Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues.

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

An important step in assessing the toxicology of particles is to determine their fate after inhalation. Of particular interest to us are airborne ultrafine particles (UFPs; < 100 nm), which are abundant in ambient urban air and are of the same size as engineered nanoparticles. Translocation to extrapulmonary sites after respiratory tract deposition represents an important mechanism for these particles to cause direct effects in secondary target organs (Oberdorster et al. 2005). The extent to which this process occurs depends on several factors including particle solubility, particle or aggregate size, the site of deposition, and the integrity of the epithelial lining. UFPs deposit efficiently in all regions of the respiratory tract, depending on their size; specifically, as particle size decreases toward the smallest UFPs, nasopharyngeal deposition increases (International Committee on Radiological Protection 1994).

Studies in rats have shown translocation of soluble manganese compounds from the nose along olfactory neuronal pathways to the olfactory bulb (Dorman et al. 2004; Henriksson and Tjalve 2000; Tjalve et al. 1996; Tjalve and Henriksson 1999) after inhalation or intranasal instillation exposures. Likewise, the few studies that have examined the fate of UFPs deposited on the nasal mucosa identified translocation along the neuronal olfactory route as a pathway to the olfactory bulb of the central nervous system (CNS). These include early studies in non-human primates, which demonstrated the translocation of solid nanosized particles (30 nm poliovirus; 50 nm silver-coated gold colloids) along the axons of olfactory nerves into the olfactory bulb (Bodian and Howe 1941a, 1941b; DeLorenzo 1970). We have also shown that inhaled elemental carbon particles (13C; 35 nm, count median diameter) accumulate in rat olfactory bulb after whole-body inhalation (Oberdorster et al. 2004). Regarding penetration into deeper brain regions, Tjalve et al. (1995) demonstrated that soluble ionic Mn instilled into the olfactory chamber of pike has the ability to pass synaptic junctions and migrate from the olfactory tract to more distal regions, including the hypothalamus. Dorman et al. (2004) found Mn in the striatum and cerebellum of rats after subchronic inhalation exposure to a soluble Mn salt (sulfate); however, this was attributed to uptake from the blood. Thus, contributions to brain Mn levels from the blood need to be considered and may also be an issue for inhaled solid UFPs.

The effects of translocated particles in the brain are also important to determine. For example, preliminary information has emerged from populations of welders that some of them may develop parkinsonism 17 years earlier than the general population (Racette et al. 2001). Welding produces high amounts of fumes containing Mn UFPs (Zimmer et al. 2002). Several recent epidemiologic studies describe occupational exposure ranges of approximately 0.01–5 mg/m3 Mn in fumes from various welding processes and materials (Korczynski 2000; Li et al. 2004; Sinczuk-Walczak et al. 2001). Conflicting data emerge from animal studies, however, regarding effects of inhaled Mn compounds in the brain. Henriksson and Tjalve (2000) reported changes in glial fibrillary acidic protein (GFAP) and S-100b, markers of astrocyte activation, in several brain regions from rats exposed intranasally to Mn chloride. However, Dorman et al. (2004) did not find any evidence of changes in GFAP levels in the brain after exposure to Mn sulfate or phosphate. Potential contributing factors to the lack of concurrence in results include differences in the solubilities of the Mn salts used, the doses, and the contribution of olfactory epithelial damage.

In the present study, we sought to address the hypothesis that a major translocation route for inhaled poorly soluble Mn oxide UFPs from deposits in the nose is to the olfactory bulb in the CNS. We characterized the size, oxidation state, and in vitro solubility of gas-phase–generated Mn oxide particles and also compared the translocation kinetics to the olfactory bulb of Mn oxide and MnCl2 that were applied to the nasal epithelium of rats via instillation. We then measured the accumulation of Mn in lung, liver, and olfactory bulb after repeated inhalation exposures with both nares patent or with one naris occluded. We show that Mn oxide UFPs are translocated to and retained in the olfactory bulb (ipsilateral to the patent naris only) and present evidence of exposure-induced effects in that region of the brain. These studies demonstrate the importance of UFPs size and of solubility in olfactory translocation processes.

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Translocation of inhaled ultrafine manganese oxide particles to the central nervous system.

The basics and underlying mechanisms of mucoadhesion.

Pectin-based systems for colon-specific drug delivery via oral route

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

Gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid and the effect of food

The nasal delivery of drugs, both for systemic and local use, is an expanding field with many drugs being delivered by this route. It is known that changes in pH can affect drug absorption but there is no data regarding intranasal pH over time. We present the results of 24-h ambulatory nasal pH monitoring in four subjects, each of whom had monitoring on two separate occasions. The apparatus consisted of a pH monitor with two electrodes, thus enabling us to take readings from 1 and 4 cm behind the anterior end of the inferior turbinate. Measurements were recorded every 6 s by the posterior electrode and every 30 s by the anterior electrode. The recording apparatus was worn around the subjects waist. Analysis of the results showed that there was no diurnal variation and no significant differences between the subjects. The mean pH from the anterior electrode was higher than that from the posterior (7.1 versus 6.6). The pH did not fluctuate with daily activities such as eating, drinking or sleeping. The results are interesting and may be of importance with regard to the design of formulations for nasal drug delivery systems.

N. Washington

Papers

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

Gastrointestinal transit of a controlled-release pellet formulation of tiaprofenic acid and the effect of food

Twenty‐four hour ambulatory nasal pH monitoring

The effect of inclusion of aluminium hydroxide in alginate-containing raft-forming antacids

Effect of dose size, food and surface coating on the gastric residence and distribution of an ion exchange resin