portion of the nasal
cavities, anterior nares, and/or nasopharynx of a subject of
microorganisms, the method comprising contacting the nasal
cavities, anterior nares, and/or nasopharynx with an antimicrobial
composition in an amount effective to kill one or more
microorganisms, wherein the antimicrobial composition comprises: an
effective amount of an antimicrobial lipid component comprising a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and a
hydrophobic component which forms the greatest portion of the
composition by weight.
83. The method of claim 82 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
84. The method of claim 83 wherein the composition further
comprises a hydrophilic component.
85. A method of treating a middle ear infection in a subject, the
method comprising contacting the middle ear, tympanic membrane,
and/or Eustachian tube with an antimicrobial composition
comprising: an effective amount of an antimicrobial lipid component
comprising a (C8-C12)saturated fatty acid ester of a polyhydric
alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric
alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
86. A method of treating a middle ear infection in a subject, the
method comprising contacting the middle ear, tympanic membrane,
and/or Eustachian tube with an antimicrobial composition
comprising: an effective amount of an antimicrobial lipid component
comprising a (C8-C12)saturated fatty acid ester of a polyhydric
alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric
alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and a
hydrophobic component which forms the greatest portion of the
composition by weight.
87. The method of claim 86 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
88. A method of treating chronic sinusitis in a subject, the method
comprising contacting at least a portion of the respiratory system
with an antimicrobial composition comprising: an effective amount
of an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; and an effective amount of an enhancer
component comprising an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
wherein the composition comprises less than 0.50 percent by weight
(C6-C18)fatty acid.
89. A method of treating chronic sinusitis in a subject, the method
comprising contacting at least a portion of the respiratory system
with an antimicrobial composition comprising: an effective amount
of an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; and a hydrophobic component which forms the
greatest portion of the composition by weight.
90. The method of claim 89 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
91. A method of treating impetigo on the skin of a subject, the
method comprising contacting the affected area with an
antimicrobial composition comprising: an effective amount of an
antimicrobial lipid component comprising a (C8-C12)saturated fatty
acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty
acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether
of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; and an effective amount of an enhancer
component comprising an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations
thereof.
92. The method of claim 91 wherein the composition further
comprises a hydrophilic component, wherein the viscosity of the
composition is at least 500 cps.
93. A method of treating impetigo on the skin of a subject, the
method comprising contacting the affected area with an
antimicrobial composition comprising: an effective amount of an
antimicrobial lipid component comprising a (C8-C12)saturated fatty
acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty
acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether
of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; and a hydrophobic component which forms the
greatest portion of the composition by weight.
94. The method of claim 93 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
95. A method of treating and/or preventing an infection on the
skin, mucosal tissue, and/or wound of a subject, the method
comprising contacting the skin, mucosal tissue, and/or wound with
an antimicrobial composition in an amount effective to kill or
inactivate one or more microorganisms, wherein the antimicrobial
composition comprises: an effective amount of an antimicrobial
lipid component comprising a (C8-C12)saturated fatty acid ester of
a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a
polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric
alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric
alcohol, an alkoxylated derivative thereof, or combinations
thereof, wherein the alkoxylated derivative has less than 5 moles
of alkoxide per mole of polyhydric alcohol; with the proviso that
for polyhydric alcohols other than sucrose, the esters comprise
monoesters and the ethers comprise monoethers, and for sucrose the
esters comprise monoesters, diesters, or combinations thereof, and
the ethers comprise monoethers, diethers, or combinations thereof;
an effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof; a hydrophilic component; and a hydrophobic
component which forms the greatest portion of the composition by
weight.
96. A method of treating and/or preventing an infection on the
skin, mucosal tissue, and/or wound of a subject, the method
comprising contacting the skin, mucosal tissue, and/or wound with
an antimicrobial composition in an amount effective to kill or
inactivate one or more microorganisms, wherein the antimicrobial
composition comprises: an effective amount of an antimicrobial
lipid component comprising a (C8-C12)saturated fatty acid ester of
a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a
polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric
alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric
alcohol, an alkoxylated derivative thereof, or combinations
thereof, wherein the alkoxylated derivative has less than 5 moles
of alkoxide per mole of polyhydric alcohol; with the proviso that
for polyhydric alcohols other than sucrose, the esters comprise
monoesters and the ethers comprise monoethers, and for sucrose the
esters comprise monoesters, diesters, or combinations thereof, and
the ethers comprise monoethers, diethers, or combinations thereof;
an effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof; a surfactant; and a hydrophobic component
which forms the greatest portion of the composition by weight.
97. A method of treating and/or preventing an infection on the
skin, mucosal tissue, and/or wound of a subject, the method
comprising contacting the skin, mucosal tissue, and/or wound with
an antimicrobial composition in an amount effective to kill or
inactivate one or more microorganisms, wherein the antimicrobial
composition comprises: an effective amount of an antimicrobial
lipid component comprising a (C8-C12)saturated fatty acid ester of
a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a
polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric
alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric
alcohol, an alkoxylated derivative thereof, or combinations
thereof, wherein the alkoxylated derivative has less than 5 moles
of alkoxide per mole of polyhydric alcohol; with the proviso that
for polyhydric alcohols other than sucrose, the esters comprise
monoesters and the ethers comprise monoethers, and for sucrose the
esters comprise monoesters, diesters, or combinations thereof, and
the ethers comprise monoethers, diethers, or combinations thereof;
and a hydrophobic component which forms the greatest portion of the
composition by weight.
98. The method of claim 97 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
99. A method of treating a burn, the method comprising contacting
the burned area of a subject with an antimicrobial composition in
an amount effective to kill or inactivate one or more
microorganisms, wherein the antimicrobial composition comprises: an
effective amount of an antimicrobial lipid component comprising a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
100. A method of treating a burn, the method comprising contacting
the burned area of a subject with an antimicrobial composition in
an amount effective to kill or inactivate one or more
microorganisms, wherein the antimicrobial composition comprises: an
effective amount of an antimicrobial lipid component comprising a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and a
hydrophobic component which forms the greatest portion of the
composition by weight.
101. The method of claim 100 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
102. A method of killing or inactivating microorganisms on the
skin, mucosal tissue, and/or in a wound of a subject, the method
comprising contacting the affected area with an antimicrobial
composition in an amount effective to kill or inactivate one or
more microorganisms, the antimicrobial composition comprising: an
effective amount of an antimicrobial lipid component comprising a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
103. The method of claim 102 wherein the composition further
comprises a hydrophilic component, wherein the viscosity of the
composition is at least 500 cps.
104. A method of killing or inactivating microorganisms on the
skin, mucosal tissue, and/or in a wound of a subject, the method
comprising contacting the affected area with an antimicrobial
composition in an amount effective to kill or inactivate one or
more microorganisms, the method comprising: an effective amount of
an antimicrobial lipid component comprising a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; and a hydrophobic component which forms the
greatest portion of the composition by weight.
105. The method of claim 104 wherein the composition further
comprises an effective amount of an enhancer component comprising
an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
106. A method of providing residual antimicrobial efficacy on the
skin, mucosal tissue, and/or in a wound of a subject, the method
comprising contacting the skin, mucosal tissue, and/or wound with
an antimicrobial composition comprising: an effective amount of an
antimicrobial lipid component comprising a (C8-C12)saturated fatty
acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty
acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether
of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; and a surfactant and/or a
hydrophilic component.
107. A method of providing residual antimicrobial efficacy on the
skin, mucosal tissue, and/or in a wound of a subject, the method
comprising contacting the skin, mucosal tissue, and/or wound with
an antimicrobial composition comprising: an effective amount of an
antimicrobial lipid component comprising a (C8-C12)saturated fatty
acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty
acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether
of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
comprise monoesters and the ethers comprise monoethers, and for
sucrose the esters comprise monoesters, diesters, or combinations
thereof, and the ethers comprise monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
comprising an alpha-hydroxy acid, a beta-hydroxy acid, a chelating
agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic
acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl
carboxylic acid, a phenolic compound, a (C1-C10)alkyl alcohol, an
ether glycol, or combinations thereof; and a hydrophobic component
which forms the greatest portion of the composition by weight.
108. A method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial infection,
the method comprising contacting at least a portion of the
respiratory system of a subject with an antimicrobial composition
in an amount effective to kill or inactivate one or more
microorganisms that cause a common cold and/or respiratory
affliction; wherein the antimicrobial composition comprises: an
effective amount of an antimicrobial lipid component comprising a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters comprise monoesters and the
ethers comprise monoethers, and for sucrose the esters comprise
monoesters, diesters, or combinations thereof, and the ethers
comprise monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component comprising an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof.
109. A method of making an antimicrobial composition comprising an
antimicrobial lipid component, an enhancer component, a hydrophobic
vehicle, and a hydrophilic component, the method comprising:
dissolving the enhancer component in the hydrophilic component;
combining the hydrophobic vehicle and the hydrophilic component
with the enhancer component dissolved therein with mixing to form a
mixture; optionally heating the hydrophobic vehicle to a
temperature sufficient to form a pourable liquid before or after
combinint it with the hydrophilic component and enhancer component;
adding the antimicrobial lipid component to the mixture; and
cooling the mixture before or after adding the antimicrobial lipid
component.
110. A method of making an antimicrobial composition comprising an
antimicrobial lipid component, an enhancer component, and a
hydrophobic vehicle, the method comprising: combining the enhancer
component and the hydrophobic vehicle with mixing to form a
mixture; optionally heating the hydrophobic vehicle to a
temperature sufficient to make a pourable liquid before or after
combining it with the enhancer component; adding the antimicrobial
lipid component to the mixture with mixing; and cooling the mixture
before or after adding the antimicrobial lipid component.
Description
BACKGROUND
[0001] The use of antimicrobial agents plays an important part in
current medical therapy. This is particularly true in the fields of
dermatology as well as skin and wound antisepsis, where the most
effective course of treatment for skin or mucous membranes (e.g.,
as in the nasal cavities and in particular the anterior nares),
which are afflicted with bacterial, fungal, or viral infections or
lesions, frequently includes the use of a topical antimicrobial
agent. For decades medicine has relied primarily upon antibiotics
to fight systemic as well as topical infections. For example,
bacitracin, neomycin sulfate, polymyxin B sulfate, gentamicin,
framycetin-gramicidin, lysostaphin, methicillin, rifampin,
tobramycin, nystatin, mupirocin, and combinations thereof, as well
as many others, have been used with varying success.
[0002] Antibiotics are generally effective at very low levels and
are often safe with very few, if any, side effects. Often
antibiotics have little or no toxicity to mammalian cells. Thus,
they may not retard, and can even enhance, wound healing.
Antibiotics are generally of a narrow spectrum of antimicrobial
activity. Furthermore, they often act on very specific sites in
cell membranes or on very specific metabolic pathways. This can
tend to make it relatively easy for bacteria to develop resistance
to the antibiotic(s) (i.e., the genetically acquired ability to
tolerate much higher concentrations of antibiotic) either through
natural selection, transmission of plasmids encoding resistance,
mutation, or by other means.
[0003] For example, there are multiple reports of resistance to
mupirocin when used as a nasal decolonizing agent. Resistance rates
have been reported as high as 25% and even as high as 50% (see, for
example, E. Perez-Roth et al., Diag. Micro. Infect. Dis.,
43:123-128 (2002) and H. Watanabe et al., J. Clin. Micro., 39(10):
3775-3777 (2001)). Even though presurgical decolonization of the
anterior nares using mupirocin has been shown to decrease the risk
of surgical site infection by as much as 2 to 10 times (T. Perl et
al., Ann. Pharmacother., 32:S7-S 16 (1998)), the high resistance
rates to this antibiotic make it unsuitable for routine use. Not
only does resistance eliminate the ability of a medication to treat
an affliction, but it can also put the patient at further risk,
especially if the antibiotic is one that is routinely used
systemically.
[0004] Antiseptics, on the other hand, tend to have broader
spectrum of antimicrobial activity and often act by nonspecific
means such as disruption of cell membranes, oxidation of cellular
components, denaturation of proteins, etc. This nonspecific
activity makes it difficult for resistance to develop to
antiseptics. For example, there are almost no reports of true
resistance to antiseptics such as iodine, lower alcohols (ethanol,
propanol, etc.), chlorhexidine, quaternary amine surfactants,
chlorinated phenols, and the like. These compounds, however, need
to be used at concentrations that often result in irritation or
tissue damage, especially if applied repeatedly. Furthermore,
unlike antibiotics, many antiseptics are not active in the presence
of high levels of organic compounds. For example, formulations
containing iodine or quaternary ammonium compounds have been
reported to be inactivated by the presence of organic matter such
as that in nasal or vaginal secretions, and perhaps even on
skin.
[0005] Also, for certain applications, especially in the nose and
mouth, it is particularly desirable for the compositions to have
little or no color, little or no odor, and an acceptable taste.
This is not the case for many antiseptics such as iodine and
iodophors, which have an orange to brown color and a definite
odor.
[0006] Some conventional antimicrobial compositions have used
various carboxylic acids or fatty acids for the suppression of
fungi, bacteria, molds, and the like. These compositions vary
widely in their efficacy, stability, and levels of persistence.
Plus, they possess an even wider variety of side effects. For
example, many of these materials are viewed as irritants,
particularly the C8-C12 fatty acids. This is particularly true for
sensitive mucosal tissues, such as the anterior nares and nasal
cavities, which can have a generally high level of microbial
colonization in certain otherwise healthy individuals, as well as
individuals with infectious diseases such as chronic siniusitis.
Additionally, due to the irritating nature many of these agents
would be unsuitable for application to irritated or infected dermal
tissue such as lesions from impetigo and shingles or sensitive
tissues such as the nasal cavities and especially the anterior
nares.
[0007] Also, many conventional antimicrobial compositions are too
low in viscosity and/or too hydrophilic in nature to maintain
sufficient substantivity and persistence to provide sufficient
antimicrobial activity on moist tissue, such as the anterior nares
or open, exuding, or infected lesions, and the like.
[0008] Thus, there is still a need for additional antimicrobial
compositions.
SUMMARY OF THE INVENTION
[0009] The present invention provides antimicrobial compositions
and methods of using and making the compositions. Such compositions
are typically useful when applied topically, particularly to
mucosal tissues (i.e., mucous membranes), although a wide variety
of surfaces can be treated. They can provide effective reduction,
prevention, or elimination of microbes, particularly bacteria,
fungi, and viruses. Preferably, the microbes are of a relatively
wide variety such that the compositions of the present invention
have a broad spectrum of activity.
[0010] Compositions of the present invention provide effective
topical antimicrobial activity and are accordingly useful in the
local treatment and/or prevention of conditions that are caused, or
aggravated by, microorganisms (including viruses, bacteria, fungi,
mycoplasma, and protozoa) on skin and/or mucous membranes.
[0011] Significantly, certain embodiments of the present invention
have a very low potential for generating microbial resistance.
Thus, such compositions can be applied multiple times over one or
more days to treat topical infections or to eradicate unwanted
bacteria (such as nasal colonization of Staphylococcus aureus).
Furthermore, compositions of the present invention can be used for
multiple treatment regimens on the same patient without the fear of
generating antimicrobial resistance. This can be particularly
important for chronically ill patients who are in need of
decolonization of the anterior nares before hemodialysis, for
example, or for antiseptic treatment of chronic wounds such as
diabetic foot ulcers.
[0012] Also, preferred compositions of the present invention have a
generally low irritation level for skin, skin lesions, and mucosal
membranes (including the anterior nares, nasal cavities, and
nasopharangyl cavity). Also, certain preferred compositions of the
present invention are substantive for relatively long periods of
time to ensure adequate efficacy.
[0013] Compositions of the present invention include an
antimicrobial lipid component that includes a fatty acid ester of a
polyhydric alcohol, a fatty ether of a polyhydric alcohol,
alkoxylated derivatives thereof (of either the ester or ether), or
combinations thereof. Certain compositions further include an
enhancer component. Other components that can be included as well
are surfactants, hydrophilic components, and hydrophobic
components. Compositions with hydrophobic components are typically
used on skin, mucosal tissue, wounds, and medical devices that come
in contact with such surfaces, whereas compositions with
hydrophilic components are typically used on these surfaces as well
as other hard surfaces (e.g., floor tiles).
[0014] In one embodiment, the present invention provides an
antimicrobial composition that includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
that includes an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof; a
surfactant; a hydrophilic component; and a hydrophobic component;
wherein the hydrophobic component forms the greatest portion of the
composition. Preferably, water is present in less than 10 percent
by weight (wt-%).
[0015] In one embodiment, the present invention provides an
antimicrobial composition that includes: 0.01 wt-% to 20 wt-% of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; 0.01 wt-% to 20 wt-% of an enhancer component
that includes an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
0.1 wt-% to 10 wt-% of a surfactant; 1 wt-% to 40 wt-% of a
hydrophilic component; 50 wt-% to 95 wt-% of a hydrophobic
component; and less than 10 wt-% water.
[0016] In one embodiment, the present invention provides an
antimicrobial composition that includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
that includes an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof; a
surfactant; and a hydrophilic component; wherein the viscosity of
the composition is at least 500 Centipoise (cps).
[0017] In one embodiment, the present invention provides an
antimicrobial composition that includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; an effective amount of an enhancer component
that includes an alpha-hydroxy acid, a beta-hydroxy acid, a
chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof; a
surfactant; a hydrophilic component; a hydrophobic component; and
less than 10 wt-% water; wherein the hydrophilic component forms
the greatest portion of the composition by weight.
[0018] In one embodiment, the present invention provides an
antimicrobial composition that includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty
ether of a polyhydric alcohol, an alkoxylated derivative thereof,
or combinations thereof, wherein the alkoxylated derivative has
less than 5 moles of alkoxide per mole of polyhydric alcohol; with
the proviso that for polyhydric alcohols other than sucrose, the
ethers include monoethers, and for sucrose the ethers include
monoethers, diethers, or combinations thereof; an effective amount
of an enhancer component that includes an alpha-hydroxy acid, a
beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic
acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic
acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
and a hydrophobic component which forms the greatest portion of the
composition by weight.
[0019] In one embodiment, the present invention provides an
antimicrobial composition that includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty
ether of a polyhydric alcohol, an alkoxylated derivative thereof,
and combinations thereof, wherein the alkoxylated derivative has
less than 5 moles of alkoxide per mole of polyhydric alcohol; with
the proviso that for polyhydric alcohols other than sucrose, the
ethers include monoethers, and for sucrose the ethers include
monoethers, diethers, or combinations thereof; an effective amount
of an enhancer component that includes an alpha-hydroxy acid, a
beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic
acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic
acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
and a hydrophilic component which forms the greatest portion of the
composition; wherein the viscosity of the composition is at least
500 cps.
[0020] Preferably, the antimicrobial lipid component is present in
an amount of at least 0.1 wt-%. Unless otherwise specified, all
weight percents are based on the total weight of a "ready to use"
or "as used" composition. Preferably, if the antimicrobial lipid
component includes a monoester of a polyhydric alcohol, a monoether
of a polyhydric alcohol, or an alkoxylated derivative thereof, then
there is no more than 50 wt-%, more preferably no more than 40
wt-%, even more preferably no more than 25 wt-%, and even more
preferably no more than 15 wt-% of a diester, diether, triester,
triether, or alkoxylated derivative thereof present, based on the
total weight of the antimicrobial lipid component.
[0021] Preferably, the antimicrobial lipid component includes
glycerol monolaurate, glycerol monocaprate, glycerol monocaprylate,
propylene glycol monolaurate, propylene glycol monocaprate,
propylene glycol monocaprylate, and combinations thereof.
[0022] Preferably, the surfactant includes a sulfonate, a sulfate,
a phosphonate, a phosphate, a poloxamer, a cationic surfactant, or
mixtures thereof.
[0023] Preferably, the hydrophilic component includes a glycol, a
lower alcohol ether, a short chain ester, and combinations thereof,
wherein the hydrophilic component is soluble in water in an amount
of at least 20 wt-% at 23.degree. C.
[0024] The present invention also provides various methods of use
of compositions of the present invention. In one embodiment, the
present invention provides a method of preventing and/or treating
an affliction caused, or aggravated by, a microorganism on skin
and/or a mucous membrane. The method includes contacting the skin
and/or mucous membrane with an antimicrobial composition of the
present invention.
[0025] In one embodiment, the present invention provides a method
of decolonizing at least a portion of the nasal cavities, anterior
nares, and/or nasopharynx of a subject of microorganisms. The
method includes contacting the nasal cavities, anterior nares,
and/or nasopharynx with an antimicrobial composition of the present
invention in an amount effective to kill one or more
microorganisms.
[0026] In one embodiment, the present invention provides a method
of decolonizing at least a portion of the nasal cavities, anterior
nares, and/or nasopharynx of a subject of microorganisms. The
method includes contacting the nasal cavities, anterior nares,
and/or nasopharynx with an antimicrobial composition in an amount
effective to kill one or more microorganisms, wherein the
antimicrobial composition includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; optionally, an effective amount of an
enhancer component that includes an alpha-hydroxy acid, a
beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic
acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic
acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof; a
hydrophobic component which forms the greatest portion of the
composition by weight; and optionally, a hydrophilic component.
[0027] In one embodiment, the present invention provides a method
of treating a middle ear infection in a subject. The method
includes contacting the middle ear, Eustachian tube, and/or
tympanic membrane with an antimicrobial composition that includes:
an effective amount of an antimicrobial lipid component that
includes a (C8-C12)saturated fatty acid ester of a polyhydric
alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric
alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters include monoesters and the
ethers include monoethers, and for sucrose the esters include
monoesters, diesters, or combinations thereof, and the ethers
include monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component that includes an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof. An alternative composition for treating a
middle ear infection includes an effective amount of an
antimicrobial lipid component, optionally an effective amount of an
enhancer component, and a hydrophobic component which forms the
greatest portion of the composition by weight (i.e., the
hydrophobic component forms a vehicle for the active agent(s)).
[0028] In one embodiment, the present invention provides a method
of treating chronic sinusitis in a subject. The method includes
contacting at least a portion of the respiratory system
(particularly the upper respiratory system including the nasal
cavities, anterior nares, and/or nasopharynx) with an antimicrobial
composition that includes: an effective amount of an antimicrobial
lipid component that includes a (C8-C12)saturated fatty acid ester
of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of
a polyhydric alcohol, a (C8-C12)saturated fatty ether of a
polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; and an effective amount of an enhancer
component that includes an alpha-hydroxy acid, a beta-hydroxy acid,
a chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
wherein the composition includes less than 0.50 percent by weight
(C6-C18)fatty acid. An alternative composition for treating chronic
sinusitis includes an effective amount of an antimicrobial lipid
component, optionally an effective amount of an enhancer component,
and a hydrophobic component which forms the greatest portion of the
composition by weight.
[0029] In one embodiment, the present invention provides a method
of treating impetigo on the skin of a subject. The method includes
contacting the affected area with an antimicrobial composition that
includes: an effective amount of an antimicrobial lipid component
that includes a (C8-C12)saturated fatty acid ester of a polyhydric
alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric
alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters include monoesters and the
ethers include monoethers, and for sucrose the esters include
monoesters, diesters, or combinations thereof, and the ethers
include monoethers, diethers, or combinations thereof; an effective
amount of an enhancer component that includes an alpha-hydroxy
acid, a beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl
carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl
carboxylic acid, a (C6-C12)alkaryl carboxylic acid, a phenolic
compound, a (C1-C10)alkyl alcohol, an ether glycol, or combinations
thereof; and optionally a hydrophilic component, wherein the
viscosity of the composition is less than 500 cps. An alternative
composition for treating impetigo includes an effective amount of
an antimicrobial lipid component, optionally an effective amount of
an enhancer component, and a hydrophobic component which forms the
greatest portion of the composition by weight.
[0030] In one embodiment, the present invention provides a method
of treating and/or preventing an infection on the skin, mucosal
tissue, and/or wound of a subject. The method includes contacting
the skin, mucosal tissue, and/or wound with an antimicrobial
composition in an amount effective to kill or inactivate one or
more microorganisms, wherein the antimicrobial composition
includes: an effective amount of an antimicrobial lipid component
that includes a (C8-C12)saturated fatty acid ester of a polyhydric
alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric
alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters include monoesters and the
ethers include monoethers, and for sucrose the esters include
monoesters, diesters, or combinations thereof, and the ethers
include monoethers, diethers, or combinations thereof; an effective
amount of an enhancer component that includes an alpha-hydroxy
acid, a beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl
carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl
carboxylic acid, a (C6-C12)alkaryl carboxylic acid, a phenolic
compound, a (C1-C10)alkyl alcohol, an ether glycol, or combinations
thereof; a hydrophilic component or a surfactant or both; and a
hydrophobic component which forms the greatest portion of the
composition by weight. An alternative composition for treating
and/or preventing an infection on the skin, mucosal tissue, and/or
wound of a subject includes an effective amount of an antimicrobial
lipid component, optionally an effective amount of an enhancer
component, and a hydrophobic component which forms the greatest
portion of the composition by weight.
[0031] In one embodiment, the present invention provides a method
of treating a burn. The method includes contacting the burned area
of a subject with an antimicrobial composition in an amount
effective to kill or inactivate one or more microorganisms, wherein
the antimicrobial composition includes: an effective amount of an
antimicrobial lipid component that includes a (C8-C12)saturated
fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated
fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty
ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether
of a polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; and an effective amount of an enhancer
component that includes an alpha-hydroxy acid, a beta-hydroxy acid,
a chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof. An
alternative composition for treating burns includes an effective
amount of an antimicrobial lipid component, optionally an effective
amount of an enhancer component, and a hydrophobic component which
forms the greatest portion of the composition by weight.
[0032] In other embodiments, the present invention provides methods
for killing or inactivating microorganisms. Herein, to "kill or
inactivate" means to render the microorganism ineffective by
killing them (e.g., bacteria and fungi) or otherwise rendering them
inactive (e.g., viruses). The present invention provides methods
for killing bacteria such as Staphylococcus spp., Streptococcus
spp., Escherichia spp., Enterococcus spp., and Pseudamonas spp.
bacteria, and more particularly Staphylococcus aureus (including
antibiotic resistant strains such as methicillin resistant
Staphylococcus aureus), Staphylococcus epidermidis, Escherichia
coli (E. coli), Pseudomonas aeruginosa (Pseudomonas ae.), and
Streptococcus pyogenes, which often are on or in the skin or
mucosal tissue of a subject. The method includes contacting the
microorganism with an antimicrobial composition of the present
invention in an amount effective to kill one or more microorganisms
(e.g., bacteria and fungi) or inactivate one or more microorganisms
(e.g., viruses, particularly herpes virus).
[0033] For example, in one embodiment, the present invention
provides a method of killing or inactivating microorganisms on the
skin, mucosal tissue, and/or in a wound of a subject. The method
includes contacting the affected area with an antimicrobial
composition that includes: an effective amount of an antimicrobial
lipid component that includes a (C8-C12)saturated fatty acid ester
of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of
a polyhydric alcohol, a (C8-C12)saturated fatty ether of a
polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a
polyhydric alcohol, an alkoxylated derivative thereof, or
combinations thereof, wherein the alkoxylated derivative has less
than 5 moles of alkoxide per mole of polyhydric alcohol; with the
proviso that for polyhydric alcohols other than sucrose, the esters
include monoesters and the ethers include monoethers, and for
sucrose the esters include monoesters, diesters, or combinations
thereof, and the ethers include monoethers, diethers, or
combinations thereof; and an effective amount of an enhancer
component that includes an alpha-hydroxy acid, a beta-hydroxy acid,
a chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl
carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a
(C6-C12)alkaryl carboxylic acid, a phenolic compound, a
(C1-C10)alkyl alcohol, an ether glycol, or combinations thereof;
and optionally a hydrophilic component, wherein the viscosity of
the composition is at least 500 cps. An alternative composition for
killing or inactivating microorganisms on the skin, mucosal tissue,
and/or in a wound of a subject includes an effective amount of an
antimicrobial lipid component, optionally, an effective amount of
an enhancer component, and a hydrophobic component which forms the
greatest portion of the composition by weight.
[0034] The compositions of the present invention can also be used
for providing residual antimicrobial efficacy on a surface that
results from leaving a residue or imparting a condition to the
surface (e.g., skin, mucosal tissue, wound, or medical device that
comes in contact with such tissues, but particularly skin, mucosal
tissue, and/or wound) that remains effective and provides
significant antimicrobial activity.
[0035] For example, in one embodiment, the present invention
provides a method of providing residual antimicrobial efficacy on
the skin, mucosal tissue, and/or in a wound of a subject, the
method includes contacting the skin, mucosal tissue, and/or wound
with an antimicrobial composition that includes: an effective
amount of an antimicrobial lipid component that includes a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, or combinations thereof, wherein
the alkoxylated derivative has less than 5 moles of alkoxide per
mole of polyhydric alcohol; with the proviso that for polyhydric
alcohols other than sucrose, the esters include monoesters and the
ethers include monoethers, and for sucrose the esters include
monoesters, diesters, or combinations thereof, and the ethers
include monoethers, diethers, or combinations thereof; and an
effective amount of an enhancer component that includes an
alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a
(C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid,
a phenolic compound, a (C1-C10)alkyl alcohol, an ether glycol, or
combinations thereof; and a surfactant and/or a hydrophilic
component. An alternative composition for providing residual
antimicrobial efficacy includes an effective amount of an
antimicrobial lipid component, an effective amount of an enhancer
component, and a hydrophobic component which forms the greatest
portion of the composition by weight.
[0036] In another embodiment, the present invention provides
methods of preventing and/or treating a subject for a common cold
and/or respiratory affliction caused by a microbial infection. The
method includes contacting the subject with a composition of the
present invention in at least a portion of the subject's
respiratory system (such as but not limited to, at least a portion
of the nasal cavities, etc.) in an amount effective to kill or
inactivate one or more microorganisms that cause a common cold
and/or respiratory affliction. An exemplary antimicrobial
composition for use in this method includes an effective amount of
an antimicrobial lipid component and an effective amount of an
enhancer component.
[0037] Methods of manufacture are also provided.
Definitions
[0038] The following terms are used herein according to the
following definitions.
[0039] "Effective amount" means the amount of the antimicrobial
lipid component and/or the enhancer component when in a
composition, as a whole, provides an antimicrobial (including, for
example, antiviral, antibacterial, or antifungal) activity that
reduces, prevents, or eliminates one or more species of microbes
such that an acceptable level of the microbe results. Typically,
this is a level low enough not to cause clinical symptoms, and is
desirably a non-detectable level. It should be understood that in
the compositions of the present invention, the concentrations or
amounts of the components, when considered separately, may not kill
to an acceptable level, or may not kill as broad a spectrum of
undesired microorganisms, or may not kill as fast; however, when
used together such components provide an enhanced (preferably
synergistic) antimicrobial activity (as compared to the same
components used alone under the same conditions). Also, it should
be understood that (unless otherwise specified) the listed
concentrations of the components are for "ready to use" or "as
used" compositions. The compositions can be in a concentrated form.
That is, certain embodiments of the compositions can be in the form
of concentrates that would be diluted by the user with an
appropriate vehicle.
[0040] "Hydrophilic" or "water-soluble" refers to a material that
will dissolve in water (or other aqueous solution as specified) at
a temperature of 23.degree. C. in an amount of at least 7% by
weight, preferably at least 10% by weight, more preferably at least
20% by weight, even more preferably at least 25% by weight, and
most preferably at least 40% by weight, based on the total weight
of the hydrophilic material and the water.
[0041] "Hydrophobic" or "water-insoluble" refers to a material that
will not significantly dissolve in water at 23.degree. C. No
significant amount means less than 5% by weight, preferably less
than 1% by weight, more preferably less than 0.5% by weight, and
even more preferably less than 0.1% by weight, based on the total
weight of the hydrophobic material and the water.
[0042] "Stable" means physically stable or chemically stable, which
are both defined in greater detail below.
[0043] "Enhancer" means a component that enhances the effectiveness
of the antimicrobial lipid component such that when the composition
less the antimicrobial lipid component and the composition less the
enhancer component are used separately, they do not provide the
same level of antimicrobial activity as the composition as a whole.
For example, an enhancer component in the absence of the
antimicrobial lipid component may not provide any appreciable
antimicrobial activity. The enhancing effect can be with respect to
the level of kill, the speed of kill, and/or the spectrum of
microorganisms killed, and may not be seen for all microorganisms.
In fact, an enhanced level of kill is most often seen in Gram
negative bacteria such as Escherichia coli. An enhancer may be a
synergist such that when combined with the remainder of the
composition, the composition as a whole displays an activity that
is greater than the sum of the activity of the composition less the
enhancer component and the composition less the antimicrobial lipid
component.
[0044] "Microorganism" or "microbe" or "microorganism" refers to
bacteria, yeast, mold, fungi, protozoa, mycoplasma, as well as
viruses (including lipid enveloped RNA and DNA viruses).
[0045] "Antibiotic" means an organic chemical produced by
microorganisms that has the ability in dilute concentrations to
destroy or inhibit microorganisms and is used to treat infectious
disease.
[0046] "Antiseptic" means a chemical agent that kills pathogenic
and non-pathogenic microorganisms.
[0047] "Mucous membranes," "mucosal membranes," and "mucosal
tissue" are used interchangeably and refer to the surfaces of the
nasal (including anterior nares, nasoparangyl cavity, etc.), oral
(e.g., mouth), outer ear, middle ear, vaginal cavities, and other
similar tissues. Examples include mucosal membranes such as buccal,
gingival, nasal, ocular, tracheal, bronchial, gastrointestinal,
rectal, urethral, ureteral, vaginal, cervical, and uterine mucosal
membranes.
[0048] "Affliction" means a condition to a body resulting from
sickness, disease, injury, bacterial colonization, etc.
[0049] "Treat" or "treatment" means to improve the condition of a
subject relative to the affliction, typically in terms of clinical
symptoms of the condition.
[0050] "Decolonization" refers to a reduction in the number of
microorganisms (e.g., bacteria and fungi) present in or on tissue
that do not necessarily cause immediate clinical symptoms. Examples
of decolonization include, but are not limited to, decolonization
of the nasal cavity and wounds. Ordinarily fewer microorganisms are
present in colonized tissue than in infected tissue.
[0051] "Subject" and "patient" includes humans, sheep, horses,
cattle, pigs, dogs, cats, rats, mice, or other mammal.
[0052] "Wound" refers to an injury to a subject which involves a
break in the normal skin barrier exposing tissue below, which is
caused by, for example, lacerations, surgery, burns, damage to
underlying tissue such as pressure sores, poor circulation, and the
like. Wounds are understood to include both acute and chronic
wounds.
[0053] The terms "comprises" and variations thereof do not have a
limiting meaning where these terms appear in the description and
claims.
[0054] As used herein, "a," "an," "the," "at least one," and "one
or more" are used interchangeably. The term "and/or" means one or
all of the listed elements (e.g., preventing and/or treating an
affliction means preventing, treating, or both treating and
preventing further afflications).
[0055] Also herein, the recitations of numerical ranges by
endpoints include all numbers subsumed within that range (e.g., 1
to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
[0056] The above summary of the present invention is not intended
to describe each disclosed embodiment or every implementation of
the present invention. The description that follows more
particularly exemplifies illustrative embodiments. In several
places throughout the application, guidance is provided through
lists of examples, which examples can be used in various
combinations. In each instance, the recited list serves only as a
representative group and should not be interpreted as an exclusive
list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0057] The present invention provides antimicrobial (including,
e.g., antiviral, antibacterial, and antifungal) compositions. These
compositions include one or more antimicrobial lipids such as a
fatty acid ester of a polyhydric alcohol, a fatty ether of a
polyhydric alcohol, or alkoxylated derivatives thereof (of either
the ester or ether). In certain embodiments the compositions also
include one or more enhancers. Certain compositions also include
one or more surfactants, one or more hydrophilic compounds, and/or
one or more hydrophobic compounds.
[0058] Such compositions adhere well to bodily tissues (e.g., skin,
mucosal tissue, and wounds) and thus are very effective topically.
Thus, the present invention provides a wide variety of uses of the
compositions. Particularly preferred methods involve topical
application, particularly to mucosal tissues (i.e., mucous
membranes including the anterior nares and other tissues of the
upper respiratory tract), as well as skin (e.g., skin lesions) and
wounds.
[0059] For certain applications in which limited antimicrobial
activity is desired, compositions containing an antimicrobial lipid
component can be used, whereas in other applications in which more
broad antimicrobial activity is desired, compositions containing
both an antimicrobial lipid component and an enhancer component are
used. For example, in certain situations it may be desirable to
kill or inactivate only one type of microorganism as opposed to all
the microorganisms present. In such situations, compositions of the
present invention that contain an antimicrobial lipid component
without an enhancer component may be suitable.
[0060] Compositions of the present invention can be used to provide
effective topical antimicrobial activity. For example, they can be
used for hand disinfection, particularly in presurgical scrubs.
They can be used to disinfect various body parts, particularly in
patient presurgical skin antiseptics.
[0061] Compositions of the present invention can be used to provide
effective topical antimicrobial activity and thereby treat and/or
prevent a wide variety of afflications. For example, they can be
used in the treatment and/or prevention of afflictions that are
caused, or aggravated by, microorganisms (e.g., Gram positive
bacteria, Gram negative bacteria, fungi, protozoa, mycoplasma,
yeast, viruses, and even lipid-enveloped viruses) on skin and/or
mucous membranes, such as those in the nose (anterial nares,
nasopharangyl cavity, nasal cavities, etc.), outer ear, and middle
ear, mouth, rectum, vagina, or other similar tissue. Particularly
relevant organisms that cause or aggravate such afflications
include Staphylococcus spp., Streptococcus spp., Pseudomonas spp.,
Enterococcus spp., and Esherichia spp., bacteria, as well as herpes
virus, Aspergillus spp., Fusarium spp., and Candida spp.
Particularly virulent organisms include Staphylococcus aureus
(including resistant strains such as Methicillin Resistant
Staphylococcus Aureus (MRSA), Staphylococcus epidermidis,
Streptococcus pneumoniae, Enterococcus faecalis, Vancomycin
Resistant Enterococcus (VRE), Pseudomonas auerginosa, Escherichia
coli, Aspergillus niger, Aspergillus fumigatus, Aspergillus
clavatus, Fusarium solani, Fusarium oxysporum, Fusarium
chlamydosporum, Candida albicans, Candida glabrata, and Candida
krusei.
[0062] Compositions of the present invention can be used for the
prevention and/or treatment of one or more microorganism-caused
infections or other afflictions. In particular, compositions of the
present invention can be used for preventing and/or treating one or
more of the following: skin lesions, conditions of the skin such as
impetigo, eczema, diaper rash in infants as well as incontinent
adults, inflammation around ostomy devices, shingles, and bacterial
infections in open wounds (e.g., cuts, scrapes, burns, lacerations,
chronic wounds); necrotizing faciitis; infections of the outer ear;
acute or chronic otitis media (middle ear infection) caused by
bacterial, viral, or fungal contamination; fungal and bacterial
infections of the vagina or rectum; vaginal yeast infections;
bacterial rhinitis; ocular infections; cold sores; genital herpes;
colonization by Staphylococcus aureus in the anterior nares (e.g.
prior to surgery or hemodialysis); mucositis (i.e., inflammation as
opposed to infection of a mucous membrane typically induced by
non-invasive fungus); chronic sinusitis (e.g., that caused by
bacterial or viral contamination); non-invasive fungus-induced
rhinosinusitis; chronic colitis; Crohn's disease; burns; napkin
rash; tinea pedis (i.e., athlete's foot); tinea curis (i.e., jock
itch); tinea corporis (i.e., ringworm); candidiasis; strep throat,
strep pharyngitis, and other Group A Streptococci infections;
rosacea (often called adult acne); common cold; and respiratory
afflictions (e.g., asthma). In sum, compositions of the present
invention can be used for preventing and/or treating a wide variety
of topical afflictions caused by microbial infection (e.g., yeast,
viral, bacterial infections).
[0063] Compositions of the present invention can be used on a wide
variety of surfaces. For example, they can be used on skin, mucosal
tissue, wounds, and hard surfaces such as medical (e.g., surgical)
devices, floor tiles, countertops, tubs, dishes, as well as on
gloves (e.g., surgical gloves). They can also be impregnated into
cloth, sponges, and paper products (e.g., paper towels and wipes),
for example. Typically, compositions with hydrophobic components
are used on skin, mucosal tissue, wounds, and medical devices that
come in contact with such surfaces, whereas compositions with
hydrophilic components are used on these surfaces as well as other
hard surfaces (e.g., floor tiles).
[0064] Thus, the present invention also provides various methods of
use of compositions of the present invention. Various embodiments
of the present invention include: a method of preventing an
affliction caused, or aggravated by, a microorganism on skin and/or
a mucous membrane; a method of decolonizing at least a portion of
the nasal cavities, anterior nares, and/or nasopharynx of a subject
of microorganisms; a method of treating a middle ear infection in a
subject (through the middle ear, the Eustachian tube, and/or the
tympanic membrane); a method of treating chronic sinusitis in a
subject (by treating at least a portion of the respiratory system,
particularly the upper respiratory system, including the nasal
cavities, anterior nares, and/or nasopharynx); a method of treating
impetigo on the skin of a subject; a method of treating and/or
preventing an infection on the skin, mucosal tissue, and/or wound
of a subject; a method of treating a burn; a method of killing or
inactivating microorganisms (e.g., killing bacteria and/or fungi,
or inactivating viruses); a method for providing residual
antimicrobial efficacy (e.g., antibacterial, antfungal, and/or
antiviral efficacy) that results from leaving a residue or
imparting a condition on a surface (such as skin, mucosal tissue,
wound, and/or medical device that contacts such surfaces) that
remains effective and provides significant antimicrobial activity;
and a method of preventing and/or treating a subject for a common
cold and/or respiratory affliction caused by a microbial
infection.
[0065] It should be understood that compositions of the present
invention can be used in situations in which there are no clinical
indications of an affliction. For example, compositions of the
present invention can be used in methods of decolonizing at least a
portion of the nasal cavities (i.e., space behind the vestibule of
the nose), anterior nares (i.e., the opening in the nose to the
nasal cavities, also referred to as the external nares), and/or
nasopharynx (i.e., the portion of the pharynx, i.e., throat, that
lies above the point of food entry into the pharynx) of a subject
of microorganisms. A suitable model to test for the effectiveness
of compositions to decolonize the anterior nares has been
established and is described by K. Kiser et al., Infect and
Immunity, 67(10), 5001-5006 (1999). Compositions of the present
invention can also be used to decolonize microorganisms from
wounds.
[0066] Decolonization methods using compositions of the present
invention are particularly useful in immunocompromised patients
(including oncology patients, diabetics, HIV patients, transplant
patients an the like), particularly for fungi such as Aspergillus
spp. and Fusarium spp.
[0067] In particular, compositions of the present invention can be
used in chronic wounds to eliminate methicillin-resistant
Staphylococcus aureus, which may or may not show clinical signs of
infection such as inflammation, pus, exudate, etc. Also, it is of
significance to note that certain compositions of the present
invention can kill lipid-enveloped viruses, which can be very
difficult to kill and can cause shingles (Herpes), chronic
sinusitis, otitis media, and other local diseases.
[0068] Those of ordinary skill in the art will readily determine
when a composition of the present invention provides antimicrobial
activity using assay and bacterial screening methods well known in
the art. One readily performed assay involves exposing selected
known or readily available viable microorganism strains, such as
Enterococcus spp., Aspergillus spp., Escherichia spp.,
Staphylococcus spp., Streptococcus spp., Pseudomonas spp., or
Salmonella spp., to a test composition at a predetermined bacterial
burden level in a culture media at an appropriate temperature. For
the preferred compositions of the present invention this is most
conveniently done by the Antimicrobial Kill Rate Test described in
the Examples Section. Briefly, after a sufficient contact time, an
aliquot of a sample containing the exposed bacteria is collected,
diluted, and plated out on agar. The plated sample of bacteria is
incubated for forty-eight hours and the number of viable bacterial
colonies growing on the plate is counted. Once colonies have been
counted the reduction in the number of bacteria caused by the test
composition is readily determined. Bacterial reduction is generally
reported as log.sub.10 reduction determined by the difference
between the log.sub.10 of the initial inoculum count and the
log.sub.10 of the inoculum count after exposure. Preferred
compositions of the present invention have an average of at least a
4 log reduction in test bacteria in 10 minutes.
[0069] Many of the preferred compositions were tested as described
in the Examples Section for antimicrobial activity against MRSA
(Gram positive, ATCC Number 16266), E. coli (Gram negative, ATCC
Number 11229), and Pseudomonas aeruginosa (Gram negative, ATCC
Number 15442). In general, the Pseudomonas aeruginosa is often the
most difficult to kill. Preferred compositions of the present
invention also exhibit very rapid antimicrobial activity. As shown
in the Examples Section, preferred formulations are able to achieve
an average log reduction of at least 4 log against these three
organisms after a 10 minute exposure and preferably after a 5
minute exposure. More preferred compositions are able to achieve an
average log reduction of at least 5 log and even more preferred at
least 6 log against these three organisms after a 10 minute
exposure and preferably after a 5 minute exposure.
[0070] For residual antimicrobial efficacy, compositions of the
present invention preferably maintain an average log reduction of
at least 1 log, more preferably at least 1.5 log, and even more
preferably at least 2 log, for at least 0.5 hour, more preferably
at least 1 hour, and even more preferably at least 3 hours after
application to an affected site or after testing the composition on
the forearm of a subject. To test this, a composition was applied
to the forearm of a subject as a uniform wet coating in an amount
of approximately 4 milligrams per square centimeter (mg/cm.sup.2)
to the forearm of a healthy subject and allowed to thoroughly dry
(typically a minimum of 10 minutes) over an area of approximately
5.times.5 cm. The dried composition was gently washed with
23.degree. C. normal saline (0.9% by weight sodium chloride). The
saline washed site was exposed to a known quantity of bacteria in
an innoculum of about 10.sup.6 bacteria/ml (typically
Staphylococcus epidermidis or E. coli) for 30 minutes. The bacteria
were recovered and treated with an effective neutralizer and
incubated to quantify the bacteria remaining. Particularly
preferred compositions retain at least 1 log reduction and
preferably at least 2 log reduction of bacteria after a gentle
rinse with 500 ml saline.
[0071] Significantly, certain embodiments of the present invention
have a very low potential for generating microbial resistance. For
example, preferred compositions of the present invention have an
increase in the ratio of final to initial MIC levels (i.e., minimum
inhibitory concentration) of less than 16, more preferably less
than 8, and even more preferably less than 4. Thus, such
compositions can be applied multiple times over one or more days to
treat topical infections or to eradicate unwanted bacteria (such as
nasal colonization of Staphylococcus aureus).
[0072] Preferred compositions of the present invention have a
generally low irritation level for skin, skin lesions, and mucosal
membranes (including the anterior nares, nasal cavities,
nasopharangyl cavity and other portions of the upper respiratory
tract). For example, certain preferred compositions of the present
invention are no more irritating than BACTROBAN ointment (on skin)
or BACTROBAN NASAL (in the anterior nares) products available from
Glaxo Smith Kline.
[0073] Preferred compositions of the present invention are
substantive for relatively long periods of time to ensure adequate
efficacy. For example, certain compositions of the present
invention remain at the site of application with antimicrobial
activity for at least 4 hours and more preferably at least 8
hours.
[0074] Preferred compositions of the present invention are
physically stable. As defined herein "physically stable"
compositions are those that do not significantly change due to
substantial precipitation, crystallization, phase separation, and
the like, from their original condition during storage at
23.degree. C. for at least 3 months, and preferably for at least 6
months. Particularly preferred compositions are physically stable
if a 10-milliliter (10-ml) sample of the composition when placed in
a 15-ml conical-shaped graduated plastic centrifuge tube (Corning)
and centrifuged at 3,000 revolutions per minute (rpm) for 10
minutes using a Labofuge B, model 2650 manufactured by Heraeus
Sepatech GmbH, Osterode, West Germany has no visible phase
separation in the bottom or top of the tube.
[0075] Preferred compositions of the present invention exhibit good
chemical stability. This can be especially a concern with the
antimicrobial fatty acid esters, which can often undergo
transesterification, for example. Preferred compositions retain at
least 85%, more preferably at least 90%, even more preferably at
least 92%, and even more preferably at least 95%, of the
antimicrobial lipid component after aging for 4 weeks at 40.degree.
C. (an average of three samples) beyond the initial 5-day
equilibration period at 23.degree. C. The most preferred
compositions retain an average of at least 97% of the antimicrobial
lipid component after aging for 4 weeks at 40.degree. C. in a
sealed container beyond the initial 5-day equilibration period at
23.degree. C. The percent retention is understood to mean the
weight percent of antimicrobial lipid component retained. This is
determined by comparing the amount remaining in a sample aged
(i.e., aged beyond the initial 5-day equilibration period) in a
sealed container that does not cause degradation, to the actual
measured level in an identically prepared sample (preferably from
the same batch) and allowed to sit at 23.degree. C. for five days.
The level of antimicrobial lipid component is preferably determined
using gas chromatography as described in the Aging Study Using Gas
Chromatography test method included in the Examples Section.
[0076] Antimicrobial Lipid Component
[0077] The antimicrobial lipid component is that component of the
composition that provides at least part of the antimicrobial
activity. That is, the antimicrobial lipid component has at least
some antimicrobial activity for at least one microorganism. It is
generally considered the main active component of the compositions
of the present invention. The antimicrobial lipid component
includes one or more fatty acid esters of a polyhydric alcohol,
fatty ethers of a polyhydric alcohol, or alkoxylated derivatives
thereof (of either or both of the ester and ether), or combinations
thereof. More specifically and preferably, the antimicrobial
component is selected from the group consisting of a
(C8-C12)saturated fatty acid ester of a polyhydric alcohol, a
(C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a
(C8-C12)saturated fatty ether of a polyhydric alcohol, a
(C12-C22)unsaturated fatty ether of a polyhydric alcohol, an
alkoxylated derivative thereof, and combinations thereof.
Preferably, the esters and ethers are monoesters and monoethers,
unless they are esters and ethers of sucrose in which case they can
be monoesters, diesters, monoethers, or monoethers. Various
combinations of monoesters, diesters, monoethers, and diethers can
be used in a composition of the present invention.
[0078] A fatty acid ester of a polyhydric alcohol is preferably of
the formula (R.sup.1--C(O)--O).sub.n--R.sup.2, wherein R.sup.1 is
the residue of a (C8-C12)saturated fatty acid or a (C8-C22)
unsaturated (including polyunsaturated) fatty acid, R.sup.2 is the
residue of a polyhydric alcohol (typically and preferably,
glycerin, propylene glycol, and sucrose, although a wide variety of
others can be used including pentaerythritol, sorbitol, mannitol,
xylitol, etc.), and n=1 or 2. The R.sup.2 group includes at least
one free hydroxyl group (preferably, residues of glycerin,
propylene glycol, or sucrose). Preferred fatty acid esters of
polyhydric alcohols are esters derived from C8, C10, and C12
saturated fatty acids. For embodiments in which the polyhydric
alcohol is glycerin or propylene glycol, n=1, although when it is
sucrose, n=1 or 2.
[0079] Exemplary fatty acid monoesters include, but are not limited
to, glycerol monoesters of lauric (monolaurin), caprylic
(monocaprylin), and capric (monocaprin) acid, and propylene glycol
monoesters of lauric, caprylic, and capric acid, as well as lauric,
caprylic, and capric acid monoesters of sucrose. Other fatty acid
monoesters include glycerin and propylene glycol monoesters of
oleic (18:1), linoleic (18:2), linolenic (18:3), and arachonic
(20:4)unsaturated (including polyunsaturated) fatty acids. As is
generally know, 18:1, for example, means the compound has 18 carbon
atoms and 1 carbon-carbon double bond. In certain preferred
embodiments, the fatty acid monoesters that are suitable for use in
the present composition include known monoesters of lauric,
caprylic, and capric acid, such as that known as GML or the trade
designation LAURICIDIN (the glycerol monoester of lauric acid
commonly referred to as monolaurin or glycerol monolaurate),
glycerol monocaprate, glycerol monocaprylate, propylene glycol
monolaurate, propylene glycol monocaprate, propylene glycol
monocaprylate, and combinations thereof.
[0080] Exemplary fatty acid diesters of sucrose include, but are
not limited to, lauric, caprylic, and capric diesters of sucrose as
well as combinations thereof.
[0081] A fatty ether of a polyhydric alcohol is preferably of the
formula (R.sup.3--O).sub.n--R.sup.4, wherein R.sup.3 is a
(C8-C12)saturated aliphatic group or a (C8-C22)unsaturated
(including polyunsaturated) aliphatic group, R.sup.4 is the residue
of glycerin, sucrose, or propylene glycol, and n=1 or 2. For
glycerin and propylene glycol n=1, and for sucrose n=1 or 2.
Preferred fatty ethers are monoethers of (C8-C12)alkyl groups.
[0082] Exemplary fatty monoethers include, but are not limited to,
laurylglyceryl ether, caprylglycerylether, caprylylglyceryl ether,
laurylpropylene glycol ether, caprylpropyleneglycol ether, and
caprylylpropyleneglycol ether. Other fatty monoethers include
glycerin and propylene glycol monoethers of oleyl (18:1), linoleyl
(18:2), linolenyl (18:3), and arachonyl (20:4)unsaturated and
polyunsaturated fatty alcohols. In certain preferred embodiments,
the fatty monoethers that are suitable for use in the present
composition include laurylglyceryl ether, caprylglycerylether,
caprylyl glyceryl ether, laurylpropylene glycol ether,
caprylpropyleneglycol ether, caprylylpropyleneglycol ether, and
combinations thereof.
[0083] The alkoxylated derivatives of the aforementioned fatty acid
esters and fatty ethers (e.g., one which is ethoxylated and/or
propoxylated on the remaining alcohol group(s)) also have
antimicrobial activity as long as the total alkoxylate is kept
relatively low. Preferred alkoxylation levels are disclosed in U.S.
Pat. No. 5,208,257 (Kabara). In the case where the esters and
ethers are ethoxylated, the total moles of ethylene oxide is
preferably less than 5, and more preferably less than 2.
[0084] The fatty acid esters or fatty ethers of polyhydric alcohols
can be alkoxylated, preferably ethoxylated and/or propoxylated, by
conventional techniques. Alkoxylating compounds are preferably
selected from the group consisting of ethylene oxide, propylene
oxide, and mixtures thereof, and similar oxirane compounds.
[0085] The compositions of the present invention include one or
more fatty acid esters, fatty ethers, alkoxylated fatty acid
esters, or alkoxylated fatty ethers at a suitable level to produce
the desired result. Such compositions preferably include a total
amount of such material of at least 0.01 percent by weight (wt-%),
more preferably at least 0.1 wt-%, even more preferably at least
0.25 wt-%, even more preferably at least 0.5 wt-%, and even more
preferably at least 1 wt-%, based on the total weight of the "ready
to use" or "as used" composition. In a preferred embodiment, they
are present in a total amount of no greater than 20 wt-%, more
preferably no greater than 15 wt-%, even more preferably no greater
than 10 wt-%, and even more preferably no greater than 5 wt-%,
based on the "ready to use" or "as used" composition. Certain
compositions may be higher in concentration if they are intended to
be diluted prior to use.
[0086] Preferred compositions of the present invention that include
one or more fatty acid monoesters, fatty monoethers, or alkoxylated
derivatives thereof can also include a small amount of a di- or
tri-fatty acid ester (i.e., a fatty acid di- or tri-ester), a di-
or tri-fatty ether (i.e., a fatty di- or tri-ether), or alkoxylated
derivative thereof. Preferably, such components are present in an
amount of no more than 50 wt-%, more preferably no more than 40
wt-%, even more preferably no more than 25 wt-%, even more
preferably no more than 15 wt-%, even more preferably no more than
10 wt-%, even more preferably no more than 7 wt-%, even more
preferably no more than 6 wt-%, and even more preferably no more
than 5 wt-%, based on the total weight of the antimicrobial lipid
component. For example, for monoesters, monoethers, or alkoxylated
derivatives of glycerin, preferably there is no more than 15 wt-%,
more preferably no more than 10 wt-%, even more preferably no more
than 7 wt-%, even more preferably no more than 6 wt-%, and even
more preferably no more than 5 wt-% of a diester, diether,
triester, triether, or alkoxylated derivatives thereof present,
based on the total weight of the antimicrobial lipid components
present in the composition. However, as will be explained in
greater detail below, higher concentrations of di- and tri-esters
may be tolerated in the raw material if the formulation initially
includes free glycerin because of transesterification
reactions.
[0087] Although in some situations it is desirable to avoid di- or
tri-esters as a component of the starting materials, it is possible
to use relatively pure tri-esters in the preparation of certain
compositions of the present invention and have effective
antimicrobial activity.
[0088] Enhancer Component
[0089] Compositions of the present invention include an enhancer
(preferably a synergist) to enhance the antimicrobial activity
especially against Gram negative bacteria, such as E. coli. The
enhancer component may include an alpha-hydroxy acid, a
beta-hydroxy acid, other carboxylic acids, a (C1-C4)alkyl
carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl
carboxylic acid, a (C6-C12)alkaryl carboxylic acid, a phenolic
compound (such as certain antioxidants and parabens), a
(C1-C10)monohydroxy alcohol, or a glycol ether (i.e., ether
glycol). Various combinations of enhancers can be used if
desired.
[0090] The alpha-hydroxy acid, beta-hydroxy acid, and other
carboxylic acid enhancers are preferably present in their
protonated, free acid form. It is not necessary for all of the
acidic enhancers to be present in the free acid form, however, the
preferred concentrations listed below refer to the amount present
in the free acid form. Furthermore, the chelator enhancers that
include carboxylic acid groups are preferably present with at least
one, and more preferably at least two, carboxylic acid groups in
their free acid form. The concentrations given below assume this to
be the case.
[0091] One or more enhancers may be used in the compositions of the
present invention at a suitable level to produce the desired
result. In a preferred embodiment, they are present in a total
amount of at least 0.01 wt-%, based on the total weight of the
ready to use composition. In a preferred embodiment, they are
present in a total amount of no greater than 20 wt-%, based on the
total weight of the ready to use composition. Such concentrations
typically apply to alpha-hydroxy acids, beta-hydroxy acids, other
carboxylic acids, chelating agents, phenolics, ether glycols,
(C5-C10)monohydroxy alcohols. Generally, higher concentrations are
needed for (C1-C4)monohydroxy alcohols, as described in greater
detail below.
[0092] The total concentration of the enhancer component relative
to the total concentration of the antimicrobial lipid component is
preferably within a range of 10:1 to 1:300, and more preferably 5:1
and 1:10, on a weight basis.
[0093] An additional consideration when using an enhancer is the
solubility and physical stability in the compositions. Many of the
enhancers discussed herein are insoluble in preferred hydrophobic
components such as petrolatum. It has been found that the addition
of a minor amount (typically less than 30 wt-%, preferably less
than 20 wt-%, and more preferably less than 12 wt-%) of a
hydrophilic component not only helps dissolve and physically
stabilize the composition but improves the antimicrobial activity
as well. These hydrophilic components are described below.
[0094] Alpha-hydroxy Acids. An alpha-hydroxy acid is typically a
compound represented by the formula:
R.sup.5(CR.sup.6OH).sub.nCOOH
[0095] wherein: R.sup.5 and R.sup.6 are each independently H or a
(C1-C8)alkyl group (straight, branched, or cyclic), a (C6-C12)aryl,
or a (C6-C12)aralkyl or alkaryl group (wherein the alkyl group is
straight, branched, or cyclic), wherein R.sup.5 and R.sup.6 may be
optionally substituted with one or more carboxylic acid groups; and
n=1-3, preferably, n=1-2.
[0096] Exemplary alpha-hydroxy acids include, but are not limited
to, lactic acid, malic acid, citric acid, 2-hydroxybutanoic acid,
3-hydroxybutanoic acid, mandelic acid, gluconic acid, glycolic
acid, tartaric acid, alpha-hydroxyethanoic acid, ascorbic acid,
alpha-hydroxyoctanoic acid, hydroxycaprylic acid, as well as
derivatives thereof (e.g., compounds substituted with hydroxyls,
phenyl groups, hydroxyphenyl groups, alkyl groups, halogens, as
well as combinations thereof). Preferred alpha-hydroxy acids
include lactic acid, malic acid, and mandelic acid. These acids may
be in D, L, or DL form and may be present as free acid, lactone, or
partial salts thereof. All such forms are encompassed by the term
"acid." Preferably, the acids are present in the free acid form. In
certain preferred embodiments, the alpha-hydroxy acids useful in
the compositions of the present invention are selected from the
group consisting of lactic acid, mandelic acid, and malic acid, and
mixtures thereof. Other suitable alpha-hydroxy acids are described
in U.S. Pat. No. 5,665,776 (Yu).
[0097] One or more alpha-hydroxy acids may be used in the
compositions of the present invention at a suitable level to
produce the desired result. In a preferred embodiment, they are
present in a total amount of at least 0.25 wt-%, more preferably,
at least 0.5 wt-%, and even more preferably, at least 1 wt-%, based
on the total weight of the ready to use composition. In a preferred
embodiment, they are present in a total amount of no greater than
10 wt-%, more preferably, no greater than 5 wt-%, and even more
preferably, no greater than 3 wt-%, based on the total weight of
the ready to use composition. Higher concentrations may become
irritating.
[0098] The ratio of alpha-hydroxy acid enhancer to total
antimicrobial lipid component is preferably at most 10:1, more
preferably at most 5:1, and even more preferably at most 1:1. The
ratio of alpha-hydroxy acid enhancer to total antimicrobial lipid
component is preferably at least 1:20, more preferably at least
1:12, and even more preferably at least 1:5. Preferably the ratio
of alpha-hydroxy acid enhancer to total antimicrobial lipid
component is within a range of 1:12 to 1:1.
[0099] Beta-hydroxy Acids. A beta-hydroxy acid is typically a
compound represented by the formula: 1
[0100] wherein: R.sup.7, R.sup.8, and R.sup.9 are each
independently H or a (C1-C8)alkyl group (saturated straight,
branched, or cyclic group), a (C6-C12)aryl, or a (C6-C12)aralkyl or
alkaryl group (wherein the alkyl group is straight, branched, or
cyclic), wherein R.sup.7 and R.sup.8 may be optionally substituted
with one or more carboxylic acid groups; m=0 or 1; n=1-3
(preferably, n=1-2); and R.sup.21 is H, (C1-C4)alkyl or a
halogen.
[0101] Exemplary beta-hydroxy acids include, but are not limited
to, salicylic acid, beta-hydroxybutanoic acid, tropic acid, and
trethocanic acid. In certain preferred embodiments, the
beta-hydroxy acids useful in the compositions of the present
invention are selected from the group consisting of salicylic acid,
beta-hydroxybutanoic acid, and mixtures thereof. Other suitable
beta-hydroxy acids are described in U.S. Pat. No. 5,665,776
(Yu).
[0102] One or more beta-hydroxy acids may be used in the
compositions of the present invention at a suitable level to
produce the desired result. In a preferred embodiment, they are
present in a total amount of at least 0.1 wt-%, more preferably at
least 0.25 wt-%, and even more preferably at least 0.5 wt-%, based
on the total weight of the ready to use composition. In a preferred
embodiment, they are present in a total amount of no greater than
10 wt-%, more preferably no greater than 5 wt-%, and even more
preferably no greater than 3 wt-%, based on the total weight of the
ready to use composition. Higher concentrations may become
irritating.
[0103] The ratio of beta-hydroxy acid enhancer to total
antimicrobial lipid component is preferably at most 10:1, more
preferably at most 5:1, and even more preferably at most 1:1. The
ratio of beta-hydroxy acid enhancer to total antimicrobial lipid
component is preferably at least 1:20, more preferably at least
1:15, and even more preferably at least 1:10. Preferably the ratio
of beta-hydroxy acid enhancer to total antimicrobial lipid
component is within a range of 1:15 to 1:1.
[0104] In systems with low concentrations of water, or that are
essentially free of water, transesterification may be the principle
route of loss of the Fatty Acid MonoEster (FAME), Fatty
AlkylMonoETHer (FAMEth), and alkoxylated derivatives of these
active ingredients. Thus, certain alpha-hydroxy acids (AHA) and
beta-hydroxy acids (BHA) are particularly preferred since these are
believed to be less likely to transesterify the ester antimicrobial
lipid or other ester by reaction of the hydroxyl group of the AHA
or BHA. For example, salicylic acid may be particularly preferred
in certain formulations since the phenolic hydroxyl group is a much
more acidic alcohol and thus much less likely to react. Other
particularly preferred compounds in anhydrous or low-water content
formulations include lactic, mandelic, malic, citric, tartaric, and
glycolic acid.
[0105] Other Carboxylic Acids. Carboxylic acids other than alpha-
and beta-carboxylic acids are suitable for use in the enhancer
component. These include alkyl, aryl, aralkyl, or alkaryl
carboxylic acids typically having equal to or less than 12 carbon
atoms. A preferred class of these can be represented by the
following formula:
R.sup.10(CR.sup.11.sub.2).sub.nCOOH
[0106] wherein: R.sup.10 and R.sup.11 are each independently H or a
(C1-C4)alkyl group (which can be a straight, branched, or cyclic
group), a (C6-C12)aryl group, a (C6-C12) group containing both aryl
groups and alkyl groups (which can be a straight, branched, or
cyclic group), wherein R.sup.10 and R.sup.11 may be optionally
substituted with one or more carboxylic acid groups; and n=0-3,
preferably, n=0-2. Preferably, the carboxylic acid is a
(C1-C4)alkyl carboxylic acid, a (C6-C12)aralkyl carboxylic acid, or
a (C6-C12)alkaryl carboxylic acid. Exemplary acids include, but are
not limited to, acetic acid, propionic acid, benzoic acid, benzylic
acid, nonylbenzoic acid, and the like. Particularly preferred is
benzoic acid.
[0107] One or more carboxylic acids may be used in the compositions
of the present invention at a suitable level to produce the desired
result. In a preferred embodiment, they are present in a total
amount of at least 0.1 wt-%, more preferably at least 0.25 wt-%,
even more preferably at least 0.5 wt-%, and most preferably at
least 1 wt-%, based on the ready to use concentration composition.
In a preferred embodiment, they are present in a total amount of no
greater than 10 wt-%, more preferably no greater than 5 wt-%, and
even more preferably no greater than 3 wt-%, based on the ready to
use composition.
[0108] The ratio of the total concentration of carboxylic acids
(other than alpha- or beta-hydroxy acids) to the total
concentration of the antimicrobial lipid component is preferably
within a range of 10:1 to 1:100, and more preferably 2:1 to 1:10,
on a weight basis.
[0109] Chelators. A chelating agent (i.e., chelator) is typically
an organic compound capable of multiple coordination sites with a
metal ion in solution. Typically these chelating agents are
polyanionic compounds and coordinate best with polyvalent metal
ions. Exemplary chelating agents include, but are not limited to,
ethylene diamine tetraacetic acid (EDTA) and salts thereof (e.g.,
EDTA(Na).sub.2, EDTA(Na).sub.4, EDTA(Ca), EDTA(K).sub.2), sodium
acid pyrophosphate, acidic sodium hexametaphosphate, adipic acid,
succinic acid, polyphosphoric acid, sodium acid pyrophosphate,
sodium hexametaphosphate, acidified sodium hexametaphosphate,
nitrilotris(methylenephosphonic acid),
diethylenetriaminepentaacetic acid, 1-hydroxyethylene,
1,1-diphosphonic acid, and
diethylenetriaminepenta-(methylenephosphonic acid). Certain
carboxylic acids, particularly the alpha-hydroxy acids and
beta-hydroxy acids, can also function as chelators, e.g., malic
acid and tartaric acid.
[0110] In certain preferred embodiments, the chelating agents
useful in the compositions of the present invention include those
selected from the group consisting of ethylenediaminetetraacetic
acid and salts thereof, succinic acid, and mixtures thereof.
Preferably, either the free acid or the mono- or di-salt form of
EDTA is used.
[0111] One or more chelating agents may be used in the compositions
of the present invention at a suitable level to produce the desired
result. In a preferred embodiment, they are present in a total
amount of at least 0.01 wt-%, more preferably at least 0.05 wt-%,
even more preferably at least 0.1 wt-%, and even more preferably at
least 1 wt-%, based on the weight of the ready to use composition.
In a preferred embodiment, they are present in a total amount of no
greater than 10 wt-%, more preferably no greater than 5 wt-%, and
even more preferably no greater than 1 wt-%, based on the weight of
the ready to use composition.
[0112] The ratio of the total concentration of chelating agents
(other than alpha- or beta-hydroxy acids) to the total
concentration of the antimicrobial lipid component is preferably
within a range of 10:1 to 1:100, and more preferably 1:1 to 1:10,
on a weight basis.
[0113] Phenolic Compounds. A phenolic compound enhancer is
typically a compound having the following general structure: 2
[0114] wherein: m is 0 to 3 (especially 1 to 3), n is 1 to 3
(especially 1 to 2), each R.sup.12 independently is alkyl or
alkenyl of up to 12 carbon atoms (especially up to 8 carbon atoms)
optionally substituted with 0 in or on the chain (e.g., as a
carbonyl group) or OH on the chain, and each R.sup.13 independently
is H or alkyl or alkenyl of up to 8 carbon atoms (especially up to
6 carbon atoms) optionally substituted with 0 in or on the chain
(e.g., as a carbonyl group) or OH on the chain, but where R.sup.13
is H, n preferably is 1 or 2.
[0115] Examples of phenolic enhancers include, but are not limited
to, butylated hydroxy anisole, e.g.,
3(2)-tert-butyl-4-methoxyphenol (BHA),
2,6-di-tert-butyl-4-methylphenol (BHT),
3,5-di-tert-butyl-4-hydroxybenzyl- phenol,
2,6-di-tert-4-hexylphenol, 2,6-di-tert-4-octylphenol,
2,6-di-tert-4-decylphenol, 2,6-di-tert-butyl-4-ethylphenol,
2,6-di-tert-4-butylphenol, 2,5-di-tert-butylphenol,
3,5-di-tert-butylphenol, 4,6-di-tert-butyl-resorcinol, methyl
paraben (4-hydroxybenzoic acid methyl ester), ethyl paraben, propyl
paraben, butyl paraben, 2-phenoxyethanol, as well as combinations
thereof. A preferred group of the phenolic compounds is the phenol
species having the general structure shown above where R.sup.13=H
and where R.sup.12 is alkyl or alkenyl of up to 8 carbon atoms, and
n is 0, 1, 2, or 3, especially where at least one R.sup.12 is butyl
and particularly tert-butyl, and especially the non-toxic members
thereof. Some of the preferred phenolic synergists are BHA, BHT,
methyl paraben, ethyl paraben, propyl paraben, and butyl paraben as
well as combinations of these.
[0116] One or more phenolic compounds may be used in the
compositions of the present invention at a suitable level to
produce the desired result. The concentrations of the phenolic
compounds in medical-grade compositions may vary widely, but as
little as 0.001 wt-%, based on the total weight of the composition,
can be effective when the above-described esters are present within
the above-noted ranges. In a preferred embodiment, they are present
in a total amount of at least 0.01 wt-%, more preferably at least
0.10 wt-%, and even more preferably at least 0.25 wt-%, based on
the ready to use composition. In a preferred embodiment, they are
present in a total amount of no greater than 8 wt-%, more
preferably no greater than 4 wt-%, and even more preferably no
greater than 2 wt-%, based on the ready to use composition.
[0117] It is preferred that the ratio of the total phenolic
concentration to the total concentration of the antimicrobial lipid
component be within a range of 10:1 to 1:300, and more preferably
within a range of 1:1 to 1:10, on a weight basis.
[0118] The above-noted concentrations of the phenolics are normally
observed unless concentrated formulations for subsequent dilution
are intended. On the other hand, the minimum concentration of the
phenolics and the antimicrobial lipid components to provide an
antimicrobial effect will vary with the particular application.
[0119] Monohydroxy Alcohols. An additional enhancer is a
monohydroxy alcohol having 1-10 carbon atoms. This includes the
lower (i.e., C1-C4) monohydroxy alcohols (e.g., methanol, ethanol,
isopropanol, and butanol) as well as longer chain (i.e., C5-C10)
monohydroxy alcohols (e.g., iosbutanol, t-butanol, octanol, and
decanol). In certain preferred embodiments, the alcohols useful in
the compositions of the present invention are selected from the
group consisting of methanol, ethanol, isopropyl alcohol, and
mixtures thereof.
[0120] One or more alcohols may be used in the compositions of the
present invention at a suitable level to produce the desired
result. In a preferred embodiment, the short chain (i.e., C1-C4)
alcohols are present in a total amount of at least 10 wt-%, even
more preferably at least 15 wt-%, even more preferably at least 20
wt-%, and even more preferably at least 25 wt-%, based on the total
weight of the ready to use composition. In a preferred embodiment,
the (C1-C4)alcohols are present in a total amount of no greater
than 90 wt-%, more preferably no greater than 70 wt-%, and even
more preferably no greater than 60 wt-%, based on the total weight
of the ready to use composition. In another preferred embodiment
longer chain (i.e., C5-C10) alcohols are present in a total amount
of at least 0.1 wt-%, more preferably at least 0.25 wt-%, and even
more preferably at least 0.5 wt-%, and most preferably at least
1.0%, based on the ready to use composition. In a preferred
embodiment, the (C6-C10)alcohols are present in a total amount of
no greater than 10 wt-%, more preferably no greater than 5 wt-%,
and even more preferably no greater than 2 wt-%, based on the total
weight of the ready to use composition.
[0121] Ether glycols. An additional enhancer is an ether glycol.
Exemplary ether glycols include those of the formula:
R'--O--(CH.sub.2CHR"O).sub.n(CH.sub.2CHR"O)H
[0122] wherein R'=H, a (C1-C8)alkyl, or a (C6-C12)aralkyl or
alkaryl; and R"=H, methyl, or ethyl; and n=0-5, preferably 1-3.
Examples include dipropylene glycol, triethylene glycol, the line
of products available under the trade designation DOWANOL DB
(di(ethylene glycol)butyl ether), DOWANOL DPM (di(propylene
glycol)monomethyl ether), and DOWANOL TPnB (tri(propylene
glycol)monobutyl ether), as well as many others available from Dow
Chemical, Midland Mich.
[0123] One or more ether glycols may be used in the compositions of
the present invention at a suitable level to produce the desired
result. In a preferred embodiment, they are present in a total
amount of at least 0.01 wt-%, based on the total weight of the
ready to use composition. In a preferred embodiment, they are
present in a total amount of no greater than 20 wt-%, based on the
total weight of the ready to use composition.
[0124] Surfactants
[0125] Compositions of the present invention can include one or
more surfactants to emulsify the composition and to help wet the
surface to aid in contacting the microorganisms. As used herein the
term "surfactant" means an amphiphile (a molecule possessing both
polar and nonpolar regions which are covalently bound) capable of
reducing the surface tension of water and/or the interfacial
tension between water and an immiscible liquid. The term is meant
to include soaps, detergents, emulsifiers, surface active agents
and the like. The surfactant can be cationic, anionic, nonionic, or
amphoteric. This includes a wide variety of conventional
surfactants; however, certain ethoxylated surfactants can reduce or
eliminate the antimicrobial efficacy of the antimicrobial lipid
component. The exact mechanism of this is not known and not all
ethoxylated surfactants display this negative effect. For example,
poloxamer (polyethylene oxide/polypropylene oxide) surfactants have
been shown to be compatible with the antimicrobial lipid component,
but ethoxylated sorbitan fatty acid esters such as those sold under
the trade name TWEEN by ICI have not been compatible. It should be
noted that these are broad generalizations and the activity could
be formulation dependent. One skilled in the art can easily
determine compatibility of a surfactant by making the formulation
and testing for antimicrobial activity as described in the Examples
Section. Combinations of various surfactants can be used if
desired.
[0126] Preferred surfactants are those that have an HLB (i.e.,
hydrophile to lipophile balance) of at least 4 and more preferably
at least 8. Even more preferred surfactants have an HLB of at least
12. Most preferred surfactants have an HLB of at least 15.
[0127] Examples of the various classes of surfactants are described
below. In certain preferred embodiments, the surfactants useful in
the compositions of the present invention are selected from the
group consisting of sulfonates, sulfates, phosphonates, phosphates,
poloxamer (polyethylene oxide/polypropylene oxide block
copolymers), cationic surfactants, and mixtures thereof. In certain
more preferred embodiments, the surfactants useful in the
compositions of the present invention are selected from the group
consisting of sulfonates, sulfates, phosphates, and mixtures
thereof.
[0128] One or more surfactants may be used in the compositions of
the present invention at a suitable level to produce the desired
result. In a preferred embodiment, they are present in a total
amount of at least 0.1 wt-%, more preferably at least 0.5 wt-%, and
even more preferably at least 1.0 wt-%, based on the total weight
of the ready to use composition. In a preferred embodiment, they
are present in a total amount of no greater than 10 wt-%, more
preferably no greater than 5 wt-%, and even more preferably no
greater than 2 wt-%, based on the total weight of the ready to use
composition. The ratio of the total concentration of surfactant to
the total concentration of the antimicrobial lipid component is
preferably within a range of 5:1 to 1:100, more preferably 3:1 to
1:10, and most preferably 2:1 to 1:3, on a weight basis.
[0129] Cationic Surfactants. Exemplary cationic surfactants
include, but are not limited to, salts of optionally
polyoxyalkylenated primary, secondary, or tertiary fatty amines;
quaternary ammonium salts such as tetraalkylammonium,
alkylamidoalkyltrialkylammonium, trialkylbenzylammonium,
trialkylhydroxyalkylammonium, or alkylpyridinium halides
(preferably chlorides or bromides); imidazoline derivatives; amine
oxides of a cationic nature (e.g., at an acidic pH).
[0130] In certain preferred embodiments, the cationic surfactants
useful in the compositions of the present invention are selected
from the group consisting of tetralkyl ammonium,
trialkylbenzylammonium, and alkylpyridinium halides, and mixtures
thereof.
[0131] Also particularly preferred are amine oxide surfactants
including alkyl and alkylamidoalkyldialkylamine oxides of the
following formula:
(R.sup.14).sub.3--N.fwdarw.O
[0132] wherein R.sup.14 is a (C1-C30)alkyl group (preferably a
(C1-C14)alkyl group) or a (C6-C18)aralklyl or alkaryl group,
wherein any of these groups can be optionally substituted in or on
the chain by N-, O-, or S-containing groups such as amide, ester,
hydroxyl, and the like. Each R.sup.14 may be the same or different
provided at least one R.sup.14 group includes at least eight
carbons. Optionally, the R.sup.14 groups can be joined to form a
heterocyclic ring with the nitrogen to form surfactants such as
amine oxides of alkyl morpholine, alkyl piperazine, and the like.
Preferably two R.sup.14 groups are methyl and one R.sup.14 group is
a (C12-C16)alkyl or alkylamidopropyl group. Examples of amine oxide
surfactants include those commercially available under the trade
designations AMMONYX LO, LMDO, and CO, which are
lauryldimethylamine oxide, laurylamidopropyldimethylamine oxide,
and cetyl amine oxide, all from Stepan Company.
[0133] Anionic Surfactants. Exemplary anionic surfactants include,
but are not limited to, sarcosinates, glutamates, alkyl sulfates,
sodium alkyleth sulfates, ammonium alkyleth sulfates, ammonium
laureth-n-sulfates, laureth-n-sulfates, isethionates, glycerylether
sulfonates, sulfosuccinates, alkylglyceryl ether sulfonates, alkyl
phosphates, aralkyl phosphates, alkylphosphonates, and
aralkylphosphonates. These anionic surfactants may have a metal or
organic ammonium counterion. In certain preferred embodiments, the
anionic surfactants useful in the compositions of the present
invention are selected from the group consisting of:
[0134] 1. Sulfonates and Sulfates. Suitable anionic surfactants
include sulfonates and sulfates such as alkyl sulfates, alkylether
sulfates, alkyl sulfonates, alkylether sulfonates, alkylbenzene
sufonates, alkylbenzene ether sulfates, alkylsulfoacetates,
secondary alkane sulfonates, secondary alkylsulfates, and the like.
Many of these can be represented by the formulas:
R.sup.14--(OCH.sub.2CH.sub.2).sub.n(OCH(CH.sub.3)CH.sub.2).sub.p--(Ph).sub-
.a--(OCH.sub.2CH.sub.2).sub.m--(O).sub.b--SO.sub.3.sup.-M.sup.+
and
R.sup.14--CH[SO.sub.3-M.sup.+]-R.sup.15
[0135] wherein: a and b=0 or 1; n, p, and m=0-100 (preferably 0-20,
and more preferably 0-10); R.sup.14 is defined as above provided at
least one R.sup.14 or R.sup.15 is at least C8; R.sup.15 is a
(C1-C12)alkyl group (saturated straight, branched, or cyclic group)
that may be optionally substituted by N, O, or S atoms or hydroxyl,
carboxyl, amide, or amine groups; Ph=phenyl; and M is a cationic
counterion such as H, Na, K, Li, ammonium, or a protonated tertiary
amine such as triethanolamine or a quaternary ammonium group.
[0136] In the formula above, the ethylene oxide groups (i.e., the
"n" and "m" groups) and propylene oxide groups (i.e., the "p"
groups) can occur in reverse order as well as in a random,
sequential, or block arrangement. Preferably for this class,
R.sup.14 includes an alkylamide group such as
R.sup.16--C(O)N(CH.sub.3)CH.sub.2CH.sub.2-- as well as ester groups
such as --OC(O)--CH.sub.2-- wherein R.sup.16 is a (C8-C22)alkyl
group (branched, straight, or cyclic group). Examples include, but
are not limited to: alkyl ether sulfonates such as lauryl ether
sulfates such as POLYSTEP B12 (n=3-4, M=sodium) and B22 (n=12,
M=ammonium) available from Stepan Company, Northfield, Ill. and
sodium methyl taurate (available under the trade designation NIKKOL
CMT30 from Nikko Chemicals Co., Tokyo, Japan); secondary alkane
sulfonates such as Hostapur SAS which is a Sodium
(C14-C17)secondary alkane sulfonates (alpha-olefin sulfonates)
available from Clariant Corp., Charlotte, N.C.; methyl-2-sulfoalkyl
esters such as sodium methyl-2-sulfo(C12-16)ester and disodium
2-sulfo(C12-C16)fatty acid available from Stepan Company under the
trade designation ALPHASTE PC-48; alkylsulfoacetates and
alkylsulfosuccinates available as sodium laurylsulfoacetate (under
the trade designation LANTHANOL LAL) and
disodiumlaurethsulfosuccinate (STEPANMILD SL3), both from Stepan
Company; alkylsulfates such as ammoniumlauryl sulfate commercially
available under the trade designation STEPANOL AM from Stepan
Company; dialkylsulfosuccinates such as dioctylsodiumsulfosuccinate
available as Aerosol OT from Cytec Industries.
[0137] 2. Phosphates and Phosphonates. Suitable anionic surfactants
also include phosphates such as alkyl phosphates, alkylether
phosphates, aralkylphosphates, and aralkylether phosphates. Many
may be represented by the formula:
[R.sup.14--(Ph).sub.a--O(CH.sub.2CH.sub.2O).sub.n(CH.sub.2CH(CH.sub.3)O).s-
ub.p].sub.q--P(O)[O.sup.-M.sup.+].sub.r
[0138] wherein: Ph, R.sup.14, a, n, p, and M are defined above; r
is 0-2; and q=1-3; with the proviso that when q=1, r=2, and when
q=2, r=1, and when q=3, r=0. As above, the ethylene oxide groups
(i.e., the "n" groups) and propylene oxide groups (i.e., the "p"
groups) can occur in reverse order as well as in a random,
sequential, or block arrangement. Examples include a mixture of
mono-, di- and tri-(alkyltetraglycolether)-o-phospho- ric acid
esters generally referred to as trilaureth-4-phosphate commercially
available under the trade designation HOSTAPHAT 340KL from Clariant
Corp., as well as PPG-5 ceteth 10 phosphate available under the
trade designation CRODAPHOS SG from Croda Inc., Parsipanny, N.J.,
and mixtures thereof.
[0139] Amphoteric Surfactants. Surfactants of the amphoteric type
include surfactants having tertiary amine groups, which may be
protonated, as well as quaternary amine containing zwitterionic
surfactants. Those that have been particularly useful include:
[0140] 1. Ammonium Carboxylate Amphoterics. This class of
surfactants can be represented by the following formula:
R.sup.17--(C(O)--NH).sub.a--R.sup.18--N.sup.+(R.sup.19).sub.2--R.sup.20--C-
OO.sup.-
[0141] wherein: a=0 or 1; R.sup.17 is a (C7-C21)alkyl group
(saturated straight, branched, or cyclic group), a (C6-C22)aryl
group, or a (C6-C22)aralkyl or alkaryl group (saturated straight,
branched, or cyclic alkyl group), wherein R.sup.17 may be
optionally substituted with one or more N, O, or S atoms, or one or
more hydroxyl, carboxyl, amide, or amine groups; R.sup.19 is H or a
(C1-C8)alkyl group (saturated straight, branched, or cyclic group),
wherein R.sup.19 may be optionally substituted with one or more N,
O, or S atoms, or one or more hydroxyl, carboxyl, amine groups, a
(C6-C9)aryl group, or a (C6-C9)aralkyl or alkaryl group; and
R.sup.18 and R.sup.20 are each independently a (C1-C10)alkylene
group that may be the same or different and may be optionally
substituted with one or more N, O, or S atoms, or one or more
hydroxyl or amine groups.
[0142] More preferably, in the formula above, R.sup.17 is a
(C1-C18)alkyl group, R.sup.19 is a (C1-C2)alkyl group preferably
substituted with a methyl or benzyl group and most preferably with
a methyl group. When R.sup.19 is H it is understood that the
surfactant at higher pH values could exist as a tertiary amine with
a cationic counterion such as Na, K, Li, or a quaternary amine
group.
[0143] Examples of such amphoteric surfactants include, but are not
limited to: certain betaines such as cocobetaine and cocamidopropyl
betaine (commercially available under the trade designations MACKAM
CB-35 and MACKAM L from McIntyre Group Ltd., University Park,
Ill.); monoacetates such as sodium lauroamphoacetate; diacetates
such as disodium lauroamphoacetate; amino- and
alkylamino-propionates such as lauraminopropionic acid
(commercially available under the trade designations MACKAM 1L,
MACKAM 2L, and MACKAM 151L, respectively, from McIntyre Group
Ltd.).
[0144] 2. Ammonium Sulfonate Amphoterics. This class of amphoteric
surfactants are often referred to as "sultaines" or "sulfobetaines"
and can be represented by the following formula
R.sup.17--(C(O)--NH).sub.a--R.sup.18--N.sup.+(R.sup.19).sub.2--R.sup.20--S-
O.sub.3.sup.-
[0145] wherein R.sup.17-R.sup.20 and "a" are defined above.
Examples include cocamidopropylhydroxysultaine (commercially
available as MACKAM 50-SB from McIntyre Group Ltd.). The
sulfoamphoterics may be preferred over the carboxylate amphoterics
since the sulfonate group will remain ionized at much lower pH
values.
[0146] Nonionic Surfactants. Exemplary nonionic surfactants
include, but are not limited to, alkyl glucosides, alkyl
polyglucosides, polyhydroxy fatty acid amides, sucrose esters,
esters of fatty acids and polyhydric alcohols, fatty acid
alkanolamides, ethoxylated fatty acids, ethoxylated aliphatic
acids, ethoxylated fatty alcohols (e.g., octyl phenoxy
polyethoxyethanol available under the trade name TRITON X-100 and
nonyl phenoxy poly(ethyleneoxy)ethanol available under the trade
name NONIDET P-40, both from Sigma, St. Louis, Mo.), ethoxylated
and/or propoxylated aliphatic alcohols (e.g., that available under
the trade name PLURONIC F127 from Sigma), ethoxylated glycerides,
ethoxylated block copolymers with ethylene diaminetetraacetic acid
(EDTA), ethoxylated cyclic ether adducts, ethoxylated amide and
imidazoline adducts, ethoxylated amine adducts, ethoxylated
mercaptan adducts, ethoxylated condensates with alkyl phenols,
ethoxylated nitrogen-based hydrophobes, ethoxylated
polyoxypropylenes, polymeric silicones, fluorinated surfactants
(e.g., those available under the trade names FLUORAD-FS 300 from
Minnesota Mining and Manufacturing Co., St. Paul, Minn., and ZONYL
from Dupont de Nemours Co., Wilmington, Del.), and polymerizable
(reactive) surfactants (e.g., SAM 211 (alkylene polyalkoxy sulfate)
surfactant available under the trade name MAZON from PPG
Industries, Inc., Pittsburgh, Pa.). In certain preferred
embodiments, the nonionic surfactants useful in the compositions of
the present invention are selected from the group consisting of
Poloxamers such as PLURONIC from BASF, sorbitan fatty acid esters,
and mixtures thereof.
[0147] Hydrophilic Component
[0148] Compositions of the present invention can include a
hydrophilic or water-soluble component to help solubilize and/or
physically stabilize the enhancer component in the composition. In
addition, it has been found that the hydrophilic component can help
to improve antimicrobial activity both in terms of speed of kill
and extent of kill. Certain compositions may be solutions,
emulsions (one liquid/gel/paste dispersed in another
liquid/gel/paste), or dispersions (solid in liquid/paste/gel).
[0149] A hydrophilic material is typically a compound that has a
solubility in water of at least 7 wt-%, preferably at least 10
wt-%, more preferably at least 20 wt-%, even more preferably at
least 25 wt-%, and even more preferably at least 40 wt-%, at
23.degree. C. Most preferably, a hydrophilic component is
infinitely miscible with water at 23.degree. C.
[0150] Exemplary hydrophilic components include, but are not
limited to, water, polyhydric alcohols, lower alkyl ethers (i.e.,
having a sufficiently small number of carbon atoms to meet the
solubility limit above), N-methylpyrrolidone, alkyl esters (i.e.,
having a sufficiently small number of carbon atoms to meet the
solubility limit above), and the lower monohydroxy alcohols
discussed above as enhancers, as well as combinations thereof.
Thus, a lower monohydroxy alcohol can function as both a
hydrophilic compound and an enhancer. Preferably, the hydrophilic
components include polyhydric alcohols, lower alkyl ethers, and
short chain esters. More preferably, the hydrophilic components
include polyhydric alcohols.
[0151] Suitable polyhydric alcohols (i.e., organic compounds having
more than one hydroxyl group) have a molecular weight of less than
500, preferably less than 400, and more preferably less than 200.
Examples of polyhydric alcohols include, but are not limited to,
glycerol, propylene glycol, dipropylene glycol, polypropylene
glycol, polyethylene glycol, diethylene glycol, pentaerythritol,
trimethylolpropane, trimethylolethane, trimethylolbutane, sorbitol,
mannitol, xylitol, pantothenol, ethylene glycol adducts of
polyhydric alcohol, propylene oxide adducts of polyhydric alcohol,
1,3-butanediol, dipropylene glycol, diglycerine, polyglycerine,
erythritol, sorbitan, sugars (e.g., sucrose, glucose, fructose,
mannose, xylose, saccharose, trehalose), sugar alcohols, and the
like. Certain preferred polyhydric alcohols include glycols (i.e.,
those containing two hydroxyl groups) including glycerin and
propylene glycol. Certain other preferred polyhydric alcohols
include sucrose.
[0152] Ethers include materials such as dimethylisosorbide,
polyethylene glycol and methoxypolyethylene glycols, block and
random copolymers of ethylene oxide and propylene oxide, and
laureth-4. Alkyl esters include triacetin, methyl acetate, esters
of polyethoxylated glycols, and combinations thereof.
[0153] In certain preferred embodiments, the hydrophilic components
useful in the compositions of the present invention include those
selected from the group consisting of glycols, and in particular
glycerin and propylene glycol, and mixtures thereof. Most
preferably, the hydrophilic component is selected to match the
polyhydric alcohol portion of any fatty acid monoester of a
polyhydric alcohol antimicrobial present. For example, if the
antimicrobial agent was glycerolmonolaurate (monolaurin) the most
preferred hydrophilic component is glycerin. In this manner, any
transesterification reaction that may occur with the carrier
solvent does not produce an undesirable by-product.
[0154] One or more hydrophilic materials may be used in the
compositions of the present invention at a suitable level to
produce the desired result. In certain preferred embodiments that
also include the hydrophobic component as the primary component
(i.e., the component used in the greatest amount and referred to as
a "vehicle"), the hydrophilic component is present in a total
amount of at least 0.1%, preferably at least 1 wt-%, more
preferably at least 4 wt-%, and even more preferably at least 8
wt-%, based on the weight of the ready to use composition. In a
preferred embodiment, the hydrophilic component is present in a
total amount of no greater than 60 wt-%, more preferably no greater
than 40 wt-%, and even more preferably no greater than 20 wt-%,
based on the ready to use composition. When the hydrophilic
component is present in the greatest amount it is referred to as a
"vehicle."
[0155] If water is used in certain embodiments, it is preferably
present in an amount of less than 10 wt-%, more preferably less
than 5 wt-%, and even more preferably less than 2 wt-%, based on
the ready to use composition. For certain other embodiments, water
can be used in a much greater amount, and can even be the primary
component, as long as the composition is highly viscous.
Preferably, such highly viscous compositions have a viscosity of at
least 500 centipoise (cps), more preferably at least 1,000 cps,
even more preferably at least 10,000 cps, even more preferably at
least 20,000 cps, even more preferably at least 50,000 cps, even
more preferably at least 75,000 cps, even more preferably at least
100,000 cps, and even more preferably at least 250,000 cps (and
even as high as about 500,000 cps, 1,000,000 cps, or more). The
viscosity can be measured as described below in the Viscosity
Test.
[0156] Hydrophobic Component
[0157] Certain preferred compositions of the present invention also
include one or more hydrophobic materials. A hydrophobic material
is typically an organic compound, which at 23.degree. C. is a
liquid, gelatinous, semisolid or solid and has a solubility in
water of less than 5% by weight, preferably less than 1% by weight,
more preferably less than 0.5% by weight, and even more preferably
less than 0.1% by weight. These materials include compounds
typically considered emollients in the cosmetic art.
[0158] Examples of general emollients include, but are not limited
to, short chain (i.e, C1-C6)alkyl or (C6-C12)aryl esters of long
(i.e., C8-C36) straight or branched chain alkyl or alkenyl alcohols
or acids and polyethoxylated derivatives of the alcohols; short
chain (i.e., C1-C6)alkyl or (C6-C12)aryl esters of (C4-C12)diacids
or (C4-C12)diols optionally substituted in available positions by
--OH; (C2-C18)alkyl or (C6-C12)aryl esters of glycerol,
pentaerythritol, ethylene glycol, propylene glycol, as well as
polyethoxylated derivatives of these; (C12-C22)alkyl esters or
(C12-C22)ethers of polypropylene glycol; (C12-C22)alkyl esters or
(C12-C22)ethers of polypropylene glycol/polyethylene glycol
copolymer; and polyether polysiloxane copolymers. Additional
examples of hydrophobic components include cyclic dimethicones,
polydialkylsiloxanes, polyaryl/alkylsiloxanes, silicone copolyols,
long chain (i.e., C8-C36)alkyl and alkenyl esters of long (i.e.,
C8-C18) straight or branched chain alkyl or alkenyl alcohols or
acids, long chain (i.e., C8-C36)alkyl and alkenyl amides of long
straight or branched chain (i.e., C8-C36)alkyl or alkenyl amines or
acids; hydrocarbons including straight and branched chain alkanes
and alkenes such as squalene, and mineral oil, polysiloxane
polyalkylene copolymers, dialkoxy dimethyl polysiloxanes;
(C12-C22)alkyl and (C12-C22)alkenyl alcohols, and petroleum derived
alkanes such as isoparafins, petrolatum, petrolatum USP, and blends
thereof. In certain preferred embodiments, the hydrophobic
components useful in the compositions of the present invention
include those selected from the group consisting of petrolatum USP
and short chain (i.e., C1-C6)alkyl or (C6-C12)aryl esters of long
(i.e., C8-C36) straight or branched chain alkyl or alkenyl alcohols
or acids and polyethoxylated derivatives of the alcohols; short
chain (i.e., C1-C6)alkyl or (C6-C12)aryl esters of (C4-C12)diacids
or (C4-C12)diols optionally substituted in available positions by
--OH (such as diisopropyladipate, diisopropylsebacate);
(C1-C9)alkyl or (C6-C12)aryl esters of glycerol, pentaerythritol,
ethylene glycol, propylene glycol (such as glyceryl
tricaprylate/caprate); and mixtures thereof. For certain
particularly preferred embodiments, the hydrophobic component is
petrolatum.
[0159] One or more hydrophobic materials may be used in the
compositions of the present invention at a suitable level to
produce the desired result. In a preferred embodiment (in which the
compositions include very little or no water), the hydrophobic
component is present in a total amount of at least 50 wt-%, more
preferably at least 70 wt-%, and even more preferably at least 80
wt-%, based on the ready to use composition. In a preferred
embodiment, the hydrophobic component is present in a total amount
of no greater than 99 wt-%, more preferably no greater than 95
wt-%, and even more preferably no greater than 92 wt-%, based on
the ready to use composition. When the hydrophobic component is
present in the greatest amount it is referred to as a
"vehicle."
[0160] Optional Additives
[0161] Compositions of the present invention may additionally
employ adjunct components conventionally found in pharmaceutical
compositions in their art-established fashion and at their
art-established levels. Thus, for example, the compositions may
contain additional compatible pharmaceutically active materials for
combination therapy (such as supplementary antimicrobials,
anti-parasitic agents, antipruritics, astringents, local
anaesthetics, or anti-inflammatory agents), or may contain
materials useful in physically formulating various dosage forms of
the present invention, such as excipients, dyes, perfumes,
lubricants, thickening agents, stabilizers, skin penetration
enhancers, preservatives, or antioxidants.
[0162] It will be appreciated by the skilled artisan that the
levels or ranges selected for the required or optional components
described herein will depend upon whether one is formulating a
composition for direct use, or a concentrate for dilution prior to
use, as well as the specific component selected, the ultimate
end-use of the composition, and other factors well known to the
skilled artisan.
[0163] It will also be appreciated that additional antiseptics,
disinfectants, or antibiotics may be included and are contemplated.
These include, for example, addition of metals such as silver,
copper, zinc; iodine and iodophors; chlorhexidine and its various
salts such as chlorhexidine digluconate;
polyhexamethylenebiguanide, parachlorometaxylenol, triclosan,
antimicrobial quaternarly amines including polymeric quaternary
amines, "azole" antifungal agents including clortrimazole,
miconazole, econazole, ketoconazole, and salts thereof; and the
like. Antibiotics such as neomycin sulfate, bacitracin, mupirocin,
and the like, also may be included.
[0164] Formulations and Methods of Preparation
[0165] Many of the compositions of the present invention have
exceptional broad spectrum antimicrobial activity and thus are
generally not terminally sterilized but if necessary may be
sterilized by a variety of industry standard techniques. For
example, it may be preferred to sterilize the compositions in their
final packaged form using electron beam. It may also be possible to
sterilize the sample by gamma radiation or heat. Other forms of
sterilization may be acceptable. It may also be suitable to include
preservatives in the formulation to prevent growth of certain
organisms. Suitable preservatives include industry standard
compounds such as Parabens (methyl, ethyl, propyl, isopropyl,
isobutyl, etc), 2 bromo-2 nitro-1,3, diol; 5 bromo-5-nitro-1,3
dioxane, chlorbutanol, diazolidinyl urea; iodopropylnyl
butylcarbamate, phenoxyethanol, halogenated cresols,
methylchloroisothiazolinone and the like, as well as combinations
of these compounds.
[0166] The compositions of the present invention preferably adhere
well to skin, mucosal tissue, and wounds, in order to deliver the
antimicrobial to the intended site over a prolonged period even in
the presence of perspiration, drainage (e.g., mucosal secretions),
or mild lavage. The compositions are typically non-aqueous,
although high viscosity compositions can include a large amount of
water. The component in the greatest amount (i.e., the vehicle) in
the formulations of the invention may be any conventional vehicle
commonly used for topical treatment of human or animal skin. The
formulations are typically selected from one of the following three
types: (1) anhydrous or nearly anhydrous formulations with a
hydrophobic vehicle (i.e., the hydrophobic component, which can
include one or more hydrophobic compounds, is present in the
greatest amount); (2) anhydrous or nearly anhydrous formulations
with a hydrophilic vehicle (i.e., the hydrophilic component, which
can include one or more hydrophilic compounds, is present in the
greatest amount); and (3) highly viscous water-based formulations.
These are discussed below.
[0167] (1) Anhydrous or Nearly Anhydrous Formulations with a
Hydrophobic Vehicle. In certain preferred embodiments of the
present invention, the compositions include an antimicrobial lipid
component in a hydrophobic vehicle in combination with
surfactant(s), an enhancer component, and a small amount of a
hydrophilic component. In most instances the enhancers are not
soluble in the hydrophobic component at room temperature although
they may be at elevated temperatures. The hydrophilic component is
generally present in a sufficient amount to stabilize (preferably
to solubilize) the enhancer(s) in the composition. For example,
when formulating with organic acid enhancers or certain solid
surfactants in petrolatum many enhancers and surfactants will
dissolve into the petrolatum at temperatures above 85.degree. C.;
however, upon cooling, the enhancer and/or surfactant crystals or
precipitates back out of solution making it difficult to produce a
uniform formulation. If at least 0.1% and preferably at least 1.0%
of a hydrophilic compound (e.g., a glycol) is added a stable
formulation can be obtained. It is believed that these formulations
produce an emulsion in which the enhancer and/or surfactant is
dissolved, emulsified, or dispersed in the hydrophilic component
which is emulsified into the hydrophobic component(s). These
compositions are stable upon cooling and centrifuging.
[0168] The hydrophilic component also helps to stabilize many of
the surfactants used in preferred formulations. For example,
dioctylsulfosuccinate sodium salt (DOSS) dissolves in glycerin at
elevated temperatures and helps keep the DOSS physically stable in
the composition. Furthermore, it is believed that incorporation of
the hydrophilic component in the formulation improves the
antimicrobial activity. The mechanism for this is unknown; however,
it may speed the release of the enhancer component and/or the
antimicrobial lipid component.
[0169] The water content of these formulations is preferably less
than 10 wt-%, more preferably less than 5 wt-%, and even more
preferably less than 2 wt-%, in order to minimize hydrolysis of any
ester based antimicrobial lipid present.
[0170] Furthermore, it has been found that it is particularly
desirable where the antimicrobial lipid component includes an ester
to use either glycerin or propylene glycol in the hydrophilic
component. It is most preferred to use a hydrophilic compound that
is identical to the glycol portion of the antimicrobial lipid,
e.g., propylene glycol with the propylene glycol esters and
glycerin with the glycerin esters. In this manner,
transesterification of the antimicrobial lipid ester with the
hydrophilic compound will not result in additional chemical species
present. In fact, there is some evidence to show that use of
glycerolmonolaurate, which is 95% pure, when formulated with
glycerin as a hydrophilic compound results in formation of
additional glycerol monolaurate due to transesterification of the
diester with the glycerin to produce two moles of the monoester.
For this reason, it may be possible to initially formulate with
lower grade glycerin ester that contains considerable levels of
diester present, as long as it transesterifies during manufacture
and/or storage to produce a formulation that includes less than 15%
diester and preferably less than 5% diester based on the total
weight of antimicrobial lipid present.
[0171] These formulations can be relatively easily manufactured by
first heating the hydrophobic component to 85.degree. C., adding in
the surfactant, hydrophilic component, and enhancer component,
cooling to 65.degree. C., and adding the antimicrobial lipid
component above its melting point. Alternatively, the enhancer
component can be predissolved in the hydrophilic component
(optionally along with the surfactant) and added to the hydrophobic
component either before or after addition of the antimicrobial
lipid component. If either the antimicrobial lipid component or the
hydrophobic component are solids at room temperature this is done
at the minimum temperature necessary to melt all components.
Exposure of ester containing antimicrobial lipids to enhancers that
include either acid or ether groups to elevated temperatures for
extended periods of time should be avoided to prevent
transesterification reactions (unless this is deliberate in the
case of utilizing lower purity fatty acid esters in combination
with glycol hydrophilic components to produce the monoesters as
discussed above).
[0172] Thus, the present invention provides methods of manufacture.
One preferred method involves: dissolving the enhancer component in
the hydrophilic component; combining the hydrophobic vehicle and
the hydrophilic component with the enhancer component dissolved
therein with mixing to form a mixture; optionally heating the
hydrophobic vehicle to a temperature sufficient to form a pourable
liquid (which for many hydrophobic vehicles this is above its
melting point) before or after combining it with the hydrophilic
component and enhancer component; adding the antimicrobial lipid
component to the mixture; and cooling the mixture before or after
adding the antimicrobial lipid component.
[0173] The hydrophilic component may or may not be present in the
formulations that include a hydrophobic vehicle. Thus, another
preferred method of manufacture involves: combining the enhancer
component and the hydrophobic vehicle with mixing to form a
mixture; optionally heating the hydrophobic vehicle to a
temperature sufficient to form a pourable liquid (which for many
hydrophobic vehicles is above its melting point) before or after
combining it with the enhancer component; adding the antimicrobial
lipid component to the mixture with mixing; and cooling the mixture
before or after adding the antimicrobial lipid component.
[0174] Surprisingly, it has been found that these compositions are
significantly less irritating than formulations using completely
hydrophilic components. In blind human trials participants were
asked to instill 0.5 gram (g) of ointments based on hydrophobic
components (e.g., petrolatum) that include an AHA enhancer,
surfactant, and 10% hydrophilic component (e.g., glycerin) as well
as ointments based on hydrophilic components (e.g., PEG 400) using
the same enhancer and surfactant. Surprisingly, the ointments based
on the hydrophobic component was preferred by 100% of the
participants.
[0175] The viscosity of these formulations intended for use on skin
or in the anterior nares is preferably relatively high to prevent
excessive drainage off the treatment site. In this regard the
viscosity is preferably at least 500 Centipoise (cps), more
preferably at least 1,000 cps, even more preferably at least 10,000
cps, even more preferably at least 20,000 cps, even more preferably
at least 50,000 cps, even more preferably at least 75,000 cps, even
more preferably at least 100,000 cps, and even more preferably at
least 250,000 cps (and even as high as about 500,000 cps, 1,000,000
cps, or more). The viscosity can be measured as described below in
the Viscosity Test.
[0176] Most preferably, the formulations intended for use on skin,
anterior nares, or where drainage would be a concern are
essentially gelatinous at room temperature, having a significant
yield point such that they do not flow readily at temperatures
below 35.degree. C. The viscosity is measured using the viscosity
test described herein. Certain gelatinous vehicles may also have a
characteristic temperature at which they "melt" or begin to
dramatically lose viscosity. Preferably this is higher than body
temperature also to ensure that excess drainage of the composition
of the treatment site does not occur. Therefore, the melting point
of the composition is preferably greater than 32.degree. C., more
preferably greater than 35.degree. C., and even more preferably
greater than about 37.degree. C. The melting point is taken as the
lowest temperature at which the viscosity becomes dramatically less
or is equal to or less than 100,000 cps.
[0177] Similarly the viscosity and/or melt temperature can be
enhanced by either incorporating a crystalline or semicrystalline
hydrophobic carrier such as a higher melting petrolatum, addition
of an insoluble filler/thixotrope, or by addition of a polymeric
thickener (e.g., a polyethylene wax in a petrolatum vehicle).
Polymeric thickeners may be linear, branched, or slightly
crosslinked. It is important for comfort that the formulations are
relatively soft and that they spread easily to allow easy
application, especially over a wound, rash, or infected area or in
the anterior nares. A particularly preferred vehicle for use on
skin, in the anterior nares, or in other areas where high viscosity
is desirable is white petrolatum USP having a melting point greater
than 40.degree. C.
[0178] (2) Anhydrous or Nearly Anhydrous Formulations with a
Hydrophilic Vehicle. Antimicrobial lipid components of this
invention can be formulated into a water-soluble component such as
that based on the hydrophilic compounds discussed above in
combination with the synergist(s) and surfactant(s). Particularly
preferred are polyethylene glycols (PEGs) including blends of
different molecular weight PEGs. When using a hydrophilic component
as the vehicle (i.e., the component used in the greatest amount,
which can include one or more hydrophilic compounds), it should be
preferably selected to maintain viscosity and melt temperature
characteristics similar to those stated above for the anhydrous or
nearly anhydrous formulations using a hydrophobic vehicle.
[0179] Similarly the viscosity can be enhanced by either
incorporating a crystalline or semicrystalline hydrophilic compound
such as a PEG, addition of an insoluble filler/thixotrope, or by
addition of a polymeric thickener. Polymeric thickeners may be
linear, branched, or slightly crosslinked. It is important for
comfort that the formulations are relatively soft and that they
spread easily to allow easy application, especially over a wound,
rash, or infected area or in the anterior nares. For this reason, a
particularly preferred vehicle is based on a blend of a liquid or
semi-solid PEG (PEG 400-1000) with a more crystalline PEG (PEG
1000-2000). Particularly preferred is a blend of PEG 400 with PEG
1450 in a ratio of 4:1.
[0180] In certain preferred embodiments of the present invention,
the compositions are in the form of an ointment or cream. That is,
the compositions are in the form of a relatively viscous state such
that they are suitable for application to nasal passageways.
Preferably, such compositions have a viscosity of at least 500
Centipoise (cps), more preferably at least 1,000 cps, even more
preferably at least 10,000 cps, even more preferably at least
20,000 cps, even more preferably at least 50,000 cps, even more
preferably at least 75,000 cps, even more preferably at least
100,000 cps, and even more preferably at least 250,000 cps (and
even as high as about 500,000 cps, 1,000,000 cps, or more). The
viscosity can be measured as described below in the Viscosity
Test.
[0181] (3) Water-based Formulations. Aqueous compositions of the
present invention are those in which water is present in the
greatest amount, thereby forming the "vehicle." For these systems
it is particularly important that a relatively high viscosity be
imparted to the composition to ensure that the antimicrobial
composition is not rapidly dispersed off the afflicted area. These
formulations also adhere well to tissue and thus deliver the
antimicrobial to the intended site over a prolonged period even in
the presence of perspiration, drainage (e.g., mucosal secretions),
or mild lavage. Such a high viscosity can be imparted by a
thickener system. The thickener system of the invention is
compatible with the antimicrobial lipid composition described above
in order to provide suitable antimicrobial efficacy, chemical and
physical stability, acceptable cosmetic properties, and appropriate
viscosity for retention in the afflicted area.
[0182] Preferably, compositions of this invention have a viscosity
of at least 500 Centipoise (cps), more preferably at least 1,000
cps, even more preferably at least 10,000 cps, even more preferably
at least 20,000 cps, even more preferably at least 50,000 cps, even
more preferably at least 75,000 cps, even more preferably at least
100,000 cps, and even more preferably at least 250,000 cps (and
even as high as about 500,000 cps, 1,000,000 cps, or more). The
viscosity can be measured as described below in the Viscosity Test.
Because certain optional ingredients, such as enhancers,
hydrophilic compounds, hydrophobic compounds, and the like, may
effect the viscosity (either positively or negatively), the
measured viscosity is that of the final composition.
[0183] Preferred thickener systems used in the compositions of the
present invention are capable of producing viscoelastic
compositions that are very stable. By varying the amount and type
of thickener, the degree of elasticity can be adjusted from almost
a purely viscous composition to a highly elastic and even gel-like
composition. If emollients are added, increasing the elasticity
and/or yield stress of the system imparts added stability to
prevent separation of immiscible emollients. Excessive elasticity,
however, is not preferred because an elastic composition usually
does not provide a cosmetically appealing product.
[0184] Significantly, thickener systems used in the present
invention are capable of achieving high viscosities at relatively
low total concentrations. The total concentration of the thickener
system is preferably less than 8 wt-%, more preferably less than 5
wt-%, and most preferably less than 3 wt-%, based on the total
weight of the ready to use composition. Preferably, the total
concentration of the thickener system can be as little as 0.5 wt-%,
based on the total weight of the composition. For certain
embodiments, however, the total concentration of thickener system
is greater than 1 wt-%, based on the total weight of the ready to
use composition.
[0185] The thickener system can include organic polymers or
inorganic thixotropes such as silica gel, clays (such as betonite,
laponite, hectorite, montmorrillonite and the like), as well as
organically modified inorganic particulates materials, and the
like. As used herein, an organic polymer is considered part of the
thickener system if its presence in the composition results in an
increase in the viscosity of the composition. Certain polymers that
do not have these characteristics may also be present in the
composition but do not contribute significantly to the viscosity of
the composition. For purposes of this invention, they are not
considered part of the thickener system. For example, certain
nonionic polymers such as lower molecular weight polyethylene
glycols (e.g., those having a molecular weight of less than 20,000)
do not increase the viscosity of the composition significantly.
These are considered part of the hydrophilic component, for
example, rather than part of the thickener system.
[0186] The thickener system can be prepared from one or more
nonionic, cationic, anionic, zwitterionic, or associative polymers
as long as they are compatible with the antimicrobial lipid and
enhancer components of the composition. For example, certain acidic
enhancers such as those that include carboxylic acid groups are
most effective in their protonated form. This requires that the
composition has an acidic pH. For this reason, many anionic
thickeners based on neutralized carboxylic acid groups would not be
suitable. For example, Carbopol-type thickeners based on
polyacrylic acid salts do not typically thicken well at pH values
of less than 5 and certainly less than a pH of 4.5. Therefore, at
lower pH values (i.e., when acidic enhancers are present) if the
aqueous compositions are thickened with anionic polymers, the
polymers are preferably based on sulfonic acid, sulfate, phosphonic
acid, or phosphate groups. These polymers are able to thicken at
much lower pH values due to the lower pKa of these acid groups.
Preferred polymers of this class include ARISTOFLEX HMB (ammonium
acryloyldimethyltaurate/beheneth-25 methacrylate crosspolymer) and
ARISTOFLEX ASV (ammonium acryloyldimethyltaurate/NVP copolymer)
from Clariant Corporation. Other preferred sulfonic acid polymers
are those described in U.S. Pat. No. 5,318,955.
[0187] Preferably, the compositions that include an acidic enhancer
component are thickened using cationic or nonionic thickeners since
these perform well at low pH. In addition, many of the nonionic and
cationic polymers can tolerate higher levels of salts and other
additives and still maintain high viscosity.
[0188] A preferred group of nonionic polymeric thickeners include
modified celluloses, guar, xanthan gum, and other natural polymers
such as polysaccharides and proteins, associative polymers based on
nonionic ethylenically unsaturated monomers wherein at least one
comonomer has at least 16 carbon atoms, and polymers based on
ethylenically unsaturated monomers selected from the group
consisting of acrylates, acrylamides, vinyl lactams, vinyl acetate
and its hydrolyzed derivatives, methyl vinyl ethers, styrene, and
acrylonitrile.
[0189] A preferred group of cationic polymeric thickeners include
cationically modified celluloses, quaternized natural
amino-functional polymers, and polymers based on ethylenically
unsaturated monomers selected from the group consisting of
acrylates, acrylamides, vinyl lactams, vinyl acetates, methyl vinyl
ethers, styrene, and acrylonitrile.
[0190] Cationic polymers for use in the compositions of this
invention can be selected from both permanently charged quaternary
polymers (those polymers with quaternary amines such as
Polyquaternium 4, 10, 24, 32, and 37, described below) as well as
protonated primary, secondary, and tertiary amine functional
polymers that have been protonated with a suitable protonic acid.
Preferred protonated cationic polymers are based on tertiary
amines. The protonated cationic polymers are preferably protonated
with suitable acids that will not result in undue skin irritation.
These include, for example, (C1-C10)alkylcarboxylic acids
optionally substituted by oxygen (e.g., acetic acid, alpha-hydroxy
acids such as lactic acid, gluconic acid, benzoic acid, mandelic
acid, and the like), (C1-C10)alkylsulfonic acids (e.g.,
methylsulfonic acid and ethylsulfonic acid),
(C1-C10)alkylhydrogensulfates (e.g., methylhydrogensulfate) and
mineral acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, and the like).
[0191] The charge on protonated cationic polymers is pH dependent.
For this reason, in order to ensure the polymer is sufficiently
protonated, the pH is adjusted appropriately and should be in the
range of preferably 2-9.5, more preferably 2-8, and most preferably
2.5-7.5. The pH of preferred compositions that include acidic
enhancers should be lower and is typically 2-5, and preferably 2-4.
It should be noted that it is not necessary to have all of the
amines on a particular polymer protonated. The level of protonation
will to a certain extent be pH dependent. With certain polymers in
order to obtain optimum thickening with low skin irriation it may
be beneficial to only protonate a small percentage of the available
amine groups while with other polymers it may be beneficial to
protonate substantially all of the amine groups. This will be
easily determined by one skilled in the art.
[0192] The quaternary, tertiary, secondary, and primary amine
functional polymers may be chosen from natural polymers, modified
natural polymers, as well as synthetic polymers. These polymers may
be soluble or swellable in the aqueous solvent. Furthermore, these
polymers may also possess hydrophobic side chains and thus be
associative polymers.
[0193] Polymers can be classified as soluble, swellable, or
associative in the aqueous compositions. Some polymers may fall
into one or more of these classes. For example, certain associative
polymers can be soluble in the aqeuous system. Whether they are
considered soluble, swellable, or associative in the aqueous
system, suitable polymers for use in the compositions of the
present invention may be film forming or not. Film forming polymers
may retain the active antimicrobial component at the afflicted site
for longer periods of time. This may be desirable for certain
applications. For example, some film forming polymers may produce
compositions that could not be easily washed off with water after
being applied and dried.
[0194] As used herein, a soluble polymer is one that in dilute
solution (i.e., 0.01-0.1 wt-% in the desired aqueous solvent system
defined as containing water and any other hydrophilic compounds),
after heating for a sufficient time to ensure solubilization of any
potentially soluble components, has no significant observable
particles of greater than 1 micron in particle size, as determined
by light scattering measurements using, for example, Malvern
Masterisizer E Laser Particle Size Analyzer available from Malvern
Co., Boston, Mass.
[0195] As used herein, a swellable polymer is one that in dilute
solution (i.e., 0.01-0.1 wt-% in the desired aqueous solvent
system), after heating for a sufficient time to ensure
solubilization of any potentially soluble components, has a
significant (i.e., detectable) number of observable particles of
greater than 1 micron in particle size, as determined by light
scattering measurements using, for example, Malvern Masterisizer E
Laser Particle Size Analyzer.
[0196] As used herein, an associative polymer is one that has
greater than 2 hydrophobic chains per polymer molecule of greater
than 16 carbon atoms. Examples of such polymers are as follows.
[0197] Soluble Polymers--Cationic Natural Polymer Derivatives.
Cationic modified cellulosic polymers are reported in the
literature to be soluble in water. Such polymers have been found to
be useful in the present invention. The most preferred modified
cellulose products are sold under the trade names CELQUAT (National
Starch and Chemicals Corp., Bridgewater, N.J.) and UCARE (Amerchol
Corporation, Edison, N.J.). CELQUAT is a copolymer of a
polyethoxylated cellulose and dimethyldiallyl ammonium chloride and
has the Cosmetic, Toiletry and Fragrance Association (CTFA)
designation Polyquaternium-4.
[0198] An alkyl modified quaternary ammonium salt of hydroxyethyl
cellulose and a trimethyl ammonium chloride substituted epoxide can
also be used. The polymer conforms to the CTFA designation
Polyquaternium 24 and is commercially available as QUATRISOFT
LM-200 from Amerchol Corp., Edison, N.J.
[0199] A particularly suitable type of cationic polysaccharide
polymer that can be used is a cationic guar gum derivative, such as
guar hydroxypropyltrimonium chloride (Commercially available from
Rhone-Poulenc under the trade designation JAGUAR).
[0200] Soluble Polymers--Cationic Synthetic Polymers. Synthetic
cationic linear polymers useful in the present invention are
preferably quite high in cationic charge density--generally having
greater than 10 wt-% cationic monomer, preferably greater than 25
wt-%, and more preferably greater than 50 wt-%. This ensures a good
cosmetic feel and may actually improve water solubility. In
general, the polymers useful in the present invention have
sufficient molecular weight to achieve thickening at generally less
than 5 wt-% polymer, but not too high that the
lotion/cream/ointment feels slimy and stringy. While the
composition of the polymer will dramatically affect the molecular
weight at which sufficient thickening will occur, the polymers
preferably have a molecular weight of at least 250,000 daltons, and
more preferably at least 500,000 daltons. The polymers preferably
have a molecular weight of no greater than 3,000,000 daltons, and
more preferably no greater than 1,000,000 daltons. The homopolymers
are preferably prepared from methacryloyloxyalkyl trialkyl ammonium
salt, acryloyloxyalkyl trialkyl ammonium salt, and/or quaternized
dialkylaminoalkylacrylamidine salt. Preferably the polymers are
copolymers of at least two monomers selected from the group
consisting of trialkylaminoalkyl acrylate and methacrylate salts,
dialkyldiallyl ammonium salts, acrylamidoalkyltrialkyl salts,
methacrylamidoalkyltrialkyl salts, and alkyl imidazolinium salts,
N-vinyl pyrrolidinone, N-vinyl caprolactam, methyl vinyl ether,
acrylates, methacrylates, styrene, acrylonitrile, and combinations
thereof. Typically, for the salts the counterions are preferably
F.sup.-, Cl.sup.-, Br.sup.-, and
CH.sub.3(CH.sub.2).sub.nSO.sub.4.sup.- where n=0-4.
[0201] A variety of quaternary copolymers of varying
quaternization, can be synthesized based on homo or copolymers of
amino acrylates with methyl, ethyl, or propyl side chains. These
monomers could also be copolymerized with other nonionic monomers
including quaternary acrylic homopolymers, such as homopolymers of
2-methacryloxyethyl trimethylammonium chloride and
2-methacryloxyethyl methyl diethyl ammonium bromide; and copolymers
of quaternary acrylate monomers with a water-soluble monomers, such
as Petrolite Product No. Q-0043, a proprietary copolymer of a
linear quaternary acrylate and acrylamide at high molecular weight
(4-5 million MW).
[0202] Another useful soluble cationic polymer is
N,N-dimethylaminopropyl-- N-acrylamidine (which is quaternized with
diethylsulfate) bound to a block of polyacrylonitrile. This block
copolymer is available under the trade designation Hypan QT-100
from Lipo Chemicals Inc., Paterson, N.J. It is quite effective at
thickening aqueous systems and has a good cosmetic feel. This
polymer as received, however, has an objectionable amine odor. The
odor could probably be masked with the proper fragrance, but is
preferably removed prior to formulation (e.g., with a solvent
cleaning process) so that the formulation can be supplied without
fragrance.
[0203] Suitable cationic polymers include, for example, copolymers
of 1-vinyl-2-pyrrolidine and 1-vinyl-3-methyl-imidazolium salt
(e.g. chloride salt), referred to in the industry by the Cosmetic,
Toiletry, and Fragrance Association, (CTFA) as Polyquaternium-16.
This material is commercially available from BASF Wyandotte Corp.
(Parsippany, N.J., USA) under the LUVIQUAT tradename (e.g. LUVIQUAT
FC 370); copolymers of 1-vinyl-2-pyrrolidine and dimethylaminoethyl
methacrylate, referred to in the industry (CTFA) as
Polyquaternium-11. This material is available commercially from Gaf
Corp., Wayne, N.J., under the trade designation GAFQUAT; cationic
diallyl quaternary ammonium-containing polymers including, for
example, dimethyldiallyammonium chloride homopolymer and copolymers
of acrylamide and dimethyldiallylammonium chloride, referred to in
the industry (CTFA) as Polyquaternium 6 and Polyquaternium 7,
respectively.
[0204] Soluble Polymers-Nonionic. A variety of cellulosic ethers
are reported in the literature to be soluble in water. Materials in
this class that are nonionic and have been shown to be useful
include: methylhydroxypropylcellulose, available as BENECEL MP 943
from Aqualon, Wilmington, Del.; hydroxypropylcellulose, available
as KLUCEL (LF, GF, MF, HF) from Aqualon;
hydroxybutylmethylcellulose (3.5% hydroxybutyl and 30% methoxyl)
from Scientific Polymer Products, Ontario, N.Y.; and
hydroxyethylcelluloses, available under the trade designation
NATROSOL from Aqualon. Xanthan gum, guar, locust bean gum, and
other polysaccharides may also be suitable. These polymers may be
produced from plant sources or can be produced through microbial
cell culture. Protein thickeners such as gelatin and pectin may
also be useful.
[0205] Amine oxide polymers such as those described in U.S. Pat.
No. 6,123,933 and those commercially available under the trade
designation DIAFORMER Z-711, Z-712, Z-731, and Z-751 from Clariant
Corp. are useful. Additionally, zwitterionic polymers, such as
methacryloyl ethyl betaine/acrylate copolymer that are commercially
available under the trade designation DIAFORMER Z-400 from Clariant
Corp. can also be used. Zwitterionic polymers described in U.S.
Pat. No. 6,590,051 may also be useful.
[0206] Carboxylic acid functional polymers including naturally
occurring carboxylic acid functional polymers such as hyaluronic
acid and derivatives of natural polymers such as
carboxymethylcellulose, alginic acid and other alginate polymers,
Fucogel (a polysaccharide consisting of three mono-saccharides,
fucose, galactose, and galacturonic acid), hyaluronic acid, and the
like, also may be useful. Synthetic polymers may also be useful,
such as those based on carboxylic acid, phosphonic acid, or
sulfonic acid functional monomers, including but not limited to,
polymers derived from acrylic acid, methacrylic acid, maleic
anhydride, itaconic anhydride, sodium AMPS (the sodium salt of
2-acrylamido-2-methylpropane sulfonic acid), sulfopropyl acrylate
or methacrylate, sulphomethylated acrylamide, allyl sulphonate,
sodium vinyl sulphonate, combinations thereof, or other
water-soluble forms of these or other polymerizable carboxylic or
sulphonic acids.
[0207] Swellable Polymers. Many swellable polymers, which are
slightly crosslinked, function as viscosifiers in aqueous solvent
systems. In general, these swellable polymers are preferred because
they tend to be far less "slimy" going on and once the hands
perspire and are exposed to water after treatment. Excessive
crosslinking will result in polymers that do not swell sufficiently
to increase the viscosity of the composition. In order to ensure
adequate swelling, if a chemical crosslinker is used, the
concentration of crosslinker is quite low, e.g., less than about
1000 parts per million (ppm), and preferably less than 500 ppm,
based on the weight of the dry polymer.
[0208] A class of crosslinked polymers suitable for use in the
compositions of the present invention include acrylamide and at
least one other quaternary monomer selected from the group
consisting of trialkylaminoalkylacrylate and methacrylate salts,
dialkyldiallyl ammonium salts, acrylamidoalkyltrialkyl ammonium
salts, methacrylamidoalkyltrialkyl ammonium salts, and monomers
that include imidazolinium salts. The counterions are preferably
F.sup.-, Cl.sup.-, Br.sup.-, and
CH.sub.3(CH.sub.2).sub.nSO.sub.4.sup.- where n=0-4. Other
comonomers may also be added including N-vinyl pyrrolidone, N-vinyl
caprolactam, methyl vinyl ether, acrylates, methacrylates, styrene,
and the like. A particularly preferred polymer is a
poly(2-methacryloxyethyl trimethyl ammonium chloride)
polydimethylaminoethyl methacrylate, which conforms to the CTFA
designation Polyquaternium 37. Another preferred polymer includes
acrylamide and methacryloyloxyethyl trimethyl ammonium chloride,
which conforms to the CTFA designation Polyquaternium 32. These are
commercially available from Allied Colloids Inc. of Suffolk, Va. as
SALCARE SC95, SC96, and SC92.
[0209] Other swellable polymers (i.e., slightly crosslinked
polymers) can be prepared using ionizing radiation to crosslink.
For example, polymers of N-vinyl lactams, such as N-vinyl
pyrrolidone, when exposed to gamma radiation increase in molecular
weight and may actually crosslink. This crosslinking allows for
more efficient thickening (less polymer required to achieve a
certain viscosity) and an improved cosmetic feel. Other polymers
that when exposed to gamma radiation result in crosslinking,
include polymers such as LUVIQUAT HM 552 (copolymers of
vinylimidazolium methochloride and vinylpyrrolidone, which conforms
to the CTFA designation Polyquaternium-16), and GAFQUAT HS-100
(vinylpyrrolidone/methacrylamidopropyltrimethylammonium chloride
copolymer which conforms to the CTFA designation
Polyquaternium-28).
[0210] Chemical crosslinking using polyunsaturated monomers such as
diallyl maleate may also prove useful. Other suitable crosslinkers
are multi-ethylenically unsaturated compounds wherein the ethylenic
groups are vinyl groups (including substituted vinyl groups, such
as isopropenyl groups), allyl groups, and/or methallyl groups,
which groups are bonded to nitrogen or oxygen atoms. Vinyl, allyl,
and methallyl groups, as used herein, include substituted
derivatives. Exemplary compounds include divinyl, diallyl, or
dimethallyl esters, ethers, amides, or ureas. Specific examples are
disclosed in U.S. Pat. No. 5,225,473 (Duan) and U.S. Pat. No.
4,931,282 (Asmus et al.).
[0211] A range of crosslinked polyvinylpyrrolidone (PVP) materials
have been prepared via covalent crosslinking with diallyl maleate
or by radiation crosslinking of linear PVP powders. Crosslinked PVP
prepared under these techniques can produce colloidal particles
which are highly swellable in aqueous solutions and thereby produce
viscous solutions. The polymers are also nonionic and have
excellent compatibility with cationic excipients.
[0212] Anionic swellable polymeric thickeners may also be useful.
As described above preferred anionic polymers for use with
antimicrobial compositions which include carboxylic acid functional
enhancers (and are thus formulated at lower pH) are polymers having
sulfonic acid, sulfonate, phosphonic acid, or phosphate groups.
[0213] Associative Polymers. Associative polymers can be used to
thicken the compositions of the present invention as well. Such
polymers thicken as a result of hydrophobic or Van de Waals
association of hydrophobic side chains. Such associative polymers
can form viscous to gelled aqueous solutions despite their
relatively low molecular weights. Polymers that are alcoholic
soluble can be modified by the addition of a long chain hydrophobic
group. A preferred class of such associative polymers are based on
nonionic ethylenically unsaturated monomers wherein at least one
comonomer has at least 16 carbon atoms.
[0214] An example is cetyl hydroxyethylcellulose, available as
NATROSOL PLUS from Aqualon, which utilizes an associative mechanism
to enhance the viscosity it produces. Grafted side chains of cetyl
alkyl groups can associate with neighboring alkyl hydrophobes.
These interpolymer associations can dramatically increase the
viscosification efficiency of the polymer. Longer chain alklyl,
alkenyl, and aralkyl groups may also be suitable. For example,
another preferred associative polymer is Arsitoflex HMB, which is
ammonium acryloyldimethyltaurate/beheneth-25 methacrylate
crosspolymer and is available from Clariant Corp.
[0215] Viscosity
[0216] Certain preferred compositions of the present invention have
a viscosity of at least 500 Centipoise (cps) for ease of
application topically. More preferably, compositions of the present
invention have a viscosity of at least 1,000 cps, even more
preferably at least 10,000 cps, even more preferably at least
20,000 cps, even more preferably at least 50,000 cps, even more
preferably at least 75,000 cps, even more preferably at least
100,000 cps, and even more preferably at least 250,000 cps (and
even as high as about 500,000 cps, 1,000,000 cps, or more). Lower
viscosity compositions can be used, however, in certain
applications, such as for the treatment of middle ear infection and
chronic sinusitis. For example, afflictions of the middle ear
(e.g., otitis media or infection of the middle ear) may be treated
with compositions of the present invention having a viscosity lower
than 1000 cps more readily by administration through the nose and
into the Eustachian tubes.
[0217] Delivery
[0218] In the methods of the present invention, the antimicrobial
compositions may be provided as a formulation suitable for delivery
to skin and/or mucosal surfaces, for example. Suitable formulations
can include, but are not limited to, creams, gels, foams,
ointments, lotions, balms, waxes, salves, solutions, suspensions,
dispersions, water in oil or oil in water emulsions,
microemulsions, pastes, powders, oils, lozenges, boluses, and
sprays, and the like. Spray formulations may include propellents
such as those common to the industry including but not limited to
dimethyl ether, lower alkanes such as propane and butane, HCFCs,
perflouroalkanes, and the like. In some embodiments, compositions
of the present invention can be formulated into various consumer
products, such as deodorants, shampoos, shower gels, detergents,
household cleaning products, etc.
[0219] Topical antimicrobial treatment regimens according to the
practice of this invention include applying a safe and effective
amount of the compositions described herein directly to the
infected or at-risk skin or mucous membrane; particularly, the
nasal nares and passages that are particularly susceptible to
microbial contamination. Compositions of the present invention can
be delivered using a variety of techniques. Typically, the
compositions are delivered to the skin and/or mucosal tissue in a
manner that allows them to penetrate into the skin and/or mucosal
tissue, as opposed to through the tissue into the blood stream.
This concentrates the compositions locally at the site in need
thereof. This can be accomplished by spraying, dipping, wiping,
dropping, pouring, toweling, or the like, onto the area to be
treated.
[0220] Various modes of administration can be used as needed. For
example, afflictions of the middle ear (e.g., otitis media or
infection of the middle ear) may be treated with compositions of
the present invention by administration through the nose and into
the Eustachian tubes or they can be instilled directly into the
middle ear through the tympanic membrane. The formulations may
traverse the tympanic membrane with the aid of a syringe or do so
by diffusion. Penetration enhancers may be used to enhance
diffusion across the tympanic membrane. Various other methods will
be well known to one of skill in the art depending on the desired
location for contact of the antimicrobial compositions of the
present invention.
[0221] An antimicrobial composition may be applied to a mucosal
surface with the use of a delivery device such as cervical caps,
diaphragms and solid matrices such as tampons, cotton sponges,
cotton swabs, foam sponges, and suppositories. Accordingly,
compositions of the present invention can also be incorporated in
(e.g., impregnated into) cloth, sponges, paper products (e.g.,
paper towels, towelletes, and wipes), tampons, undercast padding,
and dental floss, for example.
[0222] In some embodiments, an applicator may be used to place the
device and/or antimicrobial composition in the proper location, for
example, on the mucosal surface of a vagina, nasal cavity, rectum,
or the like. Examples of such applicators include, for example,
cardboard or plastic tube applicators commonly used for inserting
tampons or suppositories.
[0223] Also, compositions of the present invention can be coated
onto medical devices that contact skin, mucous membranes, wounds,
etc. Examples of such devices include catheters such as urinary
tract catheters and vascular access catheters.
[0224] The dose and frequency of application will depend on many
factors including the condition to be treated, the concentration of
antimicrobial lipid and enhancer, the microbe to be killed, etc.
Typically, the compositions will be delivered in dosages of 0.1
gram to 5 grams for most applications. Application can be made
once, or preferably several times daily for one or more days.
Typically the composition is applied 1 or 2 times/day for 1-7 days.
For example, decolonization of the anterior nares may require a
dose of 0.25 gram (g) per nare applied 1-3 times per day for 1-5
days. Treatment of impetigo may require about 0.5 g/15 cm.sup.2
applied 1-3 times/day for 3-10 days.
Test Protocols
[0225] Antimicrobial Kill Rate Test
[0226] Antimicrobial compositions were challenged with test
cultures of Methicillin Resistant Staphyloccus aureus (MRSA) #MS
16266 and Staphylococcus aureus (S. aureus), ATCC #25923
(commercially available from American Type Culture Collection,
Rockville, Md.), Escherichia coli (E. coli), ATCC # 11229, and
Pseudomonas aeruginosa (Pseudomonas ae.), ATCC # 15442.
[0227] Bacteria Culture Preparation:
[0228] Bacteria were grown in Tryptic Soy Broth (TSB) (commercially
available from Difco, Detroit, Mich.) at 35.degree. C. for 18-24
hours (hrs). A 0.3 milliliter (ml) culture suspension was spread on
the surface of a Tryptic Soy Agar plate that was incubated at
35.degree. C. for 18-24 hrs. Bacterial cells were harvested from
the agar plate with a glass L-rod by adding 3 ml of TSB and were
transferred into a snap cap 5 ml polypropylene culture tube. The
resulting cell suspension was called the working culture.
[0229] Ointment Test Procedure:
[0230] A 50 ml centrifuge tube was filled with 10 ml of each
ointment antimicrobial composition. The tube was placed in a
temperature controlled water bath equipped with stirring
capability. The temperature of the composition was adjusted to
40.degree. C. +/-2.degree. C. where most of the compositions became
softened and could be easily mixed. Other compositions may require
higher or lower temperatures. Importantly, the temperature should
not be increased above about 45.degree. C. at which point the
bacteria will perish from temperature effects. It should be
confirmed that the temperature did not kill the bacteria in the
absence of the antimicrobial composition.
[0231] Liquid Test Procedure:
[0232] A 25 ml Erlenmeyer flask containing a magnetic stirring bar
was filled with 20.0 ml of a liquid antimicrobial composition. The
flask was placed in a temperature controlled water bath equipped
with stirring capability. The magnetic stirrer was turned on and
temperature of the composition was adjusted to 23.degree. C.
+/-2.degree. C.
[0233] Exposure of Bacteria to the Compositions:
[0234] At the start of each exposure time, 0.1 ml of Methicillin
Resistant Staphyloccus aureus, Staphylococus aureus, Escherichia
coli, or Pseudomonas aeruginosa working culture was added to the
antimicrobial composition. The exposure times were 2 minutes, 5
minutes and 10 minutes. At the end of each exposure time, 1 ml of
suspension was transferred to a test tube containing 9 ml Letheen
broth (VWR Scientific, Batavia, Ill.) at 23.degree. C. or
40.degree. C. (10.sup.-1 cell suspension). After vortexing, the
neutralized 10.sup.-1 cell suspension was further diluted to
10.sup.-2 by transferring 1 ml into 9 ml Letheen broth tubes. From
each of the two dilutions, 0.1 ml volume was plated onto a TSA
plate and spread with the L-rod producing 10.sup.-2 and 10.sup.-3
dilutions. The plates were incubated at 35.degree. C. .+-.2.degree.
C. for 48 hrs and colony-forming units (CFU) were counted and
recorded. The procedure was repeated using three to five replicate
samples of each composition. The diluted bacterial suspensions were
plated in duplicate.
[0235] Data Analysis:
[0236] Microbial kill rate was reported as a log.sub.10 reduction
which was determined by calculating the difference between the
log.sub.10 of the initial inoculum count and the log.sub.10 of the
inoculum count after exposure to compositions or components of the
composition for 2-minute (T.sub.2), 5-minute (T.sub.5), and
10-minute (T.sub.10) intervals.
[0237] The two duplicate plates at the selected dilution level were
averaged and the initial inoculum count was calculated using the
following formula:
Initial Inoculum Count=T.sub.0=Ave. CFU of 3
replicates.times.1/dilution level.times.0.005
[0238] Where the sample inoculums were diluted (0.1 ml in 10 ml of
the compositions, the initial inoculum were reduced by 0.1 ml/10
ml, which equals 0.010).
[0239] For the test plates of each organism at each time period,
the CFU's on all the 10.sup.-2 and 10.sup.-3 plates were counted.
The dilution level that had counts between 25 and 250 was
determined. The two duplicate plates at the selected dilution level
were averaged and the test plate count at the given time was
calculated using the following formula:
T.sub.2, T.sub.5, and T.sub.10=CFU of 3 replicates.times.1/dilution
level
[0240] where the plate count of 3 replicates are at 2 minute, 5
minute, and 10 minute intervals, respectively.
[0241] For the compositions the log reduction was determined by
taking the logarithm to the base 10 of T.sub.0, T.sub.2, T.sub.5,
and T.sub.10 and using the following formulas:
Log reduction at 2 minutes=log.sub.10T.sub.0-log.sub.10T.sub.2
Log reduction at 5 minutes=log.sub.10T.sub.0-log.sub.10T.sub.5
Log reduction at 10
minutes=log.sub.10T.sub.0-log.sub.10T.sub.10
[0242] The average of the replicates was calculated by averaging
the log reductions at each time period.
[0243] Aging Study Using Gas Chromatography
[0244] Antimicrobial Compositions were prepared and while in a
well-mixed, liquid state, were poured into individual vials to
solidify. The zero time (To) vials were refrigerated at 4.degree.
C. and the other vials were placed in a LAB LINE Orbital
Environmental Incubator and incubated at either 23.degree. C. or
40.degree. C. and 65.degree. C. at 200 RPM. Compositions incubated
at 65.degree. C. were in the liquid state. These compositions were
incubated with and without shaking to see if agitation contributed
to loss of GML. One vial of each composition was removed after 7
days and after 4 weeks. After they were removed, they were shaken
until they solidified and refrigerated at 4.degree. C. until
assayed.
[0245] The internal standard, which was used for all extractions,
contained 0.4 mg/ml monodecyl glycerol (GMC.sub.10) from
Sigma-Aldrich in chloroform and was prepared and stored in a clean
glass bottle which was sealed with a TEFLON lined screw cap. At the
time of assay, methanol was mixed with the stock standard in the
ratio of 2 parts chloroform to 1 part methanol giving a stock
internal standard which was 0.267 mg/ml in GMC.sub.10.
[0246] The stock standard (1.8 mg/ml) was prepared by adding 18 mg
of GML from Sigma-Aldrich to a tared 10 ml volumetric flask,
recording the exact weight, filling it to the mark with the stock
internal standard, and mixing it well. The solution was transferred
to a clean glass vial, which was sealed with a TEFLON lined screw
cap.
[0247] The working standard was diluted using volumetric pipettes,
additional stock internal standard, and clean glass vials according
to the following scheme.
1 Volume of Standard Volume of Internal GML level Standard Standard
Standard (mg/ml) 1 Stock 5 5 0.9 2 Standard 1 2 4 0.3 3 Stock 1 8
0.2 4 Standard 3 3 3 0.1
[0248] The dilutions were stored in clean glass vials and sealed
with TEFLON lined screw caps.
[0249] All test samples and matrices were allowed to reach room
temperature before assay. They were mixed well by stirring with
clean glass rods. Using graduated pipettes and clean glass vials
which held 7-8 ml, the extractions were performed as follows:
Triplicate 50 mg samples of each aged composition were added to
tared vials and the exact weights recorded. (For samples that were
emulsions with a larger droplet size, larger samples were needed to
ensure a uniform sample. In those cases, a larger sample size was
obtained and processed proportionately.) To these 5.0 ml of
internal standard were added. The samples were mixed until they
dissolved or were evenly dispersed and then 1.7 ml of 0.4 weight
percent potassium chloride solution was added to each. The vials
were capped, vortexed for 1 minute, and then centrifuged at top
speed on a clinical centrifuge (IEC) until 2 clear phases resulted
(3-5 minutes). The lower phase (organic) was separated from the
upper phase (aqueous) by suction using a Pasteur Pipette, which had
been inserted through the upper phase. It was transferred to a
second vial containing a small amount (approximately 200 milligrams
(mg)) of sodium sulfate in order to dry the sample. A portion was
then transferred to an auto sampler for GC analysis.
[0250] Single extracts of each of the four standards were made in
the same manner as the samples except that 50 mg of formulation
matrix (formulated without GML, with the difference made up with
another component (petrolatum or glycerin for Comparative Example
D)) was added to each extraction vial followed by 5.0 ml of each of
the working standards. An internal standard blank was also
extracted as well as a sample matrix without any internal
standard.
[0251] The order of analysis was: Internal Standard blank,
standards (lowest to highest), solvent blank, samples (in random
order), and calibration checks every 16 injections and at the end
(level 2 standard). Each sample and standard was injected once.
[0252] The Gas Chromatography Conditions were:
2 Instrument HP 5890 or 6890 Column 15 meter ZB-5, 0.25 micon
(.mu.) film 0.25 mm ID Carrier He, 22 pounds per square inch (psi)
constant pressure (6890-constant flow 1 millilters per minute
(ml/min)) Injection 2 microliter (.mu.l) split 1:60, injector temp
350.degree. C. Liner Restek SILTEK deactivated liner with SILTEK
deactivated glass wool (Cat. No. 22406-213.5) Program 110.degree.
C. initial, 4.degree. C./min to 210.degree. C., 25.degree. C./min
to 350.degree. C., hold 5 minutes (min) Detector FID at 350.degree.
C.
[0253] The triplicate samples of each time point were prepared and
analyzed once. The area ratio of GML/internal standard (GMC.sub.10)
was converted into mg GML/sample using the standard curves, which
was then divided by the sample weight (100 mg) and multiplied by
100 to obtain a weight percent of GML in the sample. The weight
percent from each of the triplicate samples were then averaged and
a standard deviation was obtained.
[0254] Good linearity was obtained with correlation coefficient,
R>0.999 over the range of analysis. Response factors for the
standard calibration checks were less than or equal to 2.6 percent
of that standard in the initial curve.
[0255] Emergence of Resistance Test
[0256] Overnight cultures of each of 30 MRSA isolates and 30
Methicillin Susceptible Stapyloccus aureus (MSSA) isolates were
grown in Mueller-Hinton broth (MHB) at 35.degree. C. in room air.
Bacteria in the broth were concentrated by centrifugation for 15
minutes at 2,200 revolustions per minute (rpm). The spent broth was
decanted and replaced with fresh MHB containing 0.5 .mu.L per mL of
each of three antimicrobial compositions (Examples 31 (IPA), 32
(IPA), and 33 (IPA)) or 0.125 .mu.g/mL of mupirocin lithium salt
(Sigma Aldrich, Milwaukee, Wis.). The cultures were returned to the
incubator for 18 hours. Following incubation, each culture was
again centrifuged and the bacterial pellet was divided into two
aliquots. One aliquot was resuspended in MHB containing fresh
antimicrobial compositions at twice the previous concentrations and
returned to the incubator for continued exposure.
[0257] The second aliquot was screened for MRSA and MSSA by
incubation with 2 mL of MHB containing 4 .mu.g/mL of mupirocin or
1,200 .mu.g/mL of Examples 31 (IPA) or 32 (IPA) or 33 (IPA). The
resistance screens were incubated overnight at 35.degree. C. in
room air. After incubation, each screen was subcultured to fresh
MHB and incubated for 4 to 6 hours. Minimum inhibitory
concentration (MIC) testing was performed on logarithmically
growing bacteria recovered from the screen. This procedure was
repeated for 8 days. After 8 days of serial exposure, each
bacterial pellet was resuspended in bland MHB and incubated
overnight. The MIC of each antimicrobial composition or mupirocin
was determined as the MIC.sub.90 (range) before and daily during
serial passage.
[0258] Viscosity Test
[0259] In the following Examples (except where indicated) viscosity
was measured at 23.degree. C. at ambient pressure using a
Brookfield LVDV-I.sup.+ viscometer equipped with a model D
Brookfield heliopath and T spindles B-F. The spindle and speed was
chosen for each particular sample such that the viscometer was
operating in the middle of its range. All samples were allowed to
equilibrate at 23.degree. C. for 24 hours prior to measurement.
Preferably the viscosity is taken at the lowest speed possible
while staying within 20-80% of the viscometer range and more
preferably between 30-70% of the range. In all cases the sample
size and container geometry was chosen to ensure that there were no
wall effects. By "wall effects" it is meant the viscosity value is
not affected by the container and is essentially equivalent to the
viscosity taken in an infinitely large container. For this reason
lower viscosity samples required a larger sample size to
accommodate the larger spindles. The following table outlines
preferred spindles for various sample viscosities.
3 Sample Viscosity T Spindle to Use 1,000-100,000 B 1,000-200,000 C
5,000-500,000 D 10,000-1,250,000 E .sup. 500,000-3,000,000.sup.
F
[0260] The viscosity of each sample was taken as the highest
relatively stable reading achieved on the first path the spindle
traversed using the heliopath adapter.
EXAMPLES
[0261] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to unduly limit
this invention.
Glossary of Components
[0262]
4 Acronym Trade Name Description Source/Address GML LAURICIDIN
Glycerol monolaurate MedChem Laboratories, Inc./Galena, IL PURAC
Lactic Acid (88%) Purac America/ HIPURE 88 Lincolnshire, IL
Mandelic Acid Sigma-Aldrich/ St. Louis, MO Benzoic acid
Mallinckrodt Baker Inc./Paris, KY Salicylic acid Mallinckrodt Baker
Inc. C.sub.10H.sub.23 glycerin ether (Preparation described in
Example 18) Propylene glycol Uniquema/ monocaprate Wilmington, DE
CRODAPHOS PPG-5 ceteth-10 Croda Inc./ SG phosphate Parsipanny, NJ
DOSS, COMPLEMIX Dioctylsulfosuccinate, Cytec Industries/ 100%
sodium salt (Docusate, West Paterson, NJ sodium) DOSS, AEROSOL GPG
Dioctylsulfosuccinate, Cytec Industries 70% sodium salt, 70% in
ethanol/water POLYSTEP Sodium laureth-4 Stepan Company/ B12 sulfate
Northfield, IL MACKAM Lauramidopropylhydroxy McIntyre Group Ltd./
50-SB sultaine University Park, IL HOSTAPUR Sodium C14-C17 Sec
Clariant Corp./ SAS 93G alkyl sulfonate, 93% Charlotte, NC solids
HOSTAPUR Sodium C14-C17 Sec Clariant Corp SAS 60 alkyl sulfonate,
60% solids LMDO AMMONYX Lauramidopropyldimethy Stepan Company LMDO
lamine oxide HYDROLITE 5 1,2 pentane diol Dragoco Inc./ Totowa, NJ
PEG-400 CARBOWAX Polyethylene glycol, Union Carbide 400 MW = 400
DMI ARLASOLVE dimethylisosorbide Uniqema DMI NIAX LG650 Glycerin
initiated Lyondell Chemical polypropylene glycol, Worldwide Inc./
equivalent wt = 89 Houston, TX DOWANOL Tripropyleneglycol Sigma
Aldrich TPnB Glycerin USP Mallinkrodt Baker Inc. Pet Snow White
White Petrolatum Penreco PET USP White beeswax Acros PRISORINE
Isopropyl isostearate Unichem 2021 FINSOLV TN C.sub.12-C.sub.15
benzoate Finetex ester IPM Isopropyl myristate Cognis Corp./
Houston, TX CRODAMOL Glycerol Croda Inc. GTCC tricaprylate/caprate
FILIPPOBENO Olive oil, Imported by Salov Olive Oil 100% Olive Oil
North America Corp./ Hackensack, NJ CETIOL OE Dioctylether Cognis
Corp. Mineral oil, USP Paddock Laboratories Inc./Minneapolis, MN
BHA Butylated Eastman Chemical/ hydroxyanisole Kingsport, TN EDTA
Sodium salt of W. R. Grace/ (Na).sub.2 ethylene diamine Nashua, NH
tetraacetic acid Methyl paraben Nipa/Wilmington, DE Propyl paraben
Nipa/Wilmington, DE Glycolic acid Sigma-Aldrich PLURONIC
Poloxamer/block BASF Corp./ P-65 copolymer of Parsippany, NJ
propylene oxide and ethylene oxide ARISTOFLEX Ammonium Clariant
Corp. HMB acryloyldimethltaurate/ beheneth 25 methacrylate
crosspolymer SALCARE Copolymer of acrylamide Ciba Specialty SC92
and Chemicals Corp./ trimethylaminoethylmeth High Point, NC
acrylate chloride salt NATROSOL Cetyl hydroxyethyl Hercules,
Aqualon PLUS TYPE cellulose Division/Wilmington, DE
Examples 1-2 and Comparative Example A
[0263] Antimicrobial compositions were prepared using the
components shown in Table 1a. White petrolatum was heated in a
beaker to at least approximately 82.degree. C. In another beaker,
glycerin and DOSS were heated until the DOSS was dissolved and this
solution was allowed to cool to approximately 82.degree. C. Next
the contents of the first beaker was mixed with the contents of the
second beaker with a mixing propeller. Mixing was continued until
the mixture cooled to 71.degree. C. at which point the GML was
added and mixing continued as the mixture continued to cool. When
the mixture had cooled to about 54.degree. C., the lactic acid was
added and mixing continued until the composition was about to
congeal. Just before the composition congealed at approximately
43.degree. C., the composition was removed from the mixer and
poured into ointment jars.
5 TABLE 1a Components (weight percent) Lactic Example Acid DOSS
White No. GML (88%) (100%) Glycerin Petrolatum 1 3.02 1.11 0.97
9.82 85.08 2 3.01 1.13 0.00 10.00 85.86 Compar- 0.00 0.00 0.99
10.07 88.94 ative A
[0264] The compositions of Examples 1-2 and Comparative Example A
were evaluated using the Antimicrobial Kill Rate Test and the
results are shown in Table 1b.
6 TABLE 1b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 1 3.02 3.84 6.47 3.59 5.25
5.29 2 <3.02 3.02 3.14 2.88 3.54 3.16 Compar- 2.15 2.50 2.73
2.42 2.42 2.82 ative A
[0265] The results indicate that the full formulation of Example 1
had good kill against both MRSA (Gram positive) and E. coli (Gram
negative) organisms. The log reduction was in excess of 3.5 logs
after 5 minutes and 5 logs after 10 minutes. Elimination of the
surfactant from the formulation (Example 2) resulted in a
significant reduction in antimicrobial efficacy. Elimination of the
antimicrobial lipid and enhancer resulted in poor kill rate--less
than 3 log reduction after 10 min (Comparative Example A).
Examples 3-7
[0266] Antimicrobial compositions were prepared as described in
Examples 1-2 using the components shown in Table 2a. Mandelic acid
was ground into a fine powder using a mortar and pestle and added
to the glycerin and DOSS and heated to about 88.degree. C. for
Examples 3 and 4 or added directly to the hot, molten petrolatum at
about 82.degree. C. for Examples 5 and 6.
7 TABLE 2a Components (weight percent) Example Mandelic DOSS White
No. GML Acid (100%) Glycerin Petrolatum 3 3.00 1.00 1.00 10.00
85.00 4 3.03 0.92 0.00 10.11 85.94 5 3.00 1.00 1.00 0.00 95.00 6
3.00 1.00 0.00 0.00 96.00 7 2.97 0.90 0.00 0.96 95.17
[0267] Compositions of Examples 3-7 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table 2b
and 2c.
8 TABLE 2b MRS A (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 3 3.6 5.7 5.9 4.0 5.6 6.1 4
2.8 3.9 4.3 5.7 5.6 6.0 5 5.0 5.8 5.4 5.4 5.8 6.3 6 2.4 2.6 3.6 3.2
3.3 3.7 7 2.3 3.1 4.1 4.0 3.9 4.7
[0268]
9TABLE 2c Example Pseudomonas ae. (log reduction) No. After 2
minutes After 5 minutes After 10 minutes 3 4.4 6.4 6.5 4 3.3 4.2
5.1 5 4.0 4.6 5.7 6 2.9 2.9 3.2 7 2.9 3.6 3.9
[0269] Example 3 contained a hydrophilic component (glycerin) and
surfactant (DOSS) in addition to the antimicrobial lipid (GML) and
enhancer (mandelic acid). This sample had the best antimicrobial
activity overall, achieving greater than 5.9 log reduction against
all three organisms at 10 minutes. Example 4 contained no
surfactant (no DOSS), which led to a decrease in activity over
Example 3. Example 5 which contained no hydrophilic component had
decreased activity over Example 3 but the effect was not as great
as elimination of the surfactant. Example 6 containing no
hydrophilic component or surfactant showed relatively poor
antimicrobial activity. Addition of only 1% hydrophilic component
(Example 7) showed an improvement in antimicrobial activity.
Example 8
[0270] An antimicrobial composition was prepared using the
components listed in Table 3a. GML, isopropyl isosterate, beeswax
and FINSOLV TN were combined in a beaker, heated and stirred with a
propeller mixer until a clear solution was obtained. Stirring was
continued while cooling the solution to about 48.degree. C. when
the lactic acid was added. Stirring and cooling continued until the
temperature was 43.degree. C. when the composition was removed from
the mixer and poured into the ointment jar.
10 TABLE 3a Components (weight percent) Example Lactic White
Isopropyl FINSOLV No. GML acid (88%) Beeswax isosterate TN 8 10.00
1.00 20.00 29.00 40.00
[0271] The composition of Example 8 was evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table 3b
and 3c.
11 TABLE 3b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 8 >6.3 >6.3 >6.3
7.3 7.3 7.3
[0272]
12TABLE 3c Example Pseudomonas ae. (log reduction) No. After 2
minutes After 5 minutes After 10 minutes 8 8.0 8.0 8.0
[0273] The results indicated that the antimicrobial lipid plus
enhancer in a non-petrolatum-based petrolatum-based ointment had an
exceptional kill rate of MRSA, E. coli, and Pseudomonas ae.
Examples 9-16
[0274] Antimicrobial Compositions were prepared as described in
Examples 1-2 using the components shown in Table 4a. The
surfactants were added like DOSS in Example 1.
13 TABLE 4a Components (weight percent) Example Lactic Surfactant
Component No. GML acid Glycerin Type Amt. Type Amt. 9 3.00 1.00
10.00 CRODAFOS SG 2.00 Pet 84.00 10 3.00 1.00 10.00 DOSS (100%)
2.00 Pet 84.00 11 3.00 1.00 10.00 POLYSTEP B12 2.00 Pet 84.00 12
3.00 1.00 10.00 MACKAM 50-SB 2.00 Pet 84.00 13 3.00 1.00 10.00
HOSTAPUR SAS 93G 2.00 Pet 84.00 14 3.00 1.00 10.00 LMDO 2.00 Pet
84.00 15 3.00 1.00 10.00 DOSS (100%) 2.00 PEG 84.00 16 3.00 1.00
10.00 HOSTAPUR SAS 60 2.00 Pet 84.00
[0275] The compositions of Examples 9-16 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table
4b.
14 TABLE 4b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 9 6.41 6.17 6.41 5.29 5.56
2.65 10 3.33 3.38 6.17 5.85 5.54 6.14 11 5.74 6.41 5.88 3.49 4.34
6.11 12 4.18 5.05 5.90 2.63 2.80 4.47 13 5.73 6.11 6.11 6.03 6.23
6.23 14 3.45 5.16 5.78 2.69 3.40 4.05 15 6.11 6.11 6.11 6.23 6.23
6.23 16 5.73 5.02 6.22 6.07 6.17 6.17
[0276] The results indicated that Examples 9, 13, 15, and 16 had
exceptional kill rates (>5 logs) after only 2 minutes against
both MRSA and E. coli. The surfactants in these examples were
anionic (sulfate, sulfonate, and phosphate). Example 11 also had
very a good kill rate; however, the ethoxylation on this surfactant
may have contributed to the lower efficacy shown against E. coli at
the 2-minute and 5-minute time intervals. Example 10 contained
DOSS, which had an exceptional kill rate (>6 logs) against both
MRSA and E. coli after 10 minutes of exposure. Examples 12 and 14
contained zwitterionic and amine oxide surfactants, respectively,
and the kill rate, while still good, was not as good as that of the
anionic surfactants.
Example 17
[0277] The preparation of the C.sub.10H.sub.23 Glycerin Ether was a
two step process.
[0278] First isopropylidene glycerol was prepared by adding 100
grams (g) glycerol, 400 ml acetone, 0.65 g p-toluenesulfonic acid,
and 50 g of 3A molecular sieves to a 1-liter NALGENE bottle with a
cap. Rolling the bottle on a roller for 24 hours mixed the contents
of the bottle. Next 0.95 g potassium carbonate (K.sub.2CO.sub.3)
was added to the contents. The mixture was filtered, passed through
an activated alumina column, concentrated on a rotary evaporator,
and distilled using a water aspirator to pull a vacuum (boiling
point (bp) approximately 100.degree. C.). The final product was
then used to prepare glycerol ether.
[0279] Second a 1-liter round-bottomed flask was purged with
nitrogen and 500 ml xylene, 42 g isopropylidene glycerol, and 53.5
g potassium hydroxide (KOH) were added to the flask. The reaction
flask was fitted with an overhead stirrer and a Dean-Stark trap.
The contents were heated at reflux for approximately 15 hrs with
azeotropic removal of H.sub.2O. While continuing to heat at reflux,
61.4 g decyl bromide in 100 ml xylene was added dropwise to the
reaction. After the addition was completed, the reaction was heated
an additional 24 hrs at reflux. The contents were cooled,
transferred to a separatory funnel, washed with deionized water 5
times using 100 ml of water each time, dried over magnesium sulfate
(MgSO.sub.4), filtered and concentrated on a rotarevaporator. The
final product was distilled at reduced pressure (boiling point (bp)
was approximately 136.degree. C. at 0.5 millimeter (mm) Hg).
[0280] An antimicrobial composition was prepared using the
components in Table 5a. The white petrolatum was heated to
approximately 93.degree. C. and the DOSS and the glyceryl ether
were added to it while stirring using a mixing propeller. The
mixture was stirred while being held at 93.degree. C. until a clear
solution was formed. The mixture was allowed to start cooling with
continuous stirring. When the mixture reached approximately
65.degree. C. the glycerin was added and the cooling and stirring
continued. When the mixture reached approximately 49.degree. C. the
lactic acid was added and cooling and stirring continued until the
composition was about to congeal (approximately 38.degree. C.) and
then it was poured into an ointment jar.
15 TABLE 5a Components (weight percent) 88% C.sub.10H.sub.23
Example Lactic glycerin 100% White No. Acid ether DOSS Glycerin
petrolatum 17 1.13 1.46 1.02 10.07 88.94
[0281] The compositions of Example 17 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table
5b.
16 TABLE 5b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 17 3.16 3.70 4.51 4.68 5.88
5.47
[0282] The results indicated that over 3 log reductions after 2
minutes of exposure and over 4.5 log reductions after 10 minutes of
exposure occurred for both MRSA and E. coli using an antimicrobial
glycerin ether in combination with a enhancer (alpha-hydroxy
acid).
Example 18
[0283] An antimicrobial composition was prepared using the
components in Table 6a as described for Examples 1 and 2 but
propylene glycol monocaprate was substituted for GML.
17 TABLE 6a Components (weight percent) 88% Propylene Example
Lactic glycol 100% White No. Acid monocaprate DOSS Glycerin
petrolatum 18 1.12 3.01 1.00 9.92 84.95
[0284] The compositions of Example 18 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table
6b.
18 TABLE 6b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 18 6.54 6.54 6.54 5.64 5.88
5.88
[0285] The results indicated that the antimicrobial composition
containing propylene glycol monocaprate and an enhancer (lactic
acid, an alpha-hydroxy acid) achieved an exceptional kill rate
against MRSA (over 6 log reduction in 2 minutes) as well as an
exceptional kill rate against E. coli (over 5.5 log reduction in 2
minutes).
Example 19-24
[0286] Antimicrobial compositions were prepared as described for
Examples 1-2 using the components in Table 7a. However, hydrophilic
components were substituted for the glycerin.
19 TABLE 7a Components (weight percent) Example 88% 100%
Hydrophilic component White No. GML Lactic Acid DOSS Type Amt.
petrolatum 19 3.02 1.10 0.97 HYDROLITE 5 9.64 85.28 20 3.00 1.13
1.00 PEG 400 9.97 84.90 21 3.01 1.15 1.00 DMI 9.95 84.90 22 3.01
1.12 0.98 NIAX LG650 9.85 85.04 23 3.00 1.13 1.00 DOWANOL TPnB
10.05 84.82 24 1.45 1.13 0.98 Glycerin 9.89 86.55
[0287] The compositions of Examples 19 and 21-24 were evaluated
using the Antimicrobial Kill Rate Test and the results are shown in
Table 7b.
20 TABLE 7b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 19 >4.78 >4.78
>4.78 4.65 4.65 >4.65 21 3.10 >4.78 >4.78 2.07 3.67
4.42 22 3.1 4.18 4.69 2.07 3.67 4.42 23 4.78 >4.78 >4.78
>4.65 >4.65 >4.65 24 4.04 5.57 5.49 3.87 3.67 5.79
[0288] The results indicated that good kill rates were achieved
against both MRSA and E. coli (>4 log reduction at 10 minutes)
with a wide variety of hydrophilic components. The best results
appear to be in antimicrobial compositions containing small
molecule glycols (Examples 19 and 24) as well as with the
tripropyleneglycolmonobutyl ether (Example 23).
Examples 25-30
[0289] Antimicrobial compositions were prepared using the method
described for Examples 1-2 and the components in Table 8a. The
hydrophobic components were heated in a beaker to at least
approximately 82.degree. C. instead of the white petrolatum and the
hydrophilic components were substituted for the glycerin. In
Example 30 salicylic acid was substituted for lactic acid.
21 TABLE 8a Components (weight percent) 88% Hydrophilic Example
Lactic 100% Component Hydrophobic Component No. GML Acid DOSS Type
Amt. Type Amt. 25 3.01 1.11 0.99 Glycerin 9.89 CRODAMOL GTCC 84.99
26 3.01 1.11 0.97 Glycerin 9.69 Olive Oil 85.22 27 3.01 1.12 0.98
Glycerin 9.80 CETIOL OE 85.10 28 3.01 1.11 0.98 DMI 9.83 CRODAMOL
GTCC 85.08 29 3.01 1.12 0.99 Glycerin 9.83 Mineral oil 85.06 30
3.00 0.25.sup.1 1.00 DMI 9.97 CRODAMOL GTCC 85.77 .sup.1The
enhancer used was salicylic acid.
[0290] The composition of Example 28 was evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table
8b.
22 TABLE 8b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 28 6.45 >6.45 >6.45
4.62 5.88 >5.88
[0291] Example 28 had an exceptional kill rate against MRSA as well
as E. coli. The use of the DMI improved the composition's stability
over that of Example 25, which tended to split into distinct phases
upon standing.
Examples 31-33 and 31 (IPA)-33 (IPA)
[0292] Antimicrobial Compositions were prepared using the
components shown in Table 9a. White petrolatum and DOSS were placed
in a beaker and heated until a solution was formed at about
104.degree. C. While mixing with an overhead air mixer (Model No.
1AM-NCC-12, Gast, Benton Harbor, Mich.) glycerin and the acid
(enhancer) were added. Next the composition was cooled to
66.degree. C. and the GML was added while holding the temperature
between 60.degree. C. and 66.degree. C. When all of the components
were in solution, it was cooled to about 46.degree. C., removed
from the mixer, and poured into an ointment jar.
23 TABLE 9a Components (weight percent) Example Enhancer DOSS White
No. GML Type Amt. (100%) Glycerin Petrolatum 31 3.00 88% Lactic
1.00 1.00 10.00 85.00 Acid 32 3.00 Mandelic Acid 1.00 1.00 10.00
84.99 33 3.00 Benzoic Acid 0.50 1.00 10.00 85.49
[0293] The compositions of Examples 31 and 33 were evaluated using
the Antimicrobial Kill Rate Test and the results are shown in Table
9b.
24 TABLE 9b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 31 2.70 3.16 5.53 1.11 1.41
3.41 33 4.59 4.54 >4.62 5.25 >5.32 >5.32
[0294] Compositions 31-33 were instilled twice a day for two days
in the nose of one of the inventors without any indication of
irritation. No odor or taste was detected.
[0295] Isopropyl alcohol (IPA) was substituted for petrolatum and
glycerin in the compositions from Examples 31 and 32. The amounts
of each component are shown in Table 9c.
25 TABLE 9c Components (weight percent) Example Enhancer DOSS
Isopropyl No. GML Type Amt. (100%) alcohol 31(IPA) 3.00 88% Lactic
Acid 1.00 1.00 95.00 32(IPA) 3.00 Mandelic Acid 1.00 1.00 95.00
33(IPA) 3.00 Benzoic Acid 0.50 1.00 96.50
[0296] The compositions were prepared by mixng the ingredients
until the components were fully dissolved.
[0297] The IPA modified antimicrobial compositions were tested
using the Emergence of Resistance Test. The results are shown at
baseline (T.sub.0), after eight days (T.sub.8) and the ratio of
T.sub.0 to T.sub.8 in Table 9d.
26 TABLE 9d MRSA MSSA Example Initial Final Initial Final Number
(T.sub.0) (T.sub.8) T.sub.0/T.sub.8 (T.sub.0) (T.sub.8)
T.sub.0/T.sub.8 Mupirocin 0.25 64 256 0.25 128 512 31(IPA) 60 240 4
60 60 1 32(IPA) 120 60 0.5 60 60 1 33(IPA) 60 60 1 60 60 1
[0298] The results indicate that the MIC to mupirocin increased
dramatically while the MIC of the compositions of the present
invention increased less than 4 fold and some did not increase at
all. This shows that there was significant resistance was generated
to mupirocin but not to the compositions of the present
invention.
[0299] In-vivo efficacy was demonstrated against a clinical isolate
of MRSA using a murine model based on K, Cante-Kiser J, Lee J.
Development and characterization of staphylococcus aureus nasal
colonization model in mice. 1999 Infect and Immunity 67(10)
5001-5006. Prior to evaluation of the active compositions the
lowest number of S. aureus required to establish nasal colonization
in 70% of mice detectable 5 days after challenge and persisting at
least 10 days after challenge was determined. This was using an
innoculum of 10.sup.8 cfu/nare. Mice (239 described as 25 g to 30 g
Hsd:ICR) were challenged intranasally with 10.sup.8 MRSA #561 (a
clinical isolate of methicillin resistant staphylococcus obtained
from Mayo Clinic, Rochester, Minn.) and arbitrarily assigned to one
of five treatment regimens: mupirocin ointment, bland ointment,
antimicrobial compositions of Examples 31, 32, and 33. The bland
ointment consisted of petrolatum (89%), glycerin (10%) and DOSS
(1%). Mice received either no treatment (none) or treatment with 10
.mu.L per nare of warmed (42.degree. C.) ointment (one of five) to
each nare, three times daily for two days Three days after
treatment, both anterior nares were swabbed and cultured for MRSA.
Colonies appearing to be S. aureus were confirmed with a latex
agglutination test. S. aureus was detected in 160 colonization
cultures from 239 mice challenged. These mice continued to be
studied. The results of the treatments are listed in Table 9e as
the number of animals with no MRSA detected after treatment
(successful), the percent of the animals treated successfully, the
number of animals with MRSA (failure), and the percent of animals
whose treatment failed.
27TABLE 9e Number of Percent Number of Percent Whose Example Mice
without Treated Mice with Treatment Number MRSA Successfully MRSA
Failed None 1 10 9 90 Bland 12 32 26 68 Ointment Mupirocin 19 50 19
50 31 18 46 21 54 32 24 71 10 29 33 33 89 7 17
[0300] The results of MRSA nasal decolonization indicated that the
antimicrobial composition of Example 33 was more active than
mupirocin and that the antimicrobial compositions of Examples 31
and 32 were as active as mupirocin as measured by eradication of
MRSA from the anterior nasopharynx.
[0301] Using the Fisher's exact test. Results of treatment with
mupirocin, Ex 31, Ex. 32 and Ex. 33 were significantly (P<0.05)
different than was no treatment. Treatment with Ex. 33 or Ex. 32
was significantly (P<0.05) more active than treatment with bland
ointment. Treatment with Ex. 33 was significantly (P<0.002) more
active than mupirocin. Treatment with Ex. 31 (P=0.46) was not
significantly different than treatment with mupirocin. Treatment
with Ex. 32 showed a trend toward being more effective than
treatment with mupirocin (P=0.06).
Example 34
[0302] Example 34 was prepared using the components given in Table
10a. White petrolatum and GML were heated in a beaker to at least
approximately 93.degree. C. In another beaker, glycerin, DOSS, and
lactic acid were heated until the DOSS was dissolved at
approximately 143.degree. C. This solution was mixed with a mixing
propeller and allowed to cool to approximately 59.degree. C. Next
the contents of the second beaker was mixed with the contents of
the first beaker with a mixing propeller. Mixing and cooling
continued until the composition was about to congeal at
approximately 46.degree. C. Just before the composition congealed
it was removed from the mixer and poured into ointment jars.
28 TABLE 10a Components (weight percent) Example 88% Lactic DOSS
White No. GML Acid (100%) Glycerin Petrolatum 34 3.00 1.00 1.00
10.00 85.00
[0303] The composition appeared very similar to that of Example 31
using this alternative process.
Examples 35-37
[0304] Antimicrobial Compositions were prepared using the
components shown in Table 11a. PEG 400 and PEG 1450 were melted
together in one beaker at about 82.degree. C. In a second beaker,
the glycerin was heated to about 60.degree. C. and the GML was
dissolved in the heated glycerin. The enhancers and surfactants
were added to the first beaker of melted PEGs and mixed with a
propeller mixer while keeping the temperature at about 82.degree.
C. After the surfactants and enhancers were dissolved in the PEG
component, the solution was mixed and cooled to about 63.degree. C.
Then the contents of the second beaker, glycerin and GML were added
with constant mixing. The compositions were cooled with continual
mixing to just above the congealing point (about 38.degree. C.) and
poured into ointment jars.
29 TABLE 11a Components (weight percent) Ex. Enhancer Gly-
Surfactant PEG PEG No. GML Type Amt. cerin Type Amt. 400 1450 35
3.00 88% Lactic Acid 1.00 20.00 DOSS USP (50%) 2.00 59.00 15.00 36
3.00 Mandelic Acid 1.00 10.00 Pluronic P65 5.00 60.00 21.00 37 3.00
Mandelic Acid 1.00 20.00 DOSS USP (50%) 2.00 59.00 15.00
[0305] The compositions of Examples 35-37 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table 1
lb.
30 TABLE 11b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 35 >5.11 >5.11
>5.11 5.20 5.25 >5.36 36 >6.14 >6.14 >6.14 >6.57
>6.57 >6.57 37 >6.14 >6.14 >6.14 6.29 6.39 6.48
[0306] The antimicrobial kill rate of these compositions was
excellent against all three organisms indicating broad spectrum
kill. The antimicrobial kill rate was greater than log reduction at
2, 5, and 10 minutes.
Examples 38-41
[0307] Antimicrobial Compositions were prepared using the
components shown in Table 12a. The white petrolatum was melted in a
beaker on a hot plate with gentle stirring with a propeller mixer
while heating from about 88.degree. C. to 93.degree. C. In a second
beaker the enhancers were dissolved or suspended in the glycerin at
about 77.degree. C. The DOSS was added to the hot petrolatum
(88.degree. C. to 93.degree. C.) in the first beaker and mixed
until a clear solution was obtained. The contents of the second
beaker (glycerin-enhancer mixture) were added to the first beaker
and the composition cooled with constant stirring. When the
composition had cooled to about 71.degree. C. the GML was added
with constant stirring. The compositions were cooled with continual
mixing to just above the congealing point (about 43.degree. C.) and
poured into ointment jars.
31 TABLE 12a Components (weight percent) White Example Enhancer
Gly- DOSS Petrolatum No. GML Type Amt. cerin (100%) USP 38 3.00
Salicylic Acid 0.20 10.00 1.00 85.80 39 3.00 BHA 0.10 10.00 1.00
85.80 EDTA (Na).sub.2 0.10 40 3.00 BHA 0.10 10.00 0.00 86.69 EDTA
(Na).sub.2 0.10 Methyl paraben 0.10 Propyl paraben 0.01 41 3.00
Benzoic acid 0.50 10.00 1.00 85.50
[0308] The compositions of Examples 38-41 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table 12b
and 12c.
32 TABLE 12b MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 38 3.50 6.26 6.88 3.20 6.74
6.74 39 3.55 4.13 6.45 3.20 3.98 4.13 40 3.33 4.79 5.84 4.66 6.33
6.74 41 4.49 4.54 4.62 5.25 5.32 5.32
[0309]
33 TABLE 12c Pseudomonas ae. (log reduction) Example No. After 2
minutes After 5 minutes After 10 minutes 38 6.54 6.54 6.54 39 3.35
6.05 6.20 40 3.39 6.08 6.20 41 5.89 6.41 6.37
[0310] The results indicated that at least a 4 log reduction kill
rate at 5 minutes was achieved using the compositions of Examples
3841. This indicated a rapid broad spectrum activity.
Examples 42-43, Comparative Examples B-E, Examples 31-32, and
Examples 38-49
Aging Study using Gas Chromatography
[0311] Aging studies were done for some of the antimicrobial
compositions. Gas chromatography (GC) was used to determine what
components were being lost and what components might be used to
prevent that loss.
[0312] Additional antimicrobial compositions with different
enhancers and without enhancers were prepared as described for
Examples 38-41 using the components in Table 13a.
34 TABLE 13a Components (weight percent) Example Enhancer DOSS Gly-
White No. GML Type Amt (100%) cerin Petrolatum 42 3.00 Benzoic Acid
0.20 1.00 10.00 85.80 43 3.00 Glycolic Acid 1.00 1.00 10.00 85.00
Compar- 3.00 None 0.00 0.00 0.00 97.00 ative B Compar- 3.00 None
0.00 0.00 10.00 87.00 ative C Compar- 3.00 None 0.00 1.00 10.00
86.00 ative D Compar- 30.00 None 0.00 0.00 70.00 0.00 ative E
[0313] The compositions of Examples 31-32, 38-40, and 42-43, and
Comparative Examples B-E were evaluated using the Aging Study with
GC as described in the Test Protocols and the results are shown in
Table 13b, 13c, 13d and 13e.
[0314] Example 31 contains lactic acid and Example 32 contains
mandelic acid. The results in Table 13b and Table 13c indicate the
difference in aging of the two compositions at 23.degree. C. for 9
months and at 40.degree. C. for 4 weeks.
35 TABLE 13b GML in grams remaining after aging at 40.degree. C.
for: (weeks) Percent Example retention No. Initial 2 3 4 after 4
weeks 31 3.06 2.90 2.97 2.96 97 32 3.04 2.78 2.82 2.80 92
[0315]
36 TABLE 13c GML in grams remaining after aging at 23.degree. C.
for (months) Percent retention after Example No. Initial 5 9 9
months 31 3.06 3.01 3.09 103 32 3.04 2.99 3.01 100
[0316] The results in Table 13d indicate the quantitative results
of GML loss after aging at the indicated temperatures for 7 days.
The compositions that were incubated at 65.degree. C. were in the
liquid state so they were phase split and incubated with and
without shaking to see if agitation itself contributed further to
the GML loss.
37 TABLE 13d GML in grams remaining after aging 7 days at:
10.degree. C. 23.degree. C. 40.degree. C. 65.degree. C. 65.degree.
Example No. static static static static shaken Comparative B 3.03
.+-. 0.04 2.96 .+-. 0.01 3.04 .+-. 0.03 2.94 .+-. 0.05 2.97 .+-.
0.02 Comparative C 3.05 .+-. 0.05 3.03 .+-. 0.02 3.14 .+-. 0.03
3.22 .+-. 0.12 3.20 .+-. 0.04 Comparative D 3.00 .+-. 0.10 3.05
.+-. 0.04 3.14 .+-. 0.03 3.12 .+-. 0.19 3.20 .+-. 0.02 31 3.21 .+-.
0.05 3.08 .+-. 0.01 3.02 .+-. 0.01 2.73 .+-. 0.01 2.70 .+-. 0.01 32
3.17 .+-. 0.02 3.03 .+-. 0.02 2.91 .+-. 0.03 2.39 .+-. 0.01 2.54
.+-. 0.05 Comparative E Not done Not done 30.33 .+-. 0.13 29.38
.+-. 0.23 29.98 .+-. 0.12
[0317] The results in Table 13e indicate the quantitative results
of GML loss after aging at the 40.degree. C. for 28 days. The
compositions contain a variety of enhancers: lactic acid (Example
31), salicylic acid (Example 38), BHA and EDTA (Example 39), methyl
and propyl paraben (Example 40), benzoic acid (Example 42), and
glycolic acid (Example 43).
38 TABLE 13e Example GML in grams remaining after 4 weeks at: No.
Initial 40.degree. C. Percent retention 31 3.03 .+-. 0.01 2.85 .+-.
0.02 94 38 2.85 .+-. 0.07 2.64 .+-. 0.07 93 39 2.97 .+-. 0.02 3.00
.+-. 0.02 101 40 3.03 .+-. 0.01 2.85 .+-. 0.02 94 42 3.11 .+-. 0.01
2.91 .+-. 0.01 94 43 2.94 .+-. 0.01 2.70 .+-. 0.01 92
[0318] Examples in Table 13e may all have acceptable aging in that
after 4 weeks at 40.degree. C. they had >90% retention of GML.
Examples 39, 31, 40, and 42, showed the best
[0319] Subject Acceptability First Panel Evaluation
[0320] A panel of 10 normal healthy volunteers of either gender
over 18 years of age evaluated a component composition without
active antimicrobial lipid to determine acceptability and to
develop evaluation methodology for future evaluations.
[0321] The compositions evaluated are shown in Table 14.
39 TABLE 14 Components (weight percent) Docuate White Compo- Lactic
Glycerin sodium petrolatum PEG PEG sition Acid USP USP USP (50%)
USP 400 NF 3350 NF W 1.00 10.00 2.00 87.00 0.00 0.00 X 1.00 20.00
2.00 0.00 59.00 18.00
[0322] Test Procedure
[0323] A dose was 0.5 ml of Composition W or X applied using a
preloaded 1 cm.sup.-3 plastic syringe. The volunteers applied the
first dose after viewing a demonstration of the technique. The
volunteers applied a second and third dose during Day 1.
[0324] One-half of the volunteers (5) were dosed with Composition W
and one-half of the volunteers were dosed with Composition X on Day
1 and given a Rhinoscopic Examination of Nares before and after
application on Day 1 and after 24 hours on Day 2. On Day 8 those
volunteers dosed with Composition W on Day 1 received Composition X
and those dosed with Composition X on Day received Composition W.
They were given a Rhinoscopic Examination of Nares before and after
application on Day 8 and after 24 hours on Day 9.
[0325] Volunteers completed a questionnaire on Day 1 and on Day
9.
[0326] Results:
[0327] All 10 volunteers successfully completed both periods of the
study. Descriptive analysis was provided for each categorical
variable in the study.
[0328] Composition W was preferred by 10/10 of the volunteers. Five
of ten volunteers could not complete all three application of
Composition X. They cited stinging, burning and runny noses as
primary reasons. Composition X caused more rhinorrhea than
Composition W. Volunteers using Composition X felt they could use
the ointment for a shorter period of time than with Composition W.
Composition W could be felt to remain in the nasal vestibule longer
(mean 218 minutes) than Composition X (mean 145 minutes).
[0329] Subject Acceptability Second Panel Evaluation
[0330] A second panel evaluation was done to determine
acceptability of essentially anhydrous ointments based hydrophobic
vehicles containing lactic acid or mandelic acid. The criteria for
the panel were the same as for the first panel. The compositions
evaluated are given in Table 15.
40 TABLE 15 Components (weight percent) Lactic White Compo- Acid
Mandelic DOSS USP Glycerin petrolatum sition USP Acid (50%) USP USP
Y 1.00 0.00 2.00 10.00 87.00 Z 0.00 1.00 2.00 10.00 87.00
[0331] The test procedure was the same as that used for the first
panel except a cotton swab was used to apply the composition rather
than a tube.
[0332] Results:
[0333] Both ointments were acceptable with minimal, if any, side
effects. The preference for the two ointments was fairly equally
divided. Four of ten volunteers expressed a slight preference for
the mandelic acid composition, three of ten volunteers expressed a
slight preference for the lactic acid composition, and three of ten
volunteers noticed no difference between the compositions.
[0334] Each volunteer applied 0.5 ml of composition; however,
approximately 0.1 gram was routinely left on the swab. Therefore
the dose was about 0.2 ml per nare. The time that the ointments
remained in the volunteers' noses varied between volunteers, but
there were indications that the ointment remained in place up to 24
hours. Two volunteers reported that the ointment appeared to
accumulate from application to application.
[0335] The feel of the ointment in the nose and smell were the most
noticed characteristics of both ointments, but the characteristics
were all in the acceptable range.
Examples 44-47
[0336] Aqueous antimicrobial compositions were prepared using the
components listed in Table 16a. Water or glycerin (Example 44),
GML, mandelic acid, and PLURONIC P-65 were mixed and heated
together to 70.degree. C. The mixture was sheared on a Silverson
Homogenizer for 1 minute to emulsify the components. A polymer was
added to the warm solution for Examples 45-47. The composition was
shaken, sealed in glass jars, and the jars were placed on a roller
to mix and cool.
41 TABLE 16a Components (weight percent) Ex. Mandelic 70% Polymer
Water or No. GML acid DOSS Type Amt. POLOXAMER glycerin.sup.1 44
3.00 1.00 1.43 None 0.00 0.00 94.57.sup.1 45 1.00 1.00 2.86
ARISTOFLEX HMB 1.50 10.00 83.64 46 0.94 0.94 2.70 SALCARE SC92 8.50
9.43 77.49 47 1.00 1.00 2.83 NATROSOL Plus Type 2.08 9.89 83.24
.sup.1Example 44 contains glycerin not water
[0337] The pH of Examples 44-47 was determined using a pH meter
(Denver Instrument, Model 225 from VWR Scientific) and a gel
filled, epoxy, combination pH probe (VWR Scientific) and the
results are shown in Table 16b. The Brookfield viscosity was
determined as described above using the Helipath spindles and speed
of rotation in rotations per minute (rpm) indicated with the
results shown in Table 16b.
42TABLE 16b Example Helipath No. PH Viscosity (cps) spindle Speed
(rpm) 44 ND.sup.1 46000 E 1.5 45 2.3 66000 D 1.0 46 2.7 >1.35
Million F 0.5 47 2.6 2000 B 12.0 .sup.1ND means not done.
[0338] The compositions of Examples 44-47 were evaluated using the
Antimicrobial Kill Rate Test and the results are shown in Table 16c
and 16d.
43 TABLE 16c MRSA (log reduction) E. coli (log reduction) Example
After 2 After 5 After 10 After 2 After 5 After 10 No. minutes
minutes minutes minutes minutes minutes 44 >6.17 >6.17
>6.17 >5.93 >5.93 >5.93 45 >6.17 >6.17 >6.17
>5.93 >5.93 >5.93 46 >5.94 >5.94 >5.94 5.83
>6.10 5.87 47 >6.17 >6.17 >6.17 5.88 >5.93
>5.93
[0339]
44TABLE 16d Example Pseudomonas ae. (log reduction) No. After 2
minutes After 5 minutes After 10 minutes 44 >6.06 >6.06
>6.06 45 4.86 6.55 6.31 46 >6.01 >6.01 >6.01 47 5.98
>6.06 >6.06
[0340] The antimicrobial kill rate of these compositions was
excellent against all three organisms indicating broad spectrum
kill. The antimicrobial kill rate was greater than 4 log reduction
at 2 minutes and greater than a 5 log reduction at 5 and 10 minutes
for all three bacteria. In fact, for many time points complete kill
was achieved (as indicated by a ">" sign).
[0341] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. Various
modifications and alterations to this invention will become
apparent to those skilled in the art without departing from the
scope and spirit of this invention. It should be understood that
this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein as follows.
* * * * *