Transdermal Delivery of Naltrexol and Skin Permeability Lifetime after Microneedle Treatment in Hairless Guinea Pigs

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. MN 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 nonlipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3072-3080, 2010     

Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin

The passive delivery rate of naltrexone (NTX) through intact skin is too slow to achieve therapeutic plasma levels in humans from a reasonably sized transdermal patch. A physical enhancement method--microneedles (MNs)--has been shown to afford a substantial increase in the percutaneous flux of NTX hydrochloride in vitro. However, for better therapeutic effect and decrease in the transdermal patch area, further enhancement is desired. The purpose of this study was to identify a NTX salt that would (1) provide elevated in vitro percutaneous drug transport across MN-treated skin as compared with that of the NTX hydrochloride and (2) prove nonirritating to the skin in vivo. The pH-solubility profiles of NTX salts were investigated with three drug salts showing improved solubility at physiologically relevant skin surface pH of 5.0. The skin-irritation potential of NTX glycolate and lactate gels was not greater than that of placebo gel in the guinea pig model. Additionally, in vitro diffusion studies indicated that NTX glycolate provides around 50% enhancement in the flux through MN-treated skin at the cost of doubling the drug concentration in the donor solution. Overall, a new NTX glycolate salt appears to be a promising candidate for MN-assisted transdermal drug delivery system.     

Effect of Lipophilicity on Microneedle-Mediated Iontophoretic Transdermal Delivery Across Human Skin In Vitro

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pK_a but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol).     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.     

Development of Hydrogels for Microneedle-Assisted Transdermal Delivery of Naloxone for Opioid-Induced Pruritus

Transdermal naloxone delivery could be a potential option for treating opioid-induced pruritus, but naloxone does not permeate skin well because of its hydrophilic nature. Microneedles (MNs) could overcome the skin barrier by painlessly creating microchannels in the skin to permit naloxone absorption to therapeutic levels. This study investigated how ionization correlates with naloxone permeation across MN-treated skin. Hydrogels containing 0.2, 0.5, or 1% naloxone were formulated with 1% cross-linked polyacrylic acid (polymer) and adjusted to pH 5, 6.5, or 7.4. Porcine skin was treated with MNs and naloxone gel, and in vitro permeation studies were performed using an in-line diffusion setup. Gel structural properties were evaluated using rheology. All gels had viscoelastic properties and good spreadability. Naloxone permeation through intact skin was highest from pH 7.4 gels when naloxone is unionized, in contrast with undetectable concentrations permeated from pH 5 gels with 100% ionization. Combining MN treatment with pH 5 gels significantly enhanced permeation and resulted in steady-state flux that would achieve therapeutic delivery. Absorption lag time was affected by MN length and naloxone gel concentration. Polymer concentration did not influence drug permeability. This study demonstrates that transdermal naloxone delivery with MNs is a viable treatment option for opioid-induced pruritus.     

Review of patents on microneedle applicators

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, transdermal delivery is not available to many promising therapeutic agents, especially high molecular weight hydrophilic compounds. This is due to the excellent barrier property of the superficial skin layer, the stratum corneum (SC). Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Of the several active approaches used to enhance the transport of drugs through the SC, the use of microneedles (MNs) has recently been shown to be very promising and has attracted considerable attention by researchers from both industry and academia. MNs, when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. However, for effective performance of these MNs in drug delivery applications, irrespective of the type, material, height and density, it is imperative that they penetrate into the skin with the greatest possible accuracy and reproducibility. Due to the inherent elasticity and irregular surface topography of the skin, it remains a major challenge to the reproducibility of MN penetration. Therefore, in order to achieve uniform and reproducible MN penetration into skin, an external source of assistance could be very useful. Accordingly, this review deals with various innovative applicator designs developed by industry and research centres in the context of effective application of MN arrays for transdermal drug delivery, as disclosed in the recent patent literature.     

Optimization of Naltrexone Diclofenac Codrugs for Sustained Drug Delivery Across Microneedle-Treated Skin

Purpose

The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone.

Methods

Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship.

Results

The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement.

Conclusion

The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.     

Lipid, sugar and liposaccharide based delivery systems

Although there are formidable barriers to the oral delivery of biologically active drugs, considerable progress in the field has been made, using both physical and chemical strategies of absorption enhancement. A possible method to enhance oral absorption is to exploit the phenomenon of lipophilic modification and mono and oligosaccharide conjugation. Depending on the uptake mechanism targeted, different modifications can be employed. To target passive diffusion, lipid modification has been used, whereas the targeting of sugar transport systems has been achieved through drugs conjugated with sugars. These drug delivery units can be specifically tailored to transport a wide variety of poorly absorbed drugs through the skin, and across the barriers that normally inhibit absorption from the gut or into the brain. The delivery system can be conjugated to the drug in such a way as to release the active compound after it has been absorbed (i.e. the drug becomes a prodrug), or to form a biologically stable and active molecule (i.e. the conjugate becomes a new drug moiety). Examples where lipid, sugar and lipid-sugar conjugates have resulted in enhanced drug delivery will be highlighted in this review.     

Microneedle-based drug delivery systems: Microfabrication,drug delivery,and safety

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500?Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN.     

Identification of a novel skin penetration enhancement peptide by phage display peptide library screening

Skin is an important site for local or systemic application of drugs. However, a majority of drugs have poor permeability through the skin's topmost layer, stratum corneum (SC). The aim of this study was to identify safe and smaller peptides that could enhance the skin penetration of drug molecules. By screening phage display peptide library, we have identified a T2 peptide (LVGVFH), which enhanced the penetration of bacteriophages (~800 nm long bacterial viruses) across porcine and mouse skin. Pretreating the skin with synthetic T2 peptide at pH 4.5 resulted in significant penetration enhancement of hydrophilic drug 5-fluorouracil (5-FU) across skin. FTIR spectroscopy showed that the T2 peptide interacted with skin lipids to enhance the skin penetration. Pretreating the skin with T2 peptide enhanced the partitioning of small molecules with different lipophilicities (5-FU, fluorescein isothiocyanate, and rhodamine 123 hydrochloride) into skin. Fluorescence studies showed that T2 peptide enhanced the diffusion of these molecules into intercellular lipids of SC and thus enhanced the penetration into the skin. Histidine at the c-terminus of T2 peptide was identified to be critical for the skin penetration enhancement. T2 peptide interacted with skin lipids to cause skin penetration enhancement. The study identified a novel, safe, and noninvasive peptide to improve the skin penetration of drugs without chemical conjugation.     

Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate

Available formulations of sumatriptan succinate (SS) have low bioavailability or are associated with site reactions. We developed various types of self-dissolving microneedle arrays (MNs) fabricated from sodium hyaluronate as a new delivery system for SS and evaluated their skin permeation and irritation in terms of clinical application. In vitro permeation studies with human skin, physicochemical properties (needle length, thickness and density), and penetration enhancers (glycerin, sodium dodecyl sulfate and lauric acid diethanolamide) were investigated. SS-loaded high-density MNs of 800?µm in length were the optimal formulation and met clinical therapeutic requirements. Penetration enhancers did not significantly affect permeation of SS from MNs. Optical coherence tomography images demonstrated that SS-loaded high-density MNs (800?µm) uniformly created drug permeation pathways for the delivery of SS into the skin. SS-loaded high-density MNs induced moderate primary skin irritations in rats, but the skin recovered within 72?h of removal of the MNs. These findings suggest that high-density MNs of 800?µm in length are an effective and promising formulation for transdermal delivery of SS. To our knowledge, this is the first report of SS permeation across human skin using self-dissolving MNs.     

Pharmaceutical nanocrystals: A promising approach for improved topical drug delivery

The barrier function of skin and the non-optimal physicochemical properties of drugs present challenges to the skin penetration of many drugs, thus motivating the development of novel drug delivery systems. Recently, nanocrystal-based formulations have been investigated for topical drug delivery and have demonstrated improved skin penetration. This review highlights barriers in skin penetration, current techniques to improve topical delivery and application of nanocrystals in conquering obstacles for topical delivery. Nanocrystals can improve delivery through the skin by mechanisms including the creation of a higher concentration gradient across skin resulting in increased passive diffusion, hair follicle targeting, formation of diffusional corona, and adhesion to skin. The recent research would be of interest for formulation scientists seeking to develop products involving molecules that are ‘difficult-to-deliver’ topically.     

Fabrication of Rapidly Separable Microneedles for Transdermal Delivery of Metformin on Diabetic Rats

In this work, the rapidly separable microneedles (MNs) consisted of needle-tips and supporting bases have been fabricated by a step-by-step coating method. Poly (vinyl alcohol) (PVA) have been used to prepare the needle-tips of MNs in which they are capped on the solvable supporting bases consisted of sodium bicarbonate, poly (vinyl pyrolidone) (PVP), and tartaric acid (TA) (NaHCO₃/PVP/TA). After insertion into the skin, the needle-tips can be separated rapidly from the patches within 90 s due to the generation of air bubbles in the supporting bases by the reaction between NaHCO₃ and TA after absorption of tissue fluid, leading to the needle-tips remaining in the skin tissue. Metformin, a hypoglycemic drug, encapsulated in the needle-tips of MNs can be released due to swelling and decomposition of PVA by the absorption of tissue fluid. To investigate the pharmacological effect via transdermal delivery route, metformin-loaded MNs are applied on the diabetic SD rats induced by streptozotocin (STZ). They exhibit a longer hypoglycemic effect in vivo than that of subcutaneous injection. These results indicated the as-fabricated rapidly separable MNs present a promising platform for transdermal delivery of drugs against diabetic patients.     

Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.     

In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery

Microneedles (MNs) system for transdermal drug delivery has the potential to improve therapeutic efficacy, proving an approach that is more convenient and acceptable than traditional medication systems. This study systematically researched dissolving polymer MNs fabricated from various common FDA-approved biocompatible materials, including gelatine, chitosan, hyaluronic acid (HA) and polyvinyl alcohol (PVA). Upon application of MN patches to the porcine cadaver skin, the MNs effectively perforated the skin and delivered drugs to subcutaneous tissue on contact with the interstitial fluid. Both the in vitro and in vivo drug release tests showed the similar trends but different release rates among the prepared MNs. Interestingly, the drug-release kinetics of PVA MNs were able to be altered by changing the molecular weight. To evaluate the feasibility using the proposed MNs for treating diabetes, an in vivo insulin absorption study in diabetic mice was performed. The results showed different insulin release properties of MNs fabricated from various kinds of polymer, leading to different decrease in blood glucose levels. We made a systematic and comprehensive study of some drug-loaded polymer MNs, and anticipated that dissolving polymer MNs have potential to improve therapeutic efficacy through controlled drug release.     

A novel method to enhance the efficiency of drug transdermal iontophoresis delivery by using complexes of drug and ion-exchange fibers

The main reason for generally low efficiency of the transdermal iontophoretic drug delivery is that the fraction of the total current contributed by the drug ions is very small. The objective of this study was to find a method to increase the fraction of the total current contributed by the drug ions so as to enhance the drug's iontophoretic delivery. Iontophoretic transport of diclofenac solution and diclofenac assisted by ion exchange materials, including ion-exchange resin, ion-exchange membrane and ion-exchange fiber, across the rat skin were investigated. Both in vitro and in vivo iontophoretic transport experiments showed the amount of diclofenac permeated across rat skin from the diclofenac-fibers was highest among those from the diclofenac simple solutions and ion exchange materials complexes. The results of this study suggested that there is an enhancement of drug across rat skin by ion-exchange fibers in ion-exchange fibers assisted iontophoresis. The present study has demonstrated the potential of a new approach using ion-exchange fibers to enhance transdermal iontophoretic transport of an ionizable drug.     

Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin?) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 μm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1^nu showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 10¹⁰ ± 2.5 × 10¹⁰ and 3.8 × 10⁹ ± 1.6 × 10⁹ p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.     

Transdermal drug delivery using electroporation. I. Factors influencing in vitro delivery of terazosin hydrochloride in hairless rats

The use of electroporation pulses as a physical means of enhancing the permeability of skin to deliver drugs is in the early stages of development. In this article, a systematic study examining the parameters influencing electroporative transdermal delivery of terazosin hydrochloride to hairless rat skin are reported. It was found that voltage, pulse length (tau), and number of pulses were the three most important parameters, in that order. For creating a significant enhancement in drug delivery to the skin, without causing any apparent change in its external appearance, it was necessary to deliver five or more exponentially decaying electroporation pulses, at 88 +/- 2.5 V (voltage across the skin), with a decay time constant of 20 ms. Electrodes with larger area could attain the same voltages across the skin with a much lower applied voltage and possessed other advantages with regard to performance of the drug delivery system.     

Release characteristics of anionic drug compounds from liquid crystalline gels III. Chemical and iontophoretic enhancement of delivery across non-rate-limiting membranes

This paper investigates the release and transport of a range of anionic drugs from liquid crystalline gels using chemical and physical enhancement techniques. Previous papers [Fitzpatrick, D., Corish, J., 2005. Release characteristics of anionic drug compounds from liquid crystalline gels. I. Passive release across non-rate limiting membranes. Int. J. Pharm. 301, 226-236; Fitzpatrick, D., Corish, J., 2006. Release characteristics of anionic drug compounds from liquid crystalline gels. II. The effects of ion pairing and buffering on the passive delivery of anionic drugs across non rate-limiting membranes. Int. J. Pharm.] have reported on the passive release profiles and those resulting from the incorporation of a chemical enhancer in the vehicle. This paper investigates the behaviour of the system under iontophoretic conditions and also under those of combined physical and chemical enhancement. The data presented here are directly comparable to previous work by Nolan et al. [; Nolan, L.M.A., Corish, J., Corrigan, O.I., Fitzpatrick, D., 2006. Combined effects of iontophoretic and chemical enhancement on drug delivery. II. Transport across human and hairless murine skin. Int. J. Pharm., submitted for publication] which investigated the behaviour of cationic compounds under analogous conditions. The iontophoretic release of diclofenac in the presence of model enhancers is thoroughly investigated. It is also shown that a range of anionic drug molecules undergo an electrochemical change during the course of the experiments which leads to their poor detection. This may be a factor in the under reporting of iontophoretic delivery of anionic drugs in the literature. However, it has been shown that the transport of the drugs is greatly enhanced by the application of an iontophoretic current. Results of combined enhancement studies provide a positive basis on which to proceed with in vitro studies of the system across human skin.     

Recent advances in liposome technologies and their applications for systemic gene delivery

The recent clinical successes experienced by liposomal drug delivery systems stem from the ability to produce well-defined liposomes that can be composed of a wide variety of lipids, have high drug-trapping efficiencies and have a narrow size distribution, averaging less than 100 nm in diameter. Agents that prolong the circulation lifetime of liposomes, enhance the delivery of liposomal drugs to specific target cells, or enhance the ability of liposomes to deliver drugs intracellularly can be incorporated to further increase the therapeutic activity. The physical and chemical requirements for optimum liposome drug delivery systems will likely apply to lipid-based gene delivery systems. As a result, the development of liposomal delivery systems for systemic gene delivery should follow similar strategies.