Michael Mezei

Liposomes - a selective drug delivery system for the topical route of administration I. Lotion dosage form

Abstract The applicability of liposomes as drug carriers for the topical route of administration was investigated using triamcinolone as a model drug. The liposomal encapsulation favourably altered the drug dipposition; the concentration of the drug decreased at the site of its adverse effects and increased at the site where its activity is desired.

Dermal drug delivery by liposome encapsulation: Clinical and electron microscopic studies

The fate of liposomes and the encapsulated drug was studied after topical application on the skin. Lidocaine applied on the forearm of human volunteers produced greater local anaesthetic effect in the liposomal form than in the cream form (p less than or equal to 0.001 after 1 h application). Autoradiography demonstrated higher concentration (p less than or equal to 0.01) of 14C-lidocaine in the epidermis and dermis of guinea pigs treated with liposome-encapsulated lidocaine as opposed to lidocaine in Dermabase cream. Electron microscopic observations, using colloidal iron as an electrodense marker, indicated that intact liposomes penetrated into the skin and deposited in the dermis where they acted as a slow release depot system. On the basis of results in the human volunteers and animals, a hypothetical model for liposome-skin interaction is proposed.

Liposome ocular delivery systems

Abstract Liposomes are microscopic vesicles composed of membrane-like lipid bilayers surrounding aqueous compartments. This unique feature imparts the ability of liposomes to encapsulate both lipophilic and hydrophilic compounds. Consequently liposomes have been investigated extensively as a drug carrier system by various routes of administration. One of the more recent applications is the concept of employing liposomes as drug carriers in ophthalmology. Traditional drug therapy in the eye consists of the administration of solutions and suspensions. These dosage forms are compromised in their effectiveness by several limitations including rapid nasolacrimal drainage, poor corneal penetration, nonproductive conjunctival losses and unwanted systemic exposure. The need for an ocular drug delivery system which has the convenience of a drop, but will localize and maintain drug activity at its site of action, is apparent. Liposomes offer a promising avenue to achieve this goal. The simplicity of preparation and the versatility in physical characteristics confer a unique and useful property to liposomes for use as an ocular drug deliverer. In this review, a historical account of the studies is presented to illustrate the potential of liposomes in ophthalmology. Consideration is given to methods of preparation, advantages of liposomes as drug carriers as well as some of the general issues surrounding liposomes as a pharmaceutically acceptable dosage form. Various routes of administration such as topical instillation, intravitreal, subconjunctival and systemic injection are also discussed. Significant progress has been made in these areas and a complete understanding of the liposome interaction with ocular tissues should enable the design of liposomal products suitable for ocular drug delivery.

Pharmacokinetics of Inhaled Liposome-encapsulated Fentanyl

BackgroundPulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and th

Liposomal ophthalmic drug delivery. III. Pharmacodynamic and biodisposition studies of atropine

Abstract The potential of liposomes as an ophthalmic drug delivery system was investigated by comparing disposition and pupillary dilatory effect of atropine base and atropine sulphate in solution and various liposomal forms when topically instilled to the rabbit eye. Atropine base entrapped in multilamellar lipid vesicles (MLVs) with positive surface charge displayed the most prolonged effect lasting up to 12 h. MLVs with neutral and negative charges maintained the effect for 9 h while atropine in solution form was effective for only 7 h. Preparations containing atropine sulphate displayed a similar pattern although were shorter-acting than corresponding base products. All preparations whether salt or base, were equally effective in producing maximal response. In vivo drug disposition studies indicated the liposomal form produced significantly higher drug levels in the anterior tissues of the eye up to 8 h after instillation. Increased ocular bioavailability of atropine to these tissues was attributed to enhancement of pulse entry with little evidence of sustained drug release. It could be concluded that liposome encapsulation extended the duration of action and favourably altered disposition of atropine when topically instilled to the rabbit eye.

Liposomal ophthalmic drug delivery system. I: Triamcinolone acetonide

Abstract The potential of liposomes as an ophthalmic drug delivery system was investigated in the rabbit. Triamcinolone acetonide as a model compound for lipophilic drugs was encapsulated into large multilamellar vesicles and instilled into the eye. A suspension form served as a control preparation. Drug distribution was determined at various time intervals. Compared to the suspension, the liposomal form produced significantly higher drug levels in the ocular tissues up to 5 h after the drug administration. The results suggest that liposomal encapsulation of the drug may be a superior drug delivery system for ocular therapy.

Evidence for a long-lasting single administration contraceptive vaccine in wild grey seals

A single-administration birth control vaccine based on liposome delivery of porcine zona pellucida antigens reduced pup production in grey seals (Halichoerus grypus) by about 90%. Anti-porcine zona pellucida titers of individual seals with two or more recaptures were variable but without a diminishing trend during the 5 year post-immunization period. Seals that produced at least one or more pups during the 2-5 year post-immunization period when the vaccine is fully effective, had an average anti-porcine zona pellucida titer of 5% of the reference serum. In contrast, the subset of seals that did not reproduce but were recaptured during the breeding season had an average titer of 31% of the reference serum. As measured by antibody titers and pup production, there were no differences in efficacy of the vaccine in 14-, 20- and 21-year-old female grey seals.

Liposomal ophthalmic drug delivery system. II: Dihydrostreptomycin sulfate

Abstract The carrier ability of liposomes for a model hydrophilic compound vas investigated in the rabbit eye. Dihydrostreptomycin sulfate was encapsulated in various types of liposomes, i.e. large and small uni- and multilamellar vesicles having either positive or neutral surface charge. An aqueous solution served as control preparation. Results indicated that liposomal encapsulation reduced the ocular drug con- centration. Addition of empty liposomes to the control solution did not alter drug levels in most of the ocular tissues. Among the liposomal preparations the large multi- and unilamellar vesicles provided higher drug concentration in all ocular tissue than the small unilamellar ones. Introduction of a positive charge on liposome surface enhanced liposome-conjunctiva interactions. The results suggest that liposomal encapsulation alters drug disposition in the eye lepending on the type of liposomes and the physicochemical properties of the encapsulated drug. In the case of the dihydrostreptomycin sulfate and possibly other hydrophilic drugs the liposomal encapsulation provides no advantages as far as drug delivery is concerned.

Comparative topical anaesthesia of EMLA and liposome-encapsulated tetracaine

BackgroundThe eutectic mixture of local anaesthetics (EMLA) provides effective topical anaesthesia after a minimum of 60 to 90 mm application. Since liposome-encapsulated tetracaine (LET) can provide rapid dermal penetration, the goal of this study was to compare the local anaesthetic effects of EMLA and LET in human volunteers after 60 mm application.MethodsAfter obtaining institutional approval and informed consent, healthy volunteers were recruited in a double blind, crossover, randomized trial. The study creams (0.5 ml EMLA and 0.5 ml LET 5%) were applied randomly to opposite arms for 60 min. The discomfort of iv cathetenzation was assessed using a visual analogue pain score (VAS). Cutaneous side effects of the creams were recorded.ResultsSixty-one subjects were studied. Twenty-one were excluded because of technical difficulties. Forty subjects completed the study and were included in the data analysis. The mean (±SD) VAS was lower for LET than for EMLA (10.9 ± 9.0 mm vs 22.7 ± 17.1 mm, P < 0.001). Erythema secondary to vasodilatation occurred more frequent in the LET group than in the EMLA group (33 vs 3. P < 0.001). One subject with a history of atopy developed a rash at the LET application site.ConclusionLiposome-encapsulated tetracaine can provide a more effective topical anaesthesia than EMLA for intravenous catheterization after 60 min application. Clinical evaluations are necessary to determine the efficacy and safety of LET in providing topical anaesthesia for vanous invasive percutaneous procedures in other patient populations.RésuméObjectifLe mélange eutectique d’anesthésique local (EMLA) appliqué pendant 60 à 90 minutes procure une anesthésie topique efficace. On sait que tétracaïne encapsulée dans les liposomes (LET) pénètre le derme rapidement. Cette étude a été entreprise pour comparer les effets anesthésiques locaux de l’EMLA et du LET chez des volontaires humains après 60 mm d’application.MéthodesAprès obtention de l’approbation des instances appropriées et du consentement éclairé, des volontaires ont été recrutés dans une étude aléatoire croisée à double insu. Les crèmes (EMLA 0.5 ml et LET 5% 0,5 ml) ont été appliquées aléatoirement sur des bras opposés pendant 60 min. L’inconfort de la canulation veineuse a été évalué sur une échelle visuelle analogique (ÉVA). Les effets secondaires ont été notés.RésultatsSoixante et un sujets ont participé à l’étude dont vingt et un ont été rejetés à cause de problèmes techniques. Quarante sujets ont complété l’étude et ont été conservés pour l’analyse des données. L’ÉVA moyenne (±ÉT) du LET était inférieure à celle de l’EMLA (10.9 ± 9.0 mm vs 22,7 ± 17.1. P < 0,001). L’érythème secondaire à la vasodilatation était plus fréquent dans le groupe LET que dans le groupe EMLA (33 vs 3, P < 0.001). Un des sujets considéré comine atopique a présenté de l’érythème au site d’application du LET.ConclusionLa tétracaïne encapsulée dans les liposomes peut procurer une anesthésie topique plus efficace que l’EMLA pour la canulation veineuse après 60 min d’application. Des évaluations cliniques sont nécessaires pour déterminer l’efficacité et l’innocuité du LET pour l’anesthésie topique pendant des manipulations percutanées diverses chez d’autres groupes de patients.

Effect of Wallerian Degeneration on Histamine Concentration of the Peripheral Nerve

One sciatic nerve of a White Leghorn hen was severed and the distal portion was allowed to undergo Wallerian degeneration. The change in histamine and DNA concentration and mast cell number was measured at different times following nerve sectioning in the proximal regenerating, distal degenerating, and intact, contralateral nerves. The experimental results revealed a significant accumulation of histamine in the proximal desheathed segment and in the contralateral “functional nerve,” whereas the biogenic amine in the distal desheathed nerve significantly decreased. The pattern of change of histamine in the distal and proximal nerve sheaths was different: it dropped at 2 h and then rose in the later stages of Wallerian degeneration. In the distal desheathed nerves and in both the proximal and distal nerve sheaths DNA increased significantly by 14 days. The number of mast cells appeared to be highest in the 14‐day distal nerve and in the 7‐day proximal nerve sheaths. These results support a dual localization of histamine in the peripheral nerve, and are consistent with the interpretation that the amine has either some role in neurotransmission or in the process of growth and regeneration.