Aqueous suspensions of tmc278

Inactive Publication Date: 2009-07-09
TIBOTEC PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]The invention further concerns a method of treating a subject infected with HIV, said method comprising the administration, by intramuscular or subcutaneous injection, of an anti-HIV effective amount pharmaceutical composition as specified above or hereinafter. Or, alternatively, the invention concerns the use of a pharmaceutical composition as specified above or hereinafter, for the manufacture of a medicament for treating HIV infection. In one embodiment, the composition is for the long-term treatment of HIV infection.
[0017]In another aspect, there is provided a method for the long term treatment of a subject infected with HIV, said method comprising the administration of an effective amount of a pharmaceutical composition as specified above or hereinafter, for administration by intramuscular or subcutaneous injection; wherein the composition is administered or is to be administered intermittently at a time interval that is in the range of one week to one year, or one week to two years. Or, alternatively, the invention concerns the use of a pharmaceutical composition as specified above or hereinafter, for the manufacture of a medicament for the long term treatment of a subject infected with HIV, for administration by intramuscul

Problems solved by technology

The treatment of Human Immunodeficiency Virus (HIV) infection, known as cause of the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge.
Although effective in suppressing HIV, each of these drugs, when used alone, is confronted with the emergence of resistant mutants.
However, none of the currently available drug therapies is capable of completely eradicating HIV.
Even HAART can face the emergence of resistance, often due to non-adherence and non-persistence with antiretroviral therapy.
A high pill burden is undesirable for many reasons, such as the frequency of intake, often combined with the inconvenience of having to swallow large dosage forms, as well as the need to store and transport a large number or volume of pills.
A high pill burden increases the risk of patients not taking their entire dose, thereby failing to comply with the prescribed dosage regimen.
As well as reducing the effectiveness of the treatment, this also leads to the emergence of viral resistance.
The problems associated with a high pill burden are prominent in anti-HIV therapy where a patient must take a large number of different anti-HIV agents.
HIV can never completely be eradicated so that persons infected with HIV pose a continuous risk of infecting others.
Despite these measures there is always an imminent risk of individuals being in contact with HIV infected persons of becoming infected.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Nanosuspensions

[0111]Glass bottles of 250 ml and ZrO2 beads, used as the milling media, were sterilized in an autoclave. Five grams of drug substance were put into the 250 ml glass bottle as well as a solution of 1.25 g Pluronic F108 in 60 ml of water for injection. Three hundred grams of ZrO2-beads with an average particle size of 500 μm were added. The bottle was placed on a roller mill. The suspension was micronized at 100 rpm during 72 hours. At the end of the milling process the concentrated nanosuspension was removed with a syringe and filled into vials. The resulting formulation is Formulation 1 in the following table. Determination of the concentration was done by HPLC / UV. A dilution was made to a final concentration of 25 mg / ml of TMC278. The resulting suspension was shielded from light.

[0112]Using similar procedures, Formulations 2, 3 and 4 were prepared. These were titrated with sodium hydroxide 1N solution to a pH of about 7. In formulations 2, 3 and 4 the...

example 2

Kinetic Study

[0113]The present study demonstrates that an injectable formulation of nanonised TMC278 or its HCl-salt results in stable blood plasma levels during a prolonged period of time. This study compares the plasma kinetics of TMC278 base and hydrochloric salt after single intramuscular (IM) or subcutaneous injection of a nanosuspension (Formula I of the previous example) at 5 mg / kg in male beagle dogs.

[0114]Six healthy male beagle dogs with body weights ranging from 8 to 16 kg at the start of the study, were used. Each dog was identified by an ear tattoo number. Two dogs were dosed intramuscularly (IM) in the left and right m. biceps femoris (treatment group A). Two dogs were dosed IM with TMC278.HCl (treatment group B). Two dogs were dosed subcutaneously (SC) in the left and right thoracal region. The injection volume was 2×0.1 ml / kg in all treatment groups. A 20 G needle was used.

[0115]Blood samples of 3 ml were taken from the left jugular vein from all dogs on day 0 at 0 h...

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Abstract

This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the NNRTI compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.

Description

FIELD OF THE INVENTION[0001]This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the NNRTI compound TMC278, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of HIV infection.BACKGROUND OF THE INVENTION[0002]The treatment of Human Immunodeficiency Virus (HIV) infection, known as cause of the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. HIV is able to evade immunological pressure, to adapt to a variety of cell types and growth conditions and to develop resistance against currently available drug therapies. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs) and the more recent fusion inhibitors.[0003]Al...

Claims

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Application Information

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IPC IPC(8): A61K31/505A61P31/12
CPCA61K9/0019A61K9/145A61K9/146A61K47/10A61K9/14A61K31/505A61K31/00A61P31/00A61P31/12A61P31/18A61K9/10A61K47/34
InventorBAERT, LIEVEN ELVIRE COLETTEDRIES, WILLY ALBERT MARIO CARLOSCHUELLER, LAURENT BRUNOFRANCOIS, MARC KAREL JOSEFVAN REMOORTERE, PETER JOZEF MARIA
OwnerTIBOTEC PHARMA