Microneedle-based interstitial fluid extraction for drug analysis:Advances,challenges,and prospects / 药物分析学报

Similar to blood,interstitial fluid(ISF)contains exogenous drugs and biomarkers and may therefore substitute blood in drug analysis.However,current ISF extraction techniques require bulky instruments and are both time-consuming and complicated,which has inspired the development of viable alterna-tives such as those relying on skin or tissue puncturing with microneedles.Currently,microneedles are widely employed for transdermal drug delivery and have been successfully used for ISF extraction by different mechanisms to facilitate subsequent analysis.The integration of microneedles with sensors enables in situ ISF analysis and specific compound monitoring,while the integration of monitoring and delivery functions in wearable devices allows real-time dose modification.Herein,we review the progress in drug analysis based on microneedle-assisted ISF extraction and discuss the related future opportunities and challenges.

Application of microneedle-assisted percutaneous drug delivery system in treatment of rheumatoid arthritis:a review / 中国中药杂志

Rheumatoid arthritis(RA) is a chronic degenerative joint disease characterized by inflammation. Due to the complex causes, no specific therapy is available. Non-steroidal anti-inflammatory agents and corticosteroids are often used(long-term, oral/injection) to interfere with related pathways for reducing inflammatory response and delaying the progression of RA, which, however, induce many side effects. Microneedle, an emerging transdermal drug delivery system, is painless and less invasive and improves drug permeability. Thus, it is widely used in the treatment of RA and is expected to be a new strategy in clinical treatment. This paper summarized the application of microneedles in the treatment of RA, providing a reference for the development of new microneedles and the expansion of its clinical application.

Mechanical properties and immunotherapeutic effects of dissolving microneedles with different drug loadings based on hyaluronic acid

Abstract Improving vaccine immunity and reducing antigen usage are major challenges in the clinical application of vaccines. Microneedles have been proven to be painless, minimally invasive, highly efficient, and have good patient compliance. Compared with traditional transdermal drug delivery, it can effectively deliver a large-molecular-weight drug into the skin, resulting in a corresponding immune response. However, few studies have examined the relationship between microneedle loading dose and immune effects. In this study, the hyaluronic acid (HA) conical and pyramidal dissolving microneedles were prepared by the two-step vacuum drying method, respectively. The model drug ovalbumin (OVA) was added to HA to prepare dissolving microneedles with different loading amounts. The mass ratios of HA to OVA were 5:1, 5:3, and 5:5. The mechanical properties of the dissolving microneedles were characterized using nanoindentation and in vitro puncture studies. The immune effects of the matrix and drug content were studied in Sprague-Dawley (SD) rats. Finally, the diffusion behavior of OVA and the binding mode of HA and OVA in the microneedles were simulated using Materials Studio and Autodocking software. The experimental results showed that the conical microneedles exhibited better mechanical properties. When the mass ratio of HA to OVA was 5:3, the immune effect can be improved by 37.01% compared to subcutaneous injection, and achieved a better immune effect with relatively fewer drugs. This conclusion is consistent with molecular simulations. This study provides theoretical and experimental support for the drug loading and efficacy of microneedles with different drug loadings

Effect of microneedle radiofrequency combined with supramolecular salicylic acid on facial photoaging / 中华医学美学美容杂志

Objective:To explore the efficacy and safety of microneedle radiofrequency combined with supramolecular salicylic acid in improving facial photoaging.Methods:Thirty patients treated for facial photoaging were randomly divided into the combined treatment group and the microneedle radiofrequency group. All patients were female, aged between 30 and 50 years, with an average age of (39.4±4.1) years. The combined treatment group was treated with microneedle radiofrequency combined with supramolecular salicylic acid, and the Microneedle radiofrequency group was treated with microneedle radiofrequency alone. The patients were followed up 3 days, 7 days, 14 days, 28 days and 3 months after treatment. The results of VISIA, skin physiology and patients' satisfaction were used to compare the two groups of patients after treatment.Results:After 3 months of treatment, the skin pores (11.98±2.14 vs. 15.54±1.52), brown spots (12.40±1.85 vs. 15.84±1.42), ultraviolet spots (6.74±0.87 vs. 11.20±1.70), skin physiological status (transepidermal water loss): 11.84±1.80 vs 13.09±1.96 g/(h·m) 2, stratum corneum water content: 84.91±2.86 % vs 80.29±3.58 %, melanin index: 110.07±15.02 vs. 122.30±9.97, erythema index: 220.43±19.69 vs. 236.30±16.55), elasticity (75.98±3.94 vs. 69.89±3.58), epidermal thickness (1401.33±178.43 vs. 1217.13±139.77), skin color improvement (effective rate 86.7% vs. 40.0%) and patients' satisfaction (total satisfaction was 93.3% vs 67.0%) in the combined treatment group were significantly superior than those in the microneedle radiofrequency group, and the differences were statistically significant ( P<0.05). The reaction of moderate and severe erythema (the incidence rate 40.0% vs. 86.7%) and edema (the incidence rate 26.7% vs. 80.0%) in the combined treatment group was also significantly lower than that in the microneedle radiofrequency group ( P<0.05). No adverse pigmentation was reported in both groups after treatment. Conclusions:The combination of microneedle radiofrequency and supramolecular salicylic acid in the treatment of facial photoaging has definite clinical effect and high safety, which is worthy of clinical application.

Progress on drug delivery of iontophoresis / 药学实践杂志

Iontophoresis is a non-invasive physical permeation technology, which has been widely applied in transdermal and transmucosal administration. Compared with other permeation technologies, iontophoresis have the advantages of high efficacy, high patient compliance and controllable delivery dose. With the development of microneedles and nano-carrier technology, the combination of iontophoresis and other penetration promotion technologies has gradually become a research hotspot. The penetration mechanism and influencing factors of iontophoresis, and the study on the combination of iontophoresis with hydrogel, microneedles or nano-carrier were reviewed in this paper.

Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency

Growth hormone deficiency (GHD) has become a serious healthcare burden, and presents a huge impact on the physical and mental health of patients. Here, we developed an actively separated microneedle patch (PAA/NaHCO3-Silk MN) based on silk protein for sustained release of recombinant human growth hormone (rhGH). Silk protein, as a friendly carrier material for proteins, could be constructed in mild full-water conditions and ensure the activity of rhGH. After manually pressing PAA/NaHCO3-Silk MN patch to skin for 1 min, active separation is achieved by absorbing the interstitial fluid (ISF) to trigger HCO3 ‒ in the active backing layer to produce carbon dioxide gas (CO2). In rats, the MN patch could maintain the sustained release of rhGH for more than 7 days, and produce similar effects as daily subcutaneous (S.C.) injections of rhGH in promoting height and weight with well tolerated. Moreover, the PAA/NaHCO3-Silk MN patch with the potential of painless self-administration, does not require cold chain transportation and storage possess great economic benefits. Overall, the PAA/NaHCO3-Silk MN patch can significantly improve patient compliance and increase the availability of drugs, meet current unmet clinical needs, improve clinical treatment effects of GHD patients.

Advances of microneedle vaccines in transcutaneous immunization / 药学学报

Vaccination is an effective way to reduce the morbidity and mortality of infectious diseases. As a needle-free transcutaneous immunization (NF-TCI) vaccination technology, microneedles (MNs), composed of multiple micro-needles orderly attached to a substrate, can overcome the problems of low immune efficiency, poor compliance and waste of resources that exists in the conventional vaccination by injection, thus becoming a research hotspot in biomedicine. The microneedle vaccine can directly break through the stratum corneum barrier of the skin without touching nerves and blood vessels in the dermis, and effectively delivers the vaccine to the immune cells in the skin tissue to initiate the immune response of the body, thus triggering strong humoral and cellular immune processes. Vaccine delivery via the MNs system possesses the advantages of high safety, satisfying immune effect and practical economy, and shows great prospect in the prevention and treatment of infectious diseases and antineoplastic therapy. This article reviews the development background of MNs in transcutaneous immunization, the types of vaccine delivery, the factors affecting the immune effect, the problems to be solved and development direction in the future.

Preparation technology of platelet-rich-plasma lysate combined with hyaluronic acid microneedles and wound healing effect / 中国输血杂志

【Objective】 To investigate the application prospect of platelet-rich plasma lysate (PL) microneedles in the treatment of wound healing by optimizing the preparation process and evaluating the activity of platelet growth factor. 【Methods】 Firstly, hyaluronic acid (HA) was used as needle matrix material, and the concentration of HA was preliminarily determined by investigating the fluidity of HA solution, shape of needle, pressure change performance and puncture performance.Combined with the results of HA dissolution in PL, mechanical properties of PL microneedles and skin puncture, the preparation process of platelet-rich plasma lysis microneedles (PLMN) was optimized to investigate the growth factor activity of PLMN and evaluate the effect of PLMN on wound healing in rats. 【Results】 When the concentration of HA was 30 mg/mL, the solution had good fluidity.The HA microneedles could pierce three layers of sealing film, with the puncture rate at 70%, and the solution had good mechanical properties.When HA was dissolved in PL at a concentration of 30 mg/mL at 4℃, the solution had no crystallization and was with good fluidity.The prepared PLMN showed good needle shape and no bending under HD microscope and scanning electron microscope.In vitro transdermal simulation results showed that PLMN could penetrate 4 layers of sealing membrane, and the puncture rate of the first three layers was more than 85%.In vivo lysis experiment showed that PLMNs could be completely dissolved within 10 min after being inserted into the body.Forty minutes later, the micropores left after the insertion of the microneedle were almost closed, without redness, swelling, erythema and other adverse reactions.In vitro and in vivo transdermal experiments showed that clear blue holes were visible after PLMNs penetrated the skin stain, indicating that the microneedles could pierce the skin barrier.Growth factor detection results showed that the content of platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGFβ1) in platelet lysate were (17.67±1.23) ng/mL and (105.95±2.16) ng/mL, respectively.After PLMNs were prepared and stored at room temperature for 1 week, the content of PDGF-BB(ng/mL) and TGFβ1(ng/mL) were 15.48±2.12 and 56.26±1.53, respectively.Compared with PL(vs 17.67±1.23 and 105.95±2.16), the content of PDGF-BB and TGFβ1 decreased, but still maintained the activity of growth factors.The results of wound healing experiment in rats showed that the wound healing rate (%) of PLMN group on the third day was significantly different from that of the control group(52.51±6.15 vs 33.31±3.60, P<0.05). 【Conclusion】 The PLMN prepared in this experiment has good mechanical properties and can successfully pierce the skin cuticle.It can also maintain the activity of growth factors, and has a good effect on wound healing in rats, which provides a new idea for minimally invasive treatment in the field of tissue repair.

Immune effects of Clostridium difficile toxoid B vaccine formulated with different mucosal adjuvants through microneedle immunization / 中华微生物学和免疫学杂志

Objective:To investigate the immune effects of Clostridium difficile toxoid B (CdtB) vaccine formulated with different mucosal adjuvants through microneedle immunization, and to provide ideas for the prevention and treatment of Clostridium difficile infection. Methods:CdtB vaccine was prepared with purified Clostridium difficile toxin B(TcdB) after formaldehyde detoxification. Female BALB/c mice were immunized with different doses of vaccine alone or in combination with mucosal adjuvants. The titers of specific serum IgG and fecal IgA were detected at 0 d, 7 d, 14 d, 28 d and 42 d after immunization. The protective effects of CdtB vaccine were evaluated by cell neutralization assay and Clostridium difficile challenge infection. Results:(1) With the increase of immune dose, the mice immunized with CdtB vaccine alone by microneedle not only produced better serum specific IgG, but also had higher level of IgA in feces. (2) When the mice were immunized with CdtB vaccine containing LT or CTB adjuvant by microneedle, the trend of serum specific IgG titer in each group increased with the increase of immune dose, especially in the group containing LT adjuvant. There were significant differences in the trend of specific IgA titer in feces between the adjuvant groups and the group without adjuvant, but the adjuvant effect was not obvious. (3) No significant difference in serum IgG titer was observed between the mice immunized with 10 μg CdtB by microneedle or intraperitoneal injection, but microneedle immunization significantly increased fecal IgA level. (4) The neutralization titers of specific antibodies in mouse serum after immunization and the test results of challenge protection in mice confirmed that the use of CdtB vaccine had certain protective effects.Conclusions:CdtB vaccine had better immune effects in mice through microneedle immunization, but the adjuvant effects of LT and CTB were not significant.

Efficacy of microneedle radiofrequency for treatment of moderate acne vulgaris / 中华医学美学美容杂志

Objective:To evaluate the clinical efficacy of microneedle radiofrequency in the treatment of moderate acne vulgaris.Methods:From August 2018 to August 2020, 393 patients (192 males and 201 females, aged 15-38 years) with moderate acne were enrolled in the Department of Dermatology, the First Affiliated Hospital of Shantou University Medical College and Shantou Chaonan Minsheng Hospital, including 201 patients in experimental group and 192 patients in control group. In the experimental group, microneedle radiofrequency therapy was used once every 2 weeks for 3 times in total. The control group adopted the fire needle, once every 2 weeks, a total of 3 times. The efficacy of both groups was evaluated at week 8.Results:A total of 378 patients were actually completed: 196 patients in the experimental group, and 182 patients in the control group. At the eighth week of follow-up, the total effective rate was 81.12% in the experimental group and 70.43% in the control group. The efficacy of the two groups was statistically different (χ 2=4.42, P<0.05). Conclusions:The efficacy of microneedle radiofrequency therapy in the treatment of moderate acne vulgaris is better than that of fire needle, with good tolerance, short recovery period, few adverse reactions and high compliance, which has clinical promotion value.

Clinical efficacy of injection of recombinant humanized type Ⅲ collagen in facial rejuvenation / 中华医学美学美容杂志

Objective:To evaluate the efficacy of recombinant humanized type Ⅲ collagen injected by microneedles in facial rejuvenation.Methods:Twenty-five cases recruited from July to December 2021 were included as the research objects in this study. Recombinant humanized type Ⅲ collagen was injected into the face skin using microneedles. Images were collected before the treatment and 1, 2, and 3 months after the end of the treatment. The VISIA image analysis system was used for comparative analysis. Patient′s satisfaction evaluation and the occurrence of complications after treatment were also recorded.Results:According to results of VISIA, the scores of spots were (32.06±6.92) and (27.59±7.69); red areas were (32.79±11.80) and (27.74±9.49); pores were (17.66±9.79) and (14.60±7.07) and brown spots were (43.61±11.93) and (37.59±16.22) after the treatment were lower than those before treatment, and the results were statistically different ( F=3.442, 4.209, 7.473, 7.113, P<0.05). One month after the end of the of treatment. Patient′s self-satisfaction reached 84% (21 cases); three months after the end of the treatment, the patient′s self-satisfaction reached 80% (20 cases). No serious adverse reactions were occurred. Conclusions:The recombinant humanized type Ⅲ collagen injected by microneedles can be effective and durable for facial rejuvenation and get high patient satisfaction. It has high safety and is worthy of clinical promotion.

Enhanced uptake and anti-maturation effect of celastrol-loaded mannosylated liposomes on dendritic cells for psoriasis treatment

Psoriasis is an autoimmune skin disease in which dendritic cells (DCs) trigger the progression of psoriasis by complex interactions with keratinocytes and other immune cells. In the present study, we aimed to load celastrol, an anti-inflammatory ingredient isolated from Chinese herbs, on mannosylated liposomes to enhance DC uptake as well as to induce DC tolerance in an imiquimod-induced psoriasis-like mouse model. Mannose was grafted onto liposomes to target mannose receptors on DCs. The results demonstrated that compared with unmodified liposomes, DCs preferred to take up more fluorescence-labeled mannosylated liposomes. After loading celastrol into mannose-modified liposomes, they effectively inhibited the expression of maturation markers, including CD80, CD86 and MHC-II, on DCs both in vitro and in vivo. Additionally, after intradermal injection with a microneedle, celastrol-loaded mannose-modified liposomes (CEL-MAN-LPs) achieved a superior therapeutic effect compared with free drug and celastrol-loaded unmodified liposomes in the psoriasis mouse model in terms of the psoriasis area and severity index, histology evaluation, spleen weight, and expression of inflammatory cytokines. In conclusion, our results clearly revealed that CEL-MAN-LPs was an effective formulation for psoriasis treatment and suggested that this treatment has the potential to be applied to other inflammatory diseases triggered by activated DCs.

Application progress of microneedle in cosmetic and plastic surgery / 中华内分泌外科杂志

This article introduces the concept, classification and application of microneedle in the field of cosmetology. It summarizes and analyzes the use of microneedle in promoting skin graft and flap survival, scar repair, facial rejuvenation, local anesthesia, hair loss treatment, skin relaxation, acne treatment, reducing color sink and other aspects, and looks forward to the bright prospects of microneedle applications in plastic surgery.

Transdermal delivery of Chinese herbal medicine extract using dissolvable microneedles for hypertrophic scar treatment

Hypertrophic scars are unfavorable skin diseases characterized by excessive collagen deposition. Although systemic treatments exist in clinic to manage hypertrophic scars, they pose significant side effects and tend to lose efficacy over prolonged applications. Traditional Chinese medicine (TCM) offers as a promising candidate to treat pathological scars. A large number of TCMs have been studied to show anti-scarring effect, however, the natural barrier of the skin impedes their penetration, lowering its therapeutic efficacy. Herein, we reported the use of dissolvable hyaluronic acid (HA) microneedles (MNs) as a vehicle to aid the transdermal delivery of therapeutic agent, a model TCM called shikonin for the treatment of hypertrophic scars. Here, shikonin was mixed with HA to make MNs with adequate mechanical strength for skin penetration, making its dosage controllable during the fabrication process. The therapeutic effect of the shikonin HA MNs was studied

Influencing factors and evaluation methods of skin microchannels formation and closure after microneedles application / 药学学报

As a novel transdermal drug delivery technology of minimally invasive, safe and efficient, microneedles have received increasing attention. The microchannels formation by microneedles onto the skin is a prerequisite and key for microneedles to deliver drugs. However, there is still a lack of systematic evaluation in skin microchannels. This review summarized influencing factors and evaluation methods in microchannels formation and healing by microneedles, including geometric parameters, materials for preparation, drugs, penetration parameters, differences among the skin of subjects, and presence or absence of occlusion. This review provides reference for other scholars to further study the effectiveness and security of microneedle applications.

Preparation and characterization of dissolving microneedles with nano-enhanced mechanical properties / 药学学报

In this paper, the effects of the blend of nanoparticles and microneedle matrix materials on the mechanical properties of dissolving microneedles were studied mainly, so as to construct microneedles with excellent mechanical properties. Different kinds of nanoparticles (calcium carbonate, hydroxyapatite, silica), particle sizes (20, 60, 100 nm) and the proportion of prescription (2%, 6%, 10%) were blended with the matrix material [polyvinyl pyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate)(PVP/VA)] to form dissolving microneedles. The effects of nanoparticles on the elastic modulus and hardness of the microneedles were investigated using a nanoindenter. The results showed that the elastic modulus and hardness of PVP microneedles were significantly improved by nano-calcium carbonate (P < 0.001), and the elastic modulus and hardness of PVP/VA microneedles were significantly improved by nano-hydroxyapatite (P < 0.001). When the particle size of hydroxyapatite was 20 nm, the elastic modulus of PVP/VA microneedles was (10.6 ± 1.0) GPa, and the hardness was (0.47 ± 0.06) GPa. As the size of the nanoparticles increases, the mechanical performance of the microneedles decreases. When the mass proportion of nano-hydroxyapatite increased from 2% to 6%, the elastic modulus and hardness of the microneedles were significantly improved (P < 0.001), but the effect of continue increasing the proportion of nanoparticles on the microneedles was not significant. The nano-enhanced PVP/VA dissolving microneedles has no irritant effect on intact skin and has a slight irritation to damaged skin, but they disappear completely after 72 h. Animal experiments have been approved by the Laboratory Animal Welfare and Ethics Committee of Zhejiang University of Technology. Therefore, the nano-enhanced dissolving microneedles has good biological safety. To sum up, it is necessary to select the appropriate kind of nanoparticle, particle size, and prescription ratio when microneedles constructing with a given matrix material, so as to effectively improve its mechanical performance.

Minimally invasive dissolving microneedles for ocular brinzolamide delivery / 药学学报

The permeation and pharmacodynamics of ocular drugs are influenced by the corneal barrier. Here, a hard-soluble drug, brinzolamide, was selected as the model drug and used for preparation of minimally invasive dissolving microneedles. Brinzolamide was dissolved in ethanol and polyvinylpyrrolidone (PVP) K90 was added and dissolved. The mixture solution was casted into the dissolving microneedles mold and dried and brinzolamide dissolving microneedles (BMN) were obtained after demolding. The stereoscopic and scanning electron microscopic images showed that BMN were conical needles with the height of 750 μm, the bottom diameter of 300 μm, and the inter-tip distance of 500 μm. The dissolving microneedles patch was composed of 10×10 arrays with the area of 1 cm2 and the high drug load of 7.3 mg·cm-2. BMN showed a rapid in vitro drug release with 93% accumulative release at 2 h and the high drug corneal permeation amount of 877 ± 105 μg. BMN exhibited the high mechanical strength of 0.32 N/needle, leading to easy rat corneal insertion with the depth of 200 μm. Moreover, BMN were rapidly dissolved in the cornea, and more importantly, the damaged cornea were quickly self-healed within 24 h. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical and the experiments were conducted in accordance with relevant guidelines and regulations. Ocular minimally invasive dissolving microneedles have the advantages of corneal minimal wounds and rapid healing, high drug loading, and high permeability, favoring the treatment of ocular diseases.

Microneedles in diagnosis and treatment: a review / 生物工程学报

Microneedles have been developed rapidly in the field of transdermal administration in the past few decades. In recent years, the development of microelectronics technology has expanded the applications of microneedles by combining with microelectronic systems, especially in biological diagnosis and treatment. Different types of microneedles have been designed to extract blood and tissue fluids for detection, or as electrodes to directly detect blood sugar, melanoma and pH in real-time in vivo, both show good prospects for real-time detection applications. In this paper, we review the design of materials and structure of microelectronic-based microneedles, and discuss their advances in biological diagnosis.

Priorización de nuevas vacunas e innovación al servicio de estrategias de vacunación / New vaccines prioritization and immunization-related innovation

La vacunación es el medio más efectivo para controlar la morbilidad y mortalidad relacionadas con enfermedades infecciosas. Para lograr esto, necesitamos vacunas inmunogénicas y seguras que faciliten y mejoren sus condiciones de transporte, almacenamiento y administración. Gracias a los avances en inmunología y bioinformática, es posible impulsar el descubrimiento de nuevas vacunas para enfrentar la tuberculosis, el virus respiratorio sincicial, el Streptococcus agalactiae, la enfermedad meningocócica invasora, entre otros. Así también, nuevas tecnologías, como la producción de vacunas utilizando plantas transgénicas y parches de microagujas, los cuales podrían facilitar la producción, disminuir los costos y efectos adversos. Sin embargo, no solo necesitamos las vacunas, sino que debemos conocer la epidemiología de las enfermedades prevenibles con vacuna para tomar decisiones fundadas, con el objetivo de planificar estrategias sanitarias, medir su impacto y evaluar la seguridad de su utilización, para alcanzar las metas de salud pública y la confianza de la población.

Vaccination is the most effective strategy to avoid morbidity and mortality related to infectious diseases. To achieve this, we need immunogenic and safe vaccines that facilitate and improve its transport, storage and administration conditions. Thanks to current advances in immunology and bioinformatics, it is possible to boost the discovery of new vaccines to deal with tuberculosis, the respiratory syncytial virus, Streptococcus agalactiae, meningococcal invasive disease, among others. In addition to new technologies such as the production of plant-based vaccines, and microneedles patches, which can facilitate its production, reducing costs and adverse effects. However, vaccines is not the only thing that we need, because we must know the epidemiology and burden of disease to take informed decisions to design optimal strategies, measuring their impact and assessing the safety of their use in order to achieve the goals health and population confidence.

Microneedles: An advancement to transdermal drug delivery system approach

Novel drug delivery system offers several advantages which could outweigh the benefits of other drug deliverysystems. The transdermal drug delivery system being one of them offers supremacy by by-passing the first passmetabolism which eventually helps in eradication of gastrointestinal irritation. However, the major drawback of thetransdermal drug delivery system is the hindrance created via the stratum corneum. This protective barrier of the skindoes not allow required penetration of the drug via skin into the systemic circulation. Thus, in order to overcome thishurdle, a replacement to this type of novel drug delivery system, namely, “microneedle drug delivery system” helpedto improve various pitfalls of transdermal drug delivery system, such as skin barrier function, restrictions towardusing of specific drugs only, bioavailability, patient compliance, diffusion rate, and plasma concentration level. Amicroneedle drug delivery system, thus, is advancement to transdermal drug delivery system which includes deliveryof drug via microneedle into systemic circulation, thus increasing patient compliance and avoiding problems renderedby transdermal drug delivery system.