Intra-articular (IA) ropivacaine microparticle suspensions reduce pain, inflammation, cytokine, and substance p levels significantly more than oral or IA celecoxib in a rat model of arthritis.

Current therapeutic treatment options for osteoarthritis entail significant safety concerns. A novel ropivacaine crystalline microsuspension for bolus intra-articular (IA) delivery was thus developed and studied in a peptidoglycan polysaccharide (PGPS)-induced ankle swelling rat model. Compared with celecoxib controls, both oral and IA, ropivacaine IA treatment resulted in a significant reduction of pain upon successive PGPS reactivation, as demonstrated in two different pain models, gait analysis and incapacitance testing. The reduction in pain was attended by a significant reduction in histological inflammation, which in turn was accompanied by significant reductions in the cytokines IL-18 and IL-1ß. This may have been due to inhibition of substance P, which was also significantly reduced. Pharmacokinetic analysis indicated that the analgesic effects outlasted measurable ropivacaine levels in either blood or tissue. The results are discussed in the context of pharmacologic mechanisms both of local anesthetics as well as inflammatory arthritis.

NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery.

BACKGROUND: Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. METHODS: NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. RESULTS: Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. CONCLUSION: These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

Anion effects on electrostatic charging of sterically stabilized, water insoluble drug particles.

Water-insoluble suspensions of itraconazole and budesonide were sterically stabilized using nonionic polymers (poloxamer 188 or polysorbate 80) and probed for polymer-anion interactions by measuring changes in particle zeta potential. Anions comprising a range of functionalities and aqueous solubilities were examined. Results showed that the more hydrophobic anions partitioned to the particle interface, and a simple model for predicting anion adsorption was developed from their calculated properties. Anions with a calculated Klopman water solubility less than 10 microM or a calculated log P>3.5 were adsorbed to the particle-polymer interface effectively increasing the overall particle charge. Anions of similar hydrophobicities with sulfonate or sulfate functionalities showed a much higher degree of particle charging compared with their carboxylate and phosphonate analogs at pH 9.5. In addition, the electrostatic charging of particles occurred at lower solution concentrations of sulfonate derivatives. These results suggest that the relative basicity of the oxoanion functionality may influence protonation or ion-pairing phenomena of the anions when adsorbed at the particle-polymer interface. Cetyltetramethylammonium bromide (CTAB) produced a positively charged particle consistent with the model developed for anion adsorption. Particle charging of sterically stabilized drug suspensions appeared largely independent of drug and polymer type. Anion hydrophobicity (solubility) and headgroup functionality dictated the observed charging behavior.

Physicochemical stability of phospholipid-dispersed suspensions of crystalline itraconazole.

The physicochemical stability of an aqueous, phospholipid-based dispersion of itraconazole microcrystals was studied as a model water-insoluble drug suspension. The particle size, phospholipid concentrations, free fatty acid (FFA) content, pH, and zeta potential of two test suspensions were followed over 63 days at 5 and 40 degrees C storage conditions. Hydrolysis of a control suspension containing Lipoid E80 led to rapid FFA formation, pH drop, and subsequent particle aggregation. In the second suspension, sodium oleate used in conjunction with Lipoid E80 significantly enhanced the suspension physicochemical stability. Oleate anions effectively (1) increased the anionic charge of the phospholipid surface layer, (2) buffered the suspension near pH 7, and (3) reduced the specific production of oleic acid as a phosphatidylcholine (PC) degradant. The observed hydrolysis rate constants k(obs) approximately 2 x 10(-7) (Lipoid only) and k(obs) approximately 5 x 10(-8) (Lipoid and oleate) were consistent with the pH dependent behavior reported for saturated soybean PC solutions. Mechanistically, FFA formed initially in the control suspension partitioned to the aqueous phase with limited influence on the phospholipid microenvironment at the itraconazole particle surface. Phospholipid stabilization of water-insoluble drugs was demonstrated with clear benefits from fatty acid anions as co-additives to influence the surface microenvironment, reduce hydrolysis kinetics, and enhance suspension physicochemical stability.