Successful application of large microneedle patches by human volunteers.
ABSTRACT: We describe, for the first time, the design, production and evaluation of large microneedle patches. Such systems, based on 16 individual microneedle arrays (needle height 600?m), were prepared from aqueous blends of 15% w/w Gantrez® S97 and 7.5% w/w poly(ethyleneglycol) 10,000Da. Ester-based crosslinking was confirmed by FTIR and mechanical strength was good. Insertion depths in a validated skin model were approximately 500?m. Ten human volunteers successfully self-inserted the microneedles of these larger patches in their skin, following appropriate instruction, as confirmed by transepidermal water loss measurements. The mean insertion depth ranged between 300 and 450?m over the area of the large patches. That this was not significantly different to a single unit MN patch self-applied by the same volunteers is encouraging. Microneedle patch sizes much larger than the 1-2cm2 will be required if this technology is to be successfully translated to clinic for delivery of drug substances. The work described here suggests that use of such larger patches by patients can be successful, potentially opening up the possibility for a significant expansion of the size of the market for transdermal drug delivery.
Project description:Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.
Project description: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.
Project description:The clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive alternative. In this study, the translation of a dissolving microneedle patch designed for simple, painless self-administration of biopharmacetucials that generates no sharp biohazardous waste is assessed. To study the pharmacokinetics and safety of this approach, human growth hormone (hGH) was encapsulated in 600 ?m-long dissolving microneedles composed of carboxymethylcellulose and trehalose using an aqueous, moderate-temperature process that maintained complete hGH activity after encapsulation and retained most activity after storage for up to 15 months at room temperature and humidity. After manual insertion into the skin of hairless rats, hGH pharmacokinetics were similar to conventional subcutaneous injection. After patch removal, the microneedles had almost completely dissolved, leaving behind only blunt stubs. The dissolving microneedle patch was well tolerated, causing only slight, transient erythema. This study suggests that a dissolving microneedle patch can deliver hGH and other biopharmaceuticals in a manner suitable for self-administration without sharp biohazardous waste.
Project description:Abnormal (keloid and hypertrophic) scars are a significant affliction with no satisfactory single modality therapy to-date. Available options are often ineffective, painful, potentially hazardous, and require healthcare personnel involvement. Herein a self-administered microneedle device based on drug-free physical contact for inhibiting abnormal scars is reported. Its therapeutic activity through microneedle contact eliminates hazards associated with toxic anti-scarring drugs while self-treatment enables administration flexibility.The microneedle patch was fabricated with FDA-approved liquid crystalline polymer under good manufacturing practice. It was first tested to ascertain its ability to inhibit (keloid) fibroblast proliferation. Later the microneedle patch was examined on the rabbit ear hypertrophic scar model to explore its potential in inhibiting the generation of abnormal scars post-injury. Finally, the microneedle patch was applied to the caudal region of a hypertrophic scar located on a female patient's dorsum to verify clinical efficacy.On untreated control cultures, barely any non-viable fibroblasts could be seen. After 12-h treatment with the microneedle patch, the non-viable proportion increased to 83.8 ± 11.96%. In rabbit ear hypertrophic scar model, 100% of the control wounds without the presence of patches on rabbit ears generated regions of raised dermis originating from the wound site (3/3), whereas microneedle treatment prevented dermis tissue thickening in 83.33% of the wounds (15/18). In the clinical test, the microneedle patch was well tolerated by the patient. Compared to the untreated region, microneedle treatment decreased the number of infiltrated inflammatory cells, with less disrupted dermis tissue architecture and more flattened appearance.A self-administered, drug-free microneedle patch appears highly promising in reducing abnormal scarring as observed from in vitro, in vivo and clinical experiments. Larger cohort clinical studies need to be performed to validate its efficacy on abnormal scars.
Project description:This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring.
Project description:The goal of this study is to develop thermostable microneedle patch formulations for influenza vaccine that can be partially or completely removed from the cold chain. During vaccine drying associated with microneedle patch manufacturing, ammonium acetate and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer salts stabilized influenza vaccine, surfactants had little effect during drying, drying temperature had weak effects on vaccine stability, and drying on polydimethylsiloxane (PDMS) led to increased stability compared with drying on stainless steel. A number of excipients, mostly polysaccharides and some amino acids, further stabilized the influenza vaccine during drying. Over longer time scales of storage, combinations of stabilizers preserved the most vaccine activity. Finally, dissolving microneedle patches formulated with arginine and calcium heptagluconate had no significant activity loss for all three strains of seasonal influenza vaccine during storage at room temperature for 6 months. We conclude that appropriately formulated microneedle patches can exhibit remarkable thermostability that could enable storage and distribution of influenza vaccine outside the cold chain.
Project description:While therapeutic drugs are routinely self-administered by patients, there is little precedent for self-vaccination. Convenient self-vaccination may expand vaccination coverage and reduce administration costs. Microneedle patches are in development for many vaccines, but no reports exist on usability or acceptability. We hypothesized that naïve patients could apply patches and that self-administered patches would improve stated intent to receive an influenza vaccine. We conducted a randomized, repeated measures study with 91 venue-recruited adults. To simulate vaccination, subjects received placebo microneedle patches given three times by self-administration and once by the investigator, as well as an intramuscular injection of saline. Seventy participants inserted patches with thumb pressure alone and the remainder used snap-based devices that closed shut at a certain force. Usability was assessed by skin staining and acceptability was measured with an adaptive-choice analysis. The best usability was seen with the snap device, with users inserting a median value of 93-96% of microneedles over three repetitions. When a self-administered microneedle patch was offered, intent to vaccinate increased from 44% to 65% (CI: 55-74%). The majority of those intending vaccination would prefer to self-vaccinate: 64% (CI: 51-75%). There were no serious adverse events associated with use of microneedle patches. The findings from this initial study indicate that microneedle patches for self-vaccination against influenza are usable and may lead to improved vaccination coverage.
Project description:Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify the logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID??) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 min, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage.
Project description:Currently available measles vaccines are administered by subcutaneous injections and require reconstitution with a diluent and a cold chain, which is resource intensive and challenging to maintain. To overcome these challenges and potentially increase vaccination coverage, microneedle patches are being developed to deliver the measles vaccine. This study compares the cost-effectiveness of using microneedle patches with traditional vaccine delivery by syringe-and-needle (subcutaneous vaccination) in children's measles vaccination programs.We built a simple spreadsheet model to compute the vaccination costs for using microneedle patch and syringe-and-needle technologies. We assumed that microneedle vaccines will be, compared with current vaccines, more heat stable and require less expensive cool chains when used in the field. We used historical data on the incidence of measles among communities with low measles vaccination rates.The cost of microneedle vaccination was estimated at US$0.95 (range US$0.71-US$1.18) for the first dose, compared with US$1.65 (range US$1.24-US$2.06) for the first dose delivered by subcutaneous vaccination. At 95 % vaccination coverage, microneedle patch vaccination was estimated to cost US$1.66 per measles case averted (range US$1.24-US$2.07) compared with an estimated cost of US$2.64 per case averted (range US$1.98-US$3.30) using subcutaneous vaccination.Use of microneedle patches may reduce costs; however, the cost-effectiveness of patches would depend on the vaccine recipients' acceptability and vaccine effectiveness of the patches relative to the existing conventional vaccine-delivery method. This study emphasizes the need to continue research and development of this vaccine-delivery method that could boost measles elimination efforts through improved access to vaccines and increased vaccination coverage.
Project description:Although dissolving microneedles have garnered considerable attention as transdermal delivery tools, insufficient drug loading remains a challenge owing to their small dimension. Herein, we report a one-step process of synthesizing semi-dissolving microneedle (SDMN) patches that enable effective transdermal drug delivery without loading drugs themselves by introducing TEMPO-oxidized bacterial cellulose nanofibers (TOBCNs), which are well dispersed, while retaining their unique properties in the aqueous phase. The SDMN patch fabricated by the micro-molding of a TOBCN/hydrophilic biopolymer mixture had a two-layer structure comprising a water-soluble needle layer and a TOBCN-containing insoluble backing layer. Moreover, the SDMN patch, which had a hole in the backing layer where TOBCNs are distributed uniformly, could offer novel advantages for the delivery of large quantities of active ingredients. In vitro permeation analysis confirmed that TOBCNs with high water absorption capacity could serve as drug reservoirs. Upon SDMN insertion and the application of drug aqueous solution through the drug inlet hole, the TOBCNs rapidly absorbed the solution and supplied it to the needle layer. Simultaneously, the needle layer dissolved in body fluids and the drug solution to form micro-channels, which enabled the delivery of larger quantities of drugs to the skin compared to that enabled by solution application alone.