Transdermal delivery of insulin using microneedle rollers in vivo

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Abstract

This study characterizes skin perforation by commercially available microneedle rollers and evaluates the efficacy of transdermal delivery of insulin to diabetic rats. Three different needle lengths, 250, 500 and 1000 μm, were used in this work. Creation and resealing of the skin holes that were produced by the needles were observed by Evan's blue (EB) staining and transepidermal water loss (TEWL) measurements. EB clearly showed that microchannels were formed in the skin and that the pores created by the longest microneedle (1000 μm) persisted no longer than 8 h, while the hypodermic injury was still observed 24 h later. TEWL significantly increased after the application of the needles and then decreased with time, which explains the recovery of skin barrier function and agrees well with EB results. The extent of permeation was demonstrated by insulin delivery in vivo. The rapid reduction of blood glucose levels in 1 h was caused by the increased permeability of the skin to insulin after applying microneedle rollers. The reduced decrease after 1 h is closely associated with hole recovery. In conclusion, microneedle rollers with 500-μm or shorter lengths are safe and useful in transdermal delivery of insulin in vivo.

Introduction

Despite the advantages of drug delivery through the skin, such as extreme convenience, good patient compliance, prolonged therapy, avoidance of the liver's first-pass metabolism and degradation in the gastrointestinal tract, transdermal drug delivery is only used with a small subset of drugs. This is because the stratum corneum (SC), which is the outermost layer of the skin, constitutes the major barrier (Naik et al., 2000, Prausnitz and Langer, 2008). In recent years, microneedle technology as proposed by Henry et al. (1998) has been developed as an advanced technique for penetration of large molecular weight and hydrophilic compounds into the skin. Four different types of microneedle designs such as poke-and-patch (Martanto et al., 2004, Verbaan et al., 2007, Li et al., 2009), coat-and-poke (Cormier et al., 2004, Widera et al., 2006), poke-and-release (Pearton et al., 2005, Ito et al., 2006), and poke-and-flow (Martanto et al., 2006a, Nordquist et al., 2007) have been developed and investigated in vitro and in animals, even in humans (Bal et al., 2008, Gill et al., 2008, Haq et al., 2009, Van Damme et al., 2009).

Poke-and-patch provides a simple method to enable delivery of hydrophilic drugs and macromolecules from a transdermal patch (Prausnitz, 2004). Solid microneedle arrays can be pressed onto the skin to create microscopic holes; drugs from a patch or topical formulation can then be administered. From a review of the literature, getting a flat microneedle array to pierce the skin using a manual application is far from easy (Yang and Zahn, 2004, Teo et al., 2006). With the help of the electric applicator, a short needle length was able to pierce the mouse's skin (Ding et al., 2009a). Most of the studies which have demonstrated in vivo delivery of drugs using microneedle arrays have utilized some sort of high-velocity impact applicator or longer needle lengths to aid the penetration of microneedle arrays into the skin (Verbaan et al., 2008, Ding et al., 2009b). However, in some vitro experiments, these microneedle arrays can increase the skin's permeability when applied manually with shorter needle lengths. These findings are not in agreement with those obtained from in vivo experiments (Teo et al., 2005, Kolli and Banga, 2008). This result is probably due to the “bed-of-nails” effect and the thick subcutaneous fat and muscle layers in vivo, which render microneedle penetration more difficult in vivo (Martanto et al., 2006a, Martanto et al., 2006b).

To circumvent the above difficulties, we used another microneedle denoted the microneedle roller, which is commercially available for cosmetic purposes. The microchannels in the skin formed by rolling the microneedle roller are similar to those created by microneedle arrays; the former is technologically simplified and easier to handle. The needles of the rollers are made from stainless steel with good biocompatibility and torsional properties (Disegi and Eschbach, 2000). An in vitro evaluation of skin penetration by the microneedle roller had been reported (Badran et al., 2009). However, there is little information available regarding their in vivo character and efficacy. In this work, we conduct systematic studies in vivo, including EB staining, TEWL, and transdermal drug delivery. The response over time of the treated skin to microneedle injury as assessed by EB staining and TEWL provides information which is highly significant in determining drug safety and drug delivery time. Insulin was chosen as a model drug for macromolecule tests due to the ease of analyzing its pharmacodynamic action, as well as the substantial barrier to transdermal permeation by passive diffusion. Diabetes is one of the leading lethal diseases in China and around the world and is often treated by hypodermic injection of insulin, which creates problems such as pain when insulin delivery is performed by those who are inexperienced with the technique. These factors can result in reduced patient compliance. So injection is generally not an ideal method for the administration of these drugs, especially in the context of long-term treatment. Transdermal delivery of insulin by microneedle rollers is convenient and easy to handle and would overcome these limitations. Three different needle lengths were used to evaluate the efficiency of skin perforation and the degree of insulin penetration enhancement, with a special focus on the method used to select a microneedle roller that was found to be safe and effective in the context of manual application. It is noteworthy that drug delivery by microneedle rollers is also suitable for other macromolecules.

Section snippets

Materials

Recombinant human insulin was purchased from Dongbao Enterprise Group Co. Ltd. (JiLin, China). Streptozotocin (STZ), sodium pentobarbital and Evan's blue (EB) were purchased from Sigma–Aldrich Chemical Company (Shanghai, China). All other materials used in this study were obtained from Chemical Reagent Company (Beijing, China) and were of analytical grade.

Male Sprague–Dawley rats were procured from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China).

EB staining studies for microchannel visualization

Monitoring the presence of skin punctures provides a primary indication of skin healing followed the application of microneedle rollers and hypodermic needles. Fig. 3 shows that microchannels were formed in the skin after these needle applications. There was a positive correlation between pore size and microneedle size. The same result was also obtained with regard to scab healing time; the values obtained were approximately 2, 3 and 8 h for the 250-, 500- and 1000-μm microneedle rollers,

Discussion

In this study, microneedle rollers commonly used for cosmetic purposes have been utilized to disrupt the barrier posed by the skin. The ability of microneedle rollers to produce pores and the related ability of holes in the skin to reseal was determined by EB staining and measurement of TEWL in vivo. Furthermore, the efficiency of drug transdermal delivery through the microchannels produced by the microneedle roller was demonstrated by in vivo studies of insulin. We systematically compared

Conclusions

In this study, we have shown that microneedle rollers with different needle lengths can be used to improve transdermal drug delivery. The ability of microneedles to create transport pathways and the extent of hole resealing were successfully assessed by staining and TEWL data. Such data have rarely been obtained through in vivo studies on animals. The enhanced transdermal delivery of insulin was also demonstrated in vivo by effective control of blood glucose level. Taken together, our results

Acknowledgement

This work was supported by the National Natural Science Fund (grant number is 60976086).

References (29)

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    In rolling, the membrane is disrupted by shearing forces acting along the y-axis rather than perpendicular to the y-axis. The degree of membrane rupture may vary depending on the number of rolls performed and the number of planes through which the microneedles are rolled [47–49]. However, other research has employed multilateral rolling, which results in overlapping micropores, instead of rolling the microneedles unilaterally as was done in this work.

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