| Summary: | A comprehensive review of the nasal route of administration, in particular the nasal drug
delivery system has been presented. The physicochemical properties, mode of action and
pharmacology of H1-receptor antagonists, in particular cyclizine HCl, have been
highlighted. The techniques for the assessment of toxicity (in-vitro ciliary beat frequency
(CBF) studies for human nasal explants and morphology studies of the rat nasal mucosa),
synthesis of cyclizine lactate, solubility studies of both cyclizine HCI and cyclizine
lactate, viscosity determination of the gel formulated and assessment of the deposition
and distribution of the hydroxypropylmethyl cellulose (HPMC) dispersions within the
human nasal cavity model were conducted.
In this study, preliminary studies on the toxicity of the various formulation components
(excipients and active ingredient) were carried out. Results from these studies indicated
that for both the excipients and the drug, pH significantly affects the ciliary motility
hence all ciliary beat frequency determinations were conducted at nasal pH. Furthermore,
effects of the various concentrations (0.0625%(w/v), 0.125%(w/v), 0.25%(w/v),
0.5%(w/v) and l%(w/v)) of the excipients on ciliary motility were investigated.
Transmission electron microscopy (TEM) studies proved useful in evaluating the
integrity and changes in the surface morphology of the rat nasal mucosa post treatment
with the various excipients (carboxymethyl cellulose, hydroxypropylmethyl cellulose,
trimethyl chitosan 36.3% DQ, Carbopol P934 and polysorbate-80) at varying
concentrations.
Of the excipients investigated, hydroxypropylmethyl cellulose (HPMC) showed ciliofriendliness
since there was no apparent ultra structural damage, although a slight
decrease in ciliary beat frequency (CBF) was observed at the highest viscosity. Moreover,
hydroxypropylmethyl cellulose (HPMC) is said to be a bioadhesive excipient, which
would therefore confer its bioadhesive properties to the intranasal preparation to enhance
the retention time between the absorbing mucosa and the drug and hence increase nasal
drug absorption. This excipient was therefore selected as the ideal for use in the
formulation of the intranasal preparation.
The aqueous solubility of a drug plays an important role in nasal administration since it is
required that the drug component be applied in a limited volume of about 200pl. To
enhance the aqueous solubility of the sparingly water-soluble cyclizine HCl, a lactate salt
was synthesised and characterised. This compound was found to be highly soluble in
water. The intranasal preparation was therefore manufactured using the lactate form of
cyclizine.
A single blind study was conducted to determine and compare the pharmacokinetic
parameters for both Valoid oral tablets containing 100mg cyclizine HCl (reference
drug) and cyclizine lactate intranasal preparation 125mglml (study drug). The results
obtained indicated a significant improvement in the bioavailability of cyclizine. For oral
administration Cmax = 200.79ng/ml at tmax = 5.57h and for the intranasal preparation Cmax = 5354.22ng/ml at tmax = 1.59h.
A 19.2-fold increase in drug bioavailability was observed after intranasal administration
(AUCin = 122860.70ng/ml/h) compared with oral administration (AUCpo =
5943.48ng/ml/h). This enhanced bioavailability through nasal administration indicated
that enhanced nasal drug absorption and hence increased bioavailability not only depends
on the favourable anatomical and physiological characteristics of the nasal mucosa but
possibly on the inherent physico-chemical characteristics of the drug molecule and the
formulation components. Thus chemical modification of the sparingly water-soluble
cyclizine HCl to the highly water-soluble cyclizine lactate facilitated the dissolution of
more solute in a limited volume of solvent. This new feature therefore may have
impacted positively to the transport of cyclizine across the nasal mucosa. Furthermore,
the hydroxypropylmethyl cellulose (HPMC), component of the formulation, could have
conferred its mucoadhesive properties to the preparation. Perhaps it increased the
retention time of the dosage form within the nasal passages through bond formation with
the nasal mucosa thereby increasing the contact time between the absorbing mucosa and
the dosage form. This interaction between the mucoadhesive and the nasal mucosa may
have resulted in the modification of tissue permeability (possibly transient opening of the
tight junctions) and eventual increase in the drug penetration/absorption. === Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2004.
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