Solvent-Free Polycaprolactone Dissolving Microneedles Generated via the Thermal Melting Method for the Sustained Release of Capsaicin

(1) Background: Dissolving microneedles (DMNs), a transdermal drug delivery system, have been developed to treat various diseases in a minimally invasive, painless manner. However, the currently available DMNs are based on burst release systems due to their hydrophilic backbone polymer. Although hydrophobic biodegradable polymers have been employed on DMNs for sustained release, dissolution in an organic solvent is required for fabrication of such DMNs. (2) Method: To overcome the aforementioned limitation, novel separable polycaprolactone (PCL) DMNs (SPCL-DMNs) were developed to implant a PCL-encapsulated drug into the skin. PCL is highly hydrophobic, degrades over a long time, and has a low melting point. Under thermal melting, PCL encapsulated capsaicin and could be fabricated into a DMN without the risk of toxicity from an organic solvent. (3) Results: Optimized SPCL-DMNs, containing PCL (height 498.3 ± 5.8 µm) encapsulating 86.66 ± 1.13 µg capsaicin with a 10% (w/v) polyvinyl alcohol and 20% (w/v) polyvinylpyrrolidone mixture as a base polymer, were generated. Assessment of the drug release profile revealed that this system could sustainably release capsaicin for 15 days from PCL being implanted in porcine skin. (4) Conclusion: The implantable SPCL-DMN developed here has the potential for future development of toxicity-free, sustained release DMNs

Drug dose control via contact and drying cycle.

<p>(A) The amount of rhodamine B rose exponentially as the number of contact and drying cycles and PVP concentration increased (n = 3). Data are shown as mean ± s.e.m. Images indicate that rhodamine B-encapsulated spherical structures created through contact and drying cycles increased when using 20 (upper) and 40% (bottom) PVP solution. (B) After the microneedle formation step, Troy MNs were fabricated as sharp tips without drug (white arrow) over inner spherical structures containing drug (gray arrow). Scale bars, 500 μm.</p

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

Schematic illustration of the CCDP process.

<p>The total process consisted of two independent steps. (A) In the first step (drug encapsulation), pillars were contacted with a mixed drug-polymer solution and then lifted and dried with air blowing. This contact and drying cycle was repeated to optimize drug encapsulation, producing spherical structures on each pillar. (B) In the second step (microneedle formation), polymer solution without drug was used to prevent loss of drug during DMN fabrication, resulting in sharp tipped-DMNs on the end surface of the pillars.</p

DMN-separation study with agarose gel and schematic illustration of DMN-separation mechanism.

<p>(A) DMN-separation efficiency according to side junction depth. Rhodamine B-encapsulated DMNs (1 × 3) were inserted into agarose gel and examined right after removing pillars at each designated application time. Side junction depths were set to 30 (contact, not immersion), 200 and 400 μm, and the number of contact (dipping) and drying cycles was set to 5 and 8 times for each depth. As the side junction depth and number of cycles increased, DMN-separation efficiency decreased. Troy system DMNs separated within 5 s due to their minimum binding shape, and DMN volume did not influence separation time (n = 4). Data are shown as mean ± s.e.m. (B) DMN-separation efficiency according to top junction area. Three pillar types with different diameters (170, 350 and 500 μm) were used for Troy MN fabrication, with a uniform side junction depth of 30 μm and 8 contact and drying cycles. Pillar diameter influenced DMN-separation time due to the larger top junction area as pillar diameter increased, necessitating more time for complete DMN-separation (n = 4). Data are shown as mean ± s.e.m. (C) Two different DMNs with different binding shapes between the polymer matrix and pillars were penetrated into the skin. The Troy MN (left) was made only on the end surface of the pillars, while the deep-dipped DMN (right) had a greater side junction area. (D) Interstitial fluid easily permeated to the top junction of the Troy MNs (left square), but the additional polymer matrix on the pillar side walls of the deep-dipped DMNs inhibited interstitial fluid permeation to the top junction (right square). (E) After a few seconds, Troy MNs rapidly separated from the pillar, while more separation time was required for deep-dipped DMNs.</p

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

<div><p>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. <i>In vivo</i> 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.</p></div

<i>In vivo</i> skin penetration study.

<p>(A) Troy MNs were assembled with an applicator into an array (5 × 5). (B) The applicator was applied to rat dorsal skin vertically by hand. (C) Image of skin with applied Troy MNs. The array of red spots indicates the penetrated site of rhodamine B-encapsulated Troy MNs and the white dotted line represents the vertically sliced line used to obtain sectional tissue. (D) Skin sectional image. Red spots mark delivered rhodamine B in the skin and the white arrow indicates undissolved parts of DMNs. Scale bars, 10 mm (A, B) and 1.0 mm (C, D).</p

Evaluation of skin insertion failure.

<p>(A) DMNs created by 1 to 5 drying cycles completely penetrated the skin, but DMNs generated by 7 or more cycles did not due to the fact that the maximum axial diameter of the MNs was roughly 2.5 folds larger than the pillar after 7 contact and drying cycles (n = 4). Data are shown as mean ± s.d. (B) Skin insertion failure. Broken DMN on the pillar after application. Scale bars, 500 μm.</p