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Combination formulation of two antiviral compounds

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

Inactive Publication Date: 2014-11-12
GILEAD PHARMASSET LLC
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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

[0234] Example 1: Synthesis of Amorphous Ledipasvir

[0235] The methods for preparing various forms of ledipasvir can be found in US Publication Nos. 2013 / 0324740 and 2013 / 0324496. Both of these applications are incorporated herein by reference. The following is the method to isolate ledipasvir amorphous free base.

[0236] Combine ledipasvir acetone solvate (191.4 g) and acetonitrile (1356 g) in a reaction vessel, and mix the contents until a solution is formed. The ledipasvir solution in acetonitrile was slowly added to another reaction vessel, which contained vigorously stirred water (7870g). Stir the contents at about 23°C for about 30 minutes. The contents were filtered and dried at about 40-45°C until a constant weight was reached to obtain an amorphous solid of ledipasvir (146.4 g, 82% yield).

Embodiment 2

[0237] Example 2: Preparation and formulation of tablets

[0238] A. Dosage selection of tablets

[0239] i.Sofosbuvir

[0240] The dose of sofosbuvir selected for the tablet is 400 mg 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 choice of the dose of 400mg sofosbuvir.

[0241] The average AUC of the main metabolite of sofosbuvir at a dose of 400 mg sofosbuvir tau For approximately 77% of the maximum change in HCV RNA measured from baseline based on this model, this value is the plateau apex of the exposure-response S-shaped curve. E in S shape max In the model, there is a relatively linear exposure-response relationship between 20% and 80% of the maximum effect range. Therefore, given that the sofosbuvir exposure of the 200 mg tablet is dose-proportional to a single dose of up to 1200 mg, doses below 400 mg are expected to show a considerable reduction in the magnitude of the ...

Embodiment 3

[0277] Example 3: PK, stability and dissolution properties of Ledipasvir single-drug tablets and Ledipasvir / Sofosbuvir tablets, as well as reduction of food effect and gastric acid inhibitor effect

[0278] A. Bioavailability of Ledipasvir single-drug tablets

[0279] A series of in vivo tests were conducted to evaluate the potential benefits of the solid dispersion method compared to conventional formulations, and the solid dispersion was optimized by identifying the optimal polymer type and the relative polymer concentration in the dispersion.

[0280] In the canine model pretreated with pentagastrin, a preparation containing an amorphous form of free base (4% w / w, 10 mg amorphous free base tablets) and a preparation containing ledipasvir D-tartrate (5.85% w / w) , 10mg D-tartrate tablets) have equivalent bioavailability, and these two preparations are conventional preparations. The results are shown in Table 7. Five gastrin is a synthetic peptide that can stimulate the secretion of...

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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] Cross references to related applications [0002] This application requires U.S. provisional application number 61 / 759,320 filed on January 31, 2013, U.S. provisional application number 61 / 772,292 filed on March 4, 2013, and May 30, 2013 under 35U.SC §119(e). U.S. Provisional Application No. 61 / 828,899 filed on August 27, 2013, U.S. Provisional Application No. 61 / 870,729 filed on October 30, 2013, U.S. Provisional Application No. 61 / 897,793 filed on October 30, 2013, and November 21, 2013 Of the United States Provisional Application No. 61 / 907,332. The entire contents of these provisional applications are incorporated herein by reference. Background technique [0003] Hepatitis C is considered to be a chronic viral disease of the liver, which is characterized by liver disease. Although drugs that target the liver have been widely used, they also have curative effects, but toxicity and other side effects limit the use of these drugs. Hepatitis C virus (HCV) inhibitors can ...

Claims

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Application Information

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IPC IPC(8): A61K9/16A61K9/20A61K31/501A61K31/513
CPCA61K31/675A61K31/7076A61K31/5025A61K9/28A61K31/4184A61K31/513A61K31/4025A61K31/4985A61K9/2054A61K31/7056A61K31/5377A61K31/7072A61K31/497A61K38/00A61K31/4709A61K9/1635A61K9/1623A61K31/381A61K2300/00A61K9/209A61K31/439A61P1/16A61P31/12A61P31/14A61K9/2009A61K9/2013A61K9/2018A61K9/2027A61K31/4178
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 PHARMASSET LLC
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