Development of a Sustained Transdermal Delivery System of Amiloride for Management of Resistant Hypertension

Resistant hypertension is a condition in which blood pressure remains above the ideal value (120/80mmHg), despite concurrent use of three antihypertensive agents of different classes taken at maximally tolerated doses. Amiloride, a potassium-sparing diuretic agent, when added to the treatment regimen of these drugs has been found suitable for the management of resistant hypertension, especially in diabetic patients and those resistant to a similar diuretic, spironolactone. Currently, it is available as an oral tablet, administered once daily. The oral bioavailability of amiloride is 50%, which gets reduced to 30% when administered with food. In addition, gastrointestinal side effects are also reported. Patient’s adherence to the multi-drug treatment regimen has been found to be low in patients with resistant hypertension and hence, administering amiloride in the oral forms may not solve the problem, in spite of its proven pharmacological efficacy in such situations. Thus, considering the low oral bioavailability, associated side-effects, and prospects of better patient compliance with a skin patch of amiloride, our long term goal is to design a long-acting skin patch for transdermal delivery of amiloride in patients with resistant hypertension. The current study aims to investigate the passive transdermal delivery of amiloride and evaluate the effects of chemical and physical enhancement techniques on its permeation through dermatomed porcine ear skin. High performance liquid chromatography (HPLC) method for amiloride was developed. Absence of skin interference in the assay was confirmed using blank skin extract. Solubility of amiloride was screened in different solvents, some of which included propylene glycol, phosphate buffer saline, oleic acid in propylene glycol, etc. In vitro permeation of amiloride across intact and microneedle-treated (500 µm long stainless needles applied for 2 min) porcine ear skin was evaluated using Franz Diffusion cells over 30 h. The optimized reverse-phase HPLC method involved isocratic elution on Kinetex® 5 µm, 100 Ao, 250 X 4.6 mm C18 column using 100% mobile phase (0.2 M phosphate buffer, pH 4.5) at a flow rate of 0.8 mL/min, column temperature of 40°C, and UV detection at 360 nm. Drug retention time was found to be around 4 min. Amiloride was found to be most soluble in propylene glycol (57.18 ± 2.41 mg/mL) with least solubility in phosphate buffer saline (0.311 ± 0.004 mg/mL). Microneedles were found to significantly enhance the permeation flux of amiloride by 16 folds as compared to the control intact skin (

Rapidly Dissolving Polymeric Microneedle Skin Patch of Naloxone for Opioid Overdose Treatment

Rapidly Dissolving Polymeric Microneedle Skin Patch of Naloxone for Opioid Overdose Treatment Tijani Akeemat1, Maria J. Peláez2, Prashant Dogra2,3, Ashana Puri1 1 Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614. 2 Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA 3 Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA Worldwide opioid abuse affects over 16 million people. A major cause of death in abusers is overdosing. Naloxone (NAL) is an opioid inhibitor that reverses its respiratory depressing effect. The use of this drug is limited mostly to invasive delivery: intravenous (IV), intramuscular (IM) and subcutaneous (SC) due to its significant hepatic clearance and poor oral bioavailability (2%). These routes are painful and worse still is the need for frequent injections for patient stabilization due to the short half-life of NAL. Non-invasive intranasal forms exist but this is fraught with a couple of limitations such as nasal damage and epistaxis. The need for alternatives without these limitations is thus evident. The feasibility of the use of metal microneedles (MNs) for the transdermal delivery of NAL was demonstrated in-vitro and through in-vitro in-vivo correlation modeling in our lab. The goal of the current study was to design a rapidly dissolving polymeric MN patch with delivery and pharmacokinetic (PK) properties comparable to that seen with the commercially available NAL products, eliminating their highlighted limitations. NAL loaded rapidly dissolving polyvinyl pyrrolidone-based MN arrays (500 µm, 100 needles) were fabricated by the mold casting technique. The permeation profile of fabricated MNs over a predetermined time were assessed via an in-vitro permeation set up using porcine ear skin. Samples were analyzed via HPLC. To improve on drug flux and amount permeated, the effect of increasing MN length and density (no. of needles/unit area) were assessed by fabricating MNs 300 µm longer and those with density double that of the initial array. Factors such as drug load and polymer strength influenced the needle fabrication. Compared to passive permeation, a reduced lag time of about 15 min was observed with a significant drug flux of 15.09 ± 7.68 g/cm2/h seen in the first 1 h (pin-vitro in-vivocorrelation we were able to predict an optimized design of the patch that can reproduce the clinical PK of NAL obtained with commercial devices. Increasing needle density and/or patch area was found to be of greater significance. Overall, drug flux seen over 1 h depicts the applicability of fabricated needles in opioid overdose emergencies with delivery properties comparable to that with IM and IN delivery

Transdermal Route: A Viable Option for Systemic Delivery of Antidepressants

The high rise in the population suffering from depression depicts the need for improved and highly effective treatment options for this condition. Efforts to develop existing drugs into user-friendly dosage forms with a number of advantages in major depressive states, including but not limited to: sustained drug release, reduced drug dosing frequency, improved tolerance and adherence, suitability for use in diverse populations and different treatment scenarios, as well as less central nervous system side effects are required. One such non-invasive drug delivery route that could provide the aforementioned benefits in the treatment of depression is the transdermal route. A number of conventional and emerging transdermal delivery strategies have been investigated for some potent antidepressants and results depict the potential of this route as a viable means for systemic delivery of therapeutically relevant doses of the tested agents, with Emsam®, the commercially available patch of selegiline, being an evidence for the same. The investigated approaches include the formulation of transdermal patches, use of vesicular drug carriers, pro-drug approach, microemulsification, chemical as well as physical enhancement technologies. This review provides a comprehensive account of the rationale, developments made till date, scope and future prospects of delivering antidepressants via the transdermal1 route of administration

Characterization of Microneedles and Microchannels for Enhanced Transdermal Drug Delivery

Microneedle (MN)-based technologies are currently one of the most innovative approaches that are being extensively investigated for transdermal delivery of low molecular weight drugs, biotherapeutic agents and vaccines. Extensive research reports, describing the fabrication and applications of different types of MNs, can be readily found in the literature. Effective characterization tools to evaluate the quality and performance of the MNs as well as for determination of the dimensional and kinetic properties of the microchannels created in the skin, are an essential and critical part of MN-based research. This review paper provides a comprehensive account of all such tools and techniques

Development of an Iontophoresis-Coupled Microneedle Skin Patch of Naloxone for Emergency Treatment of Opioid Overdose

The use of naloxone (NAL) for opioid overdose treatment is limited mostly to parenteral (intravenous, intramuscular, and subcutaneous) or intranasal route due to significant first-pass metabolism associated with oral delivery. Injectables are painful and frequent administrations by the existing routes for patient stabilization due to the short half-life of NAL are needed. Alternative delivery systems would be beneficial if they provide a balance between sustained release properties and a comparable rapid release as is achievable with the available parenteral forms. Thus, the goal of our study is to design a clinically viable polymeric microneedle (MN) patch for NAL. MNs of varying geometric dimensions were fabricated. In vitro skin permeation data for the best-performing patch was mathematically modeled and predictions on geometric parameters for a MN patch of comparable pharmacokinetic properties to parenteral and intranasal NAL as seen in the market were determined. From these evaluations, the need to devise ways to improve flux and amount of drug released from a patch per time was identified. We explored the influence of iontophoretically driving ionized drug content in MN patches on cumulative permeation of NAL from the best-performing MN patch. To optimize the iontophoresis parameters, the influence of citrate phosphate buffer strength on drug release profile was evaluated. Also, the impact of combining iontophoresis and higher drug loading was evaluated. A reduced lag time of about 5-15 min was observed with fabricated polymeric MN patches. From the polymeric MN patch P1 loaded with 50 mg/mL of NAL, a significant drug flux of 15.09 ± 7.68 ��g/cm2/h was observed in the first 1 h (p.Increasing MN length and density (P2 and P3) made a significant difference in the amount permeated and flux (pin-vitrorelease from the best-performing patch (P3) revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL from the MN patches. With this approach, an optimized design of the patch that can reproduce the clinical pharmacokinetics of NAL obtained with commercial devices was predicted. Investigation on the influence of iontophoresis in improving flux from the P3 patch shows about a 2-fold (

In Vitro Percutaneous Absorption Studies of Cannabidiol Using Human Skin: Exploring the Effect of Drug Concentration, Chemical Enhancers, and Essential Oils

Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41 ± 12.17 µg/cm) and 10% (232.79 ± 20.82 cm) cannabidiol solutions. However, 1% delivered (23.02 ± 4.74 µg/cm) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07 ± 10.11 µg/cm) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98 ± 3.40 µg/cm) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study\u27s findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders

Development of a Skin Patch of Baclofen for Sustained Management of Multiple Sclerosis Associated Spasticity

Multiple sclerosis (MS) is a chronic neurological disease where immune cells from the periphery enter the central nervous system and attack the myelin sheaths resulting in damage to the axons. It is an unpredictable disease that affects each person differently. One of the symptoms of MS includes muscle spasticity and depending on the severity it can cause gait and mobility issues. Oral baclofen is the first-line recommendation to treat spasticity in people with MS whose treatment goals include improving mobility or easing pain and discomfort. Baclofen works pre- and post-synaptically as a gamma aminobutyric acid-B agonist at the spinal cord to reduce the amount of excitatory neurotransmitters that are responsible for muscle contractions. Oral baclofen has been used to treat spasticity, however its short half-life of 2-6 hours warrants its need for three times a day dosing schedule. The multiple daily dosing can be a burden to the patient taking it and for the caregiver who will be giving the medication which can negatively affect adherence and acceptability. The goal of the current study was to design and assess baclofen loaded dissolving microneedle (MN) patch on the amount permeated and sustained delivery of baclofen in the management of spasticity. A 1.5 mg/mL MN patch was initially made by dissolving baclofen in polyvinylpyrrolidone (PVP) and fabricated using the mold casting technique. The permeation profile of fabricated baclofen loaded MNs over a predetermined time was assessed in vitro through dermatomed porcine ear skin using Franz Diffusion cells. Employing the use of MNs significantly increased the flux from 2.10 ± 0.35 µg/sq.cm/h to 5.92 ± 4.17 µg/sq.cm/h and the average cumulative amount permeated from 92.67 ± 11.25 µg/sq.cm to 457.11 ± 111.47 µg/sq.cm over 72 h (p\u3c0.05). However, because of baclofen’s hydrophilic nature, drug permeation across skin is limited, so a nanosuspension with reduced particle size was formulated to be used for MN fabrication to increase drug loading and permeation. Baclofen was formulated into a suspension through wet media milling followed by mechanical homogenization using PVP K30 and sodium dodecyl sulfate as stabilizers. The suspension was successfully loaded in dissolving PVP-based MNs. The donor chamber of the cell contained the MN patch mounted onto the porcine skin and the receptor chamber contained phosphate buffered saline. The receptor was sampled over 72 h and analyzed using HPLC. The baclofen suspension loaded MNs produced an average drug flux of 26.51 ± 4.17 µg/sq.cm/h and an average cumulative amount of 1718.96 ± 217.12 µg/sq.cm over 72 h. The use of suspension loaded MNs was found to enhance the permeation and produce a sustained delivery of baclofen across skin and depicts the applicability of fabricated needles for sustained delivery in the management of muscle spasticity in multiple sclerosis

Delivering Therapeutic Cannabinoids via Skin: Current State and Future Perspectives

Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date

Qualitative and Quantitative Analysis of Drug Diffusion Into and Across Derma planed Skin

Dermaplaning is a non-surgical cosmeceutical approach gaining popularity for skin rejuvenation. It works to peel off dead layers of skin and re-initiate skin remodeling. The potential of this approach as an active permeation enhancement strategy when used alone or in synergism with other active approaches was envisaged. To date, no study has evaluated the influence of dermaplaning on the transdermal delivery of drugs. In this study we sought to evaluate the influence of this approach on the transdermal permeation of a typical hydrophilic drug, baclofen. The influence of user variation on dermaplaning was evaluated. Moving at an angle of 45° from one end of skin sections \u3c 1mm thick and of area 1 sq.cm, a dermaplane was stroked 4 times across distances of 0.2 inches through the entire skin area. Treated skin were mounted on Franz cells in in vitro diffusion set-ups. Interindividual variability in use and the consequence of this on permeation was assessed by having 3 different individuals work with different samples of skin (n = 4). Skin resistance was determined before and after dermaplaning. The histological evaluation of the dermaplaned skin was done with heamatoxylin and eosin staining of transverse skin sections and compared to the control (no dermaplaning). Methylene blue staining of treated area was done to confirm the removal of stratum corneum (SC). Confocal imaging to validate effect of dermaplane on permeation was also done by evaluating the permeation depth of fluorescein, a hydrophilic dye. A significant drop in electrical resistance post skin treatment with dermaplane strokes was observed for all treatment groups, signifying the depletion of barrier properties of SC. Consequently, significant drug flux and permeation was observed for the model drug, baclofen in 2 h. The average drug flux over 2 h were 159.65 18.90, 213.15 20.19, 169.06 25.06 μg/cm2/h for users 1,2,3, respectively. These were significantly higher compared to the flux for the control (0 μg/cm2/h, p0.05). Histology studies depicted the removal of SC and some parts of viable epidermis. Confocal imaging of the permeation of hydrophylic dye shows deeper diffusion of dermaplaned skin compared to intact control skin. Dermaplaned skin pieces were heavily stained with methylene blue compared to control pieces indicating the loss of SC and exposure of hydrophilic viable epidermis and or dermis to the dye.The results depict the effectiveness of dermaplaning as a transdermal permeation enhancement strategy