Microneedle System Research Articles

Administration of a Sol-Gel Formulation of Phenylephrine Using Low-Temperature Hollow Microneedle for Treatment of Intermittent Fecal Incontinence.

A low temperature hollow microneedle system was devised to deliver sol-gel transition formulation near the surface of the skin for extended release and local delivery of drug by a non-invasive method. This new system can improve treatment of intermittent fecal incontinence. The low-temperature system was integrated with a hollow microneedle to maintain the low temperature of the sol formulation. Various sol-gel formulations using Pluronic F-127 (PF-127) and Hydroxy-propyl-methyl-cellulose (HPMC) were prepared, and their gelation temperature, flow property, and diffusion retardation were observed. Resting anal sphincter pressure in response to a phenylephrine (PE) sol-gel formulation was measured using an air-charged catheter. The biocompatibility of the sol-gel PE formulation was evaluated by observing the immunological response. When the PF-127 25%, HPMC 1% and PE formulation (PF25-HPMC1-PE) was injected through the peri-anal skin of the rat in vivo, the highest pressure on the anal sphincter muscle occurred at 6-8h and anal pressure increased and lasted twice as long as with the phosphate-buffered saline (PBS)-PE formulation. There was no significant difference in the number of mast cells after administration into the rat in vivo between the PF25-HPMC1-PE formulation and the PBS-PE formulation. The combination of a low-pain hollow microneedle system and an injectable sol-gel formulation improved the efficacy of treatment of intermittent fecal incontinence. A low-temperature hollow microneedle system using a sol-gel formulation has many applications in medical treatments that require depot effect, local targeting, and pain control.

Dissolvable layered microneedles with core-shell structures for transdermal drug delivery

Microneedle (MN) systems for painless transdermal drug delivery have been developed in the past few years to overcome the issues of hypodermic injections. This study introduces a novel dissolvable layered microneedle (LMN) with core-shell structure for efficient transdermal drug delivery. Fabricated by three-step-casting method, the LMNs encapsulated the drug into the HA layer as a “shell”, which is supported by PVA layer as core and base. When the LMNs are inserted into the skin, the drug would be released immediately once the HA layer were separated or dissolved. What's more, little drug would be wasted on the residual base after insertion. It is demonstrated that the mechanical property of LMNs is kept well with 100% insertion percentage at 60% relative humidity. Moreover, in the transdermal delivery in vivo test, almost 90% of drug in LMNs could be successful delivered into the skin with 10s, while the homogeneous HA MNs with wide drug distribution need more than 120s to reach the same efficiency. Owing to the advantages of stable mechanical property and rapid efficient drug delivery, the LMNs are more reliable and satisfied for the self-administration in the future.

Enhancing immunogenicity of antigens through sustained intradermal delivery using chitosan microneedles with a patch-dissolvable design

This study developed implantable chitosan microneedles (MNs) with a patch-dissolvable design for the sustained intradermal (ID) delivery of antigens and demonstrated their antigen dose-sparing potential. We found that rats immunized with chitosan MNs containing low-dose OVA had persistently high antibody levels for 18 weeks, which were significantly higher than those observed after an intramuscular injection of full-dose OVA, demonstrating at least 2.5-fold dose sparing. Our results indicate that chitosan MNs can not only serve as an efficient vaccine delivery system but also exert their promising adjuvant activity by forming an ID depot for prolonged antigen exposure and activating dendritic cells for promoting immune responses.

Microneedle Manufacture: Assessing Hazards and Control Measures

Transdermal microneedles have captured the attention of researchers in relation to a variety of applications, and silicone-based moulds required to produce these systems are now widely available and can be readily manufactured on the lab bench. There is however some concern over the potential for accidental needlestick injuries and, as with any sharp hazard, the potential for blood-borne pathogen transmission must be considered. This follows from recent governmental concerns over the use of microneedle systems in dermabrasion. Despite the piercing nature of the microneedle patch sharing many similarities with conventional hypodermic needles, there are notable factors that mitigate the risk of contamination. A range of microneedle systems has been prepared using micromoulding techniques, and their puncture capability assessed. A critical assessment of the potential for accidental puncture and the control measures needed to ensure safe utilisation of the patch systems is presented.

Novel dissolving microneedles for enhanced transdermal delivery of levonorgestrel: In vitro and in vivo characterization

Dissolving microneedles (DMN) have been studied as a drug delivery system to enhance the transport of drug molecules across the skin with almost no pain. However, the poor dissolving ability of microneedles in the skin and low drug loading have limited their potential application. The aim of this study was to develop a novel dissolving microneedle system with improved dissolving ability for the delivery of poorly water soluble contraception drug, levonorgestrel (LNG). Chitosan and beta-sodium glycerophosphate (β-GP) were incorporated in the formulation of microneedles. It was found that 69.32±4.23% of the microneedles penetrated through the skin and dissolved within the first 2h, which was almost 2-fold higher than that of the conventional microneedles. In addition, drug loading was significantly increased by packaging LNG into the molecules of hydroxypropyl beta cyclodextrin (HP-β-CD) to form LNG-HP-β-CD inclusion compounds. The use of chitosan and β-GP together with HP-β-CD inclusion compounds was shown to enhance the bioavailability of LNG transdermally. This novel DMN system resulted in a similar pharmacokinetic profile as that following oral administration. In addition to similar Cmax and AUC values, drug concentrations in the blood were more consistent following the DMN in comparison to oral administration.

Experimental and modelling characterisation of adjustable hollow Micro-needle delivery systems

BackgroundHollow micro-needles have been used increasingly less in practice because the infusion into the skin is limited by the tissue resistance to flow. The relationship between the infusion flow rate and tissue resistance pressure is not clear. MethodsA custom-made, hollow micro-needle system was used in this study. The driving force and infusion flow rate were measured using a force transducer attached to an infusion pump. Evans blue dye was injected into the air, polyacrylamide gel and in-vivo mouse skin at different flow rates. Two different micro-needle lengths were used for in-vivo infusion into the mouse. A model was derived to calculate the driving force of the micro-needle infusion into the air, and the results were compared to experimental data. ResultsThe calculated driving forces match the experimental results with different infusion flow rates. The pressure loss throughout the micro-needle delivery system was found to be two orders smaller than the resistance pressure inside the gel and mouse skin, and the resistance pressure increased with increasing flow rate. A portion of liquid backflow was observed when the flow rate was relatively larger, and the backflow was associated with a sudden larger increase in resistance pressure at a higher flow rate. ConclusionsThe current micro-needle delivery system is capable of administering liquid into the mouse skin at a flow rate of up to 0.15 ml/min, without causing significant backflow on the surface. The resistance pressure increases with increasing flow rate, causing infusion restriction at higher flow rates.

Drug-Delivery System Based on Salmon DNA Nano- and Micro-Scale Structures

Microneedles, fabricated by nano-moulding technology show great promise in the field of drug delivery by enabling the painless self-administration of drugs in a patient-friendly manner. In this study, double-stranded salmon DNA (SDNA) was used as both a drug-delivery vehicle and structural material with a microneedle system. SDNA is non-toxic and demonstrates good mechanical robustness, mouldability, biocompatibility, bio-absorbability, and binding affinity with drug molecules for bio-functional applications. Benign fabrication conditions to protect temperature-sensitive biomolecules are used to produce SDNA structures of various sizes with a high aspect ratio (4: 1). Unlike existing dissolving microneedle structure materials, the special binding characteristics of doxorubicin hydrochloride, anti-cancer drug molecules, and SDNA demonstrate the stability of drug-molecule encapsulation via UV-absorption and photoluminescence analyses. Based on COMSOL simulation and in vitro analysis of the stratum corneum of porcine skin, the mechanical functionality of SDNA microneedles was evaluated in vitro by penetrating the stratum corneum of porcine skin. The SDNA microneedle dissolved and drug permeation was assessed using rhodamine, a drug surrogate. Owing to its many beneficial characteristics, we anticipate that the SDNA microneedle platform will serve as an effective alternative for drug delivery.

Formulation and characterisation of dissolving microneedles for the transdermal delivery of therapeutic peptides

The highly effective barrier properties of the stratum corneum (SC) limit the application of transdermal delivery to relatively small, lipophilic molecules. Microneedles (MNs) however, offer a route to effectively deliver a wide range of pharmaceuticals through the skin, bypassing the SC in a non-invasive and pain-free manner. This study presents a dissolving MN system composed of polyvinylpyrrolidone (PVP) and trehalose to encapsulate active pharmaceutical peptides within the MN matrix. Rapid systemic delivery is then achieved once the needles have penetrated the SC and dissolved in the interstitial fluid of the skin. A variety of characterisation techniques were carried out to determine the optimum formulation. A model peptide, polymyxin B, was then incorporated into the MN system and delivered through porcine skin. In addition, the activity of the model drug was monitored during all stages of the formulation process.

Novel Approach of Using Near-Infrared Responsive PEGylated Gold Nanorod Coated Poly(l-lactide) Microneedles to Enhance the Antitumor Efficiency of Docetaxel-Loaded MPEG-PDLLA Micelles for Treating an A431 Tumor.

The combination of chemotherapy and photothermal therapy (PTT) plays a significant role in synergistic tumor therapy. However, a high dosage of chemotherapy drugs or photothermal agents may cause series side effects. To overcome these challenges, we designed a near-infrared (NIR) responsive PEGylated gold nanorod (GNR-PEG) coated poly(l-lactide) microneedle (PLLA MN) system (GNR-PEG@MN) to enhance antitumor efficiency of docetaxel-loaded MPEG-PDLLA (MPEG-PDLLA-DTX) micelles for treating an A431 tumor. The as-made GNR-PEG@MNs contained only 31.83 ± 1.22 μg of GNR-PEG per patch and exhibited excellent heating efficacy both in vitro and in vivo. Meanwhile, GNR-PEG@MN with the height of 480 μm had good skin insertion ability and was harmless to the skin. On the other hand, GNR-PEG@MN had good heating transfer ability in vivo, and the tumor sites could reach 50 °C within 5 min. In comparison with chemotherapy and PTT alone, the combination of low dosage MPEG-PDLLA-DTX micelles (5 mg/kg) and GNR-PEG@MNs completely eradicated the A431 tumor without recurrence in vivo, demonstrating a remarkable synergetic effect. Hence, GNR-PEG@MN could be a promising carrier to enhance the antitumor effect of MPEG-PDLLA-DTX micelles for treating superficial tumors and is expected to have a great potential in clinical translation for human epidermoid cancer therapy.

Silk Fibroin Microneedles for Transdermal Vaccine Delivery.

Microneedles represent an exciting departure from the existing parenteral injection paradigm for drug delivery, particularly for the administration of vaccines. While the benefit of delivering vaccine antigens to immunocompetent tissue in the skin has been established, there have been varying degrees of success using microneedles to do so. Here, we investigate the use of silk fibroin protein to produce microneedles and evaluate their ability to deliver vaccines against influenza, Clostridium difficile, and Shigella. Fibroin protein from the silkworm Bombyx mori possesses suitable properties for use in a microneedle system, including all-aqueous processing, mechanical strength in dried formats, biocompatibility, and the ability to temperature stabilize biomacromolecules. As such, this biomaterial combines the processing and biocompatibility advantages of a dissolving microneedle system with the product stability and mechanical strength of coated insoluble microneedles. Through successful vaccination of mice against three separate antigens, we establish that silk fibroin is well-suited for use as a solid-coated microneedle delivery system and offers long-term potential similar to that of the leading microneedle biomaterials.

Near-infrared light triggered and separable microneedles for transdermal delivery of metformin in diabetic rats.

Near-infrared light triggered and separable microneedles (MNs) were fabricated by a unique molding method. The photothermal conversion agent (Prussian blue nanoparticles, PB NPs) and hypoglycemic drug (metformin) were embedded into the separable polycaprolactone (PCL) MNs arrowheads. These MNs arrowheads were capped on dissolving polyvinyl alcohol/polyvinyl pyrrolidone (PVA/PVP) solid supporting substrate. The as-fabricated MNs exhibited excellent photothermal conversion properties under near-infrared light (NIR) irradiation, causing the MNs arrowheads to melt due to the photothermal conversion of PB NPs. After applying on skin, the separable MNs arrowheads could be embedded in the skin due to the dissolution of supporting substrates after absorbing the interstitial fluid. When the embedded MNs arrowheads were exposed to NIR irradiation, the MNs arrowheads underwent a rapid thermal ablation from a solid to a liquid state, thus enabling the release of encapsulated metformin to be NIR modulated. They allowed on-demand control of timing and dose of the drug released. This suggests that the developed NIR-triggered and separable MNs are a promising transdermal drug delivery system that enables the patient or physician to adjust therapy precisely in an active manner, thus improving treatment efficiency and reducing side-effects.

Electrochemical Dissolution of a Microneedle System for Controlled Drug Release in Smart Devices

The majority of conventional controlled release technologies tend to be based around encapsulant systems in which a polymeric binder or gel typically responds to changes in the local environment in which the delivery device has been placed. The contents are often released when the particle, capsule, film or droplet is exposed to the appropriate physico-chemical trigger (typically a change in pH) with the time-release-dose delivery characteristics controlled through manipulation of the encapsulant formulation. In this communication, the adaptation of this core strategy for use in the next generation of transdermal microdevices or smart patch is explored. The core rationale of this work relates to the development of microneedle patches through which a drug could be transported across the skin barrier upon activation by an appropriate electrochemical trigger. The microneedle in this case serves as the entry point through the strateum corneum whilst acting as a physical barrier to the transport of the drug from a reservoir within the patch. Upon activation, the microneedle dissolves thereby allowing the release of the therapeutic agent as indicated in Figure 1A,B. The methodology proposed herein focuses on the ability to control the dissolution of the conductive composite microneedle through an application of a specified potential trigger. Central to this approach is the design and fabrication of a novel nanostructured conductive film based on a composite of carbon nanoparticles and cellulose acetate phthalate (CAP). This is created through the solvent cast method onto a silicone microneedle template shown in Figure 1C. Under normal conditions, the conductive coating remains intact but, upon imposing a reducing potential on the carbon composite layer, the local pH is increased which results in the solubilisation of the pH sensitive CAP binder components. The latter is the structural glue that holds the microneedle together and thus the subsequent swelling effectively leads to the dissolution of the microneedle architecture and the release of the drug. The presentation covers three aspects: the design and characterisation of the carbon composite microneedles, the ability to electrochemically manipulate the structural integrity of the needles and the ability to effect the controlled release of model drugs such as codeine, methotrexate and fentanyl. Figure 1

Modeling of Drug Delivery by A Pump Driven Micro-Needle Array System.

Background:Micro-needles were proposed as one of the alternatives to deliver drugs painlessly passing through stratum corneum in recent years. In this work, a mathematical model is presented to characterize the in fusion flow of a hollow micro-needle array driven by a micro-pump. Methods:By assuming the injection of each micro-needle undergoes a spherical expansion and diffusion, the model is able to calculate the time-varying expansion radius, and the diffusion boundary, provided that the material properties and the micro-needle system parameters are known. Results and Conclusion:The calculation results show that the expansion caused by the infusion of micro-needles stops and the flow rate drops to zero in a short time. However, the diffusion boundary is much bigger than the expansion and the infusion continues if the surrounding material is absorptive. The experimental results of jet infusion through a single needle in silicon rubber and polyacrylamide gel agree with the calculation results qualitatively.

Thermal Response of In Vivo Human Skin to Fractional Radiofrequency Microneedle Device.

Background. Fractional radiofrequency microneedle system (FRMS) is a novel fractional skin resurfacing system. Data on thermal response to this fractional resurfacing technique is limited. Objectives. To investigate histologic response of in vivo human skin to varying energy settings and pulse stacking of a FRMS in dark-skinned subjects. Methods. Two female volunteers who were scheduled for abdominoplasty received treatment with a FRMS with varying energy settings at 6 time periods including 3 months, 1 month, 1 week, 3 days, 1 day, and the time immediately before abdominoplasty. Biopsy specimens were analyzed using hematoxylin and eosin (H&E), Verhoeff-Van Gieson (VVG), colloidal iron, and Fontana-Masson stain. Immunohistochemical study was performed by using Heat Shock Protein 70 (HSP70) antibody and collagen III monoclonal antibody. Results. The average depth of radiofrequency thermal zone (RFTZ) ranged from 100 to 300 μm, correlating with energy levels. Columns of cell necrosis and collagen denaturation followed by inflammatory response were initially demonstrated, with subsequent increasing of mucin at 1 and 3 months after treatment. Immunohistochemical study showed positive stain with HSP70. Conclusion. A single treatment with a FRMS using appropriate energy setting induces neocollagenesis. This wound healing response may serve as a mean to improve the appearance of photodamaged skin and atrophic scars.

Near-Infrared Light-Activatable Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy.

Because of the aggressive and recurrent nature of cancers, repeated and multimodal treatments are often necessary. Traditional cancer therapies have a risk of serious toxicity and side effects. Hence, it is crucial to develop an alternative treatment modality that is minimally invasive, effectively treats cancers with low toxicity, and can be repeated as required. We developed a light-activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy and chemotherapy to superficial tumors and exert synergistic anticancer effects. This system consists of embeddable polycaprolactone MNs containing a photosensitive nanomaterial (lanthanum hexaboride) and an anticancer drug (doxorubicin; DOX), and a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone supporting array patch. Because of this supporting array, the MNs can be completely inserted into the skin and embedded within the target tissue for locoregional cancer treatment. When exposed to near-infrared light, the embedded MN array uniformly heats the target tissue to induce a large thermal ablation area and then melts at 50 °C to release DOX in a broad area, thus destroying tumors. This light-activated heating and releasing behavior can be precisely controlled and switched on and off on demand for several cycles. We demonstrated that the MN-mediated synergistic therapy completely eradicated 4T1 tumors within 1 week after a single application of the MN and three cycles of laser treatment. No tumor recurrence and no significant body weight loss of mice were observed. Thus, the developed light-activatable MN with a unique embeddable feature offers an effective, user-friendly, and low-toxicity option for patients requiring long-term and multiple cancer treatments.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Abstract A51: Intradermal delivery of polymeric nanoparticle based vaccine formulation using a hollow microneedle system

Abstract Introduction: Nanoparticle (NP)-based anticancer vaccine delivery systems provide a number of advantages including spatial repetitive display of the antigen, size dependent lymphatic and intracellular trafficking, and the depot effect of persistence and sustained release of antigens/adjuvants. However, the optimal NP delivery mode and route of administration need additional investigation. To achieve reproducible intradermal PLGA NP vaccine delivery using an in-vivo rat model, we used a hollow microneedle array system (1). The profile of the resulting humoral and cellular immune responses was compared to that resulting from conventional intramuscular (IM) injection of the same formulation. Methods: Immunostimulatory Nanoparticles (ISNPs) loaded with imiquimod and monophosphoryl Lipid A (MPL-A) were created using emulsion- solvent evaporation technique. All vaccine formulations for the in vivo study contained 2 mg of ISNPs as the adjuvant component. Antigen was given either in the form of soluble OVA solution or OVA encapsulated PLGA NPs at equivalent doses of OVA (16 µg). Two doses of vaccine (prime and boost) were administered to Crl:CD(SD) rats three weeks apart via IM or ID delivery. ID delivery was enabled by a plastic, hollow microneedle array with 18 microneedles, each <1mm in length, similar to those referenced previously (1). Blood collection was carried out three weeks after each dose. Serially-diluted serum was incubated with OVA coated plate for IgG1/IgG2a titer test by ELISA. Spleens were harvested at the endpoint of the experiment (three weeks after the booster dose) for splenocyte isolation. The T cell response was determined by pulsing the splenocyte culture with OVA antigen using a Mabtech rat Interferon gamma ELISpot kit. Results and Discussion: ISNPs promoted high antigen-specific antibody response in both IM and ID vaccination groups. Compared to the soluble form, antigen encapsulated in NPs triggered significantly stronger IgG1 antibody response three weeks after priming dose regardless of administration route. Not only did the NP formulation demonstrate faster kinetics in mounting antibody response, but the antibody avidity, determined by Urea ELISA, was also better in the OVA NP formulation when compared to the soluble OVA formulation, indicating quicker progress of antibody affinity maturation. However, three weeks after the boost, IgG1 level of all groups were comparable, reaching a titer plateau. In contrast to the IgG1 response, antigen OVA encapsulated in NPs and delivered intradermally via the microneedles resulted in the highest IgG2a titer among all experimental groups at both time points after both priming and booster doses. IgG2a is widely considered a surrogate biomarker for Th1 response, while IgG1 is a biomarker for Th2 response. The relative strength of Th1/Th2 response could be assessed from IgG1/IgG2a ratio (2). Among the different groups, ID delivery of the OVA NP formulation demonstrated the highest relative strength of Th1 response. This result was further confirmed by the secretion of Th1 cytokine Interferon gamma by splenocytes upon antigen recall response. These data suggest that for a NP vaccine carrier, the skin is a vaccination priming locus that enhances Th1 response, which is considered essential for effective induction of anti-tumor immunity. Conclusion: A polymer-based NP vaccine formulation delivered intradermally via hollow microneedles elicited robust humoral and cellular immunity. When compared to IM injection, the unique combination of the polymeric NP formulation and the ID route of administration led to an optimal Th1 immune response.

Poly-γ-glutamic acid microneedles with a supporting structure design as a potential tool for transdermal delivery of insulin

Incomplete insertion is a common problem associated with polymer microneedles (MNs) that results in a limited drug delivery efficiency and wastage of valuable medication. This paper presents a fully insertable MN system that is composed of poly-γ-glutamic acid (γ-PGA) MNs and polyvinyl alcohol (PVA)/polyvinyl pyrrolidone (PVP) supporting structures. The PVA/PVP supporting structures were designed to provide an extended length for counteracting skin deformation during insertion and mechanical strength for fully inserting the MNs into the skin. When inserted into the skin, both the supporting structures and MNs can be dissolved in the skin within 4min, thus quickly releasing the entire drug load from the MNs. To evaluate the feasibility and reproducibility of using the proposed system for treating diabetes, we administered insulin-loaded MNs to diabetic rats once daily for 2days. The results indicated that the hypoglycemic effect in the rats receiving insulin-loaded MNs was comparable to that observed in rats receiving subcutaneous insulin injections. The relative pharmacological availability and relative bioavailability of the insulin were in the range of 90–97%, indicating that the released insulin retained its pharmacological activity. We observed no significant differences in the plasma insulin concentration profiles between the first and second administrations, confirming the stability and accuracy of using the proposed MN system for insulin delivery. These results indicated that the γ-PGA MNs containing the supporting structure design enable complete and efficient delivery of encapsulated bioactive molecules and have great potential for the relatively rapid and convenient transdermal delivery of protein drugs. Statement of SignificanceIncomplete insertion of microneedles largely limits drug delivery efficiency and wastage of valuable medication. To address this problem, we developed a fully insertable poly-glutamic acid microneedles with a supporting structure design to ensure complete and efficient delivery of encapsulated drugs. The supporting structures were designed to provide an extended length for counteracting skin compressive deformation during puncture and mechanical strength for fully inserting the microneedles into the skin. When inserted into the skin, both the supporting structures and microneedles can be dissolved in the skin within 4min, thus quickly releasing the entire drug load. This study demonstrated that the proposed microneedle system featuring this unique design allows more convenient and efficient self-administration of drugs into the skin.

Phase‐Transition Microneedle Patches for Efficient and Accurate Transdermal Delivery of Insulin

Utilizing the unique virtue of polyvinyl alcohol (PVA) of forming microcrystalline domains as the cross‐linking junctions, a new microneedle system, phase‐transition microneedle (PTM) patch, is invented, which enables highly efficient transdermal delivery of insulin without depositing the needle tip materials to the skin. PTM, formed of biocompatible PVA as the main component, is sufficiently strong for its needle tip to penetrate the epidermis in the dry state, release preloaded cargos by absorbing body fluid in the dermis layer nearly as fast as subcutaneous injection, and retain mechanical toughness in the hydrated state to ensure complete removal from the skin. The microcrystalline cross‐linking enables a protein‐friendly fabrication process free of hazardous cross‐linking agents required for chemical and ionic cross‐linking. Pharmacokinetic and efficacy studies of insulin‐loaded PTM using pig models indicate a transdermal bioavailability over 20%, similar deviations and peak width, only 18 min behind Tmax, and lower glycated hemoglobin (HbA1c) as compared with injection pens. The complete removability of hydrated needle tips may endow PTM with an additional safety insurance, terminating medication whenever hypoglycemia becomes a concern. PTM patch is practically applicable to a variety of protein/peptide medicines requiring frequent dosing by offering painless administration, freedom of refrigeration, and minimal safety concerns.

A New Paradigm for Numerical Simulation of Microneedle-Based Drug Delivery Aided by Histology of Microneedle-Pierced Skin

Microneedle (MN) is a relatively recent invention and an efficient technology for transdermal drug delivery (TDD). Conventionally, mathematical models of MNs drug delivery define the shape of the holes created by the MNs in the skin as the same as their actual geometry. Furthermore, the size of the MN holes in the skin is considered to be either the same or a certain fraction of the length of the MNs. However, the histological images of the MN-treated skin indicate that the real insertion depth is much shorter than the length of the MNs and the shapes may vary significantly from one case to another. In addressing these points, we propose a new approach for modeling MN-based drug delivery, which incorporates the histology of MN-pierced skin using a number of concepts borrowed from image processing tools. It is expected that the developed approach will provide better accuracy of the drug diffusion profile. A new computer program is developed to automatically obtain the outline of the MNs-treated holes and import these images into computer software for simulation of drug diffusion from MN systems. This method can provide a simple and fast way to test the quality of MNs design and modeling, as well as simulate experimental studies, for example, permeation experiments on MN-pierced skin using diffusion cell. The developed methodology is demonstrated using two-dimensional (2D) numerical modeling of flat MNs (2D). However, the methodology is general and can be implemented for three dimensional (3D) MNs if there is sufficient number of images for reconstructing a 3D image for numerical simulation. Numerical modeling for 3D geometry is demonstrated by using images of an ideal 3D MN. The methodology is not demonstrated for real 3D MNs, as there are not sufficient numbers of images for the purpose of this paper.