Huisuk Yang

Droplet-born air blowing: Novel dissolving microneedle fabrication

The microneedle-mediated drug delivery system has been developed to provide painless self-administration of drugs in a patient-friendly manner. Current dissolving microneedle fabrication methods, however, require harsh conditions for biological drugs and also have problems standardizing the drug dose. Here, we suggested the droplet-born air blowing (DAB) method, which provides gentle (4-25 °C) and fast (≤10min) microneedle fabrication conditions without drug loss. The amount of drug in the microneedle can be controlled by the pressure and time of droplet dispenser and the air blowing shapes this droplet to the microneedle, providing a force sufficient to penetrate skin. Also, the introduction of a base structure of two layered DAB-microneedle could provide complete drug delivery without wasting of drug. The DAB-based insulin loaded microneedle shows similar bioavailability (96.6±2.4%) and down regulation of glucose level compared with subcutaneous injection. We anticipate that DAB described herein will be suitable to design dissolving microneedles for use in biological drug delivery to patients.

Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule

Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell’s cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 μm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs.

Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles

Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery.

Centrifugal Lithography: Self-Shaping of Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer Drops

Polymeric microstructures encapsulating biopharmaceutics must be fabricated in a controlled environment to preserve the biological activity. There is increasing demand for simple methods designed to preserve the biological activity by utilizing the natural properties of polymers. Here, the paper shows that centrifugal lithography (CL) can be used for the fabrication of such microstructures in a single centrifugation, by engineering the self-shaping properties of hyaluronic acid (HA). In this method, HA drops are self-shaped into hourglass-microstructures to produce two dissolving microneedles (DMN), which facilitate transdermal delivery via implantation on the skin. In addition, tuberculin purified protein derivatives are encapsulated into HA DMNs under refrigerated conditions (4 °C) during CL. Therefore, the tuberculin skin test (TST) with the DMNs indicates minimal damage, as opposed to the case of TST with traditional hypodermic needles. These findings on the fabrication of polymeric microstructures with biopharmaceutics may trigger the development of various biomedical devices and therapies.

Rapid implantation of dissolving microneedles on an electrospun pillar array.

Dissolving microneedles (DMNs), designed to release drugs and dissolve after skin insertion, have been spotlighted as a novel transdermal delivery system due to their advantages such as minimal pain and tissue damage, ability to self-administer, and no associated hazardous residues. The drug delivery efficacy of DMNs, however, is limited by incomplete insertion and the extended period required for DMN dissolution. Here, we introduce a novel DMN delivery system, DMN on an electrospun pillar array (DEPA), which can rapidly implant DMNs into skin. DMNs were fabricated on a pillar array covered by a fibrous sheet produced by electrospinning PLGA solution (14%, w/v). DMNs were implanted into the skin by manual application (press and vibration for 10 s) by tearing of the fibers hung on the 300-μm pillars. Separation of DMNs from the fibrous sheet was dependent on both pillar height and the properties of the fibrous sheet. After evaluation of the implantation and dissolution of DMNs with diffusion of red dye by taking cross-sectional images of porcine skin, the hypoglycemic effect of insulin loaded DEPA was examined using a healthy mouse model. This DMN array overcomes critical issues associated with the low penetration efficiency of flat patch-based DMNs, and will allow realization of patient convenience with the desired drug efficacy.

4‐n‐butylresorcinol dissolving microneedle patch for skin depigmentation: a randomized, double‐blind, placebo‐controlled trial

For effective skin depigmentation, the skin depigmentation agent must be delivered to melanocytes, where melanin is synthesized. Although dissolving microneedle (DMN) is one of the best transdermal drug delivery systems to deliver the active compound, no clinical trial has been conducted in terms of safety and efficacy.

The Troy Microneedle: A Rapidly Separating, Dissolving Microneedle Formed by Cyclic Contact and Drying on the Pillar (CCDP).

In dissolving microneedle (DMN)-mediated therapy, complete and rapid delivery of DMNs is critical for the desired efficacy. Traditional patch-based DMN delivery, however, may fail due to incomplete delivery from insufficient skin insertion or rapid separation of microneedles due to their strong bond to the backing film. Here, we introduce the Troy microneedle, which was created by cyclic contact and drying on the pillar (CCDP), and which enabled simultaneous complete and rapid delivery of DMN. This CCDP process could be flexibly repeated to achieve a specific desired drug dose in a DMN. We evaluated DMN separation using agarose gel, and the Troy microneedle achieved more complete and rapid separation than other, more deeply dipped DMN, primarily because of the Troy’s minimal junction between the DMN and pillar. When Troy microneedles were applied to pig cadaver skin, it took only 15 s for over 90% of encapsulated rhodamine B to be delivered, compared to 2 h with application of a traditional DMN patch. In vivo skin penetration studies demonstrated rapid DMN-separation of Troy microneedles still in solid form before dissolution. The Troy microneedle overcomes critical issues associated with the low penetration efficiency of flat patch-based DMN and provides an innovative route for DMN-mediated therapy, combining patient convenience with the desire drug efficacy.

Physicochemical study of ascorbic acid 2-glucoside loaded hyaluronic acid dissolving microneedles irradiated by electron beam and gamma ray

A dissolving microneedle (DMN) patch encapsulated with ascorbic acid 2-glucoside (AA2G) in a needle-shaped hyaluronic acid (HA) backbone was fabricated and sterilized by electron beam (e-beam, 5-40kGy) and gamma ray (γ-ray, 5-30kGy). DMN structures maintained their morphologies and fracture force regardless of e-beam and γ-ray irradiation doses. Both e-beam (40kGy) and γ-ray (20 and 30kGy) met the product sterility requirements for cosmetics and vaccines; however, γ-ray irradiation significantly degraded the encapsulated AA2G, while e-beam maintained AA2G activity. Thus, an e-beam dose of 40kGy, which satisfied the sterility requirements without loss of AA2G, is suitable for terminal sterilization of DMNs. Moreover, we confirmed that the optimized irradiation (e-beam, 40kGy) did not affect dissolution rate and drug release profile of DMNs. Further, we confirmed that HA, the backbone polymer of DMNs, could be utilized as a stabilizer that inhibits degradation of encapsulated AA2G by irradiation. This detailed analysis can be developed further to optimize various biological drugs in transdermal drug delivery systems.

Effects of two droplet-based dissolving microneedle manufacturing methods on the activity of encapsulated epidermal growth factor and ascorbic acid

Abstract Dissolving microneedle (DMN) is an attractive, minimally invasive transdermal drug delivery technology. The drugs encapsulated in the DMNs are exposed to a series of thermal, chemical, and physical stresses during the fabrication process, decreasing their therapeutic activity. Current DMN fabrication methods, such as micro‐molding, drawing lithography, droplet‐born air blowing, and centrifugal lithography, undergo different manufacturing processes involving differing stress conditions. Among the methods, we compared the effects of two droplet‐based methods, droplet‐born air blowing and centrifugal lithography, on the activity of encapsulated drugs using epidermal growth factor and ascorbic acid as model drugs. Although the appearance and physical properties of DMNs fabricated by the two methods were similar, the immunoreactivity of encapsulated epidermal growth factor in centrifugal lithography and droplet‐born air blowing was 92.08 ± 2.86% and 80.67 ± 8.00%, respectively, at baseline, and decreased to 75.32 ± 19.40% and 41.75 ± 16.17%, respectively, 24 h after drug‐loading. The free‐radical scavenging activity of ascorbic acid was maintained at 88.24 ± 0.78% in DMNs fabricated by centrifugal lithography, but decreased over time to 67.02 ± 1.11% in DMNs fabricated by droplet‐born air blowing. These findings indicate that the manufacturing conditions of centrifugal lithography exert less stress on the drug‐loaded DMNs, minimizing activity loss over time, and therefore that centrifugal lithography is suitable for fabricating DMNs loaded with fragile biological drugs. Graphical abstract Figure. No caption available.

Exendin-4-encapsulated dissolving microneedle arrays for efficient treatment of type 2 diabetes

Dissolving microneedles (DMNs) are microscopic needles capable of delivering encapsulated compounds and releasing them into the skin in a minimally invasive manner. Most studies indicate that encapsulating therapeutics in DMNs is an efficacious approach; however, the importance of evaluating the activity of encapsulated compounds, during the fabrication process, has not been examined in detail. Conducting an analysis of thermal, chemical, and physical stress factors, including temperature, pH, and the interaction of the polymer and therapeutics mixture during preparation, is essential for retaining the activity of encapsulated therapeutics during and after fabrication. Here, we optimised the thermal, chemical, and physical parameters for the fabrication of exendin-4 (Ex-4)–encapsulated DMNs (Ex-4 DMNs). Ex-4, a peptide agonist of glucagon-like peptide (GLP) receptor, is used for glycaemic control in patients with type 2 diabetes. Our findings indicate that optimising the parameters involved in DMN fabrication retained the activity of Ex-4 by up to 98.3 ± 1.5%. Ex-4 DMNs reduced the blood-glucose level in diabetic mice with efficiency similar to that of a subcutaneous injection. We believe that this study paves way for the commercialisation of an efficient and minimally invasive treatment for patients with type 2 diabetes.