Nifedipine is a photolabile calcium channel antagonist which undergoes rapid photodegradation in solution and in solid-state with an accompanying loss of pharmacological potency and clinical efficacy. Nifedipine photostabilization which has received considerable attention has principally been achieved by physical obscuration and through the use of colourants or ultraviolet light absorbers incorporated into liquid preparations, translucent packaging materials, gelatin capsules and/or their fillings and tablet coatings or cores. This study was initiated by a South African pharmaceutical manufacturer in response to increasing evidence that cyclodextrin (CD) inclusion complexation may improve drug photostability. The brief was to evaluate the potential of selected cyclodextrins as photoprotecting agents for nifedipine in the solid-state. Areas of investigation included i) quantitative method development and validation for selective determination of nifedipine, ii) phase solubility studies to establish the solubilizing potential and complexing tendencies of selected cyclodextrins, iii) preparation of solid-state nifedipine - cyclodextrin binary systems using an industrially applicable method, iv) pre-formulation photostability studies to determine the effects of the cyclodextrins on solid-state nifedipine photostability and v) comparative in vitro dissolution assessments of nifedipine, the nifedipine - cyclodextrin binary systems and their respective physical mixtures. Phase solubility studies demonstrated that soluble nifedipine - cyclodextrin complexes were formed in aqueous solution, but the magnitude of the interactions were generally low as reflected by the calculated stability constants which decreased in the rank order, heptakis (2,6-dimethyI)-β-CD (DM-β-CD) > randomly methylated-β-CD (RM-β-CD) > β-CD ≈ 2-hydroxypropyl-β-CD (2HP-β- CD) > γ-CD ≥ 2-hydroxypropyl-γ-CD (2HP-γ-CD). An industrially applicable kneading method yielded binary systems with spectral and thermal characteristics similar to the respective physical mixtures, implying weak solid-state inclusion complexation. Preparation of an amorphous nifedipine - RM-β-CD product using a heating method is reported. A 1.7- and 1.9-fold improvement in solid-state nifedipine photostability was observed for I : 1 molar ratio β-CD and γ-CD kneaded products, respectively, when exposed to window-filtered daylight and could be attributed to changes in opacity of the crystalline kneaded products. The remaining cyclodextrins produced negligible nifedipine photostabilization. Nifedipine in vitro dissolution was improved considerably from γ-CD and RM-β-CD .kneaded products as a result of increased nifedipine wettability, solubility and reduced particle size. iii

"2+" in the title is superscript. / "December 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 179-204) / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

The role of Ca++ in olfactory responses was investigated with inorganic and organic calcium channel antagonists. Electrophysiological responses to odorants were recorded from frog olfactory mucosa before and after aerosol application of different agents. Electroolfactogram responses were blocked by certain inorganic ions with the order of effectiveness Zn++ >Ln+++>Cd++>Ca++>Co++>Sr++>Mg++. Ba++ potentiated olfactory responses, and is known to potentiate calcium channel-mediated responses in other tissues. Certain local anesthetics which are thought to act through calcium channel blockade were inhibitory to olfactory responses, with the order of effectiveness being dibucaine>tetracaine>procaine. These data support the idea that Ca++ is involved in olfaction, perhaps acting as a current carrier and/or a second messenger. Preliminary experiments on channel localization were performed using a silicon-labeled amine. Attempts to localize the silicon label were inconclusive, although silicon was detected in the olfactory tissue.

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Graduation date: 2006 / We hypothesized that calpain activity is elevated in response to muscle damage. To test this hypothesis, we examined the degradation of α-fodrin into its 150 and 145 kDa fragments following either 20 eccentric or isometric contractions. In addition, experiments were performed in the presence or absence of E-64-d, a calpain inhibitor. Both EDL and SOL muscles displayed significant differences (p<0.003 and p<0.002 respectively) between the raw and normalized 150 and 145 kDa α-fodrin fragments of the DMSO + E-64-d compared to the other bath treatments. Based on our model of exercise-induced muscle damage, we expected to see greater levels of 150 and 145 kDa α-fodrin fragments in those muscles that performed the eccentric protocol. However, there was no evidence that eccentric muscle damage increased the levels of 150 and 145 kDa α-fodrin fragments over the levels observed in the isometric trials. These findings suggest that the magnitude of damage was insufficient to activate calpains.

The oral route of drug administration is most extensively used due to the obvious ease of administration. Verapamil hydrochloride is a WHO listed phenylalkylarnine, L-type calcium channel antagonist that is mainly indicated for cardiovascular disorders such as angina pectoris, supraventricular tachycardia and hypertension. Due to its relatively short half-life of approximately 4.0 hours, the formulation of a sustained-release dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Direct compression and wet granulation were initially used as methods for tablet manufacture. The direct compression method of manufacture produced tablets that exhibited formulation and manufacturing difficulties. Mini-tablets containing veraparnil hydrochloride were then prepared by wet granulation using Surelease® E-7-19010.and Eudragit® NE 30D as the granulating agents after which the granules were incorporated with an hydrophilic matrix material, Carbopol® 974P NF. Granule and powder blends were evaluated using the angle of repose, loose and tapped bulk density, Can's compressibility index, Hausner's ratio and drug content. Granules with good flow properties and satisfactory compressibility were used for further studies. Tablets were subjected to thickness, diameter and weight variation tests, crushing strength, tensile strength, friability and content uniformity studies. Tablets that showed acceptable pharmaco-technical properties were selected for further analysis. Drug content uniformity and dissolution release rates were determined using a validated isocratic HPLC method. Initially, USP apparatus 1 and 3 dissolution apparatus were used to determine in-vitro drug release rates from the formulations over a 22-hour period. USP apparatus 3 was finally selected as it offers the advantages of mimicking, in part, the changes in the physicochemical environment experienced by products in the gastro-intestinal tract. Differences in release rates between the test formulations and a commercially available product, Isoptin® SR were observed at different pH's using USP apparatus 1. The release of veraparnil hydrochloride from matrix tablets was pH dependent and was markedly reduced at higher pH values. This may be due, in part, to the poor solubility of veraparnil hydrochloride at these pH values and also the possible interaction of verapamil hydrochloride with anionic polymers used in these formulations. Swelling and erosion behaviour of the tablets were evaluated and differences in behaviour were observed which may be attributed to the physico-chemical characteristics of the polymers used in this study. In-vitro dissolution profiles were characterized by the difference (j1) and similarity factor (j2) and also by a new similarity factor, Sct. In addition, the mechanism of drug release from these dosage forms was mainly evaluated using the Korsmeyer-Peppas model and the kinetics of drug release assessed using other models, including Zero order, First order, Higuchi, HixsonCrowell, Weibull and the Baker-Lonsdale model. Dissolution kinetics were best described by application of the Weibull model, and the Korsmeyer-Peppas model. The release exponent, n, confirmed that drug release from these dosage forms was due to the mixed effects of diffusion and swelling and therefore, anomalous release kinetics are predominant. In conclusion, two test batches were found to be comparable to the reference product Isoptin® SR with respect to their in-vitro release profiles.

The purpose of my study was to determine and compare the effects of three calcium antagonists on systemic hemodynamics, ECG, blood flow distribution, tissue conductance and venous tone of the rat. The effects of a representative drug from Spedding's (1985) three subclasses of calcium antagonists on systemic hemodynamics, ECG, cardiac output and the distribution of blood flow were investigated by the microsphere technique in pentobarbital-anesthetized rats. The representative drugs were: I, nifedipine (12 and 35 µg/kg/min); II, verapamil (43 and 83 µg/kg/min) and III, flunarizine (174 and 275 µg/kg/min). Low and high doses were selected to give a decrease in mean arterial pressure of 10 and 20 mmHg, respectively, compared with control rats. At equal depressor levels, all the drugs similarly decreased total peripheral resistance while slightly but not significantly increasing cardiac output (CO) and stroke volume. Heart rate was decreased by verapamil and flunarizine, but increased by nifedipine. The high dose of nifedipine decreased contractility as measured by dP/dt and had no effect on PR-interval, while verapamil decreased dP/dt and prolonged the PR-interval. The low dose of nifedipine and both doses of flunarizine slightly but not significantly decreased dP/dt and had no effect on PR-interval. All three drugs similarly affected the distribution of blood flow. Blood flow to lungs, liver, and heart was increased while flow to the intestine, kidneys, spleen and skin was decreased. Arterial conductances in lungs, liver, heart and skeletal muscle were increased by the three drugs. These results show that representative drugs from the three subclasses of calcium antagonists had similar effects on the distribution of blood flow and arterial conductances but different chronotropic, dromotropic and inotropic effects. A final set of experiments were designed to evaluate calcium antagonist actions on venous tone, as venous tone is a primary determinant of CO and the calcium antagonists generally increase CO. The effects of three calcium antagonists, verapamil, nifedipine and flunarizine on mean arterial pressure (MAP), heart rate (HR) and mean circulatory filling pressure (MCFP), an index of total body venous tone, were investigated in the. conscious rat. Infusions of all three drugs caused a dose-dependent decrease in MAP and an increase in MCFP, compared with the corresponding values in control rats. HR was decreased by verapamil and flunarizine and slightly increased by nifedipine. Further experiments investigated whether the increase in MCFP by verapamil was indirectly caused by reflex activation of the autonomic nervous system. Rats were pretreated with a continuous infusion of the ganglionic blocker hexamethonium prior to infusion of verapamil. After treatment with hexamethonium, verapamil did not increase the MCFP. In fact the highest dose of verapamil significantly decreased MCFP. The results suggest that calcium antagonists have greater dilator effects in arterioles compared to veins. It appears that any direct venodilator effects of verapamil in conscious rats are masked due to reflex activation of the autonomic nervous system. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

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