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Treatments of gastrointestinal disorders

Inactive Publication Date: 2014-01-02
IRONWOOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a stable pharmaceutical composition comprising linaclotide, a cation or salt thereof, and a sterically hindered amine selected from meglumine, histidine, or a mixture thereof, and optionally, a polymer. The invention also provides stable low-dose and pediatric pharmaceutical compositions of linaclotide. The technical effects include improved stability of the pharmaceutical composition and reduced risk of degradation, particularly at low dosages and in pediatric applications.

Problems solved by technology

These difficulties may be exacerbated when producing pediatric formulations and other low-dose formulations of linaclotide, e.g., because the linaclotide is more dispersed and has greater surface area exposure to aqueous environments such as during preparation.

Method used

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  • Treatments of gastrointestinal disorders
  • Treatments of gastrointestinal disorders
  • Treatments of gastrointestinal disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0120]Linaclotide beads were prepared in the following manner using the components set forth in Table 1. First, a linaclotide solution was prepared by combining linaclotide, polyvinyl alcohol, calcium chloride, meglumine and water in the concentrations set forth in Table 1. The linaclotide solution was then pH-adjusted to about 2.5 and mixed until clear. Next, the linaclotide solution was layered onto isomalt beads by spraying the beads with the linaclotide solution using a Wurster process. The linaclotide-layered beads were then dried until the product loss on drying (LOD) was less than about 3%.

TABLE 1Linaclotide beads, 5 μg / 50 mgComponentsWeight (g)Wt. %Linaclotide0.240.012Isomalt191595.8Meglumine2.60.1Calcium chloride dihydrate2.00.1PVA804HClQ.S.QSPurified water*1000QSTOTAL2000100.0*Water is removed during the manufacturing process

[0121]The stability performance of the linaclotide beads were assessed following storage of the beads for 1 month at 40° C. and 75% RH in 45 cc HDPE b...

example 2

[0122]Linaclotide beads were prepared in the following manner using the components set forth in Table 3. First, a linaclotide solution was prepared by combining linaclotide, polyvinyl alcohol, calcium chloride, histidine and water in the concentrations set forth in Table 3. The linaclotide solution was then pH-adjusted to about 2.5 and mixed until clear. Next, the linaclotide solution was layered onto isomalt beads by spraying the beads with the linaclotide solution using a Wurster process. The linaclotide-layered beads were then dried until the product loss on drying (LOD) was less than about 3%.

TABLE 3Linaclotide beads, 5 μg / 50 mgComponentsWeight (g)Wt. %Linaclotide0.240.012Isomalt191695.8Histidine20.1Calcium chloride dihydrate2.00.1PVA804HClQ.S.—Purified water*1000—TOTAL2000100.0*Water is removed during the manufacturing process

example 3

[0123]Linaclotide beads were prepared in the manner described in Example 2 using the components set forth in Table 4.

TABLE 4Linaclotide beads, 5 μg / 50 mgComponentsWeight (g)Wt. %Linaclotide0.240.012Isomalt191695.8Leucine20.1Calcium chloride dihydrate2.00.1PVA804HClQ.S.—Purified water*1000—TOTAL2000100.0*Water is removed during the manufacturing process

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Abstract

The present invention relates to stable pharmaceutical compositions comprising linaclotide or pharmaceutically acceptable salts thereof, as well as to various methods and processes for the preparation and use of the compositions.

Description

CLAIM OF PRIORITY[0001]This application claims priority under 35 USC §119(e) to U.S. Provisional Patent Application Ser. No. 61 / 372,804, filed on Aug. 11, 2010, the entire contents of which is hereby incorporated by reference.SEQUENCE LISTING[0002]This application incorporates by reference in its entirety the Sequence Listing entitled “Single_linaclotide_listing_ST25.txt” (1 kilobyte) which was created Aug. 11, 2011 and filed electronically herewith.FIELD OF THE INVENTION[0003]The present invention relates to stable pharmaceutical compositions of linaclotide and methods for treating gastrointestinal disorders (e.g., irritable bowel syndrome or chronic constipation) by administering the pharmaceutical compositions.BACKGROUND OF THE INVENTION[0004]Linaclotide is a peptide that is useful as an agonist of the guanylate cyclase C (GC-C) receptor in the treatment of gastrointestinal disorders. Linaclotide is described, for example, in U.S. Pat. Nos. 7,304,036 and 7,371,727, the contents o...

Claims

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Application Information

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IPC IPC(8): A61K38/10
CPCA61K38/10A61K9/1611A61K9/1641A61K9/1676A61K38/12A61P1/00A61P1/04A61P1/10A61K47/18
Inventor MO, YUNFRETZEN, ANGELIKACALI, BRIANDEDHIYA, MAHENDRA
Owner IRONWOOD PHARMA
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