Microneedle-Mediated Permeation Enhancement of Chlorhexidine Digluconate: Mechanistic Insights Through Imaging Mass Spectrometry.

PURPOSE: Chlorhexidine digluconate (CHG) is a first-line antiseptic agent typically applied to the skin as a topical solution prior to surgery due to its efficacy and safety profile. However, the physiochemical properties of CHG limits its cutaneous permeation, preventing it from reaching potentially pathogenic bacteria residing within deeper skin layers. Thus, the utility of a solid oscillating microneedle system, Dermapen®, and a CHG-hydroxyethylcellulose (HEC) gel were investigated to improve the intradermal delivery of CHG. METHODS: Permeation of CHG from the commercial product, Hibiscrub®, and HEC-CHG gels (containing 1% or 4% CHG w/w) was assessed in intact skin, or skin that had been pre-treated with microneedles of different array numbers, using an Franz diffusion cells and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). RESULTS: Gels containing 1% and 4% CHG resulted in significantly increased depth permeation of CHG compared to Hibiscrub® (4% w/v CHG) when applied to microneedle pre-treated skin, with the effect being more significant with the higher array number. ToF-SIMS analysis indicated that the depth of dermal penetration achieved was sufficient to reach the skin strata that typically harbours pathogenic bacteria, which is currently inaccessible by Hibiscrub®, and showed potential lateral diffusion within the viable epidermis. CONCLUSIONS: This study indicates that HEC-CHG gels applied to microneedle pre-treated skin may be a viable strategy to improve the permeation CHG into the skin. Such enhanced intradermal delivery may be of significant clinical utility for improved skin antisepsis in those at risk of a skin or soft tissue infection following surgical intervention.

Designing a unique feedback mechanism for hydrogel-forming microneedle array patches: a concept study.

Although microneedle array patch (MAP) technology is reaching ever closer to regulatory approval, it remains imperative that approaches to further improve patient acceptance are still explored. Addressing this perception, a water-filled reservoir was incorporated into a hydrogel-forming MAP system to provide a novel feedback mechanism. To confirm successful MAP skin insertion, the end user would both hear and feel the rupture of the water-filled reservoir. Interestingly, a 50-µL water-filled reservoir ruptured at 30.27 ± 0.39 N, which has previously been shown as the mean application force for MN insertion in human subjects following appropriate instruction. Importantly, no significant difference in % cumulative permeation of FITC-dextran 10 kDa and fluorescein sodium after 24 h was observed between a 50-µL reservoir and the current method of application that has been successfully used in both in vitro and in vivo studies (p > 0.05). Therefore, as drug delivery was not affected, this proof-of-concept study has shown that a water-filled reservoir feedback mechanism has the potential to serve as a viable tool for consistent MAP skin insertion.

Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion.

Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.

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.

Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii.

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility. Herein, we report the development of dissolving MNs (DMNs) containing ART (MN-ART) and LUM (MN-LUM) as an alternative treatment regimen for malaria in low-resource settings. To incorporate the drugs into the MNs, nanosuspensions (NSs) for both molecules were developed separately to enhance drug solubility. The NSs were freeze-dried and the powder form was incorporated directly in an aqueous polymeric blend with poly-vinyl-pyrrolidone for MN-ART and a sodium hyaluronate hydrogel for MN-LUM. The in vivo bioavailability studies were performed using a MN reapplication scheme (1 × a day for 3 days), illustrating that an extended-release profile was achieved for both drugs when MNs were applied intradermally, and when compared to conventional oral treatment. The ART-LUM oral treatment was used as a positive control. For antimalarial activity, studies with animals infected with 106Plasmodium yoelii 17XNL (12 days) were also conducted using female C57BL/6JUnib mice, demonstrating a 99.5% reduction in parasitemia by day 12 post-infection. By abolishing the infection, MN-ART and MN-LUM may serve as a promising controlled intradermal delivery device for antimalarial drugs to be explored in endemic areas.

Dendrimer-mediated permeation enhancement of chlorhexidine digluconate: Determination of in vitro skin permeability and visualisation of dermal distribution.

Chlorhexidine digluconate (CHG) is a cationic bisbiguanide used in the UK as the first-line skin antiseptic prior to surgery in the UK due to its favourable efficacy and safety profile, high affinity for skin binding and minimal reports of resistance. Despite this, bacteria remain within deeper skin layers, furrows and appendages that are considered inaccessible to CHG, due to its poor dermal penetration. In this study a third generation, polyamidoamine dendrimer (G3 PAMAM-NH2) was utilised to improve dermal penetration of CHG. A topical gel formulation was optimised to maximise CHG delivery (containing 0.5% gelling agent and 4% drug), followed by drug and dendrimer co-formulation into a commercially viable gel. The gel containing 4% CHG and 1 mM PAMAM dendrimer significantly increased the depth permeation of CHG compared to the commercial benchmark (Hibiscrub®, containing 4% w/v CHG) (p < 0.05). The optimised formulation was further characterised using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS), which indicated that the depth of dermal penetration achieved was sufficient to reach the skin strata that typically harbours pathogenic bacteria, which is currently inaccessible by commercial CHG formulations. This study therefore indicates that a G3 PAMAM-NH2 dendrimer gel may be viable as a permeation enhancer of CHG, for improved skin antisepsis in those at risk of a skin or soft tissue infection as a result of surgical intervention.

A Drug Content, Stability Analysis, and Qualitative Assessment of Pharmacists' Opinions of Two Exemplar Extemporaneous Formulations.

Despite a decline in the number of active pharmaceutical ingredients prepared extemporaneously using proprietary products, there remains a need for such products in the community (for example, liquid medicines for paediatrics which may be otherwise commercially unavailable). A lack of experience and quality assurance systems may have diminished pharmacist's confidence in the extemporaneous preparation process; therefore, pharmacists were asked to prepare two proprietary products, omeprazole and amlodipine. The resulting products were characterised in terms of variability in drug quantity, stability, particle size and antimicrobial properties. Furthermore, a self-administered questionnaire was used to assess 10 pharmacists' opinions on the perceived complexity of the extemporaneous compounding process and their overall confidence in the final extemporaneously compounded products. Drug content studies revealed that 88.5% and 98.0% of the desired drug content was obtained for omeprazole and amlodipine, respectively. Antimicrobial properties were maintained for both drugs, however variability in particle size, particularly for amlodipine, was evident between formulations. While pharmacists who partook in the study had some or high confidence in the final products, they reported difficulty formulating the suspensions. Findings from this study provide insight into pharmacists' views on two extemporaneously prepared products and highlight the variability obtained in preparations prepared by different pharmacists.

Microneedle Mediated Transdermal Delivery of Protein, Peptide and Antibody Based Therapeutics: Current Status and Future Considerations.

The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 [1], and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the stratum corneum barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.