U.S. patent application number 12/503432 was filed with the patent office on 2009-11-05 for therapy for the treatment of disease.
This patent application is currently assigned to THERAVIDA, INC.. Invention is credited to Mehdi Paborji.
Application Number | 20090275629 12/503432 |
Document ID | / |
Family ID | 37502599 |
Filed Date | 2009-11-05 |
United States Patent
Application |
20090275629 |
Kind Code |
A1 |
Paborji; Mehdi |
November 5, 2009 |
THERAPY FOR THE TREATMENT OF DISEASE
Abstract
Disclosed herein are pharmaceutical compositions comprising
various combinations of an antimuscarinic or an anticholinergic
agent, a compound that causes stimulation of salivary glands, and a
compound that relieves constipation. Also disclosed are methods of
treating a patient suffering from overactive bladder comprising
administering to the patient the above pharmaceutical
composition.
Inventors: |
Paborji; Mehdi; (Cupertino,
CA) |
Correspondence
Address: |
TechLaw LLP
10755 Scripps Poway Parkway, Suite 465
San Diego
CA
92131
US
|
Assignee: |
THERAVIDA, INC.
San Mateo
CA
|
Family ID: |
37502599 |
Appl. No.: |
12/503432 |
Filed: |
July 15, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11467760 |
Aug 28, 2006 |
|
|
|
12503432 |
|
|
|
|
60714150 |
Sep 2, 2005 |
|
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|
Current U.S.
Class: |
514/397 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/4172 20130101; A61K 31/216 20130101; A61K 31/439 20130101;
A61K 36/482 20130101; A61P 25/00 20180101; A61K 36/72 20130101;
A61P 7/12 20180101; A61K 45/06 20130101; A61P 1/00 20180101; A61K
31/137 20130101; A61K 31/00 20130101; A61P 13/10 20180101; A61K
31/4178 20130101; A61K 33/06 20130101; A61K 31/717 20130101; A61K
36/68 20130101; A61P 13/06 20180101; A61K 31/4025 20130101; A61K
31/46 20130101; A61K 31/00 20130101; A61K 2300/00 20130101; A61K
31/137 20130101; A61K 2300/00 20130101; A61K 31/216 20130101; A61K
2300/00 20130101; A61K 31/4025 20130101; A61K 2300/00 20130101;
A61K 31/4178 20130101; A61K 2300/00 20130101; A61K 31/439 20130101;
A61K 2300/00 20130101; A61K 31/46 20130101; A61K 2300/00 20130101;
A61K 31/4172 20130101; A61K 2300/00 20130101; A61K 31/717 20130101;
A61K 2300/00 20130101; A61K 33/06 20130101; A61K 2300/00 20130101;
A61K 36/482 20130101; A61K 2300/00 20130101; A61K 36/68 20130101;
A61K 2300/00 20130101; A61K 36/72 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/397 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61P 25/00 20060101 A61P025/00 |
Claims
1. A method of improving quality of sleep in a patient suffering
from overactive bladder, the method comprising identifying a
patient in need thereof, and administering to the patient a
therapeutically effective amount of oxybutynin or tolterodine, or a
free base thereof or a pharmaceutically acceptable salt thereof,
and pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, whereby the quality of sleep in the
patient is improved.
2. The method of claim 1, comprising administering oxybutynin, a
free base thereof, or a pharmaceutically acceptable salt
thereof.
3. The method of claim 1, comprising administering tolterodine, a
free base thereof, or a pharmaceutically acceptable salt
thereof.
4. The method of claim 1, wherein the oxybutynin or tolterodine, or
a free base thereof or a pharmaceutically acceptable salt thereof,
and the pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are administered more or less
simultaneously.
5. The method of claim 1, wherein the oxybutynin or tolterodine, or
a free base thereof or a pharmaceutically acceptable salt thereof,
is administered prior to the pilocarpine, or a free base thereof or
a pharmaceutically acceptable salt thereof.
6. The method of claim 1, wherein the oxybutynin or tolterodine, or
a free base thereof or a pharmaceutically acceptable salt thereof,
is administered subsequent to the pilocarpine, or a free base
thereof or a pharmaceutically acceptable salt thereof.
7. The method of claim 1, wherein the oxybutynin or tolterodine, or
a free base thereof or a pharmaceutically acceptable salt thereof,
and the pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are together disposed in the same dosage
form.
8. The method of claim 1, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered at a dose of between 0.5 mg to 2 mg.
9. The method of claim 1, wherein the tolterodine, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered at a dose of between 0.05 mg to 50 mg.
10. The method of claim 1, wherein the pilocarpine, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered at a dose of between 0.05 mg to 50 mg.
11. A method of improving quality of sleep in a patient suffering
from overactive bladder, the method comprising identifying a
patient in need thereof, and administering to the patient
oxybutynin, or a free base thereof or a pharmaceutically acceptable
salt thereof, at a dose of between 0.5 mg to 2 mg and pilocarpine,
or a free base thereof or a pharmaceutically acceptable salt
thereof at a dose of between 0.05 mg to 50 mg, whereby the quality
of sleep in the patient is improved.
12. The method of claim 11, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, and the
pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are administered more or less
simultaneously.
13. The method of claim 11, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered prior to the pilocarpine, or a free base thereof or a
pharmaceutically acceptable salt thereof.
14. The method of claim 11, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered subsequent to the pilocarpine, or a free base thereof
or a pharmaceutically acceptable salt thereof.
15. The method of claim 11, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, and the
pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are together disposed in the same dosage
form.
16. A method of improving quality of sleep in a patient suffering
from overactive bladder, the method comprising identifying a
patient in need thereof, and administering to the patient
tolterodine, or a free base thereof or a pharmaceutically
acceptable salt thereof, at a dose of between 0.05 mg to 50 mg and
pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof at a dose of between 0.05 mg to 50 mg,
whereby the quality of sleep in the patient is improved.
17. The method of claim 16, wherein the oxybutynin, or a free base
thereof or a pharmaceutically acceptable salt thereof, and the
pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are administered more or less
simultaneously.
18. The method of claim 16, wherein the tolterodine, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered prior to the pilocarpine, or a free base thereof or a
pharmaceutically acceptable salt thereof.
19. The method of claim 16, wherein the tolterodine, or a free base
thereof or a pharmaceutically acceptable salt thereof, is
administered subsequent to the pilocarpine, or a free base thereof
or a pharmaceutically acceptable salt thereof.
20. The method of claim 16, wherein the tolterodine, or a free base
thereof or a pharmaceutically acceptable salt thereof, and the
pilocarpine, or a free base thereof or a pharmaceutically
acceptable salt thereof, are together disposed in the same dosage
form.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 11/467,760, filed, Aug. 28, 2006, by Mehdi Paborji, and
entitled "THERAPY FOR THE TREATMENT OF DISEASE," which in turn
claims priority to U.S. Provisional Application No. 60/714,150,
filed Sep. 2, 2005, by Mehdi Paboiji, and entitled "THERAPY FOR THE
TREATMENT OF DISEASE," both of which are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is in the field of pharmaceutical
compositions and methods of using the same for the treatment of
overactive bladder and reduction of various side effects
thereof.
[0004] 2. Description of the Related Art
[0005] Overactive bladder (OAB) is characterized by involuntary
contractions of the detrusor muscle during bladder filling. These
contractions may be asymptomatic or may cause the three common
symptoms that clinically define OAB: frequency of urination;
urgency; and urge, or reflex, incontinence. Frequency is an
increase in the number of micturitions, to as many as eight or more
a day. Urgency is the strong and sudden desire to urinate. Urge
incontinence, or reflex incontinence, is the situation where the
urge to urinate cannot be controlled. Nocturia, or nighttime
urinary frequency that disturbs sleep (more than twice a night), is
often included as a fourth symptom. The symptoms of OAB may appear
individually or together, and it is not known whether they have a
pathologic or neurogenic cause.
[0006] Incontinence is present in over half of female patients with
OAB. This condition affects more than 33 million Americans and
imposes considerable economic, social, and psychological burdens.
Although continued research in the pharmacologic management of
lower urinary tract disorders have led to alternative treatment
options, the symptoms of OAB are generally underreported by
patients and under-treated by healthcare professionals.
[0007] Several classes of medications have been used to treat and
manage OAB, including calcium channel blockers, tricyclic
antidepressants, alpha-adrenergic antagonists, estrogen, and
anticholinergic agents. Anticholinergic agents, which exert their
effects at muscarinic receptors and suppress or diminish the
intensity of involuntary detrusor muscle contractions, are the
first-choice pharmacotherapy for OAB, and may be the only therapy
available whose efficacy is not in question. Oxybutynin chloride
and tolterodine tartrate are the most extensively studied of the
anticholinergic agents, and the most widely used. A recent
evidence-based systematic review of controlled clinical trials of
several agents concluded that anticholinergic therapies
significantly improved several indices of lower urinary tract
function, including frequency of micturition and number of
incontinence episodes. A major limitation of these agents is that
they lack specificity for bladder tissue, with resultant bothersome
side effects such as dry mouth and constipation.
[0008] Tolterodine has generally been associated with less dry
mouth than oxybutynin. This property is thought to be due to the
decreased selectivity of tolterodine for any one of the 5
muscarinic receptor subtypes (M1-M5), such as the M3 receptor that
predominates in parotid tissue. Oxybutynin, more than tolterodine,
has a high affinity for this receptor, which also mediates bladder
contraction. It has been argued on the basis of animal data that
tolterodine has a greater selectivity than oxybutynin for bladder
than for parotid muscarinic receptors, but such a mechanism remains
to be elucidated. Effects on M2 receptors, which populate bladder
smooth muscle though not glandular tissue, and for which
tolterodine shows a greater affinity than oxybutynin, have also
been invoked to explain the relatively slightly lower degree of dry
mouth that is associated with the therapeutic effect of
tolterodine.
[0009] Additional reports that the higher extent of dry mouth with
oxybutynin is attributed to formation of the major metabolite,
desethyloxybutynin, which appears to have a greater affinity for
the M3 subtype receptors also expressed in the salivary glands.
However, the newer extended-release formulations of oxybutynin and
tolterodine provide comparable or perhaps slightly better efficacy
and enhanced tolerability compared with immediate-release
formulations. More recently approved agents including trospium
chloride, solifenacin succinate (Vesicare) and darifenacin
(Enablex) appear to have a better side effect profile, i.e.,
slightly less dry mouth. Nonetheless, the dry mouth and
constipation continue to be problematic and patients stop taking
the medication after short period of therapy.
[0010] Thus, there exists a need in the art for a medication that
provides sufficient efficacy for the treatment of OAB, with much
reduced level of side effects in order to increase patient
compliance, comfort, and efficacy.
SUMMARY OF THE INVENTION
[0011] Disclosed herein are pharmaceutical compositions comprising
a therapeutically effective amount of a first compound and a
therapeutically effective amount of a second compound, wherein the
first compound is an antimuscarinic or an anticholinergic agent and
the second compound causes stimulation of salivary glands. Also,
disclosed herein are pharmaceutical compositions comprising a
therapeutically effective amount of a first compound and a
therapeutically effective amount of a second compound, wherein the
first compound is an antimuscarinic or an anticholinergic agent and
the second compound relieves constipation. Further, disclosed
herein are pharmaceutical compositions comprising a therapeutically
effective amount of a first compound, a therapeutically effective
amount of a second compound, and a therapeutically effective amount
of a third compound, wherein the first compound is an
antimuscarinic or an anticholinergic agent, the second compound
causes stimulation of salivary glands, and the third compound
relieves constipation.
[0012] Disclosed herein are methods of treating a patient
comprising administering to a patient in need thereof a
therapeutically effective amount of a first compound and a
therapeutically effective amount of a second compound, wherein the
first compound is an antimuscarinic or an anticholinergic agent and
the second compound causes stimulation of salivary glands. Also
disclosed herein are methods of treating a patient comprising
administering to a patient in need thereof a therapeutically
effective amount of a first compound and a therapeutically
effective amount of a second compound, wherein the first compound
is an antimuscarinic or an anticholinergic agent and the second
compound causes stimulation of salivary glands. Further, disclosed
herein are methods of treating a patient comprising administering
to a patient in need thereof a therapeutically effective amount of
a first compound, a therapeutically effective amount of a second
compound, and a therapeutically effective amount of a third
compound, wherein the first compound is an antimuscarinic or an
anticholinergic agent, the second compound causes stimulation of
salivary glands, and the third compound relieves constipation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a graph showing the amount of saliva flow
collected in a human subject subsequent to the administration of
oxybutynin (.diamond-solid., diamond), pilocarpine (.box-solid.,
square), both ( , circle), and neither (.tangle-solidup.,
triangle).
[0014] FIG. 2 is a graph showing the percentage of saliva flow with
reference to time zero.
[0015] FIG. 3 is a graph showing the effect of time delay for the
administration of pilocarpine, with oxybutynin being administered
at t=0 for all experiments, except for placebo (.tangle-solidup.,
triangle) where there was no oxybutyln, and pilocarpine being
administered at t=0 (.box-solid., square), t=30 min ( , circle),
and t=60 min (.diamond-solid., diamond).
[0016] FIG. 4 is a graph showing the effect of different dose
ratios between oxybutynin and pilocarpine on saliva flow.
[0017] FIG. 5 is a graph showing the comparison of stimulated
salivary output following oral administration of 5 mg oxybutynin (
, circle), 30 mg cevimeline (.diamond-solid., diamond), placebo
(.tangle-solidup., triangle), and a combination of oxybutynin and
cevimeline (THVD-102) (.box-solid., square).
[0018] FIG. 6 is a graph showing the comparison of stimulated
salivary output following oral administration of 2 mg tolterodine
tartrate, with various combinations (2 mg tolterodine/5 mg
pilocarpine and 2 mg tolterodine/10 mg pilocarpine with pilocarpine
administered at different times), and placebo.
[0019] FIG. 7 is a graph showing the relationship of time of
administration of 10 mg of pilocarpine on stimulated salivary
output after oral administration of 2 mg tolterodine tartrate.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0020] The major limitations of treatment of overactive bladder
(OAB) are the dry mouth and constipation side effects. The current
approach to address the dry mouth is development of sustained
release of the active moiety, such as oxybutynin or tolterodine.
Patients taking OAB medications still suffer from these side
effects and thus their quality of life is hampered significantly to
the extend that majority of patients discontinue the mediations
after about 4-6 months.
[0021] Thus, in the first aspect, the present invention relates to
a pharmaceutical composition comprising a therapeutically effective
amount of a first compound and a therapeutically effective amount
of a second compound, wherein the first compound is an
antimuscarinic or an anticholinergic agent and the second compound
causes stimulation of salivary glands.
[0022] The first compound of the pharmaceutical compositions
described herein is a compound useful in the treatment of
overactive bladder. In some embodiments, the first compound is an
agonist of M2 or M3 muscarinic receptors. In further embodiments,
the first compound may be selected from the group consisting of
oxybutynin, tolterodine, solifenacin, darifenacin, trospium,
fesoterodine, or a pharmaceutically acceptable salt or prodrug
thereof. Other compounds known now or later developed for the
treatment of OAB are within the scope of the present
disclosure.
[0023] In some embodiments, the first compound is a compound of
Formula I
##STR00001##
or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0024] R.sub.1-R.sub.9 are each independently selected from the
group consisting of hydrogen, alkyl, nitro, amino, cyano, hydroxy,
alkoxy, carboxylate, and amide; and
[0025] m and n are each independently selected from 1, 2, 3, 4, and
5.
[0026] In some embodiments, each R.sub.1 and R.sub.2 is
independently selected from the group consisting of hydrogen,
alkyl, hydroxy, and alkoxy. In certain embodiments, each R.sub.1
and R.sub.2 is hydrogen.
[0027] In some embodiments, R.sub.3 is selected from the group
consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain
embodiments, R.sub.3 is hydroxy.
[0028] In some embodiments, R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
alkyl, hydroxy, and alkoxy. In certain embodiments, R.sub.4 and
R.sub.5 are each independently an alkyl. In further embodiments,
R.sub.4 and R.sub.5 are each independently selected from the group
consisting of methyl, ethyl, propyl, n-butyl, isobutyl, and
tert-butyl. In other embodiments, R.sub.4 and R.sub.5 are each
independently ethyl.
[0029] In some embodiments, R.sub.6-R.sub.9 are each independently
selected from the group consisting of hydrogen, alkyl, hydroxy, and
alkoxy. In certain embodiments, R.sub.6-R.sub.9 are each
independently a hydrogen.
[0030] In some embodiments, the first compound is oxybutynin, or a
pharmaceutically acceptable salt or prodrug thereof. Oxybutynin is
the active ingredient found in drugs such as Ditropan.RTM.;
Ditropan XL.RTM.; and Oxytrol.RTM.. Oxybutynin is an
anticholinergic drug, thereby suppressing involuntary contractions
of the bladder's smooth muscle. Oxybutynin is also believed to have
muscarinic receptor activity, which further enhances its OAB
efficacy, but also may be the reason behind its most prevalent side
effect, dry mouth.
[0031] In some embodiments, the first compound is tolterodine, or a
pharmaceutically acceptable salt or prodrug thereof. Tolterodine,
which has the chemical name
(R)-2-[3-[bis(1-methylethyl-amino]-1-phenylpropyl]-4-methylphenol
[R-(R*,R*)]-2,3-dihydroxybutanedionic acid, is a muscarinic
receptor antagonist and is the active ingredient found in drugs
such as Detrol.RTM. (as tolterodine tartrate). In another
embodiment, the first compound is the 5-hydroxymethyl derivative of
tolterodine.
[0032] The term "pharmaceutically acceptable salt" refers to a
formulation of a compound that does not cause significant
irritation to an organism to which it is administered and does not
abrogate the biological activity and properties of the compound.
Pharmaceutical salts can be obtained by reacting a compound of the
invention with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
succinic acid, tartaric acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicylic acid and the like.
Pharmaceutical salts can also be obtained by reacting a compound of
the invention with a base to form a salt such as an ammonium salt,
an alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl) methylamine, and salts
thereof with amino acids such as arginine, lysine, and the
like.
[0033] Throughout the present disclosure, when a particular
compound is named, it is understood that the name refers to both
the free base, or free acid, of the compound, and the
pharmaceutically acceptable salts thereof. Thus, for example, the
scope of the term "tolterodine" covers both the free base of
tolterodine, i.e.,
(R)-2-[3-[bis(1-methylethyl-amino]-1-phenylpropyl]-4-methylphenol
[R-(R*,R*)]-2,3-dihydroxybutanedionic acid, and its various
pharmaceutically acceptable salts, for example tolterodine
tartrate.
[0034] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug, or
may demonstrate increased palatability or be easier to formulate.
An example, without limitation, of a prodrug would be a compound of
the present invention which is administered as an ester (the
"prodrug") to facilitate transmittal across a cell membrane where
water solubility is detrimental to mobility but which then is
metabolically hydrolyzed to the carboxylic acid, the active entity,
once inside the cell where water-solubility is beneficial. A
further example of a prodrug might be a short peptide
(polyaminoacid) bonded to an acid group where the peptide is
metabolized to provide the active moiety.
[0035] In some embodiments, the second compound is a cholinergic
agonist. In certain embodiments, the second compound is selected
from the group consisting of pilocarpine, cevimeline, and
amifostine (the latter agent known chemically as
2-[(3-aminopropyl)amino]ethanethiol dihydrogen phosphate (ester)),
or a pharmaceutically acceptable salt or prodrug thereof. In
further embodiments, the second compound is pilocarpine, or a
pharmaceutically acceptable salt or prodrug thereof. In other
embodiments, the second compound is cevimeline, or a
pharmaceutically acceptable salt or prodrug thereof.
[0036] In some embodiments, the second compound is a compound of
Formula II
##STR00002##
or a pharmaceutically acceptable salt or prodrug thereof,
wherein
[0037] R.sub.1-R.sub.9 are each independently selected from the
group consisting of hydrogen, alkyl, nitro, amino, cyano, hydroxy,
alkoxy, carboxylate, and amide.
[0038] In some embodiments, R.sub.1 and R.sub.2 are each
independently selected from the group consisting of hydrogen,
alkyl, hydroxy, and alkoxy. In certain embodiments, R.sub.1 and
R.sub.2 are each independently an alkyl. In further embodiments,
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of methyl, ethyl, propyl, n-butyl, isobutyl, and
tert-butyl. In other embodiments, R.sub.1 and R.sub.2 are each
independently methyl.
[0039] In some embodiments, R.sub.3-R.sub.9 are each independently
selected from the group consisting of hydrogen, alkyl, hydroxy, and
alkoxy. In certain embodiments, R.sub.3-R.sub.9 are each
independently a hydrogen.
[0040] In another aspect, the present invention relates to a
pharmaceutical composition comprising a therapeutically effective
amount of a first compound and a therapeutically effective amount
of a second compound, wherein the first compound is an
antimuscarinic or an anticholinergic agent, as described above, and
the second compound relieves constipation.
[0041] In certain embodiments, the second compound is selected from
the group consisting of a stool softener, a laxative, a fiber
treatment, and a 5HT.sub.4 receptor partial agonist. In some
embodiments, the second compound is selected from the group
consisting of bisacodyl, carboxymethylcellulose, casanthranol,
cascara sagrada, castor oil, danthron, dehydrocholic acid, docusate
calcium, docusate sodium, glycerin, lactulose, magnesium citrate,
magnesium hydroxide, magnesium oxide, magnesium sulfate, malt soup
extract, methylcellulose, milk of magnesia, mineral oil, mucilloid,
polycarbophil, polyethylene glycol 3350, poloxamer 188, psyllium,
psyllium hydrophilic, senna, sennosides, and sodium phosphate.
[0042] In certain embodiments, the second compound is a compound of
Formula III
##STR00003##
or a pharmaceutically acceptable salt or prodrug thereof,
wherein
[0043] R.sub.1-R.sub.9 are each independently selected from the
group consisting of hydrogen, alkyl, nitro, amino, cyano, hydroxy,
alkoxy, carboxylate, and amide, and
[0044] m is selected from 1, 2, and 3.
[0045] In some embodiments, R.sub.1 is selected from the group
consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain
embodiments, R.sub.1 is a hydroxy or an alkoxy. In further
embodiments, R.sub.1 is selected from the group consisting of
hydroxy, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, and
tert-butoxy. In other embodiments, R.sub.1 is methoxy.
[0046] In some embodiments, each R.sub.2 and R.sub.3-R.sub.9 are
each independently selected from the group consisting of hydrogen,
alkyl, hydroxy, and alkoxy. In certain embodiments, each R.sub.2
and R.sub.3-R.sub.9 are each independently a hydrogen. In some
embodiments, R.sub.9 is selected from the group consisting of
hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments,
R.sub.9 is an alkyl. In further embodiments, R.sub.9 is selected
from the group consisting of methyl, ethyl, propyl, n-butyl,
isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In other
embodiments, R.sub.9 is n-pentyl.
[0047] In certain embodiments, the second compound is tegaserod, or
a pharmaceutically acceptable salt or prodrug thereof. In some of
these embodiments, the pharmaceutically acceptable salt of
tegaserod is selected from the group consisting of the nitrate,
lactate, succinate, sulphate, mesylate, esylate, and hydrogen
sulfate salts. However, other salts of tegaserod are also within
the scope of the present invention.
[0048] Throughout the present disclosure, when a particular
compound is mentioned by name, for example, oxybutynin,
tolterodine, pilocarpine, cevimeline, or tegaserod, it is
understood that the scope of the present disclosure encompasses
pharmaceutically acceptable salts, esters, amides, or prodrugs of
the named compound. Also, if the named compound comprises a chiral
center, the scope of the present disclosure also includes
compositions comprising the racemic mixture of the two enantiomers,
as well as compositions comprising each enantiomer individually
substantially free of the other enantiomer. Thus, for example,
contemplated herein is a composition comprising the S enantiomer
substantially free of the R enantiomer, or a composition comprising
the R enantiomer substantially free of the S enantiomer. By
"substantially free" it is meant that the composition comprises
less than 10%, or less than 8%, or less than 5%, or less than 3%,
or less than 1% of the minor enantiomer. If the named compound
comprises more than one chiral center, the scope of the present
disclosure also includes compositions comprising a mixture of the
various diastereomers, as well as compositions comprising each
diastereomer substantially free of the other diastereomers. Thus,
for example, commercially available oxybutynin is a racemic mixture
comprising two separate enantiomers. The recitation of "oxybutynin"
throughout this disclosure includes compositions that comprise the
racemic mixture of oxybutynin, the compositions that comprise the
(+) enantiomer substantially free of the (-) enantiomer, and the
compositions that comprise the (-) enantiomer substantially free of
the (+) enantiomer. Further, for example, commercially available
pilocarpine, which is a naturally occurring alkaloid, comprises two
stereocenters. The scope of the present invention includes
pharmaceutical compositions comprising all four diastereomers,
pharmaceutical compositions comprising the racemic mixture of R,R
and S,S isomers, pharmaceutical compositions comprising the racemic
mixture of R,S and S,R isomers, pharmaceutical compositions
comprising the R,R enantiomer substantially free of the other
diastereomers, pharmaceutical compositions comprising the S,S
enantiomer substantially free of the other diastereomers,
pharmaceutical compositions comprising the R,S enantiomer
substantially free of the other diastereomers, and pharmaceutical
compositions comprising the S,R enantiomer substantially free of
the other diastereomers.
[0049] In yet another aspect, the present invention relates to a
pharmaceutical composition comprising a therapeutically effective
amount of a first compound, a therapeutically effective amount of a
second compound, and a therapeutically effective amount of a third
compound, wherein the first compound is an antimuscarinic or an
anticholinergic agent, as described above, the second compound
causes stimulation of salivary glands, as described above, and the
third compound relieves constipation, as described above.
[0050] In certain embodiments, the present invention relates to a
pharmaceutical composition comprising oxybutynin and pilocarpine.
In other embodiments, the present invention relates to a
pharmaceutical composition comprising tolterodine and pilocarpine.
In yet other embodiments, the present invention relates to a
pharmaceutical composition comprising trospium and pilocarpine. In
some embodiments, the present invention relates to a pharmaceutical
composition comprising solifenacin and pilocarpine. In further
embodiments, the present invention relates to a pharmaceutical
composition comprising darifenacin and pilocarpine. In yet other
embodiments, the present invention relates to a pharmaceutical
composition comprising fesoterodine and pilocarpine. In other
embodiments, ments, the present invention relates to a
pharmaceutical composition comprising oxybutynin and cevimeline. In
other embodiments, the present invention relates to a
pharmaceutical composition comprising tolterodine and
cevimeline.
[0051] In certain embodiments disclosed herein, an individual is
given a pharmaceutical composition comprising a combination of two
or more compounds to treat overactive bladder. In some of these
embodiments, each compound is a separate chemical entity. However,
in other embodiments, the two compounds are joined together by a
chemical linkage, such as a covalent bond, so that the two
different compounds form separate parts of the same molecule. The
chemical linkage is selected such that after entry into the body,
the linkage is broken, such as by enzymatic action, acid
hydrolysis, base hydrolysis, or the like, and the two separate
compounds are then formed.
[0052] In other embodiments, the chemical linkage is selected such
that it is not broken under physiological conditions and is
impervious to enzymatic attack. In these embodiments, the two parts
of the compound remain intact in the patient's body. By "not
broken" and "impervious" it is meant that the half-life of the
chemical reaction leading to the breaking of the bond between the
two parts of the molecule is longer than the pharmacological
half-life of the joint compound, that is, the joint compound is
excreted or metabolized faster than the bond between the two parts
is broken.
[0053] Thus, in another aspect, the present invention relates to
synthetic routes to novel molecules in which oxybutynin,
tolterodine, trospium, solifenacin, and darifenacin is linked by a
flexible linker to a pilocarpine moiety or other salivary gland
stimulants.
[0054] The compounds useful for the compositions and methods
described herein may be used in various formulations. Certain
formulations affect the rate at which the compound enters the blood
stream of the patient. Thus, some formulations are immediate
release formulations while other formulations are delayed release,
sustained release, or extended release formulations.
[0055] Thus, in some embodiments, the first compound is in
immediate formulation, while in other embodiments the first
compound is in delayed release formulation, and in yet other
embodiments the first compound is in sustained release formulation,
and in further embodiments the first compound is in extended
release formulation. In some embodiments, the second compound is in
immediate release formulation, while in other embodiments the
second compound is in delayed release formulation, and in yet other
embodiments the second compound is in sustained release
formulation, and in further embodiments the second compound is in
extended release formulation. In some embodiments, the third
compound is in immediate release formulation, while in other
embodiments the third compound is in delayed release formulation,
and in yet other embodiments the third compound is in sustained
release formulation, and in further embodiments the third compound
is in extended release formulation.
[0056] The compositions described herein are particularly useful in
alleviating the major side effects in the treatment of OAB, namely
dry mouth and/or constipation, improving tolerability, and
enhancing patient compliance while increasing the patient's quality
of life.
[0057] In another aspect, the present invention relates to a method
of treating a patient comprising administering to a patient in need
thereof a therapeutically effective amount of a first compound and
a therapeutically effective amount of a second compound, wherein
the first compound is an antimuscarinic or an anticholinergic
agent, as described above, and the second compound causes
stimulation of salivary glands, as described above.
[0058] A patient in need of the treatment methods disclosed herein
may be a patient who suffers from overactive bladder. The patient
may also be one who finds current therapies for overactive bladder
uncomfortable and/or the side effects of the therapy, such as the
dry mouth or constipation, intolerable enough so as to require
adjunct therapy to alleviate the side effects. The patient may also
be one who is considering discontinuing therapy for overactive
bladder due to the side effects of the therapy. In some
embodiments, a patient who is recently diagnosed with overactive
bladder but yet has not been treated therefore is a patient in need
of the treatment methods and compositions disclosed herein. In
these embodiments, the patient begins the therapy using the methods
and combinations disclosed herein so that the patient does not
experience any of the side effects, or experience the side effects
to a lesser degree.
[0059] In some embodiments, the patient may be suffering from
overactive bladder, urge, stress, and mixed incontinence.
[0060] In some embodiments the first compound and the second
compound are administered more or less simultaneously. In other
embodiments the first compound is administered prior to the second
compound. In yet other embodiments, the first compound is
administered subsequent to the second compound.
[0061] In another aspect, the present invention relates to a method
of treating a patient comprising identifying a patient suffering
from overactive bladder, and administering to the patient a
therapeutically effective amount of a first compound and a
therapeutically effective amount of a second compound, wherein the
first compound is an antimuscarinic or an anticholinergic agent, as
described above, and second compound relieves constipation, as
described above.
[0062] In some embodiments, the patient may be suffering from
overactive bladder, urge, stress, and mixed incontinence.
[0063] In yet another aspect, the present invention relates to a
method of treating a patient comprising administering to a patient
in need thereof a therapeutically effective amount of a first
compound, a therapeutically effective amount of a second compound,
and a therapeutically effective amount of a third compound, wherein
the first compound is an antimuscarinic or an anticholinergic
agent, as described above, the second compound causes stimulation
of salivary glands, as described above, and the third compound
relieves constipation, as described above.
[0064] In some embodiments, the patient may be suffering from
overactive bladder, urge, stress, and mixed incontinence.
[0065] In some embodiments in the above methods, the first compound
and the second compound are administered more or less
simultaneously. In other embodiments the first compound is
administered prior to the second compound. In yet other
embodiments, the first compound is administered subsequent to the
second compound.
[0066] In certain embodiments in the above methods, the first
compound and the second compound are administered individually. In
other embodiments, the first compound and the second compound may
be covalently linked to each other such that they form a single
chemical entity. The single chemical entity is then digested and is
metabolized into two separate physiologically active chemical
entities, one of which is the first compound and the other one is
the second compound. Both chemical entities once metabolized exert
their therapeutic effect independently or synergistically. In
further embodiments the bond between the two parts of the compound
is not broken and each part of the joint molecule exerts its
therapeutic effect independently, without the necessity of the
cleavage of linker between the two parts.
[0067] It should be noted that simply taking commercially available
pilocarpine HCl, e.g., Salagen.RTM. tablets, or any other salivary
gland stimulants in conjunction with an OAB drug is not effective
to alleviate the dry mouth side effect. Certain effective
treatments match the pharmacokinetics profile of each salivary
gland stimulants, such as pilocarpine, cevimeline HCl, and
amifostine, with the pharmacokinetics profiles of the OAB agents,
for example oxybutynin, tolterodine, solifenacin, darifenacin,
trospium, and other approved agents or in development.
[0068] Therefore, in certain embodiments in the above methods, the
first and second compounds are administered such that the peak
plasma concentration for the first compound occurs at nearly the
same time after administration as the peak plasma concentration for
the second compound. Thus, the two compounds may be administered
simultaneously, but be formulated such that the delay in their
release causes the two peak plasma concentrations to occur at
nearly the same time. In other embodiments, one compound is
administered at a time interval after the other compound in order
to ensure that the peak plasma concentrations occur at nearly the
same time.
[0069] In other embodiments in the above methods, the first and
second compounds are administered such that the time point at which
the lowest saliva flow occurs because of the action of the first
compound nearly corresponds to the time point at which the highest
saliva flow occurs because of the action of the second compound.
Thus, the two compounds may be administered simultaneously, but be
formulated such that the delay in their release causes the peak
saliva flow time point for the second compound to occur at nearly
the same time as the lowest saliva flow time point for the first
compound. In other embodiments, one compound is administered at a
time interval after the other compound in order to ensure that peak
and trough saliva flow time points match.
[0070] In some embodiments in the above methods, the first and
second compounds are administered such that the ratio of their
plasma concentrations, at a given point in point following their
administration, is a predetermined value. Those of ordinary skill
in the art recognize that the ratio of plasma concentrations is not
necessarily the same as the ratio of the amount of compound
administered. Compounds are digested differently in the gut, pass
the gut wall differently, and have a different rate of first-pass
metabolism in the liver. Furthermore, the clearance rate by the
kidney is different for various compounds. Thus, for example, even
if two compounds are administered in equivalent molar amounts,
their plasma concentrations at a point in time after the
administration may be significantly different. The methods
disclosed herein take into account the pharmacokinetics of drug
intake and metabolism, such that the ratio of the two compounds at
the time of administration is adjusted so that the two compounds
would have a predetermined concentration ratio in the plasma.
[0071] In yet other embodiments in the above methods, the first and
second compounds are administered such that the time point for the
maximum therapeutic effect of the compound that stimulates saliva
flow matches the time point for the maximum side effect of the OAB
therapeutic compound. Thus, the two compounds may be administered
simultaneously, but be formulated such that the delay in their
release causes the maximum therapeutic effect of the second
compound to occur at nearly the same time as the maximum side
effect of the first compound. In other embodiments, one compound is
administered at a time interval after the other compound in order
to ensure that the maximum therapeutic effect of the second
compound to occur at nearly the same time as the maximum side
effect of the first compound.
[0072] In some embodiments the dosage form is designed as sustained
release of one agent combined with either sustained release or
immediate release of the second agent to ensure that the peak
plasma concentrations occur at nearly the same time. Further the
dosage from can be designed based on the pharmacokinetics profiles
where the peak plasma concentration of one compound, for example
the salivary gland stimulant agent, e.g., pilocarpine, corresponds
to maximum amount of mouth dryness caused by the OAB drug, for
example oxybutynin.
[0073] Thus, some of the pharmaceutical compositions contemplated
for use in the methods disclosed herein include, but are not
limited to:
[0074] immediate release oxybutynin, tolterodine, solifenacin,
darifenacin, trospium, or fesoterodine, in combination with
pilocarpine and tegaserod;
[0075] delayed (whether sustained or extended) release oxybutynin
and delayed (whether sustained or extended) release
pilocarpine;
[0076] delayed (whether sustained or extended) release oxybutynin
and delayed (whether sustained or extended) release pilocarpine and
sustained release tegaserod;
[0077] immediate release oxybutynin, tolterodine, solifenacin,
darifenacin, trospium, or fesoterodine, and delayed (whether
sustained or extended) formulation of pilocarpine and
tegaserod;
[0078] delayed (whether sustained or extended) release oxybutynin,
tolterodine, solifenacin, darifenacin, trospium, or fesoterodine,
and delayed (whether sustained or extended) release of pilocarpine
and sustained release tegaserod;
[0079] delayed (whether sustained or extended) release oxybutynin,
tolterodine, solifenacin, darifenacin, trospium, or fesoterodine,
and delayed (whether sustained or extended) formulation of
pilocarpine and immediate release formulation of tegaserod.
[0080] Without being bound by a particular theory, the improved
treatment disclosed here of OAB in addressing the dry mouth and
constipation is based on a mechanistic approach working at the
receptor level, i.e., the adverse effect of these M2/M3 muscarinic
antagonists is counteracted or negated with cholinergic agents that
work in the opposite direction but in concert with the intended
therapy.
[0081] Besides reducing the adverse side effects experienced by
those being treated for overactive bladder, the methods and
compositions disclosed herein have additional advantages.
Currently, the dose of treatment drugs, such as oxybutynin, is
limited because of the side effects. Some patients who suffer from
overactive bladder cannot tolerate dosages that provide adequate
therapy because of the adverse side effects, e.g., dry mouth. These
patients continue to suffer from overactive bladder even though
they take their medications, solely because the medication is not
administered at an effective dose. By lowering the side effects
using the methods and compositions disclosed herein, the patient
can be prescribed to take treatment drugs, such as oxybutynin, at
higher doses. These higher doses result in having a less active
bladder and also result in an increase in intrinsic bladder
capacity.
[0082] Thus, in another aspect, the present invention relates to a
method of increasing intrinsic bladder capacity, comprising
administering to a patient in need thereof a therapeutically
effective amount of a first compound and a therapeutically
effective amount of a second compound, wherein the first compound
is an antimuscarinic or an anticholinergic agent, as described
above, and the second compound causes stimulation of salivary
glands, as described above.
[0083] In another aspect, the present invention relates to a method
of increasing intrinsic bladder capacity, comprising administering
to a patient in need thereof a therapeutically effective amount of
a first compound and a therapeutically effective amount of a second
compound, wherein the first compound is an antimuscarinic or an
anticholinergic agent, as described above, and the second compound
relieves constipation, as described above.
[0084] In another aspect, the present invention relates to a method
of increasing intrinsic bladder capacity, comprising administering
to a patient in need thereof a therapeutically effective amount of
a first compound, a therapeutically effective amount of a second
compound, and a therapeutically effective amount of a third
compound, wherein the first compound is an antimuscarinic or an
anticholinergic agent, as described above, the second compound
causes stimulation of salivary glands, as described above, and the
third compound relieves constipation, as described above.
[0085] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of:
[0086] an antimuscarinic or an anticholinergic agent, as described
herein, and a compound that causes stimulation of salivary glands,
as described herein;
[0087] an antimuscarinic or an anticholinergic agent, as described
herein, and a compound that relieves constipation, as described
herein; or
[0088] an antimuscarinic or an anticholinergic agent, as described
herein, a compound that causes stimulation of salivary glands, as
described herein, and a compound that relieves constipation, as
described herein; and
[0089] a physiologically acceptable carrier, diluent, or excipient,
or a combination thereof.
[0090] The term "pharmaceutical composition" refers to a mixture of
a compound of the invention with other chemical components, such as
diluents, lubricants, bulking agents, desentegrant or carriers. The
pharmaceutical composition facilitates administration of the
compound to an organism. Multiple techniques of administering a
compound exist in the art including, but not limited to, oral,
injection, inhalation, aerosol, parenteral, and topical
administration. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like.
[0091] The term "carrier" defines a chemical compound that
facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized
carrier as it facilitates the uptake of many organic compounds into
the cells or tissues of an organism.
[0092] The term "diluent" defines chemical compounds diluted in
water that will dissolve the compound of interest as well as
stabilize the biologically active form of the compound. Salts
dissolved in buffered solutions are utilized as diluents in the
art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low
concentrations, a buffered diluent rarely modifies the biological
activity of a compound.
[0093] In certain embodiments, the same substance can act as a
carrier, diluent, or excipient, or have any of the two roles, or
have all three roles. Thus, a single additive to the pharmaceutical
composition can have multiple functions.
[0094] The term "physiologically acceptable" defines a carrier or
diluent that does not abrogate the biological activity and
properties of the compound.
[0095] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or suitable carriers or excipient(s).
Techniques for formulation and administration of the compounds of
the instant application may be found in "Remington's Pharmaceutical
Sciences," Mack Publishing Co., Easton, Pa., 18th edition,
1990.
[0096] Suitable routes of administration may, for example, include
oral, transdermal, rectal, transmucosal, or intestinal
administration; parenteral delivery, including intramuscular,
subcutaneous, intravenous, intramedullary injections, as well as
inhalation, intrathecal, direct intraventricular, intraperitoneal,
intranasal, or intraocular injections.
[0097] Alternately, one may administer the compound in a local
rather than systemic manner, for example, via injection of the
compound directly in the renal or cardiac area, often in a depot or
sustained, extended, or delayed release formulation. In addition,
one may administer the composition by transdermal approach.
[0098] The pharmaceutical compositions of the present invention may
be manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0099] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen and desired pharmacokinetics profiles of each
component of combination therapy. Any of the well-known techniques,
carriers, and excipients may be used as suitable and as understood
in the art; e.g., in Remington's Pharmaceutical Sciences,
above.
[0100] For injection, the agents of the invention may be formulated
in aqueous solutions, preferably in physiologically compatible
buffers such as Hanks's solution, Ringer's solution, or
physiological saline buffer. For transmucosal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the
art.
[0101] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by mixing
one or more solid excipient with pharmaceutical combination of the
invention, optionally grinding the resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as sugars,
including lactose, sucrose, mannitol, or sorbitol; cellulose
preparations such as, for example, maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinylpyrrolidone (PVP). If desired, disintegrating
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0102] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0103] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0104] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0105] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas.
[0106] Many of the compounds used in the pharmaceutical
combinations of the invention may be provided as salts with
pharmaceutically compatible counterions. Pharmaceutically
compatible salts may be formed with many acids, including but not
limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic,
succinic, and the like. Salts tend to be more soluble in aqueous or
other protonic solvents than are the corresponding free acids or
base forms.
[0107] Pharmaceutical compositions suitable for use in the present
invention include compositions where the active ingredients are
contained in an amount effective to achieve its intended purpose.
More specifically, a therapeutically effective amount means an
amount of compound effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated.
[0108] Typically, the dose range of the composition administered to
the patient can be from about 0.5 to 1000 mg/kg of the patient's
body weight. The dosage may be a single one or a series of two or
more given in the course of one or more days, as is needed by the
patient. Note that for almost all of the specific compounds
mentioned in the present disclosure, human dosages for treatment of
at least some condition have been established. For example, for
oxybutynin, tolterodine, solifenacin, darifenacin, trospium,
fesoterodine the preferred dosage is between 0.1 mg to 50 mg, and
the more preferred dosage is between 1 mg to 30 mg. Other dose
ranges include between 10 to 50 mg, between 20 to 50 mg, between 30
to 50 mg, between 40 to 50 mg, between 20 to 40 mg, between 10 to
20 mg, between 10 to 30 mg, between 20 to 30 mg, and between 30 to
40 mg. The dose may also be at 10 mg, 20 mg, 30 mg, 40 mg, or 50
mg. For pilocarpine, the preferred dosage is between 0.1 mg to 50
mg, and the more preferred dosage is between 1 mg to 30 mg. Other
dose ranges include between 10 to 50 mg, between 20 to 50 mg,
between 30 to 50 mg, between 40 to 50 mg, between 20 to 40 mg, and
between 30 to 40 mg. The dose may also be at 10 mg, 20 mg, 30 mg,
40 mg, or 50 mg. For tegaserod, the preferred dosage is between
0.05 mg to 50 mg, and the more preferred dosage is between 0.5 mg
to 2 mg. Other dose ranges include between 10 to 50 mg, between 20
to 50 mg, between 30 to 50 mg, between 40 to 50 mg, between 20 to
40 mg, between 30 to 40 mg, between 0.5 to 1 mg, and between 1 to 2
mg. The dose may also be at 0.5 mg, 1 mg, 1.5 mg, and 2 mg.
[0109] Although the exact dosage can be determined on a
drug-by-drug basis, in most cases, some generalizations regarding
the dosage can be made. The daily dosage regimen for an adult human
patient may be, for example, an oral dose of between 0.001 mg and
1000 mg of each ingredient, preferably between 0.01 mg and 500 mg,
for example 1 to 200 mg or each ingredient of the pharmaceutical
compositions of the present invention or a pharmaceutically
acceptable salt thereof calculated as the free base or free acid,
the composition being administered 1 to 4 times per day or per
week. Alternatively the compositions of the invention may be
administered by continuous such as sustained, delayed, or extended
release, preferably at a dose of each ingredient up to 500 mg per
day. Thus, the total daily dosage by oral administration of each
ingredient will typically be in the range 0.1 mg to 2000 mg.
Suitably the compounds will be administered for a period of
continuous therapy, for example for a day, a week or more, or for
months or years.
[0110] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0111] The amount of composition administered will, of course, be
dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0112] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present invention. Therefore, it should be
clearly understood that the forms of the present invention are
illustrative only and are not intended to limit the scope of the
present invention.
EXAMPLES
[0113] The examples below are non-limiting and are merely
representative of various aspects of the invention.
Example 1
Combination of an OAB Drug and a Salivary Gland Stimulant for the
Treatment of Individual with Overactive Bladder
[0114] An individual with overactive bladder is identified. The
individual is given 5 mg of oxybutynin two to four times a day in
addition to 5 mg of pilocarpine two or three times a day. If the
individual continues to complain about dry mouth, the dose of
pilocarpine is increased to 10 mg two or three times a day. The
dose can be increased up to 20 mg, or 50 mg, if needed. Each dose
of oxybutynin can be increased to 10, 15, 20, or 30 mg.
Example 2
Combination of an OAB Drug and a Tegaserod for the Treatment of
Individual with Overactive Bladder
[0115] An individual with overactive bladder is identified. The
individual is given 5 mg of oxybutynin two to four times a day in
addition to 2 mg of tegaserod twice a day. If the individual
continues to complain about constipation, the dose of tegaserod is
increased to 6 mg twice a day. The dose can be increased up to 12
mg, 20 mg, or 50 mg, if needed. The dose of oxybutynin can be
increased to 10, 15, 20, or 30 mg.
Example 3
Clinical Study Protocol Synopsis
[0116] A study is conducted to evaluate the effect of oxybutynin
and pilocarpine, alone and in combination versus placebo on
salivary output in healthy volunteers. The objectives of the study
are to determine salivary flow and degree of dry mouth after oral
administration of oxybutynin and pilocarpine, alone and in
combination, vs. placebo, and to determine the effect of oxybutynin
and pilocarpine, alone and in combination, on urine volume/void and
vital signs.
[0117] At each treatment period, following an overnight fast,
subjects enter the clinic and after baseline measurements have been
made, they are randomized to one of four medications
[0118] Oxybutynin (5 mg) followed 30 minutes later by placebo
[0119] Pilocarpine (5 mg) followed 30 minutes later by placebo
[0120] Placebo followed 30 minutes later by placebo
[0121] Oxybutynin (5 mg) followed 30 minutes by pilocarpine (5
mg)
[0122] The following measurements are made just prior to and at
frequent intervals for up to 6 hours post dose: [0123] Salivary
flow is determined by chewing Parafilm for 2 minutes [0124] Dry
mouth is determined by VAS [0125] Urine volume/void and frequency
over 6 hours post dose is measured [0126] Blood samples are taken
for pharmacokinetics at pre-dose, and at 0.5, 1, 2, 3, 4, and 6
hours post dose [0127] Food and water intake are standardized over
the 6 hour period
[0128] The study is a double blind, randomized, placebo-controlled,
with 4 sequences (4 doses over 4 weeks) with the drugs being
administered orally as a single dose. There is a One-week washout
between study days. The study population is chosen as follows:
[0129] Healthy volunteers [0130] 12 subjects [0131] .gtoreq.18
years males or non-pregnant females [0132] Weight 18-28 BMI [0133]
No known allergy to antimuscarinic agents [0134] No previous
history of glaucoma, urinary retention, cardiac arrhythmias [0135]
No OTC medications, nutriceuticals or vitamins within 10 days of
study enrollment and throughout the study
[0136] Assessments (except for urine output) is performed at: 0.5
hr and within 10 minutes pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,
4.5, 5, and 6 hours post dose. The following are assessed:
[0137] 1) Stimulated salivary flow
[0138] 2) Dry mouth (VAS)
[0139] 3) Urine volume/void over 6 hours post dose
[0140] 4) Pharmacokinetics of oxybutynin and pilocarpine
[0141] The standard safety precautions, such as physical exam,
medical history, con-meds, ECG, hematology, clinical chemistry,
urinalysis performed at screening and study termination, urine
drug/alcohol screening at pre-dose for each period, vital signs (HR
and BP) at: pre-dose, and at 30 min intervals for 6 hours, and an
awareness of adverse events throughout and between study period,
are taken.
Example 4
Case Study for a Combination of Oxybutynin and Pilocarpine
[0142] In this study, the effect of oxybutynin, pilocarpine, the
combination of the two, and placebo was measured in six separate,
yet identical, studies in a single individual.
[0143] Effect of Oxybutynin--A healthy human subject was given a 5
mg dose of oxybutynin HCl and the amount of salivation was measured
with time over an 8 hour period. As shown in FIG. 1
(.diamond-solid., diamond), the amount of saliva flow collected
over 2 minutes periods decreased after dosing of oxybutynin and the
saliva flow remained low after 3 hrs. The amount of saliva flow
started increasing after 3 hrs and continued increasing reaching
the pre-dose level after 8 hrs post-dosing. The data generated in
this study is consistent with the literature data.
[0144] Effect of Pilocarpine--In a separate human study the effect
of pilocarpine HCl was evaluated in a healthy human subject to
ensure that pilocarpine indeed increases salivary gland flow. This
was demonstrated as shown in FIG. 1 (.box-solid., square). The
amount of saliva collected over 2 minute periods increased sharply
after dosing and the saliva flow started decreasing after the peak
observed at half an hour. The decrease in saliva flow continued
until it reached about the normal saliva flow and pre-dosing level
after about 5 hrs.
[0145] Effect of Placebo--In the third leg of the human study, the
effect of placebo was evaluated. Since this was an unblinded trial,
the salivary flow was measured by not taking any medication or a
true placebo but the same protocol was followed as in the other
studies. As shown in the FIG. 1 (.tangle-solidup., triangle), the
variation in salivary flow with time is minimal and the average
salivary flow is about 2 g/2 min, consistent with the published
literature.
[0146] Effect of Combination of Oxybutynin and Pilocarpine--In a
separate human study, the combination of oxybutynin and pilocarpine
was administered to a healthy human subject. To the subject 5 mg of
oxybutynin followed by 5 mg of pilocarpine after 30 min of dosing
was administered. Saliva flow was measured as before. Results are
shown in FIG. 1 ( , circle).
[0147] As shown in FIG. 1, the decreased in salivary flow caused by
oxybutynin was compensated well by the increase in salivary flow
induced by pilocarpine. As a result, the amount of salivary flow
remained about the same as the pre-dose level. FIG. 1 further shows
that the amount of salivary flow measured for the combination study
was similar to that of the placebo study. Therefore, administration
of 5 mg pilocarpine at half hour after the administration of 5 mg
of oxybutynin completely neutralized the adverse side effect of
oxybutynin.
[0148] The percentage of saliva flow deviation from baseline
following administration of pilocarpine, oxybutynin, combination of
pilocarpine and oxybutynin (with pilocarpine administered 30 min
after oxybutynin), and placebo were plotted against time and are
shown in FIG. 2. The percent deviation for the combination study,
where pilocarpine was administered 30 min after oxybutynin, ( ,
circle) is minimal and not significantly different from the
baseline or the placebo (.tangle-solidup., triangle) suggesting
that the combination approach eliminates the major side effect of
OAB therapy.
[0149] Effect of Timing of the Administration of Pilocarpine with
Respect to the Administration of Oxybutynin--In two additional
human studies, the effect of the timing of administration of
pilocarpine was measured. In one study, the combination of
oxybutynin and pilocarpine was administered to a healthy human
subject. To the subject 5 mg of oxybutynin and 5 mg of pilocarpine
were administered simultaneously. Saliva flow was measured as
before. Results are shown in FIG. 3 (.box-solid., square). In the
last study, the combination of oxybutynin and pilocarpine was
administered to a healthy human subject. To the subject 5 mg of
oxybutynin followed by 5 mg of pilocarpine after 60 min of dosing
was administered. Saliva flow was measured as before. Results are
shown in FIG. 3 (.diamond-solid., diamond).
[0150] FIG. 3 shows the effect of time delay for the administration
of pilocarpine. All studies are compared to placebo
(.tangle-solidup., triangle). When oxybutynin and pilocarpine are
administered at the same time (.box-solid., square), there is an
initial large increase in saliva flow, which reaches a maximum at
about t=30 min to less than about t=60 min, but then drops to
normal (placebo) levels at about t=1 hr and stays at this level.
When pilocarpine is administered 60 minutes after oxybutynin
(.diamond-solid., diamond), there is a precipitous drop in saliva
flow which last until about t=1 hr, after which there is a large
increase in saliva flow, with a maximum occurring at about t=3 hrs.
The saliva flow returns to normal (placebo) at about t=5 hrs.
However, when pilocarpine is administered 30 minutes after
oxybutynin ( , circle), there is a small drop in saliva flow with a
minimum at about t=30 min, but it returns to normal (placebo)
within one hour.
[0151] Effect of Dose Ratio Between Oxybutynin and Pilocarpine--In
this experiment the results of two separate dose ratios between
oxybutynin and pilocarpine were compared with the results of
placebo and administration of oxybutynin alone. In one experiment,
5 mg of oxybutynin was administered to a healthy individual and
saliva flow was measured for 8 hours. The results are shown in FIG.
4 (.diamond-solid., diamond). Using a similar protocol, 5 mg of
oxybutynin was administered to a healthy individual at t=0,
followed by 5 mg of pilocarpine at t=30 min. The results are shown
in FIG. 4 ( , circle). Similarly, 10 mg of oxybutynin was
administered to a healthy individual at t=0, followed by 5 mg of
pilocarpine at t=30 min. The results are shown in FIG. 4 (-, dash).
Finally, the results were compared with the administration of
placebo (FIG. 4 (.tangle-solidup., triangle)).
[0152] The results shown in FIG. 4 suggest that increasing
oxybutynin from 5 to 10 mg lead to decrease in salivation. The
increase in ratio from 1:1 to 2:1 perturbs the balance between the
decreased salivation by oxybutynin and increased salivation by
pilocarpine, respectively. It is noted that the saliva flow for the
2:1 oxybutynin:pilocarpine ratio is similar to that of the 5 mg
oxybutynin alone, suggesting that the amount of 5 mg pilocarpine in
this experiment is not sufficient to compensate the decrease in
saliva flow caused by the increase in amount of oxybutynin from 5
to 10 mg. Therefore, an effective dose ratio for the combination
oxybutynin and pilocarpine is when 5 mg of each is administered to
a patient.
[0153] Plasma Concentration of Oxybutynin--In a separate study, the
plasma concentration of oxybutynin was measured in two groups of
subjects: one group received 5 mg of oxybutynin alone and another
group received 5 mg of oxybutynin followed by 5 mg pilocarpine
after 30 min. The plasma concentrations were measured before the
administration of oxybutynin and in hours 1, 2, 3, 4, and 6 after
its administration. The results are shown in Tables 1 and 2, below.
Table 1 shows the plasma levels of oxybutynin after the
administration of 5 mg of oxybutynin alone in a placebo controlled,
blinded, four way crossover clinical trial in 12 male subjects.
Table 2 presents the plasma levels of oxybutynin after the
administration of 5 mg of oxybutynin followed by the administration
of 5 mg of pilocarpine 30 min after the administration of
oxybutynin in a placebo controlled, blinded, four way crossover
clinical trial in 12 male subjects.
TABLE-US-00001 TABLE 1 Plasma Level of Oxybutynin (ng/mL) Time
(Hour) After Oxybutynin Administration Subject Number 0 1 2 3 4 6 1
0.000 0.980 1.760 1.620 0.869 0.786 2 0.000 5.380 2.910 2.410 1.490
1.150 3 0.000 9.840 3.870 2.320 1.840 1.150 4 0.120 3.250 1.990
1.270 1.070 0.783 5 0.020 16.000 9.260 3.920 4.690 1.900 6 0.000
2.600 1.400 1.230 1.140 1.330 7 0.000 15.420 6.110 2.700 2.390
0.650 8 0.000 7.600 2.890 1.530 0.010 0.000 9 0.000 3.910 2.580
0.440 0.210 0.190 10 0.000 7.230 3.120 1.330 0.880 0.190 11 0.000
4.900 1.820 0.970 0.340 0.560 12 0.000 3.200 1.520 0.790 0.230
0.000 Mean 0.012 6.693 3.269 1.711 1.263 0.724 STD 0.034597
4.861029 2.289476 0.969634 1.291618 0.585548
TABLE-US-00002 TABLE 2 Plasma Level of Oxybutynin (ng/mL) Time
(Hour) After Oxybutynin Administration Subject Number 0 1 2 3 4 6 1
0.000 1.830 1.380 0.980 0.977 0.740 2 0.000 5.260 2.490 1.220 1.820
1.100 3 0.000 1.720 2.120 6.920 5.150 3.100 4 0.020 3.080 2.790
2.230 1.460 0.150 5 0.000 14.600 6.580 2.550 5.010 1.580 6 0.000
2.750 1.690 1.280 1.020 0.000 7 0.000 20.800 11.100 5.310 3.060
2.110 8 0.000 1.180 0.470 0.230 0.270 0.000 9 0.000 8.580 2.920
1.410 0.940 0.550 10 0.000 9.200 3.650 1.870 1.110 0.340 11 0.000
7.490 1.710 1.340 0.600 0.680 12 0.000 3.480 1.520 0.930 0.560
0.260 Mean 0.001538 6.228462 3.109231 2.251538 1.998231 1.277692
STD 0 5.967714 2.92391 1.961773 1.67978 0.948956
[0154] As can be seen from the tables, in both groups, the plasma
concentration of oxybutynin reaches a maximum at about an hour,
followed by a gradual decline. Moreover, the plasma concentration
of oxybutynin follows the same curve for both groups. Therefore,
addition of 5 mg of pilocarpine does not affect the plasma
concentration of oxybutynin at all. Two conclusions follow from
this observation. First, pilocarpine does not affect the absorption
of oxybutynin in the gut, nor does it affect the first-pass
metabolism of pilocarpine in the liver. Second, pilocarpine does
not affect the binding ability of oxybutynin, since the
concentration of free oxybutynin in the plasma remains the same
between the two groups. Further, the presence of pilocarpine in the
combination does not interfere with the pharmacokinetics of
oxybutynin. Thus, the antimuscarinic activity of oxybutynin
responsible for therapeutic effect of oxybutynin on OAB remains
unaffected.
Example 5
Case Study for a Combination of Oxybutynin and Cevimeline
[0155] In this study, the effect of oxybutynin, cevimeline, the
combination of the two, and placebo was measured in separate
studies in a single individual.
[0156] Effect of Oxybutynin--A healthy human subject was given a 5
mg dose of oxybutynin HCl and the amount of salivation was measured
with time over an 8 hour period. As shown in FIG. 5 ( , circle),
the amount of saliva flow collected over 2 minutes periods
decreased after dosing and the saliva flow remained low after 3
hrs. The amount of saliva flow started increasing after 3 hrs and
continued increasing reaching the pre-dose level after 8 hrs
post-dosing. The data generated in this study is consistent with
the literature data.
[0157] Effect of Cevimeline--In a separate human study the effect
of administering 30 mg of cevimeline was evaluated in a healthy
human subject to ensure that cevimeline indeed increases salivary
gland flow. This was demonstrated as shown in FIG. 5
(.diamond-solid., diamond). The amount of saliva collected over 2
minute periods increased sharply after dosing and the saliva flow
started decreasing after the peak observed at close to two hours.
The decrease in saliva flow continued until it reached about the
normal saliva flow and pre-dosing level after about 6 hrs.
[0158] Effect of Placebo--In the third leg of the human study, the
effect of placebo was evaluated. Since this was an unblinded trial,
the salivary flow was measured by not taking any medication or a
true placebo but the same protocol was followed as in the other
studies. As shown in the FIG. 5 (.tangle-solidup., triangle), the
variation in salivary flow with time is minimal and the average
salivary flow is about 2.5 g/2 min, consistent with the published
literature.
[0159] Effect of Combination of Oxybutynin and Cevimeline--In a
separate human study, the combination of oxybutynin and cevimeline
was administered to a healthy human subject. To the subject 5 mg of
oxybutynin followed simultaneously by 30 mg of cevimeline, with no
time delay, was administered. Saliva flow was measured as before.
Results are shown in FIG. 5 (.box-solid., square), where the
combination is referred to as THVD-102.
[0160] The results of the above experiments are also shown in the
Table 3, below, which shows the data for the evaluation of the
combination of oxybutynin and cevimeline on stimulated salivary
flow. FIG. 5 is a graphic illustration of the data set forth in
Table 3.
TABLE-US-00003 TABLE 3 Agent Cevimeline Cev + Oxy Oxybutynin
Placebo Oxybutynin, mg 0 5 5 0 Cevimeline, mg 30 30 0 0 Amount of
Saliva Amount of Saliva Time (hr) Collecetd over 2 min Collecetd
over 2 min -0.17 2.4808 2.862 2.2208 1.7143 0 2.6273 2.9442 2.4536
1.4786 0.5 2.7791 2.3742 1.8558 1.959 1 4.1213 2.4091 1.2308 2.0143
1.5 4.6029 3.0437 1.2326 1.9861 2 3.7314 2.2793 1.3548 2.0671 2.5
3.7641 2.4445 n/d* n/d 3 3.5888 2.0601 1.1829 1.6538 3.5 3.9316
2.5827 n/d n/d 4 3.5914 2.4358 1.5868 1.9866 5 2.6099 2.312 2.1475
1.8417 6 2.205 2.4915 2.0096 2.3332 8 1.7973 2.4158 2.3028 2.0182
*Not determined
[0161] As shown in FIG. 5, the decreased in salivary flow caused by
oxybutynin was compensated well by the increase in salivary flow
induced by cevimeline. As a result, the amount of salivary flow
remained about the same as the pre-dose level. FIG. 5 further shows
that the amount of salivary flow measured for the combination study
was similar to that of the placebo study. Therefore, administration
of 30 mg cevimeline simultaneously with the administration of 5 mg
of oxybutynin completely neutralized the adverse side effect of
oxybutynin.
Example 6
Case Study for a Combination of Tolterodine and Pilocarpine
[0162] In this study, the effect of tolterodine, pilocarpine, the
combination of the two, and placebo was measured in separate, yet
identical, studies in a single individual.
[0163] Effect of Tolterodine--A healthy human subject was given a 2
mg dose of tolterodine tartrate and the amount of salivation was
measured with time over an 8 hour period. As shown in FIGS. 6 and 7
(.diamond-solid., diamond), the amount of saliva flow collected
over 2 minute periods decreased after dosing and the saliva flow
remained low after 3 hrs. The amount of saliva flow started
increasing after about 4 hrs and continued increasing, but did not
completely reach the pre-dose levels even after 8 hrs
post-dosing.
[0164] Effect of Pilocarpine--The effect of the administration of
pilocarpine individually has been studied and the data is shown
above.
[0165] Effect of Placebo--In another leg of the human study, the
effect of placebo was evaluated. Since this was an unblinded trial,
the salivary flow was measured by not taking any medication or a
true placebo but the same protocol was followed as in the other
studies. As shown in the FIGS. 6 and 7 ( , closed circle), the
variation in salivary flow with time is minimal and the average
salivary flow is about 2.5 g/2 min, consistent with the published
literature.
[0166] Effect of Dose Ratio Between Tolterodine and Pilocarpine--In
this experiment the results of two separate dose ratios between
tolterodine and pilocarpine were compared with the results of
placebo and administration of tolterodine alone. In one experiment,
2 mg of tolterodine was administered to a healthy individual and
saliva flow was measured for 8 hours. The results are shown in FIG.
6 (.diamond-solid., diamond). Using a similar protocol, 2 mg of
tolterodine was administered to a healthy individual at t=0,
followed by 5 mg of pilocarpine at t=30 min. The results are shown
in FIG. 6 (.tangle-solidup., closed triangle). Similarly, 2 mg of
tolterodine was administered to a healthy individual at t=0,
followed by 10 mg of pilocarpine at t=30 min. The results are shown
in FIG. 6 ( , open circle). Finally, the results were compared with
the administration of placebo (FIG. 6 (e, closed circle)). The
results shown in FIG. 6 suggest that increasing pilocarpine from 5
to 10 mg lead to increase in salivation. The decrease in ratio from
2:5 to 2:10 (tolterodine:pilocarpine) restores the balance between
the decreased salivation by tolterodine and increased salivation by
pilocarpine, respectively. It is noted that the saliva flow for the
2:5 tolterodine:pilocarpine ratio is similar to that of the 2 mg
tolterodine alone, suggesting that the amount of 5 mg pilocarpine
in this experiment is not sufficient to compensate the decrease in
saliva flow caused by 2 mg of tolterodine. Therefore, an effective
dose ratio for the combination oxybutynin and pilocarpine is when 2
mg of tolterodine is combined with 10 mg of pilocarpine.
[0167] Effect of Combination of Tolterodine and Pilocarpine--In a
separate human study, the combination of tolterodine and
pilocarpine was administered to a healthy human subject. To the
subject 2 mg of tolterodine followed by 10 mg of pilocarpine were
administered with various delays in the administration of
pilocarpine. Saliva flow was measured as before. Results are shown
in FIG. 7.
[0168] In one study, 10 mg of pilocarpine was administered to the
subject 15 minutes after the administration of 2 mg of tolterodine.
Saliva flow was measured as before. Results are shown in FIG. 7
(.DELTA., open triangle). In another study, 10 mg of pilocarpine
was administered to the subject 22 minutes after the administration
of 2 mg of tolterodine. Saliva flow was measured as before. Results
are shown in FIG. 7 (.quadrature., open square). In the last study,
10 mg of pilocarpine was administered to the subject 30 minutes
after the administration of 2 mg of tolterodine. Saliva flow was
measured as before. Results are shown in FIG. 7 (.smallcircle.,
open circle).
[0169] As shown in FIG. 7, the decreased in salivary flow caused by
tolterodine was compensated well by the increase in salivary flow
induced by pilocarpine. As a result, the amount of salivary flow
remained about the same as the pre-dose level, when pilocarpine was
administered 22 minutes after the administration of tolterodine.
FIG. 7 further shows that the amount of salivary flow measured for
the combination study, with a 22 min delay for pilocarpine, was
similar to that of the placebo study. Therefore, administration of
10 mg pilocarpine at 22 minutes after the administration of 2 mg of
tolterodine completely neutralized the adverse side effect of
oxybutynin.
[0170] Considering that the high doses are not tolerated because of
the severity of the dry mouth, the disclosed approach allows
administration of higher doses of oxybutynin, tolterodine,
solifenacin, darifenacin, trospium, fesoterodine, and other
approved or compounds in development, thus leading to a more
tolerable, effective, and economical treatment.
* * * * *