Design and development of multivesicular liposomal depot delivery system for controlled systemic delivery of acyclovir sodium

The aim of the present study was to design a depot delivery system of acyclovir sodium using multivesicular liposomes (MVLs) to overcome the limitations of conventional therapies and to investigate its in vivo effectiveness for sustained delivery. MVLs of acyclovir were prepared by the reverse phase evaporation method. The loading efficiency of the MVLs (45%–82%) was found to be 3 to 6 times higher than conventional multilamellar vesicles (MLVs). The in vitro release of acyclovir from MVL formulations was found to be in a sustained manner and only 70% of drug was released in 96 hours, whereas conventional MLVs released 80% of drug in 16 hours. Following intradermal administration to Wistar rats, the MVL formulations showed effective plasma concentration for 48 hours compared with MLVs and free drug solution (12–16 hours). Cmax values of MVL formulations were significantly less (8.6–11.4 μg/mL) than MLV and free drug solution (12.5 μg/mL). The AUC0–48 of the MVL formulations was 1.5- and 3-fold higher compared with conventional liposomes and free drug solution, respectively. Overall, formulations containing phosphatidyl glycerol as negatively charged lipid showed better results. The MVL delivery system as an intradermal depot offers the advantage of a very high loading and controlled release of acyclovir for an extended period of time. The increase in AUC and decrease in Cmax reflects that the MVL formulations could reduce the toxic complications and limitations of conventional IV and oral therapies

CNS drug delivery: Opioid peptides and the blood-brain barrier

Peptides are key regulators in cellular and intercellular physiological responses and possess enormous promise for the treatment of pathological conditions. Opioid peptide activity within the central nervous system (CNS) is of particular interest for the treatment of pain owing to the elevated potency of peptides and the centrally mediated actions of pain processes. Despite this potential, peptides have seen limited use as clinically viable drugs for the treatment of pain. Reasons for the limited use are primarily based in the physiochemical and biochemical nature of peptides. Numerous approaches have been devised in an attempt to improve peptide drug delivery to the brain, with variable results. This review describes different approaches to peptide design/modification and provides examples of the value of these strategies to CNS delivery of peptide drugs. The various modes of modification of therapeutic peptides may be amalgamated, creating more efficacious “hybrid” peptides, with synergistic delivery to the CNS. The ongoing development of these strategies provides promise that peptide drugs may be useful for the treatment of pain and other neurologically-based disease states in the futur

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier.

This review considers efflux of substances from brain parenchyma quantified as values of clearances (CL, stated in µL g-1 min-1). Total clearance of a substance is the sum of clearance values for all available routes including perivascular pathways and the blood-brain barrier. Perivascular efflux contributes to the clearance of all water-soluble substances. Substances leaving via the perivascular routes may enter cerebrospinal fluid (CSF) or lymph. These routes are also involved in entry to the parenchyma from CSF. However, evidence demonstrating net fluid flow inwards along arteries and then outwards along veins (the glymphatic hypothesis) is still lacking. CLperivascular, that via perivascular routes, has been measured by following the fate of exogenously applied labelled tracer amounts of sucrose, inulin or serum albumin, which are not metabolized or eliminated across the blood-brain barrier. With these substances values of total CL ≅ 1 have been measured. Substances that are eliminated at least partly by other routes, i.e. across the blood-brain barrier, have higher total CL values. Substances crossing the blood-brain barrier may do so by passive, non-specific means with CLblood-brain barrier values ranging from  1000 for water and CO2. CLblood-brain barrier values for many small solutes are predictable from their oil/water partition and molecular weight. Transporters specific for glucose, lactate and many polar substrates facilitate efflux across the blood-brain barrier producing CLblood-brain barrier values > 50. The principal route for movement of Na+ and Cl- ions across the blood-brain barrier is probably paracellular through tight junctions between the brain endothelial cells producing CLblood-brain barrier values ~ 1. There are large fluxes of amino acids into and out of the brain across the blood-brain barrier but only small net fluxes have been observed suggesting substantial reuse of essential amino acids and α-ketoacids within the brain. Amyloid-β efflux, which is measurably faster than efflux of inulin, is primarily across the blood-brain barrier. Amyloid-β also leaves the brain parenchyma via perivascular efflux and this may be important as the route by which amyloid-β reaches arterial walls resulting in cerebral amyloid angiopathy