U.S. patent application number 16/514722 was filed with the patent office on 2020-06-11 for formulations for parenteral delivery of compounds and uses thereof.
This patent application is currently assigned to Wyeth, LLC. The applicant listed for this patent is Wyeth, LLC. Invention is credited to Nataliya Bazhina, Mahdi B. Fawzi, Christian Ofslager, Syed M. Shah.
Application Number | 20200179270 16/514722 |
Document ID | / |
Family ID | 39033508 |
Filed Date | 2020-06-11 |
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United States Patent
Application |
20200179270 |
Kind Code |
A1 |
Shah; Syed M. ; et
al. |
June 11, 2020 |
FORMULATIONS FOR PARENTERAL DELIVERY OF COMPOUNDS AND USES
THEREOF
Abstract
The present invention provides formulations that achieve
effective delivery of methylnaltrexone compositions. The provided
formulations are useful for preventing, treating delaying,
diminishing or reducing the severity of side effects resulting from
use of analgesic opioids.
Inventors: |
Shah; Syed M.; (Delray
Beach, FL) ; Ofslager; Christian; (Newburgh, NY)
; Fawzi; Mahdi B.; (Morristown, NJ) ; Bazhina;
Nataliya; (Tappan, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth, LLC |
Madison |
NJ |
US |
|
|
Assignee: |
Wyeth, LLC
Madison
NJ
|
Family ID: |
39033508 |
Appl. No.: |
16/514722 |
Filed: |
July 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15158967 |
May 19, 2016 |
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16514722 |
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14105805 |
Dec 13, 2013 |
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15158967 |
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12726113 |
Mar 17, 2010 |
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14105805 |
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11890034 |
Aug 3, 2007 |
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12726113 |
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60835574 |
Aug 4, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 1/14 20180101; A61P 41/00 20180101; A61K 47/183 20130101; A61P
1/10 20180101; A61P 1/18 20180101; A61P 35/00 20180101; A61P 25/36
20180101; A61K 9/0019 20130101; A61P 7/06 20180101; A61P 1/00
20180101; A61P 9/10 20180101; A61P 27/02 20180101; A61P 37/02
20180101; A61P 43/00 20180101; A61K 31/485 20130101; A61P 17/00
20180101; A61P 25/04 20180101; A61K 47/02 20130101; A61P 1/04
20180101; A61P 13/00 20180101; A61P 1/16 20180101; A61P 39/00
20180101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/02 20060101 A61K047/02; A61K 31/485 20060101
A61K031/485; A61K 47/18 20060101 A61K047/18 |
Claims
1-38. (canceled)
39. A method of preparing a methylnaltrexone formulation for
parenteral administration, the method comprising the steps of:
preparing a solution comprising methylnaltrexone or a
pharmaceutically acceptable salt thereof, an isotonic agent and a
calcium salt chelating agent; and sterilizing the resulting
solution and distributing to one or more sealed containers.
40. The method of claim 39, wherein the calcium salt chelating
agent is selected from the group calcium ethylenediaminetetraacetic
acid (EDTA), calcium diethylenetriaminepentaacetic acid (DTPA),
calcium hydroxyethylenediaminetriacetic acid (HEDTA), calcium
ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid
(EGTA), calcium nitrilotriacetic acid (NTA), calcium citrate, and
calcium salt derivatives thereof.
41. The method of claim 39 wherein the active compound is
methylnaltrexone bromide.
42. The method of claim 39, wherein the solution comprises an
isotonic agent.
43. The method of claim 42 wherein the isotonic agent is selected
from the group consisting of sodium chloride, mannitol, lactose,
dextrose, glycerol, and sorbitol.
44. The method of claim 43, wherein the isotonic agent comprises a
delivery vehicle selected from the group consisting of 5% Dextrose,
Lactated Ringer's Injection and 0.65% NaCl and 0.9% NaCl.
45. The method of claim 39, wherein the solution comprises water
for injection.
46. The method of claim 39, wherein the calcium salt chelating
agent is calcium ethylenediaminetriacetic acid (EDTA) or calcium
ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid
(EGTA) or a calcium salt derivative thereof.
47. The method of claim 39 wherein the solution comprises a
stabilizing agent.
48. The method of claim 47, wherein the stabilizing agent is
glycine.
49. The method of claim 48, wherein an effective amount of glycine
maintains pH at about 3.0 to about 4.0.
50. The method of claim 49, wherein the pH is about 3.5.
51. A method of preparing a methylnaltrexone formulation, the
method comprising the steps of: preparing a solution comprising
methylnaltrexone or a pharmaceutically acceptable salt thereof, an
isotonic agent, a calcium salt chelating agent and a stabilizing
agent; adjusting the pH of the solution to between pH 2.0 and pH
6.0; and sterilizing the resulting solution and distributing to one
or more sealed containers.
52. The method of claim 51, wherein the calcium salt chelating
agent is selected from the group calcium ethylenediaminetetraacetic
acid (EDTA), calcium diethylenetriaminepentaacetic acid (DTPA),
calcium hydroxyethylenediaminetriacetic acid (HEDTA), calcium
ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid
(EGTA), calcium nitrilotriacetic acid (NTA), calcium citrate, and
calcium salt derivatives thereof.
53. The method of claim 51, wherein the active compound is
methylnaltrexone bromide.
54. The method of claim 51, wherein the isotonic agent is selected
from the group consisting of sodium chloride, mannitol, lactose,
dextrose, glycerol, and sorbitol.
55. The method of claim 54, wherein the isotonic agent comprises a
delivery vehicle selected from the group consisting of 5% Dextrose,
Lactated Ringer's Injection and 0.65% NaCl and 0.9% NaCl.
56. The method of claim 51, wherein the aqueous solution comprises
water for injection.
57. The method of claim 52, wherein the calcium salt chelating
agent is calcium ethylenediaminetriacetic acid (EDTA) or calcium
ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid
(EGTA), or a calcium salt derivative thereof.
58. The method of claim 51, wherein the stabilizing agent is
glycine.
59. The method of claim 58, wherein the glycine is glycine-HCl.
60. The method of claim 51, wherein an effective amount of glycine
maintains pH at about 3.0 to about 4.0.
61. The method of claim 60, wherein the pH is about 3.5.
62-70. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/158,967 filed May 19, 2016, which, in turn,
is a continuation of U.S. application Ser. No. 14/105,805, filed
Dec. 13, 2013, which, in turn, is a continuation of U.S.
application Ser. No. 12/726,113, filed Mar. 17, 2010, which, in
turn, is a continuation of U.S. application Ser. No. 11/890,034,
filed Aug. 3, 2007, which, in turn, claims priority to U.S.
Provisional Application No. 60/835,574, filed Aug. 4, 2006. The
entire contents of each of the aforementioned applications are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Opioids are widely used in patients with advanced cancers
and other terminal diseases to lessen suffering. 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. Most notable are the effects
in the gastrointestinal tract (GI) where opioids inhibit gastric
emptying and propulsive motor activity of the intestine, thereby
decreasing the rate of intestinal transit which can produce
constipation. The effectiveness of opioids for pain is often
limited due to resultant side effects, which can be debilitating
and often cause patients to cease use of opioid analgesics.
[0003] In addition to analgesic opioid induced side effects,
studies have suggested that endogenous opioid compounds and
receptors may also affect activity of the gastrointestinal (GI)
tract and may be involved in normal regulation of intestinal
motility and mucosal transport of fluids in both animals and man.
(Koch, T. R, et al., Digestive Diseases and Sciences 1991, 36,
712-728; Schuller, A. G. P., et al., Society of Neuroscience
Abstracts 1998, 24, 524, Reisine, T., and Pasternak, G., Goodman
& Gilman's The Pharmacological Basis of Therapeutics Ninth
Edition 1996, 521-555 and Bagnol, D., et al., Regul. Pept. 1993,
47, 259-273). Thus, an abnormal physiological level of endogenous
compounds and/or receptor activity may lead to bowel
dysfunction.
[0004] For example, patients who have undergone surgical
procedures, especially surgery of the abdomen, often suffer from
bowel dysfunction, such as post-operative (or post-surgical) 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 is thought to be caused by similar natural
opioid fluctuations as a result of birthing stress. Bowel
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 opioid analgesics to a patient after
surgery, 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.
[0005] Opioid antagonists such as naloxone, naltrexone, and
nalmefene, have been studied as a means of antagonizing undesirable
peripheral effects of opioids. However, these agents act not only
on peripheral opioid receptors, but also on central nervous system
sites, so that they sometimes reverse the beneficial analgesic
effects of opioids, or cause symptoms of opioid withdrawal.
Preferable approaches for use in controlling opioid-induced side
effects include use of peripheral opioid antagonist compounds that
do not readily cross the blood-brain barrier. For example, the
peripheral .mu. opioid antagonist compound methylnaltrexone and
related compounds have been disclosed for use in curbing
opioid-induced side effects in patients (e.g., constipation,
pruritus, nausea, and/or vomiting). See, e.g., U.S. Pat. Nos.
5,972,954, 5,102,887, 4,861,781, and 4,719,215; and Yuan, C.-S. et
al. Drug and Alcohol Dependence 1998, 52, 161.
[0006] Formulations of peripheral .mu. opioid receptor antagonist
methylnaltrexone have been described (e.g., see, for example, U.S.
Pat. Nos. 6,608,075, 6,274,591, and 6,559,158). However,
methylnaltrexone in certain mediums and under certain conditions
has been found to form degradation products. For example, see US
2004266806A1. It is desirable to provide dosage forms that are
capable of effective delivery of methylnaltrexone without extensive
degradation of the methylnaltrexone under refrigeration and/or room
temperature conditions.
SUMMARY OF THE INVENTION
[0007] The present invention provides certain methylnaltrexone
formulations. In some embodiments, the invention provides
formulations having improved shelf-life stability characteristics
of active compound under refrigeration as well as at room
temperature conditions. Provided formulations are useful for
parenteral administration of methylnaltrexone. The invention
includes methods for production and use of such formulations, as
well as products and kits containing provided formulations.
[0008] In certain embodiments a pharmaceutical composition is
provided containing an effective amount of at least one active
compound selected from at least methylnaltrexone, or a
pharmaceutically acceptable salt thereof, and a calcium salt
chelating agent in an aqueous solution.
[0009] In other embodiments, liquid formulations containing
methylnaltrexone, or a pharmaceutically acceptable salt thereof, a
calcium salt, a chelating agent, an isotonic agent, and an aqueous
solvent are provided. In certain embodiments, a calcium salt and a
chelating agent are provided together as a calcium salt chelating
agent. In some embodiments, a calcium salt chelating agent is
selected from calcium ethylenediaminetetraacetic acid (EDTA),
calcium diethylenetriaminepentaacetic acid (DTPA), calcium
hydroxyethylenediaminetriacetic acid (HEDTA), calcium ethylene
glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA),
calcium nitrilotriacetic acid (NTA), calcium citrate, and calcium
salt derivatives thereof. In some embodiments a calcium salt
chelating agent is calcium EDTA.
[0010] In some embodiments, formulations further comprise an
additional stabilizing agent. In some embodiments, a stabilizing
agent is selected from glycine, benzoic acid, citric, glycolic,
lactic, malic, and maleic acid. In certain embodiments, a
stabilizing agent is glycine.
[0011] In certain embodiments, a formulation comprises
methylnaltrexone or a pharmaceutically acceptable salt thereof, a
calcium chelating agent, a stabilizing agent, an isotonic agent,
and an aqueous solvent. In some embodiments, a formulation
comprises methylnaltrexone or a pharmaceutically acceptable salt
thereof, calcium EDTA, glycine, and sodium chloride, in an aqueous
solution.
[0012] In general, provided formulations are useful for preventing,
treating or reducing severity of side effects resulting from use of
opioids, including inhibition of gastrointestinal dysfunction
(e.g., constipation, bowel hypomotility, impaction, gastric
hypomotility, GI sphincter constriction, increased sphincter tone,
inhibition of gastrointestinal motility, inhibition of intestinal
motility, inhibition of gastric emptying, delayed gastric emptying,
incomplete evacuation, nausea, emesis (vomiting), bloating,
abdominal distension), cutaneous flushing, sweating, dysphoria,
pruritis, urinary retention, etc. Provided formulations are useful
for administration to patients receiving short term opioid
treatment (e.g., patients recovering from surgery (abdominal,
orthopedic, surgery from trauma injuries etc.), patients recovering
from trauma injuries, and patients recovering from child birth).
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 cardiovascular patient); subjects receiving chronic
opioid therapy for pain management (e.g., back pain); subjects
receiving opioid therapy for maintenance of opioid withdrawal).
[0013] Additional uses of provided formulations include prevention,
treatment or reduction of severity of symptoms associated with
disorders or conditions resulting from normal or aberrant activity
of endogenous opioids. Such disorders or conditions include, among
others, ileus (e.g., post-partum ileus, paralytic ileus),
gastrointestinal dysfunction that develops following abdominal
surgery (e.g., colectomy, including but not limited to, right
hemicolectomy, left hemicolectomy, transverse hemicolectomy,
colectomy takedown, and low anterior resection) such as
post-operative ileus, and idiopathic constipation. Provided
formulations are also useful in treatment of conditions including,
for example, cancers involving angiogenesis, inflammatory disorders
(e.g., irritable bowel disorder), immune suppression,
cardiovascular disorders (e.g., bradycardia, hypotension) chronic
inflammation and/or chronic pain, sickle cell anemia, vascular
wounds, and retinopathy, decreased biliary secretion, decreased
pancreatic secretion, biliary spasm, and increased gastroesophageal
reflux.
BRIEF DESCRIPTION OF THE DRAWING
[0014] FIG. 1A and FIG. 1B: Effect of CaEDTA and NaEDTA on the
formation of 2',2-bis methylnaltrexone in the presence of iron at
40.degree. C. (FIG. 1A) and room temperature, 25.degree. (FIG. 1B).
Both calcium EDTA and sodium EDTA are effective inhibitors of
formation of the 2',2' bis methylnaltrexone degradant.
[0015] FIGS. 2A, 2B, 2C, and 2D: Effect of CaEDTA on the formation
of 7-dihydroxy methylnaltrexone in solutions. The effect of CaEDTA
and NaEDTA on the formation of 7-dihydroxy methylnaltrexone in the
presence of iron at 40.degree. C. (FIG. 2A) and room temperature,
25.degree. (FIG. 2B) was assessed. Calcium EDTA but not sodium EDTA
is an effective inhibitor of formation of the
7-dihydroxy-methylnaltrexone degradant. The effect of CaEDTA on the
formation of 7-dihydroxy methylnaltrexone in solution following one
month storage at room temperature (FIG. 2C) and at 40.degree. C.
(FIG. 2D) was assessed. The presence of CaEDTA reduced formation of
7-dihydroxy methylnaltrexone at either temperature. After one month
at room temperature, the level was reduced from 0.34% to 0.11%; and
at 40.degree. C./75% RH, the level was reduced from 0.64% to 0.14%.
The presence of NaEDTA in the samples may even increase levels of
7-dihydroxy methylnaltrexone formed.
[0016] FIG. 3A and FIG. 3B: Effect of CaEDTA in methylnaltrexone
solution on the formation of a methylnaltrexone degradant having an
RRT 0.79 ("the 0.79 degradant"). The effect of CaEDTA and NaEDTA on
the formation of the 0.79 degradant at room temperature, 25.degree.
(FIG. 3A) and at 40.degree. C. (FIG. 3B) was assessed. Calcium EDTA
was not effective at inhibiting formation of the 0.79 degradant,
and may increase levels of degradant formation.
[0017] FIG. 4 depicts identified degradants of methylnaltrexone,
respective relative retention times (RRT), and associated catalysis
and/or inhibitors of formation which have been identified.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0018] Provided are pharmaceutical formulations having improved
stability characteristics under certain conditions. Compositions,
kits, and products including provided formulations allow for
extended storage periods and also for storage under favorable room
temperature conditions. Compositions and kits and products
containing provided formulations thus allow for improved delivery
of therapeutics to subjects benefiting from use of
methylnaltrexone.
[0019] For example, provided formulations are useful to treat,
prevent, delay, or decrease severity or incidence of side effects
associated with opioid administration, including gastrointestinal
dysfunction (e.g., constipation, bowel hypomotility, impaction,
gastric hypomotility, GI sphincter constriction, increased
sphincter tone, inhibition of gastrointestinal motility, inhibition
of intestinal motility, inhibition of gastric emptying, delayed
gastric emptying, incomplete evacuation, nausea, emesis (vomiting),
bloating, abdominal distension), 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, etc. Additional effects of opioid
administration can include, 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). Formulations are useful for administration to patients
receiving short term treatment with opioids (e.g., patients
suffering from post-operative gastrointestinal dysfunction
receiving short term opioid administration). Formulations are also
useful for administration to subjects receiving chronic opioid
administration (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 receiving opioid therapy for maintenance of
opioid withdrawal).
[0020] Further uses of provided formulations include, for example,
prevention, delay, treatment or reduction of severity of symptoms
associated with disorders or conditions resulting from normal or
aberrant activity of endogenous opioids. Such disorders or
condition include, among others, ileus (e.g., post-partum ileus,
paralytic ileus), gastrointestinal dysfunction that develop
following abdominal surgery (e.g., colectomy, including but not
limited to, right hemicolectomy, left hemicolectomy, transverse
hemicolectomy, colectomy takedown, and low anterior resection) such
as post-operative ileus, and idiopathic constipation. Provided
formulations are also useful in treatment of conditions including
cancers involving angiogenesis, immune suppression, sickle cell
anemia, vascular wounds, retinopathy, and treatment of inflammation
associated disorders (e.g., irritable bowel syndrome), immune
suppression, and chronic inflammation.
Definitions
[0021] The term "dose-concentrate" refers to a pharmaceutical
composition comprising a provided formulation, wherein the
concentration of active agent(s) is higher than a typical unit
dosage form concentration administered directly to a subject. A
dose-concentrate may be used as provided for administration to a
subject, but is generally further diluted to a typical unit dosage
form concentration in preparation for administration to a subject.
The entire volume of a dose-concentrate, or aliquots thereof, may
be used in preparing unit dosage form(s) for treatment, for
example, by the methods provided herein. In some embodiments, a
dose-concentrate is about 2 fold, about 5-fold, about 10-fold,
about 25-fold, about 50-fold, about 100-fold, or about 200-fold
more concentrated than a unit dosage form. In certain embodiments,
a dose concentrate is about 50-fold, about 100-fold, or about
200-fold more concentrated than a unit dosage form.
[0022] As used herein, an "effective amount" of a compound or
pharmaceutically acceptable 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 containing a compound, which is sufficient for treating
one or more symptoms of a disorder or condition associated with
modulation of peripheral .mu. opioid receptors, such as side
effects associated with opioid analgesic therapy (e.g.,
gastrointestinal dysfunction (e.g., dysmotility constipation,
etc.), nausea, emesis, (e.g., vomiting), etc.). In certain
embodiments, an "effective amount" of a compound, or formulation
containing a compound, is sufficient for treating symptoms
associated with, a disease associated with aberrant endogenous
peripheral opioid or .mu. opioid receptor activity (e.g.,
idiopathic constipation, ileus, etc.).
[0023] The term "formulation" refers to a composition that includes
at least one pharmaceutically active compound (e.g., at least
methylnaltrexone) in combination with one or more excipients or
other pharmaceutical additives for administration to a subject. In
general, particular excipients and/or other pharmaceutical
additives are typically selected with the aim of enabling a desired
stability, release, distribution and/or activity of active
compound(s) for applications.
[0024] The term "subject", as used herein, means a mammal to whom a
formulation or composition comprising a formulation is
administered, and includes human and animal subjects, such as
domestic animals (e.g., horses, dogs, cats, etc.).
[0025] "Therapeutically active compound" or "active compound"
refers to a substance, including a biologically active substance,
that is useful for therapy (e.g., human therapy, veterinary
therapy), including prophylactic and/or therapeutic treatment.
Therapeutically active compounds can be 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. Alternatively or
additionally, therapeutically active compounds can be any substance
used as a medicine for treatment, prevention, delay, reduction or
amelioration of a disease, condition, or disorder. Among
therapeutically active compounds useful in the formulations of the
present invention are opioid antagonist compounds, opioid analgesic
compounds, and the like. Further detailed description of compounds
useful as therapeutically active compounds is provided below. A
therapeutically active compound 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.
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.
[0026] The expression "unit dosage" as used herein refers to a
physically discrete unit of a formulation appropriate for a subject
to be treated. It will be understood, however, that the total daily
usage of a formulation of the present invention 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 compound employed; specific composition
employed; age, body weight, general health, sex and diet of the
subject; time of administration, and rate of excretion of the
specific active compound 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.
[0027] The expression "dosage form" refers to means by which a
formulation is stored and/or administered to a subject. For
example, the formulation may be stored in a vial or syringe. The
formulation may also be stored in a container which protects the
formulation from light (e.g., UV light). Alternatively a container
or vial which itself is not necessarily protective from light may
be stored in a secondary storage container (e.g., an outer box,
bag, etc.) which protects the formulation from light.
[0028] The present invention provides formulations and dosage forms
for parenteral administration of methylnaltrexone, including
pharmaceutically acceptable salts thereof. As used herein,
"methylnaltrexone" includes N-methylnaltrexone and salts thereof.
Methylnaltrexone is described for example in U.S. Pat. Nos.
4,176,186; 4,719,215; 4,861,781; 5,102,887; 5,972,954; 6,274,591;
United States published patent application numbers 20020028825 and
20030022909; and PCT publications WO99/22737 and WO98/25613; the
contents of each of which are hereby incorporated by reference.
[0029] In general, pharmaceutically acceptable salts include, but
are not limited to, chloride, bromide, iodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, pantothenate, bitartrate,
carbonate, ascorbate, succinate, maleate, gentisinate, fumarate,
gluconate, glucaronate, saccharate, formate, carboxylate, benzoate,
glutamate, sulfonate, methanesulfonate, ethanesulfonate,
benzensulfonate, p-toluenesulfonate, selenate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts of compounds. In
some embodiments, salts of use in formulations of the invention are
those that have been described for methylnaltrexone, e.g.,
methylnaltrexone bromide, etc. However, the invention is not
limited to these specific salts. Other salts and mixtures thereof
can be adapted and used in a dose formulation according to the
invention so as to achieve the appropriate compound delivery
profiles of the invention (e.g., chloride, sulfate, bisulfate,
tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate,
bromide, iodide, fumarate, sulfonate, carboxylate, or succinate
salts, etc.). Alternatively or additionally, peripheral opioid
receptor antagonist (e.g., methylnaltrexone) base, chemical and
chiral derivatives thereof and other salts can be used, as
appropriate.
[0030] The bromide salt of methylnaltrexone is also referred to,
for example, N-methylnaltrexone bromide, N-methylnaltrexone
hydrobromide, methylnaltrexone bromide, methylnaltrexone
hydrobromide, naltrexone methobromide, N-methylnaltrexone, MNTX,
SC-37359, MRZ-2663-BR, and
N-cyclopropylmethylnoroxy-morphine-metho-bromide. Methylnaltrexone
is available in a powder form from Mallinckrodt Pharmaceuticals,
St. Louis, Mo., provided as a white crystalline powder freely
soluble in water. Its melting point is 254-256.degree. C. In some
embodiments, the invention provides formulations in a vial. In
certain embodiments, a formulation is provided in a vial containing
a unit dosage of methylnaltrexone. In such embodiments, a
formulation may comprise about 0.5 mg to about 200 mg
methylnaltrexone bromide. In some embodiments, a unit dosage can
contain from about 1 mg to about 80 mg, from about 5 mg to about 40
mg, or from about 8 mg to 12 mg to about 18 mg to about 24 mg.
[0031] Methylnaltrexone has chiral centers and can therefore occur
as stereochemical isomers by virtue of the substituent placement on
those chiral centers. Such stereochemical isomers are within the
scope of the compounds contemplated for use in the present
formulations. In the compositions and methods of the present
invention, compounds employed may be individual stereoisomers, as
well as mixtures of stereoisomers. In certain aspects, methods of
the present invention utilize compounds which are substantially
pure stereoisomers. All tautomers are also intended to be
encompassed within the compositions of the present invention.
[0032] The terms "R" and "S" are used herein, as commonly used in
organic chemistry nomenclature, to denote specific configuration of
a chiral center. The term "R" refers to "right" and is used to
designate the configuration of a chiral center with a clockwise
relationship of group priorities (highest to second lowest) when
viewed along the bond toward the lowest priority group. The term
"S" or "left" is used to designate the configuration of a chiral
center with a counterclockwise relationship of group priorities
(highest to second lowest) when viewed along the bond toward the
lowest priority group. The priority of groups is based upon their
atomic number (heaviest isotope first). A partial list of
priorities and a discussion of stereochemistry is contained in the
book: The Vocabulary of Organic Chemistry, Orchin, et al., John
Wiley and Sons Inc., page 126 (1980), which is incorporated herein
by reference in its entirety.
[0033] In some embodiments, isolated R--N isomers of
methylnaltrexone may be utilized in formulations and methods. As
used herein, the designation of "R--N-isomer" of methylnaltrexone
refers to such compounds in the (R) configuration with respect to
the nitrogen. Isolated isomer compounds include, but are not
limited to, R--N isomer methylnaltrexone compounds described in
U.S. patent application Ser. No. 11/441,395 filed May 25, 2006,
published WO2006/127899, which is hereby incorporated herein by
reference. In some embodiments, the active compound is an R--N
isomer methylnaltrexone, or a salt thereof. The R--N isomer of
methylnaltrexone has been found in U.S. Ser. No. 11/441,395 to be
an opioid antagonist.
[0034] In some embodiments, isolated S--N isomers of
methylnaltrexone may be utilized in formulations and methods. As
used herein, the designation of "S--N-isomer" of methylnaltrexone
refers to such compounds in the (S) configuration with respect to
the nitrogen. Isolated isomer compounds include, but are not
limited to, S--N isomer of methylnaltrexone compounds described in
U.S. patent application Ser. No. 11/441,452, filed May 25, 2006,
published WO2006/127898, which is hereby incorporated by reference.
In some embodiments, the active compound is an S--N isomer
methylnaltrexone, or a salt thereof. The S--N isomer of
methylnaltrexone has been found in U.S. Ser. No. 11/441,452 to be
an opioid agonist.
[0035] In certain embodiments, the methylnaltrexone of formulations
described herein is a mixture of stereoisomers characterized in
that it has an opioid antagonist effect. For example, the
methylnaltrexone may be a mixture of R--N and S--N methylnaltrexone
such that a mixture itself has an antagonist effect and would be
useful for methods of use described herein for opioid antagonists.
In certain embodiments, R--N methylnaltrexone is used which is
substantially free of S--N methylnaltrexone.
[0036] In certain embodiments of the present invention, at least
about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of
methylnaltrexone is in the (R) configuration with respect to
nitrogen. Methods for determining the amount of (R)--N-isomer,
present in a sample as compared to the amount of (S)--N-isomer
present in that same sample, are described in detail in
WO2006/127899, the entirety of which is hereby incorporated herein
by reference. In other embodiments, methylnaltrexone contains
0.15%, 0.10%, or less (S)--N-isomer.
[0037] The exact amount of methylnaltrexone (or combination of
methylnaltrexone and any other particular active agent) that is
required to achieve a pharmaceutically effective amount will vary
from subject to subject, depending on species, age, and general
condition of a subject, severity of the side effects or disorder,
identity of the particular compound(s), mode of administration, and
the like. A total daily dosage of methylnaltrexone (e.g.,
methylnaltrexone bromide) will typically be in the range 10-200 mg,
preferably 20-100 mg for a 70 kg adult human. A unit dosage
formulation according to the invention will usually contain 1-250
mg of active compound (e.g., methylnaltrexone bromide) per unit,
5-100 mg of active compound per unit, 10-50 mg of active compound
per unit, or about 8 mg or about 12 mg or about 24 mg of active
compound per unit. In certain embodiments, an effective amount of a
methylnaltrexone for administration to a 70 kg adult human may
comprise about 10 mg to about 50 mg of compound (e.g.,
methylnaltrexone bromide) per unit dosage, to be administered one
or more times a day. It will be appreciated that dose ranges set
out above provide guidance for the administration of active
compound to an adult. The amount to be administered to for example,
an infant or a baby can be determined by a medical practitioner or
person skilled in the art and can be lower or the same as that
administered to an adult.
Formulations
[0038] The present invention provides formulations that are capable
of maintenance of integrity of methylnaltrexone without substantial
production of degradants following storage, including storage at
room temperature. Thus, the provided formulations are capable of
conferring improved storage stability characteristics of delivered
methylnaltrexone. For example, in some embodiments, a formulation
comprises methylnaltrexone, a calcium salt chelating agent, an
isotonic agent, and a carrier. In some embodiments, a formulation
comprises methylnaltrexone, a calcium salt chelating agent, an
isotonic agent, a stabilizing agent, and a carrier. In some
embodiments, the pH of the formulation is between about a pH of 2
to about a pH of 5.
[0039] The present invention provides formulations and methods for
delivery of methylnaltrexone for improved storage and maintenance
of pharmaceutical compositions. In particular, the present
invention provides formulations that are stable formulations for
parenteral administration of methylnaltrexone compositions.
Formulations provided for parenteral administration may include
sterile solution for injection, sterile suspension for injection,
sterile emulsions, and dispersions.
[0040] For example, in some embodiments, formulations comprise
methylnaltrexone, and a calcium salt-chelating agent in an isotonic
solution. In some embodiments, fomulations comprise
methylnaltrexone, a calcium salt chelating agent, and a stabilizing
agent in an isotonic solution.
[0041] Generally, provided formulations will include one or more
active compound(s) together with one or more excipients, such as,
for example, one or more chelating agents, a calcium ion, isotonic
agents, carriers, buffers, co-solvents, diluents, preservatives,
and/or surfactants, or combinations thereof. One skilled in the art
will readily appreciate that the same ingredient can sometimes
perform more than one function, or can perform different functions
in the context of different formulations, and/or portions of a
formulation, depending upon the amount of the ingredient and/or the
presence of other ingredients and/or active compound(s). Active
compound may comprise about 0.5 mg to about 200 mg methylnaltrexone
bromide. In some embodiments, active compound may comprise about 1
mg to about 80 mg, from about 5 mg to about 40 mg, or about 8, or
about 12 mg, about 16 mg, about 18 mg, or about 24 mg
methylnaltrexone bromide.
[0042] In some embodiments, the formulation comprises a chelating
agent. In some embodiments, a chelating agent may be present in an
amount from about 0.01 mg/mL to about 2 mg/mL or about 0.1 mg/mL to
about 1 mg/mL in the formulation, or about 0.2 mg/mL to about 0.8
mg/mL of the formulation. In some embodiments, a chelating agent
may be present in an amount from about 0.2 mg/mL, about 0.3 mg/mL,
about 0.4 mg/mL, about 0.5 mg/mL, or about 0.6 mg/mL, in the
formulation.
[0043] We have found use of a chelating agent is effective as
inhibiting at least one degradant formation. Thus, addition of at
least one chelating agent is particularly useful in formulations
that include methylnaltrexone, and provides protection from
metal-catalyzed degradant production, and/or from precipitation.
Appropriate chelating agents include any pharmaceutically
acceptable chelating agents and salts thereof. Examples of
chelating agents include, but are not limited to
ethylenediaminetetraacetic acid (also synonymous with EDTA, edetic
acid, versene acid, and sequestrene), and EDTA derivatives, such as
sodium EDTA, and potassium EDTA, diammonium EDTA, dipotassium EDTA,
disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA,
trisodium EDTA, HEDTA, and trisodium HEDTA, and related salts
thereof. Other chelating agents include niacinamide and derivatives
thereof and sodium desoxycholate and derivatives thereof, ethylene
glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) and
derivatives thereof, diethylenetriaminepentaacetic acid (DTPA) and
derivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and
derivatives thereof, nitrilotriacetic acid and derivatives thereof.
Still other chelating agents include citric acid and derivatives
thereof. Citric acid also is known as citric acid monohydrate.
Derivatives of citric acid include anhydrous citric acid and
trisodiumcitrate-dihydrate. In some embodiments, chelating agent is
selected from EDTA or an EDTA derivative or EGTA or an EGTA
derivative. In some embodiments chelating agent is EDTA disodium
such as, for example, EDTA disodium hydrate.
[0044] In some embodiments, a provided formulation comprises a
calcium salt. In some embodiments, a calcium salt may be present in
an amount from about 0.01 mg/mL to about 2 mg/mL or about 0.1 mg/mL
to about 1 mg/mL in the formulation, or about 0.2 mg/mL to about
0.8 mg/mL of the formulation. In some embodiments, a calcium salt
may be present in an amount from about 0.2 mg/mL, about 0.3 mg/mL,
about 0.4 mg/mL, about 0.5 mg/mL, or about 0.6 mg/mL, in the
formulation.
[0045] We have found the presence of a calcium ion is effective as
inhibiting formation of at least one degradant. Thus, addition of
at least one calcium salt is particularly useful in formulations
that include methylnaltrexone, and provides protection from
metal-catalyzed degradant production, and/or from precipitation.
Appropriate calcium salts include any pharmaceutically acceptable
calcium salts. Examplary of calcium salts include, but are not
limited to calcium chloride, calcium acetate, calcium citrate,
calcium sulfate, etc.
[0046] In some embodiments, a formulation comprises a calcium ion
and a chelating agent included as a single component of the
formulation. Thus in some embodiments a calcium salt chelating
agent may be present in an amount from about 0.01 mg/mL to about 2
mg/mL or about 0.1 mg/mL to about 1 mg/mL in the formulation, or
about 0.2 mg/mL to about 0.8 mg/mL of the formulation. In some
embodiments, calcium salt chelating agent may be present in an
amount from about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL,
about 0.5 mg/mL, or about 0.6 mg/mL, in the formulation.
[0047] We have found use of a calcium salt chelating agent is
particularly effective as inhibiting formation of at least one
degradant. Thus, addition of at least one calcium salt chelating
agent is particularly useful in formulations that include
methylnaltrexone, and provides protection from metal-catalyzed
production of 2,2' bis-methylnaltrexone, and 7-dihydroxy
methylnaltrexone, and/or from precipitation. In some embodiments,
the formulation comprises a calcium salt chelating agent.
[0048] Appropriate calcium salt chelating agents include any
pharmaceutically acceptable chelating agents and calcium salts
thereof. Common calcium salt chelating agents include, but are not
limited to calcium ethylenediaminetetra acetic acid (EDTA) and
calcium salt EDTA derivatives, calcium ethylene
glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA) and
calcium salt EGTA derivatives, calcium
diethylenetriaminepentaacetic acid (DTPA) and calcium salt DTPA
derivatives, calcium N,N-bis(carboxymethyl)glycine (NTA) and
calcium salt NTA derivatives, and calcium citrate and derivatives
thereof. In some embodiments, chelating agent is selected from
calcium EDTA or a calcium salt EDTA derivative or calcium EGTA or a
calcium salt EGTA derivative. In some embodiments chelating agent
is calcium EDTA disodium such as, for example, calcium EDTA
disodium hydrate.
[0049] In some embodiments, a provided formulation comprises at
least methylnaltrexone, a calcium salt chelating agent and an
isotonic agent. An isotonic agent useful in the present
formulations can be any pharmaceutically acceptable isotonic agent.
Common isotonic agents include agents selected from the group
consisting of sodium chloride, mannitol, lactose, dextrose (hydrous
or anhydrous), sucrose, glycerol, and sorbitol, and solutions of
the foregoing. In certain embodiments, the formulation comprises
methylnaltrexone, an isotonic agent which is sodium chloride, and a
calcium salt chelating agent which is calcium EDTA or a calcium
salt EDTA derivative. In some embodiments, the EDTA is calcium EDTA
disodium.
[0050] In some embodiments, the formulation comprises at least
methylnaltrexone, an isotonic agent, a calcium salt chelating agent
and a carrier vehicle. In certain embodiments, the carrier vehicle
is an aqueous carrier. Aqueous carrier vehicles are known in the
art, and include, but are not limited to sterile water, water for
injection, sodium chloride, Ringer's injection, isotonic dextrose
injection, dextrose and lactated Ringers injection. In some
embodiments, the formulation comprises water for injection. In some
embodiments, formulations comprise methylnaltrexone or a
pharmaceutically acceptable salt thereof, calcium EDTA or a calcium
salt EDTA derivative, water for injection, and sodium chloride in
an amount such that the final solution is isotonic (e.g., 0.1%,
0.25%, 0.45% 0.65%, 0.9% sodium chloride). In some embodiments, the
sodium chloride is present in an isotonic amount, such that final
concentration of sodium chloride is 0.65%.
[0051] Still additional components such as stabilizing agents,
buffers, co-solvents, diluents, preservatives, and/or surfactants,
etc. may be included in provided formulations. In some embodiments,
formulations may contain such additional agents which comprise from
about 1% to about 30% or about 1% to about 12% of the formulation
or about 1% to about 10%, based upon total weight of the
formulation. In some embodiments, additional agents may comprise
from about 1%, about 2%, about 5%, about 8% or about 10% of the
formulation, based upon total weight of the formulation. Optionally
included additional ingredients are described below.
[0052] In some embodiments, provided formulations comprise a
stabilizing agent. In some embodiments, stabilizing agent may be
present in an amount from about 0.01 mg/mL to about 2 mg/mL or
about 0.05 mg/mL to about 1 mg/mL in the formulation, or about 0.1
mg/mL to about 0.8 mg/mL in the formulation. In some embodiments,
stabilizing agent may be present in an amount from about 0.15
mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about
0.35 mg/mL, or about 0.4 mg/mL.
[0053] Suitable stabilizing agents for use in formulations of the
invention include, but are not limited to glycine, benzoic acid,
citric, glycolic, lactic, malic, and maleic acid. In some
embodiments, the formulation comprises glycine. In some
embodiments, glycine comprises glycine-HCl. In some embodiments,
formulations comprise methylnaltrexone, calcium EDTA or a calcium
salt EDTA derivative, water for injection, sodium chloride in an
amount such that the final concentration is 6.5 mg/mL isotonic
sodium chloride, and glycine such as glycine HCl.
[0054] In certain embodiments, a stabilizing agent is added to the
formulation in an amount sufficient to adjust and maintain the pH
of the formulation. Thus, in some embodiments, a stabilizing agent
acts as a buffer function in addition to its role as a stabilizer.
In some embodiments, a stabilizing agent may act as a buffer agent,
so as to maintain the pH of the formulation. In certain
embodiments, the pH is between about pH 2.0 and about pH 6.0. In
some embodiments, the pH of the formulation is between about pH 2.6
and about pH 5.0. In some embodiments, the pH of the formulation is
between about pH 3.0 and about pH 4.0. In some embodiments, the pH
of the formulation is between about pH 3.4 and about pH 3.6. In
some embodiments, the pH of the formulation is about pH 3.5.
[0055] In some embodiments, provided formulations comprise
methylnaltrexone, calcium EDTA or a calcium salt EDTA derivative,
water for injection, sodium chloride in an amount such that the
final concentration is 6.5 mg/mL isotonic sodium chloride, glycine,
and the pH of the formulation is between about pH 3.0 and about pH
4.0. In some embodiments, formulations comprise methylnaltrexone or
a pharmaceutically acceptable salt thereof, calcium EDTA or a
calcium salt EDTA derivative, water for injection, sodium chloride
in an amount such that the final concentration is 6.5 mg/mL
isotonic sodium chloride, glycine, and the pH of the formulation is
between about pH 3.4 and about pH 3.6. In some embodiments,
formulations comprise methylnaltrexone bromide, calcium EDTA or a
calcium salt EDTA derivative, water for injection, sodium chloride
in an amount such that the final concentration is 6.5 mg/mL
isotonic sodium chloride, and glycine, and the formulation has a pH
of about 3.5. In certain embodiments, the pH is adjusted with
glycine. In some embodiments, glycine is glycine HCl.
[0056] In some embodiments, provided formulations comprise
methylnaltrexone bromide, calcium EDTA, water for injection,
isotonic sodium chloride, glycine HCl, and the formulation has a pH
between about 3.4 and about 3.6. In some embodiments, provided
formulations comprise methylnaltrexone bromide at a concentration
about 20 mg/mL, calcium EDTA at a concentration about 0.4 mg/mL,
sodium chloride in an amount such that the final concentration is
6.5 mg/mL isotonic sodium chloride, and glycine HCl at a
concentration about 0.3 mg/mL, and the formulation has a pH of
about 3.5. In some embodiments, formulations comprise
methylnaltrexone bromide at a concentration about 10 mg/mL, calcium
EDTA at a concentration about 0.2 mg/mL, sodium chloride in an
amount such that the final concentration is 3.25 mg/mL isotonic
sodium chloride, and glycine HCl at a concentration about 0.15
mg/mL, and the formulation has a pH of about 3.5.
[0057] One of ordinary skill in the art will recognize that
additional pH adjustments may be required to ensure that a provided
formulation has desired pH. Thus, in certain embodiments, further
pH adjustment is performed with hydrochloric acid and/or sodium
hydroxide.
Additional Components
[0058] In some embodiments, formulations may comprise one or more
additional agents for modification and/or optimization of release
and/or absorption characteristics. For example, as mentioned above,
incorporation of buffers, co-solvents, diluents, preservatives,
and/or surfactants may facilitate dissolution, absorption,
stability, and/or improved activity of active compound(s), and may
be utilized in formulations of the invention. In some embodiments,
where additional agents are included in a formulation, the amount
of additional agents in the formulation may optionally include:
buffers about 10% to about 90%, co-solvents about 1% to about 50%,
diluents about 1% to about 10%, preservative agents about 0.1% to
about 8%, and/or surfactants about 1% to about 30%, based upon
total weight of the formulation, as applicable.
[0059] Suitable co-solvents (i.e., water miscible solvents) are
known in the art. For example, suitable co-solvents include, but
are not limited to ethyl alcohol, propylene glycol.
[0060] Physiologically acceptable diluents may optionally be added
to improve product characteristics. Physiologically acceptable
diluents are known in the art and include, but are not limited to,
sugars, inorganic salts and amino acids, and solutions of any of
the foregoing. Representative examples of acceptable diluents
include dextrose, mannitol, lactose, and sucrose, sodium chloride,
sodium phosphate, and calcium chloride, arginine, tyrosine, and
leucine, and the like, and aqueous solutions thereof.
[0061] Suitable preservatives are known in the art, and include,
for example, benzyl alcohol, methyl paraben, propyl paraben, sodium
salts of methyl paraben, thimerosal, chlorobutanol, phenol.
Suitable preservatives include but are not limited to:
chlorobutanol (0.3-0.9% W/V), parabens (0.01-5.0% W/V), thimerosal
(0.004-0.2% W/V), benzyl alcohol (0.5-5% W/V), phenol (0.1-1.0%
W/V), and the like.
[0062] Suitable surfactants are also known in the art and include,
e.g., 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, cetyl alcohol, glycerol
fatty acid esters (e.g., triacetin, glycerol monostearate, and the
like), polyoxymethylene stearate, sodium lauryl 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 the formulation
may further comprise a surfactant.
Dosage Forms
[0063] As indicated, the present invention provides dosage forms
including unit dosage forms, dose-concentrates, etc. for parenteral
administration. Parenteral administration of provided formulations
may include any of intravenous injection, intravenous infusion,
intradermal, intralesional, intramuscular, subcutaneous injection
or depot administration of a unit dose. A unit dosage may or may
not constitute a single "dose" of active compound(s), as a
prescribing doctor may choose to administer more than one, less
than one, or precisely one unit dosage in each dose (i.e., each
instance of administration). For example, unit dosages may be
administered once, less than once, or more than once a day, for
example, once a week, once every other day (QOD), once a day, or 2,
3 or 4 times a day, more preferably 1 or 2 times per day.
[0064] In certain embodiments, a provided dosage form is
administered to a rehab patient (patients undergoing rehabilitation
for orthopaedic surgery, e.g. joint replacement) every other day or
every day. In other embodiments, provided dosage is 12 mg
methylnaltrexone.
[0065] In certain embodiments, a provided dosage form is
administered to a chronic pain patient every other day or every
day. In some embodiments, the pain is malignant or nonmalignant. In
other embodiments, provided dosage is 12 mg methylnaltrexone.
[0066] The present invention provides variety of different dosage
forms useful for parenteral administration, including, for example,
a methylnaltrexone formulation provided in a container (e.g., a
vial, ampoule, syringe, bag, dispenser, etc).
[0067] In one embodiment, the formulation is in a vial filled with
methylnaltrexone solution, where the solution comprises at least
one active compound which is methylnaltrexone, and a calcium salt
chelating agent, in an isotonic solution. In one embodiment, a
provided formulation is in a vial where the vial is filled with a
provided formulation, as described above and herein. In some
embodiments, provided formulation is in a vial from about 1 mL
capacity to about 50 mL capacity. In some embodiments, a vial is
about 1 mL, about 2 mL, about 5 mL, about 10 mL, about 25 mL or
about 50 mL capacity.
[0068] In one embodiment, a provided formulation is in a syringe or
other dispenser filled a provided formulation as described above
and herein. In some embodiments, a syringe or dispenser has a
capacity from about 1 mL to about 20 mL. In some embodiments a
syringe or dispenser has a capacity of about 1 mL, about 2 mL,
about 2.5 mL, about 5 mL, about 7.5 mL, about 10 mL, about 15 mL,
or about 20 mL. In some embodiments, a syringe or dispenser
utilizes a hypodermic needle for administration of contents of the
syringe or dispenser to a subject. In certain embodiments, a
syringe or dispenser utilized a needle-less adapter for transfer of
contents of the container to a subject, or, alternatively to a
second container for mixing and/or dilution of contents with
another solution. A dose-concentrate of a provided formulation can
be in a sealed container holding an amount of the pharmaceutical
formulation of the invention to be employed over a standard
treatment interval such as immediately upon dilution, or up to 24
hours after dilution, as necessary. A solution for intravenous
administration can be prepared, for example, by adding a
dose-concentrate formulation to a container (e.g., glass or plastic
bottles, vials, ampoules) in combination with diluent so as to
achieve desired concentration for administration. The amount of
dose concentrate added to diluent is a sufficient amount to treat a
subject for a period ranging from about 6 hours to about 1 week,
but preferably from about 6 or 12 hours to about 24 hours. The
container preferably also contains an empty space of sufficient
size to permit (i) addition of aqueous solvent plus (ii) additional
space as necessary to permit agitation and effect complete mixture
of diluted dose concentrate formulation with the added aqueous
solvent. A container may be equipped with a penetrable or spikable
top, for example, a rubber seal, such that aqueous solvent may be
added by penetrating the seal with a hypodermic syringe or other
type non-needle based, penetrable seal in order to transfer
concentrate contents. In certain embodiments, a provided
formulation is provided in a spikable vial. In some embodiments, a
provided formulation is provided in a 10 mL spikable vial.
[0069] Addition of aqueous solvent to a liquid dose concentrate may
be conveniently used to form unit dosages of liquid pharmaceutical
formulations by removing aliquot portions or entire contents of a
dose concentrate for dilution. Dose concentrate may be added to an
intravenous (IV) container containing a suitable aqueous solvent.
Useful solvents are standard solutions for injection as previously
described (e.g., 5% dextrose, saline, lactated ringer's, or sterile
water for injection, etc.). Typical unit dosage IV bags are
conventional glass or plastic containers having inlet and outlet
means and having standard (e.g., 25 mL, 50 mL, 100 mL and 150 mL)
capacities. Dose concentrate solution of a pharmaceutical
formulation of the invention is added to a unit dosage IV container
in an amount to achieve a concentration of about 0.1 to about 1.0
mg of methylnaltrexone per mL and preferably from about 0.24 to
about 0.48 mg per mL.
[0070] In other embodiments, it may be desirable to package a
provided dosage form in a container to protect the formulation from
light until usage. In some embodiments, use of such a
light-protective container may inhibit one or more degradation
pathways. For example, a vial may be a light container which
protects contents from being exposed to light. Additionally and/or
alternatively, a vial may be packaged in any type of container
which protects a formulation from being exposed to light (e.g.,
secondary packaging of a vial). Similarly, any other type of
container may be a light protective container, or packaged within a
light protective container.
Preparation of Provided Formulations
[0071] Formulations of the present invention may be prepared in
accordance with any of a variety of known techniques, for example
as described by M. E. Aulton in "Pharmaceutics: The Science of
Dosage Form Design" (1988) (Churchill Livingstone), the relevant
disclosures of which are hereby incorporated by reference.
[0072] In one embodiment, a provided formulation is prepared as
follows: dry components of a formulation, including active compound
(e.g., methylnaltrexone bromide), and calcium salt chelating agent
(e.g., calcium EDTA) are dissolved in an appropriate solvent (e.g.,
an isotonic solution (e.g., isotonic sodium chloride for
injection)). Optionally, additional dry and/or wet ingredients
(e.g., solvent (e.g., water)), stabilizing agent, or surfactant,
may be added. Optionally, additional components, such as
stabilizing agents, or surfactants are added to solvent prior to
dissolving other components. A provided formulation may be prepared
under low oxygen conditions.
[0073] In another embodiment, a provided formulation is prepared as
follows: dry components of a formulation, including active compound
(e.g., methylnaltrexone bromide), and calcium salt chelating agent
(e.g., calcium EDTA) are dissolved in an appropriate solvent (e.g.,
an isotonic solution (e.g., isotonic sodium chloride for
injection)). Alternatively, dry components of a formulation,
including active compound (e.g., methylnaltrexone bromide), and
isotonic agent (e.g., sodium chloride) are dissolved in an aqueous
solvent (e.g., water for injection) to generate an active compound
in an isotonic solution (e.g., methylnaltrexone in isotonic sodium
chloride for injection), followed by further addition and
dissolution of calcium salt chelating agent (e.g., calcium EDTA) to
the solution. Next, the pH of the solution may be adjusted. For
example, addition of glycine may adjust the pH to the desired
level. For example, addition of glycine HCl may be utilized for
addition to the solution to adjust pH to a desired pH (e.g., pH
3-4, pH 3.4-3.6, pH 3.5). Optionally, additional dry and/or wet
ingredients (e.g., solvent (e.g., water), stabilizing agent (e.g.,
glycine), or surfactant, may be added. Optionally, additional
components, such as stabilizing agents, surfactants are added to
solvent prior to dissolving other components. A provided
formulation may be prepared under low oxygen conditions.
[0074] In one embodiment, prepared formulations are incorporated
into vials, ampoules, syringes, or dispensers, either alone, or
with additional excipients. Typical excipients added to a provided
formulation include, but are not limited to surfactants,
preservatives, diluents, buffers, co-solvents, etc. Typical amounts
of additional excipients added to a solution may include, for
example, buffers about 10% to about 90%, co-solvents about 1% to
about 50%, diluents about 1% to about 10%, preservative agents
about 0.1% to about 8%, and surfactants about 1% to about 30%,
based upon total weight.
[0075] A prepared formulation may be subjected to a filtration
process in advance of packaging. The filtration process may
include, for example in the case of injection preparations, a
sterilizing filtration and/or an ultra filtration of the processing
solution before packaging to eliminate microorganisms or other
contaminating matter from the processing solution.
[0076] A prepared formulation may be subjected to a distributing
process to vials (e.g., clear glass vial, amber vials), ampoules,
syringes, or dispensers (e.g., auto-dispensers). The distributing
process includes, for example in the case of vial packaging, a
process distributing a suitable volume of the solution into vials
taking the concentration of methylnaltrexone into consideration in
order that contained products carry a desired amount of
methylnaltrexone.
Isolation and Identification of Degradant Products
[0077] We have identified degradants occurring in methylnaltrexone
solutions, as well as certain catalysis routes for formation of
degradant(s). Still further, in certain respects, we have
identified means to control formation of degradants, thus resulting
in lower levels of degradants in liquid formulations containing
methylnaltrexone. Provided in further detail in the Example 1
herein are methods and results of such identification, including
structures of resulting degradant compounds. Additional Examples
further provide characterization of prepared solutions, and
identification of mechanisms of catalysis of formation and/or
inhibition of formation of degradants.
[0078] Thus, provided are methods for determining the presence of
one or more degradants in methylnaltrexone formulations. In certain
embodiments, methods of detection of degradants below a designated
level are preferred for production of a methylnaltrexone
formulation. Detection of individual degradant formation in a
methylnaltrexone formulation by HPLC analysis and determining a
formulation comprises one or more degradants below a specified
level are preferred. In some embodiments the method provides
analyzing a methylnaltrexone formulation by HPLC analysis and
determining that the level of one or more specified degradants is
not exceeded. Preferred concentration levels which are not exceeded
for one or more degradants are described in the following
paragraphs relating to levels of degradants in provided
formulations.
[0079] Further provided are formulations which inhibit formation of
methylnaltrexone degradant(s), and confer improved stability
characteristics to formulations and compositions and products
containing methylnaltrexone formulations. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration of total degradation products does not exceed about
2% of methylnaltrexone in the preparation following twelve or
eighteen months of storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration of total degradation products does not exceed about
1.5% of methylnaltrexone in the preparation following twelve or
eighteen months of storage conditions. In more particular
embodiments, methylnaltrexone formulations are provided wherein the
concentration of total degradation products does not exceed about
1% of methylnaltrexone in the preparation following twelve or
eighteen months of storage conditions. Preferred storage conditions
include room temperature storage.
[0080] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of total degradation products
does not exceed about 1.5% of methylnaltrexone in the preparation
following six months of room temperature storage conditions. In
some embodiments, methylnaltrexone formulations are provided
wherein the concentration of total degradation products does not
exceed about 1% of methylnaltrexone in the preparation following
six months of room temperature storage conditions. In more
particular embodiments, methylnaltrexone formulations are provided
wherein the concentration of total degradation products does not
exceed about 0.5% of methylnaltrexone in the preparation following
six months of room temperature storage conditions.
[0081] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of 2,2' bis-methylnaltrexone
degradant product (RRT 1.55) does not exceed about 0.5% of
methylnaltrexone in the preparation following six months of room
temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration 2,2' bis-methylnaltrexone degradant product (RRT
1.55) does not exceed about 0.2% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of 2,2'
bis-methylnaltrexone degradant product (RRT 1.55) does not exceed
about 0.1% of methylnaltrexone in the preparation following six
months of room temperature storage conditions.
[0082] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of 7-dihydroxymethylnaltrexone
degradant product (RRT 0.67) does not exceed about 0.5% of
methylnaltrexone in the preparation following six months of room
temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration 7-dihydroxymethylnaltrexone degradant product (RRT
0.67) does not exceed about 0.2% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of
7-dihydroxymethylnaltrexone degradant product (RRT 0.67) does not
exceed about 0.1% of methylnaltrexone in the preparation following
six months of room temperature storage conditions.
[0083] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of the ring contracted
methylnaltrexone degradant product (RRT 0.79) does not exceed about
0.5% of methylnaltrexone in the preparation following six months of
room temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration the ring contracted methylnaltrexone degradant
product (RRT 0.79) does not exceed about 0.2% of methylnaltrexone
in the preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of the ring
contracted methylnaltrexone degradant product (RRT 0.79) does not
exceed about 0.1% of methylnaltrexone in the preparation following
six months of room temperature storage conditions.
[0084] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of the aldol dimer
methylnaltrexone degradant product (RRT 1.77) does not exceed about
0.5% of methylnaltrexone in the preparation following six months of
room temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration the aldol dimer methylnaltrexone degradant product
(RRT 1.77) does not exceed about 0.2% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of the aldol
dimer methylnaltrexone degradant product (RRT 1.77) does not exceed
about 0.1% of methylnaltrexone in the preparation following six
months of room temperature storage conditions.
[0085] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of the Hoffman elimination
methylnaltrexone degradant product (RRT 2.26) does not exceed about
0.5% of methylnaltrexone in the preparation following six months of
room temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration the Hoffman elimination methylnaltrexone degradant
product (RRT 2.26) does not exceed about 0.2% of methylnaltrexone
in the preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of the Hoffman
elimination methylnaltrexone degradant product (RRT 2.26) does not
exceed about 0.1% of methylnaltrexone in the preparation following
six months of room temperature storage conditions.
[0086] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of O-methyl methylnaltrexone
(RRT 1.66) does not exceed about 0.5% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions. In some embodiments, methylnaltrexone formulations are
provided wherein the concentration O-methyl methylnaltrexone (RRT
1.66) does not exceed about 0.25% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions. In more particular embodiments, methylnaltrexone
formulations are provided wherein the concentration of O-methyl
methylnaltrexone (RRT 1.66) does not exceed about 0.15% of
methylnaltrexone in the preparation following six months of room
temperature storage conditions.
[0087] In some embodiments, methylnaltrexone formulations where the
amount of S--N methyl naltrexone in the starting formulation is
less than 0.5 wt % (relative to the total amount of
methylnaltrexone) are provided wherein the concentration of the
S-methylnaltrexone degradant product (RRT 0.89) does not exceed
about 0.5% of methylnaltrexone in the preparation following six
months of room temperature storage conditions. In some embodiments,
methylnaltrexone formulations are provided wherein the
concentration the S-methylnaltrexone degradant product (RRT 0.89)
does not exceed about 0.2% of methylnaltrexone in the preparation
following six months of room temperature storage conditions. In
more particular embodiments, methylnaltrexone formulations are
provided wherein the concentration of the 5-methylnaltrexone
degradant product (RRT 0.89) does not exceed about 0.1% of
methylnaltrexone in the preparation following six months of room
temperature storage conditions.
[0088] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of total degradation products
does not exceed about 1.25% of methylnaltrexone in the preparation
following six months of room temperature storage conditions, the
concentration 2,2' bis-methylnaltrexone degradant product (RRT
1.55) does not exceed about 0.2% of methylnaltrexone, wherein the
concentration 7-dihydroxymethylnaltrexone degradant product (RRT
0.67) does not exceed about 0.2% of methylnaltrexone, the
concentration the ring contracted methylnaltrexone degradant
product (RRT 0.79) does not exceed about 0.2% of methylnaltrexone,
the aldol dimer methylnaltrexone degradant product (RRT 1.77) does
not exceed about 0.2% of methylnaltrexone, the Hoffman elimination
methylnaltrexone degradant product (RRT 2.26) does not exceed about
0.2% of methylnaltrexone, and the concentration of O-methyl
methylnaltrexone (RRT 1.66) does not exceed about 0.25% of
methylnaltrexone in the preparation following six months of room
temperature storage conditions.
[0089] In some embodiments, methylnaltrexone formulations are
provided wherein the concentration of total degradation products
does not exceed about 0.75% of methylnaltrexone in the preparation
following six months of room temperature storage conditions, the
concentration of 2,2' bis-methylnaltrexone degradant product (RRT
1.55) does not exceed about 0.1% of methylnaltrexone, wherein the
concentration of 7-dihydroxymethylnaltrexone degradant product (RRT
0.67) does not exceed about 0.1% of methylnaltrexone, the
concentration of the ring contracted methylnaltrexone degradant
product (RRT 0.79) does not exceed about 0.15% of methylnaltrexone,
the concentration of aldol dimer methylnaltrexone degradant product
(RRT 1.77) does not exceed about 0.05% of methylnaltrexone, the
concentration of the Hoffman elimination methylnaltrexone degradant
product (RRT 2.26) does not exceed about 0.1% of methylnaltrexone,
and the concentration of O-methyl methylnaltrexone (RRT 1.66) does
not exceed about 0.15% of methylnaltrexone in the preparation
following six months of room temperature storage conditions.
[0090] In other embodiments, methylnaltrexone formulations are
provided wherein the concentration of 2,2' bis-methylnaltrexone
degradant product (RRT 1.55) does not exceed about 0.2% of
methylnaltrexone, wherein the concentration of
7-dihydroxymethylnaltrexone degradant product (RRT 0.67) does not
exceed about 0.2% of methylnaltrexone, the concentration of the
ring contracted methylnaltrexone degradant product (RRT 0.79) does
not exceed about 0.2% of methylnaltrexone, and the concentration of
the Hoffman elimination methylnaltrexone degradant product (RRT
2.26) does not exceed about 0.2% of methylnaltrexone in the
preparation following six months of room temperature storage
conditions.
Combination Products and Combined Administration
[0091] In some embodiments, formulations include one or more other
active compounds in addition to methylnaltrexone. In such
combination formulations, additional compound(s) may be included in
one or more portion(s) that includes methylnaltrexone, may be
missing from one or more portions that include methylnaltrexone,
and/or may be included in one or more portions that does not
include methylnaltrexone. Specifically, the invention encompasses
formulations that deliver at least methylnaltrexone and at least
one other active compound. Additionally, the invention encompasses
formulations that deliver at least two independent portions of
methylnaltrexone, and that further deliver at least one other
active compound(s).
[0092] In some embodiments, formulations comprise both an opioid
and methylnaltrexone (e.g., a .mu. opioid receptor antagonist).
Such combination products, containing both an opioid and an opioid
antagonist, would 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), etc.).
[0093] Opioids useful in treatment of 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, 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 another particular embodiment, the opioid
is hydromorphone. 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.
[0094] The amount of additional active compound(s) present in
combination compositions of this invention will typically be no
more than the amount that would normally be administered in a
composition comprising that active compound as the only therapeutic
agent. In certain embodiments, the amount of additional active
compound will range from about 50% to 100% of the amount normally
present in a composition comprising that compound as the only
therapeutic agent.
[0095] In certain embodiments, formulations may also be used in
conjunction with and/or in combination with additional active
compounds and/or conventional therapies for treatment of
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.,
diphelymethane laxatives, cathartic laxatives, osmotic laxatives,
saline laxatives, etc), bulk forming agents and laxatives,
lubricants, intravenous hydration, and nasogastric
decompression.
Kits and Uses of Formulations
[0096] Uses
[0097] As discussed above, the present invention provides
formulations useful in antagonizing undesirable side effects of
opioid analgesic therapy (e.g., gastrointestinal effects (e.g.,
delayed gastric emptying, altered GI tract motility), etc.).
Furthermore, formulations of the invention may be used to treat
subjects having disease states that are ameliorated by binding .mu.
opioid receptors, or in any treatment wherein temporary suppression
of the .mu. opioid receptor system is desired (e.g., ileus, etc.).
In certain embodiments, methods of use of formulations are in human
subjects.
[0098] Accordingly, administration of provided formulations may be
advantageous for treatment, prevention, amelioration, delay or
reduction of side effects of opioid administration, such as, for
example, gastrointestinal dysfunction (e.g., inhibition of
intestinal mobility, 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,
etc, or combinations thereof. Use of provided formulations may thus
be beneficial from a quality of life standpoint for subjects
receiving administration 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.
[0099] In some embodiments, provided formulations are useful for
administration to a subject receiving short term opioid
administration. In some embodiments, provided formulations are
useful for administration to patients suffering from post-operative
gastrointestinal dysfunction.
[0100] In other embodiments, provided formulations are also useful
for administration to subjects receiving chronic opioid
administration (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 receiving opioid therapy for maintenance of
opioid withdrawal). In some embodiments, the subject is a subject
using opioid for chronic pain management. In some embodiments, the
subject is a terminally ill patient. In other embodiments the
subject is a person receiving opioid withdrawal maintenance
therapy.
[0101] Additional uses for formulations described herein may be to
treat, reduce, inhibit, or prevent effects of opioid administration
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 musculokeletal
system such as osteoporosis, arthritis, osteitis, periostitis,
myopathies, and treatment of autoimmune diseases.
[0102] In certain embodiments, formulations of the invention 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, paralytic ileus, 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) or hernia repair), and delayed absorption of orally
administered medications or nutritive substances.
[0103] 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.
[0104] In still further embodiments, veterinary applications (e.g.,
treatment of domestic animals, e.g. horse, dogs, cats, etc.) of use
of 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 antagonists has been described, e.g., in
U.S. Patent Publication No. 20050124657 published Jan. 20,
2005.
[0105] It will also be appreciated that formulations of the present
invention can be employed in combination therapies, that is,
methylnaltrexone and compositions thereof, 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".
[0106] In other embodiments, provided formulations and dosage forms
are useful in preparation of medicaments, including, but not
limited to medicaments useful in the treatment of side effects of
opioid administration (e.g., gastrointestinal side effects (e.g.,
inhibition of intestinal motility, GI sphincter constriction,
constipation, nausea, emesis) dysphoria, pruritis, etc.) or a
combination thereof. Provided formulations are useful for
preparations of medicaments, useful in treatment of patients
receiving short term opioid therapy (e.g., patients suffering from
post-operative gastrointestinal dysfunction receiving short term
opioid administration) or subjects using opioids chronically (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; or subjects
receiving 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 musculokeletal 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), and
treatment of disorders such as cancers involving angiogenesis,
chronic inflammation and/or chronic pain, sickle cell anemia,
vascular wounds, and retinopathy.
Pharmaceutical Kits and Packaging
[0107] Still further encompassed by the invention are
pharmaceutical packs and/or kits. Pharmaceutical packs and/or kits
provided may comprise a formulation and a container (e.g., a vial,
ampoule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a suitable
aqueous carrier for dilution of the reconstitute for preparation of
administration to a subject via IV administration. In some
embodiments, contents of provided formulation container and solvent
container combine to form a unit dosage form.
[0108] In some embodiments, a formulation of the invention may be
useful in conjunction with patient controlled analgesia (PCA)
devices, wherein a patient can administer opioid analgesia as
required for pain management. In such instances, co-administration
of provided formulations may be useful to prevent adverse side
effects of opioid administration. Thus, kits of the invention may
comprise a formulation for administration of methylnaltrexone
contained within a cartridge for use in conjunction with PCA
device.
[0109] In some embodiments, a formulation of the invention may be
useful in conjunction with a diluent container suitable for frozen
storage, wherein a formulation is diluted in suitable diluent, and
provided in a container suitable for freezing. In some embodiments,
such frozen containers may be thawed prior to intravenous
administration of methylnaltrexone to a subject. Thus, kits of the
invention may comprise a formulation for administration of
methylnaltrexone in a container suitable for frozen storage, and
thawing prior to administration to a subject. In some embodiment,
such a container is a frozen intravenous bag.
[0110] Optionally, a single container may comprise one or more
compartments for containing lyophilized formulation, and/or
appropriate aqueous carrier for dilution. In some embodiments, a
single container may be appropriate for modification such that the
container may receive a physical modification so as to allow
combination of compartments and/or components of individual
compartments. For example, a foil or plastic bag may comprise two
or more compartments separated by a perforated seal which may be
broken so as to allow combination of contents of two individual
compartments once the signal to break the seal is generated. A
pharmaceutical pack or kit may thus comprise such multi-compartment
containers including lyophilized formulation and appropriate
solvent for reconstitution and/or appropriate aqueous carrier for
dilution of reconstitute. Optionally, instructions for use are
additionally provided in such kits.
[0111] In some embodiments, a pharmaceutical kit comprises a
formulation in a dilution package or container wherein a
needle-less exchange mechanism allows for combination of
formulation and with isotonic solution for preparation for
intravenous administration. For example, in certain non-limiting
examples, a formulation of the invention may be utilized in
conjunction with a MINIBAG.RTM. Plus diluent container system
(Baxter), or an ADD VANTAGE.RTM. diluent container (Hospira)
system.
[0112] Optionally, instructions for use are additionally provided
in such kits of the invention. Such instructions may provide,
generally, for example, instructions for dosage and administration.
In other embodiments, instructions may further provide additional
detail relating to specialized instructions for particular
containers and/or systems for administration. Still further,
instructions may provide specialized instructions for use in
conjunction and/or in combination with additional therapy. In one
non-limiting example, the formulations of the invention may be used
in conjunction with opioid analgesia administration, which may,
optionally, comprise use of a patient controlled analgesia (PCA)
device. Thus, instructions for use of provided formulations may
comprise instructions for use in conjunction with PCA
administration devices.
[0113] 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.
EXEMPLIFICATION
Part I: Stability of Provided Formulations
Example 1
Identification and Characterization of Degradants of
Methylnaltrexone Formulations.
[0114] Previously, at least three degradation products were
demonstrated from HPLC analysis in 20 mg/mL isotonic saline
solution (identified as RRT peaks at about 0.72, 0.89, and 1.48
when products were analyzed by HPLC). See, e.g., US Patent
Application Publication No. 20040266806A1, published Dec. 30, 2004.
We examined 20 mg/mL saline methylnaltrexone solutions for
production of degradants, and identification of degradants, as well
as identification of inhibitors of formation of different degradant
products. We have identified and characterized degradants which
accumulate in certain methylnaltrexone solutions. In these
degradation experiments, and in the formulations prepared in the
examples, R--N-methylnaltrexone was used having less than 0.15
weight percent S--N-methylnaltrexone based on the total weight of
methylnaltrexone.
[0115] For HPLC analysis, two (2) different methods were utilized
to obtain the data set forth herein. These methods are summarized
below:
Method A:
[0116] Column: Prodigy ODS-3 15 cm.times.2.0 mm, 3 .mu.m particles
(Phenomenex) [0117] Flow rate: 0.25 mL/min [0118] Detection: UV,
280 nm [0119] Mobile phase: strength: Isocratic: 75:25 (v/v) 0.1%
TFA in Water/Methanol [0120] Mobile phase: purity: Gradient as
follows: [0121] Solvent A: 95:5 (v/v) 0.1% TFA in Water/Methanol
[0122] Solvent B: 35:65 (v/v) 0.1% TFA in Water/Methanol [0123]
Sample Solvent: 0.05M Dibasic Sodium Phosphate pH 6.8 [0124]
Gradient Program:
TABLE-US-00001 [0124] Time (Min) % Mobile Phase A 0 100 45 50 45.1
100 60 100
[0125] Column Temperature: 50.degree. C.
Method B: (Purity)
[0125] [0126] Column: Prodigy ODS-3 15 cm.times.4.6 mm, 3 .mu.m
particles (Phenomenex) [0127] Flow rate: 1.5 mL/min [0128]
Detection: UV, 280 nm [0129] Mobile phase: Gradient as follows:
[0130] Solvent A: 95:5 (v/v) 0.1% TFA in Water/Methanol [0131]
Solvent B: 25:75 (v/v) 0.1% TFA in Water/Methanol [0132] Sample
Solvent: 0.05M Dibasic Sodium Phosphate pH 6.8 [0133] Gradient
Program:
TABLE-US-00002 [0133] Time (Min) % Mobile Phase A 0 100 45 50 45.1
100 60 100
Method B: (Strength)
[0134] Column: Prodigy ODS-3 15 cm.times.4.6 mm, 3 .mu.m particles
(Phenomenex) [0135] Flow rate: 1.0 mL/min [0136] Detection: UV, 280
nm [0137] Mobile phase: Gradient as follows: [0138] Solvent A: 95:5
(v/v) 0.1% TFA in Water/Methanol [0139] Solvent B: 25:75 (v/v) 0.1%
TFA in Water/Methanol [0140] Sample Solvent: 0.05M Dibasic Sodium
Phosphate pH 6.8 [0141] Gradient Program:
TABLE-US-00003 [0141] Time (Min) % Mobile Phase A 0 95 1.0 85 12.0
50 15.0 95 20.0 95
[0142] The following compounds were identified in the stability
studies using HPLC analysis (Method A) of samples under the
indicated storage conditions, and, unless otherwise noted, had the
following associated calculated relative retention times:
TABLE-US-00004 ##STR00001## RRT 1.00 ##STR00002## RRT 1.17
##STR00003## RRT 0.86 or 0.89 ##STR00004## RRT 0.89 (for Tables
11C-2, 11C-3, 12A-2, 12B-2, 12C-2, 12D-2) ##STR00005## RRT 0.49
##STR00006## RRT 1.77 ##STR00007## RRT 1.66 ##STR00008## RRT
1.55
[0143] Naltrexone base, S-methylnaltrexone, and O-methyl
methylnaltrexone are each compounds found in initial production
samples. Additional impurities/degradants formed and identified in
methylnaltrexone formulations include 8-ketomethylnaltrexone
bromide (RRT 0.49), the aldol dimer (RRT 1.77), O-methyl
methylnaltrexone (RRT 1.66), and the 2,2 bis-methylnaltrexone (RRT
1.55), as well as additional degradants resulting at relative
retention time of 0.67, 0.79 and 2.26.
[0144] Each of the three additional degradants were identified by
NMR analysis following isolation from column eluates, and further
characterized as described herein. The 0.67 degradant has been
identified as 7-dihydroxy methylnaltrexone; the 0.79 degradant has
been identified as a ring contracted form
((3R,4R,4aS,6aR,11bS)-6-carboxy-3-(cyclopropylmethyl)-4a,6,8-trihydroxy-3-
-methyl-1,2,3,4,4a,5,6,6a-octahydro-4,11-methano[1]benzofuro[3',2':2,3]cyc-
lopenta[1,2-c]pyridin-3-ium); and the 2.26 degradant has been
identified as a Hoffman elimination product (see the following
compound names, relative retention times, and associated structure;
see also, FIG. 4).
TABLE-US-00005 ##STR00009## RRT 0.67 ##STR00010## RRT 0.79
##STR00011## RRT 2.26
[0145] Results of stability studies in tables set forth in the
following examples demonstrate resulting levels of each of the
degradants identified in samples using HPLC analysis. Stability
test procedures used in the following examples include standard
pharmaceutical stability studies according to ICH guidelines, under
conditions of 25.degree. C./60% relative humidity, 40.degree.
C./65% relative humidity, and/or 70.degree. C. FIG. 4 depicts three
of the major resulting degradants, and the associate proposed
mechanisms for catalysis of formation and/or methods of inhibition
of formation which have been identified and further described in
the examples that follow.
[0146] One of ordinary skill in the art will appreciate that minor
modifications in an HPLC method or sample preparation can result in
a shift of RRT. Thus, it will be appreciated that the RRT values
reported herein may shift depending upon actual conditions.
Example 2
Inhibition of Metal and Calcium Mediated Degradation of
Methylnaltrexone Formulations.
[0147] Inhibition of Metal-Catalyzed Formation of 2,2'Bis
Methylnaltrexone.
[0148] We have found Fe3.sup.+ facilitates degradation of
methylnaltrexone bromide in solution, resulting in formation of a
2,2'bis methylnaltrexone degradant. We have found by HPLC analysis
(Method B) the 2,2'bis methylnaltrexone degradant results in a peak
having an RRT about 1.55. Fe.sup.3+ is an ion that can get into the
liquid formulation from several sources. For example, it can be
leached from stainless steel process equipment, syringe needles,
stoppers and amber vials. EDTA, as a metal chelating agent
sequesters the available Fe.sup.3+ in the solution, thereby
preventing catalysis of the undesirable metal-catalyzed reactions.
Methylnaltrexone solutions were prepared in 0.9% NaCl, in the
presence of iron and various concentrations of sodium EDTA and
calcium EDTA. Used throughout the experiments sodium EDTA is EDTA
disodium dihydrate, and the terms sodium EDTA, EDTA disodium
dihydrate, and NaEDTA are used interchangeably throughout. Used
throughout the experiments calcium EDTA is calcium EDTA disodium,
and the terms calcium EDTA, calcium EDTA disodium, and CaEDTA are
used interchangeably throughout. Formation of 2,2'bis
methylnaltrexone was assessed at room temperature as well as at
40.degree. C. Addition of either sodium or calcium EDTA solution
was effective at inhibiting formation of the 2,2'bis
methylnaltrexone degradant. See FIG. 1A and FIG. 1B. Thus,
chelating action will facilitate methylnaltrexone bromide stability
in solution at room temperature.
[0149] Inhibition of Metal-Catalyzed Formation of
7-dihydroxy-methylnaltrexone.
[0150] We have found EDTA inhibits metal catalyzed formation of a
7-dihydroxy-methylnaltrexone degradant in methylnaltrexone
solution. We have found by HPLC analysis (Method B) the 0.67 peak
degradant to be the presence of 7-dihydroxy methylnaltrexone.
Methylnaltrexone solutions were prepared in 0.9% NaCl, in the
presence of iron and various concentrations of EDTA. Formation of
7-dihydroxy methylnaltrexone was assessed. Addition of either EDTA
solution was effective at inhibiting formation of the 7-dihydroxy
methylnaltrexone degradant. See Table 1.
TABLE-US-00006 TABLE 1 Peak area of RRT 0.67 degradant of 20 mg/ml
MNTX at room temperature in presence of 1 mm Fe + 3 Sample name
Initial 1 hour 2 hours 3 hours 4 hours MNTX + 1 0.7 0.7 0.99 1.16
1.42 mmFe + 3 (0.017%) (0.019%) (0.024%) (0.028%) (0.035%) MNTX + 0
0.72 0.88 0.9 1.2 0.25 (0.018%) (0.019%) (0.022%) (0.029%) mmEDTA +
1 mm Fe + 3 MNTX + 0.5 0 0.6 0.87 0.95 1.19 mmEDTA + (0.015%)
(0.02%) (0.023%) (0.029%) 1 mm Fe + 3 MNTX + 0 0.58 0.62 0.75 0.81
0.75 (0.014%) (0.013%) (0.018%) (0.02%) mmEDTA + 1 mm Fe + 3 MNTX +
1 0 0.46 0.57 0.68 0.68 mmEDTA + (0.011%) (0.012%) (0.016%)
(0.016%) 1 mm Fe + 3
[0151] We have found Ca.sup.2+ chelating agent provides additional
inhibition of formation of a 7-dihydroxy-methylnaltrexone degradant
as compared to Na.sup.2+ chelating agent. Methylnaltrexone
solutions were prepared in 0.9% NaCl, in the presence of iron and
various concentrations of sodium EDTA and calcium EDTA. Formation
of 7-dihydroxy-methylnaltrexone was assessed at room temperature as
well as at 40.degree. C. Addition of calcium EDTA solution was
highly effective at inhibiting formation of the
7-dihydroxy-methylnaltrexone degradant at both temperatures. See
FIG. 2A and FIG. 2B. Use of calcium facilitates methylnaltrexone
bromide stability in solution at room temperature. Furthermore,
long term storage of solution at either room temperature or
40.degree. C./75% relative humidity also demonstrated stabilization
and inhibition of 7-dihydroxy methylnaltrexone degradant formation
when calcium EDTA was present. After one month at room temperature,
resultant production of 7-dihydroxy-methylnaltrexone was reduced
from 0.34% to 0.11% in the presence of calcium EDTA. Furthermore,
at 40.degree. C./75% RH, degradant was reduced from 0.64% in saline
solution alone to 0.14% in sample containing calcium EDTA. See FIG.
2C and FIG. 2D.
[0152] Preparation of an Improved Room Temperature Methylnaltrexone
Formulation.
[0153] Our results have shown a methylnaltrexone formulation
comprising a saline solution of active compound plus calcium
salt-chelating agent results in a formulation having improved room
temperature stability characteristics. Preparation of such improved
formulations comprise use of the following exemplary
components:
TABLE-US-00007 Active Methylnaltrexone bromide (5 to 40 mgs)
Chelating agent Calcium EDTA (0.05 to 1.5 mgs) Isotonic Delivery
Vehicle 0.9% Normal Saline (1 to 1.25 mL)
[0154] For a 0.6 mL fill or 1.25 mL fill, 20 or 30 mgs of
methylnaltrexone bromide were dissolved in 0.9% sodium chloride;
and 0.24 mg or 0.5 mg of calcium EDTA were also dissolved in the
solution. Resulting solutions were prepared and filter sterilized
at ambient conditions, and resulting formulations filled into clear
glass vials, ampoules, syringes or auto-dispensers.
TABLE-US-00008 TABLE 2 Formulation INGREDIENTS 0.6 mL/VIAL 1.25
mL/VIAL Methylnaltrexone bromide 20 mg 30 mg Calcium EDTA, NF 0.24
mg 0.5 mg Sodium Chloride 0.65% 0.65%
Example 3
Inhibition of pH Dependent Degradation of Methylnaltrexone
Formulations
[0155] Inhibition of pH Influenced Formation of Methylnaltrexone
Degradants.
[0156] We have found in the presence of Ca.sup.2+ and EDTA,
degradation of methylnaltrexone bromide in solution occurs under
some stability conditions, resulting in formation of a
third-methylnaltrexone degradant. We have found by HPLC analysis
(Method B) the degradant results in a peak having an RRT about
0.79. Identification and production of the 0.79 degradant is
described in U.S. provisional patent application 60/835,687, filed
Aug. 4, 2006, filed concurrently with the present application, the
contents of which are incorporated herein in their entirety by
reference.
[0157] Formation of the 0.79 methylnaltrexone degradant was lower
at room temperature in the CaEDTA formulation described in Example
2 above as compared to refrigerated methylnaltrexone in saline
solution. Methylnaltrexone solution as described in Example 2
containing CaEDTA was compared to a control refrigerated
methylnaltrexone solution in saline and formulations assessed for
production of 0.79 degradant formation (room temperature CaEDTA
0.03% vs. refrigerated control saline 0.06%). See FIG. 3A and FIG.
3B. Use of calcium EDTA appears to facilitate production of the
0.79 degradant under our accelerated stability conditions, however,
as it was found at 40.degree. C./75% RH the 0.79 degradant
increases from control 0.19% to 0.38% in the presence of CaEDTA.
Furthermore, the peak RRT 0.79 degradant increases from 0.03% at
room temperature to 0.4% at 40.degree. C./75% RH in 1 month. Thus,
while the formulation described above in Example 2 controls
degradants RRT 0.67 and RRT 1.55, degradant appearing at RRT 0.79
remains under accelerated stability conditions of 40.degree. C./75%
RH.
[0158] We found reduction in pH as well as the presence of glycine
resulted in stabilization of the 0.79 degradant. Table 4,
summarizes the formulation stability without pH control at
70.degree. C. The formulation has a pH of 5.6. The data confirms
that a formulation containing Ca EDTA does limit the formation of
0.67 and RRT 1.55 but does not reduce RRT 0.79. After only a few
days RRT 0.79 grows to over 1.0%. Each of the peaks resulting in
the HPLC is represented in the table. For those products identified
by the peaks: RRT 0.89 represents S-MNTX; RRT 1.17 represents
naltrexone base; RRT 1.55 represent 2,2 bis methylnaltrexone; RRT
1.66 represents O-methyl-methylnaltrexone; RRT 1.77 represents
aldol dimer formation; and RRT 2.26 represents Hoffman elimination
degradant formation. BRL=below recordable limit.
[0159] We tested whether the 0.79 degradant is pH dependent, and
the optimum pH range for a solution. Table 5 summarizes the
stability of prepared solutions. Additionally, Table 6 summarizes
stability of prepared solutions at 40.degree. C./75% Relative
Humidity and at 70.degree. C., with and without pH adjustment with
glycine. We found that as additional glycine HCl is added to
solution, the amount of degradant at RRT 0.79 formed is greatly
reduced and confirms the stability of the formulation with respect
to RRT 0.79 is stabilized by the presence of glycine. See Tables 5
and 6.
TABLE-US-00009 TABLE 4 Stability data of MNTX 12 mg/vial, 0.28
mg/vial CaEDTA and 0.65% Sodium Chloride pH(5.6) at 70.degree. C.
Initial RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT (mg)
0.38 0.49 0.67 0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96 2.01 2.26
Total Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5 0.15 0.5 0.2
0.2 0.2 0.5 NA Initial 20 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL
BRL BRL BRL 0.12 (100) 70.degree. C. Time and Days 3 19.9 BRL BRL
0.07 1.0 BRL BRL BRL 0.13 BRL BRL BRL BRL 1.02 2.22 (99.5) 7 19.7
BRL BRL 0.09 1.5 BRL BRL BRL 0.11 BRL BRL BRL BRL 1.58 3.28
(98.5)
TABLE-US-00010 TABLE 5 Stability of MNTX formulation 20 mg/ml, 0.4
mg/ml CaEDTA, 0.65% Sodium Chloride with pH adjusted with Glycine
HCl Initial RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT
(mg) 0.38 0.49 0.67 0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96 2.01
2.26 Total Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5 0.15 0.5
0.2 0.2 0.2 0.5 NA pH 3 at 40.degree. C./75% Relative Humidity Time
and Days Initial 19.8 BRL BRL BRL BRL BRL BRL BRL 0.11 BRL BRL BRL
BRL BRL 0.11 14 19.9 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL
BRL BRL 0.12 21 19.9 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL
BRL BRL 0.12 30 20.1 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL
BRL BRL 0.12 pH 3.5 at 40.degree. C./75% Relative Humidity Initial
19.9 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 7
20.1 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 14
20.0 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 21
20.3 BRL BRL BRL BRL BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 30
20.1 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 pH 4
at 40.degree. C./75% Relative Humidity Initial 20.0 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 14 20.1 BRL BRL BRL BRL
BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 21 20.1 BRL BRL BRL BRL
BRL BRL BRL 0.14 0.06 BRL BRL BRL BRL 0.20 30 19.9 BRL BRL BRL BRL
BRL BRL BRL 0.11 0.06 BRL BRL BRL BRL 0.17
TABLE-US-00011 TABLE 6 Stability of MNTX formulation 20 mg/ml, 0.4
mg/ml CaEDTA, 0.65% Sodium Chloride with pH adjusted with Glycine
HCl Initial RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT
(mg) 0.38 0.49 0.67 0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96 2.01
2.26 Total Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5 0.15 0.5
0.2 0.2 0.2 0.5 NA pH 3 at 70.degree. C. Time and Days Initial 19.8
BRL BRL BRL BRL BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 (100) 10
19.6 BRL BRL 0.04 0.04 BRL BRL BRL 0.12 BRL BRL BRL BRL 0.06 0.12
(99) 14 BRL BRL 0.07 0.05 BRL BRL BRL 0.11 BRL BRL BRL BRL 0.09
0.32 pH 3.5 at 70.degree. C. Initial 19.9 BRL BRL BRL BRL BRL BRL
BRL 0.12 BRL BRL BRL BRL BRL 0.12 (100) 5 20.2 BRL BRL 0.06 BRL BRL
BRL BRL 0.13 BRL BRL BRL BRL 0.08 0.27 (101.5) 7 20.1 BRL BRL 0.08
0.07 BRL BRL BRL 0.12 BRL BRL BRL BRL 0.11 0.38 12 20.2 BRL BRL
0.06 0.15 BRL BRL BRL 0.11 0.06 BRL BRL BRL 0.18 0.56 pH 4 at
70.degree. C. Initial 20.0 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL
BRL BRL BRL 0.12 (100) 10 19.9 BRL BRL 0.05 0.21 BRL BRL BRL 0.13
BRL BRL BRL BRL 0.23 0.39 (99.5) 14 BRL BRL 0.04 0.27 BRL BRL BRL
0.13 BRL BRL BRL BRL 0.28 0.72
[0160] Preparation of a pH Adjusted, Improved Room Temperature
Formulation.
[0161] Listed below, in Table 7 and Table 8, are developed
formulations containing glycine HCl, including a pH adjustment step
in the process, where the range of pH is 3.4-3.6 with a target pH
3.5. While not being bound by theory, this is based on the idea
that while pH 3.0 is stable, the amount of irritation and sting at
the site of injection would be undesirable. Furthermore, at pH 4.0,
RRT 0.79 degradant begins to form. Glycine HCl is commonly used in
subcutaneous formulations for pH adjustment, and has less
propensity to cause site of injection stinging as results with use
of citrate buffer. When glycine HCl is used to adjust the pH of
formulations containing methylnaltrexone, controlling degradation
is also evident. A solution containing methylnaltrexone including
both CaEDTA and 0.3 mg/mL glycine HCl where the pH is adjusted to
3.4-3.6 will inhibit the formation of RRT 1.55 and greatly reduce
the formation of degradants RRT 0.67 and RRT 0.79. A room
temperature liquid formulation consisting of methylnaltrexone,
CaEDTA, 0.65% NaCl, 0.3 mg/mL glycine HCl with a pH to 3.5 may be
developed as either a subcutaneous administration or intravenous
administration formulation.
[0162] Preparation of such improved formulations comprises use of
the following exemplary components:
TABLE-US-00012 Active Methylnaltrexone bromide (5 to 40 mgs)
Chelating agent Calcium EDTA (0.05 to 1.5) Isotonic Delivery
Vehicle 0.65% Normal Saline (0.5 to 1.75 mL) Stabilizer glycine HCl
0.3 mg/mL QS to final Volume pH 3.4-3.6
TABLE-US-00013 TABLE 7 Formulation INGREDIENTS 12 Mg/VIAL.sup.A 16
Mg/VIAL.sup.A Methylnaltrexone 12 mg 16 mg 20 mg/mL bromide Calcium
EDTA disodium 0.24 mg 0.0.32 mg 0.4 mg/mL dihydrate, NF Sodium
Chloride 3.9 mg 5.20 mg 6.5 mg/mL Glycine HCL 0.18 mg 0.0.24 mg 0.3
mg/mL pH 3.5 pH 3.5 pH 3.5 Water for Injection, QS to 0.6 QS to 0.8
USP .sup.A3 mL West flint glass vial with 13 mm West 4432/50
Fluorotec stopper and West 13 FO CS TE 3769 Blue Cap.
[0163] For example, for preparation of a 12 mg/Vial, 12 mgs of
methylnaltrexone bromide and 3.9 mg sodium chloride were dissolved
in water for injection; then 0.24 mg of calcium EDTA added and
dissolved the final solution brought to a final fill volume of 0.6
mL. The pH was adjusted with Glycine HCl to between 3.4-3.6,
optimally pH 3.5. Resulting solution was prepared, and filtered
through 0.45 and 0.22 micron PVDF filters. Resulting solution was
filled into clear glass vials under low oxygen conditions. Any
suitable containers, including vials, ampoules, syringes or
auto-dispensers may be utilized. Resulting preparations are stored
at or below room temperature, without freezing. Resultant
formulation may be used for parenteral administration, either for
subcutaneous administration, or for intravenous administration
applications. See Table 7.
[0164] Similarly, the levels of ingredients may be adapted to a
final fill volume of 0.8 (or any other preferred final volume) to
obtain the same concentrations. See Table 7.
TABLE-US-00014 TABLE 8 Formulation INGREDIENTS 12 Mg/VIAL.sup.A 16
Mg/VIAL.sup.A Methylnaltrexone 12 mg 16 mg 10 mg/mL bromide Calcium
EDTA 0.24 mg 0.0.32 mg 0.2 mg/mL disodium dihydrate, NF Sodium
Chloride 3.9 mg 5.20 mg 3.25 mg/mL Glycine HCL 0.18 mg 0.0.24 mg
0.15 mg/mL pH 3.5 pH 3.5 pH 3.5 Water for Injection, QS to 1.2 QS
to 1.6 USP .sup.A3 mL West flint glass vial with 13 mm West 4432/50
Fluorotec stopper and West 13 FO CS TE 3769 Blue Cap.
[0165] In an alternative exemplary formulation, for a 12 mg/Vial,
12 mgs of methylnaltrexone bromide and 3.9 mg sodium chloride were
dissolved in water for injection; then 0.24 mg of calcium EDTA
added and dissolved and the final solution brought to a final fill
volume of 1.2 mL. The pH was adjusted with Glycine HCl to between
3.4-3.6, optimally pH 3.5. Resulting solution was prepared, and
filtered through 0.45 and 0.22 micron PVDF filters. Resulting
solution was filled into clear glass vials under low oxygen
conditions. Any suitable containers, including vials, ampoules,
syringes or auto-dispensers may be utilized. Resulting preparations
are stored at or below room temperature, without freezing.
Resultant formulation may be used for parenteral administration,
either for subcutaneous administration, or for intravenous
administration applications. See Table 8.
[0166] Similarly, the levels of ingredients may be adapted to a
final fill volume of 1.6 (or any other preferred final volume) to
obtain the same concentrations. See Table 8.
Example 4
Comparison and Evaluation of Buffer Compatibility
[0167] Evaluation of Phosphate Buffers Solution Stability.
[0168] We have also assessed different buffers to determine
compatibility and whether various conditions would convey further
stability to methylnaltrexone solutions. Table 9 and Table 10 show
results (HPLC Method A) of total degradant formation over time in
methylnaltrexone solutions prepared in phosphate solution (Table
9), and glycine solution (Table 10). We found at pH 7, glycine
provides better stability characteristics to samples than
phosphate.
TABLE-US-00015 TABLE 9 Stability of MNTX in pH 7, 0.02M Phosphate*
Solution Total Impurities Elapsed Strength % (% Total pH of
Appearance and Condition Time (mg/ml) Initial Area) Formulation
Description Room 0 time 0.988 100 0.025 7.09 Clear, colorless
Temperature solution 1 day 0.988 100 0.134 7.12 Clear, colorless
solution 2 days 0.996 100.8 0.262 7.11 Clear, colorless solution 6
days 0.999 101.1 0.786 7.14 Clear, colorless solution 9 days 0.999
101.1 1.25 7.14 Clear, colorless solution 14 days 0.988 100.0 1.561
7.14 Clear, colorless solution 21 days 0.971 98.3 2.07 7.09 Clear,
colorless solution 40.degree. C. 0 time 1.092 100 0.06 7.08 Clear,
colorless solution 1 day 1.069 97.9 0.471 7.15 Clear, colorless
solution 2 days 1.066 97.6 1.771 7.36 Clear, colorless solution 6
days 1.043 95.5 4.297 7.12 Clear, colorless solution 9 days 1.027
94.0 5.648 7.11 Clear, colorless solution 14 days 1.006 92.1 8.3
7.09 Clear, very slightly yellow sol. 21 days 0.973 89.1 11.613
7.08 Clear, very slightly yellow sol. 60.degree. C. 0 time 1.092
100 0.06 7.08 Clear, colorless solution 1 day 1.028 94.1 6.109 7.12
Clear, colorless solution 2 days 0.991 90.8 10.291 7.17 Clear,
colorless solution 6 days 0.877 80.3 22.512 7.08 Clear, colorless
solution 9 days 0.806 73.8 28.351 7.06 Clear, yellow solution 14
days 0.726 66.5 35.59 7.04 Clear, yellow solution 21 days 0.745
68.2 42.23 6.94 Clear, yellow solution *Phosphate Buffer:
KH.sub.2PO.sub.4 and Na.sub.2HPO.sub.4
TABLE-US-00016 TABLE 10 Stability of MNTX in pH 7, 0.02M Glycine*
Solution Total Impurities Elapsed Strength % (% Total pH of
Appearance and Condition Time (mg/ml) Initial Area) Formulation
Description Room 0 time 0.993 100 0.11 7.06 Slightly Temperature
yellowish, clear solution 1 day 0.993 100 0.076 6.91 Clear,
colorless solution 2 days 0.994 100.1 0.14 7.11 Clear, colorless
solution 6 days 0.987 99.4 0.302 7.37 Slight precipitate on the
bottom 9 days 1.005 101.2 0.425 7.99 Slightly hazy on the bottom 14
days 0.998 100.5 0.32 7.21 Slightly hazy on the bottom 21 days
0.989 99.6 0.62 7.16 Clear, colorless solution 40.degree. C. 0 time
1.051 100 0.097 7.15 Clear, colorless solution 1 day 1.04 99.0
0.403 7.53 Clear, colorless solution 2 days 1.039 98.9 0.379 7.69
Clear, colorless solution 6 days 1.043 99.2 0.468 7.50 Clear,
colorless solution 9 days 1.039 98.9 0.669 7.16 Clear, colorless
solution 14 days 1.036 98.6 0.74 7.55 Clear, colorless solution 21
days 1.01 96.1 0.975 7.26 Clear, colorless solution 60.degree. C. 0
time 1.051 100 0.097 7.15 Clear, colorless solution 1 day 1.032
98.2 1.046 7.20 Clear, colorless solution 2 days 1.032 98.2 1.757
7.27 Clear, colorless solution 6 days 1.002 95.3 4.043 6.98 Clear,
colorless solution 9 days 0.977 93.0 5.294 6.95 Clear, light yellow
solution 14 days 0.959 91.2 6.51 6.94 Clear, light yellow solution
21 days 0.937 89.2 9.122 6.37 Clear, light yellow solution *Glycine
Buffer: Glycine and NaOH
[0169] Preparation of a Methylnaltrexone Formulation Comprising
Sodium EDTA and Citrate Buffer.
[0170] Methylnaltrexone formulations consisting of
methylnaltrexone, sodium EDTA, and sodium chloride in citrate
buffer have been described (see US Patent Application Publication
US2004/0266806A1, published Dec. 30, 2004). We have prepared
solutions comprising the same components for stability comparison
studies with our present formulations.
[0171] Formulations containing 20 mg/mL methylnaltrexone bromide in
either A-0.7 mg/mL NaEDTA/pH 3.5 adjusted with citrate buffer; and
B-0.4 mg/mL CaEDTA/0.65% NaCl/pH 3.5 adjusted with glycine buffer
were prepared. Each of the formulations were assessed over time for
presence of degradant formation, the results are shown in Table
11.
[0172] Formulations containing 5 mg/mL methylnaltrexone bromide (12
mg/vial or 24 mg/vial) were prepared as described in Example 12,
below. Each of the formulations were assessed over time for
presence of degradant formation, the results are shown in Table
12.
[0173] Under aggressive stability conditions, solutions containing
sodium EDTA, even high levels of sodium EDTA, the 0.67 and the 0.79
degradant begin to increase. It is believed the formulations and
methods provided herein for production of methylnaltrexone
solutions will provide for compositions which retain stability and
will maintain acceptable degradant levels over extended time
periods.
TABLE 11 Stability Comparisons of 20 mg/mL Methylnaltrexone
Formulation
TABLE-US-00017 TABLE 11A Stability data for liquid formulation
containing 20 mg/ml MNTX, 0.7 mg/ml NaEDTA 0.4% Sodium Chloride and
pH 3.5 adjusted with Citric buffer (HPLC Method B) Initial RRT RRT
RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT (mg) 0.38 0.49 0.67
0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96 2.01 2.26 Total
Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5 0.15 0.5 0.2 0.2
0.2 0.5 NA Initial 20.1 BRL BRL BRL BRL BRL BRL BRL 0.11 BRL BRL
BRL BRL BRL 0.11 Room Temperature Time and Days 7 20.2 BRL BRL BRL
BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 14 20.0 BRL BRL BRL
BRL BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 30 20.1 BRL BRL BRL
BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 40.degree. C./75%
Relative Humidity 7 20.1 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL
BRL BRL BRL 0.12 14 20.2 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL
BRL BRL BRL 0.12 30 20.0 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL
BRL BRL BRL 0.12 70.degree. C. 7 20.0 BRL BRL 0.1 0.06 BRL BRL BRL
0.13 BRL BRL BRL BRL 0.09 0.38 14 19.9 BRL BRL 0.16 0.15 BRL BRL
BRL 0.12 0.06 BRL BRL BRL 0.15 0.64 30 20.0 BRL BRL 0.10 0.38 0.05
BRL 0.10 0.14 BRL BRL 0.14 BRL 0.30 1.21
TABLE-US-00018 TABLE 11B Stability data for liquid formulation 20
mg/ml MNTX, 0.4 mg/ml CaEDTA and 0.65% Sodium Chloride with pH 3.5
adjusted with Glycine Hydrochloride (HPLC Method B) Initial RRT RRT
RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT (mg) 0.38 0.49 0.67
0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96 2.01 2.26 Total
Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5 0.15 0.5 0.2 0.2
0.2 0.5 NA pH 3.5 at Room Temperature Time and Days Initial 20.2
BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 7 20.1
BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.11 14 20.1
BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 30 19.8
BRL BRL BRL BRL BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 pH 3.5 at
40.degree. C./75% Relative Humidity Initial 19.9 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 7 20.1 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 14 20.0 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 21 20.3 BRL BRL BRL BRL
BRL BRL BRL 0.11 BRL BRL BRL BRL BRL 0.11 30 20.1 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 pH 3.5 at 70.degree. C.
Initial 19.9 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL
0.12 5 20.2 BRL BRL 0.06 BRL BRL BRL BRL 0.13 BRL BRL BRL BRL 0.08
0.27 7 20.0 BRL BRL 0.08 0.07 BRL BRL BRL 0.12 BRL BRL BRL BRL 0.11
0.38 12 19.9 BRL BRL 0.06 0.15 BRL BRL BRL 0.11 0.06 BRL BRL BRL
0.18 0.56
TABLE-US-00019 TABLE 11C Stability Data for Methylnaltrexone
Bromide, 20 mg/mL Injection, CaEDTA Formulation Description Edetate
Calcium Reconstituted Disodium Storage Time Solution Strength pH
Content Specification Clear solution, colorless to 90.0-110.0%
3.0-5.0 0.36-0.44 pale yellow, essentially LC mg/mL free of visible
particulates Method HPLC Method A L28228-147 USP <791>
L34449-051 Initial Conforms 98.2, 97.2, 3.7, 3.6 97.6 25.degree.
C./60% RH 1 Month No change 99.0 3.6, 3.5 0.41 3 Months No change
99.1 3.6, 3.6 0.41 6 Months No change 100.3 3.4, 3.4 0.41 9 Months
No change 99.2 3.4, 3.4 0.41 30.degree. C./75% RH 1 Month No change
99.0 3.5, 3.5 NT 3 Months No change 100.1 3.5, 3.5 0.39 6 Months No
change 100.9 3.4, 3.4 0.40 9 Months No change 97.8 3.4, 3.4 0.40
40.degree. C./75% RH 1 Month No change 99.1 3.6, 3.6 NT Inverted 3
Months No change 100.1 3.6, 3.5 0.40 6 Months No change 99.9 3.5,
3.5 0.39 40.degree. C./75% RH 1 Month No change 99.6 3.5, 3.5 NT
Upright 3 Months No change 100.3 3.5, 3.5 0.40 6 Months No change
100.7 3.5, 3.5 0.39 Light Study Exposed No change 101.3 3.6 0.40
Packaged No change 98.7 3.5 0.40 Degradation/Impurities (HPLC
Method A) 7- RRT RRT Dihydroxy S- Ring Naltrexone 2,2'-bis 0.49
0.89 MNTX MNTX Contraction Base MNTX Specification NMT NMT NMT NMT
NMT NMT 0.2% 0.2% 0.5% 0.5% 0.5% 0.5% Storage Time w/w w/w w/w w/w
w/w FIO w/w Initial BRL BRL BRL BRL BRL BRL BRL 25.degree. C./ 1
Month BRL BRL BRL BRL BRL BRL BRL 60% RH 3 months BRL BRL BRL BRL
BRL BRL BRL 6 months BRL BRL BRL BRL BRL BRL BRL 9 months BRL BRL
BRL BRL BRL BRL BRL 30.degree. C./ 1 Month BRL BRL BRL BRL BRL BRL
BRL 75% RH 3 months BRL BRL BRL BRL BRL BRL BRL 6 months BRL BRL
BRL BRL BRL BRL BRL 9 months BRL BRL BRL BRL BRL BRL BRL 40.degree.
C./ 1 Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months BRL BRL BRL
BRL BRL BRL BRL Inverted 6 months BRL BRL 0.07 BRL BRL BRL BRL
40.degree. C./ 1 Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months
BRL BRL 0.06 BRL BRL BRL BRL Upright 6 months BRL BRL 0.07 BRL BRL
BRL BRL Method HPLC Method A Light Exposed BRL 2.13.sup.c BRL BRL
BRL BRL 0.56 Study Packaged BRL BRL BRL BRL BRL BRL BRL
Degradation/Impurities (HPLC Method A) Any Unspecified Total
O-Methyl Aldol- Hofmann (Unidentified) Degradants/ MNTX Dimer
Degradation Degradant Impurities Specification NMT NMT NMT NMT 0.5%
0.5% 0.2% 2.0% Storage Time FIO w/w w/w w/w w/w Initial 0.06 BRL
BRL BRL BRL 25.degree. C./ 1 Month 0.07 BRL BRL BRL BRL 60% RH 3
months 0.07 BRL BRL BRL BRL 6 months 0.06 BRL BRL BRL BRL 9 months
0.08 BRL BRL BRL BRL 30.degree. C./ 1 Month 0.06 BRL BRL BRL BRL
75% RH 3 months 0.07 BRL BRL BRL BRL 6 months 0.06 BRL BRL BRL BRL
9 months 0.06 BRL BRL BRL BRL 40.degree. C./ 1 Month 0.07 BRL BRL
BRL BRL 75% RH 3 months 0.07 BRL BRL BRL BRL Inverted 6 months 0.06
BRL BRL BRL 0.1 40.degree. C./ 1 Month 0.07 BRL BRL BRL BRL 75% RH
3 months 0.07 BRL BRL BRL 0.1 Upright 6 months 0.06 BRL BRL BRL 0.1
Method HPLC Method A Light Exposed 0.06 BRL BRL 0.21.sup.c
(RRT1.69), .sup. 4.4 Study 0.36 (RRT 0.54), 0.22 (RRT 0.62), 0.06
(RRT 1.21), 0.09 (RRT 1.41), 0.05 (RRT 1.56), 0.46 (RRT 1.58), 0.07
(RRT2.01), 0.14 (RRT 2.03) Packaged 0.06 BRL BRL BRL BRL BRL =
Below reporting limit (0.05%); NT = Not tested; NMT = Not more
than; RRT = Relative retention time; FIO = For information only. a.
Only one determination for pH was performed (n = 1). .sup.bProcess
impurities found in the drug substance. Tested for information
.sup.cThe unspecified degradant at RRT 1.69 co-elutes with the
process impurity O-Methylnaltrexone Methobromide. The total
degradant reported at RRT 1.69 is 0.27% of which 0.06% is the
process impurity O-Methylnaltrexone Methobromide and 0.21% is the
unspecified degradant/impurity.
TABLE 12 Stability Comparisons of 5 mg/mL (12 mg/Vial or 24
mg/Vial) Methylnaltrexone Formulation
TABLE-US-00020 TABLE 12A Stability Data for Methylnaltrexone
Bromide, 5 mg/mL(12 mg/vial) IV Solution for Injection, CaEDTA
Formulation Edetate Calcium Disodium Storage Time Strength pH
Content Specification 90.0-110.0% LC 3.0-5.0 0.09 0.11 g/mL Method
HPLC Method A USP <791> L34449-051 Initial 98.9, 98.3, 98.8
3.6, 3.6 0.094 25.degree. C./60% RH 1 month 100.1 3.5, 3.5 0.095
Inverted 3 months 100.4 3.7, 3.7 0.095 6 months 99.7 3.6, 3.6 0.097
30.degree. C./75% RH 1 month 99.9 3.5, 3.5 0.094 Inverted 3 months
100.8 3.9, 3.7 0.096 6 months 99.6 3.6, 3.6 0.099 40.degree. C./75%
RH 1 month 100.2 3.5, 3.6 0.094 Inverted 3 months 100.9 3.7, 3.8
0.095 6 months 100.4 3.7, 3.6 0.097 Light Exposed 103.1 3.7, 3.7
0.091 Study Packaged 99.4 3.6, 3.6 0.095 Degradation/Impurities 7-
RRT RRT Dihydroxy S- Ring Naltrexone 2,2'-bis 0.49 0.89 MNTX MNTX
Contraction Base MNTX Specification NMT NMT NMT NMT NMT NMT 0.2%
0.2% 0.4 0.4 0.4 0.4 w/w w/w w/w w/w w/w FIO w/w Storage Time HPLC
Method A Initial BRL BRL BRL BRL BRL BRL BRL 25.degree. C./ 1 Month
BRL BRL BRL BRL BRL BRL BRL 60% RH 3 months BRL BRL BRL BRL BRL BRL
BRL Inverted 6 months BRL BRL BRL BRL BRL BRL BRL 30.degree. C./ 1
Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months BRL BRL BRL BRL
BRL BRL BRL Inverted 6 months BRL BRL BRL BRL BRL BRL BRL
40.degree. C./ 1 Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months
BRL BRL 0.06 BRL BRL BRL BRL Inverted 6 months BRL BRL 0.07 BRL BRL
BRL BRL Light Exposed BRL 2.97 0.22 BRL BRL BRL 0.28 Study Packaged
BRL BRL BRL BRL BRL BRL BRL Degradation/Impurities Any Unspecified
Total O-Methyl Aldol- Hofmann (Unidentified) Degradants/ MNTX Dimer
Degradation Degradant Impurities Specification NMT NMT NMT NMT 0.4
0.4 0.2% 2.0% FIO w/w w/w w/w w/w Storage Time HPLC Method A
Initial 0.06 BRL BRL BRL BRL 25.degree. C./ 1 Month 0.07 BRL BRL
BRL BRL 60% RH 3 months 0.07 BRL BRL BRL BRL Inverted 6 months 0.06
BRL BRL BRL BRL 30.degree. C./ 1 Month 0.06 BRL BRL BRL BRL 75% RH
3 months 0.07 BRL BRL BRL BRL Inverted 6 months 0.06 BRL BRL BRL
BRL 40.degree. C./ 1 Month 0.07 BRL BRL BRL BRL 75% RH 3 months
0.07 BRL BRL BRL 0.06 Inverted 6 months 0.06 BRL BRL BRL 0.07 Light
Exposed 0.06.sup.c BRL BRL 0.28 (RRT = 0.60), 5.5 Study 0.08 (RRT =
0.63) 0.05 (RRT = 0.71), 0.13 (RRT = 1.21) 0.08 (RRT = 1.42), 0.99
(RRT = 1.65) 0.31 (RRT = 1.71), 0.09 (RRT = 2.09) Packaged 0.07 BRL
BRL BRL BRL BRL = Below reporting limit (0.05%) NT = Not tested NMT
= Not more than RRT = Relative retention time FIO = For information
only.
TABLE-US-00021 TABLE 12B Stability Data for Methylnaltrexone
Bromide, 5 mg/mL(24 mg vial) IV Solution for Injection, CaEDTA
Terminally Sterilized Edetate Calcium Disodium Storage Time
Strength pH Content Specification 90.0-110.0% LC 3.0-5.0 0.09 0.11
g/mL Method HPLC Method A USP <791> L34449-051 Initial 99.4,
99.7, 99.7 3.6, 3.7 0.093 25.degree. C./60% RH 1 month 100.2 3.6,
3.6 0.096 Inverted 3 months 100.4 3.6 3.6 0.094 6 months 99.6 3.7,
3.7 0.096 30.degree. C./75% RH 1 month 98.7 3.6, 3.6 0.098 Inverted
3 months 100.4 3.6, 3.7 0.093 6 months 100.6 3.7, 3.7 0.096
40.degree. C./75% RH 1 month 99.5 3.6, 3.6 0.096 Inverted 3 months
100.6 3.7, 3.7 0.094 6 months 100.2 3.7, 3.7 0.094 Light Study
Exposed 100.3 3.7, 3.6 0.095 Packaged 99.6 3.7, 3.7 0.090
Degradation/Impurities 7- RRT RRT Dihydroxy S- Ring Naltrexone
2,2'-bis 0.49 0.89 MNTX MNTX Contraction Base MNTX Specification
NMT NMT NMT NMT NMT NMT 0.2% 0.2% 0.4 0.4 0.4 0.4 w/w w/w w/w w/w
w/w FIO w/w Storage Time HPLC Method A Initial BRL BRL BRL BRL BRL
BRL BRL 25.degree. C./ 1 Mon BRL BRL BRL BRL BRL BRL BRL 60% RH 3
mon BRL BRL BRL BRL BRL BRL BRL Inverted 6 mon BRL BRL BRL BRL BRL
BRL BRL 30.degree. C./ 1 Mon BRL BRL BRL BRL BRL BRL BRL 75% RH 3
mon BRL BRL BRL BRL BRL BRL BRL Inverted 6 mon BRL BRL BRL BRL BRL
BRL BRL 40.degree. C./ 1 Mon BRL BRL BRL BRL BRL BRL BRL 75% RH 3
mon BRL BRL 0.06 BRL BRL BRL BRL Inverted 6 mon BRL BRL BRL BRL BRL
BRL BRL Light Exposed BRL 3.00.sup.a 0.23.sup.a BRL BRL BRL
0.29.sup.a Study Packaged BRL BRL BRL BRL BRL BRL BRL
Degradation/Impurities Any Unspecified Total O-Methyl Aldol-
Hofmann (Unidentified) Degradants/ MNTX Dimer Degradation Degradant
Impurities Specification NMT NMT NMT NMT 0.4 0.4 0.2% 2.0% FIO w/w
w/w w/w w/w Storage Time HPLC Method A Initial 0.07 BRL BRL BRL BRL
25.degree. C./ 1 Mon 0.06 BRL BRL BRL BRL 60% RH 3 mon 0.07 BRL BRL
BRL BRL Inverted 6 mon 0.07 BRL BRL BRL BRL 30.degree. C./ 1 Mon
0.07 BRL BRL BRL BRL 75% RH 3 mon 0.07 BRL BRL BRL BRL Inverted 6
mon 0.06 BRL BRL BRL BRL 40.degree. C./ 1 Mon 0.06 BRL BRL BRL BRL
75% RH 3 mon 0.07 BRL BRL BRL 0.06 Inverted 6 mon 0.08 BRL BRL BRL
BRL Light Exposed 0.06.sup.c BRL BRL 0.30 (RRT = 0.60), 5.6 Study
0.08 (RRT = 0.63) 0.05 (RRT = 0.71), 0.14 (RRT = 1.21) 0.09 (RRT =
1.42), 0.97 (RRT = 1.65) 0.35 (RRT = 1.71), 0.09 (RRT = 2.09)
Packaged 0.07 BRL BRL BRL BRL BRL = Below reporting limit (0.05%);
NT = Not tested NMT = Not more than; RRT = Relative retention time;
FIO = For information only.
TABLE-US-00022 TABLE 12C Stability Data for Methylnaltrexone
Bromide, 5 mg/mL(24 mgvial) IV Solution for Injection, CaEDTA
Formulation Edetate Calcium Disodium Storage Time Strength pH
Content Specification 90.0-110.0% LC 3.0-5.0 0.09 0.11 g/mL Method
HPLC Method A USP <791> L34449-051 Initial 99.8, 99.3, 99.2
3.6, 3.6 0.09 25.degree. C./60% RH 1 month 100.5 3.5, 3.5 0.094
Inverted 3 months 100.8 3.7, 3.7 0.095 6 months 99.8 3.5, 3.5 0.098
30.degree. C./75% RH 1 month 100.5 3.5, 3.5 0.094 Inverted 3 months
100.7 3.7, 3.7 0.095 6 months 99.9 3.6, 3.6 0.094 40.degree. C./75%
RH 1 month 100.3 3.5, 3.5 0.095 Inverted 3 months 100.2 3.8, 3.8
0.095 6 months 100.3 3.7, 3.6 0.098 Light Study Exposed 102.6 3.5,
3.6 0.092 Packaged 99.8 3.6, 3.6 0.095 Degradation/Impurities 7-
RRT RRT Dihydroxy S- Ring Naltrexone 2,2'-bis 0.49 0.89 MNTX MNTX
Contraction Base MNTX Specification NMT NMT NMT NMT NMT NMT 0.2%
0.2% 0.4 0.4 0.4 0.4 w/w w/w w/w w/w w/w FIO w/w Storage Time HPLC
Method A Initial BRL BRL BRL BRL BRL BRL BRL 25.degree. C./ 1 Month
BRL BRL BRL BRL BRL BRL BRL 60% RH 3 months BRL BRL BRL BRL BRL BRL
BRL Inverted 6 months BRL BRL BRL BRL BRL BRL BRL 30.degree. C./ 1
Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months BRL BRL BRL BRL
BRL BRL BRL Inverted 6 months BRL BRL BRL BRL BRL BRL BRL
40.degree. C./ 1 Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months
BRL BRL BRL BRL BRL BRL BRL Inverted 6 months BRL BRL 0.06 BRL BRL
BRL BRL Light Exposed BRL 2.23.sup.a 0.19.sup.a BRL BRL BRL 0.21
Study Packaged BRL BRL BRL BRL BRL BRL BRL Degradation/Impurities
Any Unspecified Total O-Methyl Aldol- Hofmann (Unidentified)
Degradants/ MNTX Dimer Degradation Degradant Impurities
Specification NMT NMT NMT NMT 0.4 0.4 0.2% 2.0% FIO w/w w/w w/w w/w
Storage Time HPLC Method A Initial 0.07 BRL BRL BRL BRL 25.degree.
C./ 1 Month 0.06 BRL BRL BRL BRL 60% RH 3 months 0.06 BRL BRL BRL
BRL Inverted 6 months 0.07 BRL BRL BRL BRL 30.degree. C./ 1 Month
0.06 BRL BRL BRL BRL 75% RH 3 months 0.07 BRL BRL BRL BRL Inverted
6 months 0.07 BRL BRL BRL BRL 40.degree. C./ 1 Month 0.06 BRL BRL
BRL BRL 75% RH 3 months 0.07 BRL BRL BRL BRL Inverted 6 months 0.06
BRL BRL BRL 0.06 Light Exposed 0.07 BRL BRL 0.18 (RRT = 0.60), 4.3
Study 0.10 (RRT = 1.21) 0.06 (RRT = 1.42), 1.00 (RRT = 1.65) 0.25
(RRT = 1.71), 0.07 (RRT = 2.09) Packaged 0.06 BRL BRL BRL BRL BRL =
Below reporting limit (0.05%) NT = Not tested NMT = Not more than
RRT = Relative retention time FIO = For information only.
TABLE-US-00023 TABLE 12D Stability Data for Methylnaltrexone
Bromide, 5 mg/mL(24 mgvial) IV Solution for Injection, CaEDTA
Formulation(Terminally Sterilized) (HPLC Method A) Edetate Calcium
Disodium Storage Time Strength pH Content Specification 90.0-110.0%
LC 3.0-5.0 0.09 0.11 g/mL Method L28228-147 USP <791>
L34449-051 Initial 99.7, 99.8, 98.2 3.5, 3.5 0.095 25.degree.
C./60% RH 1 month 99.7 3.5, 3.5 0.093 Inverted 3 months 101.5 3.6,
3.6 0.091 6 months 100.8 3.6, 3.5 0.095 30.degree. C./75% RH 1
month 99.9 3.5, 3.5 0.099 Inverted 3 months 99.8 3.6, 3.6 0.094 6
months 101.1 3.6, 3.6 0.094 40.degree. C./75% RH 1 month 99.5 3.6,
3.6 0.095 Inverted 3 months 100.3 3.6, 3.6 0.095 6 months 100.2
3.7, 3.8 0.095 Light Study Exposed 103.1 3.7, 3.6 0.093 Packaged
100.1 3.6, 3.6 0.092 Degradation/Impurities 7- RRT RRT Dihydroxy S-
Ring Naltrexone 2,2'-bis 0.49 0.89 MNTX MNTX Contraction Base MNTX
Specification NMT NMT NMT NMT NMT NMT 0.2% 0.2% 0.4 0.4 0.4 0.4
Storage Time w/w w/w w/w w/w w/w FIO w/w Method HPLC Method A
Initial BRL BRL BRL BRL BRL BRL BRL 25.degree. C./ 1 Month BRL BRL
BRL BRL BRL BRL BRL 60% RH 3 months BRL BRL BRL BRL BRL BRL BRL
Inverted 6 months BRL BRL BRL BRL BRL BRL BRL 30.degree. C./ 1
Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months BRL BRL BRL BRL
BRL BRL BRL Inverted 6 months BRL BRL 0.06 BRL BRL BRL BRL
40.degree. C./ 1 Month BRL BRL BRL BRL BRL BRL BRL 75% RH 3 months
BRL BRL BRL BRL BRL BRL BRL Inverted 6 months BRL BRL 0.09 BRL BRL
BRL BRL Light Exposed BRL 2.33.sup.a .sup. 0.20.sup.a BRL BRL BRL
0.24.sup.a Study Packaged BRL BRL BRL BRL BRL BRL BRL
Degradation/Impurities Any Unspecified Total O-Methyl Aldol-
Hofmann (Unidentified) Degradants/ MNTX Dimer Degradation Degradant
Impurities Specification NMT NMT NMT NMT 0.4 0.4 0.2% 2.0% Storage
Time FIO w/w w/w w/w w/w Method HPLC Method A Initial 0.06 BRL BRL
BRL BRL 25.degree. C./ 1 Month 0.06 BRL BRL BRL BRL 60% RH 3 months
0.07 BRL BRL BRL BRL Inverted 6 months 0.06 BRL BRL BRL BRL
30.degree. C./ 1 Month 0.06 BRL BRL BRL BRL 75% RH 3 months 0.07
BRL BRL BRL BRL Inverted 6 months 0.07 BRL BRL BRL 0.06 40.degree.
C./ 1 Month 0.06 BRL BRL BRL BRL 75% RH 3 months 0.07 BRL BRL BRL
BRL Inverted 6 months 0.07 BRL BRL BRL 0.09 Light Exposed 0.06 BRL
BRL 0.20 (RRT = 0.60), 4.6 Study 0.05 (RRT = 0.63) 0.11 (RRT =
1.21), 0.07 (RRT = 1.42) 1.08 (RRT = 1.65), 0.29 (RRT = 1.71) 0.07
(RRT = 2.09) Packaged 0.07 BRL BRL BRL BRL BRL = Below reporting
limit (0.05%) NT = Not tested NMT = Not more than RRT = Relative
retention time FIO = For information only.
Example 5
[0174] The stability of a formulation containing 5.0 mg/mL IV (12
mg/vial or 24 mg/vial) was tested to determine the effect of light
exposure. The formulations were assessed over time for presence of
degradant formation (HPLC Method A). The results of the light
stability test is shown in Tables 13A and 13B.
TABLE-US-00024 TABLE 13A Effect Of Room Light Exposure on The
Stability of 5.0 mg/mL IV (12 mg/Vial): vials filled at ambient
condition RRT 0.67 7- dihydroxy RRT 0.79 RRT RRT 1.45 RRT 1.66 RRT
1.72 Strength RRT MNTX mz Contracted RRT 0.91 (2,2 (O- Aldol
Condition (mg/ml) 0.63 388 Ring 0.89 SMNTX BisMNTX) Methyl) Dimer
Total 5 mg/mL (12 mg/vial) L34325-122 AS (Aseptically Filled Clear
Vials) Initial 4.99 BDL BDL BDL BDL BDL 0.01 0.06 0.04 0.05 5 Days
4.95 BDL BDL BDL BDL BDL BDL 0.05 0.03 0.03 10 Days 4.98 BDL 0.04
BDL BDL BDL BDL 0.05 0.04 0.08 16 Days 4.97 BDL 0.03 BDL BDL BDL
0.02 0.05 0.03 0.08 5 mg/mL (12 mg/vial) L34325-122 TS (Terminally
Sterilized for 15 minutes Clear vials) Initial 5.00 BDL 0.02 BDL
BDL BDL 0.02 0.06 0.02 0.06 5 Days 4.98 BDL 0.05 BDL BDL BDL 0.046
0.05 BDL 0.10 10 Days 4.95 BDL 0.07 BDL BDL BDL 0.09 0.05 BDL 0.16
16 Days 4.99 0.01 0.10 BDL BDL 0.01 0.10 0.06 0.02 0.24 5 mg/mL (12
mg/vial) L34325-122 AS-AMB (Aseptically Filled Amber Vials) Initial
5.21 BDL 0.03 BDL BDL BDL BDL 0.06 0.04 0.07 5 Days 4.95 BDL BDL
BDL BDL BDL BDL 0.05 0.03 0.03 10 Days 4.96 BDL BDL BDL BDL BDL BDL
0.05 0.03 0.03 16 Days 5.01 BDL BDL BDL BDL BDL BDL 0.06 0.03 0.03
5 mg/mL (12 mg/vial) L34325-122 TS_AMB (Terminally Sterilized for
15 minutes Amber vials) Initial 5.02 BDL 0.03 0.02 BDL BDL 0.01
0.06 0.02 0.08 5 Days 4.97 BDL 0.03 BDL BDL BDL BDL 0.06 BDL 0.03
10 Days 5.01 BDL 0.06 BDL BDL BDL BDL 0.05 0.02 0.08 16 Days 4.99
BDL 0.04 0.01 BDL BDL 0.01 0.06 0.02 0.08 Note: RRT 1.66 (O-Methyl)
is not added into the Total BDL: Below detection limit of 0.01%
BRL: Below Reporting limit of 0.05%
TABLE-US-00025 TABLE 13B Effect of Room Light Exposure on The
Stability of 5.0 mg/mL IV (24 mg/Vial): vials filled at Ambient
condition RRT 0.67 7- dihydroxy RRT 0.79 RRT RRT 1.45 RRT 1.66 RRT
1.72 Strength RRT MNTX mz Contracted RRT 0.91 (2,2 (O- Aldol
Condition (mg/ml) 0.63 388 Ring 0.89 SMNTX BisMNTX) Methyl) Dimer
Total 5 mg/mL (24 mg/vial) L34325-122 AS (Aseptically Filled Clear
Vials) Initial 5.04 BDL 0.01 BDL ND BDL ND 0.05 0.03 0.04 5 Days
5.07 BDL 0.02 BDL ND BDL ND 0.05 0.04 0.06 10 Days 5.00 BDL 0.02
BDL 0.01 BDL 0.02 0.05 0.03 0.08 16 Days 5.03 BDL 0.03 BDL ND BDL
0.03 0.06 0.04 0.1 5 mg/mL (24 mg/vial) L34325-122 TS (Terminally
Sterilized for 15 minutes Clear vials) Initial 5.01 BDL 0.03 BDL
BDL BDL ND 0.06 0.02 0.05 5 Days 5.01 BDL 0.02 BDL BDL BDL 0.03
0.06 0.02 0.07 10 Days 5.01 BDL 0.06 BDL BDL BDL 0.049 0.06 0.02
0.13 16 Days 5.01 BDL 0.07 BDL BDL 0.01 0.08 0.06 0.02 0.18 5 mg/mL
(24 mg/vial) L34325-122 AS-AMB (Aseptically Filled Amber Vials)
Initial 4.99 BDL 0.02 BDL BDL BDL BDL 0.05 0.04 0.06 5 Days 5.01
BDL BDL BDL BDL BDL BDL 0.05 0.03 0.03 10 Days 5.01 BDL 0.02 BDL
BDL BDL BDL 0.06 0.03 0.05 16 Days 5.02 BDL BDL BDL BDL BDL BDL
0.06 0.03 0.03 5 mg/mL (24 mg/vial) L34325-122 TS_AMB (Terminally
Sterilized for 15 minutes Amber vials) Initial 4.98 BDL 0.04 BDL
BDL BDL BDL 0.06 0.02 0.06 5 Days 5.02 BDL 0.04 BDL BDL BDL BDL
0.06 0.02 0.06 10 Days 5.01 BDL 0.04 BDL BDL BDL BDL 0.05 0.02 0.06
16 Days 5.04 BDL 0.03 BDL BDL BDL BDL 0.05 0.02 0.05 Note: RRT 1.66
(O-Methyl) is not added into the Total BDL: Below detection limit
of 0.01% BRL: Below Reporting limit of 0.05%
Example 6
Evaluation of Stopper Compatibility
[0175] We assessed various available stoppers used in vial closures
for their compatibility with methylnaltrexone solutions, and
determined whether any had effects on formation of degradants in
solution.
[0176] Identical preparations prepared as described in Example 4
were stored in parallel in vials having either a 13 mm WPS S2-F451
4432/50 Gray B2-40 Westar RS stopper (West Pharmaceutical Services)
or a 13 mm S2-F451 RS D 777-1 RB2 40 stopper (Daikyo Seiko, Ltd)
under various conditions. Each of the stoppers has a FluoroTec.RTM.
fluorocarbon film; the Westar 4432/50 stopper is chlorobutyl
rubber, while the RB2-40 RS D 777-1 stopper is bromobutyl rubber.
The presence of accumulation of degradant was assessed for each of
the configurations (HPLC Method A). Table 14 depicts the results of
these studies. Under accelerated storage conditions, the stopper
containing bromobutyl rubber appears to accumulate aldol dimer
formation at a higher rate than the comparable chlorobutyl
stopper.
TABLE-US-00026 TABLE 14 Stopper compatibility evaluation of
Methylnaltrexone with 13 mm WPS S2-F451 4432/50 Gray B2-40 Westar
RS stopper (West Pharmaceutical Services) and 13 mm S2-F451 RS-D
777-1 B2 40 from Daikyo Seiko Ltd. at Room Temperature and
40.degree. C. Initial RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT RRT
RRT RRT (mg) 0.38 0.49 0.67 0.79 0.89 1.17 1.55 1.66 1.77 1.89 1.96
2.01 2.26 Total Specifications NA 0.2 0.5 0.5 0.5 0.15 0.15 0.5
0.15 0.5 0.2 0.2 0.2 0.5 NA Initial 20.2 BRL BRL BRL BRL BRL BRL
BRL 0.12 BRL BRL BRL BRL BRL 0.12 Control at Room Temperature 1
hours 20.1 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL
0.12 4 hours 20.0 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL
BRL 0.12 13 mm WPS S2-F451 4432/50 Gray B2-40 Westar RS stopper
(West Pharmaceutical Services) at Room Temperature 1 hours 20.3 BRL
BRL BRL BRL BRL BRL BRL 0.06 BRL BRL BRL BRL BRL 0.06 4 hours 20.1
BRL BRL BRL BRL BRL BRL BRL 0.06 BRL BRL BRL BRL BRL 0.06 13 mm
S2-F451 RS-D 777-1 B2 40 from Daikyo Seiko Ltd. at Room Temperature
1 hours 20.3 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL BRL
0.12 4 hours 20.2 BRL BRL BRL BRL BRL BRL BRL 0.12 BRL BRL BRL BRL
BRL 0.12 Control at 40.degree. C. 1 hours 20.3 BRL BRL BRL BRL BRL
BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 4 hours 20.3 BRL BRL BRL BRL
BRL BRL BRL 0.12 BRL BRL BRL BRL BRL 0.12 13 mm WPS S2-F451 4432/50
Gray B2-40 Westar RS stopper (West Pharmaceutical Services) at
40.degree. C. 1 hours 20.1 BRL BRL BRL BRL BRL BRL BRL 0.06 BRL BRL
BRL BRL BRL 0.06 4 hours 20.2 BRL BRL BRL BRL BRL BRL BRL 0.06 0.05
BRL BRL BRL BRL 0.06 13 mm S2-F451 RS-D 777-1 B2 40 from Daikyo
Seiko Ltd. at 40.degree. C. 1 hours 20.1 BRL BRL BRL BRL BRL BRL
BRL 0.12 0.05 BRL BRL BRL BRL 0.17 4 hours 19.9 BRL BRL BRL BRL BRL
BRL BRL 0.12 0.05 BRL BRL BRL BRL 0.17
Example 7
Stability of Frozen Intravenous Bags
[0177] The following formulation of methylnaltrexone 5 mg/ml, 0.8
mg of NaCL, 0.1 mg CaEDTA, 0.1 mg Glycine Hydrochloride, and water
for injection was infused in 100 ml IV bags of 0.9% of Normal
Saline and frozen at -200 C. The study was conducted for two
concentrations of methylnaltrexone: 12 mg/100 ml and 24 mg/100 ml.
B/Braun bags NDC 0264-1800-32 with 0.9% of Normal Saline were
used.
[0178] Two batches of the formulation were prepared and subjected
to stability determination. The first batch was the above
methylnaltrexone IV formulation: 5 mg/ml methylnaltrexone, 0.8 mg
of NaCL, 0.1 mg CaEDTA, 0.1 mg Glycine Hydrochloride infused in the
0.9% Normal Saline IV bag. The second batch was just 5 mg/ml
methylnaltrexone infused in 0.9% Normal Saline IV bag. The bags
were frozen and kept at -20.degree. C. The stability data showed
that over a period of 2 months both batches were stable with no
degradants formed. An additional benefit to the frozen bag storage
is that no protection from light is required.
[0179] Two months stability study (HPLC Method A) showed no
degradation was formed thereby demonstrating that the formulation
is stable under frozen conditions, that the period of use and shelf
life can be longer than 6 months, and that there is no need for the
hospital staff to infuse the IV bags with the drug. The bags come
user ready only need to be thawed. Table 15 summarizes the results
of these studies.
TABLE-US-00027 TABLE 15 5 mg/ml Methylnaltrexone, 0.8 mg of NaCL,
0.1 mg CaEDTA, 0.1 mg Glycine HCl Impurities Sample Strength, RRT
RRT RRT RRT RRT RRT name mg/ml 0.67 0.79 0.89 1.55 1.76 2.24 Total
12 mg/100 ml of 0.9% Normal Saline bag Initial 0.11 ND ND ND ND ND
ND NA 2 weeks 0.11 ND ND ND ND ND ND NA 1 month 0.11 ND ND ND ND ND
ND NA 2 months 0.12 ND ND ND ND ND ND NA 24 mg/100 ml bag of 0.9%
Normal Saline bag Initial 0.22 ND ND ND ND 0.07 ND 0.07 2 weeks
0.22 ND ND ND ND 0.07 ND 0.07 1 month 0.23 ND ND ND ND 0.06 ND 0.06
2 months 0.23 ND ND ND ND 0.06 ND 0.06
Example 8
[0180] The effect of sodium tungstate (HPLC Method A) on the
subcutaneous formulation described herein is summarized in Table
16, below.
TABLE-US-00028 TABLE 16 Effect of 1 mM Sodium Tungstate on
Subcutaneous Formulation 7-Di- Ring hydroxy Contraction O-Methyl
Sample MNTX Degradant MNTX Total Room Temperature Methylnaltrexone
Initial BRL BRL 0.12 0.12 Methylnaltrexone 1 hour BRL BRL 0.12 0.12
Methylnaltrexone 2 hours 0.02 BRL 0.12 0.14 Methylnaltrexone 3
hours 0.02 BRL 0.12 0.14 Methylnaltrexone 4 hours 0.02 BRL 0.12
0.14 Methylnaltrexone 5 hours 0.02 BRL 0.12 0.14 Methylnaltrexone +
1 mM BRL BRL 0.12 0.12 Sodium Tungstate Initial Methylnaltrexone +
1 mM 0.02 BRL 0.12 0.14 Sodium Tungstate 1 hour Methylnaltrexone +
1 mM 0.02 BRL 0.12 0.14 Sodium Tungstate 2 hours Methylnaltrexone +
1 mM 0.03 BRL 0.12 0.15 Sodium Tungstate 3 hours Methylnaltrexone +
1 mM 0.03 BRL 0.12 0.15 Sodium Tungstate 4 hours Methylnaltrexone +
1 mM 0.03 BRL 0.12 0.15 Sodium Tungstate 5 hours 40.degree. C.
Methylnaltrexone Initial BRL BRL 0.12 0.12 Methylnaltrexone 1 hour
BRL BRL 0.12 0.12 Methylnaltrexone 2 hours 0.02 BRL 0.12 0.14
Methylnaltrexone 3 hours 0.02 BRL 0.12 0.14 Methylnaltrexone 4
hours 0.02 BRL 0.12 0.14 Methylnaltrexone 5 hours 0.03 BRL 0.12
0.15 Methylnaltrexone + 1 mM BRL BRL 0.12 0.12 Sodium Tungstate
Initial Methylnaltrexone + 1 mM 0.02 BRL 0.12 0.14 Sodium Tungstate
1 hour Methylnaltrexone + 1 mM 0.02 BRL 0.12 0.14 Sodium Tungstate
2 hours Methylnaltrexone + 1 mM 0.03 BRL 0.12 0.15 Sodium Tungstate
3 hours Methylnaltrexone + 1 mM 0.03 BRL 0.12 0.15 Sodium
Tungstate4 hours Methylnaltrexone + 1 mM 0.03 BRL 0.12 0.15 Sodium
Tungstate 5 hours
Part II: Subcutaneous Formulations
Example 9
[0181] A room temperature methylnaltrexone formulation 20 mg/mL
subcutaneous solution for injection, CaEDTA formulation consists of
20 mg/mL methylnaltrexone bromide, 0.4 mg/mL edetate calcium
disodium (CaEDTA), 0.3 mg/mL glycine hydrochloride and 0.65% sodium
chloride in water for injection. The product, which is stable at
room temperature storage conditions, is filled aseptically in
single-use vials at 0.6 mL volume or 12 mg methylnaltrexone per
vial to be administered subcutaneously.
[0182] The sodium chloride concentration is adjusted to 0.65% to
maintain the tonicity of the formulation.
[0183] Such a room temperature formulation for subcutaneous
administration was prepared as summarized in Tables 17A, 17B, and
17C below:
TABLE-US-00029 TABLE 17A Methylnaltrexone 20 mg/mL Subcutaneous
Solution for Injection, SC Commercial Formulation Strength 20 mg/mL
Type Liquid Solution Container/Closure Vial 3 mL Stopper 13 mm
mg/vial Methylnaltrexone 12 mg CaEDTA 0.32 Glycine HCl 0.24 NaCl
5.20 Overage 33% (0.2 ml) Processing Sterilization Aseptic Nitrogen
Flush Yes Fill Volume 0.8 mL Dispensing Container Syringe Dilution
None
TABLE-US-00030 TABLE 17B Methylnaltrexone 20 mg/mL Subcutaneous
Solution for Injection, Room Temperature MNTX 20 mg/mL CaEDTA.sup.#
0.40 mg/mL Glycine HCL 0.30 mg/mL NaCl 6.5 mg/mL Osmolarity
(mOsm/Kg) 286 pH 3-5 Volume of injection (mL) 0.6
TABLE-US-00031 TABLE 17C Methylnaltrexone 20 mg/mL Subcutaneous
Solution for Injection, Quantitative Composition Methylnaltrexone
20 mg/mL Subcutaneous Solution for Injection, CaEDTA Formulation,
Batch Size: 5000 mL Input/ Dosage Unit Ingredient % WT/WT Input
Unit Naltrexone Methobromide 1.985 16 mg Calcium EDTA, USP 0.040
0.32 mg Sodium Chloride, USP 0.644 5.2 mg Glycine Hydrochloride
0.030 0.24 mg Water for Injection, USP NA QS to 0.80 mL
Hydrochloric Acid, NF.sup.b N/A N/A Sodium Hydroxide, NF.sup.b N/A
N/A
[0184] In certain embodiments, the above formulation for
subcutaneous administration may be dosed according to the following
table. Patients whose weight falls outside the recited ranges may
be dosed at 0.15 mg/kg.
TABLE-US-00032 Patient Weight Injection Pounds Kilograms Volume
Dose 84 to less than 38 to less than 62 0.4 mL 8 mg 136 136 to 251
62 to 114 0.6 mL 12 mg
[0185] In other embodiments, in patients with severe renal
impairment (creatinine clearance less than 30 mL/min) the above
formulation for subcutaneous administration dose may be reduced by
one-half.
Example 10
[0186] As described herein, the present invention provides a
pre-filled syringe containing a methylnaltrexone formulation in
accordance with the present invention. Such a pre-filled syringe is
described below in Table 18.
TABLE-US-00033 TABLE 18 Pre-filled Syringe Concentration/Limits
Active Ingredients Methylnaltrexone Bromide 20 mg/mL Excipients
Calcium Disodium Edetate 0.4 mg/mL Glycine Hydrochloride 0.3 mg/mL
Sodium Chloride 6.5 mg/mL Water for Injection (WFI) Ad 1.0 mL
Primary Packaging Materials Type Material SCF Syringe 1 mL-l with
BD Glass: Rigid Needle Shield (RNS) Type 1 Needle: Stainless steel
AISI 304, CN18/10, 27G1/2, 5-bevel Soft needle shield: FM27/0
modified Rigid shell: Polypropylene SCF Stopper BD Basic raw
material: bromobutyl rubber, 4023/50, grey Coating: contact side
with Daikyo foil, remaining part: B2-40 coated
Example 11
Subcutaneous Formulation--Bioequivalency Study
[0187] A bioequivalency study comparing the subcutaneous
formulation described at Example 9 and a formulation containing
only methylnaltrexone in saline was performed in an open-label,
single-dose, randomized, 2-period, 2-sequence crossover,
inpatient/outpatient study in healthy subjects conducted at a
single investigational site. Doses were administered after an
overnight fast of at least 10 hours. Healthy men and nonlactating
and nonpregnant women aged 18 to 50 years were eligible for
enrollment if all other qualifying criteria were met. At
approximately 0800 on day 1 of periods 1 and 2, each subject
received an SC injection containing 0.15 mg/kg of methylnaltrexone
(the period 1, day -1 weight was used to determine the dose to be
administered). Standard medium fat-meals, served according to the
clinic's schedule, could start 3 hours after test article
administration. Vital signs, ECGs, laboratory evaluations, and
pharmacokinetic (PK) sample collection were completed at designated
times on days 1, 2, and 3 of period 1 and 2 as per the study
flowchart.
[0188] Each subject was to receive a single SC dose of 0.15 mg/kg
of the assigned formulation of methylnaltrexone on day 1 of each
period after an overnight fast of at least 10 hours. The injection
was administered SC into the upper arm and the same arm was to be
used for each injection. The injection site was to be healthy
appearing skin. Every attempt was made to have the same person
administer both formulations to each subject. The dose was
determined from the subject's weight on day -1 of period 1. The
syringes were weighed before and after test article administration
to verify the volume injected. Each single dose was separated by a
washout interval of at least 7 days. Blood samples were obtained
for the determination of the pharmacokinetics of methylnaltrexone.
Blood samples (6 mL) were collected from an indwelling catheter or
by direct venipuncture. If a catheter was used for blood
collection, then approximately 0.5 mL of blood were to be discarded
before collecting the sample at each sampling time. Blood samples
were collected in each period on day 1 within 2 hours before test
article administration and at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 3,
4, 6, 8, 12, 16, 24, 36, and 48 hours after test article
administration. Results of pharmaceokinetic studies are set forth
in Table 19, below.
TABLE-US-00034 TABLE 19 Methylnaltrexone Pharmacokinetic Parameters
for SC Methylnaltrexone Formulations in 27 Healthy Subjects at a
Dose of 0.15 mg/kg C.sub.max AUC.sub.t AUC.sub..infin. T.sub.1/2
t.sub.max Formulation ng/mL ng h/ml ng h/ml (h) (h) Saline 119 .+-.
33 221 .+-. 36 223 .+-. 36 9.2 .+-. 2.5 0.41 (min, max) (62.6, 197)
(163, 333) (168, 335) (7.0, 19.4) (0.08, 1.0) Example 9 127 .+-. 34
218 .+-. 37 220 .+-. 37 8.4 .+-. 1.4 0.34 (min, max) (82.9, 188)
(165, 333) (172, 335) (6.4, 13.8) (0.08, 1.0)
[0189] As shown in Table 19 above, the mean methylnaltrexone
concentration-versus-time profile after the SC administration of a
formulation of Example 9 was essentially identical to that seen
with a saline formulation. Plasma methylnaltrexone concentrations
increased sharply in response to SC administration of either
formulation, with a mean C max of 127 ng/mL for a provided
formulation and 119 ng/mL for the saline formulation, observed
mostly within the first hour (mean t max of 0.34 h and 0.41 h,
respectively).
Example 12
Pharmacokinetic Screening of Methylnaltrexone Subcutaneous
Formulation in Dogs
[0190] Three different methylnaltrexone formulations administered
subcutaneously were evaluated in dogs. Pharmacokinetics of
methylnaltrexone following a single subcutaneous 0.15 mg/kg dose in
male beagle dogs. Eight male dogs (9.4-15 kg) were divided into two
groups, four dogs per group. To both groups of dogs, 0.15 mg/kg
methylnaltrexone in normal saline (Batch 1) was administered
subcutaneously as a reference formulation during period 1. A week
later, during period 2, Group 1 (SAN 1-4) received 0.15 mg/kg
methylnaltrexone subcutaneously in saline containing 0.5 mg/vial
Na. EDTA and 0.6 mM Citrate (Batch 2) and Group 2 (SAN 5-8)
received 0.15 mg/kg methylnaltrexone subcutaneously in saline
containing 0.5 mg/vial Ca. EDTA (Batch 3). Blood samples were drawn
at 0 (predose), 0.0833, 0.167, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and
12 hours after dosing, plasma was separated and assayed for
methylnaltrexone content.
[0191] Bioanalytical results were obtained, and pharmacokinetic
(PK) assessment was performed. Individual dog plasma
methylnaltrexone concentration-time profiles were subjected to
noncompartmental PK analyses (WinNonlin, Model 200). The following
pharmacokinetic parameters were determined for each dog, and
descriptive statistics were calculated for comparison among
formulations: AUC, C.sub.max, t.sub.max and t.sub.1/2. See Table
20.
TABLE-US-00035 TABLE 20 Individual and Mean (.+-.SD) Dog Plasma
Methylnaltrexone Pharmacokinetic Parameters After a Single
Subcutaneous Administration (~0.15 mg/kg) of Three Injectable
Formulations Batch 1 2 Test/ Batch 1 3 Test/ Formulation SAN
Reference Test Reference SAN Reference Test Reference Dose Mean
0.149 0.150 1.01 Mean 0.152 0.154 1.02 AUC.sub.0-12 Mean 87.8 98.9
1.12 Mean 85.4.sup.# 90.5 0.97 (hr ng/mL) SD 10.7 30.8 0.24 SD
5.1.sup.# 20.5 0.15 AUC.sub.0-.infin. Mean 102 111 1.09 Mean 106
112 0.99 (hr ng/mL) SD 9.4 27.9 0.19 SD 9.3 21.2 0.12 AUC.sub.0-12/
Mean 590 656 1.11 Mean 570.sup.# 585 0.95 Dose SD 64.2 178 0.22 SD
45.0.sup.# 122 0.15 C.sub.max (ng/mL) Mean 83.7 107 1.35 Mean
128.sup.# 130 1.01 SD 33.8 44.4 0.50 SD 22.5.sup.# 34.6 0.42
T.sub.max (hr) Mean 0.33 0.19 0.71 Mean 0.19.sup.# 0.15 0.92 SD
0.19 0.04 0.34 SD 0.05.sup.# 0.08 0.44 t.sub.1/2 (1/hr) Mean 10.1*
9.3* 1.15 Mean 13.0* 13.8* 1.20 SD 5.0 3.3 0.79 SD 4.0 3.5 0.19
Part III: Intravenous Formulations
Example 12
[0192] In certain embodiments, the present invention provides a
methylnaltrexone formulation for intravenous administration.
Provided intravenous formulations can be prepared in 12 mg/vial or
24 mg/vial concentrations. Both 12 mg/vial and 24 mg/vial strengths
use a 5 mg/mL concentration of methylnaltrexone. In certain
embodiments, provided intravenous formulations utilize a 10 mL
spikable vial designed to be used with Baxter mini-bags or any
other spikable infusion system. In some embodiments, provided
formulations were subjected to terminal sterilization by heating at
121.degree. C. for 15 minutes.
[0193] Formulations prepared in 12 mg/vial or 24 mg/vial
concentrations are set forth in Tables 20A and 20B, respectively,
below. Such formulations can be administered at doses of 24 mg, or
also, for example, 0.3 mg/kg, every 6 hours as a 20-minute
infusion. In certain embodiments, such administration is continued
for 3 days (total of 12 doses). Each methylnaltrexone formulation
is diluted to 50 mL and administered using a calibrated pump.
TABLE-US-00036 TABLE 20A Methylnaltrexone IV formulation for 12
mg/Vial Input/ Dosage Unit Ingredient % WT/WT Input Unit Naltrexone
Methobromide 0.496 25.2 mg Calcium EDTA, USP 0.0099 0.504 mg Sodium
Chloride, USP 0.833 42.336 mg Glycine Hydrochloride 0.0099 0.504 mg
Water for Injection, USP NA QS to 2.54 mL IV Formulation Strength 5
mg/mL Type Liquid Solution Container/Closure Vial 10 mL 10 mL
Stopper 20 mm 20 mm mg/vial Methylnaltrexone 12 mg 24 mg CaEDTA
0.24 mg 0.48 mg Glycine HCl 0.24 mg 0.48 mg NaCl 20.16 mg 40.32 mg
Overage 5% 5% Processing Sterilization Terminal Terminal Nitrogen
Flush No * No * Fill Volume 2.52 ml 5.04 ml (12 mg/vial); (24
mg/vial) Dispensing Container Syringe/spike Syringe/spike Dilution
Dilution/admix Dilution/admix
TABLE-US-00037 TABLE 20B Methylnaltrexone IV formulation for 24
mg/Vial AMT. NEEDED DESCRIPTION PER UNIT Methylnaltrexone 25.2 mg
Calcium EDTA, USP 0.504 mg Sodium Chloride, USP 42.336 mg Glycine
Hydrochloride 0.504 mg Water for Injection, USP.sup.a 5.08.sup.c g
Hydrochloric Acid, NF.sup.b As needed NA Sodium Hydroxide, NF.sup.b
As needed NA Containers & Closures 10 mL Schott flint glass
vial with 20 mm neck 20 MM, GREY, S10-F451 4432/50 FLUROTEC PLUG
XKD484 20 mm, Aluminum seal with Flip-top Input/ Dosage Unit
Ingredient % WT/WT Input Unit Methylnaltrexone 0.496 25.2 mg
Calcium EDTA, USP 0.0099 0.504 mg Sodium Chloride, USP 0.833 42.336
mg Glycine Hydrochloride 0.0099 0.504 mg Water for Injection, USP
NA QS to 5.04 mL
[0194] In certain embodiments, fill volume is at least 2.6 mL for a
2.4 mL extractable volume, and at least 5.1 mL for a 4.8 mL
extractable volume. Table 20C below describes vial contents
dilution when using a traditional syringe or a spikable vial.
TABLE-US-00038 TABLE 20C Overage and Reconstitution of Sample
spikable technique with traditional syringe Baxter Mini-bag
withdrawal Concentration 5 mg/mL 5 mg/mL 5 mg/mL 5 mg/mL mg/vial 12
mg 24 mg 12 mg 24 mg Overage 5% 5% 5% 5% Fill volume 2.52 5.04 2.52
5.04 Reconstitution 8.0 mL of 5.0 mL of 8.0 mL of 5.0 mL of volume
saline saline saline saline solution solution solution solution
Withdrawal Spike Spike Withdraw Withdraw amount full full 10.0 mL
10.0 mL via contents contents via syringe of vial of vial
syringe
Example 14
[0195] In certain embodiments, a provided intravenous formulation
is administered to a patient 90 minutes post surgery, where the
surgery is hernia repair. In some embodiments, the hernia repair
patient is administered opioids via PCA pump. Such formulations can
be administered at doses of 12 mg or 24 mg, or also, for example,
0.3 mg/kg, every 6 hours as a 20-minute infusion. In certain
embodiments, such administration is continued for 10 days, the
patient is discharged, or 24 hours post-bowel movement.
[0196] 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.
[0197] Patents, patent applications, publications, and the like are
cited throughout the application. The disclosures of each of these
documents are incorporated herein by reference in their
entirety.
* * * * *