FORMULATIONS FOR PARENTERAL DELIVERY OF COMPOUNDS AND
USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims priority to United States provisional patent
application serial number 60/835,574, filed August 4, 2006, the entirety of which is hereby
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 postsurgical)
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 μ 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 μ 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, hi 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] Figure 1A and Figure 1B: Effect of CaEDTA and NaEDTA on the formation of
2',2 -bis methylnaltrexone in the presence of iron at 40° C (Figure 1 A) and room temperature,
25° (Figure 1B). Both calcium EDTA and sodium EDTA are effective inhibitors of formation of
the 2',2' bis methylnaltrexone degradant.
[0015] Figures 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° C (Figure 2A) and room temperature,
25° (Figure 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 (Figure 2C) and at 40° C (Figure 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° 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] Figure 3A and Figure 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°
(Figure 3A) and at 40° C (Figure 3B) was assessed. Calcium EDTA was not effective at
inhibiting formation of the 0.79 degradant, and may increase levels of degradant formation.
[0017] Figure 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 μ 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 μ
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 methylnaltrcxonc) 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 United States patents 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°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 serial number 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 USSN 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 serial number 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 USSN 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, arid 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,Nl, 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)grycine (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 malcic 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 6.5mg/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 6.5mg/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 6.5mg/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 6.5mg/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 20mg/mL, calcium
EDTA at a concentration about 0.4mg/mL, sodium chloride in an amount such that the final
concentration is 6.5mg/mL isotonic sodium chloride, and glycine HCl at a concentration about
0.3mg/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 1mL capacity to
about 50mL capacity. In some embodiments, a vial is about 1mL, about 2mL, about 5mL, about
10mL, about 25mL or about 50mL 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 lmL to about 20mL. In some embodiments a syringe or
dispenser has a capacity of about 1mL, about 2mL, about 2.5mL, about 5mL, about 7.5mL, about
10mL, about 15mL, or about 20mL. 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., 25mL, 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 S-
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 end 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 μ 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, hydfomorphone, 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
Uses
[0096] 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 μ
opioid receptors, or in any treatment wherein temporary suppression of the μ opioid receptor
system is desired (e.g., ileus, etc.). In certain embodiments, methods of use of formulations are
in human subjects.
[0097] 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.

[0098] 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.
[0099] 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.
[00100] 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.
[00101] 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, gastroesophageal 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.
[00102] 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.
[00103] 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 January 20, 2005.
[00104] 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".
[00105] 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
[00106] 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.
[00107] 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.

[00108] 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 roethylnaltrexone 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.
[00109] 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.
[00110] 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® Plus diluent container system (Baxter), or an ADD VANTAGE*
diluent container (Hospira) system.
[00111] 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.
[00112] 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 ofdegradants of methylnaltrexone formulations.
[00113] 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 December 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.
[00114] For HPLC analysis, two (2) different methods were utilized to obtain the data set
forth herein. These methods are summarized below:
Method A:
Column: Prodigy ODS-3 15cm X 2.0mm, 3um particles (Phenomenex)
Flow rate: 0.25 mL/min
Detection: UV, 280 nm
Mobile phase: strength: Isocratic: 75:25 (v/v) 0.1% TFA in Water/Methanol
Mobile phase: purity: Gradient as follows:
Solvent A: 95:5 (v/v) 0.1% TFA in Water/Methanol
Solvent B: 35:65 (v/v) 0.1% TFA in Water/Methanol
Sample Solvent: 0.05M Dibasic Sodium Phosphate pH 6.8
Gradient Program:

Time % Mobile Phase A
(Min)
0 100
45 50
45.1 100
60 100
Column Temperature: 50°C
Method B: (purity)
Column: Prodigy ODS-3 15cm X 4.6 mm, 3pm particles (Phenomenex)
Flow rate: 1.5 mL/min
Detection: UV, 280 nm
Mobile phase: Gradient as follows:
Solvent A: 95:5 (v/v) 0.1% TFA in Water/Methanol
Solvent B: 25:75 (v/v) 0.1% TFA in Water/Methanol
Sample Solvent: 0.05M Dibasic Sodium Phosphate pH 6.8
Gradient Program:
Time % Mobile Phase A
(Min)
0 100
45 50
45.1 100
60 100
Method B: (strength)
Column: Prodigy ODS-3 15cm X 4.6 mm, 3um particles (Phenomenex)
Flow rate: 1.0 mL/min
Detection: UV, 280 nm
Mobile phase: Gradient as follows:
Solvent A: 95:5 (v/v) 0.1% TFA in Water/Methanol
Solvent B: 25:75 (v/v) 0.1% TFA in Water/Methanol
Sample Solvent: 0.05M Dibasic Sodium Phosphate pH 6 8
Gradient Program:
Time % Mobile Phase A
(Min)
0 95
1.0 85
12.0 50
15.0 95
20.0 95
[00115] 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:
Methylnaltrexone bromide RRT 1.00

[00116] 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.S5), as well as additional degradants resulting at relative retention time
of 0.67, 0.79 and 2.26.
[00117] 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 cyclopenta[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, Figure 4).



[00118] 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°C/60%
relative humidity, 40°C/65% relative humidity, and/or 70°C. Figure 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.
[00119] 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.
[00120] Inhibition of metal-catalyzed formation of 2.2'bis methylnaltrexone. We have
found Fe3+ 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. Fe3+ 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 Fe3+ 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 methylnallrexone was assessed at room
temperature as well as at 40 °C. Addition of either sodium or calcium EDTA solution was
effective at inhibiting formation of the 2,2'bis methylnaltrexone degradant. See Figure 1A and
Figure 1B. Thus, chelating action will facilitate methylnaltrexone bromide stability in solution
at room temperature.
[00121] Inhibition of metal-catalyzed formation of 7-dihvdroxv-methvlnaltrexone. 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.

[00122] We have found Ca2+ chelating agent provides additional inhibition of formation of
a 7-dihydroxy-methylnaltrexone degradant as compared to Na2+ 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° C. Addition of calcium
EDTA solution was highly effective at inhibiting formation of the 7-dihydroxy-methylnaltrexone
degradant at both temperatures. See Figure 2A and Figure 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°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°C/75% RH, degradant was reduced from 0.64% in saline solution alone to
0.14% in sample containing calcium EDTA. See Figure 2C and Figure 2D.
[00123] Preparation of an improved room temperature methvlnaltrexone forumulation.
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:
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)
[00124] For a 0.6 mL fill or 1.25mL fill, 20 or 30 mgs of methylnaltrexone bromide were
dissolved in 0.9% sodium chloride; and 0.24mg 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.


Example 3
Inhibition of pH dependent degradation of methylnaltrexone formulations
[00125] Inhibition of pH influenced formation of methylnaltrexone degradants. We have
found in the presence of Ca2+ 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 August 4, 2006, filed concurrently with the
present application, the contents of which are incorporated herein in their entirety by reference.
[00126] 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 Figure 3A and Figure 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°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°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°C/75%
RH.
[00127] 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°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.
[00128] 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°C/75% Relative Humidity and at 70°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.

Preparation of a pH adjusted, improved room temperature formulation. 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 0.3mg/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,
0.3mg/mL glycine HCl with a pH to 3.5 may be developed as either a subcutaneous
administration or intravenous administration formulation.
[00129] Preparation of such improved formulations comprises use of the following
exemplary components:
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
pH 3.4 -3.6
QS to final Volume


[00130] 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 0.6mL..
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.
[00131] 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.

[00132] 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.
[00133] 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
[00134] Evaluation of phosphate buffers solution stability. 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.

[00135] Preparation of a methvlnaltrexone forumulation comprising sodium EDTA and
citrate buffer. Methylnaltrexone formulations consisting of methylnaltrexone, sodium EDTA,
and sodium chloride in citrate buffer have been described (see US Patent Application Publication
US2004/0266806A1, published December 30, 2004). We have prepared solutions comprising
the same components for stability comparison studies with our present formulations.
[00136] 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.

[00137] 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.
[00138] 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.

Example 5
[00139] 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.



Example 6
Evaluation of Stopper Compatibility
[00140] 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.
[00141] Identical preparations prepared as described in Example 4 were stored in parallel
in vials having either a 13mm WPS S2-F451 4432/50 Gray B2-40 Westar RS stopper (West
Pharmaceutical Services) or a 13mm S2-F451 RS D 777-1 RB2 40 stopper (Daikyo Seiko, Ltd)

under various conditions. Each of the stoppers has a FluoroTec® 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.

Example 7
Stability of Frozen Intravenous Bags
[00142] The following formulation of methylnaltrexone 5 mg/ml, 0.8mg 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 -200C. The study was conducted for two concentrations
of methylnaltrexone: 12mg/100 ml and 24 mg/100ml. B/Braun bags NDC 0264-1800-32 with
0.9% of Normal Saline were used.
[00143] Two batches of the formulation were prepared and subjected to stability
determination. The first batch was the above methylnaltrexone TV formulation: 5 mg/ml
methylnaltrexone, 0.8mg 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°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.
[00144] 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.

Example 8
[00145] The effect of sodium tungstate (HPLC Method A) on the subcutaneous
formulation described herein is summarized in Table 16, below.


PART II: Subcutaneous Formulations
Example 9
[00146] 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.
[00147] The sodium chloride concentration is adjusted to 0.65% to maintain the
tonicity of the formulation.
[00148] Such a room temperature formulation for subcutaneous administration
was prepared as summarized in Tables 17A, 17B, and 17C below:

[00150] 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
[00151] 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.

Example 11
Subcutaneous Formulation - Bioequivalency Study
[00152] 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 rnethylnaltrexone (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.
[00153] 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 pharmacokinetic studies are set forth in
Table 19, below.


[00154] 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 Cmax of 127 ng/mL for a provided formulation and 119 ng/mL for the saline
formulation, observed mostly within the first hour (mean tmax of 0.34 h and 0.41 h,
respectively).
Example 12
Pharmacokinetic Screening of Methylnaltrexone Subcutaneous Formulation in Dogs
[00155] 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.
[00156] 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, Cmax, tmax and t½-
See Table 20.

PART HI: Intravenous Fonnulations
Example 12
[00157] In certain embodiments, the present invention provides a methylnaltrexone
formulation for intravenous administration. Provided intravenous fonnulations 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 °C for 15 minutes.
[00158] Fonnulations 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.



[00159] 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.


Example 14
[00160] 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.
[00161] 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.
[00162] 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.

WE CLAIM:
1. A pharmaceutical composition consisting of an effective amount of methylnaltrexone, or
a pharmaceutically acceptable salt thereof, a calcium salt chelating agent, an isotonic
agent, and a glycine stabilizing agent, in an aqueous solution wherein the solution has a
pH of between about 2.5 and about pH 6.
2. The composition according to claim 1, wherein the methylnaltrexone is methylnaltrexone
bromide.
3. The composition according to claim 2, wherein the methylnaltrexone bromide is
provided at a concentration of 20 mg/mL
4. The composition according to any one of claims 1 to 3, wherein the calcium salt
chelating agent is calcium EDTA disodium.
5. The composition according to any one of claims 1 to 4, wherein the isotonic agent is
sodium chloride.
6. The composition according to any one of claims 1 to 5, wherein the glycine stabilizing
agent is glycine hydrochloride.
7. The composition according to any one of claims 1 to 6, wherein the solution has a pH of
about 3.5.
8. A pharmaceutical composition comprising methylnaltrexone bromide, calcium EDTA
disodium, sodium chloride, and glycine hydrochloride, in an aqueous solution wherein
the solution has a pH of between 2.5 and pH 6.
9. The composition according to any one of claims 2 to 8, wherein the methylnaltrexone
bromide is provided at a concentration of 20 mg/mL.

10. The composition according to any one of claims 4 to 9, wherein the calcium EDTA
disodium is provided at a concentration of about 0.1 to about 1.0 mg/mL.
11. The composition according to claim 10, wherein the calcium EDTA disodium is provided
at a concentration of about 0.4 mg/mL.
12. The composition according to any one of claims 6 to 9, wherein the glycine
hydrochloride is provided at a concentration of about 0.5 to about 1.0 mg/mL.
13. The composition according to claim 12, wherein the glycine hydrochloride is provided at
a concentration of about 0.3 mg/mL.
14. The composition according to claim 8, wherein the methylnaltrexone bromide is
provided at a concentration of about 20 mg/mL, the calcium EDTA disodium is provided
at a concentration of about 0.4 mg/mL, the glycine hydochloride is provided at a
concentration of about 0.3 mg/mL, and the solution has a pH of about 2.6 to about 5.0.

The present invention provides formulations that achieve effective delivery of methylnallrexone compositions. The provided formulations are useful for preventing, treating delaying, diminishing or reducing the severity of side effects resulting from use of analgesic opioids.