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`Formulations of Guanylate Cyclase C Agonists and
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`Formulations of Guanylate Cyclase C Agonists and Methods of Use
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`Electronically Filed
`Date of Deposit: March 15, 2012
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`Attny Ref.: 40737-509001US
`
`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND
`
`METHODSOF USE
`
`RELATED APPLICATIONS
`
`[01]
`
`This application is a continuation-in-part of PCT/US2011/051805 filed on September
`
`15, 2011, which claims the benefit of priority to U.S. Provisional Application No. 61/383,156
`
`filed on September 15, 2010, U.S. Provisional Application No. 61/387,636 filed on
`
`September 29, 2010, and U.S. Provisional Application No. 61/392,186 filed on October 12,
`
`2010, the contents of which are incorporated by reference in their entireties.
`
`FIELD OF THE INVENTION
`
`[02]
`
`The present invention relates to low-dose formulations of guanylate cyclase C peptide
`
`agonists useful for the treatment and prevention of various diseases and disorders.
`
`BACKGROUNDOF THE INVENTION
`
`[03]
`
`Guanylate cyclase C is a transmembrane form of guanylate cyclase that is expressed
`
`on variouscells, including gastrointestinal epithelial cells (reviewed in Vaandrager 2002 Mol.
`
`Cell. Biochem. 230:73-83). It was originally discovered as the intestinal receptor for the heat-
`
`stable toxin (ST) peptides secreted by enteric bacteria and which cause diarrhea. The ST
`
`peptides share a similar primary amino acid structure with two peptides isolated from
`
`intestinal mucosa and urine, guanylin and uroguanylin (Currie, et al., Proc. Nat’! Acad. Sci.
`
`USA 89:947-951 (1992); Hamra,et al., Proc. Nat’l Acad. Sci. USA 90:10464-10468 (1993);
`
`Forte, L., Reg. Pept. 81:25-39 (1999); Schulz,et al., Cell 63:941-948 (1990); Guba, ef al.,
`
`Gastroenterology 111:1558-1568 (1996); Joo, et al., Am. J. Physiol. 274:G633-G644 (1998)).
`
`[04]
`
`In the intestines, guanylin and uroguanylin act as regulators of fluid and electrolyte
`
`balance. In response to high oral salt intake, these peptides are released into the intestinal
`
`lumen where they bind to guanylate cyclase C localized on the luminal membrane of
`
`enterocytes (simple columnar epithelial cells of the small intestines and colon). The binding
`
`of the guanylin peptides to guanylate cyclase C induces electrolyte and water excretion into
`
`0004
`
`0004
`
`

`

`the intestinal lumen via a complex intracellular signaling cascadethatis initiated by an
`
`increase in cyclic guanosine monophosphate (CGMP).
`
`[05]
`
`The cGMP-mediated signaling that is initiated by the guanylin peptidesis critical for
`
`the normal functioning of the gut. Any abnormality in this process could lead to
`
`gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel
`
`diseases. Inflammatory bowel disease is a general name given to a group of disorders that
`
`cause the intestines to become inflamed, characterized by red and swollen tissue. Examples
`
`include ulcerative colitis and Crohn’s disease. Crohn's disease is a serious inflammatory
`
`disease that predominantly affects the ileum and colon, but can also occurin other sections of
`
`the gastrointestinal tract. Ulcerative colitis is exclusively an inflammatory disease of the
`
`colon, the large intestine. Unlike Crohn's disease, in which all layers of the intestine are
`
`involved, and in which there can be normal healthy bowel in between patches of diseased
`
`bowel, ulcerative colitis affects only the innermost lining (mucosa) of the colon in a
`
`continuous manner. Depending on whichportion of the gastrointestinal tract is involved,
`
`Crohn's disease may bereferred to as ileitis, regional enteritis, colitis, etc. Crohn's disease
`
`and ulcerative colitis differ from spastic colon orirritable bowel syndrome, which are
`
`motility disorders of the gastrointestinal tract. Gastrointestinal inflammation can be a chronic
`
`condition,
`
`It is estimated that as many as 1,000,000 Americansare afflicted with
`
`inflammatory bowel disease, with male and female patients appearing to be equally affected.
`
`Mostcases are diagnosed before age 30, but the disease can occurin the sixth, seventh, and
`
`later decadesoflife.
`
`[06]
`
`IBS and chronic idiopathic constipation are pathological conditions that can cause a
`
`great deal of intestinal discomfort and distress but unlike the inflammatory bowel diseases,
`
`IBS does not cause the serious inflammation or changes in boweltissue andit is not thought
`
`to increase the risk of colorectal cancer. In the past, inflammatory boweldisease, celiac
`
`disease and IBS were regarded as completely separate disorders. Now, with the description
`
`of inflammation, albeit low-grade, in IBS, and of symptom overlap between IBS and celiac
`
`disease, this contention has come under question. Acute bacterial gastroenteritis is the
`
`strongestrisk factor identified to date for the subsequent development of postinfective
`
`irritable bowel syndrome. Clinical risk factors include prolonged acute illness and the
`
`absence of vomiting. A genetically determined susceptibility to inflammatory stimuli may
`
`also be a risk factor for irritable bowel syndrome. The underlying pathophysiology indicates
`2
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`0005
`
`0005
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`

`

`increased intestinal permeability and low-grade inflammation, as well as altered motility and
`
`visceral sensitivity. Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut
`
`function and is knownto play a majorrole in pathophysiology of IBS. The activity of 5-HTis
`
`regulated by cGMP.
`
`[07] While the precise causes of IBS and inflammatory bowel diseases (IBD) are not
`
`known,a disruption in the process of continual renewal of the gastrointestinal mucosa may
`
`contribute to disease pathology in IBD and aggravate IBS. The renewal process of the
`
`gastrointestinal lining is an efficient and dynamic process involving the continual
`
`proliferation and replenishment of unwanted damagedcells. Proliferation rates of cells lining
`
`the gastrointestinal mucosa are very high, second only to the hematopoietic system.
`
`Gastrointestinal homeostasis depends on both the proliferation and programmedcellular
`
`death (apoptosis) of epithelial cells lining the gut mucosa. Cells are continually lost from the
`
`villus into the lumenofthe gut and are replenished at a substantially equal rate by the
`
`proliferation of cells in the crypts, followed by their upward movementto the villus. The
`
`rates of cell proliferation and apoptosis in the gut epithelium can be increased or decreased in
`
`a variety of circumstances, e.g., in response to physiological stimuli such as aging,
`
`inflammatory signals, hormones, peptides, growth factors, chemicals and dietary habits. In
`
`addition, an enhanced proliferation rate is frequently associated with a reduction in turnover
`
`time and an expansion ofthe proliferative zone. The proliferation index is much higherin
`
`pathological states such as ulcerative colitis and other gastrointestinal disorders. Intestinal
`
`hyperplasia is a major promoter of gastrointestinal inflammation. Apoptosis and cell
`
`proliferation together regulate cell number and determine the proliferation index. Reduced
`
`rates of apoptosis are often associated with abnormal growth, inflammation, and neoplastic
`
`transformation. Thus, both increased proliferation and/or reduced cell death may increase the
`
`proliferation index of intestinal tissue, which mayin turn lead to gastrointestinal
`
`inflammatory diseases.
`
`[08]
`
`In addition to a role for uroguanylin and guanylin as modulators of intestinal fluid and
`
`ion secretion, these peptides mayalso be involved in the continual renewal of gastrointestinal
`
`mucosa by maintaining the balance betweenproliferation and apoptosis. For example,
`
`uroguanylin and guanylin peptides appear to promote apoptosis by controlling cellular ion
`
`flux. Given the prevalence of inflammatory conditions in Western societies a need exists to
`
`0006
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`0006
`
`

`

`improve the treatment options for inflammatory conditions, particularly of the gastrointestinal
`
`tract.
`
`[09]
`
`Peptide agonists of guanylate cyclase C agonists (“GCC agonists”) are described in
`
`U.S. Patent Nos. 7,041,786, 7,799,897, and U.S. Patent Application Publication Nos.
`
`US2009/0048175, US 2010/0069306, US 2010/0120694, US 2010/0093635, and US
`
`2010/0221329. However, the formulation of peptides for pharmaceutical delivery presents a
`
`numberof special problems. For example, peptides are subject to structural modifications by
`
`a variety of degradation mechanismsresulting in problems of chemical and physical
`
`instability of the formulation.
`
`SUMMARYOF THE INVENTION
`
`[10]
`
`The present invention provides low-dose formulations of peptide agonists of
`
`guanylate cyclase C (“GCC”) and methodsfor their use in the treatment and prevention of
`
`humandiseases and disorders, such as a gastrointestinal motility disorder, irritable bowel
`
`syndrome,a functional gastrointestinal disorder, gastroesophagealreflux disease, functional
`
`heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic
`
`intestinal pseudo-obstruction, colonic pseudo-obstruction; Crohn's disease, ulcerative colitis,
`
`inflammatory bowel disease, colonic pseudo-obstruction, obesity, congestive heart failure,
`
`and benign prostatic hyperplasia. In certain embodiments, the formulations are stabilized
`
`against chemical degradation of the peptide. The low-dose formulations of the invention
`
`have unexpected efficacy in humansin a dosage range that was not predicted based on
`
`studies in primates. The formulations of the invention are particularly useful for the
`
`treatment or prevention of chronic idiopathic constipation. In certain embodiments, the GCC
`
`agonists are analogs of uroguanylin and bacterial ST peptides. In preferred embodiments, the
`
`analogs have superior properties compared to the naturally occurring or “wild-type” peptides.
`
`Examples of such superior properties include a high resistance to degradation at the N-
`
`terminus and C-terminus from carboxypeptidases, aminopeptidases, and/or by other
`
`proteolytic enzymes present in the stimulated humanintestinal juices and humangastric
`
`juices. Examples of GCC agonists that can be used in the formulations and methodsof the
`
`invention are described in moredetail below and in U.S. Patent Nos. 7,041,786, 7,799,897,
`
`and U.S. Patent Application Publication Nos. US2009/0048175, US 2010/0069306, US
`
`4
`
`0007
`
`0007
`
`

`

`2010/0120694, US 2010/0093635, and US 2010/0221329, each of which is incorporated
`
`herein by reference in its entirety.
`
`[11]
`
`The invention provides an oral dosage formulation comprising one or more
`
`pharmaceutically acceptable excipients and at least one GCC agonist peptide, wherein the
`
`amount of GCC agonist peptide per unit dose is from 0.01 mg to 10 mg, and wherein the
`
`GCC agonist peptide is selected from the group consisting of SEQ ID NOs: 1-54 and 56-249.
`
`In one embodiment, the GCC agonist peptide has a chromatographic purity of no less than
`
`90%, no less than 90.5%, no less than 91%, no less than 92%, no less than 93%, no less than
`
`94%, no less than 95%, no less than 96%, no less than 97%, no less than 98%, or no less than
`
`99%. The chromatographic purity of the GCC agonist peptide is determined as area percent
`
`by HPLC. In one embodiment, the GCC agonist peptide is selected from the group
`
`consisting of SEQ ID NOs: 1, 8, 9, or 56. In one embodiment, the GCC agonist peptide is
`
`selected from the group consisting of SEQ ID NOs: 1 and 9. In one embodiment, the GCC
`
`agonist peptide is selected from the group consisting of SEQ ID NOs: 8 and 9.
`
`In one
`
`embodiment, the amount of GCC agonist peptide per unit dose is 0.1 mg, 0.3 mg, 0.6 mg, 1.0
`
`mg, 3.0 mg, 6.0 mg, 9.0 mg or 9.5 mg.
`
`[12]
`
`In one embodiment, the GCC agonist peptide has a total impurity content of no
`
`greater than 10%, no greater than 9.5%, no greater than 9%, no greater than 8%, no greater
`
`than 7%, no greater than 6%, no greater than 5%, no greater than 4%, no greater than 3%, no
`
`greater than 2%, or no greater than 1%. The total impurity content is determined as total area
`
`percentages of impurities by HPLC. The impurities do not include any pharmaceutically
`
`acceptable excipient used for the formulation. In one embodiment, the formulation is
`
`substantially free of inorganic acids and carboxylic acids, e.g., HCl, phosphoric acid, or
`
`acetic acid. In this context, carboxylic acids do not include aminoacids or peptides. In this
`
`context “substantially” free of acids meansthat the acid content of the formulation at the time
`
`of packaging is preferably less than 0.2%, less than 0.1%, less than 0.05%, less than 0.01%,
`
`less than 0.005%, or less than 0.001% of the total weight of the formulation. In one
`
`embodiment, the formulation is free of HCl.
`
`[13]
`
`In one embodiment, the formulation is a solid formulation.
`
`In one embodiment, the
`
`formulation is in the form of a powder, granule, sachet, troche, tablet, or capsule. In another
`
`embodiment, the formulation is a liquid formulation and the GCC agonist peptide is in
`
`5
`
`0008
`
`0008
`
`

`

`solution or suspension in a lipophilic liquid. In one embodiment, the liquid is a refined
`
`specialty oil or a medium chain triglyceride or related ester. In one embodiment, the refined
`
`specialty oil is selected from Arachis oil, Castor oil, cottonseed oil, maize (corn) oil, olive oil,
`
`sesame oil, soybean oil, and sunfloweroil. In one embodiment, the medium chain
`
`triglyceride or related ester is AKOMED E, AKOMED R, CAPTEX 355, LABRAFAC CC,
`
`LABRAPAC PG, LAUROGLYCOL FCC, MIGLYOL 810, MIGLYOL 812, MIGLYOL
`
`829, MIGLYOL 840, and SOFTISAN 645. In one embodiment, the liquid is selected from
`
`the group consisting of medium chain triglycerides, propylene glycol dicaprylocaprate,
`
`vitamin E, soybean oil, Cremaphor, PG, and PG 400. In one embodiment, the unit dose is a
`
`powder,tablet, or capsule. In one embodiment, the unit dose is a liquid-filled capsule. In one
`
`embodiment, the capsule or tablet is in a blister pack or strip. Preferably, the blister pack or
`
`strip is made of a material that is impermeable to water vapor and oxygen. In one
`
`embodimentthe blister pack is comprised of a metal foil. In one embodimentthe blister pack
`
`is a FOIL/FOILblister pack. In one embodiment, the container of the blister pack is flushed
`
`with an inert gas such as nitrogen or argon.
`
`In one embodiment, the container further
`
`includes a desiccant. In a preferred embodimentthe desiccant is a molecular sieve. In one
`
`embodiment, the unit dose is in a high density polyethylene bottle having a seal. In one
`
`embodiment, the bottle further comprises a desiccant.
`
`In one embodiment, the bottle further
`
`comprises an oxygen scavenger or molecular sieve. In one embodiment, the bottle is nearly
`
`impermeable to oxygen and water vapor(e.g., much more impermeable than a HDPEbottle),
`
`such as an OxyGuardbottle.
`
`[14]
`
`In one embodiment, the one or more pharmaceutically acceptable excipients include
`
`an inert carrier. In one embodiment, the inert carrier is a selected from mannitol, lactose, a
`
`microcrystalline cellulose, or starch.
`
`In one embodiment, the inert carrier has a particle size
`
`of from 50 to 900 microns, from 50 to 800 microns, from 50 to 300 microns, from 50 to 200
`
`microns, from 75 to 150 microns, from 75 to 200 microns, or from 75 to 300 microns.
`
`[15]
`
`In one embodiment, the GCC agonist peptide is stabilized against chemical or
`
`physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity, or
`
`at least 18 monthsat 25 °C and 60% relative humidity, or at least 18 months at 2-8 °C.
`
`[16]
`
`In one embodiment, the one or more pharmaceutically acceptable excipients include a
`
`divalent cation salt such as calcium chloride. In one embodiment, the one or more
`
`6
`
`0009
`
`0009
`
`

`

`pharmaceutically acceptable excipients comprise an amino acid, such as leucine,histidine, or
`
`arginine, or an amine such TRIS or TRIS/HC1.
`
`[17]
`
`In one embodiment, the oral dosage formulation consists of the GCC agonist peptide
`
`described herein, an inert carrier (e.g., Celphere SCP-100, Avicel PH 102, or Avicel PH 112),
`
`and a lubricant(e.g., magnesium stearate). In one embodiment, the formulation consists of
`
`the GCC agonist peptide, an inert carrier (e.g., Avicel PH 200), a divalent cation salt (e.g.,
`
`calcium chloride or calcium ascorbate), an aminoacid (e.g., leucine, histidine, or arginine) or
`
`a protective amine(e.g., TRIS), a coating agent (e.g., Methocel ES Premium LV) and
`
`optionally a lubricant (e.g., magnesium stearate) or another additive (e.g., trehalose). In one
`
`embodiment, the formulation consists of the GCC agonist peptide, a binder (e.g., Provsolv
`
`SMCC 90 LM), and a disintegrant(e.g., Explotab). In one embodiment, the formulation
`
`consists of the GCC agonist peptide, a diluent (e.g., Mannogem EZ), a binder(e.g., Provsolv
`
`SMCC 90 LM), a disintegrant(e.g., Explotab), a lubricant(e.g., Pruv).
`
`[18]
`
`The invention also provides a process for making the oral dosage formulations
`
`described herein, wherein the process comprises a step of dry granulation, wet granulation, or
`
`spray coating followed by drying. In another embodiment, the process comprises a step of
`
`dry mixing. In a preferred embodimentthe step of dry mixing includes geometric blending.
`
`In one embodiment, the process comprises a step of direct compression. In one embodiment,
`
`the process for making the oral dosage formulations described herein is a spray coating-
`
`drying process which includes (a) providing an aqueoussolution comprising: a GCC agonist
`
`peptide selected from the group consisting of SEQ ID NOs: 1-54 and 56-249, and one or
`
`more pharmaceutically acceptable excipients, wherein the concentration of the GCC agonist
`
`peptide ranges from 10 to 60 mg/mL;and (b) applying the aqueoussolution to a
`
`pharmaceutically acceptable carrier to generate a GCC agonist peptide-coatedcarrier.
`
`[19]
`
`In one embodimentof the spray coating-drying process above, the one or more
`
`pharmaceutically acceptable excipients comprise a divalent cation salt wherein the divalent
`cation is selected from Ca**, Mg", Zn**, and Mn**.
`In one embodiment, the one or more
`
`pharmaceutically acceptable excipients comprise an amino acid selected from leucine,
`
`isoleucine, and valine. In one embodiment, the one or more pharmaceutically acceptable
`
`excipients comprise a coating agent (such as hypromellose Methocel E5 PremLV). In one
`
`embodiment, the aqueoussolution has a pH greater than 4 (e.g., 4.5-5.5, 5-6, about 5, or
`
`7
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`0010
`
`0010
`
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`

`greater than 5) or even greater than 7. In one embodiment, the aqueoussolutionis
`
`substantially free of inorganic acids and carboxylic acids. In one embodiment, the GCC
`
`agonist peptide is selected from the group consisting of SEQ ID NOs: 1, 8, 9, and 56. In one
`
`embodiment, the process further includes drying the GCC agonist peptide-coated carrier.
`
`[20]
`
`The invention further provides an oral dosage formulation made by the process
`
`described herein. Preferably, the GCC agonist peptide as made is stabilized against chemical
`
`or physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity,
`
`or at least 18 months at 25 °C and 60% relative humidity, or at least 18 monthsat 2-8 °C.
`
`[21]
`
`The invention also provides a method for treating or preventing a disease or disorder
`
`in a subject in need thereof, comprising administering to the subject an oral dosage
`
`formulation comprising at least one GCC agonist peptide, wherein the amount of GCC
`
`agonist peptide per unit dose is from 0.01 mg to 10 mg, and wherein the GCC agonist peptide
`
`is selected from the group consisting of SEQ ID NOs: 1-54 and 56-249. Preferably, the
`
`subject is a human subject. In one embodiment, the GCC agonist peptide is selected from the
`
`group consisting of SEQ ID NOs: 1, 8, 9, or 56. In one embodiment, the GCC agonist
`
`peptide is selected from the group consisting of SEQ ID NOs: 1 and 9. In one embodiment,
`
`the amount of GCC agonist peptide per unit dose is 0.1 mg, 0.3 mg, 0.6 mg, 1.0 mg, 3.0 mg,
`
`6.0 mg, 9.0 mg, 9.5 mg, or 10 mg.
`
`[22]
`
`In one embodiment, the disease or disorderis a gastrointestinal disease or disorder
`
`selected from the group consisting of irritable bowel syndrome, non-ulcer dyspepsia, chronic
`
`intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction,
`
`duodenogastric reflux, gastro esophageal reflux disease, constipation, gastroparesis,
`
`heartburn, gastric cancer, and H. pylori infection. In a preferred embodiment, the
`
`gastrointestinal disease or disorder is chronic idiopathic constipation.
`
`[23]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amountof an inhibitor of a cGMP-specific phosphodiesterase. In one embodiment,
`
`the cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of
`
`suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil.
`
`0011
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`0011
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`

`[24]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amount of at least one laxative. In one embodiment, the at least one laxative is
`
`selected from the group consisting of SENNA, MIRALAX,PEG,or calcium polycarbophil.
`
`[25]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amountof at least one anti-inflammatory agent.
`
`[26]
`
`The invention also provides pharmaceutical compositions comprising the
`
`formulations described herein.
`
`[27]
`
`Other features and advantages of the invention will be apparent from and are
`
`encompassedbythe following detailed description and claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[28]
`
`Figure 1: Plecanatide (SP-304) treatment reduced timeto first BM following daily
`
`dose.
`
`[29]
`
`Figure 2: Effect of daily treatment with plecanatide on spontaneous bowel
`
`movements (SBM)in chronic constipation patients.
`
`[30]
`
`Figure 3: Effect of daily treatment with plecanatide on complete spontaneous bowel
`
`movements (CSBM)in chronic constipation patients.
`
`[31]
`
`Figure 4: Effect of daily treatment with plecanatide on Bristol Stool Form Scores
`
`(BSFS) in chronic constipation patients.
`
`[32]
`
`Figure 5: Effect of daily treatment with plecanatide on straining scores in chronic
`
`constipation patients
`
`[33]
`
`Figure 6: Percentage of subjects reporting improvements in abdominal discomfort
`
`scores after 14-days of daily treatment with plecanatide.
`
`DETAILED DESCRIPTION
`
`[34]
`
`The invention provides pharmaceutical formulations of peptide GCC agonists. It is
`
`intended that the formulations of the invention are “pharmaceutical” formulations, meaning
`9
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`0012
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`0012
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`

`

`that they are suitable for pharmaceutical use. Accordingly, the term “formulations” as used
`
`herein is meant to encompass pharmaceutical formulations even if “pharmaceutical” is not
`
`expressly stated. Pharmaceutical compositions comprising the formulations described herein
`
`are also provided by the invention. The formulations of the invention preferably provide
`
`stability against chemical and physical degradation of the peptide, e.g., plecanatide (i.e., SEQ
`
`ID #1).
`
`[35]
`
`The invention is based in part upon the discovery that mannitol mixes very effectively
`
`with the GCC agonist peptides described herein and providesstability against degradation,
`
`allowing the peptides to be formulated at very low doses. The invention is also based in part
`
`on the discovery that very low doses of the GCC agonist peptides described herein are
`
`effective for the treatment of diseases and disorders in humans. The dosage range found to
`
`be effective was not predicted based on animal studies. The invention is also based in part
`uponthe discovery that a divalent cation (e.g., Ca’*) and/or an aminoacid(e.g., leucine or
`
`arginine) stabilize the GCC agonist peptides described herein during a process(e.g., spray
`
`coating-drying process) of manufacturing a formulation of the GCC agonist peptides and
`
`providesstability against degradation both during the manufacturing process and storage of
`
`the formulation.
`
`[36]
`
`Plecanatide is a charged peptide due to the presence of four carboxylic acids and
`
`single amine group with a calculated pKa of approximately 3.5. Therefore plecanatide is
`
`likely to interact with ions in solution or in the solid state. Plecanatide is a hygroscopic
`
`peptide requiring the control of water during manufacture and storage to promote long term
`
`stability. Plecanatide is prone to degradation by oxidation in the presence of residual
`
`peroxides or formaldehyde contaminants that are formed from peroxide reaction with
`
`polymeric excipients. The present invention discloses a manufacturing process and dry solid
`
`formulation compositions that minimizes water content. The formulations are comprised of
`
`components to minimize levels of residual formaldehyde and peroxides commonly found in
`
`many pharmaceutical excipients. The invention also discloses additives (i.e. CaClz) that may
`
`function as local desiccants in the formulation. Divalent cation salts such as calcium
`
`ascorbate, MgCh, ZnCl, MnCl, and CaCl, bind plecanatide andsterically hinder reactive
`
`species such as water or oxygen from causing plecanatide degradation by molecular
`
`displacement. The invention further includes scavengers of residual formaldehyde (amines
`
`such as TRIS or TRIS/HC]Ior aminoacids such as leucine, isoleucine and valine), and
`10
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`0013
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`0013
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`discloses packaging confirmations to minimize oxygen exposure and water vapor during
`
`storage. The invention also discloses a stable manufacturing process comprised ofinitially
`
`dissolving plecanatide in cold water to minimize solution degradation, followed by spray
`
`coating the peptide solution on particles and drying to remove moisture.
`
`[37]
`
`The formulations of the invention are particularly useful for the treatment or
`
`prevention of a gastrointestinal disease or disorder selected from the group consisting of
`
`irritable bowel syndrome, non-ulcer dyspepsia, chronic intestinal pseudo-obstruction,
`
`functional dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastro esophageal
`
`reflux disease, chronic idiopathic constipation, gastroparesis, heartburn, gastric cancer, and
`
`H. pylori infection.
`
`[38]
`
`In one embodiment, the formulations of the invention are used in a method for the
`
`treatment of constipation. Clinically accepted criteria that define constipation range from the
`
`frequency of bowel movements, the consistency of feces and the ease of bowel movement.
`
`One commondefinition of constipation is less than three bowel movements per week. Other
`
`definitions include abnormally hard stools or defecation that requires excessive straining.
`
`Constipation may be idiopathic (functional constipation or slow transit constipation) or
`
`secondary to other causes including neurologic, metabolic or endocrine disorders. These
`
`disorders include diabetes mellitus, hypothyroidism, hyperthyroidism, hypocalcaemia,
`
`Multiple sclerosis, Parkinson's disease, spinal cord lesions, Neurofibromatosis, autonomic
`
`neuropathy, Chagas disease, Hirschsprung disease and cystic fibrosis. Con