Design and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod

Clinical use of the imidazoquinoline immunomodulator imiquimod for the topical treatment of dysplastic and neoplastic lesions has increased markedly in recent years. However, despite guidance from the manufacturer of the proprietary imiquimod cream, there seems to be little consensus between clinicians as to the topically applied dose. Given that patients often apply the cream themselves at home, further dosing variability is expected and, consequently, accurate comparison of the results of different published studies is dif?cult. This paper describes, for the ?rst time, the formulation and physicochemical characterisation of a bioadhesive patch for dose-controlled topical delivery of imiquimod as well as a new HPLC method for sensitive ?uorescence determination of imiquimod released from such systems. Patches containing imiquimod loadings of 4.75, 9.50 and 12.50 mg cm-2 all released signi?cantly more drug across a model membrane than the proprietary cream over a period of 6 h. Inclusion of imiquimod in patches did not adversely affect their physicochemical properties. Of major importance, patches contained de?ned drug loadings per unit area; therefore, their use could reduce inter-clinician variability. This would make critical comparison of clinical studies and determination of an appropriate imiquimod dose for successful treatment much simpler. Since bioadhesive formulations are capable of adhering to body tissues in moist environments, the use of a bioadhesive patch system may allow extension of the clinical uses of imiquimod to the treatment of neoplastic conditions of the oral cavity and cervix, as well as the vulva. © 2005 Elsevier B.V. All rights reserved.

Neighboring Group-Controlled Hydrolysis: Towards “Designer” Drug Release Biomaterials

To give the first demonstration of neighboring group-controlled drug delivery rates, a series of novel, polymerizable ester drug conjugates was synthesized and fully characterized. The monomers are suitable for copolymerization in biomaterials where control of drug release rate is critical to prophylaxis or obviation of infection. The incorporation of neighboring group moieties differing in nucleophilicity, geometry, and steric bulk in the conjugates allowed the rate of ester hydrolysis, and hence drug liberation, to be rationally and widely controlled. Solutions (2.5 x 10-5 mol dm-3) of ester conjugates of nalidixic acid incorporating pyridyl, amino, and phenyl neighboring groups hydrolyzed according to first-order kinetics, with rate constants between 3.00 ( 0.12 10-5 s -1 (fastest) and 4.50 ( 0.31 10- 6 s-1 (slowest). The hydrolysis was characterized using UV-visible spectroscopy. When copolymerized with poly(methyl methacrylate), free drug was shown to elute from the resulting materials, with the rate of release being controlled by the nature of the conjugate, as in solution. The controlled molecular architecture demonstrated by this system offers an attractive class of drug conjugate for the delivery of drugs from polymeric biomaterials such as bone cements in terms of both sustained, prolonged drug release and minimization of mechanical compromise as a result of release. We consider these results to be the rationale for the development of 'designer' drug release biomaterials, where the rate of required release can be controlled by predetermined molecular architecture.

Photosensitiser delivery for photodynamic therapy. Part 1: Topical carrier platforms

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitising drug and visible light causes destruction of selected cells. Due to the lack of true selectivity of preformed photosensitisers for neoplastic tissue and their high molecular weights, PDT of superficial skin lesions has traditionally been mediated by topical application of the porphyrin precursor 5-aminolevulinic acid (ALA). Objective: This article aims to review the traditional formulation-based approaches taken to topical delivery of ALA and discusses the more innovative strategies investigated for enhancement of PDT mediated by topical application of ALA and preformed photosensitisers. Methods: All of the available published print and online literature in this area was reviewed. As drug delivery of agents used in PDT is still something of an emerging field, it was not necessary to go beyond literature from the last 30 years. Results/conclusion: PDT of neoplastic skin lesions is currently based almost exclusively on topical application of simple semisolid dosage forms containing ALA or its methyl ester. Until expiry of patents on the current market-leading products, there is unlikely to be a great incentive to engage in design and evaluation of innovative formulations for topical PDT, especially those containing the more difficult-to-deliver preformed photosensitisers.

Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platforms

Background: The treatment of solid tumours and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitiser (PS) to destroy target cells through a combination of visible light irradiation and molecular oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramolecular delivery platforms can improve PDT selectivity by exploiting cellular and physiological specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumour neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. in addition, polymeric prodrug delivery platforms triggered by the acidic nature of the tumour environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.

Microporation Techniques for Enhanced Delivery of Therapeutic Agents

Perhaps the greatest barrier to development of the field of transmembrane drug delivery is that only a limited number of drugs are amenable to administration by this route. The highly lipophilic nature and barrier function of the uppermost layer of the skin, the stratum corneum, for example, restricts the permeation of hydrophilic, high molecular weight and charged compounds into the systemic circulation. Other membranes in the human body can also present significant barriers to drug permeation. In order to successfully deliver hydrophilic drugs, and macromolecular agents of interest, including peptides, DNA and small interfering RNA, many research groups and pharmaceutical companies Worldwide are focusing on the use of microporation methods and devices. Whilst there are a variety of microporation techniques, including the use of laser, thermal ablation, electroporation, radiofrequency, ultrasound, high pressure jets, and microneedle technology, they share the common goal of enhancing the permeability of a biological membrane through the creation of transient aqueous transport pathways of micron dimensions across that membrane. Once created, these micropores are orders of magnitude larger than molecular dimensions and, therefore, should readily permit the transport of hydrophilic macromolecules. Additionally, microporation devices also enable minimally-invasive sampling and monitoring of biological fluids. This review deals with the innovations relating to microporation-based methods and devices for drug delivery and minimally invasive monitoring, as disclosed in recent patent literature. © 2010 Bentham Science Publishers Ltd.

Delivery of Methylene Blue and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate from cross-linked poly(vinyl alcohol) hydrogels: A potential means of photodynamic therapy of infected wounds

Poly(vinyl alcohol)-borate complexes were evaluated as a potentially novel drug delivery platform suitable for in vivo use in photodynamic antimicrobial chemotherapy (PACT) of wound infections. An optimised formulation (8.0%w/w PVA, 2.0% w/w borax) was loaded with 1.0 mg ml(-1) of the photosensitisers Methylene Blue (MB) and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP). Both drugs were released to yield receiver compartment concentrations (>5.0 mu g ml(-1)) found to be phototoxic to both planktonic and bicifilm-grown methicillin-resistant Staphylococcus aureus (MRSA), a common cause of wound infections in hospitals. Newborn calf serum, used to simulate the conditions prevalent in an exuding wound, did not adversely affect the properties of the hydrogels and had no significant effect on the rate of TMP-mediated photodynamic kill of MRSA, despite appreciably reducing the fluence rate of incident light. However, MB-mediated photodynamic kill of MRSA was significantly reduced in the presence of calf serum and when the clinical isolate was grown in a biofilm. Results support the contention that delivery of MB or TMP using gel-type vehicles as part of PACT could make a contribution to the photodynamic eradication of MRSA from infected wounds. (C) 2009 Elsevier B.V. All rights reserved.

Modulation of gel formation and drug-release characteristics of lidocaine-loaded poly(vinyl alcohol)-tetraborate hydrogel systems using scavenger polyol sugars

Polyol sugars, displaying a plurality Of hydroxyl groups, were shown to modulate tetra hydroxyborate (borate) cross-linking in lidocaine hydrochloride containing poly(vinyl alcohol) scini-solid hydrogels. Without polyol, demixing of borate cross-linked PVA hydrogels into two distinct phases was noticeable upon lidocaine hydrochloride addition, preventing further use as a topical System. D-Mannitol incorporation was found to be particularly suitable in cicumventing network constriction induced by ionic and pH effects upon adding the hydrochloride salt of lidocaine. A test formulation (4% w/v lidocaine HCl, 2% W/V D-mannitol, 10% w/v PVA and 2.5%, w/v THB) was shown to constitute an effective delivery system, which was characterised by an initial burst release and a drug release mechanism dependent on temperature, changing from a diffusion-controlled system to one with the properties of a reservoir system. The novel flow properties and innocuous adhesion of PVA-tetrahydroxyborate hydrogels Support their application for drug delivery to exposed epithelial surfaces, Such as lacerated wounds. Furthermore, addition of a polyol, such as mannitol, allows incorporation of soluble salt forms of active therapeutic agents by modulation of cross-linking density. (C) 2008 Elsevier B.V. All rights reserved.

Physicochemical characterisation and drug release properties of celecoxib hot melt extruded glass solutions

Formulation of Celecoxib into solid dosage forms is difficult due to the physical properties of the drug powder. However for the first time, this paper reports on the drug delivery characteristics glass solutions of celecoxib and polyvinylpyrrolidone prepared by hot melt extrusion, together with use of supercritical carbon dioxide to achieve a porous structure, in order to achieve a stable and enhanced drug release.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Development of liposome-based freeze-dried rods for vaginal vaccine delivery against HIV-1

The present investigation deals with development and characteriza- tion of the liposomes-based freeze-dried rods for the vaginal delivery of gp140 antigen in mice. Positively charged, negatively charged and neutral liposomes were prepared and characterized for various parameters e.g. morphology, size, polydispersity index, zeta potential and antigen encapsulation efficiency. To further improve the efficacy of vaccine delivery, antigen encapsulated liposomes were formulated as polymer gel-based freeze-dried rods, which were then characterized for moisture content. The redispersibility of the liposomes-based freeze- dried rods was determined in simulated vaginal fluid and liposome gel was investigated for mucoadhesion. The developed liposome-based freeze-dried rods systems could offer potential as stable and practical dosage form for the mucosal immunization against HIV-1 infection.

Microneedle-mediated vaccine delivery:harnessing cutaneous immunobiology to improve efficacy

INTRODUCTION: Breaching the skin's stratum corneum barrier raises the possibility of the administration of vaccines, gene vectors, antibodies and even nanoparticles, all of which have at least their initial effect on populations of skin cells. AREAS COVERED: Intradermal vaccine delivery holds enormous potential for improved therapeutic outcomes for patients, particularly those in the developing world. Various vaccine-delivery strategies have been employed, which are discussed in this review. The importance of cutaneous immunobiology on the effect produced by microneedle-mediated intradermal vaccination is also discussed. EXPERT OPINION: Microneedle-mediated vaccines hold enormous potential for patient benefit. However, in order for microneedle vaccine strategies to fulfill their potential, the proportion of an immune response that is due to the local action of delivered vaccines on skin antigen-presenting cells, and what is due to a systemic effect from vaccines reaching the systemic circulation, must be determined. Moreover, industry will need to invest significantly in new equipment and instrumentation in order to mass-produce microneedle vaccines consistently. Finally, microneedles will need to demonstrate consistent dose delivery across patient groups and match this to reliable immune responses before they will replace tried-and-tested needle-and-syringe-based approaches.

Influence of skin model on in vitro performance of drug-loaded soluble microneedle arrays

A plethora of studies have described the in vitro assessment of dissolving microneedle (MN) arrays for enhanced transdermal drug delivery, utilising a wide variety of model membranes as a representation of the skin barrier. However, to date, no discussion has taken place with regard to the choice of model skin membrane and the impact this may have on the evaluation of MN performance. In this study, we have, for the first time, critically assessed the most common types of in vitro skin permeation models - a synthetic hydrophobic membrane (Silescol(®) of 75 µm) and neonatal porcine skin of definable thickness (300-350 µm and 700-750 µm) - for evaluating the performance of drug loaded dissolving poly (methyl vinyl ether co maleic acid) (PMVE/MA) MN arrays. It was found that the choice of in vitro skin model had a significant effect on the permeation of a wide range of small hydrophilic molecules released from dissolving MNs. For example, when Silescol(®) was used as the model membrane, the cumulative percentage permeation of methylene blue 24h after the application of dissolvable MNs was found to be only approximately 3.7% of the total methylene blue loaded into the MN device. In comparison, when dermatomed and full thickness neonatal porcine skin were used as a skin model, approximately 67.4% and 47.5% of methylene blue loaded into the MN device was delivered across the skin 24h after the application of MN arrays, respectively. The application of methylene blue loaded MN arrays in a rat model in vivo revealed that the extent of MN-mediated percutaneous delivery achieved was most similar to that predicted from the in vitro investigations employing dermatomed neonatal porcine skin (300-350 µm) as the model skin membrane. On the basis of these results, a wider discussion within the MN community will be necessary to standardise the experimental protocols used for the evaluation and comparison of MN devices.