DRY POWDER COMPOUND FORMULATIONS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present invention claims priority to United States provisional patent
application serial number 60/843,437, filed September 8, 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 administration 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-operatve (or post-
surgical) ileus, that may be caused by fluctuations in natural opioid levels. Similarly, women
who have recently given birth commonly suffer from post-partum ileus, which is thought to
be caused by similar natural opioid fluctuations as a result of birthing stress. Bowel

dysfunction associated with post-operative or post partum ileus can typically last for 3 to 5
days, with some severe cases lasting more than a week. Administration of opioid analgesics
to a patient after surgery, which is now an almost universal practice, may exacerbate bowel
dysfunction, thereby delaying recovery of normal bowel function, prolonging hospital stays,
and increasing medical care costs.
[0005] Opioid antagonists such as naloxone, naltrexone, and nalmefene, have been
studied as a means of antagonizing undesirable peripheral effects of opioids. However, these
agents act not only on peripheral opioid receptors, but also on central nervous system sites, so
that they sometimes reverse the beneficial analgesic effects of opioids, or cause symptoms of
opioid withdrawal. Preferable approaches for use in controlling opioid-induced side effects
include administration of peripheral opioid antagonist compounds that do not readily cross
the blood-brain barrier. For example, the peripheral u 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 peripheral methylnaltrexone
without extensive degradation of the methylnaltrexone under refrigeration and/or room
temperature conditions. It is desirable to provide a process for production of a stabilized
methylnaltrexone formulation suitable for intravenous administration to a subject in need
thereof. It is also desirable to provide a product with solid state stability at room temperature
and reconstitution stability for dosing to a subject.
SUMMARY OF THE INVENTION
[0007] The present invention provides dry powder formulations of methylnaltrexone.
In some embodiments, provided formulations are a dry powder containing methylnaltrexone
and a filler or a cryoprotectant, but lacking other agents typically found in dry powder (e.g.,
lyophilized) preparations. In some embodiments, provided formulations consist essentially of
methylnaltrexone and a single filler or single cryoprotectant. In some embodiments, provided

formulations are a dry, amorphous cake. In some embodiments, provided formulations are
storage-stabile. In some embodiments, provided formulations are stable to extended storage
at room temperature. For example, provided formulations may be storage stable for a period
of at least about one month, two months, three months, four months, five months, six months,
or more. In some embodiments, provided formulations are storage stable for 12 months or
for more than 24 months.
[0008] Provided formulations are useful for administration to subjects. For example,
in some embodiments, provided formulations are suitable for parenteral administration of
methylnaltrexone. In some embodiments, provided formulations contain an amount of
methylnaltrexone suitable for single dose administration. In other embodiments, provided
formulations contain an amount of methylnaltrexone suitable for multiple dose
administration.
[0009] The present invention also, provides methods for preparing dry powder
formulations, as well as liquid formulations reconstituted from or prepared into such dry
powder formulations. In some embodiments, dry powder formulations are prepared by
lyophilization; in some embodiments dry powder formulations are prepared by spray drying
of a super critical solution. In some embodiments, reconstituted formulations may contain an
amount of methylnaltrexone appropriate for direct dosing, or may contain an amount of
methylnaltrexone appropriate for further dilution (e.g., for intravenous administration).
Additionally provided are methods for production and use of formulations, as well as
products and kits containing the provided formulations.
[0010] In general, provided formulations are useful for preventing, treating, delaying
onset of or reducing severity and/or incidence of side effects resulting from use of opioids,
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).

[0011] In some embodiments, 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/or patients recovering from child birth). In some embodiments, provided
formulations are 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). In some
embodiments of the invention, provided formulations are useful for administration to patients
suffering from paralytic ileus, whether resulting from administration of opioids (typically
prolonged or excessive use of opioids), from normal or aberrant activity of endogenous
opioids, or from other causes. In some embodiments, paralytic ileus results from peritonitis,
pneumonia, pancreatitis, nerve trauma or decreased blood supply to the intestinal wall,
metabolic disturbances (e.g., affecting potassium levels), spinal injury, etc.
[0012] In some embodiments, provided formulations are useful, for example, in
prevention, treatment, delay, or reduction of severity and/or incidence of symptoms
associated with disorders or conditions resulting from normal or aberrant activity of
endogenous opioids. Such disorders or conditions can include, among others, ileus (e.g.,
post-partum ileus), 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), such as post operative ileus,
and idiopathic constipation. In some embodiments, provided formulations are useful in
prevention, treatment, delay, or reduction of severity and/or incidence of symptoms
associated with 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, chronic inflammation.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0013] In certain embodiments, the present invention provides pharmaceutical
compositions having improved stability characteristics. Opioid antagonist formulations
comprising methylnaltrexone are provided which are useful to prevent, treat, delay or reduce
the severity and/or incidence of undesirable side effects of opioid administration or activity.
In some embodiments, provided compositions, and kits and products including them, allow

for extended storage periods and/or for storage under favorable room temperature conditions.
Provided compositions, and kits and products containing them, thus allow for improved
delivery of therapeutics to subjects benefiting from use of methylnaltrexone.
[0014] For example, provided formulations are useful to treat, prevent, delay, or
decrease severity and/or incidence of side effects associated with opioid administration,
including gastrointestinal dysfunction (e.g., constipation, bowel hypomotility, impaction,
gastric hypomotility, Gl 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 administration 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).
[0015] In certain embodiments, provided 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). In some
embodiments, provided formulations are 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).
[0016] Alternatively or additionally, certain provided formulations may be useful, for
example, in prevention, treatment, delay, or reduction of severity and/or incidence 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-
operative ileus, post-partum ileus, paralytic ileus), 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 idiopathic constipation. In some embodiments of the invention, provided
formulations are useful in treatment, prevention, delay, or reduction of severity and/or
incidence of side effects in 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.
Definitions
[0017] The expression "dosage preparation" refers to the form or context in which a
formulation is stored and/or used prior to or during administration to a subject. For example,
a "dosage preparation" containing a formulation may constitute or comprise the formulation
in the context of a vial or syringe appropriate for storage and/or administration. A dosage
preparation may constitute or comprise a formulation in the context of a container which
protects the formulation from light (e.g., UV light). Alternatively, a dosage preparation may
constitute or comprise a formulation in the context of a container which does not protect the
formulation from exposure to light. In some embodiments, a dosage preparation may contain
a single unit dosage of methyl naltrexone. In some embodiments, a dosage preparation may
contain more or less than a single unit dosage of methylnaltrexone. In some embodiments, a
dosage preparation may contain an amount of methylnaltrexone that is a multiple of a unit
dosage.
[0018] The term "dose-concentrate," as used herein, refers to a pharmaceutical
composition having a concentration of active agent(s) higher than a typical unit dosage
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
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(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. In certain embodiments, a dose concentrate is
about 50-fold, about 100-fold, or about 200-fold more concentrated than a unit dosage. A
dose-concentrate may be formed by reconstitution of a dry powder formulation by addition of
aqueous solvent to a provided formulation.
[0019] The term, "dry powder formulation" or "dry powder composition" refers to a
dry, solid composition, and encompasses dried compositions prepared by freeze-drying (e.g.,
lyophilization) or other appropriate methods (e.g., spray drying, super critical fluid formation,
etc.) to achieve production of a dried amorphous cake form. Lyophilization is a process of
freeze-drying in which water is sublimed from the product after it is frozen, optionally by

applying a vacuum. Specifics of lyophilizing or freeze-drying are known in the art and
described, for example, in Remington's Pharmaceutical Sciences, Chapter 84, page 1565,18th
Edition, A. R. Gennaro, Editor, 1990, Mack Publishing Company. Techniques other than
lyophilization which may also be used for preparation of dry powder formulation(s) (e.g.,
dried samples), and particularly for preparation of amorphous dry powder formulations, are
known in the art, include, but are not limited to, sterile powder filling of the components,
singly, or as a complete blend, spray drying, tray drying, sizing processes including milling
and/or screening and precipitation. In certain embodiments, inventive dry powder
formulations are in the form of a cake (e.g., an amorphous cake).
[0020] 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 u 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 u opioid receptor activity (e.g., idiopathic constipation, ileus, etc.).
[0021] The term "formulation", in general, refers to a preparation that includes at
least one pharmaceutically active compound (e.g., at least methylnaltrexone, in any
appropriate form) optionally 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 activity of active compound(s) for applications.
According to the present invention, formulations that "consist essentially of
methylnaltrexone and a single filler or single cryoprotectant generally include only
methylnaltrexone and the single filler or cryoprotectant, potentially in the presence of low
level contaminants (e.g., process contaminants), degradation products (particularly of the
methylnaltrexone) and/or buffering agents. It is understood in the art that preparation of
materials and/or formulations sometimes involves the introduction of unavoidable
contaminants; compositions containing such contaminants at sufficiently low levels that
relevant characteristics of the overall formulation are not materially affected can be within
the scope of the present invention.

[0022] The term "stable", as used herein, refers to a formulation whose composition
does not change materially over a selected period of time and under selected conditions. For
example, in general, a stable formulation of containing methylnaltrexone does not accumulate
methylnaltrexone degradation products to a level above 2% over a designated period of time.
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, cows, etc.). In some embodiments, the subject is a
primate, a domestic animal, or a human. In some embodiments, the subject is a human.
[0023] "Therapeutically active agent" or "active agent" refers to a substance,
including a biologically active substance, that is useful for therapy (e.g., human therapy,
veterinary therapy), including prophylactic and/or therapeutic treatment. Therapeutically
active agents 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 agents can be any substance used as a medicine for
treatment, prevention, delay, reduction or amelioration of a disease, condition, or disorder.
Among therapeutically active agents useful in the formulations of the present invention are
opioid antagonist compounds, opioid analgesic compounds, and the like. Further detailed
description of agents useful as therapeutically active agents is provided below. The term
"therapeutically active agent" can also refer to a first agent that increases the effect or
effectiveness of a second agent, for example, by enhancing potency, increasing availability,
and/of or reducing adverse effects of a second agent.
[0024] The expression "unit dosage" as used herein refers to a physically discrete unit
of formulation appropriate for a subject to be treated. It will be understood, however, that
total daily usage of the compositions of the present invention will be decided by the attending
physician within the scope of sound medical judgment. A specific effective dose level for
any particular subject or organism may depend upon a variety of factors including the
disorder being treated and the severity and/or incidence 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.
Methylnaltrexone
[0025] The present invention provides formulations and dosage preparations for
parenteral administration of methylnaltrexone. When a formulation, dosage preparation or
method described herein is said to utilize "methylnaltrexone," it should be understood that
any appropriate form of methylnaltrexone (e.g. N- methylnaltrexone and/or any
pharmaceutically acceptable salts thereof) having desired activity may be utilized.
Methylnaltrexone is described for example in U.S. Pat Nos. 4,176,186; 4,719,215;
4,861,781; 5,102,887; 5,972,954; 6,274,591; U.S. patent application Nos. 20020028825 and
20030022909; and PCT publication Nos. WO 99/22737 and WO 98/25613; the contents of
each of which are hereby incorporated by reference.
(0026] 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, rumarate, gluconate, glucoronate, saccharate, formate,
carboxylate, benzoate, glutamate, sulfonate, methanesulfonate, ethanesulfonate,
benzensulfonate, p-toluenesulfonate, selenate, and pamoate (i.e., l,l'-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 (e.g., chloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate,
malate, maleate, bromide, iodide, fumarate, sulfonate, carboxylate, or succinate salts, etc.)
and/or mixtures thereof can be adapted and used in a dose formulation according to the
invention so as to achieve an appropriate compound delivery profile of the invention.
Alternatively or additionally, peripheral opioid receptor antagonist (e.g., methylnaltrexone)
base, chemical and chiral derivatives thereof and salts can be used, as appropriate.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] In certain embodiments, the methylnaltrexone utilized in formulations or
dosage preparations described herein is a mixture of stereoisomers characterized in that it has
opioid antagonistic effect. For example, the methylnaltrexone may be a mixture of R-N and
S-N methylnaltrexone such that a mixture itself acts as an antagonist 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.
[0033] 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.
[0034] It will be understood by those skilled in the art that, where reference is made
herein to amounts of methylnaltrexone utilized in formulations, dosage preparations, or
methods, those amounts may refer to total amount of methylnaltrexone (or salt thereof), or to
amount of relevant active form of methylnaltrexone for a particular purpose (e.g., opioid
antagonism), whether or not other forms of methylnaltrexone are also present. Furthermore,
as indicated herein, dosages or amounts are sometimes defined with reference to a particular
form of methylnaltrexone (e.g., N-methylnaltrexone bromide). Where a different form or salt
of methylnaltrexone is used, those of ordinary skill in the art will appreciate that such dosages
or amounts may be adjusted to a dose or amount that provides an equivalent amount of active
methylnaltrexone.
[0035] Furthermore, those of ordinary skill in the art appreciate that, as with any
biologically active agent, the exact amount of methylnaltrexone that is required to achieve a
pharmaceutically effective amount may vary from subject to subject, depending on species,
age, weight, and general condition of a subject, severity and/or incidence of the side effects or
disorder, identity of the particular compound(s), mode of administration, other therapies
being received and/or disorders or conditions suffered, and the like.

[0036] The exact amount of methylnaltrexone (or combination of methylnaltrexone
and any other particular active agent) that is required to achieve a pharmaceutically effective
amount will vary from subject to subject, depending on species, age, and general condition of
a subject, severity of the side effects or disorder, identity of the particular compound(s), mode
of administration, and the like. A total daily dosage of methylnaltrexone (e.g.,
methylnaltrexone bromide) will typically be in the range 10-200 mg, preferably 20-100 mg
for a 70 kg adult human. A unit dosage formulation according to the invention will usually
contain 1-250 mg of active compound (e.g., methylnaltrexone bromide) per unit, 5-100 mg of
active compound per unit, 10-50 mg of active compound per unit, or about 8 mg or about 12
mg or about 16 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.
[0037J In certain embodiments of the invention, an effective amount of
methylnaltrexone bromide for administration to a 70 kg adult human may comprise about 10
mg to about 50 mg of compound per unit dosage, to be administered one or more times a day,
an amount of methylnaltrexone equivalent to about 10-50 mg of methylnaltrexone bromide.
[0038] A once daily unit dosage preparation according to the invention will usually
contain an amount of methylnaltrexone equivalent to about 1-250 mg of methylnaltrexone
bromide per unit. In some embodiments, a once daily unit dosage preparation will contain an
amount equivalent to about 5-100 mg of methylnaltrexone bromide per unit, or to about 10-
50 mg of methylnaltrexone bromide per unit, or to about 8 mg or 12 mg or 16 mg or 24 mg of
methylnaltrexone bromide per unit.
[0039] A unit dosage preparation according to the invention may contain an amount
of methylnaltrexone equivalent to about 1-250 mg of methylnaltrexone bromide per unit. In
some embodiments, such a unit dosage preparation may contain an amount equivalent to
about 1-200 or 10-100 mg of methylnaltrexone bromide per unit, or to about 15-50 mg of
methylnaltrexone bromide per unit, or to about 20-30 mg of methylnaltrexone bromide per
unit. In some embodiments, inventive unit dosage preparations contain an amount of
methylnaltrexone equivalent to about 10-50 mg of methylnaltrexone bromide. In certain

embodiments, the present invention provides unit dosage preparations containing about 12
mg of methylnaltrexone bromide. In other embodiments, the present invention provides unit
dosage preparations containing about 24 mg of methylnaltrexone bromide.
Formulations
[0040] It has been surprisingly found that lyophilization of methylnaltrexone with a
single filler or a single cryoprotectant, in the absence of additional excipients, provides a
stable form of methylnaltrexone which may be stored for extended periods. Thus, the present
invention demonstrates provides dry powder formulations (e.g., an amorphous powder,
optionally in the form of a cake) of methylnaltrexone and a single filler or single
cryoprotectant. Such dry powder formulations may be stored, then utilized for administration
to a subject, when desirable, by reconstitution with a liquid. The present invention provides
stable dry powder compositions, and associated methods, that deliver methylnaltrexone. In
certain embodiments, provided formulations can maintain integrity without substantial
production of degradants following storage, including storage under room temperature. Thus,
provided formulations can confer improved storage stability of methylnaltrexone. In some
embodiments, provided formulations contain reduced levels of a degradant produced by
Hofmann elimination of methylnaltrexone.
[0041] In particular, the present invention provides stable formulations for
administration to subjects. In some embodiments, provided formulations are useful for
parenteral administration. Provided formulations and compositions, or dosage preparations
comprising them, may include dry powder (e.g., lyophilized) compositions, solutions for
injection, suspensions for injection, dry powder compositions for reconstitution by
combination with an appropriate solvent or other medium prior to use, emulsions,
dispersions, etc. In some embodiments, such formulations, compositions, and/or dosage
preparations are sterile.
[0042] In some embodiments, a formulation according to the present invention is a
dry material that consists essentially of methylnaltrexone and a single other agent. In some
embodiments, the dry material is in cake form.
[0043] In certain embodiments, inventive dry powder formulations are amorphous.
The term "amorphous" means a physical state lacking significant crystal lattice structure and
may be verified by X-ray diffraction, solid-state NMR (SSNMR) and/or other supportive
means known in the art, such as observation with a polarized light microscope and
Differential Scanning Calorimetry (DSC). In some embodiments, provided dry powder

formulations are substantially free of detectable discrete crystals. Without wishing to be
bound by any particular theory, Applicants note that formulations lacking discrete crystals
may be particularly desirable both because they permit intimate contact between
methylnaltrexone and the filler or cryoprotectant, and because they typically have consistent
solubility profiles, etc. By contrast, if discrete crystals are present in a formulation, those
crystals may have different stability and/or solubility characteristics than other portions of the
formulation. In some embodiments, the present invention provides an amorphous dry
material consisting essentially of methylnaltrexone and a single filler or single cryoprotectant.
[0044] In some embodiments, a dry powder formulation is reconstituted in
appropriate liquid, so that a solution, suspension, emulsion or dispersion consisting
essentially of methylnaltrexone, a single filler or single cryoprotectant, and a reconstituting
liquid is generated. The present invention comprises methods of preparing and/or
administering such reconstituted solutions, suspensions, emulsions, or dispersions to
subject(s). Thus, provided by the present invention are methods for preparing a composition
comprising a formulation consisting of essentially of methylnaltrexone and a single filler or
single cryoprotectant in an appropriate liquid. In some embodiments, reconstituted
preparations are further diluted with an aqueous carrier, e.g., for intravenous administration.
[0045] In some embodiments of the invention, methylnaltrexone may comprise from
about 10% to about 90% of the formulation. In some embodiments, methylnaltrexone may
comprise from about 5%, 10%, about 20%, about 30%, about 40%, about 50%, about 60%,
70%, 80%, or about 90% of the formulation. In some embodiments, the formulation may
comprise an amount of methylnaltrexone equivalent to about 5%, 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, or 90% methylnaltrexone bromide.
[0046] In many embodiments, provided formulations include methylnaltrexone
together with a single filler or single cryoprotectant. Those of ordinary skill in the art will
appreciate that any material capable of providing bulk can act as a filler. The present
invention encompasses the recognition that merely providing filling/bulking capability may
help stabilize composition of methylnaltrexone. In some embodiments, a particular agent
may further have particular stabilizing attributes, for example due to its ability to interact
with methylnaltrexone, thereby potentially affecting reactions, including degradation
reactions available to the compound. Agents with such stabilizing attributes generally are
often termed "preservatives" in the art. Agents with stabilizing attributes under conditions of
freeze drying are often termed "cryoprotectants".

[0047] In some embodiments, a filler or cryoprotectant may comprise from about
10%, about 20%, about 30%, about 40%, about 50%, about 60%, 70%, 80%, 90% or about
95% of the formulation, based upon total weight of the formulation. In some embodiments, a
cryoprotectant may comprise from about 25%, about 35%, about 45%, about 55%, about
65% or about 75% of the formulation, based upon total weight of the formulation.
[0048] In some embodiments, filler or cryoprotectant may be present in a ratio with
methylnaltrexone that is close to 1:1; in other embodiments, the
filler/cryoprotectant:methylnaltrexone ratio may be within the range of about 2:1, 3:1, 4:1,
5:1 or more. In some embodiments of the invention, formulations including smaller amounts
of methylnaltrexone have a higher ratio of filler or cryoprotectant to methylnaltrexone.
[0049] In some embodiments of the invention, dry powder formulations containing
filler or cryoprotectant have fewer methylnaltrexone degradation products than do otherwise
identical formulations, stored under comparable conditions for a comparable amount of time,
that lack filler or cryoprotectant. In some embodiments of the invention, dry powder
formulations containing a higher ratio of filler/cryoprotectant to methylnaltrexone have fewer
methylnaltrexone degradation products than do otherwise identical formulations, stored under
comparable conditions for a comparable amount of time, mat contain lower ratios. In either
such comparison, the phrase "fewer methylnaltrexone degradation products" can refer either
to a smaller number of degradation products or to a lower amount of a particular degradation
product. In some embodiments, a lower amount of a degradation product produced by
Hofrnann elimination of methylnaltrexone is present.
[0050] In some embodiments, provided dry powder formulations consist essentially
of methylnaltrexone and a single other agent and do not contain more than 2% of
methylnaltrexone degradation products. That is, in general, a stable formulation of
containing methylnaltrexone does not accumulate methylnaltrexone degredation products to a
level above 2% over a designated period of time. In some embodiments, no material increase
(as compared with an initial amount present at production of the formulation) in degradation
products is observed over a designated period of time. In some embodiments, such a stable
formulation containing methylnaltrexone does not accumulate methylnaltrexone degredants
to a level above 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,
0.3%, 0.2%, 0.15%, 0.1% or less.
[0051] Any of a variety of agents may be utilized as a filler or cryoprotectant
according to the present invention. For example, histidine, polyethylene qlycol, polyvinyl
pyrrolidine, lactose, dextran, sucrose, and/or mannitol may be utilized, in any appropriate

form. In some embodiments lactose is utilized; in some embodiments, the lactose is lactose
monohydrate. Without wishing to be bound by any particular theory, we note that lactose
monohydrate is a reducing sugar and has certain abilities to bind with other molecules that
may impart cryoprotectant characteristics.
[0052] In some embodiments of the invention, where a dry powder formulation
contains a filler or cryoprotectant other than lactose monohydrate, it contains an amount or
percentage that is equivalent to the recited amount or percentage of lactose monohydrate.
[0053] In some embodiments, the formulation consists essentially of
methylnaltrexone (in any appropriate form), and a single filler or single cryoprotectant. In
some embodiments, the formulation consists essentially of methylnaltrexone and lactose. In
some embodiments lactose is lactose monohydrate. In certain embodiments the formulation
consists essentially of methylnaltrexone bromide and lactose monohydrate. Thus, the present
invention provides dry preparations that consist essentially of methylnaltrexone bromide and
lactose monohydrate. In some embodiments such dry preparations are in the form of an
amorphous cake.
[0054] In certain embodiments, a formulation consists essentially of
methylnaltrexone, wherein the methylnaltrexone is present in an amount equivalent to about
2 mg to about 200 mg of methylnaltrexone bromide, and a single filler or single
cryoprotectant, present in an amount equivalent to about 10 mg to about 200 mg of lactose
monohydrate. In certain embodiments, is present in an amount equivalent to about 2 mg to
about 100 mg of methylnaltrexone bromide, and filler or cryoprotectant is present in an
amount equivalent to about 10 mg to about 100 mg of lactose monohydrate. In some
embodiments, methylnaltrexone is present in an amount equivalent to about 5 mg to about 50
mg, or to about 5 mg to about 25 mg, or to about 8 mg to about 25 mg, or to about 12 mg to
about 25 mg of methylnaltrexone bromide, and filler or cryoprotectant is present in an
amount equivalent to about 10 mg to about 50 mg, or to about 20 mg to about 50 mg, or to
about 25 mg to about 45 mg, or to about 30 mg to about 42 mg, or to about 35 mg to about 40
mg of lactose monohydrate.
[0055] In some embodiments, provided dry powder formulations consisting
essentially of methylnaltrexone and a single filler or a single cryoprotectant are stable for at
least one month, two months, three months, four months, five months, six months or more.
In some embodiments, provided formulations are stable for 12 months or more. In some
embodiments, provided formulations are stable at room temperature.

[0056] Dry powder formulations may be reconstituted with a liquid carrier so as to
generate a resulting reconstitute composition. In many embodiments, the liquid carrier will
be an aqueous carrier. Reconstituted compositions may thus comprise an admixture of
methylnaltrexone, filler or cryoprotectant, and an appropriate liquid carrier. An appropriate
liquid carrier for reconstitution of dry powder compositions may comprise an aqueous carrier
such as water (e.g., sterile water or water for injection) or an isotonic solution. A
reconstituted composition, for example, may be prepared, for example, to have
methylnaltrexone at a concentration with a range of about 0.1 mg/mL to about 50 mg/ml, or
within a range of about 0.2 mg/mL to about 48 mg/mL, or within a range of about 0.24
mg/mL to about 4.8 mg/mL. In certain embodiments, the present invention provides a
reconstituted composition having methylnaltrexone at a concentration of about 5 mg/mL.
[0057] Aqueous carriers are known in the art, and include, but are not limited to
sterile water, water for injection, or an isotonic solution. An isotonic solution comprises an
isotonic agent solution. Pharmaceutically acceptable isotonic solutions include, but are not
limited to sodium chloride solution, Ringer's injection, isotonic dextrose injection, dextrose
and lactated Ringers injection. In some embodiments, provided compositions comprises
water for injection. In some embodiments, the present invention provides reconstituted
formulations that consist essentially of methylnaltrexone, cryoprotectant and water. In some
embodiments, reconstituted formulations consist essentially of methylnaltrexone, a
cryoprotectant, and an isotonic solution.
[0058] An isotonic agent useful according to the present invention can be any
pharmaceutically acceptable isotonic agent, or a solution thereof. Common isotonic agents
include agents selected from the group consisting of sodium chloride, mannitol, lactose,
dextrose (hydrous or anhydrous), sucrose, glycerol, and sorbitol, or a solution of any of the
foregoing. In certain embodiments, a provided reconstituted formulation comprises an
isotonic agent which is sodium chloride or a solution thereof. In some embodiments, sodium
chloride is present in an isotonic amount, such that final concentration of sodium chloride is
about 0.1%, about 0.25%, about 0.65% or about 0.9%.
[0059] In some embodiments, a provided reconstituted formulation consists
essentially of methylnaltrexone, lactose, and an isotonic solution. In some embodiments, a
provided reconstituted formulation consists essentially of methylnaltrexone, lactose, water
for injection, and sodium chloride in an amount such that the final concentration is isotonic
sodium chloride (e.g., 0.9% 0.65%, 0.25%, 0.1% sodium chloride). In any such

embodiments, methylnaltrexone may comprise methylnaltrexone bromide, and the lactose
may comprise lactose monohydrate.
Dosage, Administration, and Dosage preparations
[0060] Dry powder formulations may be prepared, and/or may be reconstituted, for
administration to subject(s). For example, dry powder formulations may be prepared and/or
reconstituted for parenteral administration.
[0061] Parenteral administration of a composition comprising a reconstituted
formulation may include any of intravenous injection, intravenous infusion, intradermal,
intralesional, intramuscular, subcutaneous injection or depot administration of a unit dosage.
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 dosage(s)
may be administered once, less than once, or more than once a day, for example, once a
week, once every other day, once a day, or 2, 3 or 4 times a day, usually 1 to 3 times a day,
more preferably 1 or 2 times per day. In some embodiments, particularly where a unit dosage
is to be delivered intravenously, it is delivered by periodic infusion several times a day over a
series of days (that may be continuous or interrupted). In some embodiments, intravenous
formulations are delivered by periodic infusions spaced apart by several (e.g., about 2-10)
hours over several (e.g., about 2-20, about 4-15, about 6-12, about 10) days. In some
embodiments, intravenous formulations are delivered over consecutive days. As will be
appreciated by those of ordinary skill in the art, the administration regimen may be adjusted,
for example, according to the characteristics of the individual receiving treatment and/or of
the precise situation (e.g., treatment of side effect associated with chronic opioid therapy,
associated with acute opioid exposure, and/or associated with activity of endogenous opioids,
etc.). To give but one example, a shorter administration regimen may be appropriate for
rescue applications, whereas other applications may involve correlating methylnaltrexone
therapy with term or timing of opioid exposure or activity.
[0062] The present invention provides variety of different dosage preparations useful
for parenteral administration, including, for example, formulations provided in a container
(e.g., a vial, ampoule, syringe, bag, dispenser, etc.). In some embodiments, a formulation is
provided in a vial or syringe. In some embodiments, a formulation is provided in a vial or
syringe containing a unit dosage of methylnaltrexone. In such embodiments, a formulation
may comprise about 1 mg to about 200 mg methylnaltrexone bromide. In some

embodiments, the unit dosage contains from about 1 mg to about 80 mg, from about 5 mg to
about 50 mg, or from about 7.5 mg to about 40 mg. In some embodiments, the unit dosage
contains about 8 mg, about 12 mg, about 16 mg, or about 24 mg methylnaltrexone; if such
methylnaltrexone is not in the form of methylnaltrexone bromide, then it may be present in an
amount equivalent to the recited amount of methylnaltrexone bromide.
[0063] In one embodiment, a formulation is provided in a vial containing dry powder
that consists essentially of methylnaltrexone, and a filler or cryoprotectant. In one
embodiment, a formulation is provided in a syringe containing dry powder that consists
essentially of methylnaltrexone, and a filler or cryoprotectant.
[0064] In one embodiment, provided is a vial containing a dry powder formulation
consisting essentially of methylnaltrexone and a filler or cryoprotectant, and sufficient room
to allow addition of an appropriate solvent for reconstitution of the dry powder formulation.
In one embodiment, a composition can be prepared by adding to an appropriate liquid (e.g.,
solvent) a dry powder formulation consisting essentially of methylnaltrexone and lactose
(e.g., lactose monohydrate).
[0065] In one embodiment, provided is a syringe or dispenser containing a dry
powder formulation that consists essentially of methylnaltrexone and a filler or
cryoprotectant, and sufficient room to allow addition of an appropriate solvent or liquid for
reconstitution. In one embodiment, a formulation in a syringe or dispenser is prepared with
reconstituted methylnaltrexone formulation, where the solution consists essentially of
methylnaltrexone, lactose (in an appropriate form, e.g., lactose monohydrate), and an
appropriate liquid carrier. In one embodiment, a composition can be prepared comprising a
dry powder formulation consisting essentially of methylnaltrexone, and a filler or
cryoprotectant, in an isotonic solution.
[0066] In certain embodiments, dosage preparations are provided that allow
reconstitution of a dry powder formulation as a dose concentrate. A dose concentrate may be
used over a standard treatment interval such as immediately upon reconstitution or up to
about 24 hours after reconstitution, as appropriate. In certain embodiments, a dose-
concentrate is prepared by reconstituting a dry powder formulation in a container (e.g., glass
or plastic bottle, vial, ampoule, etc.) in a sufficient amount to treat a subject for a period
ranging from 6 hours to 1 week, but preferably from 12 hours to 24 hours. A suitable
container may desirably have an empty space of sufficient size to permit (i) addition of liquid
carrier plus (ii) additional space as necessary to permit agitation and effect complete solution
or suspension of the dry powder composition in the added liquid carrier. A container may be

equipped with a penetrable top, for example, a rubber seal, so that the liquid carrier may be
added (and/or reconstituted composition may be removed) by penetrating the seal with a
hypodermic syringe. In some embodiments, a needle-less penetrable seal is utilized.
[0067] An example of a dosage preparation useful for preparation of a unit dose or a
dose concentrate can include a vial having a capacity of from about 1 mL to about 100 mL, or
any appropriate capacity in between (e.g., 5 mL, 10 mL, 20 mL, 25 mL, 50 mL, 75 mL, etc.)
In some embodiments, a vial with a capacity from about 1 mL to about 100 mL may contain
about 1 mg to about 4 g of dry powder formulation. In some embodiments, a 10 mL glass
vial is utilized, containing about 5 mg to about 400 mg of methylnaltrexone. In some
embodiments, a 10 mL glass vial contains about 5 mg to about 200 mg, or about 5 mg to
about 100 mg, or about 10 mg to about 75 mg, or about 25 mg of methylnaltrexone. If the
methylnaltrexone is not in the form of methylnaltrexone bromide, an amount equivalent to
the recited amount of methylnaltrexone bromide may be present.
[0068] In certain embodiments, a 10 mL glass vial contains about 8 mg of
methylnaltrexone, about 12 mg of methylnaltrexone, or about 24 mg of methylnaltrexone. If
the methylnaltrexone is not in the form of methylnaltrexone bromide, an amount equivalent
to the recited amount of methylnaltrexone bromide may be present.
[0069J In some embodiments, a 10 mL glass vial contains about 5 mg to about 200
mg of dry powder formulation, about 5 mg to about 100 mg of dry powder formulation, about
10 mg to about 75 mg of dry powder formulation, or about 50 mg of dry powder formulation.
[0070] A non-limiting specific example of a provided dosage preparation is a 10 mL
glass vial with a rubber seal having a 1 dry powder formulation containing methylnaltrexone
and a filler or cryoprotectant such as lactose (e.g., lactose monohydrate). In some
embodiments, empty space is present around the solid composition contents of the container,
allowing ample room for addition of a liquid carrier such as a solvent or diluent (e.g., sterile
water for injection, isotonic solution (e.g., saline)), plus additional room sufficient to allow
for agitation of contents.
[0071] Addition of liquid carrier to a dry powder formulation can be used to prepare a
unit dose or a dose concentrate which may then be conveniently used to form unit dosages of
liquid pharmaceutical formulations by removing aliquot portions or entire contents for further
dilution. Reconstituted dose concentrate can be added, for example, to an intravenous (IV)
container containing a suitable aqueous carrier for administration to a subject. Useful
aqueous carriers include standard solutions for injection as previously described (e.g., 5%
dextrose, saline, or sterile water etc.). Typical unit dosage IV bags are conventional glass or

plastic containers having inlet and outlet means and having standard (e.g., 50 mL, 100 mL
and 150 mL) capacities. A dose concentrate solution can be added to a unit dosage IV bag in
an amount sufficient to achieve a concentration of about 0.1 mg/mL to about 1.0 mg/mL of
methylnaltrexone, or about 0.24 mg/mL to about 0.48 mg/mL in the unit dosage IV bag.
[0072] In one embodiment, a provided formulation is in a syringe or other dispenser
filled with 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 lmL, about 2mL, about 2.5mL, about 5mL,
about 7.5mL, about lOmL, 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.
[0073] 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 OTder 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.
[0074] 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.
[0075] 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 Dry Powder Formulations
[0076] Dry powder 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.
[0077] Dry powder formulations may be prepared by conventional lyophilization
methods or by other techniques such as spray drying, or blending of dry powders of the
appropriate salts of the individual or combined ingredients. Lyophilization methods can
include tray lyophilization and vial lyophilization. Vial lyophilization methods may be
advantageous for preparing multiple dosage preparations, each containing a unit dosage of
methylnaltrexone.
[0078] In certain embodiments, lyophilized formulations, are prepared by first
providing a solution or suspension of methylnaltrexone and/or appropriate filler or
cryoprotectant in an appropriate solvent. If desired, prepared methylnaltrexone solution or
suspension may be subjected to a filtration process before lyophilization. Such a filtration
process may include, for example, a sterilizing filtration and/or an ultra filtration of the
processing solution before lyophilization to eliminate microorganisms or other contaminating
matter from the processing solution before lyophilization.
[0079] If desired, methylnaltrexone solution or suspension may be subjected to a
distributing process before lyophilization. A distributing process may include, for example in
the case of vial lyophilizations, distributing a suitable volume of the processing solution
before lyophilization into vials, taking the concentration of methylnaltrexone into
consideration in order that vial products carry a desired amount of methylnaltrexone.
[0080] In some embodiments, lyophilization of the composition is performed by a
controlled freeze-drying process. For example, a methylnaltrexone solution can be subjected
to a temperature treating process (e.g., to improve cake characteristics), and then can be dried
in a high vacuum for sublimating liquid carrier. For example, a solution may first be frozen,
then subjected to a low pressure environment (e.g., vacuum) to facilitate sublimation, and
then gently heated to optimize drying rate of the product.

[0081] Any available technique can be employed to obtain a liquid solution or
suspension containing methylnaltrexone and filler or cryoprotectant suitable for
lyophilization. For example, a solution or suspension of methylnaltrexone may be prepared
or obtained to which filler/cryoprotectant is added; a solution or suspension of
filler/cryoprotectant may be prepared or obtained to which methylnaltrexone is added, or both
methylnaltrexone and filler/cryoprotectant can be added to a liquid carrier (e.g.,
simultaneously or sequentially, including in interdigitated amounts).
[0082] To give but one example, methylnaltrexone (in any appropriate form, e.g.,
methylnaltrexone bromide, etc.) can be dissolved or suspended in a suitable amount of liquid
carrier (e.g., water, isotonic saline), and optionally mixed. A suitable filler or cryoprotectant
(e.g., lactose, for example in the form of lactose monohydrate) is added and optionally mixed.
In some embodiments, a liquid carrier may be an aqueous solvent such as water, purified
water, water for injection, or isotonic sodium chloride solution. In some embodiments, the
liquid carrier is water for injection.
[0083] A typical process for preparing a lyophilized composition comprises
sequential steps of: (a) preparing or obtaining a solution or suspension consisting essentially
of methylnaltrexone, an aqueous solvent and a filler or cryoprotectant, (b) freezing the
composition to a temperature of from about -10 "C to about -75 *C, wherein the temperature
is maintained for at least about 30 minutes to about 5 hours, (c) applying a vacuum for at
least about 5-30 minutes during or after freezing; (d) carrying out a primary drying by
changing the temperature to a primary drying temperature from about -30"C to about 30°C,
and maintaining the temperature at the primary drying temperature for at least about 10-40
hours to produce a primary lyophilate, and (e) carrying out a secondary drying comprising
raising the temperature to a secondary drying temperature from about 0 "C to about 60 °C,
and maintaining the temperature at the secondary drying temperature for at least about 5
hours, or until the lyophilate reaches a particular temperature, resulting in production of a
lyophilized formulation consisting essentially of methylnaltrexone and a filler or
cryoprotectant.
[0084] One particular process may comprise the sequential steps of: (a) dissolving
lyophilized composition ingredients comprising: methylnaltrexone bromide and a single filler
or single cryoprotectant (e.g., lactose (e.g., lactose monohydrate) in an aqueous solvent (e.g.,
water for injection); (b) cooling the solution of step (a) to a temperature below -35 °C. and
maintaining the solution below -35 °C for a period; (c) evacuating the lyophilizer to a
pressure of about 300 uM Hg (40 pascals) or less, and maintaining such reduced pressure for

an additional period of at most about 10-30 minutes; (d) heating the product in the lyophilizer
on a shelf set to about +20 °C; (e) maintaining these conditions, under subatmospheric
pressure for a time sufficient (e.g., about 10-15 hours) to yield a solid lyophilized product; (f)
drying at about +35 °C. Preferably, step (b) is performed for a time period of at least 2 hours,
and step (e) is preferably conducted for a period of at least 14 hours and step (f) is performed
at a subatmospheric pressure less than about 100 mTorr (40 pascals) and conditions are
maintained for 5 hours after the shelf temperature at +40 °C has been achieved, or until the
product temperature is above 30 °C.
[0085] Provided methylnaltrexone compositions may be subjected to a distributing
process to vials (e.g., clear glass vial, amber vials), ampoules, syringes, or dispensers (e.g.,
auto-dispensers) before or after lyophilization. Such a distributing process may include, for
example in the case of vial packaging, a process distributing a suitable amount of dry powder
composition into vials, taking the concentration or amount of methylnaltrexone into
consideration in order that vial products carry a desired amount of methylnaltrexone.
[0086] In one embodiment, dry powder compositions are incorporated into vials,
ampoules, syringes, or dispensers, either before or after lyophilization or other drying
process, as described herein. Various packaging systems may optionally be utilized in
conjunction with provided compositions.
Combination Products and Combined Administration
[0087] In some embodiments, provided formulations may optionally be used in
combination or in conjunction with compositions comprising at least one other active
compound. In some embodiments, provided 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 include methylnaltrexone, may
be missing from one or more portions that include methylnaltrexone, and/or may be included
in one or more portions that do not include methylnaltrexone. Some embodiments of the
invention therefore provide 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).
[0088] For example, a reconstituted dose concentrate provided herein may be further
diluted in a carrier suitable for IV administration in conjunction or in combination with a
composition for IV administration which comprises an opioid and/or opioid 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.).
[0089] Opioids useful in analgesic applications are known in the art. For example,
opioid compounds include, but are not limited to, alfentanil, anileridine, asimadoline,
bremazocine, burprenorphine, butorphanol, codeine, dezocine, diacetylmorphine (heroin),
dihydrocodeine, diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine,
hydrocodone, hydromorphone, levallorphan, levomethadyl acetate, levorphanol, loperamide,
meperidine (pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine,
nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum, pentazocine,
propiram, propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, and tramadol. In
some embodiments the opioid is at least one opioid selected from alfentanil, buprenorphine,
butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, nicomorphine,
oxycodone, oxymorphone, papaveretum, pentazocine, propiram, propoxyphene, sufentanil
and/or tramadol. In certain embodiments, the opioid is selected from morphine, codeine,
oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tramadol, and mixtures
thereof. In a particular embodiment, the opioid is loperamide. In another particular
embodiment, the opioid is hydromorphone. In other embodiments, the opioid is a mixed
agonist such as butorphanol. In some embodiments, the subjects are administered more than
one opioid, for example, morphine and heroin or methadone and heroin.
(0090] The amount of additional active compound(s) present in combination
compositions or used in conjunction with 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.
[0091] In certain embodiments, provided formulations may also be used in
conjunction with and/or in combination with conventional therapies for gastrointestinal
dysfunction to aid in the amelioration of constipation and bowel dysfunction, For example,
conventional therapies include, but may not be limited to functional stimulation of the
intestinal tract, stool softening agents, laxatives (e.g., diphelymethane laxatives, cathartic
laxatives, osmotic laxatives, saline laxatives, etc), bulk forming agents and laxatives,
lubricants, intravenous hydration, and nasogastric decompression.

Kits and Uses of Inventive Formulations
Uses
[0092] As discussed above, the present invention provides methods and formulations
useful in antagonizing undesirable side effects of opioid activity, including of opioid
analgesic therapy (e.g., gastrointestinal effects (e.g., delayed gastric emptying, altered GI
tract motility), etc.). In certain embodiments, formulations of the invention may be used to
treat subjects having disease states that are ameliorated by any treatment where temporary
suppression of the u, opioid receptor system is desired (e.g., ileus, etc.). In certain
embodiments, provided formulations are used in human subjects.
[0093] 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.
[0094] 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.
[0095] In other embodiments, provided formulations are 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.

[0096] 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.
[0097] 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 or postpartum ileus, paralytic 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.
[0098] 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.
[0099] 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 ina death-inducing shock, while a long-term case of constipation may

also cause a horse's death. Treatment of equihes with peripheral opioid antagonists has been
described, e.g., in U.S. Patent Publication No. 20050124657 published January 20, 2005.
[00100] It will also be appreciated that formulations of the present invention can be
employed in combination therapies, that is, methylnaltrexone compositions 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".
[00101] In other embodiments, provided formulations, as well as compositions and
products comprising the provided formulations, 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 musculoskeletal system such as osteoporosis,
arthritis, osteitis, periostitis, myopathies, treatment of autoimmune diseases and immune
suppression, therapy of post-operative gastrointestinal dysfunction following abdominal
surgery (e.g., colectomy (e.g., right hemicolectomy, left hemicolectomy, transverse
hemicolectomy, colectomy takedown, low anterior resection) or hernia repair), 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. For example, as described herein, dry powder formulations may be reconstituted
with appropriate solvent. Reconstitute may be utilized as prepared as a medicament for
treatment of the foregoing disorders. Additionally or alternatively, reconstitute may be
further diluted for preparation of a medicament useful for treatment of the foregoing
disorders.
Pharmaceutical Kits and Packaging
[00102] 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, contents of provided formulation in a container combine to form a
unit dosage. In some embodiments, contents of provided formulation in a container can be
reconstituted in a solvent to form a dose concentrate.
(00103] In some embodiments, provided kits may optionally further include a second
container comprising appropriate solvent or diluent, and/or instructions for use of appropriate
solvent or diluent for preparation of reconstituted formulation. In some embodiments,
contents of provided formulation in a first container and solvent in a second container
combine to form a unit dosage. In some embodiments, contents of provided formulation in a
container and solvent in a second container combine to form a dose concentrate. In some
embodiments, contents of provided formulation, container and solvent container combine to
form a unit dosage. In some embodiments, contents of provided formulation container and
solvent container combine to form a dose concentrate.
[00104] In still other embodiments, a third container comprising a suitable aqueous
carrier for further dilution of a reconstitute for preparation of administration to a subject via
IV administration.
[00105] In some embodiments, a reconstituted 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 reconstituted 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 suitable for reconstitution
and for use in conjunction with PCA device.
[00106] Optionally, a single container may comprise one or more compartments for
containing a dry powder formulation, appropriate liquid carrier for reconstitution, 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 dry powder 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.
[00107] In some embodiments, a pharmaceutical kit comprises a dry powder
formulation in a reconstitution package or container wherein a needle-less exchange
mechanism allows for combination of lyophilate and aqueous carrier for dilution and/or with
isotonic diluent for preparation for intravenous administration. For example, in certain non-
limiting examples, a dry powder formulation of the invention may be utilized in conjunction
with a MINIBAG® Plus reconstitution package system (Baxter), or an ADD VANTAGE®
reconstitution package (Hospira) system.
[00108] 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 device (PCA). Thus, instructions
for use of provided formulations may comprise instructions for use in conjunction with PCA
administration devices.
[00109] 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
Example 1
Preparation of a lyophilized methylnaltrexone formulation.
[00110] We have found while an aqueous solution of methylnaltrexone is not stable
when maintained at room temperature for extended periods, a lyophilized amorphous solid
cake containing methylnaltrexone and a single filler or single cryoprotectant (e.g., lactose
monohydrate) is room temperature stable. For example, such lyophilized compositions may
be prepared using the following components:

[00111] AH equipment and equipment change parts were washed and sterilized prior to
initiation of preparation. Clean, sterile depyrogenated vials and clean, sterile rubber stoppers
were used during manufacture.
[00112] Formulations may be prepared with various amounts of methylnaltrexone and
filler. For example, three formulations and corresponding amounts of reagents for
preparation are shown in Table 1. For a 10 mL vial, 8.4, 12.6 or 25.2 mgs of
methylnaltrexone bromide was dissolved in sterile water for injection; and 42.0, 37.8 or 25.2
mgs of lactose monohydrate dissolved in the methylnaltrexone solution, to a total volume of
2.625 mL. In the particular studies described and formulations prepared in these examples,
R-N-methylnaltrexone was used having less than 0.15 weight percent S-N-methylnaltrexone
based on the total weight of methylnaltrexone; other stereoisomers, or mixtures thereof, could
alternatively be employed.
[00113] Solutions were prepared, filter sterilized using 0.45um and 0.22um filters, and
resulting sterilized solution filled under low oxygen conditions into containers for
lyophilization. Any suitable vial, ampoule, syringe or auto-dispenser may be utilized for
filling in advance of lyophilization.


[00114] For lyophilization of mixture: shelf temperature was set to 20 °C or to 25 °C,
then vials were loaded into the lyophilizer, and the shelf temperature was lowered to -45 °C
or below at 1 °C/ min, and was held for at least 2 hours. A vacuum of at least 100 mTorr was
applied for freeze-drying, then the shelf temperature was held at at -45 °C for an additional 20
minutes. Primary drying was initiated by raising the shelf temperature to +5 °C or +20 °C at
0.5 °C/ minute, and maintaining for at least 14-17 hours.
[00115] Shelf temperature was next raised to +35 °C or to +40 °C at 0.5 °C/ minute for
a secondary (terminal) drying, and was maintained for at least 5 hr or until the product
temperature was above 30 °C. The product was cooled to 25 °C at 0.5 °C/ minute, then the
product chamber vacuum was released with 0.22 um filtered nitrogen to lA atm or 500 mBar
(7.5 PSI).
[00116] Lyophilized formulation was packaged under nitrogen at Vi atm in a 10 mL
vial with a 20 mm neck. Resulting lyophilized formulations may be stored at room
temperature. Specifically, such formulations can be stored at 25 °C or below, and can tolerate
excursions to 30 °C.
[00117] Stoppers utilized were WPS V10-F597W 4432/50 B2TR Westar RS stoppers,
which allow for needle-less transfer of reconstituted methylnaltrexone to a final
reconstitution container for further dilution in preparation for administration to a subject. The
needle-less function of this reconstitution container for preparation of intravenous solution
aids the end user by not having to use a needle syringe to transfer the contents of the vial to a
standard intravenous bag.
[00118] Vials were often protected from light, and were not frozen.
[00119] When desired for administration, lyophilized cake can be reconstituted with 10
mL of appropriate solvent such as, for example, Water for Injection USP. Solvent may
typically be supplied with lyophilized methylnaltrexone, in a separated container (e.g., vial).
Dissolution is achieved by addition of solvent and gentle agitation of the vial, resulting in a
final drug concentration of 0.8, 1.2, or 2.4 mg/mL, as appropriate for each concentration.

Following dissolution of the lyophilized cake, resulting solution is then diluted to a final
methylnaltrexone bromide concentration of 0.04mg/mL, 0.24 mg/mL, or 0.48 mg/mL by
addition of 50 mL of an appropriate isotonic solution for intravenous delivery to a subject.
Packaged formulations can be used to transfer dose concentrate to any appropriate
intravenous container comprising appropriate diluent solution. In certain embodiments, dose
concentrate is further diluted by addition of the reconstitute to a Minibag Plus
Reconstitution Container (Baxter) for intravenous administration.
Example 2
Stability of a lyophilized methylnaltrexone formulation
[00120] We determined the stability of lyophilized formulations by assessment of the
presence of various degradant formation in the sample following a period of days of storage
under specified conditions using HPLC analysis of samples following storage conditions
under dark conditions in variable temperature/humidity as well as under variable light
conditions. Stability studies were performed using standard pharmaceutical stability studies
carried out according to ICH guidelines.
[00121] Specifically, as discussed in that patent application, at least three previously
known degradation products of methylnaltrexone 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.
[00122] For HPLC analysis a Prodigy ODS-3 15cm X 2.0mm, 3um particles
(Phenomenex) HPLC column at a flow rate of 0.25 mL/min, using a water/methanol gradient
was used. The following specifications were utilized for HPLC column:
Mobile Phase: Strength (Isocratic: 75:25 (v/v) 0.1% TFA in Water/Methanol
Purity: (Gradient):
Mobile Phase A = 95:5 (v/v) 0.1% TFA in Water/Methanol
Mobile Phase B = 35:65 (v/v) 0.1 % TFA in Water/Methanol


Flow: 0.25 mL/minute
Detection: UV,280nm
Injection: Strength: 5 μL
Purity: 20 μL
Sample Solvent: 0.05M Dibasic Sodium Phosphate pH 6.8
[00123] The following compounds were identified in the stability studies using HPLC
analysis of samples under the indicated storage conditions, and had the following associated
calculated relative retention times:



[00124] Naltrexone base, S-methylnaltrexone, and O-methyl Methylnaltrexone are
each compounds found in initial production samples. Additional impurities/degradants
formed and identified in methylnaltrexone formulations include 8-ketomethylnaltrexone
bromide (RRT 0.49), the aldol dimer (RRT 1.77), O-methyl methylnaltrexone (RRT 1.66),
and the 2,2 bis-methylnaltrexone (RRT 1.55), as well as additional degradants resulting at
relative retention time of 0.67, 0.79 and 2.26.

[00125] 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,llbS)-6-carboxy-3-
(cyclopropylmethyI)-4a,6,8-trihydroxy-3-methyl-l,2,3.4,4a,5,6,6a-octahydro-4,ll-
methano[1]benzofuro[3',2':2,3]cyclopentat[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).

(3R,4R,4aS,6aR,llbS)-6-carboxy-3-(cyclopropylmethyl)-4a,6,8-trihydroxy-3-methyI-
l,2,3,4)4a,5,6,6a-octahydro^,ll-methano[l]benzofuro[3',2,:2,3]cycIopenta[l,2-c]pyridin-3-iurn)

[00126] Table 2 summarizes the formulation stability data from the high concentration
methylnaltrexone formulation (24 mg/vial) at room temperature or 40°C/75% relative
humidity from initial preparation until after 28 days of storage of sample. The data confirm

that a lyophilized formulation consisting of methylnaltrexone and a single filler or single
cryoprotectant remains stable, with total degradant formation remaining below 0.3% after 28
days of storage conditions. Furthermore, no degradant formation beyond those seen at initial
preparation accumulated after 28 days of storage. Each of the peaks resulting in the NMR are
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 dimmer
formation; RRT 2.26 represents the Hoffman elimination product. Tables 2A and 2B
summarize stability data for a 24 mg/vial formulation until 6 or 12 months. Tables 2C and
2D summarize stability data for a 12 mg/vial formulation until 6 or 12 months.
[00127) Table 3 summarizes the formulation light stability data from middle
concentration methylnaltrexone formulation (12 mg/vial) after storage of sample under dark
or light conditions. The data confirms that a lyophilized formulation consisting of
methylnaltrexone and cryoprotectant remains stable, with total degradant formation
remaining below 0.12% after storage in light exposure.

Example 3
[00128] In certain embodiments, the present invention provides a methylnaltrexone
formulation for intravenous administration. Provided intravenous formulations can be
prepared in 12 mg/vial or 24 mg/vial concentrations. Both 12 mg/vial and 24 mg/vial
strengths use a 5 mg/mL concentration of methylnaltrexone. In certain embodiments,
provided intravenous formulations utilize a 10 mL spikable vial designed to be used with
Baxter mini-bags or any other spikable infusion system. In some embodiments, provided
formulations were subjected to terminal sterilization by heating at 121°C for 15 minutes.
{00129] In certain embodiments, formulations are prepared in 12 mg/vial or 24 mg/vial
concentrations. 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 rnL and administered using a calibrated pump.
[00130] 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 5 below describes vial
contents dilution when using a traditional syringe or a spikable vial.

Example 4
[00l31] 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.
Equivalents
[00132] 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.
[00133] 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.

CLAIMS
We claim:
1. An amorphous dry powder formulation consisting essentially of methylnaltrexone, or
a pharmaceutically acceptable salt thereof, and a filler.
2. The formulation of claim 1, wherein the methylnaltrexone is methylnaltrexone
bromide.
3. The formulation of claim 1 or claim 2, wherein the filler is selected from the group
consisting of a lactose, mannitol, and dextran.
4. The formulation of claim 3, wherein the filler is a lactose.
5. The formulation of claim 4, wherein lactose is lactose monohydrate.
6. The formulation of claim 1, consisting essentially of:
about 5 to about 500 mg of methylnaltrexone bromide; and
lactose monohydrate.
7. The formulation of any one of claims 1 to 6, wherein the methylnaltrexone and filler
are present in approximately equal amounts by weight.
8. The formulation of any one of claims 1 to 6, wherein the methylnaltrexone and filler
are present in a ratio within the range of about 1:1 to about 1:5 by weight.
9. A solution consisting essentially of water and the formulation of any one of claims 1
to 8.
10. The solution of claim 9, wherein methylnaltrexone bromide is present in a
concentration of about 0.5 mg/mL to about 25 mg/mL.

11. A method of producing a stable, sterile pharmaceutical product comprising steps of:
obtaining the solution of claim 9 or claim 10; and
lyophilizing the composition.
12. The method of claim 11, wherein the lyophilizing step comprises the steps of:
a. exposing the solution at a temperature of about -10°C to about -75"C, for at least
about 30 minutes to about S hours,
b. applying a vacuum during or after the exposing, and maintaining for at least 5
minutes;
c. raising the temperature to a first drying temperature within the range of about -
30°C to about 30°C, and maintaining the temperature at the first drying
temperature for at least about 15 hours to about 40 hours to produce a primary
lyophilate,
d. raising the temperature to a second drying temperature within the range of about
00C to about 600C, and maintaining the temperature at the second drying
temperature for at least about 5 hours,
to produce an amorphous solid.
13. The method of claim 12, wherein the composition is maintained at a temperature from
about 10 0C to about 30 °C.
14. The method of claim 12, wherein step (a) comprises exposing to a temperature of
from about -30 °C to about -50°C.
15. The method of claim 14, wherein the primary drying temperature in the primary
drying stage is maintained for at least about 15 hours to about 30 hours.
16. The method of claim 15, wherein the second drying temperature is from about 20 °C
to about 40 °C.
17. The method of claim 12, wherein (a) the first drying temperature is from about -10 °C
to about 0 °C, (b) the first drying stage is carried out at a pressure of about 200 micron Hg or
less, and (c) the first drying temperature is maintained for at least about 15 hours to about 30
hours.

18. The method of claim 17, wherein (a) the second drying temperature is from about 20
°C. to about 40 °C, (b) the second drying temperature is maintained for at least about 2 hours
to about 10 hours, and (c) the second drying stage is carried out at a pressure of about 200
micron Hg or less.
19. The method of claim 18, wherein (a) the first drying temperature is from about -10 °C
to about 0 °C, (b) the first drying stage is carried out at a pressure of about 200 micron Hg or
less, and (c) the first drying temperature is maintained for at least about 15 hours to about 30
hours (d) the second drying temperature is from about 20 °C. to about 40 °C, (e) the second
drying temperature is maintained for at least about 2 hours to about 10 hours, and (f) the
second drying stage is carried out at a pressure of about 200 micron Hg or less.
20. A pharmaceutical dosage preparation comprising a solid pharmaceutical formulation
consisting essentially of methylnaltrexone, or a pharmaceutically acceptable salt thereof, and
a filler, in a sealed container.
21. The pharmaceutical dosage preparation of claim20, wherein the filler is selected from
the group consisting of a lactose, mannitol, and dextran.
22. The pharmaceutical dosage preparation of claim21, wherein the filler is a lactose.
23. The pharmaceutical dosage preparation of claim22, wherein the lactose is lactose
monohydrate.
24. A method for reducing the side effects of opioid therapy in a subject receiving opioid
treatment or use comprising administering to a subject in need thereof a regimen comprising
reconstituting a formulation according to any one of claim 1 to 8 in a pharmaceutically
acceptable aqueous solvent, and administering the solution to the subject.
25. The method according to claim24, wherein the reconstituting step is followed by
diluting the reconstituted formulation in an isotonic carrier, and administering the diluted
solution to the subject.

26. A kit comprising a first container containing a formulation according to any one of
claims 1 to 8, and a second container containing an aqueous carrier.

The present invention provides lyophilized formulations comprising methylnaltrexone, and processes for preparation
of provided formulations. Additionally provided are compositions and products containing the methylnaltrexone formulation,
as well as methods for producing formulations, compositions and products. Provided formulations as well as compositions and
products containing methylnaltrexone formulations are useful for preventing, treating delaying, diminishing or reducing the severity
and/or incidence of side effects resulting from administration of analgesic opioids.