Microneedle patch designs to increase dose administered to human subjects
Graphical abstract
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.
Section snippets
Design of microneedle patches
Eighteen kinds of MN patches were designed in this study with different parameters, including MN length, number of MNs per patch, patch area, space between each MN and diameter of MN base (Table 1, Fig. S1 in Supplementary Information). The MNs were fabricated using water-soluble materials (i.e., PVA and sucrose) so that the portion of the MN that penetrated into skin would dissolve, thereby enabling us to determine the depth and efficiency of MN insertion.
The resulting patches contained MNs
Application of microneedle patches to human subjects
Our first objective was to assess the effects of MN patch design on the amount and efficiency of drug delivery to the skin. After MN patch application to the skin, partial or complete MN dissolution was observed (Fig. 1, middle row). MN structures consisted of an upper conical portion designed to contain a drug or other material for delivery to the skin and a lower less steeply tapered base component that the MN is mounted on and is not intended to contain drug or dissolve in the skin (Fig. 1,
Microneedle insertion depth and dose delivery efficiency
This study designed 18 MN patches with different attributes, including MN length, MN number, patch area, space between MNs and base diameter of MNs. Although patches with long MNs (e.g., 1000 μm to 1500 μm) could generally penetrate skin deeper than those patches with shorter MNs (Fig. 2e), the dissolved fraction of MNs (i.e., dose delivery efficiency) was typically less than for short MN patches (Fig. 2a), as there were still more non-inserted parts of the MNs outside the skin (Fig. 2f). For
Conclusion
In this study, we designed and fabricated 18 MN patches with different geometrical parameters, including MN length, MN number, patch area, space between MNs and base diameter of MNs. All of the patches showed over 90% skin penetration efficiency. Patches with the shortest MNs (800 μm) displayed relatively higher dose delivery efficiency than patches having longer MNs. There was no significant difference of dose delivery efficiency for short MN patches that had the same MN length (i.e., 800 μm),
Author contributions
W. Li: Conceptualization, methodology, investigation, formal analysis, validation, visualization, writing – original draft; S. Li: Investigation, methodology; X. Fan: Investigation, methodology; M. R. Prausnitz: Conceptualization, project administration, supervision, writing – review & editing, funding acquisition. All authors gave approval to the final version of the manuscript.
Competing interests
M.R.P. is an inventor of patents licensed to companies developing MN-based products, a paid advisor to companies developing MN-based products, and a founder/shareholder of companies developing MN-based products (Micron Biomedical). This potential conflict of interest has been disclosed and is managed by Georgia Institute of Technology.
Acknowledgement
We thank Donna Bondy for administrative support and collaborators at Family Health International (FHI 360) and the U.S. Agency for International Development (USAID) for input on study design. This publication is made possible by the generous support of the American people through USAID and was prepared under a subcontract funded by FHI 360 under Cooperative Agreement No. AID-OAA-15-00045, funded by USAID. The content of this publication does not necessarily reflect the views, analysis or
References (35)
- et al.
Past, present, and future technologies for oral delivery of therapeutic proteins
J. Pharm. Sci.
(2008) - et al.
Recent advances of microneedles for biomedical applications: drug delivery and beyond
Acta Pharm. Sin. B
(2019) - et al.
Microneedles for drug and vaccine delivery
Adv. Drug Deliv. Rev.
(2012) - et al.
Insulin delivery systems combined with microneedle technology
Adv. Drug Deliv. Rev.
(2018) - et al.
Advances in transdermal insulin delivery
Adv. Drug Deliv. Rev.
(2019) - et al.
Microneedle-mediated transdermal drug delivery for treating diverse skin diseases
Acta Biomater.
(2021) - et al.
Trends of microneedle technology in the scientific literature, patents, clinical trials and internet activity
Biomaterials
(2021) - et al.
The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial
Lancet
(2017) - et al.
Polymeric microneedles for controlled transdermal drug delivery
J. Control. Release
(2019) - et al.
End-user acceptability study of the nanopatch; a microarray patch (MAP) for child immunization in low and middle-income countries
Vaccine
(2019)
Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects
Biomaterials
Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development
Mater. Sci. Eng. R
Successful application of large microneedle patches by human volunteers
Int. J. Pharm.
The hyperelastic and failure behaviors of skin in relation to the dynamic application of microscopic penetrators in a murine model
Acta Biomater.
Microneedles for drug delivery: trends and progress
Drug Deliv.
Engineering microneedle patches for vaccination and drug delivery to skin
Ann. Rev. Chem. Biomol. Eng.
Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety
Drug Deliv.
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These authors contributed equally to this work.