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.

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.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.