Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake.

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds. The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats. After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g - Tmax 3 days) when compared with RPV IM injection (18 ng/g - Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g - Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

The Role of 3D Printing Technology in Microengineering of Microneedles.

Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation of complex MN prototypes with high accuracy and offers customizable MN devices with a desired shape and dimension. Moreover, 3D printing shows great potential in producing advanced transdermal drug delivery systems and medical devices by integrating MNs with a variety of technologies. This review aims to demonstrate the advantages of exploiting 3D printing technology as a new tool to microengineer MNs. Various 3D printing methods are introduced, and representative MNs manufactured by such approaches are highlighted in detail. The development of advanced MN devices is also included. Finally, clinical translation and future perspectives for the development of MNs using 3D printing are discussed.

Nestorone nanosuspension-loaded dissolving microneedles array patch: A promising novel approach for "on-demand" hormonal female-controlled peritcoital contraception.

"On demand" hormonal female-controlled pericoital contraception is one strategy which could be used to minimize the impact of unintended pregnancy. Nestorone (NES) is a potent contraceptive, with relatively few side effects in comparison with other contraceptives. NES presents an attractive option for "on demand" pericoital contraceptive. Unfortunately, the drug is inactive if taken orally, but it has high progestational activity and antiovulatory potency if administered parenterally. Current drug delivery systems, such as a transdermal hydrogel are not so satisfactory. Dissolving microneedles array (DMNs) are an attractive alternative, minimally-invasive, delivery system. In this study, we report, for the first time, development of tip-loaded NES-nanosuspension (NES-NS)-loaded bilayer DMNs to deliver NES intradermally for subsequent release. NES-NS was prepared and optimised, freeze-dried and then used to fabricate DMNs using a blend of two biocompatible polymers, namely poly(vinyl alcohol) and poly(vinyl pyrrolidone). Both NES-NS and the NES-NS-loaded DMNs were fully characterised and the performance of the DMNs was evaluated in vivo using Sprague Dawley rats. Results showed that the finalised NES-NS had particle size and PDI values of 666.06 ± 1.86 nm and 0.183 ± 0.01, respectively. The NES-NS-DMNs had relatively high tips-localised drug loading (approximately 2.26 ± 1.98 mg/array) and exhibited satisfactory mechanical and insertion properties. In Sprague Dawley rats, DMNs delivered NES into the skin, with the drug then appearing in blood and rapidly reaching its maximum concentration (Cmax of 32.68 ± 14.06 ng/mL) within 1 h post-DMNs application. Plasma levels above 3.4 ng/mL were maintained for 2 days. This suggests that DMNs are a promising drug delivery system that could be used to deliver NES as an "On demand" hormonal female-controlled pericoital contraceptive.

HPLC method for levothyroxine quantification in long-acting drug delivery systems. Validation and evaluation of bovine serum albumin as levothyroxine stabilizer.

Deficiency of thyroid hormones (hypothyroidism) is treated with oral levothyroxine (LEVO). However, the effectiveness of oral administration is highly dependent on the co-administration of food and other drugs. This factor, in combination with the chronic nature of this condition, mean that there are concerns with patient compliance. Development of long acting formulations to treat hypothyroidism could potentially solve this problem. However, LEVO instability in solution could be problematic. In order to develop long acting LEVO delivery systems in vitro drug release experiments should be carried out. However, short term LEVO stability in aqueous solution will prevent this. BSA was used as a stabiliser for LEVO; extending the stability of the drug in aqueous solutions from a few hours to 2 weeks. In order to achieve this, the required concentration of the protein was 0.1% w/v. Subsequently, an HPLC method capable of separating LEVO from the protein was developed and validated following ICH guidelines. The analysis was carried out using a reverse phase HPLC method on an Agilent 1220 Infinity II LC system. The column used to achieve separation was a Zorbax Eclipse plus C18 (95 Špore size, 250 mm length x 4.6 mm internal diameter; 5 µm particle size). The mobile phase used was composed of acetonitrile and 0.1% trifluoroacetic acid at a ratio of 50:50% v/v. UV detection of LEVO sodium was carried out at 225 nm. The retention time for the drug was 6.6 minutes. The method showed a limit of detection of 0.03 µg/mL and a limit of quantification of 0.09 µg/mL. Finally, this method was used to evaluate the release from implants containing 20% w/w of LEVO. These devices were prepared using a solvent casting method with poly(caprolactone) and LEVO. These devices showed an initial burst release over the first 3 days. Subsequently, they were capable of providing a linear release rate over the following 25 days.

The role of microneedle arrays in drug delivery and patient monitoring to prevent diabetes induced fibrosis.

Diabetes affects approximately 450 million adults globally. If not effectively managed, chronic hyperglycaemia causes tissue damage that can develop into fibrosis. Fibrosis leads to end-organ complications, failure of organ systems occurs, which can ultimately cause death. One strategy to tackle end-organ complications is to maintain normoglycaemia. Conventionally, insulin is administered subcutaneously. Whilst effective, this delivery route shows several limitations, including pain. The transdermal route is a favourable alternative. Microneedle (MN) arrays are minimally invasive and painless devices that can enhance transdermal drug delivery. Convincing evidence is provided on MN-mediated insulin delivery. MN arrays can also be used as a diagnostic tool and monitor glucose levels. Furthermore, sophisticated MN array-based systems that integrate glucose monitoring and drug delivery into a single device have been designed. Therefore, MN technology has potential to revolutionise diabetes management. This review describes the current applications of MN technology for diabetes management and how these could prevent diabetes induced fibrosis.

From the laboratory to the end-user: a primary packaging study for microneedle patches containing amoxicillin sodium.

As microneedle (MN) patches progress towards commercialisation, there is a need to address issues surrounding their translation from the laboratory to the end-user. One important aspect of MN patches moving forward is appropriate primary packaging. This research focuses on MN patches containing amoxicillin (AMX) sodium for the potential treatment of neonatal sepsis in hot and humid countries. A MN patch consists of a hydrogel-forming MN array and a drug-containing reservoir. Improper primary packaging in hot and humid countries may result in degradation of active pharmaceutical ingredients, with the use of substandard medicines a major health concern. The research presented here, for the first time, seeks to investigate the integrity of MN patches in different primary packaging when stored under accelerated storage conditions, according to international guidelines. At pre-defined intervals, the performance of the MN patch was investigated. Major causes of drug instability are moisture and temperature. To avoid unnecessary degradation, suitable primary packaging was sought. After 168 days, the percentage of AMX sodium recovered from drug-containing reservoirs packaged in Protect™ 470 foil was 103.51 ± 7.03%. However, packaged in poly(ester) foil, the AMX sodium content decreased significantly (p = 0.0286), which is likely due to the degradation of AMX sodium by the imbibed moisture. Therefore, convincing evidence was provided as to the importance of investigating the stability of MN patches in primary packaging intended for MN-mediated transdermal delivery so that they are 'fit for purpose' when it reaches the end-user. Future work will include qualitative studies to assess MN patch usability.

Directly Compressed Tablets: A Novel Drug-Containing Reservoir Combined with Hydrogel-Forming Microneedle Arrays for Transdermal Drug Delivery.

Microneedle (MN) patches consist of a hydrogel-forming MN array and a drug-containing reservoir. Drug-containing reservoirs documented in the literature include polymeric films and lyophilized wafers. While effective, both reservoir formulations are aqueous based, and so degradation can occur during formulation and drying for drugs inherently unstable in aqueous media. The preparation and characterization of novel, nonaqueous-based, directly compressed tablets (DCTs) for use in combination with hydrogel-forming MN arrays are described for the first time. In this work, a range of drug molecules are investigated. Precipitation of amoxicillin (AMX) and primaquine (PQ) in conventional hydrogel-forming MN arrays leads to use of poly(vinyl alcohol)-based MN arrays. Following in vitro permeation studies, in vivo pharmacokinetic studies are conducted in rats with MN patches containing AMX, levodopa/carbidopa (LD/CD), and levofloxacin (LVX). Therapeutically relevant concentrations of AMX (≥2 µg mL-1 ), LD (≥0.5 µg mL-1 ), and LVX (≥0.2 µg mL-1 ) are successfully achieved at 1, 2, and 1 h, respectively. Thus, the use of DCTs offers promise to expand the range of drug molecules that can be delivered transdermally using MN patches.

Two-Photon Polymerisation 3D Printing of Microneedle Array Templates with Versatile Designs: Application in the Development of Polymeric Drug Delivery Systems.

PURPOSE: To apply a simple and flexible manufacturing technique, two-photon polymerisation (2PP), to the fabrication of microneedle (MN) array templates with high precision and low cost in a short time. METHODS: Seven different MN array templates were produced by 2PP 3D printing, varying needle height (900-1300 µm), shape (conical, pyramidal, cross-shaped and with pedestal), base width (300-500 µm) and interspacing (100-500 µm). Silicone MN array moulds were fabricated from these templates and used to produce dissolving and hydrogel-forming MN arrays. These polymeric MN arrays were evaluated for their insertion in skin models and their ability to deliver model drugs (cabotegravir sodium and ibuprofen sodium) to viable layers of the skin (ex vivo and in vitro) for subsequent controlled release and/or absorption. RESULTS: The various templates obtained with 2PP 3D printing allowed the reproducible fabrication of multiple MN array moulds. The polymeric MN arrays produced were efficiently inserted into two different skin models, with sharp conical and pyramidal needles showing the highest insertion depth values (64-90% of needle height). These results correlated generally with ex vivo and in vitro drug delivery results, where the same designs showed higher drug delivery rates after 24 h of application. CONCLUSION: This work highlights the benefits of using 2PP 3D printing to prototype variable MN array designs in a simple and reproducible manner, for their application in drug delivery.

Development, Evaluation, and Pharmacokinetic Assessment of Polymeric Microarray Patches for Transdermal Delivery of Vancomycin Hydrochloride.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause harmful and potentially deadly infections. Vancomycin remains the first-line antibiotic treatment for MRSA-derived infections. Nevertheless, as a peptide drug, it is poorly absorbed when administered orally because of its high molecular weight and low permeability in the gastrointestinal tract and is therefore administered intravenously for the treatment of systemic diseases. In order to circumvent some of the many drawbacks associated with intravenous injection, other routes of drug delivery should be investigated. One of the strategies which has been employed to enhance transdermal drug delivery is based on microarray patches (MAPs). This work, for the first time, describes successful transdermal delivery of vancomycin hydrochloride (VCL) using dissolving MAPs (DMAPs) and hydrogel-forming MAPs (HFMAPs). VCL was formulated into DMAPs and reservoirs [film dosage forms, lyophilized wafers, and compressed tablets (CSTs)] using excipients such as poly(vinyl pyrrolidone), poly(vinyl alcohol), sodium hyaluronate, d-sorbitol, and glycerol. In this study, HFMAPs were manufactured using aqueous blends containing poly(methylvinyl ether-co-maleic acid) cross-linked by esterification with poly(ethylene glycol). The VCL-loaded CSTs (60% w/w VCL) were the most promising reservoirs to be integrated with HFMAPs based on the physicochemical evaluations performed. Both HFMAPs and DMAPs successfully delivered VCL in ex vivo studies with the percentage of drug that permeated across the neonatal porcine skin recorded at 46.39 ± 8.04 and 7.99 ± 0.98%, respectively. In in vivo studies, the area under the plasma concentration time curve from time zero to infinity (AUC0-∞) values of 162.04 ± 61.84 and 61.01 ± 28.50 µg h/mL were achieved following the application of HFMAPs and DMAPs, respectively. In comparison, the AUC0-∞ of HFMAPs was significantly greater than that of the oral administration control group, which showed an AUC0-∞ of 30.50 ± 9.18 µg h/mL (p < 0.05). This work demonstrates that transdermal delivery of VCL is feasible using DMAPs and HFMAPs and could prove effective in the treatment of infectious diseases caused by MRSA, such as skin and soft tissue infections, lymphatic-related infections, and neonatal sepsis.

Novel Design Approaches in the Fabrication of Polymeric Microarray Patches via Micromoulding.

The focus on novel systems for transdermal delivery of therapeutic agents has increased considerably over recent years, as this administration route comes with many advantages. Polymeric microarray patches (MAPs) are minimally invasive devices that enable systemic delivery of a wide range of drugs by overcoming the outer skin barrier. Conventionally, MAPs fabricated by micromoulding have a low needle density. In this study, the performance of hydrogel-forming MAPs cast using novel industrially manufactured micromoulds with a high needle density (600 needles/0.75 cm2) was compared to that of MAPs obtained using conventional moulds with a lower density (196 needles/0.89 cm2). Surrounding holders for micromoulds were designed for time-efficient fabrication of MAPs. The influence of needle densities on mechanical strength, insertion efficiency and in vitro permeation of ibuprofen sodium (IBU) was analysed. Insertion of both MAPs into an artificial skin model and neonatal porcine skin was comparable. No significant difference was observed in permeation studies of IBU (p > 0.05), with a delivery of 8.7 ± 1.7 mg for low-density and 9.5 ± 0.1 mg for high-density MAPs within 24 h. This highlights the potential of these novel micromoulds for manufacturing polymeric MAPs with a higher needle density for future applications.

A sensitive HPLC-UV method for quantifying vancomycin in biological matrices: Application to pharmacokinetic and biodistribution studies in rat plasma, skin and lymph nodes.

Vancomycin (VCN) is an antibiotic used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA)-derived infections. As it has a relatively narrow therapeutic window, it is imperative to develop a sensitive and reliable analytical method for drug monitoring and pharmacokinetic purposes. In the present study, quick sample preparations and a sensitive high-performance liquid chromatography method using UV detection (HPLC-UV) have been developed and validated. The analytical method for detection and quantification of VCN in rat plasma, skin and lymph node samples was validated based on the Food and Drug Administration (FDA) and European Medicine Agency (EMEA) bioanalytical method validation guidelines. The optimised plasma sample preparation involved a simple protein precipitation step, with extraction recovery of 100.3 ±â€¯0.92 %. VCN in all biological matrices was analysed in a HPLC-UV system (215 nm) using a Cortecs® C18 column (4.6 × 150 mm, 2.7 µm particle size) fitted with a guard cartridge set at 20 °C. Reverse phase HPLC under gradient conditions, with mobile phase consisting of 20 mM phosphate buffer containing 0.5 % v/v of triethylamine and a mixture of methanol - acetonitrile (70:30, v/v), and runtime of 12 min/sample was employed. The calibration standards used for plasma ranged between 0.1-50 µg/ml, while in the skin and lymph node matrices, standards ranged between 0.05-50 µg/ml with correlation coefficients (R2) of ≥ 0.9995 for all matrices. The method was selective, sensitive, accurate and precise for detecting and quantifying VCN in the biological matrices used. The validated method was successfully utilised in the detection of VCN in a pharmacokinetic and organ biodistribution study carried out in rats following oral and IV bolus administration of the drug. This validated bioanalytical method offers a wide range of potential applications in clinical therapeutic drug monitoring, pharmacokinetics and toxicology.

Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery.

Treatment resistant depression is, by definition, difficult to treat using standard therapeutic interventions. Recently, esketamine has been shown as a viable rescue treatment option in patients in depressive crisis states. However, IV administration is associated with a number of drawbacks and advanced delivery platforms could provide an alternative parenteral route of esketamine dosing in patients. Hydrogel-forming microneedle arrays facilitate transdermal delivery of drugs by penetrating the outer layer of the skins surface, absorbing interstitial skin fluid and swelling. This subsequently facilitates permeation of medicines into the dermal microcirculation. This paper outlines the in vitro formulation development for hydrogel-forming microneedle arrays containing esketamine. Analytical methods for the detection and quantitation of esketamine were developed and validated according to International Conference on Harmonisation standards. Hydrogel-forming microneedle arrays were fully characterised for their mechanical strength and skin insertion properties. Furthermore, a series of esketamine containing polymeric films and lyophilised reservoirs were assessed as drug reservoir candidates. Dissolution testing and content drug recovery was carried out, followed by permeation studies using 350 µm thick neonatal porcine skin in modified Franz cell apparatus. Lead reservoir candidates were selected based on measured physicochemical properties and brought forward for testing in female Sprague-Dawley rats. Plasma samples were analysed using reverse phase high performance liquid chromatography for esketamine. Both polymeric film and lyophilised reservoirs candidate patches achieved esketamine plasma concentrations higher than the target concentration of 0.15-0.3 µg/ml over 24 h. Mean plasma concentrations in rats, 24 h post-application of microneedle patches with drug reservoir F3 and LW3, were 0.260 µg/ml and 0.498 µg/ml, respectively. This developmental study highlights the potential success of hydrogel-forming microneedle arrays as a transdermal drug delivery platform for ESK and supports moving to in vivo tests in a larger animal model.

Semisynthetic Derivative of Artemisia annua-Loaded Transdermal Bioadhesive for the Treatment of Uncomplicated Malaria Caused by Plasmodium falciparum in Children.

According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 µm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 µg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation.

Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride.

We investigated, for the first time, the potential for a hydrogel-forming microneedle (MN) patch to deliver the high-dose drug metformin HCl transdermally in a sustained manner. This may minimize some gastrointestinal side effects and small intestine absorption variations associated with oral delivery. Patches (two layers) were assembled from a lyophilised drug reservoir layer, with the MN layer made from aqueous blend of 20% w/w poly (methylvinylether-co-maleic acid) crosslinked by esterification with 7.5% w/w poly (ethylene glycol) 10,000 Da. >90% of metformin was recovered from homogeneous drug reservoirs. Drug reservoir dissolution time in PBS (pH 7.4) was <10 min. MN penetrated a validated skin model Parafilm® M consistently. Permeation of metformin HCl across dermatomed neonatal porcine skin in vitro was enhanced by using MN. The combined MN and metformin HCl reservoir patch (containing 75 mg or 50 mg metformin HCl, respectively) delivered 9.71 ±â€¯2.22 mg and 10.04 ±â€¯1.92 mg at 6 h, respectively, and 28.15 ±â€¯2.37 mg and 23.25 ±â€¯3.58 mg at 24 h, respectively.In comparison, 0.34 ±â€¯0.39 mg and 0.85 ±â€¯0.68 mg was delivered at 6 h, respectively, and 0.39 ±â€¯0.39 mg and 1.01 ±â€¯0.84 mg was delivered at 24 h, respectively, from a control set-up employing only the drug reservoirs. In vivo, metformin HCl was detected in rat plasma at 1 h post MN application at a concentration of 0.62 ±â€¯0.51 µg/mL, increasing to 3.76 ±â€¯2.58 µg/ml at 3 h. A maximal concentration of 3.77 ±â€¯2.09 µg/ml was achieved at 24 h. Css was 3.2 µg/mL. Metformin transdermal bioavailability using MNs was estimated as 30%.Hydrogel-forming MN are a promising technology that has demonstrated successful transdermal delivery of metformin HCl. Potential clearly exists for administration of other high-dose drugs using this system.

The Use of a Pressure-Indicating Sensor Film to Provide Feedback upon Hydrogel-Forming Microneedle Array Self-Application In Vivo.

PURPOSE: To evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo. METHODS: Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film. RESULTS: Microneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 µm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion. CONCLUSIONS: For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use.

Microneedle applications in improving skin appearance.

Microneedles (MNs) are micron-sized, minimally invasive devices that breach the outermost layer of the skin, the stratum corneum (SC), creating transient, aqueous pores in the skin and facilitating the transport of therapeutic molecules into the epidermis. Following many years of extensive research in the area of MN-mediated trans- and intra-dermal drug delivery, MNs are now being exploited in the cosmeceutical industry as a means of disrupting skin cell architecture, inducing elastin and collagen expression and deposition. They are also being used as vehicles to deliver cosmeceutic molecules across the skin, in addition to their use in combinatorial treatments with topical agents or light sources. This review explores the chronology of microneedling methodologies, which has led to the emergence of MN devices, now extensively used in cosmeceutical applications. Recent developments in therapeutic molecule and peptide delivery to the skin via MN platforms are addressed and some commercially available MN devices are described. Important safety and regulatory considerations relating to MN usage are addressed, as are studies relating to public perception of MN, as these will undoubtedly influence the acceptance of MN products as they progress towards commercialisation.

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.

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 1.5mg 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 33mg (90%) of the drug initially loaded into the arrays was delivered over 24h. 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 (263µgml(-1) at the 24h 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 10cm(2) 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.

Microneedles for intradermal and transdermal drug delivery.

The formidable barrier properties of the uppermost layer of the skin, the stratum corneum, impose significant limitations for successful systemic delivery of broad range of therapeutic molecules particularly macromolecules and genetic material. Microneedle (MN) has been proposed as a strategy to breach the stratum corneum barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves use of micron sized needles fabricated of different materials and geometries to create transient aqueous conduits across the skin. MN, alone or with other enhancing strategies, has been demonstrated to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo experiments. This suggested the promising use of MN technology for various possible clinical applications such as insulin delivery, transcutaneous immunisations and cutaneous gene delivery. MN has been proved as minimally invasive and painless in human subjects. This review article focuses on recent and future developments for MN technology including the latest type of MN design, challenges and strategies in MNs development as well as potential safety aspects based on comprehensive literature review pertaining to MN studies to date.