Nanosuspension of a poorly soluble drug via microfluidization process

Toxicokinetics (TK) is generation of kinetic data for systemic exposure and toxicity assessment of the drug. These studies help us to estimate the observed toxicity to that dose. TK evaluation is very important in drug development phase in both regulatory and scientific perspective. There are several guidelines to conduct TK study in animals recommended by regulatory bodies (OECD). TK evaluation is useful in selection of dose, dosing form, alternative dosing route, evaluation of toxicological mechanism, and also used for the setting safe dose level in clinical phases. This TK studies also used to reduces the animal number (replacement, reduction and refinement). On the other hand, TK data are practically used for the purpose of drug discovery such as lead-optimization and candidate-selection. Email:marketing@medicilon.com.cn web:www.medicilon.com

There are advantages and disadvantages to each approach. Published particle size data for homogenization processes indicate that this approach typically produces a dispersion with slightly broader particle size distribution relative to what has been achievable using the wet milling approach. Also, high-energy wet milling typically uses a proprietary milling media in which contact points between the media and the drug particles bring about particle size reduction. The media used in Elan's NanoCrystal technology approach, for example, comprises highly cross-linked polystyrene spheres that have been engineered to withstand high shear forces, thereby minimizing concerns about media wear during manufacturing. The result is a population of drug nanoparticles characterized by high purity and a tight, reproducible particle-size distribution profile.

Formulating poorly water-soluble molecules using the various nano-sizing approaches adds tremendous value throughout the drug development cycle. NanoCrystal formulations can be prepared with as a little as 10 mg of active ingredient, and are often times used as clips to identify the optimal development candidate based on bioavailability and efficacy. These formulations can be dosed via multiple routes of administration, and since the formulations are well-tolerated and provide maximal exposure for a poorly water-soluble compound, they are an invaluable tool for toxicokinetic studies and target product profile.

A major challenge in realizing the full commercial potential of nanosizing is the successful conversion of stable drug nanoparticles into acceptable dosage forms. Furthermore, while microfluidization process has been used in connection with injectable formulations, the use of that process is much less common in connection with oral formulations. Regardless of the success in development of nanosizing technologies, the existing drawbacks trigger a need for more sophisticated procedures to obtain oral nanosuspensions of poorly soluble drugs with improved bioavailability.

In one embodiment, provided is a method of preparation of an oral nanosuspension of a poorly soluble drug with improved bioavailability using a microfluidization process. In certain embodiment, the method of preparation of an oral nanosuspension of a poorly soluble drug comprises a step of stirring the drug, which has been micronized, in an aqueous polymeric excipient solution for wetting and dispersing in the absence of surfactants, followed by a step of passing the resulting mixture through a high-shear microfluidizer processor.

In one embodiment, provided is a nanosuspension of a poorly soluble drug with improved bioavailability made using a microfluidization process in the absence of surfactants, wherein said nanosuspension is suitable for a long term storage. In certain embodiments, the oral nanosuspension is stable for at least 2 months at room temperature. In certain embodiments, the oral nanosuspension is stable for at least 6 months at 5°C.

In another embodiment, provided is a method of administration of an oral nanosuspension of a poorly soluble drug with improved bioavailability comprising the step of microfluidization of the nanosuspension of a poorly soluble drug in the absence of surfactants and the step of dilution of the nanosuspension immediately before the administration in the presence of surfactants. Examples of surfactants include, but are not limited to, vitamin E-TPGS, Labrasol and Tween 20. In a specific embodiment, the surfactants are ionic surfactants. In certain embodiments, ionic surfactants include, but are not limited to, Sodium Lauryl Sulfate (SLS), i.e., SDS.

In one embodiment, provided is a nanosuspension formulation of a poorly soluble drug with improved bioavailability.

In yet another embodiment, provided is a formulation of a poorly soluble drug comprising a deagglomerated and particle size controlled nanosuspension with improved bioavailability.

Poorly water soluble drugs often have limited exposure for toxicology and toxicokinetic studies and clinical trials. It was discovered that drug particles having a specific average particle size can be prepared by microfluidization process and that these particles are relatively stable. These particles are formulated into pharmaceutical compositions exhibiting improved bioavailability. The resulting pharmaceutical compositions can be used in toxicology formulations.

The methods and compositions provided herein can be practiced with a wide variety of drug substances. The drug substance is typically poorly soluble and dispersible in at least one liquid medium. In one embodiment, by “poorly soluble” it is meant that the drug substance has a solubility in the liquid dispersion medium of less than about 10 mg/ml. In another embodiment, “poorly soluble” means a solubility of less than 1 mg/ml. In yet another embodiment, “poorly soluble” means a solubility of less than 10 μg/ml.

The methods and compositions provided herein can be practiced with a liquid dispersion medium such as water and other liquid media in which a drug substance is poorly soluble and dispersible including, but is not limited to, aqueous salt solutions, sunflower oil and solvents. Solvents include, but are not limited to, ethanol, t-butanol, hexane and glycol. The pH of the aqueous dispersion media can be adjusted by techniques known to those skilled in the art.