High throughput screening techniques that are routinely used in modern drug discovery processes result in a higher prevalence of poorly water-soluble drugs. Such drugs often have poor bioavailability issues due to their poor dissolution and/or permeability to achieve sufficient and consistent systemic exposure, resulting in sub-optimal therapeutic efficacies, particularly via oral administration. Alternative formulations and delivery routes are demanded to improve their bioavailability. Nanoparticulate formulations of poorly water-soluble drugs offer improved dissolution profiles. The physiology of the lung makes it an ideal target for non-invasive local and systemic drug delivery for poorly water-soluble drugs. In Chapter 2, a particle engineering process ultra-rapid freezing (URF) was utilized to produce nanostructured aggregates of itraconazole (ITZ), a BCS class II drug, for pulmonary delivery with approved biocompatible excipients. The obtained formulation, ITZ:mannitol:lecithin (1:0.5:0.2, w/w), i.e. URF-ITZ, was a solid solution with high surface area and ability to achieve high magnitude of supersaturation. An aqueous colloidal dispersion of URF-ITZ was suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic ITZ levels when inhaled by mice. The significantly improved systemic bioavailability of inhaled URF-ITZ was mainly ascribed to the amorphous morphology that raised the drug solubility. The effect of supersaturation of amorphous URF-ITZ relative to nanocrystalline ITZ on bioavailability following inhalation was evaluated in Chapter 3. The nanoparticulate amorphous ITZ composition resulted in a significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation. In Chapter 4, pharmacokinetics of inhaled nebulized aerosols of solubilized ITZ in solution versus nanoparticulate URF-ITZ colloidal dispersion were investigated, under the hypothesis that solubilized ITZ can be absorbed faster through mucosal membrane than the nanoparticulate ITZ. Despite similar ITZ lung deposition, the inhaled solubilized ITZ demonstrated significantly faster systemic absorption across lung epithelium relative to nanoparticulate ITZ in mice, due in part to the elimination of the phase-to-phase transition of nanoparticulate ITZ. / text

Poorly water soluble drugs have been manipulated to make them more soluble, increasing the bioavailability of these drugs. Several cryogenic processes allow for production of drug nanoparticles, without mechanical stress that could cause degradation. The Ultra Rapid Freezing (URF) process is a technique which improves water solubility of drugs by reducing primary drug particle size by producing amorphous solid dispersions. Heat conduction is improved, using a cryogenic material with a high thermal conductivity relative to the solution being frozen to maintain the surface temperature and heat transfer rate while the solution is being frozen. With URF technology, the freezing rate is fixed, which drives the particle formation and determines its characteristics. Supersaturation of drug in aqueous solution can allow for better absorption of the drug via the oral and pulmonary routes. Drug formulations that supersaturate the dissolution media show the possibility for increased bioavailability from an amorphous drug form. If the concentration of drug in solution is significantly increased, higher chemical potential will lead to an increase in flux across an exposed membrane, leading to higher blood levels for an amorphous drug, compared to an identical crystalline formulation. During oral delivery, supersaturated drug concentrations would also saturate PGP efflux sites in the gut lumen, increasing the drug's bioavailability. Saturated PGP sites show zero order efflux kinetics, so increasing the drug concentration in supersaturated biological fluid will increase serum drug levels. High supersaturation levels maintained for prolonged periods would have a beneficial effect on a drug's absolute bioavailability. Pulmonary administration offers therapeutic advantages over more invasive routes of administration. Limited amount of metabolizing enzymes like CYP 3A4 in lung tissue along with avoidance of first pass metabolism are advantages to pulmonary delivery. The objective of the research presented in this dissertation is to show the versatility of nanoparticulate poorly water soluble drug formulations. Due to the reduced particle size and the URF manufacturing process, a wide range of applications can be used with these nanoparticles. Oral and pulmonary administration routes can be explored using nanoparticles, but in vitro cell culture testing can show clinical benefits from this type of processing technology. / text

Inledning: Sjuka barn behöver anpassad vård och säkra, effektiva och väldokumenterade läkemedel. Förskrivning och uttag av preparat för pediatriska populationen ökar, men en tydlig uppskattning på problematik finns inte. Problem kan uppstå, när en lämplig beredning saknas, när redan registrerade läkemedel saknar avdelade doser för barn eller är tillgängliga enbart som en tablett med vuxen dos. Varje barn sägs vara en individ med unika läkemedelsomsättning, metabolism och biverkningspanorama, vilket komplicerar behandling. Lösningen på detta är i många fall ett extemporeläkemedel eller ett licenspreparat, men långa ledtider och dålig tillgänglighet kan medföra svårigheter att kunna ge rätt terapi. Syftet med denna studie är att i) kartlägga behov och befintliga lösningar, ii) testa handhållna pulverdispenser (HPD) Quantos, som en lämplig metod för fasta beredningar för att tillhandahålla individuella läkemedelsdoser till barn i de fall godkända läkemedel inte räcker.  Metod: Databassökning, intervjuer av hälso-sjukvårdspersonal, samt laborativt arbete för att omformulera registrerade läkemedel i tablettformer till individanpassade doser i hårdgelatin-kapslar med hjälp av Mettler-Toledos handhållna pulverdoseringsinstrument HPD Quantos. Resultat: Litteraturstudien och intervjuer överensstämmer med varandra: behov av barnanpassade läkemedel finns. HPD Quantos kan vara en alternativ metod för fasta beredningar för att tillhandahålla mängderför uppdosering med en femte- och/ eller en sjättedel av en tablett. Slutsats: För att ombesörja behoven för barnanpassade doser på ett sjukhus, måste HPD Quantos automatiseras till en inbyggd doseringsstation. Detta kommer att säkerställa dosering, dölja obehaglig smak, samt minska arbetsmiljörisken vid exponering av toxiska läkemedel.