Xin Dong Guo

Rapidly separating microneedles for transdermal drug delivery

UNLABELLED The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. STATEMENT OF SIGNIFICANCE Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery.

A fabrication method of microneedle molds with controlled microstructures.

Microneedle (MN) offers an attractive, painless and minimally invasive approach for transdermal drug delivery. Polymer microneedles are normally fabricated by using the micromolding method employing a MN mold, which is suitable for mass production due to high production efficiency and repeat-using of the mold. Most of the MN molds are prepared by pouring sylgard polymer over a MN master to make an inverse one after curing, which is limited in optimizing or controlling the MN structures and failing to keep the sharpness of MNs. In this work we describe a fabrication method of MN mold with controlled microstructures, which is meaningful for the fabrication of polymer MNs with different geometries. Laser micro-machining method was employed to drill on the surface of PDMS sheets to obtain MN molds. In the fabrication process, the microstructures of MN molds are precisely controlled by changing laser parameters and imported patterns. The MNs prepared from these molds are sharp enough to penetrate the skin. This scalable MN mold fabrication method is helpful for future applications of MNs.

Fabrication of coated polymer microneedles for transdermal drug delivery

Abstract As an alternative to hypodermic needles, coated polymer microneedles (MNs) are able to deliver drugs to subcutaneous tissues after being inserted into the skin. The dip‐coating process is a versatile, rapid fabricating method that can form coated MNs in a short time. However, it is still a challenge to fabricate coated MNs with homogeneous and precise drug doses in the dip‐coating process. In this study, to fabricate coated polymer microneedles with controlled drug loading, an adjustable apparatus that can be lifted and lowered was designed to immerse a polylactic acid (PLA) MN patch in the coating solutions. Using the coating solution containing 0.5% (w/w) sulforhodamine B, the drug loadings were up to 12 ng, 14 ng, and 18 ng per needle for the MNs with heights of 550 &mgr;m, 650 &mgr;m, and 750 &mgr;m, respectively. Moreover, for the MNs with a 650‐&mgr;m height, when increasing the viscosity of the coating solutions from 150 mPa·s to 1360 mPa·s, 2850 mPa·s, and 8200 mPa·s, the drug loading increased from 2.5 ng to 5 ng, 14 ng, and 22 ng per needle, respectively. Meanwhile, the drug delivery efficiencies of these MNs were approximately 90%. In the insertion experiments, the MNs could successfully penetrate the skin and deliver the coated drug with approximately 90% efficiency when the MN tips were exposed to the outer environment. In vivo studies in mice indicated that the coated polymer MNs continuously delivered drugs, and the skin recovered without any injuries. These results demonstrated that the coated polymer MN was a safe and effective method for transdermal drug delivery. Graphical abstract Figure. No Caption available.

Microneedles with Controlled Bubble Sizes and Drug Distributions for Efficient Transdermal Drug Delivery.

Drug loaded dissolving microneedles (DMNs) fabricated with water soluble polymers have received increasing attentions as a safe and efficient transdermal drug delivery system. Usually, to reach a high drug delivery efficiency, an ideal drug distribution is gathering more drugs in the tip or the top part of DMNs. In this work, we introduce an easy and new method to introduce a bubble with controlled size into the body of DMNs. The introduction of bubbles can prevent the drug diffusion into the whole body of the MNs. The heights of the bubbles are well controlled from 75 μm to 400 μm just by changing the mass concentrations of polymer casting solution from 30 wt% to 10 wt%. The drug-loaded bubble MNs show reliable mechanical properties and successful insertion into the skins. For the MNs prepared from 15 wt% PVA solution, bubble MNs achieve over 80% of drug delivery efficiency in 20 seconds, which is only 10% for the traditional solid MNs. Additionally, the bubble microstructures in the MNs are also demonstrated to be consistent and identical regardless the extension of MN arrays. These scalable bubble MNs may be a promising carrier for the transdermal delivery of various pharmaceuticals.

Compatibility studies between an amphiphilic pH-sensitive polymer and hydrophobic drug using multiscale simulations

The compatibility of an amphiphilic pH-sensitive polymer (docosahexaenoic acid–histidine–lysine, DHA–HisXLys10) and hydrophobic drug (doxorubicin, DOX) was investigated using multiscale simulations at different pH conditions, including Blends and dissipative particle dynamics simulations. Some important elements obtained from the computer simulations were analyzed, such as Flory–Huggins interaction parameters, binding energy distributions, phase diagrams and radius distribution function. In conclusion, the pH values and the number of pH-sensitive segments (histidine) significantly influence the compatibility of DHA–HisXLys10 and DOX, resulting in different drug loading capacity and system structural stability. According to the simulation results, the compatibility of the systems at pH > 6.0 is better than that at pH 6.0. Using DPD simulation, the compatibility of DHA–HisXLys10 (X = 10 or 15) and DOX is optimal when the pH is higher than 6.0, which falls in line with the results obtained from Blends simulation. Overall, when the number of histidine residues is 10 or 15 and the pH is larger than 6.0, DOX and DHA–HisXLys10 have better compatibility. So it is obvious that polymeric micelles self-assembled from DHA–His10Lys10/DHA–His15Lys10 as an ideal drug carrier have higher drug-loading capacity and more excellent stability. This work has demonstrated that multiscale simulations could be a powerful method to investigate the compatibility between polymers and drugs.

Mesoscopic simulation studies on the formation mechanism of drug loaded polymeric micelles.

In this work, the formation of polymeric micelles as drug delivery vehicles in an aqueous environment is investigated by dissipative particle dynamics (DPD) simulations. Doxorubicin (DOX) is selected as the model drug, whereas docosahexaenoic acid (DHA) conjugated His10Lys10 (DHA-His10Lys10) as the drug carrier. It is shown from DPD simulation that drug molecules and DHA-His10Lys10 molecules could aggregate and form micelles under a defined composition recipe; drug molecules are homogeneously distributed inside the carrier matrix, on whose surface the stabilizer lysine segments are absorbed. Under different compositions of drug and water, aggregate morphologies of polymeric micelles are observed as spherical, columnar, and lamellar structures. We finally proposed the formation mechanism of drug loaded polymeric micelles and apply it in practice by analyzing the simulated phenomena. All the results can effectively guide the experimental preparation of drug delivery system with desired properties or explore a novel polymeric micelle with high performance.

Application of mesoscale simulation to explore the aggregate morphology of pH-sensitive nanoparticles used as the oral drug delivery carriers under different conditions

The pH-sensitive nanoparticles are selected as the potentially promising oral protein and peptide drug carriers due to their excellent performance. With the poly (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate (PLGA/HP55) nanoparticle as a model nanoparticle, the structure-property relationship of nanoparticles with different conditions is investigated by dissipative particle dynamics (DPD) simulations in our work. In the oral drug delivery system, the poly (lactic-co-glycolic acid) (PLGA) is hydrophobic polymer, hydroxypropyl methylcellulose phthalate (HP55) is pH-sensitive enteric polymer which used to protect the nanoparticles through the stomach and polyvinyl alcohol (PVA) is hydrophilic polymer as the stabilizer. It can be seen from DPD simulations that all polymer molecules form spherical core-shell nanoparticles with stabilizer PVA molecules adsorbed on the outer surface of the PLGA/HP55 matrix at certain compositions. The DPD simulation study can provide microscopic insight into the formation and morphological changes of pH-sensitive nanoparticles which is useful for the design of new materials for high-efficacy oral drug delivery.

Controlled Delivery of Insulin Using Rapidly Separating Microneedles Fabricated from Genipin-Crosslinked Gelatin

Rapidly separating genepin-crosslinked gelatin (RS-GC) microneedles (MNs) mounted on the polyvinyl alcohol (PVA)-coated polylactic acid (PLA) MNs (RS-PGC-MNs) are fabricated, in which GC-MNs deliver insulin within the skin and the PLA supporting array is easily separated by the dissolution of the PVA layer. The release of insulin is controlled by utilizing the virtue of genipin as a crosslinking agent for producing biocompatible GC-MNs. The degree of crosslinking enhances the mechanical strength as well as humidity resistance. The in vitro and in vivo insulin release tests show significant changes in the release rates in the RS-PGC-MNs with different crosslinking degree. The hypoglycemic effect in diabetic mice demonstrate that the higher crosslinking GC-MNs result in characteristic controlled insulin release compared with other treatments and prolonged effectiveness of the RS-PGC-MNs. The proposed RS-PGC-MNs is a promising device for effective use as a noninvasive and painless controlled insulin delivery system.

Assessment of mechanical stability of rapidly separating microneedles for transdermal drug delivery

The rapidly separating microneedles (RS-PP-MNs), composed of PVA (separable arrow head) MNs and a poly(L-lactide-co-D, L-lactide) (PLA) supporting array, are used for transdermal delivery system at high humidity. The fabricated RS-PP-MNs should have sufficient mechanical strength at different humidity. In general, the water adsorption rate was increased with increasing humidity; by contrast, storage time was decreased with increasing humidity. The higher water adsorption rate indicated the lower mechanical strength, thereby lowering drug delivery efficiency. The prepared RS-PP-MNs could be successfully inserted within the skin at high humid atmosphere due to PLA supporting array. The bright field and fluorescence microscopic images suggested the probable real-time applicability of RS-PP-MNs. The in vitro and in vivo assay suggested that RS-PP-MNs potentially were able to deliver the drugs at high humidity condition. The significant improvement in the drug delivery efficiency and skin penetration ability was observed compared with the traditional MNs. In addition, the fabrication of RS-PP-MNs is facile and scalable. Therefore, the prepared RS-PP-MNs with supporting solid PLA array might be advantageous in real-time applications. This study is of great importance for the MN field as it offers more theoretical support for clinical applications.