U.S. patent application number 12/508537 was filed with the patent office on 2010-04-08 for methods of administering topical antifungal formulations for the treatment of fungal infections.
Invention is credited to Gregor Cevc, Ulrich Vierl.
Application Number | 20100086504 12/508537 |
Document ID | / |
Family ID | 41358304 |
Filed Date | 2010-04-08 |
United States Patent
Application |
20100086504 |
Kind Code |
A1 |
Cevc; Gregor ; et
al. |
April 8, 2010 |
METHODS OF ADMINISTERING TOPICAL ANTIFUNGAL FORMULATIONS FOR THE
TREATMENT OF FUNGAL INFECTIONS
Abstract
The present invention relates to topical antifungal formulations
comprising one or more antifungal (e.g., terbinafine), a lipid and
a surfactant, and uses thereof for the treatment of skin and nail
fungal infections.
Inventors: |
Cevc; Gregor; (Gauting,
DE) ; Vierl; Ulrich; (Groebenzell, DE) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Family ID: |
41358304 |
Appl. No.: |
12/508537 |
Filed: |
July 23, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61083115 |
Jul 23, 2008 |
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61102111 |
Oct 2, 2008 |
|
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61150187 |
Feb 5, 2009 |
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61168122 |
Apr 9, 2009 |
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Current U.S.
Class: |
424/61 ;
514/655 |
Current CPC
Class: |
A61P 31/00 20180101;
A61K 9/0014 20130101; A61K 47/26 20130101; A61P 17/00 20180101;
A61K 31/137 20130101; A61K 9/06 20130101; A61P 31/10 20180101; A61K
47/24 20130101 |
Class at
Publication: |
424/61 ;
514/655 |
International
Class: |
A61K 8/40 20060101
A61K008/40; A61K 31/135 20060101 A61K031/135 |
Claims
1. A method for treating a fungal infection in a human subject
comprising topically administering to the subject an aqueous
pharmaceutical formulation comprising terbinafine or a
pharmaceutically acceptable salt thereof, a phospholipid and a
surfactant, wherein the formulation comprises 0.5-10% terbinafine
or a pharmaceutically acceptable salt thereof by weight, 2-10%
phospholipid by weight, and 1-5% surfactant by weight, and wherein
the molar ratio of phospholipid to surfactant in the formulation is
1/1 to 5/1.
2. The method of claim 1 wherein the fungal infection is
onychomycosis.
3. The method of claim 1, wherein the pharmaceutical formulation is
a cream, lotion, ointment, gel, solution, spray, lacquer or film
forming solution.
4.-7. (canceled)
8. The method of claim 1, wherein the formulation comprises about
1.5% by weight terbinafine or a pharmaceutically acceptable salt
thereof.
9.-12. (canceled)
13. The method of claim 1, wherein the phospholipid is
phosphatidylcholine.
14. The method of claim 1, wherein the surfactant is a
polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a
polyhydroxyethylene laurylether.
15. The method of claim 1, wherein the surfactant is polysorbate 80
(Tween 80).
16. The method of claim 1, wherein said topically administering
comprises applying the formulation to the subject's nail and/or the
surrounding skin.
17. (canceled)
18. A method for the delivery of terbinafine to a subject's nail in
an amount effective for treating onychomycosis comprising topically
administering to the nail a pharmaceutical formulation comprising a
therapeutically effective amount of terbinafine or a
pharmaceutically acceptable salt thereof, a phospholipid and a
surfactant wherein the formulation comprises 2-10% phospholipid by
weight and 1-5% surfactant by weight, and wherein the molar ratio
of phospholipid to surfactant in the formulation is 1/1 to 5/1.
19. The method of claim 18, wherein the pharmaceutical formulation
is a cream, lotion, ointment, gel, solution, spray, lacquer or film
forming solution.
20.-23. (canceled)
24. The method of claim 18, wherein the formulation comprises about
1.5% by weight terbinafine or a pharmaceutically acceptable salt
thereof.
25.-27. (canceled)
28. The method of claim 18, wherein the phospholipid is
phosphatidylcholine.
29. (canceled)
30. The method of claim 18, wherein the surfactant is a
polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a
polyhydroxyethylene laurylether.
31. The method of claim 18, wherein the surfactant is polysorbate
80 (Tween 80).
32. The method of claim 18, wherein said topically administering
comprises applying the formulation to the subject's nail and/or the
surrounding skin.
33. (canceled)
34. (canceled)
35. A pharmaceutical formulation suitable for topical delivery of
terbinafine comprising terbinafine or a pharmaceutically acceptable
salt thereof, a lipid and a surfactant, in an aqueous solution,
wherein the formulation comprises 0.5-10% terbinafine or a
pharmaceutically acceptable salt thereof by weight, 2-10% lipid by
weight, and 1-5% surfactant by weight, wherein the formulation is
suitable for topical delivery.
36. The formulation of claim 35, wherein the formulation further
comprises a thickener, an antioxidant, and an antimicrobial
agent.
37.-40. (canceled)
41. The formulation of claim 35, wherein the aqueous solution has a
pH ranging from 4.0 to 7.5.
42. The formulation of claim 35, wherein the lipid is a
phospholipid.
43. The formulation of claim 42, wherein the molar ratio of
phospholipid to surfactant is from about 1/1 to 5/1.
44. (canceled)
45. The formulation of claim 35, wherein the lipid is
phosphatidylcholine.
46. (canceled)
47. The formulation of claim 35, wherein the surfactant is a
polyoxyethylene sorbitan, a polyhydroxyethylene stearate, or a
polyhydroxyethylene laurylether.
48. The formulation of claim 35, wherein the surfactant is
polysorbate 80 (Tween 80).
49.-153. (canceled)
154. A method of administering terbinafine to the nail tissue of a
human comprising topically administering a formulation to the nail
and/or surrounding skin of a human subject, wherein said
formulation comprises terbinafine or a pharmaceutically acceptable
salt thereof, a lipid and a surfactant, and wherein said
administration results in a mean concentration of terbinafine per
gram of nail tissue of at least about 2.5 mg/g; wherein the mean
concentration is determined at least two weeks after ceasing
administration of said formulation; and wherein said administering
results in a mean serum concentration of terbinafine in the human
subject of less than 10 ng/mL.
155. (canceled)
156. The method of claim 154, wherein said administering results in
a mean serum concentration of terbinafine in the human subject of
less than 5 ng/mL.
157. The method of claim 154, wherein said administering results in
a mean serum concentration of terbinafine in the human subject of
less than 1 ng/mL.
158. The method of claim 154, wherein said formulation comprises
about 3.0 mg of terbinafine.
159. The method of claim 154, wherein said formulation is
administered twice daily.
160. The method of claim 159, wherein said formulation is
administered for at least two weeks.
161.-189. (canceled)
190. A method of causing a greater than 90% mycological cure rate
in the treatment of a fungal infection in a human subject,
comprising topically administering to the subject an aqueous
pharmaceutical formulation comprising terbinafine or a
pharmaceutically acceptable salt thereof, a phospholipid and a
surfactant.
Description
PRIORITY
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/083,115, filed Jul. 23, 2008, U.S. Provisional
Application No. 61/102,111, filed Oct. 2, 2008, U.S. Provisional
Application No. 61/150,187, filed Feb. 5, 2009, and U.S.
Provisional Application No. 61/162,122, filed Apr. 9, 2009. The
contents of each of these applications is hereby incorporated by
reference herein their entirety.
1. FIELD OF INVENTION
[0002] The present invention relates to topical formulations of an
antifungal comprising one or more antifungals, a lipid and a
surfactant, and uses thereof for the treatment of skin and nail
fungal infections.
2. BACKGROUND
[0003] Onychomycosis is a fungal infection of the fingernails and
toenails that results in thickening, discoloration, splitting of
the nails and lifting of the nails from the nail bed. The disease
is caused by dermophytes and has a high incidence within the
general population, especially among older individuals.
Onychomycosis is most commonly caused by Trichophyton rubrum (T.
rubrum), Trichophyton mentagrophytes (T. mentagrophytes), and
Epidermophyton floccusum (E. floccusum). Onychomycosis due to
nondermatophytes is usually caused by Candida species, such as
Candida albicans, and is more likely to cause invasive nail disease
in fingernails than in toenails of immunocompetent individuals.
[0004] Rates of onychomycosis vary with the population considered.
A recent study of the general United States population revealed a
prevalence of 2% to 3%, while a study reported in Finland reported
a rate of 13% (Elewski et. al., J. Am. Acad. Dermatol. 2000;
42(1)(Pt 1): 1-20., and Heikkila et. al., Br. J. Dermatol. 1995;
133(5): 699-703). Onychomycosis may affect up to about 15% of
persons between the ages of 40 and 60 years (Kepka et. al. U.S.
Patent Pub. No. 2006/0067898).
[0005] Terbinafine is an antimycotic currently indicated as an oral
therapy for the treatment of onychomycosis (Lamisil.TM., Novartis
International AG, Basel, Switzerland). Other treatment options
including chemical or surgical removal of the infected nail(s) can
lead to nail bed shrinkage and dorsal dislocation of the nail
bed.
[0006] Citation of any reference in this section of the application
is not an admission that the reference is prior art to the
application.
3. SUMMARY OF THE INVENTION
[0007] The present invention provides topical formulations of one
or more antifungals, which may be used to treat fungal infections
in a human subject. The topical antifungal formulations of the
invention comprise one or more antifungals and one or more lipids
and one or more surfactants in a pharmaceutically acceptable
carrier. In certain embodiments, the antifungal is terbinafine,
salts of terbinafine, or derivatives or analogs of terbinafine,
either alone or in combination with one or more antifungals. In
certain embodiments, the antifungal is abafungin, acrisorcin,
albaconazole, albendazole, amorolfine, amphotericin B,
anidulafungin, arasertaconazole, azithromycin, becliconazole,
benzodithiazole, bifonazole, butoconazole, butenafine, calbistrin,
caspofungin, N-chlorotaurine, chloroxine, chlorphenesin,
ciclopirox, cioteronel, clotrimazole, croconazole, cytoporins,
deoxymulundocandin, eberconazole, econazole, efungumab,
fenticonazole, flavanoid glycosides, fluconazole, flucytosine,
flutrimazole, fosfluconazole, genaconazole, gentian violet,
griseofulvin, griseofulvin PEG, haloprogin, hydroxy itraconazole,
isoconazole, itraconazole, ketoconazole, lanoconazole, letrazuril,
liranaftate, luliconazole, micafungin, miconazole, mycophenolic
acid, naftifine, natamycin, nitazoxanide, nitro-ethylene based
antifungals, nystatin, omocanazole, oxiconazole, polyene macrolide,
polyene macrolide, posaconazole, pramiconazole, quinolone analogs,
rapamycin, ravuconazole, rilopirox, samidazole, sertaconazole,
sitamaquine, sordaricin, squalestatin, squalene, a squalene
epoxidase inhibitor, sulconazole, sultriecin, tafenoquine,
terconazole, tioconazole, tolnaftate, voriconazole, or a compound
of Formula I:
##STR00001##
or a single enantiomer, a mixture of enantiomers, or a mixture of
diastereomers thereof; or a pharmaceutically acceptable solvate,
hydrate, or salt thereof; where R is C.sub.1-12 alkyl, C.sub.1-12
acyl, or heteroaryl-C.sub.6-14 aryl; X is halo; Y is N or CH; and Z
is CH.sub.2 or O. In certain embodiments, the topical antifungal
formulations of the invention comprise terbinafine, one or more
phospholipids and one or more nonionic surfactants. In certain
embodiments, the topical antifungal formulations of the invention
comprise terbinafine and an additional antifungal, one or more
phospholipids and one or more nonionic surfactants. In certain
embodiments, the topical antifungal formulations provided herein
comprise one of itraconazole, ketoconazole, posaconazole,
saperconazole, SCH-50002, terconazole, butenafine, and
griseofulvin; and hydrates, solvates, and salts thereof; one or
more phospholipids, and one or more nonionic surfactants. In
certain embodiments, the antifungal formulations provided herein
comprise an antifungal agent that is from a class of antifungal
agents that include, bur are not limited to, antimetabolites,
macrolides, echinocadins, imidazoles, triazoles, benzylamines,
griseofulvins, allylamines, polyenes, thiocarbamates, and
halogenated phenol ethers. The disclosure relates to topical
formulations, such as solutions, suspensions, gels, fluid gels,
emulsions, emulsion gels, lotions, ointments, film forming
solutions, creams, sprays and lacquers.
[0008] In particular, the antifungal formulations of the invention
may be used to treat or prevent onychomycosis in a human subject.
The antifungal formulations of the invention may also be used to
treat or prevent fungal infections of the skin including, but not
limited to tinea corporis, tinea cruris, tinea pedis, pityriasis
(tinea) versicolor. The antifungal formulations of the invention
may also be used to treat fungal infections commonly caused by
Trichophyton (e.g., T. rubru, T. mentagrophytes, T. verrucosum, T.
violaceum), Microsporum canis, Epidermophyton floccusum (E.
floccusum) and yeasts of the genus Candida (e.g., Candida
albicans), as well as Malassezia furfur.
[0009] The antifungal formulations of the invention facilitate the
delivery of antifungal to the infected area in an amount sufficient
to treat the fungal infection. In the case of onychomycosis, the
formulation can be administered to the nail and/or the surrounding
skin. The formulation may also be administered to the entire toe
and/or finger tip. The formulation may preferably be administered
to the distal phalanx of the finger or toe. In the case of skin
infection, the formulation can be administered to the infected area
of the skin. In one embodiment, the topical terbinafine formulation
is applied to the surface of the nail (i.e., the nail plate) and to
the skin surrounding the nail. In another embodiment, the topical
terbinafine formulation is applied epicutaneously.
[0010] In one embodiment, provided herein is a method for treating
onychomycosis comprising topically administering to a subject, a
pharmaceutical formulation comprising a therapeutically effective
amount of one or more antifungals as described herein, e.g.,
terbinafine, a lipid, preferably a phospholipid, and a surfactant,
preferably a nonionic surfactant. In another embodiment, the
invention encompasses a method for the delivery of antinfungal to
the nail in an amount effective for treating onychomycosis
comprising topically administering to a subject a pharmaceutical
formulation comprising one or more antifungals as described herein,
e.g., terbinafine, a lipid and a surfactant. In some embodiments,
the method comprises administering to a subject the topical
antifungal formulations as described herein in combination with a
second antifungal formulation (either topically administered or
otherwise).
[0011] Provided herein is a regimen for the treatment of
onychomycosis in a human subject comprising the administration of a
composition comprising an antifungal, e.g., terbinafine, a lipid
and a surfactant to an infected nail and/or to the skin tissue
surrounding the infected nail. The composition is to be
administered for a period of time spanning two or more weeks,
including three, four, five, six, seven, eight, nine, ten, eleven,
twelve weeks or more. In one embodiment, the composition is to be
administered for a period of ten to twelve weeks. The composition
is to be administered for a period of time to result in a
mycological cure rate, preferably greater than about 70%, 75%, 80%,
85%, 90%, 95%, 96%, 97%, 98%, or 99% in the infected nail in the
human subject.
[0012] As used herein, the terms "treat", "treating" or "treatment
of" mean that the severity of a subject's condition is reduced or
at least partially improved or ameliorated and/or that some
alleviation, mitigation or decrease in at least one clinical
symptom is achieved and/or there is an inhibition or delay in the
progression of the condition and/or delay in the progression of the
onset of disease or illness. The terms "treat", "treating" or
"treatment of" also means managing the disease state, e.g.,
onychomycosis.
[0013] The degree of treatment of onychomycosis in a subject may be
measured by the mycological cure rate. The mycological cure rate is
defined by negative microscopy of nail samples and negative culture
for dermatophytes in nails treated with an antifungal.
[0014] Another way to determine the success of a treatment is by
measuring the clinical cure rate. The clinical cure rate may be
defined by normal growth of toe nail of at least 2 mm after 24
weeks and 5 mm after 48 weeks according to published methods
(Tavakkol, et. al. The American Journal of Geriatric
Pharmacotherapy. 2006; 4: 1-13).
[0015] In one embodiment, the topical formulation is administered
to nail tissue and/or surrounding skin of a human subject to
achieve a mean concentration of the antifungal per gram of nail
tissue of from about 1 mg/g to about 50 mg/g, from about 1 mg/g to
about 25 mg/g, from about 1 mg/g to about 5 mg/g, or from about 1
mg/g to about 10 mg/g. In another embodiment, the topical
formulation is administered to nail tissue and/or surrounding skin
of a human subject to achieve a mean concentration of the
antifungal per gram of nail tissue of at least 1.5 mg/g, 2.0 mg/g,
2.1 mg/g, 2.2 mg/g, 2.3 mg/g, 2.4 mg/g, 2.5 mg/g, 2.6 mg/g, 2.7
mg/g, 2.8 mg/g, 2.9 mg/g, 3.0 mg/g, 5 mg/g, 10 mg/g. 15 mg/g, 20
mg/g, 25 mg/g, 30 mg/g. 35 mg/g, 40 mg/g, 45 mg/g, or 50 mg/g. In
yet another embodiment, the topical formulation is administered to
nail tissue and/or surrounding skin of a human subject to achieve a
mean concentration of the antifungal per gram of nail tissue of
about 0.1 to about 15 mg/g; about 0.2 to about 12.5 mg/g, about 0.5
to about 10 mg/g, about 1 to about 7.5 mg/g, or about 2 to about 5
mg/g. The mean concentration may be determined one, two or three
weeks after ceasing administration of the topical formulation.
[0016] In certain embodiments of the methods, the administration of
topical antifungal formulations of the invention also results in a
mean serum concentration of terbinafine in the human subject of
less than 10.0 ng/ml, 5.0 ng/ml, 4.0 ng/ml, 3.0 ng/ml, 2.0 ng/ml,
1.0 ng/ml, 0.5 ng/ml or 0.2 ng/ml.
[0017] In some embodiments of the method, the topical formulation
comprises about 3.0 mg of terbinafine. The topical formulation can
be administered, for example, twice daily. In certain embodiments,
the topical formulation is administered for at least three
weeks.
[0018] In another aspect, the invention provides a method of
administering a topical formulation comprising terbinafine, a
lipid, and a surfactant, wherein the method comprises administering
the topical formulation to nail tissue twice daily for at least
one, two or three weeks.
[0019] In some embodiments of the method, the topical formulation
comprises from about 0.1 to about 5.0 mg, preferably 1.0 to about
5.0 mg of terbinafine. For instance, the topical formulation can
comprise about 3.0 mg of terbinafine.
[0020] In some embodiments of the method, the terbinafine in the
topical formulation is in salt form.
[0021] In another aspect, the invention provides a method of
treating a fungal infection of nail tissue in a human subject
comprising administering a pharmaceutical composition to the
infected nail tissue of the human subject to target a mean
concentration of terbinafine per gram of nail tissue of about 0.1
to about 15 mg/g, about 0.2 to about 12.5 mg/g, about 0.5 to about
10.0 mg/g, about 1.0 to about 7.5 mg/g or about 2.0 to about 5.0
mg/g. The mean concentration can be determined one, two or three
weeks after ceasing administration of the pharmaceutical
composition. The administration also results in a mean serum
concentration of terbinafine in the human subject of less than 10
ng/mL, 5.0 ng/ml, 4.0 ng/ml, 3.0 ng/ml, 2.0 ng/ml, 1.0 ng/ml, 0.5
ng/ml or 0.2 ng/ml. The pharmaceutical composition comprises
terbinafine, a lipid, and a surfactant.
[0022] In some embodiments of the method, the topical formulation
comprises from about 1 to about 20 mg of the antifungal. In some
embodiments of the method, the topical formulation comprises about
1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 8 mg,
about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, or
about 20 mg of the antifungal. The topical formulation can be
administered, for example, once or twice daily. In certain
embodiments, the topical formulation is administered for at least
three weeks.
[0023] In some embodiments of the method, the lipid in the
pharmaceutical composition is a phospholipid.
[0024] In certain embodiments of the method, the antifungal in the
pharmaceutical composition is in salt form. In certain embodiments,
a certain portion of the antifungal in the pharmaceutical
composition is in salt form.
[0025] In another aspect, the invention provides a method of
treating a fungal infection of nail tissue in a human subject
comprising administering a pharmaceutical composition to the
infected nail tissue of the human subject twice daily for at least
three weeks, wherein the pharmaceutical composition comprises an
antifungal, a lipid, and a surfactant.
[0026] In some embodiments of the method, the pharmaceutical
composition comprises from about 1 to about 20 mg of the
antifungal. For instance, the pharmaceutical composition can
comprise about 1, about 2, about 3, about 4, about 5, about 6,
about 7, about 8, about 9, about 10, about 11, about 12, about 13,
about 14, about 15, about 16, about 17, about 18, about 19, or
about 20 mg of the antifungal.
[0027] In certain embodiments of the method, the lipid in the
pharmaceutical composition is a phospholipid.
[0028] In some embodiments of the method, the terbinafine in the
pharmaceutical composition is in salt form.
[0029] Further provided herein is a regimen for the treatment of
onychomycosis in a human subject comprising the administration of a
pharmaceutically acceptable formulation comprising an antifungal as
described herein, e.g., terbinafine, a lipid, preferably a
phospholipid, and a surfactant, preferably a nonionic surfactant,
to an infected nail and/or to the skin surrounding the infected
nail. The formulation is to be administered for a period of time,
preferably spanning two or more weeks, including three, four, five,
six, seven, eight, nine, ten, eleven, twelve weeks or more. In one
embodiment, the formulation is to be administered for a period of
ten to twelve weeks. The formulation is to be administered for a
period of time to result in a mycological cure rate, preferably
greater than about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or
99% in the infected nail in the human subject. Alternatively, the
formulation is administered for a period of time to prevent
recurrence of fungal infection.
[0030] As used herein, the term "pharmaceutically acceptable" when
used in reference to the formulations of the invention denotes that
a formulation does not result in an unacceptable level of
irritation in the subject to whom the formulation is administered.
Preferably such level will be sufficiently low to provide a
formulation suitable for approval by regulatory authorities.
[0031] As used herein, a "sufficient amount," "amount effective to"
or an "amount sufficient to" achieve a particular result refers to
an amount of terbinafine or a salt thereof that is effective to
produce a desired effect, which is optionally a therapeutic effect
(i.e., by administration of a therapeutically effective amount).
Alternatively stated, a "therapeutically effective" amount is an
amount that provides some alleviation, mitigation, and/or decrease
in at least one clinical symptom. Clinical symptoms associated with
the disorder that can be treated by the methods of the invention
are well-known to those skilled in the art. Further, those skilled
in the art will appreciate that the therapeutic effects need not be
complete or curative, as long as some benefit is provided to the
subject. For example, a "sufficient amount" or "an amount
sufficient to" can be an amount that is effective to treat
onychomycosis, may be defined as a mycological cure.
[0032] Embodiments of the invention are useful in preparations for
the application, administration and/or transport of an antifungal,
especially for medicinal or biological purposes, into and through
barriers and constrictions, such as the skin or nail of mammalian
subject (e.g., humans). As a result, the topical antifungal
formulations may reach the site of infection, for example the nail
bed, in amount sufficient and in physical form adequate to treat
onychomycosis.
[0033] In certain embodiments, the antifungal formulations provided
herein preferably form vesicles or other extended surface
aggregates (ESAs), wherein the vesicular preparations have improved
permeation capability through the semi-permeable barriers, such as
skin and/or nails. While not to be limited to any mechanism of
action, the preferred antifungal formulations are able to form
vesicles characterized by their deformability and/or adaptability.
The vesicles' deformability and/or adaptability allows the vesicles
to penetrate the pores of the skin and/or nails and deliver
antifungal to the site of infection in an amount sufficient to
treat the infection. The adaptability or deformability of the
vesicles may be determined by the ability of the vesicles to
penetrate a barrier with pores having an average pore diameter at
least 50% smaller than the average vesicle diameter before the
penetration. Thus, in certain embodiments, the formulation
comprises deformable vesicles capable of penetrating a barrier with
pores having an average pore diameter at least 50% smaller than the
average vesicle diameter before the penetration. In some
embodiments, the pores are human skin pores or animal skin pores.
In some embodiments, the average pore diameter is from about 10
microns to about 100 microns, about 30 to about 70 microns, or
about 40 to about 60 microns.
[0034] Deformability can be assessed using the following method: 1)
measure the flux (j.sub.a) of the aggregate or ESA suspension
through a semi-permeable membrane (e.g., gravimetrically) for
different transport-driving trans barrier pressures (.DELTA.p); 2)
calculate the pressure dependence of barrier penetratability P for
the suspension by dividing each measured flux value by the
corresponding pressure value:
P(.DELTA.p)=j.sub.a(.DELTA.p)/.DELTA.p; 3) monitor the ratio of
final and starting vesicle diameter 2 r.sub.ves(.DELTA.p)/2
r.sub.ves,0 (e.g. by dynamic light scattering), wherein 2
r.sub.ves(.DELTA.p) is the vesicle diameter after semi-permeable
barrier passage driven by .DELTA.p and 2 r.sub.ves,0 is the
starting vesicle diameter, and if necessary make corrections for
the flow-effects; and 4) align both data sets P(.DELTA.p) vs.
r.sub.ves(.DELTA.p)/r.sub.ves,0 to determine the co-existence range
for high aggregate adaptability and stability.
[0035] In certain embodiments, the mycological cure rate is greater
than about 70%, 75%, 80%, 85%, 90%, 95% or 99% in human subjects
after about 14-weeks, 12-weeks, 10-weeks, 8-weeks, 6-weeks, 4-weeks
or 2-weeks of treatment.
[0036] In certain embodiments, the clinical cure rate is greater
than about 70%, 75%, 80%, 85%, 90%, 95% or 99% in human subjects
after about 48-weeks, 24-weeks, 12-weeks, 10-weeks, 8-weeks,
6-weeks, 4-weeks or 2-weeks of treatment.
[0037] The amount of the antifungal administered per administration
to a subject in an area affected by onychomycosis according to
certain embodiments of the methods of the invention may be from
about 0.25 mg to about 20.0 mg, about 0.5 mg to about 10.0 mg,
about 0.5 mg to about 5.0 mg, about 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg,
5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 11.0 mg, 12.0 mg,
13.0 mg, 14.0 mg, 15.0 mg, 16.0 mg, 17.0 mg, 18.0 mg, 19.0 mg or
20.0 mg. Such amount may be increased above 20.0 mg (e.g., to 30,
40. 50, 75 or 100 mg) if desired in any particular patient for an
appropriate length of time. As used herein with respect to
numerical values, the term "about" means a range surrounding a
particular numeral value which includes that which would be
expected to result from normal human error in making a measurement.
For example, in certain embodiments, the term "about" when used in
connection with a particular numerical value means .+-.1%, .+-.2%,
.+-.3%, .+-.4%, .+-.5% or .+-.10% of the numerical value. The
antifungal formulations of the invention may be administered about
once-a-day, twice-a-day, three times daily, four times daily, every
two days, every three days or once weekly.
[0038] In certain embodiments for the administration of the topical
antifungal formulations provided herein, the total daily dosage of
the antifungal administered to a specific site infected with
onychomycosis may be from about 0.25 mg to about 20 mg, from about
0.5 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10
mg to about 15 mg, or from about 15 mg to about 20 mg. In specific
embodiments, the daily dose of the antifungal administered to a
site of infection is about 1 mg, about 1.5 mg, about 3 mg, about 6
mg, about 9 mg, or about 12 mg. In certain embodiments, the total
daily dosage of the antifungal administered to a subject is from
about 1 mg to about 40 mg, from about 1 mg to about 10 mg, from
about 10 mg to about 20 mg, from about 20 mg to about 20 mg, or
from about 20 mg to about 40 mg. In specific embodiments, the daily
dose of the antifungal administered to a subject is about 1.5 mg,
about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about
6 mg, about 9 mg, about 12 mg, about 15 mg, about 18 mg, about 21
mg, or about 24 mg.
[0039] In certain embodiments, the topical antifungal formulations
disclosed herein result in mycological cure in human subjects when
other topical formulations of anti-mycotics (e.g. terbinafine or
itraconazole) have failed to successfully treat the infection
according to the mycological cure rate. In certain embodiments, the
topical antifungal formulations disclosed herein demonstrate a
mycological cure rate of greater than 90% in human toes 14 weeks
after the initial application of the topical formulation to the
infected nail and/or the surrounding skin. In certain embodiments,
the topical antifungal formulations disclosed herein result in a
higher mycological cure rate(s) than currently available topical
antifungal formulations. The preferred topical antifungal
formulations of the invention achieve clean nail growth comparable
to oral terbinafine. The preferred topical antifungal formulations
of the invention achieve a higher mycological cure rate than oral
terbinafine. The preferred topical antinfungal formulations of the
invention achieve rates of treatment as effective as oral
terbinafine.
[0040] In certain embodiments, the topical antifungal formulations
disclosed herein are used to deliver antifungal non-invasively and
predominately to the site of infection via topical administration.
The topical antifungal formulations disclosed herein may be
administered in place of oral antimycotics, or they may be
administered in combination with oral antimycotics. The antifungal
formulations disclosed herein should result in a relatively high
concentration of the antinfungal in the nail and/or the nail bed
compared with the systemic concentration of the antifungal.
[0041] The antifungal formulations disclosed herein may be safer
than oral, systemic terbinafine formulations. Because the
antifungal formulations of the invention are only applied to the
site of the infection, the risk of side-effects associated with
e.g., oral terbinafine, is reduced, gastrointestinal effects (e.g.,
feelings of fullness, loss of appetite, dyspepsia, nausea,
abdominal pain, diarrhea), skin reactions (e.g., rash, urticaria),
musculoskeletal reactions (arthralgia or myalgia) or malaise or
tiredness. Other risks reduced by the antifungal formulations
disclosed herein include elevated liver enzymes and/or liver
failure.
[0042] In one embodiment, the invention encompasses a method for
preventing onychomycosis, particularly recurrence of onychomycosis,
comprising topically administering to a subject a pharmaceutical
formulation comprising a therapeutically effective amount of an
antifungal described herein, e.g., terbinafine, a lipid, and a
surfactant. The antifungal formulations disclosed herein may result
in a low rate of recurrence of onychomycosis in a patient. More
specifically, the antifungal formulations disclosed herein may have
a lower rate of recurrence of onychomycosis than currently
available treatments (e.g., Lamisil.TM. Cream, Lamisil.TM. Lotion,
Lamisil.TM. Gel or oral Lamisil) after 2 weeks, 6 weeks, 12 weeks,
24 weeks and 48 weeks after last administration.
4. DETAILED DESCRIPTION OF THE INVENTION
[0043] Generally, the nomenclature used herein and the laboratory
procedures in organic chemistry, medicinal chemistry, and
pharmacology described herein are those well known and commonly
employed in the art. Unless defined otherwise, all technical and
scientific terms used herein generally have the same meaning as
commonly understood by one of ordinary skill in the art to which
this disclosure belongs.
[0044] The term "alkyl" refers to a linear or branched saturated
monovalent hydrocarbon radical, wherein the alkyl may optionally be
substituted with one or more substituents Q as described herein.
The term "alkyl" also encompasses both linear and branched alkyl,
unless otherwise specified. In certain embodiments, the alkyl is a
linear saturated monovalent hydrocarbon radical that has 1 to 20
(C.sub.1-20), 1 to 15 (C.sub.1-15), 1 to 12 (C.sub.1-12), 1 to 10
(C.sub.1-10), or 1 to 6 (C.sub.1-6) carbon atoms, or a branched
saturated monovalent hydrocarbon radical of 3 to 20 (C.sub.3-20), 3
to 15 (C.sub.3-15), 3 to 12 (C.sub.3-12), 3 to 10 (C.sub.3-10), or
3 to 6 (C.sub.3-6) carbon atoms. As used herein, linear C.sub.1-6
and branched C.sub.3-6 alkyl groups are also referred as "lower
alkyl." Examples of alkyl groups include, but are not limited to,
methyl, ethyl, propyl (including all isomeric forms), n-propyl,
isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,
sec-butyl, t-butyl, pentyl (including all isomeric forms), and
hexyl (including all isomeric forms). For example, C.sub.i-6 alkyl
refers to a linear saturated monovalent hydrocarbon radical of 1 to
6 carbon atoms or a branched saturated monovalent hydrocarbon
radical of 3 to 6 carbon atoms.
[0045] The term "aryl" refers to a monocyclic aromatic group and/or
multicyclic monovalent aromatic group that contain at least one
aromatic hydrocarbon ring. In certain embodiments, the aryl has
from 6 to 20 (C.sub.6-20), from 6 to 15 (C.sub.6-15), or from 6 to
10 (C.sub.6-10) ring atoms. Examples of aryl groups include, but
are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,
phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to
bicyclic or tricyclic carbon rings, where one of the rings is
aromatic and the others of which may be saturated, partially
unsaturated, or aromatic, for example, dihydronaphthyl, indenyl,
indanyl, or tetrahydronaphthyl (tetralinyl). In certain
embodiments, aryl may also be optionally substituted with one or
more substituents Q as described herein.
[0046] The term "heteroaryl" refers to a monocyclic aromatic group
and/or multicyclic aromatic group that contain at least one
aromatic ring, wherein at least one aromatic ring contains one or
more heteroatoms independently selected from O, S, and N. Each ring
of a heteroaryl group can contain one or two O atoms, one or two S
atoms, and/or one to four N atoms, provided that the total number
of heteroatoms in each ring is four or less and each ring contains
at least one carbon atom. The heteroaryl may be attached to the
main structure at any heteroatom or carbon atom which results in
the creation of a stable compound. In certain embodiments, the
heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring
atoms. Examples of monocyclic heteroaryl groups include, but are
not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl,
furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups
include, but are not limited to, indolyl, benzothiazolyl,
benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl,
quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl,
thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
Examples of tricyclic heteroaryl groups include, but are not
limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl,
phenanthridinyl, and xanthenyl. In certain embodiments, heteroaryl
may also be optionally substituted with one or more substituents Q
as described herein.
[0047] The term "alkenoyl" as used herein refers to --C(O)-alkenyl.
The term "alkenyl" refers to a linear or branched monovalent
hydrocarbon radical, which contains one or more, in one embodiment,
one to five, carbon-carbon double bonds. The alkenyl may be
optionally substituted with one or more substituents Q as described
herein. The term "alkenyl" also embraces radicals having "cis" and
"trans" configurations, or alternatively, "Z" and "E"
configurations, as appreciated by those of ordinary skill in the
art. As used herein, the term "alkenyl" encompasses both linear and
branched alkenyl, unless otherwise specified. For example,
C.sub.2-6 alkenyl refers to a linear unsaturated monovalent
hydrocarbon radical of 2 to 6 carbon atoms or a branched
unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
In certain embodiments, the alkenyl is a linear monovalent
hydrocarbon radical of 2 to 30 (C.sub.2-30), 2 to 24 (C.sub.2-24),
2 to 20 (C.sub.2-20), 2 to 15 (C.sub.2-15), 2 to 12 (C.sub.2-12), 2
to 10 (C.sub.2-10), or 2 to 6 (C.sub.2-6) carbon atoms, or a
branched monovalent hydrocarbon radical of 3 to 30 (C.sub.3-30), 3
to 24 (C.sub.3-24), 3 to 20 (C.sub.3-20), 3 to 15 (C.sub.3-15), 3
to 12 (C.sub.3-12).sub., 3 to 10 (C.sub.3-10, or 3 to 6 (C.sub.3-6)
carbon atoms. Examples of alkenyl groups include, but are not
limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and
4-methylbutenyl. In certain embodiments, the alkenoyl is
mono-alkenoyl, which contains one carbon-carbon double bond. In
certain embodiments, the alkenoyl is di-alkenoyl, which contains
two carbon-carbon double bonds. In certain embodiments, the
alkenoyl is poly-alkenoyl, which contains more than two
carbon-carbon double bonds.
[0048] The term "heterocyclyl" or "heterocyclic" refers to a
monocyclic non-aromatic ring system and/or multicyclic ring system
that contains at least one non-aromatic ring, wherein one or more
of the non-aromatic ring atoms are heteroatoms independently
selected from O, S, or N; and the remaining ring atoms are carbon
atoms. In certain embodiments, the heterocyclyl or heterocyclic
group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8,
from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the
heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic
ring system, which may include a fused or bridged ring system, and
in which the nitrogen or sulfur atoms may be optionally oxidized,
the nitrogen atoms may be optionally quaternized, and some rings
may be partially or fully saturated, or aromatic. The heterocyclyl
may be attached to the main structure at any heteroatom or carbon
atom which results in the creation of a stable compound. Examples
of such heterocyclic radicals include, but are not limited to,
acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzoisoxazolyl,
benzisoxazinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,
benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl,
benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl,
benzoxazinyl, benzoxazolyl, benzothiazolyl, .beta.-carbolinyl,
carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl,
decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl,
dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl,
dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,
furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl,
imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl,
indolizinyl, indolyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl,
isocoumarinyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl,
morpholinyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl,
oxadiazolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl,
oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenathrolinyl,
phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl,
purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,
pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydropyranyl, tetrahydrothienyl, tetrazolyl,
thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl,
thiazolidinyl, thiazolyl, thienyl, triazinyl, triazolyl, and
1,3,5-trithianyl. In certain embodiments, heterocyclic may also be
optionally substituted with one or more substituents Q as described
herein.
[0049] The term "halogen", "halide" or "halo" refers to fluorine,
chlorine, bromine, and/or iodine.
[0050] The term "optionally substituted" is intended to mean that a
group, including alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
aralkyl, heteroaryl, and heterocyclyl, may be substituted with one
or more substituents Q, in one embodiment, one, two, three or four
substituents Q, where each Q is independently selected from the
group consisting of cyano, halo, oxo, nitro, C.sub.1-6 alkyl,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-14 aralkyl,
heteroaryl, heterocyclyl, --C(O)R.sup.e, --C(O)OR.sup.e,
--C(O)NR.sup.fR.sup.g, --C(NR.sup.e)NR.sup.fR.sup.g, --OR.sup.e,
--OC(O)R.sup.e, --OC(O)OR.sup.e, --OC(O)NR.sup.fR.sup.g,
--OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OS(O)R.sup.e,
--OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g,
--OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g,
--NR.sup.eC(O)R.sup.f, --NR.sup.eC(O)OR.sup.f,
--NR.sup.eC(O)NR.sup.fR.sup.g,
--NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eS(O)R.sup.f,
--NR.sup.eS(O).sub.2R.sup.f, --NR.sup.eS(O)NR.sup.fR.sup.g,
--NR.sup.eS(O).sub.2NR.sup.fR.sup.g, --SR.sup.e, --S(O)R.sup.e,
--S(O).sub.2R.sup.e, and --S(O).sub.2NR.sup.fR.sup.g, wherein each
R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7
cycloalkyl, C.sub.6-14 aryl, C.sub.7-14 aralkyl, heteroaryl, or
heterocyclyl; or R.sup.f and R.sup.g together with the N atom to
which they are attached form heterocyclyl.
[0051] The terms "optically active" and "enantiomerically active"
refer to a collection of molecules, which has an enantiomeric
excess of no less than about 50%, no less than about 70%, no less
than about 80%, no less than about 90%, no less than about 91%, no
less than about 92%, no less than about 93%, no less than about
94%, no less than about 95%, no less than about 96%, no less than
about 97%, no less than about 98%, no less than about 99%, no less
than about 99.5%, or no less than about 99.8%.
[0052] In describing an optically active compound, the prefixes R
and S are used to denote the absolute configuration of the molecule
about its chiral center(s). The (+) and (-) are used to denote the
optical rotation of the compound, that is, the direction in which a
plane of polarized light is rotated by the optically active
compound. The (-) prefix indicates that the compound is
levorotatory, that is, the compound rotates the plane of polarized
light to the left or counterclockwise. The (+) prefix indicates
that the compound is dextrorotatory, that is, the compound rotates
the plane of polarized light to the right or clockwise. However,
the sign of optical rotation, (+) and (-), is not related to the
absolute configuration of the molecule, R and S.
[0053] The term "solvate" refers to a compound provided herein or a
salt thereof, which further includes a stoichiometric or
non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
[0054] The antifungal formulations provided herein comprise an
antifungal, a lipid, preferably a phospholipid, a surfactant,
preferably a nonionic surfactant, and an aqueous solution, having a
pH ranging from 3.5 to 9.0, preferably from 4 to 7.5. The
antifungal formulations provided herein may contain an antifungal,
or a pharmaceutically acceptable solvate, hydrate, or salt of the
antifungal. The antifungal formulations may optionally contain
buffers, antioxidants, preservatives, microbicides, antimicrobials,
and/or thickeners. In certain embodiments, a certain portion of the
antifungal in the pharmaceutical composition is in salt form.
[0055] While not to be limited by any mechanism of action, the
terbinafine formulations of the invention preferably form vesicles
or other extended surface aggregates (ESAs), wherein the vesicular
preparations have improved permeation capability through the
semi-permeable barriers, such as skin and/or nails. The vesicles or
extended surface aggregates of the present invention are comprised
of terbinafine, a lipid, and one or more membrane destabilizing
agents, such as surfactants.
[0056] 4.1. Antifungals
[0057] The pharmaceutical compositions disclosed herein comprise
one or more antifungals. Antifungals include but are not limited to
terbinafine, terbinafine derivatives and analogs, allylamines or
structurally related analogs, triazoles and/or imidazoles,
liranaftate and tolnaftate, grisefulvin, and mixtures and/or
combinations thereof.
[0058] 4.1.1. Terbinafine
[0059] Terbinafine belongs to the class of allylamine
anti-mycotics. The structure of terbinafine is shown in formula I
below:
##STR00002##
[0060] Terbinafine may be used as the antifungal in the
formulations disclosed herein in its free base or salt form. In a
specific embodiment, terbinafine is used as a hydrochloride (HCl)
salt, herein referred to as terbinafine-HCl. The term "terbinafine"
as used herein includes the free base form of this compound as well
as therapeutically acceptable acid addition salts thereof. Suitable
salt forms include chloride, bromide, iodide, acetate, and
fumarate, but in principle any pharmaceutically acceptable anion
can be used.
[0061] The pharmaceutical formulations containing terbinafine
provided herein allow for the topical administration of
terbinafine, and comprise a therapeutically effective amount of
terbinafine and at least one lipid and at least one surfactant,
wherein the formulation comprises 0.25-25.0% terbinafine in terms
of dry "total lipid" weight being defined as the sum total of dry
weights of all included lipids, surfactants, lipophilic excipients
and the drug. The pharmaceutical formulations containing
terbinafine provided herein may also comprise 0.25 to 30%
terbinafine by weight or about 0.5% to about 10% by weight. In
specific embodiments, the pharmaceutical formulations containing
terbinafine provided herein may comprise from about 0.25% to about
0.5%, about 0.5% to about 1.0%, about 1.0% to about 1.5%, about
1.5% to about 2.0%, about 2.0% to about 2.5%, about 2.5% to about
3.0%, about 3.0%, to about 4.0%, about 5.0% to about 6.0%, about
6.0% to about 7.0%, about 7.0% to about 8.0%, about 8.0% to about
9.0%, about 9.0% to about 10% terbinafine, from about 10% to about
12%, about 12% to about 14%, about 14% to about 16%, about 16% to
about 18%, about 18% to about 20%, about 22% to about 24%, about
26%, to about 28%, about 28% to about 30% terbinafine by weight. In
an embodiment, the pharmaceutical formulations containing
terbinafine comprise about 1.5% terbinafine by weight.
[0062] The pharmaceutical formulations containing terbinafine
provided herein contain terbinafine in an amount ranging from about
0.25 mg/g to about 200 mg/g. In certain embodiments, the amount of
terbinafine may range from about 0.25 mg/g to about 200 mg/g, from
about 0.5 mg/g to about 175 mg/g, from about 0.5 mg/g to about 150
mg/g, from about 0.5 mg/g to about 100 mg/g, from about 0.5 mg/g to
about 75 mg/g, from about 0.5 mg/g to about 50 mg/g, from about 0.5
mg/g to about 25 mg/g, from about 0.5 mg/g to about 20 mg/g, from
about 0.5 mg/g to about 10 mg/g, from about 0.5 mg/g to about 5
mg/g, from about 0.5 mg/g to about 4 mg/g, from about 0.5 mg/g to
about 3 mg/g, from about 0.5 mg/g to about 2 mg/g, and from about
0.5 mg/g to about 1.5 mg/g.
[0063] The pharmaceutical formulations containing terbinafine
provided herein also typically comprise a polar liquid medium. The
terbinafine formulations of the invention is typically administered
in an aqueous medium. The terbinafine formulations of the present
invention may be in the form of a solution, suspension, gel, fluid
gel, emulsion, emulsion gel, cream, lotion, ointment, spray, film
forming solution, lacquer or a patch soaked with the
formulation.
[0064] 4.1.2. Terbinafine Derivatives and Analogs
[0065] The antifungal of the pharmaceutical formulations provided
herein can also comprise allyamines, including terbinafine
derivatives and analogs. In some embodiments, the terbinafine
derivative or analog is a compound of formula IA,
##STR00003##
wherein (a) R.sup.1 represents a group of formula
##STR00004##
and R.sup.2 represents hydrogen or lower alkyl, or R.sup.1 and
R.sup.2 together represent a group of formula
##STR00005##
[0066] whereby in the formulae IIa to IIi, R.sup.7 and R.sup.8
represent, independently, hydrogen, halogen, trifluoromethyl,
hydroxy, nitro, lower alkyl, lower alkoxy, or
[0067] --C(.dbd.O)--R.sup.15, wherein R.sup.15 represents H,
hydroxyl, lower alkyl, alkoxy (so that R.sup.15 together with the
carbonyl group is an ester), or amino (so that R.sup.15 together
with the carbonyl group is carbamoyl);
R.sup.9 represents hydrogen, halogen, hydroxy, lower alkyl or lower
alkoxy, X represents oxygen, sulphur, imino, lower alkyl imino or a
radical of formula --(CH.sub.2).sub.r--,
[0068] p is 1, 2 or 3,
[0069] r is 1, 2 or 3,
s 3, 4 or 5,
[0070] t is 2, 3 or 4, and
[0071] v is 3, 4, 5 or 6;
[0072] R.sup.3 and R.sup.5 represent, independently, hydrogen or
lower alkyl, and
[0073] R.sup.4 represents C.sub.1-6 alkyl or C.sub.3-8
cycloalkyl-(C.sub.1-6)-alkyl; and
[0074] R.sup.6 represents a group of formula
##STR00006##
[0075] wherein R.sup.11 represents hydrogen, (C.sub.1-6) alkyl,
optionally .alpha.-hydroxy substituted alkyl; alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, phenyl, phenalkyl or thienyl,
[0076] R.sup.12, R.sup.13 and R.sup.14 represent, independently,
hydrogen or lower alkyl, and
##STR00007##
[0077] represents a C.sub.5-8 cycloalkylidene radical optionally
containing a double bond; or
[0078] (b) R.sup.1 represents a group of formula IIa to IIg as
defined under (a),
[0079] R.sup.2 represents hydrogen or lower alkyl,
[0080] R.sup.3 and R.sup.4 together form a group
--(CH.sub.2).sub.u--, wherein u is an integer of 1 to 8, and
[0081] R.sup.5 and R.sup.6 have the meanings given under (a).
[0082] Any lower alkyl or lower alkoxy radical has preferably 1 to
4 carbon atoms, especially 2 or 1 carbon atoms. Unless otherwise
stated alkyl moieties preferably have 1 to 12 carbon atoms
especially 2 to 8 carbon atoms, particularly 2 to 6 carbon atoms
and most preferably 3 to 5 carbon atoms and if bridging 1 to 4
particularly 1 or 2 carbon atoms. Any alkenyl or alkynyl radical
has preferably 3 to 6 carbon atoms, especially 3 to 4 carbon atoms,
e.g. allyl, propenyl or propynyl. Such alkyl, alkoxy, alkenyl and
alkinyl groups can be straight-chain or branched. A preferred
cycloalkylidene radical is cyclohexylidene. The term cycloalkyl is
to be understood as including polycyclo groups such as bornyl or
adamantyl but is preferably cyclohexyl or cyclopentyl.
[0083] In specific embodiments, R.sup.7 and R.sup.8 are identical
and are both hydrogen. In specific embodiments, R.sup.9 is hydrogen
or halogen. In specific embodiments, IIh and IIc the bond to the
carbon atom to which R.sup.2 and R.sup.3 are attached is attached
meta to X and para to the ring nitrogen, respectively. In specific
embodiments, X is sulphur, imino or lower alkylamino. R.sup.1 is
preferably a radical of formula IIh, IIc or IId, or especially IIa.
R.sup.2 is preferably hydrogen. R.sup.3 is preferably hydrogen and
R.sup.4 is, in specific embodiments, alkyl. In specific
embodiments, R.sup.5 is hydrogen.
[0084] In specific embodiments, the values of p, r, s, t, u and v
are chosen to produce a seven- preferably a five- or six-membered
ring.
[0085] The double bond between R.sup.6 and the nitrogen atom
preferably has the trans-configuration. Halogen stands for
fluorine, chlorine or bromine, preferably chlorine or bromine.
[0086] In certain embodiments, the compound of formula IA is as
defined in U.S. Pat. No. 4,755,534, the disclosure of which is
hereby incorporated by reference in its entirety.
[0087] In a specific embodiment the compound of formula IA is:
##STR00008##
which is also known as terbinafine.
[0088] In a specific embodiment, the compound of formula IA is:
##STR00009##
which is also known as naftifine.
[0089] In a specific embodiment, the compound of formula IA is:
##STR00010##
which is described in Ryder et al. 1992, Current Topics in Medical
Mycology. Vol. 4, pp. 158-188.
[0090] In certain embodiments, analogs of terbinafine are described
by U.S. Patent Publication No. 2007/0244336 the disclosure of which
is hereby incorporated by reference in its entirety. In certain
embodiments, salts of terbinafine are described by U.S. Patent
Publication No. 2006/0004230, the disclosure of which is hereby
incorporated by reference in its entirety. In certain embodiments,
antifungal allylamine derivatives are described by U.S. Patent
Publication No. 2005/0032904, the disclosure of which is hereby
incorporated by reference in its entirety.
[0091] 4.1.2. Allylamines or Structurally Related Analogs
[0092] Allyamines or structurally related analog that are suitable
for use in the topical antifungal formulations provided herein
include, but are limited to, amorolfine, butenafine, and
naftifine.
[0093] In one embodiment, the allyamine or structurally related
analog in the topical antifungal formulations provided herein is
amorolfine having the structure of:
##STR00011##
[0094] In another embodiment, the allyamine or structurally related
analog in the topical antifungal formulations provided herein is
butenafine having the structure of:
##STR00012##
[0095] In yet another embodiment, the allyamine or structurally
related analog in the topical antifungal formulations provided
herein is naftifine having the structure of:
##STR00013##
[0096] The allyamine or structurally related analog may be used in
the formulations provided herein in its free base, or its
pharmaceutically acceptable solvate, hydrate, or salt form. In a
specific embodiment, the allyamine or structurally related analog
is used as a hydrochloride (HCl) salt. The term "allyamine or
structurally related analog" as used herein includes the free base
form of the compound as well as pharmaceutically acceptable
solvate, hydrate, or salt form. Suitable salt forms include, but
not are limited to chloride, bromide, iodide, acetate, and
fumarate.
[0097] The pharmaceutical formulations provided herein allow for
the topical administration of the allyamine or structurally related
analog, and comprise a therapeutically effective amount of the
allyamine or structurally related analog and at least one lipid and
at least one surfactant, wherein the formulation comprises
0.25-25.0% of the allyamine or structurally related analog in terms
of dry "total lipid" weight being defined as the sum total of dry
weights of all included lipids, surfactants, lipophilic excipients,
and the allyamine. The formulations provided herein may also
comprise 0.25 to 30% by weight or about 0.5% to about 10% by weight
of the allyamine or structurally related analog. In specific
embodiments, the topical formulations may comprise from about 0.25%
to about 0.5%, from about 0.5% to about 1%, from about 1% to about
1.5%, from about 1.5% to about 2%, from about 2% to about 2.5%,
from about 2.5% to about 3%, from about 3% to about 4%, from about
4% to about 5%, from about 5% to about 6%, from about 6% to about
7%, from about 7% to about 8%, from about 8% to about 9%, from
about 9% to about 10%, from about 10% to about 12%, from about 12%
to about 14%, from about 14% to about 16%, from about 16% to about
18%, from about 18% to about 20%, from about 22% to about 24%, from
about 26% to about 28%, or from about 28% to about 30% by weight of
the allyamine or structurally related analog.
[0098] The pharmaceutical formulations provided herein contain the
allyamine or structurally related analog in an amount ranging from
about 0.25 mg/g to about 200 mg/g. In certain embodiments, the
amount of the allyamine or structurally related analog in the
pharmaceutical formulations may range from about 0.25 mg/g to about
200 mg/g, from about 0.5 mg/g to about 175 mg/g, from about 0.5
mg/g to about 150 mg/g, from about 0.5 mg/g to about 100 mg/g, from
about 0.5 mg/g to about 75 mg/g, from about 0.5 mg/g to about 50
mg/g, from about 0.5 mg/g to about 25 mg/g, from about 0.5 mg/g to
about 20 mg/g, from about 0.5 mg/g to about 10 mg/g, from about 0.5
mg/g to about 5 mg/g, from about 0.5 mg/g to about 4 mg/g, from
about 0.5 mg/g to about 3 mg/g, from about 0.5 mg/g to about 2
mg/g, or from about 0.5 mg/g to about 1.5 mg/g.
[0099] In certain embodiments, the topical formulations provided
herein also comprise a polar liquid medium. In certain embodiments,
the topical formulations provided herein are administered in an
aqueous medium. The topical formulations provided herein may be in
the form of a solution, suspension, gel, fluid gel, emulsion,
emulsion gel, cream, lotion, ointment, spray, film forming
solution, lacquer or a patch soaked with the formulation.
[0100] 4.1.3. Triazoles and/or Imidazoles
[0101] In certain embodiments, the antifungal formulations
disclosed herein include triazoles and or imidazoles, e.g., having
the structure of Formula I:
##STR00014##
or a single enantiomer, a mixture of enantiomers, or a mixture of
diastereomers thereof; or a pharmaceutically acceptable solvate,
hydrate, or salt thereof; wherein:
[0102] R is C.sub.1-12 alkyl, C.sub.1-12 acyl, or
heteroaryl-C.sub.6-14 aryl;
[0103] X is halo;
[0104] Y is N or CH; and
[0105] Z is CH.sub.2 or O.
[0106] The groups, R, X, Y, and Z in Formula I are further defined
herein. All combinations of the embodiments provided herein for
such groups are within the scope of this disclosure.
[0107] In certain embodiments, R is C.sub.1-12 alkyl. In certain
embodiments, R is isopropyl. In certain embodiments, R is
C.sub.1-12 acyl. In certain embodiments, R is acetyl. In certain
embodiments, R is heteroaryl-C.sub.6-14 aryl. In certain
embodiments, R is 1-sec-butyl-1H-1,2,4-triazol-5(4H)-one-4-yl,
1-(2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one-4-yl, or
1-((2S,3R)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one-4-yl.
[0108] In certain embodiments, each X is independently fluoro or
chloro. In certain embodiments, X is fluoro. In certain
embodiments, X is chloro.
[0109] In certain embodiments, Y is N. In certain embodiments, Y is
CH.
[0110] In certain embodiments, Z is CH.sub.2. In certain
embodiments, Z is O.
[0111] In one embodiment, provided herein is a compound of Formula
I, wherein R is isopropyl, acetyl,
1-sec-butyl-1H-1,2,4-triazol-5(4H)-one-4-yl,
1-(2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one-4-yl, or
1-((2S,3R)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one-4-yl;
each X is independently fluoro or chloro; Y is N or CH; and Z is
CH.sub.2 or O.
[0112] In one embodiment, the compound of Formula I is itraconazole
having the structure of:
##STR00015##
or a single enantiomer or a mixture of diastereomers thereof or a
pharmaceutically acceptable solvate, hydrate, or salt thereof.
[0113] In another embodiment, the compound of Formula I is
ketoconazole having the structure:
##STR00016##
or a pharmaceutically acceptable solvate, hydrate, or salt
thereof.
[0114] In yet another embodiment, the compound of Formula I is
posaconazole having the structure of:
##STR00017##
or a pharmaceutically acceptable solvate, hydrate, or salt
thereof.
[0115] In yet another embodiment, the compound of Formula I is
terconazole having the structure of:
##STR00018##
or a pharmaceutically acceptable solvate, hydrate, or salt
thereof.
[0116] In yet another embodiment, the compound of Formula I is
SCH-50002 having the structure of:
##STR00019##
or a single enantiomer or a mixture of diastereomers thereof; or a
pharmaceutically acceptable solvate, hydrate, or salt thereof.
[0117] In still another embodiment, the compound of Formula I is
saperconazole having the structure of:
##STR00020##
or a single enantiomer or a mixture of diastereomers thereof; or a
pharmaceutically acceptable solvate, hydrate, or salt thereof.
[0118] In still another embodiment, the triazole and/or imidazole
antifungal is fluconazole, having the structure of:
##STR00021##
or a single enantiomer or a mixture of diastereomers thereof; or a
pharmaceutically acceptable solvate, hydrate, or salt thereof.
[0119] In still another embodiment, the triazole and/or imidazole
antifungal is voriconazole, having the structure of:
##STR00022##
or a single enantiomer or a mixture of diastereomers thereof; or a
pharmaceutically acceptable solvate, hydrate, or salt thereof.
[0120] Triazole and/or imidazole antifungals as provided herein may
be used in the formulations provided herein as a single enantiomer,
a mixture of enantiomers, or a mixture of diastereomers thereof; or
a pharmaceutically acceptable solvate, hydrate, or salt thereof. In
a specific embodiment, triazole and/or imidazole antifungals are
used in their free base forms. The term "a triazole and/or
imidazole antifungal" as used herein includes the free base form of
the compound, including single enantiomers, mixtures of
enantiomers, and mixtures of diastereomers of the compound; as well
as pharmaceutically acceptable solvates, hydrates, and salts of the
compound, including its single enantiomers, mixtures of
enantiomers, and mixtures of diastereomers.
[0121] The pharmaceutical formulations provided herein allow for
the topical administration of triazole and/or imidazole
antifungals, e.g., itraconazole, ketoconazole, posaconazole,
saperconazole, SCH-50002, terconazole, fulconazole, or
voriconazole, and comprise a therapeutically effective amount of a
triazole or imidazole antifungal provided herein, and at least one
lipid and at least one surfactant, wherein the formulation
comprises 0.25-25% of the antifungal in terms of dry "total lipid"
weight being defined as the sum total of dry weights of all
included lipids, surfactants, lipophilic excipients, and the
antifungal. The formulations provided herein may also comprise 0.25
to 30% by weight or about 0.5% to about 10% by weight of the
antifungal. In specific embodiments, the topical antifungal
formulations may comprise from about 0.25% to about 0.5%, from
about 0.5% to about 1%, from about 1% to about 1.5%, from about
1.5% to about 2%, from about 2% to about 2.5%, from about 2.5% to
about 3%, from about 3% to about 4%, from about 4% to about 5%,
from about 5% to about 6%, from about 6% to about 7%, from about 7%
to about 8%, from about 8% to about 9%, from about 9% to about 10%,
from about 10% to about 12%, from about 12% to about 14%, from
about 14% to about 16%, from about 16% to about 18%, from about 18%
to about 20%, from about 22% to about 24%, from about 26% to about
28%, or from about 28% to about 30% by weight of the triazole
and/or imidazole antifungal.
[0122] The pharmaceutical formulations provided herein contain the
triazole and/or imidazole antifungal in an amount ranging from
about 0.25 mg/g to about 200 mg/g. In certain embodiments, the
amount of the triazole or imidazole antifungal in the
pharmaceutical formulations may range from about 0.25 mg/g to about
200 mg/g, from about 0.5 mg/g to about 175 mg/g, from about 0.5
mg/g to about 150 mg/g, from about 0.5 mg/g to about 100 mg/g, from
about 0.5 mg/g to about 75 mg/g, from about 0.5 mg/g to about 50
mg/g, from about 0.5 mg/g to about 25 mg/g, from about 0.5 mg/g to
about 20 mg/g, from about 0.5 mg/g to about 10 mg/g, from about 0.5
mg/g to about 5 mg/g, from about 0.5 mg/g to about 4 mg/g, from
about 0.5 mg/g to about 3 mg/g, from about 0.5 mg/g to about 2
mg/g, or from about 0.5 mg/g to about 1.5 mg/g.
[0123] In certain embodiments, the antifungal formulations provided
herein also comprise a polar liquid medium. In certain embodiments,
the antifungal formulations provided herein are administered in an
aqueous medium. The antifungal formulations provided herein may be
in the form of a solution, suspension, gel, fluid gel, emulsion,
emulsion gel, cream, lotion, ointment, spray, film forming
solution, lacquer or a patch soaked with the formulation.
[0124] The antifungals provided herein are intended to encompass
all possible stereoisomers, including enantiomers and diastereomers
and mixtures thereof, unless a particular stereochemistry is
specified. Where an antifungals provided herein contains an alkenyl
or alkenylene group, the antifungal may exist as a cis (Z) or trans
(E) isomer or as a mixture of geometric cis/trans (or Z/E) isomers.
Where structural isomers are interconvertible via a low energy
barrier, the antifungal may exist as a single tautomer or a mixture
of tautomers. This can take the form of proton tautomerism in the
antifungal that contains, for example, an imino, keto, or oxime
group; or so-called valence tautomerism in the antifungal that
contain an aromatic moiety. It is understood that a single
antifungal may exhibit more than one type of isomerism.
[0125] The antifungals provided herein may be enantiomerically
pure, such as a single enantiomer or a single diastereomer, or may
be stereoisomeric mixtures, such as a mixture of enantiomers, a
racemic mixture, or a diastereomeric mixture. As such, one of skill
in the art will recognize that administration of a compound in its
(R) form is equivalent, for compounds that undergo epimerization in
vivo, to administration of the compound in its (S) form.
Conventional techniques for the preparation/isolation of individual
enantiomers include synthesis from a suitable optically pure
precursor, asymmetric synthesis from achiral starting materials, or
resolution of an enantiomeric mixture, for example, chiral
chromatography, recrystallization, resolution, diastereomeric salt
formation, or derivatization into diastereomeric adducts followed
by separation.
[0126] When the antifungals provided herein contain an acidic or
basic moiety, they may also be provided as pharmaceutically
acceptable salts (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19;
and "Handbook of Pharmaceutical Salts, Properties, and Use," Stahl
and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
[0127] Suitable acids for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic
acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic
acid, benzoic acid, 4-acetamidobenzoic acid, boric acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
cyclohexanesulfamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxoglutaric acid,
glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,
hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0128] Suitable bases for use in the preparation of
pharmaceutically acceptable salts include, but are not limited to,
inorganic bases, such as magnesium hydroxide, calcium hydroxide,
potassium hydroxide, zinc hydroxide, or sodium hydroxide; and
organic bases, such as primary, secondary, tertiary, and
quaternary, aliphatic and aromatic amines, including L-arginine,
benethamine, benzathine, choline, deanol, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, secondary amines, triethanolamine, trimethylamine,
triethylamine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.
[0129] 4.1.4. Liranaftate and Tolnaftate
[0130] Liranaftate is an antifungal having the structure of:
##STR00023##
[0131] Tolnaftate is an antifungal having the structure of:
##STR00024##
[0132] Liranaftate or tolnaftate may be used in the formulations
provided herein in its free form, or its pharmaceutically
acceptable solvate, hydrate, or salt form. In a specific
embodiment, liranaftate or tolnaftate is used in its free form. The
term "liranaftate" as used herein includes the free form of the
compound as well as pharmaceutically acceptable solvate, hydrate,
or salt form. The term "tolnaftate" as used herein includes the
free form of the compound as well as pharmaceutically acceptable
solvate, hydrate, or salt form.
[0133] The pharmaceutical formulations provided herein allow for
the topical administration of liranaftate or tolnaftate, and
comprise a therapeutically effective amount of liranaftate or
tolnaftate and at least one lipid and at least one surfactant,
wherein the formulation comprises 0.25-25% liranaftate or
tolnaftate in terms of dry "total lipid" weight being defined as
the sum total of dry weights of all included lipids, surfactants,
lipophilic excipients, and liranaftate or tolnaftate. The
formulations provided herein may also comprise 0.25 to 30% by
weight or about 0.5% to about 10% by weight of liranaftate or
tolnaftate. In specific embodiments, the topical formulations may
comprise from about 0.25% to about 0.5%, from about 0.5% to about
1%, from about 1% to about 1.5%, from about 1.5% to about 2%, from
about 2% to about 2.5%, from about 2.5% to about 3%, from about 3%
to about 4%, from about 4% to about 5%, from about 5% to about 6%,
from about 6% to about 7%, from about 7% to about 8%, from about 8%
to about 9%, from about 9% to about 10%, from about 10% to about
12%, from about 12% to about 14%, from about 14% to about 16%, from
about 16% to about 18%, from about 18% to about 20%, from about 22%
to about 24%, from about 26% to about 28%, or from about 28% to
about 30% by weight of liranaftate or tolnaftate.
[0134] The pharmaceutical formulations provided herein contain
liranaftate or tolnaftate in an amount ranging from about 0.25 mg/g
to about 200 mg/g. In certain embodiments, the amount of
liranaftate or tolnaftate in the pharmaceutical formulations may
range from about 0.25 mg/g to about 200 mg/g, from about 0.5 mg/g
to about 175 mg/g, from about 0.5 mg/g to about 150 mg/g, from
about 0.5 mg/g to about 100 mg/g, from about 0.5 mg/g to about 75
mg/g, from about 0.5 mg/g to about 50 mg/g, from about 0.5 mg/g to
about 25 mg/g, from about 0.5 mg/g to about 20 mg/g, from about 0.5
mg/g to about 10 mg/g, from about 0.5 mg/g to about 5 mg/g, from
about 0.5 mg/g to about 4 mg/g, from about 0.5 mg/g to about 3
mg/g, from about 0.5 mg/g to about 2 mg/g, or from about 0.5 mg/g
to about 1.5 mg/g.
[0135] In certain embodiments, the topical formulations provided
herein also comprise a polar liquid medium. In certain embodiments,
the topical formulations provided herein are administered in an
aqueous medium. The topical formulations provided herein may be in
the form of a solution, suspension, gel, fluid gel, emulsion,
emulsion gel, cream, lotion, ointment, spray, film forming
solution, lacquer or a patch soaked with the formulation.
[0136] 4.1.5. Grisefulvin
[0137] Griseofulvin is an antifungal having the structure of:
##STR00025##
[0138] Griseofulvin may be used in the formulations provided herein
in its free form, or its pharmaceutically acceptable solvate,
hydrate, or salt form. In a specific embodiment, griseofulvin is
used in its free form. The term "griseofulvin" as used herein
includes the free form of the compound as well as pharmaceutically
acceptable solvate, hydrate, or salt form.
[0139] The pharmaceutical formulations provided herein allow for
the topical administration of griseofulvin, and comprise a
therapeutically effective amount of griseofulvin and at least one
lipid and at least one surfactant, wherein the formulation
comprises 0.25-25% griseofulvin in terms of dry "total lipid"
weight being defined as the sum total of dry weights of all
included lipids, surfactants, lipophilic excipients, and
griseofulvin. The formulations provided herein may also comprise
0.25 to 30% by weight or about 0.5% to about 10% by weight of
griseofulvin. In specific embodiments, the topical griseofulvin
formulations may comprise from about 0.25% to about 0.5%, from
about 0.5% to about 1%, from about 1% to about 1.5%, from about
1.5% to about 2%, from about 2% to about 2.5%, from about 2.5% to
about 3%, from about 3% to about 4%, from about 4% to about 5%,
from about 5% to about 6%, from about 6% to about 7%, from about 7%
to about 8%, from about 8% to about 9%, from about 9% to about 10%,
from about 10% to about 12%, from about 12% to about 14%, from
about 14% to about 16%, from about 16% to about 18%, from about 18%
to about 20%, from about 22% to about 24%, from about 26% to about
28%, or from about 28% to about 30% by weight of griseofulvin.
[0140] The pharmaceutical formulations provided herein contain
griseofulvin in an amount ranging from about 0.25 mg/g to about 200
mg/g. In certain embodiments, the amount of griseofulvin in the
pharmaceutical formulations may range from about 0.25 mg/g to about
200 mg/g, from about 0.5 mg/g to about 175 mg/g, from about 0.5
mg/g to about 150 mg/g, from about 0.5 mg/g to about 100 mg/g, from
about 0.5 mg/g to about 75 mg/g, from about 0.5 mg/g to about 50
mg/g, from about 0.5 mg/g to about 25 mg/g, from about 0.5 mg/g to
about 20 mg/g, from about 0.5 mg/g to about 10 mg/g, from about 0.5
mg/g to about 5 mg/g, from about 0.5 mg/g to about 4 mg/g, from
about 0.5 mg/g to about 3 mg/g, from about 0.5 mg/g to about 2
mg/g, or from about 0.5 mg/g to about 1.5 mg/g.
[0141] In certain embodiments, the griseofulvin formulations
provided herein also comprise a polar liquid medium. In certain
embodiments, the griseofulvin formulations provided herein are
administered in an aqueous medium. The griseofulvin formulations
provided herein may be in the form of a solution, suspension, gel,
fluid gel, emulsion, emulsion gel, cream, lotion, ointment, spray,
film forming solution, lacquer or a patch soaked with the
formulation.
[0142] 4.2. Lipid
[0143] In the sense of this invention, a "lipid" is any substance,
which has properties like or similar to those of a fat. As a rule,
it has an extended apolar group (the "chain", X) and generally also
a water-soluble, polar hydrophilic part, the "head" group (Y) and
has the basic formula II.
X--Y.sub.n (II)
[0144] wherein n is equal to or larger than zero. Lipids with n=0
are referred to as apolar lipids and lipids with n.gtoreq.1 are
referred to as polar lipids. In this sense, all amphiphilic
substances, including, but not limited to glycerides,
glycerophospholipids, glycerophosphinolipids,
glycerophosphonolipids, sulfolipids, sphingolipids, isoprenoid
lipids, steroids or sterols and carbohydrate-containing lipids can
generally be referred to as lipids, and are included as such in
this invention. A list of relevant lipids and lipid related
definitions is provided in EP 0 475 160 A1 (see, e.g. p. 4, 1. 8 to
p. 6, 1. 3) and U.S. Pat. No. 6,165,500 (see, e.g., col. 6, 1. 10
to col. 7, 1. 58), which are herewith incorporated by
reference.
[0145] A phospholipid is, for example, a compound of formula
III:
R.sup.1--CH.sub.2--CHR.sup.2--CR.sup.3H--O--PHO.sub.2--O--R.sup.4
(III)
[0146] wherein R.sup.1 and R.sup.2 cannot both be hydrogen, OH or a
C.sub.1-C.sub.3 alkyl group, and typically are independently, an
aliphatic chain, most often derived from a fatty acid or a fatty
alcohol. R.sup.3 generally is a hydrogen. The OH-group of the
phosphate is a hydroxyl radical or hydroxyl anion (i.e., hydroxide)
form, dependent on degree of the group ionization. Furthermore,
R.sup.4 may be a proton or a short-chain alkyl group, substituted
by a tri-short-chain alkylammonium group, such as a
trimethylammonium group, or an amino-substituted short-chain alkyl
group, such as 2-trimethylammonium ethyl group (cholinyl) or
2-dimethylammonium short alkyl group.
[0147] A sphingophospholipid is, for example, a compound of formula
IIIB:
R.sup.1-Sphingosine-O--PHO.sub.2--O--R.sup.4 (IIIB)
wherein R.sup.1 is a fatty-acid attached via an amide bond to the
nitrogen of the sphingosine and R.sup.4 has the meanings given
under formula III.
[0148] A lipid preferably is a substance of formulae III or IIIB,
wherein R.sup.1 and/or R.sup.2 are acyl or alkyl, n-hydroxyacyl or
n-hydroxyalkyl, but may also be branched, with one or more methyl
groups attached at almost any point of the chain; usually, the
methyl group is near the end of the chain (iso or anteiso). The
radicals R.sup.1 and R.sup.2 may moreover either be saturated or
unsaturated (mono-, di- or poly-unsaturated). R.sup.3 is hydrogen
and R.sup.4 is 2-trimethylammonium ethyl (the latter corresponds to
the phosphatidyl choline head group), 2-dimethylammonium ethyl,
2-methylammonium ethyl or 2-aminoethyl (corresponding to the
phosphatidyl ethanolamine head group). R.sup.4 may also be a proton
(giving phosphatidic acid), a serine (giving phosphatidylserine), a
glycerol (giving phosphatidylglycerol), an inositol (giving
phosphatidylinositol), or an alkylamine group (giving
phosphatidylethanolamine in case of an ethylamine), if one chooses
to use a naturally occurring glycerophospholipid. Otherwise, any
other sufficiently polar phosphate ester, such that will form a
lipid bilayer, may be considered as well for making the
formulations of the invention.
[0149] Table 1 lists preferred phospholipids in accordance with the
invention.
TABLE-US-00001 TABLE 1 Preferred (phospho)lipids for use in
combination with the antifungal Phospholipid Length: Type/Charge
Fatty chain nr. of double Phosphatidylcholine/+ Sphingomyelin/+
Phosphatidylglycerol/- Phosphatidylinositol/- Phosphatidic acid/-
Name(s) bonds Main lipid, L1 Main lipid, L1 Aux. lipid, L2 Aux.
lipid, L2 Aux. lipid, L2 C24 Behen(o)yl C22 Eruca(o)yl C22:1-13cis
Arachin(o)yl C20 Gadolen(o)yl C20:1-11cis Arachidon(o)yl
C20:4-5,8,11,14cis Ole(o)yl C18:1-9cis DOPC SM-oleyl DOPG DOPI DOPA
Stear(o)yl C18 Linol(o)yl C18:2-9,12cis (Soy-PC/ Brain SM (Soy-PC/
(Soy-PI/ (Soy-PA/ Linole(n/o)yl C18:3-9,12,15cis Egg-PC) Egg-PC)
Liver-PI) Egg-PA) Palmitole(o)yl C18:1-9cis Palmit(o)yl C16
Myrist(o)yl C14 DMPC SM-myristyl DMPG DMPI Laur(o)yl C12 DLPC
SM-lauryl DLPA Capr(o)yl C10 Rel. concentration range L1/L2 1/0 1/0
10/1-1/1 10/1-3/1 10/1-5/1 (M/M) "Total Lipid"* concentration range
0.5-45 0.5-45 0.5-40 0.5-40 0.5-40 (w-%) *Total Lipid includes
phospholipid(s), surfactant, antifungal, and all lipophilic
excipients The antifungal is incorporated in up to 15 rel. w-% into
acidic formulations and up to 10 rel. w-% into neutral pH
formulations
[0150] The preferred basic lipids in context of this invention are
uncharged and form stable, well hydrated bilayers;
phosphatidylcholines and sphingomyelins are the most prominent
representatives of such lipids. Either of those can have chains as
listed in the Table 1, the ones forming fluid phase bilayers, in
which lipid chains are in disordered state, being preferred.
[0151] Different negatively charged, i.e., anionic, lipids can also
be incorporated into vesicular lipid bilayers to modify the
(cationic) drug loading into or release from the resulting lipid
aggregates. Attractive examples of such charged lipids are
phosphatidylglycerols, phosphatidylinositols and, somewhat less
preferred, phosphatidic acid (and its alkyl ester) or
phosphatidylserine. It will be realised by anyone skilled in the
art that it is less commendable to make vesicles just from the
charged lipids than to use them in a combination with
electro-neutral bilayer component(s). In case of using charged
lipids, buffer composition and/or pH care must selected so as to
ensure the desired degree of lipid head-group ionization and/or the
desired degree of electrostatic interaction between the,
oppositely, charged drug and lipid molecules. Moreover, as with
neutral lipids, the charged bilayer lipid components can in
principle have any of the chains listed in the Table 1. The chains
forming fluid phase lipid bilayers are clearly preferred, however,
both due to vesicle adaptability increasing role of increasing
fatty chain fluidity and due to better ability of lipids in fluid
phase to mix with each other, and with drugs.
[0152] The fatty acid- or fatty alcohol-derived chain of a lipid is
typically selected amongst the basic aliphatic chain types given in
the following tables:
TABLE-US-00002 TABLE 2 The (most) preferred basic, straight,
saturated fatty chain residues Shorthand designation Systematic
name Trivial name 12:0 Dodecanoic Lauric 13:0 Tridecanoic 14:0
Tetradecanoic Myristic 15:0 Pentadecanoic 16:0 Hexadecanoic
Palmitic 17:0 Heptadecanoic Margaric 18:0 Octadecanoic Stearic 19:0
Nonadecanoic 20:0 Eicosanoic Arachidic 21:0 Heneicosanoic 22:0
Docosanoic Behenic 23:0 Tricosanoic 24:0 Tetracosanoic
Lignoceric
TABLE-US-00003 TABLE 3 The (most) preferred monoenoic fatty chain
residues Shorthand designation Systematic name Trivial name
9-14:1/14:1(n-5) cis-9-Tetradecenoic Myristoleic 7-16:1/16:1(n-9)
cis-7-Hexadecenoic 9-16:1/16:1(n-7) cis-9-Hexadecenoic Palmitoleic
9-18:1/18:1(n-9) cis-9-Octadecenoic Oleic 11-18:1/18:1(n-7)
cis-11-Octadecenoic cis-Vaccenic 11-20:1/20:1(n-9)
cis-11-Eicosenoic Gondoic 14-20:1/20:1(n-6) cis-14-Eicosaenoic
13-22:1/22:1(n-9) cis-13-Docosenoic Erucic 15-24:1/24:1(n-9)
cis-15-Tetracosenoic Nervoni 3t-18:1 trans-3-Hexadecenoi 9t-18:1
trans-9-Octadecenoic Elaidic 11t-18:1 trans-11-Octadecenoic
Vaccenic
TABLE-US-00004 TABLE 4 The (most) preferred dienoic and polyenoic
fatty chain residues Shorthand designation Systematic name Trivial
name 10,13c-16:2/16:2(n-3) 10-cis,13-cis-Hexadecadienoic
7,10c-16:2/16:3(n-6) 7-cis,10-cis-Hexadecadienoic
7,10,13c-16:3/16:3(n-3) 7-cis,10-cis,13-cis-Hexadecatrienoic
12,15c-18:2/18:2(n-3) 12-cis,15-cis-Octadecadienoic
.alpha.-Linoleic 10,12t-18:2/18:2(n-6)
trans-10,trans-12-Octadecadienoic 9,12c-18:2/18:2(n-6)
9-cis,12-cis-Octadecadienoic .gamma.-Linoleic
9,12,15c-18:3/18:3(n-3) 9-cis,12-cis,15-cis-Octadecatrienoic
.alpha.-Linolenic 6,9,12c-18:3/18:3(n-6)
6-cis,9-cis,12-cis-Octadecatrienoic .gamma.-Linolenic
9c,11c,13t-18:3 9-cis,11-trans,13-trans-Octadecatrienoic
.alpha.-Eleostearic 8t,10t,12c-18:3
8-trans,10-trans,12-cis-Octadecatrienoic Calendic
6,9,12,15c-18:4/18:4(n-3) 6,9,12,15-Octadecatetraenoic Stearidonic
3,6,9,12c-18:4/18:4(n-6) 3,6,9,12-Octadecatetraenoic
3,6,9,12,15c-18:5/18:5(n-3) 3,6,9,12,15-Octadecapentaenoic
14,17c-20:2/20:2(n-3) 14-cis,17-cis-Eicosadienoic
11,14c-20:2/20:2(n-6) 11-cis,14-cis-Eicosadienoic
11,14,17c-20:3/20:3 (n-3) 8-cis,11-cis,14-cis-Eicosatrienoic
Dihomo-.alpha.-linolenic 8,11,14c-20:3/20:3(n-6)
8-cis,11-cis,14-cis-Eicosatrienoic Dihomo-.gamma.-linolenic
5,8,11c-20:3 20:3(n-9) 5,8,11all-cis-Eicosatrienoic `Mead's`
5,8,11,14c-20:4/20:4(n-6) 5,8,11;14-all-cis-Eicosatetraenoic
Arachidonic 8,11,14,17c-20:4/20:4(n-3)
8,11,14,17-all-cis-Eicosatetraenoic 5,8,11,14,17c-20:5
5,8,11,14,17-all-cis-Eicosapentaenoic or 20:5(n-3) 13,16c-22:2
13,16-Docosadienoic 13,16,19c-22:3/22:3(n-3)
13,16,19-Docosatrienoic 10,13,16c-22:3/22:3(n-6)
10,13,16-Docosatrienoic 7,10,13,16c-22:4/22:4(n-6)
7,10,13,16-Docosatetraenoic Adrenic 4,7,10,13,16c-22:5
4,7,10,13,16-Docosapentaenoic or 22:5(n-6) 4,7,10,13,16,19c-22:5
4,7,10,13,16,19-Docosahexaenoic or 22:6(n-3)
[0153] Other double bond combinations or positions are possible as
well.
[0154] Suitable fatty residues can furthermore be branched, for
example, can contain a methyl group in an iso or anteiso position
of the fatty acid chain, or else closer to the chain middle, as in
10-R-Methyloctadecanoic acid or tuberculostearic chain. Relatively
important amongst branched fatty acids are also isoprenoids, many
of which are derived from
3,7,11,15-tetramethylhexadec-trans-2-en-1-ol, the aliphatic alcohol
moiety of chlorophyll. Examples include
5,9,13,17-tetramethyloctadecanoic acid and especially
3,7,11,15-tetramethylhexadecanoic (phytanic) and
2,6,10,14-tetramethylpentadecanoic (pristanic) acids. A good source
of 4,8,12-trimethyltridecanoic acid are marine organisms.
Combination of double bonds and side chains on a fatty residue are
also possible.
[0155] Alternatively, suitable fatty residues may carry one or a
few oxy- or cyclic groups, especially in the middle or towards the
end of a chain. The most prominent amongst the later, alicyclic
fatty acids, are those comprising a cyclopropane (and sometimes
cyclopropene) ring, but cyclohexyl and cycloheptyl rings can also
be found and might be useful for purposes of this invention.
2-(D)-Hydroxy fatty acids are more ubiquitous than alicyclic fatty
acids, and are also important constituents of sphingolipids. Also
interesting are 15-hydroxy-hexadecanoic and 17-hydroxy-octadecanoic
acids, and maybe 9-hydroxy-octadeca-trans-10,trans-12-dienoic
(dimorphecolic) and 13-hydroxy-octadeca-cis-9,trans-11-dienoic
(coriolic) acid. Arguably the most prominent hydroxyl-fatty acid in
current pharmaceutical use is ricinoleic acid,
(D-(-)12-hydroxy-octadec-cis-9-enoic acid, which comprises up to
90% of castor oil, which is also often used in hydrogenated form.
Epoxy-methoxy-, and furanoid-fatty acids are of only limited
practical interest in the context of this invention.
[0156] Generally speaking, unsaturation, branching or any other
kind of derivatization of a fatty acid is best compatible with the
intention of present invention of the site of such modification is
in the middle or terminal part of a fatty acid chain. The
cis-unsaturated fatty acids are also more preferable than
trans-unsaturated fatty acids and the fatty radicals with fewer
double bonds are preferred over those with multiple double bonds,
due to oxidation sensitivity of the latter. Moreover, symmetric
chain lipids are generally better suited than asymmetric chain
lipids.
[0157] A preferred lipid of the formula III is, for example, a
natural phosphatidylcholine, which used to be called lecithin. It
can be obtained from egg (rich in palmitic, C.sub.16:0, and oleic,
C.sub.18:1, but also comprising stearic, C.sub.18:0, palmitoleic,
C.sub.16:1, linolenic, C.sub.18:2, and arachidonic, C.sub.20:4,
radicals), soybean (rich in unsaturated C.sub.18 chains, but also
containing some palmitic radical, amongst a few others), coconut
(rich in saturated chains), olives (rich in monounsaturated
chains), saffron (safflower) and sunflowers (rich in n-6 linoleic
acid), linseed (rich in n-3 linolenic acid), from whale fat (rich
in monounsaturated n-3 chains), from primrose or primula (rich in
n-3 chains). Preferred, natural phosphatidyl ethanolamines (used to
be called cephalins) frequently originate from egg or soybeans.
Preferred sphingomyelins of biological origin are typically
prepared from eggs or brain tissue. Preferred phosphatidylserines
also typically originate from brain material whereas
phosphatidylglycerol is preferentially extracted from bacteria,
such as E. Coli, or else prepared by way of transphosphatidylation,
using phospholipase D, starting with a natural phosphatidylcholine.
The preferably used phosphatidylinositols are isolated from
commercial soybean phospholipids or bovine liver extracts. The
preferred phosphatidic acid is either extracted from any of the
mentioned sources or prepared using phospholipase D from a suitable
phosphatidylcholine.
[0158] Furthermore, synthetic phosphatidyl cholines (R.sup.4 in
formula III corresponds to 2-trimethylammonium ethyl), and R.sup.1
and R.sup.2 are aliphatic chains, as defined in the preceding
paragraph with 12 to 30 carbon atoms, preferentially with 14 to 22
carbon atoms, and even more preferred with 16 to 20 carbon atoms,
under the proviso that the chains must be chosen so as to ensure
that the resulting ESAs comprise fluid lipid bilayers. This
typically means use of relatively short saturated and of relatively
longer unsaturated chains. Synthetic sphingomyelins (R.sup.4 in
formula IIIB corresponds to 2-trimethylammonium ethyl), and R.sup.1
is an aliphatic chain, as defined in the preceding paragraph, with
10 to 20 carbon atoms, preferentially with 10 to 14 carbon atoms
per fully saturated chain and with 16-20 carbon atoms per
unsaturated chain.
[0159] Synthetic phosphatidyl ethanolamines (R.sup.4 is
2-aminoethyl), synthetic phosphatidic acids (R.sup.4 is a proton)
or its ester (R.sup.4 corresponds, for example, to a short-chain
alkyl, such as methyl or ethyl), synthetic phosphatidyl serines
(R.sup.4 is L- or D-serine), or synthetic phosphatidyl
(poly)alcohols, such as phosphatidyl inositol, phosphatidyl
glycerol (R.sup.4 is L- or D-glycerol) are preferred as lipids,
wherein R.sup.1 and R.sup.2 are fatty residues of identical or
moderately different type and length, especially such as given in
the corresponding tables given before in the text. Moreover,
R.sup.1 can represent alkenyl and R.sup.2 identical hydroxyalkyl
groups, such as tetradecylhydroxy or hexadecylhydroxy, for example,
in ditetradecyl or dihexadecylphosphatidyl choline or ethanolamine,
R.sup.1 can represent alkenyl and R.sup.2 hydroxyacyl, such as a
plasmalogen (R.sup.4 trimethylammonium ethyl), or R.sup.1 can be
acyl, such as lauryl, myristoyl or palmitoyl and R.sup.2 can
represent hydroxy as, for example, in natural or synthetic
lysophosphatidyl cholines or lysophosphatidyl glycerols or
lysophosphatidyl ethanolamines, such as 1-myristoyl or
1-palmitoyllysophosphatidyl choline or -phosphatidyl ethanolamine;
frequently, R.sup.3 represents hydrogen.
[0160] A lipid of formula IIIB is also a suitable lipid within the
sense of this invention. In formula IIIB, n=1, R.sup.1 is an
alkenyl group, R.sup.2 is an acylamido group, R.sup.3 is hydrogen
and R.sup.4 represents 2-trimethylammonium ethyl (choline group).
Such a lipid is known under the name of sphingomyelin.
[0161] Suitable lipids furthermore are a lysophosphatidyl choline
analog, such as 1-lauroyl-1,3-dihydroxypropane-3-phosphoryl
choline, a monoglyceride, such as monoolein or monomyristin, a
cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmalogen,
a ganglioside or a glyceride, which does not contain a free or
esterified phosphoryl or phosphono or phosphino group in the 3
position. An example of such a glyceride is diacylglyceride or
1-alkenyl-1-hydroxy-2-acyl glyceride with any acyl or alkenyl
groups, wherein the 3-hydroxy group is etherified by one of the
carbohydrate groups named, for example, by a galactosyl group such
as a monogalactosyl glycerin.
[0162] Lipids with desirable head or chain group properties can
also be formed by biochemical means, for example, by means of
phospholipases (such as phospholilpase A1, A2, B, C and, in
particular, D), desaturases, elongases, acyl transferases, etc.,
from natural or synthetic precursors.
[0163] Furthermore, a suitable lipid is any lipid, which is
contained in biological membranes and can be extracted with the
help of apolar organic solvents, such as chloroform. Aside from the
lipids already mentioned, such lipids also include, for example,
steroids, such as estradiol, or sterols, such as cholesterol,
beta-sitosterol, desmosterol, 7-keto-cholesterol or
beta-cholestanol, fat-soluble vitamins, such as retinoids,
vitamins, such as vitamin A1 or A2, vitamin E, vitamin K, such as
vitamin K1 or K2 or vitamin D1 or D3, etc.
[0164] The less soluble amphiphilic components comprise or
preferably comprise a synthetic lipid, such as myristoleoyl,
palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or
trans-vaccenoyl, linolyl, linolenyl, linolaidyl,
octadecatetraenoyl, gondoyl, eicosaenoyl, eicosadienoyl,
eicosatrienoyl, arachidoyl, cis- or trans-docosaenoyl,
docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl,
tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl,
stearoyl or nonadecanoyl, glycerophospholipid or corresponding
derivatives with branched chains or a corresponding dialkyl or
sphingosin derivative, glycolipid or other diacyl or dialkyl
lipid.
[0165] The more soluble amphiphilic components(s) is/are frequently
derived from the less soluble components listed above and, to
increase the solubility, substituted and/or complexed and/or
associated with a butanoyl, pentanoyl, hexanoyl, heptanoyl,
octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several,
mutually independent, selected substituents or with a different
material for improving the solubility.
[0166] A further suitable lipid is a diacyl- or
dialkyl-glycerophosphoetha-nolamine azo polyethoxylene derivative,
a didecanoylphosphatidyl choline or a
diacylphosphoolligomaltobionamide.
[0167] In certain embodiments, the amount of lipid in the
formulation is from about 1% to about 10%, about 2% to about 10%,
about 1% to about 4%, about 4% to about 7% or about 7% to about 10%
by weight. In a specific embodiment, the lipid is a phospholipid.
In another specific embodiment, the phospholipid is a
phosphatidylcholine. In one embodiment, the topical formulations of
the invention contain one or more antifungals (e.g., terbinafine),
phosphatidylcholine and a surfactant, wherein the formulation
contains 1-10% by weight of phosphatidylcholine.
[0168] 4.3. Surfactant
[0169] The term "surfactant" has its usual meaning A list of
relevant surfactants and surfactant related definitions is provided
in EP 0 475 160 A1 (see, e.g., p. 6, 1. 5 to p. 14. 1.17) and U.S.
Pat. No. 6,165,500 (see, e.g., col. 7, 1. 60 to col. 19, 1. 64)
which are herewith incorporated by reference, and in appropriate
surfactant or pharmaceutical Handbooks, such as Handbook of
Industrial Surfactants or US Pharmacopoeia, Pharm. Eu. In some
embodiments of the invention, the surfactants are those described
in Tables 1-18 of U.S. Patent Application Publication No.
2002/0012680 A1, published Jan. 31, 2002, the disclosure of which
is hereby incorporated by reference in its entirety. The following
list therefore only offers a selection, which is by no means
complete or exclusive, of several surfactant classes that are
particularly common or useful in conjunction with present patent
application. Preferred surfactants to be used in accordance with
the invention include those with an HLB greater than 12. The list
includes ionized long-chain fatty acids or long chain fatty
alcohols, long chain fatty ammonium salts, such as alkyl- or
alkenoyl-trimethyl-, -dimethyl- and -methyl-ammonium salts, alkyl-
or alkenoyl-sulphate salts, long fatty chain dimethyl-aminoxides,
such as alkyl- or alkenoyl-dimethyl-aminoxides, long fatty chain,
for example alkanoyl, dimethyl-aminoxides and especially dodecyl
dimethyl-aminoxide, long fatty chain, for example
alkyl-N-methylglucamide-s and alkanoyl-N-methylglucamides, such as
MEGA-8, MEGA-9 and MEGA-10, N-long fatty
chain-N,N-dimethylglycines, for example
N-alkyl-N,N-dimethylglycines, 3-(long fatty
chain-dimethylammonio)-alkane-sulphonates, for example
3-(acyidimethylammonio)-alkanesulphonates, long fatty chain
derivatives of sulphosuccinate salts, such as
bis(2-ethylalkyl)sulphosuccinate salts, long fatty
chain-sulphobetaines, for example acyl-sulphobetaines, long fatty
chain betaines, such as EMPIGEN BB or ZWITTERGENT-3-16, -3-14,
-3-12, -3-10, or -3-8, or polyethylen-glycol-acylphenyl ethers,
especially nonaethylen-glycol-octyl-phenyl ether, polyethylene-long
fatty chain-ethers, especially polyethylene-acyl ethers, such as
nonaethylen-decyl ether, nonaethylen-dodecyl ether or
octaethylene-dodecyl ether, polyethyleneglycol-isoacyl ethers, such
as octaethyleneglycol-isotridecyl ether,
polyethyleneglycol-sorbitane-long fatty chain esters, for example
polyethyleneglycol-sorbitane-acyl esters and especially
polyoxyethylene-monolaurate (e.g. polysorbate 20 or Tween 20),
polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween
80), polyoxyethylene-sorbitan-monolauroleylate,
polyoxyethylene-sorbitan-monopetroselinate,
polyoxyethylene-sorbitan-monoelaidate,
polyoxyethylene-sorbitan-myristoleylate,
polyoxyethylene-sorbitan-palmitoleinylate,
polyoxyethylene-sorbitan-p-etroselinylate, polyhydroxyethylene-long
fatty chain ethers, for example polyhydroxyethylene-acyl ethers,
such as polyhydroxyethylene-lauryl ethers,
polyhydroxyethylene-myristoyl ethers,
polyhydroxyethylene-cetylst-earyl, polyhydroxyethylene-palmityl
ethers, polyhydroxyethylene-oleoyl ethers,
polyhydroxyethylene-palmitoleoyl ethers,
polyhydroxyethylene-lino-leyl, polyhydroxyethylen-4, or 6, or 8, or
10, or 12-lauryl, miristoyl, palmitoyl, palmitoleyl, oleoyl or
linoeyl ethers (Brij series), or in the corresponding esters,
polyhydroxyethylen-laurate, -myristate, -palmitate, -stearate or
-oleate, especially polyhydroxyethylen-8-stearate (Myrj 45) and
polyhydroxyethylen-8-oleate, polyethoxylated castor oil 40
(Cremophor EL), sorbitane-mono long fatty chain, for example
alkylate (Arlacel or Span series), especially as
sorbitane-monolaurate (Arlacel 20, Span 20), long fatty chain, for
example acyl-N-methylglucamides, alkanoyl-N-methylglucamides,
especially decanoyl-N-methylglucamide,
dodecanoyl-N-methylglucamide, long fatty chain sulphates, for
example alkyl-sulphates, alkyl sulphate salts, such as
lauryl-sulphate (SDS), oleoyl-sulphate; long fatty chain
thioglucosides, such as alkylthioglucosides and especially heptyl-,
octyl- and nonyl-beta-D-thioglucopyranoside; long fatty chain
derivatives of various carbohydrates, such as pentoses, hexoses and
disaccharides, especially alkyl-glucosides and maltosides, such as
hexyl-, heptyl-, octyl-, nonyl- and decyl-beta-D-glucopyranoside or
D-maltopyranoside; further a salt, especially a sodium salt, of
cholate, deoxycholate, glycocholate, glycodeoxycholate,
taurodeoxycholate, taurocholate, a fatty acid salt, especially
oleate, elaidate, linoleate, laurate, or myristate, most often in
sodium form, lysophospholipids, n-octadecylene-glycerophosphatidic
acid, octadecylene-phosphorylglycerol,
octadecylene-phosphorylserine, n-long fatty
chain-glycero-phosphatidic acids, such as
n-acyl-glycero-phosphatidic acids, especially lauryl
glycero-phosphatidic acids, oleoyl-glycero-phosphatidic acid,
n-long fatty chain-phosphorylglycerol, such as
n-acyl-phosphorylglycerol, especially lauryl-, myristoyl-, oleoyl-
or palmitoeloyl-phosphorylglycerol, n-long fatty
chain-phosphorylserine, such as n-acyl-phosphorylserine, especially
lauryl-, myristoyl-, oleoyl- or palmitoeloyl-phosphorylserine,
n-tetradecyl-glycero-phosphatidic acid,
n-tetradecyl-phosphorylglycerol, n-tetradecyl-phosphorylserine,
corresponding-, elaidoyl-, vaccenyl-lysophospholipids,
corresponding short-chain phospholipids, as well as all surface
active and thus membrane destabilising polypeptides. Surfactant
chains are typically chosen to be in a fluid state or at least to
be compatible with the maintenance of fluid-chain state in carrier
aggregates.
[0170] Table 5 lists preferred surfactants in accordance with the
invention.
TABLE-US-00005 TABLE 5 Preferred nonionic surfactants for use in
combination with antifungal Nonionic surfactants (S) Head/Type/TM
POE- POE- POE- Length: POE-sorbitan- ether ester phenoxy- Fatty
chain nr. of double ester Brij, Myrj, ether Selected Name(s) bonds
Tween Macrogol Nonex Triton brandnames C24 Behen(o)yl C22
Eruca(o)yl C22:1-13cis Arachin(o)yl C20 Gadolen(o)yl C20:1-11cis
Arachidon(o)yl C20:4-5,8,11,14cis Ole(o)yl C18:1-9cis Tween 80 Brij
98 Simulsol- TritonX100** 2599 Stear(o)yl C18 Tween 60 Myrj-52
Linol(o)yl C18:2-9,12cis Linole(n/o)yl C18:3-9,12,15cis
Palmitole(o)yl C18:1-9cis Palmit(o)yl C16 Tween 40 NN Myrist(o)yl
C14 Laur(o)yl C12 Tween 20 Brij 35 NN Capr(o)yl C10 Rel.
concentration range L/S (M/M) 5/1-1/1 5/1-1/1 5/1-1/1 4/1-3/2 NN:
not readily available in the market but in principle suitable
**Triton is not an oleate, but an octylphenoxy-POE derivative
Myrj-45: Stearoyl-EO8; Myrj-49: Stearoyl-EO20 (not in the market);
Myrj-59: Stearoyl-EO100; Myrj-52: Stearoyl-EO40; Simulsol-2599 =
Macrogol-10-oleate Brij-98: Oleoyl-EO20 Brij-35: Lauryl-EO23
[0171] In certain embodiments, the surfactant is a nonionic
surfactant. The surfactant may be present in the formulation in
about 1% to about 10%, about 1% to about 4%, about 4% to about 7%
or about 7% to about 10% by weight. In certain embodiments, the
nonionic surfactant is selected from the group consisting of:
polyoxyethylene sorbitans (polysobate surfactants),
polyhydroxyethylene stearates or polyhydroxyethylene laurylethers
(Brij surfactants). In a specific embodiment, the surfactant is a
polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween
80).
[0172] 4.4. Formulations
[0173] The antifungal formulations of the invention may contain 1
to 10% by weight, 1 to 15% by weight, 1 to 20% by weight, or 1 to
30% antifungal by weight. The topical antifungal formulations of
the invention may contain 1 to 10% by weight, 1 to 15% by weight, 1
to 20% by weight, or 1 to 30% lipid by weight. The antifungal
formulations of the invention may contain 1 to 10% by weight, 1 to
15% by weight, 1 to 20% by weight, 1 to 30% by weight, 1 to 40% by
weight or 1 to 50% surfactant by weight.
[0174] The antifungal formulations of the invention may have a
range of lipid to surfactant ratios. The ratios may be expressed in
terms of molar terms (mol lipid/mol surfactant). The molar ratio of
lipid to surfactant in the antifungal formulations of the invention
may be from about 1:2 to about 10:1. In certain embodiments, the
ratio is from about 1:1 to about 5:1, about 1:1 to about 2:1, from
about 2:1 to about 3:1, from about 3:1 to about 4:1, from about 4:1
to about 5:1 or from about 5:1 to about 10:1. In specific
embodiments, the lipid to surfactant ratio is about 1.0:1.0, about
1.25:1.0, about 1.5/1.0, about 1.75/1.0, about 2.0/1.0, about
2.5/1.0, about 3.0/1.0 or about 4.0/1.0.
[0175] The antifungal formulations of the invention may have
varying ratios of antifungal to lipid. The ratios may be expressed
in terms of molar ratios (mol antifungal/mol lipid). The molar
ratio of antifungal to lipid in the topical antifungal formulations
of the invention may be from about 0.2:1 to about 2:1. In certain
embodiments, the ratio is from about 0.2:1 to about 0.7:1, from
about 0.7:1 to about 1.2:1, from about 1.2:1 to about 1.7:1 or from
about 1.7:1 to about 2:1.
[0176] The antifungal formulations of the invention may also have
varying amounts of total amount of the following three components:
antifungal, lipid and surfactant combined (TA). The TA amount may
be stated in terms of weight percent of the total composition. In
one embodiment, the TA is from about 1% to about 40%, about 5% to
about 30%, about 7.5% to about 15%, about 5% to about 10%, about
10% to about 20% or about 20% to about 30%. In specific
embodiments, the TA is 8%, 9%, 10%, 15% or 20%.
[0177] Selected ranges for total lipid amounts, lipid/surfactant
ratios (mol/mol) and antifungal/surfactant ratios (mol/mol) for
topical antifungal formulations of the invention are described in
Table 6 below:
TABLE-US-00006 TABLE 6 Total Lipid, Lipid to Surfactant Ratios and
Antifungal to Lipid Ratios TA (antifungal, lipid and
Lipid/Surfactant Antifungal/Lipid surfactant) (%) (mol/mol)
(mol/mol) 5 to 10 1.0 to 1.25 0.20 to 0.75 5 to 10 1.0 to 1.25 0.75
to 1.25 5 to 10 1.0 to 1.25 1.25 to 2.00 5 to 10 1.25 to 1.75 0.20
to 0.75 5 to 10 1.25 to 1.75 0.75 to 1.25 5 to 10 1.25 to 1.75 1.25
to 2.00 5 to 10 1.75 to 2.25 0.20 to 0.75 5 to 10 1.75 to 2.25 0.75
to 1.25 5 to 10 1.75 to 2.25 1.25 to 2.00 5 to 10 2.25 to 3.00 0.20
to 0.75 5 to 10 2.25 to 3.00 0.75 to 1.25 5 to 10 2.25 to 3.00 1.25
to 2.00 5 to 10 2.25 to 3.00 2.00 to 2.25 5 to 10 3.00 to 4.00 0.20
to 0.75 5 to 10 3.00 to 4.00 0.75 to 1.25 5 to 10 3.00 to 4.00 1.25
to 2.00 5 to 10 3.00 to 4.00 2.00 to 2.25 10 to 20 1.0 to 1.25 0.20
to 0.75 10 to 20 1.0 to 1.25 0.75 to 1.25 10 to 20 1.0 to 1.25 1.25
to 2.00 10 to 20 1.25 to 1.75 0.20 to 0.75 10 to 20 1.25 to 1.75
0.75 to 1.25 10 to 20 1.25 to 1.75 1.25 to 2.00 10 to 20 1.75 to
2.25 0.20 to 0.75 10 to 20 1.75 to 2.25 0.75 to 1.25 10 to 20 1.75
to 2.25 1.25 to 2.00 10 to 20 2.25 to 3.00 0.20 to 0.75 10 to 20
2.25 to 3.00 0.75 to 1.25 10 to 20 2.25 to 3.00 1.25 to 2.00 10 to
20 2.25 to 3.00 2.00 to 2.50 10 to 20 3.00 to 4.00 0.20 to 0.75 10
to 20 3.00 to 4.00 0.75 to 1.25 10 to 20 3.00 to 4.00 1.25 to 2.00
10 to 20 3.00 to 4.00 2.00 to 2.50
[0178] The antifungal formulations of the invention may optionally
contain one or more of the following ingredients: co-solvents,
chelators, buffers, antioxidants, preservatives, microbicides,
emollients, humectants, lubricants and thickeners. Preferred
amounts of optional components are described in Table 7.
[0179] The antifungal formulations of the invention may include a
buffer to adjust the pH of the aqueous solution to a range from pH
3.5 to pH 9, pH 4 to pH 7.5, or pH 4 to pH 6.5. Examples of buffers
include, but are not limited to, acetate buffers, lactate buffers,
phosphate buffers, and propionate buffers.
[0180] The antifungal formulations of the invention is typically
formulated in aqueous media. The formulations may be formulated
with or without co-solvents, such as lower alcohols.
[0181] A "microbicide" or "antimicrobial" agent is commonly added
to reduce the bacterial count in pharmaceutical formulations. Some
examples of microbicides are short chain alcohols, including ethyl
and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl
alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds,
such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol,
dichlorophene, hexachlorophene, povidon-iodine; parabenes,
especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or
butyl-paraben, benzyl paraben; acids, such as sorbic acid, benzoic
acid and their salts; quaternary ammonium compounds, such as
alkonium salts, e.g., a bromide, benzalkonium salts, such as a
chloride or a bromide, cetrimonium salts, e.g., a bromide,
phenoalkecinium salts, such as phenododecinium bromide,
cetylpyridinium chloride and other salts; furthermore, mercurial
compounds, such as phenylmercuric acetate, borate, or nitrate,
thiomersal, chlorhexidine or its gluconate, or any antibiotically
active compounds of biological origin, or any suitable mixture
thereof.
[0182] Examples of "antioxidants" are butylated hydroxyanisol
(BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol
(LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-5119,
BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl
gallate (PG), 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ);
aromatic amines (diphenylamine, p-alkylthio-o-anisidine,
ethylenediamine derivatives, carbazol, tetrahydroindenoindol);
phenols and phenolic acids (guaiacol, hydroquinone, vanillin,
gallic acids and their esters, protocatechuic acid, quinic acid,
syringic acid, ellagic acid, salicylic acid, nordihydroguaiaretic
acid (NDGA), eugenol); tocopherols (including tocopherols (alpha,
beta, gamma, delta) and their derivatives, such as
tocopheryl-acylate (e.g., -acetate, -laurate, myristate,
-palmitate, -oleate, -linoleate, etc., or an y other suitable
tocopheryl-lipoate), tocopheryl-POE-succinate; trolox and
corresponding amide and thiocarboxamide analogues; ascorbic acid
and its salts, isoascorbate, (2 or 3 or 6)-o-alkylascorbic acids,
ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl,
or linoleoyl-L-ascorbic acid, etc.). Also useful are the
preferentially oxidised compounds, such as sodium bisulphite,
sodium metabisulphite, thiourea; chellating agents, such as EDTA,
GDTA, desferral; miscellaneous endogenous defence systems, such as
transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion,
heamopexin, albumin, glucose, ubiquinol-10); enzymatic
antioxidants, such as superoxide dismutase and metal complexes with
a similar activity, including catalase, glutathione peroxidase, and
less complex molecules, such as beta-carotene, bilirubin, uric
acid; flavonoids (flavones, flavonols, flavonones, flavanonals,
chacones, anthocyanins), N-acetylcystein, mesna, glutathione,
thiohistidine derivatives, triazoles; tannines, cinnamic acid,
hydroxycinnamatic acids and their esters (coumaric acids and
esters, caffeic acid and their esters, ferulic acid, (iso-)
chlorogenic acid, sinapic acid); spice extracts (e.g., from clove,
cinnamon, sage, rosemary, mace, oregano, allspice, nutmeg);
carnosic acid, carnosol, carsolic acid; rosmarinic acid,
rosmaridiphenol, gentisic acid, ferulic acid; oat flour extracts,
such as avenanthramide 1 and 2; thioethers, dithioethers,
sulphoxides, tetralkylthiuram disulphides; phytic acid, steroid
derivatives (e.g., U74006F); tryptophan metabolites (e.g.,
3-hydroxykynurenine, 3-hydroxyanthranilic acid), and
organochalcogenides.
[0183] "Thickeners" are used to increase the viscosity of
pharmaceutical formulations to and may be selected from selected
from pharmaceutically acceptable hydrophilic polymers, such as
partially etherified cellulose derivatives, comprising
carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl-
or methyl-cellulose; completely synthetic hydrophilic polymers
comprising polyacrylates, polymethacrylates, poly(hydroxyethyl)-,
poly(hydroxypropyl)-, poly(hydroxypropylmethyl)methacrylate,
polyacrylonitrile, methallyl-sulphonate, polyethylenes,
polyoxiethylenes, polyethylene glycols, polyethylene
glycol-lactide, polyethylene glycol-diacrylate,
polyvinylpyrrolidone, polyvinyl alcohols,
poly(propylmethacrylamide), polypropylene fumarate-co-ethylene
glycol), poloxamers, polyaspartamide, (hydrazine cross-linked)
hyaluronic acid, silicone; natural gums comprising alginates,
carrageenan, guar-gum, gelatine, tragacanth, (amidated) pectin,
xanthan, chitosan collagen, agarose; mixtures and further
derivatives or co-polymers thereof and/or other pharmaceutically,
or at least biologically, acceptable polymers.
[0184] The antifungal formulations of the present invention may
also comprise a polar liquid medium. The topical antifungal
formulations of the invention may be administered in an aqueous
medium. The antifungal formulations of the present invention may be
in the form of a solution, suspension, emulsion, cream, lotion,
ointment, gel, spray, film forming solution or lacquer.
[0185] In one embodiment, the invention specifically relates to the
use of antifungal, a phospholipid and a nonionic surfactant for the
preparation of a pharmaceutical composition for treating
onychomycosis. In this context, the invention relates to a
formulation or pharmaceutical composition comprising antifungal for
the treatment of onychomycosis wherein the formulation or
pharmaceutical composition is formulated for topical delivery.
[0186] Table 7 lists preferred excipients for the formulation.
TABLE-US-00007 TABLE 7 Preferred excipients for use in combinations
with antifungal Designated activity Molar (M) Rel. Antioxydant or w
%* Primary Butylated hydroxyanisole, BHA 0.1-8 Butylated
hydroxytoluene, BHT 0.1-4 Thymol 0.1-1 Metabisulphite (MW = 190.1)
1-5 mM Bisulphite 1-5 mM Thiourea (MW = 76.12) 1-10 mM
Monothioglycerol (MW = 108.16) 1-20 mM Propyl gallate (MW = 212.2)
0.02-0.2 Ascorbate (MW = 175.3+ ion) 1-10 mM Palmityl-ascorbate
0.01-1 Tocopherol-PEG 0.5-5 Secondary (chelator) EDTA (MW = 292)
1-10 mM EGTA (MW = 380.35) 1-10 mM Desferal (MW = 656.79) 0.1-5 mM
Molar (M) or Antibiotic Weight-% Acetate 30-150 mM Benzyl alcohol
0.1-3 Butylparabene 0.1-3 Ethylparabene 0.1-3 Imidurea (MW =
388.30) 0.1-1 Dimethoxane (MW = 0.03-0.1 174.2) Methylparabene
0.1-5 Phenoxyethanol 0.1-5 Benzalkonium chloride 0.01-0.2
Benzethonium chloride 0.01-0.1 Phenol 0.05-2 Phenylethyl alcohol
0.1-1 Thimerosal 0.005-0.1 Buffer Molar Acetate 30-150 mM Phosphate
10-50 mM Triethanolamine.cndot.HCL 30-150 mM *As percentage of
Total Lipid quantity EGTA = Ethylene
glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid EDTA =
Ethylenedioxy-diethylene-dinitrilo-tetraacetic acid
[0187] 4.4. Vesicular Formulations
[0188] While not to be limited to any mechanism of action or any
theory, the formulations of the invention may form vesicles or ESAs
characterized by their adaptability, deformability, or
penetrability.
[0189] The term vesicle or aggregate "adaptability" which governs
the "tolerable surface curvature" is defined as the ability of a
given vesicle or aggregate to change easily its properties, such as
shape, elongation ratio, and surface to volume ratio. The vesicles
of this invention may be characterized by their ability to adjust
the aggregates' shape and properties to the anisotropic stress
caused by pore crossing. Sufficient adaptability implies that a
vesicle or an aggregate can sustain different unidirectional forces
or stress, such as one caused by pressure, without extensive
fragmentation, which defines a "stable" aggregate. If an aggregate
passes through a barrier fulfilling this condition the terms
"adaptability" and (shape) "deformability" plus "permeability" are
essentially equivalent. A "barrier" in the context of this
invention is (as in, for example, EP 0 475 160 and WO 98/17255) a
body with through-extending narrow pores, such narrow pores having
a radius which is at least 25% smaller than the radius of the ESAs
(considered as spherical) before said ESAs permeate through such
pores.
[0190] The term "narrow" used in connection with a pore implies
that the pore radius is significantly, typically at least 25%,
smaller than the radius of the entity tested with regard to its
ability to cross the pore. The necessary difference typically
should be greater for the narrower pores. Using 25% limit is
therefore quite suitable for >150 nm diameter whereas >100%
difference requirement is more appropriate for the smaller systems,
e.g., with <50 nm diameter. For diameters around 20 nm,
aggregate diameter difference of at least 200% is often
required.
[0191] The term "semipermeable" used in connection with a barrier
implies that a solution can cross transbarrier openings whereas a
suspension of non-adaptable aggregates (large enough for the above
definition of "narrow" pores to apply) cannot. Conventional lipid
vesicles (liposomes) made from any common phosphatidylcholine in
the gel lamellar phase or else from any biological
phosphatidylcholine/cholesterol 1/1 mol/mol mixture or else
comparably large oil droplets, all having the specified relative
diameter, are three examples for such non-adaptable aggregates.
[0192] The term "stable" means that the tested aggregates do not
change their diameter spontaneously or under the transport related
mechanical stress (e.g. during passage through a semipermeable
barrier) unacceptably, which most often means only to a
pharmaceutically acceptable degree. A 20-40% change is normally
considered acceptable; the halving or doubling of aggregate
diameter is borderline and a greater change in diameter is
typically unacceptable. Alternatively and very conveniently, the
change in aggregate diameter resulting from pore crossing under
pressure is used to assess system stability; the same criteria are
then applied as for "narrow" pores, mutatis mutandis. To obtain the
correct value for aggregate diameter change, a correction for
flux/vortex effects may be necessary. These procedures are
described in greater detail in the publications of the applicant in
Cevc et. al., Biochim. Biophys. Acta 2002; 1564:21-30.
[0193] Non-destructing passage of ultradeformable, mixed lipid
aggregates through narrow pores in a semi-permeable barrier is thus
diagnostic of high aggregate adaptability. If pore radius is two
times smaller than the average aggregate radius the aggregate must
change its shape and surface-to-volume ratio at least 100% to pass
without fragmentation through the barrier. An easy and reversible
change in aggregate shape inevitably implies high aggregate
deformability and requires large surface-to-volume ratio
adaptation. A change in surface-to-volume ratio per se implies: a)
high volume compressibility, e.g. in the case of compact droplets
containing material other than, and immiscible with, the suspending
fluid; b) high aggregate membrane permeability, e.g. in the case of
vesicles that are free to exchange fluid between inner and outer
vesicle volume.
[0194] 4.5 Methods of Administration
[0195] Another aspect of the invention provides methods of
administering a pharmaceutical composition comprising antifungal, a
lipid, and a surfactant. Generally, the pharmaceutical composition
is administered to nail tissue. For instance, in some embodiments,
it is administered topically to the nail tissue.
[0196] As used herein, the term "nail tissue," is used to describe
any tissue that is a component of the "nail unit." The nail unit is
comprised of the matrix, the nail plate, the nail bed, the cuticle,
the lunula and the hyponychium. The matrix is where the cells
multiply and keratinize before being incorporated into the nail
plate. This tissue starts about 5 mm proximal to the nail fold and
covers all the area called "lunula" or "half moon". The matrix is
protected from infection by the cuticle, a fold of modified stratum
corneum proximal to the nail plate.
[0197] In one embodiment, the topical formulation is administered
to nail tissue and/o surrounding skin of a human subject which
results in a mean concentration of antifungal per gram of nail
tissue of about at least 1.5 mg/g, 2.0 mg/g, 2.1 mg/g, 2.2 mg/g,
2.3 mg/g, 2.4 mg/g, 2.5 mg/g, 2.6 mg/g, 2.7 mg/g, 2.8 mg/g, 2.9
mg/g and 3.0 mg/g. In another embodiment, the topical formulation
is administered to nail tissue of a human subject which results in
a mean concentration of antifungal per gram of nail tissue of about
0.1 to about 15 mg/g, about 0.2 to about 12.5 mg/g, about 0.5 to
about 10.0 mg/g, about 1.0 to about 7.5 mg/g or about 2.0 to about
5.0 mg/g. The mean concentration can be determined one, two or
three weeks after ceasing administration of the topical
formulation. The invention also provides a method of treating a
fungal infection of nail tissue in a human subject comprising
administering a topical formulation to the infected nail tissue
and/or surrounding skin of the human subject which results in a
mean concentration of antifungal per gram of nail tissue of about
0.1 to about 15 mg/g, about 0.2 to about 12.5 mg/g, about 0.5 to
about 10.0 mg/g, about 1.0 to about 7.5 mg/g or about 2.0 to about
5.0 mg/g. The mean concentration can be determined one, two or
three weeks after ceasing administration of the pharmaceutical
composition.
[0198] In certain embodiments of the methods, the administration of
topical antifungal formulations of the invention also results in a
mean serum concentration of antifungal in the human subject of less
than 10.0 ng/ml, 5.0 ng/ml, 4.0 ng/ml, 3.0 ng/ml, 2.0 ng/ml, 1.0
ng/ml, 0.5 ng/ml or 0.2 ng/ml.
[0199] In some embodiments of the methods, the topical formulation
comprises about 1.0 to about 5.0 mg of antifungal. In a specific
embodiment of the method, the pharmaceutical composition comprises
3.0 mg of antifungal. The topical formulation can be administered,
for example, twice daily. In certain embodiments, the composition
may also be administered, once every two days, once daily, three
times a day or four times a day. In certain embodiments, the
topical formulation is administered for at least three weeks. In
other embodiments, the topical formulation is administered for 3 to
48 weeks, 3 to 36 weeks or 3 to 24 weeks, 3 to 12 weeks or 3 to 6
weeks.
[0200] In a specific embodiment of the methods, the topical
formulation is administered for 12 weeks to treat nail fungal
infection, followed by an assessment to determine whether a
mycological cure has been achieved. If a mycological cure has been
achieved, further administration of the topical formulation is
ceased. If a mycological cure has not been achieved, then the
topical formulation is again administered for another 12 week
period, followed by a second assessment to determine whether the
regiment has achieved a cure. The cycle can be repeated until the
regimen achieves a mycological cure. In certain embodiments, the
formulations are adapted to cause a greater than 90% mycological
cure rate.
[0201] In another embodiment, a topical formulation comprising
antifungal, a lipid, and a surfactant is administered to nail
tissue and/or surrounding skin twice daily for at least one, two or
three weeks. The invention also provides a method of treating a
fungal infection of nail tissue in a human subject comprising
administering a topical formulation to the infected nail tissue and
surrounding skin of the human subject twice daily for at least one,
two or three weeks, wherein the topical formulation comprises
antifungal, a lipid, and a surfactant.
[0202] In certain embodiments of the methods, the topical
formulation may also be administered, once every two days, daily,
three times a day or four times a day. In specific embodiments, the
topical formulation is administered for 3 to 48 weeks, 3 to 36
weeks, 3 to 24 weeks, 3 to 12 weeks or 3 to 6 weeks.
[0203] In some embodiments of the methods, the topical formulation
comprises from about 1.0 to about 5.0 mg of antifungal. For
instance, the topical formulation can comprise about 3.0 mg of
antifungal.
[0204] In a particular embodiment, the fungal infection being
treated comprises onychomycosis.
[0205] In some embodiments of the methods described herein, the
topical formulation is administered for a period longer than 12
weeks. For instance, in some embodiments, the topical formulation
is administered for at least 24 weeks, for at least 36 weeks, or
for at least 48 weeks.
[0206] In some embodiments of the methods, a cyclical treatment
regimen is employed. Such regimens employ treatment cycles
involving the administration of the topical formulation for a
period of time, followed by a period wherein no formulation is
administered, and, if necessary, repeating this sequence, i.e., the
cycle. Treatment cycles can include, for example, administering,
the topical formulation consecutively for a period of 12 weeks,
e.g., using twice daily administration, followed a period of time
wherein no formulation is administered, followed by another period
where the formulation is again administered consecutively for
another 12 weeks.
[0207] Certain embodiments of the methods include treatment
regimens, wherein the topical formulation is administered to treat
nail fungal infection for a period of time, followed by an
assessment of the subject to determine whether the administration
has achieved a mycological cure in the subject. If a mycological
cure has been achieved, further administration of the topical
formulation is ceased. If a mycological cure has not been achieved,
then the topical formulation is again administered during a second
administration period, which is followed by a second assessment to
determine whether the regimen has achieved a cure. The cycle can be
repeated until the regimen achieves a mycological cure.
[0208] In certain embodiments, the invention relates to using the
methods of administration described herein to treat specific
patient populations. In some embodiments, a population of patients
who suffer chronically from nail fungal infection can be treated
with the methods of administration described herein. In a specific
embodiment, a population of patients who suffer from persistent
re-infection can be treated using the methods described herein. For
instance, the topical formulation may be administered to such a
population during first administration period, (e.g., a first 12
week period) and then again for a second subsequent administration
period (e.g., an additional 12 week period) to prevent re-infection
of nail tissue.
[0209] In other embodiments, the methods of administration
described herein may be used prophylactically in order to prevent
re-infection of nail tissue in a population of patients who suffer
chronically from nail fungal infections.
[0210] 4.5 Kits
[0211] The invention further includes a pharmaceutical pack or kit
comprising one or more containers filled with a antifungal
formulation of the invention for the treatment or prevention of a
fungal infection in a human subject. The invention provides kits
that can be used in the above-described methods.
[0212] In one embodiment, a kit comprises one or more containers
comprising an antifungal formulation of the invention. The kit may
further comprise instructions for administering the antifungal
formulations of the invention for the treating or preventing skin
and/or nail infections, as well as side effects and dosage
information. Optionally associated with such container(s) can be a
notice in the form prescribed by a governmental agency regulating
the manufacture, use or sale for human administration.
5. EXAMPLES
5.1 Example 1
Antifungal Formulations
[0213] Antifungal formulations for topical application may be
prepared by the following procedure:
1. Organic Phase Production, which Contains all Lipophilic
Excipients
[0214] The organic phase is produced by weighing the lipid, the
surfactant, antifungal hydrochloride and any additional lipophilic
excipients into suitable containers followed by mixing these
components into anoptically isotropic phase which appears as a
clear solution. During mixing, the organic phase will be heated up,
but temperature must not rise above 45.degree. C.
2. Aqueous Phase Production
[0215] The aqueous phase is prepared by weighing the non-lipophilic
components and water, which serves as solvent, into suitable
containers and then mixing these components into a clear solution.
During mixing, the temperature will be elevated to 40.degree.
C.
3. Production of a Concentrated Intermediate by Combination of Both
Phases
[0216] The isotropic organic phase and the clear aqueous phase are
combined under stirring in a suitable vessel. Before and during the
combination the temperature of both phases must be kept between
35.degree. C. and 45.degree. C. The resulting intermediate is
homogenised mechanically at 40.degree. C. Before starting
homogenisation, the pressure in the production vessel is lowered to
-0.08 MPa. The desired average carrier size is typically reached
after 10 minutes of homogenisation.
[0217] Three process parameters must be controlled carefully during
the production of the concentrated intermediate: temperature,
homogeniser circulation velocity, and overall processing time.
4. Production of the Final Bulk Product by Mixing the Concentrated
Intermediate with Dilution Buffer.
[0218] The concentrated intermediate is diluted with the dilution
buffer to the intended final concentration. The mixture is
carefully stirred in the mixing vessel at 20.degree. C. to
homogeneity.
[0219] Table 8 describes the amount of surfactant, lipid, and one
or more antifungal (e.g., terbinafine) in preferred antifungal
formulations of the invention. The amount of one or more
antifungal, lipid, lipid and surfactant combined is described in
terms of the percent total in the formulation. One of the
terbinafine formulations described below was tested for efficacy in
vivo.
TABLE-US-00008 TABLE 8 Preferred Antifungal Formulations of the
Invention Table 8A This table lists the relative amounts of each of
the components of Preferred Antifungal Formulations of the
Invention Surfactant Lipid mg/g mg/g antifungal (1 to 10% (1 to 10%
by Buffer Antimicrobials Antioxidants Emollient Other Chelator
(1-50 mg/g) by wt.) wt.) (pH 4-7.5) (0-10 mg/g) (0-10 mg/g) (0-50
mg/g) (0-50 mg/g) (0-25 mg/g) 1 10 47.944 42.056 4 5.250 0.700
30.000 30.000 3.000 2 15 53.750 31.250 4 5.250 0.700 30.000 15.000
3.000 3 30 90.561 79.439 4 5.250 0.700 30.000 30.000 3.000 4 10
47.944 42.056 5 5.250 0.700 30.000 30.000 3.000 5 5 50.607 44.393 5
5.250 0.700 0.000 10.000 3.000 6 30 90.561 79.439 5 5.250 0.700
30.000 30.000 3.000 7 7.5 49.276 43.224 6.5 5.250 0.700 30.000
30.000 3.000 8 15 53.750 31.250 6.5 5.250 0.200 30.000 0.000 3.000
9 30 90.561 79.439 6.5 5.250 0.200 30.000 20.000 3.000 10 10 41.351
48.649 4 5.250 0.200 30.000 30.000 3.000 11 15 47.882 37.118 4
5.250 0.200 0.000 30.000 3.000 12 30 95.764 74.236 4 5.250 0.200
30.000 30.000 3.000 13 10 65.676 24.324 5 5.250 0.200 0.000 25.000
3.000 14 15 62.027 22.973 5 5.250 0.200 0.000 30.000 3.000 15 30
124.054 45.946 5 5.250 0.200 15.000 30.000 3.000 16 5 62.687 32.313
6.5 5.250 0.200 15.000 0.000 3.000 17 15 41.853 43.147 6.5 5.250
0.200 30.000 30.000 3.000 18 30 95.764 74.236 6.5 5.250 0.200 0.000
30.000 3.000 19 15 47.882 37.118 6.5 5.250 0.200 0.000 0.000 3.000
20 10 45.000 45.000 6.5 5.250 0.200 0.000 0.000 3.000 21 10 31.935
58.065 5 5.250 0.200 30.000 15.000 3.000 22 15 42.500 42.500 6.5
5.250 0.200 30.000 0.000 3.000 23 10 38.276 51.724 4 5.250 0.200
0.000 30.000 3.000 24 15 42.500 42.500 4 5.250 0.200 0.000 15.000
3.000 25 30 85.000 85.000 4 5.250 0.200 30.000 30.000 3.000 26 10
38.276 51.724 5 5.250 0.200 30.000 0.000 3.000 27 15 36.429 48.571
5 5.250 0.200 30.000 30.000 3.000 28 30 72.299 97.701 5 5.250 0.200
30.000 15.000 3.000 29 7.5 46.250 46.250 6.5 5.250 0.700 0.000
20.000 3.000 30 15 38.804 46.196 6.5 5.250 0.700 15.000 30.000
3.000 31 30 36.667 33.333 6.5 5.250 0.700 30.000 10.000 3.000 32 10
66.667 23.333 4 5.250 0.200 0.000 0.000 3.000 33 12.5 45.833 41.667
4 5.250 0.200 30.000 0.000 3.000 34 30 31.957 38.043 4 5.250 0.200
0.000 30.000 3.000 35 10 47.143 42.857 5 5.250 0.200 30.000 25.000
3.000 36 15 96.905 88.095 5 5.250 0.200 30.000 20.000 3.000 37 30
31.957 38.043 5 5.250 0.200 0.000 30.000 3.000 38 10 35.455 54.545
6.5 5.250 0.700 30.000 0.000 3.000 39 15 84.457 100.543 6.5 5.250
0.700 30.000 30.000 3.000 40 30 89.048 80.952 6.5 5.250 0.700
30.000 30.000 3.000 41 10 41.087 48.913 4 5.250 0.700 30.000 30.000
3.000 42 15 45.280 39.720 4 5.250 0.700 0.000 0.000 3.000 43 30
107.500 62.500 4 5.250 0.700 30.000 30.000 3.000 44 5 77.243 67.757
4 5.250 0.700 0.000 15.000 3.000 45 15 45.280 39.720 5 5.250 0.700
0.000 20.000 3.000 46 30 90.561 79.439 5 5.250 0.700 0.000 30.000
3.000 47 10 47.944 42.056 5 5.250 0.700 0.000 10.000 3.000 48 5
50.607 44.393 5.5 5.250 0.700 30.000 0.000 3.000 49 30 107.500
62.500 5.5 5.250 0.700 30.000 0.000 3.000 50 10 47.944 42.056 5.5
5.250 0.700 30.000 30.000 3.000 51 15 46.364 38.636 4 5.250 0.200
30.000 25.000 3.000 52 15 46.364 38.636 4 5.250 0.200 0.000 20.000
3.000 53 10 46.098 43.902 5 5.250 0.200 15.000 30.000 3.000 54 15
43.537 41.463 5 5.250 0.200 30.000 0.000 3.000 55 10 45.000 45.000
5 5.250 0.200 0.000 30.000 3.000 56 10 59.492 30.508 6.5 5.250
0.200 30.000 30.000 3.000 57 15 39.054 45.946 6.5 5.250 0.200 0.000
0.000 3.000 58 30 35.854 34.146 6.5 5.250 0.200 30.000 0.000 3.000
59 10 50.000 40.000 6.5 5.250 0.700 30.000 30.000 3.000 60 10
38.571 51.429 6.5 5.250 0.700 30.000 30.000 3.000 61 7.5 41.954
50.546 6.5 5.250 0.700 30.000 30.000 3.000 62 10 42.632 47.368 6.5
5.250 0.700 30.000 30.000 3.000 63 10 46.098 43.902 6.5 5.250 0.700
30.000 30.000 3.000 64 10 39.721 50.279 6.5 5.250 0.700 30.000
30.000 3.000 65 5 44.198 50.802 6.5 5.250 0.700 30.000 30.000 3.000
66 2.5 46.453 51.047 6.5 5.250 0.700 30.000 30.000 3.000 67 5
51.221 43.779 6.5 5.250 0.700 30.000 30.000 3.000 68 2.5 54.167
43.333 6.5 5.250 0.700 30.000 30.000 3.000 69 10 66.440 23.560 6.5
5.250 0.700 30.000 30.000 3.000 70 10 66.440 23.560 6.5 5.250 0.700
30.000 30.000 3.000 71 10 66.440 23.560 6.5 5.250 0.700 30.000
30.000 3.000 72 10 40.000 50.000 6.5 5.250 0.700 30.000 30.000
3.000 73 10 40.000 50.000 6.5 5.250 0.700 30.000 30.000 3.000 74 10
40.000 50.000 5.5 0.000 0.700 30.000 30.000 3.000 75 10 40.000
50.000 6.5 5.250 0.700 30.000 30.000 3.000 76 10 40.000 50.000 6.5
5.250 0.700 30.000 30.000 3.000 77 10 40.000 50.000 6.5 5.250 0.700
30.000 30.000 3.000 78 10 66.440 23.560 6.5 5.250 0.700 30.000
30.000 3.000 79 10 66.440 23.560 6.5 5.250 0.700 30.000 30.000
3.000 80 10 40.000 50.000 5.5 0.000 0.700 30.000 30.000 3.000 81 10
40.000 50.000 5.5 5.250 0.700 30.000 30.000 3.000 82 10 44.444
55.556 5.5 5.250 0.700 30.000 30.000 3.000 83 10 66.440 23.560 5.5
5.250 0.700 30.000 30.000 3.000 84 10 54.000 36.000 4 5.250 0.700
30.000 30.000 3.000 85 10 50.000 40.000 4 5.250 0.700 30.000 30.000
3.000 86 12.5 48.611 38.889 4 5.250 0.700 30.000 30.000 3.000 87 15
46.575 38.425 4 5.250 0.700 30.000 30.000 3.000 88 15 46.575 38.425
4 5.250 0.700 30.000 30.000 3.000 89 15 46.575 38.425 4 5.250 0.700
30.000 30.000 3.000 90 10 50.000 40.000 4.5 5.250 0.700 30.000
30.000 3.000 91 30 94.444 75.556 4 5.250 0.700 30.000 30.000 3.000
92 15 46.712 38.288 4 5.250 0.700 30.000 30.000 3.000 93 12 48.889
39.111 4 5.250 0.700 30.000 30.000 3.000 94 10 39.721 50.279 6.5
5.250 0.700 30.000 30.000 3.000 95 10 90.000 0.000 6.5 5.250 0.700
30.000 30.000 3.000 96 15 46.575 38.425 4 0.000 0.700 0.000 0.000
3.000 97 15 46.575 38.425 4 0.000 0.700 0.000 0.000 3.000 98 15
54.643 30.357 4 5.250 0.700 0.000 0.000 3.000 99 10 39.72 50.279
6.5 5.250 0.700 30.000 30.000 3.000 100 10 90.00 6.5 5.250 0.700
30.000 30.000 3.000 101 15 46.57 38.425 4 0.700 3.000 102 15 46.75
38.425 4 0.700 3.000 103 15 54.64 30.357 4 0.700 3.000 104 6.1
46.575 38.425 6.5 5.250 0.700 0.000 30.000 3.000 105 6.1 64.516
35.484 6.5 5.250 0.700 0.000 30.000 3.000 106 6.1 66.440 23.560 6.5
5.250 0.700 0.000 30.000 3.000 107 10 46.575 38.425 6.5 5.250 0.700
0.000 30.000 3.000 108 10 64.516 35.484 6.5 5.250 0.700 0.000
30.000 3.000 109 10 66.440 23.560 6.5 5.250 0.700 0.000 30.000
3.000 Table 8B The table lists the specific components of the
formulas listed above. Formula Lipid Surfactant Buffer
Antimicrobial Antioxidants Emollient Chelator Other 1-4
Sphingomyelin, e.g., Tween 80 Lactate Benzyl alcohol BHT (0.200)
Glycerol EDTA Ethanol brain sodium metabisulfite (0.500) 5-7
Sphingomyelin, Brij 98 Acetate Benzyl alcohol BHT (0.200) Glycerol
EDTA Ethanol lauroyl sodium metabisulfite (0.500) 8-12 Phosphatidyl
choline + Brij 98 Phosphate Benzyl alcohol HTHQ Glycerol EDTA
Ethanol Phosphatidylglycerol 13-16 Phosphatidyl Span 20 Acetate
Benzyl alcohol HTHQ Glycerol EDTA Ethanol choline +
phosphatidylinositol 17-20 Phosphatidyl Tween 80 Phosphate Benzyl
alcohol BHT Glycerol EDTA Ethanol choline + phosphatidic acid 21-28
Phosphatidyl Cremophor Lactate Thimerosal BHA Glycerol EDTA Ethanol
choline 29-31 Phosphatidyl Tween 80 Phosphate Thimerosal BHT
(0.200) Glycerol EDTA Ethanol ethanolamine sodium metabisulfite
(0.500) 32-37 Phosphatidyl Brij 98 Acetate Benzyl alcohol BHT
Glycerol EDTA Ethanol glycerol 38-40 Phosphatidyl Cremophor
phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol
ethanolamine sodium metabisulfite (0.500) 41-47 Phosphatidyl Tween
80 Propionate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol
glycerol sodium metabisulfite (0.500) 48-50 Phosphatidyl serine
Brij 98 Phosphate Thimerosal BHT (0.200) Glycerol EDTA Ethanol
sodium metabisulfite (0.500) 51-58 Phosphatidyl Brij 98 Acetate
Benzyl alcohol BHT Glycerol EDTA Ethanol glycerol 59-68
Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 69-71
Phosphatidyl choline Brij 98 Phosphate Benzyl alcohol BHT (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 72-73
Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 74 Phosphatidyl
choline Tween 80 Acetate BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite (0.500) 75 Phosphatidyl choline Tween 80 Phosphate
Paraben BHT (0.200) Glycerol EDTA Ethanol sodium metabisulfite
(0.500) 76 Phosphatidyl choline Brij 98 Phosphate Benzalkonium BHT
(0.200) Glycerol EDTA Ethanol chloride sodium metabisulfite (0.500)
77 Phosphatidyl choline Tween 80 Phosphate Paraben BHT (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 78 Phosphatidyl
choline Brij 98 Phosphate Benzalkonium BHT (0.200) Glycerol EDTA
Ethanol chloride sodium metabisulfite (0.500) 79 Phosphatidyl
choline Brij 98 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA
Ethanol sodium metabisulfite (0.500) 80 Phosphatidyl choline Tween
80 Acetate BHT (0.200) Glycerol EDTA Ethanol sodium metabisulfite
(0.500) 81 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT
(0.200) Glycerol EDTA Ethanol sodium metabisulfite (0.500) 82-83
Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 84-88
Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHA (0.200)
Glycerol EDTA Ethanol sodium metabisulfite (0.500) 89 Phosphatidyl
choline Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA
Ethanol sodium metabisulfite (0.500) 90-93 Phosphatidyl choline
Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA
Ethanol
sodium metabisulfite (0.500) 94 Phosphatidyl choline Tween 80
Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite (0.500) 95 Phosphatidyl choline Tween 80 Phosphate
Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite (0.500) 96-98 Phosphatidyl choline Tween 80 Acetate
BHT (0.200) EDTA sodium metabisulfite (0.500) 99 Phosphatidyl
choline Tween 80 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA
Ethanol sodium metabisulfite (0.500) 100 Phosphatidyl choline
Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite (0.500) 101-103 Phosphatidyl choline Tween 80
Phosphate BHT (0.200) EDTA sodium metabisulfite (0.500) 104-109
Phosphatidyl choline Tween 80 Phosphate Benzyl Alcohol BHT (0.200)
EDTA Ethanol sodium metabisulfite (0.500)
Example Formulation 1
[0220] Formulation 1 comprises antifungal (10 mg/g), sphingomyelin
(brain) (47.944 mg/g) as a lipid, Tween 80 (42.056 mg/g) as a
surfactant, lactate buffer (pH 4), benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.0500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 2
[0221] Formulation 2 comprises antifungal (15 mg/g), sphingomyelin
(brain) (53.750 mg/g) as a lipid, Tween 80 (31.250 mg/g) as a
surfactant, lactate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 3
[0222] Formulation 3 comprises antifungal (30 mg/g), sphingomyelin
(brain) (90.561 mg/g) as a lipid, Tween 80 (79.439 mg/g) as a
surfactant, lactate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 4
[0223] Formulation 4 comprises antifungal (10 mg/g), sphingomyelin
(brain) (47.944 mg/g) as a lipid, Tween 80 (42.056 mg/g) as a
surfactant, lactate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 5
[0224] Formulation 5 comprises antifungal (5 mg/g), sphingomyelin
lauroyl (50.607 mg/g) as a lipid, Brij 98 (44.393 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating
agent, and ethanol (10.000 mg/g).
Example Formulation 6
[0225] Formulation 6 comprises antifungal (30 mg/g), sphingomyelin
lauroyl (90.561 mg/g) as a lipid, Brij 98 (79.439 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 7
[0226] Formulation 7 comprises antifungal (7.5 mg/g), sphingomyelin
lauroyl (49.276 mg/g) as a lipid, Brij 98 (79.439 mg/g) as a
surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 8
[0227] Formulation 8 comprises antifungal (15 mg/g), phosphatidyl
choline and phosphatidyl glycerol (53.750 mg/g) as a lipid, Brij 98
(31.250 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as
a chelating agent.
Example Formulation 9
[0228] Formulation 9 comprises antifungal (30 mg/g), phosphatidyl
choline and phosphatidyl glycerol (90.561 mg/g) as a lipid, Brij 98
(79.439 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 10
[0229] Formulation 10 comprises antifungal (10 mg/g), phosphatidyl
choline and phosphatidyl glycerol (41.351 mg/g) as a lipid, Brij 98
(48.649 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 11
[0230] Formulation 11 comprises antifungal (15 mg/g), phosphatidyl
choline and phosphatidyl glycerol (47.882 mg/g) as a lipid, Brij 98
(37.118 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol, EDTA (3.000 mg/g) as a chelating
agent, and ethanol (30.000 mg/g).
Example Formulation 12
[0231] Formulation 12 comprises antifungal (30 mg/g), phosphatidyl
choline and phosphatidyl glycerol (95.764 mg/g) as a lipid, Brij 98
(74.236 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 13
[0232] Formulation 13 comprises antifungal (10 mg/g), phosphatidyl
choline and phosphatidylinositol (66.676 mg/g) as a lipid, Span 20
(24.324 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl
alcohol (5.250 mg/g), HTHQ (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (25.000 mg/g).
Example Formulation 14
[0233] Formulation 14 comprises antifungal (15 mg/g), phosphatidyl
choline and phosphatidylinositol (62.027 mg/g) as a lipid, Span 20
(22.973 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and
ethanol (30.000 mg/g).
Example Formulation 15
[0234] Formulation 15 comprises antifungal (30 mg/g), phosphatidyl
choline and phosphatidylinositol (124.054 mg/g) as a lipid, Span 20
(45.946 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 16
[0235] Formulation 16 comprises antifungal (5 mg/g), phosphatidyl
choline and phosphatidylinositol (62.687 mg/g) as a lipid, Span 20
(32.313 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g)
as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a
chelating agent.
Example Formulation 17
[0236] Formulation 17 comprises antifungal (15 mg/g), phosphatidyl
choline and phosphatidic acid (41.853 mg/g) as a lipid, Tween 80
(43.147 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as
an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and
ethanol (30.000 mg/g).
Example Formulation 18
[0237] Formulation 18 comprises antifungal (30 mg/g), phosphatidyl
choline and phosphatidic acid (95.764 mg/g) as a lipid, Tween 80
(74.236 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as
an antioxidant, EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 19
[0238] Formulation 19 comprises antifungal (15 mg/g), phosphatidyl
choline and phosphatidic acid (47.882 mg/g) as a lipid, Tween 80
(37.118 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as
an antioxidant, and EDTA (3.000 mg/g).
Example Formulation 20
[0239] Formulation 20 comprises antifungal (10 mg/g), phosphatidyl
choline and phosphatidic acid (45.000 mg/g) as a lipid, Tween 80
(45.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol (5.250 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as
antioxidant, and EDTA (3.000 mg/g).
Example Formulation 21
[0240] Formulation 21 comprises antifungal (10 mg/g), phosphatidyl
choline (31.935 mg/g) as a lipid, cremophor (58.065 mg/g) as a
surfactant, lactate (pH 5) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol
(15.000 mg/g).
Example Formulation 22
[0241] Formulation 22 comprises antifungal (15 mg/g), phosphatidyl
choline (42.500 mg/g) as a lipid, cremophor (42.500 mg/g) as a
surfactant, lactate (pH 6.5) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 23
[0242] Formulation 23 comprises antifungal (10 mg/g), phosphatidyl
choline (38.276 mg/g) as a lipid, cremophor (51.724 mg/g) as a
surfactant, lactate (pH 4) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 24
[0243] Formulation 24 comprises antifungal (15 mg/g), phosphatidyl
choline (42.500 mg/g) as a lipid, cremophor (42.500 mg/g) as a
surfactant, lactate (pH 4) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 25
[0244] Formulation 25 comprises antifungal (30 mg/g), phosphatidyl
choline (85.000 mg/g) as a lipid, cremophor (85.000 mg/g) as a
surfactant, lactate (pH 4) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 26
[0245] Formulation 26 comprises antifungal (10 mg/g), phosphatidyl
choline (38.276 mg/g) as a lipid, cremophor (51.276 mg/g) as a
surfactant, lactate (pH 5) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, and EDTA
(3.000 mg/g) as a chelating agent.
Example Formulation 27
[0246] Formulation 27 comprises antifungal (15 mg/g), phosphatidyl
choline (36.429 mg/g) as a lipid, cremophor (48.571 mg/g) as a
surfactant, lactate (pH 5) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 28
[0247] Formulation 28 comprises antifungal (30 mg/g), phosphatidyl
choline (72.299 mg/g) as a lipid, cremophor (97.701 mg/g) as a
surfactant, lactate (pH 5) buffer, thimerosal (5.250 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 29
[0248] Formulation 29 comprises antifungal (7.5 mg/g), phosphatidyl
ethanolamine (46.250 mg/g) as a lipid, Tween 80 (46.250 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating
agent, and ethanol (20.000 mg/g).
Example Formulation 30
[0249] Formulation 30 comprises antifungal (15 mg/g), phosphatidyl
ethanolamine (38.804 mg/g) as a lipid, Tween 80 (46.196 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as an antioxidant, glycerol (15.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 31
[0250] Formulation 31 comprises antifungal (30 mg/g), phosphatidyl
ethanolamine (36.667 mg/g) as a lipid, Tween 80 (33.333 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, thimerosal (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 32
[0251] Formulation 32 comprises antifungal (10 mg/g), phosphatidyl
glycerol (23.333 mg/g) as a lipid, Brij 98 (66.667 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, and
EDTA (3.000 mg/g) as a chelating agent .
Example Formulation 33
[0252] Formulation 33 comprises antifungal (12.5 mg/g),
phosphatidyl glycerol (45.833 mg/g) as a lipid, Brij 98 (41.667
mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250
mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an
antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a
chelating agent.
Example Formulation 34
[0253] Formulation 34 comprises antifungal (30 mg/g), phosphatidyl
glycerol (31.957 mg/g) as a lipid, Brij 98 (38.043 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 35
[0254] Formulation 35 comprises antifungal (10 mg/g), phosphatidyl
glycerol (47.143 mg/g) as a lipid, Brij 98 (42.857 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant,
glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and
ethanol (25.000 mg/g).
Example Formulation 36
[0255] Formulation 36 comprises antifungal (15 mg/g), phosphatidyl
glycerol (96.905 mg/g) as a lipid, Brij 98 (88.095 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant,
glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and
ethanol (20.000 mg/g).
Example Formulation 37
[0256] Formulation 37 comprises antifungal (30 mg/g), phosphatidyl
glycerol (31.957 mg/g) as a lipid, Brij 98 (38.043) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, EDTA
(3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 38
[0257] Formulation 38 comprises antifungal (10 mg/g), phosphatidyl
ethanolamine (35.455 mg/g) as a lipid, cremophor (54.545 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 39
[0258] Formulation 39 comprises antifungal (15 mg/g), phosphatidyl
ethanolamine (84.457 mg/g) as a lipid, cremophor (100.543 mg/g) as
a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250
mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 40
[0259] Formulation 40 comprises antifungal (30 mg/g), phosphatidyl
ethanolamine (89.048 mg/g) as a lipid, cremophor (80.952 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g),
BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as
antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 41
[0260] Formulation 41 comprises antifungal (10 mg/g), phosphatidyl
glycerol (41.087 mg/g) as a lipid, Tween 80 (48.913 mg/g) as a
surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 42
[0261] Formulation 42 comprises antifungal (15 mg/g), phosphatidyl
glycerol (45.280 mg/g) as a lipid, Tween 80 (39.720 mg/g) as a
surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g), and EDTA (3.000 mg/g) as a chelating
agent.
Example Formulation 43
[0262] Formulation 43 comprises antifungal (30 mg/g), phosphatidyl
glycerol (107.500 mg/g) as a lipid, Tween 80 (62.500 mg/g) as a
surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 44
[0263] Formulation 44 comprises antifungal (5 mg/g), phosphatidyl
glycerol (77.243 mg/g) as a lipid, Tween 80 (67.757 mg/g) as a
surfactant, propionate (pH 4) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 45
[0264] Formulation 45 comprises antifungal (15 mg/g), phosphatidyl
glycerol (45.280 mg/g) as a lipid, Tween 80 (39.720 mg/g) as a
surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 46
[0265] Formulation 46 comprises antifungal (30 mg/g), phosphatidyl
glycerol (90.561 mg/g) as a lipid, Tween 80 (79.439 mg/g) as a
surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a
chelating agent, and ethanol (30.000 mg/g).
Example Formulation 47
[0266] Formulation 47 comprises antifungal (10 mg/g), phosphatidyl
glycerol (47.944 mg/g) as a lipid, Tween 80 (42.056 mg/g) as a
surfactant, propionate (pH 5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a
chelating agent, and ethanol (10.000 mg/g).
Example Formulation 48
[0267] Formulation 48 comprises antifungal (5 mg/g), phosphatidyl
serine (50.607 mg/g) as a lipid, Brij 98 (44.393 mg/g) as a
surfactant, phosphate (pH 5.5) buffer, thimerasol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), and EDTA
(3.000 mg/g) as a chelating agent.
Example Formulation 49
[0268] Formulation 49 comprises antifungal (30 mg/g), phosphatidyl
serine (107.500 mg/g) as a lipid, Brij 98 (62.500 mg/g) as a
surfactant, phosphate (pH 5.5) buffer, thimerasol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), and EDTA
(3.000 mg/g) as a chelating agent.
Example Formulation 50
[0269] Formulation 50 comprises antifungal (10 mg/g), phosphatidyl
serine (47.944 mg/g) as a lipid, Brij 98 (42.056 mg/g) as a
surfactant, phosphate (pH 5.5) buffer, thimerasol (5.250 mg/g) as
an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 51
[0270] Formulation 51 comprises antifungal (15 mg/g), phosphatidyl
glycerol (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol
(25.000 mg/g).
Example Formulation 52
[0271] Formulation 52 comprises antifungal (15 mg/g), phosphatidyl
glycerol (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000
mg/g) as a chelating agent, and ethanol (20.000 mg/g).
Example Formulation 53
[0272] Formulation 53 comprises antifungal (10 mg/g), phosphatidyl
glycerol (46.098 mg/g) as a lipid, Brij 98 (43.902 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol
(15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol
(30.000 mg/g).
Example Formulation 54
[0273] Formulation 54 comprises antifungal (15 mg/g), phosphatidyl
glycerol (43.537 mg/g) as a lipid, Brij 98 (41.463 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 55
[0274] Formulation 55 comprises antifungal (10 mg/g), phosphatidyl
glycerol (45.000 mg/g) as a lipid, Brij 98 (45.000 mg/g) as a
surfactant, acetate (pH 5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 56
[0275] Formulation 56 comprises antifungal (10 mg/g), phosphatidyl
glycerol (59.492 mg/g) as a lipid, Brij 98 (30.508 mg/g) as a
surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol
(30.000 mg/g).
Example Formulation 57
[0276] Formulation 57 comprises antifungal (15 mg/g), phosphatidyl
glycerol (39.054 mg/g) as a lipid, Brij 98 (45.946 mg/g) as a
surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, and EDTA
(3.000 mg/g) as a chelating agent.
Example Formulation 58
[0277] Formulation 58 comprises antifungal (30 mg/g), phosphatidyl
glycerol (35.854 mg/g) as a lipid, Brij 98 (34.146 mg/g) as a
surfactant, acetate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol
(30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 59
[0278] Formulation 59 comprises antifungal (10 mg/g), phosphatidyl
choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 60
[0279] Formulation 60 comprises antifungal (10 mg/g), phosphatidyl
choline (38.571 mg/g) as a lipid, Tween 80 (51.429 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g), and ethanol (30.000 mg/g).
Example Formulation 61
[0280] Formulation 61 comprises antifungal (7.5 mg/g), phosphatidyl
choline (41.954 mg/g) as phospholipid, Tween 80 (50.546 mg/g) as
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g), and ethanol (30.000 mg/g).
Example Formulation 62
[0281] Formulation 62 comprises antifungal (10 mg/g), phosphatidyl
choline (42.632 mg/g) as a lipid, Tween 80 (47.368 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 63
[0282] Formulation 63 comprises antifungal (10 mg/g), phosphatidyl
choline (46.098 mg/g) as a lipid, Tween 80 (43.902 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 64
[0283] Formulation 64 comprises antifungal (10 mg/g), phosphatidyl
choline (39.721 mg/g) as a lipid, Tween 80 (50.279 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 65
[0284] Formulation 65 comprises antifungal (5 mg/g), phosphatidyl
choline (44.198 mg/g) as a lipid, Tween 80 (50.802 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 66
[0285] Formulation 66 comprises antifungal (2.5 mg/g), phosphatidyl
choline (46.453 mg/g) as a lipid, Tween 80 (51.047 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 67
[0286] Formulation 67 comprises antifungal (5 mg/g), phosphatidyl
choline (51.221 mg/g) as a lipid, Tween 80 (43.779 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 68
[0287] Formulation 68 comprises antifungal (2.5 mg/g), phosphatidyl
choline (54.167 mg/g) as a lipid, Tween 80 (43.333 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 69
[0288] Formulation 69 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example
formulation 69 is an emulsion.
Example Formulation 70
[0289] Formulation 70 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example
formulation 70 is a suspension.
Example Formulation 71
[0290] Formulation 71 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 72
[0291] Formulation 72 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example
formulation 72 is an emulsion.
Example Formulation 73
[0292] Formulation 73 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example
formulation 73 is a suspension.
Example Formulation 74
[0293] Formulation 74 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 75
[0294] Formulation 75 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, paraben (5.250 mg/g) as an
antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 76
[0295] Formulation 76 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Brij 98 (50.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.250
mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 77
[0296] Formulation 77 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, paraben (5.250 mg/g) as an
antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 78
[0297] Formulation 78 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.250
mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 79
[0298] Formulation 79 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.250 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 80
[0299] Formulation 80 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 81
[0300] Formulation 81 comprises antifungal (10 mg/g), phosphatidyl
choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a
surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 82
[0301] Formulation 82 comprises antifungal (10 mg/g), phosphatidyl
choline (44.444 mg/g) as a lipid, Tween 80 (55.556 mg/g) as a
surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 83
[0302] Formulation 83 comprises antifungal (10 mg/g), phosphatidyl
choline (66.440 mg/g) as a lipid, Tween 80 (23.560 mg/g) as a
surfactant, acetate (pH 5.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 84
[0303] Formulation 84 comprises antifungal (10 mg/g), phosphatidyl
choline (54.000 mg/g) as a lipid, Tween 80 (36.000 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 85
[0304] Formulation 85 comprises antifungal (10 mg/g), phosphatidyl
choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 86
[0305] Formulation 86 comprises antifungal (12.5 mg/g),
phosphatidyl choline (48.611 mg/g) as a lipid, Tween 80 (38.889
mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250
mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 87
[0306] Formulation 87 comprises antifungal (15 mg/g), phosphatidyl
choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g). Example formulation
87 is an emulsion.
Example Formulation 88
[0307] Formulation 88 comprises antifungal (15 mg/g), phosphatidyl
choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g). Example formulation
88 is suspension.
Example Formulation 89
[0308] Formulation 89 comprises antifungal (15 mg/g), phosphatidyl
choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 90
[0309] Formulation 90 comprises antifungal (10 mg/g), phosphatidyl
choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a
surfactant, acetate (pH 4.5) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 91
[0310] Formulation 91 comprises antifungal (30 mg/g), phosphatidyl
choline (94.444 mg/g) as a lipid, Tween 80 (75.556 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 92
[0311] Formulation 92 comprises antifungal (15 mg/g), phosphatidyl
choline (46.712 mg/g) as a lipid, Tween 80 (38.288 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 93
[0312] Formulation 93 comprises antifungal (12 mg/g), phosphatidyl
choline (48.889 mg/g) as a lipid, Tween 80 (39.111 mg/g) as a
surfactant, acetate (pH 4) buffer, benzyl alcohol (5.250 mg/g) as
an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500
mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as
a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 94
[0313] Formulation 94 comprises antifungal (10 mg/g), phosphatidyl
choline (39.721 mg/g) as a lipid, Tween 80 (50.279 mg/g) as a
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.25 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000
mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 95
[0314] Formulation 95 comprises antifungal (10 mg/g), phosphatidyl
choline (90.000 mg/g) as a lipid, phosphate buffer (pH 6.5), benzyl
alcohol as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g),
EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000
mg/g).
Example Formulation 96
[0315] Formulation 96 comprises antifungal (15 mg/g), phosphatidyl
choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, and EDTA (3.000 mg/g)
as a chelating agent. Example formulation 96 is an emulsion.
Example Formulation 97
[0316] Formulation 97 comprises antifungal (15 mg/g), phosphatidyl
choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, and EDTA (3.000 mg/g).
Example formulation 97 is a suspension.
Example Formulation 98
[0317] Formulation 98 comprises antifungal (15 mg/g), phosphatidyl
choline (54.643 mg/g) as a lipid, Tween 80 (30.357 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, and EDTA (3.000 mg/g)
as a chelating agent.
Example Formulation 99
[0318] Formulation 99 comprises antifungal (10 mg/g), phosphatidyl
choline (39.72 mg/g) as a lipid, Tween 80 (50.279 mg/g) as
surfactant, phosphate (pH 6.5) buffer, benzyl alcohol (5.25 mg/g)
as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g) as emollient,
EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000
mg/g).
Example Formulation 100
[0319] Formulation 100 comprises antifungal (10 mg/g), phosphatidyl
choline (90.00 mg/g) as a lipid, phosphate (pH 6.5) buffer, benzyl
alcohol as antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite
(0.500 mg/g) as antioxidants, glycerol (30.000 mg/g) as emollient,
EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000
mg/g).
Example Formulation 101
[0320] Formulation 101 comprises antifungal (15 mg/g), phosphatidyl
choline (46.57 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, and EDTA (3.000 mg/g)
as the chelating agent. Formulation 101 is formulated as an
emulsion.
Example Formulation 102
[0321] Formulation 102 comprises antifungal (15 mg/g), phosphatidyl
choline (46.57 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, and EDTA (3.000 mg/g)
as the chelating agent. Formulation 102 as a suspension.
Example Formulation 103
[0322] Formulation 103 comprises antifungal (15 mg/g), phosphatidyl
choline (54.64 mg/g) as a lipid, Tween 80 (30.357 mg/g) as a
surfactant, phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium
metabisulfite (0.200 mg/g) as antioxidants, EDTA (3.000 mg/g) as
the chelating agent.
Example Formulation 104
[0323] Formulation 104 comprises antifungal (6.1 mg/g),
phosphatidyl choline (46.58 mg/g) as a lipid, Tween 80 (38.43 mg/g)
as a surfactant, benzyl alcohol (5.25 mg/g) as an antimicrobial,
phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the chelating
agent, ethanol (30.000 mg/g), and optionally BHA (0.500 mg/g) and
sodium metabisulfite (0.200 mg/g) as antioxidants.
Example Formulation 105
[0324] Formulation 105 comprises antifungal (6.1 mg/g),
phosphatidyl choline (64.52 mg/g) as a lipid, Tween 80 (35.484
mg/g) as a surfactant, benzyl alcohol (5.25 mg/g) as an
antimicrobial, phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the
chelating agent, ethanol (30.000 mg/g), and optionally BHA (0.500
mg/g) and sodium metabisulfite (0.200 mg/g) as antioxidants.
Example Formulation 106
[0325] Formulation 106 comprises antifungal (6.1 mg/g),
phosphatidyl choline (66.44 mg/g) as a lipid, Tween 80 (23.56 mg/g)
as a surfactant, benzyl alcohol (5.25 mg/g) as an antimicrobial,
phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the chelating
agent, ethanol (30.000 mg/g), and optionally BHA (0.500 mg/g) and
sodium metabisulfite (0.200 mg/g) as antioxidants.
Example Formulation 107
[0326] Formulation 107 comprises antifungal (10 mg/g), phosphatidyl
choline (46.58 mg/g) as a lipid, Tween 80 (38.43 mg/g) as a
surfactant, benzyl alcohol (5.25 mg/g) as an antimicrobial,
phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the chelating
agent, ethanol (30.000 mg/g), and optionally BHA (0.500 mg/g) and
sodium metabisulfite (0.200 mg/g) as antioxidants.
Example Formulation 108
[0327] Formulation 105 comprises antifungal (10 mg/g), phosphatidyl
choline (64.52 mg/g) as a lipid, Tween 80 (35.484 mg/g) as a
surfactant, benzyl alcohol (5.25 mg/g) as an antimicrobial,
phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the chelating
agent, ethanol (30.000 mg/g), and optionally BHA (0.500 mg/g) and
sodium metabisulfite (0.200 mg/g) as antioxidants.
Example Formulation 109
[0328] Formulation 109 comprises antifungal (10 mg/g), phosphatidyl
choline (66.44 mg/g) as a lipid, Tween 80 (23.56 mg/g) as a
surfactant, benzyl alcohol (5.25 mg/g) as an antimicrobial,
phosphate (pH 6.5) buffer, EDTA (3.000 mg/g) as the chelating
agent, ethanol (30.000 mg/g), and optionally BHA (0.500 mg/g) and
sodium metabisulfite (0.200 mg/g) as antioxidants.
[0329] Example Formulations 1 through 109 may also optionally
include thickeners such as pectin, xanthan gum, HPMC gel,
methylcellulose or carbopol. Example Formulations 1 through 103 may
contain antifungal, salts of antifungal, or derivatives or analogs
of terbinanfine.
[0330] Example Formulations 1 through 109 may be prepared using any
antifungal disclosed herein, e.g., terbinafine, salts of
terbinafine, or derivatives or analogs of terbinafine.
Example 2
In-Vivo Study of Antifungal Formulation Efficacy and
Pharmacokinetics
[0331] The efficacy and pharmacokinetics of topical antifungal
formulations containing terbinafine were studied for the treatment
of onychomycosis. The first purpose of the study was to determine
the mycological cure rate after 12 weeks of treatment with the
terbinafine formulations disclosed herein. The terbinafine
formulations were administered to each subject on two target areas,
such that 3.0 mg terbinafine is delivered to each target area twice
daily (b.i.d.) for 12 weeks of application. After 12 weeks of
continuous application patients discontinued treatment. The target
area was defined as a 20 cm.sup.2 area on and around each infected
toe nail. Two weeks after discontinuing treatment (week 14 of the
study), nail specimens were examined microscopically, followed by
mycological culture and evaluation.
[0332] 5.1.1. Measurements for Evaluating the Mycological Cure
Rate
[0333] The mycological cure rate is defined by negative microscopy
of potassium hydroxide (KOH) samples and negative culture for
dermatophytes.
[0334] Mycological samples are taken from the patients. A central
laboratory is used for processing the mycological samples. Patients
may have an additional screening visit if the KOH microscopy is
positive and the culture is negative for dermatophytes so they can
be recultured. If the result of repeat culture is positive for
dermatophytes, the patient can be enrolled as long as he/she is
within approximately 3 weeks from screening visit.
Specimen Collection
[0335] To collect nail clippings for analysis, a Mycotrans
collection envelope was positioned under the nail. The target nail
was clipped using a nail clipper as far back as possible from the
free edge of the target toenail without excessive patient
discomfort. The crumbling subungual debris from under the trimmed
edge of the nail was collected by scraping. The hyperkeratotic nail
bed and subungual debris was included in the sample. Samples were
also collected from any discolored, dystrophic or brittle parts of
the large target toenail.
[0336] A KOH wet mount microscopy and a mycological culture for
dermatophytes of the target toenail specimen was performed on the
mycological samples. Samples of clinical specimens were plated onto
Selective agar for pathogenic fungi, Merck, Darmstadt, Germany
(product no.: 1.10415.0001) in order to isolate and identify the
following species: T. rubrum, T. interdigitale, T. tonsurans, and
other pathogenic dermatophytes, as well as C. albicans, and S.
brevicaulis. Plates were incubated at 28.degree. C. for one to four
weeks, examined weekly, and suspicious colonies are examined
microscopically and/or bio chemically tested for
identification.
[0337] The mycological cure rate was determined for 81 toe nails,
14-weeks after the initiation of treatments with terbinafine
formulations, and two weeks after treatment was completed. Of the
81 infected toe nails, 73 demonstrated complete mycological cure,
while 8 did not. A summary of the data is shown in Table 9.
TABLE-US-00009 TABLE 9 Mycological Cure Rate at 14-weeks Exact
Confidence Limits for Proportions Mycological % of 90% CI cure
(imputed) N Total Exact yes 73 90.12 [82.88, 94.99] no 8 9.88
[5.01, 17.12] Total 81 100.0
[0338] 5.1.2. Determination of Terbinafine Serum and Nail Tissue
Concentrations
[0339] The pharmacokinetics of topical terbinafine formulations
were studied as well. The purpose of this study was to determine
the terbinafine concentration in the serum and in target nail
tissue for subjects who were administered topical terbinafine
formulations.
[0340] Blood samples (2.7 ml) for the determination of terbinafine
concentrations in serum were taken before the first application (0
hour) and 0.5, 1, 2, 4, 8, and 12 hours after administration of a
6.0 mg dose of topical terbinafine. The sample 12 hours following
the first administration was taken before the second daily
administration of the topical terbinafine formulation.
[0341] Serum samples for terbinafine were analyzed by LC-MSMS. The
internal standard used was naftifine. Samples were prepared by
adding 50 .mu.L serum to 50 .mu.L methanol and 300 .mu.L of
internal standard solution (50 .mu.g/L naftifine in 9:1
acetonitrile/methanol solution). The solution was allowed to stand
for 5 minutes, and then subjected to centrifugation. After
centrifugation, 50 .mu.L of the supernatant was added to 450 .mu.L
of the mobile phase solution.
[0342] The serum concentrations were measured at day 1 and week 12
of the study. For all individuals at each time point test, the
serum samples were shown to contain less than 1 ng/ml terbinafine
at steady state and for all trough levels.
[0343] The concentration of terbinafine in target nails that were
treated with the topical terbinafine formulations of the invention
was also determined. The collected nail clippings were subjected to
alkaline hydrolysis, followed by extraction with hexane. All
samples were diluted 1:100. The terbinafine concentration was then
determined by LC-MSMS. Nail samples that were collected for this
study showed a mean value of 3.4 mg/g nail tissue (STD 2.9) at week
14 of the study, which was two weeks after the cessation of
administration of the topical terbinafine formulation. The median
value for the data collected at this time was 2.3 mg/g nail tissue
and the geometric mean was 2.4 mg/g nail tissue.
[0344] 5.1.3. Evaluation of the Clinical Cure
[0345] Clinical cure is defined by normal growth of the toe nails
of at least 2 mm after 24 weeks using standard methods known in the
art (see, e.g., Tavakkol, et. al. The American Journal of Geriatric
Pharmacotherapy. 2006; 4: 1-13). For assessment of clinical cure
rate the length of the nails from the visible proximal margin of
nail is measured and evaluated whether and how many mm of the nail
growth is normal. In case of a normal nail growth of 2 mm (at week
24) from the proximal margin the nail is considered to be
cured.
[0346] 5.1.4. Conclusion
[0347] These results demonstrate that the antifungal formulations
disclosed herein, comprising one or more antifungal (e.g.,
terbinafine), a lipid and a surfactant, are effective in treating
onychomycosis in a human subject when administered topically to the
nail plate and the surrounding skin. The antinfungal formulations
are able to effectively provide greater than 90% mycological cure
rate in human subjects suffering from onychomycosis. The topical
antifungal formulations provide an effective treatment for
onychomycosis where prior topical formulations of antifungals have
demonstrated to be ineffective in successfully curing the nail
infection.
* * * * *