Stuart A. Jones

Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects

The protective function of human skin imposes physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have adequate lipophilicity and also a molecular weight <500 Da. These requirements have limited the number of commercially available products based on transdermal or dermal delivery. Various strategies have emerged over recent years to optimize delivery and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This article provides a detailed review of the next generation of active delivery technologies.

Hyaluronic acid : a unique topical vehicle for the localized delivery of drugs to the skin

Hyaluronic acid (HA) is a naturally occurring polyanionic, polysaccharide that consists of N‐acetyl‐d‐glucosamine and β‐glucoronic acid. It is present in the intercellular matrix of most vertebrate connective tissues especially skin where it has a protective, structure stabilizing and shock‐absorbing role. The unique viscoelastic nature of HA along with its biocompatibility and non‐immunogenicity has led to its use in a number of clinical applications, which include: the supplementation of joint fluid in arthritis; as a surgical aid in eye surgery; and to facilitate the healing and regeneration of surgical wounds. More recently, HA has been investigated as a drug delivery agent for various routes of administration, including ophthalmic, nasal, pulmonary, parenteral and topical. In fact, regulatory approval in the USA, Canada and Europe was granted recently for 3% diclofenac in 2.5% HA gel, Solaraze®, for the topical treatment of actinic keratoses, which is the third most common skin complaint in the USA. The gel is well tolerated, safe and efficacious and provides an attractive, cost‐effective alternative to cryoablation, curettage or dermabrasion, or treatment with 5‐fluorouracil. The purpose of this review is to describe briefly the physical, chemical and biological properties of HA together with some details of its medical and pharmaceutical uses with emphasis on this more recent topical application.

Hyaluronan: Pharmaceutical Characterization and Drug Delivery

Hyaluronic acid (HA), is a polyanionic polysaccharide that consists of N-acetyl-D-glucosamine and β-glucoronic acid. It is most frequently referred to as hyaluronan because it exists in vivo as a polyanion and not in the protonated acid form. HA is distributed widely in vertebrates and presents as a component of the cell coat of many strains of bacteria. Initially the main functions of HA were believed to be mechanical as it has a protective, structure stabilizing and shock-absorbing role in the body. However, more recently the role of HA in the mediation of physiological functions via interaction with binding proteins and cell surface receptors including morphogenesis, regeneration, wound healing, and tumor invasion, as well as in the dynamic regulation of such interactions on cell signaling and behavior has been documented. The unique viscoelastic nature of hyaluronan along with its biocompatibility and nonimmunogenicity has led to its use in a number of cosmetic, medical, and pharmaceutical applications. More recently, HA has been investigated as a drug delivery agent for ophthalmic, nasal, pulmonary, parenteral, and dermal routes. The purpose of our review is to describe the physical, chemical, and biological properties of native HA together with how it can be produced and assayed along with a detailed analysis of its medical and pharmaceutical applications.

Systemic inflammation and decline in lung function in a general population: a prospective study

Background: An increase in levels of C-reactive protein (CRP), a marker of systemic inflammation, is associated with reduced forced expiratory volume in 1 s (FEV1), supporting the hypothesis that the pathophysiology of chronic obstructive pulmonary disease has a systemic inflammatory component. However, few large studies have assessed the relationship between systemic inflammation as measured by CRP and decline in lung function prospectively in a randomly selected population. Methods: In 1991, data were collected on FEV1 and forced vital capacity (FVC) and a blood sample was taken from 2442 randomly selected adults in a community-based cohort. In 2000 these measures were repeated in 1301 individuals. The level of serum CRP was analysed in these samples from 1991 and 2000. Results: In cross-sectional analyses of data from 1991 and 2000, serum CRP levels were inversely related to FEV1 and FVC. After adjustment for smoking and other confounders, the difference in FEV1 was reduced by −9 ml (95% CI –13 to –5) and –7 ml (95% CI –13 to –2) for each mg/l increment in serum CRP in 1991 and 2000, respectively. There was no significant association between baseline serum CRP levels and decline in FEV1 and FVC over 9 years. Conclusions: Although serum CRP levels are inversely associated with lung function in cross-sectional studies, there was no effect of a marker of systemic inflammation on decline in lung function over 9 years.

Nail Swelling as a Pre-formulation Screen for the Selection and Optimisation of Ungual Penetration Enhancers

IntroductionTargeting drug treatment to fungal infections that reside within or below the nail plate is problematic due to the highly restrictive barrier of the human nail. To optimise topical formulations for ungual drug delivery, inclusion of an effective penetration enhancer (PE) is imperative. At present, in vitro nail permeation studies can take weeks or months in order to obtain any meaningful data because the lack of a simple in vitro model to identify and develop nail PEs makes the selection and optimisation of novel PEs an empirical and inefficient process. The aim of this study was to compare three methods for pre-formulation screening of putative ungual PEs and then to select the most suitable technique for screening candidates that may enhance the permeation of therapeutic agents through the human nail.MethodsThree screening techniques were evaluated; nail swelling (weight increase of human nail clippings), horse hoof swelling (weight increase of horse hoof clippings) and nail penetration of a radiolabelled permeability probe. Four test PEs were evaluated using each screening method and nail swelling was identified as a simple, rapid, economic, relevant and reliable technique. This screen was then used to evaluate 20 potential PEs. Thioglycolic acid (TA), hydrogen peroxide (H2O2) and urea H2O2 produced the greatest nail weight increases; 71.0 ± 4.6%, 69.2 ± 6.6%, and 69.0 ± 9.9 respectively. To confirm the relationship between human nail swelling and altered ungual barrier function, a permeation study was performed in human nails using caffeine as a model penetrant.Results and DiscussionHuman nails pre-treated with TA in vitro had a 3.8-fold increase in caffeine flux compared to the control (TA-free solution). This study illustrated the potential to use human nail clipping swelling as a surrogate marker of PE activity for topical ungual drug delivery.

Quantitative assessment of nanoparticle surface hydrophobicity and its influence on pulmonary biocompatibility.

To date, the role of nanoparticle surface hydrophobicity has not been investigated quantitatively in relation to pulmonary biocompatibility. A panel of nanoparticles spanning three different biomaterial types, pegylated lipid nanocapsules, polyvinyl acetate (PVAc) and polystyrene nanoparticles, were characterized for size, surface charge, and stability in biofluids. Surface hydrophobicity of five nanoparticles (50-150nm) was quantified using hydrophobic interaction chromatography (HIC) and classified using a purpose-developed hydrophobicity scale: the HIC index, range from 0.00 (hydrophilic) to 1.00 (hydrophobic). This enabled the relationship between the nanomaterial HIC index value and acute lung inflammation after pulmonary administration to mice to be investigated. The nanomaterials with low HIC index values (between 0.50 and 0.64) elicited little or no inflammation at low (22cm(2)) or high (220cm(2)) nanoparticle surface area doses per animal, whereas equivalent surface area doses of the two nanoparticles with high HIC index values (0.88-0.96) induced neutrophil infiltration, elevation of pro-inflammatory cytokines and adverse histopathology findings. In summary, a HIC index is reported that provides a versatile, discriminatory, and widely available measure of nanoparticle surface hydrophobicity. The avoidance of high (HIC index>~0.8) surface hydrophobicity appears to be important for the design of safe nanomedicines for inhalation therapy.

Pharmaceutical foams: are they the answer to the dilemma of topical nanoparticles?

UNLABELLED Nanoparticulate systems have the potential to improve topical drug delivery because of their capacity to enhance drug loading and dissolution, protect chemically unstable therapeutic agents, and improve product aesthetics. However, the commercial use of nanoparticles in topical products is limited because the evidence that they penetrate intact skin is contradictory, and their ability to release active agents in traditional semisolid vehicles is poor. One way to overcome this problem is to formulate nanoparticles in a dynamic delivery system--that is, one that induces a change upon dose actuation so as to promote drug release. Pressurized pharmaceutical foams are one type of dynamic system that can drive a change of state and excipient concentration after dose actuation. This review summarizes the current status of topical products containing nanoparticles, discusses the recent scientific advances in foam production, and investigates the prospect of incorporating nanoparticles into dynamic topical foams. Recent literature suggests that dynamic foams have the potential to break down the nanoparticles loaded within them, improve drug release from nanoparticles, and enhance topical efficacy. Although the published data to support the use of dynamic systems are limited, it is clear that they provide a promising solution to enhance drug release from nanoparticles, and future research work should aim to investigate these systems in more detail. FROM THE CLINICAL EDITOR The use of nanoparticulate systems in topical products is limited as skin penetration and release of active agents remains controversial. Pressurized pharmaceutical foams represent a dynamic system characterized by a change of state and excipient concentration after dose actuation. The review summarizes the current status of topical nanoparticles utilizing this delivery system.

Dynamic foams in topical drug delivery

Objectives Pharmaceutical foams are not new inventions and their application in topical therapy can be traced back three decades. However, foam formulations have been gaining in popularity with over 100 patents published globally in the last 10 years alone. The aim of this paper is to review the current status and explore the future potential of dynamic foam vehicles in the field of topical drug delivery.

Effect of a novel penetration enhancer on the ungual permeation of two antifungal agents.

Objectives The aim of this study was to demonstrate the effect of a novel permeation enhancer system using two existing marketed nail lacquers and the delivery of terbinafine through human nail samples in vitro.

A dynamic topical hydrofluoroalkane foam to induce nanoparticle modification and drug release in situ

Topical nanoparticles are usually applied using semi-solid formulations, but the delivery process is often inefficient due to the poor drug release from the particles. The aim of this study was to investigate the capability of a dynamic foam to break open nanoparticles upon application to the skin and enhance drug delivery efficiency. Vitamin E acetate (VEAc) was selected as a model drug and loaded into lipid nanoparticles (50-60 nm) prepared by phase inversion. The highest drug loading was 18.9+/-1.2 mg/ml and the corresponding encapsulation efficiency was 81.5+/-4.1%. Dynamic foams were generated by emulsifying VEAc-loaded nanoparticle suspensions with hydrofluoroalkane using pluronic L62D. An in vitro permeation study demonstrated that VEAc did not release from the nanoparticles when administered as an aqueous suspension, but attained a flux of 18.0+/-2.1 (microg cm(-2) h(-1)) when applied using the foam. Drug release from the foam was shown to be a consequence of nanoparticle modification after dose administration and this led to the foam delivering 0.7+/-0.3% VEAc into the stratum corneum (SC) when applied to human skin.