U.S. patent application number 13/688576 was filed with the patent office on 2013-04-18 for perfluorocarbon gel formulations.
This patent application is currently assigned to OXYGEN BIOTHERAPEUTICS, INC.. The applicant listed for this patent is OXYGEN BIOTHERAPEUTICS, INC.. Invention is credited to Gary Clauson, Aharon Grossman, Gary Huvard, Richard Kiral, Maxine Quitaro, Gubhagat Sandhu, Deborah P. Thompson.
Application Number | 20130096190 13/688576 |
Document ID | / |
Family ID | 42231799 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130096190 |
Kind Code |
A1 |
Huvard; Gary ; et
al. |
April 18, 2013 |
PERFLUOROCARBON GEL FORMULATIONS
Abstract
A perfluorocarbon gel composition is disclosed with numerous
uses including topical medical and cosmetic uses.
Inventors: |
Huvard; Gary; (Chesterfield,
VA) ; Kiral; Richard; (Costa Mesa, CA) ;
Quitaro; Maxine; (Chesterfield, VA) ; Thompson;
Deborah P.; (Durham, NC) ; Grossman; Aharon;
(Durham, NC) ; Clauson; Gary; (Costa Mesa, CA)
; Sandhu; Gubhagat; (Manakin-Sabot, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OXYGEN BIOTHERAPEUTICS, INC.; |
Costa Mesa |
CA |
US |
|
|
Assignee: |
OXYGEN BIOTHERAPEUTICS,
INC.
Costa Mesa
CA
|
Family ID: |
42231799 |
Appl. No.: |
13/688576 |
Filed: |
November 29, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12590996 |
Nov 17, 2009 |
8343515 |
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13688576 |
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12589202 |
Oct 19, 2009 |
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12590996 |
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61200254 |
Nov 25, 2008 |
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61204785 |
Jan 9, 2009 |
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61205499 |
Jan 21, 2009 |
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Current U.S.
Class: |
514/458 ;
514/588; 514/747 |
Current CPC
Class: |
A61P 17/02 20180101;
A61K 8/70 20130101; A61K 9/0014 20130101; A61K 8/315 20130101; A61K
8/042 20130101; A61K 31/025 20130101; A61K 9/0034 20130101; A61Q
19/08 20130101; A61K 9/06 20130101; A61Q 19/00 20130101; A61K
31/355 20130101; A61P 17/00 20180101 |
Class at
Publication: |
514/458 ;
514/747; 514/588 |
International
Class: |
A61K 31/025 20060101
A61K031/025; A61Q 19/08 20060101 A61Q019/08; A61K 8/31 20060101
A61K008/31 |
Claims
1. A perfluorocarbon gel composition comprising 10-90 wt %
perfluorocarbon and 8-70 wt % water relative to the total weight of
the gel, wherein the perfluorocarbon is
perfluoro(tert-butylcyclohexane).
2. (canceled)
3. The perfluorocarbon gel composition of claim 1, wherein the
composition further comprises 1-5 wt % surfactants.
4. The perfluorocarbon gel composition of claim 3, wherein the
surfactants include polyoxyethylene-polyoxypropylene block
copolymers.
5. The perfluorocarbon gel composition of claim 4, wherein the
polyoxyethylene-polyoxypropylene block copolymers include Poloxamer
105 and/or Poloxamer 188.
6. The perfluorocarbon gel composition of claim 1, wherein the
composition further comprises 0.01-10 wt % Vitamin E.
7. The perfluorocarbon gel composition of claim 6, wherein the
composition comprises 0.03 wt % Vitamin E.
8. The perfluorocarbon gel composition of claim 1, wherein the
composition further comprises 0.02-3.20 wt % preservatives.
9. The perfluorocarbon gel composition of claim 8, wherein the
preservatives include poly(diallyldimethylammonium chloride),
poly(acrylamide-co-diallyldimethylammonium chloride) and/or
ethylene diamine tetraacetic acid.
10. (canceled)
11. The perfluorocarbon gel composition of claim 3, wherein the
composition comprises 30-50 wt % perfluorocarbon, 48-70 wt % water,
and 2 wt % surfactants.
12. (canceled)
13. (canceled)
14. The perfluorocarbon gel composition of claim 8, wherein the
preservatives include 0-0.40 wt % poly(diallyldimethylammonium
chloride), 0.01-0.80 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.01-2.00
wt % ethylene diamine tetraacetic acid.
15. The perfluorocarbon gel composition of claim 14, wherein the
composition comprises 84-88 wt % perfluoro(tert-butylcyclohexane),
9-11 wt % water, 2-3 wt % Poloxamer 105, 0.01-1 wt % Poloxamer 188,
0-0.40 wt % poly(diallyldimethylammonium chloride), 0.01-0.80 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.01-2.00
wt % ethylene diamine tetraacetic acid.
16. The perfluorocarbon gel composition of claim 15, wherein the
composition comprises 85.98 wt % perfluoro(tert-butylcyclohexane),
10.28 wt % water, 2.45 wt % Poloxamer 105, 0.31 wt % Poloxamer 188,
0.74 wt % poly(acrylamide-co-diallyldimethylammonium chloride) and
0.25 wt % ethylene diamine tetraacetic acid.
17. The perfluorocarbon gel composition of claim 15, wherein the
composition comprises 86.73 wt % perfluoro(tert-butylcyclohexane),
10.37 wt % water, 2.47 wt % Poloxamer 105, 0.31 wt % Poloxamer 188,
0.10 wt % poly(acrylamide-co-diallyldimethylammonium chloride) and
0.03 wt % ethylene diamine tetraacetic acid.
18. The perfluorocarbon gel composition of claim 15, wherein the
composition comprises 85.98 wt % perfluoro(tert-butylcyclohexane),
10.28 wt % water, 2.45 wt % Poloxamer 105, 0.31 wt % Poloxamer 188,
0.25 wt % poly(diallyldimethylammonium chloride), 0.50 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.25 wt %
ethylene diamine tetraacetic acid.
19. The perfluorocarbon gel composition of claim 15, wherein the
composition comprises 86.73 wt % perfluoro(tert-butylcyclohexane),
10.37 wt % water, 2.47 wt % Poloxamer 105, 0.31 wt % Poloxamer 188,
0.03 wt % poly(diallyldimethylammonium chloride), 0.07 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.03 wt %
ethylene diamine tetraacetic acid.
20. (canceled)
21. (canceled)
22. The perfluorocarbon gel composition of claim 1, characterized
by that it continuously delivers oxygen to a tissue at a rate of
0.2 cc/hour-20.0 cc/hour for up to 24 hours.
23. The perfluorocarbon gel composition of claim 22, wherein the
composition continuously delivers oxygen to the tissue at a rate of
2.0 cc/hour for 24 hours.
24. The perfluorocarbon gel composition of claim 1, further
comprising urea hydrogen peroxide.
25. A method of continuously delivering oxygen to a tissue at a
rate of 0.2 cc/hour-20.0 cc/hour for up to 24 hours by contacting
the tissue with the perfluorocarbon gel composition of claim 1.
26. A method of treating a wound, a burn injury, acne or rosacea in
a subject suffering therefrom comprising topically administering to
the skin of the subject the perfluorocarbon gel composition of
claim 1 effective to treat the subject's wound, burn injury, acne
or rosacea.
27. A method of increasing the firmness of the skin or reducing the
appearance of fine lines, wrinkles or scars in a subject comprising
topically administering to the skin of the subject the
perfluorocarbon gel composition of claim 1 effective to increase
the firmness of the subject's skin or reduce the appearance of fine
lines, wrinkles or scars on the subject's skin.
28. A process of manufacturing a perfluorocarbon gel composition
comprising the steps: i) mixing aqueous phase components in a
vessel; ii) homogenizing the mixture; iii) adding perfluorocarbon
to the mixture over time during high speed homogenization; and iv)
obtaining the gel.
29-36. (canceled)
Description
[0001] This is a continuation-in-part of U.S. patent application
Ser. No. 12/589,202, filed Oct. 19, 2009, and claims the benefit of
1) U.S. Provisional Application No. 61/205,499, filed Jan. 21,
2009, 2) U.S. Provisional Application No. 61/204,785, filed Jan. 9,
2009, and 3) U.S. Provisional Application No. 61/200,254, filed
Nov. 25, 2008, the entire content of each of which is hereby
incorporated by reference herein.
[0002] Throughout this application various publications, published
patent applications, and patents are referenced. The disclosures of
these documents in their entireties are hereby incorporated by
reference into this application in order to more fully describe the
state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] Perfluorocarbons (PFCs) possess the ability to dissolve
large quantities of many gases at concentrations much larger than
water, saline and plasma. In addition, PFCs can transport these
gases to diffuse across distances. Thus, PFCs can be a convenient
and inexpensive means to deliver high levels of oxygen or other
therapeutic gases to tissues and organ systems.
[0004] PFCs that are commonly used in medical research are
non-toxic, biologically inert, biostatic liquids at room
temperature with densities of about 1.5-2.0 g/mL and high
solubilities for oxygen and carbon dioxide. Such PFCs have been
found to be efficient carriers of gases, both as emulsions for
intravenous use and as neat liquids for liquid ventilation
applications.
SUMMARY OF THE INVENTION
[0005] The subject application provides for a perfluorocarbon gel
composition comprising 10-90 wt % perfluorocarbon and 8-70 wt %
water relative to the total weight of the gel.
[0006] The subject application also provides for a method of
continuously delivering oxygen to a tissue at a rate of 0.2
cc/hour-20.0 cc/hour for up to 24 hours by contacting the tissue
with a perfluorocarbon gel composition described herein.
[0007] The subject application also provides for a method of
treating a wound, a burn injury, acne or rosacea in a subject
suffering therefrom comprising topically administering to the skin
of the subject a perfluorocarbon gel composition described herein
effective to treat the subject's wound, burn injury, acne or
rosacea.
[0008] The subject application also provides for a method of
increasing the firmness of the skin or reducing the appearance of
fine lines, wrinkles or scars in a subject comprising topically
administering to the skin of the subject a perfluorocarbon gel
composition described herein effective to increase the firmness of
the subject's skin or reduce the appearance of fine lines, wrinkles
or scars on the subject's skin.
[0009] The subject application also provides for a method of
manufacturing a perfluorocarbon gel composition comprising the
steps: a) mixing aqueous phase components in a vessel; b)
homogenizing the mixture; c) adding perfluorocarbon to the mixture
over time during high speed homogenization; and d) obtaining the
gel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows the schematic of an experiment as described
herein where a liter of liquid A (perfluoro(tert-butylcyclohexane)
or "FtBu") and a liter of liquid B (water), each initially void of
oxygen, are allowed to absorb oxygen from the air.
[0011] FIG. 2 shows Henry's Law sorption isotherms for
perfluoro(tert-butylcyclohexane) and water. The amount of dissolved
oxygen in the liquid is measured after equilibration with a gas.
The partial pressure of the gas (here, oxygen) is varied. The
partial pressure of oxygen in air is 0.21 atm.
[0012] FIG. 3 shows a schematic of a thought experiment. The
perfluoro(tert-butylcyclohexane) is actually heavier than water and
would sink if it is tried. The purpose of this thought experiment
is to determine if the concentration of oxygen in the water is
different at equilibrium if a layer of
perfluoro(tert-butylcyclohexane) is placed on top of the water.
[0013] FIG. 4 shows another thought experiment. In case A, there is
a small amount of well-stirred water in contact with air. However,
the air is divided into two layers.
[0014] FIG. 5 shows the concentration of oxygen in the water in
FIG. 4 as time goes on.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the Invention
[0015] The subject application provides for a perfluorocarbon gel
composition comprising 10-90 wt % perfluorocarbon and 8-70 wt %
water relative to the total weight of the gel.
[0016] In one embodiment, the perfluorocarbon is
perfluoro(tert-butylcyclohexane). In another embodiment, the
perfluorocarbon is perfluorodecalin. In another embodiment, the
perfluorocarbon is trimethyl perfluorodecalin or
perfluoroisopropyldecalin.
[0017] In yet another embodiment, the composition further comprises
1-wt % surfactants. In another embodiment, the surfactants include
polyoxyethylene-polyoxypropylene block copolymers. In another
embodiment, the polyoxyethylene-polyoxypropylene block copolymers
include Poloxamer 105 and/or Poloxamer 188.
[0018] In one embodiment, the composition further comprises 0.01-10
wt % Vitamin E. In another embodiment, the composition comprises
0.03 wt % Vitamin E.
[0019] In one embodiment, the composition further comprises
0.02-3.20 wt % preservatives. In another embodiment, the
preservatives include poly(diallyldimethylammonium chloride),
poly(acrylamide-co-diallyldimethylammonium chloride) and/or
ethylene diamine tetraacetic acid.
[0020] In one embodiment, the composition comprises 90 wt %
perfluorocarbon, 8 wt % water, and 2 wt % surfactants. In another
embodiment, the composition comprises 30-50 wt % perfluorocarbon,
48-70 wt % water, and 2 wt % surfactants. In another embodiment,
the composition comprises 86.86 wt % perfluorocarbon, 10.42 wt %
water, 2.69 wt % surfactants and 0.03 wt % Vitamin E. In yet
another embodiment, the composition comprises 86.86 wt %
perfluoro(tert-butylcyclohexane), 10.42 wt % water, 2.43 wt %
Poloxamer 105, 0.26 wt % Poloxamer 188 and 0.03 wt % Vitamin E.
[0021] In one embodiment, the preservatives include 0-0.40 wt %
poly(diallyldimethylammonium chloride), 0.01-0.80 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.01-2.00
wt % ethylene diamine tetraacetic acid. In another embodiment, the
composition comprises 84-88 wt % perfluoro(tert-butylcyclohexane),
9-11 wt % water, 2-3 wt % Poloxamer 105, 0.01-1 wt % Poloxamer 188,
0-0.40 wt % poly(diallyldimethylammonium chloride), 0.01-0.80 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.01-2.00
wt % ethylene diamine tetraacetic acid.
[0022] In one embodiment, the composition comprises 85.98 wt %
perfluoro(tert-butylcyclohexane), 10.28 wt % water, 2.45 wt %
Poloxamer 105, 0.31 wt % Poloxamer 188, 0.74 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.25 wt %
ethylene diamine tetraacetic acid.
[0023] In one embodiment, the composition comprises 86.73 wt %
perfluoro(tert-butylcyclohexane), 10.37 wt % water, 2.47 wt %
Poloxamer 105, 0.31 wt % Poloxamer 188, 0.10 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.03 wt %
ethylene diamine tetraacetic acid.
[0024] In one embodiment, the composition comprises 85.98 wt %
perfluoro(tert-butylcyclohexane), 10.28 wt % water, 2.45 wt %
Poloxamer 105, 0.31 wt % Poloxamer 188, 0.25 wt %
poly(diallyldimethylammonium chloride), 0.50 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.25 wt %
ethylene diamine tetraacetic acid.
[0025] In one embodiment, the composition comprises 86.73 wt %
perfluoro(tert-butylcyclohexane), 10.37 wt % water, 2.47 wt %
Poloxamer 105, 0.31 wt % Poloxamer 188, 0.03 wt %
poly(diallyldimethylammonium chloride), 0.07 wt %
poly(acrylamide-co-diallyldimethylammonium chloride) and 0.03 wt %
ethylene diamine tetraacetic acid.
[0026] In one embodiment, the composition further comprises 0.10-2
wt % copper. In another embodiment, the copper is copper (II)
oxide. In one embodiment, the perfluorocarbon gel composition is
characterized by that it continuously delivers oxygen to a tissue
at a rate of 0.2 cc/hour-20.0 cc/hour for up to 24 hours. In
another embodiment, the perfluorocarbon composition continuously
delivers oxygen to the tissue at a rate of 2.0 cc/hour for 24
hours. In yet another embodiment, the perfluorocarbon gel
composition further comprises urea hydrogen peroxide.
[0027] The subject application also provides for a method of
continuously delivering oxygen to a tissue at a rate of 0.2
cc/hour-20.0 cc/hour for up to 24 hours by contacting the tissue
with a perfluorocarbon gel composition described herein.
[0028] The subject application also provides for a method of
treating a wound, a burn injury, acne or rosacea in a subject
suffering therefrom comprising topically administering to the skin
of the subject a perfluorocarbon gel composition described herein
effective to treat the subject's wound, burn injury, acne or
rosacea.
[0029] The subject application also provides for a method of
increasing the firmness of the skin or reducing the appearance of
fine lines, wrinkles or scars in a subject comprising topically
administering to the skin of the subject a perfluorocarbon gel
composition described herein effective to increase the firmness of
the subject's skin or reduce the appearance of fine lines, wrinkles
or scars on the subject's skin.
[0030] The subject application also provides for a process of
manufacturing a perfluorocarbon gel composition comprising the
steps: a) mixing aqueous phase components in a vessel; b)
homogenizing the mixture; c) adding perfluorocarbon to the mixture
over time during high speed homogenization; and d) obtaining the
gel.
[0031] In one embodiment, in step a) the aqueous phase components
include distilled water, surfactants and/or preservatives. In
another embodiment, in step a) the vessel is a glass, polyethylene,
PET, or stainless steel vessel.
[0032] In one embodiment, in step b) the homogenizer is a rotor
stator homogenizer. In another embodiment, in step b) the mixture
is homogenized for 4-6 minutes. In another embodiment, in step b)
the mixture is homogenized for 5 minutes. In yet another
embodiment, in step b) the mixture is homogenized at 10,000-35,000
RPM.
[0033] In on embodiment, in step c) the perfluorocarbon is added in
aliquots or continuously over 10-30 minutes.
[0034] In one embodiment, the perfluorocarbon is
perfluoro(tert-butylcyclohexane).
[0035] All combinations of the various elements described herein
are within the scope of the invention.
[0036] The biochemistry of wound healing and strategies for wound
treatment is described Chin et al., (2007) "Biochemistry of Wound
Healing in Wound Care Practice" Wound Care Practice, 2.sup.nd ed.,
Best Publishing, AZ., which is hereby incorporated by
reference.
[0037] Acne treatments are described in section 10, chapter 116, pp
811-813 of The Merck Manual, 17.sup.th Edition (1999), Merck
Research Laboratories, Whitehouse Station, N.J., U.S.A. which is
hereby incorporated by reference.
TERMS
[0038] As used herein, and unless stated otherwise, each of the
following terms shall have the definition set forth below.
[0039] "Accelerates healing" as used herein means an increased rate
of burn injury/wound repair and healing as compared to the rate of
burn injury/wound repair and healing in an untreated control
subject.
[0040] "Administering to the subject" means the giving of,
dispensing of, or application of medicines, drugs, or remedies to a
subject to relieve or cure a pathological condition. Topical
administration is one way of administering the instant compounds
and compositions to the subject.
[0041] "Ameliorating" a condition or state as used herein shall
mean to lessen the symptoms of that condition or state.
[0042] "Ameliorate" with regard to skin comedones, pustules or
papules is to reduce the discomfort caused by comedones, pustules
or papules and/or to reduce their appearance and/or physical
dimensions.
[0043] "Antibacterial agent" means a bactericidal compound such as
silver nitrate solution, mafenide acetate, or silver sulfadiazine,
or an antibiotic. According to the present invention, antibacterial
agents can be present in "Curpon.TM." products. "Cupron.TM."
products utilize the qualities of copper and binds copper to
textile fibers, allowing for the production of woven, knitted and
non-woven fabrics containing copper-impregnated fibers with the
antimicrobial protection against microorganisms such as bacteria
and fungi.
[0044] "Biologically active agent" means a substance which has a
beneficial or adverse effect on living matters.
[0045] "Burn wound" means a wound resulting from a burn injury,
which is a first, second or third degree injury caused by thermal
heat, radiation, electric or chemical heat, for example as
described at page 2434, section 20, chapter 276, of The Merck
Manual, 17.sup.th Edition (1999), Merck Research Laboratories,
Whitehouse Station, N.J., U.S.A.
[0046] "Effective" as in an amount effective to achieve an end
means the quantity of a component that is sufficient to yield a
desired therapeutic response without undue adverse side effects
(such as toxicity, irritation, or allergic response) commensurate
with a reasonable benefit/risk ratio when used in the manner of
this disclosure. For example, an amount effective to promote wound
healing without causing undue adverse side effects. The specific
effective amount will vary with such factors as the particular
condition being treated, the physical condition of the patient, the
type of mammal being treated, the duration of the treatment, the
nature of concurrent therapy (if any), and the specific
formulations employed and the structure of the compounds or its
derivatives.
[0047] "Gel" means a semi-solid or solid colloid (depending on
concentration and/or temperature) of a solid/semi-solid and a
liquid wherein a liquid dispersed phase is dispersed in a
solid/semi-solid continuous medium. Some gels become fluids due to
agitation then resume their gel structure when allowed to be
undisturbed. Common pharmaceutical gels are solids which when
applied and with motion allow the product to become temporarily a
liquid phase so it applies smoothly, then becomes tacky then dries.
Other gels are semi solid which are a semi-liquid, semi-solid
mixture & when applied become tacky then dry. "Hydrogel" means
any colloid in which the particles are in the external dispersion
phase and water is in the internal dispersed phase.
[0048] "Infection" as used in respect to Propionibacterium acnes
means a detrimental colonization of the (host) subject by the
Propionibacterium acnes causing an inflammation response in the
subject.
[0049] "Oxygen tension" or "tissue oxygen tension" is the directly
measured local partial pressure of oxygen in a specific tissue.
[0050] "Oxygenated perfluorocarbon" is a perfluorocarbon which is
carrying oxygen at, for example, saturation or sub-saturation
levels.
[0051] "Pharmaceutically acceptable carrier" refers to a carrier or
excipient that is suitable for use with humans and/or animals
without undue adverse side effects (such as toxicity, irritation,
and allergic response) commensurate with a reasonable benefit/risk
ratio. It can be a pharmaceutically acceptable solvent, suspending
agent or vehicle, for delivering the instant compounds to the
subject. The carrier may be liquid or solid and is selected with
the planned manner of administration in mind.
[0052] "Pharmaceutically active compound" means the compound or
compounds that are the active ingredients in a pharmaceutical
formulation.
[0053] "Promotes alleviation of pain" means a decrease in the
subject's experience of pain resulting from a wound or an injury,
e.g., a burn injury.
[0054] "Sex organ" or "sexual organ" means any of the anatomical
parts of the body which are involved in sexual reproduction and
constitute the reproductive system in a complex organism.
[0055] In a preferred embodiment of this invention, the sex organ
is the genitalia of the subject. As used herein, the "genitalia"
refer to the externally visible sex organs: in males the penis, in
females the clitoris and vulva.
[0056] "Surfactants" means wetting agents that lower the surface
tension of a liquid, allowing easier spreading, and lower the
interfacial tension between two liquids. According to one
embodiment of the present invention, the surfactants can be
Poloxamer 105 (available from BASF Corporation of Mt. Olive, N.J.
as Pluronic.RTM. L35) or Poloxamer 188 (available from BASF
Corporation of Mt. Olive, N.J. as Pluronic.RTM. F68) Poloxamer 188
or Poloxamer 407, or a mixture thereof.
[0057] "Topical administration" of a composition as used herein
shall mean application of the composition to the skin of a subject.
In an embodiment, topical administration of a composition is
application of the composition to the epidermis of a subject.
[0058] "wt %" when referring to the percentage of a component in
the gel is percentage of the weight of the component in the gel
relative to the total weight of the gel.
Perfluoro(Tert-Butylcyclohexane)
[0059] PFCs include perfluoro(tert-butylcyclohexane)
(C.sub.10F.sub.20, CAS No. 84808-64-0) which is available, for
example, as Oxycyte.TM. from Oxygen Biotherapeutics Inc., Costa
Mesa, Calif. In an embodiment, the perfluoro(tert-butylcyclohexane)
has the following structure:
##STR00001##
[0060] Physical properties of perfluoro(tert-butylcyclohexane) are
as follows:
TABLE-US-00001 Molecular Formula C.sub.10F.sub.20 Molecular Weight
(g/mol) 500.08 Physical State @ Room Temp. Liquid Density (g/mL)
1.97 Boiling Point (.degree. C.) 147 Vapor Pressure (mmHg) @
25.degree. C. 3.8 Vapor Pressure (mmHg) @ 37.degree. C. 4.4
Kinematic Viscosity (cP) 5.378 Refractive Index @ 20.degree. C.
1.3098 Calculated Dipole Moment (Debye) 0.287 Calculated Surface
Tension (dyne/cm) 14.4
[0061] Perfluoro(tert-butylcyclohexane) carries about 43 mL of
oxygen per 100 mL of PFC, and 196 mL of CO.sub.2 per 100 mL of
PFC.
[0062] Oxycyte is a perfluorocarbon emulsion oxygen carrier. The
active ingredient in Oxycyte, perfluoro(tert-butylcyclohexane)
(C.sub.10F.sub.20, MW.about.500), also known as
F-tert-butylcyclohexane or "FtBu", is a saturated alicyclic PFC.
Perfluoro(tert-butylcyclohexane) is a colorless, completely inert,
non-water soluble, non-lipophilic molecule, which is twice as dense
as water, and boils at 147.degree. C. Oxycyte.TM. can be used in
the PFC compositions, methods and uses described herein.
[0063] Being that the PFCs are slightly lipophilic at body
temperature and would help in the transport of oxygen into and
removal of carbon dioxide from the skin tissue, PFCs can accelerate
the healing process of a wound in a tissue.
Perfluoro(tert-butylcyclohexane) is only slightly lipophilic at
body temperature and not lipophilic at room temperature.
The Perfluoro(Tert-Butylcyclohexane) Gel
[0064] In one embodiment of the present invention, the gel is
formulated as follows:
TABLE-US-00002 Component grams Wt % Vitamin E 0.017 g 0.03 (300
ppm) Pluronic .RTM. L35 1.4 g 2.43 Pluronic .RTM. F68 0.15 g 0.26
Water 6.0 g 10.42 perfluoro(tert-butylcyclohexane) 50 g 86.86
[0065] The perfluorocarbon gel compositions and methods of
manufacturing the same disclosed herein are advantageous over
existing gels and methods. Initial attempts to make the PFC gel
have not been successful. Further, existing methods for making
perfluorocarbon gels provide for yields of 15-20% at best. The
method disclosed herein provides yields of 80-100%. Through
research and experiments the inventors of the subject have
successfully manufactured the instant gel with high yields.
[0066] The PFC gel composition disclosed herein can be used as a
vehicle to deliver oxygen to various tissues, e.g., skin. The PFC
composition disclosed herein can concentrate atmospheric oxygen as
well as be pre-loaded with molecular oxygen. The composition can
deliver oxygen to a tissue or a wound via a diffusion gradient.
[0067] It is known that cells need oxygen to regenerate and thrive.
Therefore, the PFC gel described herein has numerous applications
and can be used where oxygen delivery to the cells in a tissue
e.g., aging or damaged skin tissue, is desired.
[0068] An Anecdotal Observation and Brief Discussion of PFC
Mechanism of Action
[0069] A mixture of APF-200 gel (Multifluor.RTM. APF-200
perfluoroisopropyldecalin, which is commercially available from Air
Products and Chemicals, Inc., Allentown, Pa.) with PLURONIC.RTM.
L35 liquid was applied to a scratch on a subject which was very red
and sore.
[0070] Within about three hours of the application, the subject
reported that much of the soreness had disappeared and the redness
had abated. The subject then applied more gel to the scratch.
[0071] The next morning, the long tail of the scratch was almost
invisible and the main cut had a small scab and almost no redness.
More gel was applied to the scratch that night and by the next
morning, the scratch had completely healed with no signs of
scarring.
What the PFC Gel is and is not Doing
[0072] Consider the experiment sketched in FIG. 1: Two liquids,
FtBu and water, are allowed to absorb oxygen from air. The amount
of oxygen dissolved in each when the liquids are at equilibrium
with the oxygen in the air can be found from the Henry's Law
sorption isotherms for the liquids sketched in FIG. 2.
[0073] When the solubility of a gas in a liquid is measured, the
solubility is nearly always a linear function of the partial
pressure of the gas.
[0074] For FtBu, the Henry's law constant is about 600 mg
O.sub.2/L/atm; that for water is about 8.3 mg O.sub.2/L/atm. In
contact with air (O.sub.2 at 0.21 atm), FtBu holds about 126 mg
O.sub.2 and water about 1.7 mg/L, both at 25.degree. C. Now convert
these values to a weight basis using the density of FtBu (1966 g/L)
and water (1000 g/L):
126 mg 1 L L 1966 g = 0.0631 mg O 2 / g for FtBu ##EQU00001## 1.7
mg 1 L L 1000 g = 0.0017 mg O 2 / g for FtBu ##EQU00001.2##
[0075] Assume the two liquids are mixed together (assuming that
FtBu and water are miscible) and determine how much oxygen is in
the mixture. First, determine weight fractions of each liquid in
the mix:
1966 g FtBu 1966 g FtBu + 1000 g water = 0.6628 g FtBu / g mix ;
therefore 0.3372 g water / g mix ##EQU00002##
[0076] When the liquids are mixed, assume that they are unaware of
each other, that is, assume that there are no specific molecular
interactions that occur. It is known that water can have very
strong interactions with many other solvents due to
hydrogen-bonding (for example). However, since it is to be assumed
that the two liquids are miscible in order to make a simple point,
it is easier to assume that they do not interact as well. This is
likely a valid assumption given the inertness of the PFC. Under
these conditions, the rule of volume additivity holds and the
solubility in the mixture as a weighted average of the solubilities
in the pure liquids can be computed:
0.6628 g FtBu g mix | 0.0631 mg O 2 g FtBu + 0.3372 g water g mix |
0.0017 mg O 2 g water = 0.0424 mg O 2 g mix ##EQU00003##
[0077] Mixing an oxygen-binding PFC with water (if that were
physically possible) will always give a mixture having a higher
oxygen concentration than water alone. The weighted average
calculation appears to hold for other gels that were made by the
inventors. The oxygen concentrations measured by the inventors for
gels made are in the range of 90-95% of what is expected based on
the gel composition and the known solubilities of oxygen in FtBu
and in water. The difference may lie in the difficulty of fully
saturating a gel with oxygen from the air without simultaneously
evaporating some of the water and impacting the composition of the
gel.
[0078] Now, assume the water in the previous example is replaced
with wound tissue (which is mostly water) and consider FIG. 3. The
inventors are interested in determining the concentrations of
oxygen in the water at equilibrium when FtBu is and is not present
between water and the air.
[0079] Thermodynamics teaches that equilibrium exists between
separate phases in intimate contact when the chemical potential
(denoted by .mu.) is exactly the same in each phase. At a given
temperature, the chemical potential of oxygen in air will depend
only on the composition--which is fixed. Thus, the chemical
potential of oxygen in air for the two scenarios in FIG. 3 must be
equivalent if the very small contribution of FtBu vapor in the
second case is neglected. If .mu.O.sub.2 is the same as in air in
both cases and if the air and water are in equilibrium in both
cases, then .mu.O.sub.2 in the water must also be the same in each
case (again, neglecting the tiny solubility of FtBu in the water in
the second case). As for the air, .mu.O.sub.2 in the water depends
only on the temperature and concentration of O.sub.2, therefore the
concentration of oxygen in the water must be identical in both
cases. It makes no difference how much oxygen is dissolved in the
FtBu nor does it matter how much FtBu there is. In each case, the
amount of oxygen in the water must be identically the same (or very
nearly so as the FtBu residuals in the air and water will have a
calculable but probably immeasurable impact). It can be concluded
that putting on a layer of PFC gel ON TOP OF wound tissue cannot
increase the concentration of oxygen IN the wound tissue.
[0080] Now consider FIG. 4. The air in the 1/16'' layer in case A
is identical to the air above but we will assume that we can
diffuse oxygen through this layer independently. In B, replace the
thin layer of gas with an equally thin layer of perfluorocarbon
liquid. Now, suppose the experiment begins with the water in each
case completely devoid of oxygen but saturated with nitrogen so
that no nitrogen diffusion occurs in any direction. For the PFC,
consider the case when the PFC is initially devoid of O.sub.2 and
compare that to the case when the PFC is saturated with O.sub.2
(but still none in the water). Once the oxygen start diffusing
through the air layer and through the PFC and begin dissolving in
the water, if the concentration in the water in each case is
measured and the values are plotted versus time, the graph may look
like FIG. 5 (qualitatively).
[0081] To draw FIG. 5, it is only necessary to know that the
diffusion coefficient of a gas through a gas is on the order of
10.sup.-1 cm.sup.2/s while that for a gas diffusing through a
liquid is on the order of 10.sup.-5 cm.sup.2/s. For a gas diffusing
through a high viscosity gel, the diffusion coefficient might drop
to as low as 10.sup.-6 cm.sup.2/s or lower depending on how viscous
the gel is. That is, the movement of oxygen through the FtBu layer
will be at least 10,000 times slower than the movement of oxygen
through the equivalently thick air layer in case A. It must
necessarily take a good deal longer to saturate the water in case B
than in case A, all else being the same. For the two B curves, it
is recognized that there is 1) a finite time required to get the
oxygen to break through to the other side of the FtBu in the
initially O.sub.2 devoid layer and 2) the very high capacity of
FtBu for oxygen makes the initially devoid layer a "sink" that
removes some of the diffusing oxygen from the "stream" making its
way to the water. Therefore, it must take longer to saturate the
water if the FtBu is also initially devoid of oxygen.
[0082] Therefore, the substantial difference in the diffusion
coefficients for gases diffusing through gases as opposed to gases
diffusing through liquids eliminates the possibility that a layer
of FtBu placed on top of a wound "speeds up" the delivery of oxygen
to the tissue. In fact, such a layer will substantially slow the
delivery rate. This in no way implies that the tissue would be
"starved" for oxygen. It is entirely likely that oxygen can diffuse
through a thin layer of FtBu at a rate that greatly exceeds the
rate of consumption of oxygen by the tissue. Thus, FtBu layer on
top of the tissue cannot speed up the delivery process but it
doesn't necessary deprive the tissue of oxygen.
[0083] So, if the PFC layer on top of the tissue cannot change the
concentration of oxygen in the tissue and cannot speed the delivery
of oxygen to the tissue, how can we rationalize the anecdotal
evidence that PFCs actually do speed up healing. The answer may lie
in the fact that PFCs do not stay ON TOP of the skin. When a bit of
PFC or one of the gels is rubbed onto the skin, the liquids seem to
absorb into the skin within minutes. The gels made with F68 (solid
poloxamer) leave a tacky film of F68 (the F68 "bloom") on the
surface within 2-3 minutes after application. The gels made with
L35 liquid poloxamer are more pleasant and seems to absorb slower
than does the PFC and water but eventually disappears as well.
[0084] Now return to the first experiment and calculation, but this
time, replace the water with tissue. Suppose the PFC absorbs
quickly into the tissue and either carries bound O.sub.2 with it or
independently absorbs diffusing oxygen, in either case, the PFC
will increase the average oxygen concentration in the tissue/PFC
mixture that forms.
[0085] Now the question becomes, from the tissue's perspective, is
there any difference in a higher average O.sub.2 concentration
obtained by mixing a PFC as opposed to raising the external O.sub.2
partial pressure in a hyperbaric chamber pressure? This question is
tested in Example 3.
Wound and Burns Healing and Scar Prevention and Reduction
[0086] As discussed, the PFC gel described herein has numerous
applications. For example, the PFC gel disclosed herein can be used
as a protective wound covering or a topical gel wound dressing. The
wound covering or gel wound dressing can be used with or
incorporated into a bandage. The topical gel wound dressing can be
used for an approximately 24 hour period to increase availability
of Oxygen to the skin surface in wounds such as abrasions, minor
lacerations, minor cuts, or minor scalds and burns. The gel can be
applied to humans or for veterinary use.
[0087] Oxygen is key for healing wounds. Wounds do not heal when
oxygen is blocked or decreased (e.g., due to broken capillaries).
The topically applied PFC gel creates an oxygen rich environment,
increasing oxygen concentration in the affected skin tissue,
allowing cells to multiply and heal.
[0088] The PFC gel can also be used in treating burn injuries.
Extra oxygen in blood promotes angiogenesis, the formation of new
capillaries. For severely burned subjects, the PFC gel can not only
provide oxygen to oxygen-starved unburned tissue but also promote
the establishment of new capillary beds that feed newly grafted
skin and burned but salvageable skin. Further, studies have shown
that PFCs suppress early postburn lipid peroxidation and increases
resistance of red blood cells to oxidative hemolysis (Bekyarova,
1997).
[0089] In addition to promoting healing of wounds and burns, the
PFC gel can also prevent scarring. Scars are created when there is
not enough oxygen for the skin to correctly heal. Accordingly,
increasing oxygen concentrations in the tissue can reduce the
appearance of scars.
[0090] Therefore, the PFC gel can also prevent scarring by quickly
healing minor wounds and reduce the appearance of scars by
oxygenating the skin tissue and activating the skin regenerative
function.
[0091] Similarly, the PFC gel can also be used for topical
application after procedures causing tissue damage. For example,
the PFC gel can be applied to post-surgery incisions to promote
faster healing. Capillaries ultimately oxygenate the cells/tissues.
After an injury (which includes surgical incisions), it's the
capillaries that are damaged, making them incapable of carrying
fluid to and from the damaged tissues. The result is swelling and
inflammation.
[0092] Increased oxygen levels promote angiogenesis, the growth of
new capillaries and the repair of damaged capillaries. Thus, oxygen
would accelerate healing of the capillaries and fluid could then
again be removed. The PFC gel would also oxygenate the tissues at
the same time. When swelling is reduced, the pain caused by
inflammation is also reduced. It is envisioned that any medical
procedure which causes tissue injury could potentially benefit,
e.g., pulling teeth, incisions, etc.
[0093] In another example, the PFC gel can be applied post-cosmetic
surgery (e.g, post-microdermabrasion or chemical facial peels),
both for the soothing effect as well as the acceleration of
recovery. Since these procedures literally abrade/remove the top
layers of the dermis, the PFC gel can then promotes cell turnover
and repair, which should be accelerated by the topical use.
[0094] Similarly, the gel can be used to treat burns resulting from
radiation in the same way that it treats burns in general as
previously discussed.
[0095] The PFC gel can be a component of a combination therapy or
an adjunct therapy. For example, the gel can be administered with
or without hyperbaric or supplemental oxygen. In one embodiment,
the subject can be administered the PFC gel disclosed herein in
combination with supplemental oxygen. In another embodiment, the
PFC gel can be administered in combination with the subject's own
white blood cells, increasing the efficacy of the treatment.
Anti-Aging Cosmetic Use
[0096] The PFC gel can also be used as a cosmetic agent to promote
anti-aging. The PFC gel can be used for reducing skin imperfections
associated with aging such as fine lines and wrinkles. The PFC gel
can also be used for scar reduction and promotion of skin
firmness.
[0097] Oxygen levels in the skin decrease as we age, making the
appearance of fine lines and wrinkles more noticeable. Applying an
oxygen-rich gel can restore oxygen levels and prevent fine lines
and wrinkles.
[0098] In addition, oxygen can inhibit the destructive enzyme
collagenase which breaks down collagen. Collagen is one of the
structural substances that supports the skin's surface. By
supporting collagen production (by inhibiting collagenase through
higher oxygen levels), the skin can be firmer and look more
youthful.
[0099] Therefore, the PFC gel can diminish fine lines and wrinkles
by using oxygen to activate the skin regenerative functions and
collagen production. Moreover, the PFC gel can increase the
firmness and elasticity of the skin by activating collagen and
elastin creation.
[0100] Yet another cosmetic use for the PFC gel disclosed herein is
the reduction of cellulite. By topically applying the PFC gel in
combination with caffeine and optionally dimethyl sulfoxide (DMSO),
cellulite can be reduced.
Treatment of Acne and Rosacea
[0101] The PFC gel can also be used to treat skin infirmities such
as acne or rosacea. Specially, the PFC gel can prevent, heal and
eliminate acne, providing clear & break-out free skin.
[0102] Acne is a dermatological condition that is thought to be
caused by genetic factors, increased sebum production, abnormal
keratinization of the hair follicle, host immune response, and due
to the harmful effects of increased proliferation of the anaerobic
bacteria Propionibacterium acnes. This type of bacteria is
responsible for much of the inflammatory reaction that occurs in
acne, thought to be due to its release of toxins. Inflammation
occurs when P. acnes, growing in plugged follicles, releases
chemoattractants eliciting the inflammatory response creating the
classical comedones of acne. Therefore, the clinical manifestations
appear to be the result of bacterial-induced inflammation of a
plugged sebaceous gland. Inflammation is further enhanced by
follicular rupture and subsequent leakage of lipids, bacteria, and
fatty acids into the dermis. Systemic and topical antibiotics are
used for both treatment and prophylaxis of acne. Treatments that
reduce P. acnes numbers lead to clinical improvement of acne
(Thiboutot, 1997) and, finally, to the emergence of
antibiotic-resistant P. acnes strains are linked to the failure of
antibiotic treatment (Eady et al, 1989).
[0103] Current treatment of acne consists of selection of a topical
therapy which is based on the severity and type of acne. Topical
retinoids, benzoyl peroxide, and azelaic acid are effective
treatments for mild acne. Topical tretinoin (Retin-A) which is a
derivative of vitamin A, and a comedolytic agent that normalizes
desquamation of the epithelial lining, thereby preventing
obstruction of the pilosebaceous outlet. This agent also appears to
have direct anti-inflammatory effects. Topical antibiotics and
medications with bacteriostatic and anti-inflammatory properties
are effective for treating mild to moderate inflammatory acne.
Systemic antibiotics are used for the moderate to severe patient.
Isotretinoins is used to treat severe, often nodulocystic and
inflammatory acne. Isotretinoin (Accutane) acts against the four
pathogenic factors that contribute to acne. It is the only
medication with the potential to suppress acne over the long term.
To be able to prescribe this medication, the physician must be a
registered member of the manufacturer's System to Manage
Accutane-Related Teratogenicity (SMART) program. The SMART program
was developed in conjunction with the U.S. Food and Drug
Administration (FDA) to minimize unwanted pregnancies and educate
patients about the possible severe adverse effects and
teratogenicity of isotretinoin, which is a pregnancy category X
drug.
[0104] Acne can be caused by an anaerobic bacterium infection as
well as the inflammatory reaction caused by the release of the
bacteria's toxins. Anaerobic bacteria are intolerant of oxygen,
replicating at low oxidation-reduction potential sites. Since
Propionibacterium acnes is an anaerobic bacterium, it thrives in an
environment devoid of oxygen. The addition of oxygen to an
anaerobic infection helps to kill the bacteria and improve the
dermatological condition called acne. The PFC gel disclosed herein
is able to carry a large amount of oxygen, up to approximately four
times the amount of oxygen that hemoglobin can carry. The PFC gel
is able to provide this oxygen through diffusion to an area of low
oxygen concentration, such as an anaerobic infection.
[0105] Anaerobic bacteria are more susceptible to the effects of
oxygen than the more common aerobic bacteria. The PFC gel when
applied topically provides increased local oxygen to the acne
lesions and helps eradicate Propionibacterium acnes and thus
ameliorates the acne.
[0106] The introduction of supplemental topical oxygen (in an
oxygenated perfluorocarbon or via diffusion through PFC) to a
patient who has acne enables the intensity and number of lesions to
be eradicated more efficiently than current therapeutic regiments.
It helps decrease the extent, duration, super infections and
complications (such as scarring) from acne.
[0107] Moreover, if large pores are a contributing factor to acne
and blemishes, by providing an oxygen-rich environment to the
pores, breakouts can be prevented by keeping the pores open and
clean. The PFC gel therefore provides increased oxygen to the
tissues, a healthy environment is created for cells, allowing them
to multiply and thrive.
[0108] The application of the topical form of FtBu in a cream, gel,
pomade, shampoo, conditioner, lotion, liquid, potion, foam, or
similar product, or in combination with a topical antibiotic, or
topical acne product such as retinoid, benzoyl peroxide, peroxide,
isotretionoin, etc. to the inflamed and infected area enhances the
eradication and prevention of the harmful effects of
Propionibacterium acnes. In addition, the PFC Gel helps prevent,
ameliorate and eradicate superinfections and some of the
complications (comedones, pustules, papules, etc.) that acne
causes.
[0109] Also the PFC gel can eliminate and/or reduce redness and
pustules associated with rosacea breakouts. For this indication,
the same principles described for acne and other uses apply. The
PFC gel increases oxygen levels in the face and should be
particularly effective because the capillary bed feeding the face
is so vast and they are located very close to the surface of the
skin. In addition, rejuvenation and healing mechanism described
previously is also applicable.
Enhancement of Sexual Function
[0110] The PFC gel can also be used for enhancing sexual function.
Specifically, the PFC gel can be topically used for increasing
oxygen delivery to the sex organ of a subject for enhancement of
male and female sexual function.
[0111] The PFC gel provides to the sex organ an oxygen-rich
environment and thus improves sexual response time, the frequency
of erections, and the duration of response. Specifically, the PFC
gel can be applied topically to the sex organ and absorbed into
local circulation, causing trabecular smooth muscles to relax,
which is the mechanism leading to an erection.
Other Indications and Uses
[0112] Other indications and uses are summarized as follows:
Air Deodorizer:
[0113] The PFC gel can be used for elimination of unwanted odors,
particularly in the kitchen or in the bathroom. Since PFCs are
quick to absorb gases, it would instantly absorb methane gas that
causes the bad odor which can then be quickly vented from the room.
It is important to note that unlike many other deodorizers, the PFC
gel eliminates odors and does not simply mask them.
Canker Sores:
[0113] [0114] The PFC gel can be used for reducing the time it
takes to cure canker sores. Oxygen is known to help the immune
system fight bacteria and infections. By increasing oxygen
concentrations, the body's immune system would be able to fight
infections better
Cavities:
[0114] [0115] The PFC gel can be used in a cavity fighting
mouthwash or toothpaste. At night, humans salivate less and
therefore do not wash away food particles and harmful bacteria.
These bacteria can make their ATP aerobically, but they switch to
fermentation if there is no O.sub.2 available. It is this
fermentation that lowers the pH on the teeth and cases
demineralization and decay. By increasing oxygen, the PFC gel can
prevent the fermentation process from taking place.
Decubitus Ulcer:
[0115] [0116] The PFC gel can also be used in the treatment of
decubitus ulcers, more commonly known as besores. [0117] By packing
the wound with gauze or other material containing the PFC gel or by
coating the large surface area of these types of wounds with the
PFC gel, the gel can accelerate healing of the wound from the
inside out.
Diabetic Foot Care:
[0117] [0118] The PFC gel can be used in the treatment of the
diabetic foot by providing an oxygen-rich environment to the
diabetic foot as well as adding a protective barrier which may be
provided by the surfactant, thus keeping the skin of the diabetic
foot soft, preventing it from becoming dry and then cracking, which
often leads to more serious foot wounds and infections.
Gas Gangrene:
[0118] [0119] The PFC gel can be used for fighting deadly
infections caused by gas gangrene. Gas-producing organisms (such as
those that cause toxic shock syndrome and gas gangrene and
botulism) cause their damage by releasing toxic gases into the
tissues/body. These organisms are anaerobic. Therefore, by
providing an oxygen-rich environment, the anaerobic organisms would
be destroyed by oxygen. [0120] As an additional benefit, the PFC
gel can absorb the toxic gases released from the organisms.
Hemorrhoids:
[0120] [0121] PFC gel disclosed herein can be used in the treatment
of hemorrhoids, specifically, in relieving inflammation, reducing
swelling and associated pain in addition to reducing incidence of
necrosis. Hemorrhoids are varicose veins and as such, their blood
supply is compromised. Application of an oxygen-enhancing gel will
bring needed oxygen to the area, which will prevent necrosis of the
tissues. Since inflammation is a response to tissue injury, and in
this case, the injury is caused by limited oxygen supply,
replenishing the oxygen supply would reduce the inflammation,
thereby reducing the swelling and associated pain.
Muscle Pain/Aching Muscle:
[0121] [0122] The PFC gel can be used for the treatment of muscle
pain. The gel can be applied to the muscles to provide oxygen
before, during, or after strenuous exercise. In one embodiment, the
gel can be combined with an ingredient which provides heat to the
muscles, such as camphor or eucalyptus. [0123] The gel can also be
used for speeding up the healing process of muscle tears. Strenuous
activity creates small tears in muscle tissue. The Healing of these
tears increases muscle mass. The PFC gel will increase oxygen
tension in the muscle and hence, speed up the healing process.
Nocturnal Leg Cramps:
[0123] [0124] PFC gel disclosed herein can be used in the treatment
of nocturnal leg cramps by increasing oxygen levels in the lower
leg during sleep. [0125] Nocturnal leg cramps affect nearly 70% of
the population. Various causes include dehydration, electrolyte
imbalance and decreased oxygen to the limbs (also caused by various
factors). Even when cramping is caused by dehydration/electrolyte
imbalance, it is ultimately the decrease in oxygen, secondary
possibly to the root cause that causes the muscles to cramp.
Therefore, the PFC gel can be used in the treatment of nocturnal
leg cramps by increasing oxygen levels in the lower leg during
sleep.
Pruritus Relief:
[0125] [0126] The PFC gel can be used for pruritus relief and for
providing faster healing of irritated skin. [0127] The PFC gel can
be used for pruritus relief resulting from insect bites, contact
dermatitis eczema, etc. Studies have shown that oxygen may inhibit
histamine release that is the cause of itch associated with various
conditions. It has been disclosed that an oxygen-glucose deprived
environment increases histamine release (Shen, 2007). Therefore,
the gel can be used, e.g., for relieving pruritus. Specifically,
for relieving itch from insect bites, poison ivy, etc. [0128] The
PFC gel can also treat inflammation associated with various
conditions as previously described. Thus, the PFC gel would also
reduce redness, swelling and irritation related to insect bites.
[0129] By increasing oxygen concentrations, pruritus and general
skin irritation are alleviated. s an additional benefit, the PFC in
the gel also anesthetizes skin similar to the way benzocaine does.
Reduction of Toxic Gases from Cigarettes: [0130] The PFC gel can
also be used in the reduction of toxic gases from cigarettes.
[0131] The toxic gases found in tobacco smoke include carbon
monoxide, nitrogen oxides, hydrogen cyanide, ammonia, acrolein,
freon, formaldehyde and many others. These toxins are partly
responsible for conditions commonly seen in smokers, such as
bronchitis and emphysema. Hydrogen cyanide was the gas used in gas
chambers in WWII and is a known toxin to the central nervous
system. [0132] After absorption through the lungs, CO combines with
hemoglobin in the red blood cells and reduces the amount of oxygen
in the blood and tissues. CO combined with nicotine is believed to
play a part in accelerating the deposition of cholesterol in the
inner lining of arteries, which eventually leads to
arteriosclerosis. [0133] Impairment of blood flow and reduced
oxygen carrying capacity due to CO reduce the supply of oxygen to
the heart at the same time that the heart's need for oxygen is
increased by the stimulant effect of nicotine on the rate and force
of the heart's contractions, damaging the heart and increasing the
severity of a heart attack. [0134] CO+nicotine are also important
factors in causing peripheral vascular disease, which can lead to
gangrene of the feet. [0135] By saturating the filter of cigarettes
with Oxycyte.TM. emulsion or by injecting the PFC gel into the
filter, the PFC binds many of the harmful/toxic gases found in
tobacco smoke, trapping them in the filter and reducing the amount
that is inhaled into the lungs. This provides the benefit of
reducing harmful/irritating/toxic gases from smoking. In this
application PFCs are contained in a filter so as to trap any
burning PFCs can release dangerous chemicals.
Safety Equipment for Manufacturing Facilities:
[0135] [0136] The PFC gel can also be used to absorb dangerous
gases to prevent potential disasters arising from gas leaks in
chemical manufacturing plants since PFCs are quick to absorb gases.
[0137] In one embodiment, the PFC can be incorporated into
sprinkler systems on site. In another embodiment, the PFC gel is
sprayed in the gas-filled area in the same manner as a fire
extinguisher. In this case, the toxic gases are quickly absorbed by
the PFC gel and the gel is then hosed out of or otherwise removed
from the room.
Shampoo, Conditioner, Dandruff or Hair Loss Treatment:
[0137] [0138] The PFC gel can also be incorporated into hair
products such as shampoo and conditioners, enhancing oxygen
concentration when applied. Pollutants in the air are known to make
hair drab and dull. By increasing oxygen to the hair, the hair
would be revitalized. [0139] The gel would also moisturize hair and
protects it from heat when styling. The gel can also reduce frizz
in hair. [0140] At the same time, oxygenating and moisturizing the
scalp creates a healthy and hydrated scalp. Having a healthy and
hydrated scalp would reduce the likelihood of dandruff and
therefore, of fungal colonization of the scalp that is often caused
by dandruff. [0141] Moreover, the PFC gel can aid in hair growth.
The PFC gel can increase generation of capillaries that feed the
scalp, thereby increasing blood flow and oxygenation to hair
follicles.
Skin Graft:
[0141] [0142] The PFC gel can also accelerate skin graft uptake and
increase in skin graft survival. [0143] For skin grafts, it is
critical to restore the circulation to the grafted tissues as soon
as possible. As discussed previously, oxygen promote angiogenesis,
the growth of new capillaries and the repair of damaged
capillaries. Again, it is the capillaries which feed the tissues by
carrying fluid to and from the tissues. [0144] By topically
applying the PFC gel and promoting angiogenesis, the gel can
promote re-epithelialization, healing and graft acceptance by
bringing additional oxygen to the epithelial cells.
[0145] The perfluorocarbon employed in the compositions and methods
described herein may be in compositions which may further comprise
pharmaceutically acceptable carrier or cosmetic carrier and
adjuvant(s) suitable for topical administration. Compositions
suitable for topical administration are well known in the
pharmaceutical and cosmetic arts. These compositions can be adapted
to comprise the oxygenated perfluorocarbon. The composition
employed in the methods described herein may also comprise a
pharmaceutically acceptable additive.
[0146] The multiplicity of configurations may contain additional
beneficial biologically active agents which further promote tissue
health.
[0147] The compositions of this invention may be administered in
forms detailed herein. The use of perfluorocarbon may be a
component of a combination therapy or an adjunct therapy. The
combination therapy can be sequential or simultaneous. The
compounds and compositions can be administered independently by the
same route or by two or more different routes of administration
depending on the dosage forms employed.
[0148] The dosage of the compounds and compositions administered in
treatment will vary depending upon factors such as the
pharmacodynamic characteristics of a specific therapeutic agent and
its mode and route of administration; the age, sex, metabolic rate,
absorptive efficiency, health and weight of the recipient; the
nature and extent of the symptoms; the kind of concurrent treatment
being administered; the frequency of treatment with; and the
desired therapeutic effect.
[0149] A dosage unit of the compounds and compositions may comprise
a single compound or mixtures thereof with other compounds. The
compounds can be introduced directly into the targeted tissue,
using dosage forms well known to those of ordinary skill in the
cosmetic and pharmaceutical arts.
[0150] The compounds and compositions can be administered in
admixture with suitable pharmaceutical diluents, extenders,
excipients, or carriers (collectively referred to herein as a
pharmaceutically acceptable carrier) suitably selected with respect
to the intended form of administration and as consistent with
conventional pharmaceutical and cosmetic practices. The compounds
can be administered alone but are generally mixed with a
pharmaceutically acceptable carrier. This carrier can be a solid or
liquid, and the type of carrier is generally chosen based on the
type of administration being used. Examples of suitable liquid
dosage forms include solutions or suspensions in water,
pharmaceutically acceptable fats and oils, alcohols or other
organic solvents, including esters, emulsions, syrups or elixirs,
suspensions, solutions and/or suspensions reconstituted from
non-effervescent granules and effervescent preparations
reconstituted from effervescent granules. Such liquid dosage forms
may contain, for example, suitable solvents, preservatives,
emulsifying agents, suspending agents, diluents, sweeteners,
thickeners, and melting agents.
[0151] Techniques and compositions for making dosage forms useful
in the present invention are described in the following references:
7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes,
Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et
al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd
Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack
Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical
Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in
Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones,
James McGinity, Eds., 1995); Aqueous Polymeric Coatings for
Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences,
Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate
Carriers: Therapeutic Applications: Drugs and the Pharmaceutical
Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the
Gastrointestinal Tract (Ellis Horwood Books in the Biological
Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S.
Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the
Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.
Rhodes, Eds.). All of the aforementioned publications are
incorporated by reference herein.
[0152] The PFC compositions may contain the any of the following
non-toxic auxiliary substances:
[0153] The PFC compositions may contain antibacterial agents which
are non-injurious in use, for example, thimerosal, benzalkonium
chloride, methyl and propyl paraben, benzyldodecinium bromide,
benzyl alcohol, or phenylethanol.
[0154] The PFC compositions may also contain buffering ingredients
such as sodium chloride, sodium acetate, gluconate buffers,
phosphates, bicarbonate, citrate, borate, ACES, BES, BICINE,
BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS,
PIPES, TAPS, TES, and Tricine.
[0155] The PFC compositions may also contain a non-toxic
pharmaceutical organic carrier, or with a non-toxic pharmaceutical
inorganic carrier. Typical of pharmaceutically acceptable carriers
are, for example, water, mixtures of water and water-miscible
solvents such as lower alkanols or aralkanols, vegetable oils,
peanut oil, polyalkylene glycols, petroleum based jelly, ethyl
cellulose, ethyl oleate, carboxymethyl-cellulose,
polyvinylpyrrolidone, isopropyl myristate and other conventionally
employed acceptable carriers.
[0156] The PFC compositions may also contain non-toxic emulsifying,
preserving, wetting agents, bodying agents, as for example,
polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000,
1,500, 4,000, 6,000 and 10,000, antibacterial components such as
quaternary ammonium compounds, phenylmercuric salts known to have
cold sterilizing properties and which are non-injurious in use,
thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl
ethanol, buffering ingredients such as sodium borate, sodium
acetates, gluconate buffers, and other conventional ingredients
such as sorbitan monolaurate, triethanolamine, oleate,
polyoxyethylene sorbitan monopalmitylate, dioctyl sodium
sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine
tetracetic.
[0157] The PFC compositions may also contain surfactants that might
be employed include polysorbate surfactants, polyoxyethylene
surfactants, phosphonates, saponins and polyethoxylated castor
oils, but preferably the polyethoxylated castor oils. These
surfactants are commercially available. The polyethoxylated castor
oils are sold, for example, by BASF under the trademark
Cremaphor.
[0158] The PFC compositions may also contain wetting agents
commonly used in ophthalmic solutions such as
carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin,
mannitol, polyvinyl alcohol or hydroxyethylcellulose and the
diluting agent may be water, distilled water, sterile water, or
artificial tears, wherein the wetting agent is present in an amount
of about 0.001% to about 10%.
[0159] The formulation of this invention may be varied to include
acids and bases to adjust the pH; tonicity imparting agents such as
sorbitol, glycerin and dextrose; other viscosity imparting agents
such as sodium carboxymethylcellulose, microcrystalline cellulose,
polyvinylpyrrolidone, polyvinyl alcohol and other gums; suitable
absorption enhancers, such as surfactants, bile acids; stabilizing
agents such as antioxidants, like bisulfites and ascorbates; metal
chelating agents, such as sodium edetate; and drug solubility
enhancers, such as polyethylene glycols. These additional
ingredients help make commercial solutions with adequate stability
so that they need not be compounded on demand.
[0160] Finally, the formulation of this invention can be adjusted
so that the PFC composition is the form of a cream, pomade,
shampoo, conditioner, lotion, liquid, potion, foam, or similar
product, which are suitable for topical application.
[0161] Other materials as well as processing techniques and the
like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
and International Programme on Chemical Safety (IPCS), which is
incorporated herein by reference.
[0162] All combinations of the various elements are within the
scope of the invention.
[0163] It is understood that where a parameter range is provided,
all integers within that range, and tenths thereof, are also
provided by the invention. For example, "10-90 wt %" includes 10.0
wt %, 10.1 wt %, 10.2 wt %, 10.3 wt %, 10.4 wt % etc. up to 90.0 wt
%.
[0164] This invention will be better understood by reference to the
Experimental Details which follow, but those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention as described more fully in the
claims which follow thereafter.
EXPERIMENTAL DETAILS
Example 1
Testing for Oxycyte.TM. Toxicity
[0165] An Oxycyte.TM. emulsion (60% wt/vol. PFC) was tested
systemically via intravenous administration in Sprauge Dawley rats,
Cynomolgus Monkeys and humans.
[0166] The Oxycyte.TM. emulsion was found to be well tolerated and
had no toxicity.
Example 2
Stable Gels A-E
Summary
[0167] Five gel recipes, named Gels A-E, have been deemed most
successful considering the stability and viscosity of the resulting
gel. Each gel is composed of water, a surfactant (Pluronic F-68 or
Pluronic F-127), and a perfluorocarbon (perfluorodecalin (PFD) or
recycled perfluoro(tert-butylcyclohexane) (FtBu)). Experimental
materials and procedures are described below as well as relevant
percent yields.
Materials
[0168] 1. Pluronic F-68: [Sigma-Aldrich P1300-500G Batch #097K0116
CAS 9003-11-6]; [0169] 2. Pluronic F-127: [Sigma-Aldrich P2443-250G
Batch #038K0113 CAS 9003-11-6]; [0170] 3. Perfluorodecalin, 95%
mixture of cis and trans (PFD): [Sigma-Aldrich T3251-100G Batch
#078K1882 CAS 10191-41-0]; [0171] 4. Recycled
t-butylperfluorocyclohexane (FtBu): [Oxygen Biotherapeutics, Inc.
Costa Mesa, Calif. 92626]; [0172] 5. Ethyl Alcohol, absolute, 200
proof, 99.5%, A.C.S. reagent: [ACROS 61509-0040, CAS 64-17-5];
[0173] 6. Distilled H.sub.2O; [0174] 7. 20-100 mL glass beakers;
[0175] 8. 5-20 mL glass beakers; [0176] 9. 20-50 mL Corning
centrifuge tubes; [0177] 10. 5-60 mL Teflon capped, glass jars;
[0178] 11. OMNI Macro ES Homogenizer; [0179] 12. 750 Watt, 20 kHz
Ultrasonic Processor; [0180] 13. Fisherbrand Spoonulet Lab Spoon;
[0181] 14. Spatula; [0182] 15. Pipet; [0183] 16. 5 mL
NORM-JECT.RTM. luer lock, airtight syringe; and [0184] 17. B-D.RTM.
26 gauge 1/2 inch, luer lock, Precision Glide.RTM. syringe
needle.
Experimental Procedures
Gel A
[0185] 16.25 g of distilled water was weighed into a 100 mL glass
beaker. 20 g of PFD was added to the beaker followed by 5 g of
F-68. The contents of the beaker were then manually stirred with a
spatula for 30 seconds. The tip of an OMNI Macro ES Homogenizer was
submerged into the contents of the beaker, and the stirred mixture
was homogenized for approximately 5 minutes at 4000 rpm. The
homogenized mixture was poured into a 50 mL Corning centrifuge
tube. The procedure was then repeated three times in order to
prepare 4 centrifuge tubes. All 4 centrifuge tubes were centrifuged
in an IEC Clinical Centrifuge for 30 minutes. The off-fluid of each
tube was poured out and weighed separately. The gel remaining in
each tube was scooped out using a Fisherbrand Spoonulet Lab Spoon
and weighed into a 60 mL Teflon capped, glass jar. The jar was
labeled GEL A.
Gel B
[0186] 16.25 g of distilled water was weighed into a 100 mL glass
beaker. 20 g of PFD was added to the beaker followed by 5 g of
F-68. The contents of the beaker were then manually stirred with a
spatula for 30 seconds. The tip of a 750 Watt, 20 kHz Ultrasonic
Processor was submerged into the contents of the beaker, and the
stirred mixture was sonicated for approximately 5 minutes at 20%
amplitude. The sonicated mixture was poured into a 50 mL Corning
centrifuge tube. The procedure was then repeated three times in
order to prepare 4 centrifuge tubes. All 4 centrifuge tubes were
centrifuged in an IEC Clinical Centrifuge for 30 minutes. The
off-fluid of each tube was poured out and weighed separately. The
gel remaining in each tube was scooped out using a Fisherbrand
Spoonulet Lab Spoon and weighed into a 60 mL Teflon capped, glass
jar. The jar was labeled GEL B.
Gel C
[0187] 16.25 g of distilled water was weighed into a 100 mL glass
beaker. 20 g of FtBu was added to the beaker followed by 5 g of
F-127. The contents of the beaker were then manually stirred with a
spatula for 30 seconds. The tip of an OMNI Macro ES Homogenizer was
submerged into the contents of the beaker, and the stirred mixture
was homogenized for approximately 5 minutes at 4000 rpm. The
homogenized mixture was poured into a 50 mL Corning centrifuge
tube. The procedure was then repeated three times in order to
prepare 4 centrifuge tubes. All 4 centrifuge tubes were centrifuged
in an IEC Clinical Centrifuge for 30 minutes. The off-fluid of each
tube was poured out and weighed separately. The gel remaining in
each tube was scooped out using a Fisherbrand Spoonulet Lab Spoon
and weighed into a 60 mL Teflon capped, glass jar. The jar was
labeled GEL C.
Gel D
[0188] 16.25 g of distilled water was weighed into a 100 mL glass
beaker. 20 g of FtBu was added to the beaker followed by 5 g of
F-127. The contents of the beaker were then manually stirred with a
spatula for 30 seconds. The tip of a 750 Watt, 20 kHz Ultrasonic
Processor was submerged into the contents of the beaker, and the
stirred mixture was sonicated for approximately 5 minutes at 20%
amplitude. The sonicated mixture was poured into a 50 mL Corning
centrifuge tube. The procedure was then repeated three times in
order to prepare 4 centrifuge tubes. All 4 centrifuge tubes were
centrifuged in an IEC Clinical Centrifuge for 30 minutes. The
off-fluid of each tube was poured out and weighed separately. The
gel remaining in each tube was scooped out using a Fisherbrand
Spoonulet Lab Spoon and weighed into a 60 mL Teflon capped, glass
jar. The jar was labeled GEL D.
Gel E
[0189] 16.25 g of distilled water was weighed into a 100 mL glass
beaker. 20 g of FtBu was added to the beaker followed by 5 g of
F-68. The contents of the beaker were then manually stirred with a
spatula for 30 seconds. The tip of an OMNI Macro ES Homogenizer was
submerged into the contents of the beaker, and the stirred mixture
was homogenized for approximately 5 minutes at 4000 rpm. The
homogenized mixture was poured into a 50 mL Corning centrifuge
tube. The procedure was then repeated three times in order to
prepare 4 centrifuge tubes. All 4 centrifuge tubes were centrifuged
in an IEC Clinical Centrifuge for 30 minutes. The off-fluid of each
tube was poured out and weighed separately. The gel remaining in
each tube was scooped out using a Fisherbrand Spoonulet Lab Spoon
and weighed into a 60 mL Teflon capped, glass jar. The jar was
labeled GEL E.
Determination of Perfluorocarbon Yields
[0190] Approximately 5 g of each gel was placed individually into
20 mL glass beakers. Using a pipet, 2.80 g, 2.90 g, 7.00 g, 6.32 g,
and 5.48 g of ethanol were added to each beaker containing Gel A,
Gel B, Gel C, Gel D, and Gel E, respectively. Each gel/ethanol
mixture was stirred for 5 minutes using a spatula. Each stirred
mixture was allowed to sit for 3 minutes in order for two layers,
an aqueous layer and a perfluorocarbon layer, to separate. The
perfluorocarbon layer was removed from the beaker using a 5 mL
syringe with a 26 gauge, 2 inch syringe needle. The weight of the
perfluorocarbon layer was recorded. This weight divided by the
initial (-5 g) gel weight for each gel sample gave the
perfluorocarbon yield for each gel.
Results
Yield Data
[0191] The perfluorocarbon yield is defined as the percentage of
perfluorocarbon added during the preparation that remained as part
of the recovered gel. The perfluorocarbon yields were as
follows.
TABLE-US-00003 Percent Gel A 95.8 Gel B 94.0 Gel C 48.8 Gel D 34.1
Gel E 90.8
[0192] The percent gel yield is defined as the total weight of
recovered gel relative to the total weight of components added
during preparation. The gel yields were as follows.
TABLE-US-00004 Percent Gel A 65.8 Gel B 85.6 Gel C 43.8 Gel D 40.0
Gel E 40.5
Example 3
Stable Gels 1-4
[0193] Table 1 shows four preferred embodiments of the subject
invention (Gels 1-4).
TABLE-US-00005 TABLE 1 grams/gram of gel Gel 1 Gel 2 Gel 3 Gel 4
Component 75, 25-T 75, 25-H (PQ).sup.2-T (PQ).sup.2-H
perfluoro(tert- 85.980% 86.726% 85.980% 86.726% butylcyclohexane)
Distilled Water 10.277% 10.366% 10.277% 10.366% Pluronic .RTM. F-68
0.307% 0.310% 0.307% 0.310% Pluronic .RTM. L-35 2.446% 2.467%
2.446% 2.467% Polyquaternium-6 0.000% 0.000% 0.248% 0.033%
Polyquaternium-7 0.743% 0.099% 0.495% 0.066% EDTA 0.248% 0.033%
0.248% 0.033% Pluronic .RTM. is a trade name of BASF Corporation
(Mt. Olive, NJ). Pluronic F-68 and Pluronic L-35 are
hydroxyl-terminated ethylene oxide-propylene oxide block
copolymers. They have the general formula:
HO(C.sub.2H.sub.4O).sub.a(C.sub.3H.sub.6O).sub.b(C.sub.2H.sub.4O).sub.cH.
Subscripts a and c are usually about equal and subscript b is
usually 15 or higher. F-68 is a solid with a molecular weight of
about 8400; L-35 is a liquid with a molecular weight of about
1900.
[0194] The chemical structures for Polyquaternium-6 and
Polyquaternium-7 are shown below:
##STR00002##
Polyquaternium 6 ionic surfactant/preservative
Poly(diallyldimethylammonium chloride)
(CAS No. 26062-79-3) (Nalco Merquat.RTM. 100)
##STR00003##
[0195] Polyquaternium 7 ionic surfactant/preservative
Poly(acrylamide-co-diallyldimethylammonium chloride)
(CAS No. 26590-05-06) (Nalco Merquat.RTM. 740)
[0196] These materials are sold by several companies including
Nalco Company of Naperville, Ill. Both chemicals contain highly
polar dimethylammonium chloride quaternary salts. There are many
other polyquat salts as shown in Table 2. However, not all are used
as preservatives.
TABLE-US-00006 TABLE 2 Product CAS RN polyquaternium 1 75345-27-6
polyquaternium 2 68555-36-2 polyquaternium 4 92183-41-0
polyquaternium 5 26006-22-4 polyquaternium 6 26062-79-3
polyquaternium 7 26590-05-6 polyquaternium 10 68610-92-4
polyquaternium 11 53633-54-8 polyquaternium 12 68877-50-9
polyquaternium 13 68877-47-4 polyquaternium 14 27103-90-8
polyquaternium 15 35429-19-7 polyquaternium 16 95144-24-4
polyquaternium 22 53694-17-0 polyquaternium 24 107987-23-5
polyquaternium 28 131954-48-8 polyquaternium 31 136505-02-7
polyquaternium 32 35429-19-7 polyquaternium 33 69418-26-4
polyquaternium 37 26161-33-1 polyquaternium 44 150599-70-5
polyquaternium 46 174761-16-1 polyquaternium 57 9004-97-1
[0197] EDTA is ethylene diamine tetraacetic acid. The disodium salt
and tetrasodium salt of EDTA are more frequently used than the
tetraacid as cosmetic preservatives. However, these salts (in fact,
any ionizable salt) will break the gel or prevent the gel from
forming.
[0198] The concentrations of the three preservatives are based
either on the total basic gel weight (including the FtBu),
designated "-T" gels or the concentration is based on the weight of
the water and Pluronics only, designated "-H" gels. The 75, 25-T
gel (Gel 1) contains 7500 ppm of Polyquat-7 and 2500 ppm of EDTA,
both based on the total formulation weight including the FtBu. Gel
(PQ).sup.2-H (Gel 4) contains 2500 ppm PQ-6, 5000 ppm PQ-7, and
2500 ppm EDTA--each based on the weight of the aqueous phase in the
gel only.
Gel Formation and Processing
[0199] The formation of gels 1-4 proceeds by first mixing the
aqueous phase components (distilled water, F-68, L-35, and the
preservatives of choice) in a glass, polyethylene, PET, or 316
stainless steel vessel. The mixture is homogenized for about 5
minutes with a rotor/stator homogenizer at 10,000-35,000 RPM. The
homogenizer can be handheld for small samples (<2 L), a bench
top unit for larger (2-5 L) samples, or a larger, floor mounted
version of these mixers for commercial scale production (>5
L).
[0200] During mixing of the aqueous phase, not all components need
be completely soluble. The F-68 has limited solubility in water and
homogenization mostly disperses this solid as very fine particles
once the saturation limit for F-68 in water has been reached.
Similarly, high concentrations of EDTA can result in a fine
particle dispersion after the solubility limit for EDTA in water
has been attained (-500 ppm in water at 20.degree. C.).
[0201] After homogenization of the aqueous phase mixture, the
perfluorocarbon (PFC) is added either in aliquots or slowly and
continuously over the course of the next 10-30 minutes of high
speed homogenization. Gel formation tends to occur only at the
latter stages of PFC addition. The gels that form do not require
centrifugation and separation as taught by Moore in U.S. Pat. No.
4,569,784, which is hereby incorporated by reference herein.
[0202] Continued homogenization past the 25-30 minutes typical for
gel formation creates more viscous gels. For some formulations, the
long term stability of the gel improves with longer mixing. The
formulations which will exhibit this behavior can be determined by
trial and error. Other PFC gels can be obtained by this process.
For example, very stable gels can be formed using APF-200
(available from Exfluor Corporation, Round Rock, Tex.) or
perfluorodecalin in similar recipes. This method is anticipated to
be applicable to a wide range of perfluorocarbon solvents and,
possibly, to hydrofluorocarbons or hydrochlorofluorocarbons.
Factors Affecting Gel Formation and Processing
[0203] There are many compounds and materials that are incompatible
with the disclosed gels.
Alcohols
[0204] Trace levels of alcohols will immediately or eventually
cause the gel to break. The inventors have observed this behavior
with trace amounts of methanol, ethanol, isopropanol, tecopherol,
chlorhexidine digluconate, chlorphenesin, and glycerol. It appears
that any compound having a primary, secondary, or tertiary hydroxyl
or phenolic group will break the gel or prevent the formation of
the gel.
Highly Ionized salts
[0205] Highly ionized compounds (salts) can prevent the formation
of the gel or break the gel once formed. While low levels (<5000
ppm) of EDTA can be incorporated successfully, the di- and
tetrasodium salts of EDTA prevent formation. Tap water contains
sufficient levels of ions to break the gel in a period of 1-24
hours after contact. While polymeric quaternary ammonium compounds
have been successfully added, benzalkonium chloride will prevent
gel formation at ppt levels or lower. If highly ionized salts
contact the gel after formation, the salts can break the gel even
if not mechanically mixed into the bulk. It is often sufficient for
gel destruction to contact one surface of the gel with a quiescent
aqueous puddle of the offensive compound. Once the gel begins to
break, it tends to continue to unravel over a period of hours to
days.
Highly Nonpolar Solid Surfaces
[0206] Highly nonpolar solid surfaces are incompatible with these
gels and will break the gels quickly or over time. This occurs
whenever the perfluorocarbon can "wet" a solid surface and form a
film of the pure PFC. The film tends to segregate gravitationally
and sink slowly to the bottom of the vessel holding the gel. This
process "renews" or frees the surface to contact more gel and
separate more PFC. The process continues slowly until a large part
of the gel has broken and formed two distinct phases. The inventors
have observed this behavior for packaging films having heat seal
lacquer coatings and for Teflon.RTM. surfaces. Teflon is an
especially aggressive gel breaker. Thus far, it appears that glass,
polyethylene, PET, nylon, and other non-PFC wettable surfaces are
compatible with the gels.
Metal Surfaces
[0207] Certain metal surfaces are incompatible with gels but for
differing reasons. Aluminum surfaces are easily wetted by the PFC
and cause separation and eventually breaking of the gels. 304
stainless steel, unlike 316 stainless, is attacked and corroded by
the gels. The surface of 304 stainless is passivated by an oxide
coating that is easily breached by the chloride anion of the
polyquat salts. Once breached, the surface is attacked by the EDTA
and corroded. It is anticipated that other incompatible metals will
be observed with more testing. Clearly, the choice of materials of
construction is important for commercial production of these
gels.
Packaging Materials
[0208] Some packaging materials are inappropriate for the gels. In
particular, those plastics that are highly permeable to water will
be poor choices since loss of the aqueous phase by diffusion
through the plastics will degrade and eventually break the gels. A
good example is PET. A single layer of PET will allow water in the
gel to escape. However, if PET is sandwiched with polyethylene or
polypropylene, the poor solubility of water in the polyolefins will
lower the permeation loss rate to an acceptable level and the gel
will remain secure.
Example 4
Measuring Oxygen Tension in Tissue
[0209] A material which binds oxygen (fluorescent marker) is
injected into skin tissue. The combination is fluorescent and the
more oxygen that is present, the stronger the fluorescent signal.
(representing the oxygen tension in the tissue).
[0210] First it is determined that fluorescence chemistry is
unaffected by the PFCs and poloxamers. Then as a control, the
fluorescent marker is injected into the skin, and oxygen tension is
obtained. Finally, the same area is treated with a PFC or a PFC gel
and oxygen tension is again obtained.
[0211] Result: oxygen tension reading begins to spike after
injection of the marker into the area treated with PFC, then starts
to decline as the PFC is eliminated from the tissue.
[0212] Conclusion: the absorption of an oxygen-binding PFC like
FtBu or APF-200 substantially increases local oxygen tension in the
tissue. The resulting increase in local oxygen concentration may
serve both to increase rates of wound healing and rates of
free-radical deactivation.
Example 5
Wound and Burn Healing and Scar Prevention and Reduction
Example 5A
[0213] A perfluorocarbon gel composition as described herein is
administered topically to a subject. Specifically, the gel is
administered topically to a wound on the subject.
[0214] The PFC gel increases oxygen level and oxygen tension in the
wound tissue. In addition, the gel accelerates wound healing.
Moreover, the perfluorocarbon is well tolerated and has no
toxicity.
Example 5B
[0215] A perfluorocarbon gel composition as described herein is
administered topically to a subject. Specifically, the gel is
administered topically to a burn wound on the subject.
[0216] The PFC gel increases oxygen level and oxygen tension in the
burnt tissue and surrounding tissue. In addition, the gel
accelerates the healing of the burn wound. Moreover, the
perfluorocarbon is well tolerated and has no toxicity.
Example 5C
[0217] A perfluorocarbon gel composition as described herein is
administered topically to a subject. Specifically, the gel is
administered topically to a wound or a scar on the subject.
[0218] The PFC gel increases oxygen level and oxygen tension in the
wound or scarred tissue. In addition, the gel accelerates wound
healing and ameliorates and reduces the appearance of the scar.
Moreover, the perfluorocarbon is well tolerated and has no
toxicity.
Example 6
Promotion of Anti-Aging
Example 6A
[0219] A perfluorocarbon gel composition as described herein is
administered topically to a subject. Specifically, the gel is
administered topically to the skin on the subject.
[0220] The PFC gel increases oxygen level and oxygen tension in the
skin tissue. In addition, the gel reduces the appearance of skin
imperfection associated with aging including fine lines and
wrinkles. Also, the gel improves the firmness of the skin where
applied. Moreover, the perfluorocarbon is well tolerated and has no
toxicity.
Example 6B
[0221] A perfluorocarbon gel composition as described herein mixed
with caffeine is administered topically to a subject. Specifically,
the gel mixture is administered topically to the cellulite-affected
skin on the subject.
[0222] The PFC gel mixture increases oxygen level and oxygen
tension in the skin tissue. In addition, the gel mixture reduces
the appearance the cellulite where applied. Moreover, the
perfluorocarbon is well tolerated and has no toxicity.
Example 7
Treatment of Acne and Rosacea
Example 7A
[0223] A perfluorocarbon gel composition as described herein is
topically administered to the skin of a subject suffering from acne
at the site of the acne. Topical administration of the PFC gel is
effective to treat the subject's acne. Acne reduction is
noticeable, as is a reduction in skin appearance characteristics
associated with acne.
Example 7B
[0224] A perfluorocarbon gel composition as described herein is
topically administered to the skin a subject suffering from acne
vulgaris at the site of the acne vulgaris. Topical administration
of the PFC gel is effective to reduce acne-scarring in the subject
by reducing the severity of existing acne vulgaris and preventing
or reducing the severity of further acne vulgaris in the
subject.
Example 7C
[0225] A perfluorocarbon gel composition as described herein is
topically administered a subject suffering from a Propionibacterium
acnes infection of a skin follicle of the subject. The composition
is applied to the skin follicle or the area of skin surrounding the
skin follicle. Topical administration of the PFC gel is effective
to reduce the Propionibacterium acnes infection of the skin
follicle of the subject.
Example 7D
[0226] A perfluorocarbon gel composition as described herein is
topically administered to the skin of a subject suffering from a
Propionibacterium acnes infection of the dermis of the subject. The
composition is applied to the skin comprising the infected dermis.
Topical administration of the PFC gel is effective to reduce the
Propionibacterium acnes proliferation in the dermis of the
subject.
Example 7E
[0227] A perfluorocarbon gel composition as described herein is
topically administered to the skin of a subject susceptible to
acne. Topical administration of the PFC gel is effective to prevent
or reduce the subject's acne.
Example 7F
[0228] A perfluorocarbon gel composition as described herein is
topically administered to the skin of a subject wherein there are
Propionibacterium acnes in and/or on the skin. Topical
administration of the PFC gel is effective to kill
Propionibacterium acnes in and/or on the skin of the subject.
[0229] In the above examples the administration of the composition
is one, two or three times per day. The administration can be
repeated daily for a period of one, two, three or four weeks, or
longer. The administration can be continued for a period of months
or years as necessary.
Example 7G
[0230] A perfluorocarbon gel composition as described herein is
topically administered to the skin of a subject suffering from
rosacea at the site of the rosacea. Topical administration of the
composition comprising the perfluorocarbon or oxygenated
perfluorocarbon is effective to treat the subject's rosacea.
Rosacea reduction is noticeable, as is a reduction in skin
appearance characteristics associated with rosacea.
Example 8
Sexual Enhancement
Example 8A
[0231] A perfluorocarbon gel composition as described herein is
administered topically to sex organs of a human male subject. Local
oxygen tension and nocturnal erections are evaluated. Changes in
Quality of life (QOL) data is also collected and assessed.
[0232] Oxygen level and oxygen tension in the tissue increases. In
addition, Quality of life of the subject improves. Moreover, the
perfluorocarbon is well tolerated and has no toxicity.
Example 8B
[0233] A perfluorocarbon gel composition as described herein is
topically administered to sex organs of male and female human
subjects. The PFC gel is administered once or twice daily. Local
oxygen tension and nocturnal erections (in males) are evaluated.
Changes in Quality of life (QOL) data is also collected and
assessed.
[0234] Oxygen level and oxygen tension in the tissue is increases.
In addition, Quality of life of the subject improves. Moreover, the
perfluorocarbon composition is well tolerated and has no
toxicity.
REFERENCES
[0235] 1. U.S. Pat. No. 4,569,784, issued Feb. 11, 1986 to Robert
E. Moore. [0236] 2. Bekyarova, G., et al. (1997) "Suppressive
effects of FC-43 perluorocarbon emulsion on enhanced oxidative
haemolysis in the early postburn phase." Burns. (23).sub.2:
117-121. [0237] 3. Davis, Stephen C., et al. (2007) "Topical Oxygen
Emulsion: A Novel Wound Therapy" Arch Dermatol. 143(10): 1252-1256.
[0238] 4. Eady et al., (1989) "Erythromycin resistant
propionibacteria in antibiotic treated acne patients: Association
with therapeutic failure" Br J. Dermatol. 1989 July; 121(1):51-7.
[0239] 5. Kaneda, Megan M., et al. (2009) "Perfluorocarbon
nanoemulsions for quantitative molecular imaging and targeted
therapeutics" Ann Biomed Eng. 37(10) October 2009. NDN
230-1024-9131-6. [0240] 6. Shen, Yao, et al. (2007) "Carnosine
attenuates mast cell degranulation and histamine release induced by
oxygen-glucose deprivation" Cell Biochemistry and Function.
26(3):334-338. [0241] 7. Thiboutot et al., (1997) "Acne. An
overview of clinical research findings" Dermatol Clin. 1997
January; 15(1):97-109.
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