Polymer-mediated disruption of drug crystallinity

Ibuprofen (IB), a BCS Class II compound, is a highly crystalline substance with poor solubility properties. Here we report on the disruption of this crystalline structure upon intimate contact with the polymeric carrier cross-linked polyvinylpyrrolidone (PVP-CL) facilitated by low energy simple mixing. Whilst strong molecular interactions between APIs and carriers within delivery systems would be expected on melting or through solvent depositions, this is not the case with less energetic mixing. Simple mixing of the two compounds resulted in a significant decrease in the differential scanning calorimetry (DSC) melting enthalpy for IB, indicating that approximately 30% of the crystalline content was disordered. This structural change was confirmed by broadening and intensity diminution of characteristic IB X-ray powder diffractometry (PXRD) peaks. Unexpectedly, the crystalline content of the drug continued to decrease upon storage under ambient conditions. The molecular environment of the mixture was further investigated using Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) spectroscopy. These data suggest that the primary interaction between these components of the physical mix is hydrogen bonding, with a secondary mechanism involving electrostatic/hydrophobic interactions through the IB benzene ring. Such interactions and subsequent loss of crystallinity could confer a dissolution rate advantage for IB. (C) 2006 Elsevier B.V. All rights reserved.

Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude

Amphiphilic chitosan-based polymers (M-w < 20 kDa) self-assemble in aqueous media at low micromolar concentrations to give previously unknown micellar clusters of 100-300 nm in size. Micellar clusters comprise smaller 10-30 nm aggregates, and the nanopolarity/drug incorporation efficiency of their hydrophobic domains can be tailored by varying the degree of lipidic derivatization and molecular weight of the carbohydrate. The extent of drug incorporation by these novel micellar clusters is 1 order of magnitude higher than is seen with triblock copolymers, with molar polymer/drug ratios of 1:48 to 1:67. On intravenous injection, the pharmacodynamic activity of a carbohydrate propofol formulation is increased by 1 order of magnitude when compared to a commercial emulsion formulation, and on topical ocular application of a carbohydrate prednisolone formulation, initial drug aqueous humor levels are similar to those found with a 10-fold dose of prednisolone suspension.

Preventing drug related morbidity: a process for facilitating changes in practice

Aim: To describe how quantitative data obtained from applying a series of indicators for preventable drug related morbidity (PDRM) in the electronic patient record in English general practice can be used to facilitate changes aimed at helping to improve medicines management. Design: A multidisciplinary discussion forum held at each practice facilitated by a clinical researcher. Subjects and setting: Eight English general practices. Outcome measures: Issues discussed at the multidisciplinary discussion forum and ideas generated by practices for tackling these issues. Progress made by practices after 1, 3, and 6 months. Results: A number of clinical issues were raised by the practices and ideas for moving them forward were discussed. The issues that were easiest and most straightforward to deal with (for example, reviewing specific patient groups) were quickly addressed in most instances. Practices were less likely to have taken steps towards addressing issues at a systems level. Conclusions: Data generated from applying PDRM indicators can be used to facilitate practice-wide discussion on medicines management. Different practices place different priority levels on the issues they wish to pursue. Individual practice "ownership'' of these, together with having a central committed figure at the practice, is key to the success of the process.

Liposomes and skin: From drug delivery to model membranes

The early eighties saw the introduction of liposomes as skin drug delivery systems, initially promoted primarily for localised effects with minimal systemic delivery. Subsequently, a novel ultradeformable vesicular system (termed "Transfersomes" by the inventors) was reported for transdermal delivery with an efficiency similar to subcutaneous injection. Further research illustrated that the mechanisms of liposome action depended on the application regime and the vesicle composition and morphology. Ethical, health and supply problems with human skin have encouraged researchers to use skin models. 'IYaditional models involved polymer membranes and animal tissue, but whilst of value for release studies, such models are not always good mimics for the complex human skin barrier, particularly with respect to the stratum corneal intercellular lipid domains. These lipids have a multiply bilayered organization, a composition and organization somewhat similar to liposomes, Consequently researchers have used vesicles as skin model membranes. Early work first employed phospholipid liposomes and tested their interactions with skin penetration enhancers, typically using thermal analysis and spectroscopic analyses. Another approach probed how incorporation of compounds into liposomes led to the loss of entrapped markers, analogous to "fluidization" of stratum corneum lipids on treatment with a penetration enhancer. Subsequently scientists employed liposomes formulated with skin lipids in these types of studies. Following a brief description of the nature of the skin barrier to transdermal drug delivery and the use of liposomes in drug delivery through skin, this article critically reviews the relevance of using different types of vesicles as a model for human skin in permeation enhancement studies, concentrating primarily on liposomes after briefly surveying older models. The validity of different types of liposome is considered and traditional skin models are compared to vesicular model membranes for their precision and accuracy as skin membrane mimics. (c) 2008 Elsevier B.V. All rights reserved.

Targeting the plasmepsin 4 orthologs of Plasmodium sp with "Double Drug" inhibitors

Plasmepsin 4 (PM4) is a digestive vacuole enzyme found in all Plasmodium species examined to date. While P. falciparum has three additional aspartic proteinases in its digestive vacuole in addition to plasmepsin 4, other Plasmodium species have only PM4 in their digestive vacuole. Therefore, PM4 may be a good target for the development of an antimalarial drug. This study presents data obtained with PM4s from several Plasmodium species. Low nanomolar K-i values have been observed for all PM4s studied.

Causes of preventable drug-related hospital admissions: a qualitative study

Objective: To explore the causes of preventable drug-related admissions (PDRAs) to hospital. Design: Qualitative case studies using semi-structured interviews and medical record review; data analysed using a framework derived from Reason's model of organisational accidents and cascade analysis. Participants: 62 participants, including 18 patients, 8 informal carers, 17 general practitioners, 12 community pharmacists, 3 practice nurses and 4 other members of healthcare staff, involved in events leading up to the patients' hospital admissions. Setting: Nottingham, UK. Results: PDRAs are associated with problems at multiple stages in the medication use process, including prescribing, dispensing, administration, monitoring and help seeking. The main causes of these problems are communication failures ( between patients and healthcare professionals and different groups of healthcare professionals) and knowledge gaps ( about drugs and patients' medical and medication histories). The causes of PDRAs are similar irrespective of whether the hospital admission is associated with a prescribing, monitoring or patient adherence problem. Conclusions: The causes of PDRAs are multifaceted and complex. Technical solutions to PDRAs will need to take account of this complexity and are unlikely to be sufficient on their own. Interventions targeting the human causes of PDRAs are also necessary - for example, improving methods of communication.

Polymer-drug conjugates: current status and future trends

Polymer conjugates are nano-sized, multicomponent constructs already in the clinic as anticancer compounds, both as single agents or as elements of combinations. They have the potential to improve pharmacological therapy of a variety of solid tumors. Polymer-drug conjugation promotes passive tumor targeting by the enhanced permeability and retention (EPR) effect and allows for lysosomotropic drug delivery following endocytic capture. In the first part of this review, we analyze the promising results arising from clinical trials of polymer-bound chemotherapy. The experience gained on these studies provides the basis for the development of a more sophisticated second-generation of polymer conjugates. However, many challenges still lay ahead providing scope to develop and refine this field. The "technology platform'' of polymer therapeutics allows the development of both new and exciting polymeric materials, the incorporation of novel bioactive agents and combinations thereof to address recent advances in drug therapy. The rational design of polymer drug conjugates is expected to realize the true potential of these "nanomedicines".

Can drug-bearing liposomes penetrate intact skin?

Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variability allows for multiple functions ranging from local to transdermal effects. Application to dissimilar skins (animal or human) via diverse protocols may reveal different mechanisms of action with possible vesicle skin penetration reaching different depths, from surface assimilation to (rarely) the viable tissue and subsequent systemic absorption.

Drug interaction and location in liposomes: correlation with polar surface areas

An important step in liposome characterization is to determine the location of a drug within the liposome. This work thus investigated the interaction of dipalmitoylphosphatidylcholine liposomes with drugs of varied water solubility, polar surface area (PSA) and partition coefficient using high sensitivity differential scanning calorimetry. Lipophilic estradiol (ES) interacted strongest with the acyl chains of the lipid membrane, followed by the somewhat polar 5-fluorouracil (5-FU). Strongly hydrophilic mannitol (MAN) showed no evidence of interaction but water soluble polymers inulin (IN) and an antisense oligonucleotide (OLG), which have very high PSAs, interacted with the lipid head groups. Accordingly, the drugs could be classified as: hydrophilic ones situated in the aqueous core and which may interact with the head groups; those located at the water-bilayer interface with some degree of penetration into the lipid bilayer; those lipophilic drugs constrained within the bilayer. (c) 2004 Elsevier B.V. All rights reserved.

Communicating risk of medication side effects: an empirical evaluation of EU recommended terminology

Two experiments compared people's interpretation of verbal and numerical descriptions of the risk of medication side effects occurring. The verbal descriptors were selected from those recommended for use by the European Union (very common, common, uncommon, rare, very rare). Both experiments used a controlled empirical methodology, in which nearly 500 members of the general population were presented with a fictitious (but realistic) scenario about visiting the doctor and being prescribed medication, together with information about the medicine's side effects and their probability of occurrence. Experiment 1 found that, in all three age groups tested (18 - 40, 41 - 60 and over 60), participants given a verbal descriptor (very common) estimated side effect risk to be considerably higher than those given a comparable numerical description. Furthermore, the differences in interpretation were reflected in their judgements of side effect severity, risk to health, and intention to comply. Experiment 2 confirmed these findings using two different verbal descriptors (common and rare) and in scenarios which described either relatively severe or relatively mild side effects. Strikingly, only 7 out of 180 participants in this study gave a probability estimate which fell within the EU assigned numerical range. Thus, large scale use of the descriptors could have serious negative consequences for individual and public health. We therefore recommend that the EU and National authorities suspend their recommendations regarding these descriptors until a more substantial evidence base is available to support their appropriate use.

A qualitative exploration of the underlying causes of preventable drug-related morbidity in primary care, resulting in hospitalisation

This study has explored the underlying causes of preventable drug-related admissions to hospital, from primary care through semi-structured interviews and review of patients’ medical records. Analysis of the data has revealed that communication failures between different groups of healthcare professionals and between healthcare professionals and patients contribute to preventable drug-related admissions, as do knowledge gaps about medication in both healthcare professionals and patients. In addition, working conditions for community pharmacists severely limit their ability to effectively act as a safety barrier to patients receiving inappropriate medication. Limitations include heavy workloads, lack of access to patients’ clinical information, poor relationships with general practitioners and time restrictions. The results of this study represent an important addition to our understanding of the contribution of human error as an underlying cause of preventable drug-related morbidity, and the factors which contribute to errors occurring in the primary healthcare setting.

Stochiometrically governed molecular interactions in drug: Poloxamer solid dispersions

This study probes the molecular interactions between model drugs and poloxamers that facilitate dissolution rate improvements using solid dispersions. Ibuprofen and ketoprofen solid dispersions were prepared at different mole ratios using poloxamers 407 and 188. The carbonyl stretching vibration of the ibuprofen dimer shifted to higher wavenumber in the infrared spectra of 2:1 drug:carrier mole ratio solid dispersions, indicating disruption of the ibuprofen dimer concomitant with hydrogen bond formation between the drug and carrier. Solid dispersions with mole ratios >2:1 drug:carrier (up to 29:1) showed both ibuprofen hydrogen-bonded to the poloxamer, and excess drug present as dimers. X-ray diffraction studies confirmed these findings with no evidence of crystalline drug in 2:1 mole ratio systems whereas higher drug loadings retained crystalline ibuprofen. Similar results were found with ketoprofen-poloxamer solid dispersions. Thermal analysis of ibuprofen-poloxamer 407 solid dispersions and their resultant phase diagram suggested solid solutions and a eutectic system were formed, depending on drug loading. Dissolution studies showed fastest release from the solid solutions; dissolution rates from solid solutions were 12-fold greater than the dissolution of ibuprofen powder whereas the eutectic system gave a 6-fold improvement over the powder. When designing solid dispersions to improve the delivery of poorly-water soluble drugs, the nature of drug:carrier interactions, which are governed by the stochiometry of the composition, can affect the dissolution rate improvement.

The cell cycle and drug discovery: The promise and the hope

In recent years, there have been major developments in the understanding of the cell cycle. It is now known that normal cellular proliferation is tightly regulated by the activation and deactivation of a series of proteins that constitute the cell cycle machinery. The expression and activity of components of the cell cycle can be altered during the development of a variety of diseases where aberrant proliferation contributes to the pathology of the illness. Apart from yielding a new source of untapped therapeutic targets, it is likely that manipulating the activity of such proteins in diseased states will provide an important route for treating proliferative disorders, and the opportunity to develop a novel class of future medicines.