Expert Opinion on Drug Delivery

Objective: The principle objective of this study was to develop 1,2-diacyl-sn-glycero-3-phospho-l-serine (PS)-coated gelatin nanoparticles (GNPs) bearing amphotericin B (AmB) for specific targeting to the macrophages involved in visceral leishmaniasis (VL). Method: The two-step desolvation method has been used for the preparation of GNPs with AmB, which was further coated with PS (PS-AmB-GNPs). The targeting potential of it was compared with uncoated AmB-loaded GNPs (AmB-GNPs) for in vitro and in vivo macrophage uptake. Results: The results of flow cytometric data revealed enhanced uptake of PS-AmB-GNPs in J774A.1 macrophage cell lines compared with AmB-GNPs. In vivo organ distribution studies in Wistar rats demonstrated a significantly higher extent of accumulation of PS-AmB-GNPs compared with AmB-GNPs in macrophage-rich organs, particularly in liver and spleen. The in vivo anti-leishmanial activity of plain AmB, AmB-GNPs and PS-AmB-GNPs was tested against VL in Leishmania donovani-infected hamsters. Highly significant anti-leishmanial activity (p < 0.05 compared with AmB-GNPs) was observed with PS-AmB-GNPs, causing 85.3 ± 7.89% inhibition of splenic parasitic burden. AmB-GNPs and plain AmB caused only 71.0 ± 3.87 and 50.5 ± 5.12% parasite inhibitions, respectively, in Leishmania-infected hamsters (p < 0.05 for PS-AmB-GNPs versus plain AmB and AmB-GNPs versus plain AmB). Conclusion: The objective of the preparation was achieved and high accumulation of AmB in liver and spleen has been found, which resulted in enhanced anti-leishmanial activity.

Introduction: Antisense oligonucleotides, siRNA, anti-microRNA are designed to selectively bind to target mRNAs, and silence disease-causing or -associated proteins. The clinical development of nucleic acid drugs has been limited by their poor bioavailability. Areas covered: This review article examines the strategies that have been utilized to improve the bioavailability of nucleic acids. The chemical modifications made to nucleic acids that have improved their resistance against nuclease degradation are briefly discussed. The design of cationic and neutral lipid nanoparticles that enable the systemic delivery of nucleic acids in vivo is reviewed, and the proof-of-concept evidence that intravenous administration of nucleic acids incorporated into lipid nanoparticles leads to decreased expression of target genes in humans. Preclinical results of the neutral BP-100-1.01 nanoparticle are highlighted. Expert opinion: To further improve the clinical potential of nucleic acid cancer drugs, we predict research on the next generation of lipid nanoparticles will focus on: i) enhancing nucleic acid delivery to poorly vascularized tumors, as well as tumors behind the blood-brain barrier; and ii) improving the accessibility of nucleic acids to the cytoplasm by enhancing endosomal escape of nucleic acids and/or reducing exocytosis of nucleic acids to the external milieu.

Introduction: First-line disease-modifying drugs for the treatment of multiple sclerosis (MS) are mostly administered by injection. Although these treatments can control the symptoms and progression of the disease to some extent, patients often fail to adhere to their therapy in the long term, so may not obtain the maximum clinical benefits. As injection-related problems are common barriers to adherence, autoinjectors have been developed to improve the ease and convenience of self-injection. Areas covered: This article discusses RebiSmart™, an electronic autoinjector for the subcutaneous administration of interferon β-1a, focusing on the device features and data from clinical trials of the device. An overview of other available autoinjectors for first-line MS therapies is provided for context. Expert opinion: The device is the first electronic autoinjector for use in MS and offers several innovative features, including adjustable injection settings and an electronic dosing log, which may improve adherence. The dosing log can be reviewed with the patient, allowing the physician to open a dialogue to discuss possible issues with treatment adherence. The use of multidose cartridges also provides a softer impact on the environment and easier disposal. The hidden needle helps avoid needle phobia and reduces the risk of needle stick injury.

Introduction: The major drawbacks associated with most of the anti-cancer drugs are their potential adverse effects. Distribution of these drugs throughout the body causes untoward adverse effects and less accumulation of drug at the site of tumors also causes decrease in therapeutic efficacy. Targeted nanomedicines are the emerging systems to improve the targetability of drug to the tumor site and to reduce the toxicity with maximum efficacy. Copolymers of poly-lactic acid (PLA) and D-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin-E TPGS or TPGS) are innovative materials being actively investigated for the fabrication of non-targeted and targeted nanomedicines for diagnosis and therapy of cancer. Areas covered: In this review, different nanomedicines of copolymers such as poly-lactic acid - polyoxyethylene sorbitan monooleate (PLA - Tween® 80), poly-lactic acid - poly-ethyleneglycol (PLA-PEG), poly-lactic acid-D-α-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS) and TPGS-based nanomedicines (i.e., TPGS emulsified polymeric nanoparticles, TPGS prodrugs, TPGS liposomes, and TPGS micelles) for the diagnosis and therapy of cancer have been discussed. Expert opinion: PLA, PLA-Tween® 80, PLA-PEG, PLA-TPGS, and TPGS are the promising polymeric biomaterials well studied as cancer nanomedicines. These biomaterials have proved that they could be applied in the fabrication of multifunctional nanomedicines for the future needs in simultaneous diagnosis of cancer as well as targeted chemotherapy.

Liposomes, phospholipids, nanosized bubbles with a bilayered membrane structure, have drawn a lot of interest as pharmaceutical carriers for drugs and genes. In particular, liposomes are widely used for drug delivery into tumors. In many cases, to enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of different specific ligands, such as monoclonal antibodies. Thus, this review analyzes the application of antibody-targeted liposomes loaded with various chemotherapeutic agents and various liposomal products under development at experimental and preclinical level. The papers published on the subject of cancer-targeted liposomes mainly over the last 10 - 15 years are discussed. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications.

During the last decade, cell-penetrating peptides have been investigated for their ability to overcome the plasma membrane barrier of mammalian cells for the intracellular or transcellular delivery of cargoes as diverse as low molecular weight drugs, imaging agents, oligonucleotides, peptides, proteins and colloidal carriers such as liposomes and polymeric nanoparticles. Their ability to cross biological membranes in a non-disruptive way without apparent toxicity is highly desired for increasing drug bioavailability. This review provides an overview of the application of cell-penetrating peptides as transmembrane drug delivery agents, according to the recent literature, and discusses critical issues and future challenges in relation to fully understanding the fundamental principles of the cell-penetrating peptide-mediated membrane translocation of cargoes and the exploitation of their therapeutic potential.

Cell-penetrating peptides (CPPs) are small peptides that can facilitate the uptake of macromolecular drugs, such as proteins or nucleic acids, into mammalian cells. Cytosolic delivery of CPPs could be beneficial to bypass conventional endocytosis in order to avoid degradation in the lysosomes. Oligoarginine conjugates have characteristics similar to CPPs in terms of cell translocation and are used in the intracellular delivery of plasmid DNA. In these cases, oligoarginine length and/or charge are important factors in the cellular uptake of oligoarginine alone. The arginine moiety of oligoarginine-modified particles may also be a decisive factor for vectors to deliver plasmid DNA. Oligoarginine-PEG-lipids can form self-assembled particles and modify the surface of lipid- and polymer-based particles. This review focuses on the influence of: i) oligoarginine-modified particles such as micelles, liposomes and polymer-based particles; ii) the morphology of oligoarginine-PEG-lipid complexed with plasmid DNA by decreasing the charge ratio; and iii) the oligoarginine length in the complex on its cellular uptake, transfection efficiency and uptake mechanism. The oligoarginine length of oligoarginine-modified particle complexed with plasmid DNA governs the cellular uptake pathway that determines the destiny of intracellular trafficking and finally transfection efficiency. The new aspects of surface-functionalized particle vectors with oligoarginine are discussed.

The supersaturatable self-emulsifying drug delivery system (S-SEDDS) represents a new thermodynamically stable formulation approach wherein it is designed to contain a reduced amount of a surfactant and a water-soluble cellulosic polymer (or other polymers) to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. The S-SEDDS formulations can result in enhanced oral absorption as compared with the related self-emulsifying drug delivery systems (SEDDS) formulation and the reduced surfactant levels may minimise gastrointestinal surfactant side effects.

Photodynamic therapy (PDT) combines a drug (a photosensitiser or photosensitising agent) with a specific type of light to kill cancer cells. It is a minimally invasive treatment, with great potential in malignant disease and premalignant conditions. Following the administration of the photosensitiser, light of the appropriate wavelength is directed onto the abnormal tissue where the drug has preferentially accumulated. Upon light activation, the photosensitiser transfers its excess energy to molecular oxygen to produce an excited state (i.e., the highly reactive singlet oxygen) that causes oxidative damage at the site of its generation. The energy transfer occurs either directly to oxygen or through an indirect mechanism that requires the formation of intermediate radical species. Many photosensitisers have been developed, but only a few have been approved for therapy in humans. Basic research in model systems (animals, cell lines) has unravelled some fundamental cellular processes involved in the cell response to PDT. The exploitation of relevant molecular observations, the discovery and introduction of new sensitisers, the progress in the light delivery systems and light dosimetry are all concurring to the increase of PDT therapeutic efficacy. However, this field has not yet reached maturity. This review briefly analyses the relevant properties of most photosensitisers and their field of application. Special attention is dedicated to the effects observed in model cancer systems; speculation and suggestions of possible future research directions are also offered.

The 17th biennial congress of the International Society for Aerosols in Medicine (ISAM) was held in Monterey, California, between 10 and 14 May 2009. The congress was attended by approximately 300 delegates from 18 countries. Podium presentations were focused on advances in pulmonary drug delivery, but clearance of materials from the lungs by a variety of processes and the potential harmful effects of inhaled particles were also covered. There were > 100 proffered posters, and a commercial exhibition in which 20 companies displayed their products. There were excellent networking opportunities, and the inauguration of more formal networking groups will allow dialogue to continue. Abstracts of podium and poster presentations were provided in the Journal of Aerosol Medicine and Pulmonary Drug Delivery, and it is likely that some of the podium presentations will appear as full papers in that journal in due course. The next conference in this series takes place in Rotterdam, The Netherlands, in June 2011.

This international meeting brought together approximately 250 delegates from the pharmaceutical industry, academia, hospitals and government agencies, to discuss the latest research and development on areas related to inhalation aerosols. Fundamental science and applied research encompassing both the biological and physicochemical aspects were presented. There was a wide range of topics covered, from immune modulation to pharmaceutical regulatory issues, including aerosol clearance; industry innovations; aerosols and in utero effects; technical advances in imaging; inhalation catastrophes; as well as recent advances and future directions in aerosol delivery systems. This biennial congress has provided an excellent forum for stimulating fruitful discussion of aerosols in medicine.

Introduction: Harnessing RNA interference as a therapeutic approach has the potential to significantly expand the druggable target space, offering new hope for treatment of diseases that cannot be addressed with existing classes of drugs. A number of siRNA therapeutics have already progressed into preclinical and clinical development. Of these, lipid-based systems have emerged as one of the most mature classes of systemic delivery technologies. Despite tremendous advances in development, a number of significant challenges must still be addressed to enable commercialization of a lipid-based siRNA pharmaceutical product. Areas covered: This review addresses specific challenges inherent to the pharmaceutical development of lipid-based siRNA therapeutics. Focus is placed on the development of a robust manufacturing process, the setting of appropriate product specifications and controls, development of strategies to assess and ensure product stability, and the evaluation of product comparability throughout development. Expert opinion: Discovering and developing a lipid-based siRNA therapeutic that can be commercialized requires engineering a particle that selectively and efficiently delivers the cargo to the target tissue and cellular compartment. The particle assembly must be strictly controlled and physical properties thoroughly characterized to successfully develop an understanding of particle attributes that influence in vivo pharmaceutical properties. Correlation of particle physio-chemical properties to product performance is the foundation for advancements in discovery and assuring quality in a commercial drug product. Although difficult, we believe these development challenges can be addressed with appropriate scientific resources and that the industry will continue to progress siRNA therapeutic candidates through clinical development.

Objectives: To develop an oral solid dosage form of levamisole suitable for the paediatric population in terms of dose accuracy, palatability, stability and ease of administration. Methods: Small undividable tablets (Ø5 - 8 mm) in four different strengths were manufactured to allow for flexible and accurate dosing. In vitro dissolution testing was used to determine drug release in different media. The bitter taste of levamisole was masked using a film-coat and assessed in healthy volunteers. Suitability and acceptability of the tablets were evaluated in 100 patients with nephrotic syndrome aged 2 - 18 years participating in a double blind, placebo-controlled, randomised trial. Results: All tablet strengths showed good taste-masking characteristics and similar, pH independent, dissolution profiles. Successful taste masking was achieved without affecting the dissolution rate. In a total of 100 paediatric patients, more than 20,000 levamisole tablets were swallowed without any difficulties, choking or aspiration. Conclusion: The formulated tablets were found to be suitable for children aged 2 - 18 years and to provide good dose accuracy.

BACKGROUND: Targeted liposomes can be broadly defined as liposomes that are engineered to interact with a particular population of cells with the objective of delivering a payload or increasing their retention within the targeted cell population by means of a chemical interaction with cell-surface molecules or other tissue-specific ligands. OBJECTIVE: The authors review recent advances in the field with an emphasis on pre-clinical studies and place them in the context of historical developments. METHODS: The review focuses on immunoliposomes (antibody-mediated targeting) as these constructs are presently the most prevalent. Conclusion: The field has advanced in tandem with advances in liposome design and antibody and protein engineering. Targeted liposomes have been used in diagnosis to deliver magnetic resonance contrast agents and radionuclides for magnetic resonance and nuclear medicine imaging, respectively. They have been used in gene therapy to deliver a variety of gene expression modifiers, including plasmids, anti-sense oligonucleotides and short interfering RNA. Targeted liposomes provide a delivery advantage over untargeted liposomes not because of increased localization to tumor sites but because of increased interaction with the target cell population once localized to the tumor site. The increased interaction can take on the form of fusion with the cellular membrane or internalization by endocytosis. To the extent that the spatial distribution of targeted liposomes within a solid tumor may become more non-uniform than has been found for untargeted liposomes, this may be a drawback. However, systematic comparisons of the spatial distribution in tumors of targeted versus untargeted liposomes have yet to be performed. The majority of reported studies have been in the area of chemotherapy delivery. Their use in radionuclide and chemo- and radiosensitizer delivery is just emerging. Multifunctional liposomes containing 'layered functionalities' could potentially be the future direction in targeted liposome-based therapy.

The meeting was dedicated to novel aspects of nanomedicine, including polymer drug delivery systems (DDS) and biomaterials. Self-assembled micellar DDS have been evaluated in terms of morphology, biological properties, and results of clinical trials. Important advances in the design of nanoparticles as DDS have been highlighted in various presentations. Unexpected issues of polymer-related biological effects, including gene expression, were stressed in relation to polymer DDS. Great potential of nanofabrication of biomaterials, and preliminary data on the design of polymer scaffolds were demonstrated in a number of reports. This symposium demonstrated how timely the development of nanosised DDS is, with advances in understanding the disease-related mechanisms, and outlined the major areas of application of nanomedicine technology.

Objectives: The 12-month observational PERSIST study (NCT01405872) evaluated adherence associated with the intramuscular IFNβ-1a (i.m. IFN-β-1a) autoinjector pen in multiple sclerosis (MS) patients. Methods: MS patients initiating i.m. IFN-β-1a autoinjector treatment were prospectively assessed for physician-reported persistence (percentage of patients remaining on therapy) and patient-reported outcomes, including adherence (percentage of unmissed injections), compliance (percentage of patients missing no injections), tolerability (injection-site reactions [ISRs] and pain) and satisfaction. Results: The intent-to-treat population included 232 patients; of the 188 physician-reported 12-month completers, 182 patients remained on treatment (96.8% persistence). Monthly compliance rates were 87.5 - 96.2%. Mean monthly pain scores were 1.5 - 1.8 (scale: 0 = 'no pain'; 10 = 'extremely painful'). At 12 months, 73.5% of respondents reported no ISRs, 94.9% were satisfied/very satisfied with the autoinjector and 88.2% found using the device easy/very easy. Injection fear, injection anxiety and need for injection assistance by caregivers decreased from the initial visit to 12 months. No new safety signals were observed. Conclusions: The autoinjector pen is associated with high levels of persistence, compliance, adherence, and satisfaction, little-to-no pain and low need for caregiver assistance. Although these data are limited by reliance on patient questionnaires and the absence of a direct comparator group, this treatment may reduce barriers to injection therapy, while supporting long-term MS management.

Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy. The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a). In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12. At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% - 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple. The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.

The first ever symposium dedicated solely to drug delivery to the nail following topical application was held on the 2nd April 2007, in London, UK, organised by Dr Clive Roper (Charles River Laboratories, Scotland) and Dr Sudaxshina Murdan (School of Pharmacy, University of London, UK), under the auspices of Skin Forum. The 1-day meeting was attended by approximately 35 delegates from industry, academia and hospitals, and provided a much-needed forum for the presentation and discussion of research and problems in this emerging field. Topical drug delivery is especially suitable for onychomycosis (fungal infections of the nail plate and/or nail bed) and nail psoriasis, which affect 2 - 13 and 1 - 3% of the general population, respectively, and make up the bulk of nail disorders. Topical therapy would avoid the adverse events and drug interactions of systemic antifungal agents and the pain of injection when antipsoriatic agents are injected into affected nail folds. However, successful topical therapy is extremely challenging due to the very low permeability of the nail plate. Five speakers spoke about various aspects of topical drug delivery to the nail, including review of the nail plate structure, function, diseases, their existing therapies (systemic and topical), limitations and global sales. The need for effective topical drug delivery to the nail to overcome the problems associated with present treatment, and the fact that there are few topical formulations available for the treatment of nail fungal infections and psoriasis, and the even fewer effective formulations, was highlighted.

The Socrates Intensive Programme offers annual courses focusing on the specific aspects of innovative therapeutics. The 2004 meeting was coordinated by the University of Parma and covered various subjects in the field of advanced drug delivery and pharmaceutical technology, including sessions on biopharmaceutics, pharmacokinetics, polymers, oral delivery, colloidal vectors, peptide and protein delivery, vaccines, oligonucleotide delivery, gene delivery, non-conventional routes of administration, and a graduate student symposium. The meeting had a highly interactive character and provided a unique opportunity for young scientists to present and discuss their work in an international setting.

There were approximately 700 delegates who attended Respiratory Drug Delivery X (RDD-X) at the Boca Raton Resort and Club in Boca Raton, Florida, between the 24th and 27th April 2006. Participants from North America, Europe and many other parts of the world came together to hear a series of invited podium presentations covering the latest scientific developments in pulmonary and nasal drug delivery, along with regulatory and quality control issues. A total of 150 proffered posters were also presented, and a Technology Exhibition involved the products of 78 companies. The conference also provided unparalleled networking opportunities. The proceedings of RDD-X will prove to be an invaluable resource for years to come.

Introduction: In the last decade the development of orally disintegrating tablets (ODTs) and thin-film platforms has grown enormously in the field of pharmaceutical industry. A wide variety of new masking technologies combined with the aforementioned platforms have been developed in order to mask the taste of bitter active substances and achieve patient compliance. The commercial success and viability of such products requires the development of robust formulations with excellent palatability, disintegration times, physicochemical stability and pharmacokinetic profiles. Areas covered: In this review, emerging taste-masking technologies applied to solid dosage form manufacturing are summarized. The unique features and principles of taste-masking approaches used with ODT platforms are discussed, including the advantages and limitations of each technology. A brief discussion is also included on the taste masking of thin-film technologies, owing to their similar applications and requirements. Expert opinion: This review elucidates the unique features of current commercially available or highly promising ODT and thin-film technologies, along with taste-masking approaches used in the manufacturing of oral solid dosage forms. A better understanding of these drug delivery approaches will help researchers to select the appropriate platform, or to develop innovative products with improved safety, compliance and clinical value.

The use of nanoparticles as drug delivery vehicles for anticancer therapeutics has great potential to revolutionise the future of cancer therapy. As tumour architecture causes nanoparticles to preferentially accumulate at the tumour site, their use as drug delivery vectors results in the localisation of a greater amount of the drug load at the tumour site; thus improving cancer therapy and reducing the harmful nonspecific side effects of chemotherapeutics. In addition, formulation of these nanoparticles with imaging contrast agents provides a very efficient system for cancer diagnostics. Given the exhaustive possibilities available to polymeric nanoparticle chemistry, research has quickly been directed at multi-functional nanoparticles, combining tumour targeting, tumour therapy and tumour imaging in an all-in-one system, providing a useful multi-modal approach in the battle against cancer. This review will discuss the properties of nanoparticles that allow for such multiple functionality, as well as recent scientific advances in the area of multi-functional nanoparticles for cancer therapeutics.

ICS-283 was developed within Intradigm Corporation as a system that is designed for the systemic delivery of therapeutic small interfering (siRNA) to sites of pathological angiogenesis. The non-viral siRNA delivery system is based on synthetic nanoparticles, known as Targe (Intradigm Corporation), which functions as a broad-platform technology to deliver siRNA to specific target cells in diseased tissues. The system is constructed to incorporate different functionalities that address critical needs for successful nucleic acid delivery. The TargeTran synthetic vector is a self-assembling, layered nanoparticle that protects and targets siRNA to specific cell types in pathological tissues. At present, ICS-283 is the only antiangiogenic siRNA delivery system that is designed for intravenous administration to treat angiogenesis-driven diseases.

Limited accessibility of drugs to the tumor tissues, the requirement of high doses, intolerable cytotoxicity, the development of multiple drug resistance and non-specific targeting are obstacles to the clinical use of cancer drugs and cancer therapy. Drug delivery through carrier systems to cancerous tissue is no longer simply wrapping up cancer drugs in a new formulation for different routes of delivery, rather the focus is on targeted cancer therapy. This review summarizes the exploitation of drug-loaded nanocarrier conjugates with various targeting moieties for the delivery and targeting of anticancer drugs and describes the current status of and challenges in the field of nanocarrier-aided drug delivery and drug targeting. The discovery of targeting ligand to cancer cells and the development of ligand-targeted therapy will help us to improve therapeutic efficacy and reduce side effects. Unlike other forms of therapy, it will allow us to maintain quality of life for patients, while efficiently attacking the cancer tissue. It indicates that ligands have a pivotal role in cancer cell targeting.