Brian John Meakin

Modulation of aerosol clouds produced by pressurised inhalation aerosols

The inclusion of non-volatile components such as glycerol or polyethylene glycol in hydrofluoralkane (HFA) solution formulations for pressurised metered dose inhalers (pMDIs), greatly increases the particle size of the aerosol. Cloud characteristics can be further modulated by permuting this factor with the choice of propellant and the dimensions of the actuator, to give a chosen fine particle dose and particle diameter. This principle has been used to design solutions which closely match the performance of chlorofluorocarbon based suspension formulations containing beclomethasone dipropionate, budesonide and ipratropium bromide as assessed for pharmaceutical equivalence using the Andersen Cascade impactor.

Plume temperature emitted from metered dose inhalers

The temperature of the drug cloud emitted from a pressurised metered dose inhaler (pMDI) may result in patient discomfort and inconsistent or non-existent dose delivery to the lungs. The effects of variations in formulation (drug, propellant, co-solvent content) and device hardware (metering volume, actuator orifice diameter, add-on devices) upon the temperature of pMDI plumes, expressed as replicate mean minimum values (MMPT), collected into a pharmacopoeial dose unit sampling apparatus (DUSA), have been investigated. Ten commercially available and two development products, including chlorofluorocarbon (CFC) suspensions and hydrofluoroalkane (HFA) solutions or suspensions, were examined together with a number of drug products in late stage development and a variety of HFA 134a placebo pMDIs. Plume temperatures were observed to be lowest in the proximity of the products actuator mouthpiece where rapid flashing and evaporation of the formulations propellant and volatile excipients cause cooling. The ability to control plume temperature by judicious choice of formulation co-solvent content, metering volume and the actuator orifice diameter is identified. An ethanol based HFA 134a formulation delivered through a fine orifice is inherently warmer than one with 100% HFA 134a vehicle delivered through a coarse actuator orifice. Of the 10 commercial products evaluated, MMPTs ranged from -54 to +4°C and followed the formulation class rank order, HFA suspensions<CFC suspensions<HFA solutions. For all systems examined it was possible to raise pMDI plume temperature to that of the ambient surroundings by use of an add-on or integrated spacer device.

Evaluation of the anti-acanthamoebal activity of five contact lens disinfectants☆

Abstract We investigated the ability of five commercially available contact lens disinfectants to kill Acanthamoeba cysts. Two methods were employed: a microtiter plate method (using Acanthamoeba polyphaga SHI and A. castellanii CLAP 150112 g), which determines the presence or absence of growth after a challenge and measures efficacy by total kill only, and a bacterial lawn plaque method (A. polyphaga only), which quantitates the number of cysts surviving different periods of exposure. With the microtiter method, there was no growth of excysted Acanthamoeba after exposure to LENS PLUS ® Oxysepto ® 1 Disinfecting Solution ∗ for 4 hours or to Allergan ® HYDROCARE ® Cleaning and Disinfecting Solution ∗ for 6 hours. Excysted Acanthamoeba were recovered in all trials after exposure to ReNu ®, † Opti-Soft ®, † or AOSept ®† for up to 24 hours. With the bacterial lawn plaque method, HYDROCARE and Oxysept 1 (with or without Ultrazyme TM Enzymatic Cleaner) reduced the challenge cysts to zero recovery by the 8- and 24-hour time points, respectively; ReNu, Opti-Soft, and AOSept disinfectants showed poor anti-Acanthamoebal activity, reducing the cyst challenge by only 66, 66, and 79%, respectively, at 24 hours. The difference in the efficacies of Oxysept 1 and AOSept (both nominally 3% hydrogen peroxide) is probably due to the initial rapid neutralization of hydrogen peroxide in the AOSept system during the disinfection soaking cycle.

The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate)

The extent of the interaction between chlorhexidine digluconate and poly(2‐hydroxyethyl methacrylate), (PHEMA), is independent of temperature between 22–50 °C which is consistent with an ion‐ion interaction mechanism. Different contact lens materials exhibit different affinities for chlorhexidine digluconate, the extent of uptake correlating in rank order with the number of free carboxylic acid sites in the polymers. Esterification of the carboxyl groups with diazomethane, resulted in a reduction in the affinity of the treated polymers for chlorhexidine to a near basal level. The uptake of chlorhexidine in soaking solution experiments involving lenses made from PHEMA and the more ionic material, poly(2‐hydroxyethyl methacrylate ‐ co‐isobutyl methacrylate ‐ co ‐ methacrylic acid), was consistent with their carboxylate content. However, the fraction of bound disinfectant released was lower from the terpolymer, suggesting there are differences in bonding strengths between chlorhexidine and different contact lens hydrogels.

Contact lens solutions in theUnited Kingdom

Brian Meakin is Senior Lecturer in Pharmaceutics, University of Bath. The author is a member of the Committee on Surgical and Dental Materials (C.D.S.M.) and the Sub-committee on Ophthalmic Products (S.C.O.P.), both of which have a concern with the licensing of contact lens products. The views expressed by the author in this presentation are his own opinions and do not necessarily reflect the official viewpoint of the DHSS as the licensing authority.

A CHLORHEXIDINE CONTACT LENS DISINFECTION TABLET: DESIGN CRITERIA AND ANTIMICROBIAL EFFICACY IN POTABLE TAP WATER

Abstract A contact lens disinfection system (OptimEyes) is described, based on a tablet formulation, which, when added to 10ml of rising mains tap water, provides a disinfection solution containing 0.004% chlorhexidine gluconate in a safe, ophthalmically acceptable vehicle. The design criteria associated with the formulation development are discussed and microbiological efficacy data against bacteria ( Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Bacillus sp.), moulds and yeasts ( Candida albicans, Aspergillus niger ), virus ( Herpes simplex ), and Acanthamoeba ( A. castellaniiv A. polyphaga ), are provided for the tablet dissolved in representative samples of water. The results demonstrate that rising mains tap water as modified by the OptimEyes formulation provides a microbiologically safe, simple, and highly effective method for lens disinfection, which should promote care regimen compliance.

Anti-acantamoeba activity of chlorhexidine and hydrogen peroxide

In recent years the reported incidence of the rare condition, Acanthamoeba keratitis, has increased and there is reasonable evidence to suggest that the use of contact lenses predisposes the wearer to the condition (StehrGreen 1987). A review of recent epidemiological studies by us clearly indicates that lack of compliance with lens care re~mens are the main reason for this predisposition. Various reports (Stehr-Green 1987, Chun 1987) show that non-comp.liance with care regimens including infrequent disinfection amongst patients varies from 4080 %. Many of the patients exhibRing Acanthamoeba keratitis used home-made saline prepared by adding non-sterile salt tablets to non-sterile water. The method of disinfection used by infected wearers does not appear to be important; patients using chemical disinfectants were no more susceptible than patients thermally disinfecting their lenses. These reports have caused the withdrawal of conventionally bottled large volume nonpreserved sterile saline from the market and non-sterile salt tablets have to carry, a cautionary label. Despite these findings, there is a real fear, particularly in the U.S.A., that chemical antimicrobial agents used to kill bacteria during the disinfection of contact lenses do not have adequate anti-Acanthamoeba activity. This fear is due in a large part to the findings of Ludwig et al (1986). Inspection of this paper led us to believe that the results m i # t be a function of the experimental method rather than a true reflection of the anti-Acanthamoeba activity of the disinfectants evaluated. One of us (Davies 1975) has previously warned of the necessity of carefully controlling all aspects of experiments carried out to test the antimicrobial efficiency of preserved mult-dose sterile solutions. In order to obtain unequivocal results on the anti-Acanthamoeba activity of disinfectants, the same careful control of the protocol

The compatibility of benzalkoniumchloride with a CAB lens material

Summary The compatibility of benzalkonium chloride, adisinfectant and preservative used in hard contact lens solutions, with a commercial CAB lens material has been assessed by determining the level of uptake from isotonic buffered solution at pH 7.0, a commercial soaking solution and a commercial wetting solution at temperatures of 15° and 30°. The results, using polymer materials in both powdered form and as lenses showed, that in all studies, the level of interaction of benzalkonium chloride was less with the CAB material than with poly-methyl methacrylate. The average uptake from the commercial soaking solution was 7.6μg per lens by CAB lenses compared to 10μg per lens for PMMA lenses whilst for the wetting solution the corresponding figures were 1.5μg and 6.8μg respectively. A parallel study involving microscopic examination of lens surfaces and determination of lens parameters showed no physical changes in the CAB lenses after two months storage at 34° in the soaking formulation to which 0.2% benzalkonium chloride had been added. It is concluded that, in contrast to statements in the literature (1, 2), benzalkonium chloride is not incompatible with at least the commercial CAB material used in this study.

THE DETERMINATION OF THIOMERSAL IN THE PRESENCE OF ITS BREAKDOWN PRODUCTS: AN EVALUATION OF THE NEURATH METHOD

At a previous British Pharmaceutical Conference, during discussion of a paper concerned with the storage of thiomersal and chlorhexidine gluconate in glass and plastics containers (McTaggart et a1 1979), it was claimed that the dithizone method of Neurath (1961) was stability indicating for thiomersal.The Neurath method involves extraction of the complex formed between thiomersal and dithizone in the cold into toluene and determination of the absorbance in the solvent at 610 nm. It thus differs from the commonly used hot oxidation method (Richardson et a1 1977) which converts organic to inorganic mercury before complex formation with dithizone. Clearly the latter cannot be stability-indicating and since no evidence was offered to substantiate the claim made for the Neurath method,both dithizone techniques have been evaluated against an improved HPLC method for thiomersal in the presence of its breakdown products.

IMMOBILISED CATALASE AND HYDROGEN PEROXIDE - A NOVEL CONTACT LENS DISINFECTION SYSTEM

Hydrogen peroxide has been used for several years as a disinfectant for contact lenses. This report details a novel neutralisation system for the peroxide, utilising catalase immobilised to the inner surface of a contact lens case by covalent attachment to a hydrolysed nylon surface.