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Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects

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Abstract

To support translation of microneedle patches from pre-clinical development into clinical trials, this study examined the effect of microneedle patch application on local skin reactions, reliability of use and acceptability to patients. Placebo patches containing dissolving microneedles were administered to fifteen human participants. Microneedle patches were well tolerated in the skin with no pain or swelling and only mild erythema localized to the site of patch administration that resolved fully within seven days. Microneedle patches could be administered by hand without the need of an applicator and delivery efficiencies were similar for investigator-administration and self-administration. Microneedle patch administration was not considered painful and the large majority of subjects were somewhat or fully confident that they self-administered patches correctly. Microneedle patches were overwhelmingly preferred over conventional needle and syringe injection. Altogether, these results demonstrate that dissolving microneedle patches were well tolerated, easily usable and strongly accepted by human subjects, which will facilitate further clinical translation of this technology.

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... Their in vivo breakdown in the presence of degrading enzymes resulted in non-toxic end products. This characteristic of polymers decreases the probability of infection inside the body [49]. ...
... Among all types, dissolvable MNs are popular and use biodegradable polymers with dissolving abilities [47,48]. The metabolic end products are not toxic, resulting in reduced chances of side effects in the body [49]. However, besides biodegradation, the polymeric microneedle requires enough strength for insertion into the [46] stratum corneum. ...
... The patches were well tolerated, with no swelling and only slight transient erythema at the application site. This proved the suitability of designing the microneedle patches using PVA as a matrix polymer [49]. ...
Article
The skin serves as the major organ in the targeted transdermal drug delivery system for many compounds. The microneedle acts as a novel technique to deliver drugs across the different layers of the skin, including the major barrier stratum corneum, in an effective manner. A microneedle array patch comprises dozens to hundreds of micron-sized needles with numerous structures and advantages resulting from their special and smart designs. Microneedle approach is much more advanced than conventional transdermal delivery pathways due to several benefits like minimally invasive, painless, self-administrable, and enhanced patient compliance. The microneedles are classified into hollow, solid, coated, dissolving, and hydrogel. Several polymers are used to fabricate microneedle, such as natural, semi-synthetic, synthetic, biodegradable, and swellable polymers. Researchers in the preparation of microneedles also explored the combinations of polymers. The safety of the polymer used in microneedle is a crucial aspect to prevent toxicity in vivo. Thus, this review aims to provide a detailed review of microneedles and mainly focus on the various polymers used in the fabrication of microneedles.
... Placebo dissolving MNP (PLA-MNP) data as well as data on the use of dissolving MNP to deliver the inactivated influenza vaccine (IIV) in humans are available [57,58]. ...
... A PLA-MNP, formulated using a comparable approach as used to formulate the MRV-MNP, has been assessed in healthy human adult subjects [58]. This MNP does not contain the active vaccine, only the water-soluble excipients designed to dissolve and release the vaccine on application. ...
... Over a 7-day period following application, the MNP was well tolerated [58]. All participants experienced grade 1 or 2 erythema at the site of injection on the day of MNP application although this resolved in all cases by day 7 following MNP application. ...
Article
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Background New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. Methods This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18–40 years] followed by 120 toddlers [15–18 months] and 120 infants [9–10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. Discussion This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination.
... 4 Few studies have reported on acceptability and usability of vaccine microarray patch (MAP) administration with healthcare workers (HCWs): some have reported on actual administration or simulation, 5 while others have examined hypothetical administration. 6,7 Some studies have examined preferences amongst adult laypeople, which suggest that MAP vaccination is favored over IM. 4,[8][9][10][11][12] Previously, we have reported on the acceptability of the Vaxxas HD-MAP in healthy adults aged 18 to 45 years as part of clinical trials . 8,9 Building on an earlier study -a simulation of HD-MAP vaccine administration with children in Low and Middle-Income Countries (LMICs), 5 the primary objective of this study was to assess acceptability and usability of the Vaxxas prototype HD-MAP applicator through a simulation vaccination experience in a High-Income Country (HIC) real-world setting. ...
... [28][29][30] Vaccination with HD-MAP may improve this issue given the absence of an IM. 8,9,12 Limitations Simulation may have limited participants' understanding of the actual HD-MAP vaccination experience. The impact on acceptability of potential skin site reactions following immunization were not able to be captured with this study design. ...
Article
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Background: High-density microarray patch (HD-MAP) vaccines may increase vaccine acceptance and use. We aimed to ascertain whether professional immunizers (PIs) and other healthcare workers (HCWs) in Australia, a High-Income Country (HIC), found the HD-MAP applicator usable and acceptable for vaccine delivery. Methods: This feasibility study recruited PIs and HCWs to administer/receive simulated HD-MAP administration, including via self-administration. We assessed usability against essential and desirable criteria. Participants completed a survey, rating their agreement to statements about HD-MAP administration. A subset also participated in an interview or focus group. Survey data were analyzed using descriptive statistics, and interviews were transcribed and subject to thematic analysis. Results: We recruited 61 participants: 23 PIs and 38 HCWs. Findings indicated high usability and acceptability of HD-MAP use across both groups by a healthcare professional or trained user and for self-administration with safety measures in place. Most administrations met essential criteria, but PIs, on average, applied the HD-MAP for slightly less time than the required 10-seconds, which the HCWs achieved. PIs perceived safety concerns about home administration but found layperson self-administration acceptable in an emergency, pandemic, and rural or remote settings. Conclusions: Participants found HD-MAP administration usable and acceptable. Usability and acceptability are likely to be improved through end-user education and training.
... By targeting the skin, vaccination by MNPs has been shown to have a number of immunological advantages in comparison to traditional intramuscular administration in adult and young mouse models including dose sparing, stronger humoral and cellular immune responses, greater duration of immunity and broader cross-protection against heterologous virus strains (10)(11)(12)(13)(14)(15)(16)(17). In addition, MNPs as a delivery system are generally preferred by patients (18)(19)(20) including older people (21). We have previously reported that MNP vaccination decreased the age-dependent decline of the functional antibodies compared to intramuscular injection. ...
... Blinding was not possible due to small number of investigators. [12][13][14][15][16][17][18][19] x from 0.03 mg/ml HA to 0.368 mg/ml HA or 0.574 mg/ml HA, respectively, and the stocks were combined and HA content was determined by SRID assay as previously described (27,28) using strain-specific reagents from the Center for Biologics Evaluation and Research (Kensington, MD). These vaccines are pandemic-type 2009 strains protective against challenge with A/California/07/09 H1N1 virus. ...
Article
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Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2’3 cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.
... However, the stability of embedded liquid vaccine solutions is not guaranteed. In contrast, both soluble MN and coated MN exhibited longer shelf life at room temperature and even higher [87]. The integrity of the gene-drug is maintained during manufacture, upon drying, and subsequent storage. ...
... It has been reported that factors affecting the acceptability of MN-mediated vaccination mainly stem from the convenience of the MN patch; patient acceptance of the reliability of MN; and outcome assessment of MN toxicity [94]. Arya [87] evaluates the tolerability, usability, and acceptability of dissolving microneedle patches in human skin. Without the applicator, use the microneedle patch only with the thumb pressed. ...
Article
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Gene therapy is one of the most widely studied treatments and has the potential to treat a variety of intractable diseases. The skin's limited permeability, as the body's initial protective barrier, drastically inhibits the delivery effect of gene medicine. Given the potential adverse effects and physicochemical features of the medications, improving generic drug penetration into the skin barrier and achieving an effective level of target tissues remains a challenge. Microneedles have made tremendous improvements in aided gene transfer and medication delivery as a unique method. Microneedles offer the advantage of being minimally invasive and painless, as well as the ability to distribute gene medicines straight through the stratum corneum. Microneedles have been used to penetrate skin tissue with various nucleic acids and medicines in recent years, allowing for a wide range of applications in the treatment of skin ailments. This review focuses on skin-related disorders and immunity, and it primarily discusses the progress of microneedle transdermal gene therapy in recent years. It also complements the current major vectors and related microneedle gene therapy applications.
... Upon application to skin, MNs penetrate across epidermis and into the dermis, where they dissolve and release their drug payload in the skin 15,16 . This procedure is minimally invasive, not painful and generally well-tolerated 17,18 . In addition, application of MN patches is much easier than hypodermic injection or iontophoresis, and it can be performed after brief training [19][20][21] . ...
... When human subjects experienced both MN patch application to the skin and iontophoretic sweat testing in a prior study, there was no significant difference in reported pain between the two procedures 27 . Placebo MN patches, as well as MN patches administering various drugs and vaccines, have been shown to be well tolerated, with only transient, mild erythema reported as the most common side effect 17,18,20,21,35 . Previous studies have also shown that MN patches are so simple to apply that naïve human subjects can successfully apply them after only brief training 19-21 . ...
Article
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The sweat test is the gold standard for the diagnosis of cystic fibrosis (CF). The test utilizes iontophoresis to administer pilocarpine to the skin to induce sweating for measurement of chloride concentration in sweat. However, the sweat test procedure needs to be conducted in an accredited lab with dedicated instrumentation, and it can lead to inadequate sweat samples being collected in newborn babies and young children due to variable sweat production with pilocarpine iontophoresis. We tested the feasibility of using microneedle (MN) patches as an alternative to iontophoresis to administer pilocarpine to induce sweating. Pilocarpine‐loaded MN patches were developed. Both MN patches and iontophoresis were applied on horses to induce sweating. The sweat was collected to compare the sweat volume and chloride concentration. The patches contained an array of 100 MNs measuring 600 μm long that were made of water‐soluble materials encapsulating pilocarpine nitrate. When manually pressed to the skin, the MN patches delivered >0.5 mg/cm2 pilocarpine, which was double that administered by iontophoresis. When administered to horses, MN patches generated the same volume of sweat when normalized to drug dose and more sweat when normalized to skin area compared to iontophoresis using a commercial device. Moreover, both MN patches and iontophoresis generated sweat with comparable chloride concentration. These results suggest that administration of pilocarpine by MN patches may provide a simpler and more‐accessible alternative to iontophoresis for performing a sweat test for the diagnosis of CF. This article is protected by copyright. All rights reserved.
... As microneedle technology is advancing, many clinical trials are being done to reduce the disadvantages of microneedles used commercially. Arya et al. (2017) conducted a 15-subject human trial to determine whether microneedles cause local skin reactions. ...
... The result of the study demonstrated that microneedles did not cause any swelling, pain or erythema at the site of application of the patch. More so, patients could selfadminister the patches by hand without assistance from a clinician (Arya et al., 2017). ...
Article
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The conventional drug delivery methods widely used are intravenous injection and oral administration. Microneedles are a new technology used for drug delivery, administered percutaneously. Microneedles are often presented in a series of multiple simple microneedle arrays used on the skin to facilitate systemic or topical drug delivery. There are several advantages to transdermal drug delivery, including sustained release, improvement in patient's compliance and elimination of first-pass metabolism. This study is conducted as a review paper, with relevant information collated from multiple articles, journals and peer-reviewed papers. It reviews the physiology of human skin in detail, the structures and features of microneedles, and arrives at a comprehensive conclusion on their potential to effectively deliver drugs via the percutaneous route. Results show that microneedles are used in therapeutic applications and are manufactured using various materials and fabrication techniques. They show great potential and are an emerging field in transdermal drug delivery; however, the physiology of the skin poses several challenges to research in the field. Drug delivery is limited by the stratum corneum and, hence, effective pharmacokinetics is affected. This paper highlights some of the main frontiers in the use of microneedles as an important modern technique in percutaneous drug delivery. The advances in microfabrication technology and scalability in the configuration of microneedles is a technology that is expected to experience growth in the coming decades.
... Except application pain, skin reactions induced by MNs had also been studied. Arya et al. studied the effects of applying dissolving MN patches on local skin reactions, reliability of use, and patients' acceptability [190]. Fifteen human participants were involved in this trial. ...
... Results demonstrated that dissolving MN patches showed well tolerance without any pain, erythema, or swelling at the MNs application site and were strongly accepted by human subjects. The study revealed that MN patches were preferred than conventional needle and syringe injection [190]. ...
Article
Diabetes mellitus is a metabolic disease manifested by hyperglycemia. For patients with type 1 and advanced type 2 diabetes mellitus, insulin therapy is essential. Subcutaneous injection remains the most common administration method. Non-invasive insulin delivery technologies are pursued because of their benefits of decreasing patients’ pain, anxiety, and stress. Transdermal delivery systems have gained extensive attention due to the ease of administration and absence of hepatic first-pass metabolism. Microneedle (MN) technology is one of the most promising tactics, which can effectively deliver insulin through skin stratum corneum in a minimally invasive and painless way. This article will review the research progress of MNs in insulin transdermal delivery, including hollow MNs, dissolving MNs, hydrogel MNs, and glucose-responsive MN patches, in which insulin dosage can be strictly controlled. The clinical studies about insulin delivery with MN devices have also been summarized and grouped based on the study phase. There are still several challenges to achieve successful translation of MNs-based insulin therapy. In this review, we also discussed these challenges including safety, efficacy, patient/prescriber acceptability, manufacturing and scale-up, and regulatory authority acceptability.
... Among these materials, PVA is usually used to fabricate DMNs because of its excellent biological compatibility and good mechanical properties [33][34][35][36]. Recent studies demonstrate that PVA DMNs were well tolerated, easily usable and strongly accepted by human subjects, which will facilitate further clinical translation of this technology [37]. Researches Ryan F. Donnelly et al designed a series of pre-clinical experiments for the first time to investigate impact of skin insertion on multiple occasions of polymeric MNs arrays in an animal model [38] and human volunteers in vivo [39]. ...
Article
Dissolving microneedles (DMNs) are widely used in drug delivery systems since they are based on one-step application, which is simple and convenient for patients, especially for the patients such as diabetes who need daily or long-term self-administration. In general, the matrix materials of DMNs are water-soluble materials that can release the encapsulated drugs gradually by dissolving in the skin without generating sharp needle waste. However, the matrix materials of DMNs will also leave in the skin after application. Thus, it is vital to evaluate whether the matrix material of DMNs dissolved in the skin will cause health risks such as toxicity to the body or some skin-related complications to patients who frequent or long-term administration. In this work, PVA, as one of the typical matrix materials of DMNs, was selected to prepare the DMNs to research the safety of PVA-based MNs to the body after being dissolved in the skin. Briefly, in a 160 - days trial, the healthy mice were daily administrated by PVA MNs. The results showed that PVA materials mainly accumulated in the skin tissues of mice after dissolving and the concentration of PVA in the insertion sites gradually decreased and almost undetectable at 6 days after administration. The observation of general conditions, blood hematological analysis and histological examinations of the mice demonstrated that the PVA-based MNs do not cause appreciable toxicity to the healthy mice after daily insertion in a 160 - days trial. Altogether, these results encourage further studies of PVA MNs for biomedical applications and support translation of PVA-based DMNs from pre-clinical development into clinical trials.
... MNs are arrays mechanically pierce the skin barrier, SC, to deposit vaccines in the ID space. MNs have been demonstrated as a potential strategy for pain-free vaccine administration in early clinical trials [239][240][241] These MN patches are a currently evolving technology to control vaccine kinetics. ...
Article
Treatment of neovascular ocular diseases involves intravitreal injections of therapeutic proteins using conventional hypodermic needles every 4-6 weeks. Due to the chronic nature of these diseases, these injections will be administrated to patients for the rest of their lives and their frequent nature can potentially pose a risk of sight-threatening complications and poor patient compliance. Therefore, we propose to develop nanoparticle (NP)-loaded bilayer dissolving microneedle (MN) arrays, to sustain delivery of protein drugs in a minimally invasive manner. In this research, a model protein, ovalbumin (OVA)-encapsulated PLGA NPs were prepared and optimised using a water-in-oil-in-water (W/O/W) double emulsion method. The impact of stabilisers and primary sonication time on the stability of encapsulated OVA was evaluated using an enzyme-linked immunosorbent assay (ELISA). Results showed that the lower primary sonication time was capable of sustaining release (77 days at 28.5% OVA loading) and improving the OVA bioactivity. The optimised NPs were then incorporated into a polymeric matrix to fabricate bilayer MNs and specifically concentrated into MN tips by high-speed centrifugation. Optimised bilayer MNs exhibited good mechanical and insertion properties and rapid dissolution kinetics (less than 3 min) in excised porcine sclera. Importantly, ex vivo transscleral distribution studies conducted using a multiphoton microscope confirmed the important function of MN arrays in the localisation of proteins and NPs in the scleral tissue. Furthermore, the polymers selected to prepare bilayer MNs and OVA NPs were determined to be biocompatible with retinal cells (ARPE-19). This delivery approach could potentially sustain the release of encapsulated proteins for more than two months and effectively bypass the scleral barrier, leading to a promising therapy for treating neovascular ocular diseases.
... The Micron Biomedical MR patch is currently in a phase 1/2 clinical trial underway at the Medical Research Council in The Gambia. Other MAPs for IPV, human papilloma virus, rabies, rotavirus, and hepatitis B vaccines tetanus toxoid, Bacille Calmette-Guérin, diphtheria, and anthrax are in preclinical development [39,[49][50][51][52]. With recognition that vaccine MAPs would be a powerful tool for pandemic preparedness and response, two successful phase 1 clinical trials of seasonal influenza MAP vaccines were completed, one by Micron Biomedical and one by Vaxxas [50,53]. ...
Article
Disease eradication and elimination programs drive innovations based on progress toward measurable objectives, evaluations of new strategies and methods, programmatic experiences, and lessons learned from the field. Following progress toward global measles elimination, reducing measles mortality, and increasing introductions of measles and rubella vaccines to national programs, the measles and rubella immunization program has faced setbacks in recent years. Currently available vaccine delivery methods have complicated logistics and drawbacks that create barriers to vaccination; innovations for easier, more efficient, and safer vaccine delivery are needed. Progress can be accelerated by new technologies like microarray patches (MAPs) that are now widely recognized as a potential new tool for enhancing global immunizations efforts. Clinical trials of measles-rubella vaccine MAPs have begun, and several other vaccine MAPs are in the pre-clinical development pathway. MAPs could significantly contribute to Immunization Agenda 2030 priorities, including reaching zero-dose children; increasing vaccine access, demand, coverage, and equity; and achieving measles and rubella elimination. With strong partnerships between public health agencies and biotechnology companies, translational novel vaccine delivery systems can be developed to help solve public health problems and achieve global health priorities.
... Multiple types of MN arrays, including dissolvable polymer needles and those coated with antigen, have been developed for antigen delivery into the skin [15,18,24,[55][56][57]. MNs are minimally invasive and well tolerated by patients, who reported pain-free application [58][59][60]. Because this process directly delivers antigen into the skin, there is no variability due to strength of the barrier or requirement for passive diffusion of the antigen. ...
Article
Aim: Epicutaneous immunotherapy (EPIT) with peanut has been demonstrated to be safe but efficacy may be limited by allergen uptake through the skin barrier. To enhance allergen uptake into the skin, the authors used peanut-coated microneedles and compared them with EPIT in a peanut allergy mouse model. Methods: Sensitized mice were treated with peanut-coated microneedles or peanut-EPIT and then challenged with peanut to determine protection. Results: Treatment with peanut-coated microneedles was safe and showed enhanced desensitization to peanut compared with peanut-EPIT administered via a similar schedule. Protection was associated with reduced Th2 immune responses and mast cell accumulation in the intestine. Conclusion: Peanut-coated microneedles have the potential to present a safe method of improving allergen delivery for cutaneous immunotherapy.
... Moreover, MNs can avoid unnecessary pain as their length does not reach the deep dermis layer in which sensory nerve endings are located, yielding less invasive and painless drug delivery [154,155]. It is also noteworthy that the best advantage of MN convenient application is encouraging as they might not need professional management training [156]. MNs are safer and more efficient than traditional intravenous or intratumoral injections as a new drug delivery platform. ...
Article
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The development of new effective cancer treatment methods has attracted much attention, mainly due to the limited efficacy and considerable side effects of currently used cancer treatment methods such as radiation therapy and chemotherapy. Photothermal therapy based on the use of plasmonically resonant metallic nanoparticles has emerged as a promising technique to eradicate cancer cells selectively. In this method, plasmonic nanoparticles are first preferentially uptaken by a tumor and then selectively heated by exposure to laser radiation with a specific plasmonic resonant wavelength, to destroy the tumor whilst minimizing damage to adjacent normal tissue. However , several parameters can limit the effectiveness of photothermal therapy, resulting in insufficient heating and potentially leading to cancer recurrence. One of these parameters is the patient's pain sensation during the treatment, if this is performed without use of anesthetic. Pain can restrict the level of applicable laser radiation, cause an interruption to the treatment course and, as such, affect its efficacy, as well as leading to a negative patient experience and consequential general population hesitancy to this type of therapy. Since having a comfortable and painless procedure is one of the important treatment goals in the clinic, along with its high effectiveness, and due to the relatively low number of studies devoted to this specific topic, we have compiled this review. Moreover, non-invasive and painless methods for temperature measurement during photothermal therapy (PTT), such as Raman spectroscopy and nanothermometry, will be discussed in the following. Here, we firstly outline the physical phenomena underlying the photothermal therapy, and then discuss studies devoted to photothermal cancer treatment concerning pain management and pathways for improved efficiency of photothermal therapy whilst minimizing pain experienced by the patient.
... Since sMTS is still under investigation, no previous preference study using this mode of administration has been published. Data exist for other treatments administered via patch compared to injection where variations in patients' acceptance of and satisfaction with treatment are reported [22][23][24]. Several studies highlighted a higher preference for transdermal patches versus oral medication both from patients and caregivers [25][26][27][28] in Alzheimer disease. ...
Article
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Mini abstract US patients with osteoporosis included in three focus groups identified efficacy, safety, cost, and convenience as important attributes of treatment when choosing between anabolic therapies with high stated preference for the solid Microstructured Transdermal System. Objective The current study evaluated patient perspective and relative importance of treatment attributes of in-home daily self-administration of abaloparatide-solid Microstructured Transdermal System (sMTS) compared with other anabolic agents (i.e. in-home daily subcutaneous self-injections, and monthly subcutaneous injections at doctor office) among a group of US patients with osteoporosis. Methods The current study included systematic literature reviews, experts’ consultation and three online patients focus groups (n=27), including patients ≥50 years of age at high risk for fracture. Nominal Group Technique was used by asking patients to (1) Individually identify characteristics that would be important for them when choosing between anabolic treatments, (2) Share ideas and discuss perspectives with other patients, (3) Review additional attributes generated from a systematic literature review, (4) Select and rank individually the 7 most important characteristics from the list and (5) Report their acceptability and stated preference ranking between the three treatment options. Results Twenty women and 7 men with a mean age of 65 (range 51-85 years) participated in the focus groups. Twenty-four treatment characteristics were identified through focus groups and literature review. Efficacy, safety, out-of-pocket costs, strength of evidence and the option to self-administer were ranked as the most important attributes. The majority of patients stated preference for a daily sMTS if prescribed by their doctor. Conclusions This study revealed that efficacy, safety, costs, and convenience are important attributes of osteoporosis treatment for US patients at high risk for fractures when choosing between anabolic therapies, with a high stated preference for sMTS.
... They can be tuned to provide steady extended release or timecontrolled burst release of their cargoes. They are well-tolerated, causing minimal skin irritation or pain, and most of the time preferred compared to injections [210,211]. However, these platforms pose some challenges in terms of manufacturing and safety. ...
Article
The immune system is one of the most important, complex biological networks regulating and protecting human health. Its precise modulation can prevent deadly infections and fight cancer. Accordingly, prophylactic vaccines and cancer immunotherapies are some of the most powerful technologies to protect against potential dangers through training of the immune system. Upon immunization, activation and maturation of B and T cells of the adaptive immune system are necessary for development of proper humoral and cellular protection. Yet, the exquisite organization of the immune system requires spatiotemporal control over the exposure of immunomodulatory signals. For example, while the human immune system has evolved to develop immunity to natural pathogenic infections that often last for weeks, current prophylactic vaccination technologies only expose the immune system to immunomodulatory signals for hours to days. It has become clear that leveraging sustained release technologies to prolong immunogen and adjuvant exposure can increase the potency, durability, and quality of adaptive immune responses. Over the past several years, tremendous breakthroughs have been made in the design of novel biomaterials such as nanoparticles, microparticles, hydrogels, and microneedles that can precisely control and the presentation of immunomodulatory signals to the immune system. In this review, we discuss relevant sustained release strategies and their corresponding benefits to cellular and humoral responses.
... The result showed a considerable decrease in the psoriatic plaques and thus concluded MNs are a better option than conventional cream applications [96]. This promising method is flexible enough and can be used to deliver proteins up to 100 mg that can go straight into the blood circulation [97]. In Table 5 ...
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Microneedles (MNs) are the most interesting and minimally invasive technique in pharmaceutical drug delivery systems. Recently researchers have concluded that MNs can be prominent future methods. Depending on the unique properties of MNs, they can be used widely in drug delivery systems. This delivery method has improved drug delivery avoiding many hurdles that were linked with the conventional system. The principal mechanism involved is temporarily damaging the skin layer; hence micron-size pores are created, which help the drug to reach the targeted site without any complications. The popularity of MNs in pharmaceutical and biomedical research is growing exponentially as it offers easy delivery of bio-actives to the specific site with minimal invasion. Several numbers of molecules are delivering via MNs, such as hormones, vaccines, and peptides. In this review, the efficiency of Micro-needle, their fabrication materials, as drug delivery carriers, and various associated patents are discussed.
... The design of MNs for more long-acting inhibition of hyperglycemia requires the materials and structure of MNs for intelligent release or slow release of hypoglycemic drugs in the MNs, and the ability of MNs which can be separated from the patch layer in a simple and rapid way. To realize these requirements, microneedle patches firstly need to be attached to the skin for a long time to ensure having enough time to release the drug 29 . For example, the claw-shaped MNs have been developed in which the barbs of MNs allow them to adhere firmly to the skin 30 . ...
Article
In this work, the rapidly separable microneedles (MNs) consisted of needle-tips and supporting bases have been fabricated by a step-by-step coating method. Poly (vinyl alcohol) (PVA) have been used to prepare the needle-tips of MNs in which they are capped on the solvable supporting bases consisted of sodium bicarbonate, poly (vinyl pyrolidone) (PVP), and tartaric acid (TA) (NaHCO3/PVP/TA). After insertion into the skin, the needle-tips can be separated rapidly from the patches within 90 s due to the generation of air bubbles in the supporting bases by the reaction between NaHCO3 and TA after absorption of tissue fluid, leading to the needle-tips remaining in the skin tissue. Metformin, a hypoglycemic drug, encapsulated in the needle-tips of MNs can be released due to swelling and decomposition of PVA by the absorption of tissue fluid. To investigate the pharmacological effect via transdermal delivery route, metformin-loaded MNs are applied on the diabetic SD rats induced by streptozotocin (STZ). They exhibit a longer hypoglycemic effect in vivo than that of subcutaneous injection. These results indicated the as-fabricated rapidly separable MNs present a promising platform for transdermal delivery of drugs against diabetic patients.
... Microneedle patch vaccination allows for administration by minimally trained personnel, including self-administration, which could dramatically hasten roll-out and dissemination as well as reduce the burden on the healthcare system. Acceptability studies using pressure sensitive microneedle patches with an auditory force feedback indicator found that participants reported little to no pain with self-administration and overwhelmingly preferred microneedle patches over intramuscular injections [76]. ...
Article
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Vaccines are an essential component of pandemic preparedness but can be limited due to challenges in production and logistical implementation. While vaccine candidates were rapidly developed against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), immunization campaigns remain an obstacle to achieving herd immunity. Dissolvable microneedle patches are advantageous for many possible reasons: improved immunogenicity; dose-sparing effects; expected low manufacturing cost; elimination of sharps; reduction of vaccine wastage; no need for reconstitution; simplified supply chain, with reduction of cold chain supply through increased thermostability; ease of use, reducing the need for healthcare providers; and greater acceptability compared to traditional hypodermic injections. When applied to coronavirus disease 2019 (COVID-19) and future pandemic outbreaks, microneedle patches have great potential to improve vaccination globally and save many lives.
... This property diminishes the opportunity of defilement in the body. [23] Polymers are used prodominantly in the creation of dissolving and hydrogelforming MNs clusters. [24,25] By the by, there are relatively few examinations using polymers for the making of covered, solid, and void MNs which attributed to the deficiency of the polymer mechanical strength that is most likely going to crash and burn during inclusion. ...
Article
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Today about 74% of medications are taken orally and are discovered not to be pretty much as viable as wanted. To improve such characteristics transdermal medication conveyance framework arose. Medication conveyance through the skin to accomplish a fundamental impact of medication is ordinarily known as transdermal medication conveyance and varies from conventional skin drug conveyance. Transdermal medication conveyance frameworks are measurement structures that include drug transport to reasonable epidermal as well as dermal tissues of skin for nearby restorative impact while a significant part of medication is moved into the foundational blood flow. The cement of the transdermal medication conveyance framework is essential to the wellbeing, adequacy, and nature of the item. Effective organization of restorative specialists offers numerous benefits over traditional oral and intrusive techniques for drug conveyance. A few significant benefits of transdermal medication conveyance are the limit of hepatic first-pass digestion, upgrade of remedial productivity, and upkeep of consistent plasma level of the medication.
... The results showed that the microneedles did not induce any unexpected side effects and only resulted in a low level of pain. (Arya et al. 2017) conducted a clinical trial on microneedles alone in 15 healthy volunteers aged 18-57 years. The trial used dissolving microneedles containing 100 conical microneedles with a height of 650 µm and base diameter of 200 µm. ...
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Background Transdermal delivery has the advantage of bypassing the first-pass effect and allowing sustained release of the drug. However, the drug delivery is limited owing to the barrier created by the stratum corneum. Microneedles are a transdermal drug delivery system that is painless, less invasive, and easy to self-administer, with a high drug bioavailability.Area coveredThe dose, delivery rate, and efficacy of the drugs can be controlled by the microneedle design and drug formulations. This review introduces the types of microneedles and their design, materials used for fabrication, and manufacturing methods. Additionally, recent biological applications and clinical trials are introduced.Expert opinionWith advancements made in formulation technologies, the drug-loading capability of microneedles can be improved. 3D printing and digital technology contribute to the improvement of microneedle fabrication technology. However, regulations regarding the manufacture of microneedle products should be established as soon as possible to promote commercialization.
... In addition to the advantage of cutaneous immunization, microneedles can resolve several issues associated with the use of hypodermic needles, such as pain and needlestick injuries, as well as the requirement for trained personnel, appropriate needle disposal, and expensive logistics. Moreover, solidified vaccines contained in microneedles are considerably more stable at increased temperatures than liquid-state vaccines, thereby reducing economic burden related to vaccine storage, transport, and distribution [26][27][28][29][30]. ...
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Although smallpox has been eradicated globally, the potential use of the smallpox virus in bioterrorism indicates the importance of stockpiling smallpox vaccines. Considering the advantages of microneedle-based vaccination over conventional needle injections, in this study, we examined the feasibility of microneedle-based smallpox vaccination as an alternative approach for stockpiling smallpox vaccines. We prepared polylactic acid (PLA) microneedle array patches by micromolding and loaded a second-generation smallpox vaccine on the microneedle tips via dip coating. We evaluated the effect of excipients and drying conditions on vaccine stability in vitro and examined immune responses in female BALB/c mice by measuring neutralizing antibodies and interferon (IFN)-γ-secreting cells. Approximately 40% of the virus titer was reduced during the vaccine-coating process, with or without excipients. At −20 °C, the smallpox vaccine coated on the microneedles was stable up to 6 months. Compared to natural evaporation, vacuum drying was more efficient in improving the smallpox vaccine stability. Microneedle-based vaccination of the mice elicited neutralizing antibodies beginning 3 weeks after immunization; the levels were maintained for 12 weeks. It significantly increased IFN-γ-secreting cells 12 weeks after priming, indicating the induction of cellular immune responses. The smallpox-vaccine-coated microneedles could serve as an alternative delivery system for vaccination and stockpiling.
... However, these systems still provide indirect feedback without direct validation of skin penetration and vaccine delivery, and thus, development of additional feedback mechanisms could further assure reproducible MAP application and vaccine delivery. After addressing the reproducible skin penetration and vaccine delivery concerns, MAP-mediated vaccination is expected to be preferred by the general public and healthcare workers over traditional hypodermic needle injection, which could improve patient adherence and global immunization coverage [371,386,387]. Ultimately, self-administration, without the need for medical expertise, is expected to bring many acceptability, convenience, and cost advantages, which would be especially beneficial for global vaccination efforts during pandemics. ...
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The COVID-19 pandemic is a serious threat to global health and the global economy. The ongoing race to develop a safe and efficacious vaccine to prevent infection by SARS-CoV-2, the causative agent for COVID-19, highlights the importance of vaccination to combat infectious pathogens. The highly accessible cutaneous microenvironment is an ideal target for vaccination since the skin harbors a high density of antigen-presenting cells and immune accessory cells with broad innate immune functions. Microarray patches (MAPs) are an attractive intracutaneous biocargo delivery system that enables safe, reproducible, and controlled administration of vaccine components (antigens, with or without adjuvants) to defined skin microenvironments. This review describes the structure of the SARS-CoV-2 virus and relevant antigenic targets for vaccination, summarizes key concepts of skin immunobiology in the context of prophylactic immunization, and presents an overview of MAP-mediated cutaneous vaccine delivery. Concluding remarks on MAP-based skin immunization are provided to contribute to the rational development of safe and effective MAP-delivered vaccines against emerging infectious diseases, including COVID-19.
... Generally, microneedle with a length of 50-200 µm is painless. However, when the length exceeds a certain threshold, it will prick the skin, and the penetration may be unpleasant (Gill et al., 2008;Arya et al., 2017). The longer the microneedle, the higher the pain. ...
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Microneedles have garnered significant interest as transdermal drug delivery route owing to the advantages of nonselective loading capacity, minimal invasiveness, simple operation, and good biocompatibility. A number of therapeutics can be loaded into microneedles, including hydrophilic and hydrophobic small molecular drugs, and macromolecular drugs (proteins, mRNA, peptides, vaccines) for treatment of miscellaneous diseases. Microneedles feature with special benefits for cutaneous diseases owing to the direct transdermal delivery of therapeutics to the skin. This review mainly introduces microneedles fabricated with different technologies and transdermal delivery of various therapeutics for cutaneous diseases, such as psoriasis, atopic dermatitis, skin and soft tissue infection, superficial tumors, axillary hyperhidrosis, and plantar warts.
Article
Skin microchannels (MCs) created by microneedles (MNs) provide a promising route for enhancing transdermal drug delivery. This study investigated passive and iontophoretic transport of pramipexole dihydrochloride (PXCl) across skin MCs created by polymer MN patches made of 1:2 polymethyl-vinyl-ether-co-maleic acid (PMVEMA) to polyvinyl alcohol (PVA) ratio. Permeation studies were performed in vitro using excised human skin under the conditions of (i) "poke-and-patch" and "poke-and-release" delivery approaches with varying concentration of PXCl in the formulations, (ii) drug-loaded dissolving MN (DMN) and hydrogel-forming MN (HGMN) type patches and (iii) combination of MNs and iontophoresis. The results showed that DMN patch greatly enhanced transdermal delivery of PXCl for both "poke-and-patch" and "poke-and-release" approaches as compared with the conventional delivery method. PXCl flux mainly resulted from the contribution of MC pathway created in skin and increased with increasing drug amounts in the formulations. Compared to DMN patch, HGMN patch provided more linear sustained drug delivery over 72 h. Electromigration was the main mechanism of PXCl iontophoresis through MCs and flux enhancement was found to be larger for HGMN patch than DMN patch. These results demonstrated the potential application of MN patches individually or combined with iontophoresis as an alternative method for PXCl administration.
Article
In order to develop optimum microneedle designs, researchers must first develop robust, repeatable and adaptable test methods which are representative of in vivo conditions. However, there is a lack of experimental tools which can accurately comparatively interrogate functional microneedle penetration of tissue. In this study, we seek to develop a state of the art finite element model of microneedle insertion into and penetration of human skin. The developed model employs a 3D hyperelastic, anisotropic pre-stressed multi-layered material which more accurately reflects in vivo skin conditions, while the microneedle is modeled as an array, which can capture the influence of adjacent microneedles on the overall response. Using the developed finite element model, we highlight the importance of accurate computational modeling which can decipher the mechanics of microneedle insertion, including the influence of its position within an array and how it correlates well with experimental observations. In particular, we have concluded that, for our model microneedle array, increasing skin pretension from 0 to 10% strain reduces the penetration force by 13%, ultimate local deformation about the microneedle by 22% and the ultimate penetration efficiency by 15%. We have also concluded that the presence of a base plate limits the penetration efficiency by up to 24%, while the penetration efficiency across a 5 × 1 microneedle array may vary by 27%. This model elucidates, for the first time, the combined effects of skin tension and needle geometry on accurately predicting microneedle penetration efficiency. Statement of Significance Microneedles arrays (MNAs) are medical devices with microscale protrusions, typically designed to penetrate the outermost layer of the skin, that upon optimisation, could lead to disruptive minimally-invasive disease management. However, the mechanics of MNA insertion are complex, due in part to a ‘bed of nails’ effect, and difficult to elucidate experimentally. Therefore, comparisons between designs, functional assessment of production batches and ultimately the likelihood of clinical translation are challenging to predict. Here, we have develop the most sophisticated in silico model of MNA insertion into pre-tensioned human skin to predict the extent of MNA penetration and therefore the likelihood of successful therapeutic delivery. Researchers can customise this model to predict the penetration efficiency of any MNA design.
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Chronic inflammatory skin diseases (CISDs) negatively impact a large number of patients. Injection of triamcinolone acetonide (TA), an anti‐inflammatory steroid drug, directly into the dermis of diseased skin using needle‐syringe systems is a long‐established procedure for treating recalcitrant lichenified lesions of CISDs, referred to as TA intralesional injection (TAILI). However, TAILI causes severe pain, causing patients to be stressed and reluctant to undergo treatment. Furthermore, the practitioner dependency on the amount and depth of the injected TA makes it difficult to predict the prognosis. Here, candle flame (“candlelit”)‐shaped TA‐loaded dissolving microneedles (Candlelit‐DMN) are designed and fabricated out of biocompatible and biodegradable molecules. Candlelit‐DMN distributes TA evenly across human skin tissue. Conjoined with the applicator, Candlelit‐DMN is efficiently inserted into human skin in a standardized manner, enabling TA to be delivered within the target layer. In an in vivo skin inflammation mouse model, Candlelit‐DMN inserted with the applicator effectively alleviates inflammation by suppressing inflammatory cell infiltration and cytokine gene expression, to the same extent as TAILI. This Candlelit‐DMN with the applicator arouses the interest of dermatologists, who prefer it to the current TAILI procedure.
Article
Because of the limitations of the oral drug delivery system, as well as the discomfort associated with the usage of needles in the case of injections, drug delivery research has shifted significantly toward the transdermal route of administration. Topical creams, gels, and transdermal patches are the most often utilised means of transdermal administration of drugs. Since the stratum corneum layer of the skin acts as a barrier to a drug molecule, the effect of the majority of therapeutic agents is limited. As a result, only a small number of molecules are able to reach the site of action. A new type of delivery method, known as microneedles, is being developed to improve the distribution of drugs through this route while also overcoming the various issues associated with existing formulations. Non-invasive and painless feature of microneedles have making them ideal for self-administration. This review describes various type of microneedles and their design, fabrication methodology, various materials used in fabrication of microneedles, drug release mechanism from the microneedles, evaluation parameters, it’s biological application, update about recent clinical studies and in last, challenges and future perspective of microneedles as drug delivery system.
Article
Vaccine administration by subcutaneous or intramuscular injection is the most commonly prescribed route for inoculation, however, it is often associated with many deficiencies such as low compliance, high professionalism, and risk of infection. Therefore, the application of microneedles for vaccine delivery has gained widespread interests in the past few years due to its high compliance, minimal invasiveness, and convenience. This review focuses on recent advances in the development and application of microneedles for vaccination based on different delivery mechanisms, and introduces the current status of microneedle-mediated vaccination in clinical translation. The prospects for its application including opportunities and challenges are further discussed.
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Dissolvable microneedle patches (MNPs) enable simplified delivery of therapeutics via the skin. However, most dissolvable MNPs do not deliver their full drug loading to the skin because only some of the drug is localized in the microneedles (MNs), and the rest remains adhered to the patch backing after removal from the skin. In this work, biphasic dissolvable MNPs are developed by mounting water-soluble MNs on a water-insoluble backing layer. These MNPs enable the drug to be contained in the MNs without migrating into the patch backing due to the inability of the drugs to partition into the hydrophobic backing materials during MNP fabrication. In addition, the insoluble backing is poorly wetted upon MN dissolution in the skin, which significantly reduces drug residue on the MNP backing surface after application. These effects enable a drug delivery efficiency of >90% from the MNPs into the skin 5 min after application. This study shows that the biphasic dissolvable MNPs can facilitate efficient drug delivery to the skin, which can improve the accuracy of drug dosing and reduce drug wastage.
Chapter
Biodegradation and biocompatibility are crucial for developing long-acting implantable drug delivery systems. Because of the prolonged biological residence of these implants, understanding of in vivo degradation and biocompatibility helps establish the commercial success of these implants. International Organization for Standardization has laid down various guidelines for the development and optimization of in vitro degradation studies. This chapter discusses multiple ISO guidelines and current research to understand the influence of different study parameters on biodegradation study. The chapter also summarizes the immunological consideration in the design and evaluation of long-acting implants.
Article
Microneedle (MN) patches are being developed for many different kinds of drugs, but are often limited to delivering sub-milligram doses. This is because larger patches can be more difficult to apply to the skin, and acceptability of larger MN patches by human subjects has received limited study. Here, we fabricated 18 different large MN patch designs by laser microfabrication with different MN length (800–1500 μm), number of MNs (225 to 900 MNs per patch), space between MNs (600–1100 μm), and MN base diameter (200–250 μm). After manual application of these patches to human participants, we assessed dose delivery efficiency, total dose delivered, dose delivered per MN, depth of MN penetration and whole-MN delivery efficiency. We found that all of these parameters generally increased with decreased MN length, increased number of MNs (among those ≤1000 μm in length) and increased MN-MN spacing. All MN patch designs caused less pain than a pin prick sensation and were generally considered acceptable by the study participants. The MN patches induced mild, or sometimes moderate, erythema on skin. Study participants showed higher preference for MN patches for long-acting contraception compared with conventional options, indicating strong interest and acceptability of MN patches in this study.
Article
Alopecia is the most common multifactorial hair loss disorder, affecting almost 50% of the population and even having a serious psychological impact on the patients. miR-218 has therapeutic potential for alopecia since it can activate the Wnt/β-catenin channel by down-regulating SFRP2, which is a key channel in hair follicle cycle transformation for hair regrowth. Although miR-218 has the potential to treat this disease, several barrier properties of the skin challenge miRNA's delivery to the target location, such as passing through the corneum and resistant enzymatic degradation. To address these challenges, we evaluated a device that combined the use of hyaluronic acid (HA)-based dissolving microneedle (MN) to enhance corneum permeability with the lipid polymer hybrid nanoparticles (LPNs) as a miRNA delivery carrier to protect miR-218 from degradation. The MN patches could promote LPNs/miR-218 diffusing in the dermis region, and significantly increase the bioavailability of miR-218. Furthermore, in the shaved mouse model, the MN patches showed higher efficacy in promoting hair growth than the topical smear treatment, while avoiding the safety concern. This work established a novel and effective combination device with MN and LPNs that can be used for localized transdermal miRNA delivery to promote hair regrowth.
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The development of microneedle (MN)-assisted drug delivery technologies has been highly active for nearly two decades. The microneedle array patch (MAP)-based self-application technology bypasses many of the challenges associated with injectable routes by delivering the therapeutic materials directly into the intradermal space and allowing the release of the active ingredient in a sustained or controlled manner. Different types of biodegradable solid/dissolving MAP and nanoparticle-loaded/coated polymeric MAP or hollow MN have been envisioned for long-acting sustained delivery of therapeutic payloads, aiming for reducing the side effects and administration frequency to improve patient compliance. In this chapter, we covered the different types of MAPs that are loaded with different nano/biotherapeutics for long-acting delivery for a wide range of potential clinical applications. We have outlined the future development scenario for this long-acting MAP delivery system to achieve promising clinical benefits. Finally, it discusses the challenges to realize the full potential of long-acting sustained-release MNs in the clinic.
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Photodynamic therapy (PDT) represents an attractive promising route for melanoma treatment. However, its therapeutic efficacy is compromised by inefficient drug delivery and high glutathione (GSH) levels in cancer cells. To overcome these challenges, microneedles (MNs) system loaded with GSH‐scavenging nanocomposites was presented for nitric oxide (NO) enhanced PDT. The nanocomposites consisted of S‐nitroso‐N‐acrylate penicillamine(SNAP, a NO donor) grafted 4th generation polyamide amine dendrimer(G4) and chlorins e6(Ce6). Upon local insertion of polyvinylpyrrolidone MNs, G4‐SNAP/Ce6 composites were fast delivered and significantly amplified the therapeutic effects during PDT, via GSH depletion and reactive nitrogen species (RNS) generation. Even with a single administration and low power light exposure, MNs with G4‐SNAP/Ce6 effectively halt the tumor progression. The system demonstrated better cancer ablation efficacy than Ce6 alone towards melanoma. The strategy may inspire new ideas for future PDT‐related therapy for skin tumors. This article is protected by copyright. All rights reserved.
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Acute toxicity studies of dissolvable microneedle (dMN) patches fabricated from a combination of polymers, i.e. thiolated chitosan (TCS), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP), were performed to determine the safety of polymers on white albino rabbits. The selected albino rabbits were categorized into four groups. Group I was a control group, whereas groups II, III and IV were administered different doses of polymeric dMN patches. The food and water uptake and the weight of the animals were observed before and after administration of the microneedle patch on days 1, 3, 5, 7 and 14. Hematological and serum biochemical changes were observed by taking blood samples of treated and control group rabbits on the 15th day of study. The weight of the main organs was determined and a histopathology study was also performed. Negligible alteration in body weight, meals and water uptake was observed. The control and treated animals displayed similar behavioral pattern. Moreover, the treated groups showed hematological and biochemical analysis results, which were comparable with the results of the control group animals. Animals from both control and treated groups did not present any significant difference in the results of relative organ body weight and urine analysis. A comparison of histopathology results for both treated and control animals’ vital organs confirmed the absence of lesions. The findings of antioxidant effect, dermal and cardiac toxicity studies of chitosan, thiolated chitosan and the TCS/PVA/PVP combination were compared to those of the analysis of circulating oxidative levels, demonstrating that the combination of TCS/PVA/PVP showed improved antioxidant effect, as compared to those of chitosan and thiolated chitosan alone, and showed no significant effect on skin and heart. Thus, the findings of the study established the fact that the fabricated polymeric dMNs are a safe carrier system for different drugs.
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Microneedles have the clinical advantage of being able to deliver complex drugs across the skin in a convenient and comfortable manner yet haven't successfully transitioned to medical practice. Diabetes mellitus is a complicated disease, which is commonly treated with multiple daily insulin injections, contributing to poor treatment adherence. Firstly, this review determines the clinical prospect of microneedles, alongside considerations that ought to be addressed before microneedle technology can be translated from bench to bedside. Thereafter, we use diabetes as a case study to consider how microneedle-based-technology may be successfully harnessed. Here, publications referring to insulin microneedles were evaluated to understand whether insertion efficiency, angle of insertion, successful dose delivery, dose adjustability, material biocompatibility and therapeutic stability are being addressed in early stage research. Moreover, over 3,000 patents from 1970-2019 were reviewed with the search term '"microneedle" AND "insulin"' to understand the current status of the field. In conclusion, the reporting of early stage microneedle research demonstrated a lack of consistency relating to the translational factors addressed. Additionally, a more rational design, based on a patient-centred approach is required before microneedle-based delivery systems can be used to revolutionise the lives of people living with diabetes following regulatory approval.
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Creatures in nature have evolved fascinating functions in the natural selection of superiority and inferiority to adapt to complex and harsh survival environments. Some special and excellent functions have been found to originate from the multilayered physical microstructure and chemical composition of biological surfaces, providing humans with a wide range of bionic references and inspirations. Inspired by the biological surfaces, numerous novel functional materials have sprung up to achieve unexpected results by mimicking the physical and chemical structures. Herein, some typical applications for healthcare advances of various biomimetic microstructured surfaces including sensors, adhesives, and superhydrophobic surfaces are reviewed, which are associated with the working mechanism around biological surfaces. The techniques and methods to fabricate biomimetic microstructured surfaces are also reviewed. The future challenges and opportunities for biomimetic microstructures are presented. Nature provides humans with inspiration and inspiration for a wide range of biological surfaces. This review overviews various biosurface‐inspired biomimetic microstructured surfaces for applications such as sensors, adhesives, and superhydrophobisc surfaces, which are fabricated by methods including template methods, photolithography, 3D printing, and vapor phase deposition. The development and challenges of biomimetic microstructures are outlined.
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Medical tattoos provide medical information, guide radiotherapy, and improve cosmetic outcomes of medical interventions. These tattoos are administered by repeated needle injection that causes pain, bleeding, and risk of infection, which limit more widespread use. Here, we developed single-use microneedle (MN) patches to deposit tattoos in the skin in a simple, rapid, painless, and bloodless way without biohazardous sharps waste. MN patch tattoos were designed with numbers, letters, symbols, environmentally responsive inks, and QR codes. Colored tattoos, and tattoos only visible with ultraviolet illumination for increased privacy, were developed and retained in the skin for at least one year. These MN patch tattoos recorded medical conditions such as diabetic medical alerts and vaccination status, responded to biophysical cues for possible physiological monitoring, and encoded complex personal health information. MN patches may increase safety and access to medical tattoos for improved fiducial marking, medical information storage, physiological monitoring, and cosmetic outcomes.
Article
Anti-acne microneedle technology is an emerging approach to acne vulgaris and acne scars therapy. Currently, solid microneedle is the most common one in clinical practices. Nevertheless, it needs to be operated by professionals. Additionally, there is a potential risk of needle breakage, leading to a biohazard inside the skin. This study prepared and evaluated a dissolving microneedle (DMN) containing azelaic acid (AZA), providing a novel self-administered and rapid-onset pathway for acne patients. The AZA-loaded DMN can be inserted into the skin under the loaded force of 5 N. We examined the safety, transdermal release, stability, antibacterial activity, and pharmacokinetic studies of AZA-DMN to provide reference and guarantee for clinical trials. Besides, to evaluate the efficacy of DMN containing AZA, a randomized and controlled pilot study was conducted on adult acne patients. The results indicated that AZA-DMN had good skin compatibility and formulation stability. Furthermore, there was no significant difference in AZA concentrations in rats’ plasma before and after administration, revealing that AZA-DMN mainly worked on local skin. Compared to the control groups, more remarkable inflammation subsidence appeared in the AZA-DMN group. Meanwhile, it was shown that the delivery of AZA using DMN significantly shortened the therapy cycle compared with commercially available AZA cream. In summary, our studies confirmed that AZA-loaded DMN provided a promising treatment strategy for acne patients due to the enhanced transdermal permeability of AZA and its noticeable antibacterial effect on Propionibacterium acnes and Staphylococcus epidermidis.
Article
Microneedles (MNs) have been developed for various applications such as drug delivery, cosmetics, diagnosis, and biosensing. To meet the requirements of MNs used in these areas, numerous materials have been used for the fabrication of MNs. However, MNs will be exposed to skin tissues after piercing the stratum corneum barrier. Thus, it is necessary to ensure that the matrix materials of MNs have the characteristics of low toxicity, good biocompatibility, biodegradability, and sufficient mechanical properties for clinical application. In this review, the matrix materials currently used for preparing MNs are summarized and reviewed in terms of these factors. In addition, MN products used on the market and their applications are summarized in the end. This work may provide some basic information to researchers in the selection of MN matrix materials and in developing new materials.
Article
Microneedles are a rapidly developing method for the transdermal delivery of therapeutic compounds. All types of microneedles, whether solid, hollow, coated, or dissolving function by penetrating the stratum corneum layer of the skin producing a microchannel through which therapeutic agents may be delivered. To date, coated and hollow microneedles have been the most successful, despite suffering from issues such as poor drug loading capabilities and blocked pores. Dissolving microneedles, on the other hand, have superior drug loading as well as other positive attributes that make it an ideal delivery system, including simple methods of fabrication and disposal, and abundantly available materials. Indeed, dissolvable microneedles can even be fabricated entirely from the therapeutic agent itself thus eliminating the requirement for additional excipients. This focused review presents the recent developments and trends of dissolving microneedles as well as potential future directions. The advantages, and disadvantages of dissolving microneedles as well as fabrication materials and methods are discussed. The potential applications of dissolving microneedles as a drug delivery system in different therapeutic areas in both research literature and clinical trials is highlighted. Applications including the delivery of cosmetics, vaccine delivery, diagnosis and monitoring, cancer, pain and inflammation, diabetes, hair and scalp disorders and inflammatory skin diseases are presented. The current trends observed in the microneedle landscape with particular emphasis on contemporary clinical trials and commercial successes as well as barriers impeding microneedle development and commercialisation are also discussed.
Article
Microelectromechanical system (MEMS)-based microneedles are an innovative way of drug delivery that increases the permeability of the skin. It generates microscopic pores inside the skin that leads to the passive diffusion of drugs for dermal microcirculation to take place. This phenomenon helps toward efficient drug penetration. MEMS microneedles are small-sized needles usually in the micron to millimeter range, normally having a length to width of about 150–550 µm and 50–300 µm. respectively. Their tip diameter varies from 1 to 80 µm that can pierce through the epidermis layer directly to dermal tissues devoid of any pain. In this paper, a broad overview of solid microneedles for biomedical applications has been presented. The objective of this review is to collect the state of art main features related to solid microneedles. Particularly, the challenges related to solid microneedles, such as materials and methods used in the fabrication of microneedles, design and their performance, testing, safety concerns, commercialization issues, and applications, have been discussed. Microneedles can be characterized conferring to their fabrication procedure, structure, materials, general shape and size, the shape of the tip, microneedle array thickness, and applications. This comprehensive review on solid microneedles may provide significant useful information for scientists or researchers working on the design and development of solid microneedles for biomedical applications.
Chapter
During the recent decades, dermal delivery has achieved visible popularity mainly due to the increase of chronic skin diseases and the demand for targeted delivery and patient compliance. Dermal delivery provides an attractive alternative to oral drug delivery, promoting the drug application directly at the site of action, resulting in higher localized drug concentration with reduced systemic drug exposure. Among several types of drug delivery systems used in dermal delivery are the lipid nanoparticles, which include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers have attracted great interest and have been intensively studied for their use in dermal applications. Lipid nanoparticles increase the transport of active compounds through the skin by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Moreover, these nanocarriers are composed of biologically active and biodegradable lipids that show less toxicity and offer many favorable attributes such as adhesiveness, occlusion, skin hydration, lubrication, smoothness, skin penetration enhancement, modified release, improvement of formulation appearance providing a whitening effect, and offering protection of actives against degradation.This chapter focuses on the effects of lipid nanoparticles in dermal delivery, on the types of active compounds that are used in their formulation and application, some aspects related to their possible toxicity, and a description of the most commonly used techniques for the evaluation of drug absorption on the skin.
Article
There is a tremendous need for simple-to-administer, long-acting contraception, which can increase access to improved family planning. Microneedle (MN) patches enable simple self-administration and have previously been formulated for 1-2 months' controlled release of contraceptive hormone using monolithic polymer/drug MN designs having first-order release kinetics. To achieve zero-order release, we developed a novel core-shell MN patch where the shell acts as a rate-controlling membrane to delay release of a contraceptive hormone, levonorgestrel (LNG), for 6 months. In this approach, LNG was encapsulated in a poly(lactide-co-glycolide) (PLGA) core surrounded by a poly(l-lactide) (PLLA) shell and a poly(D,l-lactide) (PLA) cap that were fabricated by sequential casting into a MN mold. Upon application to skin, the core-shell MNs utilized an effervescent interface to separate from the patch backing within 1 min. The core-shell design limited the initial 24 h burst release of LNG to 5.8 ± 0.5% and achieved roughly zero-order LNG release for 6.2 ± 0.1 months in vitro. A monolithic MN patch formulated with the same LNG and PLGA core, but without the rate-controlling PLLA shell and PLA cap had a larger LNG burst release of 22.6 ± 2.0% and achieved LNG release for just 2.1 ± 0.2 months. This study provides the first core-shell MN patch for controlled months-long drug release and supports the development of long-acting contraception using a simple-to-administer, twice-per-year MN patch.
Article
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Vaccination has produced a great improvement to the global health by decreasing/eradicating many infectious diseases responsible for significant morbidity and mortality. Thanks to vaccines, many infections affecting childhood have been greatly decreased or even eradicated (smallpox, measles, and polio). That is why great efforts are made to achieve mass vaccination against COVID-19. However, developed vaccines face many challenges with regard to their safety and stability. Moreover, needle phobia could prevent a significant proportion of the population from receiving vaccines. In this context, microneedles (MNs) could potentially present a solution to address these challenges. MNs represent single dose administration systems that do not need reconstitution or cold-chain storage. Being self-administered, pain-free, and capable of producing superior immunogenicity makes them a more attractive alternative. This review explores microneedles' types, safety, and efficacy in vaccine delivery. Preclinical and clinical studies for microneedle-based vaccines are discussed and patent examples are included. Full text available at https://link.springer.com/article/10.1208/s12249-022-02250-8
Article
Diabetes can cause various complications and affect the normal functioning of the human body. A theranostic and diagnostic platform for real-time glycemia sensing and simultaneous self-regulated release of insulin is desired to improve diabetic patients' life quality. Here, we describe a theranostic microneedle array patch, which enables the achievement of visualization quantification of glycemia and simultaneously self-regulated release of insulin. The microneedle patch (MNDF) was fabricated by crosslinking of 3-aminophenylboronic acid (ABA)-modified sodium alginate and chondroitin sulfate. The hierarchical structure consisted of a tip part containing mineralized insulin particles and glucose oxidase (GOD) for insulin release, and a base surface embodying 3,3',5,5'-tetramethylbenzidine (TMB) and (horseradish peroxidase) HRP for real-time glycemia sensing. In the presence of glucose, GOD converts glucose into H+ and H2O2, driving gradual dissolution of the calcium layer of insulin particles, resulting in long-acting release of insulin. By the bio-catalytic action of HRP, the generated H2O2 brings about a visible color change allowing the glucose level at the base surface to be read out. We believe that the theranostic microneedle array patch can act as a promising alternative for future clinical applications.
Article
Dissolving microneedles (DMNs), a kind of drug delivery platform with numerous advantages are proposed to treat skin diseases with high efficiency. It can not only avoid the inhibition of the stratum corneum but also improve the therapeutical effect, being a new choice for dermatological disease therapy. Compared with synthetic polymers, polysaccharide polymers (PS) have characteristics of wide sources, no additives, and are easy to obtain and utilize, etc. attracting the attention of many researchers and are often used as matrix materials to fabricate DMNs. In this manuscript, the brief introduction of skin diseases and PS-DMNs, the roles played by PS-DMNs in the treatment of dermatological diseases, and the widespread applications of PS-DMNs-mediated drug delivery in the dermatology field are reviewed in detail. DMNs made by PS can not only exert treatment effects with the advantages of DMNs, but also exert synergy effect with drugs using their own medicinal effect. Although there are many advantages on DMNs made by PS, some challenges have existed, that need to be addressed including the large-scale production of DMNs and the maintenance of the activity of temperature-sensitive or light-sensitive drugs encapsulated in the DMNs during the process of fabricating DMNs.
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Microneedles are being developed to administer vaccines and therapeutics to and through skin. To date there has been no qualitative or quantitative research into public and health professionals' views on this new delivery technique. Focus groups (n=7) comprising public and healthcare professionals were convened to capture the perceived advantages for, and concerns with, microneedles. Discussions were audio-recorded and transcribed. Transcript analysis identified themes that were explored using a questionnaire identifying consensus or otherwise. Participants identified many potential benefits of the microneedle delivery system, including reduced pain, tissue damage and risk of transmitting infections compared with conventional injections, as well as potential for self-administration (subject to safeguards such as an indicator to confirm dose delivery). Delayed onset, cost, accurate and reliable dosing and the potential for misuse were raised as concerns. A range of potential clinical applications was suggested. The public (100%) and professional (74%) participants were positive overall about microneedle technology. This exploratory research study captured the views of the eventual end-users of microneedle technology. Microneedle researchers should now reflect on their research and development activities in the context of stakeholder engagement in order to facilitate the transfer of this new technology 'from bench to bedside.'
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Injections using hypodermic needles cause pain, discomfort, localised trauma and apprehension. Additionally, careful use and disposal of needles is required to avoid transmission of blood-borne pathogens. As an alternative, microneedles can facilitate drug delivery without significantly impacting on pain receptors or blood vessels that reside beneath the skin outer layers. In this study we aim to determine the pain and sensory response to the application of wet-etch silicon microneedles, when used in such a way as to reliably penetrate skin, and provide a preliminary indication of how skin responds to microneedle injury with time. Twelve subjects received single-blinded insertions of a 25-G hypodermic needle and two microneedle arrays (36 needles of 180 and 280 mum height). The optimal method for microneedle application was determined in a pilot study. Pain intensity was scored using a visual analogue scale (VAS) and sensory perception determined using an adapted McGill Pain Questionnaire Short Form. Skin penetration was determined by external staining and measurement of trans-epidermal water loss (TEWL). Mean VAS scores, verbal descriptions and questionnaire responses showed that the 180 and 280 mum microneedles caused significantly less pain and discomforting sensation in participants than the hypodermic needle. Methylene blue staining and TEWL analysis confirmed that microchannels were formed in the skin following microneedle application. Evidence of microchannel repair and resealing was apparent at 8-24 h post-application. In summary, this study shows that pyramidal wet-etch microneedles can penetrate human skin with minimal pain and sensory discomfort, creating transient pathways for potential drug, vaccine and DNA delivery.
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Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study, we evaluated the immunogenicity of H1N1, H3N2, and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25 °C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by single radial diffusion (SRID) assay and immune responses to vaccination in BALB/c mice. After a single immunization, all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least 3 months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability.
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Influenza infection represents a major socioeconomic burden worldwide. Skin represents a new target that has gained much attention in recent years for delivery of influenza vaccine as an alternative to the conventional intramuscular route of immunization. In this review we describe different microneedle vaccination approaches used in vivo, including metal and dissolving microneedle patches that have demonstrated promising results. Additionally we analyze the immunological basis for microneedle skin immunization and targeting of the skin's dense population of antigen presenting cells, their role, characterization, and function. Additionally we analyze the importance of inflammatory signaling in the skin after microneedle delivery.
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Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990's when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications.
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Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a number of production processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different production methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A separate section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clinically useful in the near future.
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To design microneedles that minimize pain, this study tested the hypothesis that microneedles cause significantly less pain than a 26-gauge hypodermic needle, and that decreasing microneedle length and the number of microneedles reduces pain in normal human volunteers. Single microneedles with lengths ranging from 480 to 1450 microm, widths from 160 to 465 microm, thicknesses from 30 to 100 microm, and tip angles from 20 to 90 degrees; and arrays containing 5 or 50 microneedles were inserted into the volar forearms of 10 healthy, human volunteers in a double-blinded, randomized study. Visual analog scale pain scores were recorded and compared with each other and to the pain from a 26-gauge hypodermic needle. All microneedles investigated were significantly less painful than the hypodermic needle with microneedle pain scores varying from 5% to 40% of the hypodermic needle. Microneedle length had the strongest effect on pain, where a 3-fold increase in length increased the pain score by 7-fold. The number of microneedles also affected the pain score, where a 10-fold increase in the number of microneedles increased pain just over 2-fold. Microneedle tip angle, thickness, and width did not significantly influence pain. Microneedles are significantly less painful than a 26-gauge hypodermic needle over the range of dimensions investigated. Decreasing microneedle length and number of microneedles reduces pain.