Lidocaine-loaded dissolving microneedle for safe local anesthesia on oral mucosa for dental procedure.

BACKGROUND: Lidocaine has been widely used as a short-acting local anesthetic agent to reduce the pain caused by needle insertion. Dissolving microneedles (DMNs), which are minimally invasive, can effectively deliver drugs by overcoming the oral mucosal barrier and relieving patient discomfort. METHODS: Lidocaine solution prepared by mixing lidocaine-HCl and hyaluronic acid was used to fabricate oral lidocaine HCl-encapsulated DMNs (oral Li-DMNs) via centrifugal lithography. The dissolution, penetration ability, and local transmucosal drug delivery of oral Li-DMNs into the oral mucosa were evaluated in porcine jaws. Pharmacokinetic analysis and safety assessment were performed using rabbits. RESULTS: The insertion depth of the oral Li-DMNs satisfies the safety standard. The oral Li-DMNs were completely dissolved after 3 min of application. The local transmucosal drug delivery, pharmacokinetic, and safety evaluations showed that the oral Li-DMNs can obtain a local anesthesia effect at a relatively lower dose, and there was no oral mucosal irritation in rabbits. CONCLUSIONS: A novel and safe oral Li-DMNs have potential applications in large animals and clinical trials and would possibly enter the anesthesia market.

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.

Egg Microneedle for Transdermal Delivery of Active Liraglutide.

Liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, is promising for safely treating type 2 diabetes mellitus (T2DM), compared to insulin, by significantly reducing the risk of glucose-dependent hypoglycemia. Concerns related to injection prevent T2DM patients from taking liraglutide regularly, even though once-a-day subcutaneous (SC) injections. Dissolving microneedles (DMNs) are promising substitutes for SC injection and for improving patient convenience. However, there are two fundamental limitations: the low drug delivery due to incomplete insertion and loss of drug activity during DMN fabrication. Here, it is shown that an egg microneedle (EMN) designed with three functional layered structures can maintain the maximum activity of the loaded compound during DMN fabrication and deliver it completely into the skin, with the base layer allowing the complete delivery of liraglutide, and the shell layer maintaining the drug activity by mimicking the role of albumin in eggs. In a diabetic mouse model, liraglutide administration via EMN exhibited similar effect when compared to that of injection. Therefore, EMN-mediated liraglutide administration is a good potential option for replacing liraglutide injections in T2DM treatment.

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.

Film-trigger applicator (FTA) for improved skin penetration of microneedle using punching force of carboxymethyl cellulose film acting as a microneedle applicator.

BACKGROUND: Dissolving microneedle (DMN) is a transdermal drug delivery system that creates pore in the skin and directly deliver drug through the pore channel. DMN is considered as one of the promising system alternatives to injection because it is minimally invasive and free from needle-related issues. However, traditional DMN patch system has limitations of incomplete insertion and need of complex external devices. Here, we designed film-trigger applicator (FTA) system that successfully delivered DMN inside the skin layers using fracture energy of carboxymethyl cellulose (CMC) film via micropillars. We highlighted advantages of FTA system in DMN delivery compared with DMN patch, including that the film itself can act as DMN applicator. METHODS: FTA system consists of DMNs fabricated on the CMC film, DMN array holder having holes aligned to DMN array, and micropillars prepared using general purpose polystyrene. We analyzed punching force on the film by micropillars until the film puncture point at different CMC film concentrations and micropillar diameters. We also compared drug delivery efficiency using rhodamine B fluorescence diffusion and skin penetration using optical coherence tomography (OCT) of FTA with those of conventional DMN patch. In vivo experiments were conducted to evaluate DMN delivery efficiency using C57BL/6 mice and insulin as a model drug. RESULTS: FTA system showed enhanced delivery efficiency compared with that of the existing DMN patch system. We concluded CMC film as a successful DMN applicator as it showed enhanced DMN penetration in OCT and rhodamine B diffusion studies. Further, we applied FTA on shaved mouse dorsal skin and observed successful skin penetration. The FTA group showed higher level of plasma insulin in vivo than that of the DMN patch group. CONCLUSIONS: FTA system consisting of simple polymer film and micropillars showed enhanced DMN delivery than that of the existing DMN patch system. Because FTA works with simple finger force without sticky patch and external devices, FTA is a novel and promising platform to overcome the limitations of conventional microneedle patch delivery system; we suggest FTA as a next generation applicator for microneedle application in the future.

Optimization of Layered Dissolving Microneedle for Sustained Drug Delivery Using Heat-Melted Poly(Lactic-Co-glycolic Acid).

Dissolving microneedles (DMNs) have been used as an alternative drug delivery system to deliver therapeutics across the skin barrier in a painless manner. In this study, we propose a novel heat-melting method for the fabrication of hydrophobic poly(lactic-co-glycolic acid) (PLGA) DMNs, without the use of potentially harmful organic solvents. The drug-loaded PLGA mixture, which consisted of a middle layer of the DMN, was optimized and successfully implanted into ex vivo porcine skin. Implanted HMP-DMNs separated from the patch within 10 min, enhancing user compliance, and the encapsulated molecules were released for nearly 4 weeks thereafter. In conclusion, the geometry of HMP-DMNs was successfully optimized for safe and effective transdermal sustained drug delivery without the use of organic solvents. This study provides a strategy for the innovative utilization of PLGA as a material for transdermal drug delivery systems.