Formulations of guanylate cyclase c agonists and methods of use

Abstract

The invention provides novel formulations of guanylate cyclase-C (“GCC”) agonist peptides and methods for their use in the treatment of gastrointestinal diseases and disorders, including gastrointestinal cancer. The GCC agonist formulations of the invention can be administered either alone or in combination with one or more additional therapeutic agents, preferably an inhibitor of cGMP-dependent phosphodiesterase or a laxative.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of priority to U.S. Provisional Application No. 61 / 119,521 filed on Dec. 3, 2008, the contents of which is incorporated by reference in its entiretyFIELD OF THE INVENTION[0002]The present invention relates to novel formulations of guanylate cyclase C agonists which are optimized for delivery to specific regions of the gastrointestinal tract and are useful for the treatment and prevention of gastrointestinal diseases and disorders.BACKGROUND OF THE INVENTION[0003]Guanylate cyclase C is a transmembrane form of guanylate cyclase that is expressed on various cells, 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 ...

AI Technical Summary

Benefits of technology

[0060]Crohn's disease (CD) and ulcerative colitis (UC) are the principle syndromes encompassed by the classification of inflammatory bowel disease (IBD). While CD can affect any part of the gastrointestinal tract, it most commonly occurs in the distal ileum and colon, whereas UC by definition affects only the colon. In order to exert their anti-inflammatory therapeutic effects, orally administered GCC agonists must reach the inflamed sites in the distal ileum and colon. In accordance with one aspect of the invention, the GCC agonist is formulated for drug release at pH greater than 5.5 for the treatment of UC and CD. In one embodiment, the GCC agonist is formulated for targeted delivery to the ileum, preferably using a pH dependent release formulation for release at a pH above 5.5. pH dependent release formulations are described in more detail, infra, in Section 1.1. “Treatment” in this context refers to the effective induction and maintenance of remission. Thus, in one embodiment, the invention provides a method for the treatment of CD or UC which comprises administering to a subject in need thereof a therapeutically effective amount of a GCC agonist formulated for release at a pH above 5.5. It has recently been shown that gut pH in UC patients is generally more acidic as compared to healthy volunteers and it has also been postulated that these variations may affect pH mediated dissolution delivery of drug treatment (see Rubin, D. T. et al., Colonic pH differs depending on the activity of ulcerative colitis (UC): Report of two patients with pH measurements over time. Poster presented at the Annual Scientific Meeting of the American College of Gastroenterology, Oct. 23-28, 2009, San Diego, Calif., P1116). Further, the colonic pH rose substantially between active inflammation and subsequent clinical quiescence (see Rubin, D. T. et al., Luminal pH and transit time in patients with quiescent ulcerative colitis (US) resembles that of healthy controls. Poster presented at the Annual Scientific Meeting of the American College of Gastroenterology, Oct. 23-28, 2009, San Diego, Calif., P1114). Particularly in UC, some patients fail to achieve remission with standard outpatient therapy and this failure could possibly be due to the physiologic differences in lumenal transit time and pH. Thus, a further advantage of the present invention is to provide GCC agonist formulations specifically designed to deliver bioactive GCC agonists to the distal ileum or colon of affected patients by utilizing a pH dependent release formulation.

[0061]Another advantageous property of the targeted release formulations of the invention is that a lower effective dose of the GCC agonist is required to achieve the same therapeutic benefit as a GCC agonist whose release is not targeted. The targeted release of the GCC agonist further ensures that the agonist concentration is highest at its site of action, thus reducing the side effects that may be associated with oral administration.

[0062]In one embodiment, the GCC agonist formulation is an oral formulation optimized for delivery of a GCC agonist to the duodenum or jejunum. In a specific embodiment, this formulation comprises a core, which contains the GCC agonist, surrounded by one or more layers of a targeting material. The targeting material is chosen to provide targeted release of the GCC agonist to the duodenum or jejunum. In one embodiment, the formulation comprises an outer layer of targeting material which comprises a pH dependent polymer that is stable in the low pH environment of the stomach (pH 1-2) and begins to disintegrate in a pH range of from 4.5 to 5.5. This formulation protects the GCC agonists from the acidic environment of the stomach.

[0063]In another embodiment, the GCC agonist formulation is optimized for delivery of a GCC agonist to the ileum, terminal ileum, or ascending colon. In a specific embodiment, this formulation comprises a core, which contains the GCC agonist, surrounded by one or more layers of a targeting material. The targeting material is chosen to provide targeted release of the GCC agonist to the ileum, terminal ileum, or ascending colon. In one embodiment, the formulation comprises three layers of targeting material: (1) an outer layer which comprises a pH dependent polymer that is stable in the low pH environment of the stomach (pH 1-2) and begins to disintegrate in a pH range of from 6.5 to 7.5; (2) a middle layer which comprises a swellable polymer; and (3) an inner layer which comprises a pH dependent polymer that begins to disintegrate in a pH range of from 6.5 to 7.5. In a preferred embodiment, the pH dependent polymer is selected from among the EUDRAGIT polymers, for example, EUDRATGIT L, S, FS, and E polymers. In one embodiment, the swellable polymer is hydroxypropylmethylcellulose.

[0064]While any GCC agonist known in the art can be formulated according to the present invention, analogs of uroguanylin and bacterial ST peptides are preferred. In certain embodiments, the uroguanylin and bacterial ST peptide analogs have superior properties compared to naturally occurring, or “wild-type” peptides. For example, the uroguanylin and bacterial ST peptides for use in the present invention are preferably modified to increase their resistance to degradation at the N-terminus and C-terminus from carboxypeptidases, aminopeptidases, and / or by other proteolytic enzymes present in the stimulated human intestinal juices and human gastric juices. In certain embodiments, the GCC agonist formulation comprises a peptide consisting essentially of an amino acid sequence selected from SEQ ID NOs: 1-249. In a preferred embodiment, the peptide consists essentially of an amino acid sequence selected from SEQ ID NOs: 1, 8, 9, 55 and 56. The term “consists essentially of” refers to a peptide that is identical to the reference peptide in its amino acid sequence or to a peptide that does not differ substantially in terms of either structure or function from the reference peptide. A peptide differs substantially from the reference peptide if its primary amino acid sequence varies by more than three amino acids from the reference peptide or if its activation of cellular cGMP production is reduced by more than 50% compared to the reference peptide. Preferably, substantially similar peptides differ by no more than two amino acids and not by more than about 25% with respect to activating cGMP production. In preferred embodiments, the GCC agonist is a peptide comprising at least 12 amino acid residues, and most preferably comprising between 12 and 26 amino acids. Non-limiting examples of such analogs of uroguanylin and bacterial ST peptides are described in Section 1.1 below.

[0065]The invention provides methods for treating or preventing gastrointestinal disorders and increasing gastrointestinal motility in a subject in need thereof by administering an effective amount of a GCC agonist formulation to the subject. The term “treating” as used herein refers to a reduction, a partial improvement, amelioration, or a mitigation of at least one clinical symptom associated with the gastrointestinal disorders being treated. The term “preventing” refers to an inhibition or delay in the onset or progression of at least one clinical symptom associated with the gastrointestinal disorders to be prevented. The term “effective amount” as used herein refers to an amount that provides some improvement or benefit to the subject. In certain embodiments, an effective amount is an amount that provides some alleviation, mitigation, and / or decrease in at least one clinical symptom of the gastrointestinal disorder to be treated. In other embodiments, the effective amount is the amount that provides some inhibition or delay in the onset or progression of at least one clinical symptom associated with the gastrointestinal disorder to be prevented. The therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. The term “subject” preferably refers to a human subject but may also refer to a non-human primate or other mammal preferably selected from among a mouse, a rat, a dog, a cat, a cow, a horse, or a pig.

Problems solved by technology

Because GCC agonists can potentially act throughout the gastrointestinal tract, conventional oral formulations intended to treat IBD, for instance, may exhibit side effects due to the activity of the GCC agonist in non-target tissues.

One such side effect is diarrhea, which could interfere with treatment by a GCC agonist of GI diseases such as ulcerative colitis and Crohn's disease.

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