Micro-pillar tunnel stamp for enhanced transdermal delivery of topical drug formulations.

Dissolving microneedles (DMNs), despite their minimally invasive drug administration, face challenges in skin insertion and drug-loading capacity, which lead to less effective drug delivery. The micro-pillar tunnel stamp (MPTS) was designed to enhance the transdermal delivery efficacy of externally provided topical formulations via the creation of microchannels. The tunnel and canal of the MPTS enable the simultaneous application of DMNs and topical drugs. The application of micro-pillar-polycaprolactone (MP-PCL), which is a DMN made of a slowly dissolving polymer, exhibited a drug permeation rate 1.3-fold and 2.6-fold higher than that of micro-pillar-hyaluronic acid (MP-HA), a DMN made of a rapidly dissolving polymer, and the topical group, respectively. The base diameter of MP-PCL was set to 700 µm for maximized delivery efficacy, achieving 2.8-fold higher L-ascorbic acid accumulation than that of the topical group. In vivo analysis showed that, compared to topical administration, MPTS-delivered lidocaine had 5-fold greater permeation and the MPTS-delivered group showed 1.25-fold higher skin residual amount, confirming enhanced delivery. Thus, the optimized MPTS system can be presented as an attractive alternative to overcome the limitations of the existing MN systems such as incomplete insertion and limited drug-loading capacity, enhancing the delivery of topical formulations in the transdermal market. STATEMENT OF SIGNIFICANCE: We developed a micro-pillar tunnel stamp (MPTS) to enhance the delivery of externally provided topical formulations. The functional tunnel and canal of the MPTS enabled the simultaneous application of a dissolving microneedle (DMN) array insertion and administration of external topical drugs. Upon insertion, the DMNs created skin microchannels that allowed the externally administered drug to diffuse. DMNs were fabricated using polycaprolactone (PCL), a slowly dissolving polymer, to maintain their structure inside the skin and prolong the opening duration of the microchannels. This system achieved significantly improved delivery of topically administered external drugs via integration with slowly dissolving DMNs, while offering the possibility of its development as a universal delivery system for various topical pharmaceuticals.

Shape of dissolving microneedles determines skin penetration ability and efficacy of drug delivery.

Dissolving microneedles (DMNs) are used for minimally invasive transdermal drug delivery. Dissolution of drugs is achieved in the body after skin penetration by DMNs. Unlike injections, the insertion depth of the DMN is an important issue because the amount of dissolved DMN in the skin determines the amount of drug delivered. Therefore, the inaccurate drug delivery due to the incomplete insertion is one of the limitations of the DMN. Thus, many insertion and penetration tests have been essentially conducted in DMN studies, yet only incomplete insertion is known and the exact standard for how much it is not inserted is still unknown. Moreover, there are various shapes have been introduced in the microneedle field, there have been only few studies that have compared and evaluated the insertion depth of the shapes. Here, we present an intensive approach for DMN insertion based on DMN shape among various insertion deciding factors. We numerically analyzed the volumetric distribution of three types of DMN shapes: conical-shaped DMN, funnel-shaped DMN, and candlelit-shaped DMN, and introduced a new insertion evaluation criterion while covering previous insertion evaluations. Using optical coherence tomography, the images of DMNs embedded in the skin were analyzed in rea l-time, and the amount of drug delivered was analyzed at sectioned depth with a cryotome. The in vitro data confirmed that the insertion depth differed based on shape, and the resulting drug delivery depended on the volume assigned to the insertion depth. Insulin-loaded DMNs were applied to C57BL/6 mice, and the results of pharmacokinetic and pharmacodynamic analyses supported the results of the in vitro analysis. Our approach, which considers the correlation between DMN shape and insertion depth, will contribute to establishing criteria for various DMN design and maximizing drug delivery.

Enhanced Micro-Channeling System via Dissolving Microneedle to Improve Transdermal Serum Delivery for Various Clinical Skincare Treatments.

Topical liquid formulations, dissolving microneedles (DMNs), and microscale needles composed of biodegradable materials have been widely used for the transdermal delivery of active compounds for skincare. However, transdermal active compound delivery by topical liquid formulation application is inhibited by skin barriers, and the skincare efficacy of DMNs is restricted by the low encapsulation capacity and incomplete insertion. In this study, topical serum application via a dissolvable micro-channeling system (DMCS) was used to enhance serum delivery through micro-channels embedded with DMNs. Transdermal serum delivery was evaluated after the topical-serum-only application and combinatorial serum application by assessing the intensity of allophycocyanin (APC) loaded with the serum in the porcine skin. APC intensity was significantly higher in the skin layer at a depth of 120-270 µm upon combinatorial serum application as compared to topical-serum-only application. In addition, the combinatorial serum application showed significantly improved efficacy in the clinical assessment of skin hydration, depigmentation, improvement of wrinkles, elasticity, dermal density, skin pores, and skin soothing without any safety issues compared to the serum-only application. The results indicate that combinatorial serum application with DMCS is a promising candidate for improving skincare treatments with optimal transdermal delivery of active compounds.

Development of Clinical Weekly-Dose Teriparatide Acetate Encapsulated Dissolving Microneedle Patch for Efficient Treatment of Osteoporosis.

Teriparatide acetate (TA), which directly promotes bone formation, is subcutaneously injected to treat osteoporosis. In this study, TA with a once-weekly administration regimen was loaded on dissolving microneedles (DMNs) to effectively deliver it to the systemic circulation via the transdermal route. TA activity reduction during the drying process of various TA polymer solutions formulated with hyaluronic acid and trehalose was monitored and homogeneities were assessed. TA-DMN patches fabricated using centrifugal lithography in a two-layered structure with dried pure hyaluronic acid on the base layer and dried TA polymer solution on the top layer were evaluated for their physical properties. Rhodamine-B-loaded TA-DMNs were found to form perforations when inserted into porcine skin using a shooting device. In addition, 87.6% of TA was delivered to the porcine skin after a 5-min TA-DMN patch application. The relative bioavailability of TA via subcutaneous injection was 66.9% in rats treated with TA-DMN patches. The maximal TA concentration in rat plasma was proportional to the number of patches used. Therefore, the TA-DMN patch fabricated in this study may aid in the effective delivery of TA in a patient-friendly manner and enhance medical efficacy in osteoporosis treatment.

Identification of a Ruminococcaceae Species as the Methyl tert-Butyl Ether (MTBE) Degrading Bacterium in a Methanogenic Consortium.

The widespread use of methyl tert-butyl ether (MTBE) has caused major contamination of groundwater sources and is a concern due to its taste and odor problems, as well as its toxicity. MTBE can be degraded anaerobically which makes bioremediation of contaminated aquifers a potential solution. Nevertheless, the organisms and mechanisms that are responsible for anaerobic MTBE degradation are still unknown. The aim of our research was to identify the organisms actively degrading MTBE. For this purpose we characterized an anaerobic methanogenic culture enriched with MTBE as the sole carbon source from the New Jersey Arthur Kill intertidal strait sediment. The cultures were analyzed using stable isotope probing (SIP) combined with terminal restriction fragment length polymorphism (T-RFLP), high-throughput sequencing and clone library analysis of bacterial 16S rRNA genes. The sequence data indicated that phylotypes belonging to the Ruminococcaceae in the Firmicutes were predominant in the methanogenic cultures. SIP experiments also showed sequential incorporation of the (13)C labeled MTBE by the bacterial community with a bacterium most closely related to Saccharofermentans acetigenes identified as the bacterium active in O-demethylation of MTBE. Identification of the microorganisms responsible for the activity will help us better understand anaerobic MTBE degradation processes in the field and determine biomarkers for monitoring natural attenuation.

Evaluation of liquid and solid culture media for the recovery and enrichment of Burkholderia cenocepacia from distilled water.

Burkholderia cepacia complex (BCC) presence has been the cause of recalls of both sterile and non-sterile pharmaceutical products since these opportunistic pathogens have been implicated to cause infections to susceptible individuals. BCC are ubiquitous in nature, but in pharmaceutical settings the most common source is contaminated water systems. Some strains of BCC, previously described as Pseudomonas cepacia, were not readily detected by standard culture methods. We have explored different strategies to recover and enrich Burkholderia cenocepacia previously cultured in distilled water for 40 days. Enrichment media of varied nutrient concentrations and composition were used, including modified Tryptic Soy Agar or Broth (TSA or TSB), Reasoner's 2nd Agar or Broth (R2A or R2AB), Brain-Heart Infusion Broth (BHIB), Mueller-Hinton Broth (MHB), and Ashdown's (ASH) medium. Of the various broth media tested, cell growth was significantly greater in TSB and R2AB than in BHIB, MHB, or ASH broth. TSB and R2AB were also compared for their recovery efficiency. Generally, there was no significant difference between the numbers of B. cenocepacia grown on 15 differently modified TSA and five modified R2A solid media. Overall, however, diluted TSA and TSB media, and R2A and R2AB showed better recovery efficiency than TSA and TSB for inocula containing small numbers of cells. All strains persisted in distilled water for 40 days. Broth media were more effective than solid media for recovery of B. cenocepacia from distilled water. These results may assist in improving detection assays with recovery and enrichment strategies to maximize recovery of these fastidious organisms.