Painless Drug Delivery Research Articles

FDM printing of microneedles based on biocompatible and biodegradable thermoplastic polymers

AbstractMicroneedles are an emerging class of transdermal drug delivery systems for biomedical applications. These devices allow minimally invasive and painless drug delivery, making them an attractive alternative to hypodermic injections. This paper focuses on the study of polymer‐based solid microneedles fabrication process using the fused deposition modeling (FDM) method. Biodegradable and biocompatible polymers are selected as printing materials. For this study, the thermoplastic polylactic acid (PLA), currently used for FDM microneedle preparation was selected. To overcome the potential brittleness of PLA during transdermal application, two other materials are also studied: polycaprolactone (PCL) and a PLA/PCL blend. The effect of 3D printing parameters on the dimensional accuracy of the microneedles is studied to determine the optimum printing conditions for each filament. In addition, the dimensions and/or geometry of the microneedles are modified to print its with minimal dimensions. Then, a post‐fabrication chemical etching treatment is used to improve both, size and shape of the printed solid microneedles.

Nanozyme-Incorporated Microneedles for the Treatment of Chronic Wounds.

Acute wounds are converted to chronic wounds due to advanced age and diabetic complications. Nanozymes catalyze ROS production to kill bacteria without causing drug resistance, while microneedles (MNs) can break through the skin barrier to deliver drugs effectively. Nanozymes can be intergrateded into MNs delivery systems to improve painless drug delivery. It can also reduce the effective dose of drug sterilization while increasing delivery efficiency and effectively killing wounded bacteria while preventing drug resistance. This paper describes various types of metal nanozymes from previous studies and compares their mutual enhancement with nanozymes. The pooled results show that the MNs, through material innovation, are able to both penetrate the scab and deliver nanozymes and exert additional anti-inflammatory and bactericidal effects. The catalytic effect of some of the nanozymes can also accelerate the lysis of the MNs or create a cascade reaction against inflammation and infection. However, the issue of increased toxicity associated with skin penetration and clinical translation remains a challenge. This study reviews the latest published results and corresponding challenges associated with the use of MNs combined with nanozymes for the treatment of wounds, providing further information for future research.

A novel and biocompatible photopolymerizable resin based on cyclohexanedimethanol‐dimetacrylate designed to light‐print microneedles

AbstractMicroneedles offer a promising avenue for painless drug delivery through micro‐perforation, and additive manufacturing, particularly stereolithography, has proven effective for their fabrication. This study focuses on developing a novel biocompatible resin for 3D printing microneedles. Spectroscopic methods are employed to confirm the structures of all intended resin monomers, with a specific analysis of the crystallographic structure of cyclohexanedimethanol methacrylate (CDMM) using x‐ray diffraction. The results indicate that CDMM crystallizes in the monoclinic system, aligning with the P21/c space group. The fabricated conical microneedles, standing at approximately 655 μm in height, underwent thorough mechanical and thermal characterization. Depth analyses of micro‐perforations in Parafilm M and pig skin were performed using optical coherence tomography and histological sections, demonstrating successful penetration through the stratum corneum and epidermal layers into the superficial dermal layer (1.5–4 mm thickness) without affecting nerve endings. Cytocompatibility tests affirm the biocompatibility of the microneedles. This work highlights the potential of the newly developed biocompatible material for printable drug delivery systems, emphasizing microneedles and other implant forms.

Advances of Microneedle Patch in Diabetic Wound Healing

Wound healing is an intricate and orderly process of events that occur in response to external trauma, resulting in tissue repair and reconstruction. This process typically involves three phases, including inflammation, angiogenesis, and extracellular matrix remodeling, and any disruption to this process may delay the healing of the wound. Chronic wounds associated with diabetes, in particular, are notorious because they are difficult to handle in a timely and orderly manner. During the treatment of the disease, drugs usually accumulate in the stratum corneum due to the skin barrier, leading to a reduction of the drug's bioavailability. Encouragingly, among the treatment strategies, microneedles (MNs) represent a novel and painless drug delivery method that promotes wound healing in diabetic patients by enabling the drug to reach the dermal layer efficiently. In this review, recent advances of MNs in the treatment of diabetic wound healing are summarized by categorizing the designs and strategies. We finally provide an outlook on the prospects and challenges of MN-based therapies for diabetic wound healing in the future.

Hydrogel-Forming Microneedles with Applications in Oral Diseases Management

Controlled drug delivery in the oral cavity poses challenges such as bacterial contamination, saliva dilution, and inactivation by salivary enzymes upon ingestion. Microneedles offer a location-specific, minimally invasive, and retentive approach. Hydrogel-forming microneedles (HFMs) have emerged for dental diagnostics and therapeutics. HFMs penetrate the stratum corneum, undergo swelling upon contact, secure attachment, and enable sustained transdermal or transmucosal drug delivery. Commonly employed polymers such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone are crosslinked with tartaric acid or its derivatives while incorporating therapeutic agents. Microneedle patches provide suture-free and painless drug delivery to keratinized or non-keratinized mucosa, facilitating site-specific treatment and patient compliance. This review comprehensively discusses HFMs’ applications in dentistry such as local anesthesia, oral ulcer management, periodontal treatment, etc., encompassing animal experiments, clinical trials, and their fundamental impact and limitations, for example, restricted drug carrying capacity and, until now, a low number of dental clinical trial reports. The review explores the advantages and future perspectives of HFMs for oral drug delivery.

Microneedles: Recent advances and development in the field of transdermal drug delivery technology

Microneedles have emerged as a novel therapeutic modality in transdermal drug delivery system. The concept of microneedle has caught attention of the investigators owing to its immense utilities and unique promising features of painless drug delivery by crossing the impervious barrier layer of stratum corneum of skin efficiently in a non-invasive manner. It provides excellent therapeutic potency and bioavailability of drugs compared to most other conventional drug delivery routes. Microneedles have supremacy on avoidance of pre-systemic first pass metabolism of administered drugs, better patient compliance and avoidance of gastric irritation which outweighs the adherence of other conventional drug delivery system. As a trendy approach in the pharmaceutical and biomedical field, its applications are constantly evolving due to its ability to deliver large molecules with ionic and hydrophilic nature along with delivery of other products like insulin, vaccine, vitamins, peptides, oligonucleotides etc. The review provides an insight on recent advances of microneedles by emphasizing on various types, fabrication techniques, fabrication materials and various pharmaceutical and biomedical applications of microneedles along with some approved marketed microneedle products.
 Keywords: Microneedles, types, fabrication techniques, commercial products

A Review on Transdermal Drug Delivery: Design, Evaluation and Approach towards Painless Drug Delivery System

Transdermal drug delivery systems were developed in order to overcome the difficulties associated with oral drug delivery. Through an adhesive patch affixed to the skin, transdermal patches deliver medications into the bloodstream. This treatment may benefit damaged areas of the body. Unlike oral, topical, intramuscular, and intravenous drug delivery methods, transdermal drug delivery enables controlled drug release into the body. Body heat is used to melt thin layers of medication embedded in the adhesive through the transdermal patch's porous membrane. As a barrier against foreign invaders, the skin serves as a protective layer. A medication with a molecular weight less than 500 Da can penetrate the stratum corneum through the outermost layer of the skin. An overview of transdermal patches is provided in this review article, including matrix patches, reservoir patches, membrane patches, micro reservoir patches, and patches that contain drugs in adhesive forms. These dosage forms have also been evaluated using various methods.

Determination of Transdermal Rate of Metallic Microneedle Array through an Impedance Measurements-Based Numerical Check Screening Algorithm.

Microneedle systems have been widely used in health monitoring, painless drug delivery, and medical cosmetology. Although many studies on microneedle materials, structures, and applications have been conducted, the applications of microneedles often suffered from issues of inconsistent penetration rates due to the complication of skin-microneedle interface. In this study, we demonstrated a methodology of determination of transdermal rate of metallic microneedle array through impedance measurements-based numerical check screening algorithm. Metallic sheet microneedle array sensors with different sizes were fabricated to evaluate different transdermal rates. In vitro sensing of hydrogen peroxide confirmed the effect of transdermal rate on the sensing outcomes. An FEM simulation model of a microneedle array revealed the monotonous relation between the transdermal state and test current. Accordingly, two methods were primely derived to calculate the transdermal rate from the test current. First, an exact logic method provided the number of unpenetrated tips per sheet, but it required more rigorous testing results. Second, a fuzzy logic method provided an approximate transdermal rate on adjacent areas, being more applicable and robust to errors. Real-time transdermal rate estimation may be essential for improving the performance of microneedle systems, and this study provides various fundaments toward that goal.

Personalized and Programmable Microneedle Dressing for Promoting Wound Healing.

Microneedle (MN) dressings, with the ability of transdermal drug delivery, have played an essential role in the field of wound healing. However, patients may still feel uncomfortable when sensitive unhealing wounds are pieced by strong needles. Here, inspired by the structure of mosquito mouthparts, which possess a fixation part and a liquid-transferring part, we present a novel MN wound dressing with superfine needle tips, personalized pattern design, programmable needle length, and multiple mechanical strengths for intelligent and painless drug delivery. By simply stretching the silicone rubber (Ecoflex) molds before engraving, superfine MNs can be formed in the restored molds. Meanwhile, by utilizing intelligent image recognition, precise treatment for irregular wounds is achieved. Notably, combined with temperature-responsive N-isopropylacrylamide (NIPAM) hydrogel and inverse opal (IO) photonic crystals (PCs), a controllable drug release system has been achieved on MN dressings. Moreover, the performance of the MN dressing in facilitating wound recovery has been demonstrated by full-thickness skin wounds of a mouse model. These results indicate that novel personalized and programmable MN wound dressings are of considerable value in the field of wound management.

Laser microporation: A promising field in transdermal drug delivery

<p>Topical therapy is an expanding field not only in dermatology but also in other fields of medicine. An expanding list of systemic medications have been applied topically in several dermatologic conditions. Drugs applied topically have the advantage of fewer side effects, and bypassing the first-pass effect. Also, painless drug delivery which is especially encouraging in children, makes transdermal drug delivery even more appealing. </p>

Studies on local anesthetic lidocaine hydrochloride delivery via photo-triggered implantable polymeric microneedles as a patient-controlled transdermal analgesia system

This study aimed to develop photo-triggered implantable polymeric microneedles (MNs) for successful drug delivery in a transdermal analgesia system. The prepared iron oxide nanoparticles (Fe3O4NPs) were coated with polydopamine (PDA) followed by polyvinylpyrrolidone (PVP) and polycaprolactone (PCL). While the PCL/PVP-Fe3O4NPs synthesis, the absorption band of PVP at 1656 cm−1 shifted to 1665 cm−1 which indicate the presence of interaction between Fe+ and C = O groups. The size and morphology of PCL/PVP-Fe3O4NPs were examined by scanning electron microscope and transmission electron microscope (SEM and TEM) analysis. The results confirmed that the prepared PCL/PVP-Fe3O4NPs were spherical with sizes ranging from 9 to 11 nm. The lidocaine hydrochloride content in the microneedles was 3.72 ± 0.31 mg and A + 2.2S ≤ L representing that the drug was uniformly distributed. The insertion ability of lidocaine hydrochloride@PCL/PVP-Fe3O4NPs-DMNs was tested by porcine skin. The results demonstrated outstanding insertion ability and potential for drug delivery. In addition, near-infrared (NIR) irradiation has the potential to penetrate the skin and enhance lidocaine hydrochloride-releasing activity. The in vivo experimental data confirmed that lidocaine hydrochloride@PCL/PVP-Fe3O4NPs-DMNs allowed for painless drug delivery by breaking the barrier of the stratum corneum. To conclude, lidocaine hydrochloride can be safely delivered through the transdermal analgesic system, with a quick onset time.

Current Updates in Transdermal Therapeutic Systems and Their Role in Neurological Disorders.

The transdermal therapeutic system plays an important role in the treatment of neuropathic pain. Transdermal drug delivery is considered an ideal therapeutic approach for the management of chronic neurological disorders in the elderly population. It is a simple to use, non-invasive and painless drug delivery system, which provides sustained therapeutic plasma levels of drug for an extended period. Moreover, it bypasses the first-pass metabolism of the active agent, improves bioavailability and reduces undesired adverse effects, which in turn improves patient compliance. Several transdermal delivery systems are currently under investigation for the treatment of Parkinson's syndrome, Alzheimer's disorders, and Neurological pain. Drug delivery via the transdermal route is proposed as an alternative remedy to overcome the drawbacks associated with the conventional dosage forms for chronic neurological disorders. The management of Alzheimer's disease via transdermal drug administration exhibits the greatest therapeutic improvements in the treatment of cognition and global functioning among neuropathic patients. Technological breakthroughs in transdermal drug administration such as the microreservior system, microneedles, metered-dose transdermal spray (MDTS), needle-free injections, and ultrasound-based transdermal therapeutic systems have been successfully used to treat neurological disorders. For example, microneedle (MN) is a highly efficient and versatile device due to its distinctive properties. Ultrasounds have been very popular for the delivery of bioactive agents across the skin barrier. This review focuses on the recent advances of various technologies employed in the transdermal therapeutic systems and their applications on neurological disorders for achieving therapeutic outcomes on patients.

Medicsen Smartpatch: A New Approach to Diabetes Management

Introduction: Diabetes is a metabolic disorder characterized by a dysregulation of the glucose levels. With insulin being the main drug to be administrated for glucose levels modulation, it needs to be injected subcutaneously with daily injections, which can lead to poor patient compliance, apart from several side-effects. Although other administration methodologies have been investigated (oral or inhaled insulin), they show enough drawbacks to not to be consider as feasible alternatives for diabetes therapy. That′s why Medicsen has developed a Smartpatch that integrates a wide range of technologies, with the purpose of ensuring the correct insulin delivery from the skin′s surface to the bloodstream using a non-invasive and painless drug delivery method through a phenomenon induced by sonophoresis. Materials and Methods: Several in vitro and in vivo tests have been performed to prove the efficacy and safety of the technology, allowing us to collect experimental evidence through different methodologies that demonstrate the therapeutic potential of the device. Among these methodologies, permeability studies using Franz diffusion Cell and swine models (that prove efficacy of the technology) as well as safety studies, for both the insulin and the skin are highlighted. Results: In voltage experiments, the mean time for the disappearance of the membrane potential between the compartments separated by skin was: 334.7 (SD+/-103.6) seconds. Regarding the slope of the voltage line, as an approximation to the transfer speed, an arithmetic mean of (μ)= 0.0164 Mvolts/sec (+/- SD(σ): 0.006) was obtained. No significant differences were found between the circular dichroism spectra of samples (minimum peak at 219nm (sd+/-8.31) and that of the standard, which suggests that the molecular structure of insulin maintains stability. In the same way, HPLC studies shows no variability between the standard and all groups tested. Regardin skin safety, SEM images shows no significant damage to the skin, and ELISA test for TNF α and IL-2, as well as other biochemical tests, show no differences between control and samples. On In vivo experiments with our technology, glucose changes are comparable to those evoked through direct drug injection using conventional syringes. Lastly, the technology proved to be effective in the delivery of insulin through the skin in a non-invasive way, as observed in a Franz Diffusion Cell system and in the in vivo model of blood glucose reduction. Conclusions: Results observed during in vitro and in vivo studies indicate that the technology developed by Medicsen is effective and safe for the patient and the insulin. Following steps, including human trials, will be critical to fully demonstrate its potential in the treatment of diabetes.

Limpet Tooth‐Inspired Painless Microneedles Fabricated by Magnetic Field‐Assisted 3D Printing

AbstractMicroneedle arrays show many advantages in drug delivery applications due to their convenience and reduced risk of infection. Compared to other microscale manufacturing methods, 3D printing easily overcomes challenges in the fabrication of microneedles with complex geometric shapes and multifunctional performance. However, due to material characteristics and limitations on printing capability, there are still bottlenecks to overcome for 3D printed microneedles to achieve the mechanical performance needed for various clinical applications. The hierarchical structures in limpet teeth, which are extraordinarily strong, result from aligned fibers of mineralized tissue and protein‐based polymer reinforced frameworks. These structures provide design inspiration for mechanically reinforced biomedical microneedles. Here, a bioinspired microneedle array is fabricated using magnetic field‐assisted 3D printing (MF‐3DP). Micro‐bundles of aligned iron oxide nanoparticles (aIOs) are encapsulated by polymer matrix during the printing process. A bioinspired 3D‐printed painless microneedle array is fabricated, and suitability of this microneedle patch for drug delivery during long‐term wear is demonstrated. The results reported here provide insights into how the geometrical morphology of microneedles can be optimized for the painless drug delivery in clinical trials.

Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK

IntroductionExisting HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence. The objective of this study was to develop a novel physiologically-based pharmacokinetic (PBPK) model to simulate the systemic pharmacokinetics of cabotegravir and rilpivirine MAPs using the intradermal route. MethodsThe developed PBPK models were qualified against observed pharmacokinetic data after intramuscular (IM) and intradermal administration of long-acting nanoformulated rilpivirine to rats, and for IM administration of both drugs to healthy adults. Qualified models were then utilised to estimate suitable MAP characteristics (e.g. nanoformulation dose and release rates) and inform dosing strategies to maintain plasma concentrations above target trough concentrations for the designated dosing interval. ResultsPBPK models simulated q4-weekly loading and maintenance doses of 360 mg and 180 mg for long-acting formulated cabotegravir between the release rates of 1 × 10−3–3 × 10−3h−1 and 1 × 10−3–1.5 × 10−3h−1 respectively, for a 70 kg adult. Estimated patch size was 60 cm2 for a 360 mg dose of cabotegravir. For q4-weekly dosing, rilpivirine required a 1080 mg loading dose and a 540 mg maintenance dose with release rates of 1.5 × 10−3–2.5 × 10−3h−1 and 5 × 10−4–1 × 10−3h−1, respectively. Weekly dosing was also evaluated to assess the potential application from a smaller patch size. The ability to self-administer via a patch that is only left in place for a short duration makes longer durations less important than for some other long-acting approaches. Weekly cabotegravir required 60 mg between release rates 7 × 10−3–9 × 10−3h−1 and rilpivirine required 270 mg and 180 mg respectively between release rates of 7 × 10−3–9 × 10−3h−1. DiscussionThis model estimated optimal dose and release rates for cabotegravir and rilpivirine MAPs. Our approach provides a computational platform to support rational development of intradermal administration strategies to tackle problems associated with chronic oral ARV administration.

Transdermal patches: Design and current approaches to painless drug delivery.

Use of transdermal patches can evade many issues associated with oral drug delivery, such as first-pass hepatic metabolism, enzymatic digestion attack, drug hydrolysis and degradation in acidic media, drug fluctuations, and gastrointestinal irritation. This article reviews various transdermal patches available in the market, types, structural components, polymer role, and the required assessment tools. Although transdermal patches have medical applications for smoking cessation, pain relief, osteoporosis, contraception, motion sickness, angina pectoris, and cardiac disorders, advances in formulation development are ongoing to make transdermal patches capable of delivering more challenging drugs. Transdermal patches can be tailored and developed according to the physicochemical properties of active and inactive components, and applicability for long-term use. Therefore, a number of chemical approaches and physical techniques for transdermal patch development are under investigation.

Towards a versatile point-of-care system combining femtosecond laser generated microfluidic channels and direct laser written microneedle arrays

Microneedle-based microfluidic systems have a great potential to become well-accepted medical devices for simple, accurate, and painless drug delivery and lab-on-a-chip diagnostics. In this work, we report on a novel hybrid approach combining femtosecond direct laser written microneedles with femtosecond laser generated microfluidic channels providing an important step towards versatile medical point-of-care systems. Hollow microneedle arrays are fabricated by a laser system designed for two-photon polymerization applications. Compression tests of two different types of truncated cone-shaped microneedle arrays prepared from OrmoComp® give information about the microneedle mechanical strength, and the results are compared to skin insertion forces. Three-dimensional microchannels are directly created inside PMMA bulk material by an ultrashort pulse laser system with vertical channels having adjustable cross-sectional areas, which allow attaching of microneedles to the microfluidic system. A comprehensive parameter study varying pulse duration and repetition rate is performed on two-photon polymerization to identify an optimal laser power range for fabricating microneedles using the same pulse duration and repetition rate as for microchannels. This addresses the advantage of a single laser system process that overcomes complex fabrication methods. A proof of concept flow test with a rhodamine B dye solution in distilled water demonstrates that the combination of microneedles and microchannels qualifies for microfluidic injection and extraction applications.

Insights into the mechanism of a novel shockwave-assisted needle-free drug delivery device driven by in situ-generated oxyhydrogen mixture which provides efficient protection against mycobacterial infections

BackgroundNeedle-free, painless and localized drug delivery has been a coveted technology in the area of biomedical research. We present an innovative way of trans-dermal vaccine delivery using a miniature detonation-driven shock tube device. This device utilizes~2.5 bar of in situ generated oxyhydrogen mixture to produce a strong shockwave that accelerates liquid jets to velocities of about 94 m/s.MethodOxyhydrogen driven shock tube was optimized for efficiently delivering vaccines in the intradermal region in vivo. Efficiency of vaccination was evaluated by pathogen challenge and host immune response. Expression levels of molecular markers were checked by qRT-PCR.ResultsHigh efficiency vaccination was achieved using the device. Post pathogen challenge with Mycobacterium tuberculosis, 100% survival was observed in vaccinated animals. Immune response to vaccination was significantly higher in the animals vaccinated using the device as compared to conventional route of vaccination.ConclusionA novel device was developed and optimized for intra dermal vaccine delivery in murine model. Conventional as well in-house developed vaccine strains were used to test the system. It was found that the vaccine delivery and immune response was at par with the conventional routes of vaccination. Thus, the device reported can be used for delivering live attenuated vaccines in the future.

Device-assisted transdermal drug delivery.

Transdermal drug delivery is a prospective drug delivery strategy to complement the limitations of conventional drug delivery systems including oral and injectable methods. This delivery route allows both convenient and painless drug delivery and a sustained release profile with reduced side effects. However, physiological barriers in the skin undermine the delivery efficiency of conventional patches, limiting drug candidates to small-molecules and lipophilic drugs. Recently, transdermal drug delivery technology has advanced from unsophisticated methods simply relying on natural diffusion to drug releasing systems that dynamically respond to external stimuli. Furthermore, physical barriers in the skin have been overcome using microneedles, and controlled delivery by wearable biosensors has been enabled ultimately. In this review, we classify the evolution of advanced drug delivery strategies based on generations and provide a comprehensive overview. Finally, the recent progress in advanced diagnosis and therapy through customized drug delivery systems based on real-time analysis of physiological cues is highlighted.

Laser microporation: A promising field in transdermal drug delivery

<p>Topical therapy is an expanding field not only in dermatology but also in other fields of medicine. An expanding list of systemic medications have been applied topically in several dermatologic conditions. Drugs applied topically have the advantage of fewer side effects, and bypassing the first-pass effect. Also, painless drug delivery which is especially encouraging in children, makes transdermal drug delivery even more appealing. </p>