A once-a-day dosage form for the delivery of insulin through the nasal route: in vitro assessment and in vivo evaluation.

An in situ thermogelling, mucoadhesive formulation based on N-trimethyl chitosan chloride has been evaluated for its potential to affect the transmucosal delivery of insulin via the nasal route. In vitro studies at a physiologically relevant temperature (ca. 35 °C) have shown that the formulation releases most of its insulin load (ca. 70%) in a non-Fickian manner during the timescale over which the sol-to-gel transition (ca. 8 min) takes place, and also that, once gelation is complete, the release of the remainder of the therapeutic content follows first order kinetics over at least sixty minutes. Investigations on the effects of the application of the same formulation to a modelled nasal mucosa (Calu-3 cell monolayer) have indicated the capability of the formulation to induce the transient opening of tight junctions. Cytotoxic investigations have shown that the formulation exhibits negligible detrimental effects to the integrity of these monolayers. The in vivo potential of the nasal formulation to act as a once-a-day dosage form for the intranasal delivery of insulin has been demonstrated in a diabetic-rat model.

Thermosensitive hydrogels for nasal drug delivery: the formulation and characterisation of systems based on N-trimethyl chitosan chloride.

Towards the development of a thermosensitive drug-delivery vehicle for nasal delivery, a systematic series of N-trimethyl chitosan chloride polymers, synthesised from chitosans of three different average molecular weights, have been co-formulated into a hydrogel with poly(ethylene glycol) and glycerophosphate. Rheological evaluations have shown that hydrogels derived from N-trimethyl chitosan with a low degree of quaternisation and high or medium average molecular weight exhibit relatively short sol-gel transition times at physiologically relevant temperatures. Also, the same hydrogels display good water-holding capacity and strong mucoadhesive potential, and their mixtures with mucus exhibit rheological synergy. An aqueous hydrogel formulation, derived from N-trimethyl chitosan of medium average molecular weight and low degree of quaternisation, appears particularly promising in that it exhibits most favourable rheological and mucoadhesive behaviour and a sol-gel transition that occurs at 32.5°C within 7 min.

Physisorbed o-carborane onto lyso-phosphatidylcholine-functionalized, single-walled carbon nanotubes: a potential carrier system for the therapeutic delivery of boron.

A combination of data from ICP-MS, Raman spectroscopy, UV-vis spectrometry, atomic force microscopy, zeta-potential measurements and gel electorphoresis studies has shown that o-carborane may be immobilized on stable aqueous dispersions of lyso-phosphatidylcholine-functionalized single-walled carbon nanotubes, which in turn indicates the potential of such structures for deployment as carrier vehicles in boron neutron capture therapy.

A direct-staining method to evaluate the mucoadhesion of polymers from aqueous dispersion.

A novel technique to evaluate polymer adhesion to human buccal cells following exposure to aqueous polymer dispersion, both in vitro and in vivo, is described. Adhering polymer has been visualised by staining with 0.1% (w/v) of either Alcian blue (60 min) or Eosin (10 min) solution, uncomplexed dye being removed by 0.25 M sucrose washings. The extent of polymer adhesion was quantified by measuring the relative staining intensity of control and polymer-treated cells by image analysis. In vitro, Carbopol 974P, polycarbophil (Noveon AA-1) and chitosan (CL 113) were found to adhere to human buccal cells from 0.10% (w/w) aqueous dispersions of these polymers. Following in vivo administration as a mouthwash, these polymers persisted upon the human buccal mucosa for at least 1 h.

The gastrointestinal transit profile of 14C-labelled poly(acrylic acids): an in vivo study.

The gastrointestinal distribution profiles for three 14C-labelled poly(acrylic acid)s of different average molecular weights and degrees of cross-linking have been established using the rat model. Despite initial differences in transit times and retention characteristics, these structural features were found to be of little influence to the overall gastrointestinal transit of the materials under consideration. No evidence for the systemic absorption of any of the polymers could be identified.

An investigation of mucus/polymer rheological synergism using synthesised and characterised poly(acrylic acid)s.

A range of poly(acrylic acid)s with different average degrees of polymerisation and cross-linking densities were synthesised using a solution polymerisation process. The rheological characteristics of aqueous dispersions of these materials and those of mixtures with homogenised pigs gastric mucus were investigated using dynamic oscillatory rheology, and compared to the known mucoadhesive Carbopol 934P. From the storage moduli, the rheological synergy and relative rheological synergy were calculated, and the effects of concentration and pH on this considered. Generally, the larger the molecular weight (and degree of cross-linking), the greater the rheological synergy, with Carbopol 934P giving the most pronounced effect. Rheological synergy was seen to be concentration-dependent, and a maximum concentration to produce an optimum effect was evident. Acid pHs were seen to favour synergy, although in marked contrast to previous literature reports, the optimum mucus-polymer interaction was not observed at the half ionised value (pH = pKa) but at pH regimes that were unique to each polymer type. This could be influenced by the structural constrains imposed on potential hydrogen bonded interactions. It was concluded that synthesising poly(acrylic acid)s with better defined physicochemical properties than commercially available polymers will advance the study of the phenomenon of rheological synergy.

Synthesis of radiolabeled congeners of the carbomers: (14)C-labeled poly(acrylic acid)s.

A general method for the synthesis of (14)C-acrylic acid is described in detail. The material is used for the synthesis of a range of radiolabeled poly(acrylic acid)s in which the (14)C-label forms an integral part of the polymer backbone. The chemical structure of the synthesized polymers is examined in the light of spectroscopic data, molecular weight determinations, and rheological studies.

Preventing bacterial adhesion onto surfaces: the low-surface-energy approach.

Good-quality coatings prepared from poly(methylpropenoxyfluoroalkylsiloxane)s or poly(perfluoroacrylate)s are capable of inhibiting the bacterial colonisation of surfaces.

Azocross-linked poly(acrylic acid) for colonic delivery and adhesion specificity: synthesis and characterisation.

A new synthetic pathway to 4,4'-divinylazobenzene is presented together with a procedure for the copolymerisation of this compound with acrylic acid. The chemical structure of the synthesised series of copolymers is examined in the light of infrared spectroscopy results and nuclear magnetic resonance data. The thermal properties of the materials are assessed using a combination of thermal analysis techniques and their swelling behaviour is evaluated at physiologically relevant buffers designed to mimic the gastrointestinal environment.

Azocrosslinked poly(acrylic acid) for colonic delivery and adhesion specificity: in vitro degradation and preliminary ex vivo bioadhesion studies.

This study reports on the performance of a novel polymeric material that is capable of providing site specificity in active agent delivery and the development of mucoadhesive interactions. Azo-networks, based on an acrylic backbone crosslinked with 4,4'-divinylazobenzene, were subjected to in vitro degradation and mucoadhesion (before and after degradation) testing in order to model their performance in the gastrointestinal tract. Advanced surface characterisation techniques (SEM, AFM, FTIR microscopy) were used to examine the network morphology prior to, and after degradation. The data obtained from these studies indicate that there is an optimum crosslinking density to allow non-adhesive particles to reach the colon. Within the colonic environment, the azo network degrades to produce a structure capable of developing mucoadhesive interactions with the colonic mucosa.