Various kinds of nanoparticle formulation have been developed to improve the bioavailability of poorly water-soluble drugs. Drug nanocrystal technology using wet milling has been applied for active pharmaceutical ingredients and some of them are commercially available. Nanonization of drug as nanocrystal enables improvement of dissolution rate, dispersibility, and the formulation stability. Newly developed drug nanocrystals are expected to be used not only as oral but also as parenteral and transdermal formulations. In this review, production technology, property, and physicochemical characterization of poorly water-soluble drug nanocrystals are introduced.
Two particle design technologies executing under ultra-cryogenic environment developed by authors are introduced. In the both technologies, the drug particles are generated in liquid nitrogen as a dispersing solvent, which is super cool liquid having boiling point atｰ196ｰC. These technologies are quite unique and unprecedented approach in the pharmaceutical industry and could be categorized according to the generation process of the drug crystals and/or particles; one is micronization technology via breaking-down process and another is crystallization technology via building-up process. In this article, the specific properties of liquid nitrogen are introduced at the beginning, and then the outline of these technologies effectively utilizing its specificity will be reviewed. As an example, the case studies for formulation development of the poorly water-soluble drugs are shown to apply these technologies to the pharmaceutical industry. In addition, the technologies under glacier temperature will be differentiated from the conventional one by showing the specific physicochemical and pharmaceutical behaviors of the resultant drug crystals and/or particles.
The feasibility of trans-glycosylated materials, e.g., α-glucosyl hesperidin, α-glucosyl stevia, and α-glucosyl rutin, to improve the dissolution and bioavailability of poorly water-soluble drug was investigated. Spray-dried particles of drug/trans-glycosylated materials showed a significantly higher dissolution rate and greater absorption profile compared with the commercial drug powder. Molecularly dispersed particles of drug/trans-glycosylated materials may be prepared by spray-drying. We found that trans-glycosylated materials formed different types of aggregated-nanostructures in aqueous media. Trans-glycosylated materials self-associated into particular small micelles with a core-shell like architecture, in which the hydrophobic skeleton is segregated from the aqueous exterior to form a novel drug-loading core surrounded by a hydrophilic shell of sugar groups. The difference in the affinity among drug and associated-nanostructures may relate to the magnitude of solubility enhancement, indicating that the structural similarity of drug and trans-glycosylated materials helped the solubilizing effect.
Colloidal drug carriers such as liposomes, lipid emulsions, and polymeric nanoparticles have great potential to deliver drugs effectively. This article demonstrates recent our successful results in drug delivery using liposomal systems, mainly by oral, pulmonary and ocular routes. Especially, particle design, including modification of the liposomal surface with polymers, is a key to drug delivery with these systems.
Bacteria living in a biofilm can have significantly different properties from free-floating bacteria, as the dense and protected environment of the film allows them to cooperate and interact in various ways. This environment provides the resistance to detergents and antibiotics, as the dense extracellular matrix and the outer layer of cells protect the interior of the community. These biofilms cause the intractable infections. Therefore, the development of antibacterial drug delivery systems against the biofilm infection disease is strongly desired. In this review, we intended to design the surface modified PLGA nanoparticle and polymeric micelles for antibacterial drug delivery to the microorganisms in the biofilm. Clarithromycin-loaded drug carrier showed the stronger antibacterial effect against biofilm formed microorganisms compared with drug solution. Especially, CS-modified carrier indicated the more effective antibacterial activity and decreased the biofilm formation because nanocarrier adsorbed on the biofilm. Especially, soluplus micelles indicated the strongest anti-bacterial effect because the adsorption amount was higher than PLGA NP. Therefore, soluplus micelles with smaller particle size could access to the deeply part of biofilm which has sponge like structure.
[Serial] Front line of DDS development in pharmaceutical industries
Epoetin beta pegol (MIRCERA®) is an erythropoiesis stimulating agent created by integrating a 30kDa methoxy polyethylene glycol (PEG) polymer chain into the erythropoietin (EPO) molecule.Half-life of MIRCERA® in blood was 168-217 hours (mean) in clinical pharmacology study for Japanese hemodialysis patients. This result showed that MIRCERA® was maintained in blood for longer time than the existing recombinant human erythropoietin (rHuEPO) agents (7.5 hours for half-life of epoetin alpha, 9.99 hours for half-life of epoetin beta) and darbepoetin alpha(half-life: 34.54 hours). Based on this pharmacokinetic property, MIRCERA® was thought to be able to treat renal anemia by longer dosage interval than the existing rHuEPO agnets. Both half-lives of MIRCERA® in blood after intravenous and subcutaneous administration were approximately 200 hours which were similar between routes of administration, the drug concentration-time profiles in terminal phase were similar between routes of administration too. Based on this similar sustainability in blood between routes of administration, the unity regimen between intravenous and subcutaneous administration which was impossible for the existing rHuEPO agents was thought be able to be set. To confirm the longer dosage interval and the unity regimen between routes of administration, Phase II and III clinical studies for Japanese chronic kidney disease patients were conducted. The results of these clinical studies showed that MIRCERA® was able to treat renal anemia by longer dosage interval which was two weeks for correction period and four weeks for maintenance period. The results also showed that MIRCERA® was able to treat renal anemia by the unity regimen for intravenous and subcutaneous administration routes. Overall, the launch of MIRCERA® which takes advantage of the technology of drug delivery system in integrating PEG to EPO makes it possible to treat renal anemia by the longer dosage interval and the unity regimen between routes of administration, these features contribute to the convenience and the reduction of incidence for both patients and healthcare professionals.
[Serial] Recent advancements in instruments used for DDS research