Eric M. Gorman

Budesonide Nanoparticle Agglomerates as Dry Powder Aerosols With Rapid Dissolution

Nanoparticle technology represents an attractive approach for formulating poorly water-soluble pulmonary medicines. Unfortunately, nanoparticle suspensions used in nebulizers or metered dose inhalers often suffer from physical instability in the form of uncontrolled agglomeration or Ostwald ripening. In addition, processing such suspensions into dry powders can yield broad particle size distributions. To address these encumbrances, a controlled nanoparticle flocculation process has been developed. Nanosuspensions of the poorly water-soluble drug budesonide were prepared by dissolving the drug in organic solvent containing surfactants followed by rapid solvent extraction in water. Different surfactants were employed to control the size and surface charge of the precipitated nanoparticles. Nanosuspensions were flocculated using leucine and lyophilized. Selected budesonide nanoparticle suspensions exhibited an average particle size ranging from approximately 160 to 230 nm, high yield and high drug content. Flocculated nanosuspensions produced micron-sized agglomerates. Freeze-drying the nanoparticle agglomerates yielded dry powders with desirable aerodynamic properties for inhalation therapy. In addition, the dissolution rates of dried nanoparticle agglomerate formulations were significantly faster than that of stock budesonide. The results of this study suggest that nanoparticle agglomerates possess the microstructure desired for lung deposition and the nanostructure to facilitate rapid dissolution of poorly water-soluble drugs.

Nifedipine Nanoparticle Agglomeration as a Dry Powder Aerosol Formulation Strategy

Efficient administration of drugs represents a leading challenge in pulmonary medicine. Dry powder aerosols are of great interest compared to traditional aerosolized liquid formulations in that they may offer improved stability, ease of administration, and simple device design. Particles 1-5microm in size typically facilitate lung deposition. Nanoparticles may be exhaled as a result of their small size; however, they are desired to enhance the dissolution rate of poorly soluble drugs. Nanoparticles of the hypertension drug nifedipine were co-precipitated with stearic acid to form a colloid exhibiting negative surface charge. Nifedipine nanoparticle colloids were destabilized by using sodium chloride to disrupt the electrostatic repulsion between particles as a means to achieve the agglomerated nanoparticles of a controlled size. The aerodynamic performance of agglomerated nanoparticles was determined by cascade impaction. The powders were found to be well suited for pulmonary delivery. In addition, nanoparticle agglomerates revealed enhanced dissolution of the drug species suggesting the value of this formulation approach for poorly water-soluble pulmonary medicines. Ultimately, nifedipine powders are envisioned as an approach to treat pulmonary hypertension.

Pure Insulin Nanoparticle Agglomerates for Pulmonary Delivery

Diabetes is a set of diseases characterized by defects in insulin utilization, either through autoimmune destruction of insulin-producing cells (Type I) or insulin resistance (Type II). Treatment options can include regular injections of insulin, which can be painful and inconvenient, often leading to low patient compliance. To overcome this problem, novel formulations of insulin are being investigated, such as inhaled aerosols. Sufficient deposition of powder in the peripheral lung to maximize systemic absorption requires precise control over particle size and density, with particles between 1 and 5 microm in aerodynamic diameter being within the respirable range. Insulin nanoparticles were produced by titrating insulin dissolved at low pH up to the pI of the native protein, and were then further processed into microparticles using solvent displacement. Particle size, crystallinity, dissolution properties, structural stability, and bulk powder density were characterized. We have demonstrated that pure drug insulin microparticles can be produced from nanosuspensions with minimal processing steps without excipients, and with suitable properties for deposition in the peripheral lung.

Understanding the Dehydration of Levofloxacin Hemihydrate

Levofloxacin is a broad-spectrum antibiotic that exists as a hemihydrate under ambient conditions. In addition to the hemihydrate, there are three known crystalline anhydrate forms, denoted as α, β, and γ. In this study, differential scanning calorimetry (DSC), thermogravimetric analysis, Raman spectroscopy, single-crystal and powder X-ray diffraction, and solid-state NMR spectroscopy were used to investigate the transitions that occurred upon dehydration to the anhydrate as well as additional transitions that occurred to the anhydrous material upon heating/cooling. An enantiotropic conversion was observed in the DSC around 54°C corresponding to the conversion of the γ form to a new form, denoted as the δ form. Raman spectroscopy, powder X-ray diffraction, and solid-state NMR spectroscopy confirmed that a new crystalline form was being produced.

Photolysis of Recombinant Human Insulin in the Solid State: Formation of a Dithiohemiacetal Product at the C-Terminal Disulfide Bond

ABSTRACTPurposeExposure of protein pharmaceuticals to light can result in chemical and physical modifications, potentially leading to loss of potency, aggregation, and/or immunogenicity. To correlate these potential consequences with molecular changes, the nature of photoproducts and their mechanisms of formation must be characterized. The present study focuses on the photochemical degradation of insulin in the solid state.MethodsSolid insulin was characterized by solid-state NMR, polarized optical microscopy and scanning electron microscopy; various insulin preparations were exposed to UV light prior to product analysis by mass spectrometry.ResultsUV-exposure of solid human insulin results in photodissociation of the C-terminal intrachain disulfide bond, leading to formation of a CysS• thiyl radical pair which ultimately disproportionates into thiol and thioaldehyde species. The high reactivity of the thioaldehyde and proximity to the thiol allow the formation of a dithiohemiacetal structure. Dithiohemiacetal is formed during the UV-exposure of both crystalline and amorphous insulin.ConclusionsDithiohemiacetals represent novel structures generated through the photochemical modification of disulfide bonds. This is the first time that such structure is identified during the photolysis of a protein in the solid state.