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Therapeutic compositions for treatment of human immunodeficiency virus

A compound and pharmaceutical technology, applied in the solid oral dosage form of emtricitabine and tenofovir alafenamide, including the compound of formula I, can solve the complex decision-making problems of HIV-infected patients

Active Publication Date: 2018-07-31
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, decisions regarding the treatment of HIV-infected patients are complicated when patients require treatment for other medical conditions (eg, metformin, rifampicin, HCV antivirals, hormonal contraceptives, etc.)

Method used

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  • Therapeutic compositions for treatment of human immunodeficiency virus
  • Therapeutic compositions for treatment of human immunodeficiency virus
  • Therapeutic compositions for treatment of human immunodeficiency virus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0501] Example 1 - Single-dose Tablet of Compound of Formula II

[0502] The formulation of the compound of formula II (tablet F1) is prepared by dry granulation. Figure 5 is a flow chart illustrating the preparation of the formulation. The composition of the single-dose formulation is shown in the table below:

[0503]

[0504]

[0505] *equivalent to 75 mg of compound of formula I

[0506] **Intergranular: 2.25mg (0.75%); Extragranular: 2.25mg (0.75%)

[0507] In the pharmacokinetic study of Example 3, tablets of Formulation F1 were film-coated with 12 mg of Opadry II Yellow 85F92259. The total weight of the film-coated tablet is 312 mg.

[0508] The compound of formula II is mixed with intergranular excipients (lactose, microcrystalline cellulose and crospovidone), further blended with the intergranular portion of sodium stearyl fumarate), rolled, ground, and mixed with hard Sodium fatty acyl fumarate is finally blended to produce the final powder mix for compre...

Embodiment 2

[0509] Example 2 - compound of formula II / emtricitabine / tenofovir alafenamide bilayer tablet

[0510] A bilayer formulation of the compound of formula II, emtricitabine and tenofovir alafenamide hemifumarate (tablet F2) was prepared using the method described in Example 8. Figure 6 is a flowchart illustrating the preparation of bilayer tablets. The composition of this formulation is summarized in the table below:

[0511]

[0512] *equivalent to 75 mg of compound of formula I

[0513] **Equivalent to 25mg tenofovir alafenamide

[0514] ***Intergranular: 212.5mg (29.1%); Extragranular: 2.65mg (0.4%)

[0515] Intergranular: 2.65mg (0.4%); Extragranular: 2.65mg (0.4%)

[0516] Intergranular: 2.83mg (0.4%); Extragranular: 2.83mg (0.4%)

[0517] In the pharmacokinetic study of Example 3, tablets of formulation F2 were film coated with 21.9 mg of Opadry II Yellow 85F92259 (representing 3% weight gain). The total weight of the film-coated tablet is 752 mg.

[0518] Table...

Embodiment 3

[0524] Example 3-pharmacokinetic studies

[0525] A study was performed to evaluate the pharmacokinetic profiles of Formulations F1, F2 and F3 of Examples 1, 2 and 2A. A randomized, open-label, multi-period, fixed-sequence, crossover study was conducted to evaluate the bilayer tablet formulation F2 relative to a fixed-dose combination tablet containing emtricitabine and tenofovir alafenamide (tablet Formulation F3) Relative bioavailability of coadministered single-dose tablet formulation F1. Bioavailability was assessed in healthy individuals.

[0526] Study Design and Duration of Treatment

[0527] Three single doses of the following tablet formulations were administered orally during a total study duration of up to 21 days:

[0528] (a) Simultaneous administration of a fixed dose combination tablet comprising emtricitabine and tenofovir alafenamide (200 / 25mg-tablet F3) and a single-dose tablet containing a compound of formula I under fasting conditions ( 75mg-tablet F1...

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Abstract

A solid oral dosage form is provided, comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and emtricitabine or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] Pharmaceutical formulations suitable for the treatment of viral infections such as HIV are provided, particularly solid oral dosage forms comprising a compound of formula I, emtricitabine and tenofovir alafenamide. Background technique [0002] Human immunodeficiency virus type 1 (HIV-1) infection is a life-threatening and serious disease of major public health significance, affecting approximately 35 million people worldwide (UNAIDS). Global Report: UNAIDS Report on the Global AIDS Epidemic 2013). The standard of care for treating HIV-1 infection uses combination antiretroviral therapy (ART) to suppress viral replication below detectable limits, increase CD4 cell counts and halt disease progression. [0003] Medicines are also needed to serve populations with limited treatment options (eg, children, women, and the elderly). In some cases, these populations may have difficulty maintaining treatment because of the pill burden (number of pills taken pe...

Claims

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Application Information

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IPC IPC(8): A61K9/20A61K9/28A61K31/513A61K31/5365A61K31/675A61P31/18A61K9/24A61K31/553
CPCA61K31/5365A61K31/675A61K31/513A61K9/0053A61K9/209A61K9/2054A61K9/2013A61K9/282A61P31/18A61K2300/00A61K31/553A61K9/20A61K9/2086A61K9/2027A61K9/2833A61K31/537A61K9/2095A61K9/28
Inventor B·M·科尔曼洪蕾J·M·科兹拉
Owner GILEAD SCI INC
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