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1.  Current Aspects of Formulation Efforts and Pore Lifetime Related to Microneedle Treatment of Skin 
Expert opinion on drug delivery  2010;7(5):617-629.
Importance of this field
The efficacy of microneedles in the area of transdermal drug delivery is well-documented. Multiple studies have shown that enhancement of skin permeation via creation of microscopic pores in the stratum corneum can greatly improve the delivery rates of drugs. However, skin pretreatment with microneedles is not the only factor affecting drug transport rates. Other factors including drug formulation and rate of micropore closure are also important for optimizing delivery via this route.
Areas covered in this review
This review aims at highlighting work that has been done in these areas, with an emphasis on drug formulation parameters that affect transdermal flux.
What the reader will gain
This review creates an appreciation for the many factors affecting microneedle-enhanced delivery. Most results clearly indicate that microneedle skin pretreatment by itself may have different effects on drug transport depending on the formulation used, and formulation characteristics have different effects on the transport through untreated skin and microneedle-treated skin. Several formulation approaches are reported to optimize microneedle-enhanced drug delivery, including cosolvent use, vesicular, nanoparticulate and gel systems.
Take home message
In addition to well-established factors that affect microneedle-assisted delivery (geometry, type of microneedles, etc), formulation and pore viability are also critical factors that must be considered.
PMCID: PMC2858255  PMID: 20205604
Diffusion; Formulation; Microneedle; Micropores; Transdermal
2.  Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in Yucatan minipig: in vitro-in vivo correlation 
Molecular pharmaceutics  2013;10(10):10.1021/mp400227e.
Although microneedle-assisted transdermal drug delivery has been the subject of multiple scientific investigations, very few attempts have been made to quantitatively relate in vitro and in vivo permeation. The case of naltrexone hydrochloride is not an exception. In the present study a pharmacokinetic profile obtained following a “poke and patch” microneedle application method in Yucatan minipig is reported. The profile demonstrates rapid achievement of maximum naltrexone hydrochloride plasma concentration followed by a relatively abrupt concentration decline. No steady-state was achieved in vivo. In an attempt to correlate the present in vivo findings with formerly published in vitro steady-state permeation data, a diffusion-compartmental mathematical model was developed. The model incorporates two parallel permeation pathways, barrier thickness-dependent diffusional resistance, microchannel closure kinetics, and a pharmacokinetic module. The regression analysis of the pharmacokinetic data demonstrated good agreement with independently calculated microchannel closure rate and in vitro permeation data. Interestingly, full-thickness rather than split-thickness skin employed in in vitro diffusion experiments provided the best correlation with in vivo data. Data analysis carried out with the model presented herein provides new mechanistic insight and permits predictions with respect to pharmacokinetics coupled with altered microchannel closure rates.
PMCID: PMC3848502  PMID: 24053426
Naltrexone; microneedles; permeation; pharmacokinetics; mathematical model; IVIVC
3.  Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans 
Pharmaceutical research  2013;30(8):1947-1955.
Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals.
the purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans.
Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application.
Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n = 6), vs. 72 hours in Group 2 (placebo + naltrexone, n = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores).
This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.
PMCID: PMC3773937  PMID: 23761054
microneedle; naltrexone; transdermal; diclofenac
4.  Effect of formulation pH on transport of naltrexone species and pore closure in microneedle-enhanced transdermal drug delivery 
Molecular pharmaceutics  2013;10(6):2331-2339.
Microneedle-enhanced transdermal drug delivery greatly improves the subset of pharmacologically active molecules that can be transported across the skin. Formulation pH plays an important role in all drug delivery systems; however, for transdermal delivery it becomes specifically significant since a wide range of pH values can be exploited for patch formulation as long as it does not lead to skin irritation or sensitization issues. Wound healing literature has shown significant pH effects on barrier recovery. Stability and solubility of the drug, and thus transport across skin are all affected by formulation pH. The current study examined the role of ionization state of the drug naltrexone on transdermal flux and permeability across microneedle treated skin, as compared to intact skin. Impedance spectroscopy was done in pigs in vivo to assess the role of formulation pH on the rate of micropore closure under the influence of three different pH conditions. The data indicated that while there was significant advantage of using a lower pH formulation in terms of total transport across microneedle treated skin, the pH however did not have any significant effect on the rate of micropore closure beyond the first 24 hours.
PMCID: PMC3718312  PMID: 23590208
Microneedle; micropore closure; permeability; transdermal; impedance spectroscopy
5.  Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion 
Journal of pharmaceutical sciences  2013;102(6):1948-1956.
Microneedles provide a minimally invasive means to enhance skin permeability by creating micron-scale channels (micropores) that provide a drug delivery pathway. Adequate formation of the micropores is critical to the success of this unique drug delivery technique. The objective of these studies was to develop sensitive and reproducible impedance spectroscopy techniques to monitor micropore formation in animal models and human subjects. Hairless guinea pigs, a Yucatan miniature pig, and human volunteers were treated with 100 microneedle insertions per site following an overnight pre-hydration period. Repeated measurements were made pre- and post-microneedle treatment using dry and gel Ag/AgCl electrodes applied with light vs. direct pressure to hold the electrode to the skin surface. Impedance measurements dropped significantly post-microneedle application at all sites (p < 0.05, irrespective of electrode type or gel application), confirming micropore formation. In the Yucatan pig and human subjects, gel electrodes with direct pressure yielded the lowest variability (demonstrated by lower %RSD), whereas dry electrodes with direct pressure were superior in the guinea pigs. These studies confirm that impedance measurements are suitable for use in both clinical and animal research environments to monitor formation of new micropores that will allow for drug delivery through the impermeable skin layers.
PMCID: PMC3678392  PMID: 23589356
microneedle; impedance spectroscopy; micropore; transdermal; human
6.  Diclofenac delays micropore closure following microneedle treatment in human subjects 
Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance–time curve (AUC) was calculated. AUC was significantly higher at MN + diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions.
PMCID: PMC3725617  PMID: 22929967
Microneedle; Transdermal; Diclofenac; Micropore; Human; Clinical
7.  Will new generations of modified antimicrobial peptides improve their potential as pharmaceuticals? 
The concept of antimicrobial peptides (AMPs) as potent pharmaceuticals is firmly established in the literature, and most research articles on this topic conclude by stating that AMPs represent promising therapeutic agents against bacterial and fungal agents. Indeed, early research in this field showed that AMPs were diverse in nature, had high activities with low minimal inhibitory concentrations, had broad spectrums of activity against bacterial, fungal and viral pathogens, and could easily be manipulated to alter their specificities, reduce their cytotoxicities and increase their antimicrobial activities. Unfortunately, commercial development of these peptides, for even the simplest of applications, has been very limited. With some peptides there are obstacles with their manufacture, in vivo efficacy and in vivo retention. More recently, the focus has shifted. Contemporary research now uses a more sophisticated approach to develop AMPs that surmount many of these prior obstacles. AMP mimetics, hybrid AMPs, AMP congeners, cyclotides and stabilised AMPs, AMP conjugates and immobilised AMPs have all emerged with selective or ‘targeted’ antimicrobial activities, improved retention, or unique abilities that allow them to bind to medical or industrial surfaces. These groups of new peptides have creative medical and industrial application potentials to treat antibiotic-resistant bacterial infections and septic shock, to preserve food or to sanitise surfaces both in vitro and in vivo.
PMCID: PMC3159164  PMID: 21733662
Antimicrobial peptide mimotopes; Hybrid antimicrobial peptides; Antimicrobial peptide congeners; Stabilised antimicrobial peptides; Antimicrobial peptide conjugates; Immobilised antimicrobial peptides; Cyclotides
8.  Diclofenac Enables Prolonged Delivery of Naltrexone Through Microneedle-Treated Skin 
Pharmaceutical Research  2011;28(5):1211-1219.
The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment.
Hairless guinea pigs were treated with microneedle arrays ± daily application of Solaraze® gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles ± daily Solaraze® gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze® treatment.
Animals treated with microneedles + Solaraze® displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze®. No morphological changes resulting from microneedle treatment or COX inhibition were noted.
Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy.
PMCID: PMC3377386  PMID: 21301935
cyclooxygenase; microneedle; micropore; naltrexone
9.  Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs 
Journal of pharmaceutical sciences  2010;99(7):3072-3080.
Controlled-release delivery of 6-β-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. Microneedle pore lifetime was estimated by pharmacokinetic evaluation, transepidermal water loss (TEWL) and visualization of MN-treated skin pore diameters using light microscopy. A 3.6 fold enhancement in steady state plasma concentration was observed in vivo with MN treated skin with NTXOL·HCl, as compared to NTXOL base. TEWL measurements and microscopic evaluation of stained MN-treated guinea pig skin indicated the presence of pores, suggesting a feasible non-lipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application.
PMCID: PMC2862091  PMID: 20166200
Microneedle; 6-β-naltrexol; transdermal; hairless guinea pig; addiction therapy
10.  Challenges and opportunities in dermal/transdermal delivery 
Therapeutic delivery  2010;1(1):109-131.
Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limited to a narrow range of drugs. Further advances in transdermal delivery depend on the ability to overcome the challenges faced regarding the permeation and skin irritation of the drug molecules. Emergence of novel techniques for skin permeation enhancement and development of methods to lessen skin irritation would widen the transdermal market for hydrophilic compounds, macromolecules and conventional drugs for new therapeutic indications. As evident from the ongoing clinical trials of a wide variety of drugs for various clinical conditions, there is a great future for transdermal delivery of drugs.
PMCID: PMC2995530  PMID: 21132122

Results 1-10 (10)