U.S. patent application number 17/402807 was filed with the patent office on 2022-04-07 for chemical compositions and methods for enhancing transdermal delivery of therapeutic agents.
The applicant listed for this patent is InteguRx Therapeutics, LLC. Invention is credited to Agis Kydonieus, Kirti H. Valia.
Application Number | 20220105075 17/402807 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-07 |
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United States Patent
Application |
20220105075 |
Kind Code |
A1 |
Valia; Kirti H. ; et
al. |
April 7, 2022 |
CHEMICAL COMPOSITIONS AND METHODS FOR ENHANCING TRANSDERMAL
DELIVERY OF THERAPEUTIC AGENTS
Abstract
The present application discloses chemical compositions and
methods for enhancing the transdermal permeation of therapeutic
agents through skin. The chemical compositions and methods of the
invention can include combinations of a first fatty acid having
about 14 or more carbon atoms and a second fatty acid having about
10 or less carbon atoms. These compositions are useful for the
delivery of therapeutic agents, in particular hard to deliver drugs
such as those that have fused rings, including ondansetron, and
large drugs such as peptides. The compositions of the invention can
be formulated as transdermal gels, lotions, creams, transdermal
patches, sprays or mists.
Inventors: |
Valia; Kirti H.;
(Plainsboro, NJ) ; Kydonieus; Agis; (Kendall Park,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
InteguRx Therapeutics, LLC |
Califon |
NJ |
US |
|
|
Appl. No.: |
17/402807 |
Filed: |
August 16, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16716857 |
Dec 17, 2019 |
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17402807 |
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14858097 |
Sep 18, 2015 |
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16716857 |
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14168571 |
Jan 30, 2014 |
9186352 |
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14858097 |
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PCT/US2013/056391 |
Aug 23, 2013 |
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14168571 |
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61693135 |
Aug 24, 2012 |
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61777276 |
Mar 12, 2013 |
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International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61K 9/00 20060101 A61K009/00; A61K 47/12 20060101
A61K047/12; A61K 9/08 20060101 A61K009/08; A61K 31/439 20060101
A61K031/439; A61K 31/46 20060101 A61K031/46; A61K 31/4709 20060101
A61K031/4709; A61K 9/70 20060101 A61K009/70 |
Claims
1. A composition comprising an anti-coagulant, oleic acid, and
levulinic acid.
2. The composition of claim 1, comprising about 0.1% to about 30%,
by weight of the composition, of the oleic acid.
3. The composition of claim 1, comprising about 2.5% to about 7.5%,
by weight of the composition, of the oleic acid.
4. The composition of claim 1, comprising about 1% to about 5%, by
weight of the composition, of the oleic acid.
5. The composition of claim 1, comprising about 0.1% to about 30%,
by weight of the composition, of the levulinic acid.
6. The composition of claim 1, comprising about 1% to about 5%, by
weight of the composition, of the levulinic acid.
7. The composition of claim 1, comprising about 0.5% to about 2.5%,
by weight of the composition, of the levulinic acid.
8. The composition of claim 1, that is for use on human skin.
9. A transdermal patch comprising a composition comprising an
anti-coagulant, oleic acid, and levulinic acid.
10. The transdermal patch of claim 9, comprising about 0.1% to
about 30%, by weight of the composition, of the oleic acid.
11. The transdermal patch of claim 9, comprising about 2.5% to
about 7.5%, by weight of the composition, of the oleic acid.
12. The transdermal patch of claim 9, comprising about 1% to about
5%, by weight of the composition, of the oleic acid.
13. The transdermal patch of claim 9, comprising about 0.1% to
about 30%, by weight of the composition, of the levulinic acid.
14. The transdermal patch of claim 9, comprising about 1% to about
5%, by weight of the composition, of the levulinic acid.
15. The transdermal patch of claim 9, comprising about 0.5% to
about 2.5%, by weight of the composition, of the levulinic
acid.
16. The transdermal patch of claim 9, that is for use on human
skin.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/716,857, filed Dec. 17, 2019, which is a
continuation of U.S. patent application Ser. No. 14/858,097, filed
Sep. 18, 2015, which is a continuation of U.S. patent application
Ser. No. 14/168,571, filed Jan. 30, 2014, which is a
continuation-in-part of International Patent Application No.
PCT/US2013/056391, filed Aug. 23, 2013, which claims priority to
U.S. Provisional Patent Application No. 61/693,135 filed Aug. 24,
2012 and U.S. Provisional Patent Application No. 61/777,276 filed
Mar. 12, 2013, the entireties of which are incorporated by
reference herein for all purposes.
TECHNICAL FIELD
[0002] The present disclosure relates generally to the field of
transdermal delivery of therapeutic agents. More specifically, the
present disclosure relates to chemical compositions and methods
used to enhance the transdermal permeation of therapeutic
agents.
BACKGROUND
[0003] Fatty acids are known as chemical enhancers in the field of
transdermal delivery. Various fatty acids have been used to enhance
the delivery of several drugs. The list of fatty acids used is
extensive and encompasses saturated fatty acids such as capric
acid, unsaturated fatty acids such as linoleic acid, and branched
fatty acids C6 to C18, such as isostearic acid. Hydroxy fatty acids
such as 2-hydroxyoctanoic acid are known to plasticize the skin,
but they have not been explored for their effect on the skin
permeation of drugs.
[0004] The effect of the different fatty acids on the permeation of
drugs through skin is not well understood and it depends upon the
vehicle, the drug used and the structure and concentration of the
fatty acid. For example, oleic acid has been used to increase the
permeability of acyclovir, tetrahydrocannabinol, mannitol and
dihydroergotamine. Lauric acid has been used to increase the
permeation of naloxone, dihydroergotamine and leuprolide. The
enhancement ratio for naloxone's skin permeation using lauric acid
as the enhancer were 150, 25, 15, 10 and 3 when the vehicle was
propylene glycol, PEG 400, mineral oil, isopropanol and isopropyl
myristate respectively. What is significant from the above
references is the fact that the fatty acids increased the skin
permeability by orders of magnitude for some drugs, whereas under
similar experimental conditions the skin permeation of other
compounds was not affected much at all. This supports the
understanding that chemical enhancement is still more of an art
than science. Therefore, the enhancement cannot be predicted from
the properties of the drug and the fatty acid or that of the
vehicle.
[0005] In general the skin permeation enhancement by saturated
fatty acids is best for C10 and C12 fatty acids. C18 unsaturated
fatty acids appear to be better than saturated ones but it is not
clear that the same relationship is true for medium and low
molecular weight fatty acids. In the studies trying to determine
the effect of branching on skin permeation no difference was
observed between branched and linear fatty acids except on some
occasions. Increase in the concentration of the fatty acid in the
formulation did not show a linear response either.
[0006] However, concentrations between 2 and 10% can be used to
increase permeation and also to limit the skin irritation that can
be caused by fatty acids.
[0007] It has now been found that the compositions of two fatty
acids having different molecular weights of the present invention
have a synergistic effect and increase the transdermal permeation
of therapeutic agents to a surprising degree.
SUMMARY
[0008] Various embodiments of a composition to enhance the
transdermal permeation of a therapeutic agent are disclosed. In one
embodiment the composition comprises a first fatty acid, or
derivative or congener thereof, comprising about 14 or more carbon
atoms and a second fatty acid, or derivative or congener thereof,
comprising about 10 or less carbon atoms.
[0009] In another embodiment the composition comprises a first
fatty acid and a second fatty acid, wherein the first and second
fatty acids comprise a different number of carbon atoms. The
composition can include a first fatty acid comprising about 14 or
more carbon atoms and a second fatty acid comprising about 12 or
less carbon atoms.
[0010] In another embodiment the composition comprises a first
fatty acid, or derivative or congener thereof, a second fatty acid,
or derivative or congener thereof, and a therapeutic agent, wherein
the first fatty acid comprises about 14 or more carbon atoms and
the second fatty acid comprises about 10 or less carbon atoms.
[0011] Methods for treating a patient in need thereof are also
disclosed. In one embodiment the method for treating a patient in
need thereof comprises administering to a patient's skin a
composition comprising a first fatty acid, or derivative or
congener thereof, a second fatty acid, or derivative or congener
thereof, and a therapeutic agent, wherein the first fatty acid
comprises about 14 or more carbon atoms and the second fatty acid
comprises about 10 or less carbon atoms.
[0012] In one embodiment the method for treating a patient in need
thereof comprises administering to a patient's skin a composition
comprising a first fatty acid, a second fatty acid, and a
therapeutic agent, wherein the first fatty acid comprises about 14
or more carbon atoms and the second fatty acid comprises about 12
or less carbon atoms.
[0013] Methods for use of a composition are also disclosed. In one
embodiment the use of a composition comprising a first fatty acid,
or derivative or congener thereof, a second fatty acid, or
derivative or congener thereof, and a therapeutic agent comprises
the manufacture of a medicant for treating a disease or condition,
wherein the first fatty acid comprises about 14 or more carbon
atoms and the second fatty acid comprises about 10 or less carbon
atoms.
[0014] In one embodiment the use of a composition comprising a
first fatty acid, a second fatty acid, and a therapeutic agent
comprises the manufacture of a medicant for treating a disease or
condition, wherein the first fatty acid comprises about 14 or more
carbon atoms and the second fatty acid comprises about 12 or less
carbon atoms.
[0015] The general description and the following detailed
description are exemplary and explanatory only and are not
restrictive of the invention, as defined in the appended claims.
Other aspects of the present invention will be apparent to those
skilled in the art in view of the detailed description of the
invention as provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The summary, as well as the following detailed description,
is further understood when read in conjunction with the appended
drawings. For the purpose of illustrating the invention, there are
shown in the drawings exemplary embodiments of the invention;
however, the invention is not limited to the specific methods,
compositions, and devices disclosed. In addition, the drawings are
not necessarily drawn to scale. In the drawings:
[0017] FIG. 1 illustrates average cumulative amount of ondansetron
base that permeated through human skin over a 24 hour period
without the benefit of the present invention;
[0018] FIG. 2 illustrates average skin diffusion rate of
ondansetron base that permeated through human skin over a 24 hour
period without the benefit of the present invention;
[0019] FIG. 3 illustrates average cumulative amount of ondansetron
base that permeated through human skin over a 24 hour period when
provided in accordance with an embodiment of the present
invention;
[0020] FIG. 4 illustrates average diffusion rate of ondansetron
base that permeated through human skin over a 24 hour period when
provided in accordance with an embodiment of the present
invention;
[0021] FIG. 5 illustrates average cumulative amount of ondansetron
base that permeated through human skin over a 24 hour period when
provided in accordance with embodiments of the present
invention;
[0022] FIG. 6 illustrates average cumulative amount of ondansetron
base that permeated through human skin over a 24 hour period when
provided in accordance with embodiments of the present
invention;
[0023] FIG. 7 illustrates average cumulative amount of ondansetron
base that permeated through human skin over a 24 hour period when
provided in accordance with embodiments of the present
invention;
[0024] FIG. 8 illustrates average flux of ondansetron permeation
through human skin in accordance with embodiments of the present
invention;
[0025] FIG. 9 illustrates average flux of ondansetron permeation
through human skin in a finite dose study;
[0026] FIG. 10 illustrates average cumulative amount of ondansetron
permeated through human skin in a finite dose study;
[0027] FIG. 11 illustrates average flux of ondansetron permeation
through human skin in an infinite dose study; and
[0028] FIG. 12 illustrates average cumulative amount of ondansetron
permeated through human skin in an infinite dose study.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0029] The present invention may be understood more readily by
reference to the following detailed description taken in connection
with the accompanying figures and examples, which form a part of
this disclosure. It is to be understood that this invention is not
limited to the specific devices, methods, applications, conditions
or parameters described and/or shown herein, and that the
terminology used herein is for the purpose of describing particular
embodiments by way of example only and is not intended to be
limiting of the claimed invention. Also, as used in the
specification including the appended claims, the singular forms
"a," "an," and "the" include the plural, and reference to a
particular numerical value includes at least that particular value,
unless the context clearly dictates otherwise. The term
"plurality", as used herein, means more than one. When a range of
values is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another embodiment. All ranges are inclusive and
combinable.
[0030] It is to be appreciated that certain features of the
invention which are, for clarity, described herein in the context
of separate embodiments, may also be provided in combination in a
single embodiment. Conversely, various features of the invention
that are, for brevity, described in the context of a single
embodiment, may also be provided separately or in any
subcombination. Further, reference to values stated in ranges
include each and every value within that range. It is further noted
that the claims may be drafted to exclude any optional element. As
such, this statement is intended to serve as antecedent basis for
use of such exclusive terminology as "solely," "only" and the like
in connection with the recitation of claim elements, or use of a
"negative" limitation. Finally, while an embodiment may be
described as part of a series of steps or part of a more general
structure, each said step may also be considered an independent
embodiment in itself.
[0031] It has now been observed that when two fatty acids of
different molecular weights are used together as a composition for
enhancing transdermal permeation of a drug or biologic, the
permeation through human skin is increased by orders of magnitude
more than when each of the fatty acids is used alone. Surprisingly,
when a composition including a low molecular weight fatty acid and
a high molecular weight fatty acid is used in combination with a
drug, there is an extremely high increase in transdermal permeation
of the drug.
[0032] In particular, and as further demonstrated in the examples,
when oleic acid and levulinic acid are used together, at the same
concentration as when oleic acid or levulinic acid is used
separately, the cumulative amount of the ondansetron that permeated
through human skin increased a) 450-fold over the unenhanced
formulation, b) 255-fold over the formulation containing only
levulinic acid, c) 32-fold over a commercially available
ondansetron organogel and d) 9-fold over the formulation containing
only oleic acid.
[0033] Without limiting the invention to a particular mechanism of
action, it can now be hypothesized that the low molecular weight
fatty acids permeate into the lipid bilayers of the skin and
rapidly plasticize them. This allows for the larger lipids to
penetrate into the bilayers much more easily and in larger
quantities and thus disrupt the ordered structure of intercellular
bilayers, thus allowing greater drug permeation.
[0034] In accordance with an aspect of the present invention, there
are provided compositions that include a combination of two or more
fatty acids having different molecular weights. These compositions
are useful for enhancing the transdermal permeation of a
therapeutic agent. In particular, the invention provides for the
use of a combination enhancing system comprising a low molecular
weight fatty acid and a higher molecular weight fatty acid to
increase the transdermal permeation of difficult-to-deliver drugs
and biologics. The high molecular weight fatty acid and low
molecular weight fatty acids may be characterized by the number of
carbon atoms present in the hydrocarbon chain of the fatty acid.
Ondansetron is one such drug that has enhanced transdermal
permeation when delivered in accordance with compositions or
methods of the invention.
[0035] As used herein, the term "transdermal permeation" includes
both percutaneous delivery and transmucosal delivery, that is,
passage through skin or mucosal tissue and into the
bloodstream.
[0036] As used herein in reference to transdermal penetration, the
term "enhancing" refers to increasing the rate at which a
therapeutic agent penetrates the skin or mucosal tissue and enters
the bloodstream.
[0037] As used herein, the term "fatty acid" has its ordinary
meaning as would be understood by a person of ordinary skill in the
art and includes a molecule having a carboxylic group and a
hydrocarbon chain. Descriptions of the number of carbon atoms in a
fatty acid herein refer to the number of carbon atoms in the
hydrocarbon chain of the fatty acid, irrespective of whether the
hydrocarbon chain is straight or branched.
[0038] As used herein, the term "fatty acid" includes saturated
fatty acids, which do not contain any double or triple bonds in the
hydrocarbon chain. Saturated fatty acids include, but are not
limited to propionic acid (C3) (by way of example, C3 indicates
propionic acid has 3 carbon atoms in its hydrocarbon chain; the
number of carbon atoms in the hydrocarbon chain of other example
fatty acids is denoted in analogous fashion herein), butyric acid
(C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7),
caprylic acid (C8), pelargonic acid (C9), capric acid (C10),
undecylic acid (C11), lauric acid (C12), tridecylic acid (C13),
myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16),
margaric acid (C17), stearic acid (C18), isostearic acid (C18),
nonadecylic acid (C19), arachidic acid (C20), heneicosylic acid
(C21), behenic acid (C22), tricosylic acid (C23), lignoceric acid
(C24), pentacosylic acid (C25), cerotic acid (C26), heptacosylic
acid (C27), montanic acid (C28), nonacocylic acid (C29), melissic
acid (C30), henatriacontylic acid (C31), lacceroic acid (C32),
psyllic acid (C33), geddic acid (C34), ceroplastic acid (C35) and
hexatriacontylic acid (C36).
[0039] As used herein, the term "fatty acid" also includes
monounsaturated fatty acids, which contain one double or triple
bond in the hydrocarbon chain, and polyunsaturated fatty acids,
which contain more than one double and/or triple bond in the
hydrocarbon chain. Such acids include, but are not limited to the
omega 3, omega 6, omega 9 fatty acids, other fatty acids such as
myristoleic and palmitoleic acid and conjugated fatty acids.
Examples of monounsaturated and polyunsaturated fatty acids include
but are not limited to, (a) omega 3 fatty acids, such as
hexadecatrienoic acid (C16:3); (by way of example, C16:3 indicates
hexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain
and 3 double bonds; the number of carbon atoms and double bonds in
the hydrocarbon chain of other example unsaturated fatty acids is
denoted in analogous fashion herein), alpha linolenic acid (C18:3)
and eicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as
linoleic acid (18:2), docosadienoic acid (C22:2), arachidonic acid
(C20:4) and tetracosatetraenoic acid (C24:5), (c) omega 9 fatty
acids, such as oleic acid (C18:1), eicosenoic acid (C20:1) and
nevronic acid (C24:1), and (d) conjugated fatty acids such as
rumenic acid (C18:2), eleostatic acid (C18:3), and rumelenic acid
(C18:3).
[0040] As used herein, the term "fatty acid" also includes branched
fatty acids. Examples of branched fatty acids include, but are not
limited to, monomethyl branched fatty acids, such as 14-methyl
pentadecanoic acid, 6-methyl caprylic acid, 4-methyl-3-pentenoic
acid, (pyroterebic acid), 2-methyl-2E-butenoic acid (tiglic acid),
2-methyl-2Z-butenoic acid (angelic acid), multimethyl branched
acids, isoprenoid fatty acids (vittatalactone, all-trans-retinoic
acid), branched methoxy fatty acids and hydroxy and other fatty
acids such as 2-hydroxyoctanoic acid and 4-oxopentanoic acid
(levulinic acid).
[0041] As used herein, the term "keto acid" refers to a fatty acid
having a ketone moiety.
[0042] As used herein, the term "amino acid" refers to a fatty acid
having an amine group.
[0043] As used herein, the term "derivative" has its ordinary
meaning as would be understood by a person of skill in the art.
With reference to a fatty acid, the term "derivative" includes, but
is not limited to, a substituted fatty acid and an ester formed
from the carboxylic acid group on a fatty acid. Fatty acid
derivatives include, but are not limited to, methyl oleate, ethyl
oleate, and methyl linoleate. Other fatty acid derivatives include,
for example, glycerol monooleate.
[0044] Fatty acid derivatives also include fatty alcohols such as,
for example, lauryl alcohol, stearyl alcohol, and Oleyl alcohol.
Oleyl alcohol is a particularly preferred fatty acid
derivative.
[0045] As used herein, the term "congener" has its ordinary meaning
as would be understood by a person of skill in the art, including
in the present context referring to a fatty acid having the same
basic molecular structure as the reference fatty acid but having a
different number of substitutions or being substituted at a
different position.
[0046] As used herein, the term "therapeutic agent" refers to a
compound that, upon administration to a patient in a
therapeutically effective amount, provides a therapeutic benefit to
the patient. A therapeutic agent may be referred to herein as a
drug or biologic. Those skilled in the art will appreciate that the
term "therapeutic agent" is not limited to drugs or biologics that
have received regulatory approval.
[0047] In the present disclosure the singular forms "a," "an," and
"the" include the plural reference, and reference to a particular
numerical value includes at least that particular value, unless the
context clearly indicates otherwise. Thus, for example, a reference
to "a therapeutic agent" is a reference to at least one of such
therapeutic agents and equivalents thereof known to those skilled
in the art, and so forth.
[0048] When values are expressed as approximations by use of the
antecedent "about," it will be understood that the particular value
forms another embodiment. In general, use of the term "about"
indicates approximations that can vary depending on the desired
properties sought to be obtained by the disclosed subject matter
and is to be interpreted in the specific context in which it is
used, based on its function, and the person skilled in the art will
be able to interpret it as such. In some cases, the number of
significant figures used for a particular value may be one
non-limiting method of determining the extent of the word "about."
In other cases, the gradations used in a series of values may be
used to determine the intended range available to the term "about"
for each value.
[0049] In an embodiment of the invention a composition includes a
first fatty acid, or derivative or congener thereof, that has a
molecular structure made up of about 14 or more carbon atoms and a
second fatty acid, or derivative or congener thereof, that has a
molecular structure made up of about 10 or less carbon atoms. The
first fatty acid may be any fatty acid having about 14 or more
carbon atoms. In some embodiments the first fatty acid has about 15
or more carbon atoms and in other embodiments the first fatty acid
has about 16 or more carbon atoms. In particular, the first fatty
acid may be saturated, monounsaturated or polyunsaturated. The
hydrocarbon chain of the first fatty acid may be straight or
branched. In a preferred embodiment the first fatty acid is one or
more of oleic acid, linolenic acid, linoleic acid, myristoleic
acid, palmitoleic acid, or erucic acid. The second fatty acid may
be any fatty acid having about 10 or less carbon atoms. In some
embodiments the second fatty acid has about 9 or less carbon atoms
and in other embodiments the second fatty acid has about 8 or less
carbon atoms. In particular, the second fatty acid may be
saturated, monounsaturated or polyunsaturated. The second fatty
acid may be a keto acid or an amino acid. The hydrocarbon chain of
the second fatty acid may be straight or branched. In a preferred
embodiment the first fatty acid is an unsaturated fatty acid and
the second fatty acid is a saturated or branched fatty acid.
Preferable unsaturated fatty acids include oleic acid, linoleic
acid, and linolenic acid. Preferable saturated or branched fatty
acids include 2-hydroxyoctanoic acid and 4-oxopentanoic acid. In a
preferred embodiment the second fatty acid is one or more of
levulinic acid, 2-hydroxyoctanoic acid, 4-oxopentanoic acid,
propionic acid, valeric acid, peruvic acid, acetoacetic acid,
alanine, aspartic acid, asparagine, glutamic acid, glycine, lycine,
or valine. In another preferred embodiment the first fatty acid is
one or more of oleic acid, linolenic acid, linoleic acid,
myristoleic acid, palmitoleic acid, or erucic acid and the second
fatty acid is one or more of levulinic acid, propionic acid,
valeric acid, peruvic acid, acetoacetic acid, alanine, aspartic
acid, asparagine, glutamic acid, glycine, lycine, or valine. In a
most preferred embodiment the first fatty acid is oleic acid and
the second fatty acid is levulinic acid.
[0050] In another embodiment of the invention a composition
includes a first fatty acid that has a molecular structure made up
of about 14 or more carbons and a second fatty acid that has a
molecular structure made up of about 12 or less carbon atoms. The
first fatty acid may be any fatty acid having about 14 or more
carbon atoms. In some embodiments the first fatty acid has about 15
or more carbon atoms and in other embodiments the first fatty acid
has about 16 or more carbon atoms. In particular, the first fatty
acid may be saturated, monounsaturated or polyunsaturated. The
hydrocarbon chain of the first fatty acid may be straight or
branched. In a preferred embodiment the first fatty acid is one or
more of oleic acid, linolenic acid, linoleic acid, myristoleic
acid, palmitoleic acid, or erucic acid. The second fatty acid may
be any fatty acid having about 12 or less carbon atoms. In some
embodiments the second fatty acid has about 11 or less carbon atoms
and in other embodiments the second fatty acid has about 10 or less
carbon atoms. In particular, the second fatty acid may be
saturated, monounsaturated or polyunsaturated. The second fatty
acid may be a keto acid or an amino acid. The hydrocarbon chain of
the second fatty acid may be straight or branched. In a preferred
embodiment the second fatty acid is one or more of levulinic acid,
2-hydroxyoctanoic acid, 4-oxopentanoic acid, propionic acid,
valeric acid, peruvic acid, acetoacetic acid, alanine, aspartic
acid, asparagine, glutamic acid, glycine, lycine, or valine. In
another preferred embodiment the first fatty acid is one or more of
oleic acid, linolenic acid, linoleic acid, myristoleic acid,
palmitoleic acid, or erucic acid and the second fatty acid is one
or more of levulinic acid, propionic acid, valeric acid, peruvic
acid, acetoacetic acid, alanine, aspartic acid, asparagine,
glutamic acid, glycine, lycine, or valine. In a most preferred
embodiment the first fatty acid is oleic acid and the second fatty
acid is levulinic acid.
[0051] Compositions of the invention including a first and a second
fatty acid as described above can have amounts of first and second
fatty acid that are in equal or different proportions relative to
each other. The first fatty acid, and in some embodiments a
derivative or congener thereof, having about 14 or more carbon
atoms, can be present in the range of from about 0.1% to about 30%
by weight of the total composition, or in the range of from about
1% to about 5% by weight of the total composition, or about 2.5% by
weight of the total composition. In some embodiments, the
composition can include any amount of first fatty acid up to an
amount that is known to cause irritation in a mammal; the amount
can be up to 2% by weight. The second fatty acid, and in some
embodiments, derivatives or congeners thereof, having about 12 or
less carbon atoms, or about 10 or less carbon atoms, can be present
in the range of from about 0.1% to about 30% by weight of the total
composition, or in the range of from about 1% to about 5% by weight
of the total composition, or about 2.5% by weight of the total
composition. The composition can include up to 25 mg of second
fatty acid, and in some embodiments, derivatives or congeners
thereof, per dose. The weight percent of the first fatty acid can
be chosen independent of the weight percent of the second fatty
acid. The composition can include a first and second fatty acid in
equal proportions by weight percent, greater weight percent first
fatty acid than second fatty acid, or greater weight percent second
fatty acid than first fatty acid. In preferred embodiments the
weight percent of the first fatty acid is greater than the weight
percent of the second fatty acid, such as a composition having in
the range of from about 2.5% to about 7.5% first fatty acid and
having in the range of from about 0.5% to about 2.5% second fatty
acid, or a composition having about 5% first fatty acid and about
1% second fatty acid. All ranges are inclusive and the maxima and
minima of the specified ranges are combinable.
[0052] Compositions of the invention can have two fatty acids
comprising different molecular weights as described above and one
or more therapeutic agents. The invention is particularly effective
with therapeutic agents that are difficult to permeate through skin
or mucosal tissue. Such drugs and biologics are usually of high
molecular weight, high melting point and/or their chemical
structures contain one or more fused rings. Therapeutic agents
having a high molecular weight include drugs and biologics having a
molecular weight greater than about 300 daltons. In other
embodiments therapeutic agents having a high molecular weight
include drugs and biologics having a molecular weight greater than
about 350 daltons or greater than about 400 daltons. Therapeutic
agents having a high melting point include drugs and biologics
having a melting point greater than about 200.degree. C. In other
embodiments, therapeutic agents having a high melting point include
drugs and biologics having a melting point greater than about
225.degree. C., or greater than about 250.degree. C.
[0053] For example such therapeutic agents include, but are not
limited to, hormone antagonists such as estrogens, progestins, and
androgens for both male and female health, adrenocortical steroids
and their synthetic analogs for inflammation and/or various
manifestations of adrenal insufficiency or pituitary hormone
excess, antinausea/antiemetic drugs, tricyclic antidepressants,
migraine and other pain drugs including NSAIDs and narcotics,
hypnotics, some beta blockers, alpha blockers, neuromuscular
blocking agents, diuretics, antimalarial drugs, dermatologicals,
antimetabolites, peptides such as leuprolide, goserelin or
histrelin. In other embodiments the therapeutic agent may be, but
is not limited to, an agent to treat Alzheimer's, an anabolic
agent, an analgesic agent, an anesthetic agent, an antacid, an
anti-asthmatic agent, an anticholesterolemic agent, an anti-lipid
agent, an anti-coagulant, an anti-convulsant, an anti-diarrheal, an
antiemetic, an anti-inflammatory agent, an antifungal agent, an
anti-manic agent, an anti-migraine, an anti-nauseant, a CNS
anti-depressant, an antineoplastic agent, an anti-obesity agent, an
anti-Parkinson's agent, an anti-pyretic agent, an anti-spasmodic
agent, an anti-thrombotic agent, an anti-uricemic agent, an
anti-anginal agent, an antihistamine, an anti-tussive, an appetite
suppressant, a biological, a cerebral dilator, a central nervous
system agent, a coronary dilator, a decongestant, a diuretic, an
erythropoietic agent, an expectorant, a gastrointestinal sedative,
a hormone or hormone agonist or antagonist, an agent possessing
mixed agonist and antagonist properties on a hormone receptor, a
hyperglycemic agent, a hypoglycemic agent, a prostaglandin or
prostanoid, an estrogen or anti-estrogen, a progestogen or
anti-progestin, an androgen or anti-androgen, an opiate or opioid
agonist or antagonist, a phenothiazine, a butyrophenone, a
benzamide, a glucocorticoid, a dopamine antagonist, a hypnotic, a
hypoglycemic agent, an ion exchange resin, a laxative, a mineral
supplement, a mucolytic agent, a neuromuscular drug, an NSAID, an
oligonucleotide, an anti-Parkinson's agent, a peptide or
polypeptide, a peripheral vasodilator, a psychotropic, a
polynucleotide, a sedative, a stimulant, a thyroid agent, an
anti-thyroid agent, a uterine relaxant, a cervical ripening agent,
an agent for the induction of labor, a vitamin, a prodrug, or an
agent that promotes healing.
[0054] Specific examples of therapeutic agents suitable for use in
compositions of the invention include ropinirole, pramipexole,
sumatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan,
naratriptan, frovatriptan, zolpidem, zaleplon, eszopiclone,
ramelteon, doxepin, ketoprofen, ketorolac, piroxicam, meloxicam,
diclofenac, mifepristone, ulipristal, sildenafil, vardenafil,
tadalafil, alprostadil, letrozole, anastrozole, oxycodone,
hydrocodone, buprenorphine, fentanyl, sufentanyl, alfentanyl,
morphine, naloxone, naltrexone, leuprolide, goserelin, histrelin,
pyridoxine, doxylamine, dimenhydronate, diphenhydramine, meclizine,
promethazine, prochlorperazine, droperidol, metaclopramide,
haloperidol, prednisone, methylprednisolone, cortisol, thyrotropin,
thyrotropin-releasing hormone, estradiol, progesterone,
gonadotropin-releasing hormone, gonadotropin-releasing hormone
agonists or antagonists, and insulin.
[0055] Additional compounds suitable for use in compositions of the
invention include estrogens, which can be useful as contraceptives
and/or hormone therapies for menopause and other endocrine
conditions. Suitable estrogens not mentioned elsewhere in this
specification include ethinyl estradiol and estradiol-17beta.
[0056] Additional compounds suitable for use in compositions of the
invention include progesterones and progestins, which can be useful
as contraceptives, hormone therapies, or both, for menopause and
other endocrine conditions. Suitable progesterones and progestins
not mentioned elsewhere in this specification include:
Progesterone, Norgestimate, Norelgestromin (also called 17-deacetyl
norgestimate), Norgestrel, Levo-norgestrel, Cyproterone Acetate,
Gestodene, Desogestrel, Dienogest, Drosperinone, Norethindrone, and
Norethindrone acetate.
[0057] Other compounds suitable for use in compositions of the
invention include anti-infectives. Suitable anti-infectives not
mentioned elsewhere in this specification include Fenticonazole
(base, nitrate or both) and Fluconazole.
[0058] Additional compounds suitable for use in compositions of the
invention include nutritional supplements and vitamins. Suitable
nutritional supplements and vitamins not mentioned elsewhere in
this specification include Calcium Carbonate, Cholecalciferol (a
metabolite of Vitamin D), Folic Acid, Folate, and Metafolin.
[0059] Other compounds suitable for use in compositions of the
invention include compounds useful for treating central nervous
system (CNS) disorders. Suitable compounds useful for treating
central nervous system (CNS) disorders not mentioned elsewhere in
this specification include Methylphenidate (e.g., for ADHD),
Paroxetine (base, mesylate salt, or both), Valproic Acid, Lithium
carbonate, Fentanyl, Lidocaine, and Rivastigmine.
[0060] In preferred embodiments, a composition of the invention
includes a therapeutic agent that is a serotonin receptor
antagonist. Preferably, the serotonin receptor antagonist comprises
a 5-HT3 receptor antagonist. Even more preferably, the serotonin
receptor antagonist is selected from ondansetron, dolasetron,
granisetron, tropisetron, palonosetron, or salts thereof. In a most
preferred embodiment, a composition of the invention includes
ondansetron (also referred to herein as "ondansetron base") or
ondansetron salt. Ondansetron hydrochloride is an example of an
ondansetron salt.
[0061] Compositions of the invention may be designed to be
administered to the skin or mucosal tissue of a patient in need of
treatment. In addition to a first fatty acid, second fatty acid,
and one or more therapeutic agents as described above, compositions
of the invention may also include excipients. Compositions of the
invention may be formulated as gels, transdermal patches, lotions,
creams, sprays, mists, emulsions, or dispersions. Appropriate
excipients for formulating a gel, transdermal patch, lotion, cream,
spray, or mist are readily apparent to a person of skill in the art
and include, but are not limited to, stabilizers, emulsifiers,
thickeners, antimicrobials, humectants, propellants, spreading
agents, polymers, and adhesives, such as pressure sensitive
adhesives. In particular, excipients that may be used to form a
transdermal gel include, but are not limited to, alcohols, glycols,
glycerin, butylated hydroxytoluene (BHT), and water.
[0062] The invention also encompasses methods of treating a patient
in need thereof by administering to a patient a composition
including two fatty acids comprising different molecular weights as
described above and one or more therapeutic agents as described
above. Methods according to the invention can be used to treat a
patient with depression, Parkinson's, Alzheimer's, nausea,
migraine, pain, or any combination thereof, as well as other
diseases or ailments as would be understood by a person of skill in
the art.
[0063] The invention also encompasses the use of compositions
comprising two fatty acids each having a different molecular weight
as described above, and a therapeutic agent as described above, for
the manufacture of a medicant for treating a disease or condition.
Such disease or condition includes depression, Parkinson's,
Alzheimer's, nausea, migraine, pain, or any combination thereof, as
well as other diseases or ailments as would be understood by a
person of skill in the art.
EXAMPLES
[0064] The following examples, while illustrative individual
embodiments, are not intended to limit the scope of the described
invention, and the reader should not interpret them in this
way.
Examples 1-4. Preparation of Ondansetron Transdermal Gels without
the Enhancer System of the Invention
[0065] An amount of 296 grams of alcohol USP was placed in a
container and 1.2 grams of ondansetron base was added and mixed
until totally dissolved. Thereafter, 40 grams of propylene glycol
and 40 grams of PEG 400 were added sequentially and mixed until a
uniform solution was obtained. Thereafter 8 grams of Klucel HF was
added with mixing until well suspended. Finally, 14.8 grams of
purified water USP was added and then the total mixture was allowed
to set for 24 hours until the gelling agent, Klucel HF, swelled
uniformly. A clear, uniform gel was formed.
[0066] Similar gels, as above, were prepared without the enhancer
system of the invention, but with the addition of different
polyethylene glycols, which are components often used as
solubilizers in transdermal gel systems. The preparation procedure
was similar to the one presented in example 1 and the formulations
themselves are shown in Table 1 below:
TABLE-US-00001 TABLE 1 Non-chemically enhanced formulations of
Ondansetron Base Formulations Ingredient (grams) 1 2 3 4
Ondansetron base 1.2 1.2 1.2 1.2 Alcohol USP 296 296 296 296
Propylene glycol 40 40 40 40 PEG 400 40 -- -- -- PEG 300 -- 40 --
-- Methoxy PEG 350 -- -- 40 -- Butylene glycol -- -- -- 40 Klucel
HF Pharm 8 8 8 8 Purified water USP 14.8 14.8 14.8 14.8 TOTAL
(grams) 400 400 400 400
[0067] All four formulations were clear and uniform in
appearance
Example 5. Commercially Available Ondansetron Organogel
(Formulation 5)
[0068] An ondansetron organogel is available from the compounding
pharmacy Custom Medicine Pharmacenter. It is a complex formulation
of ondansetron hydrochloride with potency of 2 mgs per 0.1 ml. It
can be applied three times per day for a daily dose of 6
milligrams. It is a Pluronic Lecithin Organogel (PLO) with an
aqueous phase of Poloxamer 407, potassium sorbate and water and an
organic phase of lecithin, isopropyl palmitate and sorbic acid
(www.plo-gel.com/Main/plo-gel.php). This commercially available
formulation was obtained from the compounding pharmacy and used as
the positive control in the skin diffusion studies.
Example 6. Skin Permeation Studies Using Formulations 1 Through 5
Presented in Examples 1 Through 5
[0069] Skin permeation studies were performed for the above
mentioned formulations using Franz diffusion cells kept at
37.degree. C. for the duration of the experiment. The receptor
medium was phosphate buffered saline at pH 7.4, the receptor volume
12 ml and the permeation area 1.77 cm.sup.2. Human cadaver skin was
used and all tests were performed in triplicate. Four hundred
microliters of each of the formulations was placed at the donor
site of the skin diffusion cells and the experiment was initiated
with the receptor medium being continuously mixed. Samples of the
receptor phase were obtained at 2, 4, 8, 12, 24 and 48 hours and
ondansetron concentrations were obtained using HPLC [Column-Waters
C18 XBridge, 3.5 .mu.m, 4.6 mm.times.150 mm, Mobile Phase--20 mM
Potassium Phosphate Buffer pH 4.4:Acetonitrile (78:22), Flow
Rate--1 mL/min, Injection Volume--10 .mu.l, Detection--216 nm,
Column Temperature--40.degree. C., Run Time--10 minutes]. The
ondansetron skin flux and cumulative amount permeated after 24
hours were calculated and are shown in Table 2 below.
[0070] FIG. 1 compares the average cumulative amount (three
diffusion cells per formulation) of ondansetron base that permeated
through human skin over a 24 hour period for the four formulations
shown in Table 1 as well as that of the commercial organogel
discussed in example 5 (formulation 5). FIG. 2 shows the average
skin diffusion rate (3 diffusion cells per formulation) for the
five formulations mentioned above.
TABLE-US-00002 TABLE 2 Flux and Cumulative Amount Of Ondansetron
Permeated Through Human Cadaver Skin Cumulative Flux amount
permeated (microg/cm.sup.2/hr) (microg/cm.sup.2) Formulation 1 0.05
1.18 Formulation 2 0.04 1.00 Formulation 3 0.04 0.85 Formulation 4
0.04 0.92 Formulation 5 0.34 8.04
[0071] The data demonstrates that the Custom Medicine
Pharmacenter's organogel is substantially better than any of the
standard unenhanced formulations.
Example 7. Chemically Enhanced Formulations of Ondansetron Base
[0072] Hydroalcoholic gels similar to those described in examples 1
through 4 were prepared using chemical enhancers. The chemical
enhancers used were dimethyl isosorbide, oleic acid, glycerin,
levulinic acid and combinations thereof. The preferred embodiment
of the invention contained both oleic acid and levulinic acid. The
preparation of this formulation was as follows. An amount of 294
grams of alcohol USP was placed in a container and 4 grams of
ondansetron base was added and mixed until totally dissolved.
Thereafter, 40 grams of propylene glycol, 20 grams of oleic acid,
and 20 grams of levulinic acid were added sequentially and mixed
until a uniform solution was obtained. Thereafter 8 grams of Klucel
HF was added with mixing until well suspended. Finally, 12 grams of
purified water USP was added and then the total mixture was allowed
to set for 24 hours until the gelling agent, Klucel HF, swelled
uniformly. A clear, uniform gel was formed with viscosity of 21,650
cps. All of the chemically enhanced formulations prepared and
tested are shown in Table 3 below:
TABLE-US-00003 TABLE 3 Chemically enhanced formulations of
Ondansetron Base Formulations 5 Ingredient (grams) 6 7 8 9 10 11
(note 1) Ondansetron base 1.2 1.2 1.2 4.0 4.0 4.0 Alcohol USP 296
296 296 296 296 296 Propylene glycol 40 40 40 40 40 40 Klucel HF
Pharm 8 8 8 8 8 8 Purified water USP 14.8 14.8 14.8 12.0 12.0 12.0
Dimethyl 40 -- -- -- -- -- Isosorbide Oleic acid -- 20 -- 40 -- 20
Glycerin -- 20 20 -- -- -- Levulinic acid -- -- 20 -- 40 20 TOTAL
(grams) 400 400 400 400 400 400 Note 1. Custom Medicine
Pharmacenter commercial organogel formulation; exact composition
not known.
Example 8. Skin Permeation Studies Using Chemically Enhanced
Formulations 5 Through 11
[0073] Skin permeation studies were performed for the above
mentioned formulations using Franz diffusion cells kept at
37.degree. C. for the duration of the experiment. The receptor
medium was phosphate buffered saline at pH 7.4, the receptor volume
12 ml and the permeation area 1.77 cm.sup.2. Human cadaver skin was
used and all tests were performed in triplicate. The results for
skin flux and cumulative amount permeated through human skin was
calculated for a period of 24 hours, and are shown in Table 4
below:
TABLE-US-00004 TABLE 4 Flux And Cumulative Amount Of Ondansetron
Base Permeated Through Human Cadaver Skin Cumulative Flux amount
permeated (microg/cm.sup.2/hr) (microg/cm.sup.2) Formulation 5 0.60
14.3 Formulation 6 0.04 1.00 Formulation 7 1.69 40.6 Formulation 8
0.00 0.05 Formulation 9 2.17 52.0 Formulation 10 0.08 1.79
Formulation 11 18.0 456.0
[0074] The above data demonstrates that dimethyl isosorbide,
levulinic acid and levulinic acid together with glycerin do not
enhance the permeability of ondansetron base through human skin.
Oleic acid and oleic acid in combination with glycerin appear to
enhance the permeation of ondansetron base 40 to 50-fold over that
of the unenhanced formulations and about 3-fold over the commercial
organogel formulation. To our great surprise oleic acid together
with levulinic acid showed a tremendous increase in the permeation
of ondasentron, indicating a synergistic effect between the small
molecular weight (levulinic acid) fatty acid and that of the larger
molecular weight (oleic acid) fatty acid. The results are even more
surprising considering that levulinic acid by itself had no effect
on the permeation of ondansetron through human skin. The increase
in ondansetron permeation through human skin for the oleic
acid/levulinic acid combination was a) 450-fold higher than that of
the unenhanced formulations, b) 255-fold over the formulation
containing only levulinic acid, c) 32-fold over the commercially
available ondansetron organogel and d) 9-fold over the formulation
containing oleic acid.
[0075] FIG. 3 compares the average cumulative amount (three
diffusion cells per formulation) of ondansetron base that permeated
through human skin over a 24 hour period for five formulations, 1)
the formulation of the invention containing a combination of oleic
acid and levulinic acid as the enhancing system (formulation 11),
2) the formulation containing oleic acid as the enhancer
(formulation 9), 3) the formulation containing levulinic acid as
the enhancer (formulation 10), 4) the formulation containing no
enhancer (formulation 1) and 5) the formulation of the commercially
available organogel containing ondansetron. FIG. 4 shows the
average skin diffusion rate (3 diffusion cells per formulation) for
the five formulations mentioned above.
Example 9. Formulations for Skin Permeation Studies to Investigate
the Effect of Content of Fatty Acid Enhancers and Amount of
Ondansetron Base on the Skin Permeation of Ondansetron
[0076] Hydroalcoholic gels similar to those described in the above
examples were prepared having the formulations shown in Table 5.
Human skin permeation studies were performed using these four
formulations to determine the effect of a) the concentration of the
skin lipid enhancing system and b) the concentration of the drug on
the amount of drug that permeates through skin. In these
formulations butylated hydroxytoluene (BHT) was included to protect
the formulations from oxidation.
TABLE-US-00005 TABLE 5 Formulations Of The Invention Comprising
Different Concentrations Of Fatty Acid Combination Enhancers And
Drug Loadings Formulations Ingredient (grams) 12 13 14 18 5 (note
2) Ondansetron base 3.0 4.5 3.0 3.0 Alcohol USP 222 222 222 231
Propylene glycol 30 30 30 30 Klucel HF Pharm 6.0 6.0 6.0 6.0
Purified water USP 23.7 7.2 9.0 21.0 Oleic acid 7.5 15 15 3.0
Levulinic acid 7.5 15 15 3.0 BHT 0.3 0.3 -- 3.0 TOTAL (grams) 300
300 300 300 (note 2). Custom Medicine Pharmacenter commercial
organogel formulation; exact composition not known.
Example 10. Skin Permeation Studies Using Enhanced Formulations of
the Invention, 12 Through 14 and 18
[0077] Skin permeation studies were performed for formulations
12-14, 18, and 5 using Franz diffusion cells kept at 37.degree. C.
for the duration of the experiment. Formulation 5 representing the
commercial organogel was used as the positive control. The receptor
medium was phosphate buffered saline at pH 7.4, the receptor volume
12 ml and the permeation area 1.77 cm.sup.2. Human cadaver skin was
used and all tests were performed in triplicate. The results for
skin flux and cumulative amount permeated through human skin was
calculated for a period of 24 hours, and are shown in Table 6
below:
TABLE-US-00006 TABLE 6 Flux and Cumulative Amount Of Ondansetron
Base Permeated Through Human Cadaver Skin From Formulations Of the
Invention 12 through 14, and 18 Cumulative Flux amount permeated
(microg/cm.sup.2/hr) (microg/cm.sup.2) Formulation 12 21.5 514.9
Formulation 13 25.0 599.4 Formulation 14 19.6 469.5 Formulation 18
18.0 433.2 Formulation 5 0.36 8.7
[0078] The above data demonstrates that a) reducing the enhancer
concentration of the combination enhancing system by half or by 80%
did not substantially affect the permeation of ondansetron through
skin. This is important because reducing the concentration of
enhancers will reduce any skin irritation caused by the enhancing
system, b) increasing the concentration of the drug in the
formulation, as expected, increased the skin permeation of the drug
and c) the skin enhancing system of our invention provided
permeation through skin which is 54 to 69-fold higher than that of
the commercial organogel and d) the presence of the antioxidant BHT
in the formulation does not affect the permeation of the drug
through human skin.
[0079] FIG. 5 compares the average cumulative amount (three
diffusion cells per formulation) of ondansetron base that permeated
through human skin over a 24 hour period for the four formulations
12, 13, 14, and 5 of example 10. FIG. 7 compares the average
cumulative amount of ondansetron that permeated through human skin
over a 24 hour period for formulations 12, 13, 14, and 18 of
example 10. FIG. 8 compares the average skin diffusion rate (flux)
over a 24 hour period for formulations 12, 13, 14, and 18 of
example 10.
Example 11. Formulations for Skin Permeation Studies to Investigate
the Effect of the High Molecular Weight Fatty Acid of the Enhancer
Combination on the Skin Permeation of Ondansetron
[0080] Hydroalcoholic gels similar to those described in the above
examples were prepared having the formulations shown in Table 7.
Human skin permeation studies were performed using these three
formulations to determine the effect of three different high
molecular weight fatty acids of the combination enhancing system,
on the permeation of ondansetron through skin. The three fatty
acids were oleic acid, linoleic acid and linolenic acid.
TABLE-US-00007 TABLE 7 Formulations Of The Invention Comprising
Different High Molecular Weight Fatty Acids, Oleic Acid, Linoleic
Acid And Linolenic Acid Formulations Ingredient (grams) 15 16 17
Ondansetron base 3.0 4.5 3.0 Alcohol USP 222 222 222 Propylene
glycol 30 30 30 Klucel HF Pharm 6.0 6.0 6.0 Purified water USP 8.7
7.2 8.7 Linoleic acid 15 -- -- Linolenic acid -- 15 -- Oleic acid
-- -- 15 Levulinic acid 15 15 15 BHT 0.3 0.3 0.3 TOTAL (grams) 300
300 300
Example 12. Skin Permeation Studies Using Formulations 15, 16, and
17 Comprising Different High Molecular Weight Fatty Acids in the
Enhancer Combination System of the Invention
[0081] Skin permeation studies were performed for formulations
15-17 using Franz diffusion cells kept at 37.degree. C. for the
duration of the experiment. The receptor medium was phosphate
buffered saline at pH 7.4, the receptor volume 12 ml and the
permeation area 1.77 cm.sup.2. Human cadaver skin was used and all
tests were performed in triplicate. The results for skin flux and
cumulative amount permeated through human skin were calculated for
a 24 hour period, and are shown in Table 8.
TABLE-US-00008 TABLE 8 Flux and Cumulative Amount Of Ondansetron
Base Permeated Through Human Cadaver Skin From Formulations 15
through 17. Cumulative Flux amount permeated (microg/cm.sup.2/hr)
(microg/cm.sup.2) Formulation 15 24.3 583.4 Formulation 16 24.0
576.5 Formulation 17 25.0 599.4
[0082] The above data demonstrates that the permeation through skin
was about the same for the formulations 15-17 containing linoleic,
linolenic or oleic fatty acids respectively, as the high molecular
weight fatty acid in the combination enhancer system of the
invention. The data supports the conclusion that the invention is
broadly applicable for many different fatty acid combinations. FIG.
6 compares the average cumulative amount of ondansetron base that
permeated through human skin for the three formulations 15, 16 and
17 and the commercial organogel, formulation 5.
Example 13. Finite Dose Study and Infinite Dose Study
[0083] Hydroalcoholic gels similar to those described in the above
examples were prepared having the formulations shown in Table
9.
TABLE-US-00009 TABLE 9 Formulations of the Invention 19 and 20
Formulations Ingredient (grams) 19 (Lot 121012G-A) 20 (Lot
121012G-B) Ondansetron base 0.39 0.90 Alcohol USP 23.70 21.90
Propylene glycol 3.00 3.00 Klucel HF Pharm 0.60 0.60 Purified water
USP 1.32 0.00 Oleic acid 0.30 1.50 Levulinic acid 0.30 1.50 BHT
0.39 0.60 TOTAL (grams) 30.00 30.00
[0084] Finite dose and infinite dose skin permeation studies were
performed for the commercial organogel and formulations 19 and 20
using Franz diffusion cells kept at 37.degree. C. for the duration
of the experiment. The receptor medium was phosphate buffered
saline at pH 7.4, the receptor volume 12 ml and the permeation area
1.77 cm.sup.2. Human cadaver skin was used and all tests were
performed in triplicate.
[0085] Finite dose experiments more closely simulate the
transdermal application of drugs by topical means such as for gels,
creams, sprays, and lotions because the amount of formulation that
can be applied to skin is limited to a couple of mgs per cm.sup.2.
For the finite dose study, an average of 3.76 mg/1.77 cm.sup.2
(2.13 mg/cm.sup.2) formulation was applied to human cadaver skin.
The reference product (an ondansetron PLO gel, 2 mg/0.1 mL,
described in example 5) was applied 3.85 mg/1.77 cm.sup.2 (2.18
mg/cm.sup.2). The results for skin flux and cumulative amount
permeated through human skin were calculated after 0, 2, 4, 8, 12,
24 and 48 hour periods, and are shown in Table 10, FIG. 9 (flux)
and FIG. 10 (cumulative amount permeated) for the finite dose
study.
[0086] Infinite dose experiments more closely simulate the
transdermal application from patches, both matrix and reservoir,
because of their ability to provide large reservoirs for drugs and
enhancers per unit surface area of skin. For the infinite dose
study, an average of 56.1 mg/1.77 cm.sup.2 (31.7 mg/cm.sup.2)
formulation was applied to human cadaver skin. The reference
product (an ondansetron PLO gel, 2 mg/0.1 mL, described in example
5) was applied 3.85 mg/1.77 cm.sup.2 (2.18 mg/cm.sup.2) on dry
basis. The results for skin flux and cumulative amount permeated
through human skin were calculated after 0, 2, 4, 8, 12, 24 and 48
hour periods, and are shown in Table 11, FIG. 11 (flux) and FIG. 12
(cumulative amount permeated) for the infinite dose study.
TABLE-US-00010 TABLE 10 Finite Dose Study - Flux and Cumulative
Amount Of Ondansetron Base Permeated Through Human Cadaver Skin
From Formulations 19 and 20 Compared to Ondansetron Reference
Product Cumulative amount permeated Flux (microg/cm.sup.2)
(microg/cm.sup.2/hr) Formulation 19 0 hours 0.000 0.000 2 hours
0.058 0.029 4 hours 0.247 0.062 8 hours 1.94 0.243 12 hours 5.29
0.441 24 hours 12.8 0.534 48 hours 19.6 0.409 Formulation 20 0
hours 0.000 0.000 2 hours 0.363 0.181 4 hours 0.723 0.181 8 hours
2.80 0.350 12 hours 6.54 0.545 24 hours 16.59 0.691 48 hours 27.58
0.575 Ondansetron Reference Product (2 mg Ondansetron/0.1 mL) 0
hours 0.000 0.000 2 hours 0.000 0.000 4 hours 0.000 0.000 8 hours
0.000 0.000 12 hours 0.155 0.013 24 hours 0.892 0.037 48 hours 3.03
0.063
TABLE-US-00011 TABLE 11 Infinite Dose Study - Flux and Cumulative
Amount Of Ondansetron Base Permeated Through Human Cadaver Skin
From Formulations 19 and 20 Cumulative amount permeated Flux
(microg/cm.sup.2) (microg/cm.sup.2/hr) Formulation 19 0 hours 0.000
0.000 2 hours 0.000 0.000 4 hours 6.56 1.64 8 hours 65.3 8.17 12
hours 166.3 13.9 24 hours 377.8 15.7 48 hours 479.5 9.99
Formulation 20 0 hours 0.000 0.000 2 hours 6.92 3.46 4 hours 44.0
11.0 8 hours 226.5 28.3 12 hours 457.4 38.1 24 hours 1056.6 44.0 48
hours 1397.8 29.1 Ondansetron Reference Product (2 mg
Ondansetron/0.1 mL) 0 hours 0.000 0.000 2 hours 0.000 0.000 4 hours
0.000 0.000 8 hours 0.000 0.000 12 hours 0.155 0.013 24 hours 0.892
0.037 48 hours 3.03 0.063
Example 14. Patch Preparation
[0087] Patches incorporating the compositions of the invention can
be readily prepared using methods known to those in the art. For
example, the first and second fatty acids, or fatty acid
derivatives, are added to a pressure sensitive adhesive solution
such as, for example, Durotak.TM. 87-2677 (Henkel Corporation,
Rocky Hill, Conn.). The therapeutic agent, such as, for example,
ondansetron or ondansetron hydrochloride, is dissolved in a
suitable solvent such as, for example, acetone, ethanol, or
methanol, and mixed. This mixture is added to the pressure
sensitive adhesive solution.
[0088] The pressure sensitive adhesive (PSA) mass is spread onto,
for example, an aluminum polyester backing film to the desired
thickness. One suitable backing is Scotchpak.TM. 9736 (3M, St.
Paul, Minn.). The thickness of the mass that will be applied to the
backing film can be controlled using, for example, a pilot coater
such as those available from Werner Mathis USA (Concord, N.C.). The
coated product is allowed to dry at, for example, 75.degree. C. all
volatile solvents are volatilized away, approximately 15 to 20
minutes. A release liner such as Scotchpak.TM. 9741 (3M, St. Paul,
Minn.) is then applied on the PSA side of the coated mass. The
resulting product is cut into individual patches of the desired
size and pouched using a pouching film, for example Barex.TM.
containing film T-1601 (American Packaging Corporation, Rochester,
N.Y.).
[0089] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations, and subcombinations of ranges for
specific embodiments therein are intended to be included.
[0090] The disclosures of each patent, patent application, and
publication cited or described in this document are hereby
incorporated herein by reference, in its entirety.
[0091] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *