Recent Innovations in Antibody-Mediated, Targeted Particulate Nanotechnology and Implications for Advanced Visualisation and Drug Delivery

Research into the targeting of drug substances to a specific disease site has enjoyed sustained activity for many decades. The reason for such fervent activity is the considerable clinical advantages that can be gained when the delivery system plays a pivotal role in determining where the drug is deposited. When compared to conventional formulations where no such control exists, such as parenteral and oral systems, the sophisticated targeting device can reduce side effects and limit collateral damage to surrounding normal tissue. No more so is this important than in the area of oncology when dose-limiting side effects are often encountered as an ever present difficulty. In this review, the types of colloidal carrier commonly used in targeted drug delivery are discussed, such as gold and polymeric colloids. In particular, the process of attaching targeting capabilities is considered, with reference to antibody technologies used as the targeting motifs. Nanotechnology has brought together a means to carry both a drug and targeting ligand in self-contained constructs and their applications to both clinical therapy and diagnosis are discussed.

Novel semi-interpenetrating hydrogel networks with enhanced mechanical properties and thermoresponsive engineered drug delivery, designed as bioactive endotracheal tube biomaterials

Thermoresponsive polymeric platforms are used to optimise drug delivery in pharmaceutical systems and bioactive medical devices. However, the practical application of these systems is compromised by their poor mechanical properties. This study describes the design of thermoresponsive semi-interpenetrating polymer networks (s-IPNs) based on cross-linked p(NIPAA) or p(NIPAA-co-HEMA) hydrogels containing poly(e-caprolactone) designed to address this issue. Using DSC, the lower critical solution temperature of the co-polymer and p(NIPAA) matrices were circa 34 °C and 32 °C, respectively. PCL was physically dispersed within the hydrogel matrices as confirmed using confocal scanning laser microscopy and DSC and resulted in marked changes in the mechanical properties (ultimate tensile strength, Young's modulus) without adversely compromising the elongation properties. P(NIPAA) networks containing dispersed PCL exhibited thermoresponsive swelling properties following immersion in buffer (pH 7), with the equilibrium-swelling ratio being greater at 20 °C than 37 °C and greatest for p(NIPAA)/PCL systems at 20 °C. The incorporation of PCL significantly lowered the equilibrium swelling ratio of the various networks but this was not deemed practically significant for s-IPNs based on p(NIPAA). Thermoresponsive release of metronidazole was observed from s-IPN composed of p(NIPAA)/PCL at 37 °C but not from p(NIPAA-co-HEMA)/PCL at this temperature. In all other platforms, drug release at 20 °C was significantly similar to that at 37 °C and was diffusion controlled. This study has uniquely described a strategy by which thermoresponsive drug release may be performed from polymeric platforms with highly elastic properties. It is proposed that these materials may be used clinically as bioactive endotracheal tubes, designed to offer enhanced resistance to ventilator associated pneumonia, a clinical condition associated with the use of endotracheal tubes where stimulus responsive drug release from biomaterials of significant mechanical properties would be advantageous. © 2012 Elsevier B.V. All rights reserved.

Influence of a pore-forming agent on swelling, network parameters, and permeability of poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels:Application in transdermal delivery systems

We characterized hydrogels, prepared from aqueous blends of poly(methyl vinyl ether-co-maleic acid) (PMVE/MA) and poly(ethylene glycol) (PEG 10,000 Daltons) containing a pore-forming agent (sodium bicarbonate, NaHCO ). Increase in NaHCO content increased the equilibrium water content (EWC) and average molecular weight between crosslinks (M ) of hydrogels. For example, the %EWC was 731, 860, 1109, and 7536% and the M was 8.26, 31.64, 30.04, and 3010.00 × 10 g/mol for hydrogels prepared from aqueous blends containing 0, 1, 2, and 5% w/w of NaHCO , respectively. Increase in NaHCO content also resulted in increased permeation of insulin. After 24 h, percentage permeation was 0.94, 3.68, and 25.71% across hydrogel membranes prepared from aqueous blends containing 0, 2, and 5% w/w of NaHCO , respectively. Hydrogels containing the pore-forming agent were fabricated into microneedles (MNs) for transdermal drug delivery applications by integrating the MNs with insulin-loaded patches. It was observed that the mean amount of insulin permeating across neonatal porcine skin in vitro was 20.62% and 52.48% from hydrogel MNs prepared from aqueous blends containing 0 and 5% w/w of NaHCO . We believe that these pore-forming hydrogels are likely to prove extremely useful for applications in transdermal drug delivery of biomolecules. © 2012 Wiley Periodicals, Inc.

Solvent induced phase inversion-based in situ forming controlled release drug delivery implants

In situ forming (ISF) drug delivery implants have gained tremendous levels of interest over the last few decades. This is due to their wide range of biomedical applications such as in tissue engineering, cell encapsulation, microfluidics, bioengineering and drug delivery. Drug delivery implants forming upon injection has shown a range of advantages which include localized drug delivery, easy and less invasive application, sustained drug action, ability to tailor drug delivery, reduction in side effects associated with systemic delivery and also improved patient compliance and comfort. Different factors such as temperature, pH, ions, and exchange of solvents are involved in in situ implant formation. This review especially focuses on ISF implants that are formed through solvent induced phase inversion (SPI) technique. The article critically reviews and compares a wide range of polymers, solvents, and co-solvents that have been used in SPI implant preparation for control release of a range of drug molecules. Major drawback of SPI systems has been their high burst release. In this regard, the article exhaustively discusses factors that affect the burst release and different modification strategies that has been utilised to reduce the burst effect from these implants. Performance and controversial issues associated with the use of different biocompatible solvents in SPI systems is also discussed. Biodegradation, formulation stability, methods of characterisation and sterilisation techniques of SPI systems is comprehensively reviewed. Furthermore, the review also examines current SPI-based marketed products, their therapeutic application and associated clinical data. It also exemplifies the interest of multi-billion dollar pharma companies worldwide for further developments of SPI systems to a range of therapeutic applications. The authors believe that this will be the first review article that extensively investigate and discusses studies done to date on SPI systems. In so doing, this article will undoubtedly serve as an enlightening tool for the scientists working in the concerned area.

Hydrogel-Forming Microneedles Prepared from ‘‘Super Swelling’’ Polymers Combined with Lyophilised Wafers for Transdermal Drug Delivery

We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 µg/ml achieved in this time. The plasma concentration had fallen to 71±6.7 µg/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36±17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61±4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.

The role of microneedles for drug and vaccine delivery

INTRODUCTION: Transdermal drug delivery offers a number of advantages for the patient, not only due to its non-invasive and convenient nature, but also due to factors such as avoidance of first-pass metabolism and prevention of gastrointestinal degradation. It has been demonstrated that microneedles (MNs) can increase the number of compounds amenable to transdermal delivery by penetrating the skin's protective barrier, the stratum corneum, and creating a pathway for drug permeation to the dermal tissue below.

AREAS COVERED: MNs have been extensively investigated for drug and vaccine delivery. The different types of MN arrays and their delivery capabilities are discussed in terms of drugs, including biopharmaceutics and vaccines. Patient usage and effects on the skin are also considered.

EXPERT OPINION: MN research and development is now at the stage where commercialisation is a viable possibility. There are a number of long-term safety questions relating to patient usage which will need to be addressed moving forward. Regulatory guidance is awaited to direct the scale-up of the manufacturing process alongside provision of clearer patient instruction for safe and effective use of MN devices.

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.

A dynamic mechanical method for determining the silicone elastomer solubility of drugs and pharmaceutical excipients in silicone intravaginal drug delivery rings

The silicone elastomer solubilities of a range of drugs and pharmaceutical excipients employed in the development of silicone intravaginal drug delivery rings (polyethylene glycols, norethisterone acetate, estradiol, triclosan, oleyl alcohol, oxybutynin) have been determined using dynamic mechanical analysis. The method involves measuring the concentration-dependent decrease in the storage modulus associated with the melting of the incorporated drug/excipient, and extrapolation to zero change in storage modulus. The study also demonstrates the effect of drug/excipient concentrations on the mechanical stiffness of the silicone devices at 37°C.