`Application No.: 13/421,769
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`. Pursuant to
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`134704012 v1
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`MYLAN - EXHIBIT 1022 Part 15 of 16
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`MYLAN - EXHIBIT 1022 Part 15 of 16
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`Attorney Docket No.: SYPA-009/X01US 321994-2142
`Application No.: 13/421,769
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`Title of Invention:
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`Formulations of Guanylate Cyclase C Agonists and Methods of Use
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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
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`(43) International Publication Date
`19 September 2013 (19.09.2013)
`
`WIPO!) PCT
`
`\a
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`(10) International Publication Number
`WO 2013/138352 Al
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL
`NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU,
`RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`GD)
`
`International Patent Classification:
`A61K 38/10 (2006.01)
`AGIP 1/10 (2006.01)
`A61P 1/00 (2006.01)
`
`(81)
`
`QD
`
`International Application Number:
`
`PCT/US2013/030551
`
`(22)
`
`International Filing Date:
`
`12 March 2013 (12.03.2013)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(7)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`13/421,769
`
`15 March 2012 (15.03.2012)
`
`US
`
`Applicant: SYNERGY PHARMACEUTICALS INC.
`[US/US]; 420 Lexington Avenue, Suite 1609, New York,
`NY 10170 (US).
`
`Inventors; and
`Applicants
`(or US only): COMISKEY, Stephen
`[US/US]; 105 Steeplechase Drive, Doylestown, PA 18902
`(US). FENG, Rong [CA/US]; 74 Pine Glen Road, Lang-
`horne, PA 19047 (US). FOSS, John [US/US]; 525 Linden
`Avenue,
`Doylestown,
`PA
`18901-4435
`(US).
`SHATLUBHAT, Kunwar
`[US/US]; 2707 Bald Fagle
`Cirelc, Audubon, PA 19403 (US).
`
`(74)
`
`Agents: ELRIFI, Ivor, R. et al.; Mintz Levin Cohn Ferris
`Glovsky and Popeo, P.C., One Financial Center, Boston,
`MA 02111 (US).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR,NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`with sequencelisting part ofdescription (Rule 5.2(a))
`
`(54) Title: FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND METHODS OF USE
`
`(57) Abstract: The invention provides low-dose formulations of guanylate cyclase-C ("GCC") agonist peptides and methods for
`their use. The formulations of the invention can be administered either alone or in combination with one or more additional thera -
`peutic agents, preferably an inhibitor of cGMP-dependent phosphodiesterase or a laxative.
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`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND
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`METHODSOF USE
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`RELATED APPLICATIONS
`
`[01]
`
`This application claims priority to U.S. Patent Application No. 13/421,769 filed on
`
`March 15, 2012, the content of which is incorporated by reference in its entirety.
`
`FIELD OF THE INVENTION
`
`[02]
`
`The present invention relates to low-dose formulations of guanylate cyclase C peptide
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`agonists uscful for the treatment and prevention of various discascs and disordcrs.
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`BACKGROUNDOF THE INVENTION
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`10
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`[03]
`
`Guanylate cyclase C is a transmembrane form of guanylate cyclase that is expressed
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`on variouscells, including gastrointestinal epithelial cells (reviewed in Vaandrager 2002 Mol.
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`Cell. Biochem, 230:73-83). It was originally discovered as the intestinal receptor for the heat-
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`stable toxin (ST) peptides secreted by enteric bacteria and which cause diarrhea. The ST
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`peptides share a similar primary amino acid structure with two peptides isolated from
`
`15
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`intestinal mucosa and urine, guanylin and uroguanylin (Currie, et al., Proc. Nat’l Acad. Sci.
`
`USA 89:947-951 (1992); Hamra, et al., Proc. Nat’l Acad. Sci. USA 90:10464-10468 (1993);
`
`Forte, L., Reg. Pept. 87:25-39 (1999); Schulz, et al., Cell 63:941-948 (1990); Guba, et al.,
`
`Gastroenterology 111:1558-1568 (1996); Joo, et al., Am. J. Physiol. 274:G633-G644 (1998)).
`
`[04]
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`Inthe intestines, guanylin and uroguanylin act as regulators of fluid and electrolyte
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`20
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`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
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`enterocytes (simple columnarepithelial cells of the small intestines and colon). The binding
`
`of the guanylin peptides to guanylate cyclase C induces electrolyte and water excretion into
`
`the intestinal lumen via a complex intracellular signaling cascade thatis initiated by an
`
`25
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`increase in cyclic guanosine monophosphate (cGMP).
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`[05]
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`The cGMP-mcdiated signaling that is initiated by the guanylin peptidesis critical for
`
`the normal functioning of the gut. Any abnormality in this process could lead to
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`gastrointestinal disorders such asirritable 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
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`the gastrointestinal tract. Ulcerative colitis is exclusively an inflammatory disease of the
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`colon, the large intestine. Unlike Crohn's disease, in which all layers of the intestine are
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`10
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`involved, and in which there can be normal healthy bowel in between patches ofdiseased
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`bowel, ulcerative colitis affects only the innermost lining (mucosa) of the colon in a
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`continuous manner. Depending on whichportion of the gastrointestinal tract is involved,
`
`Crohn's disease may bereferred to asileitis, regional enteritis, colitis, etc. Crohn's disease
`
`and ulcerative colitis differ from spastic colonorirritable bowel syndrome, which are
`
`15
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`motility disorders of the gastrointestinal tract. Gastrointestinal inflammation can be a chronic
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`condition. It is estimated that as many as 1,000,000 Americansareafflicted with
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`inflammatory bowel disease, with male and female patients appearing to be equally affected.
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`Mostcases are diagnosed before age 30, but the disease can occur in the sixth, seventh, and
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`later decadesof life.
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`20
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`[06]
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`IBS and chronic idiopathic constipation are pathological conditions that can cause a
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`great deal of intestinal discomfort and distress but unlike the inflammatory bowel diseases,
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`IBS doesnot cause the serious inflammation or changes in boweltissue andit is not thought
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`to increase the risk of colorectal cancer. In the past, inflammatory bowel disease, celiac
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`disease and IBS were regarded as completely separate disorders. Now, with the description
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`25
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`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
`
`strongest risk factor identified to date for the subsequent development of postinfective
`
`uritable bowel syndrome. Clinical risk factors include prolonged acute illness and the
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`absence of vomiting. A genetically determined susceptibility to inflammatory stimuli may
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`30
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`also be a risk factor for irritable bowel syndrome. The underlying pathophysiology indicates
`
`increased intestinal permeability and low-grade inflammation, as well as altered motility and
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`visceral sensitivity. Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut
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`2
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`function and is known to play a major rolc in pathophysiology of IBS. The activity of 5-HT is
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`regulated by cGMP.
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`[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 discasc pathology in IBD and aggravate IBS. The renewalprocess 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
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`10
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`death (apoptosis) of epithelial cells lining the gut mucosa. Cells are continually lost from the
`
`villus into the lumen of the 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
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`rates of cell proliferation and apoptosis in the gut epithelium can be increased or decreased in
`
`a varicty of circumstanccs, e.g., in responsc to physiological stimuli such as aging,
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`15
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`inflammatory signals, hormones, peptides, growth factors, chemicals and dietary habits. In
`
`addition, an enhancedproliferation rate is frequently associated with a reduction in turnover
`
`time and an expansion of the proliferative zone. The proliferation index is much higher in
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`pathological states such as ulcerative colitis and other gastrointestinal disorders. Intestinal
`
`hyperplasia is a major promoter of gastrointcstinal inflammation. Apoptosis and ccll
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`20
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`proliferation together regulate cell number and determinethe 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 may in turn lead to gastrointestinal
`
`inflammatory diseases.
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`25
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`[08]
`
`In addition to a role for uroguanylin and guanylin as modulators of intestinal fluid and
`
`ion secretion, these peptides may also be involved in the continual renewal of gastrointestinal
`
`mucosa by maintaining the balance between proliferation 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
`
`30
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`improve the treatment options for inflammatory conditions, particularly of the gastrointestinal
`
`tract.
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`[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
`
`10
`
`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, gastroesophageal reflux disease, functional
`
`heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic
`
`intestinal pseudo-obstruction, colonic pseudo-obstruction; Crohn's disease, ulcerative colitis,
`
`15
`
`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 humans in a dosage range that was not predicted based on
`
`studies in primates. The formulations of the invention are particularly useful for the
`
`20
`
`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 comparedto 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
`
`25
`
`proteolytic enzymes present in the stimulated human intestinal juices and human gastric
`
`juices. Examples of GCC agonists that can be used in the formulations and methods of the
`
`invention are described in more detail 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
`
`2010/0120694, US 2010/0093635, and US 2010/022 1329, each of which is incorporated
`
`30
`
`herein by reference inits entirety.
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`[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.
`
`Tn 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
`
`10
`
`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: | 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
`
`meg, 3.0 mg, 6.0 mg, 9.0 mg or 9.5 mg.
`
`15
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`[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 determinedastotal area
`
`percentages of impuritics by HPLC. The impuritics do not include any pharmaccutically
`
`20
`
`acceptable excipient used for the formulation. In one embodiment, the formulation is
`
`substantially free of inorganic acids and carboxylic acids, e.g., HCI, phosphoric acid, or
`
`acetic acid. In this context, carboxylic acids do not include aminoacids or peptides. In this
`
`context “substantially” free of acids means that 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%,
`
`25
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`less than 0.005%,or less than 0.001% of the total weight of the formulation.
`
`In one
`
`embodiment, the formulation is free of HCI.
`
`[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
`
`30
`
`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,
`5
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`sesame oil, soybean oil, and sunflower oil. In one embodiment, the medium chain
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`triglyceride or related ester is AKOMED E, AKOMEDR, CAPTEX 355, LABRAFAC CC,
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`LABRAFAC PG, LAUROGLYCOL FCC, MIGLYOL 810, MIGLYOL 812, MIGLYOL
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`829, MIGLYOL 840, and SOFTISAN 645. In one embodiment, the liquid is selected from
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`the group consisting of medium chaintriglycerides, propylene glycol dicaprylocaprate,
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`vitamin E, soybean oil, Cremaphor, PG, and PG 400.
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`In one embodiment, the unit dose is a
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`powder, tablet, or capsule. In one embodiment, the unit dose is a liquid-filled capsule. In one
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`embodiment, the capsule or tablet is in a blister pack or strip. Preferably, the blister pack or
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`strip is made of a material that is impermeable to water vapor and oxygen. In one
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`embodimentthe blister pack is comprised of a metal foil. In one embodiment the blister pack
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`is a FOIL/FOIL blister pack. In one embodiment, the container of the blister pack is flushed
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`with an inert gas such as nitrogen or argon. In one embodiment, the container further
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`includes a desiccant. In a preferred embodiment the desiccant is a molecular sieve. In one
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`embodiment, the unit dose is in a high density polyethylene bottle having a seal.
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`In one
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`embodiment, the bottle further comprises a desiccant. In one embodiment, the bottle further
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`comprises an oxygen scavenger or molecular sieve. In one embodiment, the bottle is nearly
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`impermeable to oxygen and water vapor(e.g., much more impermeable than a HDPEbottle),
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`such as an OxyGuardbottle.
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`[14]
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`In one embodiment, the one or more pharmaccutically acceptable cxcipicnts include
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`an inert carrier. In one embodiment, the inert carrier is a selected from mannitol, lactose, a
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`microcrystalline cellulose, or starch. In one embodiment, the inert carrier has a particle size
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`of from 50 to 900 microns, from 50 to 800 microns, from 50 to 300 microns, from 50 to 200
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`microns, from 75 to 150 microns, from 75 to 200 microns, or from 75 to 300 microns.
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`[15]
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`In one embodiment, the GCC agonist peptide is stabilized against chemical or
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`physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity, or
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`at least 18 monthsat 25 °C and 60% relative humidity, or at least 18 months at 2-8 °C.
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`[16]
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`In one embodiment, the one or more pharmaceutically acceptable excipients include a
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`divalent cation salt such as calcium chloride. In one embodiment, the one or more
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`pharmaceutically acceptable excipients comprise an amino acid, such as leucine, histidine, or
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`arginine, or an amine such TRIS or TRIS/HC1.
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`[17]
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`In one embodiment, the oral dosage formulation consists of the GCC agonist peptide
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`described herein, an inert carrier (e.g., Celphere SCP-100, Avicel PH 102, or Avicel PH 112),
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`and a lubricant (e.g., magnesium stearate). In one embodiment, the formulation consists of
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`the GCC agonist peptide, an inert carrier (e.g., Avicel PH 200), a divalent cation salt (e.g.,
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`calcium chloride or calcium ascorbate), an aminoacid (e.g., leucine, histidine, or arginine) or
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`a protective amine (e.g., TRIS), a coating agent (e.g., Methocel ES Premium LV) and
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`optionally a lubricant (e.g., magnesium stearate) or another additive (e.g., trehalose). In one
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`embodiment, the formulation consists of the GCC agonist peptide, a binder(e.g., Provsolv
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`SMCC 90 LM), and a disintegrant (e.g., Explotab). In one embodiment, the formulation
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`consists of the GCC agonist peptide, a diluent (e.g., Mannogem EZ), a binder(e.g., Provsolv
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`SMCC 90 LM), a disintegrant (e.g., Explotab), a lubricant (e.g., Pruv).
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`[18]
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`The invention also provides a process for making the oral dosage formulations
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`described herein, wherein the process comprises a step of dry granulation, wet granulation, or
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`spray coating followed by drying. In another cmbodiment, the proccss compriscs a step of
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`dry mixing. In a preferred embodiment the step of dry mixing includes geometric blending.
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`In one embodiment, the process comprises a step of direct compression. In one embodiment,
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`the process for making the oral dosage formulations described herein is a spray coating-
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`drying process which includes (a) providing an aqueous solution comprising: a GCC agonist
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`peptide selected from the group consisting of SEQ ID NOs: 1-54 and 56-249, and one or
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`more pharmaceutically acceptable excipients, wherein the concentration of the GCC agonist
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`peptide ranges from 10 to 60 mg/mL;and (b) applying the aqueoussolution to a
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`pharmaceutically acceptable carrier to generate a GCC agonist peptide-coated carrier.
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`[19]
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`In one embodimentof the spray coating-drying process above, the one or more
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`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
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`pharmaceutically acceptable excipients comprise an amino acid selected from leucine,
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`isoleucine, and valine. In one embodiment, the one or more pharmaccutically acceptable
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`excipients comprise a coating agent (such as hypromellose Methocel ES PremLV). In one
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`embodiment, the aqueous solution has a pH greater than 4 (e.g., 4.5-5.5, 5-6, about 5, or
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`greater than 5) or even greater than 7. In one embodiment, the aqueous solution is
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`substantially free of inorganic acids and carboxylic acids. In one embodiment, the GCC
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`agonist peptide is sclected from the group consisting of SEQ ID NOs: 1, 8, 9, and 56. In one
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`embodiment, the process further includes drying the GCC agonist peptide-coated carrier.
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`[20]
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`The invention further provides an oral dosage formulation made by the process
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`described herein. Preferably, the GCC agonist peptide as madeis stabilized against chemical
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`or physical degradation for a period of at least 18 months at 30 °C and 65% relative humidity,
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`or at least 18 months at 25 °C and 60% relative humidity, or at least 18 months at 2-8 °C.
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`[21]
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`The invention also provides a method for treating or preventing a disease or disorder
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`in a subject in need thereof, comprising administering to the subject an oral dosage
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`formulation comprising at least one GCC agonist peptide, wherein the amount of GCC
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`agonist peptide per unit dose is from 0.01 mg to 10 mg, and wherein the GCC agonist peptide
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`is selected from the group consisting of SEQ ID NOs: 1-54 and 56-249. Preferably, the
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`subject is a human subject. In one embodiment, the GCC agonist peptide is selected from the
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`group consisting of SEQ ID NOs: 1, 8, 9, or 56. In one embodiment, the GCC agonist
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`peptide is selected from the group consisting of SEQ ID NOs: | and 9. In one embodiment,
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`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,
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`6.0 mg, 9.0 mg, 9.5 mg, or 10 mg.
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`[22]
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`In one embodiment, the disease or disorderis a gastrointestinal disease or disorder
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`selected from the group consisting ofirritable bowel syndrome, non-ulcer dyspepsia, chronic
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`intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction,
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`duodenogastric reflux, gastro esophageal reflux disease, constipation, gastroparesis,
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`heartburn, gastric cancer, and H. pylori infection. In a preferred embodiment, the
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`gastrointestinal disease or disorder is chronic idiopathic constipation.
`
`[23]
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`In one embodiment, the method further comprises administering to the subject an
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`effective amount of an inhibitor of a cGMP-specific phosphodiesterase. In one embodiment,
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`the cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of
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`suldinac sulfone, zaprinast, and motapizone, vardenifil, and suldenifil.
`
`[24]
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`In one cmbodiment, the method further compriscs administering to the subjcct an
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`effective amount of at least one laxative. In one embodiment, the at least one laxativeis
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`selected from the group consisting of SENNA, MIRALAX, PEG,or calcium polycarbophil.
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`[25]
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`In onc cmbodiment, the method further compriscs administering to the subjcct an
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`effective amountof at least one anti-inflammatory agent.
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`[26]
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`The invention also provides pharmaceutical compositions comprising the
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`formulations described herein.
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`[27]
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`Other features and advantages of the invention will be apparent from and are
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`encompassed by the following detailed description and claims.
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[28]
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`Figure 1: Plecanatide (SP-304) treatment reduced timeto first BM following daily
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`dose.
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`[29]
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`Figure 2: Effect of daily treatment with plecanatide on spontaneous bowel
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`movements (SBM)in chronic constipation patients.
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`[30]
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`Figure 3: Effect of daily treatment with plecanatide on complete spontaneous bowel
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`movements (CSBM) in chronic constipation patients.
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`[31]
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`Figure 4: Effect of daily treatment with plecanatide on Bristol Stool Form Scores
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`(BSFS) in chronic constipation patients.
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`[32]
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`Figure 5: Effect of daily treatment with plecanatide on straining scores in chronic
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`constipation patients
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`[33]
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`Figure 6: Percentage of subjects reporting improvements in abdominal discomfort
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`scores after 14-days of daily treatment with plecanatide.
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`DETAILED DESCRIPTION
`
`[34]
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`The invention provides pharmaccutical formulations of peptide GCC agonists. It is
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`intended that the formulations of the invention are “pharmaceutical” formulations, meaning
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`that they are suitable for pharmaceutical use. Accordingly, the term “formulations” as used
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`herein is meant to encompass pharmaceutical formulations even if “pharmaceutical”is not
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`expressly stated. Pharmaceutical compositions comprising the formulations described herein
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`are also provided by the invention. The formulations of the invention prefcrably provide
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`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
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`with the GCC agonist peptides described hercin and provides stability 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
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`effective for the treatment of diseases and disorders in humans. The dosage range found to
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`be effective was not predicted based on animal studies. The invention is also based in part
`upon the discovery that a divalent cation (e.g., Ca**) and/or an aminoacid (e.g., leucine or
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