Accepted Manuscript

Tolerability, usability and acceptability of dissolving microneedle patch administration

in human subjects

Jaya Arya, Sebastien Henry, Haripriya Kalluri, Devin V. McAllister, Winston P. Pewin,
Mark R. Prausnitz

PII: S0142-9612(17)30128-X
DOI: 10.1016/j.biomaterials.2017.02.040
Reference: JBMT 17969

To appear in: Biomaterials

Received Date: 23 January 2017

Revised Date: 27 February 2017
Accepted Date: 28 February 2017

Please cite this article as: Arya J, Henry S, Kalluri H, McAllister DV, Pewin WP, Prausnitz MR,
Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects,
Biomaterials (2017), doi: 10.1016/j.biomaterials.2017.02.040.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT

1 Tolerability, usability and acceptability of dissolving microneedle patch administration

2 in human subjects

3 Jaya Arya, Sebastien Henry, Haripriya Kalluri, Devin V. McAllister, Winston P. Pewin, Mark R.

4 Prausnitz*

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5 Georgia Institute of Technology, Atlanta, GA 30332, USA

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6 * To whom correspondence should be addressed: prausnitz@gatech.edu

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7 Abstract: To support translation of microneedle patches from pre-clinical development

8 into clinical trials, this study examined the effect of microneedle patch application on local skin

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9 reactions, reliability of use and acceptability to patients. Placebo patches containing dissolving
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10 microneedles were administered to fifteen human participants. Microneedle patches were well

11 tolerated in the skin with no pain or swelling and only mild erythema localized to the site of
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12 patch administration that resolved fully within seven days. Microneedle patches could be

13 administered by hand without the need of an applicator and delivery efficiencies were similar for
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14 investigator-administration and self-administration. Microneedle patch administration was not

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15 considered painful and the large majority of subjects were somewhat or fully confident that they

16 self-administered patches correctly. Microneedle patches were overwhelmingly preferred over

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17 conventional needle and syringe injection. Altogether, these results demonstrate that dissolving
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18 microneedle patches were well tolerated, easily usable and strongly accepted by human subjects,
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19 which will facilitate further clinical translation of this technology.

20 Keywords

21 Dissolvable microneedle patch; human study; skin vaccination; acceptability; usability;

22 tolerability; drug delivery

23

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24

25 1. Introduction

26 Microneedle patches contain hundreds of microneedles less than one millimeter long to

27 deliver drugs and vaccines into skin. The patch contains an array of microneedles attached to an

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28 adhesive backing to facilitate application to the skin. In a dissolving microneedle patch, the

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29 microneedles dissolve in the skin within minutes, thereby delivering the drug contained in them

30 and not generating sharps waste. Microneedle patches are being developed as an alternative to

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31 conventional needle-and-syringe injections due to the expectation of ease of administration, good

32 tolerability in the skin and strong patient acceptance. This study is designed to assess these

33 expectations.
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34 Microneedle patches have previously been studied for delivery of a number of drugs and

35 vaccines in pre-clinical studies, but limited information is available about the use of dissolving
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36 microneedle patches in human subjects [1-7]. Microneedle patches are typically designed either
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37 as coated microneedle patches made of solid metal, silicon or polymer microneedles coated with
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38 drug that is released upon dissolution of the coating in the skin or as dissolving microneedle

39 patches containing solid, dissolving microneedles made of water-soluble materials that

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40 encapsulate the drug and release it when the microneedles dissolve in the skin.

41 Coated microneedle patches are being evaluated in clinical trials for delivery of
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42 parathyroid hormone to treat osteoporosis [8], glucagon to treat hypoglycemia [9] and
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43 zolmitriptan to treat migraine [10]. Dissolving microneedle patches are being evaluated in

44 clinical trials for delivery of parathyroid hormone as well as for influenza vaccination [11].

45 Previous clinical trials involving microneedle patches have used high velocity insertion

46 devices, which can improve reliability of microneedle penetration into skin, but add additional

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47 bulk and cost to the microneedle device. In this study, we are examining the usability of

48 dissolving microneedle patches without the use of an applicator in human subjects; the

49 microneedle patches are applied with thumb pressure only. To our knowledge, no other study has

50 evaluated the puncture and delivery efficiencies of dissolving microneedle patches in humans or

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51 the acceptability preferences regarding vaccination using dissolving microneedle patches. As

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52 dissolving microneedle patches continue being developed for clinical translation in the coming

53 years, it is important to fully characterize the insertion and dissolution of microneedles in

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54 humans.

55 The goal of this study is to evaluate skin tolerability, usability and acceptability of

56
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dissolving microneedle patches in human subjects to further clinical translation of microneedle
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57 patches for delivery of drugs and vaccines. This work was specifically designed to prepare for a

58 phase 1 clinical trial of influenza vaccination using microneedle patches of a similar design [12].
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59 We therefore developed placebo dissolving microneedle patches (i.e., not containing vaccine)
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60 and conducted a human study to assess reactions in the skin after microneedle patch application,
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61 determine microneedle patch delivery efficiency in investigator-administration and self-

62 administration, and carry out a survey about participants’ preferences concerning microneedle
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63 patch administration.

64
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65 2. Materials and methods

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66 2.1 Fabrication of dissolving microneedle patch

67 The microneedle fabrication process has been described previously [13]. In this study,

68 microneedle patches contained 100 conical microneedles measuring 650 µm in height and 200

69 µm in base diameter positioned in a ~1 cm2 area that were adhered to a medical-grade tape (3M,

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70 St. Paul, MN) that incorporated a force-feedback indicator that made a clicking sound when a

71 force greater than 10 lbf is applied. The microneedles were composed of 50% (w/w) polyvinyl

72 alcohol (molecular weight 31 kDa) and 50% (w/w) sucrose. Microneedle patches were stored for

73 2 to 4 weeks in a sealed foil pouch with silica gel desiccant (5 g of desiccant) at room

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74 temperature (20 – 25 °C) and humidity (30 – 60% rh) until used at the time of study. Each patch

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75 was visually inspected under a microscope before and after storage to verify the integrity of the

76 patch and the microneedles.

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77 2.2 Study approval and study subjects

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78 This study was approved by the Georgia Institute of Technology Institutional Review
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79 Board and informed consent was obtained from all participants. To be eligible, participants had

80 to be healthy non-pregnant adults with normal skin, no known problems with pain perception
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81 and no known allergies to the materials used in the study. Participants could not have previously

82 seen or worked with microneedle patches to be eligible for the study. Fifteen subjects (seven
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83 females and eight males), ages 18 - 57 were recruited from the Georgia Institute of Technology
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84 and other sites in Atlanta, GA.

85 2.3 Experimental design

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86 Participants received three microneedle patches – one self-administered and two investigator-
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87 administered. Participants were provided a brief overview of the study and watched a short
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88 instructional audiovisual presentation on self-administration of microneedle patches. An outline

89 of the microneedle patch administration process is shown in Figure 1.

90 Each participant first self-administered a microneedle patch to his or her forearm without

91 assistance from the investigator. After the patch removal, the investigator stained this skin site

92 (see below). The investigator then applied two microneedle patches to the participant, one on

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93 each forearm. Only one of these skin sites was stained by the investigator. The site not stained

94 was used to make measurements of skin tolerability (see below). The two stained sites were used

95 for usability measurements (see below).

96 Participants then answered a survey about microneedle patch administration to assess

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97 acceptability of the microneedle patches. Participants returned to the study site 1, 2, 3, 4 and 7

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98 days after microneedle patch administration for skin tolerability measurements.

A B C

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100 Figure 1. Procedure to apply a microneedle patch to the skin. (A) The subject or investigator
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101 picks up the patch and removes the protective cap. (B) The subject forms a fist in the other hand

102 and then the subject or investigator places the patch on the forearm. The subject or investigator
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103 pushes on the patch with the thumb and continues to apply force until hearing a ‘click’ sound,
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104 indicating that enough force has been applied. (C) The subject leaves the patch on the skin for 20

105 min, after which the subject or investigator peels the patch off the skin and the investigator saves
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106 the patch for additional analysis.

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107
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108 2.4 Skin tolerability measurements

109 Skin tolerability was measured using the skin scoring scale listed in Table S.1 (see

110 Supplementary Material). The scale was adapted for microneedle patches using established

111 guidelines for vaccine clinical trials and clinical testing of transdermal patches [14, 15]. The skin

112 site was scored for pain, tenderness, erythema (size and intensity) and swelling on a grading

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113 scale of 0 to 4. Pain and tenderness were scored based on the participant’s response whereas

114 erythema and swelling were measured by the investigator.

115 Participants were asked if they felt any pain at the skin site after microneedle patch

116 administration was complete. This pain was assessed separately from the pain during

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117 microneedle patch application, which is addressed in usability measurements. Tenderness was

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118 defined as any pain felt at the skin site when the investigator gently touched the skin site.

119 Erythema size was measured using a ruler scale and intensity by visual observation of the skin

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120 site. Since there was no erythema scale for microneedle patches already in place, the investigator

121 was trained on erythema measurements using guidelines and training available for Psoriasis Area

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Severity Index (PASI) scores [16]. Swelling was measured by the investigator by gently moving
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123 the thumb over the skin site to notice any raised surfaces on the skin. The investigator recorded a

124 numerical score for each of these criteria and photographically imaged the skin at each time
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125 point.
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126 2.5 Skin staining and microscopy to measure usability

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127 Usability was measured in terms of microneedle puncture efficiency by skin staining

128 (percentage of microneedles that penetrated the skin surface) and delivery efficiency by
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129 microscopy (percentage volume of microneedles that dissolved after administration).

130 To measure puncture efficiency, skin was stained using gentian violet 1% solution
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131 (Humco, Texarkana, TX). Immediately after microneedle patch administration, gentian violet
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132 was pooled on the skin site, dabbed dry with gauze after 1 min and cleaned with alcohol after 10

133 min. The stained skin site was imaged and microneedle puncture efficiency was measured by

134 counting the number of stained skin punctures, which appeared as blue dots. It has been

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135 previously shown that the number of stained skin punctures visible after microneedle patch

136 insertion is correlated with skin puncture by measuring trans-epidermal water loss [17].

137 To measure delivery efficiency, microneedle patches were imaged using brightfield

138 microscopy (SZX12 Olympus, Center Valley, PA) before and after administration, and the

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139 microneedle dimensions were measured to calculate the volume dissolved after microneedle

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140 patch administration. Since placebo microneedle patches (i.e., containing no drug or other active

141 substance) were used in this study, it was not possible to assay the microneedle patches for

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142 delivery efficiency of a drug or other active, and therefore this method of usability from staining

143 and microscopy was used.

144
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2.6 Survey about microneedle patch administration to measure acceptability
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145 Participants answered a short questionnaire to solicit information about the acceptability of

146 microneedle patches for delivery of drugs or vaccines. We surveyed the subjects about pain
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147 during microneedle patch application, confidence during self-administration and subject
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148 preferences regarding microneedle patches, conventional intramuscular injection and

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149 conventional oral delivery using pills.

150 Pain during microneedle patch administration was reported by participants using a visual
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151 analog scale from 0 (no pain) to 10 (worst pain ever). Participants were also asked to score their

152 confidence during self-administration of microneedle patches on a score of 1 to 5 using the

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153 following scale: (1) I’m confident that I applied the patch incorrectly, (2) I’m somewhat
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154 confident that I applied the patch incorrectly, (3) I do not know if I applied the patch correctly or

155 incorrectly, (4) I’m somewhat confident that I applied the patch correctly, (5) I’m confident that I

156 applied the patch correctly.

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157 Subjects were then asked their preferences regarding obtaining medications by

158 microneedle patches versus hypodermic needles and microneedle patches versus conventional

159 oral delivery by pill.

160 2.7 Statistical methods

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161 Statistical analysis was carried out using Prism software version 5 (Graphpad, La Jolla,

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162 CA). P values < 0.05 were considered significant. Average values of delivery efficiency by

163 microscopy were analyzed using a paired t test.

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164

165 3. Results

166 3.1 Skin tolerability

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167 We studied skin tolerability of microneedle patch administration to identify and quantify

168 local reactions in the skin that can occur. These reactions may be associated with the patch
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169 administration process and the patch excipients left in the skin after microneedle dissolution.
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170 This study did not assess the possible additional effects of delivery of a drug or other active to
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171 the skin. The investigator administered one patch onto the subject’s skin and the skin site was

172 monitored, imaged and scored once per day for 7 days.
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173 Figure 2 shows a series of images from a representative subject after microneedle patch

174 application. Immediately after microneedle patch application on Day 0, a rectangular area
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175 corresponding to the size of the microneedle array exhibited mild erythema. Faint redness was
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176 also seen in a circular area around the rectangle, corresponding to the area where the patch

177 adhesive backing contacted the skin. On Day 1, redness from the adhesive backing was fully

178 resolved and the rectangular area decreased in redness and size. For the subject in Figure 2, all

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179 erythema resolved by Day 4. There were no other skin reactions or adverse effects noted, and

180 overall the microneedle patch was well tolerated.

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182

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183

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184

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185

186

187
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Day 0
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189

190
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191

192
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Day 1 Day 2
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194
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195

196

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198 Day 3 Day 4

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199 Figure 2. Representative images of the site of microneedle patch application on the skin over

200 time. Inset shows magnified images of the skin site. Day 0 is immediately after patch application

201 and removal. These images are all from the same subject.

202

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203 We quantified skin reactions noted after microneedle patch application over time in Figure 3.

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204 Subjects were asked if they felt pain or tenderness at the skin site. Pain in this case was assessed

205 after microneedle patch application was complete, which differs from possible pain experienced

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206 during microneedle patch insertion, which is addressed in the context of the usability analysis

207 below. None of the subjects reported pain at the skin site after microneedle patch application on

208
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Day 0 through Day 7. Only one subject (out of 15) reported tenderness at the skin site on Day 0
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209 which was fully resolved by Day 1. This tenderness was reported of Grade 1 (i.e., mild

210 discomfort to touch, on a scale of 0 to 4). None of the other subjects reported tenderness at the
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211 skin site at any time.

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212 The investigator also scored the skin site for erythema and swelling. Erythema was scored
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213 based on size and intensity. Based on size, erythema, when present, was always of Grade 0.5,

214 which corresponds to a size equal to or less than the patch. As noted in Figure 3A, erythema was
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215 present in 100% of subjects on Day 0 and 80% of subjects on Day 1. Erythema continued to

216 subside over time with 13% of subjects having erythema on Day 4 and, by Day 7, erythema in all
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217 subjects was fully resolved.

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222

Day 0 Day 1 Day 2 Day 3 Day 4 Day 7

A
Pain 0% 0% 0% 0% 0% 0% Skin
reactions
absent
Tenderness

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7% 0% 0% 0% 0% 0%
Skin
Erythema 100% 80% 33% 20% 13% 0% reactions
present

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Swelling 0% 0% 0% 0% 0% 0%

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B C
100
% Subjects with erythema

Grade 1

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Grade 2 Grade 1
80
Grade 3 Erythema
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60 Grade 4

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20 Grade 2
Erythema
0
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0

7
ay

ay

ay

ay

ay

ay
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224
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225 Figure 3. Skin tolerability after microneedle patch application. Skin sites were monitored and

226 scored over a period of one week. (A) Summary of the prevalence of skin reactions at different
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227 time points. Percentages indicate the presence of skin reactions. (B) Intensity of erythema in the

228 skin after microneedle patch application. Column bars show the percentage of subjects with
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229 different grades of erythema. None of the subjects had Grade 3 or 4 erythema scores. (C)

230 Representative images of skin showing Grade 1 and Grade 2 erythema.

231

232 Figure 3B charts the score of erythema intensity on a scale of 0 – 4 over time.

233 Representative examples of Grade 1 and 2 erythema seen in the study are shown in Figure 3C.

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234 On Day 0, 13% (2 out of 15) subjects had very slight erythema (Grade 1) while 87% (13 out of

235 15) subjects had mild erythema (Grade 2). On Day 1, 47% (7 out of 15) subjects showed Grade 1

236 erythema and 33% (5 out of 15) subjects showed Grade 2 erythema. From Day 2 onwards,

237 erythema, when present, was only Grade 1. None of the subjects showed Grade 3 or Grade 4

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238 erythema at any point in the study.

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239 In addition, none of the subjects showed swelling at the skin site at any time during the

240 study. Overall the patches were tolerated very well in the skin with only mild transient erythema

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241 that resolved fully by Day 7, almost no tenderness and no pain or swelling.

242 3.2 Usability

243
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We next determined if microneedle patches could be inserted and dissolved in the skin in a
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244 reliable manner. We also determined if subjects could self-administer microneedle patches after

245 only brief training.

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246 Figure 4A charts the puncture efficiency as measured by the percentage of microneedles in a
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247 given patch that inserted into the skin after investigator-administration and self-administration.
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248 Figure 4B shows an example of the subject’s skin stained with gentian violet after microneedle

249 patch application. The blue dots show the number of sites that were punctured in the skin during
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250 microneedle patch application. The mean puncture efficiency by skin staining was 99±1% after

251 investigator-administration and 98±2% after self-administration, which indicates that

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252 microneedle insertion efficiency was excellent, independent of who administered the patches.
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253 Figure 5 charts the delivery efficiency as measured by the percentage volume of

254 microneedles in a given patch that dissolved after patch administration. The mean delivery

255 efficiency by microscopy was 74±11 % after investigator-administration and 67±23 % after self-

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256 administration (Figure 5a). These two values were not statistically different from each other (p =

257 0.16).

258 Often, microneedles are not filled with drug, but have drug preferentially toward the

259 microneedle tip. If the upper 50% of the microneedle volume toward the microneedle tip (i.e.,

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260 the upper 516 µm of the 650 µm-long microneedle) contained drug, then 100% of investigator-

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261 administered patches and 87% of self-administered patches would have delivered their full dose.

262 Together, this suggests that overall usability was similar between investigator-administration and

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263 self-administration after brief training.

264

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% Microneedles inserted in skin
(measured by skin staining)

100
A B
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50

25
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3 mm
0
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Investigator Self
Administration Administration
265
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266 Figure 4. Puncture efficiency of microneedle patch application as determined by the percentage

267 of microneedles that punctured into skin. Skin sites were stained with gentian violet dye and the
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268 number of dots were counted to measure the number of microneedles that punctured into the
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269 skin. (A) Puncture efficiency of microneedle patches after investigator-administration and self-

270 administration. Column bars represent the average percentage of microneedles that inserted into

271 skin with standard deviation error bars shown. (B) Representative magnified image of a stained

272 skin site showing a 10 x 10 array where the microneedles punctured into skin.

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Investigator Administration
% Volume of microneedles dissolved

Self Administration
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(measured by microscopy)

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50

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25

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0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Average
Subject
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Figure 5. Delivery efficiency as determined by the percentage of the volume of microneedles
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276 that dissolved during microneedle patch application to the skin. Microneedle patches were
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277 imaged by brightfield microscopy before and after insertion into the skin and image analysis was

278 used to determine the volume of microneedles dissolved. (a) Volume of microneedles dissolved
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279 is interpreted as a measure of the dose delivered, i.e., if a drug or vaccine had been incorporated
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280 into the full volume of the microneedles. Each bar represents the result from an individual

281 subject. The data are presented in descending order of investigator-administered delivery
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282 efficiency. The ‘average’ bars represent the averages of the 15 individual bars, with standard

283 deviation error bars shown. (b) Percent of subjects that delivered more than 50% of the volume
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284 of the microneedles.

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285

286 3.3 Acceptability

287 We studied acceptability of microneedle patches by surveying the subjects about pain

288 during microneedle patch application, confidence during self-administration and subject

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289 preferences regarding microneedle patches compared to conventional intramuscular injection and

290 oral delivery by pills.

291 Figure 6A shows the pain score reported by subjects during microneedle patch

292 administration. Fourteen out of the 15 subjects reported a pain score of 0 or ‘no pain’ during

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293 microneedle patch administration. One subject reported a pain score of 1 (on a scale of 0 to 10).

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294 This indicates that microneedle patch administration was not considered painful.

295 Figure 6B shows the confidence score reported by subjects during self-administration of

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296 microneedle patches. Among the subjects, 53% (8 out of 15) reported that they were confident

297 that they had applied the microneedle patch correctly (score of 5), and 33% (5 out of 15) subjects

298
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reported that they were somewhat confident that they applied the microneedle patch correctly
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299 (score of 4). Only 14% (2 out of 15) subjects reported that they did not know if they applied the

300 microneedle patch correctly or incorrectly (score of 3). None of the subjects reported that they
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301 thought that they applied the patch incorrectly (score of 1 or 2). Therefore, 86% of the subjects
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302 were somewhat or fully confident that they applied the microneedle patch correctly (confidence
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303 score of 4 or 5).

304
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A 100 100 B
305 80 80
% Subjects

% Subjects

306 60 60
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40 40
307
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20 20
308 0 0
No 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5
Pain VAS pain score Confidence during self administration

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310 C 7% Microneedle D Microneedle

Patch 20% 20% Patch

IM injection Pill

Do not care Do not care

93% either way either way

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311 Figure 6. Acceptability survey results from subjects concerning microneedle patch

312 administration. (A) Assessment of pain during microneedle patch administration scored by

313 subjects on a visual analog scale (VAS) of 0 (No pain) to 10 (Worst pain ever). (B) Confidence

314 of subjects during self-administration of microneedle patches scored by subjects on a scale of 1

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315 (least confident) to 5 (most confident); see Methods for details. (C) Preference of subjects for

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316 application of microneedle patch as compared to intramuscular injection for delivery of

317 medications. (D) Preference of subjects for microneedle patch administration as compared to oral

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318 administration by conventional pill for delivery of medications.

319

320
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Figures 6C and 6D compare the preferences reported by subjects concerning microneedle
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321 patches versus conventional delivery methods. Figure 6C shows that 93% (14 out of 15) of

322 subjects would prefer to obtain their medication by a microneedle patch as compared to a
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323 conventional intramuscular injection. Only one subject reported a preference for intramuscular
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324 injection over microneedle patch. That subject stated that the longer wear time of the
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325 microneedle patch as compared to intramuscular injection was the primary reason for preferring

326 intramuscular injection. This indicates that microneedle patches were overwhelmingly preferred
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327 over intramuscular injections.

328 Figure 6D shows that 20% (3 out of 15) subjects would prefer a microneedle patch over
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329 conventional oral delivery by pill for obtaining medication, while another 20% reported that they
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330 did not care either way. The remaining 60% (9 out of 15) subjects reported that they would

331 prefer obtaining their medication by a pill over a microneedle patch. This indicates that although

332 oral delivery was preferred, a significant fraction of subjects found the microneedle patch to be

333 similar or better than oral administration.

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334

335 4. Discussion

336 The goal of the study was to evaluate skin tolerability, usability and acceptability of

337 dissolving microneedle patch administration in human subjects to further clinical translation of

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338 dissolving microneedle patches.

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339 In this study, microneedle patches were very well tolerated in the skin with only mild,

340 transient erythema that resolved within 7 days. This excellent tolerability may be due to

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341 microneedle formulation using biocompatible materials (i.e., polyvinyl alcohol and sucrose) and

342 the minimally invasive nature of microneedle patches. It is, however, important to note that the

343
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microneedle patches used in this study were placebos and did not contain any drug or vaccine.
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344 The presence of drug or vaccine within the microneedle patches could change the incidence or

345 intensity of skin reactions. Tolerability in the skin should also be dependent upon the materials
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346 used for microneedle patch fabrication and the properties of these materials upon dissolution in
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347 the skin. For example, a prior study reported significantly greater erythema associated with
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348 application of dissolving microneedle patches composed of hyaluronic acid and containing

349 influenza vaccine in human subjects [11].

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350 This study also showed that 98% – 99% of microneedles in a given patch punctured the

351 skin’s surface based on data from skin staining, which leaves little room for improvement. Based
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352 on microscopy analysis, about 70% of the volume of microneedles was dissolved after
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353 microneedle patch administration. Because the microneedles were made of highly water-soluble

354 materials and there was a patch wear time of 20 min, we believe that the portions of the

355 microneedles that penetrated the skin were fully dissolved in the skin. We therefore expect that

356 the incomplete dissolution of the microneedles in this study was due to incomplete penetration of

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357 microneedles to their full length into skin, which is consistent with prior observations in animal

358 skin in vivo and ex vivo [11, 13, 18]. Further optimization of microneedle patch geometry,

359 materials that comprise the microneedle patch, the force of microneedle patch application, patch

360 wear time and other factors, could lead to greater delivery efficiency. Alternatively, because drug

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361 encapsulation in the microneedle need not be uniformly distributed, drug encapsulated in

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362 microneedles could be located preferentially toward the microneedle tip, thereby enabling

363 complete drug delivery even with incomplete microneedle dissolution (e.g., by localizing all of

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364 the drug in the upper 70% of the microneedles, a 70% microneedle dissolution would correspond

365 to 100% drug delivered).

366
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For most subjects, investigator-administration and self-administration delivery efficiencies
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367 were similar to each other with no statistically significant difference overall. However, there

368 were certain subjects (e.g., subjects 5 and 13) where self-administration delivery was much lower
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369 than investigator-administration. That being said, there were also subjects for whom self-
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370 administration yielded more efficient delivery than investigator-administration. Future studies
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371 should expand upon these proof-of-concept results to assess self-administration protocols in

372 larger populations and using microneedle designs that are further optimized for simple, reliable
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373 administration.

374 Microneedle patches were well accepted in this study, with no pain of insertion reported by
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375 almost all subjects, and were overwhelmingly preferred over intramuscular injection. This is
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376 consistent with previous studies reporting less pain from microneedle administration compared

377 to injection [17, 19, 20] and reporting overall preference of microneedle patches over drug or

378 vaccine delivery by injection [19, 21-23].

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379 The large majority of participants were at least somewhat confident that they self-

380 administered the microneedle patch correctly, and none reported that they thought they had

381 applied the patch incorrectly. Almost all participants preferred microneedle patch administration

382 to intramuscular injection and some preferred the patch to oral administration. This indicates that

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383 offering microneedle patch administration for medications that otherwise require injection could

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384 be a strategy to increase patient compliance with these therapies.

385

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386 5. Conclusions

387 This study evaluated skin tolerability, usability and acceptability of dissolving microneedle

388
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patch administration in humans. The microneedle patches were well tolerated in the skin with
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389 mild erythema that resolved fully within seven days and caused no pain or swelling. Microneedle

390 patches were administered by hand without the need of an applicator, and delivery efficiencies
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391 were similar between investigator-administration and self-administration. Microneedle patch

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392 administration was not painful, and the large majority of subjects were somewhat or fully
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393 confident that they self-administered the patch correctly. Microneedle patch administration was

394 overwhelmingly preferred over conventional needle and syringe injection for delivery of
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395 medications.

396 Altogether the results of this study show the feasibility of using dissolving microneedle
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397 patches for investigator-administration as well as self-administration for future applications in

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398 drug and vaccine delivery in a well-tolerated and preferred manner that offers an attractive

399 alternative to conventional hypodermic needles.

400

401 Acknowledgements

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402 The authors would like to thank Donna Bondy for administrative support; Danny Pardo

403 for help with microscopy assay development, microscopy measurements and participant

404 recruitment; and Matt Mistilis and other colleagues at Georgia Tech for help with preliminary

405 clinical assessment of microneedle patches. This work was supported by a grant from the

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406 National Institutes of Health.

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407 SH, DVM and MRP are inventors of patents that have been or may be licensed to

408 companies developing microneedle-based products; MRP is a paid advisor to companies

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409 developing microneedle-based products; SH, DVM and MRP are founders/shareholders of

410 companies developing microneedle-based products, including Micron Biomedical; and SH, WPP

411
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and DVM are currently employees of Micron Biomedical. These potential conflicts of interest
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412 have been disclosed and are being managed by Georgia Tech and/or Emory University.

413
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414 References
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473 34.
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