A. Li Wan Po

Factors affecting drug release from a pellet system coated with an aqueous colloidal dispersion

Abstract The formulation of sustained-release pellets of dextromethorphan hydrobromide is described. The system used consisted of drug-coated sugar spheres which were then overcoated with the rate-controlling membrane. The membrane was produced by spray-coating with an aqueous dispersion of ethylcellulose containing hydroxypropyi methylcellulose. It is shown that adequate post-coating conditioning is important to ensure consistency of release rates. Conditioning at 60° C for at least l h is necessary in order to ensure that the formulations produced show no ageing effects in release rates. Drug release could be made pH-independent by a choice of proper formulation.

Peptide and protein drugs: I. Therapeutic applications, absorption and parenteral administration

Abstract In this first part of a two-part review of peptide and protein drugs, the pertinent terminology is introduced and the therapeutic applications of those drugs summarised. Their absorption and the methodology commonly used for study on it are discussed. Approaches to optimising delivery of the peptide and protein drugs are highlighted.

Peptide and protein drugs: II. Non-parenteral routes of delivery

Abstract In this second part of a two-part review, the absorption and delivery of peptide and protein drugs via non-parenteral routes are discussed. Approaches considered include the absorption enhancers, iontophoretic methods, the use of absorption inhibitors and prod rugs.

Prodrugs for dermal delivery

Abstract The skin is increasingly being regarded as a portal for drug delivery. Unfortunately most of the drugs currently available are unsuitable for delivery via this route if systemic activity is required. The prodrug approach is one of the methods which have been evaluated for improving the systemicic delivery of pharmacologically active compounds. In addition to transdermal delivery, dermal delivery has also attracted much attention for a range of skin diseases including psoriasis, eczema, ichthyosis, acne and skin tumours. In this review, prodrugs which have been reported as being possibly suitable for dermal and transdermal delivery are considered. In particular, the different chemical approaches used for providing the skin with enzyme-labile links are considered in some detail along with the potential benefits claimed.

Cutaneous biotransformation as a parameter in the modulation of the activity of topical corticosteroids

Abstract The hydrolysis of betamethasone-17- and -21-valerates by hepatic and cutaneous esterases is studied with a view to explaining their different activity profiles. It is shown that the 17-ester is resistant to both esterases while the 21-ester is rapidly hydrolyzed to the free steroid alcohol. Earlier reports on the cutaneous enzymic transformation of the 17-ester fail to account for the spontaneous isomerization of the ester to the 21-ester and are therefore misleading. The resistance of the 17-ester to enzymic hydrolysis may also lead to a more pronounced reservoir effect and hence toxicity following application to the skin. This work provides useful information for the design of topically active steroids.

Improving the release characteristics of water-soluble drugs from hydrophilic sustained release matrices by in situ gas generation

Abstract Potassium chloride release from a number of compressed hydrophilic polymer tablets is investigated with a view to designing a simple zero-order release system. The approach used is based on incorporation of low levels of effervescent mixtures within the table matrix. Supporting work on related polymeric systems is also discussed.

Comparison of enzymic activities of tissues lining portals of drug absorption, using the rat as a model

Abstract Leucine aminopeptidase and cholesteryl esterase activities of five different tissues from the rat are investigated. The tissues from the intestines, the buccal cavity, the nose, the rectum and the skin were chosen, as they represent barriers to absorption for most commonly used dosage forms. It is shown that the intestinal tissue is the most active in both enzymes. Dermal tissues are the second richest in cholesteryl esterase activity, whereas rectal tissue is the least active. Aminopeptidase activity is weakest in dermal tissues. When adjusted for protein content, dermal tissues show the highest specific esterase activity. Rectal tissue remains the least active. Based on the known relatively high permeability of buccal and nasal tissues, the low aminopeptidase and cholesterol esterase activities would suggest that those routes offer better possibilities for delivering peptides and esters. However, it should be noted that enzymic degradation is only one of the barriers to peptide absorption, and for most peptide drugs an absorption enhancer or a specific delivery system is still likely to be required for successful trans-nasal or buccal absorption.

Laser velocimetry for the non-invasive assessment of the percutaneous absorption of nicotinates

Abstract The use of laser velocimetry for the non-invasive assessment of the effects of topically applied solvents and a model vasodilator, hexyl nicotinate, is reported. The importance of excluding solvent effects on the recorded response is emphasised and the value of the technique for predicting the effects of formulation changes is illustrated.

Characterisation of commercially available theophylline sustained- or controlled-release systems: in-vitro drug release profiles

Abstract Release of theophylline, either in the form of the free xanthine or complexed with choline or ethylene diamine, from commercially available dosage forms is modelled using a series of standard drug-release models. Those included the first order and the cube root models. Equations which take into account the geometrics of the products were also assessed and compared with the more generic square root of time model. It is shown that in practice discrimination between the competing models is difficult even with use of mean square errors. All the products on the U.K. market showed pH-dependency although to variable extents. Sabidal®, for example, gave good consistency within the pH range 2.1–6.9 but much slower release rates at pH 1.2. Such a profile may be desirable given the known irritant effects of theophylline in the stomach. Lasma® showed a similar pH effect but the rates of release were extremely fast at pH 2.1 and above. This suggests a potential dose-dumping effect in vivo. Phyllocontin® showed relatively little pH variability in its release profiles. Ionic strength had a dramatic effect on drug release from Lasma® tablets. Sabidal® was also markedly affected as was Pro-Vent®. These results certainly show that theophylline sustained-release products are not interchangeable without readjustment to steady-state blood levels.

Quantitative Evaluation of Drug-Induced Erythema by Using a Tristimulus Colour Analyzer: Experimental Design and Data Analysis

Pulsed-light reflectance using the Minolta Chroma Meter CR-200 was evaluated as a quantitative method for the noninvasive assessment of drug-induced erythema on the flexor surface of the forearm. Nicotinate esters were used as model vasodilators. Several parameters derived from the data were analysed using analysis of variance (ANOVA) and Tukeys multiple range tests appropriate for the study designs used. The effects of varying concentrations of methylnicotinate and of different nicotinate esters were found to be statistically significant. This non-invasive technique was found to be particularly useful in ranking the cutaneous responses elicited by the topical application of increasing concentrations of methylnicotinate in a single subject, as well as in a group of 6 volunteers.