U.S. patent application number 13/670846 was filed with the patent office on 2013-12-05 for synthesis of r-n-methylnaltrexone.
This patent application is currently assigned to PROGENICS PHARMACEUTICALS, INC.. The applicant listed for this patent is Progenics Pharmaceuticals, Inc.. Invention is credited to Harold D. Doshan, Julio Perez.
Application Number | 20130323286 13/670846 |
Document ID | / |
Family ID | 36997886 |
Filed Date | 2013-12-05 |
United States Patent
Application |
20130323286 |
Kind Code |
A1 |
Doshan; Harold D. ; et
al. |
December 5, 2013 |
SYNTHESIS OF R-N-METHYLNALTREXONE
Abstract
This invention relates to stereoselective synthesis of R-MNTX
and intermediates thereof, pharmaceutical preparations comprising
R-MNTX or intermediates thereof and methods for their use.
Inventors: |
Doshan; Harold D.;
(Riverside, CT) ; Perez; Julio; (Tarrytown,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Progenics Pharmaceuticals, Inc.; |
|
|
US |
|
|
Assignee: |
PROGENICS PHARMACEUTICALS,
INC.
Tarrytown
NY
|
Family ID: |
36997886 |
Appl. No.: |
13/670846 |
Filed: |
November 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12692083 |
Jan 22, 2010 |
8343992 |
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13670846 |
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11441395 |
May 25, 2006 |
7674904 |
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12692083 |
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60684616 |
May 25, 2005 |
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Current U.S.
Class: |
424/400 ;
424/133.1; 436/92; 514/150; 514/171; 514/238.8; 514/263.2; 514/282;
546/45 |
Current CPC
Class: |
A61P 3/02 20180101; A61P
25/00 20180101; A61P 25/36 20180101; A61P 7/06 20180101; A61P 7/08
20180101; A61P 15/00 20180101; A61P 25/04 20180101; A61P 37/04
20180101; A61P 1/12 20180101; G01N 33/15 20130101; A61K 45/06
20130101; A61K 47/02 20130101; A61P 13/02 20180101; A61P 25/06
20180101; A61P 31/18 20180101; A61P 31/14 20180101; A61P 1/00
20180101; A61P 29/00 20180101; Y10T 436/141111 20150115; A61P 1/08
20180101; A61P 43/00 20180101; C07D 489/04 20130101; A61K 9/19
20130101; A61K 9/08 20130101; A61P 1/04 20180101; A61P 13/00
20180101; A61P 25/20 20180101; A61P 31/12 20180101; A61P 35/00
20180101; C07D 489/08 20130101; A61K 31/485 20130101; A61P 5/04
20180101; A61P 25/24 20180101; A61P 29/02 20180101; A61P 25/02
20180101; A61P 1/18 20180101; A61P 1/10 20180101; A61P 19/02
20180101; A61K 9/0019 20130101; A61P 1/06 20180101; A61P 21/00
20180101; A61P 17/04 20180101; A61P 9/00 20180101 |
Class at
Publication: |
424/400 ; 436/92;
546/45; 514/282; 514/263.2; 514/238.8; 424/133.1; 514/150;
514/171 |
International
Class: |
C07D 489/04 20060101
C07D489/04; A61K 31/485 20060101 A61K031/485; A61K 45/06 20060101
A61K045/06; G01N 33/15 20060101 G01N033/15 |
Claims
1. A composition comprising R-MNTX, wherein the composition is free
of HPLC detectable S-MNTX at a detection limit of 0.02% and at a
quantitation limit of 0.05%.
2. The composition of claim 1, wherein the MNTX present in the
composition is a cation of a salt, paired by an anion.
3. The composition of claim 2, wherein the anion is selected from
the group consisting of a halide, sulfate, phosphate, nitrate, an
organic-charged anionic species, bromide, chloride, iodide, and
fluoride.
4-5. (canceled)
6. A composition comprising MNTX, wherein at least 99.6%, 99.7%,
99.8%, 99.85%, 99.9%, or even 99.95% of the MNTX in the composition
is in the R configuration with respect to nitrogen, and wherein the
MNTX is not a bromide salt of MNTX.
7. The composition of claim 6, wherein the MNTX present in the
composition is a cation of a salt, paired by an anion, wherein the
anion is selected from the group consisting of a halide, sulfate,
phosphate, nitrate and an organic anionic species.
8. (canceled)
9. The composition of claim 6 further comprising, one or more of a
buffering agent, a chelating agent, a cryoprotecting agent, a
lubricating agent, a preservative, an anti-oxidant, or a binding
agent.
10. (canceled)
11. The composition of claim 6, wherein at least 99.85% of the MNTX
in the composition is in the R configuration with respect to
nitrogen.
12. The composition of claim 6, wherein the composition is free of
HPLC detectable S-MNTX at a detection level of 0.02% and at a
quantitation level of 0.05%.
13. The composition of claim 11, wherein the MNTX present in the
composition is a cation of a salt, paired by an anion, optionally,
wherein the anion is selected from the group consisting of a
halide, sulfate, phosphate, nitrate, an organic anionic species,
bromide, chloride, iodide, and fluoride.
14-92. (canceled)
93. A pharmaceutical composition comprising the composition of
claim 1 and a pharmaceutically acceptable carrier.
94. The pharmaceutical composition of claim 93, wherein the
pharmaceutical composition comprises an enteric coating, a
sustained release formulation, a lyophilized preparation, or a
solution.
95-96. (canceled)
97. The pharmaceutical composition of claim 93, further comprising
an opioid selected from the group consisting of alfentanil,
anileridine, asimodiline, bremazocine, burprenorphine, butorphanol,
codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine,
diphenyloxylate, fedotozine, fentanyl, funaltrexamine, hydrocodone,
hydromorphone, levallorphan, levomethadyl acetate, levorphanol,
loperamide, meperidine (pethidine), methadone, morphine,
morphine-6-glucoronide, nalbuphine, nalorphine, opium, oxycodone,
oxymorphone, pentazocine, propiram, propoxyphene, remifentanyl,
sufentanil, tilidine, trimebutine, tramadol, and combinations
thereof.
98. (canceled)
99. The pharmaceutical composition of claim 93, further comprising
at least one pharmaceutical agent that is not an opioid or an
opioid antagonist; optionally wherein the at least one
pharmaceutical agent is an antiviral agent, an anti-infective
agent, an anticancer agent, an antispasmodic agent, an
anti-muscarinic agent, an anti-inflammatory agent, a pro-motility
agent, a 5HT.sub.1 agonist, a 5HT.sub.3 antagonist, a 5HT.sub.4
antagonist, a 5HT.sub.4 agonist, a bile salt sequestering agent, a
bulk-forming agent, an alpha2-adrenergic agonist, a mineral oil, an
antidepressant, a herbal medicine, an anti-emetic agent, an
anti-diarrheal agent, a laxative, a stool softener, a fiber or a
hematopoietic stimulating agent; and optionally wherein the
anti-inflammatory agent is selected from the group consisting of
non-steroidal anti-inflammatory drugs (NSAIDS), tumor necrosis
factor inhibitors, basiliximab, daclizumab, infliximab,
mycophenolate, mofetil, azothioprine, tacrolimus, steroids,
sulfasalazine, olsalazine, mesalamine, and combinations
thereof.
100-110. (canceled)
111. A method for treating or preventing opioid-induced side
effects comprising administering to a patient in need of such
treatment the composition of claim 1 in an amount effective to
treat or prevent the side effect; optionally wherein the patient is
chronically administered opioids.
112. (canceled)
113. The method of claim 111, wherein the side effect is selected
from a group consisting of constipation, immune suppression,
inhibition of gastrointestinal motility, inhibition of gastric
emptying, nausea, emesis, incomplete evacuation, bloating,
abdominal distension, increased gastroesophageal reflux,
hypotension, bradycardia, gastrointestinal dysfunction, pruritus,
dysphoria, and urinary retention.
114. A method for treating a patient receiving an opioid for pain
resulting from surgery comprising administering to the patient a
composition of claim 1 in an amount effective to promote
gastrointestinal motility, gastric emptying or relief of
constipation.
115. A method for treating or preventing endogenous opioid-induced
gastrointestinal dysfunction, comprising administering to a patient
in need of such treatment the composition of claim 1 in an amount
effective to treat the endogenous opioid-induced gastrointestinal
dysfunction; optionally wherein the gastrointestinal dysfunction is
selected from a group consisting of inhibition of gastrointestinal
motility, constipation and postoperative bowel dysfunction.
116. (canceled)
117. A method for preventing or treating idiopathic constipation
comprising administering to a patient a composition of claim 1 in
an amount effective to prevent or treat the idiopathic
constipation.
118. A method for treating irritable bowel syndrome comprising
administering to a patient in need of such treatment the
composition of claim 1 in an amount effective to ameliorate at
least one symptom of the irritable bowel syndrome; optionally
further comprising administration of at least one irritable bowel
syndrome therapeutic agent to the patient; and optionally wherein
the irritable bowel syndrome therapeutic is selected from the
groups consisting of an antispasmodic agent, an anti-muscarinic
agent, a non-steroidal or steroidal anti-inflammatory agent, a
pro-motility agent, a 5HT.sub.1 agonist, a 5HT.sub.3 antagonist, a
5HT.sub.4 antagonist, a 5HT.sub.4 agonist, a bile salt sequestering
agent, a bulk-forming agent, an alpha2-adrenergic agonist, a
mineral oil, an antidepressant, an herbal medicine, an
anti-diarrheal agent and combinations thereof.
119-120. (canceled)
121. A method for inducing laxation in a patient in need of
laxation comprising administering to a patient in need of such
treatment the composition of claim 1 in an amount effective to
induce laxation
122. A method for preventing or treating post-operative bowel
dysfunction comprising administering to a patient in need of such
prevention or treatment the composition of claim 1 in an amount
effective to prevent or ameliorate at least one symptom of
post-operative bowel dysfunction; optionally wherein the
post-operative bowel dysfunction is delayed gastric emptying or
inhibition of gastrointestinal motility.
123-146. (canceled)
147. A patient-controlled injection device comprising the
composition of claim 1.
148. (canceled)
149. A kit comprising a package containing a sealed container
comprising the pharmaceutical composition of claim 93 and
instructions for use.
150-189. (canceled)
190. A method for manufacturing R-MNTX comprising the following
steps, (a) obtaining a first composition containing R-MNTX, (b)
purifying the first composition by chromatography,
recrystallization or a combination thereof, (c) conducting HPLC on
a sample of purified first composition using S-MNTX as a standard,
(d) determining the presence or absence of S-MNTX in the
sample.
191. The method of claim 190, wherein the purifying comprises
multiple recryallization steps or multiple chromatography steps;
optionally wherein the purifying is carried out until S-MNTX is
less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05%, or is absent from
the purified first composition as determined by HPLC with a
detection limit of 0.02% and a quantitation limit of 0.05%.
192-199. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/441,395, filed May 25, 2006, entitled "SYNTHESIS OF
R--N-METHYLNALTREXONE," which claims benefit under 35 U.S.C.
.sctn.119(e) of the filing date of U.S. Provisional Application
Ser. No. 60/684,616, filed on May 25, 2005, entitled "SYNTHESIS OF
R--N-METHYLNALTREXONE," the contents of which applications are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to stereoselective synthesis of
(R)--N-methylnaltrexone (R-MNTX) and intermediates thereof,
pharmaceutical preparations comprising R-MNTX or intermediates
thereof and methods for their use.
BACKGROUND OF INVENTION
[0003] Methylnaltrexone (MNTX) is a quaternary derivative of the
pure opioid antagonist, naltrexone. It exists as a salt. Names used
for the bromide salt of MNTX in the literature include:
Methylnaltrexone bromide; N-Methylnaltrexone bromide; Naltrexone
methobromide; Naltrexone methyl bromide; MRZ 2663BR. MNTX was first
reported in the mid-70s by Goldberg et al as described in U.S. Pat.
No. 4,176,186. It is believed that addition of the methyl group to
the ring nitrogen forms a charged compound with greater polarity
and less liposolubility than naltrexone. This feature of MNTX
prevents it from crossing the blood-brain barrier in humans. As a
consequence, MNTX exerts its effects in the periphery rather than
in the central nervous system with the advantage that it does not
counteract the analgesic effects of opioids on the central nervous
system.
[0004] MNTX is a chiral molecule and the quaternary nitrogen can be
in R or S configuration. (See FIG. 1.) It is unknown whether the
different stereoisomers of MNTX exhibit different biological and
chemical properties. All of the reported functions of MNTX
described in the literature indicate that MNTX is a peripheral
opioid antagonist. Some of these antagonist functions are described
in U.S. Pat. Nos. 4,176,186, 4,719,215, 4,861,781, 5,102,887,
5,972,954, 6,274,591, 6,559,158, and 6,608,075, and in U.S. patent
application Ser. Nos. 10/163,482 (2003/0022909A1), 10/821,811
(20040266806), 10/821,813 (20040259899) and 10/821,809
(20050004155). These uses include reducing the side-effects of
opioids without reducing the analgesic effect of opioids. Such
side-effects include nausea, emesis, dysphoria, pruritus, urinary
retention, bowel hypomotility, constipation, gastric hypomotility,
delayed gastric emptying and immune suppression. The art discloses
that MNTX not only reduces the side-effects stemming from opioid
analgesic treatment but also reduces the side-effects mediated by
endogenous opioids alone or in conjunction with exogenous opioid
treatment. Such side-effects include inhibition of gastrointestinal
motility, post-operative gastrointestinal dysfunction, idiopathic
constipation and other such conditions including, but not limited
to, those mentioned above. However, it is unclear from the art
whether the MNTX used in these studies was a mixture of R and S
stereoisomers or a single stereoisomer.
[0005] The art suggests that isolated stereoisomers of a compound
sometimes may have contrasting physical and functional properties,
although it is unpredictable whether this is the case in any
particular circumstance. Dextromethorphan is a cough suppressant,
whereas its enantiomer, levomethorphan, is a potent narcotic.
R,R-methylphenidate is a drug to treat attention deficit
hyperactivity disorder (ADHD), whereas its enantiomer,
S,S-methylphenidate is an antidepressant. S-fluoxetine is active
against migraine, whereas its enantiomer, R-fluoxetine is used to
treat depression. The S enantiomer of citalopram is therapeutically
active isomer for treatment of depression. The R enantiomer is
inactive. The S enantiomer of omeprazole is more potent for the
treatment of heartburn than the R enantiomer.
[0006] Bianchetti et al, 1983 Life Science 33 (Sup I):415-418
studied three pairs of diastereoisomers of quaternary narcotic
antagonist and their parent tertiary amines, levallorphan,
nalorphine, and naloxone, to see how the configuration about the
chiral nitrogen affected in vitro and in vivo activity. It was
found that the activity varied considerably depending on how the
quaternary derivatives were prepared. In each series, only the
diastereomer obtained by methylation of the N-allyl-substituted
tertiary amine (referred to as "N-methyl diastereomer") was potent
in displacing .sup.3H-naltrexone from rat brain membranes, and
acting as a morphine antagonist in the guinea-pig ileum.
Conversely, diastereoisomers obtained by reacting
N-methyl-substituted tertiary amines with allyl halide (referred to
as "N-allyl diastereomers") did not displace 3H-naltrexone and had
negligible antagonist activity and slight agonist action in the
guinea-pig ileum. In vivo findings were generally consistent with
those in vitro. Thus only the "N-methyl" but not the "N-allyl
diastereomers" inhibited morphine-induced constipation in rats and
behaved as antagonists. The author stated that the prepared
materials appeared to be pure by .sup.1H and .sup.13C nuclear
magnetic resonance (NMR) analysis, but these methods are not
accurate. The author cites a literature reference for the
assignment of the R configuration to the "N-methyl diastereomer" of
nalorphine. No assignment is proposed for the levallorphan and
naloxone diastereomers. It would be adventurous to extrapolate the
configuration to these diastereomers (R. J. Kobylecki et al, J.
Med. Chem. 25, 1278-1280, 1982).
[0007] Goldberg et al.'s U.S. Pat. No. 4,176,186, and more recently
Cantrell et al.'s WO 2004/043964 A2 describe a protocol for the
synthesis of MNTX. Both describe a synthesis of MNTX by
quaternizing a tertiary N-substituted morphinan alkaloid with a
methylating agent. Both Goldberg et al. and Cantrell et al. are
silent as to the stereoisomer(s) produced by the synthesis. The
authors remained cautiously silent about the stereochemistry
because the stereochemistry could not be determined based on prior
art. The cyclopropylmethyl side-chain in naltrexone is different
from the prior art side-chains and may have affected the
stereochemical outcome in the synthesis of MNTX, as may other
reaction parameters such as temperature and pressure. Based on the
method of synthesis described in each, it is unknown whether the
MNTX so produced was R, S or a mixture of both.
[0008] S-MNTX in pure form, and a method of making pure S-MNTX have
not been described in the literature. Researchers would have been
unable to definitively characterize and distinguish the
stereoisomer(s) obtained by the Goldberg et al. or Cantrell et al.
synthesis in the absence of pure S-MNTX as a standard.
SUMMARY OF THE INVENTION
[0009] S-MNTX has now been produced in high purity permitting the
characterization of its relative retention time in chromatography
versus that of R-MNTX. The pure S-MNTX has been found to have
activity different from the activity of MNTX reported in the
literature. This highlights the need for methods of making and
purifying R-MNTX to high purity.
[0010] The present invention provides substantially pure R-MNTX and
intermediates thereof, crystals of substantially pure R-MNTX and
intermediates thereof, novel methods for making substantially pure
R-MNTX, methods for analyzing and quantifying R-MNTX in a mixture
of R-MNTX and S-MNTX, methods of isolating R-MNTX from a mixture of
R-MNTX and S-MNTX, pharmaceutical products containing the same and
related uses of these materials.
[0011] The invention provides synthetic routes for stereoselective
synthesis of R-MNTX, substantially pure R-MNTX, crystals of
substantially pure R-MNTX, pharmaceutical preparations containing
substantially pure R-MNTX, and methods for their use.
[0012] According to one aspect of the invention, a composition is
provided that comprises MNTX in R configuration with respect to
nitrogen present at greater than 99.5%. In other embodiments the
MNTX in R configuration with respect to nitrogen is present in the
composition in greater than about 99.6%, or about 99.7%, or about
99.8%, or about 99.9%, or about 99.95%, or even more preferably
greater than 99.95%. In one embodiment, there is no detectable
S-MNTX using the chromatographic procedures described herein.
Preferably, the composition is free of HPLC detectable S-MNTX. In
one embodiment there is no HPLC detectable S-MNTX at a detection
limit of 0.02% and a quantitation limit of 0.05%. In yet another
embodiment the composition of the invention contains 99.85% of the
MNTX is in R configuration with respect to nitrogen and it contains
HPLC detectable S-MNTX at a detection limit of 0.02% and a
quantitation limit of 0.05%.
[0013] According to one aspect of the invention a composition is
provided that comprises MNTX, wherein at least 99.6%, 99.7%, 99.8%,
99.85%, 99.9%, and even 99.95% of the MNTX in the composition is in
the R configuration with respect to nitrogen, and one or more of a
buffering agent, a chelating agent, a preserving agent, a
cryoprotecting agent, a lubricating agent, a preservative, an
anti-oxidant, or a binding agent.
[0014] R-MNTX is a salt. Therefore there will be a counterion,
which for the present application, includes the zwitterion.
Typically, the counterion a halide, sulfate, phosphate, nitrate or
an anionic-charged organic species. Halides include bromide,
iodide, chloride, and fluoride. In certain embodiments the halide
is iodide and in other important embodiments the halide is bromide.
In certain embodiments, the anionic-charged organic species is a
sulfonate or a carboxylate. Examples of sulfonates include
mesylate, besylate, tosylate, and triflate. Examples of
carboxylates include formate, acetate, citrate, and fumarate.
[0015] According to another aspect of the invention, the foregoing
compositions that comprise MNTX in R configuration with respect to
nitrogen in some important embodiments is a crystal, a solution, or
a bromide salt of MNTX. In other embodiments, the foregoing
compositions are pharmaceutical preparations, preferably in
effective amounts and with a pharmaceutically acceptable
carrier.
[0016] According to one aspect of the invention, a crystal of MNTX
is provided that is at least about 99.5%, or about 99.6% or about
99.7%, or is about 99.8%, or about 99.9%, or most preferably
greater than 99.95% of MNTX in R configuration with respect to
nitrogen.
[0017] According to one aspect of the invention, there is provided
a compound of the formula:
##STR00001##
[0018] wherein R is a hydroxyl protecting group. The hydroxyl
protecting group can be any of numerous such groups. In important
embodiments it is selected from the group consisting of:
isobutyryl, 2-methyl butyryl, tertbutyl carbonyl, silyl ethers,
2-tetrahydropyranyl ethers, and alkyl carbonates. Most preferably
the hydroxyl protecting group is isobutyryl.
[0019] According to one aspect of the invention there is provided a
compound of the formula:
##STR00002##
[0020] wherein R is a hydroxyl protecting group. The hydroxyl
protecting group is selected from the group consisting of:
isobutyryl, 2-methyl butyryl, tertbutyl carbonyl, silyl ethers,
2-tetrahydropyranyl ethers, and alkyl carbonates. Most preferably
the hydroxyl protecting group is isobutyryl. The compound in one
embodiment is isolated. By isolated it is meant the compound is at
least 50% pure. The compound can be obtained at levels of even
greater purity, such as 60%, 70%, 80%, 90%, or even greater than
95% purity. In other embodiments the compound is in R configuration
with respect to nitrogen, the R form being present in greater than
50%, 60%, 70%, 80%, 90%, 95%, 99%, or even 99.5%% versus the S
form.
[0021] According to another aspect of the invention, a method for
stereoselective synthesis of R-MNTX is provided. This method
involves adding a hydroxyl protecting group to naltrexone to yield
3-O-protected-naltrexone; methylating the 3-O-protected-naltrexone
to yield 3-O-protected-R-MNTX salt; and removing hydroxyl
protecting group to yield R-MNTX. In some embodiments of the
invention the hydroxyl protecting group can be added in the
presence of each or both: an organic solvent and/or a tertiary
amine that is not naltrexone. In some embodiments of the invention
the naltrexone is methylated by reacting the
3-O-protected-naltrexone with methyl iodide to produce
3-O-protected-R-MNTX iodide salt. The 3-O-protected-naltrexone can
be protected in important embodiments by a hydroxyl protecting
group such as isobutyryl. In a preferred embodiment of the
invention, the 3-O-protected-R-MNTX iodide salt is treated with
hydrobromic acid to remove the protecting group and produce R-MNTX
bromide/iodide salt, and the bromide/iodide salt is passed through
an anion exchange resin column (bromide form) to yield R-MNTX
bromide. In any of the foregoing aspects of the invention the
tertiary amine that is not MNTX can be triethylamine. In any of the
foregoing aspects of the invention the organic solvent can be
tetrahydrofuran. In any of the foregoing aspects of the invention
the hydroxyl protecting group can be isobutyryl.
[0022] According to another aspect of the invention a method for
isolation and purification of R-MNTX is provided, comprising
passing the crude R-MNTX through a chromatography column and
collecting the R-MNTX which elutes at the R-MNTX retention time.
This process can be in addition to the method described above,
after the deprotecting step and/or the anion exchange resin column
step.
[0023] According to another aspect of the invention a method for
analyzing R-MNTX in a mixture of R-MNTX and S-MNTX is provided. The
method involves conducting high performance liquid chromatography
(HPLC) and applying R-MNTX to the chromatography column as a
standard. The method preferably involves applying both S-MNTX and
R-MNTX as standards to determine relative retention/elution times.
Relative retention times of R and S are described herein.
[0024] Pure S-MNTX can be obtained according to the following
procedure: S-MNTX salt can be synthesized by combining
iodomethylcyclopropane or another cyclopropylmethyl derivative with
oxymorphone in a dipolar aprotic solvent. The cyclopropylmethyl
derivative contains a leaving group, preferably a halide, such as
iodine or sulfonate. The dipolar aprotic solvent may be:
N-methylpyrrolidone (NMP), dimethyl formamide, methylphosphoramide,
acetone, 1,4-dioxane, acetonitrile, or combinations thereof. The
synthesized S-MNTX can be purified by chromatography,
recrystallization, multiple recrystallizations, or a combination
thereof. The reaction can be carried out under atmospheric
conditions across a wide temperature spectrum, for example, at
70.degree. C., or under a controlled reaction temperature between
65.degree. C. to 75.degree. C. Counterions may be substituted,
optionally, for iodide by transferring the S-MNTX iodo salt to a
second solvent, such as isopropyl acetate or dioxane and exchanging
iodide for a counterion other than iodide. Examples of counterions
are bromide, chloride, fluoride, nitrate, sulfonate, or
carboxylate. The sulfonate can be mesylate, besylate, tosylate or
triflate. The carboxylate can be formate, acetate, citrate and
fumarate. The reaction in the second solvent can be conducted at
room temperature.
[0025] In one aspect of this invention, the chromatography is
conducted using two solvents, solvent A and solvent B, wherein
solvent A is an aqueous solvent and solvent B is a methanolic
solvent and wherein both A and B contain trifluoroacetic acid
(TFA). Preferably, A is 0.1% aqueous TFA and B is 0.1% methanolic
TFA. In important embodiments the column comprises a bonded,
end-capped silica. In important embodiments, the pore size of the
column gel is 5 microns. In a most preferred embodiment, the
column, flow rate and gradient program are as follows:
Column: Luna C18(2), 150.times.4 6 mm, 5.mu.
[0026] Flow Rate: 1 mL/min
Gradient Program:
TABLE-US-00001 [0027] Time (min) % A % B 0:00 95 5 8:00 65 35 12:00
35 65 15:00 0 100 16:00 95 5 18:00 95 5
[0028] Detection can be carried out conveniently by ultraviolet
(UV) wavelength @ 230 nm. Quantitation Limit is the lowest amount
of S-MNTX that can be consistently measured and reported,
regardless of variations in laboratories, analysts, instruments or
reagent lots. Detection Limit is the lowest amount of S-MNTX in a
sample which can be detected but not necessarily quantitated as an
exact value.
[0029] The foregoing HPLC also can be used to determine the
relative amount of S-MNTX and R-MNTX and the intermediates of the
synthesis thereof by determining the area under the respective R
and S curves in the chromatogram produced. According to another
aspect of the invention a method for isolation and purification of
R-MNTX and the 3-O-protected-R-MNTX salt intermediate is provided,
comprising recrystallizing the crude R-MNTX or intermediates
thereof from a solvent or a mixture of solvents. This process can
be in addition to the method described above, after the
deprotection step and/or the anion exchange resin column step.
[0030] According to another aspect of the invention, a method is
provided for stereoselective synthesis of 3-O-protected R-MNTX salt
comprising methylating a 3-O-protected-naltrexone with a
methylating agent to yield 3-O-protected-R-MNTX salt. The hydroxyl
protecting group of the 3-O-protected-naltrexone in certain
embodiments is isobutyryl, 2-methyl butyryl, tertbutyl carbonyl,
silyl ethers, 2-tetrahydropyranyl ethers, and alkyl carbonates. The
3-O-protected R-MNTX is a salt with an anion that can be, for
example, a halide, sulfate, phosphate, nitrate or an organic
anionic-charged species. The halide is bromide, iodide, chloride,
or fluoride. The organic anionic-charged species can be, for
example, a sulfonate or carboxylate. Exemplary sulfonates are
mesylate, besylate, tosylate, or triflate. Exemplary carboxylates
are formate, acetate, citrate, or fumarate. The method can further
involve exchanging the anion with a different anion. The
methylating agent can be a methyl group susceptible to nucleophilic
attack, and a leaving group. Exemplary methylating agents are
selected from the group consisting of methyl halide, dimethyl
sulfate, methyl nitrate and methyl sulfonate. Methyl halides are
methyl iodide, methyl bromide, methyl chloride and methyl fluoride.
Methyl sulfonates include methyl mesylate, methyl besylate, methyl
tosylate, and methyl triflate. In one embodiment, the methylation
is conducted at a temperature range from about >70.degree. C. to
about 100.degree. C., or from 80.degree. C. to about 90.degree. C.,
or preferably at about 88.degree. C. The methylation reaction is
conducted for about 1 hour to 24 hours, or about 5 hour to 16 hours
and in one embodiment for about 10 hours. The method can further
involve purification of the 3-O-protected R-MNTX salt using at
least one purification technique, such as chromatography or
recrystallization. The chromatography can be reverse-phase
chromatography or regular phase chromatography. In some
embodiments, the regular phase chromatography can use alumina or
silica gel. The 3-O-protected-naltrexone can be purified prior to
methylation.
[0031] According to one aspect of the invention a pharmaceutical
composition is provided that comprises R-MNTX free of detectable
S-MNTX by the chromatography procedures described herein or the
3-O-protected-R-MNTX salt intermediate and a pharmaceutically
acceptable carrier. In one embodiment the pharmaceutical
composition is a packaged unit dosage or a multi-unit dosage. In
yet another embodiment the packaged unit dosage is a solution. The
pharmaceutical composition in one embodiment is a solution. In
another embodiment it is an enteric coated solid dosage form. In
still another embodiment it is a sustained release formulation.
According to yet another aspect of the invention, a pharmaceutical
preparation containing R-MNTX or the 3-O-protected-R-MNTX salt
intermediate in a lyophilized formulation is prepared by combining
a cryoprotective agent, such as mannitol, with the R-MNTX
formulation. The lyophilized preparation may also contain any one
of, any combination of, or all of a buffering agent, an
antioxidant, an isotonicity agent and an opioid. In some embodiment
the aforementioned pharmaceutical composition can further comprise
one pharmaceutical agent that is not an opioid antagonist. In one
embodiment of the invention the aforementioned pharmaceutical
composition can comprise a pharmaceutical agent that is an opioid.
In yet another embodiment, the pharmaceutical composition can
further comprise at least one opioid, and at least one
pharmaceutical agent that is not an opioid or an opioid antagonist.
In a preferred embodiment the pharmaceutical agent that is not an
opioid or an opioid antagonist is an antiviral agent, an
anti-infective agent, an anticancer agent, an antispasmodic agent,
an anti-muscarinic agent, a steriodal or non-steriodal
anti-inflammatory agent, a pro-motility agent, a 5HT.sub.1 agonist,
a 5HT.sub.3 antagonist, a 5HT.sub.4 antagonist, a 5HT.sub.4
agonist, a bile salt sequestering agent, a bulk-forming agent, an
alpha2-adrenergic agonist, a mineral oil, an antidepressant, a
herbal medicine, an anti-diarrheal medication, a laxative, a stool
softener, a fiber or a hematopoietic stimulating agent.
[0032] The pharmaceutical compositions of the invention can be
provided in kits. The kits are a package containing a sealed
container comprising the pharmaceutical preparations of the present
invention and instructions for use. The kits contain R-MNTX that is
free of HPLC detectable S-MNTX. The kit in one embodiment contains
40 mg/mL R-MNTX. The kit in another embodiment contains 30 mg/mL of
R-MNTX. The kit can further include an opioid or opioid agonist, or
it can include at least one pharmaceutical agent that is not an
opioid or an opioid antagonist. In one embodiment, the kit is a
package containing a sealed container comprising the pharmaceutical
preparation that is or the 3-O-protected-R-MNTX salt and
instructions for use. The kit in one embodiment contains 40 mg/mL
3-O-protected-R-MNTX salt. The kit in another embodiment contains
30 mg/mL of 3-O-protected-R-MNTX salt. The kit can further include
an opioid or opioid agonist, or it can include at least one
pharmaceutical agent that is not an opioid or an opioid
antagonist.
[0033] According to another aspect of the invention, methods are
provided for ensuring the manufacture of R-MNTX (which is an opioid
antagonist) that is free of S-MNTX (which is an opioid agonist).
The methods permit for the first time the assurance that a
pharmaceutical preparation of R-MNTX which is intended for
antagonist activity is not contaminated with a compound that
opposes the activity of R-MNTX. This is particularly desirable when
R-MNTX is administered to oppose the side effects of opioid
therapy, as opioids appear to act synergistically with S-MNTX to
oppose the activity of R-MNTX. In this aspect of the invention, a
method is provided for manufacturing R-MNTX. The method
involves:
(a) obtaining a first composition containing R-MNTX, (b) purifying
the first composition by chromatography, recrystallization or a
combination thereof, (c) conducting HPLC on a sample of purified
first composition using S-MNTX as a standard, and (d) determining
the presence or absence of S-MNTX in the sample. In an important
embodiment, both R-MNTX and S-MNTX are used as standards, to
determine for example relative retention time of R-MNTX and S-MNTX.
In one embodiment, the purifying is multiple recryallization steps
or multiple chromatography steps. In another embodiment, the
purifying is carried out until S-MNTX is absent from the sample as
determined by HPLC. It should be understood, however, that the
purified first composition in some aspects of the invention is not
necessarily free of detectable S-MNTX. The presence of such S-MNTX,
for example, might indicate that further purification steps should
be conducted if purer R-MNTX is desired. The methods can further
involve packaging purified first composition that is free of HPLC
detectable S-MNTX. The methods further can include providing
indicia on or within the packaged, purified first composition
indicating that the packaged, purified first composition is free of
HPLC detectable S-MNTX. The method further can involve packaging a
pharmaceutically effective amount for treating anyone of the
conditions described herein. The first composition containing R-
and S-MNTX can be obtained by the methods described herein.
[0034] According to one aspect of the invention, the purifying is
carried out until S-MNTX is less than 0.4%, 0.3%, 0.2%, 0.15%,
0.1%, 0.05%, even is absent from the purified first composition as
determined by HPLC with a detection limit of 0.02 and a
quanitiation limit of 0.05%.
In one embodiment the method provides indicia on or with the
packaged purified first composition indicating a level of S-MNTX in
the packaged first purified composition.
[0035] According to one aspect of the invention a package is
provided that contains a composition comprising R-MNTX and indicia
on or contained within the package indicating a level of S-MNTX in
the composition. In one embodiment the level of S-MNTX is less than
0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05%, or is absent from the sample.
In yet another embodiment, the package further contains, mixed
together with the R-MNTX, one or more of a buffering agent, a
chelating agent, a preserving agent, a cryoprotecting agent, a
lubricating agent, a preservative, an anti-oxidant, or a binding
agent.
[0036] According to one aspect of the invention a method of
preparing a pharmaceutical product in provided, by selecting a
composition of R-MNTX because it contains S-MNTX at a level that is
less than 0.4%, 0.3%, 0.2%, 0.15%, 0.1%, 0.05% of, or is absent
from the composition, and formulating the composition into a unit
or multi unit dosage for administration to a patient.
[0037] According to another aspect of the invention, a packaged
product is provided. The package contains a composition comprising
R-MNTX, wherein the composition is free of HPLC detectable S-MNTX,
and indicia on or contained within the package indicating that the
composition is free of detectable S-MNTX. The composition can take
on a variety of forms, including, but not limited to, a standard
for use in laboratory experiments, a standard for use in
manufacturing protocols, or a pharmaceutical composition. If the
composition is a pharmaceutical composition, then one important
form of indicia is writing on a label or package insert describing
the characteristics of the pharmaceutical preparation. The indicia
can indicate directly that the composition is free of S-MNTX, or it
can indicate the same indirectly, by stating for example that the
composition is pure or 100% R-MNTX. The pharmaceutical composition
can be for treating any of the conditions described herein. The
pharmaceutical composition can contain an effective amount of the
pure R-MNTX and can take any of the forms described below as if
specifically recited in this summary, including, but not limited
to, solutions, solids, semi-solids, enteric coated materials and
the like.
[0038] According to one aspect of the invention, a method is
provided for treating or preventing opioid-induced side effects
comprising administering to a patient the R-MNTX free of detectable
S-MNTX by the chromatography procedures described herein or the
3-O-protected-R-MNTX salt intermediate composition of any of the
foregoing aspects of the invention in an amount effective to treat
the opioid-induced side effect. In one embodiment of the invention
the patient is chronically administered opioids. In another
embodiment the patient is acutely administered opioids. The
opioid-induced side effect is preferably selected from a group
consisting of constipation, immune suppression, inhibition of
gastrointestinal motility, inhibition of gastric emptying, nausea,
emesis, incomplete evacuation, bloating, abdominal distension,
increased gastroesophageal reflux, hypotension, bradycardia,
gastrointestinal dysfunction, pruritus, dysphoria, and urinary
retention. In one preferred embodiment the opioid-induced side
effect is constipation. In another preferred embodiment the
opioid-induced side effect is inhibition of gastrointestinal
motility or inhibition of gastric emptying. In yet another
preferred embodiment the opioid-induced side effect is nausea or
emesis. In yet another preferred embodiment the opioid-induced side
effect is pruritus. In yet another preferred embodiment the
opioid-induced side effect is dysphoria. In yet another preferred
embodiment the opioid-induced side effect is urinary retention.
[0039] According to one aspect of the invention, a method is
provided for treating a patient receiving an opioid for pain
resulting from surgery comprising administering to the patient an
R-MNTX composition free of detectable S-MNTX by the chromatography
procedures described herein or the 3-O-protected-R-MNTX salt
intermediate in an amount effective to promote gastrointestinal
motility, gastric emptying or relief of constipation.
[0040] According to another aspect of the invention, a method is
provided for inducing laxation in a patient in need of laxation,
comprising administering to the patient an R-MNTX composition free
of detectable S-MNTX by the chromatography procedures described
herein or the 3-O-protected-R-MNTX salt intermediate in an
effective amount.
[0041] According to yet another aspect of the invention, a method
is provided for preventing and/or treating impaction in a patient
in need of such prevention/treatment, comprising administering to
the patient an R-MNTX composition free of detectable S-MNTX by the
chromatography procedures described herein or the
3-O-protected-R-MNTX salt intermediate in an effective amount.
[0042] According to yet another aspect of the invention, a method
is provided for preventing and/or treating post-operative bowel
dysfunction following surgery, in particular abdominal surgery in a
patient in need of such prevention/treatment, comprising
administering to the patient an R-MNTX composition free of
detectable S-MNTX by the chromatography procedures described herein
or the 3-O-protected-R-MNTX salt intermediate in an effective
amount.
[0043] According to one aspect of the invention, a method is
provided for treating or preventing endogenous opioid-induced
gastrointestinal dysfunction comprising administering to the
patient an R-MNTX composition free of detectable S-MNTX by the
chromatography procedures described herein or the
3-O-protected-R-MNTX salt intermediate in an amount effective to
treat the endogenous opioid-induced gastrointestinal dysfunction.
The gastrointestinal dysfunction can be selected from a group
consisting of inhibition of gastrointestinal motility, constipation
and ileus. In some embodiments of the invention the ileus is
selected from the group comprising of: post-operative ileus,
post-partum ileus, paralytic ileus.
[0044] According to one aspect of the invention, a method is
provided for preventing or treating idiopathic constipation
comprising administering to the patient an R-MNTX composition free
of detectable S-MNTX by the chromatography procedures described
herein or the 3-O-protected-R-MNTX salt intermediate in an amount
effective to prevent or treat the idiopathic constipation.
[0045] According to yet another aspect of the invention, a method
is provided for treating irritable bowel syndrome comprising
administering to the patient an R-MNTX composition free of
detectable S-MNTX by the chromatography procedures described herein
or the 3-O-protected-R-MNTX salt intermediate in an amount
effective to ameliorate at least one symptom of the irritable bowel
syndrome. In some embodiments of the invention the R-MNTX
composition or the 3-O-protected-R-MNTX salt composition further
comprises at least one irritable bowel syndrome therapeutic agent.
The irritable bowel syndrome therapeutic agent can be selected from
the groups consisting of antispasmodics, anti-muscarinics,
anti-inflammatory agents, pro-motility agents, 5HT.sub.1 agonists,
5HT.sub.3 antagonists, 5HT.sub.4 antagonists, 5HT.sub.4 agonists,
bile salt sequestering agents, bulk-forming agents,
alpha2-adrenergic agonists, mineral oils, antidepressants, herbal
medicines, anti-diarrheal medication and combinations thereof.
[0046] According to one aspect of the invention methods are
provided for parenteral administration of the compounds and
compositions of the invention including but not limited to
intravenous, intramuscular and subcutaneous administration. In one
embodiment of the invention the compounds of the invention are in
pharmaceutical preparations suitable for use in pre-filled
syringes, pre-filled pen injectors, cartridges for use in pen
injectors, reusable syringes or other medical injectors, liquid dry
injectors, needleless pen systems, syrettes, autoinjectors, or
other patient-controlled injection devices.
[0047] These and other aspects of the invention are described in
greater detail herein.
BRIEF DESCRIPTION OF DRAWINGS
[0048] FIG. 1 provides the chemical structure of bromide salts of
R-MNTX and S-MNTX.
[0049] FIG. 2 is a chromatogram showing the separation of R and S
forms of MNTX in a mixture of S-- and R-MNTX.
[0050] FIG. 3 is a chromatogram of R-MNTX with the addition of
approximately 0.1% of the S-MNTX isomer.
[0051] FIG. 4 is a chromatogram of R-MNTX with the addition of
approximately 1.0% of the S-MNTX isomer.
[0052] FIG. 5 is a chromatogram of R-MNTX with the addition of
approximately 3.0% of the S-MNTX isomer.
[0053] FIG. 6 shows a reaction scheme for the synthesis of R-MNTX
using a preferred hydroxyl protecting group.
[0054] FIG. 7 shows an alternative reaction scheme for the
synthesis of R-MNTX using a preferred hydroxyl protecting
group.
[0055] FIG. 8 shows a kit according to the invention.
DETAILED DESCRIPTION
[0056] The invention provides synthetic routes for stereoselective
synthesis of R-MNTX, [morphinanium, 17R,
17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-17-methyl-6-oxo-,
salt, (5.alpha.)-(9Cl)], substantially pure R-MNTX, crystals of
substantially pure R-MNTX, pharmaceutical preparations containing
substantially pure R-MNTX, and methods for their use.
[0057] R-MNTX has the structure in the formula:
##STR00003##
[0058] wherein X.sup.- is a counterion. The counterion can be any
counter ion, including a zwitterion. Preferably the counterion is
pharmaceutically acceptable. Counterions include halides, sulfates,
phosphates, nitrates, and anionic-charged organic species. The
halide can be iodide, bromide, chloride, fluoride or a combination
thereof. In one embodiment the halide is iodide. In a preferred
embodiment the halide is bromide. The anionic-charged organic
species may be a sulfonate or carboxylate. The sulfonate may be
mesylate, besylate, tosylate, or triflate. The carboxylate may be
formate, acetate, citrate, or fumarate.
[0059] The invention further provides an R-MNTX intermediate,
isolated 3-O-protected-R-MNTX salt of the formula:
##STR00004##
[0060] wherein R is a hydroxyl protecting group, substantially pure
3-O-protected-R-MNTX salt, crystals of substantially pure
3-O-protected-R-MNTX salt, pharmaceutical preparations containing
substantially pure 3-O-protected-R-MNTX salt, and methods for their
use. The invention further provides synthetic routes for
stereoselective synthesis of 3-O-protected-R-MNTX salt.
[0061] "Alkyl", in general, refers to an aliphatic hydrocarbon
group which may be straight, branched or cyclic having from 1 to
about 10 carbon atoms in the chain, and all combinations and
subcombinations of ranges therein. "Branched" refers to an alkyl
group in which a lower alkyl group, such as methyl, ethyl or
propyl, is attached to a linear alkyl chain. In certain preferred
embodiments, the alkyl group is a C.sub.1-C.sub.5 alkyl group,
i.e., a branched or linear alkyl group having from 1 to about 5
carbons. In other preferred embodiments, the alkyl group is a
C.sub.1-C.sub.3 alkyl group, i.e., a branched or linear alkyl group
having from 1 to about 3 carbons. Exemplary alkyl groups include
methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. "Lower
alkyl" refers to an alkyl group having 1 to about 6 carbon atoms.
Preferred alkyl groups include the lower alkyl groups of 1 to about
3 carbons.
[0062] An "alkylating agent" is a compound that can be reacted with
a starting material to bind, typically covalently, an alkyl group
to the starting material. The alkylating agent typically includes a
leaving group that is separated from the alkyl group at the time of
attachment to the starting material. Leaving groups may be, for
example, halogens, halogenated sulfonates or halogenated acetates.
An example of an alkylating agent is cyclopropylmethyl iodide.
[0063] "Methylating agent" means a reactive species, having
electrophilic properties, that is capable of introducing a "methyl
group" at the nitrogen atom of naltrexone, so as to form a covalent
bond therewith. Illustrative methylating agents can be represented
by the formula CH.sub.3Z, wherein "Z" is a leaving group which,
upon its departure, enables CH.sub.3 to form a covalent bond with
the nitrogen atom of naltrexone, forming MNTX. Methylating agents
in general, and leaving groups in general, are well known to those
of ordinary skill in the art and are described extensively in both
the patent literature and in chemistry text books. Suitable Z
groups include, but are not limited to, fluoro, chloro, bromo,
iodo, --OSO.sub.2CF.sub.3, CH.sub.3OSO.sub.2O--,
--OSO.sub.2CH.sub.3, --OSO.sub.2C.sub.6H.sub.4-p-CH.sub.3,
--OSO.sub.2C.sub.6H.sub.4-p-Br.
[0064] "Alkenyl", in general, refers to an alkyl group containing
at least one carbon-carbon double bond and having from 2 to about
10 carbon atoms in the chain, and all combinations and
subcombinations of ranges therein. In certain preferred
embodiments, the alkenyl group is a C.sub.2-C.sub.10 alkyl group,
i.e., a branched or linear alkenyl group having from 2 to about 10
carbons. In other preferred embodiments, the alkenyl group is a
C.sub.2-C.sub.6 alkenyl group, i.e., a branched or linear alkenyl
group having from 2 to about 6 carbons. In still other preferred
embodiments, the alkenyl group is a C.sub.3-C.sub.10 alkenyl group,
i.e., a branched or linear alkenyl group having from about 3 to
about 10 carbons. In yet other preferred embodiments, the alkenyl
group is a C.sub.2-C.sub.5 alkenyl group, i.e., a branched or
linear alkenyl group having from 2 to about 5 carbons. Exemplary
alkenyl groups include, for example, vinyl, propenyl, butenyl,
pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl
groups.
[0065] "Alkylene", in general, refers to a straight or branched
bivalent aliphatic hydrocarbon group having from 1 to about 6
carbon atoms, and all combinations and subcombinations of ranges
therein. The alkylene group may be straight, branched or cyclic.
Exemplary alkylene groups include, for example, methylene
(--CH.sub.2--), ethylene (--CH.sub.2--CH.sub.2--) and propylene
(--(CH.sub.2).sub.3--). There may be optionally inserted along the
alkylene group one or more oxygen, sulfur or optionally substituted
nitrogen atoms, wherein the nitrogen substituent is alkyl as
described previously. Preferred alkylene groups have from about 1
to about 4 carbons.
[0066] "Alkenylene", in general, refers to an alkylene group
containing at least one carbon-carbon double bond. Exemplary
alkenylene groups include, for example, ethenylene (--CH.dbd.CH--)
and propenylene (--CH.dbd.CHCH.sub.2--). Preferred alkenylene
groups have from 2 to about 4 carbons.
[0067] "Cycloalkyl", in general, refers to any stable monocyclic or
bicyclic ring having from about 3 to about 10 carbons, and all
combinations and subcombinations of ranges therein. In preferred
embodiments, the cycloalkyl group is a C.sub.3-C.sub.8 cycloalkyl
group, i.e., a cycloalkyl group having from about 3 to about 8
carbons, with C.sub.3-C.sub.6 cycloalkyl groups, i.e., cycloalkyl
groups having from about 3 to about 6 carbons being more preferred.
The cycloalkyl group may be optionally substituted with one or more
cycloalkyl group substituents. Preferred cycloalkyl group
substituents include alkyl, preferably C.sub.1-C.sub.3 alkyl,
alkoxy, preferably C.sub.1-C.sub.3 alkoxy, or halo. Exemplary
cycloalkyl groups include, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
[0068] "Cycloalkyl-substituted alkyl", in general, refers to a
linear alkyl group, preferably a lower alkyl group, substituted at
a terminal carbon with a cycloalkyl group, preferably a
C.sub.3-C.sub.8 cycloalkyl group. Typical cycloalkyl-substituted
alkyl groups include cyclohexylmethyl, cyclohexylethyl,
cyclopentylethyl, cyclopentylpropyl, cyclopropylmethyl and the
like.
[0069] "Cycloalkenyl", in general, refers to an olefinically
unsaturated cycloalkyl group having from about 4 to about 10
carbons, and all combinations and subcombinations of ranges
therein. In preferred embodiments, the cycloalkenyl group is a
C.sub.5-C.sub.8 cycloalkenyl group, i.e., a cycloalkenyl group
having from about 5 to about 8 carbons.
[0070] "Alkoxy", in general, refers to an alkyl-O-- group where
alkyl is as previously described. Exemplary alkoxy groups include,
for example, methoxy, ethoxy, propoxy, butoxy and heptoxy.
[0071] "Alkoxy-alkyl", in general, refers to an alkyl-O-alkyl group
where alkyl is as previously described.
[0072] "Acyl", in general, means an alkyl-CO-- group wherein alkyl
is as previously described. Preferred acyl groups comprise lower
alkyl groups, such as alkyl of about 1 to about 3 carbons.
Exemplary acyl groups include acetyl, propanoyl, 2-methylpropanoyl,
and butanoyl.
[0073] "Aryl", in general, refers to an aromatic carbocyclic
radical containing 6, 10 or 14 carbons. The phenyl group may be
optionally substituted with one or two or more substituents.
Preferred aryl group substituents include alkyl groups, preferably
C.sub.1-C.sub.5 alkyl groups. Exemplary aryl groups include phenyl
and naphthyl.
[0074] "Aryl-substituted alkyl", in general, refers to an linear
alkyl group, preferably a lower alkyl group, substituted at a
carbon with an optionally substituted aryl group, preferably an
optionally substituted phenyl ring. Exemplary aryl-substituted
alkyl groups include, for example, phenylmethyl, phenylethyl and
3-(4-methylphenyl)propyl.
[0075] "Heterocyclic", in general, refers to a monocyclic or
multicylic ring system radical containing from about 4 to about 10
members, and all combinations and subcombinations of ranges
therein, wherein one or more of the members is an element other
than carbon, for example, nitrogen, oxygen or sulfur. The
heterocyclic group may be aromatic or nonaromatic. Exemplary
heterocyclic groups include, for example, isoxazole, pyrrole and
piperidine groups.
[0076] "Organic solvent" has its common ordinary meaning to those
of skill in this art. Exemplary organic solvents useful in the
invention include, but are not limited to tetrahydrofuran, acetone,
hexane, ether, chloroform, acetic acid, acetonitrile, chloroform,
cyclohexane, methanol, and toluene. Anhydrous organic solvents are
included.
[0077] "Dipolar aprotic" solvents are protophilic solvents that
cannot donate labile hydrogen atoms and that exhibit a permanent
dipole moment. Examples include acetone, ethyl acetate, dimethyl
sulfoxide (DMSO), dimethyl formamide (DMF) and
N-methylpyrrolidone.
[0078] "Dipolar protic" solvents are those that can donate labile
hydrogen atoms and that exhibit a permanent dipole moment. Examples
include water, alcohols such as 2-propanol, ethanol, methanol,
carboxylic acids such as formic acid, acetic acid, and propionic
acid.
[0079] "Tertiary amines" has its common, ordinary meaning In
general, the tertiary amines useful in the invention have the
general formula:
##STR00005##
wherein R.sub.1, R.sub.2, and R.sub.3 are identical or a
combination of different straight or branched chain alkyl groups,
alkenyl groups, alkylene groups, alkenylene groups, cycloalkyl
groups, cycloalkyl-substituted alkyl groups, cycloalkenyl groups,
alkoxy groups, alkoxy-alkyl groups, acyl groups, aryl groups,
aryl-substituted alkyl groups, and heterocyclic groups. Exemplary
tertiary amines useful according to the invention are those where
R.sub.1-3 is an alkyl group of the formula (C.sub.1H.sub.2n+1,
n=1-4), or aralkyl group of the formula (C.sub.6H.sub.5
(CH.sub.2).sub.n-- [n=1-2]. Exemplary tertiary amines useful
according to the invention also are cycloalkyl tertiary amines
(e.g., N-methylmorpholine, N-methylpyrrolidine,
N-methylpiperidine), pyridine and Proton Sponge.RTM.
(N,N,N',N'-tetramethyl-1,8-naphthalene).
[0080] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Preferred protecting groups
are those that are stable during formation, isolation and
purification. A preferred protecting group is an isobutyryl
groups,); silyl ethers (SiR.sub.3, wherein each R can be
independently C.sub.1-C.sub.6 alkyl, straight chain or branched);
2-tetrahydropyranyl ether, alkyl carbonates; a benzyloxycarbonyl
group and a tert-butyloxycarbonyl group. Other preferred protecting
groups that may be employed in accordance with the present
invention are described in Greene, T. W. and Wuts, P. G. M.,
Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons,
1991. The expression "hydroxyl protective group" as used
hereinbelow is intended to designate a group which is inserted in
place of the hydrogen atom of an OH group.
[0081] When the hydroxyl protective group is an aliphatic ester it
preferably represents an radical selected from the group consisting
of alkanoyl having 3 to 8 carbon atoms; alkenoyl having one or two
double bonds and 3 to 8 carbon atoms;
##STR00006##
[0082] wherein the cycloalkyl portion contains 3 to 7 ring atoms
and r is zero, one, two or three; phenoxyacetyl; pyridinecarbonyl;
and
##STR00007##
[0083] wherein r is zero, one, two or three and phenyl is
unsubstituted or is substituted by 1 to 3 alkyl groups each having
1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo,
trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or
alkanoylamino having 2 to 6 carbon atoms.
[0084] When the acyl group is alkanoyl, there are included both
unbranched and branched alkanoyl, for example, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl, pivalyl
(pivaloyl), 3-methylpentanoyl, 3,3-dimethylbutanoyl,
2,2-dimethylpentanoyl and the like. Pivalyl, isobutyryl and
isovaleryl are important examples.
[0085] When the acyl group is alkenoyl, there are included, for
example, crotonyl, 2,5-hexadienoyl and 3,6-octadienoyl.
[0086] When the acyl group is
##STR00008##
[0087] there are included cycloalkanecarbonyl and
cycloalkanealkanoyl groups wherein the cycloalkane portion can
optionally bear 1 or 2 alkyl groups as substituents, e.g.
cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl,
cyclopropaneacetyl, .alpha.-methylcyclopropaneacetyl,
1-methylcyclopropaneacetyl, cyclopropanepropionyl,
.alpha.-methylcyclopropanepropionyl,
2-isobutylcyclopropanepropionyl, cyclobutanecarbonyl,
3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl,
2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclopentanecarbonyl,
cyclohexaneacetyl, cyclohexanecarbonyl, cycloheptanecarbonyl and
cycloheptanepropionyl. Cyclohexanecarbonyl is especially
preferred.
[0088] When the acyl group is pyridinecarbonyl, there are included
picolinoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl)
and isonicotinoyl (4-pyridine-carbonyl).
[0089] When the acyl group is
##STR00009##
[0090] there are included, for example, benzoyl, phenylacetyl,
.alpha.-phenylpropionyl, .beta.-phenylpropionyl, p-toluoyl,
m-toluoyl, o-toluoyl, o-ethylbenzoyl, p-tert-butylbenzoyl,
3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl,
2,4,6-trimethylbenzoyl, m-methylphenylacetyl,
p-isobutylphenylacetyl, .beta.-(p-ethylphenyl)propionyl, p-anisoyl,
m-anisoyl, o-anisoyl, m-isopropoxybenzoyl, p-methoxyphenylacetyl,
m-isobutoxyphenylacetyl, m-diethylaminobenzoyl,
3-methoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl,
p-dibutylaminobenzoyl, 3,4-diethoxyphenylacetyl,
.beta.-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl,
m-bromobenzoyl, p-chlorobenzoyl, p-fluorobenzoyl,
2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl,
p-chlorophenylacetyl, .alpha.-(m-bromophenyl)propionyl,
p-trifluoromethylbenzoyl, 2,4-di(trifluoromethyl)benzoyl,
m-trifluoromethylphenylacetyl,
.beta.-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl,
p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl,
m-propionamidobenzoyl, 3-chloro-4-acetamidophenylacetyl,
p-n-butoxybenzoyl, 2,4,6-triethoxybenzoyl,
.beta.-(p-trifluoromethylphenyl)propionyl,
2-methyl-4-methoxybenzoyl, p-acetamidophenylpropionyl and
3-chloro-4-ethoxybenzoyl.
[0091] When the hydroxyl protective group is a carbonate grouping,
it has the structural formula
##STR00010##
[0092] i.e., it is an organic radical which can be considered to be
derived from a carbonic acid by removal of the hydroxyl group from
the COOH portion. Y' preferably represents alkyl having 1 to 7
carbon atoms; alkenyl having one or two double bonds and 2 to 7
carbon atoms;
cycloalkyl-C.sub.rH.sub.2r--
[0093] wherein the cycloalkyl portion contains 3 to 7 ring atoms
and r is zero, one, two or three; phenoxy; 2-, 3-, or 4-pyridyl;
or
phenyl-C.sub.rH.sub.2r--
[0094] wherein r is zero, one, two or three and phenyl is
unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4
carbon atoms, alkoxy having 1 to 4 carbon atoms, halo,
trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or
alkanoylamino having 2 to 6 carbon atoms. Most preferably, Y' is
C.sub.1-C.sub.7 alkyl, particularly ethyl or isopropyl.
[0095] Preferred protecting groups are those that can be
selectively appended to a functionality. These groups render such
functionality inert to chemical reaction conditions to which the
compound may be exposed. After the protecting group has served its
purpose it can be selectively removed from the functionality
without altering the molecular structure. Most preferred protecting
groups are those that can be selectively appended to and removed
from the functionality under mild conditions, in high yield.
[0096] Preferred protecting groups for 3-O-protected-naltrexone
include those that are more stable and sterically hindered compared
to an acetyl protecting group, which was found to be unstable
during preparation and purification, thus resulting in lower yield
and purity, and difficulty in handling. Examples of preferred
protecting groups for use in the method of the present invention
include isobutyryl, 2-methyl butyryl, tertbutyl carbonyl and the
like. In a preferred embodiment, the protecting group is
isobutyryl, due to its greater stability which results in higher
yield and purity. Such protecting groups provide yields of
3-O-protected-naltrexone of greater than 70, preferably greater
than 75%. In one embodiment, yield of 3-O-protected-naltrexone is
about 80% or greater.
[0097] Although some of the foregoing protecting groups and
tertiary amines are not substituted, those of ordinary skill in the
art will understand that substitutions can be present in some
circumstances.
[0098] The present invention provides a method for stereoselective
synthesis of R-MNTX comprising;
[0099] (a) methylating a 3-O-protected-naltrexone with a
methylating agent to yield 3-O-protected-R-MNTX salt; and
[0100] (b) hydrolysis to remove the 3-hydroxyl protecting group to
yield R-MNTX. Preferred hydroxyl protecting groups of the
3-O-protected-R-MNTX salt include isobutyryl, 2-methyl butyryl,
tertbutyl carbonyl, silyl ethers, 2-tetrahydropyranyl ethers, and
alkyl carbonates.
[0101] Unlike the method described by Goldberg et al which teaches
room temperature for three weeks or 70.degree. C. for seven days
for the methylation reaction to produce N-MNTX, the stereoselective
methylation conditions of the present invention are conducted at a
temperature above 70.degree. C., more preferably above 80.degree.
C. In one embodiment, the reaction is carried out at about
88.degree. C. Based on the standard principles of chemical
reactions involving stereoisomers, one would expect at higher
temperatures the reaction would proceed with kinetic control
resulting in a mixture of R-MNTX and S-MNTX with high percentages
of both stereoisomers. It was surprising that at elevated
temperatures the method of the present invention provided
predominantly the R-MNTX rather than a mixture with a higher
percentage of S-MNTX.
[0102] The methylation reaction of the present invention is allowed
to proceed from 1 hour to about 24 hours, preferably about 5 hours
to about 16 hours, more preferably about 8 to 12 hours, most
preferably about 10 hours. This reaction time offers a major
industrial scale advantage over the three weeks at room temperature
or seven days at 70.degree. C. taught by Goldberg et al.
[0103] In a preferred embodiment, the methylation reaction is
conducted at about 88.degree. C. for 10 hours. These reaction
parameters are highly desirable for the development of a process
amenable to scale-up in industrial scale.
[0104] The present invention further provides a method of purifying
R-MNTX from a mixture of stereoisomers of R-MNTX and S-MNTX, the
method comprising at least one, two or multiple recrystallizations.
The recrystallized product is highly enriched in R-MNTX and
substantially devoid of S-MNTX. In one embodiment the
recrystallized product is greater than 98% pure R-MNTX. It is
understood that an artisan skilled in the art can optimize this
methodology to obtain higher purity and/or higher yield of R-MNTX
in which the recrystallized product is greater than 99% pure R-MNTX
and even greater than 99.9% pure R-MNTX.
[0105] The recrystallization solvent can be an organic solvent or a
mixture of organic solvents or a mixture of organic solvent(s) plus
water. A preferred solvent is an alcohol, more preferred a low
molecular weight alcohol. In one embodiment, the low molecular
weight alcohol is methanol.
[0106] Goldberg et al., and Cantrell et al., make use of organic
solvent(s)/water for recrystallization. This is a standard practice
to clean up a reaction mixture. It is not the Goldberg et al's nor
Cantrell et al's stated goal to obtain one stereoisomer over the
other, as they do not address the existence of stereoisomers, or
whether a stereoisomer is obtained preferentially. Therefore,
neither Goldberg et al., nor Cantrell et al., address the impact
that recrystallization may have on the composition of
stereoisomers. The present invention discloses the conditions under
which recrystallization can be used advantageously to increase the
purity of R-MNTX from a mixture of R-MNTX and S-MNTX.
[0107] One aspect of the invention is a method of resolving and
identifying R-MNTX and S-MNTX in a solution of MNTX. The R-MNTX
also is useful in HPLC assay methods of quantifying an amount of
R-MNTX in a composition or mixture in which the method comprises
applying a sample of the composition or mixture to a chromatography
column, resolving the components of the composition or mixture, and
calculating the amount of R-MNTX in the sample by comparing the
percentage of a resolved component in the sample with the
percentage of a standard concentration of R-MNTX. The method is
particularly useful in reverse phase HPLC chromatography.
[0108] The pharmaceutical preparations of the invention, when used
alone or in cocktails, are administered in therapeutically
effective amounts. A therapeutically effective amount will be
determined by the parameters discussed below; but, in any event, is
that amount which establishes a level of the drug(s) effective for
treating a subject, such as a human subject, having one of the
conditions described herein. An effective amount means that amount
alone or with multiple doses, necessary to delay the onset of,
lessen the severity of, or inhibit completely, lessen the
progression of, or halt altogether the onset or progression of the
condition being treated or a symptom associated therewith. In the
case of constipation, an effective amount, for example, is that
amount which relieves a symptom of constipation, which induces a
bowel movement, which increases the frequency of bowel movements,
or which decreases oral-cecal transit time. The known and
conventional definition of constipation is (i) less than one bowel
movement in the previous three days or (ii) less than three bowel
movements in the previous week (See e.g., U.S. Pat. No. 6,559,158).
In other words, a patient is not constipated (i.e., has "regular
bowel movements" as used herein) if the patient has at least one
bowel movement every three days and at least three bowel movements
per week. Accordingly, at least one bowel movement every two days
would be considered regular bowel movements. Likewise, at least one
bowel movement per day is a regular bowel movement. Effective
amounts therefore can be those amounts necessary to establish or
maintain regular bowel movements.
[0109] In certain instances, the amount is sufficient to induce a
bowel movement within 12 hours of administration of the R-MNTX or
the R-MNTX intermediate, 3-O-protected-R-MNTX salt, 10 hours, 8
hours, 6 hours, 4 hours, 2 hours, 1 hour and even immediately upon
administration, depending upon the mode of administration.
Intravenous administration can produce an immediate effect of
laxation in chronic opioid users. Subcutaneous administration can
result in a bowel movement within 12 hours of administration,
preferably within 4 hours of administration. When administered to a
subject, effective amounts will depend, of course, on the
particular condition being treated; the severity of the condition;
individual patient parameters including age, physical condition,
size and weight; concurrent treatment and, especially, concurrent
treatment with opioids where opioids are administered chronically;
frequency of treatment; and the mode of administration. These
factors are well known to those of ordinary skill in the art and
can be addressed with no more than routine experimentation.
[0110] Patients amenable to the therapy of the present invention
include but are not limited to terminally ill patients, patients
with advanced medical illness, cancer patients, AIDS patients,
post-operative patients, patients with chronic pain, patients with
neuropathies, patients with rheumatoid arthritis, patients with
osteoarthritis, patients with chronic back pain, patients with
spinal cord injury, patients with chronic abdominal pain, patients
with chronic pancreatic pain, patients with pelvic/perineal pain,
patients with fibromyalgia, patients with chronic fatigue syndrome,
patients infected with HCV, patients with irritable bowel syndrome,
patients with migraine or tension headaches, patients with sickle
cell anemia, patients on hemodialysis, and the like.
[0111] Patients amenable to the therapy of the present invention
also include but are not limited to patients suffering from
dysfunctions caused by endogenous opioids, especially in
post-operative settings. In certain embodiments, the R-MNTX or
intermediate thereof is present in an amount sufficient to
accelerate discharge from hospital post-surgery, including
abdominal surgeries such as rectal resection, colectomy, stomach,
esophageal, duodenal, appendectomy, hysterectomy, or non-abdominal
surgeries such as orthopedic, trauma injuries, thoracic or
transplantation surgery. This treatment can be effective to shorten
the length of the time in the hospital, or to shorten the time to a
hospital discharge order written post-operatively by shortening the
time to bowel sounds after surgery, or first flatus, to first
laxation or to solid diet intake following surgery. The R-MNTX or
intermediate thereof may continue to be provided after the patient
has ceased to receive opioid pain medications post-operatively.
[0112] Certain patients particularly amenable to treatment are
patients having the symptoms of constipation and/or
gastrointestinal immotility and who have failed to obtain relief or
ceased to obtain relief or a consistent degree of relief of their
symptoms using a laxative or a stool softener, either alone or in
combination, or who are otherwise resistant to laxatives and/or
stool softeners. Such patients are said to be refractory to the
conventional laxatives and/or stool softeners. The constipation
and/or gastrointestinal immotility may be induced or a consequence
of one or more diverse conditions including, but not limited to, a
disease condition, a physical condition, a drug-induced condition,
a physiological imbalance, stress, anxiety, and the like. The
conditions inducing constipation and/or gastrointestinal immotility
may be acute conditions or chronic conditions.
[0113] The subjects can be treated with a combination of R-MNTX, or
the 3-O-protected-R-MNTX intermediate thereof, and a laxative
and/or a stool softener (and optionally, an opioid). In these
circumstances the R-MNTX or the intermediate thereof and the other
therapeutic agent(s) are administered close enough in time such
that the subject experiences the effects of the various agents as
desired, which typically is at the same time. In some embodiments
the R-MNTX or the intermediate thereof will be delivered first in
time, in some embodiments second in time, and still in some
embodiments at the same time. As discussed in greater detail
herein, the invention contemplates pharmaceutical preparations
where the R-MNTX or intermediate thereof is administered in a
formulation including the R-MNTX or the intermediate thereof and
one or both of a laxative and a stool softener (and, optionally, an
opioid). These formulations may be parenteral or oral, such as the
ones described in U.S. Ser. No. 10/821,809. Included are solid,
semisolid, liquid, controlled release, lyophilized and other such
formulations.
[0114] In an important embodiment, the administered amount of
R-MNTX is sufficient to induce laxation. This has particular
application where the subject is a chronic opioid user. Chronic
opioid use as used herein includes daily opioid treatment for a
week or more or intermittent opioid use for at least two weeks. It
previously was determined that patients receiving opioids
chronically become tolerant to opioids and need increasing doses.
Thus, a patient receiving oral doses of opioids chronically would
be receiving typically between 40 and 100 mg per day of a
morphine-equivalent dose of opioid. It likewise was determined
surprisingly that such subjects become more responsive to the
effects of MNTX and that surprisingly lower doses induced side
effects. Thus, to induce immediate laxation, it requires on the
order of only about 0.15 mg/kg MNTX intravenously. For oral
administration, a sufficient dose is believed to be less than 3
mg/kg uncoated and even less when the R-MNTX is enterically
coated.
[0115] Patients using opioids chronically include late stage cancer
patients, elderly patients with osteoarthritic changes, methadone
maintenance patients, neuropathic pain and chronic back pain
patients. Treatment of these patients is important from a quality
of life standpoint, as well as to reduce complications arising from
chronic constipation, such as hemorrhoids, appetite suppression,
mucosal breakdown, sepsis, colon cancer risk, and myocardial
infarction.
[0116] The opioid can be any pharmaceutically acceptable opioid.
Common opioids are those selected from the group consisting of
alfentanil, anileridine, asimadoline, bremazocine, burprenorphine,
butorphanol, codeine, dezocine, diacetylmorphine (heroin),
dihydrocodeine, diphenoxylate, fedotozine, fentanyl,
funaltrexamine, hydrocodone, hydromorphone, levallorphan,
levomethadyl acetate, levorphanol, loperamide, meperidine
(pethidine), methadone, morphine, morphine-6-glucoronide,
nalbuphine, nalorphine, opium, oxycodone, oxymorphone, pentazocine,
propiram, propoxyphene, remifentanyl, sufentanil, tilidine,
trimebutine, and tramadol. The opioid also may be mixed together
with the R-MNTX or intermediate thereof and provided in any of the
forms described above in connection with R-MNTX or intermediate
thereof.
[0117] Generally, oral doses of R-MNTX and intermediates thereof
will be from about 0.25 to about 19.0 mg/kg body weight per day.
Generally, parenteral administration, including intravenous and
subcutaneous administration, will be from about 0.01 to 1.0 mg/kg
body weight depending on whether administration is as a bolus or is
spread out over time such as with an I.V. drip. Generally, the I.V.
dose for post-operative bowel dysfunction (POBD) is 0.3 mg/kg. It
is expected that doses ranging from 0.01 to 0.45 mg/kg body weight
will yield the desired results. Dosage may be adjusted
appropriately to achieve desired drug levels, local or systemic,
depending on the mode of administration. For example, it is
expected that the dosage for oral administration of the opioid
antagonists in an enterically-coated formulation would be lower
than in an immediate release oral formulation. In the event that
the response in a patient is insufficient at such doses, even
higher doses (or effectively higher dosage by a different, more
localized delivery route) may be employed to the extent that the
patient tolerance permits. Multiple doses per day are contemplated
to achieve appropriate systemic levels of compounds. Appropriate
systemic levels can be determined by, for example, measurement of
the patient's peak or sustained plasma level of the drug. Peak
plasma levels below 100 ng/ml are preferred in some instances.
"Dose" and "dosage" are used interchangeably herein.
[0118] A variety of administration routes are available. The
particular mode selected will depend, of course, upon the
particular combination of drugs selected, the severity of the
condition being treated, or prevented, the condition of the
patient, and the dosage required for therapeutic efficacy. The
methods of this invention, generally speaking, may be practiced
using any mode of administration that is medically acceptable,
meaning any mode that produces effective levels of the active
compounds without causing clinically unacceptable adverse effects.
Such modes of administration include oral, rectal, topical,
transdermal, sublingual, intravenous infusion, pulmonary,
intra-arterial, intra-adipose tissue, intra-lymphatic,
intramuscular, intracavity, aerosol, aural (e.g., via eardrops),
intranasal, inhalation, intra-articular, needleless injection,
subcutaneous or intradermal (e.g., transdermal) delivery. For
continuous infusion, a patient-controlled analgesia (PCA) device or
an implantable drug delivery device may be employed. Oral, rectal,
or topical administration may be important for prophylactic or
long-term treatment. Preferred rectal modes of delivery include
administration as a suppository or enema wash.
[0119] The pharmaceutical preparations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. All methods include the
step of bringing the compounds of the invention into association
with a carrier which constitutes one or more accessory ingredients.
In general, the compositions are prepared by uniformly and
intimately bringing the compounds of the invention into association
with a liquid carrier, a finely divided solid carrier, or both, and
then, if necessary, shaping the product.
[0120] When administered, the pharmaceutical preparations of the
invention are applied in pharmaceutically acceptable compositions.
Such preparations may routinely contain salts, buffering agents,
preservatives, compatible carriers, lubricants, and optionally
other therapeutic ingredients. When used in medicine the salts
should be pharmaceutically acceptable, but non-pharmaceutically
acceptable salts may conveniently be used to prepare
pharmaceutically acceptable salts thereof and are not excluded from
the scope of the invention. Such pharmacologically and
pharmaceutically acceptable salts include, but are not limited to,
those prepared from the following acids: hydrochloric, hydrobromic,
sulfuric, nitric, phosphoric, maleic, acetic, salicylic,
p-toluenesulfonic, tartaric, citric, methanesulfonic, formic,
succinic, naphthalene-2-sulfonic, pamoic,
3-hydroxy-2-naphthalenecarboxylic, and benzene sulfonic.
[0121] It should be understood that when referring to MNTX, R- and
S-MNTX, and therapeutic agent(s) of the invention, it is meant to
encompass salts of the same. Such salts are of a variety well known
to those or ordinary skill in the art. When used in pharmaceutical
preparations, the salts preferably are pharmaceutically-acceptable
for use in humans. Bromide is an example of one such salt.
[0122] The pharmaceutical preparations of the present invention may
include or be diluted into a pharmaceutically-acceptable carrier.
The term "pharmaceutically-acceptable carrier" as used herein means
one or more compatible solid or liquid fillers, diluents or
encapsulating substances which are suitable for administration to a
human or other mammal such as non-human primate, a dog, cat, horse,
cow, sheep, pig, or goat. The term "carrier" denotes an organic or
inorganic ingredient, natural or synthetic, with which the active
ingredient is combined to facilitate the application. The carriers
are capable of being commingled with the preparations of the
present invention, and with each other, in a manner such that there
is no interaction which would substantially impair the desired
pharmaceutical efficacy or stability. Carrier formulations suitable
for oral administration, for suppositories, and for parenteral
administration, etc., can be found in Remington's Pharmaceutical
Sciences, Mack Publishing Company, Easton, Pa.
[0123] Aqueous formulations may include a chelating agent, a
buffering agent, an anti-oxidant and, optionally, an isotonicity
agent, preferably pH adjusted to between 3.0 and 3.5. Examples of
such formulations that are stable to autoclaving and long term
storage are described in co-pending U.S. application Ser. No.
10/821,811, entitled "Pharmaceutical Formulation."
[0124] Chelating agents include, for example,
ethylenediaminetetraacetic acid (EDTA) and derivatives thereof,
citric acid and derivatives thereof, niacinamide and derivatives
thereof, sodium desoxycholate and derivatives thereof, and
L-glutamic acid, N,N-diacetic acid and derivatives thereof.
[0125] Buffering agents include those selected from the group
consisting of citric acid, sodium citrate, sodium acetate, acetic
acid, sodium phosphate and phosphoric acid, sodium ascorbate,
tartaric acid, maleic acid, glycine, sodium lactate, lactic acid,
ascorbic acid, imidazole, sodium bicarbonate and carbonic acid,
sodium succinate and succinic acid, histidine, and sodium benzoate
and benzoic acid, or combinations thereof.
[0126] Antioxidants include those selected from the group
consisting of an ascorbic acid derivative, butylated hydroxy
anisole, butylated hydroxy toluene, alkyl gallate, sodium
meta-bisulfite, sodium bisulfite, sodium dithionite, sodium
thioglycollate acid, sodium formaldehyde sulfoxylate, tocopheral
and derivatives thereof, monothioglycerol, and sodium sulfite. The
preferred antioxidant is monothioglycerol.
[0127] Isotonicity agents include those selected from the group
consisting of sodium chloride, mannitol, lactose, dextrose,
glycerol, and sorbitol.
[0128] Preservatives that can be used with the present compositions
include benzyl alcohol, parabens, thimerosal, chlorobutanol and
preferably benzalkonium chloride. Typically, the preservative will
be present in a composition in a concentration of up to about 2% by
weight. The exact concentration of the preservative, however, will
vary depending upon the intended use and can be easily ascertained
by one skilled in the art.
[0129] The compounds of the invention can be prepared in
lyophilized compositions, preferably in the presence of a
cryoprotecting agent such as mannitol, or lactose, sucrose,
polyethylene glycol, and polyvinyl pyrrolidines. Cryoprotecting
agents which result in a reconstitution pH of 6.0 or less are
preferred. The invention therefore provides a lyophilized
preparation of therapeutic agent(s) of the invention. The
preparation can contain a cryoprotecting agent, such as mannitol or
lactose, which is preferably neutral or acidic in water.
[0130] Oral, parenteral and suppository formulations of agents are
well known and commercially available. The therapeutic agent(s) of
the invention can be added to such well known formulations. It can
be mixed together in solution or semi-solid solution in such
formulations, can be provided in a suspension within such
formulations or could be contained in particles within such
formulations.
[0131] A product containing therapeutic agent(s) of the invention
and, optionally, one or more other active agents can be configured
as an oral dosage. The oral dosage may be a liquid, a semisolid or
a solid. An opioid may optionally be included in the oral dosage.
The oral dosage may be configured to release the therapeutic
agent(s) of the invention before, after or simultaneously with the
other agent (and/or the opioid). The oral dosage may be configured
to have the therapeutic agent(s) of the invention and the other
agents release completely in the stomach, release partially in the
stomach and partially in the intestine, in the intestine, in the
colon, partially in the stomach, or wholly in the colon. The oral
dosage also may be configured whereby the release of the
therapeutic agent(s) of the invention is confined to the stomach or
intestine while the release of the other active agent is not so
confined or is confined differently from the therapeutic agent(s)
of the invention. For example, the therapeutic agent(s) of the
invention may be an enterically coated core or pellets contained
within a pill or capsule that releases the other agent first and
releases the therapeutic agent(s) of the invention only after the
therapeutic agent(s) of the invention passes through the stomach
and into the intestine. The therapeutic agent(s) of the invention
also can be in a sustained release material, whereby the
therapeutic agent(s) of the invention is released throughout the
gastrointestinal tract and the other agent is released on the same
or a different schedule. The same objective for therapeutic
agent(s) of the invention release can be achieved with immediate
release of therapeutic agent(s) of the invention combined with
enteric coated therapeutic agent(s) of the invention. In these
instances, the other agent could be released immediately in the
stomach, throughout the gastrointestinal tract or only in the
intestine.
[0132] The materials useful for achieving these different release
profiles are well known to those of ordinary skill in the art
Immediate release is obtainable by conventional tablets with
binders which dissolve in the stomach. Coatings which dissolve at
the pH of the stomach or which dissolve at elevated temperatures
will achieve the same purpose. Release only in the intestine is
achieved using conventional enteric coatings such as pH sensitive
coatings which dissolve in the pH environment of the intestine (but
not the stomach) or coatings which dissolve over time. Release
throughout the gastrointestinal tract is achieved by using
sustained-release materials and/or combinations of the immediate
release systems and sustained and/or delayed intentional release
systems (e.g., pellets which dissolve at different pHs).
[0133] In the event that it is desirable to release the therapeutic
agent(s) of the invention first, the therapeutic agent(s) of the
invention could be coated on the surface of the controlled release
formulation in any pharmaceutically acceptable carrier suitable for
such coatings and for permitting the release of the therapeutic
agent(s) of the invention, such as in a temperature sensitive
pharmaceutically acceptable carrier used for controlled release
routinely. Other coatings which dissolve when placed in the body
are well known to those of ordinary skill in the art.
[0134] The therapeutic agent(s) of the invention also may be mixed
throughout a controlled release formulation, whereby it is released
before, after or simultaneously with another agent. The therapeutic
agent(s) of the invention may be free, that is, solubilized within
the material of the formulation. The therapeutic agent(s) of the
invention also may be in the form of vesicles, such as wax coated
micropellets dispersed throughout the material of the formulation.
The coated pellets can be fashioned to immediately release the
therapeutic agent(s) of the invention based on temperature, pH or
the like. The pellets also can be configured so as to delay the
release of the therapeutic agent(s) of the invention, allowing the
other agent a period of time to act before the therapeutic agent(s)
of the invention exerts its effects. The therapeutic agent(s) of
the invention pellets also can be configured to release the
therapeutic agent(s) of the invention in virtually any sustained
release pattern, including patterns exhibiting first order release
kinetics or sigmoidal order release kinetics using materials of the
prior art and well known to those of ordinary skill in the art.
[0135] The therapeutic agent(s) of the invention also can be
contained within a core within the controlled release formulation.
The core may have any one or any combination of the properties
described above in connection with the pellets. The therapeutic
agent(s) of the invention may be, for example, in a core coated
with a material, dispersed throughout a material, coated onto a
material or adsorbed into or throughout a material.
[0136] It should be understood that the pellets or core may be of
virtually any type. They may be drug coated with a release
material, drug interspersed throughout material, drug adsorbed into
a material, and so on. The material may be erodible or
nonerodible.
[0137] The therapeutic agent(s) of the invention, may be provided
in particles. Particles as used herein means nano or microparticles
(or in some instances larger) which can consist in whole or in part
of the therapeutic agent(s) of the inventions or the other agents
as described herein. The particles may contain the therapeutic
agent(s) in a core surrounded by a coating, including, but not
limited to, an enteric coating. The therapeutic agent(s) also may
be dispersed throughout the particles. The therapeutic agent(s)
also may be adsorbed into the particles. The particles may be of
any order release kinetics, including zero order release, first
order release, second order release, delayed release, sustained
release, immediate release, and any combination thereof, etc. The
particle may include, in addition to the therapeutic agent(s), any
of those materials routinely used in the art of pharmacy and
medicine, including, but not limited to, erodible, nonerodible,
biodegradable, or nonbiodegradable material or combinations
thereof. The particles may be microcapsules which contain the
antagonist in a solution or in a semi-solid state. The particles
may be of virtually any shape.
[0138] Both non-biodegradable and biodegradable polymeric materials
can be used in the manufacture of particles for delivering the
therapeutic agent(s). Such polymers may be natural or synthetic
polymers. The polymer is selected based on the period of time over
which release is desired. Bioadhesive polymers of particular
interest include bioerodible hydrogels described by H. S. Sawhney,
C. P. Pathak and J. A. Hubell in Macromolecules, (1993) 26:581-587,
the teachings of which are incorporated herein. These include
polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides,
polyacrylic acid, alginate, chitosan, poly(methyl methacrylates),
poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl
methacrylate), poly(hexylmethacrylate), poly(isodecyl
methacrylate), poly(lauryl methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate),
poly(isobutyl acrylate), and poly(octadecyl acrylate).
[0139] The therapeutic agent(s) may be contained in controlled
release systems. The term "controlled release" is intended to refer
to any drug-containing formulation in which the manner and profile
of drug release from the formulation are controlled. This refers to
immediate as well as nonimmediate release formulations, with
nonimmediate release formulations including but not limited to
sustained release and delayed release formulations. The term
"sustained release" (also referred to as "extended release") is
used in its conventional sense to refer to a drug formulation that
provides for gradual release of a drug over an extended period of
time, and that preferably, although not necessarily, results in
substantially constant blood levels of a drug over an extended time
period. The term "delayed release" is used in its conventional
sense to refer to a drug formulation in which there is a time delay
between administration of the formulation and the release of the
drug therefrom. "Delayed release" may or may not involve gradual
release of drug over an extended period of time, and thus may or
may not be "sustained release." These formulations may be for any
mode of administration.
[0140] Delivery systems specific for the gastrointestinal tract are
roughly divided into three types: the first is a delayed release
system designed to release a drug in response to, for example, a
change in pH; the second is a timed-release system designed to
release a drug after a predetermined time; and the third is a
microflora enzyme system making use of the abundant enterobacteria
in the lower part of the gastrointestinal tract (e.g., in a colonic
site-directed release formulation).
[0141] An example of a delayed release system is one that uses, for
example, an acrylic or cellulosic coating material and dissolves on
pH change. Because of ease of preparation, many reports on such
"enteric coatings" have been made. In general, an enteric coating
is one which passes through the stomach without releasing
substantial amounts of drug in the stomach (i.e., less than 10%
release, 5% release and even 1% release in the stomach) and
sufficiently disintegrating in the intestinal tract (by contact
with approximately neutral or alkaline intestine juices) to allow
the transport (active or passive) of the active agent through the
walls of the intestinal tract.
[0142] Various in vitro tests for determining whether or not a
coating is classified as an enteric coating have been published in
the pharmacopoeia of various countries. A coating which remains
intact for at least 2 hours, in contact with artificial gastric
juices such as HCl of pH 1 at 36 to 38.degree. C. and thereafter
disintegrates within 30 minutes in artificial intestinal juices
such as a KH.sub.2PO.sub.4 buffered solution of pH 6.8 is one
example. One such well known system is EUDRAGIT material,
commercially available and reported on by Behringer, Manchester
University, Saale Co., and the like. Enteric coatings are discussed
further, below.
[0143] A timed release system is represented by Time Erosion System
(TES) by Fujisawa Pharmaceutical Co., Ltd. and Pulsincap by R. P.
Scherer. According to these systems, the site of drug release is
decided by the time of transit of a preparation in the
gastrointestinal tract. Since the transit of a preparation in the
gastrointestinal tract is largely influenced by the gastric
emptying time, some time release systems are also enterically
coated.
[0144] Systems making use of the enterobacteria can be classified
into those utilizing degradation of azoaromatic polymers by an azo
reductase produced from enterobacteria as reported by the group of
Ohio University (M. Saffran, et al., Science, Vol. 233: 1081
(1986)) and the group of Utah University (J. Kopecek, et al.,
Pharmaceutical Research, 9(12), 1540-1545 (1992)); and those
utilizing degradation of polysaccharides by beta-galactosidase of
enterobacteria as reported by the group of Hebrew University
(unexamined published Japanese patent application No. 5-50863 based
on a PCT application) and the group of Freiberg University (K. H.
Bauer et al., Pharmaceutical Research, 10(10), 5218 (1993)). In
addition, the system using chitosan degradable by chitosanase by
Teikoku Seiyaku K. K. (unexamined published Japanese patent
application No. 4-217924 and unexamined published Japanese patent
application No. 4-225922) is also included.
[0145] The enteric coating is typically, although not necessarily,
a polymeric material. Preferred enteric coating materials comprise
bioerodible, gradually hydrolyzable and/or gradually water-soluble
polymers. The "coating weight," or relative amount of coating
material per capsule, generally dictates the time interval between
ingestion and drug release. Any coating should be applied to a
sufficient thickness such that the entire coating does not dissolve
in the gastrointestinal fluids at pH below about 5, but does
dissolve at pH about 5 and above. It is expected that any anionic
polymer exhibiting a pH-dependent solubility profile can be used as
an enteric coating in the practice of the present invention. The
selection of the specific enteric coating material will depend on
the following properties: resistance to dissolution and
disintegration in the stomach; impermeability to gastric fluids and
drug/carrier/enzyme while in the stomach; ability to dissolve or
disintegrate rapidly at the target intestine site; physical and
chemical stability during storage; non-toxicity; ease of
application as a coating (substrate friendly); and economical
practicality.
[0146] Suitable enteric coating materials include, but are not
limited to: cellulosic polymers such as cellulose acetate
phthalate, cellulose acetate trimellitate, hydroxypropylmethyl
cellulose phthalate, hydroxypropylmethyl cellulose succinate and
carboxymethylcellulose sodium; acrylic acid polymers and
copolymers, preferably formed from acrylic acid, methacrylic acid,
methyl acrylate, ammonium methylacrylate, ethyl acrylate, methyl
methacrylate and/or ethyl methacrylate (e.g., those copolymers sold
under the trade name EUDRAGIT); vinyl polymers and copolymers such
as polyvinyl acetate, polyvinylacetate phthalate, vinylacetate
crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and
shellac (purified lac). Combinations of different coating materials
may also be used. Well known enteric coating material for use
herein are those acrylic acid polymers and copolymers available
under the trade name EUDRAGIT from Rohm Pharma (Germany). The
EUDRAGIT series E, L, S, RL, RS and NE copolymers are available as
solubilized in organic solvent, as an aqueous dispersion, or as a
dry powder. The EUDRAGIT series RL, NE, and RS copolymers are
insoluble in the gastrointestinal tract but are permeable and are
used primarily for extended release. The EUDRAGIT series E
copolymers dissolve in the stomach. The EUDRAGIT series L, L-30D
and S copolymers are insoluble in stomach and dissolve in the
intestine, and are thus most preferred herein.
[0147] A particular methacrylic copolymer is EUDRAGIT L,
particularly L-30D and EUDRAGIT L 100-55. In EUDRAGIT L-30D, the
ratio of free carboxyl groups to ester groups is approximately 1:1.
Further, the copolymer is known to be insoluble in gastrointestinal
fluids having pH below 5.5, generally 1.5-5.5, i.e., the pH
generally present in the fluid of the upper gastrointestinal tract,
but readily soluble or partially soluble at pH above 5.5, i.e., the
pH generally present in the fluid of lower gastrointestinal tract.
Another particular methacrylic acid polymer is EUDRAGIT S, which
differs from EUDRAGIT L-30D in that the ratio of free carboxyl
groups to ester groups is approximately 1:2. EUDRAGIT S is
insoluble at pH below 5.5, but unlike EUDRAGIT L-30D, is poorly
soluble in gastrointestinal fluids having a pH in the range of 5.5
to 7.0, such as in the small intestine. This copolymer is soluble
at pH 7.0 and above, i.e., the pH generally found in the colon.
EUDRAGIT S can be used alone as a coating to provide drug delivery
in the large intestine. Alternatively, EUDRAGIT S, being poorly
soluble in intestinal fluids below pH 7, can be used in combination
with EUDRAGIT L-30D, soluble in intestinal fluids above pH 5.5, in
order to provide a delayed release composition which can be
formulated to deliver the active agent to various segments of the
intestinal tract. The more EUDRAGIT L-30D used, the more proximal
release and delivery begins, and the more EUDRAGIT S used, the more
distal release and delivery begins. It will be appreciated by those
skilled in the art that both EUDRAGIT L-30D and EUDRAGIT S can be
replaced with other pharmaceutically acceptable polymers having
similar pH solubility characteristics. In certain embodiments of
the invention, the preferred enteric coating is ACRYL-EZE.TM.
(methacrylic acid co-polymer type C; Colorcon, West Point,
Pa.).
[0148] The enteric coating provides for controlled release of the
active agent, such that drug release can be accomplished at some
generally predictable location. The enteric coating also prevents
exposure of the therapeutic agent and carrier to the epithelial and
mucosal tissue of the buccal cavity, pharynx, esophagus, and
stomach, and to the enzymes associated with these tissues. The
enteric coating therefore helps to protect the active agent,
carrier and a patient's internal tissue from any adverse event
prior to drug release at the desired site of delivery. Furthermore,
the coated material of the present invention allows optimization of
drug absorption, active agent protection, and safety. Multiple
enteric coatings targeted to release the active agent at various
regions in the gastrointestinal tract would enable even more
effective and sustained improved delivery throughout the
gastrointestinal tract.
[0149] The coating can, and usually does, contain a plasticizer to
prevent the formation of pores and cracks that would permit the
penetration of the gastric fluids. Suitable plasticizers include,
but are not limited to, triethyl citrate (Citroflex 2), triacetin
(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2),
Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl
citrate, acetylated monoglycerides, glycerol, fatty acid esters,
propylene glycol, and dibutyl phthalate. In particular, a coating
comprised of an anionic carboxylic acrylic polymer will usually
contain approximately 10% to 25% by weight of a plasticizer,
particularly dibutyl phthalate, polyethylene glycol, triethyl
citrate and triacetin. The coating can also contain other coating
excipients such as detackifiers, antifoaming agents, lubricants
(e.g., magnesium stearate), and stabilizers (e.g.,
hydroxypropylcellulose, acids and bases) to solubilize or disperse
the coating material, and to improve coating performance and the
coated product.
[0150] The coating can be applied to particles of the therapeutic
agent(s), tablets of the therapeutic agent(s), capsules containing
the therapeutic agent(s) and the like, using conventional coating
methods and equipment. For example, an enteric coating can be
applied to a capsule using a coating pan, an airless spray
technique, fluidized bed coating equipment, or the like. Detailed
information concerning materials, equipment and processes for
preparing coated dosage forms may be found in Pharmaceutical Dosage
Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker,
Inc., 1989), and in Ansel et al., Pharmaceutical Dosage Forms and
Drug Delivery Systems, 6th Ed. (Media, Pa.: Williams & Wilkins,
1995). The coating thickness, as noted above, must be sufficient to
ensure that the oral dosage form remains intact until the desired
site of topical delivery in the lower intestinal tract is
reached.
[0151] In another embodiment, drug dosage forms are provided that
comprise an enterically coated, osmotically activated device
housing a formulation of the invention. In this embodiment, the
drug-containing formulation is encapsulated in a semipermeable
membrane or barrier containing a small orifice. As known in the art
with respect to so-called "osmotic pump" drug delivery devices, the
semipermeable membrane allows passage of water in either direction,
but not drug. Therefore, when the device is exposed to aqueous
fluids, water will flow into the device due to the osmotic pressure
differential between the interior and exterior of the device. As
water flows into the device, the drug-containing formulation in the
interior will be "pumped" out through the orifice. The rate of drug
release will be equivalent to the inflow rate of water times the
drug concentration. The rate of water influx and drug efflux can be
controlled by the composition and size of the orifice of the
device. Suitable materials for the semipermeable membrane include,
but are not limited to, polyvinyl alcohol, polyvinyl chloride,
semipermeable polyethylene glycols, semipermeable polyurethanes,
semipermeable polyamides, semipermeable sulfonated polystyrenes and
polystyrene derivatives; semipermeable poly(sodium
styrenesulfonate), semipermeable poly(vinylbenzyltrimethylammonium
chloride), and cellulosic polymers such as cellulose acetate,
cellulose diacetate, cellulose triacetate, cellulose propionate,
cellulose acetate propionate, cellulose acetate butyrate, cellulose
trivalerate, cellulose trilmate, cellulose tripalmitate, cellulose
trioctanoate, cellulose tripropionate, cellulose disuccinate,
cellulose dipalmitate, cellulose dicylate, cellulose acetate
succinate, cellulose propionate succinate, cellulose acetate
octanoate, cellulose valerate palmitate, cellulose acetate
heptanate, cellulose acetaldehyde dimethyl acetal, cellulose
acetate ethylcarbamate, cellulose acetate methylcarbamate,
cellulose dimethylaminoacetate and ethylcellulose.
[0152] In another embodiment, drug dosage forms are provided that
comprise a sustained release coated device housing a formulation of
the invention. In this embodiment, the drug-containing formulation
is encapsulated in a sustained release membrane or film. The
membrane may be semipermeable, as described above. A semipermeable
membrane allows for the passage of water inside the coated device
to dissolve the drug. The dissolved drug solution diffuses out
through the semipermeable membrane. The rate of drug release
depends upon the thickness of the coated film and the release of
drug can begin in any part of the GI tract. Suitable membrane
materials for such a membrane include ethylcellulose.
[0153] In another embodiment, drug dosage forms are provided that
comprise a sustained release device housing a formulation of the
invention. In this embodiment, the drug-containing formulation is
uniformly mixed with a sustained release polymer. These sustained
release polymers are high molecular weight water-soluble polymers,
which when in contact with water, swell and create channels for
water to diffuse inside and dissolve the drug. As the polymers
swell and dissolve in water, more of drug is exposed to water for
dissolution. Such a system is generally referred to as sustained
release matrix. Suitable materials for such a device include
hydropropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose and methyl cellulose.
[0154] In another embodiment, drug dosage forms are provided that
comprise an enteric coated device housing a sustained release
formulation of the invention. In this embodiment, the drug
containing product described above is coated with an enteric
polymer. Such a device would not release any drug in the stomach
and when the device reaches the intestine, the enteric polymer is
first dissolved and only then would the drug release begin. The
drug release would take place in a sustained release fashion.
[0155] Enterically coated, osmotically activated devices can be
manufactured using conventional materials, methods and equipment.
For example, osmotically activated devices may be made by first
encapsulating, in a pharmaceutically acceptable soft capsule, a
liquid or semi-solid formulation of the compounds of the invention
as described previously. This interior capsule is then coated with
a semipermeable membrane composition (comprising, for example,
cellulose acetate and polyethylene glycol 4000 in a suitable
solvent such as a methylene chloride-methanol admixture), for
example using an air suspension machine, until a sufficiently thick
laminate is formed, e.g., around 0.05 mm The semipermeable
laminated capsule is then dried using conventional techniques.
Then, an orifice having a desired diameter (e.g., about 0.99 mm) is
provided through the semipermeable laminated capsule wall, using,
for example, mechanical drilling, laser drilling, mechanical
rupturing, or erosion of an erodible element such as a gelatin
plug. The osmotically activated device may then be enterically
coated as previously described. For osmotically activated devices
containing a solid carrier rather than a liquid or semi-solid
carrier, the interior capsule is optional; that is, the
semipermeable membrane may be formed directly around the
carrier-drug composition. However, preferred carriers for use in
the drug-containing formulation of the osmotically activated device
are solutions, suspensions, liquids, immiscible liquids, emulsions,
sols, colloids, and oils. Particularly preferred carriers include,
but are not limited to, those used for enterically coated capsules
containing liquid or semisolid drug formulations.
[0156] Cellulose coatings include those of cellulose acetate
phthalate and trimellitate; methacrylic acid copolymers, e.g.
copolymers derived from methylacrylic acid and esters thereof,
containing at least 40% methylacrylic acid; and especially
hydroxypropyl methylcellulose phthalate. Methylacrylates include
those of molecular weight above 100,000 daltons based on, e.g.
methylacrylate and methyl or ethyl methylacrylate in a ratio of
about 1:1. Typical products include Endragit L, e.g. L 100-55,
marketed by Rohm GmbH, Darmstadt, Germany. Typical cellulose
acetate phthalates have an acetyl content of 17-26% and a phthalate
content of from 30-40% with a viscosity of ca. 45-90 cP. Typical
cellulose acetate trimellitates have an acetyl content of 17-26%, a
trimellityl content from 25-35% with a viscosity of ca. 15-20 cS.
An example of a cellulose acetate trimellitate is the marketed
product CAT (Eastman Kodak Company, USA). Hydroxypropyl
methylcellulose phthalates typically have a molecular weight of
from 20,000 to 130,000 daltons, a hydroxypropyl content of from 5
to 10%, a methoxy content of from 18 to 24% and a phthalyl content
from 21 to 35%. An example of a cellulose acetate phthalate is the
marketed product CAP (Eastman Kodak, Rochester N.Y., USA). Examples
of hydroxypropyl methylcellulose phthalates are the marketed
products having a hydroxypropyl content of from 6-10%, a methoxy
content of from 20-24%, a phthalyl content of from 21-27%, a
molecular weight of about 84,000 daltons, sold under the trademark
HP50 and available from Shin-Etsu Chemical Co. Ltd., Tokyo, Japan,
and having a hydroxypropyl content, a methoxyl content, and a
phthalyl content of 5-9%, 18-22% and 27-35%, respectively, and a
molecular weight of 78,000 daltons, known under the trademark HP55
and available from the same supplier.
[0157] The therapeutic agents may be provided in capsules, coated
or not. The capsule material may be either hard or soft, and as
will be appreciated by those skilled in the art, typically
comprises a tasteless, easily administered and water soluble
compound such as gelatin, starch or a cellulosic material. The
capsules are preferably sealed, such as with gelatin bands or the
like. See, for example, Remington: The Science and Practice of
Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Co.,
1995), which describes materials and methods for preparing
encapsulated pharmaceuticals.
[0158] A product containing therapeutic agent(s) of the invention
can be configured as a suppository. The therapeutic agent(s) of the
invention can be placed anywhere within or on the suppository to
favorably affect the relative release of the therapeutic agent(s).
The nature of the release can be zero order, first order, or
sigmoidal, as desired.
[0159] Suppositories are solid dosage forms of medicine intended
for administration via the rectum. Suppositories are compounded so
as to melt, soften, or dissolve in the body cavity (around
98.6.degree. F.) thereby releasing the medication contained
therein. Suppository bases should be stable, nonirritating,
chemically inert, and physiologically inert. Many commercially
available suppositories contain oily or fatty base materials, such
as cocoa butter, coconut oil, palm kernel oil, and palm oil, which
often melt or deform at room temperature necessitating cool storage
or other storage limitations. U.S. Pat. No. 4,837,214 to Tanaka et
al. describes a suppository base comprised of 80 to 99 percent by
weight of a lauric-type fat having a hydroxyl value of 20 or
smaller and containing glycerides of fatty acids having 8 to 18
carbon atoms combined with 1 to 20 percent by weight diglycerides
of fatty acids (which erucic acid is an example of). The shelf life
of these type of suppositories is limited due to degradation. Other
suppository bases contain alcohols, surfactants, and the like which
raise the melting temperature but also can lead to poor absorption
of the medicine and side effects due to irritation of the local
mucous membranes (see for example, U.S. Pat. No. 6,099,853 to
Hartelendy et al., U.S. Pat. No. 4,999,342 to Ahmad et al., and
U.S. Pat. No. 4,765,978 to Abidi et al.).
[0160] The base used in the pharmaceutical suppository composition
of this invention includes, in general, oils and fats comprising
triglycerides as main components such as cacao butter, palm fat,
palm kernel oil, coconut oil, fractionated coconut oil, lard and
WITEPSOL.RTM., waxes such as lanolin and reduced lanolin;
hydrocarbons such as VASELINE.RTM., squalene, squalane and liquid
paraffin; long to medium chain fatty acids such as caprylic acid,
lauric acid, stearic acid and oleic acid; higher alcohols such as
lauryl alcohol, cetanol and stearyl alcohol; fatty acid esters such
as butyl stearate and dilauryl malonate; medium to long chain
carboxylic acid esters of glycerin such as triolein and tristearin;
glycerin-substituted carboxylic acid esters such as glycerin
acetoacetate; and polyethylene glycols and its derivatives such as
macrogols and cetomacrogol. They may be used either singly or in
combination of two or more. If desired, the composition of this
invention may further include a surface-active agent, a coloring
agent, etc., which are ordinarily used in suppositories.
[0161] The pharmaceutical composition of this invention may be
prepared by uniformly mixing predetermined amounts of the active
ingredient, the absorption aid and optionally the base, etc. in a
stirrer or a grinding mill, if required at an elevated temperature.
The resulting composition, may be formed into a suppository in unit
dosage form by, for example, casting the mixture in a mold, or by
forming it into a gelatin capsule using a capsule filling
machine.
[0162] The compositions according to the present invention also can
be administered as a nasal spray, nasal drop, suspension, gel,
ointment, cream or powder. The administration of a composition can
also include using a nasal tampon or a nasal sponge containing a
composition of the present invention.
[0163] The nasal delivery systems that can be used with the present
invention can take various forms including aqueous preparations,
non-aqueous preparations and combinations thereof. Aqueous
preparations include, for example, aqueous gels, aqueous
suspensions, aqueous liposomal dispersions, aqueous emulsions,
aqueous microemulsions and combinations thereof. Non-aqueous
preparations include, for example, non-aqueous gels, non-aqueous
suspensions, non-aqueous liposomal dispersions, non-aqueous
emulsions, non-aqueous microemulsions and combinations thereof. The
various forms of the nasal delivery systems can include a buffer to
maintain pH, a pharmaceutically acceptable thickening agent and a
humectant. The pH of the buffer can be selected to optimize the
absorption of the therapeutic agent(s) across the nasal mucosa.
[0164] With respect to the non-aqueous nasal formulations, suitable
forms of buffering agents can be selected such that when the
formulation is delivered into the nasal cavity of a mammal,
selected pH ranges are achieved therein upon contact with, e.g., a
nasal mucosa. In the present invention, the pH of the compositions
should be maintained from about 2.0 to about 6.0. It is desirable
that the pH of the compositions is one which does not cause
significant irritation to the nasal mucosa of a recipient upon
administration.
[0165] The viscosity of the compositions of the present invention
can be maintained at a desired level using a pharmaceutically
acceptable thickening agent. Thickening agents that can be used in
accordance with the present invention include methyl cellulose,
xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose,
carbomer, polyvinyl alcohol, alginates, acacia, chitosans and
combinations thereof. The concentration of the thickening agent
will depend upon the agent selected and the viscosity desired. Such
agents can also be used in a powder formulation discussed
above.
[0166] The compositions of the present invention can also include a
humectant to reduce or prevent drying of the mucus membrane and to
prevent irritation thereof. Suitable humectants that can be used in
the present invention include sorbitol, mineral oil, vegetable oil
and glycerol; soothing agents; membrane conditioners; sweeteners;
and combinations thereof. The concentration of the humectant in the
present compositions will vary depending upon the agent
selected.
[0167] One or more therapeutic agents may be incorporated into the
nasal delivery system or any other delivery system described
herein.
[0168] A composition formulated for topical administration may be
liquid or semi-solid (including, for example, a gel, lotion,
emulsion, cream, ointment, spray or aerosol) or may be provided in
combination with a "finite" carrier, for example, a non-spreading
material that retains its form, including, for example, a patch,
bioadhesive, dressing or bandage. It may be aqueous or non-aqueous;
it may be formulated as a solution, emulsion, dispersion, a
suspension or any other mixture.
[0169] Important modes of administration include topical
application to the skin, eyes or mucosa. Thus, typical vehicles are
those suitable for pharmaceutical or cosmetic application to body
surfaces. The compositions provided herein may be applied topically
or locally to various areas in the body of a patient. As noted
above, topical application is intended to refer to application to
the tissue of an accessible body surface, such as, for example, the
skin (the outer integument or covering) and the mucosa (the
mucous-producing, secreting and/or containing surfaces). Exemplary
mucosal surfaces include the mucosal surfaces of the eyes, mouth
(such as the lips, tongue, gums, cheeks, sublingual and roof of the
mouth), larynx, esophagus, bronchial, nasal passages, vagina and
rectum/anus; in some embodiments, preferably the mouth, larynx,
esophagus, vagina and rectum/anus; in other embodiments, preferably
the eyes, larynx, esophagus, bronchial, nasal passages, and vagina
and rectum/anus. As noted above, local application herein refers to
application to a discrete internal area of the body, such as, for
example, a joint, soft tissue area (such as muscle, tendon,
ligaments, intraocular or other fleshy internal areas), or other
internal area of the body. Thus, as used herein, local application
refers to applications to discrete areas of the body.
[0170] With respect to topical and/or local administration of the
present compositions, desirable efficacy may involve, for example,
penetration of therapeutic agent(s) of the invention into the skin
and/or tissue to substantially reach a hyperalgesic site to provide
desirable anti-hyperalgesic pain relief. The efficacy of the
present compositions may be about the same as that achieved, for
example, with central opiate analgesics. But, as discussed in
detail herein, the efficacy achieved with therapeutic agent(s) of
the invention is preferably obtained without the undesirable
effects that are typically associated with central opiates
including, for example, respiratory depression, sedation, and
addiction, as it is believed that therapeutic agent(s) of the
invention does not cross the blood brain barrier.
[0171] Also in certain preferred embodiments, including embodiments
that involve aqueous vehicles, the compositions may also contain a
glycol, that is, a compound containing two or more hydroxy groups.
A glycol which is particularly preferred for use in the
compositions is propylene glycol. In these preferred embodiments,
the glycol is preferably included in the compositions in a
concentration of from greater than 0 to about 5 wt. %, based on the
total weight of the composition. More preferably, the compositions
contain from about 0.1 to less than about 5 wt. % of a glycol, with
from about 0.5 to about 2 wt. % being even more preferred. Still
more preferably, the compositions contain about 1 wt. % of a
glycol.
[0172] For local internal administration, such as intra-articular
administration, the compositions are preferably formulated as a
solution or a suspension in an aqueous-based medium, such as
isotonically buffered saline or are combined with a biocompatible
support or bioadhesive intended for internal administration.
[0173] Lotions, which, for example, may be in the form of a
suspension, dispersion or emulsion, contain an effective
concentration of one or more of the compounds. The effective
concentration is preferably to deliver an effective amount,
typically at a concentration of between about 0.1-50% [by weight]
or more of one or more of the compounds provided herein. The
lotions also contain [by weight] from 1% to 50% of an emollient and
the balance water, a suitable buffer, and other agents as described
above. Any emollients known to those of skill in the art as
suitable for application to human skin may be used. These include,
but are not limited to, the following: (a) Hydrocarbon oils and
waxes, including mineral oil, petrolatum, paraffin, ceresin,
ozokerite, microcrystalline wax, polyethylene, and
perhydrosqualene. b) Silicone oils, including
dimethylpolysiloxanes, methylphenylpolysiloxanes, water-soluble and
alcohol-soluble silicone-glycol copolymers. (c) Triglyceride fats
and oils, including those derived from vegetable, animal and marine
sources. Examples include, but are not limited to, castor oil,
safflower oil, cotton seed oil, corn oil, olive oil, cod liver oil,
almond oil, avocado oil, palm oil, sesame oil, and soybean oil. (d)
Acetoglyceride esters, such as acetylated monoglycerides. (e)
Ethoxylated glycerides, such as ethoxylated glyceryl monstearate.
(f) Alkyl esters of fatty acids having 10 to 20 carbon atoms.
Methyl, isopropyl and butyl esters of fatty acids are useful
herein. Examples include, but are not limited to, hexyl laurate,
isohexyl laurate, isohexyl palmitate, isopropyl palmitate,
isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl
stearate, decyl stearate, isopropyl isostearate, diisopropyl
adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl
sebacate, lauryl lactate, myristyl lactate, and cetyl lactate. (g)
Alkenyl esters of fatty acids having 10 to 20 carbon atoms.
Examples thereof include, but are not limited to, oleyl myristate,
oleyl stearate, and oleyl oleate. (h) Fatty acids having 9 to 22
carbon atoms. Suitable examples include, but are not limited to,
pelargonic, lauric, myristic, palmitic, stearic, isostearic,
hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic,
and erucic acids. (i) Fatty alcohols having 10 to 22 carbon atoms,
such as, but not limited to, lauryl, myristyl, cetyl, hexadecyl,
stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl,
erucyl, and 2-octyl dodecyl alcohols. (j) Fatty alcohol ethers,
including, but not limited to ethoxylated fatty alcohols of 10 to
20 carbon atoms, such as, but are not limited to, the lauryl,
cetyl, stearyl, isostearyl, oleyl, and cholesterol alcohols having
attached thereto from 1 to 50 ethylene oxide groups or 1 to 50
propylene oxide groups or mixtures thereof. (k) Ether-esters, such
as fatty acid esters of ethoxylated fatty alcohols. (l) Lanolin and
derivatives, including, but not limited to, lanolin, lanolin oil,
lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl
lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols,
ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated
lanolin, acetylated lanolin alcohols, lanolin alcohols linoleate,
lanolin alcohols ricinoleate, acetate of lanolin alcohols
ricinoleate, acetate of ethoxylated alcohols-esters, hydrogenolysis
of lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol
lanolin, and liquid and semisolid lanolin absorption bases. (m)
polyhydric alcohols and polyether derivatives, including, but not
limited to, propylene glycol, dipropylene glycol, polypropylene
glycol [M.W. 2000-4000], polyoxyethylene polyoxypropylene glycols,
polyoxypropylene polyoxyethylene glycols, glycerol, ethoxylated
glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol,
hydroxypropyl sorbitol, polyethylene glycol [M.W. 200-6000],
methoxy polyethylene glycols 350, 550, 750, 2000, 5000,
poly(ethylene oxide) homopolymers [M.W. 100,000-5,000,000],
polyalkylene glycols and derivatives, hexylene glycol
(2-methyl-2,4-pentanediol), 1,3-butylene glycol,
1,2,6,-hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol),
C.sub.15-C.sub.18 vicinal glycol and polyoxypropylene derivatives
of trimethylolpropane. (n) polyhydric alcohol esters, including,
but not limited to, ethylene glycol mono- and di-fatty acid esters,
diethylene glycol mono- and di-fatty acid esters, polyethylene
glycol [M.W. 200-6000], mono- and di-fatty esters, propylene glycol
mono- and di-fatty acid esters, polypropylene glycol 2000
monooleate, polypropylene glycol 2000 monostearate, ethoxylated
propylene glycol monostearate, glyceryl mono- and di-fatty acid
esters, polyglycerol poly-fatty acid esters, ethoxylated glyceryl
monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol
distearate, polyoxyethylene polyol fatty acid ester, sorbitan fatty
acid esters, and polyoxyethylene sorbitan fatty acid esters. (o)
Wax esters, including, but not limited to, beeswax, spermaceti,
myristyl myristate, and stearyl stearate and beeswax derivatives,
including, but not limited to, polyoxyethylene sorbitol beeswax,
which are reaction products of beeswax with ethoxylated sorbitol of
varying ethylene oxide content that form a mixture of ether-esters.
(p) Vegetable waxes, including, but not limited to, carnauba and
candelilla waxes. (q) phospholipids, such as lecithin and
derivatives. (r) Sterols, including, but not limited to,
cholesterol and cholesterol fatty acid esters. (s) Amides, such as
fatty acid amides, ethoxylated fatty acid amides, and solid fatty
acid alkanolamides.
[0174] The lotions further preferably contain [by weight] from 1%
to 10%, more preferably from 2% to 5%, of an emulsifier. The
emulsifiers can be nonionic, anionic or cationic. Examples of
satisfactory nonionic emulsifiers include, but are not limited to,
fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having
10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene
oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms
in the alkyl chain condensed with 2 to 20 moles of ethylene oxide,
mono- and di-fatty acid esters of ethylene oxide, mono- and
di-fatty acid esters of ethylene glycol where the fatty acid moiety
contains from 10 to 20 carbon atoms, diethylene glycol,
polyethylene glycols of molecular weight 200 to 6000, propylene
glycols of molecular weight 200 to 3000, glycerol, sorbitol,
sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and
hydrophilic wax esters. Suitable anionic emulsifiers include, but
are not limited to, the fatty acid soaps, e.g., sodium, potassium
and triethanolamine soaps, where the fatty acid moiety contains
from 10 to 20 carbon atoms. Other suitable anionic emulsifiers
include, but are not limited to, the alkali metal, ammonium or
substituted ammonium alkyl sulfates, alkyl arylsulfonates, and
alkyl ethoxy ether sulfonates having 10 to 30 carbon atoms in the
alkyl moiety. The alkyl ethoxy ether sulfonates contain from 1 to
50 ethylene oxide units. Among satisfactory cationic emulsifiers
are quaternary ammonium, morpholinium and pyridinium compounds.
Certain of the emollients described in preceding paragraphs also
have emulsifying properties. When a lotion is formulated containing
such an emollient, an additional emulsifier is not needed, though
it can be included in the composition.
[0175] The balance of the lotion is water or a C.sub.2 or C.sub.3
alcohol, or a mixture of water and the alcohol. The lotions are
formulated by simply admixing all of the components together.
Preferably the compound, such as loperamide, is dissolved,
suspended or otherwise uniformly dispersed in the mixture.
[0176] Other conventional components of such lotions may be
included. One such additive is a thickening agent at a level from
1% to 10% by weight of the composition. Examples of suitable
thickening agents include, but are not limited to: cross-linked
carboxypolymethylene polymers, ethyl cellulose, polyethylene
glycols, gum tragacanth, gum kharaya, xanthan gums and bentonite,
hydroxyethyl cellulose, and hydroxypropyl cellulose.
[0177] Creams can be formulated to contain a concentration
effective to deliver an effective amount of therapeutic agent(s) of
the invention to the treated tissue, typically at between about
0.1%, preferably at greater than 1% up to and greater than 50%,
preferably between about 3% and 50%, more preferably between about
5% and 15% therapeutic agent(s) of the invention. The creams also
contain from 5% to 50%, preferably from 10% to 25%, of an emollient
and the remainder is water or other suitable non-toxic carrier,
such as an isotonic buffer. The emollients, as described above for
the lotions, can also be used in the cream compositions. The cream
may also contain a suitable emulsifier, as described above. The
emulsifier is included in the composition at a level from 3% to
50%, preferably from 5% to 20%.
[0178] These compositions that are formulated as solutions or
suspensions may be applied to the skin, or, may be formulated as an
aerosol or foam and applied to the skin as a spray-on. The aerosol
compositions typically contain [by weight] from 25% to 80%,
preferably from 30% to 50%, of a suitable propellant. Examples of
such propellants are the chlorinated, fluorinated and
chlorofluorinated lower molecular weight hydrocarbons. Nitrous
oxide, carbon dioxide, butane, and propane are also used as
propellant gases. These propellants are used as understood in the
art in a quantity and under a pressure suitable to expel the
contents of the container.
[0179] Suitably prepared solutions and suspensions may also be
topically applied to the eyes and mucosa. Solutions, particularly
those intended for ophthalmic use, may be formulated as 0.01%-10%
isotonic solutions, pH about 5-7, with appropriate salts, and
preferably containing one or more of the compounds herein at a
concentration of about 0.1%, preferably greater than 1%, up to 50%
or more. Suitable ophthalmic solutions are known [see, e.g., U.S.
Pat. No. 5,116,868, which describes typical compositions of
ophthalmic irrigation solutions and solutions for topical
application]. Such solutions, which have a pH adjusted to about
7.4, contain, for example, 90-100 mM sodium chloride, 4-6 mM
dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12
mM sodium citrate, 0.5-1.5 mM magnesium chloride, 1.5-2.5 mM
calcium chloride, 15-25 mM sodium acetate, 10-20 mM D.L.-sodium,
.beta.-hydroxybutyrate and 5-5.5 mM glucose.
[0180] Gel compositions can be formulated by simply admixing a
suitable thickening agent to the previously described solution or
suspension compositions. Examples of suitable thickening agents
have been previously described with respect to the lotions.
[0181] The gelled compositions contain an effective amount of
therapeutic agent(s) of the invention, typically at a concentration
of between about 0.1-50% by weight or more of one or more of the
compounds provided herein. from 5% to 75%, preferably from 10% to
50%, of an organic solvent as previously described; from 0.5% to
20%, preferably from 1% to 10% of the thickening agent; the balance
being water or other aqueous or non-aqueous carrier, such as, for
example, an organic liquid, or a mixture of carriers.
[0182] The formulations can be constructed and arranged to create
steady state plasma levels. Steady state plasma concentrations can
be measured using HPLC techniques, as are known to those of skill
in the art. Steady state is achieved when the rate of drug
availability is equal to the rate of drug elimination from the
circulation. In typical therapeutic settings, the therapeutic
agent(s) of the invention will be administered to patients either
on a periodic dosing regimen or with a constant infusion regimen.
The concentration of drug in the plasma will tend to rise
immediately after the onset of administration and will tend to fall
over time as the drug is eliminated from the circulation by means
of distribution into cells and tissues, by metabolism, or by
excretion. Steady state will be obtained when the mean drug
concentration remains constant over time. In the case of
intermittent dosing, the pattern of the drug concentration cycle is
repeated identically in each interval between doses with the mean
concentration remaining constant. In the case of constant infusion,
the mean drug concentration will remain constant with very little
oscillation. The achievement of steady state is determined by means
of measuring the concentration of drug in plasma over at least one
cycle of dosing such that one can verify that the cycle is being
repeated identically from dose to dose. Typically, in an
intermittent dosing regimen, maintenance of steady state can be
verified by determining drug concentrations at the consecutive
troughs of a cycle, just prior to administration of another dose.
In a constant infusion regimen where oscillation in the
concentration is low, steady state can be verified by any two
consecutive measurements of drug concentration.
[0183] FIG. 8 shows a kit according to the invention. The kit 10
includes a vial 12 containing an opioid tablet. The kit 10 also
includes a vial 14 containing R-MNTX tablets which contain pellets,
some of which are enterically coated with pH sensitive material and
some of which are constructed and arranged to release the R-MNTX
immediately in the stomach. The kit also includes instructions 20
for administering the tablets to a subject who is constipated or
who has symptoms of constipation or gastrointestinal immotility.
The instructions include indicia, for example writing, indicating
that the R-MNTX is pure R-MNTX free of S-MNTX.
[0184] In some aspects of the invention, the kit 10 can include
optimally or alternatively a pharmaceutical preparation vial 16,
and a pharmaceutical preparation diluents vial 18. The vial
containing the diluents for the pharmaceutical preparation is
optional. The diluents vial contains diluents such as physiological
saline for diluting what could be a concentrated solution or
lyophilized powder of R-MNTX. The instructions can include
instructions for mixing a particular amount of the diluents with a
particular amount of the concentrated pharmaceutical preparation,
whereby a final formulation for injection or infusion is prepared.
The instructions 20 can include instructions for treating a patient
with an effective amount of R-MNTX. It also will be understood that
the containers containing the preparations, whether the container
is a bottle, a vial with a septum, an ampoule with a septum, an
infusion bag, and the like, can contain additional indicia such as
conventional markings which change color when the preparation has
been autoclaved or otherwise sterilized.
[0185] This invention is not limited in its application to the
details of construction and the arrangement of components set forth
in the following description or illustrated in the drawings. The
invention is capable of other embodiments and of being practiced or
of being carried out in various ways. Also, the phraseology and
terminology used herein is for the purpose of description and
should not be regarded as limiting. The use of "including,"
"comprising," or "having," "containing", "involving", and
variations thereof herein, is meant to encompass the items listed
thereafter and equivalents thereof as well as additional items.
EXAMPLES
Example 1
HPLC Analysis of R- and S-MNTX HPLC analysis was performed on a
Varian ProStar HPLC controlled by Varian Star software using the
following method
HPLC Method I:
Column: Luna C18(2), 150.times.4.6 mm, 5.mu.
[0186] Flow Rate: 1 mL/min
Detection: UV @ 230 nm
Gradient Program:
TABLE-US-00002 [0187] Time (min) % A % B 0:00 95 5 8:00 65 35 12:00
35 65 15:00 0 100 16:00 95 5 18:00 95 5
Mobile phase A=0.1% Aqueous TFA Mobile phase B=0.1% Methanolic TFA
TFA=trifluoroacetic acid
HPLC Method II:
[0188] Chromatographic Conditions and Parameters: Analytical Column
Description: Phenomenex Inertsil ODS-3 150.times.4.6 mm, 5 .mu.m
Column Temperature: 50.0.degree. C. Flow Rate: 1.5 mL/min Injection
Volume: 20 .mu.L Detection Wavelength: 280 nm Mobile Phase:
A=Water:MeOH:TFA (95:5:0.1%; v/v/v) B=Water:MeOH:TFA (35:65:0.1%;
v/v/v) Analysis Time: 50 min Quantitation limit: 0.05% Detection
limit: 0.02%
Gradient Profile:
TABLE-US-00003 [0189] Time (min) % A % B Curve 0:00 100 0 Initial
45 50 50 Linear 48 100 0 Linear 55 100 0 Hold
Mobile Phase A (Water:MeOH:TFA::95:5:0.1%, v/v/v) Mobile Phase B
(Water:MeOH:TFA::35:65:0.1%, v/v/v) MeOH=Methanol
TFA=trifluoroacetic acid
[0190] The synthesis and purification of R-MNTX were monitored
using the above HPLC protocol. S-MNTX is distinguished from R-MNTX
using the HPLC conditions described. Authentic S-MNTX for use as a
standard may be made using the protocol as described herein. In a
typical HPLC run, S-MNTX elutes about 0.5 minutes before R-MNTX
elutes. The retention time of S-MNTX is approximately 9.3 minutes;
the retention time of R-MNTX is about 9.8 minutes.
[0191] As illustrated in FIG. 2, the S and R forms of MNTX can be
distinguished clearly on an HPLC chromatogram. FIG. 3 is an HPLC
chromatogram of a mixture of 0.1% by weight of authentic S form
added to 99.5% by weight of authentic R form; FIG. 4 is a
chromatogram of 1.0% by weight of authentic S form added to 99.0%
by weight of authentic R form. FIG. 5 is a chromatogram of 3.0% by
weight of authentic S form added to 98.0% by weight of authentic R
form. This has permitted applicants to devise and test for the
first time stereoselective protocols for synthesis and purification
that yield highly pure R-MNTX from 3-O-protected-naltrexone.
Example 2
Stereoselective Synthesis of R-MNTX
[0192] The synthetic scheme for Example 2 is shown in FIG. 6.
[0193] General.
[0194] All anhydrous reactions were carried out in oven-dried
(130.degree. C.) glassware under an atmosphere of dry nitrogen
(N.sub.2). All commercial reagents and solvents were used without
any additional purification. Nuclear magnetic resonance (NMR)
spectra were obtained using either a Varian Gemini or Varian
Mercury 300 MHz spectrometer. Mass spectra were determined on a
Finnigan LCQ. HPLC purity was determined using a Waters 717
Autosampler and Waters 996 Photodiode Array Detector.
3-O-Isobutyryl-Naltrexone (2)
[0195] To a solution of compound (1) (1.62 g, 4.75 mmol) in
anhydrous tetrahydrofuran (THF) (120 mL) at 0.degree. C. was added
triethylamine (NEt3) (1.4 mL, 10 mmol). After the reaction was
stirred for 15 min at 0.degree. C., isobutyryl chloride (1.05 mL,
10 mmol) was added dropwise. Reaction mixture was stirred at
0.degree. C. for 1 hr, then at room temperature for 18 hr before
being quenched with saturated sodium bicarbonate (NaHCO.sub.3) (aq)
(70 mL) and 30 ml of H.sub.2O. The reaction was extracted with
methylene chloride (CH.sub.2Cl.sub.2) (2.times.200 mL). The
extracts were combined, washed with brine (130 ml), dried over
sodium sulfate (Na.sub.2SO.sub.4) (50 g), filtered and concentrated
in vacuo. The crude material was purified by flash chromatography
on silica gel (column size 40.times.450 mm, silica gel was loaded
40.times.190 mm) (9.8:0.2.fwdarw.9.6:0.4.fwdarw.9.4:0.6
CH.sub.2Cl.sub.2/MeOH) to give compound (2) (1.5 g 76.8%) as a
white solid.
[0196] .sup.1H NMR (300M Hz, CDCl.sub.3) .delta. 6.82 (d, J=8.0 Hz,
1H), 6.67 (d, J=8.0 Hz, 1H), 4.69 (s, 1H), 3.21 (d, J=6.0 Hz, 1H),
3.12-2.96 (m, 2H), 2.93-2.82 (m, 1H), 2.71 (dd, J=4.5 Hz, 1H), 2.62
(dd, J=6.2 Hz, 1H), 2.48-2.28 (m, 4H), 2.19-2.10 (m, 1H), 1.93-1.86
(m, 1H), 1.68-1.59 (m, 2H), 1.34 (d, J=0.8 Hz, 3H,
CH.sub.3-isobutyryl), 1.31 (d, J=0.8 Hz, 3H, CH.sub.3-isobutyryl),
0.90-0.83 (m, 1H, CH-cyclopropyl), 0.60-0.54 (m, 2H,
CH.sub.2-cyclopropyl), 0.18-0.13 (m, 2H, CH2-cyclopropyl). .sup.13C
NMR (75.5 MHz, CDCl.sub.3) .delta. 207.6 (CO), 174.7 (COO/Pr)
147.8, 132.8, 130.1, 130.0, 122.8, 119.2, 90.5, 70.0, 61.9, 59.2,
50.6, 43.4, 36.1, 33.8, 31.2, 30.7, 22.9, 19.0, 18.9, 9.4, 4.0,
3.8. MS[M+H].sup.+: 412.
3-O-Isobutyryl-N-Methylnaltrexone Iodide salt (3)
[0197] Compound (2) (689 mg, 1.67 mmol) was transferred by spatula
into a glass pressure vessel. The vessel was purged gently with
nitrogen on the manifold for 5 minutes and was then evacuated under
high vacuum. When the vacuum was constant, the lower part of the
vessel was immersed in liquid nitrogen. Methyl iodide (973 mg, 6.85
mmol) was dispensed into a separate flask on the manifold into a
nitrogen atmosphere and frozen in liquid nitrogen. The frozen
methyl iodide vessel was evacuated under high vacuum. The main
manifold chamber was isolated from the high vacuum pump. The methyl
iodide was allowed to warm to ambient temperature and sublime via
the main chamber onto the liquid nitrogen cooled
3-O-Isobutyryl-Naltrexone. When sublimation was complete, nitrogen
was slowly allowed to leach into the glass pressure vessel. The
vessel was then sealed tight, removed from the manifold and heated
in an oil bath at 88-90.degree. C. for 17 hrs. The vessel was
allowed to cool to ambient temperature before allowing nitrogen to
flow into the vessel. The vessel was then evacuated under high
vacuum to remove residues of unreacted methyl iodide giving a white
solid. A sample of the solid was removed for .sup.1H NMR analysis.
This showed good conversion to product. Thin layer chromatography
(TLC) of the product [dichloromethane/methanol 9:1 (v/v), normal
phase silica, UV detection] showed a trace of starting material (2)
(R.sub.f=0.8) and a diffuse region (R.sub.f=0-0.4). The solid was
dissolved in dichloromethane/methanol (4:1, minimum volume) and
applied to a silica gel column (ultrapure silica gel, 22 g in
dichloromethane, bed dimensions: 200 mm.times.20 mm id). The column
was eluted as follows:
Dichloromethane/methanol 98:2 (300 ml)
Dichloromethane/methanol 97:3 (300 ml)
Dichloromethane/methanol 94:6 (200 ml)
Dichloromethane/methanol 92:8 (400 ml)
[0198] Fractions were analyzed by TLC [dichloromethane/methanol 9:1
(v/v), normal phase silica, UV detection]. Fractions containing
exclusively the principal component (R.sub.f=0.4) were combined
rinsing together with methanol, and concentrated to yield 867 mg of
white solid. This represents a 91% yield based on
3-O-Isobutyryl-Naltrexone. .sup.1H NMR is consistent.
N-Methylnaltrexone Bromide/Iodide salt (4)
[0199] Compound (3) (862 mg, 1.56 mmol) was dissolved in methanol
(13 ml). To this mixture was added sterile water (11.5 ml) followed
by 48% aqueous hydrobromic acid (1.5 ml). The resultant mixture was
stirred under nitrogen and heated in an oil bath at 64-65.degree.
C. for 6.5 hr. TLC analysis of a sample (dispersed in methanol) of
the reaction mixture showed no starting material (3) remaining
(R.sub.f=0.4) and conversion to material at R.sub.f=0-0.15. The
mixture was concentrated on the rotary evaporator with the bath at
22-25.degree. C. until approximately 1 ml of oily liquid remained.
Acetonitrile (10 ml) was added and the mixture was reconcentrated.
This was repeated a further three times, using 10 ml of
acetonitrile, to give a ginger colored crisp foam (590 mg, 86%
crude yield).
[0200] Preparation of Anion Exchange Resin Column.
[0201] 30 g of AG 1-X8 resin was packed into an medium pressure
liquid chromatography (MPLC) column (20 mm id) using 100 ml water
to create a resin slurry. The resin bed was washed with 1.0N
aqueous hydrobromic acid (200 ml) and then sterile water until the
pH of the aqueous eluate was pH 6-7. Approximately 1.5 L of water
was required.
N-Methylnaltrexone Bromide (5)
[0202] The foam (4) (597 mg) was dispersed in water (6 ml)/methanol
(2 ml). Some dark oil remained undissolved. The clear supernatant
liquid was decanted and applied to the prepared anion exchange
resin column The residue was washed twice with methanol (0.2
ml)/water (3 ml). The supernatant liquors were applied to the
column. The column was eluted with 4.2 L of sterile water and
fractions of .about.20 ml were collected. The presence of
N-Methylnaltrexone salt was detected by liquid chromatography/mass
spectometry (LC/MS). The majority of N-Methylnaltrexone was located
in the initial 1.5 L of eluate of which the first 600 ml contained
the most pure material by TLC (4:1 dichloromethane/methanol, normal
phase silica). The first 600 ml of eluate was combined and
concentrated on the rotary evaporator to give a whitish glass. The
water bath was maintained at .about.35.degree. C. Care was needed
to control foaming of the eluate while evaporating.
Purification of N-Methylnaltrexone Bromide (5)
[0203] Recrystallization from methanol. The residue was warmed in
methanol (60 ml) under nitrogen to just below reflux and then
filtered through a glass sinter to remove a small amount of
insoluble material. This filtrate was then blown down in a stream
of nitrogen to approximately 10 ml and then cooled under nitrogen
in ice/water. Some white precipitate was formed but clearly much
solid remained in solution. The mixture was then concentrated by
evaporation to give a slightly colored gum. This was triturated
with methanol (3 ml.times.2). Methanol was cautiously decanted by
pipette between triturations. The white residue was dissolved in
methanol (60 ml) and filtered through a glass sinter. The filtrate
was concentrated to approximately 1 ml and a further portion of
methanol (1 ml) was added to triturate the solid. The supernatant
liquors were decanted as before. The solid was dried to give a
white solid, batch A (178.0 mg). HPLC analysis showed 97.31% of
R-MNTX, and 2.69% of S-MNTX.
[0204] All filtrates/supernatant liquors in methanol were combined
and concentrated to give a white glass. This residue was triturated
with methanol (3 ml.times.2) and the supernatant liquors were
removed carefully as before. The residue was dissolved in methanol
(50 ml) and filtered through a glass sinter. The filtrate was
concentrated to approximately 1 ml solution and a further portion
of methanol (1 ml) was added to triturate the solid. The
supernatant liquors were decanted as before and the residue was
triturated further with methanol (2 ml). The supernatant liquors
were decanted and the residue was dried to give a white solid,
batch B (266.0 mg). HPLC analysis of batch B showed 97.39% of
R-MNTX, and 2.61% of S-MNTX. Batches A and B together represent a
total yield of 436.8 mg (64%). .sup.1H NMR is consistent. MS
[M+H].sup.+: 356.
[0205] As demonstrated in batches A and B, recrystallization from
methanol yields product with high percentage of R-MNTX. In a
reaction carried out under the same conditions with
.sup.14CH.sub.3-labelled material, it was found that the
composition of the crude reaction mixture before recrystallization
from methanol was 94.4% R-MNTX* and 4.7% S-MNTX*. Recrystallization
from methanol yielded product containing 98.0% R-MNTX* and 1.5%
S-MNTX*. A second recrystallization from methanol yielded 98.3%
R-MNTX* and 1.2% S-MNTX*.
[0206] It should be understood that it is believed that the
synthetic protocol results in greater than 94% R form with only a
small percentage of the S form. Using synthesis Scheme 1, the
substantially pure material, could be processed further on a
chromatography column, preparative HPLC or recrystallization. In
one recrystallization following ion exchange, the purity of the R
form was greater than 98%. A second recrystallization yielded 98.3%
R-MNTX. It is understood that further recrystallizations and/or
chromatography, anywhere between one and four, (or even six or as
many as ten) times ensures greater than 99.95% R form and
eliminates traces of the S form, if present.
Example 3
Stereoselective Synthesis of R-MNTX
[0207] The synthetic scheme for Example 3 is shown in FIG. 7. In
Example 3, the method taught by Goldberg et al for protecting
groups was followed. Acetyl, Goldberg et al's preferred protecting
group, instead of isobutyryl was used as the protecting group. The
reactions were carried out as described in Example 2. It was
surprisingly found using the scheme shown in FIG. 7 that the acetyl
protecting group tended to fall off during purification of
intermediate 2 (O-acetyl-naltrexone). This made it difficult to
obtain pure intermediate 2. The yield of intermediate 2 with the
acetyl group was only 36.3% rendering the scheme shown in FIG. 7
unsuitable for commercial scale-up. In contrast using the synthetic
scheme with isobutyryl as the protecting group (FIG. 6),
intermediate 2 (3-O-isobutyryl-naltrexone) was quite stable during
purification resulting in a yield of 76.8%.
Example 4
Manufacturing Process for a Pharmaceutical Formulation of
R-MNTX
[0208] A manufacturing process can be outlined as follows: [0209]
1. Add required amount of water for injection (-80% or final
volume) to a stainless steel tank. [0210] 2. Add chelating agent to
the tank and stir till dissolved. [0211] 3. Add buffering agent to
the tank and stir till dissolved. [0212] 4. Add R-MNTX to the tank
and stir till dissolved. [0213] 5. Add isotonicity agent to the
tank and stir till dissolved. [0214] 6. Adjust the pH of the
solution to pH 3.25. [0215] 7. Add water for injection to increase
the volume to the required amount. [0216] 8. Transfer material to
supply pressure vessel. [0217] 9. Sterile filter into a sterile
stainless steel pressure vessel. [0218] 10. Fill into
bottles/vials, purge with nitrogen and then stopper the
bottles/vials. [0219] 11. Sterilize the filled vials by
autoclaving.
[0220] Exact Amount of Excipients to be Used:
[0221] Disodium edetate=0.75 mg/ml Added in step 2
[0222] Sodium citrate=0.199 mg/ml Added in step 3
[0223] Citric acid=0.35 mg/ml Added in step 3
[0224] Sodium chloride=8.5 mg/ml Added in step 5
[0225] The order of addition of excipients is described above.
Steps 2 to 5 can take place in any order.
[0226] When all excipients and drug have been added, step 6, pH of
the solution is adjusted by addition of acid. If a buffering agent
is used in the solution, pH adjustment may not be required.
[0227] There are no specifics on the temperature or the stirring
speed during the formulation. The temperature during formulation
can be as high as 80.degree. C.
Example 5
Preferred Manufacturing Process for a Pharmaceutical Formulation of
R-MNTX
[0228] A preferred manufacturing process for 100 ml of 20 mg/ml
solution of R-MNTX solution is as follows:
1. Add 80 ml of water for injection (-80% or final volume) to a
stainless steel tank. 2. Add 75 mg of disodium edetate, a chelating
agent, to the tank and stir till dissolved. 3. Add 19.9 mg of
sodium citrate and 35 mg of citric acid (as buffering agents) to
the tank and stir till dissolved. 4. Add 2000 mg of R-MNTX to the
tank and stir till dissolved. 5. Add 850 mg of sodium chloride, an
isotonicity agent, to the tank and stir till dissolved. 6. Adjust
the pH of the solution if necessary. 7. Add water for injection to
increase the volume to 100 ml. 8. Transfer the material to supply
pressure vessel. 9. Sterile filter using a 0.22 micron filter into
a sterile stainless steel pressure vessel. 10. Fill, purge with
nitrogen and then stopper the bottles/vials. 11. Sterilize the
filled vials by autoclaving.
Example 6
Preparation of a Subcutaneous Formulation of R-MNTX
[0229] A formula for a low citrate/EDTA formulation is listed
below:
TABLE-US-00004 Ingredient mg/mL R-MNTX 30 mg Sodium chloride 4 mg
Citric acid 0.0875 mg Trisodium citrate 0.0496 mg Disodium edetate
0.75 mg Water for injection q.s. to 1 g
The pH of this solution is 3.5 and can withstand an autoclaving
process.
Example 7
Manufacturing Process for a Lyophilized Pharmaceutical Formulation
of R-MNTX
[0230] The lyophilization cycle is used for the preparation of
lyophilized preparation of R-MNTX. Forty milligrams of R-MNTX is
mixed with 32 mg of the cryoprotecting agent, mannitol and q.s. to
1 mL using water for injection.
1. Load chamber at room temperature (20-25.degree. C.) 2. Lower
shelf temp to -45 degrees C. at 1.0 degrees C./min 3. Hold shelf
temp at -45 for 120 minutes 4. When condenser is below -50 degrees
C., evacuate the chamber to 100-125 ml. 5. Ramp shelf to -20
degrees C. at 0.5 degrees C./min. 6. Hold at -20 degrees C. for 16
hours 7. Ramp shelf to +27 degrees C. at 0.10 degrees C./min 8.
Hold for a minimum of 8 hours. Maintain chamber pressure at 100-125
mt for the entire cycle. 9. Restore chamber to 11.0 PSIA+ or -1.0
with sterile filtered Nitrogen and then seat the closures (2'' Hg),
then bleed to atmospheric pressure with N.sub.2 to unload. The pH
of the solution after lyophilization and reconstitution is 5.0.
[0231] The disclosures of all patents, patent applications and
scientific publications cited or referenced herein are incorporated
by reference in their entirety, including the co-pending US patent
application No.: Not yet assigned, titled:
"(S)--N-METHYLNALTREXONE", Attorney Docket No. P0453.70120US02
filed on May 25, 2006. In case of conflict between documents
incorporated by reference and the instant application, the instant
application will control.
[0232] Having thus described several aspects of at least one
embodiment of this invention, it is to be appreciated various
alterations, modifications, and improvements will readily occur to
those skilled in the art. Such alterations, modifications, and
improvements are intended to be part of this disclosure, and are
intended to be within the spirit and scope of the invention.
Accordingly, the foregoing description and drawings are by way of
example only.
* * * * *