United States Patent:  6,068,858

Assignee:  Elan Pharma International Limited (Shannon, IE)

Filed:  January 6, 1999

The present invention describes formulations of nanoparticulate HIV protease inhibitors comprising a cellulosic surface stabilizer. The nanoparticulate formulations have an increased rate of dissolution in vitro, an increased rate of absorption in vivo, a decreased fed/fasted ratio variability, and a decreased variability in absorption. The present invention is also directed to methods of making the novel formulations. In particular, nanoparticulate formulations of HIV type 1 (HIV-1) and type 2 (HV-2) protease inhibitors are described.

SUMMARY OF THE INVENTION

The present invention is directed to the surprising and unexpected discovery that the use of cellulosic surface stabilizers in nanoparticulate formulations of HIV protease inhibitors can form superior, stable, and dispersible compositions. This discovery is an improvement upon the invention described in U.S. Pat. No. 5,145,684.

It is an advantageous feature that the cellulosic surface stabilizers can be used to prepare nanoparticulate formulations of a wide range of HIV protease inhibitors.

In particular, the present invention comprises nanoparticulate HIV protease inhibitors having a cellulosic surface stabilizer adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than about 1000, and more preferably, less than about 400 nm.

The invention also provides a stable dispersion comprising a liquid dispersion medium with the above-described nanoparticles dispersed therein. The terms "dispersion" or "suspension" are synonymous and used interchangeably herein and refer to a formulation in which the ingredient nanoparticles float undissolved in a fluid such as water.

In a preferred embodiment, a pharmaceutical composition is provided comprising the above-described nanoparticulate HIV protease inhibitor, a cellulosic surface stabilizer, and a pharmaceutically acceptable carrier therefor. The pharmaceutical compositions of the invention, which exhibit unexpectedly high bioavailability, may be formulated as a liquid, gel, solid, or any other appropriate formulation.

In another embodiment of the invention, there is provided a method of preparing the above-described nanoparticulate drug particles. The method comprises dispersing an HIV protease inhibitor in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the average particle size of the HIV protease inhibitor to an effective average particle size of less than about 1000 nm, and more preferably, less than about 400 nm. The drug particles can be reduced in size in the presence of a cellulosic surface stabilizer, or the drug particles can be contacted with a cellulosic surface stabilizer after attrition.

In yet another embodiment of the invention, a method for preparing a nanoparticulate pharmaceutical composition in a tablet form is provided. In such a method, the nanoparticles are compressed into tablets. The tablets generally also comprise at least one pharmaceutically acceptable carrier.

The present invention also provides for methods of treating mammals comprising administering to a mammal a pharmaceutical composition according to the invention, either alone or in combination with other treatments.

Claim 1 of 18 Claims

1. A method of preparing a nanoparticulate composition comprising a crystalline HIV protease inhibitor having a solubility in water of less than about 10 mg/ml, said HIV protease inhibitor having adsorbed on the surface thereof a cellulosic surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm, wherein said method comprises:

(1) dispersing a HIV protease inhibitor in a liquid dispersion medium, wherein the HIV protease inhibitor is poorly soluble and dispersible in the liquid dispersion medium;

(2) wet grinding the HIV protease inhibitor in the presence of rigid grinding media having an average particle size of less than about 3 mm and a cellulosic surface stabilizer to reduce the particle size of the HIV protease inhibitor to an effective average particle size of less than about 1000 nm; and

(3) isolating the resultant nanoparticulate HIV protease inhibitor composition from the grinding media.

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