PHARMACOKINETICS/ PHARMACODYNAMICS

4. PHARMACOKINETICS/ PHARMACODYNAMICS

The pharmacokinetics (pK) of NanoCrystal particles adminis- tered parenterally is a function of the formulation and physicochemical characteristics of the API. When Nano- Crystal particles are administered intramuscularly, the pK profiles may have the following attributes:

Relatively quick onset times and sustained release plasma drug concentration vs. time profiles. Highly influenced by particle size (Fig. 1). Plasma drug levels may be as high for intramuscular administration as when the drug is administered intravenously ( Fig. 2 ).

Figure 1 Pharmacokinetics as a function of particle size for intra- muscular administration of a NanoCrystal particle formulation in rats.

364 Lee

Figure 2 Pharmacokinetics of a solution formulation dosed intra- venously compared to a NanoCrystal particle formulation dosed intravenously and intramuscularly in rats.

The pK of NanoCrystal particles administered intrave- nously may have the following attributes:

sustained release pK profile; higher plasma levels and longer circulation times compared to solution formulation; similar pK profiles to cyclodextrin-based formulations ( Fig. 3 ); good dose proportionality ( Fig. 4 ).

In the case of intramuscular administration, NanoCrys- tal particle formulations can be formulated to be physiologi- cally compatible and thus minimize myotoxicity (i.e., site of injection damage to the muscle) and pain on injection. This is due to the absence of irritating organic cosolvents, sur- factants, and pH extremes. Additionally, isotonic formulations are possible. A phase I study was completed with naproxen NanoCrystal particles administered intramuscularly. The formulation contained a high concentration of naproxen, 400 mg =mL (the aqueous solubility of naproxen is 16 mg= mL

below the pK a of the carboxylic acid moiety in naproxen

Development and Scale-Up of NanoCrystal Õ Particles 365

Figure 3 Pharmacokinetics of a NanoCrystal particle formulation compared to a cyclodextrin-solubilized formulation.

=mL at pH 7), and a microbial preservative sys- tem. The two major goals for the clinical trial were no myotoxi- city and no pain on injection. Both of these clinical endpoints were successfully achieved with this formulation.

When administering NanoCrystal particle formulat- ions intravenously to dogs, the rate of infusion needs to be relatively slow due to an acute hemodynamic effect (1). It is

Figure 4 Plasma drug concentration as a function of dose for a NanoCrystal particle formulation.

366 Lee Table 2 Hypotension in Dogs as a Function of Intravenous

Infusion Rate of a NanoCrystal Particle Formulation Concentration of

Infusion rate Dose rate solids (mg =mL)

(mL =min) (mg =min) a Hypotension 50 1 50 Yes

50 0.1 5 No 10 5 50 Yes 10 1 10 Yes

10 0.5 5 No a Based on an average dog weight of 10 kg.

based on the concentration of solids administered as a func- tion of time. This effect is not unique to NanoCrystal particle formulations and has been observed with other particulate systems such as emulsions. To eliminate the hemodynamic effect, the infusion rate should be kept to 5 mg =min (Table 2).

5. MANUFACTURING PROCESS NanoCrystal colloidal dispersions are manufactured using

a proprietary high-energy media-milling process called the NanoMill 2 process. The process consists of recirculating a

slurry comprised of API, stabilizers, and water through the NanoMill ( Fig. 5 ). This results in the comminution and dis- persion of the API crystals from an initial size of about 10 to 100 mm to a final mean diameter of about 100–200 nm. Poly-

Mill 2 Polymeric Milling Media is used during the NanoMilling process to impart mechanical and hydraulic shearing plus

impact forces within the NanoMill chamber. The API crystals are fractured and dispersed as they recirculate through the NanoMill and are sterically and =or electrostatically stabilized by non-covalent adsorption of the stabilizers onto their surface.