Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL FORMULATIONS OF XANTHINE OR XANTHINE
DERIVATIVES, AND THEIR USE
Cross-Reference To Related Applications
This application claims priority to U.S. Patent application No. 15/620.430
filed on
June 12, 2017, which is a continuation-in-part of U.S. Patent application No.
14/307,773 filed
on filed on June 18, 2014, which claims priority under 35 U.S.C. 119(e) to
U.S. Provisional
Application No. 61/836,535 filed on June 18, 2013, the contents of which are
incorporated
herein by reference in their entireties.
Field of Use
The present disclosure relates to pharmaceutical formulations comprising
xanthine or
a xanthine derivative, such as pentoxifylline, and methods for treating a
fibrotic disease, such
as Peyronie's disease by local administration.
Background of the Invention
Fibrotic diseases can be found in a variety of tissues. For example,
Peyronie's disease
(PD) is a fibromatosis (Hellstrom and Bivalacqua, 2000; Schwarzer et al.,
2001; Jarow et al.,
1997; Devine et al., 1997) of the tunica albuginea (TA), the specialized
lining of the corpora
cavernosa of the penis. Clinically, this usually leads to penile deformation
(curved penis
during erection), pain, and quite frequent erectile dysfunction. Fibrotic
disease can also be
found in other tissues, for example, pulmonary fibrosis, liver fibrosis, renal
fibrosis, and
vascular fibrosis.
It has been indicated that PD plaques and/or other fibrotic conditions can be
pharmacologically arrested or reduced in size, by decreasing collagen
synthesis and inducing
myofibroblast apoptosis (Gonzalez-Cadavid et al., US Patent No. 8, 133,903).
Oral administration of a nonspecific PDEi, e.g., pentoxifylline, has been
suggested to
be useful in reducing collagen levels in Peyronie's Disease plaques (Brant et
al., Nature
Clinical Practice Urology 2006, Vol 3, p. 111; Smith et al., Asian Journal of
Andrology 2011,
Vol 13, p. 322; Safarinejad et al., BJU International 2010, Vol 106, p. 240).
However, oral
pentoxifylline has been shown to have moderate to minimal improvement.
Therefore, there remains a need for treatment of fibrotic diseases, e.g.,
Peyronie's
disease.
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Summary of the Invention
Provided herein are pharmaceutical formulations comprising xanthine or a
xanthine
derivative, such as pentoxifylline (1-(5-oxohexyl)-3, 7-dimethylxanthine),
kits thereof, and
methods for treating a fibrotic disease by local administration.
In one aspect, provided herein is a pharmaceutical formulation comprising a
therapeutically effective amount of a compound of formula I:
0 R3
R1 N
N I )
ON "N
R2 (I),
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a
pharmaceutically
acceptable excipient or carrier suitable for local administration, wherein RI,
R2 and R3 are
each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl,
heterocyclyl,
aryl, or heteroaryl, each of which is optionally substituted.
In another aspect, provided herein is a kit comprising:
a pharmaceutical formulation containing a therapeutically effective amount of
a
compound of formula I, or a pharmaceutically acceptable salt, ester, amide or
prodrug
thereof, wherein RI, R2 and R3 are each, independently, H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6
alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is
optionally substituted;
an apparatus for locally administering the formulation;
a container for housing the formulation and the drug delivery apparatus; and
instructions for use.
In still another aspect, provided herein is a method for treating a fibrotic
disease, e.g.,
Peyronie's disease, in a subject in need thereof, comprising locally
administering to the
subject a pharmaceutical formulation comprising a therapeutically effective
amount of a
compound of formula I, or a pharmaceutically acceptable salt thereof, wherein
RI, R2 and R3
are each, independently, H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
cycloalkyl,
heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted.
RI, R2 and R3 can be each, independently, H, or optionally substituted C1-C6
alkyl. In
particular, RI, R2 and R3 are each, independently, H, Ci-C6 alkyl, or Ci-C6
alkyl substituted
with acyl.
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The compound of formula I can be a nonspecific phosphodiesterase inhibitor
(PDEi).
The compound of formula I can also be selected from the group consisting of
pentoxifylline,
caffeine, theophylline, and aminophylline.
Also provided herein is a pharmaceutical formulation comprising, consisting
essentially of, or consisting of a therapeutically effective amount of a
nonspecific PDEi or a
pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a
pharmaceutically
acceptable excipient or carrier suitable for local administration,.
In another aspect, provided herein is a kit comprising: a pharmaceutical
formulation
comprising, consisting essentially of, or consisting of a therapeutically
effective amount of a
nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or
prodrug thereof; an
apparatus for locally administering the formulation; a container for housing
the formulation
and the drug delivery apparatus; and instructions for use.
In yet another aspect, provided herein is a method for treating a fibrotic
disease, e.g.,
Peyronie's disease, in a subject in need thereof, comprising locally
administering to the
subject a pharmaceutical formulation comprising, consisting essentially of, or
consisting of a
therapeutically effective amount of a nonspecific PDEi or a pharmaceutically
acceptable salt
thereof
The nonspecific PDEi mentioned can be pentoxifylline, aminophylline,
enprofylline,
isbufylline, theophylline, theobromine, or 3-isobuty1-1-methylxanthine (IBMX).
In certain particular embodiments, the pharmaceutical formulation consists
essentially
of or consists of the therapeutically effective amount of pentoxifylline or a
pharmaceutically
acceptable salt thereof
The fibrotic disease includes Peyronie's disease, Raynaud's syndrome,
psoriasis
plaques, eczema, and keloid scars. In certain particular embodiments, the
fibrotic disease is
.. Peyronie's disease or keloid scar.
In particular embodiments, the pharmaceutical formulations, kits thereof, and
methods
described above relate to treatment of Peyronie's disease or erectile
dysfunction. The erectile
dysfunction can be associated with Peyronie's disease.
In other embodiments, the pharmaceutical formulations, kits thereof, and
methods
described above relate to treatment of keloid scars in a subject in need
thereof The
pharmaceutical formulation can comprise, consist essentially of, or consist of
a nonspecific
PDEi, e.g., pentoxifylline, and caffeine. The formulation can also comprise,
consist
essentially of, or consist of a nonspecific PDEi, e.g., pentoxifylline, and
EGCG (green tea
catechin). Furthermore, the formulation can comprise, consist essentially of,
or consist of a
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nonspecific PDEi, e.g., pentoxifylline, and a mast cell stabilizer, e.g.,
tranilast. These
formulations can be injected into the keloid scars.
The pharmaceutical formulation can further comprise a pharmaceutically
acceptable
excipient or carrier, including, but not limited to, an antioxidant, an
adjuvant or synergist, and
a preservative.
The pharmaceutical formulation can comprise an EDTA sodium salt. The EDTA
sodium salt can be 0-0.15% by weight of the formulation, for example, 0.01,
0.02, 0.03, 0.04,
0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or 0.15% by weight
of the
formulation.
The pharmaceutical formulation can also comprise an EDTA magnesium salt. The
EDTA magnesium salt can be 0-0.15% by weight of the formulation, for example,
0.01, 0.02,
0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, or
0.15% by weight of the
formulation.
The pharmaceutical formulation can further comprise ethanol. The ethanol can
be
190 proof The ethanol can be 0-15% by volume of the formulation, for example,
0, 1, 2, 3,
4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15% by volume of the formulation.
The pharmaceutical formulation can comprise benzyl alcohol. The benzyl alcohol
can
be 0-1.5% by weight of the formulation, for example, 0, 0.1, 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8,
0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the formulation.
The pharmaceutical formulation can be filtered before local administration,
such as
filtering through a 0.22 micron filter.
The pharmaceutical formulation has a pH of between 4 and 8. In particular
embodiments, the pharmaceutical formulation has a pH of between 5.5 and 6. The
pH can be
adjusted by adding acids or bases, e.g., HC1 or NaOH.
The therapeutically effective amount can be between 4 mg and 20 mg. In
particular
embodiments, the therapeutically effective amount is between 6 mg and 10 mg.
The pharmaceutical formulation can be administered one to four times in a
twenty-
four hour period. In particular embodiments, the pharmaceutical formulation is
administered
daily until desired effects are achieved.
The pharmaceutical formulation can comprise a unit dosage of the compound of
formula I. In particular embodiments, the pharmaceutical formulation comprises
a unit
dosage of pentoxifylline.
The pharmaceutical formulation can be administered topically, transdermally,
to the
penis of the subject. In particular embodiments, the pharmaceutical
formulation is
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administered by intracavernosal injection. Accordingly, the pharmaceutical
formulation can
comprise a sterile liquid composition so that the pharmaceutically acceptable
excipient or
carrier is suitable for intracavernosal injection. In other embodiments, the
pharmaceutically
acceptable excipient or carrier is suitable for topical or transdermal
administration, and the
formulation comprises a composition to be applied to a body surface, such as
an ointment,
cream, gel or lotion.
In certain embodiments, the pharmaceutical formulation is not administered
(e.g.,
intracavernosally injected) directly into the area of the fibrotic disease,
e.g., the area of the
Peyronie's disease. In certain particular embodiments for treating Peyronie's
disease, the
pharmaceutical formulation is administered (e.g., intracavernosally injected)
at the base of the
penis about 2 cm from where the penis attaches to the abdomen.
The pharmaceutical formulation can comprise a second active agent, including
nitrovasodilators, alpha receptor blocking agents, ergot alkaloids,
antihypertensive agents,
vasodilators, naturally occurring, semisynthetic and synthetic prostaglandins,
and vasoactive
intestinal peptides. The vasodilators can be alprostadil (Prostaglandin El),
papaverine, and
phentolamine.
In certain embodiments of the formulations, kits thereof, and methods for
treating
Peyronie's disease, the pharmaceutical formulation further comprises a
collagenase, such as
collagenase clostridium histolyticum, or Xiaflex0. In certain particular
embodiments, the
pharmaceutical formulation comprises, consists essentially of, or consists of
pentoxifylline
and a collagenase, e.g., collagenase clostridium histolyticum or Xiaflex0.
The formulations, kits thereof, and methods provided herein can be used as a
mono
therapy or a part of a combo therapy to treat a fibrotic disease, such as
Peyronie's disease.
For example, the formulation comprising the compound of formula I, e.g,
pentoxifylline, can
be used as a mono therapy or a part of a combo therapy. The formulation
consisting
essentially of or consisting of a nonspecific PDEi, e.g., pentoxifylline, can
also be used as a
mono therapy, or a part of a combo therapy, e.g., in combination with a
collagenase therapy,
such as collagenase clostridium histolyticum or Xiaflex0.
Also provided herein is a pharmaceutical formulation comprising a
therapeutically
effective amount of a compound of formula I:
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0 R3
ONN
R2 (I),
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, a
quantity of a
polysaccharide selected from the group consisting of hyaluronic acid, heparin,
heparin,
chondroitin, dermatan, keratin, and pharmaceutically acceptable water-soluble
salts thereof,
and a pharmaceutically acceptable excipient or carrier suitable for local
administration,
wherein each of RI, R2 and R3 is independently selected from the group
consisting of H, a CI-
C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, a
aryl, and a
heteroaryl, each of which is optionally substituted.
In an aspect, provided herein are methods for treating a fibrotic disease in a
subject in
need thereof, comprising locally administering to the subject a
therapeutically effective
amount of a pharmaceutical formulation, comprising a quantity of a compound of
formula I,
or a pharmaceutically acceptable salt thereof, wherein each of RI, R2 and R3
is independently
selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl,
cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is optionally
substituted; and a
quantity of a polysaccharide selected from the group consisting of hyaluronic
acid, heparin,
heparin, chondroitin, dermatan, keratin, and pharmaceutically acceptable water-
soluble salts
thereof
RI, R2 and R3 can each be independently selected from the group consisting of
H and
an optionally substituted C1-C6 alkyl. In particular, RI, R2 and R3 can be
independently
selected from the group consisting of H, a Ci-C6 alkyl, and a Ci-C6 alkyl
substituted with
acyl.
The compound of formula I can be a nonspecific phosphodiesterase inhibitor
(PDEi).
The nonspecific PDEi can be selected from the group consisting of
pentoxifylline, caffeine,
aminophylline, enprofylline, isbufylline, theophylline, theobromine, and 3-
isobuty1-1-
methylxanthine.
In an embodiment, the fibrotic disease is Peyronie's disease. In an embodiment
the
formulation leads to improvement of erectile dysfunction.
In an embodiment, the pharmaceutical formulation has a pH of between 5.5 and
6. In
an embodiment, the therapeutically effective amount is between 4 mg and 20 mg.
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In an embodiment, the pharmaceutical formulation further comprises a sterile
liquid
composition, wherein the excipient or carrier is suitable for intracavernosal
injection. In an
embodiment, the pharmaceutical formulation is administered locally to the
penis of the
subject. In an embodiment, the pharmaceutical formulation is administered by
intracavernosal injection.
In an embodiment, the pharmaceutical formulation further comprises a second
active
agent selected from the group consisting of alprostadil, papaverine, and
phentolamine. In an
embodiment, the pharmaceutical formulation further comprises a collagenase.
In an embodiment, the pharmaceutical formulation further comprises an active
agent
selected from the group consisting of at least one anesthetic, at least one
anti-bacterial agent,
at least one antiviral medicament, at least one antifungal medicament, and
combinations
thereof In an embodiment, the anesthetic is selected from the group consisting
of lidocaine,
tetracaine, proparacaine, procaine, dyclonine and combinations thereof.
In an embodiment, the polysaccharide is sodium hyaluronate. The polysaccharide
can
be sodium hyaluronate.
In an embodiment, the pharmaceutical formulation is ensconced within
essentially
spherical particles fabricated of a water soluble biodegradable polymer
selected from the
group consisting of poly(lactic acid-co-glycolic acid), poly(lactic acid),
poly(glycolic acid),
poly(caprolactone), and poly(hydroxybutyrate). In an embodiment, the
biodegradable
polymer is poly(lactic acid-co-glycolic acid).
In another aspect, provided herein is a pharmaceutical composition comprising
essentially spherical particles incorporating a therapeutically effective
amount of a compound
of formula I, or a pharmaceutically acceptable salt, ester, amide or prodrug
thereof and a
pharmaceutically acceptable excipient or carrier suitable for local
administration, wherein
each of RI, R2 and R3 is independently selected from the group consisting of
H, a C1-C6
alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocyclyl, a aryl,
and a heteroaryl,
each of which is optionally substituted, wherein the particles are fabricated
of a water soluble
biodegradable polymer selected from the group consisting of poly(lactic acid-
co-glycolic
acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone), and
poly(hydroxybutyrate).
In an embodiment, the biodegradable polymer is poly(lactic acid-co-glycolic
acid).
Detailed Description
This disclosure relates to the finding that local administration of a xanthine
derivative,
e.g., pentoxifylline, has produced unexpected improvement in treating a
fibrotic disease. For
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example, intracavernosal injection of a composition comprising pentoxifylline
has resulted
remarkable improvement to symptoms of PD, such as erectile dysfunction.
Furthermore,
intracavernosal injection of pentoxifylline has been found to produce fewer
side effects.
Accordingly, provided herein are pharmaceutical formulations of xanthine or a
xanthine derivative, such as pentoxifylline, kits thereof, and methods for
treating a fibrotic
disease by local administration.
Definitions
Before describing the present invention in detail, it is to be understood that
this
invention is not limited to particular drugs or drug delivery systems, as such
may vary. It is
also to be understood that the terminology used herein is for the purpose of
describing
particular embodiments only, and is not intended to be limiting.
It must be noted that, as used in this specification and the appended claims,
the
singular forms "a," "an" and "the" include plural referents unless the context
clearly dictates
otherwise. Thus, for example, reference to "a nonspecific phosphodiesterase
inhibitor"
includes a mixture of two or more nonspecific phosphodiesterase inhibitors,
and reference to
"an excipient or carrier" includes mixtures of two or more excipients or
carriers, and the like.
In describing and claiming the present invention, the following terminology
will be
used in accordance with the definitions set out below.
"Alkyl" as used herein refers to a linear or branched saturated hydrocarbon
group.
Non-limiting examples of C1-C6 alkyl include methyl, ethyl, n-, and iso-
propyl, n-, iso-, sec-,
and t-butyl, n-pentyl, n-hexyl, 1,3 - dimethylbutyl, 3,3-dimethylbutyl.
"Alkenyl" as used herein refers to an alkyl group with at least one double
bond.
"Alkynyl" as used herein refers to an alkyl groups with at least one triple
bond.
"Cycloalkyl" as used herein refers to a monocyclic or bicyclic saturated
hydrocarbon
group, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexanyl.
"Heterocycly1" as used herein refers to a cycloalkyl group with at least one
heteroatom, such as N, 0, S, and P. Non-limiting examples of heterocyclyl
include
aziridinyl, azetidinyl, pyrrolidinyl and tetrahydrofuranyl.
"Aryl" as used herein refers to a monocyclic or a bicyclic aromatic
hydrocarbon
group, including, but not limited to, phenyl and naphthyl.
"Heteroaryl" as used herein refers to an aryl group with at least one
heteroatom, such
as, N, 0, S, and P. Non-limiting examples of heteroaryl include pyrrolyl,
imidazolyl, furanyl,
pyridinyl, and pyrazinyl.
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0
`22_1L
"Acyl" as used herein refers to a group of formula R , wherein R is alkyl,
alkenyl,
alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which can be
optionally
substituted.
The term "fibrotic disease" as used herein refers to conditions where the
fibroproliferative response produces an abnormal accumulation of fibrocellular
scar tissue
that compromises the normal architecture and function of the affected tissue.
Non-limiting
examples of fibrotic disease include Peyronie's disease, Raynaud's syndrome,
psoriasis
plaques, eczema, keloid scars, pulmonary fibrosis, liver fibrosis, renal
fibrosis, and vascular
fibrosis.
The term "erectile dysfunction" is intended to include any and all types of
erectile
dysfunction, including: vasculogenic, neurogenic, endocrinologic and
psychogenic impotence
("impotence" is used herein its broadest sense to indicate an inability, or a
periodic or
consistent inability, to achieve or sustain an erection of sufficient rigidity
for sexual
intercourse; see U.S. Pat. No. 5,242,391); Peyronie's syndrome; priapism;
premature
.. ejaculation; and any other condition, disease or disorder, regardless of
cause or origin, which
interferes with at least one of the three phases of human sexual response,
i.e., desire,
excitement and orgasm (see Kaplan, Disorders of Sexual Desire (New York, N.Y.:
Brunner
Mazel Book Inc., 1979)). Generally, however, the erectile dysfunction referred
to herein is
vasculogenic erectile dysfunction, particularly vasculogenic impotence.
The terms "treating" and "treatment" as used herein refer to reduction in
severity
and/or frequency of symptoms, elimination of symptoms and/or underlying cause,
prevention
of the occurrence of symptoms and/or their underlying cause, and improvement
or
remediation of damage. The present method of "treating" a fibrotic disease, as
the term is
used herein, thus encompasses both prevention of the disorder in a predisposed
individual and
treatment of the disorder in a clinically symptomatic individual.
The term "phosphodiesterase inhibitor" as used herein is intended to mean an
agent
that is capable of inhibiting or selectively reducing the activity of any one
or more
phosphodiesterases.
The term "active agent" used herein refers to a chemical material or compound
that
induces a desired effect, e.g., reduction of fibrosis scars and/or improvement
of other
symptoms.
"Excipient or carrier" as used herein refers to excipients or carrier
materials suitable
for local drug administration. Excipient or carriers useful herein include any
such material
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known in the art which is nontoxic and does not interact with other components
of the
composition in a deleterious manner.
By an "effective" amount of a drug or pharmacologically active agent is meant
a
nontoxic but sufficient amount of the drug or agent to provide the desired
effect, e.g.,
reduction of fibrosis scars and/or improvement of other symptoms.
Additional pharmacologically active agents may be optionally delivered along
with
the primary active agent, i.e., the nonspecific phosphodiesterase inhibitor.
Non-limiting
examples of the active agent include nitrovasodilators, alpha receptor
blocking agents, ergot
alkaloids, antihypertensive agents, vasodilators, naturally occurring,
semisynthetic and
synthetic prostaglandins, and vasoactive intestinal peptide.
Non-limiting examples of nitrovasodilators include nitroglycerin, linsidomine
such as
insidomine chlorhydrate ("SIN-1"), molsidomine, organic nitrates such as
isosorbide
dinitrate, erythrityl tetranitrate and amyl nitrate, sodium nitroprusside, S-
nitrosothiols such as
S-nitroso-N-acetyl-d,l-penicillamine ("SNAP"), S-nitroso-N-cysteine and S-
nitroso-
N-glutathione ("SNO-GLU"), and diazenium diolates ("NONOates") such as (Z)-1-
{N-
methyl-
N- [6- (N-methyl-ammoniohexyl)amino] } di azen-l-ium- 1,2-diol ate, (Z)-1- [N-
(3-
ammoniopropy1)-N-(n-propyl)aminoldiazen-l-ium-1,2-diolate, (Z)-1- {N-[3-
aminopropyll-N-
[443 -aminopropy lammonio)butyl] amino } di azen- 1-ium- 1,2-diol ate and
sodium (Z)- 1-(N,N-
diethylamino)-diazen-l-ium-1,2-diolate.
Non-limiting examples of alpha receptor blocking agents include
phenoxybenzamine,
dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin,
trimazosin, alffizosin,
tamsulosin and indoramin.
Non-limiting examples of ergot alkaloids include ergotamine and ergotamine
analogs,
such as acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile,
disulergine,
ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide,
mesulergine,
metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride
and terguride.
Non-limiting examples of antihypertensive agents include diazoxide,
hydralazine and
minoxidil.
Non-limiting examples of vasodilators include nimodipine, pinacidil,
cyclandelate and
isoxsuprine.
Non-limiting examples of naturally occurring prostaglandins include PGE0,
PGE1,
PGA1, PGBI, PGF la, 19-hydroxy-PGA 1, 19-hydroxy-PGBI, PGE2, PGA2, PGB2, 19-
hydroxy-PGA2, 19-hydroxy-PGB2, PGE3, PGF3a. Non-limiting examples of
semisynthetic or
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synthetic derivatives of natural prostaglandins include carboprost
tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and
tiaprost.
Non-limiting examples of nonspecific phosphodiesterase inhibitors include
theophylline, theobromine, 3-isobuty1-1-methylxanthine (IBMX), and
pentoxifylline.
In some embodiments, additional pharmacological agents that may be optionally
delivered along with the primary active agent include anesthetic(s) (i.e.,
substances or
compounds that induce insensitivity to pain such as a temporary loss of
sensation). Those
having ordinary skill in the art will select such anesthetic(s) and their
concentrations, if
desired. As a non-binding guideline only, the concentration of an anesthetic
in the
composition may be between about 0.1 mass % and about 0.5 mass %.
Non-limiting examples of acceptable anesthetics that may be so used include
lidocaine, tetracaine, proparacaine, procaine or dyclonine.
Furthermore, if desired, other pharmacological agents, for example, without
limitations, anti-bacterial agent(s) (i.e., antibiotics), antiviral
medicament(s) or antifungal
medicament(s), may be optionally additionally included for delivery along with
the primary
active agent. Those having ordinary skill in the art will select such
additional agents and
their concentration, if desired.
The active agents may be administered, if desired, in the form of salts,
esters, amides,
prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug
or derivative is
suitable pharmacologically, i.e., effective in the present method. Salts,
esters, amides,
prodrugs and other derivatives of the active agents may be prepared using
standard
procedures known to those skilled in the art of synthetic organic chemistry
and described, for
example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and
Structure,
4th Ed. (New York: Wiley-Interscience, 1992). For example, acid addition salts
are prepared
from the free base using conventional methodology, and involve reaction with a
suitable acid.
Generally, the base form of the drug is dissolved in a polar organic solvent
such as methanol
or ethanol and the acid is added thereto. The resulting salt either
precipitates or may be
brought out of solution by addition of a less polar solvent. Suitable acids
for preparing acid
addition salts include both organic acids, e.g., acetic acid, propionic acid,
glycolic acid,
pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic
acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid,
ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like, as
well as inorganic
acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid,
and the like. An acid addition salt may be reconverted to the free base by
treatment with a
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suitable base. Particularly preferred acid addition salts of the active agents
herein are halide
salts, such as may be prepared using hydrochloric or hydrobromic acids.
Conversely,
preparation of basic salts of acid moieties which may be present on a
phosphodiesterase
inhibitor molecule are prepared in a similar manner using a pharmaceutically
acceptable base
such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium
hydroxide,
trimethylamine, or the like. Particularly preferred basic salts herein are
alkali metal salts,
e.g., the sodium salt, and copper salts. Preparation of esters involves
functionalization of
hydroxyl and/or carboxyl groups which may be present within the molecular
structure of the
drug. The esters are typically acyl-substituted derivatives of free alcohol
groups, i.e.,
.. moieties which are derived from carboxylic acids of the formula RCOOH where
R is alkyl,
and preferably is lower alkyl. Esters can be reconverted to the free acids, if
desired, by using
conventional hydrogenolysis or hydrolysis procedures. Amides and prodrugs may
also be
prepared using techniques known to those skilled in the art or described in
the pertinent
literature. For example, amides may be prepared from esters, using suitable
amine reactants,
.. or they may be prepared from an anhydride or an acid chloride by reaction
with ammonia or a
lower alkyl amine. Prodrugs are typically prepared by covalent attachment of a
moiety which
results in a compound that is therapeutically inactive until modified by an
individual's
metabolic system.
The terms "local administration" and "locally administering" as used herein
refer to
treatment of a fibrotic disease by administering at sites approximate to local
symptoms (e.g.,
PD plaques) of the fibrotic disease. It is distinguished from systemic
administrations, such as
oral administration or intravenous injection, wherein dosage of a
pharmaceutical composition
is relatively similar throughout the body of a subject. Non-limiting examples
of local
administration include intracavernosal injection, topical administration, and
transdermal
administration.
The term "intracavernosal" as used herein refers to an injection into one or
both
corpora of the corpora cavernosal tissues of the penis.
The term "transdermal" delivery includes both transdermal (or "percutaneous")
and
transmucosal administration, i.e., delivery by passage of a drug through the
body surface, i.e.,
the skin or mucosal tissue. "Transdermal" delivery is also intended to
encompass delivery of
a drug by passage across scrotal tissue. Examples of conventional transdermal
drug delivery
systems include transdermal "patches" wherein the agent is typically contained
within a
laminated structure that serves as a drug delivery device to be affixed to the
skin. In such a
structure, the drug composition is typically contained in a layer, or
"reservoir," underlying an
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upper backing layer. The laminated device may contain a single reservoir, or
it can contain
multiple reservoirs. The reservoir can comprise a polymeric matrix of a
pharmaceutically
acceptable contact adhesive material that serves to affix the system to the
skin during drug
delivery. Non-limiting examples of suitable skin contact adhesive materials
include
polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes,
and the like.
Alternatively, the drug-containing reservoir and skin contact adhesive are
present as separate
and distinct layers, with the adhesive underlying the reservoir which, in this
case, can be
either a polymeric matrix as described above, or a liquid or hydrogel
reservoir, or some other
form.
The term "topical administration" is used in its conventional sense to mean
delivery
of a topical drug or pharmacologically active agent to the skin or mucosa.
Examples of
formulations for topical drug delivery include ointments and creams. Ointments
are
semisolid preparations which are typically based on petrolatum or other
petroleum
derivatives. Creams containing the selected active agent include viscous
liquid or semisolid
emulsions, either oil-in-water or water-in-oil. Cream bases are water-
washable, and contain
an oil phase, an emulsifier and an aqueous phase. The oil phase, also
sometimes called the
"internal" phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or
stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds
the oil phase in
volume, and generally contains a humectant. The emulsifier in a cream
formulation is
generally a nonionic, anionic, cationic or amphoteric surfactant. The specific
ointment or
cream base to be used, as will be appreciated by those skilled in the art, is
one that will
provide for optimum drug delivery. As with other carriers or vehicles, an
ointment base
should be inert, stable, nonirritating and nonsensitizing.
Methods of Treatment
In one aspect, provided herein is a method for treating a fibrotic disease in
a subject in
need thereof, which comprises locally administering to the subject a
pharmaceutical
formulation comprising a therapeutically effective amount of a compound of
formula I:
0 R3
R1 N
N I )
N N
R2 (I),
or a pharmaceutically acceptable salt thereof, wherein
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RI, R2 and R3 are each, independently, H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally
substituted.
In another aspect, provided herein is a method for treating Peyronie's disease
in a
subject in need thereof, which comprises locally administering to the subject
a
pharmaceutical formulation comprising a therapeutically effective amount of a
compound of
formula I:
0 R3
R1 N
N I )
ON "N
R2 (I),
or a pharmaceutically acceptable salt thereof, wherein
RI, R2 and R3 are each, independently, H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally
substituted.
In certain embodiments of the methods, RI, R2 and R3 are each, independently,
H, or
optionally substituted CI-C6 alkyl.
In other embodiments, RI, R2 and R3 are each, independently, H, C1-C6 alkyl,
or Ci-C6
alkyl substituted with acyl.
In still other embodiments, the compound of formula I is a nonspecific
phosphodiesterase inhibitor (PDEi). In certain embodiments, the nonspecific
PDEi is
pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, or 3-
isobutyl-1-methylxanthine (TB MX).
In yet other embodiments, the compound of formula I is selected from the group
consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
In another aspect, provided herein is a method for treating a fibrotic disease
in a
subject in need thereof, which comprises locally administering to the subject
a
pharmaceutical formulation comprising, consisting essentially of or consisting
of a
therapeutically effective amount of a nonspecific PDEi or a pharmaceutically
acceptable salt
thereof, wherein the nonspecific PDEi is pentoxifylline, aminophylline,
enprofylline,
isbufylline, theophylline, theobromine, or 3-isobuty1-1-methylxanthine (IBMX).
In yet another aspect, provided herein is a method for treating Peyronie's
disease in a
subject in need thereof, which comprises injecting into at least one of the
corpus cavernosa of
the penis of the subject a pharmaceutical formulation comprising, consisting
essentially of or
consisting of a therapeutically effective amount of a nonspecific PDEi or a
pharmaceutically
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acceptable salt thereof, wherein the nonspecific PDEi is pentoxifylline,
aminophylline,
enprofylline, isbufylline, theophylline, theobromine, or 3-isobuty1-1-
methylxanthine (IBMX).
In particular embodiments of the methods provided above, the pharmaceutical
formulation consists essentially of pentoxifylline or a pharmaceutically
acceptable salt
thereof
The fibrotic disease includes Peyronie's disease, Raynaud's syndrome,
psoriasis
plaques, eczema, and keloid scars. In certain particular embodiments, the
fibrotic disease is
Peyronie's disease. In other embodiments, the fibrotic disease is keloid scar.
The treatment method leads to improvement of various fibrotic conditions, for
example, reduction of fibrotic scars. In certain particular embodiments, the
treatment of
Peyronie's disease results in reduction of PD plaques. In other embodiments,
the treatment
results in improvement of erectile dysfunction. In certain embodiments, the
erectile
dysfunction is associated with PD.
In certain embodiments, the pharmaceutical formulation is administered locally
to
treat erectile dysfunction. In particular embodiments, the erectile
dysfunction is associated
with Peyronie's disease.
In certain embodiments of the methods for treating keloid scars in a subject
in need
thereof, the pharmaceutical formulation comprises, consists essentially of or
consists of a
nonspecific PDEi, e.g., pentoxifylline, and caffeine. In other embodiments,
the formulation
comprises, consists essentially of or consists of a nonspecific PDEi, e.g.,
pentoxifylline, and
EGCG (green tea catechin). In still other embodiments, the formulation
comprises, consists
essentially of or consists of a nonspecific PDEi, e.g., pentoxifylline, and a
mast cell stabilizer,
e.g., tranilast. These formulations can be injected into the keloid scars. In
certain
embodiments, the pharmaceutical formulation further comprises a
pharmaceutically
acceptable excipient or carrier, including, but not limited to, an
antioxidant, an adjuvant or
synergist, and a preservative.
Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone
sodium
bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-
tocopherol natural, d-
a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic
acid, propyl
gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium
metabisulfite, sodium
sulfite, sodium thiosulfate, thiourea, tocopherols.
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Non-limiting examples of the adjuvant or synergist are citric acid, EDTA
(ethylenediaminetetraacetate) and salts, hydroxyquinoline sulfate, phosphoric
acid, and
tartaric acid.
In particular embodiments, the pharmaceutical formulation further comprises an
EDTA sodium salt. The EDTA sodium salt can be 0-0.15% by weight of the
formulation, for
example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11,
0.12, 0.13, 0.14, or
0.15% by weight of the formulation.
In particular embodiments, the pharmaceutical formulation further comprises an
EDTA magnesium salt. The EDTA magnesium salt can be 0-0.15% by weight of the
formulation, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08,
0.09, 0.10, 0.11, 0.12,
0.13, 0.14, or 0.15% by weight of the formulation.
Non-limiting examples of the preservative are benzalkonium chloride,
benzethonium
chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts,
cetylpyridinium
chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol,
chorhexidine
gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea,
metacresol,
methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric
acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts,r3-
Phenylethyl
alcohol, thimerosal. In particular embodiments, the preservative is benzyl
alcohol.
In particular embodiments, the pharmaceutical formulation further comprises
ethanol.
The ethanol can be 190 proof The ethanol can be 0-15% by volume of the
formulation, for
example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% by volume of
the formulation.
In other embodiments, the pharmaceutical formulation further comprises benzyl
alcohol. The benzyl alcohol can be 0-1.5% by weight of the formulation, for
example, 0, 0.1,
0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by
volume of the
formulation.
In other embodiments, the pharmaceutical formulation is filtered before local
administration. In particular embodiments, the pharmaceutical formulation is
filtered through
a 0.22 micron filter before local administration.
In other embodiments, the pharmaceutical formulation has a pH of between 4 and
8.
In particular embodiments, the pharmaceutical formulation has a pH of between
5.5 and 6.
The pH can be adjusted by adding acids or bases, e.g., HC1 or NaOH.
In other embodiments of the methods, the therapeutically effective amount is
between
4 mg and 20 mg. In particular embodiments, the therapeutically effective
amount is between
6 mg and 10 mg.
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In other embodiments of the methods, the pharmaceutical formulation is
administered
one to four times in a twenty-four hour period. In particular embodiments, the
pharmaceutical formulation is administered daily until desired effects are
achieved.
In certain embodiments of the methods, the pharmaceutical formulation
comprises a
unit dosage of the compound of formula I. In particular embodiments, the
pharmaceutical
formulation comprises a unit dosage of pentoxifylline.
The pharmaceutical formulation can be administered to a subject in need
thereof by
various local administrations. In certain embodiments, the pharmaceutical
formulation is
administered topically. In other embodiments, the pharmaceutical formulation
is
administered transderm ally. In still other embodiment, the pharmaceutical
formulation is
administered locally to the penis of the subject. In particular embodiments,
the
pharmaceutical formulation is administered by intracavernosal injection.
In certain particular embodiment, provided herein is a method for treating
Peyronie's
disease in a subject in need thereof, comprising injecting into at least one
of the corpus
cavernosa of the penis of the subject a pharmaceutical formulation consisting
essentially of a
therapeutically effective amount of pentoxifylline or a pharmaceutically
acceptable salt
thereof
In certain embodiments of the methods, the pharmaceutical formulation is not
administered (e.g., intracavernosally injected) directly into the area of the
fibrotic disease. In
particular embodiments of the methods for treating Peyronie's disease, the
pharmaceutical
formulation is not administered (e.g., intracavernosally injected) directly
into the area of the
Peyronie's disease. In other embodiments of the methods for treating
Peyronie's disease, the
pharmaceutical formulation is administered (e.g., intracavernosally injected)
at the base of the
penis about 2 cm from where the penis attaches to the abdomen.
In certain embodiments of the methods, the pharmaceutical formulation further
comprises a second active agent. In particular embodiments, the second active
agent is a
vasodilator, e.g., alprostadil (Prostaglandin El), papaverine, and/or
phentolamine. In other
embodiments, the second active agent is a nonspecific phosphodiesterase
inhibitor as defined
above, e.g., pentoxifylline, aminophylline, enprofylline, isbufylline,
theophylline,
theobromine, and/or 3-isobuty1-1-methylxanthine (IBMX). In still other
embodiments, the
second active agent is selected from the group consisting of
nitrovasodilators, alpha receptor
blocking agents, ergot alkaloids, antihypertensive agents, vasodilators,
naturally occurring,
semisynthetic and synthetic prostaglandins, and/or vasoactive intestinal
peptide.
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In other embodiments of the methods for treating Peyronie's disease, the
pharmaceutical formulation further comprises a collagenase, such as
collagenase clostridium
histolyticum, or Xiaflex0. In certain particular embodiments, the
pharmaceutical formulation
comprises, consists essentially of or consists of pentoxifylline and a
collagenase, e.g.,
collagenase clostridium histolyticum or Xiaflex0.
The methods provided herein can be used as a mono therapy or a part of a combo
therapy. In certain embodiments, the formulation comprising the compound of
formula I, e.g,
pentoxifylline, is used as a mono therapy. In certain particular embodiments,
the formulation
consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used as
a mono therapy to
treat a fibrotic disease, such as Peyronie's disease.
In other embodiments, the formulation comprising the compound of formula I,
e.g,
pentoxifylline, is used as a part of a combo therapy. In certain particular
embodiments, the
formulation consisting essentially of a nonspecific PDEi, e.g.,
pentoxifylline, is used to treat a
fibrotic disease, such as Peyronie's disease, in combination with a
collagenase therapy, e.g.,
collagenase clostridium histolyticum or Xiaflex0.
Pharmaceutical Formulation
In one aspect, provided herein is a pharmaceutical formulation comprising a
therapeutically effective amount of a compound of formula I:
0 R3
R1 N
N )
N N
R2 (I),
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a
pharmaceutically
acceptable excipient or carrier suitable for local administration, wherein RI,
R2 and R3 are
each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl,
heterocyclyl,
aryl, or heteroaryl, each of which is optionally substituted.
In one embodiment, RI, R2 and R3 are each, independently, H, or optionally
substituted C1-C6 alkyl.
In another embodiment, RI is CH3-C(0)-(CH2)4 and each of R2 and R3 is CH3.
In another embodiment, RI, R2 and R3 are each, independently, H, Ci-C6 alkyl,
or C1-
C6 alkyl substituted with acyl.
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In still another embodiment, the compound of formula I is a nonspecific
phosphodiesterase inhibitor (PDEi). In one embodiment, the nonspecific PDEi is
pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, or 3-
isobutyl-1-methylxanthine (TB MX).
In yet another embodiment, the compound of formula I is selected from the
group
consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
Also provided herein is a pharmaceutical formulation comprising, consisting
essentially of or consisting of a therapeutically effective amount of a
nonspecific PDEi or a
pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a
pharmaceutically
acceptable excipient or carrier suitable for local administration, wherein the
nonspecific PDEi
is pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, or 3-
isobutyl-1-methylxanthine (IBMX).
In certain particular embodiments, the pharmaceutical formulation comprises,
consists
essentially of or consists of a therapeutically effective amount of
pentoxifylline or a
.. pharmaceutically acceptable salt, ester, amide or prodrug thereof, and a
pharmaceutically
acceptable excipient or carrier suitable for local administration.
The formulations are useful in treating fibrotic diseases. The fibrotic
diseases include
Peyronie's disease, Raynaud's syndrome, psoriasis plaques, eczema, and keloid
scars. In
certain particular embodiments, the formulation is useful in treating
Peyronie's disease. In
other embodiments, the formulation is useful in treating keloid scars.
In certain embodiments, the pharmaceutical formulation results in improvement
of
fibrotic conditions, for example, reduction of fibrotic scars. In certain
particular
embodiments, the formulation reduces PD plaques. In other embodiments, the
formulation
results in improvement of erectile dysfunction. In certain embodiments, the
erectile
dysfunction is associated with PD.
In certain embodiments, the pharmaceutical formulation is administered locally
to
treat erectile dysfunction. In particular embodiments, the erectile
dysfunction is associated
with Peyronie's disease.
In certain embodiments of the formulations for treating keloid scars in a
subject in
need thereof, the pharmaceutical formulation consists essentially of a
nonspecific PDEi, e.g.,
pentoxifylline, and caffeine. In other embodiments, the formulation consists
essentially of a
nonspecific PDEi, e.g., pentoxifylline, and EGCG. In still other embodiments,
the
formulation consists essentially of a nonspecific PDEi, e.g., pentoxifylline,
and a mast cell
stabilizer, e.g., tranilast. The formulations can be injected into the keloid
scars.
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The pharmaceutically acceptable excipient or carrier includes, but is not
limited to, an
antioxidant, an adjuvant or synergist, and/or a preservative.
Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone
sodium
bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-
tocopherol natural, d-
a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic
acid, propyl
gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium
metabisulfite, sodium
sulfite, sodium thiosulfate, thiourea, and tocopherols.
Non-limiting examples of the adjuvant or synergist are citric acid, EDTA
(ethylenediaminetetraacetate) and salts, hydroxyquinoline sulfate, phosphoric
acid, and
tartaric acid.
In particular embodiments, the pharmaceutical formulation further comprises an
EDTA sodium salt. The EDTA sodium salt can be 0-0.15% by weight of the
formulation, for
example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11,
0.12, 0.13, 0.14, or
0.15% by weight of the formulation.
In particular embodiments, the pharmaceutical formulation further comprises an
EDTA magnesium salt. The EDTA magnesium salt can be 0-0.15% by weight of the
formulation, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08,
0.09, 0.10, 0.11, 0.12,
0.13, 0.14, or 0.15% by weight of the formulation.
Non-limiting examples of the preservative are benzalkonium chloride,
benzethonium
chloride, benzoic acid and salts, benzyl alcohol, boric Acid and salts,
cetylpyridinium
chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol,
chorhexidine
gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea,
metacresol,
methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric
acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, 13-
Phenylethyl
alcohol, thimerosal. In particular embodiments, the preservative is benzyl
alcohol.
In particular embodiments, the pharmaceutical formulation further comprises
ethanol.
The ethanol can be 190 proof The ethanol can be 0-15% by volume of the
formulation, for
example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% by volume of
the formulation.
In other embodiments, the pharmaceutical formulation further comprises benzyl
alcohol. The benzyl alcohol can be 0-1.5% by weight of the formulation, for
example, 0, 0.1,
0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by
volume of the
formulation.
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In other embodiments, the pharmaceutical formulation is filtered before local
administration. In particular embodiments, the pharmaceutical formulation is
filtered through
a 0.22 micron filter before local administration.
In other embodiments, the pharmaceutical formulation has a pH of between 4 to
8. In
particular embodiments, the pharmaceutical formulation has a pH of between 5.5
and 6. The
pH can be adjusted to 5.5-6 by adding acids or bases, e.g., HC1 or NaOH.
In other embodiments of the pharmaceutical formulations, the therapeutically
effective amount is between 4 mg and 20 mg. In particular embodiments, the
therapeutically
effective amount is between 6 mg and 10 mg.
In other embodiments, the pharmaceutical formulation is administered one to
four
times in a twenty-four hour period. In particular embodiments, the
pharmaceutical
formulation is administered daily until desired effects are achieved.
In certain embodiments, the pharmaceutical formulation comprises a unit dosage
of
the compound of formula I. In particular embodiments, the pharmaceutical
formulation
comprises a unit dosage of pentoxifylline.
The pharmaceutical formulation can be administered to a subject in need
thereof by
various local administration, e.g., intravacernosal injection, topical
administration, and
transdermal administration. In particular embodiments, the pharmaceutical
formulation
comprises a sterile liquid composition, and the pharmaceutically acceptable
excipient or
carrier is suitable for intracavernosal injection. In other embodiments, the
pharmaceutical
formulation is suitable for topical or transdermal administration. In certain
particular
embodiments, the pharmaceutical formulation comprises a composition to be
applied to a
body surface, and the pharmaceutically acceptable excipient or carrier is
suitable for topical
or transdermal administration. In certain embodiments, the pharmaceutical
composition is an
ointment, cream, gel or lotion.
In certain embodiments, the pharmaceutical formulation is not administered
(e.g.,
intracavernosally injected) directly into the area of the fibrotic disease. In
particular
embodiments of the pharmaceutical formulations, the pharmaceutical formulation
is not
administered (e.g., intracavernosally injected) directly into the area of the
Peyronie's disease.
In other embodiments of the pharmaceutical formulations, the pharmaceutical
formulation is
administered (e.g., intracavernosally injected) at the base of the penis about
2 cm from where
the penis attaches to the abdomen.
In certain embodiments, the pharmaceutical formulation further comprises a
second
active agent. In particular embodiments, the second active agent is a
vasodilator, e.g.,
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alprostadil (Prostaglandin El), papaverine, and/or phentolamine. In other
embodiments, the
second active agent is a nonspecific phosphodiesterase inhibitor as defined
above, e.g.,
pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, and/or 3-
isobutyl- 1-methylxanthine (IBMX). In still other embodiments, the second
active agent is
selected from the group consisting of nitrovasodilators, alpha receptor
blocking agents, ergot
alkaloids, antihypertenseive agents, vasodilators, naturally occurring,
semisynthetic and
synthetic prostaglandins, and/or vasoactive intestinal peptide.
In other embodiments, the pharmaceutical formulation further comprises a
collagenase, such as collagenase clostridium histolyticum or Xiaflex0. In
certain particular
embodiments, the pharmaceutical formulation comprises, consists essentially of
or consists of
pentoxifylline and a collagenase, e.g., collagenase clostridium histolyticum
or Xiaflex0.
The pharmaceutical formulations provided herein can be used as a mono therapy
or a
part of a combo therapy. In certain embodiments, the pharmaceutical
formulation comprising
the compound of formula I, e.g, pentoxifylline, is used as a mono therapy. In
certain
particular embodiments, the pharmaceutical formulation consisting essentially
of a
nonspecific PDEi, e.g., pentoxifylline, is used as a mono therapy to treat a
fibrotic disease,
such as PD.
In other embodiments, the formulation comprising the compound of formula I,
e.g,
pentoxifylline, is used as a part of a combo therapy. In certain embodiments,
the formulation
consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used to
treat a fibrotic
disease, such as Peyronie's disease, in combination with a collagenase
therapy, e.g.,
collagenase clostridium histolyticum or Xiaflex0.
In one particular embodiment, provided herein is a pharmaceutical formulation
consisting essentially of a therapeutically effective amount of pentoxifylline
or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
excipient or
carrier suitable for intracavernosal administration.
Kit
In one aspect, provided herein is a kit comprising: a pharmaceutical
formulation
containing a therapeutically effective amount of a compound of formula I:
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0 R3
ONN
R2 (I),
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof,
wherein
RI, R2 and R3 are each, independently, H, CI-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally
substituted;
an apparatus for locally administering the formulation;
a container for housing the formulation and the drug delivery apparatus; and
instructions for use.
In one embodiment, RI, R2 and R3 are each, independently, H, or optionally
substituted C1-C6 alkyl.
In another embodiment, RI, R2 and R3 are each, independently, H, C i-C6 alkyl,
or CI-
C6 alkyl substituted with acyl.
In still another embodiment, the compound of formula I is a nonspecific
phosphodiesterase inhibitor (PDEi). In one embodiment, the nonspecific PDEi is
pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, or 3-
isobutyl-l-methylxanthine (IBMX).
In yet another embodiment, the compound of formula I is selected from the
group
consisting of pentoxifylline, caffeine, theophylline, and aminophylline.
In another aspect, provided herein is a kit comprising: a pharmaceutical
formulation
comprising, consisting essentially of or consisting of a therapeutically
effective amount of a
nonspecific PDEi or a pharmaceutically acceptable salt, ester, amide or
prodrug thereof,
wherein the nonspecific PDEi is pentoxifylline, aminophylline, enprofylline,
isbufylline,
theophylline, theobromine, or 3-isobuty1-1-methylxanthine (IBMX); an apparatus
for locally
administering the formulation; a container for housing the formulation and the
drug delivery
apparatus; and instructions for use.
In certain particular embodiments, the pharmaceutical formulation comprises,
consists
essentially of or consists of a therapeutically effective amount of
pentoxifylline or a
pharmaceutically acceptable salt, ester, amide or prodrug thereof.
In certain embodiments, the kits are used to treat a fibrotic disease. Non-
limiting
examples of the fibrotic disease include Peyronie's disease, Raynaud's
syndrome, psoriasis
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plaques, eczema, and keloid scars. In particular embodiments, the fibrotic
disease is
Peyronie's disease. In other embodiments, the fibrotic disease is keloid
scars.
In other embodiments of the kits, the pharmaceutical formulation results in
improvement of fibrotic conditions, for example, reduction of fibrotic
plaques. In particular
embodiments, the formulation reduces PD plaques. In other embodiments, the
formulation
improves erectile dysfunction. In certain embodiments, the erectile
dysfunction is associated
with PD.
In other embodiments of the kits, the pharmaceutical formulation is
administered
locally to treat erectile dysfunction. In particular embodiments, the erectile
dysfunction is
associated with Peyronie's disease.
In certain embodiments of the formulations for treating keloid scars in a
subject in
need thereof, the pharmaceutical formulation comprises, consists essentially
of or consists of
a nonspecific PDEi, e.g., pentoxifylline, and caffeine. In other embodiments,
the formulation
comprises, consists essentially of or consists of a nonspecific PDEi, e.g.,
pentoxifylline, and
EGCG. In still other embodiments, the formulation comprises, consists
essentially of or
consists of a nonspecific PDEi, e.g., pentoxifylline, and a mast cell
stabilizer, e.g., tranilast.
The formulations can be injected into the keloid scars.
In certain embodiments, the pharmaceutical formulation further comprises a
pharmaceutically acceptable excipient or carrier, including, but not limited
to, an antioxidant,
an adjuvant or synergist, and a preservative.
Non-limiting examples of the antioxidant are a-tocopherol acetate, acetone
sodium
bisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, d- a-
tocopherol natural, d-
a-tocopherol synthetic, dithiothreitol, monothioglycerol, nordihydroguaiaretic
acid, propyl
gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium
metabisulfite, sodium
sulfite, sodium thiosulfate, thiourea, tocopherols.
Non-limiting examples of the adjuvant or synergist are citric acid, EDTA
(ethylenediaminetetraacetate) and salts, hydroxyquinoline sulfate, phosphoric
acid, and
tartaric acid.
In particular embodiments, the pharmaceutical formulation further comprises an
EDTA sodium salt. The EDTA sodium salt can be 0-0.15% by weight of the
formulation, for
example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11,
0.12, 0.13, 0.14, or
0.15% by weight of the formulation.
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In particular embodiments, the pharmaceutical formulation further comprises an
EDTA magnesium salt. The EDTA magnesium salt can be 0-0.15% by weight of the
formulation, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08,
0.09, 0.10, 0.11, 0.12,
0.13, 0.14, or 0.15% by weight of the formulation.
Non-limiting examples of the preservative are benzalkonium chloride,
benzethonium
chloride, benzoic acid and salts, benzyl alcohol, boric acid and salts,
cetylpyridinium
chloride, cetyltrimethyl ammonium bromide, chlorobutanol, chlorocresol,
chorhexidine
gluconate or chlorhexidine acetate, cresol, ethanol, imidazolidinyl urea,
metacresol,
methylparaben, nitromersol, o-phenyl phenol, parabens, phenol, phenylmercuric
acetate/nitrate, propylparaben, sodium benzoate, sorbic acids and salts, P-
Phenylethyl
alcohol, and thimerosal. In particular embodiments, the preservative is benzyl
alcohol. The
benzyl alcohol can be 0-1.5% by weight of the formulation, for example, 0,
0.1, 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5% by volume of the
formulation.
In particular embodiments, the pharmaceutical formulation further comprises
ethanol.
The ethanol can be 190 proof The ethanol can be 0-15% by volume of the
formulation, for
example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% by volume of
the formulation.
In still other embodiments of the kits, the therapeutically effective amount
is between
4 mg and 20 mg. In particular embodiments, the therapeutically effective
amount is between
6 mg and 10 mg.
In certain embodiments, the pharmaceutical formulation is administered one to
four
times in a twenty-four hour period. In other embodiments, the pharmaceutical
formulation is
administered daily until desired effects are achieved.
In still other embodiments, the pharmaceutical formulation is filtered through
a 0.22
micron filter. In particular embodiments, the pharmaceutical formulation is to
be filtered
through a 0.22 micron filter before administration.
In other embodiments, the pharmaceutical formulation has a pH of between 4 and
8.
In particular embodiments, the pharmaceutical formulation has a pH of between
5.5 and 6.
The pH can be adjusted to 5.5-6 before administration by adding acids or
bases, e.g., HC1 or
NaOH.
Furthermore, the pharmaceutical formulation is administered locally. In
certain
embodiments, the pharmaceutical formulation comprises a sterile liquid
composition and the
pharmaceutically acceptable excipient or carrier is suitable for
intracavernosal injection. In
other embodiments, the pharmaceutical formulation comprises an ointment,
cream, gel, or
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lotion, and the pharmaceutical acceptable excipient or carrier is suitable for
topical or
transdermal administration.
In certain particular embodiments, the pharmaceutical formulation consists
essentially
of a therapeutically effective amount of pentoxifylline or a pharmaceutically
acceptable salt
thereof, and a pharmaceutically acceptable excipient or carrier suitable for
intracavernosal
administration.
In certain embodiments, the pharmaceutical formulation is not administered
(e.g.,
intracavernosally injected) directly into the area of the fibrotic disease. In
particular
embodiments, the pharmaceutical formulation is not administered (e.g.,
intracavernosally
injected) directly into the area of the Peyronie's disease. In other
embodiments, the
pharmaceutical formulation is administered (e.g., intracavernosally injected)
at the base of the
penis about 2 cm from where the penis attaches to the abdomen.
In certain embodiments of the kits, the pharmaceutical formulation further
comprises
a second active agent. In particular embodiments, the second active agent is a
vasodilator,
e.g., alprostadil (Prostaglandin El), papaverine, and/or phentolamine. In
other embodiments,
the second active agent is a nonspecific phosphodiesterase inhibitor as
defined above, e.g.,
pentoxifylline, aminophylline, enprofylline, isbufylline, theophylline,
theobromine, and/or 3-
isobutyl- 1-methylxanthine (IBMX). In still other embodiments, the second
active agent is
selected from the group consisting of nitrovasodilators, alpha receptor
blocking agents, ergot
alkaloids, antihypertenseive agents, vasodilators, naturally occurring,
semisynthetic and
synthetic prostaglandins, and/or vasoactive intestinal peptide.
In some additional embodiments, the pharmaceutical composition comprises yet
another component, a polysaccharide. Some exemplary polysaccharides that may
be used
include, without limitations, any of hyaluronic acid, heparin, heparan,
chondroitin, dermatan,
keratin, keratin, and pharmaceutically acceptable water-soluble salts thereof,
and
combinations of more than one of such polysaccharides. Polysaccharides may be
used both in
compositions comprising solely compound I as an active agent and in
compositions
containing both compound I and the above-described second active compound.
In other embodiments, the pharmaceutical formulation further comprises a
collagenase, such as collagenase clostridium histolyticum, or Xiaflex0. In
certain particular
embodiments, the pharmaceutical formulation consists essentially of
pentoxifylline and a
collagenase, e.g., collagenase clostridium histolyticum or Xiaflex0.
In certain embodiments, the pharmaceutical formulation comprising the compound
of
formula I, e.g., pentoxifylline, is used as a mono therapy. In certain
particular embodiments,
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the pharmaceutical formulation consisting essentially of a nonspecific PDEi,
e.g.,
pentoxifylline, is used as a mono therapy to treat a fibrotic disease, such as
Peyronie's
disease.
In other embodiments, the formulation comprising the compound of formula I,
e.g.,
pentoxifylline, is used as a part of a combo therapy. In certain embodiments,
the formulation
consisting essentially of a nonspecific PDEi, e.g., pentoxifylline, is used to
treat a fibrotic
disease, such as Peyronie's disease, in combination with a collagenase
therapy, e.g.,
collagenase clostridium histolyticum or Xiaflex0.
In additional embodiments, the above described pharmaceutical formulations
(both
.. with and without the polysaccharide) may be incorporated within
microparticles. The
microparticles may be essentially spherical particles (shells) fabricated of a
water soluble
biodegradable polymer defining a space therein, which space is to be filled
with
pharmaceutical formulation. Thus, the microparticles represent the structures
where the water
soluble biodegradable polymer envelops the formulation securely ensconcing the
latter and
not allowing the formulation to escape or to leak out.
The formulation filled microparticles can be manufactured according to methods
and
techniques known to those having ordinary skill in the art. The size of
microparticles may be
typically less than about 100 um in diameter, and the exemplary water soluble
polymer to be
used to manufacture the shells may be, without limitations, any of poly(lactic
acid-co-
glycolic acid), poly(lactic acid), poly(glycolic acid), poly(caprolactone),
poly(hydroxybutyrate) and blends thereof In one typical example, poly(lactic
acid-co-
glycolic acid) can be used to form the shells, with the 50:50 (mass) ratio
between the units
derived of lactic and glycolic acids. Other acceptable ratios between the
lactic and glycolic
acid portions may be 65:35, 75:25 and 85:15. Those having ordinary skill in
the art using
poly(lactic acid-co-glycolic acid) may select a different ratio, if desired.
The inherent
viscosities (i.e., the ratio of the natural logarithm of the relative
viscosity to the mass
concentration of the polymer) of the polymer solutions used to form the shells
may be
between about 0.15 dL/g and about 1.20 dL/g, such as between about 0.15 dL/g
and 0.25
dL/g, or the following ranges: 0.26-0.54, 0.55-0.75, 0.62-0.65, 0.65-0.85,
0.76- 0.94 and
0.95-1.20 dL/g.
When the above described microparticles have been fabricated, they can then be
administered to a patient in need of the medication by conventional methods,
such as
intracavernosal injections.
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The following examples are provided to further elucidate the advantages and
features
of the present invention, but are not intended to limit the scope of the
invention. The
examples are for illustrative purposes only. USP pharmaceutical grade products
were used in
preparing the formulations described below.
Examples
Example 1. Preparin2 Pentoxifylline Formulations
Several pentoxifylline formulations were prepared using the compounds
described in
Table 1 in the quantities shown:
Table 1.
1. Pentoxifylline 2% (active)
2. Ethanol 10% (cosolvent)
3. Edetate Disodium 0.1% (antioxidant/preservative)
Formulation 1 4. Benzyl Alcohol 0.9% (preservative)
5. Hydrochloric Acid qs (pH adjustment/buffer)
6. Sodium Hydroxide qs (pH adjustment/buffer)
7. Water for injection qs ad
1. Pentoxifylline 0.1%-2.5%
2. Ethanol 0.1%-10%
3. Edetate Disodium 0.02%-0.1%
Formulation 2 4. Benzyl Alcohol 0.9%
5. Hydrochloric Acid qs or citric acid qs
6. Sodium Hydroxide qs or sodium citrate qs
7. Water for injection qs ad
1. Pentoxifylline 2%
2. Propylene glycol 0.5%-5%
3. Edetate Disodium 0.1%
Formulation 3 4. Benzyl Alcohol 0.9%
5. Hydrochloric Acid qs
6. Sodium Hydroxide qs
7. Water for injection qs ad
1. Pentoxifylline 2%
2. Ethanol 10%
3. Edetate Disodium 0.1%
Formulation 4 4. Benzyl Alcohol 0.9% or benzalkonium chloride 0.005-0.02% or
hydroxyquinoline sulfate 0.005%- 0.01%
5. Hydrochloric Acid qs
6. Sodium Hydroxide qs
7. Water for injection qs ad
1. Pentoxifylline 2%
Formulation 5 2. No cosolvent
3. No Antioxidant
4. Benzyl Alcohol 0.9% or any preservative
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5. Hydrochloric Acid or citric acid qs
6. Sodium Hydroxide or sodium citrate qs
7. Water for injection qs ad
1. Alprostadil 0.005%
2. Papaverine 3%
3. Phentolamine 0.3%
4. Pentoxifylline 0.6%
Formulation 9 5. Ethanol 10%
3. Edetate Disodium 0.1%
4. Benzyl Alcohol 0.9%
5. Hydrochloric Acid qs or citric acid qs
6. Sodium Hydroxide qs or sodium citrate qs
7. Water for injection qs ad
Example 2. Preparing A Caffeine Formulation
A formulation was prepared using the compounds described in Table 2 in the
quantities shown:
Table 2.
1. Caffeine 0.1-2.5% (as caffeine base or caffeine citrate) (active)
2. Ethanol 10% (cosolvent)
3. Edetate Disodium 0.1% (antioxidant/preservative)
Formulation 6 4. Benzyl Alcohol 0.9% (preservative)
5. Hydrochloric Acid qs or citric acid (pH adjustment/buffer)
6. Sodium Hydroxide qs or sodium citrate (pH adjustment/buffer)
7. Water for injection qs ad
Example 3. Preparing Aminophylline and Theophylline Formulations
The following formulations were prepared using the compounds described in
Table 3
in the quantities shown:
Table 3.
1. Aminophylline 0.1-2.5% (active)
2. Ethanol 10% (cosolvent)
3. Edetate Disodium 0.1% (antioxidant/preservative)
Formulation 7 4. Benzyl Alcohol 0.9% (preservative)
5. Hydrochloric Acid qs or citric acid (pH adjustment/buffer)
6. Sodium Hydroxide qs or sodium citrate (pH adjustment/buffer)
7. Water for injection qs ad
1. Theophylline 0.1-2.5% (active)
2. Ethanol 10% (cosolvent)
3. Edetate Disodium 0.1% (antioxidant/preservative)
Formulation 8 4. Benzyl Alcohol 0.9% (preservative)
5. Hydrochloric Acid qs or citric acid (pH adjustment/buffer)
6. Sodium Hydroxide qs or sodium citrate (pH adjustment/buffer)
7. Water for injection qs ad
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Examples 4-6. Intracavernosal Injections of a Pentoxifylline Formulation
In Example 4, a 63 year old male with erectile dysfunction found that a
combination
of three vasoactive drugs: phentolamine, alprostadil, and papaverine, had no
effect on his
erectile dysfunction. A new injection was reformulated to contain the 3
vasoactive drugs
.. mentioned above along with the addition of pentoxifylline, and was
administered to the
patient.
Various combined strengths of phentolamine, alprtostadil, papaverine and
pentoxifylline were used in an attempt to improve his erectile dysfunction
without
demonstrable effects. However, the patient did notice remarkable improvement
at a
pentoxifylline dose of 4 mg per injection. The improvement was more remarkable
at a 6 mg
dose.
In Examples 5 and 6, patients suffering from Peyronie's disease were treated.
A
therapy cycle included injections of sterile pentoxifylline. More
specifically, 6 separate
injections were to be conducted over every two weeks. The dosage was 5 mg of
pentoxifylline in a 1 ml volume. Single use vials were dispensed. The
injections were made
using a 21 gauge cannula directly into the Peyronie's plaque. A nerve block
was done around
the injection site to lessen the pain. Manual manipulation and traction
techniques were
employed to massage the area of the injection. Patients returned after two
weeks for another
injection and manual manipulation session.
Baseline measurements were collected before any treatment occurred to
characterize
the extent of the patient's disease. The degree of curvature was noted, as
well as any
pain/discomfort that the patient presently had and current sexual ability.
Psychosocial effects
related to the patient's disease were observed as well.
In Example 5, the patient suffering from Peyronie's disease was brought to the
.. procedure room, prepared and draped in the usual sterile fashion. As a
baseline characteristic
of the disease state, the patient had 40 degrees dorsal and the location of
the Peyronie's
plaque was at dorsal and mid-shaft.
A total of 1 mL of 1% lidocaine was used to perform a local block. Once the
patient
was anesthetized, the plaque was isolated between two fingers and 1 mL of 5 mg
.. pentoxyfilline was injected into the plaque in a fan-like fashion. The
patient tolerated the
procedure well. The patient held pressure, and a light compressive dressing
was applied. The
patient was instructed to keep this in place for three hours and then remove
it. He was further
instructed not to have sexual intercourse or masturbate for 24 hours.
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In Example 6, another the patient suffering from Peyronie's disease was
treated in the
same fashion as the patient in Example 5. As a baseline characteristic of the
disease state, the
patient had 40 degrees dorsal and the location of the Peyronie's plaque was at
dorsal and
distal 2x1.
The patient tolerated the procedure well and received the same instructions as
the
patient in Example 5.
Example 7. Preparin2 Pentoxifylline Formulations Containin2 a Polysaccharide
A pentoxifylline formulation (formulation 10) may be prepared using the
following
components in the amounts indicated:
(1) about 2.0 g of pentoxifylline in the form of dry powder;
(2) about 1.0 of sodium hyaluronate in the form of dry powder;
(3) about 0.515 g of sodium chloride, granulated;
(4) about 100 L of sterile water for injections.
All dry components can be mixed, weighed and mixed with about 90% of water.
The
pH can then be adjusted to be within 6.0 to 7.0 range using 1% solution of
sodium hydroxide,
followed by adding the balance of water, filtering and sealing in pre-
sterilized amber vials.
Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments and
methods
described herein. Such equivalents are intended to be encompassed by the scope
of the
following claims.
Incorporation by Reference
The entire contents of all patents, published patent applications and other
references
cited herein are hereby expressly incorporated herein in their entireties by
reference.
Although the invention has been described with reference to the above
examples, it
will be understood that modifications and variations are encompassed within
the spirit and
scope of the invention. Accordingly, the invention is limited only by the
following claims.
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