Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil.

To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aß 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.

An Update on the Routes for the Delivery of Donepezil.

Dementia is a significant public health problem in the 21st century. Alzheimer's disease (AD) is an essential factor in dementia. Currently, the drugs used for the treatment of AD are mainly acetylcholine inhibitors (AChEIs). As an AChEI, donepezil (DP) can improve patients' cognitive ability with low side effects and has been accepted by most patients and doctors. For AD patients, the dosage regimen is also crucial due to aging and diseases. Although there are DP oral tablets on the market, there are still many problems to be solved. At present, more and more research is conducted to optimize the route of administration of DP to improve the self-administration of patients. The research fields of DP administration include oral administration, injection administration, intranasal administration, and transdermal administration. This Review is to present the development of different DP administrations and evaluates the advantages and limitations of those works, hoping to optimize the DP dosage regimen for AD patients.

Dissipative Particle Dynamics Aided Design of Drug Delivery Systems: A Review.

A nanocarrier drug delivery system, effectively assisting to improve the solubility, bioavailability, and targeting of drugs in the human body, is a crucial means for treating cancer and other diseases. However, drug carriers usually possess multiple components and complex microstructures, and studies on the formation mechanism and internal structural details of nanocarriers are still incomplete by experimental methods. In order to overcome this adversity, the dissipative particle dynamics (DPD) simulation has been widely used owing to its unique simulation time-space scale and satisfying computing efficiency. In the past decades, more and more kinds of complex nanocarriers with various structures have been successfully characterized, and influencing factors in mounting numbers have also been parametrized. Not only emphasizing on the self-assembly structure of nanocarriers, but the application area of DPD simulation has also become a complete system covering from the synthesis and preparation to interaction with the biomembrane. This article reviews the application of DPD simulations in drug delivery systems. We have established the connection between existing studies and proposed some outlooks for the further combination between DPD simulation and the design of a drug delivery system.

Toward a solid microneedle patch for rapid and enhanced local analgesic action.

Analgesic creams find widespread application as adjuncts for localized anesthesia prior to surgical procedures. Nevertheless, the onset of analgesic action is protracted due to the skin barrier's inherent characteristics, which necessitates prolonged intervals of patient and clinician waiting, consequently impinging upon patient compliance and clinician workflow efficiency. In this work, a biodegradable microneedles (MNs) patch was introduced to enhance the intradermal administration of lidocaine cream to achieve rapid analgesia through a minimally invasive and conveniently accessible modality. The polylactic acid (PLA) MNs were mass-produced using a simple hot-pressing method and served the purpose of creating microchannels across the skin's surface for rapid absorption of lidocaine cream. Optical and electron microscopes were applied to meticulously scrutinize the morphology of the fabricated MNs, and the comprehensive penetration tests involving dynamometer tests, evaluation on porcine cadaver skin, artificial film, optical coherence tomography (OCT), transepidermal water loss, and analysis on rats' skins, demonstrated the robust mechanical strength of PLA MNs for successful intradermal penetration. The behavioral pain sensitivity tests on living rats using Von Frey hair filaments revealed that the MN-assisted lidocaine treatment expeditiously accelerated the onset of action from 40 to 10 min and substantially enhanced the efficacy of localized anesthesia. Furthermore, different treatment protocols encompassing the sequence of drug application relative to MN treatment, MN dimensions, and the frequency of MN insertions exhibited noteworthy influence on the resultant local anesthesia efficacy. Together, these results demonstrated that the lidocaine cream followed by diverse PLA MN treatments would be a promising strategy for rapid clinical local anesthesia with wide-ranging applications.

Dual-Action Psoriasis Therapy: Antiproliferative and Immunomodulatory Effects via Self-Locking Microneedles.

Psoriasis is a chronic, immune-mediated disorder characterized by immune regulation disorders and abnormal keratinocyte proliferation. Deucravacitinib (Deu), a selective oral Tyrosine Kinase 2 (TYK2) inhibitor, shows promise in treating psoriasis but may cause systemic side effects and fail to address persistent localized thickened lesions. Herein, a self-locking microneedle (MN) patch with a polyvinyl alcohol (PVA) inner ring loaded with Deu is developed, designed to penetrate the transdermal barriers and dissolve rapidly, downregulating the IL-23/IL-17 pathway and serve as the first line of defense against the spread of skin-originated inflammation. Additionally, Calcipotriol (Cal), a vitamin D derivative, is incorporated into a methacrylated hyaluronic acid (HAMA) backing layer and outer ring that mimics occlusive administration, maintaining localized skin surface retention for prolonged anti-proliferative therapy. The Deu@Cal MN demonstrates satisfactory adhesiveness due to swelling-mediated mechanical interlocking via the outer ring, ensuring targeted drug release at lesion site. Besides its effectiveness in alleviating both skin inflammation and proliferation, it inhibits the differentiation of Th17 cells in the spleen, suggesting potential to reduce systemic inflammation. These findings offer a new therapeutic approach for treating psoriasis and other autoimmune and inflammatory conditions.

Microneedles: a novel strategy for wound management.

Wound management is a serious concern worldwide, inflicting a huge social and economic burden on patients and healthcare systems, and research into efficient wound-management measures is crucial. Although advances have been made in traditional wound dressings for wound management to date, the complicated environment near the wound leads to inadequate drug absorption for achieving the intended therapeutic impact. Microneedles, a novel transdermal drug delivery method, can improve wound-healing efficacy by breaking down the barriers at the wound site and enhancing drug delivery efficiency. In recent years, there have been many advanced types of research on the application of microneedles to wound management to address the difficulties encountered in the wound-healing process. This article summarizes and analyzes these research efforts, classifying them according to their distinct efficacy, and addresses them in five areas: hemostasis, antibacterial effects, proliferation, anti-scar, and wound monitoring. The article concludes with a review of the current state and limitations of microneedle patches and an outlook on the future direction of microneedles in wound management as a way to inspire more efficient and smarter wound-management strategies.

Microneedle-based technology for cell therapy: current status and future directions.

With the growing technological innovations in medical treatments, cell-based therapies hold great potential as efficient tools against various previously incurable diseases by restoring or altering the function of certain sets of cells. Along this line, an essential factor to determine the success of cell therapy is the choice of cell delivery strategy. In recent years, a novel trend is blooming in the application of microneedle systems, which are based on the miniaturization of multiple needles within a patch to the micrometer dimensions, aimed at the delivery of therapeutic cells to the target site with high efficiency and in a minimally invasive manner. This review aims to demonstrate the advantages of exploiting microneedle-based technology as a new tool for cell therapy. The advancements of microneedle-based strategies for cell delivery are summarized in terms of two categories: cell-free and cell-loaded microneedle systems. The majority of research on microneedle-based cell therapy has shown promising results for tissue regeneration, cancer immunotherapy, skin immune monitoring and targeted cell delivery. Finally, current challenges and future perspectives toward the development and application of microneedles for cell therapy are also discussed.

Thermosensitive hydrogel microneedles for controlled transdermal drug delivery.

By using the prominent merit of poly(N-isopropylacrylamide) (PNIPAm) that can reversibly switch from a linear state to a coiled state with the change in temperature, in this work, gelatin was grafted with carboxylic end-capped PNIPAm as the matrix material to fabricate a physical entanglement crosslinked hydrogel microneedles (MNs) patch that can control drug release after application on the skin. The crystallization of the drug during the fabrication process of MNs was decreased due to the thermo-reversible sol-gel transition of the matrix materials. In addition, to increase the mechanical strength of the MNs and to decrease the application time, the gelatin-g-PNIPAm (GP) MNs patch was mounted onto solid MNs to fabricate a rapidly separating MNs system (RS-GP-MNs). The combination of the rapidly separating technique and the thermosensitive hydrogel provides the combined ability to efficiently deliver drug-loaded MNs into the skin within few seconds and to control drug release within the skin. Through a series of tests, we found that RS-GP-MNs showed suitable lower critical solution temperature and adequate crosslinking speed for practical application. The hypoglycemic effect in diabetic mice was characteristically controlled by insulin release through RS-GP-MNs as compared to the MNs made from unmodified gelatin. The proposed RS-GP-MNs system is potentially applicable to various hydrophilic small molecular and peptide medicines that require frequent dosing, thus providing an effective, noninvasive, and painless administration method with minimal safety concerns. STATEMENT OF SIGNIFICANCE: 1. Hydrogel microneedles that can be reversibly triggered and controllably release drugs at body temperature were fabricated. 2. Hydrogel microneedles prepared from gelatin-g-PNIPAm can avoid the use of a molecular crosslinker that is toxic and difficult to be completely removed. 3. Gelatin-g-PNIPAm with thermosensitive property showed appropriate molecular interactions with the drug and slowed down the crystallization speed of the drug in the solution.

A high-dosage microneedle for programmable lidocaine delivery and enhanced local long-lasting analgesia.

Considering the staggering global prevalence of local pain affecting hundreds of million individuals, it is of great significance to develop advanced dosage forms or delivery systems for analgesic therapy to fulfill clinical applicability. In this study, a hydrogel microneedles (MNs) system made out of gelatin-methacryloyl (GelMA) was designed to deliver lidocaine hydrochloride (LiH) in a sustained manner, and the drug loading capacity of the GelMA MNs was increased considerably by using the backing layer reservoir. The in vitro and in vivo tests showed that the fabricated GelMA MNs are strong enough for reliable skin application, and achieve high drug delivery efficiency as compared with the commercial lidocaine patches. The Spared-nerve injury (SNI) model of rats was also prepared to test behavioral pain sensitivity in response to mechanical stimuli, which proved that the LiH/GelMA MNs can enhance and prolong the anesthetic effect of LiH. In addition, with biosafety evaluation in rats, the MNs treated site restored to normal appearance within several hours of application and no dermatosis-related side effects or behavior disorders were observed during the experiment. Together these results indicated that the use of GelMA MNs for transdermal delivery of LiH is an effective, safe and simple treatment method to provide a better choice for local long-lasting analgesia.

Dissolving microneedle rollers for rapid transdermal drug delivery.

Dissolving microneedle patch (DMNP) is a minimally invasive and painless self-administration device. However, due to skin deformation, it is difficult to apply it on the large areas of skin or curved skin as the patch size increased for DMNP. Here, we propose a polyvinyl alcohol (PVA)-based dissolving microneedle roller (DMNR) device that can be used for delivering drugs rapidly on the large surface areas or curved skin and does not need to be attached on the skin all the time during drug delivery. The hypoglycemic effect of insulin-loaded DMNRs for transdermal delivery of insulin was studied on the type 1 diabetic rat models. It was found that the insulin-loaded DMNR has an immediate and effective hypoglycemic effect that the blood glucose level reduced below to 50% of original blood glucose at 1 h after DMNRs administrated.

Improved imiquimod-induced psoriasis like dermatitis using microneedles in mice.

Psoriasis is a chronic inflammatory skin disease, in which the key features are epidermis hyperplasia, hyper-keratinization, leading to low drug absorption. As an approach of transdermal drug delivery, the microneedle (MN) has received increasing attentions for its painless penetration and efficient administration. In this study, we fabricated polylactic acid polymer MNs with hot-press method and established a psoriasis-like skin inflammation model in ear and dorsal skin of mice by topical application of imiquimod (IMQ). The dynamometer and insertion test of MNs into parafilm and skin of mice were done, revealing that the MNs have sufficient mechanical properties to insert parafilm and skin of mice. The two methods (apply calcipotriol (CAL) directly and pre-treat with MNs before applying CAL) were used to treat psoriasis and observe the skin inflammation, including skin and epidermal thickening, spleen weight gain, inflammatory cell infiltration, and expression of inflammatory cytokines of TNF-α. Both methods have a therapeutic effect and the effect of the MN pretreatment group is better. In addition, there are statistical differences between the two groups (P < 0.05). These features indicated that the MNs may be promising in future clinical applications in improving the imiquimod-induced psoriasis like dermatitis.