Drug delivery strategies for the treatment of Helicobacter pylori infections

Helicobacter pylori is one of the most common pathogenic bacterial infections, colonising an estimated half of all humans. It is associated with the development of serious gastroduodenal disease - including peptic ulcers, gastric lymphoma and acute chronic gastritis. Current recommended regimes are not wholly effective and patient compliance, side-effects and bacterial resistance can be problematic. Drug delivery to the site of residence in the gastric mucosa may improve efficacy of the current and emerging treatments. Gastric retentive delivery systems potentially allow increased penetration of the mucus layer and therefore increased drug concentration at the site of action. Proposed gastric retentive systems for the enhancement of local drug delivery include floating systems, expandable or swellable systems and bioadhesive systems. Generally, problems with these formulations are lack of specificity, limited to mucus turnover or failure to persist in the stomach. Gastric mucoadhesive systems are hailed as a promising technology to address this issue, penetrating the mucus layer and prolonging activity at the mucus-epithelial interface. This review appraises gastroretentive delivery strategies specifically with regard to their application as a delivery system to target Helicobacter. As drug-resistant strains emerge, the development of a vaccine to eradicate and prevent reinfection is an attractive proposition. Proposed prophylactic and therapeutic vaccines have been delivered using a number of mucosal routes using viral and non-viral vectors. The delivery form, inclusion of adjuvants, and delivery regime will influence the immune response generated. © 2005 Bentham Science Publishers Ltd.

Spray-dried powders for pulmonary drug delivery

Powders for inhalation are traditionally prepared using a destructive micronization process such as jet milling to reduce the particle size of the drug to 2-5 μm. The resultant particles are typically highly cohesive and display poor aerosolization properties, necessitating the addition of a coarse carrier particle to the micronized drug to improve powder flowability. Spray-drying technology offers an alternative, constructive particle production technique to the traditional destructive approach, which may be particularly useful when processing biotechnology products that could be adversely affected by high-energy micronization processes. Advantages of spray drying include the ability to incorporate a wide range of excipients into the spray-drying feedstock, which could modify the aerosolization and stability characterizations of the resultant powders, as well as modify the drug release and absorption profiles following inhalation. This review discusses some of the reasons why pulmonary drug delivery is becoming an increasingly popular route of administration and describes the various investigations that have been undertaken in the preparation of spray-dried powders for pulmonary drug delivery. © 2007 by Begell House, Inc.

Development of a novel in vitro system for nasal drug delivery development

There is currently, no ideal system for studying nasal drug delivery in vitro. The existing techniques such as the Ussing chamber and cell culture all have major disadvantages. Most importantly, none of the existing techniques accurately represent the interior of the nasal cavity, with its airflow and humidity; neither do they allow the investigation of solid dosage forms.The work in this thesis represents the development of an in vitro model system in which the interior characteristics of the nasal cavity are closely represented, and solid or minimal volume dosage forms can be investigated. The complete nasal chamber consists of two sections: a lower tissue, viability chamber and an upper nasal chamber. The lower tissue viability chamber has been shown, using existing tissue viability monitoring techniques, to maintain the viability of a number of epithelial tissues, including porcine and rabbit nasal tissue, and rat ileal and Payers' patch tissue. The complete chamber including the upper nasal chamber has been shown to provide tissue viability for porcine and rabbit nasal tissue above that available using the existing Ussing chamber techniques. Adaptation of the complete system, and the development of the necessary experimental protocols that allow aerosol particle-sizing, together with videography, has shown that the new factors investigated, humidity and airflow, have a measurable effect on the delivered dose from a typical nasal pump. Similarly, adaptation of the chamber to fit under a confocal microscope, and the development of the necessary protocols has shown the effect of surface and size on the penetration of microparticulate materials into nasal epithelial tissues. The system developed in this thesis has been shown to be flexible, in allowing the development of the confocal and particle-sizing systems. For future nasal drug delivery studies, the ability to measure such factors as the size of the delivered system in the nasal cavity, the depth of penetration of the formulation into the tissue are essential. Additionally, to have access to other data such as that obtained from drug transport in the same system, and to have the tissue available for histological examination represents a significant advance in the usefulness of such an in vitro technique for nasal delivery.

The impact of ageing on the barriers to drug delivery

Generally, we like to see ageing as a process that is happening to people older than ourselves. However the process of ageing impacts on a wide range of functions within the human body. Whilst many of the outcomes of ageing can now be delayed or reduced, age-related changes in cellular, molecular and physiological functionality of tissues and organs can also influence how drugs enter, distribute and are eliminated from the body. Therefore, the changing profile of barriers to drug delivery should be considered if we are to develop more age-appropriate medicines. Changes in the drug dissolution and absorption in older patients may require the formulation of oral delivery systems that offer enhanced retention at absorption sites to improve drug delivery. Alternatively, liquid and fast-melt dosage systems may address the need of patients who have difficulties in swallowing medication. Ageing-induced changes in the lung can also result in slower drug absorption, which is further compounded by disease factors, common in an ageing population, that reduce lung capacity. In terms of barriers to drug delivery to the eye, the main consideration is the tear film, which like other barriers to drug delivery, changes with normal ageing and can impact on the bioavailability of drugs delivery using eye drops and suspensions. In contrast, whilst the skin as a barrier changes with age, no significant difference in absorption of drugs from transdermal drug delivery is observed in different age groups. However, due to the age-related pharmacokinetic and pharmacodynamic changes, dose adaptation should still be considered for drug delivery across the skin. Overall it is clear that the increasing age demographic of most populations, presents new (or should that be older) barriers to effective drug delivery. © 2012 Elsevier B.V. All rights reserved.

Particulate delivery systems for vaccines

This review focuses on the use of particulate delivery systems for the purposes of immunization. This includes poly(lactide-co-glycolide) (PLGA), ISCOMs, liposomes, niosomes, virosomes, chitosan, and other biodegradable polymers. These systems are evaluated in terms of their use as carriers for protein subunit and DNA vaccines. There is an extensive focus on recent literature, the understanding of biological interactions, and relation of this to our present understanding of immunological mechanisms of action. In addition, there is consideration of formulation techniques including emulsification, solvent diffusion, DNA complexation, and entrapment. The diversity of formulation strategies presented is a testament to the exponential growth and interest in the area of vaccine delivery systems. A case study for the application of particulate vaccine carriers is assessed in terms of vaccine development and recent insights into the possible design and application of vaccines against two of the most important pathogens that threaten mankind and for which there is a significant need: Mycobacterium tuberculosis and human immunodeficiency virus. This review addresses the rationale for the use of particulate delivery systems in vaccine design in the context of the diversity of carriers for DNA- and protein-based vaccines and their potential for application in terms of the critical need for effective vaccines. © 2005 by Begell House, Inc.

Amino acids as cryoprotectants for liposomal delivery systems

Liposomes provide an efficient delivery system for solubilisation and delivery of both small and macro molecules. However, they suffer from the disadvantage of instability when stored as aqueous dispersions. Cryoprotection of the liposomal systems provides an effective approach to overcome poor stability whilst maintaining formulation characteristics, although, the formulation of a freeze-dried product requires the consideration of not only the selection of an appropriate cryoprotectant, but also needs careful consideration of the processing parameters including pre-freezing conditions, primary and secondary drying protocols along with optimisation of cryoprotectant concentration. This current work investigates the application of amino acids as potential cryoprotectants for the stabilisation of liposomes, and results indicate that amino acids show biphasic nature of stabilisation with 4 mol of cryoprotectant per mole of the lipid exhibiting optimum cryoprotection. The investigations of process parameters showed that the pre-freezing temperatures below the glass transition of the amino acids followed by drying for over 6 h resulted in stable formulations. Studies investigating the efficiency of drug retention showed that the cryoprotection offered by lysine was similar to that shown by trehalose, suggesting that amino acids act as effective stabilisers. ESEM analysis was carried out to monitor morphology of the rehydrated liposomes. © 2007 Elsevier B.V. All rights reserved.

The use of sodium carboxymethylcellulose in the preparation of spray-dried proteins for pulmonary drug delivery

The use of sodium carboxymethylcellulose (NaCMC) as a spray-drying excipient in the preparation of inhalable formulations of proteins was investigated, using alkaline phosphatase as a model functional protein. Two spray-dried powders were investigated: a control powder comprising 100% (w/w) alkaline phosphatase and a test powder comprising 67% (w/w) NaCMC and 33% (w/w) alkaline phosphatase. Following physicochemical characterisation, the powders were prepared as both dry powder inhaler (DPI) and pressurised metered dose inhaler (pMDI) formulations. The aerosolisation performance of the formulations was assessed using a Multi-Stage Liquid Impinger, both immediately after preparation and over a 16-week storage period. Formulating the control powder as a DPI resulted in a poor fine particle fraction (FPF: 10%), whereas the FPF of the NaCMC-modified DPI formulation was significantly greater (47%). When the powders were formulated as pMDI systems, the control and NaCMC-modified powders demonstrated FPFs of 52% and 55%, respectively. Following storage, reduced FPF was observed for all formulations except the NaCMC-modified pMDI system; the performance of this formulation following storage was statistically equivalent to that immediately following preparation. Co-spray-drying proteins and peptides with NaCMC may therefore offer an alternative method for the preparation of stable and respirable pMDI formulations for pulmonary delivery. © 2010 Elsevier B.V.

Theranostic Fibers for Simultaneous Imaging and Drug Delivery

New methods for creating theranostic systems with simultaneous encapsulation of therapeutic, diagnostic, and targeting agents are much sought after. This work reports for the first time the use of coaxial electrospinning to prepare such systems in the form of core–shell fibers. Eudragit S100 was used to form the shell of the fibers, while the core comprised poly(ethylene oxide) loaded with the magnetic resonance contrast agent Gd(DTPA) (Gd(III) diethylenetriaminepentaacetate hydrate) and indomethacin as a model therapeutic agent. The fibers had linear cylindrical morphologies with clear core–shell structures, as demonstrated by electron microscopy. X-ray diffraction and differential scanning calorimetry proved that both indomethacin and Gd(DTPA) were present in the fibers in the amorphous physical form. This is thought to be a result of intermolecular interactions between the different components, the presence of which was suggested by infrared spectroscopy. In vitro dissolution tests indicated that the fibers could provide targeted release of the active ingredients through a combined mechanism of erosion and diffusion. The proton relaxivities for Gd(DTPA) released from the fibers into tris buffer increased (r1 = 4.79–9.75 s–1 mM–1; r2 = 7.98–14.22 s–1 mM–1) compared with fresh Gd(DTPA) (r1 = 4.13 s–1 mM–1 and r2 = 4.40 s–1 mM–1), which proved that electrospinning has not diminished the contrast properties of the complex. The new systems reported herein thus offer a new platform for delivering therapeutic and imaging agents simultaneously to the colon.

Stimuli-Responsive Microneedle Arrays For On-Demand Drug Delivery

Pulsatile, or “on-demand”, delivery systems have the capability to deliver a therapeutic molecule at the right time/site of action and in the right amount (1). Pulsatile delivery systems present multiple benefits over conventional dosage forms and provide higher patient compliance. The combination of stimuli-responsive materials with the drug delivery capabilities of hydrogel-forming MN arrays (2) opens an interesting area of research. In the present work we describe, a stimuli-responsive hydrogel-forming microneedle (MN) array that enable delivery of a clinically-relevant model drug (ibuprofen) upon application of UV radiation (Figure 1A). MN arrays were prepared using a micromolding technique using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) (Figure 1B). The arrays were loaded with up to 5% (w/w) ibuprofen included in a light-responsible conjugate (3,5-dimethoxybenzoin conjugate) (2). The presence of the conjugate inside the MN arrays was confirmed by Raman spectroscopy measurements. MN arrays were tested in vitro showing that they were able to deliver up to three doses of 50 mg of ibuprofen after application of an optical trigger (wavelength of 365 nm) over a long period of time (up to 160 hours) (Figure 1C and 1D). The work presented here is a probe of concept and a modified version of the system should be used as UV radiation is shown to be the major etiologic agent in the development of skin cancers. Consequently, for future applications of this technology an alternative design should be developed. Based on the previous research dealing with hydrogel forming MN arrays a suitable strategy will be to use hydrogel-forming MN arrays containing a backing layer made with the material described in this work as the drug reservoir (2). Finally, a porous layer of a material that blocks UV radiation should be included between the MN array and the drug reservoir. Therefore radiation can be applied to the system without reaching the skin surface. Therefore after modification, the system described here interesting properties as “on-demand” release system for prolonged periods of time. This technology has potential for use in “on-demand” delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care.

Release of copper complexes from a nanostructured sol–gel titania for cancer treatment

Copper complexes containing inorganic ligands were loaded on a functionalized titania (F-TiO2) to obtain drug delivery systems. The as-received copper complexes and those released from titania were tested as toxic agents on different cancer cell lines. The sol–gel method was used for the synthesis and surface functionalization of the titania, as well as for loading the copper complexes, all in a single step. The resultant Cu/F-TiO2 materials were characterized by several techniques. An “in vitro” releasing test was developed using an aqueous medium. Different concentrations (15.6–1000 µg mL−1) of each copper complex, those loaded on titania (Cu/F-TiO2), functionalized titania, and cis-Pt as a reference material, were incubated on RG2, C6, U373, and B16 cancer cell lines for 24 h. The morphology of functionalized titania and the different Cu/F-TiO2 materials obtained consists of aggregated nanoparticles, which generate mesopores. The amorphous phase (in dominant proportion) and the anatase phase were the structures identified through the X-ray diffraction profiles. These results agree with high-resolution transmission electron microscopy. Theoretical studies indicate that the copper compounds were released by a Fickian diffusion mechanism. It was found that independently of the copper complex and also the cell line used, low concentrations of each copper compound were sufficient to kill almost 100 % of cancer cells. When the cancer cells were treated with increasing concentrations of the Cu/F-TiO2 materials the number of survival cells decreased. Both copper complexes alone as well as those loaded on TiO2 had higher toxic effect than cis-Pt.

Mussel-inspired porous SiO2 scaffolds with improved mineralization and cytocompatibility for drug delivery and bone tissue engineering

Porous SiO2 scaffolds with mesopore structure (named as MS scaffolds) have been proposed as suitable for bone tissue engineering due to their excellent drug-delivery ability; however, the mineralization and cytocompatibility of MS scaffolds are far from optimal for bone tissue engineering, and it is also unclear how the delivery of drugs from MS scaffolds affects osteoblastic cells. The aims of the present study were to improve the mineralization and cytocompatibility of MS scaffolds by coating mussel-inspired polydopamine on the pore walls of scaffolds. The effects of polydopamine modification on MS scaffolds was investigated with respect to apatite mineralization and the attachment, proliferation and differentiation of bone marrow stromal cells (BMSCs), as was the release profile of the drug dexamethasone (DEX). Our results show that polydopamine can readily coat the pore walls of MS scaffolds and that polydopamine-modified MS scaffolds have a significantly improved apatite-mineralization ability as well as better attachment and proliferation of BMSCs in the scaffolds, compared to controls. Polydopamine modification did not alter the release profile of DEX from MS scaffolds but the sustained delivery of DEX significantly improved alkaline phosphatase (ALP) activity of BMSCs in the scaffolds. These results suggest that polydopamine modification is a viable option to enhance the bioactivity of bone tissue engineering scaffolds and, further, that DEX-loaded polydopamine MS scaffolds have potential uses as a release system to enhance the osteogenic properties of bone tissue engineering applications.