U.S. patent application number 10/962729 was filed with the patent office on 2005-03-03 for use of methylnaltrexone and related compounds.
Invention is credited to Drell, William, Foss, Joseph F., Moss, Jonathan, Roizen, Michael F., Yuan, Chun-Su.
Application Number | 20050048117 10/962729 |
Document ID | / |
Family ID | 26818669 |
Filed Date | 2005-03-03 |
United States Patent
Application |
20050048117 |
Kind Code |
A1 |
Foss, Joseph F. ; et
al. |
March 3, 2005 |
Use of methylnaltrexone and related compounds
Abstract
A composition for preventing or treating the opioid induced side
effect, inhibition of gastrointestinal motility is disclosed. The
composition comprises methylnaltrexone or another quaternary
derivative of noroxymorphone administered to a patient prior to the
administration of an opioid or after the onset of side effects
induced by the administration of an opioid, wherein the
methylnaltrexone or quaternary derivative is administered orally in
an enterically coated form.
Inventors: |
Foss, Joseph F.; (Chicago,
IL) ; Roizen, Michael F.; (Chicago, IL) ;
Moss, Jonathan; (Chicago, IL) ; Yuan, Chun-Su;
(Chicago, IL) ; Drell, William; (San Diego,
CA) |
Correspondence
Address: |
Edward R. Gates
Wolf, Greenfield & Sacks, P.C.
600 Atlantic Avenue
Boston
MA
02210-2206
US
|
Family ID: |
26818669 |
Appl. No.: |
10/962729 |
Filed: |
October 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10962729 |
Oct 12, 2004 |
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10278630 |
Oct 23, 2002 |
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10278630 |
Oct 23, 2002 |
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09862169 |
May 21, 2001 |
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6608075 |
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09862169 |
May 21, 2001 |
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09120703 |
Jul 22, 1998 |
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6274591 |
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09120703 |
Jul 22, 1998 |
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08962742 |
Nov 3, 1997 |
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5972954 |
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Current U.S.
Class: |
424/471 ;
424/472; 514/282 |
Current CPC
Class: |
A61K 31/485 20130101;
A61P 1/00 20180101 |
Class at
Publication: |
424/471 ;
424/472; 514/282 |
International
Class: |
A61K 009/24; A61K
031/485 |
Claims
We claim:
1. A composition for preventing or treating opioid induced
inhibition of gastrointestinal motility comprising an enterically
coated quaternary derivative of noroxymorphone.
2. The composition of claim 1 in the form of a pill, tablet,
capsule or granules.
3. The composition of claim 1, wherein the quaternary derivative of
noroxymorphone is methylnaltrexone.
4. The composition of claim 1, wherein the enteric coating is a
methacrylic acid copolymer coating.
5. The composition of claim 4, wherein the methacrylic acid
copolymer coating is Eudragit L100, Eudragit S100, or any
combination thereof.
6. The composition of claim 5, wherein the quaternary derivative of
noroxymorphone is methylnaltrexone.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
10/278,630, filed Oct. 23, 2002; which is a divisional of
application Ser. No. 09/862,169, filed May 21, 2001 (herein
incorporated by reference) now U.S. Pat. No. 6,608,075; which is a
continuation of application Ser. No. 09/120,703, filed Jul. 22,
1998 (herein incorporated by reference) now U.S. Pat. No.
6,274,591; which is a continuation-in-part of application Ser. No.
08/962,742, filed Nov. 3, 1997, now U.S. Pat. No. 5,972,954 the
disclosures of which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention is directed at the treatment of
certain side effects associated with the use of opioids as
analgesics. In particular the present invention is directed at
treating opioid-induced inhibition of gastrointestinal motility and
constipation.
BACKGROUND OF THE INVENTION
[0003] Opioids are effective analgesics. However, their use is
associated with a number of undesirable side effects. One such
effect is constipation. Opioid-induced changes in gastrointestinal
motility are almost universal when these drugs are used to treat
pain, and at times may limit their use, leaving the patient in
pain. Common treatments of bulking agents and laxatives have
limited efficacy and may be associated with side effects such as
electrolyte imbalances.
[0004] One treatment for opioid side effects is the use of opioid
antagonists which cross the blood-brain-barrier, or which are
administered directly into the central nervous system. Opioid
antagonists such as naltrexone and naloxone have been administered
intramuscularly or orally to treat opioid induced side effects.
Naltrexone and naloxone are highly lipid soluble and rapidly
diffuse across biological membranes, including the blood-brain
barrier. However, naltrexone, naloxone, nalmefene, and other opioid
antagonists which may reverse many opioid side effects have a
narrow therapeutic window before they are observed to reverse the
desired analgesic effect of the opioid being used.
[0005] Many quaternary amine opioid antagonist derivatives, such as
methylnaltrexone, do not reduce the analgesic effect of opioids.
These quaternary amine opioid antagonist derivatives, which have a
relatively higher polarity and reduced lipid solubility when
compared to the tertiary forms of the drugs, were specifically
developed to not traverse the blood-brain barrier or to traverse it
at a greatly reduced rate. However, high levels of MNTX in the
plasma can lead to undesirable side effects such as orthostatic
hypotension.
[0006] It is desirable in the treatment of many conditions to have
oral medications with prolonged effects. Such oral medications are
particularly desirable for the treatment of opioid-induced side
effects.
[0007] It is further desirable to develop a method for the
prevention of opioid-induced inhibition of gut motility and
constipation which does not counteract the analgesic effects of the
opioid, or risk increased levels of pain. Ideally, such a treatment
has few side effects either due to low drug toxicity or because
administration of small amounts are effective and/or administration
results in low circulating levels of the drug.
BRIEF DESCRIPTION OF DRAWINGS
[0008] FIG. 1A is a graph representing plasma concentrations of
MNTX following administration of 6.4 mg/kg of uncoated MNTX.
[0009] FIG. 1B is a graph representing plasma concentrations of
MNTX following administration of 6.4 mg/kg of enterically coated
MNTX.
[0010] FIG. 1C is a graph representing plasma concentrations of
MNTX following administration of 3.2 mg/kg of enterically coated
MNTX.
[0011] FIG. 2 illustrates the reversal of morphine's effect on
oral-cecal transit time following administration of 6.4 mg/kg of
uncoated MNTX. The darker line represents the average of all points
of a given treatment.
[0012] FIG. 3 illustrates the reversal of morphine's effect on
oral-cecal transit time and its decrease below baseline following
administration of 6.4 mg/kg of enterically coated MNTX. The darker
line represents the average of all points of a given treatment.
[0013] FIG. 4 illustrates the reversal of morphine's effect on
oral-cecal transit time following administration of 3.2 mg/kg of
enterically coated MNTX. The darker line represents the average of
all points of a given treatment.
SUMMARY OF THE INVENTION
[0014] The present invention is directed at methods for preventing
and treating opioid-induced inhibition of gut motility and
constipation.
[0015] An aspect of the invention is a composition for preventing
or treating opioid-induced inhibition of gastrointestinal motility
comprising administering enterically coated quaternary derivatives
of noroxymorphone as disclosed in U.S. Pat. No. 4,176,186 to
Goldberg et al. (herein incorporated by reference) to a patient. In
certain embodiments the composition is in the form of pill, tablet,
capsule or granule. The preferred quaternary derivatives of
noroxymorphone is methylnaltrexone.
DETAILED DESCRIPTION
[0016] The present invention is directed to methods for preventing
and treating opioid-induced constipation and changes in gut
motility via the oral administration of an enteric coated
quaternary derivatives of noroxymorphone (QDNM), particularly
methylnaltrexone (MNTX). Administration of non-enterically coated
MNTX results in rapid absorption of MNTX through the stomach and
early peak and sustained high levels of MNTX in the plasma.
However, an enteric coating on the QDNM, designed to prevent
dissolution and subsequent absorption of the drug in the stomach,
would be expected to produce delayed elevation of plasma levels of
the QDNM, and to produce a lower peak plasma level. Suprisingly,
however, administration of enterically coated MNTX has been found
to result in substantially lower plasma levels as compared to
non-enterically coated MNTX at the same dosage level, and
surprisingly and unexpectedly resulted in enhanced efficacy in the
reversal of opioid-induced decreases in gastrointestinal motility.
In fact, it has been found that as compared to non-enterically
coated MNTX, a significantly lower dose, e.g., less than half the
amount of coated MNTX can be used if enterically coated to achieve
the same levels of relief of opioid-induced constipation. Moreover,
such reduced dosage levels of MNTX administered with an enteric
coating results in exceedingly low peak and sustained plasma levels
of MNTX, greatly reducing the potential adverse side effects of the
MNTX. This novel improvement in the clinical indication for use of
MNTX has led to an increased therapeutic index for this drug.
[0017] When used as a treatment for the opioid- and
nonopioid-induced side effects of constipation and reduction of
gastrointestinal motility, orally administered, particularly if
enterically coated, MNTX or other quaternary derivatives of
noroxymorphone provide prolonged relief of the side effects. MNTX
has been demonstrated to have the ability to block the
gastrointestinal effects of opioids on motility when administered
intravenously or orally. The oral administration of non-enterically
coated MNTX is associated with plasma levels with an early peak (20
min) and prolonged presence (half-life of about 3 hours after
single dose of 6.4 mg/kg).
[0018] Furthermore, for treatment or prevention of constipation and
delayed gastrointestinal emptying, whether caused by extrinsic or
endogenous opioids, enteric coating surprisingly allows for equal
or better efficacy despite lower plasma levels. Idiopathic
constipation, i.e., that due to causes other than exogenous
administration of opioids, may be mediated by opioid sensitive
mechanisms. Endogenous opioid receptors have been identified in the
gut, and these receptors may modulate gut motility. Thus,
administration of an opioid antagonist with peripheral action, such
a methylnaltrexone or other quaternary derivatives of
noroxymorphone, would block the effects of endogenous opioids.
[0019] Quaternary derivatives of noroxymorphone are described in
full in Goldberg et al., (supra), and in general are represented by
the formula: 1
[0020] wherein R is allyl or a related radical such as chlorallyl,
cyclopropyl-methyl or propargyl, and X is the anion of an acid,
especially a chloride, bromide, iodide or methylsulfate anion.
[0021] The presently preferred quaternary derivative of
noroxymorphone is methylnaltrexone. Methylnaltrexone is a
quaternary amine derivative of naltrexone. Methylnaltrexone has
been found to have only 2 to 4% of the opiate antagonistic activity
of naltrexone in vivo due to its inability to pass the
blood-brain-barrier and bind to the opiate receptors in the central
nervous system.
[0022] Opioids are typically administered at a morphine equivalent
dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal
administration; 0.05 to 1.0 mg/kg body weight for intravenous
administration; 0.05 to 1.0 mg/kg body weight for intramuscular
administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal
or transdermal administration. By "morphine equivalent dosage" is
meant representative doses of other opioids which equal one
milligram of morphine, for example 10 mg meperidine, 1 mg
methadone, and 80 .mu.g fentanyl.
[0023] In accordance with the present invention, methylnaltrexone
is administered at a dosage of: 0.1 to 40.0 mg/kg body weight for
oral administration, including enteric coated methylnaltrexone.
[0024] The administration of the methylnaltrexone is preferably
commenced prior to administration of the opioid to prevent
opioid-induced inhibition of gastrointestinal motility or
constipation. It is desirable to commence internal administration
of methylnaltrexone about 20 minutes prior to administration of
opioids in order to prevent these opioid-induced side effects.
While the prevention of symptoms is preferred, methylnaltrexone
administration may also be commenced after the administration of
the opioid or after the onset of opioid induced symptoms as a
treatment for those symptoms.
[0025] Methylnaltrexone is rapidly absorbed after oral
administration from the stomach and bowel. Initial plasma levels of
the drug are seen within 5-10 minutes of the administration of
non-enteric coated compound. Addition of an enteric coating which
prevents gastric absorption is associated with lower plasma levels
of the methylnaltrexone. Surprisingly, the addition of an enteric
coating (i.e., a coating which will prevent degradation or release
in the stomach, but will release drug in the small and large bowel)
enhances the efficacy of methylnaltrexone in the prevention of
decreases in gut motility by intravenously administered opioids
(morphine).
[0026] In a preferred embodiment for the prevention and/or
treatment of constipation and inhibition of gastrointestinal
motility, the QDNM or MNTX is enterically coated and administered
orally. For oral administration, the QDNM or methylnaltrexone is
formulated with pharmacologically acceptable binders to make a
tablet or capsule with an enteric coating. An enteric coating is
one which remains intact during passage through the stomach, but
dissolves and releases the contents of the tablet or capsule once
it reaches the small intestine. Most currently used enteric
coatings are those which will not dissolve in low pH environments,
but readily ionize when the pH rises to about 4 or 5, for example
synthetic polymers such as polyacids having a pK.sub.a of 3 to
5.
[0027] The enteric coating may be made of any suitable composition.
Suitable enteric coatings are described, for example, in U.S. Pat.
No. 4,311,833 to Namikoshi, et al.; U.S. Pat. No. 4,377,568 to
Chopra; U.S. Pat. No. 4,385,078 to Onda, et al.; U.S. Pat. No.
4,457,907 to Porter; U.S. Pat. No.4,462,839 to McGinley, et al.;
U.S. Pat. No.4,518,433 to McGinley, et al.; U.S. Pat. No.4,556,552
to Porter, et al.; U.S. Pat. No. 4,606,909 to Bechgaard et al.;
U.S. Pat. No. 4,615,885 to Nakagame, et al.; U.S. Pat. No.
4,670,287 to Tsuji; U.S. Pat. No. 5,536,507 to Abramowitz, et al.;
U.S. Pat. No. 5,567,423 to Ying, et al.; U.S. Pat. No. 5,591,433 to
Michael, et al.; U.S. Pat. No. 5,597,564 to Ying, et al.; U.S. Pat.
No. 5,609,871 to Michael, et al.; U.S. Pat. No. 5,614,222 to
Kaplan; U.S. Pat. No. 5,626,875 to Rodes, et al.; and U.S. Pat. No.
5,629,001 to Michael, et al., all of which are incorporated herein
by reference.
[0028] Preferred enteric coating compositions include alkyl and
hydroxyalkyl celluloses and their aliphatic esters, e.g.,
methylcellulose, ethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, hydroxybutylcellulose,
hydroxyethylethylcellulose- , hydroxyprophymethylcellulose,
hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate,
hydroxypropylmethylcellulose phthalate and
hydroxypropylmethylcellulose acetate succinate;
carboxyalkylcelluloses and their salts, e.g.,
carboxymethylethylcellulose- ; cellulose acetate phthalate;
cellulose acetate trimellitate, polycarboxymethylene and its salts
and derivatives; polyvinyl alcohol and its esters: polyvinyl
acetate phthalate; polycarboxymethylene copolymer with sodium
formaldehyde carboxylate; acrylic polymers and copolymers, e.g.,
methacrylic acid-methyl methacrylic acid copolymer and methacrylic
acid-methyl acrylate copolymer; edible oils such as peanut oil,
palm oil, olive oil and hydrogenated vegetable oils;
polyvinylpyrrolidone; polyethylene glycol and its esters; natural
products such as shellac, and zein.
[0029] Other preferred enteric coatings include polyvinylacetate
esters, e.g., polyvinyl acetate phthalate; alkyleneglycolether
esters of copolymers such as partial ethylene glycol
monomethylether ester of ethylacrylate-maleic anhydride copolymer
or diethyleneglycol monomethylether ester of methylacrylate-maleic
anhydride copolymer, N-butylacrylate-maleic anhydride copolymer,
isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic
anhydride copolymer; and polypeptides resistant to degradation in
the gastric environment, e.g., polyarginine and polylysine. Other
suitable coatings and methods to make and use such formulations are
well known to those skilled in the art (see, e.g., Remington: The
Science and Practice of Pharmacy, 19th ed. (1995) Mack Publishing
Company, Easton, Pa.; herein incorporated by reference).
[0030] Mixtures of two or more of the above compounds may be used
as desired. The presently preferred enteric coating comprises
cellulose acetate phthalate.
[0031] The enteric coating material may be mixed with various
excipients including plasticizers such as triethyl citrate, acetyl
triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl
subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and
diethyl succinate and inert fillers such as chalk or pigments.
[0032] The composition and thickness of the enteric coating may be
selected to dissolve immediately upon contact with the digestive
juice of the intestine. Alternatively, the composition and
thickness of the external coating may be selected to be a
time-release coating which dissolves over a selected period of
time, as is well known in the art.
[0033] The amount of enteric coating depends on the particular
enteric coating composition used and is preferably sufficient to
substantially prevent the absorption of MNTX in the stomach.
[0034] Hydroxyalkyl celluloses and their aliphatic esters,
carboxyalkyl celluloses and their salts, polycarboxymethylene and
its salts and derivatives, polyvinyl alcohol and its esters,
polycarboxymethylene copolymer with sodium formaldehyde
carboxylates, poly-vinylpyrrolidone, and polyethylene glycol and
its esters can be applied as enteric coatings by first dissolving
the compound in a minimum amount of water. Alcohol is then added to
the point of incipient cloudiness. The mixture can then be applied
by conventional techniques.
[0035] Application of cellulose acetate phthalate may be
accomplished by simply dissolving the cellulose acetate phthalate
in a minimum amount of alcohol and then applying by conventional
techniques. Hydrogenated vegetable oils may be applied by first
dissolving the oil in a minimal amount of a non-polymer solvent,
such as methylene chloride, chloroform or carbon tetrachloride,
then adding alcohol to the point of incipient cloudiness and then
applying by conventional techniques.
[0036] In a particularly preferred embodiment, the MNTX is coated
with Eudragit L100 or S100, a methacrylic acid copolymer enteric
coating, at a 50% coating level to provide stability at gastric pH
and dissolution at gut pH per a US Pharmacopeia (USP) standard for
enteric coatings.
[0037] In the above description, methylnaltrexone is used as an
example of a particularly effective QDNM. It is apparent that other
QDNM's may be used as desired.
[0038] The following Examples are intended to illustrate aspects of
the invention and are not to be construed as limitations upon it.
The methylnaltrexone used in the following Examples was
manufactured by Mallinckrodt Pharmaceuticals, St. Louis, Mo. The
Enteric Coating was manufactured by Coating Place, Inc., Verona,
Wis.
EXAMPLE 1
Effects Of Enterically Coated MNTX On Oral-Cecal Transit Time and
Plasma Levels of MNTX
[0039] Oral methylnaltrexone, whether enterically coated or
uncoated, was shown to reverse the inhibitory effects of opioid
administration on gastrointestinal motility as measured by
oral-cecal transit time. As compared to non-enterically coated
MNTX, however, treatment with enterically coated MNTX enhanced the
efficacy of the drug at a lower dose while producing lower plasma
levels of MNTX.
[0040] Subjects were divided into five treatment groups A-E. With
the exception of subjects in Group A, who were given a placebo in
place of morphine, all were given an intravenous dose of morphine
at 0.05 mg/kg. Prior to morphine administration, subjects were
given either a placebo or MNTX in various doses and formulations
(see Table 1). The subjects in Group A and B were given a placebo
in place of MNTX. Group C received uncoated MNTX at 6.4 mg/kg,
Group D received enterically coated MNTX at 6.4 mg/kg active drug,
and Group E received enterically coated MNTX at 3.2 mg/kg active
drug. Table 1 shows the treatments for each group.
1TABLE 1 Group Treatment combination FIG A placebo placebo B
morphine placebo (0.05 mg/kg) C morphine methylnaltrexone uncoated
(0.05 mg/kg) (6.4 mg/kg) D morphine methylnaltrexone enteric coated
(0.05 mg/kg) (6.4 mg/kg active drug) E morphine methylnaltrexone
enteric coated 0.05 mg/kg) (3.2 mg/kg active drug)
[0041] Plasma levels of MNTX were measured following administration
of morphine and MNTX or placebo several times over the duration of
the six hour monitoring period, at the times shown in FIG. 1.
Measurements of plasma and urine MNTX levels were determined by
high performance liquid chromatography (HPLC) using the modified
method originally reported by Kim et al. (1989) Chromatographia
28:359-63, herein incorporated by reference). Methylnaltrexone was
separated from plasma by solid phase extraction (SPE). Plasma
samples (100-500 .mu.l) diluted in water with the internal standard
(naltrexone) were passed through SPE columns. Prior to use, the
columns were conditioned by methanol and washed with water. The
analytes were eluted from the columns by the mixture of n-propanol
and trifluoroacetic acid (25 mM) aqueous solution prepared in 2:1
proportion. The eluate was evaporated to dryness in a stream of
nitrogen at 55.degree. C. The residue was reconstituted in the
mobile phase, filtered through a nylon HPLC syringe filter and
subjected to HPLC analysis. A Shimadzu Corporation (Kyoto, Japan)
HPLC system was used. It consisted of the LC-10AD pump, SCL-10A
system controller, and SIL-10A auto injector equipped with sample
cooler. Used HPLC Analytical Column made by Phenomenex (Prodigy C8,
Torrance, Calif.). The electrochemical detector (ESA Coulochem,
model 5100A) worked at the following settings: detector 1, +360 mV,
detector 2+600 mV, guard cell +650 mV. Data were collected with the
use of EZChrom 2--2 HPLC software. The mobile phase consisted of 50
mM sodium acetate, 7.5% methanol at pH 4.2. The system was
calibrated daily in the range of 5-100 ng/ml (3 point calibration).
Practical limit of detection for plasma samples was approximately 2
ng/ml (100 pg/injection).
[0042] FIG. 1 shows the plasma levels of MNTX following the
treatments in Groups C, D, and E. In FIG. 1A, MNTX plasma levels in
Group C (given 6.4 mg/kg MNTX, uncoated) peaked at about 15 min.
post-MNTX administration and remained at a roughly constant level
(between about 35-50 ng/ml) for the duration of the study period (6
hours). Group D, given 6.4 mg/kg MNTX in an enterically coated
formulation, exhibited a constant low plasma level of MNTX (under
10 ng/ml) for the duration of observation (see FIG. 1B). Group E,
given 3.2 mg/kg MNTX in an enterically coated formulation, showed
plasma levels of MNTX over the course of observation that were
undetectable or at the lower limit of detection of the assay (see
FIG. 1C).
[0043] Oral-cecal transit time was used as a measure of gut
motility and propensity for constipation. Oral-cecal transit time
was measured by the lactulose-breath hydrogen method. Group A
demonstrated normal transit times as previously described in the
literature (Yuan et al. (1996) Clin. Pharmacol. Ther. 59:469-475;
Yuan et al. (1997) Clin. Pharmacol. Ther. 61:467-475). Group B had
prolongation of their oral-cecal transit times by 50-100%, while
Groups C (FIG. 2) and E (FIG. 4) had their transit times return to
baseline levels. Group D showed an obvious decrease in oral-cecal
transit time (FIG. 3).
[0044] As demonstrated in FIGS. 1-4, enterically coated MNTX
provides the therapeutic effects on gastrointestinal motility of
uncoated MNTX, but requires a lower dose of active drug and results
in significantly reduced plasma levels of MNTX. Patients provided
with a dose of 6.4 mg/kg of uncoated MNTX had gut motility return
to baseline following morphine administration (FIG. 2) and showed
plasma MNTX levels of over 40 ng MNTX/ml, while patients given the
same dose in an enterically coated formulation showed oral-cecal
transit times below baseline levels (FIG. 3) and plasma MNTX levels
under 10 ng/ml. Enterically coated formulations of MNTX with one
half the dose of active drug (3.2 mg/kg) were required to return
oral-cecal transit times to I 5 normal without increasing gut
motility. At this dosage, plasma levels of MNTX were
negligible.
[0045] As with most drugs, it is desirable to maintain the lowest
possible systemic levels of MNTX which are sufficient to provide
the desired therapeutic effect. For example, elevated circulating
levels of MNTX can result in orthostatic hypotension. The present
discovery provides an unexpected means to avoid such undesirable
drug side effects by lowering the dose administered and
subsequently minimizing circulating levels of the drug. Since
endogenous and externally supplied opioid-induced inhibition of
gastrointestinal motility and constipation is thought to result
from opioid receptors located within the gastrointestinal tract,
enterically coated MNTX or other QDNMs may provide a local
administration of the drug that does not require a circulating
level for effective prevention or treatment of symptoms. Thus, the
amount and/or frequency of drug administered can be reduced.
[0046] The preceding description and Examples are intended to be
illustrative. Those skilled in the art to which the invention
pertains will appreciate that alterations and changes in the
described protocols may be practiced without departing from the
meaning, spirit, and scope of this invention. Therefore, the
foregoing description should be read consistent with and as support
to the following claims, which are to have their fullest and fair
scope.
* * * * *