The role of phospholipids in drug delivery formulations - Recent advances presented at the Researcher's Day 2023 Conference of the Phospholipid Research Center Heidelberg.

This Focus on Meetings contribution summarizes recent advances in the research on phospholipids and their applications for drug delivery and analytical purposes that have been presented at the hybrid Researcher's Day 2023 Conference of the Phospholipid Research Center (PRC), held on July 3-5, 2023, in Bad Dürkheim, Germany. The PRC is a non-profit organization focused on expanding and sharing scientific and technological knowledge of phospholipids in pharmaceutical and other applications. This is accomplished by, e.

Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine.

By direct deposition of the drug at the local site of action, injectable depot formulations - intended for treatment of a local disease or for local intervention - are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots.

Cancer immune therapy using engineered ‛tail-flipping' nanoliposomes targeting alternatively activated macrophages.

Alternatively-activated, M2-like tumor-associated macrophages (TAM) strongly contribute to tumor growth, invasiveness and metastasis. Technologies to disable the pro-tumorigenic function of these TAMs are of high interest to immunotherapy research. Here we show that by designing engineered nanoliposomes bio-mimicking peroxidated phospholipids that are recognised and internalised by scavenger receptors, TAMs can be targeted.

The Phospholipid Research Center: Current Research in Phospholipids and Their Use in Drug Delivery.

This review summarizes the research on phospholipids and their use for drug delivery related to the Phospholipid Research Center Heidelberg (PRC). The focus is on projects that have been approved by the PRC since 2017 and are currently still ongoing or have recently been completed. The different projects cover all facets of phospholipid research, from basic to applied research, including the use of phospholipids in different administration forms such as liposomes, mixed micelles, emulsions, and extrudates, up to industrial application-oriented research.

The role of liposomes in clinical nanomedicine development. What now? Now what?

The rapid rise in interest in 'nanomedicines' in the academic world over the last twenty years and the claims of success led to calls for reflection. The main body of text of this Commentary will be on answering the question: 'where to go with nanomedicines'? Research priorities for the future will be outlined based on experience with the most successful nanomedicines family within the broad field of nanomedicine so far: liposomes. An analysis of currently clinically tested, approved and marketed liposome-drug combinations provides these insights.

Evaluation of Hydrogenated Soybean Phosphatidylcholine Matrices Prepared by Hot Melt Extrusion for Oral Controlled Delivery of Water-Soluble Drugs.

The aims of this study were to prepare hydrogenated soybean phosphatidylcholine (HSPC) matrices by hot melt extrusion and to evaluate resulting matrix potential to extend drug release in regard to drug loading and solubility for oral drug delivery of water-soluble drugs. The liquid crystalline nature of HSPC powder allowed its extrusion at 120°C, which was below its capillary melting point. Model drugs with a wide range of water solubilities (8, 20 and 240 mg/mL) and melting temperatures (160-270°C) were used.

Study on the in situ aggregation of liposomes with negatively charged phospholipids for use as injectable depot formulation.

Compared to conventional parenteral formulations injectable depot formulations, owing to a sustained drug release, offer several advantages, such as a reduced dosing frequency - and consequent improved compliance - or a predictable release profile. Additionally, fluctuations in the drug blood level may be smoothened and consequently side effects reduced. Because of their capability to encapsulate water soluble drugs and their very low toxicity profile liposomes comprising phospholipids, most certainly represent a vehicle of choice for subcutaneous (s.

Review - An update on the use of oral phospholipid excipients.

The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously. Nevertheless the present number of oral products using these excipients as essential excipient is very limited. This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies.

Molecular imaging of brain localization of liposomes in mice using MALDI mass spectrometry.

Phospholipids have excellent biocompatibility and are therefore often used as main components of liposomal drug carriers. In traditional bioanalytics, the in-vivo distribution of liposomal drug carriers is assessed using radiolabeled liposomal constituents. This study presents matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as an alternative, label-free method for ex-vivo molecular imaging of liposomal drug carriers in mouse tissue.

Molecular insights into the formation of drug-monoacyl phosphatidylcholine solid dispersions for oral delivery.

Phospholipid-based formulations provide a key technology to formulate poorly water-soluble drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-acylphospholipids upon aqueous dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility.

Amorphous drug dispersions with mono- and diacyl lecithin: On molecular categorization of their feasibility and UV dissolution imaging.

There is a growing interest in drug-phospholipid complexes and similar formulations that are mostly solid dispersions with high drug load. This study aims to explore the feasibility of such phospholipid-based solid dispersions as well as to characterize them. A particular aim was to compare monoacyl phosphatidylcholine (PC) with the diacyl excipient.

The use of natural and synthetic phospholipids as pharmaceutical excipients.

In pharmaceutical formulations, phospholipids obtained from plant or animal sources and synthetic phospholipids are used. Natural phospholipids are purified from, e.g.

Drug delivery strategies for poorly water-soluble drugs: the industrial perspective.

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas Covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes.

The apparent solubilizing capacity of simulated intestinal fluids for poorly water-soluble drugs.

Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development. Despite this importance, there is still an incomplete understanding of how poorly soluble compounds interact with these media. The aim of this study was to apply the concept of the apparent solubilization capacity to fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF, respectively).

Instant solubilization of poorly water-soluble drugs by in-situ loading of aqueous phospholipid dispersions suitable for parenteral administration.

The features of a new, in situ method for solubilizing poorly soluble drugs (SupraVail Instant Solubilization) are demonstrated. The resulting formulations are suitable for parenteral administration in preclinical and clinical studies. The technique avoids drug precipitation upon dilution and circumvents the need for co-administration of high organic solvent concentrations.

Absorption of poorly water soluble drugs subject to apical efflux using phospholipids as solubilizers in the Caco-2 cell model.

The purpose of this work was to determine the influence of liposomal solubilization of poorly water soluble drugs exhibiting apical efflux on permeation kinetics and cell toxicity in Caco-2 cells. The HIV-protease inhibitors indinavir and saquinavir were incorporated in phosphatidylcholine liposomes at maximal drug-to-lipid mass ratios and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using purely aqueous drug solutions as reference. A novel mathematical model was developed to quantitatively delineate the contribution of passive membrane permeation and carrier mediated efflux to transport across the cell monolayer and passive permeability coefficient and maximal efflux rate and affinity constant of the transporter system were determined.

Lipophilic drug transfer between liposomal and biological membranes: what does it mean for parenteral and oral drug delivery?

This review presents the current knowledge on the interaction of lipophilic, poorly water soluble drugs with liposomal and biological membranes. The center of attention will be on drugs having the potential to dissolve in a lipid membrane without perturbing them too much. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes.

Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery.

This review paper describes the present knowledge on the interaction of lipophilic, poorly water soluble, drugs with liposomal membranes and the reversibility of this interaction. This interaction is discussed in the context of equilibrium and spontaneous transfer kinetics of the drug, when the liposomes are brought in co-dispersion with other artificial or natural phospholipid membranes in an aqueous medium. The focus is on drugs, which have the potential to partition (dissolve) in a lipid membrane but do not perturb membranes.

Characteristics of a novel phospholipid-based depot injectable technology for poorly water-soluble drugs.

Phospholipid concentrates in a water miscible solvent were explored as injectable formulations for the poorly water-soluble drugs, using the anti-infective PHA 244 as model substance. Formulations containing up to 70% w/v phospholipid could dissolve 15% PHA 244. The formulations showed excellent syringe-ability and no precipitation of the drug after dilution in an excess of water.

Sustained-release injectables formed in situ and their potential use for veterinary products.

The controlled drug delivery of hydrophilic and lipophilic drug substances via the parenteral route has gained increasing importance in the development of pharmaceutical dosage forms. In particular, the animal health industry has generated strong interest in long-term drug delivery for both companion and farm animals during the past few years. At present sustained-release injectables formed in situ for s.