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Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant

A bile acid sequestrant, gastric retention technology, applied in the field of treatment of upper gastrointestinal and throat diseases

Inactive Publication Date: 2016-02-17
IRONWOOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Despite strong evidence of efficacy, PPIs have significant limitations
For example, patients who do not respond to PPI inhibitor therapy alone may not respond because although PPIs reduce acid reflux from the stomach, bile acids from the duodenum remain

Method used

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  • Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant
  • Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant
  • Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Embodiment 1: the production process of large-scale batch

[0164] 1. Intragranular mixing

[0165] The intragranular components (except magnesium stearate) were dispersed and passed through a 20 mesh screen. The components were added to the V-blender and mixed at 25 RPM for 10 minutes. Then, the intragranular magnesium stearate was dispersed and passed through a 20 mesh screen. Magnesium stearate was added to the V-blender and mixed at 25 RPM for 2 minutes. Remove the resulting intragranular blend from the V-blender.

[0166] 2. heavy pressure

[0167] A 24-station Fette tablet press was equipped with eight 0.6250" disc, flat B-shaped die elements. The intragranular blend obtained above was added to the feed hopper of the tablet press. Use 15-25 RPM The turret speed of the tablet press is used to compress the blend into a pre-compressed body with a target weight of 1200-1400mg and a hardness of 9-15kp. The process of appearance, weight, hardness and thickness is c...

Embodiment 2

[0184] Example 2: Large-Scale Batches Produced

[0185] Following the procedure described in Example 1 the following large scale batches were produced. Table 1 below summarizes the amounts of excipients used during the production of each of the 6 batches.

[0186] Table 1

[0187]

[0188] Microcrystalline cellulose (MCC) was used as a filler / compression aid in the formulation. Two types of MCC have been evaluated. One manufacturer has shown that ProsolvSMCC90, a siliconized microcrystalline cellulose, has better powder flow than non-siliconized MCC.

[0189] KG-100 is another MCC used as a substitute for SMCC90. According to one manufacturer: KG-1000 has the lowest bulk density among the MCC grades. Compared to other standard MCC grades, KG-100 exhibits superior firmness. KG-1000 particles have a very large L / D value. The particles are easily aligned upright against the force of the compacting body; thus, the contact area of ​​the MCC particles is increased. Entang...

Embodiment 3A

[0195] Example 3A: In Vitro Dissolution / Drug Release

[0196] The drug release rates of six dosage forms produced on a large scale were determined using an indirect method, considering that colesevelam and colesevelam HCl are insoluble polymers and their concentrations could not be determined by standard direct HPLC methods for soluble drugs.

[0197] The drug release rate from the tablets was determined in vitro in acetate buffer at pH 4.5 (100 mM) containing a known bile acid (glycocholic acid) at a concentration of 2 mg / mL. The bile acid consumption of the tablets during swelling and erosion was determined and compared with values ​​obtained from a series of standard solutions of known bile acid concentrations. The rate of bile acid consumption corresponds to the rate of drug release. These drug release rate results were obtained using a USPI Type II (paddle) apparatus with tablets placed in a settler. The results are summarized in figure 1 middle.

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Abstract

Disclosed herein are novel compositions and methods for controlling the release of bile acid sequestrant to the stomach in order to treat or prevent upper GI tract disorders or disorders of the throat. The methods generally include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one bile acid sequestrant dispersed in a polymeric matrix. The bile acid sequestrant composition may be administered alone or in combination with at least one proton pump inhibitor, and optionally one or more agents chosen from antacids, histamine H2-receptor antagonists, gamma-aminobutyric acid-beta (GABA-B) agonists, prodrugs of GABA-B agonists, acid pump antagonists, protease inhibitors and GC-C agonists.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 61 / 752,726, filed January 15, 2013, and US Provisional Application 61 / 914,804, filed December 11, 2013. The entire disclosures of these patent applications are hereby incorporated by reference. technical field [0003] The present disclosure relates broadly to sustained-release dosage forms for gastric retention containing bile acid sequestrants. It also relates to methods for the treatment of diseases of the upper gastrointestinal tract and throat by administration of said dosage forms. Background technique [0004] Anatomically, the upper gastrointestinal tract includes the mouth, part of the throat, esophagus, stomach, and duodenum, the uppermost part of the small intestine. [0005] The esophagus carries food, fluids, and saliva from the mouth to the stomach by coordinating the contraction of its muscular lining. The process is automatic and p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/28A61K31/785
CPCA61K9/0065A61K9/2031A61K9/2866A61K31/785A61K45/06A61K38/10A61K31/197A61K31/4439A61K31/506A61K9/2054A61P1/00A61P1/04A61P1/14A61P1/16A61P11/00A61P11/04A61P35/00A61P43/00A61K2300/00A61K9/2013
Inventor V·塞瑟拉曼D·B·赫登K·M·莱斯科
Owner IRONWOOD PHARMA
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