Recent advances in combinatorial chemistry and molecular biology have identified drug candidates that present many problems for conventional drug delivery due to poor bioavailability. This is typically a result of poor absorption across biological membranes due to low aqueous solubility or high hydrophilicity combined with large molecular weight. In addition, these compounds are often substrates for efflux transporters and metabolic enzymes present on cell membranes of absorptive surfaces, causing high intra-patient variability in absorption. The utilisation of per oral dosing in particular is becoming more challenging and alternative routes are required. Administration via the buccal mucosa has emerged as a highly acceptable alternative, whilst avoiding the gastrointestinal tract and first pass metabolism. This thesis describes the development of mucoadhesive cyclodextrin-crosslinked poly(acrylic acid) (CD-PAA) polymers designed for buccal administration of drugs with inherent delivery problems. Cyclodextrins (CDs) have been used extensively as pharmaceutical excipients due to their ability to form inclusion complexes with drugs and overcome the physicochemical factors limiting drug delivery. By combining CDs with a mucoadhesive PAA component, it was anticipated that controlled release and retention within the buccal cavity could be accomplished.
A reproducible method for esterification of the hydroxyl groups of CD with the carboxylic acid moieties of PAA was developed in which PAA was activated with excess thionyl chloride and the PAA-chloride was subsequently reacted with βCD or hydroxypropyl-βCD (HPβCD) in the presence of 4-dimethylaminopyridine. The most effective purification process consisted of five cycles of dialysis against pH 3 hydrochloric acid and three cycles of water. Through manipulation of the chemical reaction conditions, polymers with various physicochemical properties (CD amount, crosslinking density to a CD and viscosity) were synthesised.
The physicochemical and pharmacokinetic properties of the CD-PAA polymers were evaluated with respect to two model drugs, diflunisal (DIF) and fluconazole (FLZ). The ability of the functionalised CD to bind DIF and FLZ was measured by 19F NMR. A significant reduction in association (Ka) of DIF was noted for all CD-PAA polymers versus the reported value for βCD (Ka range 1096 – 4483 M-1 and 198 – 598 M-1 for HPβCD-PAA and βCD-PAA respectively, compared with 181000 M-1 for βCD and 2860 M-1 for HPβCD). A weak inverse correlation between the Kas of DIF and the calculated crosslink density to a CD was observed. In contrast, a minor change in Ka was found for FLZ and the HPβCD-PAA polymers, presumably due to the already poor association exhibited by the much bulkier molecule (Ka range 34 – 171 M-1 for the polymers compared with 68.7 M-1 for βCD and 35.0 M-1 for HPβCD).
Diffusion studies with semi-solid dispersions of the CD-PAA polymers containing the two model drugs indicated retarded drug release in comparison with PAA. The gels that exhibited a higher amount of bonds to a CD were more likely to release DIF the fastest, irrespective of the type of CD conjugated. FLZ release rates were slightly faster for βCD-PAA than HPβCD-PAA matrices and were overall faster than DIF release rates.
A βCD-PAA polymer (33.1% (w/w) βCD) and a comparable crosslink density HPβCD-PAA polymer (37.7% (w/w) HPβCD) were formulated into tablets manufactured by direct compression. Carbopol 934P, a commercially available medium crosslink density PAA, was used as a benchmark. Additional excipients were not used because of concerns they may confound the evaluation of drug release. To determine any difference in release kinetics between DIF that was physically mixed or pre-complexed in the matrix of the CD-PAA polymer, the drug and polymer was gently triturated in a mortar and pestle, or dissolved with the polymer in 50% (v/v) ethanol and lyophilised for 48 h. The HPβCD-PAA polymer (Ka of 6055 M-1), was found to retard drug release more than Carbopol and substantially more than the βCD-PAA polymer (Ka = 486 M-1). The pre-complexation of DIF also hindered release of the drug to a greater extent than the corresponding physical mixture. FLZ was physically mixed and compressed into tablets the same way to evaluate whether crosslink density was primarily responsible for the controlled release. The βCD-PAA polymer released FLZ slightly faster than Carbopol 934P, whereas the HPβCD-PAA polymer impeded release the most, perhaps due to association occurring with the CD cavity. The similarity in profiles indicated that the higher crosslink density of Carbopol did not possess much influence on release of FLZ and it may be speculated that slow release was the result of ionic interactions of the basic drug and the acidic polymer.
Mucoadhesivity of the polymer tablets was evaluated using a conventional stress controlled rheometer with a poly(dimethylsiloxane) lower plate to mimic the buccal mucosa. The results indicated that mucoadhesivity was retained but reduced relative to PAA. This study lays a foundation for the development of a tuneable buccal formulation for potent, yet poorly bioavailable drugs. Different CDs can be implemented in the development of such dosage forms and mixtures or layered tablets may provide a further avenue for tailoring the drug release.