FORMULATIONS OF PHOSPHOLIPASE ENZYME INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of United States Provisional Application No.:
60/855,569, filed on October 31, 2006, which is incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
The present invention is directed to formulations of inhibitors of
phospholipase enzymes, such as cytosolic PLA2- compositions containing the same
and processes for manufacture thereof.
BACKGROUND OF THE INVENTION
Leukotrienes and prostaglandins are important mediators of inflammation,
each of which contributes to the development of an inflammatory response in a
different way. Leukotrienes recruit inflammatory cells such as neutrophils to an
inflamed site, promote the extravasation of these cells and stimulate release of
superoxide and proteases, which damage the tissue. Leukotrienes also play a
pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g.
B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance
inflammation by increasing blood flow and therefore infiltration of leukocytes to
inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but
are instead synthesized [W. L. Smith, Biochem. J.. 259:315-324 (1989)] from
arachidonic acid in response to stimuli. Prostaglandins are produced from
arachidonic acid by the action of COX-1 and COX- 2 enzymes. Arachidonic acid is
also the substrate for the distinct enzyme pathway leading to the production of
leukotrienes.
Arachidonic acid, which is fed into these two distinct inflammatory pathways,
is released from the sn-2 position of membrane phospholipids by phospholipase A2
enzymes (hereinafter PLA2)- The reaction catalyzed by PLA2 is believed to represent
the rate-limiting step in the process of lipid mediated biosynthesis and the production
of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of

PLA2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position,
the lysophospholipid produced is the immediate precursor of platelet activating factor
(hereafter called PAF), another potent mediator of inflammation [S.I. Wasserman,
Hospital Practice, 15:49-58 (1988)].
Most anti-inflammatory therapies have focused on preventing production of
either prostaglandins or leukotrienes from these distinct pathways, but not on all of
them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs, which
inhibit the production of prostaglandins by COX-1/COX-2 inhibition, but have no
effect on the inflammatory production of leukotrienes from arachidonic acid in the
other pathways. Conversely, zileuton inhibits only the pathway of conversion of
arachidonic acid to leukotrienes, without affecting the production of prostaglandins.
None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested
as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory
response. [See, e.g., J. Chang et al, Biochem. Pharmacol.. 365:2429-2436 (1987)].
A family of PLA2 enzymes characterized by the presence of a secretion signal
sequenced and ultimately secreted from the cell have been sequenced and
structurally defined. These secreted PLA2s have an approximately 14 kD molecular
weight and contain seven disulfide bonds, which are necessary for activity. These
PLA2s are found in large quantities in mammalian pancreas, bee venom, and various
snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A.
Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is
believed to serve a digestive function and, as such, should not be important in the
production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been
determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen
and is also a secreted enzyme. This enzyme is a member of the aforementioned
family. [See, J. J. Seilhamer et al, J. Biol. Chem.. 264:5335-5338 (1989); R. M.
Kramer et al, J. Biol. Chem.. 264:5768-5775 (1989); and A. Kando et al, Biochem.
Biophvs. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is
important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-
pancreatic PLA2 is an extracellular protein, which would be difficult to regulate, and
the next enzymes in the biosynthetic pathways for these compounds are intracellular

proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and
G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378
(1989)], which are cytosolic proteins, which must act on intracellular proteins. It
would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the
high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line,
designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing
conditions, was reported to be associated with the approximately 60 kD molecule.
However, this protein was not purified to homogeneity. [See, C. C. Leslie et al,
Biochem. Biophvs. Acta.. 963:476-492 (1988)]. The references cited above are
incorporated by reference herein for information pertaining to the function of the
phospholipase enzymes, particularly PLA2.
A cytosolic phospholipase A2 alpha (hereinafter "cPLA2a") has also been
identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are
incorporated herein by reference as if fully set forth. The enzyme of these patents is
an intracellular PLA2 enzyme, purified from its natural source or otherwise produced
in purified form, which functions intracellularly to produce arachidonic acid in
response to inflammatory stimuli.
In addition to the identification of several phospholipase enzymes, efforts
have been spent in identifying chemical inhibitors of the action of specific
phospholipase enzymes, which inhibitors could be used to treat inflammatory
conditions, particularly where inhibition of production of prostaglandins, leukotrienes
and PAF are all desired results. Such inhibitors are disclosed, for example, in U.S.
Patent No. 6,797,708 and U.S. Patent Application No. 11/442,199 (filed May 26,
2006), each of which is incorporated herein by reference in their entireties.
Given the importance of these compounds as pharmaceutical agents, it can
be seen that effective formulations for delivery of the compounds, including those
having improved bioavailability, are of great import, and there is an ongoing need for
such new formulations.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions comprising:

a) a pharmaceutically effective amount of an active pharmacological
agent having the Formula I:
i
I
or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R6, X1, X2,
n1, n2, and n3 are defined as described herein; and
b) a carrier or excipient system comprising a first solubilizer, a second
solubilizer, and a diluent.
The present invention also provides pharmaceutical compositions comprising:
a) a pharmaceutically effective amount of an active pharmacological
agent having the Formula II:

ii
and pharmaceutically acceptable salts thereof, wherein R5, R6, R7, R8, X2, n1 n2, n3,
and n5 are defined as described herein; and
b) a carrier or excipient system comprising a first solubilizer, a second
solubilizer, and a diluent.
The invention further provides processes for preparing the pharmaceutical
compositions and dosage forms of the invention, and products of the processes.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph depicting the dissolution profile of a formulation according to
the invention at different pH.
FIG. 2 is a graph depicting the dissolution profiles of a formulation according
to the invention (□) and the corresponding encapsulated active pharmacological
agent having Formula I (—•—).
FIG. 3 is a graph depicting a comparison of AUC (0-t)/Dose of a formulation
according to the invention in fed versus fasted dogs.
FIG. 4 is a graph depicting the dissolution profiles of a formulation according
to the invention (■ and A) and the corresponding encapsulated active
pharmacological agent having Formula I (♦).
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the invention, a pharmaceutical composition comprises
a) a pharmaceutically effective amount of an active pharmacological
agent having Formula I:

I
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the formulae -(CH2)n-A, -(CH2)n-S-A, and -(CH2)n-O-
A, wherein A is selected from the moieties:


wherein
D is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cylcoalkyl, -CF3, or-(CH2)1-3-CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl,
thienyl and pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to
2, substituents selected independently from halogen, -CN, -CHO, -CF3, -OCF3, -OH,
C1-C6 alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH-C(O)-(C1-C6
alkyl), -NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing
1 or 2 heteroatoms selected from O, N, and S; or

F1 is selected from C1-C6 alkyl, C1-C6 fluorinated alkyl, C3-C6 cycloalkyl,
tetrahydropyranyl, camphoryl, adamantyl, -CN, -N(C1-C6 alkyl)2, phenyl, pyridinyl,
pyrimidinyl, furyl, thienyl, napthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl,
pyrrolidinyl, imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazolyl, indolyl,
benzoxazolyl, benzofuranyl, imidazolidine-2-thionyl, 7,7-dimethyl-
bicyclo[2.2.1]heptan-2-onyl, benzo[1,2,5]oxadiazolyl, 2-oxa-5-aza-
bicyclo[2.2.1]heptanyl, piperazin-2-onyl and pyrrolyl groups, each optionally
substituted by from 1 to 3, preferably 1 to 2, substituents independently selected from
halogen, -CN, -CHO, -CF3, -OCF3,-OH, C1-C6 alkyl, C1-C6 alkoxy, -NH2,-N(C1-C6

R2 is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl
and pyrrolyl groups, the ring moiety being substituted by a group of the formula -
(CH2)n4-CO2H or a pharmaceutically acceptable acid mimic or mimetic; and also
optionally substituted by 1 or 2 additional substituents independently selected from
halogen, -CN, -CHO, -CF3, -OCF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -
NH2,-N(C1-C6 alkyl)2) -NH(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), and -NO2;
R3 is selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, C1-C6 alkyl,
C1-C6 alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6 alkyl), -NH-C(O)-(C1-
C6 alkyl), and -NO2;
R4 is selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, C1-C6 alkyl,
C1-C6alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6 alkyl), -NH-C(O)-( d-
C6 alkyl), -NO2, -NH-C(O)-N(d-C3 alkyl)2 , -NH-C(O)-NH(d-C3 alkyl), -NH-C(O)-O-
(Ci-C3 alkyl), -SO2-C1-C6 alkyl, -S-C3-C6 cycloalkyl, -S-CH2-C3-C6 cycloalkyl, -SO2-C3-
C6 cycloalkyl, -SO2-CH2-C3-C6 cycloalkyl, C3-C6 cycloalkyl, -CH2-C3-C6 cycloalkyl, -O-
C3-C6 cycloalkyl, -O-CH2-C3-C6 cycloalkyl, phenyl, benzyl, benzyloxy, morpholino,
pyrrolidino, piperidinyl, piperizinyl, furanyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl,
pyrazolonyl, pyrazolyl, oxazolyl, and isoxazolyl, the rings of each of these R4 groups
each being optionally substituted by from 1 to 3 substituents selected from the group
of halogen, -CN, -CHO, -CF3, -OH, C1-C6alkyl, C1-C6 alkoxy, -NH2, -N(C1-C6 alkyl)2, -
NH(C1-C6 alkyl), -NH-C(O)-( C1-C6 alkyl), -NO2, -SO2(d-C3 alkyl), -SO2NH(d-C3
alkyl), -SO2N(Ci-C3 alkyl)2, and -OCF3;
each R5 is independently H or C-|.3 alkyl; and
R6 is H or C1.6 alkyl; and
b) a carrier or excipient system comprising:
i) about 10 to about 50% a first solubilizer by weight of the
, composition;
ii) about 10 to about 50% a second solubilizer by weight of the
composition; and
iii) about 10 to about 30% a diluent by weight of the composition.

R8 is selected from the group consisting of H, -OH, -NO2, -CF3, -OCF3, d.3
alkoxy, halogen, -CO(d.3 alkyl), -CO(OC1-3 alkyl), quinoline-5-yl, 3,5-
dimethylisoxazol-4-yl, thiophene-3-yl, -CH2-Q, and phenyl substituted by from one to
three independently selected R30 groups;
Q is OH, dialkylaminc
R20 is selected from the group consisting of H, C1-3 alkyl, and -CO(C1-3 alkyl);
and
R30 is selected from the group consisting of dialkylamino, -CN, and -OCF3;
provided that:
i) when each R5 is H, R6 is H, n5 is 0, and R8 is H, then R7 cannot be chlorine;
ii) when each R5 is H, R6 is H, n5 is 0, X2 is O or -CH2-, and R8 is H, then R7
cannot be CH3;
iii) when each R5 is H, and R6 is H, then R7 and Rs cannot both be fluorine;
iv) when each R5 is H, R6 is H, and X2 is O, then R7 and R8 cannot both be
chlorine;
v) when each R5 is H, R6 is H, X2 is O, and R8 is NO2, then R7 cannot be
fluorine; and
vi) when each R5 is H, R6 is H, X2 is SO2, and R8 is H, then R7 cannot be
fluorine or chlorine; and
b) a carrier or excipient system comprising:
i) about 10 to about 50% a first solubilizer by weight of the
composition;
ii) about 10 to about 50% a second solubilizer by weight of the
composition; and
iii) about 10 to about 30% a diluent by weight of the composition.
In some embodiments, the compound of Formula II has the Formula III:


or a pharmaceutically acceptable salt thereof, wherein:
n1 is 1 or 2;
n2 is 1 or 2;
n6 is 1 or 2;
R5 is H or CH3;
R6 is H or C1-6 alkyl; and
Rs is selected from the group consisting of H, -OH, -NO2, -CF3, -OCF3, -
OCH3, halogen, -COCH3, -COOCH3, dimethylamino, diethylamino, and -CN.
In some further embodiments, the compound of Formula I or Formula II is 4-
(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-
1/-/-indol-3-yi}propyl)benzoic acid or a pharmaceutically acceptable salt thereof.
It will be understood that the C1-C6 fluorinated alkyl groups in the definition of
Ri may be any alkyl group of 1 to 6 carbon atoms with any amount of fluorine
substitution including, but not limited to, -CF3, alkyl chains of 1 to 6 carbon atoms
terminating in a trifluoromethyl group, -CF2CF3, etc.
As used herein, the terms "heterocyclic" and "heterocyclyl" refer to a
saturated or partially unsaturated (nonaromatic) monocyclic, bicyclic, tricyclic or other
polycyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-8 ring
heteroatoms if bicyclic, or 1-10 ring heteroatoms if tricyclic, each of said heteroatoms
being independently selected from O, N, and S (and mono and dioxides thereof, e.g.,
N—>O-, S(O), SO2. A ring heteroatom or a ring carbon can serve as the point of
attachment of the heterocyclic ring to another moiety. Any atom can be substituted,

e.g., by one or more substituents. Heterocyclyl groups can include, e.g. and without
limitation, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl
(morpholino), thiomorpholinyl, pyrrolinyl, and pyrrolidinyl.
The term "heteroaromatic" refers to an aromatic monocyclic, bicyclic, tricyclic,
or other polycyclic hydrocarbon group having 1-4 ring heteroatoms if monocyclic, 1-8
ring heteroatoms if bicyclic, or 1-10 ring heteroatoms if tricyclic, each of said
heteroatoms being independently selected from O, N, and S (and mono and dioxides
thereof, e.g., N—>O", S(O), SO2). Any atom can be substituted, e.g., by one or more
substituents. Heteroaromatic rings can include, e.g. and without limitation, pyridinyl,
thiophenyl (thienyl), furyl (furanyl), imidazolyl, indolyl, isoquinolyl, quinolyl and
pyrrolyl.



wherein Ra is selected from -CF3, -CH3, phenyl, and benzyl, with the phenyl or
benzyl groups being optionally substituted by from 1 to 3 groups selected from C1-C6
alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -CF3, halogen, -OH, and -COOH; Rb is selected
from -CF3, -CH3, -NH2, phenyl, and benzyl, with the phenyl or benzyl groups being
optionally substituted by from 1 to 3 groups selected from C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 thioalkyl, -CF3, halogen, -OH, and -COOH; and Rc is selected from -CF3 and
C1-C6 alkyl.
Those of skill in the art will be able to readily ascertain pharmaceutically
effective amounts of said active pharmacological agent. Generally, the active
pharmacological agent is present in the composition in an amount of from about
0.1% to about 25 % by weight of the composition.
In some embodiments, the invention provides unit dosage forms containing
the compositions of the invention.. The term "unit dosage forms" refers to physically
discrete units suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with a suitable pharmaceutical

excipient. Thus, the unit dosage forms formulations of the present invention include
any conventionally used forms, including capsules, gels, oral liquids, and the like. In
some embodiments, the unit dosage form is a capsule.
As will be recognized, a unit dosage form, such as a capsule, tablet, or other
dosage form, will generally contain a pharmaceutically effective amount of the active
pharmacological agent. As will be recognized, the pharmacological agent can be
effective over a wide dosage range, and is generally administered in a
pharmaceutically effective amount. It will be understood, however, that the amount of
the compound actually administered will usually be determined by a physician,
according to the relevant circumstances, including the condition to be treated, the
chosen route of administration, the actual compound administered, the age, weight,
and response of the individual patient, the severity of the patient's symptoms, and the
like.
Generally, on a weight basis, the pharmaceutically effective amount is from
about 1 mg to about 125 mg of active pharmacological agent. Thus, the unit dosage
forms of the invention can contain various doses of the active pharmacological agent,
for example approximate doses of 5, 10, 25, 50, 75, 100 and 125 mg, as well as
others. Accordingly, the invention includes dosage forms that contain
pharmaceutical compositions of the invention, that include from about 3 mg to about
7 mg of active pharmacological agent, from about 8 mg to about 12 mg of active
pharmacological agent, from about 13 mg to about 19 mg of active pharmacological
agent, from about 20 mg to about 30 mg of active pharmacological agent, from about
31 mg to about 60 mg of active pharmacological agent, from about 61 mg to about 80
mg of active pharmacological agent, and from about 81 mg to about 125 mg of active
pharmacological agent. One preferred embodiment is a 500 mg capsule containing
100 mg of pharmacologically active agent (i.e. 500 mg of a composition of the
invention containing 20% pharmacologically active agent by weight of the
pharmaceutical composition).
Generally, the compositions of the invention include a first solubilizer.
Generally, the solubilizer is present in an amount of from about 10% to about 50% by
weight of the composition. Any suitable solubilizer known in the art can be used.
Suitable solubilizers include, for example, surfactants. In some embodiments, the
solubilizer is selected from polyethylene glycol 660 hydroxystearate, vitamin E

polyethylene glycol succinate, and mixtures thereof. In some embodiments, the first
solubilizer includes or consists of polyethylene glycol 660 hydroxystearate.
Generally, the compositions of the invention include a second solubilizer.
Generally, the solubilizer is present in an amount of from about 10% to about 50% by
weight of the composition. Any suitable solubilizer known in the art can be used.
Suitable solubilizers include, for example, surfactants. In some embodiments, the
solubilizer is selected from polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor
oil, polysorbate 80, and mixtures thereof. In some embodiments, the second
solubilizer includes or consists of polyoxyl 35 castor oil.
Generally, the compositions of the invention include a diluent. Generally, the
diluent is present in an amount of from about 10% to about 50% by weight of the
composition. Any suitable diluent and/or solvent, or combination thereof, may be
used for the diluent. In some embodiments, the diluent is selected from propylene
glycol monocaprylate, caprylocaproyl polyoxyglycerides, medium chain mono and
diglycerides, triglycerides of caprylic/capric acid, polyethylene glycols, propylene
glycol, propylene carbonate, and mixtures thereof. In some embodiments, the
diluent comprises propylene glycol monocaprylate.
In some embodiments of the invention, the pharmaceutical composition
comprises a carrier or excipient system comprising:
i) a first solubilizer selected from the group consisting of polyethylene
glycol 660 hydroxystearate, vitamin E polyethylene glycol succinate, and mixtures
thereof;
ii) a second solubilizer selected from the group consisting of polyoxyl 35
castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 80, and mixtures thereof;
and
iii) a diluent selected from the group consisting of propylene glycol
monocaprylate, caprylocaproyl polyoxyglycerides, medium chain monoglycerides,
medium chain diglycerides, triglycerides of caprylic/capric acid, polyethylene glycols,
propylene glycol, propylene carbonate, and mixtures thereof.
In some further embodiments, the carrier or excipient system comprises:
i) polyethylene glycol 660 hydroxystearate in an amount of from
about 10% to about 50% by weight of the composition;

ii) polyoxyl 35 castor oil in an amount of from about 10% to about
50% by weight of the composition; and
iii) propylene glycol monocaprylate in an amount of from about
10% to about 15% by weight of the composition.
In one embodiment, the invention provides a pharmaceutical composition
comprising:
a) an active pharmacological agent comprising 4-(3-{5-chloro-1-
(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1/-/-indol-3-
yl}propyl)benzoic acid or a pharmaceutically acceptable salt thereof in an amount of
about 20% by weight of the composition; and
b) a carrier or excipient system comprising:
i) polyethylene glycol 660 hydroxystearate in an amount of about
30% by weight of the composition;
ii) polyoxyl 35 castor oil in an amount of about 30% by weight of
the composition; and
iii) propylene glycol monocaprylate in an amount of about 20% by
weight of the composition.
In another embodiment, the invention provides a pharmaceutical composition
comprising:
a) an active pharmacological agent comprising 4-(3-{5-chloro-1-
(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}propyl)benzoic acid or a pharmaceutically acceptable salt thereof in an amount of
about 2% by weight of the composition; and
b) a carrier or excipient system comprising:
i) polyethylene glycol 660 hydroxystearate in an amount of about
36.75% by weight of the composition;
ii) polyoxyl 35 castor oil in an amount of about 36.75% by weight
of the composition; and
iii) propylene glycol monocaprylate in an amount of about 24.5%
by weight of the composition.
In some embodiments, the invention provides unit dosage forms comprising a
pharmaceutical composition as described above, wherein the composition contains

about 100 mg of the active pharmacological agent. As discussed above, other doses
can be made into unit dosage forms as is well known to those of skill in the art.
Because of the liquid nature of the resulting pharmaceutical composition, unit
dosage forms such as capsules are well suited for administering the pharmaceutical
composition to a patient. The invention also includes methods of preparing the
pharmaceutical composition for administration, particularly via a capsule unit dosage
form.
In some embodiments, the invention provides a process for preparing a
pharmaceutical composition as described above, comprising the steps of:
(1) mixing the first solubilizer, second solubilizer, and diluent to
produce a first homogenous solution;
(2) slowly adding the pharmacologically active agent to said first
homogenous solution; and
(3) mixing with sufficient heating until the pharmacologically active
agent is dissolved to produce a second homogenous solution.
To facilitate the mixing and dissolution of the first and second solubilizers and
the diluent, the mixture can be heated (e.g., to from about 80°C to about 90°C, or to
about 85°C) while mixing. In some embodiments, the temperature is maintained at
85 +/- 5 °C.
In some embodiments, the temperature is maintained at 85 +/-5°C during the
addition and mixing of the pharmacologically active agent.
As discussed above, the resultant product is suited for administration via a
capsule. Accordingly, the process for preparing the pharmaceutical composition may
further include encapsulating at least a portion of the second homogenous solution
into one or more unit dosage capsule forms. Those of skill in the art will appreciate
that any suitable encapsulation technique may be used.
In some embodiments, the second homogenous solution is cooled, preferably
to about 40°C, prior to encapsulation to enhance its handling and to prevent melting
or dissolution of the encapsulating material.
Those of skill in the art will readily recognize that simple modification of the
steps outlined above, and the relative amounts of each of the components, will result
in formation of a final product of desired size, strength and composition. Accordingly,

the process described above can be used to make any of the pharmaceutical
compositions described herein.
In particular, the process is useful in making such pharmaceutical
compositions where the pharmaceutically effective amount of the active
pharmacological agent is about 0.1 to about 20 % by weight of the composition.
The process is also useful in making such pharmaceutical compositions
where the solubilizer of the first and second solubilizer is selected from the group
consisting of polyethylene glycol 660 hydroxystearate, vitamin E polyethylene glycol
succinate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 80,
and mixtures thereof.
The process is also useful in making such pharmaceutical compositions
where the diluent is selected from the group consisting of propylene glycol
monocaprylate, caprylocaproyl polyoxyglycerides, medium chain monoglycerides,
medium chain diglycerides, triglycerides of caprylic/capric acid, polyethylene glycols,
propylene glycol, propylene carbonate, and mixtures thereof.
The process is also useful in making such pharmaceutical compositions
where the pharmaceutical composition comprises a pharmacologically active agent
and a carrier or excipient system wherein:
i) the first solubilizer is selected from the group consisting of
polyethylene glycol 660 hydroxystearate, vitamin E polyethylene glycol succinate,
and mixtures thereof;
ii) the second solubilizer is selected from the group consisting
polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 80, and
mixtures thereof; and
iii) the diluent is selected from the group consisting of propylene
glycol monocaprylate , caprylocaproyl polyoxyglycerides, medium chain
monoglycerides, medium chain diglycerides, triglycerides of caprylic/capric acid,
polyethylene glycols, propylene glycol, propylene carbonate, and mixtures thereof.
More particularly, the process is also useful in making such pharmaceutical
compositions where the pharmaceutical composition comprising a pharmacologically
active agent and a carrier or excipient system comprising:
i) polyethylene glycol 660 hydroxystearate in an amount of from
about 10% to about 50% by weight of the composition;

ii) polyoxyl 35 castor oil in an amount of from about 10% to about
50% by weight of the composition; and
iii) propylene glycol monocaprylate in an amount of from about
10% to about 30% by weight of the composition.
As described above, the process can be used to make various sized unit
dosage forms. Generally, the dosage forms contain from about 1 mg to about 125
mg of active pharmacological agent. Typical unit dosage forms will contain about 5,
10, 25, 50, 75, 100 or 125 mg active agent. Accordingly, the invention includes
dosage forms comprising a pharmaceutical composition of the invention, wherein the
composition comprises from about 3 mg to about 7 mg of active pharmacological
agent, from about 8 mg to about 12 mg of active pharmacological agent, from about
13 mg to about 19 mg of active pharmacological agent, from about 20 mg to about 30
mg of active pharmacological agent, from about 31 mg to about 60 mg of active
pharmacological agent, from about 61 mg to about 80 mg of active pharmacological
agent, and from about 81 mg to about 125 mg of active pharmacological agent. One
preferred embodiment is a 500 mg capsule containing 100 mg of pharmacologically
active agent (i.e. 20% by weight of the pharmaceutical composition). Another
embodiment includes a 500 mg capsule containing 10 mg of pharmacologically
active agent (i.e. 2% by weight of the pharmaceutical composition).
In one embodiment, the invention provides a process for preparing a
preferred pharmaceutical composition comprising:
a) 20% by weight of the composition of the active pharmacological agent
4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)
ethyl]-1H-indol-3-yl}propyl)benzoic acid or a pharmaceutically acceptable salt thereof;
and
b) a carrier or excipient system comprising:
i) polyethylene glycol 660 hydroxystearate in an amount of from
about 10% to about 50% by weight of the composition;
ii) polyoxyl 35 castor oil in an amount of from about 10% to about
50% by weight of the composition; and
iii) propylene glycol monocaprylate in an amount of from about
10% to about 30% by weight of the composition;
said process comprising

(1) mixing the polyethylene glycol 660 hydroxystearate, polyoxyl 35 castor
oil, and propylene glycol monocaprylate to produce a first homogenous solution;
(2) slowly adding the pharmacologically active agent;
(3) mixing with sufficient heating until the pharmacologically active agent
is dissolved to produce a second homogenous solution.
As with the other embodiments described herein, the process can further
include one or more of the additional steps of heating the polyethylene glycol 660
hydroxystearate, polyoxyl 35 castor oil, and propylene glycol monocaprylate to a
temperature sufficient to produce the first homogenous solution; cooling the first
homogenous solution prior to adding the pharmacologically active agent;
encapsulating at least a portion of the second homogenous solution into one or more
unit dosage capsule forms; and/or cooling the second homogenous solution (e.g., to
about 40°C) prior to encapsulation.
The invention further includes any product made by any of the processes
described herein.
As used herein, the terms "pharmaceutically effective amount" or
"therapeutically effective amount" mean the total amount of each active component
of the pharmaceutical composition or method that is sufficient to show a meaningful
patient benefit, i.e., treatment, healing, prevention, inhibition or amelioration of a
physiological response or condition, such as an inflammatory condition or pain, or an
increase in rate of treatment, healing, prevention, inhibition or amelioration of such
conditions. When applied to an individual active ingredient, administered alone, the
term refers to that ingredient alone. When applied to a combination, the term refers
to combined amounts of the active ingredients that result in the therapeutic effect,
whether administered in combination, serially or simultaneously.
The term "pharmaceutically acceptable" means a non-toxic material that does
not interfere with the effectiveness of the biological activity of the active ingredient(s).
The term "% by weight of the composition" and the weight percentages set
forth for each of the components of the compositions disclosed herein refer to the
percentages that each component will comprise in a final pharmaceutical
composition based on the weight of the composition, excluding any surface covering,
such as a tablet coating or encapsulating material, such as a capsule.

The term "caprylocaproyl polyoxyglycerides" refers to a lipid-based surface-
active agent. One exemplary caprylocaproyl polyoxyglycerides is PEG-8
caprylic/capric glycerides, marketed as LABRASOL® by Gattefosse. Caprylocaproyl
polyoxyglycerides are also known as "caprylocaproyl macrogolglycerides"
As used herein, the term "medium chain monoglyceride" refers to a
monoacylglycerol having from about 8 to about 18 carbon atoms in the acyl chain.
As used herein, "a medium chain diglyceride" refers to a diacylglycerol
having, independently, from about 8 to about 18 carbon atoms in each acyl chain.
As will be appreciated, some components of the formulations of the invention
can possess multiple functions. For example, a given component can act as both a
diluent and a solubilizer. In some such cases, the function of a given component can
be considered singular, even though its properties may allow multiple functionality.
The pharmaceutical formulations and excipient systems herein can also
contain an antioxidant or a mixture of antioxidants, such as ascorbic acid. Other
antioxidants, which can be used, include sodium ascorbate and ascorbyl palmitate,
optionally in conjunction with an amount of ascorbic acid. An example range for the
antioxidant(s) is from about up to about 15% by weight, e.g., from about 0.05% to
about 15% by weight, from about 0.5% to about 15% by weight, or from about 0.5%
to about 5% by weight. In some embodiments, the pharmaceutical formulations
contain substantially no antioxidant.
Additional numerous various viscosity builders, surfactant/solubilizers,
diluents/solvents, dispersing agents, excipients, dosage forms, and the like, that are
suitable for use in connection with the pharmaceutical compositions of the invention
are known in the art and described in, for example, Remington: The Science and
Practice of Pharmacy, 20th edition, Alfonoso R. Gennaro (ed.), Lippincott Williams &
Wilkins, Baltimore, MD (2000), which is incorporated herein by reference in its
entirety.
The materials, methods, and examples presented herein are intended to be
illustrative, and are not intended to limit the scope of the invention. All publications,
patent applications, patents, and other references mentioned herein are incorporated
by reference in their entirety.
EXAMPLES

1. Preparation of compounds of Formula I or Formula II
The compounds of Formula I or Formula II can be conveniently prepared from
commercially available starting materials, compounds known in the literature, or
readily prepared intermediates, by employing standard synthetic methods and
procedures known to those skilled in the art. Standard synthetic methods and
procedures for the preparation of organic molecules and functional group
transformations and manipulations can be readily obtained from the relevant
scientific literature or from standard textbooks in the field. It will be appreciated that
where typical or preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given, other process
conditions can also be used unless otherwise stated. Optimum reaction conditions
may vary with the particular reactants or solvent used, but one skilled in the art can
determine such conditions by routine optimization procedures. Those skilled in the art
will recognize that the nature and order of the synthetic steps presented may be
varied for the purpose of optimizing the formation of the compounds of the invention.
Preparation of compounds of Formula I or Formula II can involve the
protection and deprotection of various chemical groups. The need for protection and
deprotection, and the selection of appropriate protecting groups can be readily
determined by one skilled in the art. The chemistry of protecting groups can be
found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4th
Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.
Examples of compounds of Formula I or Formula II and methods for
synthesizing them can be found in U.S. Patent Nos. 6,797,708; 6,891,065 and
6,984,735 and U.S. Patent Application Nos. 10/930,534 (filed August 31, 2004),
10/948,004 (filed September 23,2004), 10/989,840 (filed November 16, 2004),
11/014,657 (filed December 16, 2004), 11/064,241 (filed February 23, 2005),
11/088,568 (filed March 24, 2005), 11/140,390 (filed May 27, 2005), 11/207,072 (filed
August 18, 2005) and 11/442,199 (filed May 26, 2006), each of which is incorporated
by reference in their entireties.
Examples of compounds of Formula I and Formula II include, but are not
limited to:

2. Formulations containing 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifiuoromethyl)benzyl] sulfonyl}amino) ethyl]-1H-indol-3-yl}propyl)benzoic
acid
A. Preparation of 100 mg dose capsule
) A 500 mg unit dosage capsule in accordance with the invention, containing a
100 mg dose of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]
sulfonyljamino) ethyl]-1/-/-indol-3-yl}propyl)benzoic acid was prepared as described in
Table 1.
Table 1

)
The pharmaceutical composition described above was prepared for
administration via a capsule as follows:
1. Polyethylene glycol 660 hydroxystearate (30 g), polyoxyl 35 castor oil (30 g),
and propylene glycol monocaprylate (20 g) were added into an appropriate
i mixing vessel equipped for temperature control.
2. The vessel was heated to 85 +/- 5°C with mixing until a homogeneous
solution was obtained.
3. The pharmacological agent (20 g) was added slowly into the solution in Step
2, with heating and mixing at 85 +/- 5°C until the drug was dissolved and a
) homogeneous solution was obtained.
4. 0.500 g of the finished solution from Step 3 was encapsulated into size #0
capsules.
Any suitable encapsulating techniques and apparatus may be used. The
resultant capsule is approximately a 500 mg capsule, which delivers approximately
> 100 mg of the pharmacological agent. Other suitable doses and capsule sizes can
be made in accordance with the disclosure herein. In particular, those of skill in the

art, will readily recognize that 10, 25, 50, 75, 100 and 125 mg unit dosage forms, and
others, can be made through similar methods.
B. Dissolution testing
The solubility of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethyl)benzyl] sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid was
measured at room temperature in water, acid and basic conditions. The intrinsic
solubility of the free acid was below the HPLC detection limit of 31 ng/mL, whereas
the anion had a solubility of 110 ng/mL.
Dissolution testing was performed on 100 mg strength capsules produced
according to the procedure described above. Capsules were placed in 900 mL of
aqueous solutions having pH 1 (0.1 N HCI), pH 6.8 (50 mM sodium phosphate buffer)
and pH 4.5 (mM sodium acetate buffer). The UV absorption of each solution was
measured at various timepoints (1 mm path length, 237 nm) and the percent
dissolution was calculated compared to a standard response at that wavelength. As
shown in Figure 1, the rate of dissolution was found to be similar at each pH tested.
C. In vivo dog exposure studies
A formulation containing 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1/-/-indol-3-yl}propyl)benzoic acid
according to the invention was studied in dogs in a high fat-fed/fasted study at
approximately 12 mg/kg . To simulate the fed state, three female beagle dogs were
fed a high-fat diet by oral gavage 30 minutes prior to dosing with 100 mg dose
capsules as described in Table 1 above. Blood samples were drawn at 0, 0.5, 1, 2,
3, 4, 6, 8, 12 and 24 hours. The dogs were then fed 2/3 of the daily food ration after
the 4 hour blood draw. Blood samples were stored on ice, centrifuged at 5 °C, and
the plasma was collected and stored at -70 °C. The plasma samples were analyzed
by LC/MS/MS to determine the amount of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid in the
sample.
To simulate the fasted state, the above procedure was repeated with the
same three female beagle dogs that were fasted overnight prior to dosing, then fed
after the 4 hour blood draw. The results of both the fed and fasted studies are

summarized in Table 2 (reported results are the average of the data from the three
test animals).


Data from a rat carrageenan-induced paw edema (CPE) study indicated the
minimum efficacious exposure of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethyl)benzyl]sulfonyl}amino) ethyl]-1H-indol-3-yl}propyl)benzoic acid was
1360 ng*hr/ml. The data in Table 2 shows that the formulation according to the
present invention results in an exposure of about 12.5 times the efficacious exposure
in the fasted state and about 26.6 times the efficacious exposure in the fed state.
These exposures translate into percent bioavailabilities of 8.4 and 18.3 when
compared to an IV formulation (15% 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1 H-indol-3-yl}propyl)benzoic acid, 10%
EtOH, 75% Solutol HS-15, diluted to 2 mg/mL with sterile water for injection).
3. Formulations containing 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1W-indol-3-yl}propyl)benzoic
acid
The solubility of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1 H-indol-3-yl}propyl)benzoic acid was
measured at room temperature in water, acid and basic conditions. The intrinsic
solubility in all conditions is below the HPLC detection limit of 21.2 ng/mL.
Due to the low solubility of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid in a
2% Tween 80 /0.5% methylcellulose (MC) vehicle (0.496 mg/ml), alternative
formulations having enhanced dissolution/solubility properties were explored. The
addition of 2% Tween 80 enhancing the 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid
solubility 23,490-fold to 0.498 mg/ml, did not afford adequate oral exposure.

Following a single oral dose of 25 mg/kg of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-
({[2-(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid
in 2% Tween/0.5% MC, the oral absorption of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-
({[2-(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1/-/-indol-3-yl}propyl)benzoic acid
in rats was found to be relatively low, resulting in an estimated bioavailability of only
about 1.8%. A liquid formulation containing 20% 4-(3-{5-chloro-1-(diphenylmethyl)-2-
[2-({[2-(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic
acid, 30% Cremophor EL, 30% Solutol HS-15 and 20% Capryol 90 (CESC) was
found to provide a faster absorption rate and increased bioavailability (about 9.7%) in
non-fasted rats at 25 mg/kg. Based on the animal data and solubility in
pharmaceutical acceptable excipients, formulation development for first in human
studies was undertaken based on this formulation.
A prototype CESC capsule formulation, batch size of 400g, was
manufactured according to methods similar to those described above in Example 2.
The dissolution profiles of the CESC liquid capsule formulation at thelOO mg strength
and encapsulated micronized 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1 H-indol-3-yl}propyl)benzoic acid are
shown in FIG. 2. These dissolution profiles were obtained in a medium containing
0.3% sodium lauryl sulfate (SLS)/ 50 mM phosphate pH 7.5 buffer. As shown in FIG.
2, the CESC liquid formulation was found to significantly improve dissolution of the 4-
(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid.
This CESC formulation was compared to five other prototype formulations
and was screened in dogs in a high fat-fed/fasted study at 10 mpk using capsule
strengths of 100 mg. The results show that the CESC formulation shows less inter-
subject variability then the other formulations (see FIG. 3).
Since the minimum efficacious exposure is 2800 ng«hr/ml (ApoE Mice),
the data in Table 3 shows an exposure of 2.1 x's the efficacious exposure in the
fasted state and 4.5 x's in the fed state. This translates into % bioavailabilities of 3.1
(fasted) and 6.8 (fed) when comparing to an IV formulation.

measured at room temperature in water, acid and basic conditions. The intrinsic
solubility over the pH range of 1 to 11 is below the HPLC detection limit of 100
ng/mL.
Due to the low solubility of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-
(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1/-/-indol-3-yl}propyl)benzoic acid in a
2% Tween 80/0.5% methylcellulose vehicle, (0.115 mg/ml), alternative formulations
having enhanced dissolution/solubility properties were explored. The addition of 2%
Tween 80 enhancing the PLA-811 solubility, did not afford adequate oral exposure.
Following a single oral dose of 25 mg/kg of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-
({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic
acid in 2% Tween/0.5% MC, the oral absorption of 4-(3-{5-chloro-1-(diphenylmethyl)-
2-[2-({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-
yl}propyl)benzoic acid in rats was found to be relatively low, resulting in an estimated
bioavailability of only <1%.
A prototype CESC capsule formulation, batch size of 10g, was manufactured
according to methods similar to those described above in Example 2. A 500 mg
capsule was prepared according to Table 5.


The dissolution profiles of the CESC liquid capsule formulation at thelOO mg
strength and encapsulated, micronized 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-
fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic
acid are presented in FIG. 4. The dissolution profiles were obtained in a medium
containing 0.3% SLS/ 50 mM phosphate pH 7.5 buffer. As shown in FIG. 4, the
CESC liquid formulation was found to significantly improve dissolution of 4-(3-{5-
chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-
(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid.
All publications mentioned herein, including but not limited to patent
applications, patents, and other references, are incorporated by reference in their
entirety.

The materials, methods, and examples presented herein are intended to be
illustrative, and are not intended to limit the scope of the invention.

R, is selected from d-C8 alkyl, CrCa fluorinated alkyl, C3-C6 cycloalkyl,
tetrahydropyranyf, camphoryl, adamantyl, CN, -N(C1-C6 a!kyl)2, phenyl. pyridinyl, pyrimidinyl,
furyl, thienyl, naphthyl, morpholinyl. triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, irnidazolyl,
piperizinyl, thiazolidinyl. thiomorpholinyl, tefrazolyl. indolyl, ber>2oxazolyl, benzofuranyl,
imidazolidine-2-thionyl, 7,7-dimethyl-bicyciot2.2.1 ]heptan-2-onyl, benzo[1,2.5]oxaciiazolyl, 2-
oxa-5-aza-bicyc!o[2.2.1]heptanyl, piperazin-2-onyl and pyrrolyl groups, each optionally
substituted by from 1 to 3 substituents independently selected from halogen, -CN, -CHO, -CF3, -
OCF3.-OH, CrCo alkyf, C,-C8 alkoxy, -NHZ, -N(Ci-Ca alkyl)2, -NHCC1-C6alkyl). -NH-C(O)-( C1-C6
alkyl)! -NO2. -SO2(C,-C3 alky»). -SO2NH2, -SO2NH(C^C3 alkyl), -SO2N(Ci-C3 alky!)2, -COOH, -
CHj-COOH. -CH2-NH(CrCfl alkyl), -CH2-N(C,-C6 alkyl)2 , -CH2-NH2 , pyridinyl. 2-methyI-
thiazolyl, morpholino. 1-ch)oro-2-methyl-propyl, C-Csthioalky!, phenyl (further optionally
substituted with one or more halogens, dialkylamino, -CN, or -OCF3)i benzyloxy. -(C,-C3
alkyl)C(O)CH3. -(CrC3 alkyl)OCH3, -C(O)NH2. or


R2 is a ring moioty seleoted from phenyl, pyridinyl, pyrimteroyl. furyl, thionyl aRd-pyfrelyJ
groupc, the ring rooioty boing substituted by a group of the formula -(CH^-CO^H or a
pharmaceuticaily acceptable acid mimic or mimetic; and also optionally substituted by 1 or 2
additional substituents independently selected from halogen, -CN, -CHO, -CF3, -OCF3, -OH, C,-

C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, -NH2, -N(C1-C6 alkyl)2, -NH(C,-C8 alkyl), -NH-C(O)-( C,-
C6 alkyl), and -NO2;
R3 is selected from H, halogen, -CN. -CHO, -CF3l -OCF5, -OH, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 thioalkyl. -NH2, -N(C1-C6 alkyl)2. -NH(C1-C6 alkyl), -NH-C(OM C1-C6 alkyl), and -NO2;
R4 is selected from H, halogen, -CN, -CHO, -CF3, -OCF3, -OH, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 thioalkyl, -NH2.-N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH-C(O)-( C1-C6 alkyl), -NO2, -MH-
C(O) N(C»-€a alkylfo -NH C(O)-NH(C4.-Ca alkyl)-, -NH C(O) Q (Gv€» alkyl). ■ SOyC4-Gra»ky», -S-
GrCrsyetoollyt, S CHrCfCfc cyoleatkyt^-SOrCyCt-Gyetealkyl, SOa-GHrGa-Cg-systeatkyt^Gr
etfoyeJoolkyl,- CHj-Ga-Ge oycloalkyl, -O-CrCs-syslealkyl. -O-CHa-C3-Cg-€y6tealkytrf>):tefiyir
benzyl, benzyloxy7 morpholino, pyrrolidino, piperidinyl, and piperizinyl, furanyl,4hionyl,
imidazQlyl. totrazolyl, pyraanyl, pyrazolonyl, pyrazolyl,..-oxazolyl, and iooxaaolyl, tho rings of
each of these-Rt groups each being optionally substituted by from-1 -to 3 substituonts selected
from tho group of halogen, -CM, CHO, CFj, -OH, Gy-Gg-alkyVCi-Cg alkoxy, -NH;.7.44(C4-G6
atftytj^.- NH(C4-€ralkyl). -NH-C(O) ( Ci-G« alkyl). -NO,. SO^^-Cj alkyl), SOgN^-Ga-ati^
^Qa^^-C, alkyl)., and OCF,;
each R5 is independently H or Cu alkyl; and
Re is H or C,^ alkyl; and
b) a carrier or excipient system comprising:
i) about 10 to about 50% a first solubilizer by weight of the composition;
ii) about 10 to about 50% a second sotubilizer by weight of the composition;
and
iii) about 10 to about 30% a diluent by weight of the composition.
2. (Currently Amended) The pharmaceutical composition of claim 1, wherein
Rt is optionally substituted phenyf; and


3. (Original) The pharmaceutical composition of claim 1. wherein said phamnaceuiically
effective amount of said active pharmacological agent is about 0.1 to about 25 % by weight of
the composition.
4. (Original) The pharmaceutical composition of claim 1, wherein said first solubilizer is
selected from the group consisting of polyethylene giycol 660 hydroxystearate, Vitamin E
polyethylene glyco! succinate, and mixtures thereof.
5. (Original) The pharmaceutical composition of claim 1, wherein said first solubilizer
comprises polyethylene giycol 660 hydroxystearate.
6. (Original) The pharmaceutical composition of claim 1 wherein said second solubilizer is
selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil.
polysorbate 80, and mixtures thereof.
7. (Original) The pharmaceutical composition of claim 1, wherein said second solubilizer
comprises polyoxyl 35 castor oil.
8. (Original) The pharmaceutical composition of claim 1, wherein said diluent is selected
from the group consisting of propylene giycol monocaprylate, a caprylocaproyl polyoxyglyceride,
a medium chain monoglyceride, a medium chain diglyceride, a triglyceride of caprylic acid, a
triglyceride of capric acid, a polyethylene glyco), propylene giycol, propyiene carbonate, and
mixtures thereof.
9. (Original) The pharmaceutical composition of claim 1, wherein said diluent comprises
propylene giycol monocaprylate.
10. (Original) The pharmaceutical composition of claim 1 wherein said carrier or exdpient
system comprises:
i) a first solubilizer selected from the group consisting of polyethylene giycol
660 hydroxystearate, Vitamin E polyethylene gtycol succinate, and mixtures (hereof;

ii) a second solubilizer selected from the group consisting of polyoxyl 35
Castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 80, and mixtures thereof; and
iii) a diluent selected from the group consisting of propylene glycol
monocaprylate. a caprylocaproyl polyoxyglyceride, a medium chain monoglyceride, a medium
chain diglyceride a triglyceride of caprylic acid, a triglyceride of capric. acid, a polyethylene
glycol, propylene glycol, propylene carbonate, and mixtures thereof.
11. (Original) The pharmaceutical composition of claim 1 wherein said carrier or
excipient system comprises:
i) about 10 lo about 50% polyethylene glycol 660 hydroxystearate by weight
of the composition;
ii) about 10 to about 50% polyoxyl 35 castor oil by weight of the
composition; and
iii) about 10 to about 30% propyfene glycol monocaprylate by weight of the
composition.
12. (Original) A pharmaceutical composition comprising:
a) a pharmaceutically effective amount of an active pharmacological agent having
the Formula II:


n5 is 0, 1 or 2;
X2 is O. -CH2 or SO2;
each R5 is independently H or C1-3 alkyl;
Re is H or C1-6 alkyl;
R7 is selected from the group consisting of -OH, benzyloxy, -CH3l -CF3, ~OCF3. C1-3
alkoxy, halogen, -CHO. -CO(C1-3 alkyl). -CO(OC1-3 a(kyi), quinoline-5-yl, 3,5-dimethylisoxazol-4-
yl, thiophene-3-yi, pyridin-4-yl, pyridine-3-yl, -CH2-Q, and phenyl optionally substituted by from
one to three independently selected R30 groups;
R9 is selected from the group consisting of H, -OH, -NOZl -CF3, -OCF3. C1-3 alkaxy.
halogen, -CO(C1-3 alkyl), -CO(OC1-3 alkyl), quinoline-5-yl, 3,5-dimethylisoxazoM-yl. thiophene-3-
yl, -CH2-Q, and phenyf substituted by from one to three independently selected R30 groups;
Q is OH, dialkylamino, , ——■
R20 is selected from the group consisting of H, C1-3 alkyl, and -CO(C1-3 alkyl); and
R30 is selected from the group consisting of dialkylamino, -CN and -OCF3;
provided that:
i) when each R5 is H, R6 is H, n5 ts 0, and R5 is H, then R7 cannot be chlorine;
ii) when each R5 is H, R5 is H, nf is 0, X2 is O or -CH2-, and R9 is H, then R7 cannot be
CH3;
iii) when each R5 is H. and R6 is H, then R7 and R6 cannot both be fluorine:
iv) when each R5 is H, R6, is H, and X2 is O, then R7 and R8 cannot both be chlorine;
v) when each R5 is H, R6 is H, X2 is O, and R6 is NO2l then R7 cannot be fluorine; and
vi) when each R5 is H. Re is H, X2 is SO2, and R6 is H, then R7 cannot be fluorine or
chlorine; and
b) a carrier or excipient system comprising:
i) about 10 to about 50% a first solubilizer by weight of the composition;
ii) about 10 to about 50% a second solubilizer by weight of the composition;
and
iii) about 10 to about 30% a diluent by weight of the composition.-

13. (Original) The pharmaceutical composition of claim 12, wherein the compound of
Formula II has the Formula III:

III
or a pharmaceutically acceptable salt thereof, wherein:
n, is 1 or 2;
n2 is 1 or 2;
n2 is 1 or 2;
R5 is H or CH3;
Re is H or C1-6 aikyl; and
Rs is selected from the group consisting of H, -OH. -NO2, -CF3, -OCF3. -OCH3l halogen, -
COCH3, -COOCH3 dimethylamino, dielhylamt'no and -CN.
14. (Original) The pharmaceutical composition of claim 12, wherein the compound of
Formula II is 4-(3-{5-chIoro-1-(diphenylmethyl)-2-[2-({f2(trifluoromethyl)benzyl]
sulfonyl}amino)€thyl]-1H'indol-3-yI}propyl)benzoic acid or a pharmaceutically acceptable salt
thereof.
15. (Original) The pharmaceutical composition of claim 12, wherein said pharmaceutically
effective amount of said active pharmacological agent is about 0.1 to about 25 % by weight of
the composition.
16. (Original) The pharmaceutical composition of claim 12, wherein said first solubilizer is
selected from the group consisting of polyethylene glycol 660 hydroxystearafe, Viiamin E
polyethylene glycol succinate, and mixtures thereof

17. (Original) The pharmaceutical composition of claim 12, wherein said first so.'ubilizer
comprises polyethylene glycol 660 hydroxystearate.
18. (Original) The pharmaceutical composition of claim 12 wherein said second solubilizer is
selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil,
polysorbate 80, and mixtures thereof.
19. (Original) The pharmaceutical composition of claim 12, wherein said second solubilizer
comprises polyoxyl 35 castor oil.
20. (Original) The pharmaceutical composition of claim 12, wherein said diluent is selected
from the group consisting of propylene glycol monocaprylate, a caprylocaproyl polyoxyglyceride,
a medium chain monoglyceride, a medium chain diglycerjde. a triglyceride of caprylic acid, a
triglyceride of capric acid, a polyethylene glycol, propylene glycol, propylene carbonate, and
mixtures {hereof.
21. (Origfnal) The pharmaceutical composition of claim 12. wherein said diluent comprises
propylene glycol monocaprylate.
22. (Original) The pharmaceutical composition of claim 12 wherein said carrier or excipient
system comprises:
i) a first solubilizer selected from the group consisting of polyethylene glycol
660 hydroxystearate, Vitamin E polyethylene glycol succinate, and mixtures thereof;
li) a second solubilizer selected from the group consisting of polyoxyl 35
Castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate 80, and mixtures thereof; and
iii) a diluent selected from the group consisting of propylene giycol
monocaprylate, a caprylocaproyl polyoxyglyceride, a medium chain monoglyceride, a medium
chain diglyceride a triglyceride of caprylic acid, a triglyceride of capric acid, a polyethylene
glycol, propylene glycol. propylene carbonate, and mixtures thereof.

23. (Original) The pharmaceutical composition of claim 12 wherein said carrier or excipient
system comprises:
. i) about 10 to about 50% polyethylene glycol 660 hydroxystearate by weight
of the composition;
ii) about 10 to about 50% polyoxyl 35 castor oil by weight of the
composition; and
iii) about 10 to about 30% propylene glycol monocaprylate by weight of the
composition. .
24. (Original) A dosage form comprising a pharmaceutical composition cf claim 12, wherein
the composition contains from about 1 mg to about 125 mg of active pharmacological agent.
25. (Original) A dosage form comprising a pharmaceutical composition of claim 12, wherein
ths composition contains from about 3 mg to about 7 mg of active pharmacological agent.
26. (Original) A dosage form comprising a pharmaceutical composition of claim 12, wherein
the composition contains from about 8 mg to about 12 mg of active pharmacological agent.
27. (Original) A dosage form comprising a pharmaceutical composition of claim 12. wherein
the composition contains from about 13 mg to about 19 mg of active pharmacological agent.
28. (Original) A dosage form comprising a pharmaceutical composition of claim 12, wherein
the composition contains from about 20 mg to about 30 mg of active pharmacological agent.
29. (Original) A dosage form comprising a pharmaceutical composition of claim 12, wherein
the composition contains from about 31 mg to about 60 mg of active pharmacological agent.
30. (Original) A dosage form comprising a pharmaceutical composition of claim 12, wherein
the composition contains from about 61 mg to about 80 mg of active pharmacological agent.
31. (Original) A dosage form comprising a pharmaceutical composition of claim 12. wherein
the composition contains from about 81 mg to about 125 mg of active pharmacological agent.

32. (Original) A pharmaceutical composition comprising:
a) about 20% by weight of the composition of the an active pharmacological agent
comprising 4'-(3-{5-ch!oro-1 -(diphenylmethyI)-2-[2-({[2(trifluoromelhyl)benzyl]
sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid or a pharmaceutically acceptable salt
thereof; and
b) a carrier or excipient system comprising:
i) about 30% by weight of the composition of polyethylene glycol 660
hydroxystearate;
ii) about 30% by weight of the composition of polyoxyl 35 castor oil; and
iii) about 20% by weight of the composition of propylene glycol
monocaprylate.
33. (Original) A dosage form comprising a pharmaceutical composition of claim 32, wherein
said composition comprises about 100 mg of said active pharmacological agent.
34. (Original) A pharmaceutical composition comprising:

a) 2% by weight of the composition of an active pharmacological agent comprising
4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-
3-yl}propyl)benzoic acid or a pharmaceutically acceptable salt thereof; and
b) a carrier or excipient system comprising:
i) about 36% to about 37% by weight of the composition of polyethylene
glycol 660 hydroxystearate;
ii) about 36% to about 37% by weight of the composition of polyoxyl 35
castor oil; and
iii) about 24% to about 25% by weight of the composition of propylene glycol
monocaprylate.
35. (Original) The pharmaceutical composition of claim 34 comprising about 10 mg of the
active pharmacological agent.
36. (Original) A process for preparing a pharmaceutical composition comprising:

a) a pharrnaceutically effective amount of an active pharmacological agent having
the Formula II:

II
or a pharmaceutically acceptable salt thereof, wherein:
n, is 1 or 2;
n? is 1 or 2;
n3 is 1 or 2;
n5 is 0, 1 or 2;
X2 is O,-CH2-orSO2;
each R5 is independently H or C1-3 alkyl;
R6 is H or C1-6 alkyl;
R7 is selected from the group consisting of -OH, benzyloxy, -CH3, -CF3, -OCF3 C1-3
alkoxy. halogen, -CHO. -CO(C1-3 alkyl), -CO(OC1-3 alkyl), quinoline-5-yl, 3,5-dimethylisoxazol-4-
yl, thiophene-3-yl, pyridin-4-yl, pyridine-3-yl, -CH2-Q. and phenyl optionally substituted by. from
one to three independently selected R30 groups;
Ra is selected .from the group consisting of H, -OH, 'NO2, -CF3. -OCF3l C1-3 aikoxy,
halogen, -CO(C1-3 alkyl), -CO(OC1-3 alkyl), quinoline-5-yl, 3,5-dimethylisoxazol-4-yl, thiophene-3-
yl, -CH^Q, and phenyl substituted by from one to three independently selected R30 groups;
Q is OH, dialkylamino.

R20 is selected from the group consisting of H. C1-3 alkyl, and -CO(C1-3 alkyl); and
R3o is selected from the group consisting of dialkylamino, -CN, and -OCF3;
provided that:

i) when each R5 is H, R3 is H, ris is 0, and R6 is H, then R7 cannot be chlorine;
ii) when each R3 is H, Rs is H, n5 is 0, X2 is O or -CH,-, and R3 is H, then R7 cannot be
CH3;
iii) when each R5 is H, and R6 is H, then R7 and R8 cannot both be fluorine;
iv) when each R5 is H, R6 is H, and X2 is O, then R7 and R3 cannot both be chlorine;
v) when each R5 is H, R8 is H, X2 is O, and R8 is NO2, then R7 cannot be fluorine; and
vi) when each R5 is H, R6 is H, X2 is SO2l and Ra is H, then R7 cannot be fluorine or
chlorine; and
b) a carrier or excipient system comprising:
i) about 10 to about 50% a first solubilizer by weight of the composition;
. ii) about 10 to about 50% a second solubilizer by weight of the composition;
and
iii) about 10 to about 30% a diluent by weight of the composition;
said process comprising:
(1) mixing the first solubilizer, second solubilizer, and diluent to form a first
homogenous solution;
(2) adding the pharmacological agent or a pharmaceutically acceptable salt thereof.
to the first homogenous solution; and
(3) mixing the pharmacological agent and the first homogenous solution at a
temperature sufficient to facilitate dissolution of the pharmacological agent to obtain a second
homogenous solution.

37. (Original) The process of claim 36, wherein step (1) further comprises heating the first
solubilizer, second solubilizer, and diluent to a temperature sufficient to form the first
homogenous solution.
38. (Original) The process of claim 37, wherein said mixing of the first solubilizer, second
solubilizer, and diluent is performed at a temperature of from about 80°C to about 90°C.
39. (Original) The process of claim 36, wherein the mixing of the pharmacologically active
agent in step {3} is performed at a temperature of from about 60°C to about 90eC.

40. (Original) The process of claim 36 further comprising encapsulating at least a portion of
said second homogenous solution into one or more unit dosage capsule forms.
41. (Original) The process of claim 40, wherein prior to encapsulation, said second
homogenous solution is screened to remove undissolved particles.
42. (Original) The process of claim 40, wherein prior to encapsulation, said third
homogenous solution is cooled.
43. (Original) The process of claim 36, wherein the pharmaceutically effective amount of the
active pharmacological agent is about 0.1 to about 20% by weight of the composition.
44. (Original) The process of claim 36, wherein the first solubilizer is selected from the group
consisting of polyethylene glycol 660 hydroxystearate, Vitamin E polyethylene glycol succinate,
and mixtures thereof.
45. (Original) The process of claim 36. wherein the first solubilizer comprises polyethylene
glycol 660 hydroxystearate.
46. (Original) The process of claim 36, wherein the second solubilizer is selected from the
group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, poiysorbate 80,
and mixtures thereof.
47. (Original) The process of claim 36, wherein the second solubilizer comprises polyoxyl 35
castor oil.
48. (Original) The process of claim 36, wherein the diluent is selected from the group
consisting of propylene glycof monocaprylate, caprylocaproyl polyoxyglycerides, a medium
chain monoglyceride, a medium chain diglyceride, a triglyceride of caprylic acid, a triglyceride of
capric acid, a polyethylene glycol, propylene glycol, propylene carbonate, and mixtures thereof.

49. (Original) The process of claim 36 wherein the diluent comprises propylone glycol
rnonocaprylate.
50. (Original) The process of claim 36, wherein said carrier or excipient system comprises:
i) a first solubilizer selected from the group consisting of polyethylene glycol
660 hydroxystearate, vitamin E polyethylene glycol succinate, and mixtures thereof;
ii) a second solubilizer selected from the group consisting of polyoxyl 35
castor oil. polyoxyl 40 hydrogenated castor oil, polysorbate 80, and mixtures thereof; and
iii) a diluent selected from the group consisting of propylene glycol
monocaprylate, a caprylocaproyl polyoxyglyeeride. a medium chain monoglyceride, a medium
chain diglyceride a triglyceride of caprylic acid, a trigiyceride of capric acid, a polyethylene
glycol, propylene glycol, propylene carbonate, and mixtures thereof.
51. (Original) The process of claim 36, wherein said carrier or excipient system comprises:
i) about 10 to about 50% polyethylene glycol 660 hydroxystearate by weight
of the composition;
ii) about 10 to about 50% polyoxyi 35 castor oil by weight of the
composition; and
iii) about 10 to about 30% propylene glycol monocaprylate by weight of the
composition.
52. (Original) The process of claim 36, wherein the active pharmacological agent of Formula
II has the Formula III:

in

or a phamnaceutically acceptable salt thereof, wherein:
n., is 1 or 2;
n2 is 1 or 2;
n6is 1 or 2;
R6 is HorCH3;
R6 is H or C1-6 alkyl; and
R6 is selected from the group consisting of H, -OH. -NO2, -CF3, -OCF3, -OCH3, halogen, -
COCHs, -COOCH3, dimeihylamino. diethylamino. and -CN.
53. (Original) The process of claim 36, wherein the active pharmacological agent comprises
4-(3-{5-chloro-1-(diphenylmeihy|)-2-[2-({[2-(trif]uoromethyl)ben2yl]sulfonyl}amino)ethyl]-1H-
indol-3-yl]propyl)benzoic acid or a pharmaceutically acceptable salt thereof.
54. (Original) A process for preparing a pharmaceutical composition comprising:

a) 20% by weight of the composition of an active pharmacological agent comprising
4-(3-{5K;h!orc^1-(diphenylrnethyl)-2-[2-({[2(trifluoromethyl)berizy!]sulfonyl}arnino)ethyl]-W-indol-
3-yl}propyl)benzoic acid or a pharmaceutically acceptable salt (hereof; and
b) a carrier or excipient system comprising:
i) about 30% polyethylene glycol 660 hydroxystearate by weight of the
composition;
ii) about 30% polyoxyl 35 castor oil by weight of the composition; and
iii) about 20% propylene glycol monocaprylate by weight of the composition;
said process comprising:
(1) mixing the polyethylene glycol 660 hydroxystearate, polyoxyl 35 castor oil. and
propylene glycol monocaprylate to form a first homogenous solution;
(2) adding the pharmacological agent or a pharmacautically acceptable salt thereof
to the first homogenous solution;
(3) mixing the pharmacological agent and the first homogenous solution at a
temperature sufficient to facilitate dissolution of said pharmacological agent to obtain a second
homogenous solution.

55. (Original) The process of claim 54, wherein step (1) further comprises heating the
.polyethylene glycol 660 hydroxystearate. polyoxyl 35 castor oil, and propylene glycol
monocaprylate to a temperature sufficient to form the first homogenous solution.
56. (Original) The process of claim 55, wherein said mixing of the polyethylene glycol 660
hydroxystearate, polyoxyl 35 castor oil, and propylene glycol monocaprylate is performed at a
temperature of from about 80°C to about 90°C.
. 57. (Original) The process of claim 54, wherein the mixing of the pharmacologically active
agent in step (3) is performed at a temperature of from about 80"C to about 90°C.
58. (Original) The process of claim 54, further comprising encapsulating at least a portion of
said second homogenous solution into one or more unit dosage capsule forms.
59. (Original) The process of claim 58, wherein prior to encapsulation, the second
homogenous solution is screened to remove undissolved particles.
60. (Original) The process of claim 58, wherein prior to encapsulation, the second
homogenous solution is cooled.
61. (Original) A process for preparing a pharmaceutical composition comprising:

a) 2% by weight of the composition of an active pharmacological agent comprising
4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-{{t2(trifluoromethyl)ben2ylJsulfonyl}amino)ethyl]-1H-indol-
3-yl}propyl)benzoic acid or a pharmaceuiicaiiy acceptable salt thereof; and
b) a earner or excipient system comprising:
i) about 36% (o about 37% by weight of the composition of polyethylene
glycol 660 hydroxystearate;
ii) about 36% to about 37% by weight of the composition of polyoxyl 35
castor oil; and iii) about 24% to about 25% by weight of the composition of propylene glycol
monocaprylate.
said process comprising:

(1) mixing the polyethylene glyco! 660 hydroxystearate, polyoxyl 35 castor oil, and
propylene glyco! monocaprylate to form a first homogenous solution;
(2) adding the pharmacological agent or a pharmaceutically acceptable salt thereof
to the first homogenous solution;
(3) mixing the pharmacological agent and the first homogenous solution at a
temperature sufficient to facilitate dissolution of the pharmacological agent to obtain a second
homogenous solution.

62. (Original) The process of claim 61, wherein step (1) further comprises heating the
polyethylene glyco! 660 hydroxystearate, polyoxyl 35 castor oil, and propylene glycol
monocaprylate to a temperature sufficient to form the first homogenous solution.
63. (Original) The process of claim 62. wherein said -mixing of the polyethylene glycol 660
hydroxystearate, polyoxyl 35 castor oil, and propylene glycol monocaprylate is performed at a
temperature of from about 80"C to about 90'C.
64. (Original) The process of claim 61. wherein the mixing of the pharmacologically active
agent in step (3) is performed at a temperature of from about 80DC to about 90°C.
65. (Original) The process of claim 61, further comprising encapsulating at least a portion of
said second homogenous solution into one or more unit dosage capsule forms.
66. (Original) The process of claim 65, wherein prior to encapsulation, said second
homogenous solution is screened to remove undissolved particles.
67. (Original) The process of claim 65, wherein prior to encapsulation, the second
homogenous solution is cooled.
68. (Original) A product made by the process any one of claims 36-67.

The present invention is directed to formulations of inhibitors of phospholipase enzymes, Such as cytosolic PLV,