Microneedle patch designs to increase dose administered to human subjects

Highlights

• Fabrication of 18 large MN patch designs with different geometrical parameters.

• Patches with 800 μm long MNs have higher delivery efficiency than longer MNs.

• Wide space between MNs can reduce “bed-of-nails” effect and enable insertion.

• All MN patches were well tolerated and caused less pain than hypodermic needle.

• High acceptability of MNs for long-acting contraception by study subjects

Abstract

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, transient 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.

Introduction

Many drugs must be administered by injection, often due to low oral bioavailability, which can reduce patient adherence and make access to medicines more difficult, especially in settings with limited heath care resources [1]. Microneedle (MN) patches have been developed to address this concern by offering a simple-to-administer drug delivery method that is well-accepted by patients and can avoid the need for administration by trained health care personnel [2]. While the small size of MN patches is attractive, it has also limited drug dose that can be administered, often to less than 1 mg [3]. Widespread applicability of MN patch delivery systems would benefit from strategies to increase drug doses that can be administered.

MNs are micrometer-scale structures that pierce just below the skin's surface to administer drugs in a minimally invasive manner, usually using a patch with MNs lining the lower surface [4]. MNs are often solid structures tapering to a sharp tip that are made of water-soluble materials including the drug, or in other cases may be non-dissolvable structures coated with a drug formulation. Drug-loaded MNs are dissolved or remain embedded under the skin surface after penetrating and entering the skin, achieving bolus or sustained release of drug from the MNs. MN patches, which usually consist of hundreds or even thousands of MNs per patch, have attracted great interest for drug delivery due to their unique properties, such as causing little to no pain; enabling self-administration; requiring low cost for manufacturing, storage and transportation; generating no biohazardous sharps waste, and thereby eliminating possibility of needle-stick injury after disposal [5].

As a result, MN patches have been widely studied for delivering many kinds of drugs, including small molecules, proteins, DNA/RNA, vaccines and particles [[6], [7], [8], [9]]. In addition to extensive pre-clinical research, MN patches have also been studied in clinical trials on naltrexone to treat opiate and alcohol dependence using metal MNs as a skin pretreatment [10], parathyroid hormone for osteoporosis treatment using drug-coated MNs [11], zolmitriptan for migraine treatment using drug-coated MNs [12] and influenza vaccine for influenza prevention using dissolvable MNs and drug-coated MNs [13,14]. While most uses of MN technology are for bolus delivery, few MNs have been made of biodegradable polymer for slow release [15,16]. For example, we recently developed biodegradable MNs that rapidly separate from the patch backing to remain embedded below the skin surface and slowly release a contraceptive hormone for 1 month [17], which motivates the current study.

Solid, dissolvable MNs frequently have a characteristic volume on the order of 10 nl each, which corresponds to a total patch volume on the order of 1 μl for a patch containing 100 MNs. For a density of 1 mg/ml, this equals ~1 mg of material in the MNs, of which only a fraction is usually drug, since the MNs typically also contain excipients to facilitate manufacturing, provide mechanical strength, enable dissolution and impart other properties.

Drug dose can be increased by increasing the number of MNs, either by increasing MN density, which makes MN insertion into skin more difficult due to the “bed-of-nails” effect [18], or by increasing MN patch area, which makes it more difficult to apply a uniform force across the whole patch as well as match patch shape to follow skin surface curvature [19]. Another option is to make larger MNs with increased MN width, which can make MNs harder to insert, or increased MN length, which can cause more pain [20]. Information is therefore needed to understand the complex relationships between MN patch designs that affect drug dose, MN penetration into skin and pain/acceptability to patients.

In this study, we addressed these questions by applying 18 different MN patch designs to the skin of human subjects, assessing outcomes such as dose delivered and delivery efficiency, and systemically investigated factors that could affect useability and acceptability of MN patches for drug delivery. The study was motivated by our goal to deliver biodegradable MNs or water-soluble MNs encapsulating biodegradable microspheres to the skin for slow release of contraceptive hormone for up to 6 months, which is expected to require administration of much more than 1 mg, and possibly more than 10 mg, of contraceptive hormone, based on drug delivery rates from existing long-acting contraceptive products [21]. For this reason, women of reproductive age were recruited as human subjects in this study. We used water-soluble placebo MNs in this study for safety (i.e., no drug and no slowly degrading polymer remaining in the skin) and to facilitate determining depth of MN insertion into skin by observing MN dissolution after use. Despite our focus on long-acting contraception, we believe that the findings from this study can broadly guide the design of MN patches with increased drug dose for other applications too.