U.S. patent application number 14/673847 was filed with the patent office on 2015-10-01 for alprostadil for treatment of premature ejaculation.
This patent application is currently assigned to Nexmed Holdings, Inc.. The applicant listed for this patent is Nexmed Holdings, Inc.. Invention is credited to Mingqi Lu, Y. Joseph Mo, Qin Wang, James L. Yeager.
Application Number | 20150272875 14/673847 |
Document ID | / |
Family ID | 33101257 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150272875 |
Kind Code |
A1 |
Mo; Y. Joseph ; et
al. |
October 1, 2015 |
ALPROSTADIL FOR TREATMENT OF PREMATURE EJACULATION
Abstract
Compositions and methods for the treatment of premature
ejaculation are provided wherein a composition comprising a topical
anesthetic, a shear-thinning polymeric thickener, a lipophilic
component that is selected from the group consisting of an
aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester, a liquid polyol and a mixture thereof, water and a
buffer system that provides a buffered pH value for the composition
in the range of about 3 to about 7.4 is administered to the penile
meatus.
Inventors: |
Mo; Y. Joseph; (Princeton,
NJ) ; Lu; Mingqi; (Lawrenceville, NJ) ; Wang;
Qin; (Plainsboro, NJ) ; Yeager; James L.;
(Lake Forest, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nexmed Holdings, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
Nexmed Holdings, Inc.
San Diego
CA
|
Family ID: |
33101257 |
Appl. No.: |
14/673847 |
Filed: |
March 30, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14463959 |
Aug 20, 2014 |
9060929 |
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14673847 |
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10806072 |
Mar 22, 2004 |
8841345 |
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14463959 |
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60456813 |
Mar 21, 2003 |
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60456604 |
Mar 21, 2003 |
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Current U.S.
Class: |
514/330 ;
514/317; 514/573 |
Current CPC
Class: |
A61K 31/5575 20130101;
A61K 31/445 20130101; A61K 31/736 20130101; A61P 15/00 20180101;
A61K 31/736 20130101; A61K 31/20 20130101; A61K 45/06 20130101;
A61K 47/10 20130101; A61K 47/26 20130101; A61K 47/14 20130101; A61K
31/5575 20130101; A61K 31/165 20130101; A61K 31/00 20130101; A61K
31/557 20130101; A61K 31/557 20130101; A61K 47/36 20130101; A61K
31/4453 20130101; A61K 31/167 20130101; A61K 9/0034 20130101; A61K
47/32 20130101; A61K 31/445 20130101; Y10S 514/947 20130101; A61K
31/167 20130101; A61K 31/465 20130101; A61K 31/465 20130101; A61K
31/165 20130101; A61K 47/18 20130101; A61K 2300/00 20130101; A61K
9/0014 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/18 20060101 A61K047/18; A61K 31/445 20060101
A61K031/445; A61K 31/167 20060101 A61K031/167; A61K 31/4453
20060101 A61K031/4453; A61K 31/5575 20060101 A61K031/5575; A61K
45/06 20060101 A61K045/06 |
Claims
1-43. (canceled)
44. A method of prolonging ejaculation latency in a patient
comprising: administering meatally to the patient a topical
composition comprising: about 0.1 mg to about 0.5 mg by weight of a
vasoactive prostaglandin selected from the group consisting of
prostaglandin E.sub.1, a pharmaceutically acceptable salt thereof,
a lower alkyl ester thereof, and a mixture thereof.
45. The method of claim 44, wherein 0.4 percent by weight based on
the weight of the composition is the vasoactive prostaglandin.
46. The method of claim 44, wherein the amount of vasoactive
prostaglandin administered is from about 0.3 mg to about 0.5
mg.
47. The method of claim 44, wherein the amount of vasoactive
prostaglandin administered is from about 0.2 mg to 0.5 mg.
48. The method of claim 44, wherein the amount of vasoactive
prostaglandin administered is about 0.2 mg to about 0.3 mg.
49. The method of claim 44, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.3
mg.
50. The method of claim 44, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.2
mg.
51. The method of claim 44, wherein the composition further
comprises about 0.1 to about 5 percent by weight based on the
weight of the composition a penetration enhancer.
52. The method of claim 51, wherein the penetration enhancer is
dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically
acceptable salt.
53. The method of claim 51, wherein 0.4 percent by weight based on
the weight of the composition is the vasoactive prostaglandin.
54. The method of claim 51, wherein the amount of vasoactive
prostaglandin administered is from about 0.3 mg to about 0.5
mg.
55. The method of claim 51, wherein the amount of vasoactive
prostaglandin administered is from about 0.2 mg to 0.5 mg.
56. The method of claim 51, wherein the amount of vasoactive
prostaglandin administered is about 0.2 mg to about 0.3 mg.
57. The method of claim 51, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.3
mg.
58. The method of claim 51, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.2
mg.
59. The method of claim 44, wherein the composition further
comprises a topical anesthetic.
60. The method of claim 59, wherein the topical anesthetic is
bupivacaine, dyclonine, or lidocaine.
61. The method of claim 59, wherein 0.4 percent by weight based on
the weight of the composition is the vasoactive prostaglandin.
62. The method of claim 59, wherein the amount of vasoactive
prostaglandin administered is from about 0.3 mg to about 0.5
mg.
63. The method of claim 59, wherein the amount of vasoactive
prostaglandin administered is from about 0.2 mg to 0.5 mg.
64. The method of claim 59, wherein the amount of vasoactive
prostaglandin administered is about 0.2 mg to about 0.3 mg.
65. The method of claim 59, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.3
mg.
66. The method of claim 59, wherein the amount of vasoactive
prostaglandin administered is from about 0.1 mg to about 0.2 mg.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/456,604, filed Mar. 21, 2003 and
60/456,813, filed Mar. 21, 2003. The entire contents of each of the
above applications are incorporated herein by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] Premature ejaculation (PE) is the most prevalent form of
male sexual dysfunction, affecting as many as 30% of American men.
The diagnostic criteria for premature ejaculation (PE) as provided
by the Diagnostic and Statistical Manual of Mental Disorders,
fourth edition (DSM-IV, 1994) are: A. Persistent or recurrent
ejaculation with minimal sexual stimulation before, on, or shortly
after penetration and before the person wishes it. The clinician
must take into account factors that affect duration of the
excitement phase, such as age, novelty of the sexual partner or
situation, and recent frequency of sexual activity. B. The
disturbance causes marked distress or interpersonal difficulty. C.
The PE is not due exclusively to the direct physiological effects
of a substance (e.g. a drug or medication) or a general medical
condition. American Psychiatric Association, Diagnostic and
statistical manual of mental disorders, fourth edition. Washington,
D.C.: American Psychiatric Association (1994).
[0003] The condition that ejaculation occurs "before the person
desires it" implies a lack of voluntary control. In some
definitions of PE, the lack of voluntary control is primary,
irrespective of time after penetration, number of thrusts or orgasm
by the partner. As a practical matter, PE is often operationally
defined as the latency to ejaculation after vaginal penetration,
although there is a lack of agreement as to the defining minimum
latency, ranging from 1 minute to 7 minutes. As an empirical
matter, it has been reported in a study of 110 men suffering from
lifelong PE that 90% had a intravaginal ejaculation latency time
(IELT) less than 1 minute when measured by stopwatch. See,
generally, Waldinger, M. D., The neurobiological approach to
premature ejaculation, J. Urol., 2002, 168: 2359-2367.
[0004] Recent neurophysiological studies have suggested that the
ejaculatory reflex consists of two reflexes: the glans-vagal reflex
that brings semen to the posterior urethra, and the urethromuscular
reflex that ejects the semen to the exterior (Shafik, A., The
mechanism of ejaculation: the glans-vasal and urethromuscular
reflexes. Arch Androl. 1998 41(2):71-8). The first reflex is
initiated by stimulation of the genital receptors, and it travels
through the pudendal nerves to the sacral cord with a final
destination at the limbic lobe and the hypothalamus. The second
reflex is transmitted from the urethra to the ejaculatory center
(segments 52-4). Efferent fibers of pudendal parasympathetic nerves
send signals to the ganglia; these signals result in the release of
neurotransmitters which, by depolarizing perineal muscles,
translate into rhythmic contractions and seminal emission. A
dysfunction of either or both of these reflexes could result in
ejaculatory disorders.
[0005] One hypothesis of PE proposes that there is a threshold or
set point level of sexual arousal at which ejaculation occurs.
Under this hypothesis, men with a lower threshold would be
predicted to have shorter IELT. However, such a hypothesis does not
specify whether the threshold is set centrally, by synaptic
interactions in the central nervous system, or by peripherally, the
threshold of the afferent sensory input. Both alternatives have
been therapeutic targets.
[0006] Topical anesthetics have been applied to the penis to block
conduction in somatosensory afferent neurons. For example, an open
pilot, unblinded study was done using lidocaine-prilocaine cream in
11 healthy, married men with premature ejaculation without organic
or erectile problems. The patients were instructed to apply 2.5 gm
of the cream 30 minutes before sexual contact and to cover the
penis with a condom. Nine of the eleven patients reported an
improvement (Berkovitch, et al. Efficacy of prilocaine-lidocaine
cream in the treatment of premature ejaculation. J Urol. 1995
154(4):1360-1).
[0007] Several pharmacological approaches have been directed at a
putative threshold setting mechanism in the central nervous system
at spinal or supraspinal levels. Many are serotonergic reuptake
inhibitors. A non-selective serotonergic reuptake inhibitor, the
tricyclic antidepressant chlomipramine, has been used to treat PE.
Several selective serotonergic reuptake inhibitors (SSRIs) have
been used to treat PE, including fluoxetine, paroxetine and
sertaline. However, the serotonergic reuptake inhibitors generally
have undesirable side-effects. See McCullough, A. R. & Melman,
"Ejaculatory Disorders," pp. 351-370 in Mulcahy, J. J., ed., Male
Sexual Function: A Guide to Clinical Management, Humana Press,
Totowa, N.J., 2001.
[0008] PE may be present with erectile dysfunction (ED) in a number
of patients, a factor that might affect the choice of treatment,
but there is no unanimity on either issue. In one study,
eighty-seven patients with PE were categorized into two groups:
primary PE and PE in sildenefil-treated ED patients (Chia, S.,
Management of premature ejaculation--a comparison of treatment
outcome in patients with and without erectile dysfunction. Int J
Androl. 2002 25(5):301-5). Both groups of patients were treated
with 50 mg sertraline four hours before the expected time of sex.
Twenty-eight percent of the sildenefil-treated ED patients
developed PE. No significant difference in the pre-treatment mean
ejaculation latency for the PE and PE+ED groups was reported (46
vs. 34.6 sec, respectively). However, a highly significant
difference in the ejaculation latency between the two groups after
treatment with sertraline for 6 months (247.2 vs. 111.6 sec for PE
and PE+ED, respectively) was reported. The study concluded that
while selective serotonin re-uptake inhibitors (SSRIs) were
effective in the management of primary PE, they were not as
effective in patients with sildenefil-corrected ED. However, a
prospective, double-blind, placebo-controlled, crossover study of
the effect of another SSRI, fluoxetine, on sexual function in men
with premature ejaculation and/or erectile dysfunction reported
that the latency to ejaculation increased significantly in the
PE+ED group (p=0.03) and in the PE and the PE+ED group taken
together (p=0.007) but not in the PE group alone. See Haensel, S.
M., et al. Fluoxetine and premature ejaculation: a double-blind,
crossover, placebo-controlled study. J Clin Psychopharmacol. 1998
18(1):72-7. And while the Chia, 2002, study reported that ED
patients may develop PE, others have reported that life-long PE
patients do not develop ED (Waldinger, 2002, p. 2364).
[0009] Prostaglandin E.sub.1 (PGE.sub.1) is a derivative of
prostanoic acid, a 20-carbon atom lipid acid, represented by the
formula:
##STR00001##
[0010] and is commercially available, e.g., from Chinoin
Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under
the designation "Alprostadil USP," from Pharmacia & Upjohn
under the designation "Caverject". Prostaglandin E.sub.1 complexed
with alpha-cyclodextrin is available as alprostatil alfadex from
Ono Pharmaceuticals (Japan) and in an injectable form under the
designation "Edex.RTM." or "Viradex.RTM." from Schwarz Pharma
(Germany).
[0011] In one commercially available form (MUSE.RTM., Vivus, Menlo
Park Calif.), alprostadil is administered in a pellet deposited in
the urethra using an applicator with a hollow stem 3.2 cm in length
and 3.5 mm in diameter (Padma-Nathan, H., et al., N. Engl. J. Med.,
336: 1-7 (1997), see especially FIG. 1). In the home treatment
portion of the Padma-Nathan et al. study, 32.7% of the patients
(10.8% of administrations) receiving MUSE.RTM. complained of penile
pain and 5.1% experienced minor urethral trauma, compared to 3.3%
and 1.0%, respectively, of the patients receiving placebo.
Frequency of report of these side effects has varied in subsequent
studies: MUSE.RTM. producing penile pain in 17-23.6% of
administrations, compared to 1.7% with placebo and minor urethral
bleeding reported by 4.8% of patients (Peterson, C. A., et al., J.
Urol., 159: 1523-1528 (1998)). In a study on a European population,
31% MUSE.RTM. patients reporting penile pain or burning sensations,
4.8% reporting urethral bleeding, and 2.9% reporting severe
testicular pain (Porst, H., Int. J. Impot. Res., 9:187-192 (1997)).
The percent of patients responding to MUSE.RTM. treatment, defined
as having at least one erection considered sufficient for
intercourse, has been reported to be 43% (Porst, 1997), 65.9%
(Padma-Nathan et al., 1997) and 70.5% (Peterson et al., 1998),
although published editorial comment has suggested that the percent
of patients responding in the latter two studies is more properly
reported as 30-40% (Benson, G., J. Urol., 159: 1527-1528
(1998)).
[0012] Intraurethral application of a preparation of 1 mg
prostaglandin E.sub.1 in phosphatidylcholine liposomes in 1 ml
polyoxyethylene glycol has been reported to be less effective than
intracavernosal injection of prostaglandin E.sub.1 (Englehardt, P.
F., et al., British J. Urology, 81: 441-444, 1998). No ED patients
receiving the liposomal preparation achieved complete penile
rigidity, and only 6 of 25 patients achieved an erection adequate
for vaginal penetration. In contrast, intracavernosal injection of
prostaglandin E.sub.1 produced erections adequate for vaginal
penetration or complete rigidity in 23 of 25 of the same ED
patients. The authors suggested that the transurethral effect of
the prostaglandin E.sub.1 probably arises by diffusion of
prostaglandin E.sub.1 first into the corpus spongiosum and then
into the corpus cavernosum.
[0013] Recently, intrameatal (also referred to as "meatal")
application of a topical PGE.sub.1 composition comprising at least
one penetration enhancer has been shown to be a non-invasive
alternative to intracavernosal injection or transurethral
suppositories for the treatment of erectile dysfunction (see U.S.
Pat. No. 6,323,241 and U.S. published patent application
2003/0220292, the contents of which are hereby incorporated in
their entirety). Intrameatal application is the application of
medication to the tip of the penis into the navicular fossa by
holding the penis upright, holding the meatus open and dropping the
medication into the navicular fossa, without introducing the
medication container into the meatus.
SUMMARY OF THE INVENTION
[0014] In one embodiment, the present invention provides a topical
composition comprising a topical anesthetic, a polymer thickener
selected from the group consisting of shear-thinning polysaccharide
gums and shear-thinning polyacrylic acid polymers, a lipophilic
component that is selected from the group consisting of an
aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester, a liquid polyol and a mixture thereof; water and a
buffer system providing a pH of the composition from about 3 to
about 7.4, preferably about 3 to about 6.5. In preferred
embodiments, the composition further comprises a vasoactive
prostaglandin suitably selected from the group consisting of
PGE.sub.1, PGA.sub.1, PGB.sub.1, PGF.sub.1.alpha.,
19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2,
PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3,
PGF.sub.3 and mixtures thereof. In more preferred embodiments, the
vasoactive prostaglandin is selected from the group consisting of
prostaglandin E.sub.1, prostaglandin E.sub.2, a pharmaceutically
acceptable salt thereof, a lower alkyl ester thereof and a mixture
thereof. Most preferably, the vasoactive prostaglandin is
PGE.sub.1. Typically the vasoactive prostaglandin is present in the
amount of about 0.1 mg to about 0.5 mg.
[0015] In other preferred embodiments, the composition further
comprises a penetration enhancer selected from the group consisting
of an alkyl-(N-substituted amino) alkanoate, an
alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted
amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol
alkanoate, a pharmaceutically acceptable salt thereof and a mixture
thereof.
[0016] In preferred embodiments, the topical anesthetic is an
aminoamide local anesthetic selected from the group consisting of
lidocaine, bupivacaine, mepivacaine, dibucaine, propivacaine,
etidocaine, tocainide, a pharmaceutically acceptable salt thereof
and a mixture thereof. In particularly preferred embodiments, the
local anesthetic is selected from the group consisting of
lidocaine, bupivacaine, dyclonine, a pharmaceutically acceptable
salt thereof and a mixture thereof. In one embodiment, the topical
anesthetic is about 0.01 to about 4 percent by weight based on the
weight of the composition. In another embodiment, the topical
anesthetic is about 0.01 to about 10 percent by weight based on the
weight of the composition.
[0017] In another aspect, the present invention provides a method
of treating premature ejaculation comprising administering
intrameatally a composition comprising vasoactive prostaglandin, a
topical anesthetic, a penetration enhancer, a polymer selected from
the group consisting of polysaccharide gums and polyacrylic acid
polymers, a lipophilic component that is selected from the group
consisting of an aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic
C.sub.8 to C.sub.30 ester, a liquid polyol and a mixture thereof;
water and an acidic buffer system. In preferred embodiments, the
vasoactive prostaglandin is selected from the group consisting of
prostaglandin E.sub.1, prostaglandin E.sub.2, a pharmaceutically
acceptable salt thereof, a lower alkyl ester thereof and a mixture
thereof. Typically the vasoactive prostaglandin is present in the
amount of about 0.1 mg to about 0.5 mg.
[0018] In certain preferred embodiments, the topical anesthetic is
an aminoamide local anesthetic selected from the group consisting
of lidocaine, bupivacaine, mepivacaine, dibucaine, propivacaine,
etidocaine, tocainide, pharmaceutically acceptable salts thereof
and mixtures thereof. In particularly preferred embodiments, the
local anesthetic is selected from the group consisting of
lidocaine, bupivacaine, dyclonine, a pharmaceutically acceptable
salt thereof and a mixture thereof. In other preferred embodiments,
the topical anesthetic comprises dyclonine
(1-(4-butoxyphenyl)-3-(1-piperidinyl)-1-propanone). Typically the
topical anesthetic comprises about 0.01 to about 10 percent by
weight based on the weight of the composition. In other
embodiments, the topical anesthetic is present in an amount of
about 0.01 to about 4 percent by weight based on the weight of the
composition.
[0019] In preferred embodiments, the shear-thinning polysaccharide
gum, is a galactomannan gum or a modified galactomannan gum. A
preferred modified galactomannan gum is a modified guar gum. In
preferred embodiments, the penetration enhancer is dodecyl 2-(N,
N-dimethylamino)-propionate or pharmaceutically acceptable salts
thereof. In preferred embodiments, the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester. In a
preferred embodiment, the lipophilic component comprises at least
one glyceryl ester selected from the group consisting of
monoglycerides, diglycerides, triglycerides, and mixtures thereof.
In another embodiment, the lipophilic component comprises least one
glyceryl ester selected from the group consisting of glyceryl
monooleate, triolein, trimyristin, tristearin, and mixtures
thereof. Typically, the buffer system provides a buffered pH value
for said composition in the range of about 3 to about 7.4,
preferably about 3 to about 6.5. In certain embodiments the
composition further comprises an emulsifier selected from the group
consisting of sucrose esters, polyoxyethylene sorbitan esters, long
chain alcohols, and glyceryl esters. Suitably, the emulsifier
comprises at least one glyceryl ester selected from the group
consisting of glyceryl monooleate, triolein, trimyristin,
tristearin, and mixtures thereof. Optionally, the composition
further comprises a fragrance. In some embodiments the composition
further comprises up to about 5 percent myrtenol, based on the
total weight of the composition. Suitably, the composition further
comprises a preservative.
[0020] In one embodiment the polysaccharide gum is a shear-thinning
polysaccharide gum, preferably a galactomannan gum or a modified
galactomannan gum. A preferred modified galactomannan gum is a
modified guar gum. In one embodiment, the penetration enhancer is
dodecyl 2-(N, N-dimethylamino)-propionate or a pharmaceutically
acceptable salt. In one embodiment, the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester. In a
preferred embodiment, the lipophilic component comprises at least
one glyceryl ester selected from the group consisting of
monoglycerides, diglycerides, triglycerides, and mixtures thereof.
In another embodiment, the lipophilic component comprises least one
glyceryl ester selected from the group consisting of glyceryl
monooleate, triolein, trimyristin, tristearin, and mixtures
thereof. Typically, the buffer system provides a buffered pH value
for said composition from about 3 to about 7.4, preferably about 3
to about 6.5. In certain embodiments the composition further
comprises an emulsifier selected from the group consisting of
sucrose esters, polyoxyethylene sorbitan esters, long chain
alcohols, and glyceryl esters. Suitably, the emulsifier comprises
at least one glyceryl ester selected from the group consisting of
glyceryl monooleate, triolein, trimyristin, tristearin, and
mixtures thereof. Optionally, the composition further comprises a
fragrance. In some embodiments the composition further comprises up
to about 5 percent myrtenol, based on the total weight of the
composition. Suitably, the composition further comprises a
preservative.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0021] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise.
[0022] "Intrameatally" or "meatally" means applying medication to
the tip of the penis into the navicular fossa by holding the penis
upright, holding the meatus open and dropping the medication into
the navicular fossa without introducing the medication container
into the meatus.
[0023] An "ejaculation latency prolonging amount" is an amount
effective to increase intravaginal ejaculation latency time to at
least two minutes.
[0024] "Alkyl" means the monovalent linear or branched saturated
hydrocarbon radical, consisting solely of carbon and hydrogen
atoms, having from one to twenty carbon atoms inclusive, unless
otherwise indicated. Examples of an alkyl radical include, but are
not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, tetradecyl,
eicosyl, and the like.
[0025] "Lower alkyl" means the monovalent linear or branched
saturated hydrocarbon radical, consisting solely of carbon and
hydrogen atoms, having from one to six carbon atoms inclusive,
unless otherwise indicated. Examples of a lower alkyl radical
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
tert-butyl, n-butyl, n-hexyl, and the like.
[0026] "Lower alkoxy" means the radical --O--R, wherein R is a
lower alkyl radical as defined above. Examples of a lower alkoxy
radical include, but are not limited to, methoxy, ethoxy,
isopropoxy, and the like.
[0027] "Halogen" means the radical fluoro, bromo, chloro, and/or
iodo.
[0028] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "optional
bond" means that the bond may or may not be present, and that the
description includes single, double, or triple bonds.
[0029] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary as well as human
pharmaceutical use.
[0030] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable, as defined above, and
that possesses the desired pharmacological activity of the parent
compound. Such salts include:
[0031] 1. acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic
acid, trifluoroacetic acid, sulfuric acid, nitric acid, phosphoric
acid, boric acid and the like; or formed with organic acids such as
acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic
acid, p-chlorobenzenesulfonic acid, cinnamic acid, citric acid,
cylcopentanepropionic acid, ethanesulfonic acid,
1,2-ethanedisulfonic acid, formic acid, fumaric acid, glucoheptonic
acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid,
heptanoic acid, o-(hydroxybenzoyl)benzoic acid, hydroxynaphtoic
acid, 2-hydroxyethanesulfonic acid, lactic acid, lauryl sulfuric
acid, maleic acid, malic acid, malonic acid, mandelic acid,
methanesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic
acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), muconic
acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic
acid, propionic acid, pyruvic acid, salicylic acid, stearic acid,
succinic acid, tartaric acid, tertiary butylacetic acid,
p-toluenesulfonic acid, trifluoromethanesulfonic acid,
trimethylacetic acid, and the like; or.
[0032] 2. salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic or inorganic base. Acceptable organic bases include
diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,
tromethamine, methylamine, ethylamine, hydroxyethylamine,
propylamine, dimethylamine, diethylamine, trimethylamine,
triethylamine, ethylenediamine, hydroethylamine, morpholine,
piperazine, and guanidine and the like. Acceptable inorganic bases
include aluminum hydroxide, ammonium hydroxide, calcium hydroxide,
potassium hydroxide, sodium carbonate, sodium hydroxide and
hydrazine. The preferred pharmaceutically acceptable salts are the
salts formed from hydrochloric acid, and trifluoroacetic acid.
[0033] "Subject" means mammals and non-mammals. "Mammals" means any
member of the class Mammalia including, but not limited to, humans,
non-human primates such as chimpanzees and other apes and monkey
species; farm animals such as cattle, horses, sheep, goats, and
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice, and guinea pigs; and
the like. Examples of non-mammals include, but are not limited to,
birds, and the like. The term "subject" does not denote a
particular age or sex.
[0034] A "therapeutically effective amount" means an amount of a
compound that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease state being treated, the severity or the
disease treated, the age and relative health of the subject, the
route and form of administration, the judgment of the attending
medical or veterinary practitioner, and other factors.
[0035] The term "pharmacological effect" as used herein encompasses
effects produced in the subject that achieve the intended purpose
of a therapy. In one preferred embodiment, a pharmacological effect
means that vasospasm symptoms of the subject being treated are
prevented, alleviated, or reduced. For example, a pharmacological
effect would be one that results in the prevention or reduction of
vasospasm in a treated subject.
[0036] "Disease state" means any disease, condition, symptom, or
indication.
[0037] "Treating" or "treatment" of a disease state includes:
[0038] 1. preventing the disease state, i.e. causing the clinical
symptoms of the disease state not to develop in a subject that may
be exposed to or predisposed to the disease state, but does not yet
experience or display symptoms of the disease state,
[0039] 2. inhibiting the disease state, i.e., arresting the
development of the disease state or its clinical symptoms, or
[0040] 3. relieving the disease state, i.e., causing temporary or
progressive regression of the disease state or its clinical
symptoms.
[0041] "Pro-drug" means a pharmacologically inactive form of a
compound which must be metabolized in vivo by a subject after
administration into a pharmacologically active form of the compound
in order to produce the desired pharmacological effect. After
administration to the subject, the pharmacologically inactive form
of the compound is converted in vivo under the influence of
biological fluids or enzymes into a pharmacologically active form
of the compound. Although metabolism occurs for many compounds
primarily in the liver, almost all other tissues and organs,
especially the lung, are able to carry out varying degrees of
metabolism. Pro-drug forms of compounds may be utilized, for
example, to improve bioavailability, mask unpleasant
characteristics such as bitter taste, alter solubility for
intravenous use, or to provide site-specific delivery of the
compound. Reference to a compound herein includes pro-drug forms of
a compound.
[0042] In a preferred embodiment, the pharmaceutical composition
comprises a topical anesthetic, a vasoactive prostaglandin, a
shear-thinning polymeric thicker, a lipophilic component, water and
a buffer system providing a pH of the composition from about 3 to
about 7.4, preferably about 3 to about 6.5. Preferably the
vasoactive prostaglandin is selected from the group consisting of
prostaglandin E.sub.1, a pharmaceutically acceptable salt thereof,
a lower alkyl ester thereof and a mixture thereof. In preferred
embodiments, the composition further comprises a penetration
enhancer selected from the group consisting of an
alkyl-(N-substituted amino) alkanoate, an
alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted
amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol
alkanoate, a pharmaceutically acceptable salt thereof and a mixture
thereof.
[0043] In another preferred embodiment, the pharmaceutical
composition comprises a topical anesthetic, a shear-thinning
polymeric thicker, a lipophilic component selected from the group
consisting of a C.sub.1 to C.sub.8 aliphatic alcohol, a C.sub.8 to
C.sub.30 aliphatic ester, a liquid polyol and a mixture thereof,
water and a buffer system providing a pH of the composition from
about 3.0 to about 7.4. In certain embodiments, the composition
further comprises a penetration enhancer selected from the group
consisting of an alkyl-(N-substituted amino) alkanoate, an
alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted
amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol
alkanoate, a pharmaceutically acceptable salt thereof and a mixture
thereof.
[0044] It has been found that that a semi-solid composition
comprising prostaglandin E.sub.1 and a topical anesthetic can be
placed advantageously in a natural enlarged space immediately
proximal to the penile meatus, the navicular fossa, resulting in an
effective treatment for premature ejaculation.
[0045] Semi-solid compositions and penetration enhancers suitable
for the practice of the present invention are described in detail
in U.S. Pat. Nos. 6,046,244, 6,118,020 and 6,323,241, the teachings
of which are incorporated herein by reference.
[0046] Vasoactive prostaglandins are those that act as peripheral
vasodilators, including naturally occurring prostaglandins such as
PGE.sub.1, PGA.sub.1, PGB.sub.1, PGF.sub.1.alpha.,
19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2,
PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3,
PGF.sub.3.alpha.; semisynthetic or synthetic derivatives of natural
prostaglandins, including carboprost tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost,
sulprostone and tiaprost. Prostaglandin E.sub.1 and prostaglandin
E.sub.2 are particularly preferred vasoactive prostaglandins for
use in conjunction with the present method and compositions.
[0047] Additionally, simultaneous administration of one or more
non-ecosanoid vasodilators may be desirable and may in some cases
exhibit a synergistic effect. The combination of prazosin with
prostaglandin E.sub.1 has been found to be particularly
advantageous in this regard.
[0048] Suitable non-ecosanoid vasodilators include, but are not
limited to: nitrates such as nitroglycerin, isosorbide dinitrate,
erythrityl tetranitrate, amyl nitrate, sodium nitroprusside,
molsidomine, linsidomine chlorhydrate ("SIN-1") and
S-nitroso-N-acetyl-d,1-penicillamine ("SNAP"); amino acids such as
L-arginine; long and short acting .alpha.-adrenergic blockers such
as phenoxybenzamine, dibenamine, phentolamine, tamsulosin and
indoramin, especially quinazoline derivatives such as alfuzosin,
bunazosin, doxazosin, terazosin, prazosin, and trimazosin;
vasodilative natural herbal compositions and bioactive extracts
thereof, such as gosyajinki-gan, Satureja obovata, bai-hua qian-hu,
lipotab, saiboku-to, vinpocetine, Gingko biloba, bacopa, Gynostemma
pentaphyllum, gypenosides, Evodia rutaecarpa, rutaecarpine,
dehydroevodiamine, dan-shen, salviae miltiorrhizae radix,
shosaikoto, Zizyphi fructus, ginseng and mixtures thereof (U.S.
Pat. No. 6,007,824); ergot alkaloids such as ergotamine and
ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride,
cianergoline, delorgotrile, disulergine, ergonovine maleate,
ergotamine tartrate, etisulergine, lergotrile, lysergide,
mesulergine, metergoline, metergotamine, nicergoline, pergolide,
propisergide, proterguride and terguride; antihypertensive agents
such as diazoxide, hydralazine and minoxidil; vasodilators such as
nimodepine, pinacidil, cyclandelate, dipyridamole and isoxsuprine;
chlorpromazine; haloperidol; yohimbine; trazodone and vasoactive
intestinal peptides.
[0049] Prostaglandin E.sub.1 is well known to those skilled in the
art. Reference may be had to various literature references for its
pharmacological activities, side effects, and normal dosage ranges.
See for example, Physician's Desk Reference, 51st Ed. (1997), The
Merck Index, 12th Ed., Merck & Co., N.J. (1996), and Martindale
The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press
(1982). Prostaglandin E.sub.1 as well as other compounds referenced
herein are intended to encompass pharmaceutically acceptable
derivatives including physiologically compatible salts and ester
derivatives thereof.
[0050] The quantity of vasoactive prostaglandin, such as
prostaglandin E.sub.1, in the pharmaceutical composition is a
therapeutically effective amount and necessarily varies according
to the desired dose, the dosage form (e.g., suppository or
topical), and the particular form of vasoactive prostaglandin used.
The term "prostaglandin" as used generically herein refers to the
prostaglandin free acid and pharmaceutically acceptable derivatives
thereof, including, for example PGE.sub.1, pharmaceutically
acceptable salts and lower alkyl esters thereof (the term "lower
alkyl" as used herein means straight chain or branched chain alkyl
containing one to four carbon atoms). The composition generally
contains between 0.001 percent to 1 percent of vasoactive
prostaglandin, e.g., prostaglandin E.sub.1, typically contains
between 0.05 percent to 1 percent, preferably from 0.1 percent to
0.5 percent, based on the total weight of the composition.
[0051] When used in combination with a vasoactive prostaglandin, a
piperazinyl quinazoline antihypertensive, such as prazosin, is
present in the amount of about 0.1 mg to about 2.0 mg per unit
dose, depending on the potency of the particular piperazinyl
quinazoline antihypertensive and the type and dose of vasoactive
prostaglandin used. The dose and the proportion of vasoactive
prostaglandin and the piperazinyl quinazoline antihypertensive can
be routinely determined by one of ordinary skill without undo
experimentation.
[0052] In preferred embodiments, the topical composition comprises
at least one local anesthetic. Suitable local anesthetics include
those approved for topical application, including, but not limited
to ambucaine, amolanone, amylocaine hydrochloride, articaine,
benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine,
butacaine, butamben, butanilicaine, butethamine, butoxycaine,
carticaine, chloroprocaine hydrochloride, cocaethylene, cocaine,
cyclomethycaine, dibucaine hydrochloride, dimethocaine, diperodon
hydrochloride, dyclonine, ecgonidine, ecgonine, ethyl chloride,
etidocaine, beta-eucaine, euprocin, fenalcomine, fomocaine,
hexylcaine hydrochloride, hydroxytetracaine, isobutyl
p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine,
mepivacaine, meprylcaine, metabutoxycaine, methyl chloride,
myrtecaine, naepaine, octacaine, orthocaine, oxethazaine,
parethoxycaine, phenacaine hydrochloride, phenol, piperocaine,
piridocaine, polidocanol, pramoxine, prilocaine, procaine,
propanocaine, proparacaine, propipocaine, propoxycaine
hydrochloride, pseudococaine, pyrrocaine, ropivacaine, salicyl
alcohol, tetracaine hydrochloride, tolycaine, trimecaine, zolamine
and mixtures thereof.
[0053] In general, with few exceptions, useful local anesthetics
contain a lipophilic radical (mostly of aromatic structure), an
intermediate chain and a hydrophilic radical (often an amino
group). Local anesthetics can be further classified chemically as
alcohols and alkyl ethers (such as chlorbutanol, benzyl alcohol,
saligenine and pistocaine), amines, amino alcohols, amino alkyl
ethers (such as pramocaine and dimethisoquine), amino ketones (such
as falicaine), carboxylic acid esters (such as benzocaine, procaine
and parophoxycaine), carboxylic acid amides (such as lidocaine and
dibucaine), carbamic acid esters (such as diperodone) and amidines
and guanidines (such as phenacaine and guanicaine). See Buchi, J.,
and Perlia, X., "Structure-Activity Relations and Physico-Chemical
Properties of Local Anesthetics. Part I. Relations between Chemical
Structure and Local Anesthetic Activity," pp. 39-130 in Int.
Encycl. Pharm. Therapeut., Local Anesthetics, Vol. I, Pergamon
Press, New York, 1971.
[0054] In preferred embodiments, the local anesthetic molecular
structure consists of a tertiary amine linked to a substituted
aromatic ring by an intermediate chain. In some embodiments, the
intermediate chain includes both a carbonyl group and one or more
alkyl groups. The intermediate chain may further contain an ester
linkage or an amide linkage. Suitable aminoamide local anesthetics
include lidocaine, bupivacaine, mepivacaine, dibucaine,
propivacaine, etidocaine and tocainide. Suitable aminoester local
anesthetics include procaine, chloroprocaine, tetracaine, isocaine,
benzocaine, and monocaine. In embodiments in which the intermediate
chain includes both a carbonyl group and one or more alkyl groups,
a preferred local anesthetic is dyclonine,
1-(4-butoxyphenyl)-3-(1-piperidynyl)-1-propanone.
[0055] Preferred local anesthetics are those producing a moderate
duration of anesthesia, more preferably those having a long
duration of anesthetic action. For example, procaine and
chloroprocaine have a short duration of action. Lidocaine,
mepivacaine and prilocaine produce a moderate duration of
anesthesia. Suitable long-acting local anesthetics include
ropivacaine, tetracaine, bupivacaine and etidocaine.
[0056] The topical anesthetic comprises about 0.01 to about 20
percent by weight, preferably about 0.01 to about 10 percent by
weight based on the weight of the composition. As can be
recognized, the suitable concentration of topical anesthetic will
vary, depending on the specific anesthetic and the presence of
other components. For example, suitable concentrations include
about 1 to about 20 percent by weight of benzocaine, about 0.25 to
about 2.5 percent by weight of dibucaine, about 0.01 to about 10
percent by weight of lidocaine, or about 0.25 to about 1 percent by
weight of tetracaine. In one embodiment, the composition includes
about 2.5 percent to about 5 percent by weight of lidocaine. In one
embodiment, the composition includes about 0.5 to about 1.0 percent
by weight of dyclonine HCl.
[0057] Working alone, most drugs, prostaglandin formulations
included, do not sufficiently permeate the skin to provide drug
concentration levels comparable to those obtained from other drug
delivery routes. To overcome this problem, topical drug
formulations typically include a skin penetration enhancer. Skin
penetration enhancers also may be referred to as absorption
enhancers, accelerants, adjuvants, solubilizers, sorption
promoters, etc. Whatever the name, such agents serve to improve
drug absorption across the skin. Ideal penetration enhancers not
only increase drug flux across the skin, but do so without
irritating, sensitizing, or damaging skin. Furthermore, ideal
penetration enhancers should not adversely affect the physical
qualities of the available dosage forms (e.g. cream or gel), or the
cosmetic quality of the topical composition.
[0058] A wide variety of compounds have been evaluated as to their
effectiveness in enhancing the rate of penetration of drugs through
the skin. See, for example, Percutaneous Penetration Enhancers,
Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton,
Fla. (1995), which surveys the use and testing of various skin
penetration enhancers, and Buyuktimkin et al., Chemical Means of
Transdermal Drug Permeation Enhancement in Transdermal and Topical
Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),
Interpharm Press Inc., Buffalo Grove, Ill. (1997). Suitable
penetration enhancers for use in prostaglandin topical compositions
are disclosed in U.S. Pat. Nos. 4,980,378, 5,082,866 and 6,118,020.
Topical compositions employing such penetration enhancers for the
delivery of prostaglandins are disclosed in U.S. Pat. Nos.
6,046,244, 6,323,241, 6,414,028, and 6,489,207.
[0059] The topical composition of the present invention can contain
one or more penetration enhancers. Among the preferred penetration
enhancers for the present invention are ethanol, propylene glycol,
glycerol, ethyl laurate, isopropyl palmitate, isopropyl myristate,
laurocapram (Azone.TM.), dioxolanes (described in U.S. Pat. No.
4,861,764), macrocyclic ketones, HP-101, oxazolidones and
biodegradable penetration enhancers (described in U.S. Pat. Nos.
4,980,378 and 5,082,866 to Wong et al. such as
alkyl-2-(N,N-disubstituted amino) alkanoates (e.g., dodecyl
N,N-dimethylamino isoproprionate (DDAIP)), N,N-disubstituted amino
alkanol alkanoates) and mixtures thereof. The penetration enhancer
is present in an amount sufficient to enhance the penetration of
the vasoactive prostaglandin, e.g., prostaglandin E.sub.1. The
specific amount varies necessarily according to the desired release
rate and the specific form of prostaglandin E.sub.1 used.
Generally, the penetration enhancer is present in an amount ranging
from about 0.1 weight percent to about 20 weight percent, based on
the total weight of the composition. Preferably, the penetration
enhancer is present in an amount ranging from about 0.5 weight
percent to about 10 weight percent of the composition. More
preferably, the penetration enhancer is present in an amount
ranging from about 0.25 weight percent to about 5 weight percent of
the composition.
[0060] In general, suitable penetration enhancers can be chosen
from those listed above as well as sulfoxides, alcohols, fatty
acids, fatty acid esters, polyols, amides, surfactants, terpenes,
alkanones, organic acids and mixtures thereof. See generally
Chattaraj, S. C. and Walker, R. B., Penetration Enhancer
Classification, pp. 5-20 in Maibach, H. I., and Smith, H. E.,
(eds.), Percutaneous Penetration Enhancers, CRC Press, Inc., Boca
Raton, Fla. (1995) and Buyuktimkin, N., et al., Chemical Means of
Transdermal Drug Permeation Enhancement, in Gosh, T. K., et al.,
(eds.) Transdermal and Topical Drug Delivery Systems, Interpharm
Press, Inc., Buffalo Grove, Ill. (1997). Suitable sulfoxides
include dimethylsulfoxide, decylmethylsulfoxide and mixtures
thereof. Suitable alcohols include ethanol, propanol, butanol,
pentanol, hexanol, octanol, nonanol, decanol, 2-butanol,
2-pentanol, benzyl alcohol, caprylic alcohol, decyl alcohol, lauryl
alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl
alcohol, olcyl alcohol, linolyl alcohol, linolenyl alcohol and
mixtures thereof. Suitable fatty acids include valeric, heptanoic,
pelargonic, caproic, capric, lauric, myristic, stearic, oleic,
linoleic, linolenic, caprylic, isovaleric, neopentanoic,
neoheptanoic, neononanoic, trimethyl hexanoic, neodecanoic and
isostearic acids and mixtures thereof.
[0061] Suitable fatty acid esters include isopropyl n-butyrate,
isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate,
isopropyl palmitate, octyldodecyl myristate, ethyl acetate, butyl
acetate, methyl acetate, methylvalerate, methylpropionate, diethyl
sebacate, ethyl oleate, ethyl laurate and mixtures thereof.
Suitable polyols include propylene glycol, polyethylene glycol,
ethylene glycol, diethylene glycol, triethylene glycol, dipropylene
glycol, glycerol, propanediol, sorbitol, dextrans, butanediol,
pentanediol, hexanetriol and mixtures thereof.
[0062] Suitable amides include urea, dimethylacetamide,
diethyltoluamide, dimethylformamide, dimethyloctamide,
dimethyldecamide, 1-alkyl-4-imidazolin-2-one, pyrrolidone
derivatives, cyclic amides, hexamethylenelauramide and its
derivatives, diethanolamine, triethanolamine and mixtures thereof.
Suitable pyrrolidone derivatives include 1-methyl-2-pyrrolidone,
2-pyrrolidone, 1-lauryl-2-pyrrolidone,
1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,
1-lauryl-4-carboxy-2-pyrrolidone, 1-decyl-thioethyl-2-pyrrolidone
(HP-101), 1-methyl-4-methoxycarbonyl-2-pyrrolidone,
1-hexyl-4-methoxycarbonyl-2-pyrrolidone,
1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone,
N-dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone,
N-tallowalkypyrrolidone, fatty acid esters of
N-(2-hydroxymethyl)-2-pyrrolidone and mixtures thereof. Suitable
cyclic amides include 1-dodecylazacycloheptane-2-one (laurocapram,
Azone.RTM.), 1-geranylazacycloheptan-2-one,
1-farnesylazacycloheptan-2-one,
1-geranylgeranylazacycloheptan-2-one,
1-(3,7-dimethyloctyl)azacycloheptan-2-one,
1-(3,7,11-trimethyloctyl)azacycloheptan-2-one,
1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2,5-dione,
1-farnesylazacyclopentan-2-one and mixtures thereof.
[0063] Suitable surfactants include anionic surfactants, cationic
surfactants, nonionic surfactants, bile salts and lecithin.
Suitable anionic surfactants include sodium laurate, sodium lauryl
sulfate and mixtures thereof. Suitable cationic surfactants include
cetyltrimethylammonium bromide, tetradecyltrimethylammonium
bromide, benzalkonium chloride, octadecyltrimethylammonium
chloride, cetylpyridinium chloride, dodecyltrimethylammonium
chloride, hexadecyltrimethylammonium chloride, and mixtures
thereof. Suitable nonionic surfactants include
.alpha.-hydro-.omega.-hydroxy-poly(oxyethylene)-poly(oxypropyl)
poly(oxyethylene)block copolymers, polyoxyethylene ethers,
polyoxyethylene sorbitan esters, polyethylene glycol esters of
fatty alcohols and mixtures thereof. Suitable
.alpha.-hydro-.omega.-hydroxy-poly(oxyethylene)-poly(oxypropyl)
poly(oxyethylene)block copolymers include Poloxamers 231, 182, and
184 and mixtures thereof. Suitable polyoxyethylene ethers include
4-lauryl ether (Brij 30), (Brij 93), (Brij 96), 20-oleyl ether
(Brij 99) and mixtures thereof. Suitable polyoxyethylene sorbitan
esters include the monolaurate (Tween 20, Span 20) the
monopalmitate (Tween 40), the monostearate (Tween 60), and the
monooleate (Tween 80) and mixtures thereof. Suitable polyethylene
glycol esters of fatty acids include the 8-oxyethylene stearate
ester (Myrj 45), (Myrj 51), the 40-oxyethylene stearate ester (Myrj
52) and mixtures thereof. Suitable bile salts include sodium
cholate, sodium salts of laurocholic, glycolic and desoxycholic
acids and mixtures thereof.
[0064] Suitable terpenes include D-limonene, .alpha.-pinene,
.beta.-enrene, .alpha.-terpineol, terpinen-4-ol, carvol, carvone,
pulegone, piperitone, menthone, menthol, geraniol, cyclohexene
oxide, limonene oxide, .alpha.-pinene oxide, cyclopentene oxide,
1,8-cineole, ylang ylang oil, anise oil, chenopodium oil,
eucalyptus oil and mixtures thereof. Suitable alkanones include
N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane,
N-tridecane, N-tetradecane, N-hexadecane and mixtures thereof.
Suitable organic acids include citric acid, succinic acid,
salicylic acid, salicylates (including the methyl, ethyl and propyl
glycol derivatives), tartaric acid and mixtures thereof.
[0065] In a preferred embodiment, the penetration enhancer is an
alkyl-2-(N-substituted amino)-alkanoate, an (N-substituted
amino)-alkanol alkanoate, or a mixture of these. For convenient
reference, alkyl-2-(N-substituted amino)-alkanoates and
(N-substituted amino)-alkanol alkanoates can be grouped together
under the label alkyl (N-substituted amino) esters.
[0066] Alkyl-2-(N-substituted amino)-alkanoates suitable for the
present invention can be represented as follows:
##STR00002##
wherein n is an integer having a value in the range of about 4 to
about 18; R is a selected from the group consisting of hydrogen,
C.sub.1 to C.sub.7 alkyl, benzyl and phenyl; R.sub.1 and R.sub.2
are selected from the group consisting of hydrogen and C.sub.1 to
C.sub.7 alkyl; and R.sub.3 and R.sub.4 are selected from the group
consisting of hydrogen, methyl and ethyl.
[0067] Preferred are alkyl (N,N-disubstituted amino)-alkanoates
such as C.sub.4 to C.sub.18 alkyl (N,N-disubstituted
amino)-acetates and C.sub.4 to C.sub.18 alkyl (N,N-disubstituted
amino)-propionates and pharmaceutically acceptable salts and
derivatives thereof. Exemplary specific alkyl-2-(N,N-disubstituted
amino)-alkanoates include dodecyl 2-(N,N dimethylamino)-propionate
(DDAIP);
##STR00003##
and dodecyl 2-(N,N-dimethylamino)-acetate (DDAA);
##STR00004##
[0068] Alkyl-2-(N-substituted amino)-alkanoates are known. For
example, dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) is
available from Steroids, Ltd. (Chicago, Ill.). In addition,
alkyl-2-(N,N-disubstituted amino)-alkanoates can be synthesized
from more readily available compounds as described in U.S. Pat. No.
4,980,378 to Wong et al., which is incorporated herein by reference
to the extent that it is not inconsistent. As described therein,
alkyl-2-(N,N-disubstituted amino)-alkanoates are readily prepared
via a two-step synthesis. In the first step, long chain alkyl
chloroacetates are prepared by reaction of the corresponding long
chain alkanols with chloromethyl chloroformate or the like in the
presence of an appropriate base such as triethylamine, typically in
a suitable solvent such as chloroform. The reaction can be depicted
as follows:
##STR00005##
wherein R, R.sub.3, R.sub.4 and n are defined as above. The
reaction temperature may be selected from about 10 degrees Celsius
to about 200 degrees Celsius or reflux, with room temperature being
preferred. The use of a solvent is optional. If a solvent is used,
a wide variety of organic solvents may be selected. Choice of a
base is likewise not critical. Preferred bases include tertiary
amines such as triethylamine, pyridine and the like. Reaction time
generally extends from about one hour to three days.
[0069] In the second step, the long chain alkyl chloroacetate is
condensed with an appropriate amine according to the scheme:
##STR00006##
wherein n, R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are defined as
before. Excess amine reactant is typically used as the base and the
reaction is conveniently conducted in a suitable solvent such as
ether. This second step is preferably run at room temperature,
although temperature may vary. Reaction time usually varies from
about one hour to several days. Conventional purification
techniques can be applied to ready the resulting ester for use in a
pharmaceutical compound.
[0070] Suitable (N-substituted amino)-alkanol alkanoates can be
represented by the formula:
##STR00007##
[0071] wherein n is an integer having a value in the range of about
5 to about 18; y is an integer having a value in the range of 0 to
about 5; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
and R.sub.7 are selected from the group consisting of hydrogen,
C.sub.1 to C.sub.8 alkyl, and C.sub.3 to C.sub.8 aryl; and R.sub.8
is a selected from the group consisting of hydrogen, hydroxyl,
C.sub.1 to C.sub.8 alkyl, and C.sub.3 to C.sub.8 aryl. The
preparation of (N-substituted amino)-alkanol alkanoates and their
use as penetration enhancers is disclosed in published PCT
International Application WO 95/09590, which is incorporated by
reference herein in its entirety.
[0072] Preferred are (N-substituted amino)-alkanol alkanoates such
as C.sub.5 to C.sub.18 carboxylic acid esters and pharmaceutically
acceptable salts thereof. Exemplary specific (N,N-disubstituted
amino)-alkanol alkanoates include
[0073] 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD);
##STR00008##
[0074] 1-(N,N-dimethylamino)-2-propanol myristate (DAIPM);
##STR00009##
[0075] 1-(N,N-dimethylamino)-2-propanol oleate (DAIPO);
##STR00010##
[0076] The (N,N-disubstituted amino)-alkanol alkanoates are readily
prepared by reacting the corresponding aminoalkinol with lauroyl
chloride in the presence of triethylamine. A solvent such as
chloroform is optional but preferred. For example,
1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl
chloride in chloroform and in the presence of triethylamine to form
1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD).
[0077] The penetration enhancer is present in an amount sufficient
to enhance the penetration of the prostaglandin E.sub.1. The
specific amount varies necessarily according to the desired release
rate and the specific form of prostaglandin E.sub.1 used.
Generally, this amount ranges from about 0.1 percent to about 10
percent, based on the total weight of the composition. Preferably,
the penetration enhancer is about 0.5 to about 10 weight percent of
the composition.
[0078] Additionally, other known transdermal penetration enhancers
can also be added, if desired. Illustrative are dimethyl sulfoxide
(DMSO), dimethyl acetamide (DMA), 2-pyrrolidone,
N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one
(Azone.TM., a registered trademark of Nelson Research),
N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium
thioglycolate, oxazolidinone, dioxolane derivatives, laurocapram
derivatives, and macrocyclic enhancers such as macrocyclic
ketones.
[0079] Natural and modified polysaccharide gums are also an
important ingredient of the composition. Suitable representative
gums are those in the natural and modified galactomannan gum
category. A galactomannan gum is a carbohydrate polymer containing
D-galactose and D-mannose units, or other derivatives of such a
polymer. There is a relatively large number of galactomannans,
which vary in composition depending on their origin. The
galactomannan gum is characterized by a linear structure of
.beta.-D-mannopyranosyl units linked (1.fwdarw.4). Single membered
.alpha.-D-manopyranosyl units, linked (1.fwdarw.6) with the main
chain, are present as side branches. Galactomannan gums include
guar gum, which is the pulverized endosperm of the seed of either
of two leguminous plants (Cyamposis tetragonalobus and psoraloids)
and locust bean gum, which is found in the endosperm of the seeds
of the carobtree (ceratonia siliqua). Suitable modified
polysaccharide gums include ethers of natural or substituted
polysaccharide gums, such as carboxymethyl ethers, ethylene glycol
ethers and propylene glycol ethers. An exemplary substituted
polysaccharide gum is methylcellulose.
[0080] Other suitable representative gums include agar gum,
carrageenan gum, ghatti gum, karaya gum, rhamsan gum and xanthan
gum. The composition of the present invention may contain a mixture
of various gums, or mixture of gums and acidic polymers.
[0081] Gums, and galactomannan gums in particular, are well-known
materials. See for instance, Industrial Gums: Polysaccharides &
Their Derivatives, Whistler R. L. and BeMiller J. N. (eds.), 3rd
Ed. Academic Press (1992) and Davidson R. L., Handbook of
Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980).
Most gums are commercially available in various forms, commonly a
powder, and ready for use in foods and topical compositions. For
example, locust bean gum in powdered form is available from Tic
Gums Inc. (Belcam, Md.).
[0082] When present, the polysaccharide gums are present in the
range from about 0.1 percent to about 5 percent, based on the total
weight of the composition, with the preferred range being from 0.5
percent to 3 percent. In one preferred embodiment, 2.5 percent by
weight of a polysaccharide gum is present. Illustrative
compositions are given in the examples, below.
[0083] An optional alternative to the polysaccharide gum is a
polyacrylic acid polymer. A common variety of polyacrylic acid
polymer is known generically as "carbomer." Carbomer is polyacrylic
acid polymers lightly cross-linked with polyalkenyl polyether. It
is commercially available from the B. F. Goodrich Company (Akron,
Ohio) under the designation "CARBOPOL.TM.." A particularly
preferred variety of carbomer is that designated as "CARBOPOL
940."
[0084] Other polyacrylic acid polymers suitable for use are those
commercially available under the designations "Pemulen.TM." (B. F.
Goodrich Company) and "POLYCARBOPHIL.TM." (A.H. Robbins, Richmond,
Va.). The Pemulen.TM. polymers are copolymers of C.sub.10 to
C.sub.30 alkyl acrylates and one or more monomers of acrylic acid,
methacrylic acid or one of their simple esters crosslinked with an
allyl ether of sucrose or an allyl ether of pentaerythritol. The
POLYCARBOPHIL.TM. enhancer is a polyacrylic acid cross-linked with
divinyl glycol.
[0085] Where polyacrylic acid polymers are present, they represent
about 0.5 percent to about 5 percent of the composition, based on
its total weight.
[0086] The semi-solid composition has a suitably chosen viscosity
such that the composition is naturally retained within the fossa
navicularis. The semi-solid composition can exhibit Newtonian or
non-Newtonian rheological characteristics. In some preferred
embodiments, the semi-solid composition of the present invention
exhibits non-Newtonian rheological characteristics, i.e. in which
the apparent viscosity is dependent on the shear rate applied to
the composition. Preferably the composition has "shear-thinning"
rheological properties. As used herein, "shear-thinning" refers to
a reduction in apparent viscosity (the ratio of shear stress to the
shear rate) with increasing shear rate, whether the reduction in
apparent viscosity is time independent (pseudoplastic), time
dependent (thixotropic) or associated with a yield stress, defined
as a stress that must be exceeded before flow starts, (Bingham
plastics and generalized Bingham plastics). See, generally, Harris,
J., & Wilkinson, W. L., "Non-newtonian Fluid," pp. 856-858 in
Parker, S. P., ed., McGraw-Hill Encyclopedia of Physics, Second
Edition, McGraw-Hill, New York, 1993. A suitable viscosity range of
the composition is from about 5,000 centipoise (cps) to about
20,000 cps, preferably from about 7,000 cps to about 13,000
cps.
[0087] In certain preferred embodiments, the vasoactive
prostaglandin is released over a period of time from a drug
reservoir. While it should be recognized that the release over time
of a vasoactive prostaglandin from a semi-solid composition
administered meatally and retained within the fossa navicularis is
an embodiment of release from a drug reservoir, in other
embodiments, the vasoactive prostaglandin can be released from
compositions comprising other polymeric carriers that have been
placed in other locations.
[0088] Another important component is a lipophilic component. As
used herein "lipophilic component" refers to an agent that is both
lipophilic and hydrophilic. One of ordinary skill in the
pharmaceutical arts will understand that the lipophilic nature, or
"lipophilicity" of a given compound is routinely quantified for
comparison to other compounds by using the partition coefficient.
The partition coefficient is defined by the International Union of
Pure and Applied Chemistry (IUPAC) as the ratio of the distribution
of a substance between two phases when the heterogeneous system (of
two phases) is in equilibrium; the ratio of concentrations (or,
strictly speaking, activities) of the same molecular species in the
two phases is constant at constant temperature.
[0089] The C.sub.1 to C.sub.8 aliphatic alcohols, the C.sub.2 to
C.sub.30 aliphatic esters, and their mixtures can serve as
lipophilic component. Illustrative suitable alcohols are ethanol,
n-propanol and isopropanol, while suitable esters are ethyl
acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl
myristate and isopropyl palmitate. As used herein, the term
"aliphatic alcohol" includes polyols such as glycerol, propylene
glycol and polyethylene glycols. In one embodiment, a mixture of
alcohol and ester is preferred, and in particular, a mixture of
ethanol and ethyl laurate is preferred.
[0090] In some embodiments, the lipophilic component includes at
least one liquid polyol. In preferred embodiments, the liquid
polyol is a polyethylene glycol selected from the group consisting
of polyethylene glycol 200, polyethylene glycol 400 and
polyethylene glycol 600. When polyethylene glycol is used,
polyethylene glycol is present in the amount of about 1 weight
percent to about 25 weight percent, based on the total weight of
the composition. A preferred polyethylene glycol is polyethylene
glycol 400 (PEG 400). When present, polyethylene glycol 400 is
about 1 weight percent to about 25 weight percent, preferably about
3 weight percent to about 20 weight percent, based on the total
weight of the composition.
[0091] In one embodiment, the C.sub.2 to C.sub.30 aliphatic esters,
and their mixtures comprising the lipophilic component include
C.sub.8 to C.sub.30 aliphatic esters of glycerol selected from the
group consisting monoglycerides, diglycerides, triglycerides, and
mixtures thereof. Suitable aliphatic esters include glyceryl esters
of saturated fatty acids, unsaturated fatty acids and mixtures
thereof. Suitable saturated fatty acids include caproic acid,
caprylic acid, capric acid, lauric acid, myristic acid, palmitic
acid, stearic acid, arachidic acid, behenic acid and lignoceric
acid. Suitable unsaturated fatty acids include oleic acid, linoleic
acid and linolenic acid. Suitable glyceryl esters include glyceryl
monooleate, triolein, trimyristin and tristearin, preferably
trimyristin.
[0092] The concentration of lipophilic component required
necessarily varies according to other factors such as the desired
semi-solid consistency and the desired skin penetration promoting
effects. Suitably the concentration of lipophilic component is in
the range of 0.5 percent to 40 percent by weight based on the total
weight of the composition. The preferred topical composition
contains lipophilic component in the range of 7 percent to 40
percent by weight based on the total weight of the composition.
[0093] Where a mixture of aliphatic alcohol and aliphatic ester are
employed, the suitable amount of alcohol is in the range of 0.5
percent to 10 percent. In one preferred embodiment, the amount of
alcohol is in the range of 5 percent to 15 percent, while that of
aliphatic ester is in the range from 2 percent to 15 percent (again
based on the total weight of the composition). In another preferred
embodiment, the amount of alcohol is in the range of 0.5 percent to
10 percent, while that of aliphatic ester is in the range from 0
percent to 10 percent (again based on the total weight of the
composition).
[0094] The concentration of lipophilic component required
necessarily varies according to other factors such as the desired
semi-solid consistency and the desired skin penetration promoting
effects. The preferred topical composition contains lipophilic
component in the range of 7 percent to 40 percent by weight based
on the total weight of the composition. Where a lipophilic
component that is a mixture of aliphatic alcohol and aliphatic
ester is used, the preferred amount of alcohol is in the range of 5
percent to 15 percent, while that of aliphatic ester is in the
range from 2 percent to 15 percent (again based on the total weight
of the composition).
[0095] An optional, but preferred, component is an emulsifier.
Although not a critical factor, a suitable emulsifier generally
will exhibit a hydrophilic-lipophilic balance number greater than
10. Sucrose esters, and specifically sucrose stearate, can serve as
emulsifiers for the composition. Sucrose stearate is a well-known
emulsifier available from various commercial sources. When an
emulsifier is used, sucrose stearate present up to about 2 percent,
based on the total weight of the composition, is preferred. The
preferred amount of sucrose stearate emulsifier can also be
expressed as a weight ratio of emulsifier to polysaccharide gum. A
ratio of 1 to 6 emulsifier to gum is preferred, and a ratio of 1 to
4 is most preferred to generate the desired semi-solid consistency
and separation resistance.
[0096] Other emulsifiers are also suitable including
polyoxyethylene sorbitan esters, long chain alcohols, preferably
cetostearyl alcohol, and fatty acid glycerides. Suitable
polyoxyethylene sorbitan esters include the monolaurate (Tween 20,
Span 20) the monopalmitate (Tween 40), the monostearate (Tween 60),
and the monooleate (Tween 80) and mixtures thereof. Preferred fatty
acid glycerides include glyceryl monooleate, triolein, trimyristin
and tristearin.
[0097] The composition includes an acid buffer system. Acid buffer
systems serve to maintain or buffer the pH of compositions within a
desired range. The term "buffer system" or "buffer" as used herein
has reference to a solute agent or agents which, when in a water
solution, stabilize such solution against a major change in pH (or
hydrogen ion concentration or activity) when acids or bases are
added thereto. Solute agent or agents which are thus responsible
for a resistance to change in pH from a starting buffered pH value
in the range indicated above are well known. While there are
countless suitable buffers, potassium phosphate monohydrate has
proven effective for compositions of the present invention.
[0098] The final pH value of the pharmaceutical composition may
vary within the physiologically compatible range. Necessarily, the
final pH value is not irritating to human skin. Without violating
this constraint, the pH may be selected to improve active agent
stability and to adjust consistency when required. In one
embodiment, the preferred pH value is about 3.0 to about 7.4, more
preferably about 3.0 to about 6.5, most preferably from about 3.5
to about 6.0.
[0099] The remaining component of the composition is water, which
is necessarily purified. The composition contains water in the
range of about 50 to about 90 percent, based on the total weight of
the composition. The specific amount of water present is not
critical, however, being adjustable to obtain the desired
consistency and/or concentration of the other components.
[0100] Prostaglandin E.sub.1 stabilizers, coloring agents,
rheological agents, and preservatives can be added to the extent
that they do not overly limit prostaglandin E.sub.1 skin
penetration or prevent the desired semi-solid consistency.
[0101] Contemplated dosage forms of the semi-solid pharmaceutical
composition are creams, gels, ointments, colloidal suspensions and
the like, also including but not limited to compositions suitable
for use with transdermal patches and like devices.
[0102] The ingredients listed above may be combined in any order
and manner that produces a stable composition comprising a
prostaglandin E.sub.1 evenly dispersed throughout a semi-solid
formulation. One available approach to preparing such compositions
involves evenly dispersing the polysaccharide gum (or polyacrylic
acid polymer) in a premixed water/buffer solution and then
thoroughly homogenizing (i.e. mixing) the resulting mixture, which
can be labeled "Part A." When present, the emulsifier is added to
the water/buffer solution before dispersing the polysaccharide gum.
Any suitable method of adjusting the pH value of Part A to the
desired level may be used, for example, by adding concentrated
phosphoric acid or sodium hydroxide.
[0103] Separately, the prostaglandin E.sub.1 is dissolved with
agitation in the lipophilic component, which itself may be a
mixture of alcohols, esters, or alcohol with ester. Next, the
penetration enhancer is added. Alternatively, when the lipophilic
component includes both an alcohol and an ester, the prostaglandin
E.sub.1 can be dissolved in the alcohol before adding the
penetration enhancer followed by the ester. In either case, the
resulting mixture can be labeled "Part B." The final step involves
slow addition (e.g. dropwise) of Part B into Part A under constant
mixing.
[0104] The resulting topical composition provides improved
prostaglandin E.sub.1 permeation and bioavailability without drug
overloading, reduced skin damage and related inflammation, and
increased flexibility in design of dosage forms. These compositions
can be used for prolonged treatment of peripheral vascular disease,
male impotency and other disorders treated by prostaglandin
E.sub.1, while avoiding the low bioavailability and rapid chemical
decomposition associated with other delivery methods. Application
of prostaglandin E.sub.1 in a topical composition to the skin of a
patient allows a predetermined amount of prostaglandin E.sub.1 to
be administered continuously to the patient and avoids undesirable
effects present with a single or multiple administrations of larger
dosages by injection. By maintaining a sustained dosage rate, the
prostaglandin E.sub.1 level in the patient's target tissue can be
better maintained within the optimal therapeutic range.
[0105] In one embodiment, a composition comprises about 0.01
percent to about 5 percent modified polysaccharide gum; about 0.001
percent to about 1 percent of a prostaglandin selected from the
group consisting of PGE.sub.1, pharmaceutically acceptable salts
thereof, lower alkyl esters thereof and mixtures thereof; about 0.5
percent to about 10 percent DDAIP or salts thereof; about 0.5
percent to about 10 percent of a lower alcohol selected from the
group consisting of ethanol, propanol, isopropanol and mixtures
thereof; about 0.5 percent to about 10 percent on an ester selected
from the group consisting of ethyl laurate, isopropyl myristate,
isopropyl laurate and mixtures thereof; based on the weight of the
composition, and an acid buffer. Preferably the composition also
comprises up to about 2 percent sucrose stearate.
[0106] Optionally the composition also comprises up to about 5
percent emulsifier. Preferably, the composition also comprises up
to about 2 percent emulsifier. Suitable emulsifiers include
polysorbates such as Tweens, glyceryl monooleate, triolein,
trimyristin and tristearin. A preferred emulsifier is
trimyristin.
[0107] The practice of the present invention is demonstrated in the
following examples. These examples are meant to illustrate the
invention rather than to limit its scope. Variations in the
treating compositions which do not adversely affect the
effectiveness of prostaglandin E.sub.1 will be evident to one
skilled in the art, and are within the scope of this invention. For
example, additional ingredients such as coloring agents,
anti-microbial preservatives, emulsifiers, perfumes, prostaglandin
E.sub.1 stabilizers, and the like may be included in the
compositions as long as the resulting composition retains desirable
properties, as described above. When present, preservatives are
usually added in amounts of about 0.05 to about 0.30%. Suitable
preservatives include methylparabens (methyl PABA), propylparabens
(propyl PABA) and butylhydroxy toluene (BHT). Suitable perfumes and
fragrances are known in the art; a suitable fragrance is up to
about 5 percent myrtenol, preferably about 2 percent myrtenol,
based on the total weight of the composition. The compositions of
the present invention can also include a small amount, about 0.01
to about 4% by weight, of a topical anesthetic, if desired. Typical
topical anesthetics include lidocaine, dyclonine, dibucaine,
pharmaceutically acceptable salts and mixtures thereof. In one
preferred embodiment, the topical anesthetic is about 0.5 percent
dyclonine, based on the weight of the composition. In another
preferred embodiment, the topical anesthetic is about 2.5 to about
5 weight percent lidocaine.
[0108] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form is a packaged preparation, where the package containing
the discrete quantities of the pharmaceutical preparation is, e.g.
a rigid plastic dispenser or flexible packet.
[0109] Another aspect of the invention is an article of manufacture
that comprises a composition for treating premature ejaculation as
described above in a suitable container, preferably in a container
such as the dispenser disclosed in U.S. Pat. No. 6,224,573, in
combination with labeling instructions. Alternatively, the
container can be a tube with a suitable orifice size, such as an
extended tip tube, pouch, packet, or squeeze bottle and made of any
suitable material, for example rigid plastic or flexible
plastic.
[0110] The labeling instructions can come in the form of a
pamphlet, a label applied to or associated with the packaging of
the article of manufacture.
[0111] The labeling instructions provide for administering a
composition of the invention to the meatus of the penis of a
patient suffering from premature ejaculation, directing the patient
to hold the penis upright, hold the meatus open and place the
composition in the navicular fossa without introducing the
container into the meatus about 5-30 minutes, before sexual
intercourse. Printed labeling instructions are functionally related
to the composition of the invention inasmuch as such labeling
instructions describe a method to treat premature ejaculation
according to the present invention. The labeling instructions are
an important aspect of the invention in that before a composition
can be approved for any particular use, it must be approved for
marketing by the responsible national regulatory agency, such as
the United States Food and Drug Administration. Part of that
process includes providing a label that will accompany the
pharmaceutical composition which is ultimately sold. While the
label will include a definition of the composition and such other
items such as the clinical pharmacology, mechanism of action, drug
resistance, pharmacokinetics, absorption, bioavailability,
contraindications and the like, it will also provide the necessary
dosage, administration and usage. Thus, the combination of the
composition with the dispenser with appropriate treatment
instructions is important for the proper usage of the drug once it
is marketed to the patient. Such treatment instructions will
describe the usage in accordance with the method of treatment set
forth herein before.
[0112] The fossa navicularis is a natural expanded chamber suitably
adapted to receive and retain semisolid medicaments. A semi-solid
medicament, such as the composition of the present invention, when
placed into the meatus has higher impedance to flow at narrowed
exits of this space, the meatus and the urethra. The impedance to
flow is proportional to the product of the cross sectional area of
the path and the path length. Thus, a semi-solid medication of
suitably chosen viscosity is naturally retained within the fossa,
facilitating the absorption of active agents such as vasodilators
and the like. The viscosity of the composition suitably ranges from
about 5,000 cps to about 20,000 cps, preferably from about 7,000
cps to about 13,000 cps. In preferred embodiments, the viscosity of
the composition is selected so that about 90% to about 99% of the
applied composition is retained in the fossa navicularis for up to
about thirty minutes. More preferably about 93% to about 98% of the
applied composition, optimally more than 98% is retained in the
fossa navicularis for up to about thirty minutes.
[0113] The quantity of active component in a unit dose preparation
may be varied or adjusted from 0.01 mg to 1 g according to the
particular application and the potency of the vasoactive
prostaglandin. For example, where the vasoactive prostaglandin is
prostaglandin E1, about 0.05 mg to about 0.8 mg prostaglandin E1 is
present, preferably about 0.1 mg to about 0.5 mg and in another
embodiment, about 0.2 mg to about 0.3 mg. The composition can, if
desired, also contain other compatible therapeutic agents, such as
a piperazinyl quinazoline antihypertensive.
[0114] The semi-solid vasoactive prostaglandin composition should
be applied to the navicular fossa of the penis about 2-30 minutes
before sexual intercourse, preferably about 10-20 minutes before
sexual intercourse.
[0115] Unless otherwise indicated, each composition is prepared by
conventionally admixing the respective indicated components
together.
Example 1
Exemplary Compositions
[0116] Exemplary Composition A was prepared as follows. Part A was
formed by dissolving 0.4 parts prostaglandin E.sub.1 (Alprostadil
USP) in 5 parts ethyl alcohol. Next, 2.5 parts dodecyl
2-(N,N-dimethylamino)-propionate were mixed into the
alcohol-prostaglandin E.sub.1 solution, followed by 5 parts ethyl
laurate.
[0117] Part B was prepared starting from a pH 5.5 water/buffer
solution. The water/buffer solution was prepared by adding
sufficient potassium phosphate monohydride to purified water to
create a 0.1 M solution. The pH of the water/buffer solution was
adjusted to 5.5 with a strong base solution (1 N sodium hydroxide)
and a strong acid (1 N phosphoric acid). The buffer solution
represented about 80 parts of the total composition. All parts
specified herein are parts by weight.
[0118] To the buffer solution, was added 0.5 parts ethyl laurate.
Next, the locust bean gum (in powder form) was dispersed in the
buffer solution and homogenized using a homogenizer. Table 1,
below, contains a list of ingredients.
[0119] The resulting composition was a spreadable, semi-solid
suitable for application to the skin without the need for
supporting devices such as patches and adhesive strips. The
composition was both homogenous in appearance and resistant to
separation.
TABLE-US-00001 TABLE 1 Topical Prostaglandin E.sub.1 Compositions
Ingredient (wt %) A B C D E F G H L prehydrated locust bean gum 3 3
3 3 3 3 3 -- -- prehydrated modified guar gum -- -- -- -- -- -- --
3 3 water/buffer (pH 5.5) 81 81 81 81 81 81 81 81 81 sucrose
stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 -- -- prostaglandin E.sub.1
0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 0.3 DDAIP 5 5 5 5 5 5 5 2.5 2.5
ethanol 5 5 5 5 5 5 10 5 5 ethyl laurate 5 5 5 5 5 5 -- 3 3
lidocaine -- -- -- -- -- -- -- 3 2.5
[0120] Additional exemplary compositions B-H were prepared in the
same manner using the components listed in Table 1. As noted above,
in other embodiments, such as Composition H, the composition may
include a modified polysaccharide gum, suitably a modified
galactomannan gum, such as a modified guar gum. Alternatively, a
polyacrylic acid polymer may be used instead of the polysaccharide
gum.
[0121] Exemplary composition L illustrates a suitable composition
comprising an ejaculation latency prolonging amount of a topical
anesthetic, in this example, 2.5% lidocaine, based on the total
weight of the composition.
Example 2
Small Safety Screening Study of Compositions Containing
Lidocaine
[0122] Eight subjects were selected for the six-week single-blind
study based on the patient inclusion and exclusion criteria.
Inclusion criteria were: male, age 20-55 years old with premature
ejaculation who complained of PE of more than three months
duration, having ejaculatory latencies less than 2 minutes and/or
sexual satisfaction rates less than 50% of their intercourses, in a
stable heterosexual relationship and having no less than 1
intercourse per week. Exclusion criteria were: abnormal physical
examinations including genitalia, abnormal blood profile or tests,
laboratory test results indicating abnormal liver and renal
function, abnormal testosterone and prolactin levels, genitourinary
tract infection, such as prostatitis, urethritis or epididymitis,
neurological disorders, or obvious psychological problems requiring
psychiatric support and administration of any anti-depressants that
might alter sexual activities, abuse of alcohol or drugs,
hypotension, cardiac infarction, heart failure or angina within six
months.
[0123] Patients had a total of four clinical visits: a screening
visit (two weeks before administration of the drug), Visit 1 (start
administration of the drug), Visit 2 (three weeks after
administration of the drug), and Visit 3 (six weeks after
administration of the drug). In the first two weeks, the
ejaculatory latency time (ELT) before treatment was measured (at
least two measurements). Each of the patients was given two
dispensers of alprostadil cream, each dispenser containing 1 mg of
prostaglandin E.sub.1. Each dispenser could provide three doses of
about 0.3 mg per dose. The patients were instructed to administer
the cream topically to the tip of the penis (i.e. intrameatally) 5
to 20 minutes before sexual intercourse.
[0124] The primary efficacy variable was ELT, as measured using a
stopwatch. The degree of satisfaction of patient was recorded in a
patient diary. Patients applied the study medication as needed, but
were instructed not to use more than one dose of about 0.3 mg
within a 24 hour period, nor less than one dose within one week. At
the end of the study, the investigators analyzed the efficacy and
safety of the study medication based on the ejaculatory latency,
sexual satisfaction rating, total efficacy evaluation and adverse
event records. The prolongation of ejaculatory latency to more than
two minutes was regarded as clinically effective. General data
regarding the subject group is summarized in Table 2, below.
TABLE-US-00002 TABLE 2 General Demographic Data Range Mean Age
25-64 years old 41.25 years old Weight 62-79 kg 67.38 kg Height
163-187 cm; 169.25 cm Alcoholic History 5 (62.50%) Smoking History
3 (37.50%)
[0125] The PE history of the subjects is summarized in Table 3,
below.
TABLE-US-00003 TABLE 3 PE History Frequency of PE Duration ELT
Intercourse Frequency of Previous Subject (Months) (sec) (per week)
PE (%) Treatment Etiology 1 14 NA 0-1 50 50 mg sildenafil
Psychogenic 2 26 30-60 1.5 50 24-50 mg sildenafil Psychogenic 3 3
60 2 40 None Psychogenic 4 180 180 2 50 Chinese Medicine
Accompanied ED 5 52 20-30 1-2 100 50 mg sildenafil Organic 6 3 30 2
30 None Accompanied ED 7 19 60 1-2 33 25 mg sildenafil Accompanied
ED 8 12 30-60 1 50 25-50 mg sildenafil Accompanied ED
[0126] Table 4, below, provides the results on a patient-by-patient
basis. The mean ELT (.+-.SE) at baseline and post-dosing in the
group was 1.03.+-.0.19 and 1.39.+-.0.39 minutes, respectively
(p>0.05). Four of the eight patients showed no change in ELT.
Only one patient, after administration of the cream, had a mean ELT
over 2 minutes, improving from 2 minutes to 4 minutes. No
significant changes from the physical examination were observed
between the baseline and study end point. All of the adverse events
of patients were mild and no medical treatment was required. At the
study end point, the analysis of safety indicated that the
application of the study medication for the treatment of premature
ejaculation is safe. The small patient population prevented any
conclusions being drawn regarding the significance of the increase
in ELT observed.
TABLE-US-00004 TABLE 4 Individual Results: Alprostadil Study (0.3
mg/dose) ELT before ELT after administration administration Subject
Age (minutes) (minutes) Adverse Event 1 64 1 1 Mild Urethral Pain 2
45 1 1 Mild Urethral Pain 3 27 0.5 1 Mild Urethral Pain 4 44 2 4 --
5 25 1.2 1.3 -- 6 39 0.5 0.8 -- 7 46 1.5 1.5 Mild Urethral Pain 8
40 0.5 0.5 Mild Urethral Pain Mean 1.03 1.39 SD 0.54 1.10 p >
0.05 SE 0.19 0.39
Example 3
Clinical Study Using a Composition Comprising Alprostadil and
Lidocaine
[0127] A larger clinical study was performed with a group of 44
patients, 43 of which completed the study. The general demographic
data are provided in Table 5 below.
[0128] Unit dose dispensers were used in the study. The contents of
the dispenser containing 0.4% alprostadil (300 mcg)/lidocaine
(2.5%) in 75 mg cream was applied each time. A minimum of a 24-hour
interval was required between every two administrations of the
medications. The patients were required to apply the medication no
less than twice a week.
TABLE-US-00005 TABLE 5 General Demographic Data Range Mean Age
21-53 years old 37 years old Weight 60-100 kg 74.18 kg Height
159-185 cm 172.93 cm Alcoholic 15 (34%) History Smoking History 4
(18%)
[0129] In the first 2 weeks, the PE baseline ejaculatory latency
time (ELT) were collected (>2 times). All of the patients were
given a minimum of 4 doses of cream. The patients were instructed
to administer the cream topically to the tip of the penis (i.e.
intrameatally) 5 to 20 min before sexual intercourse. The primary
efficacy variable was ELT, as measured using a stopwatch. The
degree of satisfaction of both patient and partner were recorded.
The clinical efficacy was assessed by the doctors based on the
patients' diaries.
[0130] General data regarding the subject group is summarized in
Table 6, below.
TABLE-US-00006 TABLE 6 Summary of PE History Number Percent
Morbidity Acquired 27 61.4 Since Entering Adulthood 17 38.6 Type
Environmental 7 9.1 General 37 84.1 Etiological Classification
Organic 7 15.9 Psychogenic 29 65.9 Accompanied with ED 8 18.18
Other 0 0
[0131] The PE history of the subjects is summarized in Table 7,
below.
TABLE-US-00007 TABLE 7 PE History PE Freq. of Dur. ELT Intercourse
Freq. of Subject (Mo.) (sec) (per week) PE (%) Type Previous
Treatment Morbidity Etiology 1 24 80 1 95 General Acquired
Psychogenic 2 6 50 3-4 100 General Since entering Psychogenic
adulthood 3 38 30 1 90 General Trazodone 50 mg bid Acquired
Psychogenic 4 8 0 2 100 General Since entering Psychogenic
adulthood 5 36 90 2 90 Environ. Trazodone 50 mg bid Acquired
Psychogenic 6 16 70 3 85 Environ. Acquired Psychogenic 7 48 30 1
100 General Baiyoujie 20 mg qd Acquired Psychogenic 8 24 40 3 80
Environ. Since entering Psychogenic adulthood 9 8 15 4 100 General
Acquired Psychogenic 10 9 20 3 90 General Acquired Psychogenic 11
96 80 1 100 General Acquired Mixed 12 72 0 1 100 General Acquired
Psychogenic 13 62 50 1 95 General Acquired Mixed 14 10 45 4 90
General Since entering Psychogenic adulthood 15 36 75 1 85 General
Acquired Mixed 16 16 30 2 75 General Acquired Psychogenic 17 10 70
5 70 General Acquired Psychogenic 18 30 35 1-2 85 General Acquired
Psychogenic 19 120 70 1-2 80 General Acquired Mixed 20 36 30 1 100
General Acquired Psychogenic 21 180 60 1-2 80 General Since
entering Organic adulthood 22 60 60 1 100 General Acquired Organic
23 165 90 2 80 General Since entering Psychogenic adulthood 24 120
90 3 100 General Chinese Medicine Since entering Organic adulthood
25 120 120 1 100 General Since entering Organic adulthood 26 60 60
1 100 General Acquired Organic 27 96 90 2 100 General Since
entering Organic adulthood 28 48 30 3 100 General Since entering
Psychogenic adulthood 29 72 60 3 50 Environ. Since entering
Psychogenic adulthood 30 96 120 2 50 Environ. Chinese Medicine
Since entering Psychogenic adulthood 31 180 120 1-2 90 General
Chinese Medicine Since entering Organic adulthood 32 36 60 2 100
General Chinese Medicine Since entering Psychogenic adulthood 33 48
60 3 100 General Since entering Psychogenic adulthood 34 84 60 2
100 General Since entering Psychogenic adulthood 35 38 60 1 80
General Chinese Medicine Acquired Psychogenic 36 85 60 0-1 95
General Acquired Psychogenic 37 2 30 0.5 100 General Acquired
Accompany w. ED 38 9 30 2 100 General Acquired Psychogenic 39 42 45
2 90 General Acquired Accompany w. ED 40 8 60 2 100 General
Acquired Accompany w. ED 41 6 60 3 70 General Clomipramine 25 mg
Acquired Psychogenic before intercourse 42 11 30 2 100 General
Clomipramine 25 mg Since entering Psychogenic before intercourse
adulthood 43 32 20 2 100 General Acquired Psychogenic 44 144 0 0-1
100 Environ. Acquired Accompany w. ED
[0132] In the alprostadil/lidocaine cream treatment group, the mean
(.+-.SE) ELT at baseline and post-dosing were 0.89.+-.0.08 and
3.12.+-.0.36 min, with a net increase of 2.23.+-.0.36 minutes
(p<0.001). See Table 8, below, where the results are presented
in seconds. The ELT in 53.5% (23/43) of all patients increased to
>2 min. The sexual satisfaction of the patients and their
partners were 72.1% (31/43) and 67.4% (43/29). The clinical
efficacy was 72.1% as assessed by the investigators. All reported
adverse events were mild and were generally transient local
engorgement pain or warmth.
TABLE-US-00008 TABLE 8 Ejaculation Latency (Seconds) ELT (seconds)
ELT (seconds) Before After Extended Time Subject Administration
Administration Seconds 1 80 80 0 2 50 300 250 3 30 45 15 4 0 150
150 5 90 110 20 6 70 455 385 7 30 225 195 8 40 45 5 9 15 210 195 10
20 290 270 11 80 145 65 12 0 110 110 13 50 50 0 14 45 360 315 15 75
160 85 16 30 60 30 18 35 195 160 19 70 90 20 20 30 30 0 21 60 60 0
22 60 60 0 23 90 90 0 24 90 90 0 25 120 600 480 26 60 120 60 27 90
90 0 28 30 30 0 29 60 60 0 30 120 300 180 31 120 300 180 32 60 120
60 33 60 120 60 34 60 90 30 35 54 505 451 36 51 299 248 37 30 375
345 38 30 146 116 39 35 409 374 40 60 206 146 41 71 372 301 42 26
141 115 43 16 109 93 44 0 329 329 Average 53.3 189 136 Standard
30.8 142.0 140.2 Deviation
[0133] The effect of treatment on the sexual satisfaction ratio of
the patient was: significantly improved, nine patients (20.93%);
improved, twenty-two patients (51.16%); unchanged, twelve patients
(27.91%). The effect of treatment on the sexual satisfaction ratio
of the patients' partner was: significantly improved, nine partners
(20.93%); improved, twenty partners (46.51%).
[0134] The total efficacy was defined as the prolongation of
ejaculatory latency .gtoreq.2 min and significant improvement or
improvement of the sexual satisfaction ratio. Twenty-four (24/43)
patients met both the above criteria, yielding a clinical efficacy
of 55.8%.
[0135] The physicians assessed the clinical efficacy as 62.79%
(27/43 patients completing the study). Thirty one of the 43
patients (72%) who completed the study stated that administration
of the study medication improved their premature ejaculation.
TABLE-US-00009 TABLE 9 Summary of Results Ejaculatory latency more
than 2 minutes 58.14% Patients' sexual satisfaction ratio 72.09%
Partners' sexual satisfaction ratio 67.44% Total Efficacy 55.80%
Clinical Efficacy Evaluation by Investigators 62.79% Global
Efficacy Assessment by Patients 72.09%
Example 4
Exemplary Compositions Comprising Dyclonine
[0136] Exemplary Composition PDC1 was prepared as follows. Part A
was formed by dissolving 0.4 parts prostaglandin E.sub.1
(Alprostadil USP) in 5 parts ethyl alcohol. Next, 0.5 parts dodecyl
2-(N,N-dimethylamino)-propionate HCl were mixed into the
alcohol-prostaglandin E.sub.1 solution, followed by 2.5 parts ethyl
laurate and the topical anesthetic.
[0137] Part B was prepared starting from a pH 5.5 water/buffer
solution. The water/buffer solution was prepared by adding
sufficient potassium phosphate monohydride to purified water to
create a 0.1 M solution. The pH of the water/buffer solution was
adjusted to 5.5 with a strong base solution (1 N sodium hydroxide)
and a strong acid (1 N phosphoric acid). The buffer solution
represented about 81 parts of the total composition. Alternatively,
phosphoric acid and sodium hydroxide were used to adjust the pH of
the composition. Purified water was added, qs. All parts specified
herein are parts by weight based on the total weight of the
composition.
[0138] To the buffer solution was added 0.5 parts ethyl laurate.
Next, the prehydrated modified guar gum (in powder form) was
dispersed in the buffer solution and homogenized using a
homogenizer. Table 10, below, contains a list of ingredients.
[0139] The resulting composition was a spreadable, semi-solid
suitable for application to the skin without the need for
supporting devices such as patches and adhesive strips. The
composition was both homogenous in appearance and resistant to
separation.
TABLE-US-00010 TABLE 10 Topical Prostaglandin E.sub.1 and Dyclonine
Compositions Ingredient (wt %) PDC1 PDC2 PDC3 PDC4 PDC5 PDC6 BLC2
BLC3 prehydrated 3 3 3 3 3 3 3 3 modified guar gum water/buffer (pH
5.5) 81 81 81 81 81 81 81 81 Prostaglandin E.sub.1 0.4 0.4 0 0.4 --
-- -- -- Dyclonine HCl 0.5 1.0 1.0 -- -- 1.0 -- -- lidocaine -- --
-- -- -- -- 5.0 5.0 DDAIP HCl 2.5 2.5 2.5 2.5 2.5 -- 2.5 -- ethanol
5 5 5 5 5 5 5 5 ethyl laurate 3 3 3 3 3 3 3 3
[0140] Additional exemplary compositions were prepared in the same
manner using the components listed in Table 10. In addition, it was
found that compositions having lower concentrations of guar gum and
DDAIP HCl were also effective; see Table 11, below.
TABLE-US-00011 TABLE 11 Further Topical Prostaglandin E.sub.1 and
Dyclonine Compositions Ingredient (wt %) DD1 DD2 DD3 DD4 DD5 DD6
DC1 DC2 prehydrated 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 modified guar
gum Prostaglandin 0.4 0.4 0 0.4 0 0 0 0 E.sub.1 Dyclonine HCl 0.5
1.0 1.0 0 0 1.0 0 0 lidocaine 0 0 0 0 0 0 5.0 5.0 DDAIP HCl 0.5 0.5
0.5 0.5 0.5 0 0.5 0 ethanol 5 5 5 5 5 5 5 5 ethyl laurate 3 3 3 3 3
3 3 3 Phosphoric acid & sodium hydroxide were used to adjust
the pH of the composition. Purified water was added, qs.
Example 5
Clinical Study Using Dyclonine Compositions
[0141] The effect of topical compositions comprising PGE.sub.1 and
a topical anesthetic in the treatment of premature ejaculation was
studied in a double-blind, crossover, and randomized clinical
study. Thirty patients were selected based on the patient
inclusion/exclusion criteria. After the screening preparation,
which included the collection and evaluation of the patients'
general and sexual function data, the patients started a four-week
double-blind study. Two additional visits were arranged during the
study (at the end of week 2 and week 4 after administration of the
drug). The investigators evaluated the clinical efficacy and safety
based on the change in ejaculatory latency time (ELT) by using a
stopwatch, the sexual satisfaction ratio of the patient and the
patient's partner and the adverse events reported. Each patient
applied 8 applications of the alprostadil cream treatment during
the study. The clinical samples were provided by NexMed
Pharmaceuticals (Zhong Shan), Ltd. Patients applied the study
medication which was packaged in a dispenser on an as-needed basis.
However, patients were instructed not to use more than one dose
during any 24 hour period, nor less than one dose during one week.
The patients were required not to use other treatments for PE while
they were in the study. The treatments for other diseases could be
continued. All patients were required to record sexual activity in
a patient diary.
[0142] Each patient had a total of four clinical visits: a
screening visit (two weeks before administration of the drug),
Visit 1 (start administration of the drug), Visit 2 (two weeks
after administration of the drug), and Visit 3 (four weeks after
administration of the drug). Each patient received a total of 8
dispensers containing the active cream in two visits, four in visit
1, four in visit 2. The patients returned after drug administration
for assessment of the safety and efficacy of the topical
compositions for treatment of PE. The study was completed in one
and a half months.
[0143] The patients were instructed to apply the medication
intrameatally. "Intrameatally" means applying medication to the tip
of the penis into the navicular fossa by holding the penis upright,
holding the meatus open and dropping the medication into the
navicular fossa without introducing the medication container into
the meatus.
[0144] General characteristics of the patient group are presented
in Table 12, below.
TABLE-US-00012 TABLE 12 Patient General Data Number of Patients %
Age Distribution 20-30 1 3.3 31-40 3 10.0 41-50 12 40.0 >50 14
46.7 Allergy History Y/N 0//30 0/100 Alcoholic History Y/N 11//19
36.7/63.3 Smoking History Y/N 9//21 30/70 PE Duration (Months):
Mean 49.1 (9, 150) (minimum, maximum) Age Range (Years): Mean
(minimum, maximum) 46.6 (28, 62) Height Range (cm): Mean (minimum,
maximum) 174.4 (165.0, 182.0) Weight Range (kg): Mean (minimum,
maximum) 75.9 (62.0, 87.0)
[0145] The characteristics of each patient in the study group are
presented in Table 13, below. All patients had PE that was
characterized as acquired and general. No patients had an ELT prior
to treatment greater than 80 seconds; the frequency of occurrence
of PE ranged from 80-100%.
TABLE-US-00013 TABLE 13 PE History [For all patients, PE Type was
General, Morbidity was Acquired] Pre- Freq. of PE Dur. treatment
Intercourse Freq. of Subject (Mo.) ELT (sec) (per week) PE (%)
Previous Treatment Etiology 1 56 63 1 80 Psychogenic 2 64 70 1-2 90
Psychogenic 3 21 38 1 90 Psychogenic 4 30 9 0-1 100 Accompanied by
ED 5 49 51 1 100 Psychogenic 6 9 79 2 80 Psychogenic 7 25 70 1 90
Trazodone 50 mg tid Psychogenic 8 150 49 0-1 100 Chinese
Traditional Organic Medicine 9 20 31 1 100 Psychogenic 10 54 58 1-2
85 Clomipramine 25 mg 30 Psychogenic min before intercourse 11 16
54 1-2 95 Psychogenic 12 113 3 1 100 Chinese Traditional
Psychogenic Medicine 13 88 61 1-2 85 Accompanied by ED 14 37 36 2
80 Psychogenic 15 37 66 1-2 90 Psychogenic 16 54 16 1 100
Psychogenic 17 35 37 1 100 Organic 18 32 65 2 80 Accompanied by ED
19 30 43 2 100 Chinese Traditional Psychogenic Medicine 20 48 58
1-3 95 Organic 21 35 65 1-2 80 Psychogenic 22 57 80 1 90
Accompanied by ED 23 74 35 1 100 Psychogenic 24 22 43 1 100
Accompanied by ED 25 18 70 2 100 Psychogenic 26 49 69 1 80 Chinese
Traditional Accompanied by ED Medicine 27 33 45 1-3 90 Accompanied
by ED 28 47 50 1 95 Psychogenic 29 74 48 2-3 90 Chinese Traditional
Psychogenic Medicine/Zhuangyang Yao (Oral) 30 97 35 1 100 Chinese
Traditional Psychogenic Medicine/Zhuangyang Yao
[0146] One primary measure was ELT, measured by the patient using a
stopwatch. The prolongation produced by each treatment was defined
as the difference between the pre-treatment ELT and the
post-treatment ELT. The data for each patient are presented in
Table 14, below.
TABLE-US-00014 TABLE 14 Prolongation of ELT Composition Patient
PDC1 PDC2 PDC3 PDC4 PDC5 PDC6 BLC2 BLC3 1 182 267 257 277 227 187
207 247 2 415 390 360 360 320 310 220 370 3 287 332 262 372 287 262
212 307 4 61 41 6 11 16 -4 -9 91 5 109 119 64 149 -1 4 4 59 6 221
301 186 211 151 121 102 171 7 170 185 60 220 190 150 100 190 8 81
38 26 56 -9 1 6 61 9 259 229 99 184 189 161 39 89 10 137 162 72 112
-8 -3 -8 112 11 286 326 246 326 256 206 186 296 12 177 217 117 197
142 117 117 187 13 249 199 269 259 194 219 269 259 14 159 84 59 74
12 34 9 84 15 104 134 129 104 -16 -9 -16 129 16 154 84 294 69 14 24
-16 134 17 63 53 13 33 23 33 23 43 18 155 165 105 115 5 25 5 95 19
247 167 92 147 12 13 16 207 20 292 242 202 252 157 182 152 232 21
225 175 135 155 115 135 125 175 22 80 60 10 30 30 60 10 85 23 195
35 275 160 -35 -35 -5 95 24 197 162 27 147 27 27 -3 157 25 240 160
90 195 30 140 0 110 26 181 161 111 171 11 51 21 101 27 450 375 345
445 280 305 185 335 28 275 260 200 210 160 180 120 230 29 102 127
112 67 7 2 62 172 30 100 105 155 140 15 10 15 75 Total 5853 5355
4378 5248 2801 2908 2148 4898 Mean 195 179 146 175 93 97 72 163
[0147] The results are summarized in Tables 15 and 16, below. The
ranking of the different treatments was the same whether the basis
was ELT after treatment, or prolongation calculated based on the
pre-treatment ELT of each patient or the average pre-treatment ELT
of the group (Table 15) or the proportion of patients achieving an
ELT >2 minutes (Table 16). Compositions comprising PGE.sub.1
produced the largest prolongation of ELT, and of these, the
compositions comprising dyclonine as well as PGE.sub.1 produced
larger prolongation of ELT. Compositions comprising local
anesthetics without PGE.sub.1 (BLC3, PDC3 and PDC6) produced
greater prolongation of ELT than the blank control PDC5. The
presence of the penetration enhancer DDAIP produced a somewhat
greater effect for 1% dyclonine compositions lacking PGE.sub.1, but
the opposite effect was seen in the results obtained with 5%
lidocaine compositions lacking PGE.sub.1.
TABLE-US-00015 TABLE 15 Summary of ELT Results Prolongation
Composition ELT after Within Between PGE1 Dyclonine Lidocaine DDAIP
Label treatment patient patients 0.40% 0.50% -- Yes PDC1 245 195
195 0.40% 1.00% -- Yes PDC2 229 180 179 0.40% -- -- Yes PDC4 225
175 175 -- -- 5.00% No BLC3 213 163 162 -- 1.00% -- Yes PDC3 193
143 146 -- 1.00% -- No PDC6 150 100 97 -- -- -- Yes PDC5 141 91 93
-- -- 5.00% Yes BLC2 118 68 72
TABLE-US-00016 TABLE 16 Results: Proportion of Patients with ELT
After Administration >2 min Patients with ELT After ELT ELT
Prolongation Administration Before After Of ELT >2 min
Administration Administration (Seconds) patient % PDC1 50 245 195
28 93.3 PDC2 50 229 179 24 80.0 PDC4 50 225 175 23 76.7 BLC3 50 213
162 22 73.3 PDC3 50 193 146 22 73.3 PDC6 50 150 97 14 46.7 PDC5 50
141 93 13 43.3 BLC2 50 118 72 11 36.7
[0148] Analysis of variance (ANOVA) indicated that variation
between treatment compositions was more significant than variation
within compositions. See Table 17, below.
TABLE-US-00017 TABLE 17 ANOVA Results Source of Variation SS Df MS
F P-value F crit Between 450692.6625 7 64384.666 6.58407155 4.2E-07
2.049195 Compositions Within 2268693.833 232 9778.8527 Compositions
Total 2719386.496 239
[0149] The effects of the various treatments were evaluated using
pairwise t-tests. The results of the analysis are presented in
Table 18, below.
TABLE-US-00018 TABLE 18 SUMMARY OF t-TEST ANALYSIS OF PROLONGATION
(ELT) DATA Component Significance of Difference of Means by
Pairwise t-Test (P = 0.05) PGE1 Dyclonine Lidocaine DDAIP Label
PDC5 PDC2 PDC3 PDC4 PDC6 BLC2 BLC3 0.4% 0.5% -- Yes PDC1 SIG NS SIG
SIG SIG SIG SIG 0.4% 1.0% -- Yes PDC2 SIG -- SIG NS SIG SIG NS 0.4%
-- -- Yes PDC4 SIG -- SIG SIG NS -- -- 5.0% No BLC3 SIG -- 1.0% --
Yes PDC3 SIG -- SIG SIG SIG NS -- 1.0% -- No PDC6 SIG -- SIG SIG --
-- -- Yes PDC5 -- -- -- 5.0% Yes BLC2 SIG -- SIG
[0150] Chi Square analysis the proportion of patients achieving an
ELT >2 minutes (Table 19, below) led to the same ranking of the
efficacy of treatments.
TABLE-US-00019 TABLE 19 SUMMARY OF Chi Square ANALYSIS OF LATENCY
(ELT) DATA Composition P values, pairwise Chi square comparisons
PGE1 Dyclonine Lidocaine DDAIP Label PDC5 PDC2 PDC3 PDC4 PDC6 BLC2
BLC3 0.40% 0.50% -- Yes PDC1 0.0002 0.222 0.080 0.519 0.012 0.001
0.136 0.40% 1.00% -- Yes PDC2 0.010 0.584 0.559 0.184 0.020 0.781
0.40% -- -- Yes PDC4 0.002 0.058 0.004 0.390 -- -- 5.00% No BLC3
0.020 -- 1.00% -- Yes PDC3 0.039 0.260 0.432 0.071 0.787 -- 1.00%
-- No PDC6 0.194 0.301 0.292 -- -- -- Yes PDC5 -- -- 5.00% Yes BLC2
0.791 0.038
[0151] At the end of the study, the efficacy and safety of the
study medication was analyzed based on the ejaculatory latency
time, sexual satisfaction ratio, adverse events records etc. The
primary efficacy was defined as the ejaculatory latency time
reached greater than 2 minutes combined with an improvement in
sexual satisfaction ratio that was improved or significantly
improved. Secondary efficacy was evaluated by the ejaculatory
latency time and sexual satisfaction ratio (improved or
significantly improved) respectively. At the study end point,
clinical efficacy evaluation and safety analysis were performed for
the 30 evaluable patients. The analysis results of the secondary
efficacy (ejaculation latency, sexual satisfaction) and the primary
efficacy for patient's sexual activities after administration are
presented in Table 20, below.
TABLE-US-00020 TABLE 20 Summary of Efficacy Results (% of patients,
ranked by Primary Efficacy) PDC1 PDC4 PDC2 BLC3 PDC3 PDC6 BLC2 PDC5
Ejaculation 93.3 76.7 80.0 73.3 73.3 46.7 36.7 43.3 Latency >2
mins Sexual 86.7 83.3 76.7 70.0 73.3 73.3 50.0 66.7 Satisfaction
Partner's Sexual 80.0 80.0 73.3 63.3 70.0 70.0 56.7 66.7
Satisfaction Primary Efficacy 83.3 77.0 70.0 67.0 63.0 53.0 40.0
36.7 Components PGE.sub.1 0.4% 0.4% 0.4% -- -- -- -- -- Dyclonine
0.5% -- 1.0% -- 1.0% 1.0% -- -- Lidocaine -- -- -- 5.0% -- -- 5.0%
-- DDAIP Yes Yes Yes No Yes No Yes Yes
[0152] All patients completed the study. The total applications
were 240. A total of 47 applications (19.6%) included adverse
events. All of the adverse events confirmed by the investigators
were related to the study medication. Forty-five of them (95.7%)
were mild, and two of them were moderate. All adverse events were
transient. All adverse events reported were either penis, urethral
or glans pain.
[0153] The rank of primary efficacy for PE treatment of the tested
compositions from high to low are:
PDC1>PDC4>PDC2>BLC3>PCD3>PDC6>BLC2>PDC5.
[0154] The efficacy results indicate that the efficacies of PDC1,
PDC2, PDC4, which contain PGE1 are 83%, 70% and 77% respectively,
greater than the efficacies of the other compositions lacking
PGE.sub.1. The efficacy of PDC4 containing PGE.sub.1 without
anesthetics, is 77%, which indicates the utility of PGE.sub.1 for
the treatment of premature ejaculation.
[0155] PDC5 is the blank control composition containing DDAIP and
base material of cream only. The efficacy of PDC5 for the treatment
of premature ejaculation is the poorest.
[0156] The efficacies of compositions PDC3, PDC6, BLC2 and BLC3,
which only contain a topical anesthetic as an active ingredient,
are less efficacious than compositions comprising PGE.sub.1,
although their primary efficacies are higher than that of the blank
control composition PDC5. The effect of the transdermal penetration
enhancer DDAIP on the efficacies of topical compositions containing
a topical anesthetic but lacking PGE.sub.1 appears to depend on the
anesthetic used.
[0157] Composition PDC1 which contains 0.5% Dyclonine and 0.4%
PGE.sub.1, demonstrated the best efficacy (83%) in this study. The
efficacy of composition PDC2, which contains 1.0% Dyclonine and
0.4% PGE.sub.1, is the second highest at 70%.
Example 5
Clinical Study Using Buvipacaine Compositions
[0158] A randomized, double-blind, placebo control clinical study
was performed. Patients were selected based on the patient
inclusion/exclusion criteria listed below. A total of 90 patients
who met the patient inclusion and exclusion criteria were randomly
proportionally distributed into the study. At the study end point,
clinical efficacy evaluation and safety analysis were performed for
the 89 evaluable patients.
[0159] The screening forms were completed after the informed
consent forms were signed. In the screening preparation, which
included the collection and evaluation of the patients' baseline
data, baseline data was recorded at least 4 times before
administration, including ejaculation latency time (ELT) and
patient satisfaction ratio. Patients started a four-week
double-blind study after the screening period. Two additional
visits were arranged during the study (at the end of week 2 and
week 4) after administration of the drug.
[0160] Table 21, below, provides the components of the placebo
composition and the test composition that included 0.4 weight
percent Prostaglandin E.sub.1 and 0.75 weight percent Bupivacaine
HCl, based on the total weight of the composition.
TABLE-US-00021 TABLE 21 Placebo and Prostaglandin
E.sub.1/Bupivacaine HCl Compositions Ingredient (wt %) Placebo Test
Composition prehydrated modified guar gum 2.5 2.5 Prostaglandin
E.sub.1 0 0.4 Bupivacaine HCl 0 0.75 DDAIP HCl 0.5 0.5 ethanol 5 5
ethyl laurate 3 3 Phosphoric acid and sodium hydroxide were used to
adjust the pH of the composition. Purified water was added, qs.
[0161] The significant difference was noted for primary efficacy
between the placebo group and study group. The significant
difference was noted for ELT and satisfaction ratio of the
patient's partner between the placebo group and study group. No
significant difference was noted for the satisfaction ratio between
the placebo group and study group.
[0162] Major efficacies included the measurement of the ejaculatory
latency from vaginal intromission to ejaculation with a stop-watch,
the degree of satisfaction of both the patients and their partners,
the anxiety scores and clinical efficacy as interpreted as
ejaculatory latency above 2 minutes and sexual satisfaction rate
increasing more than 20% over the screening period.
[0163] Patients with a history of premature ejaculation of at least
three months duration were selected based on the
inclusion/exclusion patient criteria. A total of 90 patients were
enrolled and assigned into the study groups. In the physical
examination, no abnormal physical exam result at baseline was found
in the 90 patients. Contact was lost with one patient, but no other
patients were withdrawn from further participation in the study.
Eighty-nine patients completed the study. The general patient
demographic data are found in Table 22, below.
TABLE-US-00022 TABLE 22 Patient General Demographic Data Range Mean
Age Distribution 27-62 43 Weight Distribution 62-90 kg 73 kg Height
Distribution 159-185 cm 174 cm PE Duration (Months) 3-135 31
Allergy History: 2 (Penicillin 1, Sulfonamide 1) Alcoholic History:
44 (48.9%) Smoking History: 37 (41.1%) Drug Abuse History: 0
[0164] The Patients' PE treatment history was summarized based on
pharmaco-therapy and non-pharmaco-therapy categories. Eighteen
(20%) of 90 patients accepted pharmaco-therapy; no patient accepted
non-pharmaco-therapy.
[0165] The non-PE disease history of the patients was summarized in
Table 23, below, which lists the numbers of patients having the
five most frequent diseases.
TABLE-US-00023 TABLE 23 Patient Non-PE Disease History Number %
Evaluable Patients 90 100 Cardiovascular System 3 3.33 Endocrine
System 2 2.22 Gastrointestinal System 1 1.11 Urinary System 1 1.11
Immunity System 1 1.11
[0166] Inclusion criteria were: male, age 20-60 years with PE who
complained that PE affected their sexual life; an ejaculatory
latency time less than 2 minutes and/or sexual satisfaction ratio
were less than 50%; the presence of a stable heterosexual
relationship; and at least one intercourse per week.
[0167] Exclusion criteria were: abnormal physical examination
including genitalia; abnormal blood profile or tests; laboratory
test results indicating abnormal liver and renal function, abnormal
testosterone and prolactin levels; genitourinary tract infection
such as prostatitis, urethritis or epididymitis; neurological
disorders, and obvious psychological problems requiring psychiatric
support and administration of any anti-depressants that might alter
sexual activities; alcohol or drug abuse; hypotension, cardiac
infarction, heart failure or angina in the previous six months.
[0168] A total of four clinical visits were required: a screening
visit (two weeks before administration of the study medicine),
visit 1 (start administration of the study medicine), visit 2 (two
weeks after administration of the study medicine), and visit 3
(four weeks after administration of the study medicine).
[0169] Each patient received a total of 8 doses of study medicine
in visits 1 & 2, four for each visit. Patients repeated the
visit after administration to observe the safety and efficacy of
the composition for the treatment of premature ejaculation.
Patients applied the drug intrameatally. The study was completed in
two months. The patients were required not to use other treatments
for premature ejaculation during the study, but treatments for
other diseases can be continued. All patients were required to
record their sexual activity in a patient diary.
[0170] A minimum 24-hour interval was required between every
administration of the study medicine. The patients were required to
apply the medication no less than once a week. Patients returned
any unused clinical supply to the clinical site at the end of the
study.
[0171] The primary efficacy was defined as simultaneously extending
ELT to no less than 2 minutes and improving sexual satisfaction
ratio by 20% (the satisfaction after administration defined as
sexual satisfaction reaching improved or significantly improved).
The secondary efficacy was assessed by ELT, and sexual satisfaction
ratio. Sexual satisfaction of the patient's partner was assessed as
well. The clinical effectiveness was regarded as ejaculatory
latency time extended no less than 2 minutes. The clinical
effectiveness was regarded as sexual satisfaction ratio improved by
20%. The patients who completed at least 4 administrations were
included into efficacy evaluation.
TABLE-US-00024 TABLE 24 Ejaculatory Latency Time Ejaculatory
Ejaculatory Average Evaluable Latency Before Latency After
Prolongation of Patients Administration Administration ELT + SD t p
Placebo 30 65 115 49.9 .+-. 47.0 Test 59 77 209 130.1 .+-. 86.8
4.72 <0.001
[0172] The significant difference was noted for ELT between the
group of patients receiving the placebo composition (placebo group
and the group of patients receiving the composition comprising 0.4
weight percent Prostaglandin E.sub.1 and 0.75 weight percent
Bupivacaine HCl, (study group). See Table 24, above. The results of
the analysis of sexual satisfaction reporting are summarized in
Table 25, below.
TABLE-US-00025 TABLE 25 Sexual Satisfaction Placebo Group Study
Group Patient % Patient % X.sup.2 p Evaluable Improvement of 30 100
59 98.33 Patient Sexual Satisfaction Ratio Patient .gtoreq.20% 17
56.67 45 76.27 3.62 0.057 <20% 13 43.33 14 23.73 Patient's
.gtoreq.20% 14 46.67 46 77.97 8.87 0.003 Partner <20% 16 53.33
13 22.03
[0173] No significant difference for the sexual satisfaction ratio
of patient was noted between the group A (placebo group) and group
B (study group). A significant difference was noted for the sexual
satisfaction ratio of patient's partner between group A (placebo
group) and group B (study group).
[0174] The primary efficacy results are presented in Table 26,
below. A significant difference in the primary efficacy was noted
between the group A (placebo group) and the group B (study
group).
TABLE-US-00026 TABLE 26 Efficacy Measures Placebo Group Study Group
Number % Number % X.sup.2 p Evaluable Patients 30 100.00 59 98.33
Primary Efficacy 7 23.33 44 74.58 21.34 <0.001 ELT .gtoreq.2
mins 9 30.00 50 84.75 26.67 <0.001 Secondary Improvement of
satisfaction ratio of 17 56.67 45 76.27 3.62 0.057 Efficacy patient
.gtoreq.20% Improvement of satisfaction ratio of 14 46.67 46 77.97
8.87 0.003 patient's partner .gtoreq.20%
[0175] Based on the analysis of all efficacy measures, the
significant difference was noted for primary efficacy between the
placebo group and study group, as well as for ELT and satisfaction
ratio of patient's partner. No significant difference was noted for
the satisfaction ratio between the placebo group and study
group.
[0176] Of the 89 patients who completed the study, a total of 29
(32.58%) patients experienced adverse events: 6 (20.00%) patients
in placebo group and 23 (38.98) patients in study group. All of the
adverse events were related to the study medication, which was
confirmed by the investigators. No significant difference was noted
for adverse events between the placebo group and the study group.
All adverse events were mild and transient. The average duration of
adverse events was 18.85 minutes. The longest adverse event was
46.88 minutes. Most of adverse events reported were either penis,
urethral or glans pain and itch. No other adverse event was
reported. The adverse events are summarized in the Table 27,
below.
TABLE-US-00027 TABLE 27 Adverse Events Total Placebo Group Study
Group N % N % N % X.sup.2 p Evaluable Patients 89 98.89 30 33.7 59
66.29 Adverse Event Total 29 32.58 6 20 23 38.98 3.26 0.071 Mild 29
32.58 6 20 23 38.98 3.26 0.071 Moderate 0 0 0 0 0 0 Severe 0 0 0 0
0 0 The patients with AE 0 0 0 0 0 0 0 who need treatment AE
related with study 29 32.58 6 20 23 38.98 medicine
[0177] In summary, analysis of the ejaculation latency time, and
the sexual satisfaction ratio shows a significant difference
between group A (placebo group) and group B (study group) for the
treatment of premature ejaculation. Nine (30%) patients in group A
(placebo group) and 50 (84.75) patients in group B (study group)
showed an extension of ELT to no less than 2 minutes after
application of the study medicine. The difference between the two
groups was significant (Table 25, above).
[0178] The difference in improvement of 17 (56.67%) patients in
group A (placebo group) and 45 (76.27) patients in group B (study
group) whose sexual satisfaction ratio after application of the
study medicine was improved no less than 20%. No significant
difference was noted between the two groups. There are 14 (46.67%)
patients' partners in group A (placebo group) and 46 (77.97)
patients in group B (study group) whose sexual satisfaction ratio
after application of the study medicine was improved no less than
20%. The difference between the two groups was significant (Table
25, above).
[0179] There were 7 (23.33%) patients in group A (placebo group)
and 44 (74.58) patients in group B (study group) whose ELT was
extended to no less than 2 minutes and simultaneously the sexual
satisfaction ratio after application of the study medicine was
improved no less than 20%. A significant difference was noted
between the two groups.
[0180] While the foregoing is intended to be illustrative of the
present invention, the scope is defined by the appended claims.
Numerous variations and modifications may be effected without
departing from the true spirit and scope of the invention.
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