Cyclodextrins (CyDs) were employed as protective stabilizers for the preparation of surfactant-free nanocrystals of indomethacin (IMC) by using the emulsion solvent diffusion method. The effect of changing the type and concentration of CyDs on the formation of IMC nanocrystals was investigated. Dispersions were freeze-dried to characterize the size, shape, nanoparticle yield, crystallinity, and dissolution behavior of the obtained particles. Submicron-sized particles of IMC with average diameters in the range of 300-500 nm were obtained by incorporating α-, β-, or γ-CyD in the outer phase of the primary emulsions. Quantitative determination demonstrated that more than 80% of IMC was recovered as fine particles smaller than 0.8 µm. The powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses of the freeze-dried samples confirmed the polymorphic change of IMC to the meta-stable form. A significant enhancement in the dissolution rate of IMC nanocrystals was observed when compared to the commercial powder.

The concept of mucoadhesion for the design of non-invasive drug delivery systems gained increasing attention in recent years. Within the current review, various mucoadhesive polymers, including poly(acrylates), chitosan, thiolated polymers and others, as well as their use in mucosal drug delivery are discussed. An emphasis has been put on the development of mucoadhesive formulations, and in particular on recently developed micro- and nanoparticulate systems. Moreover, the applications of the mucadhesive carrier systems for different administration routes such as the oral, nasal, pulmonary and ocular route are discussed.

Novel pH-sensitive nanospheres designed for colon-specific delivery were prepared using polymeric mixtures of poly (lactic-co-glycolic) acid (PLGA) and methacrylate copolymers. Budesonide (BSD), a topically active corticosteroid, was entrapped as a model drug. The therapeutic efficacy of the prepared nanospheres was assessed using the trinitrobenzenesulfonic acid (TNBS) colitis rat model, in comparison with conventional enteric microparticles. In addition, the colon targeting properties, systemic bioavailability, and specific uptake by the inflamed colon mucosa were evaluated using coumarin-6 (C-6) loaded nanospheres. The prepared nanospheres showed strongly pH-dependent drug release properties in acidic and neutral pH media followed by a sustained release phase at pH 7.4. Animal experiments revealed the superior therapeutic efficiency of BSD nanospheres in alleviating the conditions of TNBS-induced colitis model. The in-vivo studies using C-6-loaded nanospheres displayed higher colon levels and lower systemic availability of the fluorescent marker when compared with simple enteric coating. Moreover, quantitative analysis of the fluorescent marker and confocal laser scanning studies showed strong and specific adhesion of the nanospheres to the ulcerated and inflamed mucosal tissue of the rat colon. In conclusion, the proposed nanosphere system combined the properties of pH-sensitivity, controlled release, and particulate targeting that could be useful for colon-specific delivery in inflammatory bowel disease.

Protein therapeutics are used in the treatment of a broad variety of diseases, however, usually they are not available as peroral formulations. Oral delivery systems of proteins including insulin, glucagon like peptide, calcitonin or parathyroid hormone are highly demanded by patients suffering from chronic diseases such as diabetes or osteoporosis. The need for oral protein formulations has been recognized by researchers of various scientific disciplines and a number of patents have been filed that deal with technologies capable of facilitating oral protein delivery. Within the current review, patents based on approaches such as particulate delivery systems, multifunctional polymers, enzyme inhibitors, permeation enhancers and ligand-specific binding and uptake are discussed. In addition, the technology platforms of several innovative drug delivery companies are highlighted.

【Background】 Most of therapeutic peptide and protein drugs are administered via injection route, because they are poorly absorbed. Previously, we have investigated the role of different mucoadhesive polymers as coating materials of liposomes for enhancing oral peptide delivery. Trimethyl chitosan (TMC) is a chitosan (CS) derivative with improved permeation enhancing properties as a result of retaining its positive charge over a broad range of physiological pH values. 【Methods and results】 TMC was synthesized by reductive methylation of CS and was used for coating anionic liposomes. The efficiency of surface coating was confirmed by the inversion of surface potential and by increase in particle size. The mucoadhesive properties of TMC-coated liposomes were studied in vivo after oral administration to rats by confocal laser scanning microscopy (CLSM). The results showed comparable mucoadhesive properties of TMC-coated liposomes and CS coated liposomes. In addition, the pharmacological efficacy of calcitonin loaded liposomes was evaluated by determination of blood calcium level after oral administration. The area above blood calcium concentration-time curve (AAC) was significantly higher after oral administration of TMC-liposomes, as compared to non-coated liposomes and calcitonin solution. The obtained results showed that TMC-liposomes can contribute to the development of mucoadhesion based systems for oral peptide and protein delivery.

SUV liposomes modified with wheat germ agglutinin-carbopol (WGA-CP) polymer conjugate were prepared and characterized for oral peptide delivery. The conjugate retained the biological binding activity of WGA without any evidence of cytotoxicity. The cellular uptake of WGA-CP liposomes by Caco-2 cells was about 2-fold higher than that of non-modified or CP-modified liposomes. The uptake was dependent on the surface concentration of WGA, temperature, and incubation time, and was partially inhibited in the presence of filipin, chlorpromazine, and free WGA. Confocal microscopy confirmed the simultaneous uptake of WGA-CP conjugate and liposomes in the cytoplasm Caco-2 cells and enterocytes of rats’ small intestine after oral administration. In addition, the pharmacological efficacy of calcitonin was enhanced by more than 20 and 5 folds after oral administration of WGA-CP liposomes as compared to non modified and CP liposomes, respectively.