Microneedle technology for immunisation: Perception,acceptability and suitability for paediatric use

ObjectiveTo examine published research which explores the perception and acceptability of microneedle technology for immunisation and to investigate the suitability of this technology for paediatric use.MethodsA series of keywords and their synonyms were combined in various combinations and permutations using Boolean operators to sequentially search four databases (PubMed, Web of Science, Embase and CINAHL). Following removal of duplications and irrelevant results, 12 research articles were included in the final literature review.ResultsThe opinions of patients, parents, children and healthcare professionals (HCP) were collated. A positive perception and a high level of acceptability predominated.ConclusionMicroneedle technology research has been focussed on demonstrating efficacy with minimal focus on determining HCP/public perception and acceptability for paediatric use, exemplified by the paucity of studies presented in this review. Commercial viability will depend on HCP/public acceptability of microneedle technology. An effort must be made to identify the barriers to acceptance and to overcome them by increasing awareness and education in stakeholder groups pertaining to the paediatric population.     

Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles

We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7 ± 2 cmH₂O to a peak value of 43 ± 17 cmH₂O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein—expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence.     

微针联合硬化剂对鸡冠毛细血管网作用的实验研究

目的探讨微针联合不同种类硬化剂对浅表血管性病变作用的特点。方法选择1．5～2．0kg雄性莱航鸡30只作为研究对象。随机分成3组：A组微针＋聚桂醇，B组微针＋无水乙醇，以及C组正常鸡冠，每组均为10只。分别在微针联合硬化剂干预鸡冠后第7、14、21、28天切取鸡冠组织，进行HE染色和免疫组化染色，分别计算毛细血管数目及Ⅰ型、Ⅲ型胶原纤维面积。结果肉眼观察：鸡冠组织颜色随时间的推移而变浅；HE染色显示：两实验组鸡冠组织毛细血管数目均明显随时间的延长而减少，且A组减少更明显；Ⅰ型胶原纤维及Ⅲ型胶原纤维面积计算结果显示：A、B、C组各时段组间对比，差异无统计学意义（P〉0．05）。结论动物实验结果显示，微针联合两种硬化剂均可显著减少鸡冠组织的毛细血管数量，最终导致鸡冠颜色变浅，其中以微针＋聚桂醇效果更明显；Ⅰ型、Ⅲ型胶原纤维未见增生，所以微针联合硬化剂干预鸡冠组织后不会导致局部纤维化。     

End-user acceptability study of the nanopatch™; a microarray patch (MAP) for child immunization in low and middle-income countries

A promising new delivery technology, the microarray patch (MAPs) consists of an array of small solid-coated or dissolvable needles, up to one mm in length, that administers a dry formulation of a vaccine or pharmaceutical. This study is not a real-life evaluation study but determines the anticipated acceptability of the Nanopatch™, a solid microarray patch device, in Benin, Nepal and Vietnam for vaccine delivery, and identifies factors that could improve the acceptability of the technology to increase measles immunization coverage.This study combined several evaluation methods, including simulation of vaccine administration on children and in-depth interviews with key stakeholders, healthcare workers, community health volunteers, caretakers, and community representatives.A total of 314 people participated in the study. The overall rate of total acceptability of the patch for child immunization was 92.7%. General opinions were very positive, providing clinical studies confirm that MAP administration is demonstrated to be painless, safe and effective for infectious disease prevention. The study participants were asked to consider the best strategy to introduce such vaccine delivery innovation. Firstly, delivery by skilled healthcare workers at the healthcare facilities will be preferred to establish the technology. Following this, administration by selected volunteers and outreach delivery may be possible, though under the supervision of skilled healthcare workers.This study’s protocol received approval from the World Health Organization (WHO) Ethical Research Committee (ERC0002813) and the national IRB in Benin, Nepal and Vietnam.     

Safety,tolerability, acceptability and immunogenicity of an influenza vaccine delivered to human skin by a novel high-density microprojection array patch (Nanopatch™)

BackgroundInjection using needle and syringe (N&S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine.MethodsHealthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg haemagglutinin (HA) per dose), applied to the volar forearm (NP-HA/FA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvax® 2016 containing 15 µg of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays.FindingsNP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with N&S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p < 0.0001), with no statistical differences between the treatment groups (p > 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189–593 95% CI), 160 (74–345 95% CI), and 221 (129–380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection.InterpretationInfluenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection.     

高频微针电灼仪治疗24例中重度腋臭患者临床研究

目的 评价使用高频微针电灼仪治疗腋臭的安全性及有效性.方法 收集2015年6月至2016年6月,北京协和医院皮肤科就诊的中重度腋臭患者24例,使用高频微针电灼仪(BodyTiteTM)进行单次治疗,治疗前后使用视觉-气味计分量表(VAS)评价腋下气味,生活质量SF-36量表评估健康相关生活质量,取患者腋下皮肤组织行病理学活检.结果 VAS量表评估显示,24例中22例达到并维持≥12周的症状缓解,平均气味评分下降率(VAS％)50％ ～ 100％,1例治疗后12周腋臭复发,1例未获得临床缓解.SF-36量表评估显示,治疗前患者在社会功能、情感职能、精神健康领域得分[M(P0～P100)]分别为77.50(62.50～100.00)、66.67(33.30 ～ 100.00)、55.00(48.88 ～ 72.00),治疗后分别升至100.00(62.00 ～ 112.50)、100.00(33.30 ～ 110.00)、68.00 (48.00～ 80.00),治疗前后差异有统计学意义(均P＜ 0.05).组织病理显示,治疗后22例汗腺导管细胞出现明显变性、坏死,2例出现表皮损伤.安全性方面,1例治疗后出现单侧上肢疼痛,2例出现小面积皮肤烫伤样改变.术后平均恢复时间为7～ 14d.结论 高频微针电灼仪治疗腋臭临床有效率高,有良好的安全性,具有临床应用前景.     

Safety and efficacy of a novel microneedle device for dose sparing intradermal influenza vaccination in healthy adults

Background

Intradermal vaccine delivery has been shown to induce good immune responses with low vaccine doses. Technologies for drug-delivery which specifically target the skin may render intradermal vaccination more accessible.

Methods

We conducted a prospective, randomized trial in 180 intended-to-treat healthy adults. Study objectives were to evaluate the safety and immunogenicity of low-dose intradermal (ID) influenza vaccines delivered using a novel microneedle device (MicronJet). This device replaces a conventional needle, and is designed specifically for intradermal delivery.Subjects were randomly assigned to receive either the full-dose standard flu shot (containing 15 μg hemagglutinin per strain) delivered intramuscularly using a conventional needle (IM group), a medium dose intradermal injection (6 μg hemagglutinin per strain) delivered with the MicronJet (ID2 group), or a low-dose intradermal injection (3 μg hemagglutinin per strain) delivered with the MicronJet (ID1 group). A marketed influenza vaccine for the 2006/2007 influenza season (α-RIX^® by GSK Biologicals) was used for all injections.Adverse events were recorded over a 42-day period. Immunogenicity was evaluated by changes in hemagglutination inhibition (HAI) antibody titer, and by comparing geometric mean titers (GMTs), seroconversion, and seroprotection rates between the study groups.

Results

Local reactions were significantly more frequent following intradermal vaccination, but were mild and transient in nature. At 21 days after injection, GMT fold increase was 22, 18 and 22 in the ID1, ID2 and IM groups respectively for the H1N1 strain; 9, 9 and 16 for the H3N2 strain and 9, 13 and 11 for strain B. The CPMP criteria for re-licensure of seasonal influenza vaccines were met in full for all study groups.

Conclusions

Low-dose influenza vaccines delivered intradermally using microneedles elicited immunogenic responses similar to those elicited by the full-dose intramuscular vaccination. The microneedle injection device used in this study was found to be effective, safe, and reliable.     

Measles vaccination using a microneedle patch

Measles vaccination programs would benefit from delivery methods that decrease cost, simplify logistics, and increase safety. Conventional subcutaneous injection is limited by the need for skilled healthcare professionals to reconstitute and administer injections, and by the need for safe needle handling and disposal to reduce the risk of disease transmission through needle re-use and needlestick injury. Microneedles are micron-scale, solid needles coated with a dry formulation of vaccine that dissolves in the skin within minutes after patch application. By avoiding the use of hypodermic needles, vaccination using a microneedle patch could be carried out by minimally trained personnel with reduced risk of blood-borne disease transmission. The goal of this study was to evaluate measles vaccination using a microneedle patch to address some of the limitations of subcutaneous injection. Viability of vaccine virus dried onto a microneedle patch was stabilized by incorporation of the sugar, trehalose, and loss of viral titer was less than 1 log₁₀(TCID₅₀) after storage for at least 30 days at room temperature. Microneedle patches were then used to immunize cotton rats with the Edmonston-Zagreb measles vaccine strain. Vaccination using microneedles at doses equaling the standard human dose or one-fifth the human dose generated neutralizing antibody levels equivalent to those of a subcutaneous immunization at the same dose. These results show that measles vaccine can be stabilized on microneedles and that vaccine efficiently reconstitutes in vivo to generate a neutralizing antibody response equivalent to that generated by subcutaneous injection.     

Delivery of salmon calcitonin using a microneedle patch

Peptides and polypeptides have important pharmacological properties but only a limited number have been exploited as therapeutics because of problems related to their delivery. Most of these drugs require a parenteral delivery system which introduces the problems of pain, possible infection, and expertise required to carry out an injection. The aim of this study was to develop a transdermal patch containing microneedles (MNs) coated with a peptide drug, salmon calcitonin (sCT), as an alternative to traditional subcutaneous and nasal delivery routes. Quantitative analysis of sCT after coating and drying onto microneedles was performed with a validated HPLC method. In vivo studies were carried out on hairless rats and serum levels of sCT were determined by ELISA. The AUC value of MNs coated with a trehalose-containing formulation (250 ± 83 ng/mL min) was not significantly different as compared to subcutaneous injections (403 ± 253 ng/mL min), but approximately 13 times higher than nasal administration (18.4 ± 14.5 ng/mL min). T_max (7.5 ± 5 min) values for MN mediated administration were 50% shorter than subcutaneous injections (15 min), possibly due to rapid sCT dissolution and absorption by dermal capillaries. These results suggest that with further optimization of coating formulations, microneedles may enable administration of sCT and other peptides without the need for hypodermic injections.