C. Washington

Drug release from microdisperse systems: a critical review

Abstract The review article describes the current state of the art in the study of drug release from colloidal systems. Emphasis is placed on the practical aspects of obtaining kinetic release data from micron or submicron-sized carriers, which poses a range of experimental difficulties not encountered in the study of formulations with a larger panicle size. Potential sources of experimental error are discussed, and their effect on the interpretation of the data is examined. Mathematical models of drug release from such systems are also reviewed, and provide information which may be used to study formulation behaviour at a microscopic level.

Lipid Emulsions as Drug Delivery Systems

Colloidal carriers used for the delivery of drugs take a variety of forms to include those that are solid-like in nature, such as microspheres and nanoparticles, and liquids in the form of emulsions, or vesicles (better known as liposomes). Natural colloidal particles (lipoproteins and chylomicrons present in circulating blood, for example) have also been investigated as potential carrier systems. The recent literature covering these different systems can be found in various detailed papers, review articles, and monographs.’4 This article will consider recent studies on the use of lipid emulsions as drug delivery systems and will concentrate on the intravenous route of administration. The earlier literature has been reviewed by Davis and others2

The stability of intravenous fat emulsions in total parenteral nutrition mixtures

Abstract This article discusses methods for the study of the stability of fat emulsions in TPN mixtures, and their interpretation in the light of current knowledge of colloid stability. The emphasis is placed on methods of quantitatively calculating the stability of complex TPN mixtures; the methods currently under development by the author are described in detail.

Evaluation of non-sink dialysis methods for the measurement of drug release from colloids: effects of drug partition

Abstract The technique of non-sink dialysis across a membrane has been used in the past for determining the release profiles of drugs from colloidal formulations. It is demonstrated that in most cases the results obtained are in fact independent of the release rate, and that the observed release rate is solely dependent on the partition coefficient of the drug between the colloid and its continuous phase. It is suggested that this may form a useful method for measuring partition in disperse systems.

Physical properties and stability of two emulsion formulations of propofol

We have compared the physical properties of two commercial emulsion formulations of the intravenous anaesthetic propofol, (Diprivan, AstraZeneca, and Propofol Intravenous Emulsion, Gensia Sicor Pharmaceuticals) which appear to differ primarily in the additive content and formulation pH. Diprivan contains disodium edetate and has a pH of 7-8.5, while the Gensia product contains sodium metabisulphite and is formulated to a pH of 4.5-6.4. The average zeta potential of Diprivan at pH 8 was -50 mV while that of the Gensia product at pH 4-5 was -40 mV. This information suggests that the physical stability of Propofol Intravenous Emulsion should be lower than that of Diprivan. Three random batches of both products were subjected to a range of stability tests, including shaking, thermal cycling, and freeze-thaw cycling, and the emulsion droplet size distribution was then assessed by dynamic light scattering, light diffraction, and electrical and optical zone sensing. Both emulsions initially showed narrow submicrometre particle size distributions. An increased level of droplets larger than 5 microm could be detected in Propofol Intravenous Emulsion after as little as 4 h shaking (300 strokes/min at room temperature) and visible free oil could be detected after 8-12 h shaking. In contrast, Diprivan showed no increase in the large droplet count after shaking for times up to 16 h. A similar difference in the emulsions was found after one freeze-thaw cycle, with Propofol Intravenous Emulsion exhibiting extensive coalescence, while that of Diprivan was at the limits of detection. We conclude that these two products have different physical stability characteristics, and that this may in part be due to the reduced zeta potential in Propofol Intravenous Emulsion compared to that of Diprivan.

Mechanism of action of Azone as a percutaneous penetration enhancer: Lipid bilayer fluidity and transition temperature effects

Abstract Azone is an effective penetration enhancer for the percutaneous delivery ofcertain topically applied drugs. Fundamental physicochemical experiments have been performed to elucidate the mechanism of action of Azone. The penetration enhancing effect of Azone is believed to be due to its increasing the fluidity of the intercellular lipid bilayers of the stratum corneum. Phospholipid vesicles were chosen as a simple model to represent these bilayers. The effect of Azone on phase transition temperature and lipid fluidity was studied using turbidity and fluorescent probe (pyrene excimer) technique. Addition of increasing amounts of Azone to the bilayer resulted in lowering of phase transition temperature, shown by turbidity of vesicle suspensions, and an increase in lipid fluidity, shown by changes in pyrene fluorescence. The results suggest that Azone would interact with striatum corneum lipids in a similar manner, thereby reducing the diffusional resistance of the stratum corneum to drugs with balanced hydrophilic-lipophilic characteristics.

Toxicity of solubilized and colloidal amphotericin B formulations to human erythrocytes.

Abstract— The toxicity of a number of solubilized or colloidal amphotericin B formulations to human erythrocytes has been studied in‐vitro. All the solubilized formulations studied, using poloxamer F127 or L92, or sodium deoxycholate as solubilizing agents, showed similar toxicity, erythrocyte lysis being greater than 90% for amphotericin B concentrations between 4 to 8 μg mL−1. Emulsion formulations stabilized by poloxamers showed reduced toxicity, while those stabilized by egg lecithin showed less than 5% erythrocyte lysis up to an amphotericin B concentration of 200 μg mL−1. The mechanisms of the differential toxicity is considered to be due to the differences in the equilibrium concentration of free amphotericin B in the aqueous phase.

The electrokinetic properties of phospholipid-stabilized fat emulsions

Abstract A study has been made of the electrokinetic behaviour of fat emulsions stabilized with model phospholipid mixtures, consisting of uncharged phosphatidylcholine doped with small quantities of phosphatidylserine, phosphatidylglycerol or phosphatidic acid. All the negatively charged lipids caused a similar negative zeta (ζ) potential to be developed on the emulsion droplets in the absence of divalent ions. Increasing amounts of negative phospholipid increased the droplet charge and caused the critical flocculation concentration and point of zero charge of the emulsion to be shifted to higher electrolyte concentrations. All the model systems had critical ζ potentials in the region −22 to −28 mV. Systems with a larger proportion of negatively charged lipids developed a lower positive charge in the charge-reversed region, leading to a lower stability to high concentrations of added electrolyte. The consequences of these studies for the stability of total parenteral nutrition mixtures is discussed. In particular the wisdom of attempting to maximize droplet charge in order to achieve long shelf-life is questioned when the emulsions are used in total parenteral nutrition (TPN) mixtures of high electrolyte content.

Ageing effects in patenterai fat emulsions: the role of fatty acids

Abstract The effect of age on the pH, ζ-potential, and flocculation behaviour of a commercial fat emulsion of soybean oil stabilized by egg lecithin (‘Intralipid 10%’) has been studied. This has been compared to the behaviour of ‘Intralipid 10%’ to which oleic acid had been deliberately added. In both cases the critical flocculation concentration to calcium ions was increased, the ζ-potential became more negative, and the pH fell. The stability to electrolytes was in accord with the predictions of simple DLVO theory (Verwey and Overbeek, 1948), and the results suggested that the production of free fatty acids may account for the changes in the properties of fat emulsions with age. The implications for the formulation of total parenteral nutrition mixtures are discussed.

The effect of stabilising agents on the organ distribution of lipid emulsions

Abstract The effect of different emulsifying agents on the organ deposition and blood clearance of i.v. administered fat emulsions has been investigated in rabbits using gamma scintigraphy. Emulsions stabilized by egg lecithin were sequestered by the liver to a limited extent. Such liver uptake was enhanced by coemulsification using gelatin, thereby exploiting a receptor-mediated process involving fibronectin. Liver uptake was almost totally eliminated if the block copolymer, poloxamine 908, was employed as the emulsifier. The blood clearance and liver uptake of emulsions were little affected by the incorporation of model drugs, lasalocid and amphotericin B.