Drug Delivery Letters - Volume 6, Issue 1, 2016

Nitric oxide (NO) has a multitude of biological activities and has great potential for numerous therapeutic applications. However, its small size, short halflife and instability under physiological conditions make achieving therapeutic levels challenging. Nanoparticle carriers offer potential to overcome the various physiochemical and biological challenges for effective NO delivery. State of the art in the development and application of nanoparticle based carrier systems for the encapsulation and delivery of NO and NO-precursor molecules are critically reviewed. Specific focus is directed to the antimicrobial performance of NO delivered by polymeric, inorganic and lipid based- nanocarriers. NO-precursor molecules have been identified as effective approaches for NO delivery. Liposomes, silica particles, hydrogels and polymeric nanoparticles offer specific properties and performance to overcome the NO delivery challenges and have demonstrated enhanced therapeutic efficacy; some mechanistic insight is given. Specific antimicrobial and infected wound healing applications of NO-nanocarriers are highlighted and these show significant promise for translation to clinical application. Polymeric, inorganic and lipid based- nanocarriers are effective encapsulation and delivery systems for NO-precursors. Prospects for NO delivery in the treatment of infectious diseases and wound care management are evident.

Background: Oral drug administration is preferred by most patients; however this is a challenge for the majority of chemotherapeutic agents that are required to be given via injection, due to their unfavourable physiochemical and biopharmaceutical properties. A silica-lipid hybrid (SLH) carrier formulation has been developed to overcome the water solubility-limited oral absorption of SN-38 and to advance its clinical application as an oral dosage form. Methods: SN-38 SLH particles were engineered by freeze drying a suspension/ emulsion of SN-38, Capmul MCM, soybean lecithin and porous silica nanoparticles (Aerosil 380). SN-38 was also directly loaded in porous silica particles (silica SN-38) and used as a control formulation in in vitro (dynamic drug solubilization) and in vivo (single-dose pharmacokinetics in fasted rats at 10 mg SN-38/kg) studies. Results: The SN-38 SLH solid dosage form contains 0.5 % w/w of drug in a non-crystalline state, as confirmed by DSC and XRD analyses. The internal porous matrix structure of SN-38 SLH provided various biopharmaceutical advantages, including a two-fold improvement in drug solubilization compared to the equivalent physical mixture and superiority bioavailability compared with raw drug and silica SN-38. Conclusion: The SN-38 SLH carrier demonstrates synergistic properties of porous silica and lipid nanoparticle-based delivery systems and is a positive step in achieving safe and effective, needle-free SN-38-based chemotherapy.

Pressurised metered dose inhalers (pMDI) are still the most heavily prescribed medicines for the treatment of asthma. Various add-on devices are made available through pharmacies either on prescription, over-the-counter or off-theshelf. These include actuation aids, spacers and alternative actuators. The Sports- Haler™ is a replacement actuator for the conventional Ventolin™ actuator and offers a compact and colourful alternative to the conventional design. This article evaluates the performance of this replacement device and compares it to the standard product using Pharmacopeia methodology. In general, there were no differences in the aerosol performance and thus projected lung deposition of salbutamol sulphate. We discuss the pros and cons of such add-on devices from a pharmacy perspective and highlight potential issues that may be encountered when patients choose to modify the standard regulated pharmaceutical product. There are several considerations, which need to be reviewed when making decisions about the use of substitute and/or add-on devices.

Background: Blepharitis is considered one of the most common ocular surface conditions in optometry and ophthalmology practice. While azithromycin and dexamethasone have been used successfully to treat blepharitis, they are generally formulated as eye drops requiring frequent administration. Ocular inserts based on biodegradable polymers may overcome some of the problems associated with conventional eye drops such as the fast nasolacrimal drainage. Methods: Inserts with different β-glucan and hydroxypropyl methycellulose (HPMC) compositions were prepared using the solvent-casting method and evaluated in terms of their appearance, thickness, weight, pH, mechanical strength, bioadhesive properties and drug-polymer interactions. The ability of the ocular inserts to provide controlled release of the drugs was assessed through an in vitro release study of dexamethasone and an antibacterial assay for azithromycin. Results: All parameters were found acceptable for ocular use, with the film laminate exhibiting the highest tensile strength and mucoadhesion. Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR) revealed that the drugs were molecularly dispersed within the polymer films with no obvious interactions. Dexamethasone release was fast with 100% released within 1 hr. Azithromycin also showed a high burst release achieving the minimum inhibitory concentration after only 5 min; however, antibacterial activity was maintained for 24 hrs. Conclusion: Ocular inserts were successfully prepared and delivered both drugs over prolonged periods compared to conventional eye drops. However, additional coating may be required to further control the drug release.

In April 2014, the World Health Organization announced the beginning of a post-antibiotic era and declared antimicrobial resistance (AMR) a public health priority demanding global action. If no action is taken, by 2050 AMR will kill more people each year than cancer, with 10 million estimated annual deaths at a cost of $100 trillion to the global economy. New therapies to tackle multidrug resistant bacterial pathogens are urgently needed. Unlike traditional antibiotics, antivirulence drugs inhibit bacterial virulence instead of growth promising to offer a new class of superior therapeutics that will be ‘evolution-proof’ and ‘tailored-spectrum’. This mini-review discusses the latest emerging evidence on the promised benefits of antivirulence drugs over conventional antibiotics, also highlighting the challenges in evaluating these properties for each of the diverse virulence targets that are currently under investigation. The author argues that overcoming such challenges early in the development process constitutes an important step towards successfully progressing each of the expanding number of antivirulence strategies into next-generation therapies for common human and animal infections that are becoming increasingly refractory to all available antibiotics.

Background and Objective: Many recent studies have focused on the development of methods to overcome the barriers faced by oral drug delivery. This study describes the synthesis of three glycolipid-based drug delivery systems designed to be associated with charged drugs to improve their oral bioavailability. Methods: D-Glucose was used as a scaffold to construct charged glycolipids with anionic and/or cationic properties. Three glycolipids with positive and negative functionalities were designed, synthesized by various carbohydrate, lipid and Bocchemistry methods. The products were purified by flash column chromatography and characterized by ESI-MS and NMR. Results: The first glycolipid was synthesized by complete lipidation of D-glucose using lipoamino acids with positively charged amino groups. The negatively charged glycolipid was obtained by coupling succinate bearing a free carboxylic group to lauroylated glucose. Combining both strategies, the target compound, which can bear either positive or negative charges, was prepared through the conjugation of succinate to the carbohydrate core followed by the addition of lipoamino acids. Separation of the compounds from impurities (not fully lapidated derivatives) by flash column chromatography proved to be challenging. Conclusion: Ensuring the purity of all semi-products used in each reaction was paramount to prevent complicated purification of the final compounds. Once the three glycolipids were carefully purified, protecting groups were cleaved to give cationic and anionic properties. These glycolipids can undergo complexation with charged drugs to improve their oral bioavailability. This system has the potential to serve as a universal template for oral drug delivery.

Non-melanoma skin cancers are among the most commonly diagnosed skin cancers in the world. Ultraviolet radiation is a primary carcinogen resulting in UV induced mutations, loss of activity in tumour suppressor genes and the over expression of oncogenes in keratinocytes resulting in the development of skin malignancies. With the continued rising rate of non-melanoma skin cancer, topical therapies have become an established treatment method for effective lesion clearance. Current topical therapies include 5-fluorouracil, imiquimod, diclofenac, ingenol mebutate and photodynamic therapy. With high lesion recurrence rates still presenting as an issue following topical treatment, lack of drug selectivity for cancer cells, severe side effects from topical agent use and patient non-compliance due to prolonged treatment periods, new novel topical therapies need to be explored and developed. New therapies must target and clear both subclinical and clinically presenting skin cancers by interrupting the molecular mechanisms that induce and sustain the proliferation of neoplastic cells. Piperlongumine and EBC-46 are two naturally occurring small molecules which have demonstrated effective induction of cancer cell death. Piperlongumine, an amide isolated from the pepper, Piper longum, has demonstrated cancer cell death selectivity yet has no impact on healthy rapidly dividing primary cells. EBC-46 is a diterpene ester isolated from the seed of the fruit, Fontainea picrosperma. EBC-46 induces rapid inflammation and necrosis resulting in tumour ablation following intra-lesional injection. The development of Piperlongumine and EBC-46, as new topical agents offers a unique opportunity to further explore and exploit these selective properties for a more efficient and targeted approach to topical non -melanoma skin cancer treatment.

Background: There is significant interest in the development of oral vaccine delivery systems, with the opportunity to access the body’s immune system. Recently, the use of multi-compartmental systems to deliver vaccines has been investigated. Objective: Here, we report on the development of a lipid-based multicompartmental system for oral vaccine delivery. Specifically, the system is based on a water-in-oil-in-water (W1/O/W2) double emulsion (DE) prepared with triglyceride oil. Method: The W1/O/W2 double emulsion (DE) was prepared using a 2-stage homogenization process, with nanostructured (hydrogel or liposome) carriers loaded into the internal (W1) phase along with model antigen, ovalbumin. Physicochemical characterization of the multicompartmental system included particle size, zeta potential, confocal microscopy, along with in vitro ovalbumin release studies. In vivo studies were undertaken using 6-8 week old female OT-I and OT-II mice (C57Bl/6J). Results: The DE formulation was optimized with respect to the internal (W1) phase stability as well as demonstrating the multi-compartmental structure of the system (confocal and cryo-SEM and in vitro release studies). Finally, the delivery system performance was determined in vivo, following oral vaccination of C57Bl/6 mice with model antigen (ovalbumin) and adjuvants, with the induction of a humoral immune response observed. Conclusion: A double emulsion-based multi-compartmental subunit vaccine delivery system has been successfully prepared and characterized, and demonstrated induction of an immune response following oral delivery.