Influence of heat treatment on spray-dried mixtures of Amioca starch and Carbopol 974P used as carriers for nasal drug delivery.

A mucoadhesive spray-dried starch/poly(acrylic acid) powder underwent different heat treatments in order to induce cross-linking between the functional groups of starch (Amioca) and poly(acrylic acid) (Carbopol 974P). After heat treatment the water-absorbing capacity, viscosity and elasticity of the mucoadhesive powder increased. NMR analysis in combination with FT-IR indicated that heat treatment induced a low degree of cross-linking between the polymers. Nasal administration of Amioca/Carbopol 974P powders without heat treatment resulted in an absolute bioavailability in rabbits of 8.2+/-3.0% for insulin. Due to the difference in water-absorbing capacity (which opened the tight junctions of the nasal mucosa), elasticity and plasticity (which reduced mucociliairy clearance and prolonged residence time) heat treatment at 120 degrees C improved the bioavailability: 26.4+/-21.9, 36.5+/-11.0 and 19.3+/-17.3% after heat treatment during 30 min, 1 h and 4 h, respectively. Heat treatment at 60 degrees C was less efficient. This study demonstrated that the nasal insulin absorption improved via heat treatment of the Amioca/Carbopol 974P powder (prior to the addition of insulin). The bioavailability-enhancing effect of a 1 h heat treatment at 120 degrees C was confirmed using the same polymer matrix in combination with different drugs (salmon calcitonin, human growth hormone and metoprolol tartrate).

Effect on the nasal bioavailability of co-processing drug and bioadhesive carrier via spray-drying.

A mucoadhesive combination of a maize starch (Amioca, mainly consisting of amylopectine) and a cross-linked acrylic acid-based polymer (Carbopol 974P) was spray-dried with metoprolol tartrate (used as model molecule) in order to develop a powder suitable for nasal drug delivery via a one-step manufacturing process. The bioavailability of metoprolol tartrate after nasal administration of this powder to rabbits was compared with powders manufactured via other procedures: (a) freeze-drying of a dispersion prepared using the co-spray-dried powder, (b) freeze-drying of a dispersion prepared using a physical mixture of drug and mucoadhesive polymers. After co-processing via spray-drying a low bioavailability (BA 10.8+/-2.3%) was obtained, whereas manufacturing procedures based on freeze-drying yielded a higher BA: 37.9+/-12.8% using the co-processed powder and 73.6+/-24.9% using the physical mixture. The higher bioavailability was due to the deprotonation of poly(acrylic acid) during neutralisation of the dispersion prior to freeze-drying. This induced repulsion of the ionised carboxyl groups and a lower interaction between poly(acrylic acid) and starch, creating a less compact matrix upon hydration of the polymer and allowing an easier escape of metoprolol tartrate from the matrix. This study showed that co-processing of a mucoadhesive Amioca/Carbopol 974P formulation with metoprolol tartrate via co-spray-drying did not provide any added value towards the bioavailability of the drug after nasal administration of the mucoadhesive powder.

Spray-dried powders of starch and crosslinked poly(acrylic acid) as carriers for nasal delivery of inactivated influenza vaccine.

Mucosal vaccination has several advantages over parenteral vaccination. In this study, viscosity-enhancing mucosal delivery systems for the induction of an adaptive immune response against viral antigen were investigated. Powder formulations based on spray-dried mixtures of starch (Amioca)/poly(acrylic acid) (Carbopol 974P) in different ratios were used as carriers of the viral antigen. A comparison of these formulations for intranasal delivery of heat-inactivated influenza virus combined with LTR192G adjuvant was made in vivo in a rabbit model. Individual rabbit sera were tested for seroconversion against hemagglutinin (HA), the major surface antigen of influenza. The powder vaccine formulations were able to induce systemic anti-HA IgG responses. The presence of Carbopol 974P improved the kinetics of the immune responses and the level of IgG titers in a dose-dependent way which was correlated with moderately irritating capacities of the formulation. In contrast, mucosal IgA responses were not detected. In conclusion, it was demonstrated that the use of bioadhesive carriers based on Amioca starch and poly(acrylic acid) facilitates the induction of a systemic anti-HA antibody response after intranasal vaccination with a whole virus influenza vaccine.

Aniridia-Wilms' tumour syndrome.

The association of aniridia and Wilms' tumour constitutes a real syndrome, which is genetic. It may either be autosomal dominant or depend on a chromosomal deletion or also, according to Knudson's theory, be due to two mutational events, the initiating mutation being germinal and the promoting mutation being post-zygotical.