Formulations of guanylate cyclase c agonists and methods of use

a technology of guanylate cyclase and agonists, applied in the field of new formulations, can solve the problems of side effects of conventional oral formulations intended to treat ibd, for instance, and achieve the effects of reducing or eliminating degradation and aggregation, reducing or eliminating side effects, and reducing the exposure of gcc agonists

Inactive Publication Date: 2010-09-02
SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010]The targeted GCC agonist formulations of the invention offer several advantages over other formulations, especially conventional oral formulations. 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. Conventional oral formulations also suffer from degradation or aggregation of the GCC agonist in the stomach due to the low pH environment (Marx et al., 1998 Peptide Res. 52:229-240; Chino et al., 1998 FEBS Let. 421:27-31). In contrast, the GCC agonist formulations of the invention are optimized for the rel

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

Method used

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  • Formulations of guanylate cyclase c agonists and methods of use
  • Formulations of guanylate cyclase c agonists and methods of use
  • Formulations of guanylate cyclase c agonists and methods of use

Examples

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example 1

Synthesis and Purification of GCC Agonist Peptides

[0218]The GCC agonist peptides were synthesized using standard methods for solid-phase peptide synthesis. Either a Boc / Bzl or Fmoc / tBu protecting group strategy was selected depending upon the scale of the peptide to be produced. In the case of smaller quantities, it is possible to get the desired product using an Fmoc / tBu protocol, but for larger quantities (1 g or more), Boc / Bzl is superior.

[0219]In each case the GCC agonist peptide was started by either using a pre-loaded Wang (Fmoc) or Merrifield (Boc) or Pam (Boc) resin. For products with C-terminal Leu, Fmoc-Leu-Wang (D-1115) or Boc-Leu-Pam resin (D-1230) or Boc-Leu-Merrifield (D-1030) Thus, for peptides containing the C-terminal d-Leu, the resin was Fmoc-dLeu-Wang Resin (D-2535) and Boc-dLeu-Merrifield, Boc-dLeu-Pam-Resin(Bachem Product D-1230 and D-1590, respectively) (SP-332 and related analogs). For peptides produced as C-terminal amides, a resin with Ramage linker (Bachem ...

example 2

In Vitro Biological and Chemical Stability of SP-304 after Incubation in Simulated Gastric Fluid (SGF)

[0231]The stability of SP-304 in the presence of simulated gastric fluid (SGF) was determined by biological activity measurements and HPLC analyses (FIGS. 1A & 1B). SP-304 (final concentration of 8.5 mg / ml) was incubated in SGF (Proteose peptone (8.3 g / liter; Difco), D-Glucose (3.5 g / liter; Sigma), NaCl (2.05 g / liter; Sigma), KH2PO4 (0.6 g / liter; Sigma), CaCl2 (0.11 g / liter), KCl (0.37 g / liter; Sigma), Porcine bile (final 1× concentration 0.05 g / liter; Sigma) in PBS, Lysozyme (final 1× concentration 0.10 g / liter; Sigma) in PBS, Pepsin (final 1× concentration 0.0133 g / liter; Sigma) in PBS). SGF was made on the day of the experiment and the pH was adjusted to 2.0±0.1 using HCl or NaOH as necessary. After the pH adjustment, SGF is filter sterilized with 0.22 μm membrane filters. SP-304 (final concentration of 8.5 mg / ml) was incubated in SGF at 37° C. for 0, 15, 30, 45, 60 and 120 min, ...

example 3

In Vitro Biological and Chemical Stability of SP-304 after Incubation in Simulated Intestinal Fluid (SIF)

[0234]The stability of SP-304 was also evaluated after incubation with simulated intestinal fluid (SIF) by measuring its biological activity and by HPLC analyses (FIGS. 2A & 2B). SIF solution was prepared by the method as described in the United States Pharmacopoeia, 24th edition, p2236. The recipe to prepare SIF solution was as described below. The SIF solution contained NaCl (2.05 g / liter; Sigma), KH2PO4 (0.6 g / liter; Sigma), CaCl2 (0.11 g / liter), KCl (0.37 g / liter; Sigma), and Pacreatin 10 mg / ml. The pH was adjusted to 6 and the solution was filter sterilized. A solution of SP-304 (8.5 mg / ml) was incubated in SGF at 37° C. for 0, 30, 60, 90, 120, 150 and 300 min respectively, in triplicate aliquots. Following incubations, samples were removed and snap frozen with dry ice and stored in a −80° C. freezer until assayed in duplicate. FIG. 2A is a bar chart showing the ability of S...

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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 ...

Claims

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Application Information

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IPC IPC(8): A61K9/48A61K9/00A61K38/10A61K36/48A61K31/765A61P29/00A61P1/10A61P1/12
CPCA61K9/4891A61K31/53A61K38/04A61K45/06A61K47/32A61K47/34A61K47/36A61K47/38C07K7/08C07K14/245C07K14/47A61K38/10A61P1/00A61P1/04A61P1/10A61P1/12A61P1/14A61P29/00A61P31/04A61P35/00A61P43/00A61K2300/00A61K9/0053A61K9/4816
Inventor SHAILUBHAI, KUNWARCOMISKEY, STEPHEN
Owner SYNERGY PHARMA
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