Combination formulation of two antiviral compounds

A combined use and composition technology, applied in the direction of antiviral agents, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as restricted use

Active Publication Date: 2016-07-13
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although liver-targeting drugs are widely used and have efficacy, toxicity and other side effects limit their use

Method used

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  • Combination formulation of two antiviral compounds
  • Combination formulation of two antiviral compounds
  • Combination formulation of two antiviral compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Embodiment 1: the synthesis of amorphous Ledipasvir

[0238] Methods for preparing various forms of ledipasvir can be found in US Publication Nos. 2013 / 0324740 and 2013 / 0324496. Both applications are incorporated herein by reference. The following is the procedure for isolating ledipasvir amorphous free base.

[0239] Combine ledipasvir acetone solvate (191.4 g) and acetonitrile (1356 g) in a reaction vessel and mix the contents until a solution forms. The ledipasvir in acetonitrile solution was slowly added to another reaction vessel containing vigorously stirred water (7870 g). The contents were stirred at about 23°C for about 30 minutes. The contents were filtered and dried at approximately 40-45° C. until constant weight was reached to give ledipasvir as an amorphous solid (146.4 g, 82% yield).

Embodiment 2

[0240] Example 2: Preparation and formulation of tablets

[0241] A. Dose Selection of Tablets

[0242] i. Sofosbuvir

[0243] The dosage of sofosbuvir chosen for the tablet is 400mg once daily. E. max The PK / PD model and early virology and human exposure data support the dose of 400mg sofosbuvir, and other trials also support the dose selection of 400mg sofosbuvir.

[0244] Average AUC of major metabolites of sofosbuvir at 400mg sofosbuvir dose tau This value is approximately 77% of the maximum change from baseline in HCV RNA measured according to this model, which is the plateau apex of the exposure-response sigmoid curve. In S shape E max In the model, there was a relatively linear exposure-response relationship during the 20% to 80% maximum effect range. Therefore, given that sofosbuvir exposure from the 200 mg tablet was dose proportional to single doses up to 1200 mg, doses below 400 mg would be expected to exhibit a considerable reduction in the magnitude of chang...

Embodiment 3

[0280] Example 3: PK, Stability and Dissolution Properties of Ledipasvir Single Drug Tablets and Ledipasvir / Sofosbuvir Tablets and Reduction of Food Effect and Gastric Acid Suppressant Effect

[0281] A. Bioavailability of Ledipasvir Single Drug Tablets

[0282] A series of in vivo experiments were performed to evaluate the potential benefits of this solid dispersion approach compared to conventional formulations, and the solid dispersion was optimized by identifying the optimal polymer type and relative polymer concentration within the dispersion.

[0283] In a canine model pretreated with pentagastrin, formulations containing free base amorphous form (4% w / w, 10 mg amorphous free base tablet) and formulations containing ledipasvirD-tartrate (5.85% w / w, 10mgD-tartrate tablets) have equivalent bioavailability, wherein these two preparations are conventional preparations, see Table 7 for the results. Gogastrin is a synthetic polypeptide that stimulates the secretion of gastric...

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Abstract

Disclosed are pharmaceutical compositions having an effective amount of substantially amorphous ledipasvir and an effective amount of substantially crystalline sofosbuvir.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of January 30, 2014, an application number of 201480000286.1, and an invention title of "combined preparation of two antiviral compounds". [0002] Cross References to Related Applications [0003] This application claims under 35 U.S.C. §119(e) U.S. Provisional Application No. 61 / 759,320 filed January 31, 2013, U.S. Provisional Application No. 61 / 772,292 filed March 4, 2013, May 30, 2013 U.S. Provisional Application No. 61 / 828,899 filed August 27, 2013, U.S. Provisional Application No. 61 / 897,793 filed October 30, 2013, and November 21, 2013 Benefit of U.S. Provisional Application No. 61 / 907,332. The entire contents of these provisional applications are incorporated herein by reference. Background technique [0004] Hepatitis C is considered a chronic viral disease of the liver, characterized by liver disease. Although liver-targeting drugs are widely used...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7072A61K31/4184A61P31/14
CPCA61K31/4184A61K31/7072A61K2300/00A61K9/1623A61K9/1635A61K9/2054A61K31/513A61K31/381A61K31/4025A61K31/497A61K31/4985A61K31/5025A61K31/5377A61K31/675A61K31/7076A61K9/209A61K31/7056A61K31/4709A61K31/439A61P1/16A61P31/12A61P31/14A61K9/28A61K9/2009A61K9/2013A61K9/2018A61K9/2027A61K31/4178
Inventor 本·查尔埃里克·莫格里安雷扎·奥里亚罗克纳卡·帕克达曼迪米特里奥斯·史特凡尼迪斯瓦希德·齐亚
Owner GILEAD SCI INC
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