U.S. patent application number 14/983761 was filed with the patent office on 2016-04-21 for pharmaceutical formulation for histone deacetylase inhibitors.
The applicant listed for this patent is TetraLogic Shape UK Ltd. Invention is credited to Todd W. Chappell, Keith A. Johnson.
Application Number | 20160106700 14/983761 |
Document ID | / |
Family ID | 44903378 |
Filed Date | 2016-04-21 |
United States Patent
Application |
20160106700 |
Kind Code |
A1 |
Chappell; Todd W. ; et
al. |
April 21, 2016 |
Pharmaceutical Formulation for Histone Deacetylase Inhibitors
Abstract
A pharmaceutical composition, comprising a therapeutically
effective amount of an active pharmaceutical ingredient (API)
compound represented by the following structural formula
##STR00001## at least one acidifying agent; and a vehicle base
comprising at least one pharmaceutically acceptable non-aqueous
solvent. Values and preferred values of the variables in structural
formula (I) are defined herein.
Inventors: |
Chappell; Todd W.;
(Alexandria, VA) ; Johnson; Keith A.; (Durham,
NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TetraLogic Shape UK Ltd |
Birmingham |
|
GB |
|
|
Family ID: |
44903378 |
Appl. No.: |
14/983761 |
Filed: |
December 30, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13878994 |
Apr 11, 2013 |
9255066 |
|
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PCT/US2011/056148 |
Oct 13, 2011 |
|
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14983761 |
|
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61392855 |
Oct 13, 2010 |
|
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Current U.S.
Class: |
514/533 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 47/12 20130101; A61P 43/00 20180101; A61K 47/02 20130101; A61K
31/235 20130101; A61P 17/10 20180101; A61P 35/00 20180101; C07C
259/06 20130101; A61K 31/222 20130101; A61K 47/38 20130101; A61K
47/10 20130101; A61P 17/06 20180101; A61K 47/14 20130101; A61P
17/00 20180101; A61K 9/0014 20130101; A61K 9/06 20130101; A61P
17/14 20180101; A61P 35/02 20180101 |
International
Class: |
A61K 31/235 20060101
A61K031/235; A61K 47/02 20060101 A61K047/02; A61K 9/06 20060101
A61K009/06; A61K 47/14 20060101 A61K047/14; A61K 47/38 20060101
A61K047/38; A61K 47/12 20060101 A61K047/12; A61K 47/10 20060101
A61K047/10 |
Claims
1. A pharmaceutical composition, comprising: a therapeutically
effective amount of an active pharmaceutical ingredient (API)
compound represented by the following structural formula
##STR00011## at least one acidifying agent; and a vehicle base
comprising at least one pharmaceutically acceptable non-aqueous
solvent, wherein n is an integer from 0 to 15, R.sub.1 and R.sub.2
are each independently hydrogen, halogen, an aliphatic group, a
heteroaliphatic group, an aryl, a heteroaryl; --OR.sub.A;
--C(O)R.sub.A; --C(O)N(R.sub.A).sub.2; --CO.sub.2R.sub.A; --CN;
--SCN; --SR.sub.A; --SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2;
--N(R.sub.A).sub.2; --NHR.sub.A; --NR.sub.AC(O)R.sub.A; or
--C(R.sub.A).sub.3; and wherein R.sub.A for each occurrence is,
independently, a hydrogen, an aliphatic group, a heteroaliphatic
group, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy;
aryloxy; alkylthio, arylthio, amino, alkylamino, dialkylamino,
heteroaryloxy, or heteroarylthio moiety.
2. The pharmaceutical composition of claim 1, wherein the at least
one acidifying agent is selected from the groups consisting of
acetic acid, dehydro acetic acid, ascorbic acid, benzoic acid,
boric acid, citric acid, edetic acid, hydrochloric acid, isostearic
acid, stearic acid, lactic acid, nitric acid, oleic acid,
phosphoric acid, sorbic acid, sulfuric acid, tartaric acid, and
undecylenic acid.
3. The pharmaceutical composition of claim 2, wherein the at least
one acidifying agent is selected from citric acid, acetic acid, and
phosphoric acid.
4. The pharmaceutical composition of claim 1, wherein the at least
one pharmaceutically acceptable non-aqueous solvent is selected
from the groups consisting of ethanol, acetone, benzyl alcohol,
2-(2-ethoxyethoxy)ethanol, diethylene glycol monoethyl ether,
glycerin, propylene glycol, propylene carbonate, acetone, hexylene
glycol, isopropyl alcohol, polyethylene glycols (PEGs),
methoxypolyethylene glycols, diethyl sebacate, dimethyl isosorbide,
propylene carbonate, dimethyl sulfoxide (DMSO), diisopropyl
adipate, isopropyl myristate, vegetable oils, a mineral oil, and
isopropyl palmitate.
5. The pharmaceutical composition of claim 4, wherein the at least
one pharmaceutically acceptable non-aqueous solvent is selected
from ethanol, benzyl alcohol, propylene glycol,
2-(2-ethoxyethoxy)ethanol, hexylene glycol and diisopropyl
adipate.
6. The pharmaceutical composition of claim 1, further including at
least one humectant.
7. The pharmaceutical composition of claim 6, wherein the at least
one humectant is selected from the groups consisting of hexylene
glycol, glycerin, propylene glycol, sorbitol, lactic acid, sodium
lactate, mannitol, butylene glycol, panthenol, hyaluronic acid,
urea, chitosan, polyols, methyl gluceth-10, methyl gluceth-20, and
polyethylene glycols.
8. The pharmaceutical composition of claim 6, wherein the at least
one humectant is selected from glycerin and hexylene glycol.
9. The pharmaceutical composition of claim 1, further including at
least one emollient.
10. The pharmaceutical composition of claim 3, wherein the at least
one emollient is selected from the groups consisting of diisopropyl
adipate, isopropyl myristate, isopropyl palmitate, cetearyl
octonoate, isopropyl isostearate, myristyl lactate, octyldodecanol,
oleyl alcohol, a mineral oil, petrolatum, a vegetable oil, PPG-15
stearyl ether, PEG-4 dilaurate, lecithin, lanolin, lanolin alcohol,
polyoxyl 75 lanolin, cholesterol, cetyl esters wax, cetostearyl
alcohol, glyceryl monostearate, triglycerides of capric and
caprylic acids, dimethicone, and cyclomethicone.
11. The pharmaceutical composition of claim 9, wherein the at least
one emollient is selected from diisopropyl adipate and oleyl
alcohol.
12. The pharmaceutical composition of claim 1, further including at
least one humectant and at least one emollient.
13. The pharmaceutical composition of claim 12, wherein the at
least one humectant is selected from glycerin and hexylene glycol
and wherein the at least one emollient is selected from diisopropyl
adipate and oleyl alcohol.
14. The pharmaceutical composition of claim 1, further including at
least one skin permeation enhancer.
15. The pharmaceutical composition of claim 14, wherein the at
least one permeation enhancer is selected from one or more of oleyl
alcohol, proypylene glycol, and ethanol.
16. The pharmaceutical composition of claim 1, further including at
least one gelling agent.
17. The pharmaceutical composition of claim 16, wherein the at
least one gelling agent is a hydroxypropylcellulose.
18. The pharmaceutical composition of claim 1, further including at
least one antioxidant.
19. The pharmaceutical composition of claim 18, wherein the
antioxidant is selected from the groups consisting of alpha
tocopherol, beta tocopherol, delta tocopherol, gamma tocopherol,
tocopherols, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisol (BHA), butylated hydroxytoluene (BHT), fumaric acid,
malic acid, methionine, propyl gallate, sodium ascorbate, sodium
metabisulfate, sodium thiosulfate, sodium bisulfate.
20. The pharmaceutical composition of claim 19, wherein the
antioxidant is the butylated hydroxytoluene (BHT).
21. The pharmaceutical composition of claim 1, comprising at least
0.01% by weight of the API.
22. The pharmaceutical composition of claim 21, comprising at least
0.1% by weight of the API.
23. The pharmaceutical composition of claim 21, comprising at least
0.5% by weight of the API.
24. The pharmaceutical composition of claim 1, wherein the measured
pH is about 7.
25. The pharmaceutical composition of claim 1, wherein the measured
pH is from about 3 to about 6.
26. The pharmaceutical composition of claim 1, wherein the measured
pH is from about 3 to about 5.
27. The pharmaceutical composition of claim 1, comprising at least
0.5% by weight of the API, wherein the vehicle base comprises a
mixture of ethanol and propylene glycol; and wherein the measured
pH of the pharmaceutical composition is from about 3 to 4.
28. The pharmaceutical composition of claim 27, wherein the at
least one acidifying agent is selected from citric acid and
phosphoric acid.
29. The pharmaceutical composition of claim 27, further including
at least one humectant selected from glycerin and hexylene
glycol.
30. The pharmaceutical composition of claim 27, further including
at least one emollient selected from diisopropyl adipate and oleyl
alcohol.
31. The pharmaceutical composition of claim 27, further including
at least one permeation enhancer is selected from ethanol,
propylene glycol, or oleyl alcohol.
32. The pharmaceutical composition of claim 27, further including a
hydroxypropylcellulose gelling agent.
33. The pharmaceutical composition of claim 1, wherein n is 5, 6 or
7.
34. The pharmaceutical composition of claim 33, wherein n is 6.
35. The pharmaceutical composition of claim 1, wherein R.sub.2 is
hydrogen and R.sub.1 is selected from: a halogen, --OR.sub.A,
N(R.sub.A).sub.2, --NHR.sub.A, --C.sub.1-C.sub.6 alkyl,
--C(O)R.sub.A, --C(O)OR.sub.A, --C(O)N(R.sub.A).sub.2,
--C(O)NH.sub.2, --CHO and --NHC(O)R.sub.A, wherein R.sub.A is
hydrogen or a C.sub.1-C.sub.12 alkyl.
36. The pharmaceutical composition of claim 1, wherein: n is 6;
R.sub.2 is hydrogen and R.sub.1 is --C(O)OR.sub.A; and R.sub.A is a
C.sub.1-C.sub.12 alkyl.
37. A pharmaceutical composition, comprising: at least 0.01% by
weight of an active pharmaceutical ingredient (API) compound
represented by the following structural formula ##STR00012## at
least one acidifying agent; and at least one pharmaceutically
acceptable non-aqueous solvent, wherein: n is 6, R.sub.2 is
hydrogen and R.sub.1 is --C(O)OR.sub.A, R.sub.A is a
C.sub.1-C.sub.12 alkyl; the at least one pharmaceutically
acceptable non-aqueous solvent is a mixture of ethanol and
propylene glycol; the at least one acidifying agent is selected
from one or more of citric acid and phosphoric acid and the
measured pH of the pharmaceutical composition is from about 3 to
about 5, the pharmaceutical composition further optionally
including one or more of the following: at least one humectant
selected from glycerin and hexylene glycol; at least one emollient
selected from diisopropyl adipate and oleyl alcohol; at least one
permeation enhancer selected from ethanol, propylene glycol, or
oleyl alcohol a hydroxypropylcellulose gelling agent; and a
butylated hydroxytoluene as an antioxidant.
38. The pharmaceutical composition of claim 37, wherein the API is
a compound represented by the following structural formula
##STR00013##
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 13/878,994, filed Apr. 11, 2013, which is a U.S. National Stage
of International Application No. PCT/US2011/056148, filed Oct. 13,
2011, which claims the benefit of U.S. Provisional Application No.
61/392,855, filed on Oct. 13, 2010; the entire contents of which
are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Post-translational modification of proteins through
acetylation and deacetylation of lysine residues has a critical
role in regulating cellular functions, making histone deacetylase
an attractive biological target, particularly for the treatment of
cancer. For example, WO 2007/095584 describes small molecule
inhibitors or histone deacetylase having an esterase sensitive
ester linkage. The presence of the esterase-sensitive linker
provides an inhibitor which can achieve high local concentrations
and reduced systemic toxicity.
[0003] Some small molecules that include labile covalent bonds can
be unstable in aqueous solvents. For example, the presence of an
esterase-sensitive linker may present difficulties with respect to
preparation of a suitable formulation. As such, a need exists for
stable pharmaceutical compositions of histone deacetylase
inhibitors when the inhibitor has labile covalent bonds, such as
those described in WO 2007/095584.
SUMMARY OF THE INVENTION
[0004] The present invention relates to pharmaceutical composition
comprising a histone deacetylase inhibitor, methods of using such a
pharmaceutical composition and kits suitable for preparing such a
pharmaceutical composition.
[0005] In one embodiment, the present invention is a pharmaceutical
composition comprising a therapeutically effective amount of an
active pharmaceutical ingredient (API) compound represented by the
following structural formula
##STR00002##
at least one acidifying agent; and a vehicle base comprising at
least one pharmaceutically acceptable non-aqueous solvent. In
structural formula (I), n is an integer from 0 to 15, R.sub.1 and
R.sub.2 are each independently hydrogen, halogen, an aliphatic
group, a heteroaliphatic group, an aryl, a heteroaryl; --OR.sub.A;
--C(O)R.sub.A; --C(O)N(R.sub.A).sub.2; --CO.sub.2R.sub.A; --CN;
--SCN; --SR.sub.A; --SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2;
--N(R.sub.A).sub.2; --NHR.sub.A; --NR.sub.AC(O)R.sub.A; or
--C(R.sub.A).sub.3; and wherein R.sub.A for each occurrence is,
independently, a hydrogen, an aliphatic group, a heteroaliphatic
group, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy;
aryloxy; alkylthio, arylthio, amino, alkylamino, dialkylamino,
heteroaryloxy, or heteroarylthio moiety.
[0006] In another embodiment, the present invention is a
pharmaceutical composition. The composition comprises at least
0.01% by weight of an active pharmaceutical ingredient (API)
compound represented by the following structural formula
##STR00003##
at least one acidifying agent; and at least one pharmaceutically
acceptable non-aqueous solvent. Preferably, n is 6, R.sub.2 is
hydrogen and R.sub.1 is --C(O)OR.sub.A, R.sub.A is a
C.sub.1-C.sub.12 alkyl; the at least one pharmaceutically
acceptable non-aqueous solvent is a mixture of ethanol and
propylene glycol; the at least one acidifying agent is selected
from one or more of citric acid and phosphoric acid and the
measured pH of the pharmaceutical composition is from about 3 to
about 5 In a particular aspect of this embodiment, the
pharmaceutical composition further optionally includes one or more
of the following: at least one humectant selected from glycerin and
hexylene glycol; at least one emollient selected from diisopropyl
adipate and oleyl alcohol; at least one permeation enhancer
selected from ethanol, propylene glycol, or oleyl alcohol; a
hydroxypropylcellulose gelling agent; and a butylated
hydroxytoluene as an antioxidant.
[0007] In another embodiment, the present invention is a method of
treating a disorder in a subject in need thereof. The method
comprises cutaneously administering to the subject a
therapeutically effective amount of a pharmaceutical composition,
wherein the disorder is selected from a proliferative disorder, an
immune disorder and a skin disorder. The pharmaceutical composition
useful for practicing the method of the present invention is
described above.
[0008] In another embodiment, the present invention is a kit. The
kit comprises a first container comprising an active pharmaceutical
ingredient (API) compound represented by the following structural
formula
##STR00004##
and
[0009] a second container comprising a vehicle base comprising at
least one pharmaceutically acceptable non-aqueous solvent. Values
and preferred values of the variables in structural formula (I) are
defined herein below.
[0010] Pharmaceutical formulations of the present invention
unexpectedly combine effective API delivery with extended shelf
life at room temperature. A vehicle base comprising an acidified
non-aqueous solvent contributes to the shelf life extension by
retarding the degradation of API, for example by cleavage (e.g. by
hydrolysis or solvolysis) of the labile covalent bonds of the API
molecule.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The foregoing will be apparent from the following more
particular description of example embodiments of the invention, as
illustrated in the accompanying drawings in which like reference
characters refer to the same parts throughout the different views.
The drawings are not necessarily to scale, emphasis instead being
placed upon illustrating embodiments of the present invention.
[0012] The FIGURE is a block diagram of one embodiment of the
manufacturing process that can be employed to manufacture a
pharmaceutical composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Histone deacetylase inhibitors such as those described in WO
2007/095584, incorporated herein by reference in its entirety, are
small molecules that include labile covalent bonds that can be
unstable in aqueous solvents. It has now been surprisingly
discovered that stability and shelf-life of pharmaceutical
formulations comprising the histone deacetylase inhibitors of WO
2007/095584 can be significantly enhanced by employing non-aqueous
solvents that have been acidified.
[0014] In particular, some of the API compounds described in WO
2007/095584 include a labile bond (e.g. an ester bond), which
hydrolyzes at room temperature. The mechanism of this hydrolysis
may be either base-catalyzed or acid-catalyzed, depending on pH
level. Traditional methods of retarding hydrolysis include either
adjusting acidity (pH) of an aqueous solvent or substituting an
aqueous solvent with a non-aqueous solvent. However, available
experimental data indicates that neither one of these methods alone
provides the desired API stability. Surprisingly, the combination
of at least one non-aqueous solvent and at least one acidifying
agent provides the desired API stability. Discovery of the
suitability of this combination is unexpected. More particularly,
because the rate of hydrolysis of a labile bond in different
solvents as a function of acidity is unpredictable, the discovery
of the existence of a combination of a solvent and an acidifying
agent that provide for a sufficient stability of an API is also
unpredictable and, therefore, unexpected.
Definitions of Terms
[0015] The term "aliphatic", as used herein, means non-aromatic
group that consists solely of carbon and hydrogen and may
optionally contain one or more units of unsaturation, e.g., double
and/or triple bonds. An aliphatic group may be straight chained,
branched or cyclic.
[0016] The term "heteroaliphatic," as used herein, means an
aliphatic group in which one or more carbon atoms is replaced with
a heteroatom, e.g., by O, N, S, Si, P or the like.
[0017] The term "alkyl", as used herein, unless otherwise
indicated, means straight or branched saturated monovalent
hydrocarbon radicals of formula C.sub.nH.sub.2n+1. In some
embodiments, n is from 1 to 18. In other embodiments, n is from 1
to 12. Preferably, n is from 1 to 6. In some embodiments, n is
1-1000, for example, n is 1-100. Alkyl can optionally be
substituted with --OH, --SH, halogen, amino, cyano, nitro, a
C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 haloalkyl,
C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12 haloalkoxy,
C.sub.1-C.sub.12 alkyl sulfanyl, C.sub.2-C.sub.12 alkenyl,
C.sub.2-C.sub.12 alkynyl group, an aryl or a heteroaryl. In
addition, an alkyl can be substituted with .dbd.O, .dbd.S,
.dbd.N-alkyl. Further examples of suitable substituents on an alkyl
group include --R'OR, where each R and each R' is independently an
alkyl, an aryl or a heteroaryl group. The term alkyl can also refer
to cycloalkyl.
[0018] As used herein, an "alkenyl group," alone or as a part of a
larger moiety (e.g., cycloalkene oxide), is preferably a straight
chained or branched aliphatic group having one or more double bonds
with 2 to about 12 carbon atoms, e.g., ethenyl, 1-propenyl,
1-butenyl, 2-butenyl, 2-methyl-1-propenyl, pentenyl, hexenyl,
heptenyl or octenyl, or a cycloaliphatic group having one or more
double bonds with 3 to about 12 carbon atoms. Exemplary
substituents of an alkenyl group are described above with respect
to alkyl.
[0019] As used herein, an "alkynyl" group, alone or as a part of a
larger moiety, is preferably a straight chained or branched
aliphatic group having one or more triple bonds with 2 to about 12
carbon atoms, e.g., ethynyl, 1-propynyl, 1-butynyl,
3-methyl-1-butynyl, 3,3 -dimethyl-1-butynyl, pentynyl, hexynyl,
heptynyl or octynyl, or a cycloaliphatic group having one or more
triple bonds with 3 to about 12 carbon atoms. Exemplary
substituents of an alkynyl group are described above with respect
to alkyl.
[0020] The term "cycloalkyl", as used herein, means saturated
cyclic hydrocarbons, i.e. compounds where all ring atoms are
carbons. In some embodiments, a cycloalkyl comprises from 3 to 18
carbons. Preferably, a cycloalkyl comprises from 3 to 6 carbons.
Examples of cycloalkyl include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
Exemplary substituents of a cycloalkyl are described above with
respect to alkyl.
[0021] The term "haloalkyl", as used herein, includes an alkyl
substituted with one or more F, Cl, Br, or I, wherein alkyl is
defined above. Exemplary substituents of a haloalkyl are described
above with respect to alkyl.
[0022] The terms "alkoxy," as used herein, means an "alkyl-O--"
group, wherein alkyl is defined above. Examples of alkoxy group
include methoxy or ethoxy groups. Exemplary substituents of an
alkoxy are described above with respect to alkyl.
[0023] The terms "alkylthio," as used herein, means an "alkyl-S--"
group, wherein alkyl is defined above. Examples of alkylthio group
include CH.sub.3--S-- or CH.sub.3-CH.sub.2--S-- groups. Exemplary
substituents of an alkylthio group are described above with respect
to alkyl.
[0024] The term "aryl," as used herein, refers to a carbocyclic
aromatic group. Preferably, an aryl comprises from 6 to 18 carbons.
Examples of aryl groups include, but are not limited to phenyl and
naphthyl. Examples of aryl groups include optionally substituted
groups such as phenyl, biphenyl, naphthyl, phenanthryl,
anthracenyl, pyrenyl, fluoranthyl or fluorenyl. An aryl can be
optionally substituted on a substitutable carbon atom. Examples of
suitable substituents on an aryl include halogen, hydroxyl, cyano,
nitro, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, C1-C12
haloalkyl, C1-C12 alkoxy or haloalkoxy group, an aryloxy group, an
arylamino group, an aryl, a heteroaryl group. In addition, an aryl
can be substituted with .dbd.O, .dbd.S, .dbd.N-alkyl. Further
examples of suitable substituents on an aryl group include --R'OR,
where each R and each R' is independently an alkyl, an aryl or a
heteroaryl group.
[0025] In some embodiments, a C6-C18 aryl is selected from the
group consisting of phenyl, indenyl, naphthyl, azulenyl,
heptalenyl, biphenyl, indacenyl, acenaphthylenyl, fluorenyl,
phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl or
benzocyclooctenyl. In some embodiments, a C6-C14 aryl selected from
the group consisting of phenyl, naphthalene, anthracene,
1H-phenalene, tetracene, and pentacene.
[0026] The term "aryloxy," as used herein, means an "aryl-O--"
group, wherein aryl is defined above. Examples of an aryloxy group
include phenoxy or naphthoxy groups. Suitable substituents on an
aryloxy group are as defined above with respect to an aryl
group.
[0027] The term "arylthio," as used herein, means an "aryl-S--"
group, wherein aryl is defined above. Examples of an aryloxy group
include phenylthio or naphthylthio groups. Suitable substituents on
an arylthio group are as defined above with respect to an aryl
group.
[0028] The term "heteroaryl," as used herein, refers to aromatic
groups containing one or more heteroatoms (O, S, or N). A
heteroaryl group can be monocyclic or polycyclic, e.g. a monocyclic
heteroaryl ring fused to one or more carbocyclic aromatic groups or
other monocyclic heteroaryl groups. The heteroaryl groups of this
invention can also include ring systems substituted with one or
more oxo moieties. Examples of heteroaryl groups include, but are
not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl,
pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl,
furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl,
pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl,
benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,
pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl,
thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl,
tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl,
benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.
[0029] In other embodiments, a 5-14-membered heteroaryl group
selected from the group consisting of pyridyl, 1-oxo-pyridyl,
furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl,
oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl,
pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a
triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,
benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,
benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,
indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,
quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl,
pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and
benzothienyl.
[0030] The foregoing heteroaryl groups may be C-attached or
N-attached (where such is possible). For instance, a group derived
from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl
(C-attached).
[0031] The term "(hetero)arylthio," as used herein, means an
"(hetero)aryl-S--" group, wherein aryl is defined above. Examples
of an arylthio group include phenylthio or naphthylthio groups.
[0032] Suitable substituents for heteroaryl are as defined above
with respect to aryl group.
[0033] In some embodiments, suitable substituents for a
substitutable carbon atom in an aryl, a heteroaryl or an aryl
portion of an arylalkenyl include halogen, hydroxyl, C1-C12 alkyl,
C2-C12 alkenyl or C2-C12 alkynyl group, C1-C12 alkoxy, aryloxy
group, arylamino group and C1-C12 haloalkyl.
[0034] In the context of the present invention, an amino group may
be a primary (--NH.sub.2), secondary (--NHR.sub.p), or tertiary
(--NR.sub.pR.sub.q), wherein R.sub.p and R.sub.q may be any of the
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, aryl,
heteroaryl, and a bicyclic carbocyclic group. A (di)alkylamino
group is an instance of an amino group substituted with one or two
alkyls.
[0035] A "trialkylamino" group is a group --N.sup.+(R.sub.t).sub.3,
wherein R.sub.t is an alkyl, as defined above.
[0036] As used herein, the term "acyl" refers to alkanoyl, i.e. a n
alkyl-C(O)--, where "alkyl" is defined above.
[0037] The term (hetero)arylamine, as used herein, means an
"(hetero)aryl-NH--", an "(hetero)aryl-N(alkyl)-", or an
"((hetero)aryl).sub.2-N--" groups, wherein (hetero)aryl and alkyl
are defined above.
[0038] A "humectant," as used herein, is an excipient that can
increase the water level in the upper layers of the skin. Examples
of humectants approved for use in topical drug products by the FDA
include, but are not limited to, the following: hexylene glycol,
propylene glycol, sorbitol, lactic acid, sodium lactate, methyl
gluceth-10, methyl gluceth-20, and polyethylene glycols.
[0039] An "emollients," as used herein, is an excipient that can
improve skin feel by softening, lubricating, and refatting the
skin. Emollients may also improve the barrier function of skin and
reduce water evaporation. Examples of emollients approved for use
in topical drug products by the United States Food and Drug
Administration (FDA) include, but are not limited to, the
following: diisopropyl adipate, isopropyl myristate, isopropyl
palmitate, cetearyl octonoate, isopropyl isostearate, myristyl
lactate, octyldodecanol, oleyl alcohol, mineral oil, petrolatum,
vegetable/plaint oils (e.g., peanut, soybean, safflower, olive,
almond, coconut), PPG-15 stearyl ether, PPG-26 oleate, PEG-4
dilaurate, lecithin, lanolin, lanolin alcohol, polyoxyl 75 lanolin,
cholesterol, cetyl esters wax, cetostearyl alcohol, glyceryl
monostearate, medium chain triglyerides, dimethicone, and
cyclomethicone.
[0040] An "acidifying agent," as used herein, refers to a chemical
compound that alone or in combination with other compounds can be
used to acidify a vehicle base of a pharmaceutical composition
comprising a non-aqueous solvent. An acceptable acidifying agent
for a topical formulation is an acid with a pKa of 9.5 or less,
more preferably having a pKa of 7.0 or less, most preferably having
a pKa of 5.0 or less. Examples of acidifying agents approved for
use in topical drug products by the FDA include, but are not
limited to: acetic acid, dehydro acetic acid, ascorbic acid,
benzoic acid, boric acid, citric acid, edetic acid, hydrochloric
acid, isostearic acid, stearic acid, lactic acid, nitric acid,
oleic acid, phosphoric acid, sorbic acid, sulfuric acid, tartaric
acid, and undecylenic acid.
[0041] A "nonaqueous solvent," as used herein, is a solvent other
than water. Examples of nonaqueous solvents approved for use in
topical drug products by the FDA include, but are not limited to:
alcohol (ethanol), acetone, benzyl alcohol, diethylene glycol
monoethyl ether, glycerin, hexylene glycol, isoproypl alcohol,
polyethylene glycols, methoxypolyethylene glycols, diethyl
sebacate, dimethyl isosorbide, propylene carbonate, and dimethyl
sulfoxide. Many emollients that are liquid at room temperature can
also be used as solvents. These include, but are not limited to:
diisopropyl adipate, isopropyl myristate, vegetable/plant oils,
mineral oil, and isopropyl palmitate.
[0042] An "antioxidant," as used herein, is a substance that
inhibits oxidation of chemical compounds. Examples of typical
antioxidants include alpha tocopherol (all isomers), beta
tocopherol, delta tocopherol, gamma tocopherol, tocopherols,
ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol (BHA),
butylated hydroxytoluene (BHT), fumaric acid, malic acid,
methionine, propyl gallate, sodium ascorbate, sodium metabisulfate,
sodium thiosulfate, sodium bisulfate. The chemical compounds
protected from oxidation by an antioxidant include active
pharmaceutical ingredients (API) and excipients containing moieties
susceptible to oxidation.
[0043] A "gelling agent," as used herein, is a compound that
thickens (i.e. increases the viscosity of) a formulation. Examples
are hydroxypropylcelluloses, carbomer, hydroxyethylcelluloses,
carboxymethylcelluloses, xanthan gum, guar gum, chitosan, polyvinyl
alcohol, povidone, carrageenan, methyl cellulose, hydroxypropyl
methyl cellulose, fatty alcohols, cetyl alcohol, stearyl alcohol,
cetostearyl alcohol, and myristyl alcohol. In a particular
embodiment, the gelling agent is a pharmaceutical grade
hydroxypropylcellulose Klucel.RTM. MF ("Klucel MF PH"), available
from Hercules Incorporated of Wilmington DE, under the catalog
number 494-9.
[0044] A "skin permeation enhancer," as used herein, is a compound
that improves absorption of a pharmaceutically active ingredient
through a cutaneous membrane, e.g. skin.
[0045] "Measured pH," as used herein, is the acidity of an aliquot
of a pharmaceutical composition of the present invention as defined
herein, measured by diluting the aliquot with water to about 10% by
volume.
[0046] As used herein, the term "therapeutically effective amount"
refers to an amount of the API which is sufficient to reduce or
ameliorate the severity, duration, progression, or onset of a
disorder being treated, prevent the advancement of a disorder being
treated, cause the regression of, prevent the recurrence,
development, onset or progression of a symptom associated with a
disorder being treated, or enhance or improve the prophylactic or
therapeutic effect(s) of another therapy. The precise amount of
compound administered to a subject will depend on the type and
severity of the disease or condition and on the characteristics of
the subject, such as general health, age, sex, body weight and
tolerance to drugs. It will also depend on the degree, severity and
type of the disorder being treated. The skilled artisan will be
able to determine appropriate dosages depending on these and other
factors. When co-administered with other agents, e.g., when
co-administered with an anti-proliferative agent, a
"therapeutically effective amount" of the second agent will depend
on the type of drug used. Suitable dosages are known for approved
agents and can be adjusted by the skilled artisan according to the
condition of the subject, the type of condition(s) being treated
and the amount of a compound of the invention being used. In cases
where no amount is expressly noted, an effective amount should be
assumed.
[0047] As used herein, the terms "treat", "treatment" and
"treating" refer to the reduction or amelioration of the
progression, severity and/or duration of a disorder being treated,
or the amelioration of one or more symptoms (preferably, one or
more discernible symptoms) of a disorder being treated resulting
from the administration of one or more pharmaceutical compositions
of the present invention. In specific embodiments, the terms
"treat", "treatment" and "treating" refer to the amelioration of at
least one measurable physical parameter being treated. For example,
for a proliferative disorder, such parameters can include growth of
a tumor, not necessarily discernible by the patient. In other
embodiments the terms "treat", "treatment" and "treating" refer to
the inhibition of the progression of a disorder being treated,
either physically by, e.g., stabilization of a discernible symptom,
physiologically by, e.g., stabilization of a physical parameter, or
both. In the embodiments in which the disorder being treated is a
proliferative disorder, the terms "treat", "treatment" and
"treating" can refer to the reduction or stabilization of cancerous
cell count.
[0048] An "ointment," as used herein, is a semisolid dosage form,
usually containing less than 20% water and volatiles and more than
50% hydrocarbons, waxes, or polyols as the vehicle. This dosage
form is generally for external application to the skin or mucous
membranes.
[0049] "Semisolid," as used herein refers to the aggregate state of
the matter that is not pourable; it does not flow or conform to its
container at room temperature; it does not flow at low shear stress
and generally exhibits plastic flow behavior.
[0050] A "gel," as used herein, is a semisolid dosage form that
contains a gelling agent to thicken to a solution or fine particle
dispersion. Thickening the formulation aids in application to a
specific site on the body. A gel may contain suspended
particles.
[0051] "Fine particle dispersion," as used herein, is a system in
which fine particles of (i.e. typically less than 10-50 .mu.m) are
distributed uniformly throughout a liquid.
[0052] A "foam," as used herein, is a dosage form containing gas
bubbles dispersed in a liquid that contains less than 50% water,
and in a particular embodiment, no water.
Pharmaceutical Compositions
[0053] In one embodiment, the present invention is a pharmaceutical
composition, comprising a therapeutically effective amount of an
active pharmaceutical ingredient (API) compound represented by the
following structural formula
##STR00005##
at least one acidifying agent and a vehicle base comprising at
least one pharmaceutically acceptable non-aqueous solvent. In
structural formula (I), n is an integer from 0 to 15, R.sub.1 and
R.sub.2 are each independently hydrogen, halogen, an aliphatic
group, a heteroaliphatic group, an aryl, a heteroaryl; --OR.sub.A;
--C(O)R.sub.A; --C(O)N(R.sub.A).sub.2; --CO.sub.2R.sub.A; --CN;
--SCN; --SR.sub.A; --SOR.sub.A; --SO.sub.2R.sub.A; --NO.sub.2;
--N(R.sub.A).sub.2; --NHR.sub.A; --NR.sub.AC(O)R.sub.A; or
--C(R.sub.A).sub.3, wherein R.sub.A for each occurrence is,
independently, a hydrogen, an aliphatic group, a heteroaliphatic
group, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy;
aryloxy; alkylthio, arylthio, amino, alkylamino, dialkylamino,
heteroaryloxy, or heteroarylthio moiety.
[0054] In some embodiments, in structural formula (I), n is 5, 6 or
7, preferably, n is 6. Values and preferred values of the remainder
of the variable are as defined above with respect to structural
formula (I).
[0055] In other embodiments, in structural formula (I), R.sub.2 is
hydrogen and R.sub.1 is selected from a halogen, --OR.sub.A,
N(R.sub.A).sub.2, --NHR.sub.A, --C.sub.1-C.sub.6 alkyl,
--C(O)R.sub.A, --C(O)OR.sub.A, --C(O)N(R.sub.A).sub.2,
--C(O)NH.sub.2, --CHO and --NHC(O)R.sub.A. Values and preferred
values of the remainder of the variable are as defined above with
respect to structural formula (I). Preferably, R.sub.A is hydrogen
or a C.sub.1-C.sub.12 alkyl. Values and preferred values of the
remainder of the variable are as defined above with respect to
structural formula (I).
[0056] In other embodiments, in structural formula (I), n is 6,
R.sub.2 is hydrogen and R.sub.1 is --C(O)OR.sub.A, and R.sub.A is a
C.sub.1-C.sub.12 alkyl. Values and preferred values of the
remainder of the variable are as defined above with respect to
structural formula (I).
[0057] In some embodiments, at least one acidifying agent is
selected from the groups consisting of acetic acid, dehydro acetic
acid, ascorbic acid, benzoic acid, boric acid, citric acid, edetic
acid, hydrochloric acid, isostearic acid, stearic acid, lactic
acid, nitric acid, oleic acid, phosphoric acid, sorbic acid,
sulfuric acid, tartaric acid, undecylenic acid, fumaric acid, malic
acid, maleic acid, benzene sulfonic acid, cyclamic acid, diatrizoic
acid, deoxycholic acid, gentisic acid, glucuronic acid, glutamic
acid, and succinic acid. In a particular embodiment, at least one
acidifying agent is selected from one or more of citric acid,
acetic acid, and phosphoric acid.
[0058] In some embodiments, semi-polar non-aqueous solvents are
preferred (e.g., miscible with water such as ethanol, propylene
glycol). In other embodiments, at least one pharmaceutically
acceptable non-aqueous solvent is selected from the groups
consisting of ethanol, acetone, benzyl alcohol,
2-(2-ethoxyethoxy)ethanol, diethylene glycol monoethyl ether,
glycerin, propylene glycol, propylene carbonate, acetone, hexylene
glycol, isopropyl alcohol, polyethylene glycols (PEGs),
methoxypolyethylene glycols, diethyl sebacate, dimethyl isosorbide,
propylene carbonate, dimethyl sulfoxide (DMSO), diisopropyl
adipate, isopropyl myristate, vegetable oils, a mineral oil, and
isopropyl palmitate. In a particular embodiment, at least one
pharmaceutically acceptable non-aqueous solvent is selected from
ethanol, benzyl alcohol, propylene glycol,
2-(2-ethoxyethoxy)ethanol, hexylene glycol and diisopropyl
adipate.
[0059] In some embodiments, a pharmaceutical composition of the
present invention further includes at least one humectant. At least
one humectant is selected from the groups consisting of hexylene
glycol, glycerin, propylene glycol, sorbitol, lactic acid, sodium
lactate, mannitol, butylene glycol, panthenol, hyaluronic acid,
urea, chitosan, polyols, methyl gluceth-10, methyl gluceth-20, and
polyethylene glycols. In a particular embodiment, at least one
humectant is selected from glycerin and hexylene glycol.
[0060] In some embodiments, the pharmaceutical composition of the
present invention further includes at least one emollient. In some
embodiments, at least one emollient is selected from the groups
consisting of diisopropyl adipate, isopropyl myristate, isopropyl
palmitate, cetearyl octonoate, isopropyl isostearate, myristyl
lactate, octyldodecanol, oleyl alcohol, a mineral oil, petrolatum,
a vegetable oil, PPG-15 stearyl ether, PEG-4 dilaurate, lecithin,
lanolin, lanolin alcohol, polyoxyl 75 lanolin, cholesterol, cetyl
esters wax, cetostearyl alcohol, glyceryl monostearate,
triglycerides of capric and caprylic acids, dimethicone, and
cyclomethicone. In a particular embodiment, at least one emollient
is selected from diisopropyl adipate and oleyl alcohol.
[0061] In particular embodiments, the pharmaceutical composition of
the present invention includes at least one humectant and at least
one emollient. Values and preferred values of humectants and
emollients are listed above. In a particular embodiment, at least
one humectant is selected from one or more of glycerin and hexylene
glycol and wherein the at least one emollient is selected from
diisopropyl adipate and oleyl alcohol.
[0062] In some embodiments, the pharmaceutical composition of the
present invention further includes at least one skin permeation
enhancer. Suitable skin permeation enhancers include, but are not
limited to, dimethylsulfoxide (DMSO), decylmethylsulfoxide,
N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone,
1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
1,5-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5
carboxylic acid, propylene glycol, ethanol, isopropanol, oleic
acid, laurocapram (Azone), limonene, cineole, diethyl-m-toluamide
(DEET), sodium dodecylsulfate, trimethyl phosphine oxide,
tetrahydrofurfuryl alcohol, glycerol monolaurate, methyl oleate,
propylene glycol monolaurate, and oleyl alcohol. In a specific
aspect, at least one permeation enhancer is selected from oleyl
alcohol, propylene glycol and ethanol.
[0063] In some embodiments, the pharmaceutical composition of the
present invention further includes at least one gelling agent. In
particular embodiments, gelling agents are neutral polymers that
thicken at low pH, such as cellulose-based polymers, for example
hydroxypropylcellulose. In particular embodiments, at least one
gelling agents is selected from hydroxypropylcellulose, carbomer,
hydroxyethylcellulose, carboxymethylcellulose, xanthan gum, guar
gum, chitosan, polyvinyl alcohol, povidone, carrageenan, methyl
cellulose, hydroxypropyl methyl cellulose, fatty alcohols, cetyl
alcohol, stearyl alcohol, cetostearyl alcohol, and myristyl
alcohol. In a particular embodiment, at least one gelling agent is
a hydroxypropylcellulose such as Klucel MF PH.
[0064] In some embodiments, the pharmaceutical composition of the
present invention further includes at least one antioxidant. In a
particular embodiment, the antioxidant is selected from the groups
consisting of alpha tocopherol, beta tocopherol, delta tocopherol,
gamma tocopherol, tocopherols, ascorbic acid, ascorbyl palmitate,
butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT),
fumaric acid, malic acid, methionine, propyl gallate, sodium
ascorbate, sodium metabisulfate, sodium thiosulfate, sodium
bisulfate. In a particular embodiment, the antioxidant is the
butylated hydroxytoluene (BHT).
[0065] In various embodiments, the pharmaceutical composition of
the present invention comprises at least 0.01% by weight of the
API. In some embodiments, the pharmaceutical composition of the
present invention comprises from about 0.01% to about 15% by weight
of the API. In other embodiments, the pharmaceutical composition of
the present invention comprises at least about 0.1% by weight of
the API, alternatively--at least 0.5% by weight of the API. For
example, the pharmaceutical composition of the present invention
comprises, by weight, at least about 0.01%, 0.02%, 0.03%, 0.04%,
0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%,
4.5% or 5% of the API. In certain embodiments, the pharmaceutical
composition of the present invention comprises at least about 10%
by weight of the API.
[0066] In various embodiments, the measured pH of the
pharmaceutical composition of the present invention is about 7. In
other embodiments, the measured pH if the pharmaceutical
composition of the present invention is from about 3 to about 6. In
a particular embodiment, the measured pH is from about 3 to about
5.
[0067] An example of a pharmaceutical composition of the present
invention, is a pharmaceutical composition as defined herein above,
comprising at least 0.01% by weight of the API, wherein the vehicle
base comprises a mixture of ethanol and propylene glycol, and
wherein the measured pH of the pharmaceutical composition is from
about 3 to 5. In a particular embodiment, the at least one
acidifying agent is selected from one or more of citric acid and
phosphoric acid. In some embodiments, the pharmaceutical
composition further includes at least one humectant selected from
one of more of glycerin and hexylene glycol. In other embodiment,
the pharmaceutical composition further includes at least one
emollient selected from one or more of diisopropyl adipate and
oleyl alcohol. In a particular embodiment, the pharmaceutical
composition further includes at least one permeation enhancer
selected from one or more of oleyl alcohol, propylene glycol and
ethanol. In further embodiments, the pharmaceutical composition
further includes a hydroxypropylcellulose gelling agent such as
Klucel MF PH.
[0068] In another example, a pharmaceutical composition of the
present invention comprises at least 0.01% by weight (e.g., 0.01%,
0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.1%,
0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2%,
2.5%, 3%, 3.5%, 4%, 4.5% or 5%) of an active pharmaceutical
ingredient (API) compound represented by the following structural
formula
##STR00006##
wherein n is 6, R.sub.2 is hydrogen and R.sub.1 is --C(O)OR.sub.A,
R.sub.A is a C.sub.1-C.sub.12 alkyl. The pharmaceutical composition
can further include at least one acidifying agent, and at least one
pharmaceutically acceptable non-aqueous solvent, the at least one
pharmaceutically acceptable non-aqueous solvent is a mixture of
ethanol and propylene glycol, the at least one acidifying agent is
selected from one or more of citric acid and phosphoric acid and
the measured pH of the pharmaceutical composition is from about 3
to about 5. The pharmaceutical composition can further include at
least one humectant selected from one of more of glycerin and
hexylene glycol; at least one emollient selected from one or more
of diisopropyl adipate and oleyl alcohol; at least one permeation
enhancer selected from one or more of oleyl alcohol, propylene
glycol and ethanol; a hydroxypropylcellulose gelling agent such as
Klucel MF PH; and a butylated hydroxytoluene as an antioxidant.
[0069] In a particular embodiment, the pharmaceutical composition
of the present invention comprises the API is a compound
represented by the following structural formula
##STR00007##
[0070] In the above-described compositions of the present
invention, the amount of a pharmaceutically acceptable non-aqueous
solvent is the amount suitable to bring the composition to the
desirable volume and/or weight. For example, on the weight per
weight basis (% w/w), the amount of one or more solvents is from
about 5% to about 99.9%. For example, the amount of one or more
solvents can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In other
embodiments, on the weight per weight basis (% w/w), the amount of
one or more humectants is, for example, from about 5% to about 50%,
e.g. 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%. In other
embodiments, on the weight per weight basis (% w/w), the amount of
one or more emollients is, for example, from about 5% to about 50%,
e.g. 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%. In other
embodiments, on the weight per weight basis (% w/w), the amount of
one or more antioxidants is, for example, from about 0.01% to about
5%, e.g. 0.01%, 0.05, 0.1%, 0.15%. 0.2%, 0.5%, 1.0%, 1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, or 5.0%. In other embodiments, on the
weight per weight basis (% w/w), the amount of one or more
acidifying agents is, for example, from about 0.01% to about 5.0%,
e.g. 0.01%, 0.05, 0.1%, 0.15%. 0.2%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%,
3.0%, 3.5%, 4.0%, or 5.0%. In other embodiments, on the weight per
weight basis (% w/w), the amount of one or more gelling agents is,
for example, from about 0.5% to about 5.0%, e.g. 0.5%, 1.0%, 1.5%,
2.0%, 2.5%, 3.0%, 3.5%, 4.0%, or 5.0%.
[0071] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic and otic
solutions, sprays, foams, aerosols, creams, lotions, ointments,
gels, solutions, emulsions, suspensions, or other forms known to
one of skill in the art. See, e.g., Remington's Pharmaceutical
Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing,
Easton Pa. and Introduction to Pharmaceutical Dosage Forms (1985)
4th ed., Lea & Febiger, Philadelphia. Further, transdermal
dosage forms include "reservoir type" or "matrix type" patches,
which can be applied to the skin and worn for a specific period of
time to permit the penetration of a desired amount of active
ingredients.
[0072] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. See, e.g., Remington's Pharmaceutical
Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing,
Easton, Pa.
[0073] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue.
[0074] Different salts, hydrates or solvates of the active
ingredients can be used to further adjust the properties of the
resulting composition.
[0075] In a particular embodiment, pharmaceutical compositions of
the present invention can be formulated as non-aqueous ointments,
non-aqueous gels or non-aqueous foams.
Methods of Treatment
[0076] In some embodiments, the present invention is a method of
treating a proliferative disorder, an immune disorder and a skin
disorder in a subject in need thereof. The method comprises
cutaneously administering to the subject a therapeutically
effective amount of a pharmaceutical composition. The
pharmaceutical composition comprises a pharmaceutically effective
amount of an active pharmaceutical ingredient (API) compound
represented by the following structural formula
##STR00008##
at least one acidifying agent, and at least one pharmaceutically
acceptable non-aqueous solvent. The values and preferred values of
the variables in structural formula (I) are as defined hereinabove.
Particular and optional components and ingredients of
pharmaceutical compositions useful in treating a proliferative
disorder, an immune disorder and a skin disorder according to the
methods of the present invention have also been described
above.
[0077] In some embodiments, the present invention is a method of
treating a selected from a disorder selected from the group
consisting of cutaneous T cell lymphoma, a skin cancer, a benign
skin growth, acne, psoriasis, dermatitis, actinic keratosis, basal
cell carcinoma, neurofibromatosis, a leukemia, a malignant
melanoma, hair loss, and skin hyperpigmentation. In a particular
embodiment, the disorder is selected from cutaneous T-cell
lymphoma, neurofibromatosis, actinic keratosis, acne, basal cell
carcinoma, psoriasis, hair loss, skin pigmentation, and
dermatitis.
Kits Comprising Pharmaceutical Compositions of the Present
Invention
[0078] In some embodiments, the present invention is a kit,
comprising a first container and a second container. The first
container comprises an active pharmaceutical ingredient (API)
represented by the following structural formula
##STR00009##
[0079] Values and preferred values of the variables in structural
formula (I) are defined hereinabove. The second container comprises
a vehicle base. The vehicle base includes at least one
pharmaceutically acceptable non-aqueous solvent and at least one
acidifying agent. Particular pharmaceutically acceptable
non-aqueous solvent and acidifying agents are defined
hereinabove.
[0080] In a particular embodiment, the first container comprises a
therapeutically effective amount of the API.
[0081] In various embodiments, the kit can further include one or
more of the following components: at least one gelling agent, at
least one humectant, at least one emollient, at least one skin
permeation enhancer, and at least one antioxidant. Suitable gelling
agents, humectants, emollients, skin permeation enhancers and
antioxidants are defined hereinabove.
[0082] In some embodiments, the kit further includes a third
container comprising at least one gelling agent.
[0083] In some embodiments, the second container comprises ethanol,
benzyl alcohol, and citric acid. In other embodiments, the third
container further comprises propylene glycol, hexylene glycol,
glycerin, diisopropyl adipate, oleyl alcohol, and butylated
hydroxytoluene. In a particular embodiment, the third container
further comprises propylene glycol, hexylene glycol, glycerin,
diisopropyl adipate, oleyl alcohol, and butylated
hydroxytoluene.
[0084] Any embodiment of the kit can further include instructions
for the use of such kit. In some embodiments, the instructions
include the steps of adding the content of the first container to
the second container. In other embodiments, the instructions
include the steps of blending the contents of the first, the second
and the third containers.
[0085] Referring to the FIGURE, one example of a manufacturing
process that can be employed to produce a pharmaceutical
composition of the present invention is process 100. In step 102,
solvents and emollients are added to a vessel. In particular
embodiments, solvents and emollients are mixed to uniformity. In
step 104, one or more antioxidants are added to the mixture. In a
particular embodiment, butylated hydroxytoluene is added to the
mixture and dissolved. In step 106, an acidifying agent is added to
the vessel. In a particular embodiment, an anhydrous citric acid is
added to the mixture. In step 108, an API is added to the mixture.
In step 110, a gelling agent is added to the vessel. In a
particular embodiment, Klucel MF PH is added to the mixture. In
step 112, the mixture is aliquoted into desirable containers.
Optionally, in step 114, fill weight of each container is checked
for accuracy.
EXEMPLIFICATION
Example 1
Stability of Pharmaceutical Formulations of the Present
Invention
Materials and Methods
[0086] API used was the compound of structural formula (II). All
excipients used are listed in the United States
Pharmacopeia-National Fromulary (USP/NF). Water and acetonitrile
for HPLC analysis were HPLC grade. An Orion 710A+ meter with a Ross
Ultra electrode (Thermo Electron Corp.) was used to measure pH. The
samples were diluted 1/10 prior to pH measurement to minimize
junction potential errors in the measurement. Viscosity (at
20.+-.1.degree. C.) was measured with a Brookfield LVF viscometer
at 12 rpm using a #25 spindle and 13R sample holder. Since the
samples were stored at different temperatures, they were allowed to
equilibrate at the viscosity measurement temperature for at least
12 hours. HPLC analysis was performed using an HP 1050 system
equipped with a variable wavelength UV/Vis detector. A gradient
HPLC method is summarized in Table 1.
TABLE-US-00001 TABLE 1 Column ACE 5 micron C18 4.6 .times. 150 mm
Mobile Phase A 10% ACN/90%, 0.2% PCA Mobile Phase B 80% ACN/20%,
0.2% PCA Gradient 0.0 min. 100% A 20.0 min. 100% B 20.1 min. 100% A
Run Time 28 min. Flow Rate 1.5 mL/min UV Detector 230 nm Injection
Volume 20 .mu.L Column Temperature 30.degree. C. ACN: acetonitrile
PCA: perchloric acid
Gel Preparation
[0087] One of ordinary skill in the art would understand that the
process below can be modified, if necessary, in order to be scaled
up.
[0088] The following laboratory-scale process has been used to
manufacture gels formulations of the pharmaceutical compositions of
the present invention. (During this process, the vessel was open
part of the time to allow insertion and operation of mixing blades
attached to an overhead stirrer. To compensate for alcohol
evaporation, a 2.0% overage of this solvent was used.)
[0089] 1. Solvents and emollients were added to a suitable vessel.
A magnetic stir bar was added, the vessel was sealed and placed on
a stir plate. Mixing continued until the liquids are
homogenous.
[0090] 2. The seal was removed, BHT was added, and the seal was
replaced. The solution was mixed until the antioxidant
dissolved.
[0091] 3. The seal was removed, the acid was added, and the seal
was replaced. The solution was mixed until homogeneous. If citric
acid was used, the powder was added directly to the vessel. If
phosphoric acid was used, it was weighed into a small beaker then
rinsed into the vessel with some reserved ethanol.
[0092] 4. The seal was removed, compound (II) was added (for active
formulations only), and the seal was replaced. The solution was
mixed until the active dissolved.
[0093] 5. The seal was removed, the stir bar carefully removed, and
a propeller mixer blade attached to an overhead stirrer was
inserted. The mixing speed was adjusted to form a good vortex
without excessive cavitation or splashing.
[0094] 6. The Klucel MF PH was slowly added into the vortex to
disperse the polymer. Mixing speed was adjusted as the formulation
thickened to maintain good mixing of the drug product without
excessive aeration. The vessel was partially covered to minimize
evaporation.
[0095] 7. Approximately 20-30 minutes after adding the polymer,
thickening occurred to the point where the propeller blade was not
sufficient to keep all of the formulation mixing smoothly. The
propeller blade was carefully removed and the formulation was
drained off the blade into the vessel (this was assisted with
spatulation).
[0096] 8. A suitable anchor blade attached to an overhead stirrer
was inserted and mixing continued at a suitable speed. The vessel
was partially covered to minimize evaporation.
[0097] 9. Approximately 2 hours after adding the polymer, the gel
was homogeneous with a slightly mottled appearance. To minimize
evaporation while the polymer continued to swell, the anchor
stirrer was carefully removed (allowing the gel to drain off into
the vessel) and the vessel was sealed.
[0098] 10. The vessel was stored at room temperature protected from
light for 12-18 hours. After storage, the gel was remixed for an
additional 15 minutes. After final mixing was completed, the gel
was filled into a suitable container.
Results
[0099] In neutral ethanol at room temperature, compound (II)
degrades by approximately 50% in 24 hours.
[0100] Six active batches were prepared at the 350 g scale. The
citric acid level was reduced slightly so that the pH would move
closer to 4.0. Their compositions and initial results are
summarized in Tables 2A-2B and Tables 3A-3B, respectively.
TABLE-US-00002 TABLE 2A Compositions A, B, C and D (all values in %
w/w, dehydrated ethanol USP added to bring total to 100%) A B C D
Compound (II) 1.0 1.0 1.0 1.0 Propylene glycol, USP 15.0 -- 15.0 --
Glycerin, USP 10.0 -- 10.0 -- diethylene glycol monoethyl -- 25.0
-- 25.0 ether, USP Hexylene glycol, NF 12.0 12.0 12.0 12.0
Diisopropyl adipate 4.0 4.0 4.0 4.0 Oleyl alcohol, NF 5.0 5.0 5.0
5.0 BHT, NF 0.1 0.1 0.1 0.1 Citric acid (anhydrous), USP 0.045
0.045 -- -- Phosphoric acid (85%), USP -- -- 0.015 0.015 Klucel MF
PH 2.0 2.0 2.0 2.0
TABLE-US-00003 TABLE 2B Compositions E and F (all values in % w/w)
E F Compound (II) 0.1 0.5 Propylene 15.0 15.0 glycol, USP Glycerin,
USP 10.0 10.0 Diethylene 0.0 0.0 glycol monoethyl ether, USP
Hexylene glycol, 12.0 12.0 NF Diisopropyl 4.0 4.0 adipate Oleyl
alcohol, 5.0 5.0 NF BHT, NF 0.1 0.1 Citric acid 0.045 0.045
(anhydrous), USP Phosphoric acid 0 0 (85%), USP Klucel MF PH 2.0
2.0 Dehydrated 51.755 51.355 alcohol (ethanol), USP
TABLE-US-00004 TABLE 3A Initial results for compositions in Table
2A A B C D Compound (II), 0.994 0.995 0.996 0.995 % w/w BHT assay,
0.099 0.099 0.102 0.101 % w/w pH 3.75 3.92 3.95 3.89 Viscosity, cP
18,800 20,000 17,600 21,200 Appearance Conforms.sup.1
Conforms.sup.1 Conforms.sup.1 Conforms.sup.1 .sup.1Clear or
translucent colorless viscous liquid
TABLE-US-00005 TABLE 3B Initial results for compositions in Table
2B Property E F SHP-141 assay, % w/w 0.100 0.499 BHT assay, % w/w
0.099 0.099 pH 3.80 3.70 Viscosity, cP Not tested 24,532 Appearance
Conforms.sup.1 Conforms.sup.1 .sup.1Clear to translucent colorless
viscous liquid.
[0101] The results of a 6-month study of stability of formulations
A, B and C are presented below in Table 4 through Table 8.
TABLE-US-00006 TABLE 4 Stability of Compound (II) gels after 2
weeks of storage at 40.degree. C. A B C Compound (II), 98.3 98.5
98.1 % initial BHT, % initial 100.4 100.1 99.7 pH 3.85 3.79 3.95
Viscosity, cP 16,800 17,600 16,000 Appearance Conforms.sup.1
Conforms.sup.1 Conforms.sup.1 .sup.1Clear or translucent colorless
viscous liquid
TABLE-US-00007 TABLE 5 Stability results for Compound (II) gels
after 1 month of storage at 2-8 and 25.degree. C. A B C Compound
(II), % initial 1 month, 25.degree. C. 98.4 98.5 98.2 1 month,
2-8.degree. C. 99.9 99.8 99.4 BHT assay, % initial 1 month,
25.degree. C. 99.8 100.3 99.8 1 month, 2-8.degree. C. 99.7 99.9
99.6 pH 1 month, 25.degree. C. 3.92 3.80 3.90 1 month, 2-8.degree.
C. 3.84 3.97 3.99 Viscosity, cP 1 month, 25.degree. C. 19,200
22,400 20,000 1 month, 2-8.degree. C. 20,400 22,000 21,600
Appearance 1 month, 25.degree. C. Conforms.sup.1 Conforms.sup.1
Conforms.sup.1 1 month, 2-8.degree. C. Conforms.sup.1
Conforms.sup.1 Conforms.sup.1 .sup.1Clear or translucent colorless
viscous liquid
TABLE-US-00008 TABLE 6 Stability of Compound (II) gels after 2
months of storage at 2-8 and 25.degree. C. A B C Compound (II), %
initial 2 month, 25.degree. C. 97.1 96.9 96.5 2 month 2-8.degree.
C. 99.1 98.8 98.6 BHT assay, % initial 2 month, 25.degree. C. 99.5
99.7 99.5 2 month 2-8.degree. C. 99.8 99.8 99.5 pH 2 month,
25.degree. C. 3.85 3.91 4.02 2 month 2-8.degree. C. 3.83 3.88 3.94
Viscosity, cP 2 month, 25.degree. C. 20,400 23,200 22,800 2 month
2-8.degree. C. 20,800 21,200 23,200 Appearance 2 month, 25.degree.
C. Conforms.sup.1 Conforms.sup.1 Conforms.sup.1 2 month 2-8.degree.
C. Conforms.sup.1 Conforms.sup.1 Conforms.sup.1 .sup.1Clear or
translucent colorless viscous liquid
TABLE-US-00009 TABLE 7 Stability of Compound (II) gels after 3
months of storage at 2-8 and 25.degree. C. A B C Compound (II), %
initial 3 months, 25.degree. C. 96.4 96.1 95.6 3 months,
2-8.degree. C. 98.6 98.3 97.5 BHT assay, % initial 3 months,
25.degree. C. 99.7 99.7 99.6 3 months, 2-8.degree. C. 99.5 99.4
99.9 pH 3 months, 25.degree. C. 3.95 3.81 3.96 3 months,
2-8.degree. C. 3.82 3.84 4.05 Viscosity, cP 3 months, 25.degree. C.
24,000 24,400 24,000 3 months, 2-8.degree. C. 22,800 23,200 24,800
Appearance 3 months, 25.degree. C. Conforms.sup.1 Conforms.sup.1
Conforms.sup.1 3 months, 2-8.degree. C. Conforms.sup.1
Conforms.sup.1 Conforms.sup.1 .sup.1Clear or translucent colorless
viscous liquid
TABLE-US-00010 TABLE 8 Stability of Compound (II) gels after 6
months of storage at 2-8 and 25.degree. C. A B C Compound (II), %
initial 6 month, 25.degree. C. 95.0 94.5 93.4 6 month 2-8.degree.
C. 97.9 97.7 96.9 BHT assay, % initial 6 month, 25.degree. C. 99.4
99.2 99.0 6 month 2-8.degree. C. 99.3 99.4 99.3 pH 6 month,
25.degree. C. 3.87 3.89 4.01 6 month 2-8.degree. C. 3.85 3.94 3.95
Viscosity, cP 6 month, 25.degree. C. 23,600 23,600 25,200 6 month
2-8.degree. C. 22,000 22,400 23,600 Appearance 6 month, 25.degree.
C. Conforms.sup.1 Conforms.sup.1 Conforms.sup.1 6 month 2-8.degree.
C. Conforms.sup.1 Conforms.sup.1 Conforms.sup.1 .sup.1Clear or
translucent colorless viscous liquid
[0102] The results of a 3-month study of stability of formulations
E and F are presented below in Table 9.
TABLE-US-00011 TABLE 9 Stability of formulations E and F after 3
months of storage Property E F SHP-141 assay, % initial 3 month,
25.degree. C. 100.1 99.0 3 month, 2-8.degree. C. 100.6 99.7 BHT
assay, % initial 3 month, 25.degree. C. 99.3 103.3 3 month,
2-8.degree. C. 100.6 103.8 pH 3 month, 25.degree. C. 3.90 4.00 3
month, 2-8.degree. C. 3.90 4.00 Viscosity, cP 3 month, 25.degree.
C. 20,800 25,435 3 month, 2-8.degree. C. 21,550 25,288 Appearance 3
month, 25.degree. C. Conforms.sup.1 Conforms.sup.1 3 month,
2-8.degree. C. Conforms.sup.1 Conforms.sup.1 .sup.1Clear to
translucent colorless viscous liquid.
[0103] The results of a 6-month study of stability of formulation F
are presented below in Table 10.
TABLE-US-00012 TABLE 10 Stability of formulation F after 6 months
of storage Property F SHP-141 assay, % initial 6 month, 25.degree.
C. 99.5 6 month, 2-8.degree. C. 100.5 BHT assay, % initial 6 month,
25.degree. C. 99.5 6 month, 2-8.degree. C. 100.3 pH 6 month,
25.degree. C. 4.00 6 month, 2-8.degree. C. 3.80 Viscosity, cP 6
month, 25.degree. C. 25,448 6 month, 2-8.degree. C. 24,042
Appearance 6 month, 25.degree. C. Conforms.sup.1 6 month,
2-8.degree. C. Conforms.sup.1 .sup.1Clear to translucent colorless
viscous liquid.
[0104] The results of a 6-month study of stability of formulation E
are presented in Tables 11 and 12.
TABLE-US-00013 TABLE 11 Stability of formulation E after 6 months
of storage at 5.degree. C. Parameter E Assay 102.0 BHT 98.2 pH 3.9
Viscosity 21240 cP
TABLE-US-00014 TABLE 12 Stability of formulation E after 6 months
of storage at 25.degree. C. and 60% relative humidity Parameter E
Assay 99.3 BHT 97.3 pH 3.9 Viscosity 22480 cP
[0105] The results of a 12-month study of stability of formulation
A and F are presented in Tables 13 and 14.
TABLE-US-00015 TABLE 13 Stability of formulations A and F after 12
months of storage at 5.degree. C. Parameter F A Assay 102.5 100.9
BHT 99.2 99.2 pH 3.8 3.8 Viscosity 29910 cP 23750 cP
TABLE-US-00016 TABLE 14 Stability of formulations A and F after 12
months of storage at 25.degree. C. and 60% relative humidity
Parameter F A Assay 99.2 94.4 BHT 97.9 97.1 pH 3.9 3.8 Viscosity
27150 cP 25110 cP
Conclusions
[0106] In neutral ethanol at room temperature, compound (II)
degrades by approximately 50% in 24 hours.
[0107] It has now been discovered that compound (II) could be
successfully formulated in a acidified nonaqueous gel with
acceptable cosmesis. Under the typical temperature conditions in a
refrigerated storage (2-8.degree. C.), the formulation's saturation
solubility for compound (II) was approximately 1.6% w/w. There was
no significant change in appearance, pH, or BHT assay for 1%
compound (II) gels after storage at 2-8.degree. C. (3 months),
25.degree. C. (3 months), or 40.degree. C. (2 weeks). The viscosity
for vehicle and active gels showed a slight increase on storage at
2-8 or 25.degree. C., which is typical for nonaqueous Klucel gels.
The slight increase in viscosity did an affect pourability or
spreadability (assessed for vehicle gels, only). The compound (II)
concentration decreased on average of by 1.9 or 4.0% after three
months storage at 2-8 or 25.degree. C., respectively. Exposure to
laboratory light for up to five days did not significantly affect
the assay values for compound (II). All samples passed identity and
were clear, colorless, viscous gel solutions. All assay, impurity,
and BHT sample results are an average of three replicate
preparations, top, middle, and bottom, from single bottles.
Example 2
Formulation Kit Examples
[0108] Topical formulations of compound (II) were prepared from a
kit that contains the following components: a vial of compound (II)
powder, a vial of solvent, and a container of gel concentrate. All
three of these components are stable at controlled room
temperature. At the time of dispensing, the contents of the solvent
vial were added to the compound (II) vial to dissolve the compound.
After compound (II) had been solubilized, the solution was added to
the gel concentrate and then mixed with a suitable implement (i.e.,
spatula) until homogeneous.
[0109] Three-compartment kit examples for two formulations are
described below in Table 15 and Table 16.
TABLE-US-00017 TABLE 15 Example Kit A Amount in Amount in Amount in
Container 2, Container 3, Compound Container 1, % w/w % w/w % w/w
Compound (II) 100 -- -- Ethanol (190 proof) -- 84.95 -- Propylene
Glycol -- 15.0 15.2 Citric Acid -- 0.045 0.046 Hexylene Glycol --
-- 18.3 Glycerin -- -- 15.2 Diisopropyl Adipate -- -- 6.10 Oleyl
Alcohol -- -- 7.61 BHT -- -- 0.15 Klucel MF PH -- -- 3.05 Ethanol
(200 proof) -- -- 34.3
[0110] For 30 grams of gelled solution with a final compound (II)
concentration of 1%, the following weights of each component were
used: 0.3 g of compound (II), 10.0 g of solvent, and 19.7 g of gel
concentrate.
TABLE-US-00018 TABLE 16 Example Kit B Amount in Amount in Amount in
Container 2, Container 3, Compound Container 1, % w/w % w/w % w/w
Compound (II) 100 -- -- Ethanol (200 proof) -- 74.95 34.9 Benzyl
Alcohol 25.0 -- Citric Acid -- 0.045 0.046 Propylene Glycol -- --
20.3 Hexylene Glycol -- -- 16.2 Glycerin -- -- 13.5 Diisopropyl
Adipate -- -- 5.41 Oleyl Alcohol -- -- 6.76 BHT -- -- 0.135 Klucel
MF PH -- -- 2.70
[0111] For 30 grams of gelled solution with a final concentration
of compound (II) of 1% using Formulation B, the following weights
of each component were used: 0.3 g of compound (II), 7.5 g of
solvent, and 22.2 g of gel concentrate.
[0112] For both examples above, a homogeneous gelled formulation
was obtained after less than 4 minutes of mixing. Compound (II)
formulations prepared from a three compartment kit were stable for
at least one month at controlled room temperature or in the
refrigerator.
Example 3
Evaluation of the percutaneous absorption of Compound (II) In Vitro
Using the Franz Human Skin Finite Dose Model
[0113] In this example, solutions A and B, as described above, were
used. Control solution ("Ctrl") was a 1% by weight solution of
compound (II) in DMSO.
[0114] Three test formulations containing compound (II)--A, B and
Ctrl were tested on three replicate sections from two different ex
vivo human trunk skin donors, for the percutaneous absorption of
compound (II), and for the appearance of compound (III) depicted
below, Methylparaben, and 4-OH Benzoic acid over a 24 hour dose
period. At preselected times after dose application, the dermal
receptor solution was removed in its entirety, replaced with fresh
receptor solution, and an aliquot saved for subsequent analysis. In
addition, the stratum corneum, epidermis and dermis were recovered
and evaluated for drug content. The samples were analyzed for
compound (II), compound of structural formula (III)
##STR00010##
and 4-OH Benzoic acid content by High Performance Liquid
Chromatography (HPLC).
Materials and Methods
[0115] The in vitro Franz human skin finite dose model has proven
to be a valuable tool for the study of percutaneous absorption and
the determination of the pharmacokinetics of topically applied
drugs. The model uses human ex vivo cadaver or surgical skin
mounted in specially designed diffusion cells that allow the skin
to be maintained at a temperature and humidity that match typical
in vivo conditions. A finite dose (e.g. 4-7 mg/cm.sup.2) of
formulation is applied to the outer surface of the skin and drug
absorption is measured by monitoring its rate of appearance in the
receptor solution bathing the inner surface of the skin. Data
defining total absorption, rate of absorption, as well as skin
content can be accurately determined in this model. The method has
historic precedent for accurately predicting in vivo percutaneous
absorption kinetics.
[0116] Compound (II) degrades to less potent compounds, namely
compound (III) and Methylparaben. Compound (III) may undergo
further degradation to suberic acid. Methylparaben may undergo
degradation to 4-OH Benzoic acid. In this study compound (II),
compound (III), Methylparaben and 4-OH Benzoic acid were quantified
in the collected samples.
Study Skin Preparation
[0117] Percutaneous absorption was measured using the in vitro
Franz human skin finite dose technique. Ex vivo, human trunk skin
without obvious signs of skin disease, obtained within 24-48 hours
of death, was used in this study. It was dermatomed, prepared for
cryopreservation, sealed in a water impermeable plastic bag, and
stored at about -70 .degree. C. until the day of the experiment.
Prior to use it was thawed in about 37.degree. C. water, then
rinsed in water to remove any adherent blood or other material from
the surface.
[0118] Skin from a single donor was cut into multiple smaller
sections large enough to fit on static 1.0 cm.sup.2 Franz diffusion
cells. The dermal chamber was filled to capacity with a reservoir
solution of phosphate-buffered isotonic saline (PBS), pH
7.4.+-.0.1, and the epidermal cell (chimney) left open to ambient
laboratory conditions.
[0119] All cells were mounted in a diffusion apparatus in which the
dermal bathing solution was stirred magnetically at approximately
600 RPM and the skin surface temperature maintained at 32.0.degree.
C..+-.1.0.degree. C.
[0120] To assure the integrity of each skin section, its
permeability to tritiated water was determined before application
of the test products. Following a brief (0.5-1 hour) equilibrium
period, .sup.3H.sub.2O (NEN, Boston, Mass., sp. Act. apprx. 0.5
.mu.Ci/mL) was layered across the top of the skin so that the
entire exposed surface was covered (approximately 200-500 After 5
minutes the .sup.3H.sub.2O aqueous layer was removed. At 30 minutes
the receptor solution was collected and analyzed for radioactive
content by liquid scintillation counting. Skin specimens in which
absorption of .sup.3H.sub.2O was less than 1.56 .mu.L-equ/cm.sup.2
were considered acceptable.
Dosing and Sample Collection
[0121] Just prior to dosing, a pre-dose sample was taken and the
reservoir solution was replaced with a fresh solution of
0.1.times.PBS with 0.1% Volpo and 0.05% Citric acid (nominal pH
6.0). The chimney was removed from the Franz Cell to allow full
access to epidermal the surface of the skin. All formulations were
then applied to the skin sections using a positive displacement
pipette set to deliver 5 .mu.L formulation/cm.sup.2. The dose was
evenly distributed onto the skin using a glass rod. The rod was
retained for analysis to correct the applied dose. Five to ten
minutes after application the chimney portion of the Franz Cell was
replaced. At preselected times after dosing, (6, 12, and 24 hours)
the reservoir solution was removed in its entirety, replaced with
fresh reservoir solution, and a predetermined volume aliquot saved
for subsequent analysis.
[0122] Spare cells were available which were not dosed but used to
evaluate for the appearance of substances diffusing out of the skin
that might interfere with the analytic method.
[0123] After the last sample was collected, the surfaces were
washed twice (0.5 mL volume each) with Ethanol with 0.05% Citric
Acid to collect un-absorbed formulation from the surface of the
skin. Following the wash, the skin was tape stripped to remove the
stratum corneum. The tape strips were extracted overnight in neat
acetonitrile. The skin was then removed from the chamber, split
into epidermis and dermis. Each was extracted overnight in a
mixture of Ethanol and 0.05% citric acid over wet ice.
Analytical Methods
[0124] Samples were assayed using an HPLC/MS and/or HPLC/UV.
Results
[0125] Results are presented in Table 17 and Table 18, below. (In
Tables 17 and 18, an entry of "0" means that the parameter was
below lower limit of quantification.)
TABLE-US-00019 TABLE 17 Total Absorption and Mass Balance Results
Across Skin Donors: Percutaneous Absorption and Penetration of
Compound (II) Through ex vivo Human Trunk Skin Over 24 Hours (Mean
.+-. SE as Percent of Applied Dose and Total Mass
(.mu.g/cm.sup.2).) 1% Compound 1% Compound 1% Compound (II) Gel
(II) Gel (II) Solution Formulation A Formulation B (DMSO) of Table
3 of Table 3 (Ctrl) Total Absorption 0.284 .+-. 0.028 0 0.296 .+-.
0.098 (.mu.g/cm2) Dermis (.mu.g/cm2) 0 0 0 Epidermis (.mu.g/cm2)
0.259 .+-. 0.074 0.151 .+-. 0.004 0.429 .+-. 0.035 Stratum Corneum
0.048 .+-. 0.022 0.039 .+-. 0.039 0.016 .+-. 0.016 (.mu.g/cm2)
Surface Wash 22.12 .+-. 3.938 31.94 .+-. 0.313 10.01 .+-. 0.189
(.mu.g/cm2) Total Absorption (%) 0.594 .+-. 0.060 0 0.600 .+-.
0.199 Dermis (%) 0 0 0 Epidermis (%) 0.542 .+-. 0.158 0.325 .+-.
0.004 0.870 .+-. 0.072 Stratum Corneum (%) 0.101 .+-. 0.045 0.087
.+-. 0.087 0.032 .+-. 0.032 Surface Wash (%) 46.28 .+-. 8.538 68.56
.+-. 1.957 20.29 .+-. 0.340 Total Recovery (%) 47.52 .+-. 8.592
68.97 .+-. 2.048 21.79 .+-. 0.498
TABLE-US-00020 TABLE 18 Compound (II) Total Absorption Results
Across Donors Percutaneous: Absorption of Compound (II) Through ex
vivo Human Trunk Skin Over 24 Hours From a Single Application.
(Mean .+-. SE as Total Mass (.mu.g/cm.sup.2) and Percent of Applied
Dose.) Total Absorption Test Article (.mu.g/cm2) Total Absorption
(%) 1% Compound (II) Gel, 0.284 .+-. 0.028 0.594 .+-. 0.060
Formulation A of Table 3 1% Compound (II) Gel, 0 0 Formulation B of
Table 3 1% Compound (II) Solution 0.296 .+-. 0.098 0.600 .+-. 0.199
(DMSO), Ctrl
Conclusion
[0126] Using the in vitro finite dose model, the data demonstrates
that compound (II) penetrates into and through ex vivo human skin,
from formulations A and Ctrl, but not from formulation B (see Table
2 for the formulations A and B).
[0127] The penetration profile for compound (II) suggests that
virtually all the percutaneous absorption through the skin occurred
within 5 hours of dose application from formulations A and Ctrl,
with no compound (II) being seen in the reservoir solution from
formulation B. The majority of the detectable compound (II) was
found in the surface wash (about 20% -69%) followed by the
epidermis (about 0.3% -0.9%).
[0128] The data further indicate that all of the degradation
products to be quantified (compound (III), Methylparaben
(structural formula (IV)), and 4-OH Benzoic acid) were observed to
be present in the majority of the samples.
[0129] Further, degree of degradation was observed to be
formulation dependent with more degradation being seen in the
samples dosed with formulation Ctrl, followed by formulation A and
formulation B.
[0130] Overall mass balance (based on the amount of compound (II)
dose) as the sum across all measured compounds demonstrated about
71% recovery from the skin sections dosed with formulation B, about
55% from the skin sections dosed with formulation A, and about 51%
from the skin sections dosed with formulation Ctrl. The
unaccountable dose may represent other degradation products which
were not quantified, or binding of selected compounds to the tissue
or chamber system surfaces.
[0131] While this invention has been particularly shown and
described with references to example embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *