Elaine Merisko-Liversidge

Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules. Nanoparticle dispersions are stable and have a mean diameter of less than 1 micron. The formulations consist of water, drug, and one or more generally regarded as safe excipients. These liquid dispersions exhibit an acceptable shelf-life and can be postprocessed into various types of solid dosage forms. Drug nanoparticles have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance, providing the discovery scientist with an alternate avenue for screening and identifying superior analogs. For the toxicologist, the approach provides a means for dose escalation using a formulation that is commercially viable. In the past few years, formulating poorly water-soluble compounds using a nanoparticulate approach has evolved from a conception to a realization whose versatility and applicability are just beginning to be realized.

Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology ☆

A significant percentage of active pharmaceutical ingredients identified through discovery screening programs is poorly soluble in water. These molecules are often difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues, e.g. poor bioavailability, lack of dose proportionality, slow onset of action and other attributes leading to poor patient compliance. In addition, for parenteral products, these molecules are generally administered with co-solvents and thus have many undesirable side effects. Wet media milling is one of the leading particle size reduction approaches that have been successfully used to formulate these problematic compounds. The approach is a water-based media milling process where micron-sized drug particles are shear-fractured into nanometer-sized particles. Nanoparticle dispersions are stable and typically have a mean diameter of less than 200 nm with 90% of the particles being less than 400 nm. The formulation consists only of water, drug and one or more GRAS excipients. Drug concentrations approaching 300-400mg/g can be targeted with the use of minimal amounts stabilizer. Typically, on average, the drug to stabilizer ratio on a weight basis ranges from 2:1 to 20:1. These liquid nanodispersions exhibit acceptable shelf-life and can be post-processed into various types of solid dosage forms. Nanoparticulate-based drug products have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance providing the discovery scientist an alternate avenue for screening and identifying superior leads. In the last few years, formulating poorly water soluble compounds as nanosuspensions has evolved from a conception to a realization. The versatility and applicability of this drug delivery platform are just beginning to be realized.

Insulin Nanoparticles: A Novel Formulation Approach for Poorly Water Soluble Zn-Insulin

AbstractPurpose. To determine the feasibility of using wet milling technology to formulate poorly water soluble zinc-insulin as a stable, biologically active, nanoparticulate dispersion. Methods. The feasibility of formulating zinc-insulin as a nanoparticulate dispersion using wet milling technology was studied. An insulin nanoparticulate formulation was reproducibly obtained after milling zinc-insulin in the presence of F68, sodium deoxycholate and water at neutral pH. The physical and chemical properties of these peptide particles were studied using electron microscopy, laser light scattering, HPLC and SDS-PAGE. To verify efficacy, hyperglycemic rats were dosed subcutaneously and intraduodenally with nanoparticles or solubilized insulin. Glucose and insulin levels were monitored on blood samples collected throughout the study. Results. Zn-insulin (mean size = 16.162 μm) was processed using milling technology to form an aqueous-based nanoparticle dispersion with a mean particle size of less than 0.150 μm. The formulation was homogeneous and exhibited a unimodal particle size distribution profile using laser light diffraction techniques. Insulin, processed as a peptide-particle dispersion, was shown to be comparable to unprocessed powder using HPLC and SDS-PAGE. In addition, HPLC analyses performed on samples, heat-treated at 70 °C for 100 minutes, demonstrate that under conditions which effect the solubilized peptide, formulated as a peptide-particle dispersion, insulin was chemically stable. Also, when stored refrigerated, the insulin dispersion was chemically and physically stable. Finally, peptide particles of insulin, dosed subcutaneously and intraduodenally, were effective at lowering blood glucose levels of hyperglycemic rats. Conclusion. Water insoluble Zn-insulin can be formulated as a stable, biologically active nanometer-sized peptide particle dispersion using wet media milling technology.

Direct Suppression of Phagocytosis by Amphipathic Polymeric Surfactants

Recent studies have demonstrated that phagocytosis of colloidal particles by the mononuclear phagocytes of the liver and spleen can be controlled by either coating or stabilizing particulate carriers with the amphipathic polymeric surfactants, F108 and T908. These surfactants consist of copolymers of polypropylene oxide (PPO) and polyethylene oxide (PEO) and, when adsorbed to particulate surfaces, significantly decrease sequestration of particulates by the mononuclear phagocytes (MPS) of the liver. To evaluate these observations further, murine peritoneal macrophages were incubated for varying periods with surfactant-coated and noncoated polystyrene particles (PSPs). Phagocytosis was monitored using gamma counting and quantitative fluorescence microscopy. The data show that phagocytosis is decreased when PSPs are coated with F108 and T908. In addition, suppression of phagocytic activity was observed when cells were pretreated with the surfactant and then challenged with noncoated particles. The data confirm previous observations that polymeric surfactants consisting of PEO and PPO protect particulate carriers from rapid uptake by the MPS of the liver. Further, F108 and T908 suppress phagocytosis directly without affecting the integrity, viability, or functional state of the cell.__________

A Formulation Strategy for Gamma Secretase Inhibitor ELND006, a BCS Class II Compound: Development of a Nanosuspension Formulation with Improved Oral Bioavailability and Reduced Food Effects in Dogs

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimers disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.

Long-Acting Atypical Antipsychotics: Characterization of the Local Tissue Response

PurposeLong-acting injectables (LAIs) are increasingly recognized as an effective therapeutic approach for treating chronic conditions. Many LAIs are formulated to create a poorly soluble depot from which the active agent is delivered over time. This long residing depot can cause localized chronic-active inflammation in the tissue, which has not been well defined in the literature. The purpose of this work is to establish an experimental baseline for describing these responses.MethodsNon-human primates and rodents were used to examine the response to LAI formulations of two clinically relevant atypical antipsychotics, aripiprazole monohydrate and olanzapine pamoate monohydrate.ResultsA foreign body response develops with elevations of key cytokines such as IL-1α, IL-1β, TNFα, and IL6 at the site of injection. However, the tissue response for the two atypical antipsychotics compounds diverge as evidenced by quantitative differences observed in cytokine levels at various time points after dosing.ConclusionsOur studies show that, while the drugs are in the same therapeutic class, the response to each of these compounds can be distinguished qualitatively and quantitatively, supporting the idea that the injection site reaction involves a multiplicity of factors including the properties of the compound and cellular dynamics at the site of injection.

Delivery of long-acting injectable antivirals: best approaches and recent advances

Purpose of review Treatment of chronic disease in a manner that promotes compliance and patient adherence has necessitated the consideration for drug delivery approaches that reduce the burden of regimens requiring daily treatment. Long-acting injectable (LAI) products have been developed in many disease areas and are now being exploited for the treatment of infectious disease, most notably HIV. Recent findings Research published over the past 3 years has shown that LAI nanosuspensions of nonnucleoside reverse transcriptase inhibitors and integrase inhibitors provide extended exposure to the active drug over a period of days to weeks. Some of these candidates are currently in clinical study and are highly anticipated medications for the prevention of HIV. Summary LAIs represent a growing need in the treatment of chronic infections. To date, the approach has been most successfully applied in the treatment of HIV, but could certainly be expanded into other diseases like tuberculosis. Most importantly, LAIs can provide a means to help prevent the emergence of resistance which may be attributed to lack of compliance to regimens requiring daily, oral administration.

Nanosizing: “End-to-End” Formulation Strategy for Poorly Water-Soluble Molecules

The number of poorly water-soluble compounds in pharmaceutical research and development pipelines has steadily increased over the years. These compounds have historically been difficult to develop requiring high concentrations of solvents/co-solvents and exhibiting poor pharmacokinetic properties. In response to this unmet need, a variety of niche technologies have been explored and developed. This chapter reviews one of the more versatile “end-to-end” formulation approaches for poorly soluble compounds, i.e., nanosizing or nanonization. The approach is broadly applicable for parenteral and non-parenteral dosage forms and has been commercially validated with the launch of products such as Rapamune®, Emend®, TriCor® 145, Triglide®, Megace ES®, Invega® Sustenna®, Abraxane®, and Juvedical®.