U.S. patent application number 16/664239 was filed with the patent office on 2020-04-23 for oral formulations and lipophilic salts of methylnaltrexone.
This patent application is currently assigned to Wyeth, LLC. The applicant listed for this patent is Wyeth, LLC. Invention is credited to Kadum A. Al Shareffi, Jonathan Marc Cohen, Christopher Richard Diorio, Eric C. Ehrnsperger, Xu Meng, Syed M. Shah.
Application Number | 20200121673 16/664239 |
Document ID | / |
Family ID | 44148539 |
Filed Date | 2020-04-23 |
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United States Patent
Application |
20200121673 |
Kind Code |
A1 |
Shah; Syed M. ; et
al. |
April 23, 2020 |
ORAL FORMULATIONS AND LIPOPHILIC SALTS OF METHYLNALTREXONE
Abstract
The present invention provides compositions comprising
methylnaltrexone or a salt thereof, and compositions and
formulations thereof, for oral administration.
Inventors: |
Shah; Syed M.; (Delray
Beach, FL) ; Diorio; Christopher Richard; (Campbell
Hall, NY) ; Ehrnsperger; Eric C.; (New City, NY)
; Meng; Xu; (San Diego, CA) ; Al Shareffi; Kadum
A.; (Greensboro, NC) ; Cohen; Jonathan Marc;
(Monroe, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth, LLC |
Madison |
NJ |
US |
|
|
Assignee: |
Wyeth, LLC
Madison
NJ
|
Family ID: |
44148539 |
Appl. No.: |
16/664239 |
Filed: |
October 25, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16450157 |
Jun 24, 2019 |
10507206 |
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16664239 |
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16219159 |
Dec 13, 2018 |
10376505 |
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16450157 |
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15070555 |
Mar 15, 2016 |
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16219159 |
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13956050 |
Jul 31, 2013 |
9314461 |
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15070555 |
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13045108 |
Mar 10, 2011 |
8524276 |
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13956050 |
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61313018 |
Mar 11, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/08 20180101; A61K
9/2054 20130101; A61K 47/12 20130101; A61K 9/28 20130101; A61K
9/2009 20130101; A61K 9/0053 20130101; A61K 9/2013 20130101; A61P
1/00 20180101; A61K 47/20 20130101; A61K 31/485 20130101; A61P
25/04 20180101; A61P 13/02 20180101; A61P 43/00 20180101; C07D
489/08 20130101; A61P 1/10 20180101; A61K 9/2077 20130101; A61P
17/00 20180101; A61P 17/04 20180101; A61P 1/14 20180101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/00 20060101 A61K009/00; A61K 47/20 20060101
A61K047/20; A61K 47/12 20060101 A61K047/12; A61K 9/20 20060101
A61K009/20; A61K 9/28 20060101 A61K009/28; C07D 489/08 20060101
C07D489/08 |
Claims
1-25. (canceled)
26. A pharmaceutical composition for oral administration comprising
a solid dosage of (i) methylnaltrexone, or a pharmaceutically
acceptable salt thereof, (ii) an amphiphilic pharmaceutically
acceptable excipient, (iii) a chelating agent, and (iv) a
disintegrant.
27. The pharmaceutical composition of claim 26, wherein the
methylnaltrexone, or a pharmaceutically acceptable salt thereof, is
(R)--N-methylnaltrexone bromide.
28. The pharmaceutical composition of claim 27, wherein the
(R)--N-methylnaltrexone bromide is present at about 150 mg.
29. The pharmaceutical composition of claim 26, wherein the
chelating agent is EDTA or a salt thereof.
30. The pharmaceutical composition of claim 29, wherein the
chelating agent comprises edetate calcium disodium.
31. The pharmaceutical composition of claim 26, wherein the
disintegrant comprises a rapid acting disintegrant.
32. The pharmaceutical composition of claim 31, wherein the
disintegrant comprises an effervescent disintegrant.
33. The pharmaceutical composition of claim 26, wherein the
disintegrant comprises a combination of crospovidone and
cross-linked sodium carboxymethyl cellulose.
34. The pharmaceutical composition of claim 26, wherein the
composition is a tablet.
35. The pharmaceutical composition of claim 34, wherein the tablet
is not enterically coated.
36. The pharmaceutical composition of claim 27, wherein
(R)--N-methylnaltrexone bromide is the sole active agent.
37. The pharmaceutical composition of claim 27, wherein the
amphiphilic pharmaceutically acceptable excipient is sodium dodecyl
sulfate.
38. The pharmaceutical composition of claim 37, wherein the ratio
of (R)--N-methylnaltrexone bromide to sodium dodecyl sulphate is
about 3:1 by weight.
39. The pharmaceutical composition of claim 26, further comprising
a binder.
40. The pharmaceutical composition of claim 39, wherein the binder
comprises microcrystalline cellulose.
41. The pharmaceutical composition of claim 26, further comprising
a glidant.
42. The pharmaceutical composition of claim 41, wherein the glidant
comprises colloidal silicon dioxide.
43. A method for treating opioid induced constipation in a subject
in need thereof, comprising administering the pharmaceutical
composition of claim 26 to the subject, thereby treating opioid
induced constipation.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/450,157, filed on Jun. 24, 2019, which is a
continuation of U.S. patent application Ser. No. 16/219,159, filed
on Dec. 13, 2018, now U.S. Pat. No. 10,376,505, issued on Apr. 25,
2019, which is a continuation of U.S. patent application Ser. No.
15/070,555, filed Mar. 15, 2016, which is a continuation of U.S.
patent application Ser. No. 13/956,050, filed on Jul. 31, 2013, now
U.S. Pat. No. 9,314,461, issued on Apr. 19, 2016, which is a
continuation of U.S. patent application Ser. No. 13/045,108, filed
on Mar. 10, 2011, now U.S. Pat. No. 8,524,276, issued on Sep. 3,
2013, which claims the benefit of U.S. Provisional Application No.
61/313,018, filed Mar. 11, 2010, the entire contents of each of
which are hereby incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] Opioids are widely used in treating patients with pain. Such
patients include those with advanced cancers and other terminal
diseases and also those with chronic non-malignant pain and acute
non-malignant pain. Opioids are narcotic medications that activate
opioid receptors located in the central nervous system to relieve
pain. Opioids, however, also react with receptors outside of the
central nervous system, resulting in side effects including
constipation, nausea, vomiting, urinary retention, and severe
itching. Notable are the effects of opioids in the gastrointestinal
(GI) tract where these drugs inhibit gastric emptying and
peristalsis in the intestines, thereby decreasing the rate of
intestinal transit and producing constipation. The use of opioids
in treating pain is often limited due to these undesired side
effects, which can be debilitating and often cause patients to
refuse the use of opioid analgesics.
[0003] In addition to exogenous opioid-induced side effects,
studies have suggested that endogenous opioids and opioid receptors
may also affect the gastrointestinal (GI) tract and may be involved
in normal regulation of intestinal motility and mucosal transport
of fluids. Thus, an abnormal physiological level of endogenous
opioids and/or receptor activity may also lead to bowel
dysfunction. For example, patients who have undergone surgical
procedures, especially surgery of the abdomen, often suffer from a
particular bowel dysfunction, termed post-operative ileus, that may
be caused by fluctuations in natural opioid levels. Similarly,
women who have recently given birth commonly suffer from post
partum ileus, which may be caused by similar fluctuations in
natural opioid levels as a result of birthing stress.
Gastrointestinal dysfunction associated with post-operative or
post-partum ileus can typically last for 3 to 5 days, with some
severe cases lasting more than a week. Administration of opioids to
a patient after surgery to treat pain, which is now an almost
universal practice, may exacerbate bowel dysfunction, thereby
delaying recovery of normal bowel function, prolonging hospital
stays, and increasing medical care costs.
[0004] Opioid receptor antagonists, such as naloxone, naltrexone,
and nalmefene, have been studied as a means of antagonizing the
undesirable peripheral side effects of opioids. However, these
agents not only act on peripheral opioid receptors but also on
opioid receptors in the central nervous system, sometimes reversing
the beneficial and desired analgesic effects of opioids or causing
symptoms of opioid withdrawal. Preferable approaches for use in
controlling opioid-induced side effects include administration of
peripheral acting opioid receptor antagonists that do not readily
cross the blood-brain barrier.
[0005] The peripheral a opioid receptor antagonist methylnaltrexone
has been studied since the late 1970s. It has been used in patients
to reduce opioid-induced side effects such as constipation,
pruritus, nausea, and urinary retention (see, e.g., U.S. Pat. Nos.
5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan et al.,
Drug and Alcohol Dependence 1998, 52, 161). The dosage form of
methylnaltrexone used most often in these studies has been a
solution of methylnaltrexone for intravenous injection.
[0006] In U.S. Pat. No. 6,559,158, the dose of methylnaltrexone for
treating methadone maintenance patients was explored. It was
hypothesized in the '158 patent, based on studies of methadone
maintenance patients, that patients taking opioids chronically
would be responsive to doses of methylnaltrexone that were
previously considered to be too low to be clinically efficacious.
(Methadone maintenance patients typically have an addiction to
opiates such as heroin, oxycontin, dilaudid or hydrocone. They
would have a history of a stable dose of methadone treatment for at
least 30 days of greater than or equal to 30 mg/day, and more
typically higher.) Low doses of methylnaltrexone were administered
intravenously. These doses were between 0.01 and 0.37 mg/kg,
wherein average peak plasma levels of 162 (30-774 ng/ml) were
reported. These intravenous doses in methadone maintenance patients
induced "immediate" laxation.
[0007] Methylnaltrexone subcutaneous injection was explored and has
been clinically approved in the United States to treat
opioid-induced constipation in patients with advanced medical
illness who are receiving palliative care. The subcutaneous
injection dose found to be effective was 0.15 or 0.3 mg/kg. This
dose did not induce "immediate" laxation, but rather induced
laxation within 4 hours in a significant number of patients
treated.
[0008] Attempts have been made to make an oral dosage form of
certain opioid antagonists, including methylnaltrexone. In U.S.
Pat. No. 6,419,959, an oral dosage form is constructed so as to
release certain compounds "over the whole gastrointestinal tract."
According to the '959 patent, opioid antagonists are not always
suitable for administration in an immediate release form due to
dose limiting side effects. In addition, opioid-induced
constipation was believed to result from the direct and local
effects of opioids on receptors across the entire gastrointestinal
tract. To address these issues, the '959 patent suggests dosing
certain opioid antagonists, including methylnaltrexone, in a
controlled-release dosage form, thereby delivering these
antagonists at acceptable doses locally across the entire
gastrointestinal tract. Data respecting methylnaltrexone
specifically, however, was not reported.
[0009] In U.S. Pat. No. 6,274,591, it was demonstrated that an
enteric coated methylnaltrexone which released substantially no
methylnaltrexone in the stomach was more effective in antagonizing
the oral-cecal delay caused by morphine than was an uncoated
methylnaltrexone. The '591 patent suggests and claims delivering
effective amounts of methylnaltrexone using an oral dosage that
by-passes the stomach altogether. Data respecting laxation,
however, was not reported.
[0010] In U.S. Pat. No. 6,559,158, an oral dose of methylnaltrexone
was explored for treating constipation in methadone maintenance
patients (i.e., patients shown to be highly sensitive to the
effects of methylnaltrexone). The dose of methylnaltrexone
administered orally in a capsule was 0.3-3.0 mg/kg.
Methylnaltrexone capsules administered to these patients induced
laxation in the several patients tested, although over periods of
time between 1.2 and 24 hours depending on the dose. The fastest
response was seen in the four patients receiving 3.0 mg/kg
(5.2+/-4.5 hours, with a range of 1.2-10 hours).
[0011] Accordingly, the need exists for bioavailable oral dosage
formulations comprising methylnaltrexone.
SUMMARY OF THE INVENTION
[0012] Capsules containing enterically coated spheroids of a
formulation of methylnaltrexone were tested in patients suffering
from opioid-induced constipation. The patients in this study were
receiving opioids for non-malignant pain. (They were not chronic
methadone maintenance patients.) Patients were administered 300 mg
or 450 mg of enterically coated methylnaltrexone capsules
(approximately 4 mg/kg and 6 mg/kg, respectively), which were doses
within the ranges reported to be effective in the '591 patent. The
average peak plasma level of methylnaltrexone resulting from the
300 mg dose was less than 10 ng/mL and the average peak plasma
level of methylnaltrexone resulting from the 450 mg dose was less
than 20 ng/mL. These preparations unexpectedly were not effective
for treating opioid-induced constipation. They did not induce
laxation and did not cause more bowel movements in patients
relative to controls. This was surprising in view of the teachings
in the art.
[0013] Based on the results of the enterically coated
methylnaltrexone capsules, it was unclear whether achieving
laxation depended on the peak plasma levels of the drug, the timing
of achieving the plasma levels of the drug, or other factors such
as a local effect. Further experiments were conducted, and as a
result, the inventors turned their attention to developing an oral
formulation containing methylnaltrexone that was not enterically
coated.
[0014] Capsules containing spheroids of a formulation of
methylnaltrexone, but without the enteric coating, were tested in
patients receiving opioids for non-malignant pain. Doses of 150 mg,
300 mg, 450 mg, and 600 mg were tested. These doses resulted in
average peak plasma levels of between about 15 and 40 ng/ml. These
capsules without the enteric coating did not induce laxation and
did not cause more bowel movements in this patient population
relative to controls.
[0015] Tablets containing spheroids of a formulation of
methylnaltrexone, without an enteric coating, were tested in
patients receiving opioids for non-malignant pain. Doses of 150 mg,
300 mg, 450 mg, and 600 mg were tested. These doses resulted in
average peak plasma levels of between about 7 and 40 ng/ml, similar
to the peak plasma levels achieved with the uncoated capsules.
These tablets without an enteric coating showed activity with
statistical significance at one dose, but did not consistently
induce laxation across all doses. That there was activity with a
tablet but not a capsule would have been surprising to one of
ordinary skill in the art based on the information available in the
prior art.
[0016] The prior art did not make clear what would be required to
create an oral methylnaltrexone effective for treating opioid
induced constipation in patients receiving opioids for
non-malignant pain. First, the prior art did not make clear whether
achieving laxation depended on the overall plasma levels of the
drug, the peak plasma levels of the drug, or the timing of
achieving the plasma levels of the drug. Second, even if the
pharmacokinetics for achieving laxation were established, the prior
art did not make clear formulation methodology for predictably
controlling the pharmacokinetics of oral methylnaltrexone, other
than via dose alterations and coatings. Because of the desire to
further improve the performance of the non-enteric coated tablet,
further formulation development studies were undertaken.
[0017] Methylnaltrexone is hydrophilic and quite soluble in aqueous
solutions. The positive charge of the quaternary amine causes
methylnaltrexone to be poorly absorbed in the gastrointestinal
tract. In general, less than about 5% of methylnaltrexone is
absorbed into the bloodstream when delivered orally.
[0018] There are many possible general approaches to increasing the
absorption of an orally administered drug. It was unknown, however,
which approach might result in an improvement of the efficacy of
oral methylnaltrexone. The inventors tested tablet formulations,
capsule formulations, liquid formulations, gap junction openers,
Pgp inhibitors, active transport agents, oil suspensions,
effervescent solutions for rapid release, and others. Most of the
approaches attempted did not improve absorption in the laboratory
models used. In fact, when tested in certain dog models, some of
the approaches had the opposite of the anticipated effect, that is,
absorption was inhibited in one or more of the tested
parameters.
[0019] Ion pairing has been investigated to reduce the apparent
ionic charge on a molecule. The interaction between a hydrophilic,
charged molecule and an amphiphilic counter ion can make the
hydrophilic molecule sufficiently lipophilic to enable (or
increase) solubility of the molecule in a non-aqueous solvent.
Since ion pairing increases partitioning of the molecule into an
organic phase, much of the work in this area has been directed
towards extraction of ionic molecules into organic solvents,
separation of molecules by chromatography, reaction of hydrophilic
molecules in organic solvents, and so forth. With respect to drug
absorption, most of the work has been limited to delivery of a drug
to the skin, eyes, nasal cavity, or vaginal cavity (see, e.g., J.
Hadgraft, "Skin Deep," European Journal of Pharmaceutics and
Biopharmaceutics 58, 291-299, 2004; Quintanar-Guerrero et al.,
Application of the Ion-Pair Concept to Hydrophilic Substances with
Special Emphasis on Peptides," Pharmaceutical Research 14, 119-127,
1997). There has been only limited work reported on in the prior
art for improving the bioavailability of orally administered drugs
using ion pairs.
[0020] An ion pair between the positively charged methylnaltrexone
and a negatively charged moiety was postulated by the inventors to
make a "pair" that is more hydrophobic than methylnaltrexone
bromide and thereby enhance the absorption of methylnaltrexone in
the stomach. Various ion pairs were formed using methylnaltrexone
and anions. One such ion pair was formed between methylnaltrexone
and dodecyl (lauryl) sulfate.
[0021] It was discovered, unexpectedly, that methylnaltrexone and
an amphiphilic pharmaceutically acceptable excipient, that forms an
ion pair or salt with methylnaltrexone when dissolved in solution,
in a solid dosage form together with a rapid-acting disintegrant
(e.g., a carbon dioxide-generating disintegrant) was effective to
induce laxation.
[0022] Without wishing to be bound by any particular theory of the
invention, it is believed that there is a local gastric effect and
a systemic effect, which combine to achieve laxation when using the
formulations and preparations of the invention. Such a dual effect
could suggest that laxation can be achieved using the oral
formulations of the invention at peak plasma levels lower than
those shown to be effective for subcutaneous injection.
[0023] The present invention relates to ion pairs of
methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient, methods for forming such ion pairs, methods for
selecting such ion pairs, use of such ion pairs, compositions
including such ion pairs, solid oral formulations of
methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient, including formulations containing a rapid-acting
disintegrant (e.g., effervescent or carbon dioxide-producing
disintegrant), as well as methods of using such compositions and
formulations thereof.
[0024] In one aspect, the present invention provides a salt of
methylnaltrexone of the formula:
##STR00001##
wherein methylnaltrexone is the cation of the salt, and A.sup.- is
an anion of an amphiphilic pharmaceutically acceptable excipient.
In certain embodiments, the methylnaltrexone is
(R)--N-methylnaltrexone as shown in the formula above. The
amphiphilic pharmaceutically acceptable excipient is acidic. In
certain embodiments, the amphiphilic pharmaceutically acceptable
excipient has a pK.sub.a of about 3 or less. For example, the
amphiphilic pharmaceutically acceptable excipient may include a
sulfate, sulfonate, nitrate, nitrite, phosphate, or phosphonate
moiety. In one embodiment, the pharmaceutically acceptable
excipient comprises an (--OSO.sub.3.sup.-) group. Without wishing
to be bound by a particular theory, such chemical functional groups
with pK.sub.a values at or below about 3 allow for the ion pair to
remain bound together at the acidic pH found in the stomach. This
is because the conjugate base of the excipient remains deprotonated
and negatively charged, and methylnaltrexone is quaternary amine
that is positively charged. The pharmaceutically acceptable
excipient also includes a hydrophobic portion. In some embodiments,
the hydrophobic portion is a branched or unbranched, saturated or
unsaturated, cyclic or acyclic C.sub.4-30 aliphatic chain, which
may be optionally substituted. In some embodiments the
pharmaceutically acceptable excipient is, for example, a saturated
or unsaturated, branched or unbranched, cyclic or acyclic
C.sub.4-30 aliphatic group that is optionally substituted. In some
embodiments it is a saturated, unbranched, acyclic, unsubstituted
C.sub.4-30 alkyl group. In some embodiments, it is a saturated,
unbranched, acyclic, unsubstituted C.sub.7-15 alkyl group. In some
embodiments it is a C.sub.12 n-alkyl group. In some embodiments, it
is dodecyl (lauryl) sulfate. Without wishing to be bound by any
theory, it is believed that the aliphatic chain makes the
excipients amphiphilic and surface active in nature, which helps
transport of the ion pair through the unstirred diffusion layer
lining the inner surface of the GI tract, thus increasing
availability of methylnaltrexone to the GI membrane for local
effects on receptor sites and/or absorption across lipophilic
barriers such as the lining of the GI tract, e.g., the stomach and
upper duodenum. In certain embodiments, the methylnaltrexone ion
pair is a salt that is solid at room temperature.
[0025] According to another aspect of the invention, a composition
is provided. The composition is the salt or ion pair described
above. The salt or ion pair may comprise at least 2%, at least 5%,
at least 10%, at least 20%, at least 30%, at least 50%, at least
75%, at least 90%, at least 95% or at least 99% of the
methylnaltrexone in the composition. In some embodiments, the
composition is a pharmaceutical composition.
[0026] In another aspect of the invention, a composition for oral
administration is provided. The composition includes
methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient that form an ion pair or salt with methylnaltrexone when
dissolved in solution, thereby increasing the octanol/water
partition coefficient of methylnaltrexone. When the composition is
dissolved in an aqueous solution, the methylnaltrexone has an
apparent octanol/water partition coefficient of at least 0.25 in
acidic conditions, and in some embodiments at a pH between 1 and 4.
A pH of between 1 and 4 is used to simulate the physiological
conditions of the stomach. In certain embodiments, the apparent
octanol/water partition coefficient of methylnaltrexone is at least
0.5, 1.0, 5.0, 10, 20, or 30 at a pH between 1 and 4. Typically,
the pharmaceutically acceptable excipient has a pKa of about 3 or
less so that the conjugate base of the amphiphilic pharmaceutically
acceptable excipient remains deprotonated and will be noncovalently
bound to the cationic methylnaltrexone under physiological
conditions found in the stomach (i.e., a solution at acidic
pH).
[0027] The composition also may include a rapid-acting
disintegrant, wherein the composition dissolves within about 15
minutes in the stomach. In at least one embodiment, at least 50% of
the methylnaltrexone in the composition is dissolved in 15 minutes.
In other embodiments, at least 75%, 80%, 85%, 90%, 95%, or even 99%
of the methylnaltrexone in the composition is dissolved in 15
minutes. In any of the forgoing embodiments, the methylnaltrexone
in the composition can dissolve within 10 minutes or even within 5
minutes. The dissolution of the composition in the stomach may be
simulated by in vitro studies in a dissolution apparatus with
paddles at 100 rpm in 900 ml 0.1 N HCl at 37.degree. C. In certain
embodiments, the disintegrant is a fast-acting disintegrant. In
certain embodiments, the composition has a dissolution profile
substantially similar to the one depicted in FIG. 2. In some
embodiments, the disintegrant is an effervescent disintegrant
(i.e., one that evolves a gas). By creating gas bubbles within the
composition, the composition is more readily broken down thereby
releasing methylnaltrexone. Effervescent disintegrants were found
to be particularly useful in aiding in the dissolution tablets
containing methylnaltrexone and dodecyl sulfate. In certain
embodiments, the disintegrant is an effervescent disintegrant that
is capable of generating carbon dioxide when the composition is
contacted with an aqueous medium. In any of the embodiments, the
effervescent disintegrant can be a bicarbonate or carbonate. In any
of the embodiments, the effervescent disintegrant can be sodium
bicarbonate.
[0028] According to another aspect of the invention, a method of
preparing a methylnaltrexone formulation is provided. The method
includes combining a solid pharmaceutically acceptable salt of
methylnaltrexone (that is not an ion pair of methylnaltrexone and
an amphiphilic pharmaceutically acceptable excipient), such as
methylnaltrexone bromide or iodide, with a solid pharmaceutically
acceptable salt of the amphiphilic excipient (that is not the ion
pair of methylnaltrexone and the amphiphilic pharmaceutically
acceptable excipient) to form a mixture. The mixture may be wet
granulated. In certain embodiments, a wet granulation of
methylnaltrexone or a pharmaceutically acceptable salt thereof, an
amphiphilic pharmaceutically acceptable excipient, at least one
disintegrant, at least one binder, at least one chelating agent, at
least one wetting agent, and optionally at least one filler is
prepared and formed into a solid dosage form. In certain
embodiments, a wet granulation is formed by dry blending the
methylnaltrexone or a pharmaceutically acceptable salt thereof, a
binder, an amphiphilic pharmaceutically acceptable excipient, and
optionally a disintegrant; and granulating the dry blend with a
solution of a chelating agent and/or a wetting agent to form a wet
granulation. The wet granulation may be dried and milled, and the
milled dried granulation blended with an additional disintegrant
(e.g., sodium bicarbonate) and optionally a lubricant and/or a
glidant before a solid dosage form is prepared.
[0029] In some aspects, the present invention provides compositions
for oral administration comprising a salt of the cation
methylnaltrexone and the anion of the amphiphilic pharmaceutically
acceptable excipient (e.g., dodecyl sulfate). In some embodiments,
the compositions for oral administration are tablet formulations.
In some embodiments, the compositions for oral administration are
capsule formulations.
[0030] In general, formulations for oral administration comprise
methylnaltrexone, an amphiphilic pharmaceutically acceptable
excipient as described above, and a disintegrant, and further
optionally comprise one or more other components, such as, for
example, binders, carriers, chelating agents, antioxidants,
fillers, lubricants, wetting agents, or combinations thereof. In
any of the foregoing embodiments, oral formulations are tablet
formulations. In some embodiments, the present invention provides a
unit dosage form comprising a formulation or composition described
herein.
[0031] The present invention also provides methods of oral
administration of methylnaltrexone in any context in which such
administration is desirable. For example, formulations are useful
for preventing, treating, or reducing the severity of side effects
resulting from administration of opioids, including inhibition of
intestinal motility or gastrointestinal dysfunction (e.g.,
constipation, GI sphincter constriction), nausea, emesis, and
pruritus. The compositions and formulations are useful for
administration to patients receiving acute opioid treatment (e.g.,
patients suffering from post operative ileus or gastrointestinal
dysfunction resulting from acute opioid administration). Such
formulations are also useful for administration to subjects
receiving chronic opioid administration (e.g., terminally ill
patients receiving opioid therapy (e.g., an AIDS patient, a cancer
patient, a patient with cardiovascular disease); subjects receiving
chronic opioid therapy for pain management; subjects receiving
opioid therapy for maintenance of opioid withdrawal). In some
embodiments, the subject is undergoing opioid therapy for chronic
pain management. In other embodiments, the subject is undergoing
opioid therapy for acute pain management. In certain embodiments,
the pain is non-malignant pain (e.g., back pain, neuropathic pain,
pain associated with fibromyalgia, osteoarthritis, etc.). In
certain embodiments, the pain is chronic non-malignant pain. In
certain embodiments, the pain is malignant pain. In certain
embodiments, the present invention provides a method comprising the
step of reducing one or more side effects of opioid therapy in a
subject receiving opioid treatment comprising administering to the
subject a provided tablet formulation, as described herein. In
other embodiments, the present invention provides a method for
reducing one of more effects of endogenous opioid activity in a
subject (e.g., post partum ileus) comprising administering to the
subject a formulation. In some embodiments the subject is not a
methadone maintenance patient. In any of the foregoing embodiments,
the subject can be fasted or fed. In one important embodiment, the
subject is fasted overnight.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 shows the dissolution profile of methylnaltrexone
tablets and capsules in 900 ml 0.1 N HCl, at 37 degrees C., 100 rpm
Paddle.
[0033] FIG. 2 shows the dissolution profile of methylnaltrexone
(150 mg) tablets formulated with sodium dodecyl sulfate and an
effervescent disintegrant, sodium bicarbonate (as described in
Example 5), at 37 degrees C., 100 rpm Paddle, analyzed using a Cary
50 spectrophotometer.
[0034] FIG. 3 shows a plot of the time and the percentage of
patients having a first laxation response in patients with chronic
malignant pain administered an (R)--N-methylnaltrexone bromide (300
mg or 450 mg) SDS tablet formulation after a 10 hour fast.
[0035] FIGS. 4A-4C include characterization data for MNTX-heptyl
sulfate. FIG. 4A is the .sup.1H NMR spectrum of MNTX-heptyl
sulfate. FIG. 4B is an HPLC chromatogram for MNTX-heptyl sulfate.
FIG. 4C is the UV spectrum of MNTX-heptyl sulfate.
[0036] FIGS. 5A-5C include characterization data for MNTX-dodecyl
sulfate. FIG. 5A is the .sup.1H NMR spectrum of MNTX-dodecyl
sulfate. FIG. 5B is an HPLC chromatogram for MNTX-dodecyl sulfate.
FIG. 5C is the UV spectrum of MNTX-dodecyl sulfate.
[0037] FIGS. 6A-6C include characterization data for MNTX-sodium
laurate. FIG. 6A is the .sup.1H NMR spectrum of MNTX-sodium
laurate. FIG. 6B is an HPLC chromatogram for MNTX-sodium laurate.
FIG. 6C is the UV spectrum of MNTX-sodium laurate.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
Definitions
[0038] The term "aliphatic," as used herein, includes both
saturated and unsaturated, straight chain (i.e., unbranched),
branched, acyclic, cyclic, or polycyclic aliphatic hydrocarbons,
which are optionally substituted with one or more functional
groups. As will be appreciated by one of ordinary skill in the art,
"aliphatic" is intended herein to include, but is not limited to,
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl
moieties. Thus, as used herein, the term "alkyl" includes straight,
branched, and cyclic alkyl groups. An analogous convention applies
to other generic terms such as "alkenyl," "alkynyl," and the like.
Furthermore, as used herein, the terms "alkyl," "alkenyl,"
"alkynyl," and the like encompass both substituted and
unsubstituted groups. In certain embodiments, as used herein,
"lower alkyl" is used to indicate those alkyl groups (cyclic,
acyclic, substituted, unsubstituted, branched, or unbranched)
having 1-6 carbon atoms.
[0039] In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 1-30 aliphatic carbon
atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 10-30 aliphatic carbon
atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 5-25 aliphatic carbon
atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 5-20 aliphatic carbon
atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 10-20 aliphatic carbon
atoms. In certain embodiments, the alkyl, alkenyl, and alkynyl
groups employed in the invention contain 15-25 aliphatic carbon
atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-10 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to,
for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
--CH.sub.2-- cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,
isobutyl, tert-butyl, cyclobutyl, --CH.sub.2-cyclobutyl, n-pentyl,
sec-pentyl, isopentyl, tert-pentyl, cyclopentyl,
--CH.sub.2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl,
--CH.sub.2-cyclohexyl, heptyl, octyl (capryl), nonyl, decyl
(capric), undecyl, dodecyl (lauryl), tridecyl, tetradecyl,
hexadecyl (cetyl), heptadecyl, octadecyl (stearyl), eicosyl
(arachidyl), docosyl, tetracosyl, hexacosyl, octacosyl, triacontyl
moieties and the like, which again, may bear one or more
substituents.
[0040] Some examples of substituents of the above-described
aliphatic moieties include, but are not limited to aliphatic;
heteroaliphatic; aryl; heteroaryl; arylalkyl; heteroarylalkyl;
alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;
heteroalkylthio; heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2;
--CN; --CF.sub.3; --CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --CO.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2Rx;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x; and
--NR.sub.x(CO)R.sub.x; wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
heteroaliphatic, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
wherein any of the aliphatic, heteroaliphatic, arylalkyl, or
heteroarylalkyl substituents described above and herein may be
substituted or unsubstituted, branched or unbranched, cyclic or
acyclic, and wherein any of the aryl or heteroaryl substituents
described above and herein may be substituted or unsubstituted.
[0041] The term "amphiphilic" as used herein to describe a molecule
refers to the molecule's dual hydrophobic and hydrophilic
properties. Typically, amphiphilic molecules have a polar, water
soluble group (e.g., a phosphate, carboxylic acid, sulfate)
attached to a nonpolar, water-insoluble group (e.g., a
hydrocarbon). The term amphiphilic is synonymous with amphipathic.
Examples of amphiphilic molecules include sodium dodecyl (lauryl)
sulfate, fatty acids, phospholipids, and bile acids. Amphiphilic
molecules may be uncharged, cationic, or anionic.
[0042] As used herein, the term "dissolution rate" refers to the
amount of time it takes for an active ingredient or composition
thereof (e.g., a salt methylnaltrexone) to dissolve in a solvent.
The dissolution rate may depend on a variety of factors including
mixing, temperature, pH, solvent, particle size, etc. The
dissolution rate of a drug or composition thereof affects the
bioavailability of the drug. In certain circumstances, dissolution
rate is used to determine drug availability from solid dosage
forms.
[0043] As used herein, an "effective amount" of a compound or
pharmaceutically acceptable composition or formulation can achieve
a desired therapeutic and/or prophylactic effect. In some
embodiments, an "effective amount" is at least a minimal amount of
a compound, or formulation or composition containing a compound,
which is sufficient for treating one or more symptoms of a disorder
or condition associated with modulation of peripheral a opioid
receptors, such as side effects associated with opioid analgesic
therapy (e.g., gastrointestinal dysfunction (e.g., dysmotility
constipation, etc.), nausea, emesis, etc.). In certain embodiments,
an "effective amount" of a compound, composition, or formulation
containing a compound, is sufficient for treating symptoms
associated with, a disease associated with aberrant endogenous
peripheral opioid or a opioid receptor activity (e.g., idiopathic
constipation, ileus, etc.). In some embodiments, the term
"effective amount," as used in connection with an amount of
methylnaltrexone or salt of methylnaltrexone, means an amount of
methylnaltrexone or salt of methylnaltrexone sufficient to achieve
laxation in a patient.
[0044] The term "effervescent disintegrant," as used herein, refers
to a material that causes effervescence resulting in quick
disintegration of the dosage form following contact with aqueous
medium. Typically the effervescent disintegrant is a base (e.g.,
carbonate) which reacts with an acid (e.g., HCl in the stomach) to
form carbon dioxide. Therefore, such effervescent disintegrants
include carbon dioxide producing disintegrants. Carbonate sources
include, but are not limited to, carbonate and bicarbonate salts
such as sodium bicarbonate, sodium carbonate, potassium
bicarbonate, potassium carbonate, magnesium carbonate, sodium
sesquicarbonate, sodium glycine carbonate, L-lysine carbonate,
arginine carbonate, and calcium carbonate. Effervescent
disintegrants are known in the art for achieving
fast-disintegrating dosage forms.
[0045] As used herein, the term "lipophilicity" refers to a
compound's ability to associate with or dissolve in a fat, lipid,
oil, or non-polar solvent. Lipophilicity and hydrophobicity may be
used to describe the same tendency of a molecule to dissolve in
fats, oils, lipids, and non-polar solvents.
[0046] As used herein the term "non-functional coating" is a
coating that does not significantly affect release characteristics
of a therapeutically active compound or compounds from a
formulation when administered. Examples of a non-functional coat
include a seal coat (e.g., hydroxypropyl cellulose, hypromellose or
polyvinyl alcohol). In certain embodiments, a non-functional
coating is a polish coat or seal coat.
[0047] As used herein the term "non-malignant pain" refers to
"non-cancer pain."
[0048] The term "apparent partition coefficient," as used herein,
refers to the ratio of concentrations of a compound in any form in
the two phases of a mixture of two immiscible solvents at
equilibrium. In certain embodiments, the two immiscible solvents
are octanol and water. The apparent partition coefficient may be
determined under various conditions, for example, temperature, pH,
concentration, etc. Apparent partition coefficients have been found
useful in estimating the distribution of compounds in the body.
Higher apparent partition coefficients denote a more hydrophobic
(more lipophilic) compound, while lower apparent partition
coefficients denote a hydrophilic compound. The apparent partition
coefficient of a compound may be determined by procedures known in
the art, for example, in the U.S. Pharmacopeia. The apparent
partition coefficient may be determined by the procedure used to
determine the apparent partition coefficients of methylnaltrexone
dodecyl sulfate and methylnaltrexone heptyl sulfate in the
Examples.
[0049] The term "subject", as used herein, means a mammal and
includes human and animal subjects, such as domesticated animals
(e.g., horses, dogs, cats, etc.) and experimental animals (e.g.,
mice, rats, dogs, chimpanzees, apes, etc.).
[0050] The terms "suffer" or "suffering" as used herein refers to
one or more conditions that a patient has been diagnosed with, or
is suspected to have.
[0051] The term "spheroid", as used herein, has its art understood
meaning of a substantially spherical particulate. In many
embodiments, spheroids prepared or utilized according to the
present invention have a size within the range of about 1-1500
microns. In some embodiments, such spheroids have a size within the
range of about 20-1500 microns. In some embodiments, such spheroids
have a size within the range of about 20-1000 microns. In some
embodiments, such spheroids have a size within the range of about
20-500 microns. In some embodiments, such spheroids have a size
within the range of about 20-300 microns. In certain embodiments,
the spheroids have a size range wherein at least 80% of the
spheroids fall within the range of about 20-325 microns. In some
embodiments, the spheroids have a size range wherein at least 50%
of the spheroids fall within the range of about 45-120 microns.
[0052] The terms "treat" or "treating," as used herein, refers to
partially or completely alleviating, inhibiting, delaying onset of,
reducing the incidence of, ameliorating and/or relieving a disorder
or condition, or one or more symptoms of the disorder, disease or
condition.
[0053] "Therapeutically active agent" or "active agent" refers to a
substance, including a biologically active substance, that is
useful for therapy (e.g., human therapy, veterinary therapy),
including prophylactic and therapeutic treatment. Therapeutically
active agents include organic molecules that are drug compounds,
peptides, proteins, carbohydrates, monosaccharides,
oligosaccharides, polysaccharides, nucleoprotein, mucoprotein,
lipoprotein, synthetic polypeptide or protein, small molecules
linked to a protein, glycoprotein, steroid, nucleic acid, DNA, RNA,
nucleotide, nucleoside, oligonucleotides, antisense
oligonucleotides, lipid, hormone, and vitamin. Therapeutically
active agents include any substance used as a medicine for
treatment, prevention, delay, reduction or amelioration of a
disease, condition, or disorder. Among therapeutically active
agents useful in the formulations of the present invention are
opioid receptor antagonist compounds, opioid analgesic compounds,
and the like. Further detailed description of compounds useful as
therapeutically active agents is provided below. A therapeutically
active agent includes a compound that increases the effect or
effectiveness of a second compound, for example, by enhancing
potency or reducing adverse effects of a second compound.
[0054] The expression "unit dosage form" as used herein refers to a
physically discrete unit of a provided formulation appropriate for
the subject to be treated. It will be understood, however, that the
total daily usage of provided formulation will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular subject or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of specific active agent employed; specific formulation employed;
age, body weight, general health, sex and diet of the subject; time
of administration, and rate of excretion of the specific active
agent employed; duration of the treatment; drugs and/or additional
therapies used in combination or coincidental with specific
compound(s) employed, and like factors well known in the medical
arts.
[0055] The term "pK.sub.a," as used herein, refers to the
-log.sub.10K.sub.a, wherein K.sub.a is the acid dissociation
constant. pK.sub.a measures the strength of an acid in solution on
a logarithmic scale. The acid dissociation constant K.sub.a is the
equilibrium constant for the dissociation of a compound into a
proton and its conjugate base, symbolically written as:
HAA.sup.-+H.sup.+.
Compositions and Formulations of Methylnaltrexone
[0056] As used herein, methylnaltrexone refers to
(R)--N-methylnaltrexone. (R)--N-methylnaltrexone, a peripherally
acting a opioid receptor antagonist, has been studied and used to
treat bowel dysfunction in patients being administered opioids.
Surprisingly, enterically coated preparations of methylnaltrexone
do not consistently demonstrate a substantial effect in treating
opioid-induced constipation. Contrary to the suggestions of the
prior art concerning oral methylnaltrexone, local concentrations of
methylnaltrexone in the intestinal tract remote from the stomach,
are not effective to induce laxation and treat constipation.
[0057] In certain embodiments, the present invention provides a
composition comprising methylnaltrexone and a pharmaceutically
acceptable excipient, wherein the composition in solution yields an
octanol/water apparent partition coefficient for methylnaltrexone
of at least 0.25 under acidic conditions, in certain embodiments at
a pH between 1 and 4. In some embodiments, such compositions are
formulated for oral administration. In some embodiments, a
composition for oral administration is formulated into a tablet.
Methylnaltrexone for use in such compositions and formulations may
be in any of a variety of forms. For example, forms of
methylnaltrexone suitable for use in the inventive compositions and
formulations include pharmaceutically acceptable salts, prodrugs,
polymorphs (i.e., crystal forms), co-crystals, hydrates, solvates,
and the like. Any form of methylnaltrexone may be used in the
compositions or formulations, but the form should allow for ion
pairing with the amphiphilic pharmaceutically acceptable
excipient.
[0058] In certain embodiments, the compositions, and formulations
thereof, comprise a salt of formula I:
##STR00002##
wherein A.sup.- is a suitable anion. In certain embodiments,
A.sup.- is the anion of a Bronsted acid. Exemplary Bronsted acids
include hydrogen halides, carboxylic acids, sulfonic acids,
sulfuric acid, and phosphoric acid. In certain embodiments, A.sup.-
is chloride, bromide, iodide, fluoride, sulfate, bisulfate,
tartrate, nitrate, citrate, bitartrate, carbonate, phosphate,
malate, maleate, fumarate sulfonate, methylsulfonate, formate,
carboxylate, sulfate, methylsulfate or succinate salt. In certain
embodiments, A.sup.- is trifluoroacetate. In certain embodiments,
A.sup.- is bromide. In certain embodiments, A.sup.- is an anion of
an amphiphilic pharmaceutically acceptable excipient. In certain
embodiments, A.sup.- is an acidic amphiphilic pharmaceutically
acceptable excipient. In certain embodiments, the pharmaceutically
acceptable excipient has a pK.sub.a of about 3 or less. In certain
embodiments, the pharmaceutically acceptable excipient has a
pK.sub.a of about 2 or less. In certain embodiments, the
pharmaceutically acceptable excipient has a pK.sub.a between about
1 and about 2. In certain embodiments, the pharmaceutically
acceptable excipient has a pK.sub.a of about 1 or less. In certain
embodiments, the anion of the pharmaceutically acceptable excipient
include a sulfate, sulfonate, phosphate, phosphonate, nitrate, or
nitrite moiety. In certain embodiments, the anion of the
pharmaceutically acceptable excipient includes a sulfate
(--OSO.sub.3.sup.-) group. In certain embodiments, the anion is
butyl sulfate, pentyl sulfate, hexyl sulfate, heptyl sulfate, octyl
sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate, dodecyl
sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecyl sulfate,
hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate, eicosyl
sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate,
octacosyl sulfate, and triacontyl sulphate. In certain embodiments,
the methylnaltrexone in the composition or formulation may have
multiple anions (e.g., bromide and dodecyl (lauryl) sulfate)
associate with it.
[0059] In some embodiments, the compositions, and formulations
thereof, comprise (R)--N-methylnaltrexone bromide.
(R)--N-methylnaltrexone bromide, which is also known as "MNTX" and
is described in international PCT patent application publication
number, WO2006/12789, which is incorporated herein by reference.
The chemical name for (R)--N-methylnaltrexone bromide is
(R)--N-(cyclopropylmethyl) noroxymorphone methobromide.
(R)--N-methylnaltrexone bromide has the molecular formula
C.sub.21H.sub.26NO.sub.4Br and a molecular weight of 436.36 g/mol.
(R)--N-methylnaltrexone bromide has the following structure:
##STR00003##
where the compound is in the (R) configuration with respect to the
quaternary nitrogen. In certain embodiments of the present
invention, at least about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or
99.95% of the compound is in the (R) configuration with respect to
nitrogen. Methods for determining the amount of
(R)--N-methylnaltrexone bromide, present in a sample as compared to
the amount of (S)--N-methylnaltrexone bromide present in that same
sample, are described in detail in WO2006/127899, which is
incorporated herein by reference. In other embodiments, the
methylnaltrexone contains 0.15%, 0.10%, or less
(S)--N-methylnaltrexone bromide.
[0060] In some embodiments, a composition, or formulation thereof,
comprises from about 7% to about 75%, about 25% to about 55%, about
40%, or to about 50% (R)--N-methylnaltrexone cation, based upon
total weight of the formulation. In certain embodiments, a provided
composition, or formulation thereof, comprises from about 7%, about
8%, about 10%, about 20%, about 30%, about 40%, about 50%, about
60%, about 70%, or about 75% (R)--N-methylnaltrexone cation, based
upon the total weight of the given composition or formulation. It
will be understood that the (R)--N-methylnaltrexone cation and the
anion of the amphiphilic pharmaceutically acceptable excipient may
exist in the composition as an ion pair or may exist as separate
salts paired with other counter ions such as bromide and sodium, or
mixtures thereof.
[0061] In some embodiments, a composition, or formulation thereof,
comprises from about 7% to about 75%, about 25% to about 55%, about
40%, or to about 50% (R)--N-methylnaltrexone cation and dodecyl
sulfate anion, based upon the total weight of the composition or
formulation. In certain embodiments, a composition, or formulation
thereof, comprises from about 7%, about 8%, about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, or about 75%
(R)--N-methylnaltrexone cation and dodecyl sulfate anion, based
upon total weight of the composition or formulation.
[0062] In certain embodiments, the present invention provides a
composition comprising methylnaltrexone and an amphiphilic
pharmaceutically acceptable excipient. The amphiphilic
pharmaceutically acceptable excipient increases the lipophilicity
of the composition thereby allowing for increased transport through
the unstirred diffusion layer in the GI tract, resulting in
increased permeation through biological membranes. In certain
embodiments, the excipient increases the lipophilicity of the drug.
In certain embodiments, the excipient is a surfactant. In some
embodiments, the excipient is an anionic surfactant. In certain
embodiments, the excipient is an anionic surfactant that forms an
ion pair or salt with positively charged methylnaltrexone. Such
anionic surfactants are known in the art and are typically
characterized by having a lipophilic end and an anionic portion.
Exemplary excipients useful in the present invention include
aliphatic sulfates (e.g., sodium dodecyl (lauryl) sulfate),
aliphatic phosphates, fatty acids, and salts and derivatives
thereof.
[0063] As a measure of lipophilicity of the resulting ion pair, a
solution of the composition yields an apparent octanol/water
partition coefficient for methylnaltrexone of at least 0.25 at a pH
between 1 and 4. The apparent octanol/water partition coefficient
as used herein is determined at room temperature at a concentration
of approximately 0.5 mg/mL. Exemplary methods for the determination
of apparent octanol/water partition coefficient of methylnaltrexone
salts are described in the Examples below.
[0064] Particularly useful amphiphilic pharmaceutically acceptable
excipient includes those that increase the oral absorption of
methylnaltrexone. In certain embodiments, the excipient increases
the absorption of methylnaltrexone in the stomach. In certain
embodiments, the excipient increases the ability of
methylnaltrexone to cross lipophilic barriers. In certain
embodiments, the excipient increases the lipophilicity of
methylnaltrexone by forming an ion pair with cationic
methylnaltrexone. Ion pairing increases the partitioning of
methylnaltrexone into an organic phase such as a lipid bilayer. In
certain embodiments, the excipient forms an ion pair with
methylnaltrexone such that when the composition is in solution, the
methylnaltrexone has an apparent octanol/water partition
coefficient of at least 0.25 at a pH between 1 and 4. In certain
embodiments, the apparent octanol/water partition coefficient is at
least 0.5 at a pH between 1 and 4. In certain embodiments, the
apparent octanol/water partition coefficient is at least 0.75 at a
pH between 1 and 4. In certain embodiments, the apparent
octanol/water partition coefficient is at least 1.0 at a pH between
1 and 4. In certain embodiments, the apparent octanol/water
partition coefficient is at least 10 at a pH between 1 and 4. In
certain embodiments, the apparent octanol/water partition
coefficient is at least 15 at a pH between 1 and 4. In certain
embodiments, the apparent octanol/water partition coefficient is at
least 20 at a pH between 1 and 4. In certain embodiments, the
apparent octanol/water partition coefficient is at least 25 at a pH
between 1 and 4. In certain embodiments, the apparent octanol/water
partition coefficient is at least 30 at a pH between 1 and 4.
[0065] As used herein, the term "aliphatic sulfate" refers to a
compound having a sulfate moiety at one end and an aliphatic tail,
which is straight or branched, and saturated or unsaturated. The
aliphatic tail may be substituted and may also include cyclic
groups. In some embodiments, the aliphatic tail is a C.sub.4 to
C.sub.30 aliphatic group. In certain embodiments, the aliphatic
tail is a C.sub.7 to C.sub.20 aliphatic group. In certain
embodiments, the aliphatic tail is a C.sub.10 to C.sub.20 aliphatic
group. In certain embodiments, the aliphatic tail is a C.sub.10,
C.sub.11, C.sub.12, C.sub.13, C.sub.14, or C.sub.15 aliphatic
group. In certain embodiments, the aliphatic group is an n-alkyl
group, which is saturated, not branched, and not substituted. In
certain embodiments, the aliphatic group is C.sub.7-C.sub.20
n-alkyl. In certain embodiments, the aliphatic group is
C.sub.10-C.sub.15 n-alkyl.
[0066] In certain embodiments, the amphiphilic pharmaceutically
acceptable excipient is a compound of formula:
R.sup.1--OSO.sub.2OH
or a salt thereof, wherein R.sup.1 is a C.sub.4-30 aliphatic group
that is saturated or unsaturated, unbranched or branched, and
cyclic or acyclic, and the aliphatic group is optionally
substituted with one or more halogen or hydroxyl groups. In certain
embodiments, each R.sup.1 is a C.sub.4-10 aliphatic group. In
certain embodiments, each R.sup.1 is a C.sub.10-15 aliphatic group.
In certain embodiments, each R.sup.1 is a C.sub.15-20 aliphatic
group. In certain embodiments, each R.sup.1 is a C.sub.20-30
aliphatic group. In certain embodiments, R.sup.1 is unsaturated. In
certain embodiments, R.sup.1 is saturated. In certain embodiments,
R.sup.1 is unbranched. In certain embodiments, R.sup.1 is branched.
In certain embodiments, R1 is substituted. In certain embodiments,
R.sup.1 is unsubstituted. In certain embodiments, R.sup.1 is
saturated, unbranched, and unsubstituted. In certain embodiments,
R.sup.1 is C.sub.4-30 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.5-15 n-alkyl. In certain embodiments, R.sup.1 is C.sub.5-10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.10-15 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.6 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.7 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.8 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.9 n-alkyl. In certain embodiments, R.sup.1 is C.sub.10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.11 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.12 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.13 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.14 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.15 n-alkyl. In certain embodiments, the excipient is a sodium
salt form.
[0067] In certain embodiments, the amphiphilic pharmaceutically
acceptable excipient is a compound of formula:
R.sup.1--SO.sub.2OH
or a salt thereof, wherein R.sup.1 is a C.sub.4-30 aliphatic group
that is saturated or unsaturated, unbranched or branched, and
cyclic or acyclic, and the aliphatic group is optionally
substituted with one or more halogen or hydroxyl groups. In certain
embodiments, each R.sup.1 is a C.sub.4-10 aliphatic group. In
certain embodiments, each R.sup.1 is a C.sub.10-15 aliphatic group.
In certain embodiments, each R.sup.1 is a C.sub.15-20 aliphatic
group. In certain embodiments, each R.sup.1 is a C.sub.20-30
aliphatic group. In certain embodiments, R.sup.1 is unsaturated. In
certain embodiments, R.sup.1 is saturated. In certain embodiments,
R.sup.1 is unbranched. In certain embodiments, R.sup.1 is branched.
In certain embodiments, R1 is substituted. In certain embodiments,
R.sup.1 is unsubstituted. In certain embodiments, R.sup.1 is
saturated, unbranched, and unsubstituted. In certain embodiments,
R.sup.1 is C.sub.4-30 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.5-15 n-alkyl. In certain embodiments, R.sup.1 is C.sub.5-10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.10-15 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.6 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.7 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.8 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.9 n-alkyl. In certain embodiments, R.sup.1 is C.sub.10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.11 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.12 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.13 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.14 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.15 n-alkyl. In certain embodiments, the excipient is a sodium
salt form.
[0068] In certain embodiments, the amphiphilic pharmaceutically
acceptable excipient is a compound of formula:
R.sup.1--P(O).sub.2OH
or a salt thereof, wherein R.sup.1 is a C.sub.4-30 aliphatic group
that is saturated or unsaturated, unbranched or branched, and
cyclic or acyclic, and the aliphatic group is optionally
substituted with one or more halogen or hydroxyl groups. In certain
embodiments, each R.sup.1 is a C.sub.4-10 aliphatic group. In
certain embodiments, each R.sup.1 is a C.sub.10-15 aliphatic group.
In certain embodiments, each R.sup.1 is a C.sub.15-20 aliphatic
group. In certain embodiments, each R.sup.1 is a C.sub.20-30
aliphatic group. In certain embodiments, R.sup.1 is unsaturated. In
certain embodiments, R.sup.1 is saturated. In certain embodiments,
R.sup.1 is unbranched. In certain embodiments, R.sup.1 is branched.
In certain embodiments, R1 is substituted. In certain embodiments,
R.sup.1 is unsubstituted. In certain embodiments, R.sup.1 is
saturated, unbranched, and unsubstituted. In certain embodiments,
R.sup.1 is C.sub.4-30 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.5-15 n-alkyl. In certain embodiments, R.sup.1 is C.sub.5-10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.10-15 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.6 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.7 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.8 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.9 n-alkyl. In certain embodiments, R.sup.1 is C.sub.10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.11 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.12 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.13 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.14 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.15 n-alkyl. In certain embodiments, the excipient is a sodium
salt form.
[0069] In certain embodiments, the amphiphilic pharmaceutically
acceptable excipient is a compound of formula:
R.sup.1--OP(O).sub.2OH
or a salt thereof, wherein R.sup.1 is a C.sub.4-30 aliphatic group
that is saturated or unsaturated, unbranched or branched, and
cyclic or acyclic, and the aliphatic group is optionally
substituted with one or more halogen or hydroxyl groups. In certain
embodiments, each R.sup.1 is a C.sub.4-10 aliphatic group. In
certain embodiments, each R.sup.1 is a C.sub.10-15 aliphatic group.
In certain embodiments, each R.sup.1 is a C.sub.15-20 aliphatic
group. In certain embodiments, each R.sup.1 is a C.sub.20-30
aliphatic group. In certain embodiments, R.sup.1 is unsaturated. In
certain embodiments, R.sup.1 is saturated. In certain embodiments,
R.sup.1 is unbranched. In certain embodiments, R.sup.1 is branched.
In certain embodiments, R1 is substituted. In certain embodiments,
R.sup.1 is unsubstituted. In certain embodiments, R.sup.1 is
saturated, unbranched, and unsubstituted. In certain embodiments,
R.sup.1 is C.sub.4-30 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.5-15 n-alkyl. In certain embodiments, R.sup.1 is C.sub.5-10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.5-15 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.6 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.7 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.8 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.9 n-alkyl. In certain embodiments, R.sup.1 is C.sub.10
n-alkyl. In certain embodiments, R.sup.1 is C.sub.1 n-alkyl. In
certain embodiments, R.sup.1 is C.sub.12 n-alkyl. In certain
embodiments, R.sup.1 is C.sub.13 n-alkyl. In certain embodiments,
R.sup.1 is C.sub.14 n-alkyl. In certain embodiments, R.sup.1 is
C.sub.15 n-alkyl. In certain embodiments, the excipient is a sodium
salt form.
[0070] One of ordinary skill in the art will recognize that
methylnaltrexone may form an ion pair or salt with an anionic
amphiphilic pharmaceutically acceptable excipient. In some
embodiments, the present invention provides a compound of formula
II:
##STR00004##
wherein A.sup.- is an anionic amphiphilic pharmaceutically
acceptable excipient.
[0071] In some aspects, methylnaltrexone may form an ion pair with
any of formulae R.sup.1--COOH, R.sup.1--SO.sub.2OH,
R.sup.1--OSO.sub.2OH, R.sup.1--P(O).sub.2OH,
R.sup.1--OP(O).sub.2OH, or a salt thereof, as described herein.
Thus, according to another embodiment, the present invention
provides a compound of any of formula III, formula IV, formula V,
formula VI, or formula VII:
##STR00005##
wherein R.sup.1 is a C.sub.4-30 aliphatic group that is saturated
or unsaturated, unbranched or branched, and cyclic or acyclic, and
the aliphatic group is optionally substituted with one or more
halogen or hydroxyl groups.
[0072] In some embodiments, the amphiphilic pharmaceutically
acceptable excipient is sodium dodecyl (lauryl) sulfate (also known
as SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate,
perfluorooctanesulfonate (PFOS), and the like.
[0073] In some embodiments, compositions, i.e., pharmaceutical
compositions comprising methylnaltrexone and sodium dodecyl
(lauryl) sulfate (also known as SDS or SLS), are provided.
[0074] In some embodiments, a provided composition, or formulation
thereof, comprises from about 5% to about 80% of the amphiphilic
pharmaceutically acceptable excipient, based upon total weight of
the composition, or formulation thereof. In certain embodiments,
about 5% to about 25% of amphiphilic pharmaceutically acceptable
excipient is used in the composition or formulation. In some
embodiments, a provided composition, or formulation thereof,
comprises about 5%, about 10%, about 15%, about 20%, about 25%,
about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,
about 60%, about 65%, about 70%, about 75%, or about 80% of the
excipient, based upon total weight of the composition, or
formulation thereof.
[0075] Certain amphiphilic pharmaceutically acceptable excipients
and their corresponding methylnaltrexone ion pairs are less soluble
compared to methylnaltrexone bromide in an aqueous environment. In
certain embodiments, therefore, the present invention provides a
composition or formulation comprising methylnaltrexone, or a salt
thereof, an amphiphilic pharmaceutically acceptable excipient, and
a disintegrant. Incorporation of a suitable rapid-acting
disintegrant into compositions and formulations facilitates the
breakdown of tablets or other solid dosage forms, in particular,
the rapid breakdown of tablets or other solid dosage forms in the
stomach. Thus, the inclusion of rapid-acting disintegrants is
desired in solid dosage forms, such as tablets, that contain active
ingredient. The amount of the disintegrant will vary, depending on
the nature and amount of the amphiphilic pharmaceutically
acceptable excipient (and, optionally, other ingredients). Those
skilled in the art will understand how to manufacture a solid
dosage form which will dissolve in the stomach according to the
parameters described above. There exist in vitro models, for making
such determinations, such as the United States Pharmacopeia (USP)
dissolution test, the USP disintegration test, etc. In some
embodiments, at least 50% of the methylnaltrexone in the
composition dissolves in 15 minutes. In other embodiments, at least
75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in the
composition dissolves in 15 minutes. In some embodiments, the
amounts of methylnaltrexone indicated above dissolve in about 10
minutes, or even about 5 minutes. As used herein by dissolve a
certain percent in the stomach within a particular time period, it
is meant the percent of the methylnaltrexone, as a cation or as a
salt such as an ion pair, in the composition that will convert from
a solid into solution when the composition is placed in 900 ml of 1
N HCl at 37.degree. C., 100 rpm Paddle.
[0076] Suitable disintegrants are known in the art and include, but
are not limited to, agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, sodium carbonate, sodium
bicarbonate, crospovidone (cross-linked PVP), sodium carboxymethyl
starch (sodium starch glycolate), cross-linked sodium carboxymethyl
cellulose (croscarmellose), pregelatinized starch (starch 1500),
microcrystalline starch, water insoluble starch, calcium
carboxymethyl cellulose, magnesium aluminium silicate (Veegum), and
combinations thereof. In some embodiments, the disintegrant is
crospovidone. In certain embodiments, the disintegrant is an
effervescent disintegrant. Effervescent disintegrants are capable
of generating carbon dioxide in an aqueous medium, particularly
acidic aqueous medium such as the contents of the stomach. In
certain embodiments, the disintegrant is a bicarbonate, such as
sodium bicarbonate (NaHCO.sub.3) or potassium bicarbonate
(KHCO.sub.3). In certain embodiments, the disintegrants is a
carbonate. In certain embodiments, the disintegrant is sodium
carbonate (Na.sub.2CO.sub.3). In certain embodiments, the
disintegrant is calcium carbonate (CaCO.sub.3). In certain
embodiments, the composition or formulation comprises at least two
disintegrants. For example, the composition or formulation may
include one effervescent disintegrant and one disintegrant that is
not effervescent. In certain embodiments, the compositions or
formulation comprises sodium bicarbonate and crospovidone as
disintegrants. In some embodiments, provided formulations comprise
from about 1% to about 25%, about 1% to about 15%, about 1% to
about 10%, or about 2% to about 5% disintegrant, based upon total
weight of the formulation. In some embodiments, provided
formulations comprise from about 1%, about 2%, about 3%, about 4%,
about 5%, about 7%, about 8%, about 10%, about 12%, or about 15%
disintegrant, based upon total weight of the formulation. In
certain embodiments, the composition or formulation includes a
material and/or coating that retards or prevents dissolution of the
solid dosage form in the oral cavity. Preferably, the solid dosage
form breaks down or disintegrates rapidly in the stomach, not in
the oral cavity.
[0077] In some embodiments, the present invention provides a
formulation of methylnaltrexone which further comprises one or more
additional components, such as, for example, binders, carriers,
disintegrants, chelating agents, antioxidants, fillers, wetting
agents, or combinations thereof. In certain embodiments, a
composition is formulated into a tablet which further comprises one
or more additional components, such as, for example, binders,
carriers, disintegrants, chelating agents, antioxidants, fillers,
wetting agents, lubricants, or combinations thereof. In some
embodiments, a composition is formulated into a tablet which
further comprises an antioxidant and one or more components, such
as, for example, binders, carriers, chelating agents, fillers,
wetting agents, or combinations thereof. In some embodiments, a
composition is formulated into a tablet which further comprises a
disintegrant and one or more components, such as, for example,
binders, carriers, chelating agents, antioxidants, fillers, wetting
agents, or combinations thereof. In some embodiments, a composition
is formulated into a tablet which further comprises an antioxidant,
a disintegrant, and one or more components, such as, for example,
binders, carriers, chelating agents, fillers, wetting agents, or
combinations thereof. Such additional components are described in
detail herein, infra.
[0078] In certain embodiments, pharmaceutically acceptable
formulations of the present invention are provided as tablets which
comprise a composition comprising methylnaltrexone and an
amphiphilic pharmaceutically acceptable excipient, and a
disintegrant, and, optionally, one or more of a binder, a chelating
agent, and a wetting agent. In some embodiments such tablets
comprise a composition comprising methylnaltrexone and an
amphiphilic pharmaceutically acceptable excipient, a binder, a
chelating agent, a disintegrant, and a wetting agent. In certain
embodiments such tablets comprise a composition comprising
methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient, an antioxidant, and one or more of a binder, a chelating
agent, a disintegrant, and a wetting agent. According to some
embodiments, provided formulations comprise tablets that have a
non-functional coating. In some embodiments, provided formulations
further comprise an antioxidant.
[0079] One skilled in the art will readily appreciate that the
category under which a particular component is listed is not
intended to be limiting; in some cases a particular component might
appropriately fit into more than one category. Also, as will be
appreciated, the same component can sometimes perform different
functions, or can perform more than one function, in the context of
a particular formulation, for example depending upon the amount of
the ingredient and/or the presence of other ingredients and/or
active compound(s).
[0080] Wetting agents are well known in the art and typically
facilitate the interaction of an active agent, such as one that is
hydrophobic, with water molecules in a surrounding aqueous
environment. Exemplary wetting agents include poloxamer,
polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters
polyoxyethylene fatty acid esters, polyethylene glycol fatty acid
esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene
alkyl ether, polysorbates, such as polysorbate 80, cetyl alcohol,
glycerol fatty acid esters (e.g., triacetin, glycerol monostearate,
and the like), polyoxymethylene stearate, sodium dodecyl sulfate,
sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium
chloride, polyethoxylated castor oil, and docusate sodium, and the
like, and combinations thereof. In some embodiments, provided
tablets comprise from about 1% to about 25% wetting agent, based
upon total weight of the tablets. In some embodiments, provided
tablets comprise from about 1%, about 3%, about 4%, about 5%, about
10%, about 15%, or about 20% of wetting agent, based upon total
weight of given tablets.
[0081] In certain embodiments, a wetting agent is a polysorbate. In
some embodiments, a wetting agent is polysorbate 80, also known as
Tween 80, and is available from Sigma-Aldrich, among other sources.
In some embodiments, provided tablets comprise from about 1% to
about 25% polysorbate 80, about 1% to about 5%, about 2% to about
5%, about 3%, or to about 4% based upon total weight of given
tablet. In certain embodiments, provided tablets comprise from
about 1%, about 3%, about 4%, about 5%, about 10%, about 15%, or
about 20% polysorbate 80, based upon total weight of given tablets.
Without wishing to be bound by any particular theory, polysorbate
80 can also act as an absorption enhancer. Further, without wishing
to be bound by any particular theory, polysorbate 80 may facilitate
thinning of the mucus layer created in the gastrointestinal tract
so that remaining methylnaltrexone in the mucous layer is more
readily released for rapid absorption.
[0082] Addition of one or more chelating agents may be particularly
useful in formulations that include methylnaltrexone, and such
agents may provide protection from metal-catalyzed degradation
and/or from precipitation of methylnaltrexone. Appropriate
chelating agents are known to those skilled in the art, and include
any pharmaceutically acceptable chelating agent. Common chelating
agents include, but are not limited to ethylenediaminetetraacetic
acid (EDTA) and derivatives thereof, ethylene
glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraaceticacid (EGTA) and
derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and
derivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and
derivatives thereof, nitrilotriacetic acid and derivatives thereof,
citric acid and derivatives thereof, niacinamide and derivatives
thereof, and sodium desoxycholate and derivatives thereof.
[0083] In some embodiments, the chelating agent is selected from
the group consisting of EDTA or derivatives thereof. In some
embodiments, the chelating agent is selected from the group
consisting of calcium EDTA disodium, diammonium EDTA, dipotassium
EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA,
trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts
thereof. In some embodiments, the chelating agent is EDTA disodium,
EDTA trisodium, or calcium EDTA disodium. In some embodiments, the
chelating agent is calcium EDTA (edetate calcium) or a calcium salt
EDTA derivative or calcium EGTA or a calcium salt EGTA derivative.
In some embodiments, the chelating agent is calcium EDTA disodium,
such as, for example, calcium EDTA disodium hydrate (edetate
calcium disodium dihydrate). Calcium EDTA is available from
Sigma-Aldrich, among other sources. In some embodiments, provided
formulations comprise from about 0.01% to about 5%, about 0.01% to
about 4%, about 0.01% to about 3%, 0.01% to about 2%, 0.01% to
about 1%, about 0.1% to about 5%, about 0.1% to about 4%, 0.1% to
about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about
0.1% to about 1%, or about 0.1% to about 0.5% of the chelating
agent, based upon total weight of the formulation. In some
embodiments, provided formulations comprise from about 0.1%, about
0.2%, about 0.3%, about 0.4%, about 0.5%, or about 0.6% of the
chelating agent, based upon total weight of formulation.
[0084] Suitable binders (also referred to as "diluents" and/or
"fillers") are known in the art. For example, suitable binders
include but are not limited to starch, PVP (polyvinyl pyrrolidone),
low molecular weight HPC (hydroxypropyl cellulose),
microcrystalline cellulose (e.g., Avicel.RTM.), silicified
microcrystalline cellulose (Prosolv 50), low molecular weight HPMC
(hydroxypropyl methylcellulose), low molecular weight carboxymethyl
cellulose, ethylcellulose, alginates, gelatin, polyethylene oxide,
acacia, dextrin, sucrose, magnesium aluminum silicate, and
polymethacrylates. Fillers include agents selected from the group
consisting of microcrystalline cellulose (e.g., Avicel.RTM.),
starch, lactitol, lactose, a suitable inorganic calcium salt,
sucrose, glucose, mannitol, silicic acid, or a combination thereof.
In some embodiments, formulations comprise from about 5%, to about
90%, or about 10% to about 50%, or about 10% to about 40%, or about
10% to about 45% binder, based upon total weight of the
formulation. In some embodiments, formulations comprise from about
10%, about 15%, about 16%, about 20%, about 24%, about 25%, about
30%, about 35%, about 40%, about 45%, or about 50% binder, based
upon total weight of the tablets. In some embodiments, formulations
comprise microcrystalline cellulose as a binder. In certain
embodiments, formulations comprise the binders, microcrystalline
cellulose and silicified microcrystalline cellulose.
[0085] In certain embodiments, provided formulations may comprise
one or more antioxidants. Such antioxidants include those known to
one of ordinary skill in the art. Exemplary antioxidants include
ascorbic acid, and salts and esters thereof; citric acid, and salts
and esters thereof; butylated hydroxyanisole ("BHA"); butylated
hydroxytoluene ("BHT"); tocopherols (e.g., d-alpha tocopherol,
dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha
tocopherol acetate, beta tocopherol, delta tocopherol, gamma
tocopherol, and the like), and carotenoids (e.g., vitamin A,
lutein, and zeaxanthin). In certain embodiments, a formulation
comprises ascorbic acid. In some embodiments, a formulation
comprises up to about 10% one or more antioxidants by weight. In
some embodiments, a provided formulation comprises about 0.01% to
about 5% one or more antioxidants by weight. In some embodiments, a
provided formulation comprises about 1.0% to about 10% one or more
antioxidants by weight. In certain embodiments, a provided
formulation comprises about 1%, about 2%, about 5%, about 6%, about
7%, about 8%, about 9%, or about 10% of one or more antioxidants by
weight.
[0086] In certain embodiments, formulations may comprise a
lubricant. Lubricants, generally, are substances used in solid
dosage formulations to reduce friction during compression. Such
compounds include, by way of example and without limitation, sodium
oleate, sodium stearate, calcium stearate, zinc stearate, magnesium
stearate, polyethylene glycol, talc, mineral oil, stearic acid,
sodium benzoate, sodium acetate, sodium chloride, and other
materials known to one of ordinary skill in the art. In certain
embodiments, the lubricant is a stearate salt. In some embodiments,
formulations comprise from about 0.1% to about 7%, or about 0.2% to
about 1% lubricant, based upon total weight of given formulation.
In certain embodiments, the lubricant is magnesium stearate and is
available from Sigma-Aldrich, among other sources.
[0087] In certain embodiments, formulations may comprise a
non-functional coating. For example, in some embodiments, the
tablet may comprise a non-functional coating. In some embodiments,
the non-functional coating is a seal coat. For example, a suitable
seal coating can be applied as a solution (e.g., HPMC solution) at
a concentration of about 1% w/w to 25% w/w, and preferably 1% w/w
to about 10% w/w. Upon drying, under suitable conditions, initial
seal coating is in the range of about 1% w/w to about 3% w/w, or
about 2% w/w, of the uncoated tablet. Such a seal coating may
comprise a polymer (e.g., HPMC) and may be a commercially available
seal coating seal such as Opadry.RTM. Clear (Colorcon, Inc.), or
HPMC E3. Upon drying, seal coating may be from about 1% to about
10% of weight gain of the total coated formulation. In certain
embodiments, the formulation may comprise a coating to prevent
disintegration of the dosage form in the oral cavity.
[0088] In certain embodiments, the formulation for oral
administration comprises (a) about 7% to about 75% of
methylnaltrexone bromide, based upon the total weight of the
formulation; (b) about 5% to about 80% of an amphiphilic
pharmaceutically acceptable excipient, based upon the total weight
of the formulation; (c) about 0.01% to about 5% of a chelating
agent, based upon the total weight of the formulation; (d) about 1%
to about 25% of a wetting agent, based upon the total weight of the
formulation; (e) about 5% to about 90% of a binder, based upon the
total weight of the formulation; (f) about 1% to about 25% of a
disintegrant, based upon the total weight of the formulation; (g)
about 0.1% to about 7% of a lubricant, based upon the total weight
of the formulation; and optionally, (h) about 0.01% to about 5% of
an antioxidant, based upon the total weight of the formulation. In
certain embodiments, the methylnaltrexone bromide of the
formulation is (R)--N-methylnaltrexone bromide. In certain
embodiments, the amphiphilic pharmaceutically acceptable excipient
is sodium dodecyl (lauryl) sulfate. In certain embodiments, the
chelating agent is a salt of EDTA (e.g., calcium EDTA). In certain
embodiments, the wetting agent is polysorbate 80. In certain
embodiments, the disintegrant is sodium bicarbonate. In other
embodiments, the disintegrant is crospovidone. In certain
embodiments, the disintegrant is a combination of sodium
bicarbonate and crospovidone. In certain embodiments, the lubricant
is magnesium stearate. In certain embodiments, the antioxidant is
ascorbic acid. In certain embodiments, the invention provides a
tablet formulation for oral administration comprising about 30%
methylnaltrexone bromide, about 10% sodium dodecyl sulfate, about
11% microcrystalline cellulose, about 5% crospovidone, about 0.25%
calcium EDTA, about 2% polysorbate 80, about 30% Prosolv 50, about
11% sodium bicarbonate, about 2% talc, about 0.5% silicon dioxide
colloidal, and about 0.25 magnesium stearate. It will be understood
by those skilled in the art that, depending on the manner of making
the tablet or other formulation of the invention described herein,
the methylnaltrexone may exist paired with bromide, paired with the
anion of the amphiphilic pharmaceutically acceptable excipient, or
some combination thereof.
Production
[0089] In certain embodiments, compositions and formulations are
prepared by methods which include an extrusion/spheronization step.
In some embodiments, formulations are manufactured via
wet-granulation of a provided formulation followed by
extrusion/spheronization to form spheroids. Given spheroids are
then dried and milled to form a powder which is blended with
suitable binder(s) and disintegrant(s). The resulting mixture is
then milled and blended with a suitable lubricant and pressed into
tablets. In certain embodiments, a non-functional coating is
applied.
[0090] In some embodiments, tablets are prepared by methods which
do not include extrusion/spheronization steps and, in accordance
with such methods, are manufactured via wet-granulation. Once
dried, the granulation is milled to form a granular powder which is
blended with suitable binder(s) and disintegrant(s). The resulting
mixture is then milled and blended with a suitable lubricant and
pressed into tablets. In certain embodiments, a non-functional
coating is applied.
Unit Dosage Form
[0091] Formulations of methylnaltrexone may be prepared as a unit
dosage form. Indeed, a tablet is typically a unit dosage form. In
some embodiments, a unit dosage form contains 25 mg, 50 mg, 75 mg,
100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300
mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500
mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg,
725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925
mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg,
1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300
mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg,
or 1500 mg of methylnaltrexone bromide. In some embodiments, a unit
dosage form contains between 50 mg and 900 mg, inclusive, or
between 150 mg and 450 mg, inclusive, of methylnaltrexone bromide.
In some embodiments, a unit dosage form contains 50 mg, 75 mg, 150
mg, 225 mg, 300 mg, 450 mg, 600 mg, or 900 mg of methylnaltrexone
bromide. In some embodiments, the unit dosage form comprises
methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient, e.g., sodium dodecyl (lauryl) sulfate (also known as SDS
or SLS).
Administration
[0092] Compositions and formulations may be administered to a
patient as required to provide an effective amount of
methylnaltrexone. In certain embodiments, the patient is orally
administered methylnaltrexone or a formulation thereof at least
once a day. In other embodiments, the patient is orally
administered methylnaltrexone or a formulation thereof up to once a
day. In certain embodiments, the patient is orally administered
methylnaltrexone or a formulation thereof not more than once a day.
In certain embodiments, the patient is orally administered
methylnaltrexone or a formulation thereof as needed. In certain
embodiments, the patient is orally administered methylnaltrexone or
a formulation thereof as needed, but not more than once a day. For
example, a unit dosage form of a provided formulation may be orally
administered to a patient in a single day, for example, a unit
dosage of about 150 mg, 300 mg, or 450 mg methylnaltrexone bromide
or an equivalent molar amount of methylnaltrexone. In some
embodiments, the present invention provides a method for treating
an opioid-induced side effect in a patient in need thereof,
comprising the step of orally administering to said patient one or
more tablets of the present invention wherein said tablet provides
about 150 mg, 300 mg, or 450 mg of methylnaltrexone or an
equivalent molar amount of methylnaltrexone bromide, e.g.,
methylnaltrexone and a amphiphilic pharmaceutically acceptable
excipient such as sodium dodecyl (lauryl) sulfate (also known as
SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate,
perfluorooctanesulfonate (PFOS), and the like. In certain
embodiments, a single tablet formulation of the present invention
provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about
125 mg, about 150 mg, about 300 mg, or about 450 mg of
methylnaltrexone bromide, or equivalent moles of another salt form,
or methylnaltrexone and an amphiphilic pharmaceutically acceptable
excipient such as sodium dodecyl (lauryl) sulfate (also known as
SDS or SLS).
[0093] As defined above, in certain embodiments the term "effective
amount," as used in connection with an amount of methylnaltrexone,
means an amount of methylnaltrexone sufficient to achieve laxation
in a patient. In some embodiments, an effective amount means an
amount of methylnaltrexone sufficient to achieve laxation in a
patient within about 24 hours, within about 12 hours, within about
8 hours, within about 5 hours, within about 4 hours, within about 3
hours, within about 2 hours, or within about 1 hours of
administration to said patient. In some embodiments, effective
amount means an amount of methylnaltrexone sufficient to achieve
laxation within about 4 hours of administration to the patient. In
some embodiments, effective amount means an amount of
methylnaltrexone sufficient to achieve laxation within about 4
hours of administration to the patient for at least 99%, at least
95%, at least 90%, at least 85%, at least 80%, at least 75%, or at
least 50% of all doses administered. In some embodiments, effective
amount means an amount of methylnaltrexone sufficient to achieve
laxation within about 4 hours of administration to the patient for
all doses administered during first four weeks of dosing.
[0094] In some embodiments, the formulations are administered to a
fasted patient. As used herein, the term "fasted" means that the
patient has not eaten any food for at least 2 hours, at least 4
hours, for at least 6 hours, for at least 8 hours, for at least 10
hours, or for at least 12 hours prior to administration of a
provided formulation. In certain embodiments, the term "fasted"
means an overnight fast. It is believed that improved effects will
be seen in fasted patients than in fed patients. These effects may
be magnified in patients administered methylnaltrexone in a
provided tablet as compared with patients administered the same
dose in capsule form. Thus, administration of a provided
methylnaltrexone tablet formulation to a patient in a fasted state
is believed to be advantageous.
[0095] In other embodiments, the formulations are administered to a
patient that has not fasted. Therefore, there is no requirement
that the patient not have eaten before methylnaltrexone is
administered.
Combination Products and Combined Administration
[0096] It will also be appreciated that provided compositions and
formulations can be employed in combination therapies, that is,
provided formulations can be administered concurrently with, prior
to, or subsequent to, one or more other desired therapeutics or
medical procedures. Particular combination therapies (therapeutics
or procedures) to employ in a combination regimen will take into
account compatibility of the desired therapeutics and/or procedures
and the desired therapeutic effect to be achieved. It will also be
appreciated that therapies employed may achieve a desired effect
for the same disorder (for example, a formulation may be
administered concurrently with another compound used to treat the
same disorder), or they may achieve different effects (e.g.,
control of any adverse effects). As used herein, additional
therapeutic compounds which are normally administered to treat or
prevent a particular disease, or condition, are known as
"appropriate for the disease, or condition, being treated."
[0097] In some embodiments, methylnaltrexone or an ion pair or
formulation of the invention and one or more other active agents
may be administered together in a single formulation (e.g., unit
dosage form); in other embodiments, methylnaltrexone and one or
more other active agents may be administered as separate
formulations. In certain embodiments, methylnaltrexone and/or one
or more other active agent may be administered in multiple
doses.
[0098] In some embodiments, the other active agent administered in
combination with a methylnaltrexone ion pair or formulation of the
invention is an opioid. Combination therapy of methylnaltrexone and
an opioid can allow simultaneous relief of pain and minimization of
opioid-associated side effects (e.g., gastrointestinal effects
(e.g., delayed gastric emptying, altered GI tract motility)).
Accordingly and in certain embodiments, the present invention
provides a unit dosage form comprising a combination of
methylnaltrexone with an opioid together in a single layer dosage
form (e.g., tablet). In some embodiments, such a unit dosage form
may be a bi-layer tablet comprising methylnaltrexone in one layer
and an opioid in another layer. In a specific embodiment, the
combination unit dosage form is suitable for oral
administration.
[0099] Opioids useful for analgesia are known in the art. For
example, opioid compounds include, but are not limited to,
alfentanil, anileridine, asimadoline, bremazocine, burprenorphine,
butorphanol, codeine, dezocine, diacetylmorphine (heroin),
dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl,
funaltrexamine, hydrocodone, hydromorphone, levallorphan,
levomethadyl acetate, levorphanol, loperamide, meperidine
(pethidine), methadone, morphine, morphine-6-glucoronide,
nalbuphine, nalorphine, nicomorphine, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, propiram, propoxyphene,
remifentanyl, sufentanil, tilidine, trimebutine, and tramadol. In
some embodiments the opioid is at least one opioid selected from
alfentanil, buprenorphine, butorphanol, codeine, dezocine,
dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,
meperidine (pethidine), methadone, morphine, nalbuphine,
nicomorphine, oxycodone, oxymorphone, papaveretum, pentazocine,
propiram, propoxyphene, sufentanil and/or tramadol. In certain
embodiments of the present invention, the opioid is selected from
morphine, codeine, oxycodone, hydrocodone, dihydrocodeine,
propoxyphene, fentanyl, tramadol, and mixtures thereof. In a
particular embodiment, the opioid is loperamide. In other
embodiments, the opioid is a mixed agonist such as butorphanol. In
some embodiments, the subjects are administered more than one
opioid, for example, morphine and heroin or methadone and
heroin.
[0100] Typically, the amount of other active agent(s) administered
in combination therapy may be no more than the amount that would
normally be administered in monotherapy with the relevant agent(s).
In certain embodiments, the amount of other active agent
administered in combination therapy may be less than that normally
administered in monotherapy with the relevant agent(s). For
example, in certain embodiments of the present invention, the
amount of additional active agent can range from about 50% to 100%
of the amount normally present in a formulation comprising that
compound as the only therapeutic agent.
[0101] In certain embodiments, formulations may also be used in
conjunction with and/or in combination with conventional therapies
for gastrointestinal dysfunction to aid in the amelioration of
constipation and bowel dysfunction. For example, conventional
therapies include, but may not be limited to functional stimulation
of the intestinal tract, stool softening agents, laxatives (e.g.,
diphenylmethane laxatives, cathartic laxatives, osmotic laxatives,
saline laxatives), bulk forming agents and laxatives, lubricants,
intravenous hydration, and nasogastric decompression.
Uses and Kits of Compositions and Formulations
[0102] The present invention provides pharmaceutically acceptable
formulations as described herein comprising methylnaltrexone for
oral administration useful for the delivery of such compounds in
any context in which such delivery is desirable. In certain
embodiments, provided formulations are useful for the delivery of
methylnaltrexone in antagonizing undesirable side effects of opioid
analgesic therapy (e.g., gastrointestinal effects (e.g., delayed
gastric emptying, altered GI tract motility)). Furthermore,
formulations may be used as to treat subjects having disease states
that are ameliorated by binding opioid receptors, or in any
treatment wherein temporary suppression of the opioid receptor
system is desired (e.g., ileus). In certain embodiments of the
present invention, methods of use of provided formulations are in
human subjects.
[0103] Accordingly, administration of provided formulations may be
advantageous for treatment, prevention, amelioration, delay or
reduction of side effects of opioid use, such as, for example,
gastrointestinal dysfunction (e.g., inhibition of intestinal
motility, constipation, GI sphincter constriction, nausea, emesis
(vomiting)), biliary spasm, opioid bowel dysfunction, colic,
dysphoria, pruritis, urinary retention, depression of respiration,
papillary constriction, cardiovascular effects, chest wall rigidity
and cough suppression, depression of stress response, and immune
suppression associated with use of narcotic analgesia, or
combinations thereof. Use of a formulation may thus be beneficial
from a quality of life standpoint for subjects undergoing use of
opioids, as well as to reduce complications arising from chronic
constipation, such as hemorrhoids, appetite suppression, mucosal
breakdown, sepsis, colon cancer risk, and myocardial
infarction.
[0104] In some embodiments, provided formulations are useful for
administration to a subject undergoing acute opioid use. In some
embodiments, provided formulations are useful for administration to
patients suffering from post-operative gastrointestinal
dysfunction.
[0105] In certain embodiments, provided formulations are also
useful for administration to subjects undergoing chronic opioid use
(e.g., terminally ill patients receiving opioid therapy such as an
AIDS patient, a cancer patient, a cardiovascular patient; subjects
receiving chronic opioid therapy for pain management; subjects
undergoing opioid therapy for maintenance of opioid withdrawal). In
some embodiments, the subject is a subject using opioid therapy for
chronic pain management. In certain embodiments, the pain is
non-malignant pain (e.g., back pain, neuropathic pain, pain
associated with fibromyalgia, osteoarthritis). In some embodiments,
the subject is a terminally ill patient. In other embodiments the
subject is a person undergoing opioid withdrawal maintenance
therapy.
[0106] In certain embodiments, the formulations provided herein are
administered to subjects that have been selected for treatment with
methylnaltrexone. In specific embodiments, the subject is selected
based on the subject having an increased risk for developing one or
more of the conditions set forth above. In another embodiment, the
subject is selected based on the use of opioid therapy for pain
management, or based on having one or more of the conditions set
forth herein. In certain embodiments, the subject is constipated or
has a history of constipation due to opioid therapy. In one
embodiment, a constipated subject has not had a bowel movement in
the previous three days. In one embodiment, a constipated subject
has had less than three bowel movements in the previous week. In
certain embodiments, a constipated subject has had less than three
rescue-free bowel movements per week on average over the last four
consecutive weeks, and one or more of the following: (a) hard or
lumpy stools, (b) straining during bowel movements, and/or (c)
sensation of incomplete evacuation after bowel movements.
[0107] In certain embodiments, the subject is selected for
treatment with a methylnaltrexone formulation described herein
based on the use of opioids, e.g., for non-malignant pain. The
subject may be using opioids intermittently or regularly. In one
embodiment, the subject that is selected has been taking opioids as
needed. In one embodiment, the subject that is selected has been
taking opioids for less than one week. In one embodiment, the
subject that is selected has been taking opioids over the course of
at least one week. In another embodiment, the subject that is
selected has been taking opioids over the course of at least two
weeks. In another embodiment, the subject that is selected has been
taking opioids over the course of at least three weeks. In another
embodiment, the subject that is selected has been taking opioids
over the course of at least four weeks. In another embodiment, the
subject that is selected has been taking opioids over the course of
at least three months. In another embodiment, the subject that is
selected has been taking opioids over the course of at least six
months. In another embodiment, the subject that is selected has
been taking opioids over the course of at least twelve months. In
another embodiment, the subject that is selected has been taking
opioids over the course of more than one year. In another
embodiment, the subject that is selected has been taking opioids at
least every other day over the course of at least two weeks. In one
embodiment, the subject that is selected has been receiving at
least 7 doses >25 mg of oral morphine equivalents over at least
14 days. In one embodiment, the subject that is selected has been
receiving a daily dose of >50 mg of oral morphine equivalents
for at least 14 days. In one embodiment, the subject that is
selected is constipated due to opioid therapy and has been
receiving a daily dose of >50 mg of oral morphine equivalents
for at least 14 days. In certain embodiments, the subject has been
receiving a daily dose of >50 mg of oral morphine equivalents
for at least 14 days; and has had less than three (3) rescue-free
bowel movements per week on average over the least four consecutive
weeks that were associated with one or more of the following: (a) a
Bristol Stool Form Scale type 1 or 2 for at least 25% of the
rescue-free bowel movements, (b) straining during at least 25% of
the rescue-free bowel movements; and/or (c) a sensation of
incomplete evacuation after at least 25% of the rescue-free bowel
movements. A rescue-free bowel movement refers to a bowel movement
associated with no laxative use within the 24 hours prior to the
bowel movement.
[0108] In certain embodiments, the subject selected for treatment
with a methylnaltrexone formulation described herein is a subject
suffering from opioid-induced constipation. In certain embodiments,
the subject selected for treatment with a methylnaltrexone
formulation described herein is a subject with advanced illness who
is receiving palliative care and is suffering from opioid-induced
constipation. In certain embodiments, the subject selected for
treatment with a methylnaltrexone formulation described herein is a
subject with advanced illness who is receiving palliative care and
is suffering from opioid-induced constipation where response to
laxative therapy (e.g., bisacodyl, senokot, docusate) has not been
sufficient. In certain embodiments, the subject selected for
treatment with a methylnaltrexone formulation described herein is a
subject with non-malignant pain who is suffering from
opioid-induced constipation. In certain embodiments, the subject
selected for treatment with a methylnaltrexone formulation
described herein is a subject with non-malignant pain who is
suffering from opioid-induced constipation where response to
laxative therapy (e.g., bisacodyl, senokot, docusate) has not been
sufficient. In certain embodiments, the subject selected for
treatment with a methylnaltrexone formulation described herein has
not responded to standard laxative therapy. In certain embodiments,
the subject selected for treatment with a methylnaltrexone
formulation described herein has responded to standard laxative
therapy. In certain embodiments, the subject selected for treatment
with a methylnaltrexone formulation described herein is
concurrently administered laxative therapy.
[0109] Alternative or additional uses for provided formulations
described herein are useful for treating effects of opioid use
including, e.g., aberrant migration or proliferation of endothelial
cells (e.g., vascular endothelial cells), increased angiogenesis,
and increase in lethal factor production from opportunistic
infectious agents (e.g., Pseudomonas aeruginosa). Additional
advantageous uses of provided formulations include treatment of
opioid-induced immune suppression, inhibition of angiogenesis,
inhibition of vascular proliferation, treatment of pain, treatment
of inflammatory conditions such as inflammatory bowel syndrome,
treatment of infectious diseases and diseases of the
musculoskeletal system such as osteoporosis, arthritis, osteitis,
periostitis, myopathies, and treatment of autoimmune diseases.
[0110] In certain embodiments, provided formulations may be used in
methods for preventing, inhibiting, reducing, delaying, diminishing
or treating gastrointestinal dysfunction, including, but not
limited to, irritable bowel syndrome, opioid-induced bowel
dysfunction, colitis, post-operative or postpartum ileus, nausea
and/or vomiting, decreased gastric motility and emptying,
inhibition of the stomach, and small and/or large intestinal
propulsion, increased amplitude of non-propulsive segmental
contractions, constriction of sphincter of Oddi, increased anal
sphincter tone, impaired reflex relaxation with rectal distention,
diminished gastric, biliary, pancreatic or intestinal secretions,
increased absorption of water from bowel contents,
gastro-esophageal reflux, gastroparesis, cramping, bloating,
abdominal or epigastric pain and discomfort, constipation,
idiopathic constipation, post-operative gastrointestinal
dysfunction following abdominal surgery (e.g., colectomy (e.g.,
right hemicolectomy, left hemicolectomy, transverse hemicolectomy,
colectomy takedown, low anterior resection), hysterectomy), and
delayed absorption of orally administered medications or nutritive
substances.
[0111] Provided formulations are also useful in treatment of
conditions including cancers involving angiogenesis, immune
suppression, sickle cell anemia, vascular wounds, and retinopathy,
treatment of inflammation associated disorders (e.g., irritable
bowel syndrome), immune suppression, chronic inflammation.
[0112] In other embodiments, provided formulations and unit dose
forms are useful in preparation of medicaments, including, but not
limited to medicaments useful in the treatment of side effects of
opioid use, including gastrointestinal side effects (e.g.,
inhibition of intestinal motility, GI sphincter constriction,
constipation), nausea, emesis, vomiting, dysphoria, pruritis, or a
combination thereof. Provided formulations are useful for
preparations of medicaments, useful in treatment of patients
receiving acute opioid therapy (e.g., patients suffering from
post-operative gastrointestinal dysfunction receiving acute opioid
administration) or subjects using opioids chronically (e.g.,
terminally ill patients receiving opioid therapy such as an AIDS
patient, a cancer patient, a patient with cardiovascular disease;
subjects receiving chronic opioid therapy for pain management
(malignant or non-malignant pain); or subjects undergoing opioid
therapy for maintenance of opioid withdrawal). Still further,
preparation of medicaments useful in the treatment of pain,
treatment of inflammatory conditions such as inflammatory bowel
syndrome, treatment of infectious diseases, treatment of diseases
of the musculoskeletal system such as osteoporosis, arthritis,
osteitis, periostitis, myopathies, treatment of autoimmune diseases
and immune suppression, therapy of post-operative gastrointestinal
dysfunction following abdominal surgery (e.g., colectomy (e.g.,
right hemicolectomy, left hemicolectomy, transverse hemicolectomy,
colectomy takedown, low anterior resection), idiopathic
constipation, and ileus (e.g., post operative ileus, post partum
ileus), and treatment of disorders such as cancers involving
angiogenesis, chronic inflammation and/or chronic pain, sickle cell
anemia, vascular wounds, and retinopathy.
[0113] In still further embodiments, veterinary applications (e.g.,
treatment of domestic animals, e.g., horse, dogs, cats) of use of
provided formulations are provided. Thus, use of provided
formulations in veterinary applications analogous to those
discussed above for human subjects is contemplated. For example,
inhibition of equine gastrointestinal motility, such as colic and
constipation, may be fatal to a horse. Resulting pain suffered by
the horse with colic can result in a death-inducing shock, while a
long-term case of constipation may also cause a horse's death.
Treatment of equines with peripheral opioid receptor antagonists
has been described, e.g., in U.S. Patent Publication No.
2005/0124657, published Jan. 20, 2005, which is incorporated herein
by reference.
[0114] Still further encompassed by the invention are
pharmaceutical packs and/or kits comprising formulations described
herein, and a container (e.g., a foil or plastic package, or other
suitable container). Optionally instructions for use are
additionally provided in such kits.
[0115] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
[0116] All features of each of the aspects of the invention apply
to all other aspects mutatis mutandis. The contents of all
references, patents, pending patent applications and published
patents, cited throughout this application are hereby expressly
incorporated by reference.
EXAMPLES
Example 1
[0117] Methylnaltrexone bromide may be prepared according to the
methods described in detail in international PCT Patent Application
publication number, WO 2006/127899, or obtained from commercial
sources such as Covidien, Saint Louis, Mo. Formulations containing
methylnaltrexone were prepared using pharmaceutically acceptable
excipients. Spheroids containing methylnaltrexone were prepared.
Capsules were prepared by filling capsules with spheroids. Some
capsules were prepared to contain enterically coated spheroids,
which spheroids dissolve only after passing through the stomach.
The capsules, without an enteric coat, or after dissolution of the
enteric coat, will dissolve over 10-30 minutes. Tablets also were
prepared from spheroids, using conventional techniques. The tablets
dissolve in under 10 minutes.
[0118] The spheroids were prepared by a wet granulation process
followed by extrusion and spheronization, as described in the
following general method. Methylnaltrexone bromide and
pharmaceutically acceptable excipients were combined in an aqueous
solution. Water was added until wet mass suitable for extrusion was
obtained. The wet mass was passed through an extruder, and the
extrudate was spheronized in a spheronizer. The resulting spheroids
were dried in a fluid bed drier and passed through a screen. The
uncoated spheroids were stored in appropriate container.
Example 2
[0119] Administration of Capsules Containing Enterically Coated
Methylnaltrexone Spheroids
[0120] Capsules containing enterically coated spheroids of
methylnaltrexone as described in Example 1 were tested in patients
suffering from opioid-induced constipation. The patients in this
study were not chronic methadone maintenance patients. The patients
had chronic non-malignant (not cancer) pain where the non-malignant
condition underlying the chronic pain (e.g., osteoarthritis, back
pain, neuropathic pain) had a documented history of at least 2
months before screening, stable pain for at least 1 month. The
patients were on opioids for at least one month and at a daily dose
of greater than or equal to 20 mg of morphine equivalents per day
for at least two weeks before the screening visit and during the
screening visit period with no anticipated changes during the
study. The patients also had a history of constipation due to
opioid use for at least one month before the screening visit.
Constipation defined as less than 3 bowel movements per week on
average and 1 or more of the following: (i) hard or lumpy stools
for at least 25% of bowel movements, (ii) a sensation of incomplete
evacuation following at least 25% of bowel movements, (iii)
straining during at least 25% of bowel movements.
[0121] Patients were administered enterically coated
methylnaltrexone capsules containing 10 mg, 50 mg, 150 mg, 300 mg
or 450 mg of methylnaltrexone. The average peak plasma level of
methylnaltrexone resulting from the doses was as follows: (i) for
10 mg, less than 1 ng/ml, (ii) for 50 mg, less than 5 ng/ml, (iii)
for 150 mg, less than 5 ng/ml, (iv) for 300 mg, less than 10 ng/mL,
and (v) for 450 mg, less than 20 ng/mL. These capsules containing
enterically coated preparations of methylnaltrexone were not
effective for treating opioid-induced constipation. They did not
induce laxation and did not cause more bowel movements in patients
relative to controls.
Example 3
[0122] Administration of Capsules Containing Methylnaltrexone not
Enterically Coated
[0123] Capsules containing spheroids of methylnaltrexone, but
without the enteric coating, prepared as described in Example 1,
were tested in patients receiving opioids for non-malignant pain.
The patients in this study were not chronic methadone maintenance
patients. The patients were selected on the basis of the same
criteria as the criteria used in Example 2, except the minimum
daily dose of opioids was equal to or greater than 30 mg, instead
of 20 mg of morphine equivalents. Doses of 150 mg, 300 mg, 450 mg,
and 600 mg were tested. These doses resulted in average peak plasma
levels of between about 15 and 40 ng/ml, on the order of 3 or more
times lower than the average peak plasma levels associated with
effective doses of subcutaneous methylnaltrexone injection. These
capsules containing spheroids without the enteric coating did not
induce laxation and did not cause more bowel movements in this
patient population relative to controls.
[0124] Administration of Tablets Containing Methylnaltrexone not
Enterically Coated
[0125] Tablets containing spheroids of methylnaltrexone, without an
enteric coating, prepared as described in Example 1, were tested in
patients receiving opioids for non-malignant pain. The patients in
this study were not chronic methadone maintenance patients. The
patients were selected on the basis of the same criteria as the
criteria used in Example 3. Doses of 150 mg, 300 mg, 450 mg, and
600 mg were tested. These doses resulted in average peak plasma
levels of between about 7 and 40 ng/ml. These tablets without an
enteric coating showed statistically significant activity at one
dose, but did not consistently induce laxation across all
doses.
[0126] Both tablets and capsules containing uncoated spheroids had
similar compositions except that spheroids were compressed with
pharmaceutically acceptable excipients to form tablets, while
spheroids were encapsulated into hard gelatine shells to prepare
capsules. Once contacted with an aqueous medium, the tablets
disintegrated immediately and almost all the drug dissolved in less
than 10 minutes. In contrast, it took 10 minutes for the capsule
shells to dissolve and at least 30 minutes for the complete
dissolution of the drug from the capsules. (FIG. 1) Plasma levels
associated with both dosage forms containing uncoated spheroids
were variable (tablets produced more consistent average peak plasma
levels relative to the capsule) and overlapping among the
subjects.
Example 4
[0127] Determination of Partition Coefficient
[0128] Ion pairs of methylnaltrexone with amphiphilic
pharmaceutically acceptable excipients were prepared and the
apparent octanol-water partition coefficient (APC) was measured and
compared to that of methylnaltrexone bromide. A pre-determined
amount of each of MNTX-heptyl sulfate and MNTX-dodecyl sulfate was
dissolved in 2 mL of 1-octanol that was saturated with water. Two
mL of water that was saturated with 1-octanol was added to each
MNTX salt solution. The mixtures were shaken overnight at room
temperature, and 1 mL of the 1-octanol phase was then diluted to 10
mL with the mobile phase used for chromatographic (HPLC) analysis
of the samples. And 1 mL of the aqueous phase was diluted to 5 mL
with the mobile phase. The samples were then analyzed by HPLC to
determine the apparent partition coefficient and log P for each
MNTX salt. The pH of the aqueous phases for each of the salts was
between 4.5 and 6.8. (The reported partition coefficient for MNTX
is 0.025 and the Log P is -1.605.)
TABLE-US-00001 MNTX Salt mg used APC Log P MNTX-heptyl 21.323 1.961
0.292 sulfate MNTX-dodecyl 15.175 32.014 1.505 sulfate MNTX-laurate
12.843 2.131 0.328
Example 5
Preparation of Tablets Containing Methylnaltrexone Bromide and
Sodium Dodecyl Sulfate
[0129] The present Example describes the preparation of tablets
containing methylnaltrexone, sodium dodecyl sulfate (SDS), and an
effervescent disintegrant (sodium bicarbonate). The quantitative
formulation of methylnaltrexone (150 mg) tablets is provided in
Table 5-1.
TABLE-US-00002 TABLE 5-1 Composition of Methylnaltrexone Bromide
150 mg Uncoated Tablets with SDS Unit Dose Ingredient % w/w
mg/Tablet Granulation Methylnaltrexone Bromide.sup.a 28.95 150.00
Microcrystalline Cellulose 11.30 58.54 Sodium Dodecyl Sulfate 9.65
50.00 Crospovidone 1.83 9.48 Polysorbate 80 (vegetable grade) 2.07
10.73 Edetate Calcium Disodium 0.28 1.46 Dihydrate Purified
Water.sup.b NA 40.03 Blend Silicified Microcrystalline 28.95 150.00
Cellulose Crospovidone 3.00 15.52 Sodium Bicarbonate 11.30 58.54
Talc 1.93 10.00 Colloidal Silicon Dioxide 0.49 2.50 Final Blend
Magnesium Stearate 0.25 1.28 Total 100.0% 518.05 mg .sup.aBased
upon 100% purity "as is", quantity may be adjusted based on actual
potency, with corresponding adjustments made to microcrystalline
cellulose. .sup.bRemoved by drying. Does not appear in final dosage
form.
Method of Manufacture and Packaging: Procedure
[0130] 1. Blend methylnaltrexone bromide, microcrystalline
cellulose, sodium dodecyl sulfate (SDS), and crospovidone in a
granulator.
[0131] 2. Make a solution containing edetate calcium disodium and
polysorbate 80 in purified water.
[0132] 3. While mixing blend from Step 1, add the edetate calcium
disodium/polysorbate 80 solution for approximately 4 minutes.
Additional water might be added to obtain proper granulation. Note:
the granulation steps may be completed in sub-batches to obtain
larger batch sizes.
[0133] 4. Dry the granulation.
[0134] 5. Using suitable mill, mill the granulation from #4.
[0135] 6. Add material from #5 to a suitable blender.
[0136] 7. Record the yield for milling and adjust the levels of
excipients for the final blend.
[0137] 8. Optional screening of crospovidone, silicified
microcrystalline cellulose, sodium bicarbonate, talc, silicon
dioxide, and magnesium stearate through appropriate sieve.
[0138] 9. Add to the blender, crospovidone, sodium bicarbonate,
talc, and silicified microcrystalline cellulose, and blend
[0139] 10. Optionally screening the blend of Step 9 through
appropriate sieve and add to the blender and blend.
[0140] 11. Optionally, take a portion of the blend, add to the
silicon dioxide and bag blend.
[0141] 12. Optionally, transfer the pre-mix of the silicon dioxide
and add to the blender and blend.
[0142] 13. Take a portion of the blend, add to the magnesium
stearate and bag blend. Note: Step 13 may not be required for
batches larger than 50 kg.
[0143] 14. Transfer the pre-mix magnesium stearate and blend to the
blender and blend.
[0144] 15. Record the final yield of blend.
[0145] 16. Compress the final blend from step 15 using a suitable
compression machine fitted with tooling which can produce tablets
of the required specification.
[0146] 17. Weigh the yield of acceptable tablets.
Example 6
[0147] Tablets including methylnaltrexone bromide (150 mg), sodium
dodecyl sulfate (SDS), and sodium bicarbonate were manufactured
using the method described in Example 5. The tablet was placed in a
dissolution apparatus with paddles at 100 rpm in 900 mL of 0.1 N
HCl at 37.degree. C. Samples were then removed at specified times
points and analyzed by HPLC. The dissolution rates of two tablets
were determined. The dissolution profile of the SDS tablet with
sodium bicarbonate is shown in FIG. 2. Greater than 90% of the
methylnaltrexone from the tablets was dissolved within 11
minutes.
Example 7
[0148] Administration of Provided Formulations in GI-Physiology
Altered Dogs
[0149] Oral bioavailability and pharmacokinetic profiles of tablets
containing methylnaltrexone bromide (150 mg), sodium dodecyl
sulphate (SDS) and sodium bicarbonate, prepared as described in
Example 5, were compared with tablets containing uncoated spheroids
of methylnaltrexone, but not containing an amphiphilic
pharmaceutically acceptable carrier or an effervescent
disintegrant, prepared as described in Example 1. Using
GI-physiology altered male beagle dogs, atropine (.about.20
.mu.g/kg; IV) and pentagastrin (.about.10 .mu.g/kg; IM) were
administered 15 minutes prior to formulation administration and
another dose of pentagastrin (10 .mu.g/kg; IM) was administered 30
minutes post dose. Atropine slows down canine GI motility and
pentagastrin decreases pH resulting in GI conditions almost similar
to that of humans. The formulations (150 mg MNTX) were dosed to six
dogs (9.4-13.7 kg) via oral administration following an overnight
fast and blood samples were drawn at 0 (predose), 0.5, 1, 2, 3, 4,
6, 8, 12, 24, and 48 hours after dosing; plasma was separated and
assayed for methylnaltrexone content.
[0150] Individual dog plasma methylnaltrexone concentration-time
profiles were subjected to non-compartmental pharmacokinetic
analyses (WinNonlin, Model 200). The results are summarized in
Table 7-1 below.
TABLE-US-00003 TABLE 7-1 Individual and Mean (.+-.SD) MNTX
Pharmacokinetic Parameters in GI Physiology Regulated Dogs
Following a Single Oral Administration of 150 mg MNTX Prototype
Formulations Dose C.sub.max AUC.sub.0-.infin. Formulation Dog
(mg/kg) (ng/mL) (hr * ng/mL) Tablet no SDS Mean 15.2 .+-. 565 .+-.
2091 .+-. SD 0.46 206 572 Tablet with SDS Mean 15.7 .+-. 978 .+-.
2983 .+-. SD 0.91 322 720
[0151] As summarized in the above Table 7-1, oral administration of
prototype tablet formulation containing the ion-pairing agent
sodium dodecyl (lauryl) sulfate resulted in qualitatively greater
methylnaltrexone systemic exposures than tablets containing no ion
pairing agent.
Example 8
[0152] This example reports on the efficacy of methylnaltrexone in
the SDS tablet formulation at a dose of 300 and 450 mg administered
orally to subjects with chronic non-malignant pain. Subjects
enrolled in this study had to have a history of constipation due to
opioid use for at least one month before the screening visit. The
study was a phase 1, open-label, single dose, inpatient studies.
Subjects received methylnaltrexone as a single dose (2.times.150 mg
or 3.times.150 mg) of the SLS tablet formulation after an overnight
fast of at least 10 hours. The dose was taken orally with 240 mL of
room temperature water at approximately 0800 hours on day 1. Opioid
medication was provided at approximately the same time every day.
Each subject participated in the study for approximately 3 weeks.
This included a screening evaluation within 3 weeks before test
article administration and a 2 day/1 night inpatient period.
[0153] The results are presented in FIG. 3. This figures shows a
plot of the comparison between time and the percentage of patients
having a first laxation response in patients with chronic malignant
pain administered a methylnaltrexone (300 mg and 450 mg) SDS tablet
after a 10 hour fast. The SLS tablet formulation resulted in
increases in percentage laxation within 4 hours and within 24 hours
in subject patients.
[0154] In Example 8, the percentage of patients who laxated within
4 hours of receiving a single initial dose of 450 mg of the SDS
formulation of the invention was approximately 41%. In Example 8,
the percentage of patients who laxated within 24 hours of receiving
a single initial dose of 450 mg of the SDS formulation of the
invention was approximately 72%.
[0155] The foregoing study was not designed to establish
statistical significance of laxation. There was no placebo group.
It is noted that historically in larger studies of chronic
nonmalignant pain patients designed with similar but more rigorous
inclusion/exclusion criteria, the percentage of subjects receiving
placebo who laxated within 4 hours was on the order of about
9%-13%. One of skill in the art will appreciate that the placebo
response in the present study could be different from the previous
studies due to such factors as the smaller study size and different
inclusion/exclusion criteria. Without wishing to be bound by any
theory of the invention, it is believed that there may be a dual
mechanism involved in achieving laxation when an oral dose is
administered and that the plasma levels required to achieve
laxation when dosing orally may be less than those required when
dosing subcutaneously.
[0156] One skilled in the art will readily ascertain the essential
characteristics of the invention and understand that the foregoing
description and Examples are illustrative of practicing the
provided invention. Those skilled in the art will be able to
ascertain using no more than routine experimentation, many
variations of the detail presented herein may be made to the
specific embodiments of the invention described herein without
departing from the spirit and scope of the present invention.
* * * * *