Paclitaxel nanosuspensions for targeted chemotherapy - nanosuspension preparation, characterization, and use.

OBJECTIVE: The purpose of this work was to prepare a stable paclitaxel nanosuspension and test it for potential use as a targeted chemotherapeutic. Different particle coatings were employed to assess their impact on cellular uptake in vitro. In vivo work was then performed to demonstrate efficacy in tumor-bearing mouse models. MATERIALS AND METHOD: Paclitaxel nanosuspensions were prepared using a homogenization process and coated with excipients. Surface charge was measured by zeta potential, potency by high-performance liquid chromatography, and solubility using an in-line UV probe. Cellular uptake studies were performed via flow cytometry. In vivo experiments were performed to determine residence time, maximum tolerated dose, and the efficacy of paclitaxel nanosuspensions (Paclitaxel-NS). RESULTS: A stable paclitaxel nanosuspension was prepared and coated with various excipients. Studies in mice showed that the nanosuspension was well-tolerated and at least as effective as the IV Taxol control in prolonging mouse survival in a head and neck cancer model as well as an ovarian cancer model with a lower overall drug dose than the traditional IV administration route. CONCLUSIONS: The paclitaxel nanosuspension is suitable for cellular uptake. The nanosuspension was effective in prolonging life in two separate xenograft orthotopic murine cancer models through two separate routes of administration.

Conversion of nanosuspensions into dry powders by spray drying: a case study.

PURPOSE: Drying of nanosuspensions can cause destabilization of the particles, leading to irreversible aggregation. In order to prepare an effective solid dosage form for a nanosuspension, it is imperative that the spray-dried nanoparticles should go back to their original particle size when reconstituted in an aqueous system. This case study examines impact of various formulation and processing parameters on redispersibility of the spray dried nanoparticles. METHODS: Nanosuspensions were prepared using the microprecipitation-homogenization process. Spray drying of nanosuspensions was achieved using a lab-scale Buchi spray dryer. RESULTS: Formulation components appeared to have the most significant impact on redispersibility of spray dried particles. Absence of surface charge led to particles that could not be redispersed. On the other hand, charged particles stabilized with an appropriate sugar led to spray dried powders that were flowable and easily redispersible. Dissolution testing showed the presence of two phases--a lag phase that represented dispersion of the loose aggregates, and dissolution of the dispersed nanoparticles. CONCLUSIONS: Nanosuspensions of a poorly soluble drug could be spray dried to obtain flowable powders that could be easily redispersed. These optimized powders also showed significantly improved dissolution rates as compared to the micronized drug, or unoptimized nanosuspensions.

Advances in lipid nanodispersions for parenteral drug delivery and targeting.

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release. Thus, there is growing need to expand the array of targetable lipid-based systems to deliver a wide variety of drugs and produce stable formulations which can be easily manufactured in a sterile form, are cost-effective and at least as safe and efficacious as the earlier developed systems. These advanced parenteral lipid-based systems are at various stages of preclinical and clinical development which include nanoemulsions, nanosuspensions and polymeric phospholipid micelles. This review article will showcase these parenteral lipid nanosystems and discuss advances in relation to formulation development, processing and manufacturing, and stability assessment. Factors controlling drug encapsulation and release and in vivo biodistribution will be emphasized along with in vitro/in vivo toxicity and efficacy case studies. Emerging lipid excipients and increasing applications of injectable lipid nanocarriers in cancer chemotherapy and other disease indications will be highlighted and in vitro/in vivo case studies will be presented. As these new parenteral lipid systems advance through the clinic and product launch, their therapeutic utility and value will certainly expand.

Modeling behavior of protein C during and after subcutaneous administration.

Protein C is an important blood factor protein that regulates the blood coagulation process. Deficiency of protein C can lead to excessive coagulation that results in lack of tissue oxygenation, causing conditions such as deep vein thrombosis, pulmonary embolism, and stroke. Human protein C has been approved as a treatment for congenital protein C deficiency; however, the therapy requires frequent injections, due to the short residence time of the protein. Subcutaneous administration has been examined as an alternative to increase residence time and decrease injection frequency, thereby creating a more patient-friendly dosing regimen. In order to design an efficient injection or infusion protocol for subcutaneously administered proteins, it is important to accurately model the behavior (absorption, distribution, elimination) of these proteins in the body. However, several factors involved in a subcutaneous injection of the protein make modeling this behavior a challenging task. For example, absorption of the drug from the subcutaneous site into the blood stream can be variable depending on the site of injection, physical activity of the patient, etc. Furthermore, degradation of the protein can occur at the site of injection and further modify its absorption. The objective of this work was to demonstrate the utility of frequency response modeling as an alternative method to analyze the behavior of subcutaneously administered protein C. The results of our study indicate that if the dose range yielding the constant clearance of protein C is identified for the patient, models of that type, as presented in our study, can be used to adjust optimal dosing of protein C necessary to reach prescribed levels of the protein in this patient at desired time points, both specified by treatment requirements.

Application of drug delivery technologies in lead candidate selection and optimization.

Formulation development during early drug discovery and lead optimization, involves several challenges including limited drug supply, the need for rapid turnaround, and limited development time. It is also desirable to develop initial formulations that will be representative of final commercial formulations. Nanoparticles offer a unique platform for the formulation of poorly soluble drugs - such formulations can be injected (intravenous, subcutaneous, intramuscular), as well as administered through other routes, such as oral, ocular and inhalation. Thus, a single formulation can be used to test and eventually develop multiple dosage forms. Furthermore, nanoparticles offer the opportunity for high drug loading, for low potency compounds, and thus support toxicological evaluation of such compounds.

Polyphosphates and other phosphorus-containing polymers for drug delivery applications.

Poly(phosphate ester)s, polyphosphonates, and polyphosphazenes are three classes of phosphorus-containing polymers that have received wide attention over the past decade for their utility in biomedicine and tissue engineering. These three families of polymers can lead to a number of subclasses of polymers with varied properties. Significant research in this area has led to niche polymers with morphologies ranging from viscous gels to amorphous microparticles for utility in drug delivery. Furthermore, the pentavalency of phosphorus offers the potential for covalent linking of the drug. The classes of polymers discussed in this review are being explored in human clinical trials for vaccine delivery as well as delivery of oncolytic and CNS therapeutics. More applications in the areas of DNA delivery and tissue engineering are also being explored.

In vitro and in vivo degradation studies of a novel linear copolymer of lactide and ethylphosphate.

Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.