Ahlam Zaid Alkilani

Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5 mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33 mg (90%) of the drug initially loaded into the arrays was delivered over 24 h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263 μg ml− 1 at the 24 h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10 cm2 could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs.

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.

Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies.

Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety.

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 10⁵ cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 10⁴ microorganisms penetrated into the viable tissue and 10⁶ cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard.

Hydrogel-forming and dissolving microneedles for enhanced delivery of photosensitizers and precursors.

We present “one‐step application” dissolving and hydrogel‐forming microneedle arrays (MN) for enhanced delivery of photosensitizers/precursors. MN (280 μm) prepared from 20% w/w poly(methylvinylether/maelic acid) and cross‐linked with glycerol by esterification to form hydrogels upon skin insertion, or allowed to dissolve rapidly in skin, were combined with patches containing 19 mg cm−2 of 5‐aminolevulinic acid (ALA) or meso‐tetra (N‐methyl‐4‐pyridyl) porphine tetra tosylate (TMP) for drug delivery. Both MN types were mechanically robust, with compression forces of 20.0 N only causing height reductions of 14%. Application forces as low as 8.0 N per array allowed >95% of the MN in each array type to penetrate excised porcine skin, with the MN penetrating to approximately 220 μm. MN significantly enhanced transdermal delivery of ALA and TMP in vitro, with the hydrogel‐forming system comparable with the dissolving system for ALA delivery (approximately 3000 nmol cm−2 over 6 h), but superior for delivery of the much larger TMP molecule (approximately 14 nmol cm−2 over 24 h, compared to 0.15 nmol cm−2). As this technology clearly has potential in enhanced photodynamic therapy of neoplastic skin lesions, we are currently planning animal studies, to be followed by preliminary human evaluations. GMP manufacturing scale‐up is ongoing.

Hydrogel-forming microneedle arrays: Potential for use in minimally-invasive lithium monitoring

We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel-forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations.

Microneedle-Iontophoresis Combinations for Enhanced Transdermal Drug Delivery

It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery as well as enabling the rate of delivery to be achieved with precise electronic control. However, few reports exist on the combination of ITP with in situ drug-loaded polymeric MN delivery systems. Our in vitro permeation studies revealed that MN enhances transdermal drug delivery. The combination of dissolving MN and ITP did not further enhance the extent of delivery of the low molecular weight drug ibuprofen sodium after short application periods. However, the extent of peptide/protein delivery was significantly enhanced when ITP was used in combination with hydrogel-forming MN arrays. As such, hydrogel-forming MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach, though further technical developments will be necessary before patient benefit is realized.

Fabrication of Microneedles

Delivery of active pharmaceutical ingredients through transdermal route has been limited due to the excellent barrier properties of the stratum corneum (SC) of the skin. Only drugs with very specific physicochemical properties (molecular weight < 500 daltons, adequate lipophilicity and low melting point) can be successfully administered transdermally. Disrupting the barrier properties of the SC is one of the techniques utilised in enhancing transdermal drug delivery. With this intention, microneedle/s (MN/MNs) have been developed that can painlessly penetrate the SC and create micropores through which drug molecules can readily permeate to the dermal microcirculation for absorption. MNs consist of a plurality of micron-sized needles, generally ranging from 25 to 2000 μm in height, of a variety of different shapes and composition (e.g. silicon, metal, sugars and biodegradable polymers). Even though the concept of MNs was first conceived in 1976, it was not possible to make such micron-sized medical devices until the first exploitation of microelectromechanical systems (MEMS) for this purpose in 1998. MEMS utilise a variety of techniques and highly sophisticated tools to allow fabrication of MNs from different materials with varying designs. Now, due to the MEMS, MNs are considered as one of the few third-generation enhancement strategies that will have a significant impact on medicine. Therefore, this chapter will focus on recent progress on MN technology that includes discussion on the fabrication techniques of MNs using MEMS, the design and material consideration of MNs and the application of MNs in drug delivery and monitoring biological fluids.