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Combination formulation of three antiviral compounds

A composition and polymer technology, applied in antiviral agents, drug combinations, medical preparations of non-active ingredients, etc., can solve the problem of not giving velpatasvir, sofosbuvir and vociprevir treatment benefits, etc. question

Inactive Publication Date: 2019-02-05
GILEAD PHARMASSET LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to date there has been no therapeutic benefit of administering velpatasvir, sofosbuvir, and vociprevir in combination formulations or specific co-formulations

Method used

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  • Combination formulation of three antiviral compounds
  • Combination formulation of three antiviral compounds
  • Combination formulation of three antiviral compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0411] Example 1: Tablet Preparation and Formulation

[0412] A. Dose Selection of Tablets

[0413] i. Sofosbuvir

[0414] Sofosbuvir exhibits a variety of forms, including its crystalline forms and solvates (see, eg, US Patent Application Publication Nos: 2010 / 0298257, 2011 / 0251152, and 2015 / 0175646). In some embodiments and the examples provided herein, the tablet formulation includes sofosbuvir in Form 6 and optionally trace amounts of Form 7. Crystalline forms 6 and 7 of sofosbuvir are non-hygroscopic and have similar water solubility of > 2 mg / mL at 37°C. Form 6 of sofosbuvir is the thermodynamically stable form and remains physically stable when suspended in water. Form 7 of sofosbuvir, although physically stable in water for short periods of time, can be converted to Form 6 under prolonged agitation. Additionally, Forms 6 and 7 were not photosensitivity and remained physically and chemically stable when stored in an open container at 40°C / 75%RH for 1 month.

[0415...

Embodiment 2

[0527] Example 2: Chemical and Physical Stability

[0528] The chemical stability, physical stability and dissolution properties of Sofosbuvir / Velpatasvir SSD / Vociprevir SSD Tablets (Formulation G) were evaluated and summarized in Tables 11A, 11B. In some embodiments, film-coated tablets are packaged in 75 mL and 100 mL white HDPE bottles (lots A and B, respectively, as described in Tables 11A, 11B) with 1 g silica gel desiccant canisters and polyester fiber rings. )middle. The 75mL and 100mL HDPE bottles contain 14 and 28 tablets, respectively. Each HDPE bottle is capped with a white continuous thread, child-resistant polypropylene screw cap with an aluminum thread leading into the seal. The packaged tablets (14 and 28 counts) were evaluated for stability at 40°C / 75%RH and 25°C / 60%RH. In addition, the stability of 14-count bottles (without caps) was evaluated under open conditions of 40°C / 75%RH.

[0529] Table 11A

[0530]

[0531]

[0532] a Dissolution condition...

Embodiment 3

[0582] Embodiment 3: physicochemical properties and biological properties

[0583] A. Dissolution as a function of medium pH and composition

[0584] Obtain Sofosbuvir, Velpatasvir and Vociprevir from Sofosbuvir / Velpatasvir SSD / Vosciprevir SSD using Apparatus II (paddle), 75 rpm, with 900 mL medium at 37°C The dissolution profile of the tablet (formulation G comprising 30.77w / w% sofosbuvir, 15.38w / w% velpatasvir SSD, 15.38w / w% vociprevir SSD) was used as pH in various media The function( Figure 13-15 ). Sofosbuvir is a BCS class 3 compound with high and pH-independent water solubility. Velpatasvir is a BCS class 4 compound with pH-dependent solubility. Vociprevir is a BCS class 2 compound with pH-dependent solubility.

[0585] Such as Figure 13 As shown, the dissolution of sofosbuvir was completed within 20 minutes and was independent of medium pH and composition.

[0586] Such as Figure 14As shown, the dissolution of velpatasvir from sofosbuvir / velpatasvir SSD / voci...

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Abstract

Disclosed are pharmaceutical compositions comprising three antiviral compounds. In particular, the pharmaceutical compositions comprise an effective amount of velpatasvir, an effective amount of sofosbuvir, and an effective amount of voxilaprevir. Also disclosed are methods of use for the pharmaceutical composition.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 344,904, filed June 2, 2016, under 35 U.S.C § 119(e), which is hereby incorporated in its entirety. Background technique [0003] Hepatitis C is considered a chronic viral disease of the liver. Although drugs that target the liver are widely used and have shown effectiveness, toxicity and other side effects limit their usefulness. Inhibitors of hepatitis C virus (HCV) are useful in limiting the establishment and progression of HCV infection and in diagnostic assays for HCV. [0004] Velpatasvir, sofosbuvir, and vociprevir are known to be effective anti-HCV agents, as described, for example, in US Patent Nos. 7,964,580, 8,575,135, and 9,296,782. However, to date there has been no therapeutic benefit of administering velpatasvir, sofosbuvir and vociprevir in combination formulations or specific co-formulations. Contents of the invention [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4188A61K31/7072A61K31/4985A61K9/14A61K9/20A61P31/14
CPCA61K9/146A61K9/1611A61K9/1617A61K9/1635A61K9/1652A61K9/2009A61K9/2013A61K9/2027A61K9/2054A61K31/4188A61K31/4985A61K31/7072A61K38/06A61P31/12A61P31/14A61P43/00A61K2300/00A61K9/2077A61K31/498A61K31/661A61K31/4178A61K47/32A61K47/38
Inventor B·查尔E·尼雅蒂R·帕克达曼D·斯蒂芬尼迪斯
Owner GILEAD PHARMASSET LLC
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