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 (

Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid addiction

Opioid addiction is a serious national crisis impacting public health. Naloxone is a potent opioid antagonist administered to reverse the effects of opioid overdose. It is currently administered as an intravenous, intramuscular, subcutaneous injection and intranasal spray. The short duration of action of naloxone results in requirement of frequent re-dosing, especially in cases of larger overdoses, which may impact successful outcomes, especially when drug administration is provided by non-medical personnel as in case of intranasal sprays. These weaknesses necessitate the development of a non-injectable dosage form that has a rapid onset and extended duration of action. Delivery of drugs via skin is an attractive alternative that provides these benefits. Our study aimed to assess the effect of microneedles on the amount and lag time of permeation of naloxone across skin. In vitro permeation studies were performed to assess the delivery of naloxone through dermatomed porcine ear skin using Franz Diffusion cells. The donor and receptor chamber of the cells contained the drug solution and phosphate buffered saline, respectively. The receptor was sampled until 6 h and analyzed using HPLC. The permeation of naloxone across intact (passive) and microneedle-treated (Dr. Pen™ Ultima A6) skin was evaluated. Two microporation conditions with donor concentration of 10 mg/mL were investigated: needle lengths (500 µm and 250 µm) for 1 minute and 500 µm needle length for different durations (1 and 2 minutes). Further, the effect of application of different naloxone concentrations (10 and 20 mg/mL) on skin treated with 500 µm microneedles for 2 minutes was also tested. One-way ANOVA was applied to ascertain statistical difference between the different test groups. The amount of passive permeation after 6 h and lag time for naloxone was observed to be 8.251.06 µg/cm2 and88.58 ± 3.05 min, respectively. One minute treatment with 500 µm needles significantly enhanced the permeation to 463.24 ± 30.21 µg/cm2 and reduced the lag time to 15.90 ± 1.63 min (p0.05). Microneedles were found to enhance the permeation of naloxone across skin. The observation of quick onset of drug permeation in the in vitro settings is very encouraging and future studies would focus on developing a microneedle patch for quick onset and extended drug release

Microneedle-Mediated Transdermal Delivery of Naloxone Hydrochloride for Treatment of Opioid Overdose

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p \u3c 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment

Development, Pre-clinical Investigation and Histopathological Evaluation of Metronidazole Loaded Topical Formulation for Treatment of Skin Inflammatory Disorders

Background: Metronidazole (MTZ) is an anti-oxidant and anti-inflammatory agent with beneficial therapeutic properties. The hydrophilic nature of the molecule limits its penetration across the skin. Existing commercial formulations have limitations of inadequate drug concentration present at the target site, which requires frequent administration and poor patient compliance. Objective: The aim of the current study was to develop and evaluate water in oil microemulsion of Metronidazole with higher skin retention for the treatment of inflammatory skin disorders. Methods: Pseudo ternary phase diagrams were used in order to select the appropriate ratio of sur-factant and co-surfactant and identify the microemulsion area. The selected formulation consisted of Capmul MCM as oil, Tween 20 and Span 20 as surfactant and co-surfactant, respectively, and water. The formulation was characterized and evaluated for stability, Ex vivo permeation studies and in vivo anti-inflammatory effect (carrageenan induced rat paw edema, air pouch model), anti-p-soriatic activity (mouse-tail test). Results: The particle size analyses revealed the average diameter and polydispersity index of the selected formulation to be 16 nm and 0.373, respectively. The results of ex vivo permeation studies showed statistically higher mean cumulative amount of MTZ retained in rat skin from microemul-sion, i.e., 21.90 ± 1.92 µg/cm2, which was 6.65 times higher as compared to Marketed gel (Metro-gyl gel®) with 3.29 ± 0.11 µg/cm2 (p\u3c0.05). The results of in vivo studies suggested the microemul-sion based formulation of MTZ to be similar in efficacy to Metrogyl gel®. Conclusion: Research suggests the efficacy of the developed MTZ loaded microemulsion in the treatment of chronic skin inflammatory disorders

Therapeutic Potential of Essential Oil-based Microemulsions: Reviewing State-of-the-art

A pre-eminent emulsion-based micellar drug delivery system, microemulsion , comprising drug in oil or water phase, stabilized by surfactants and co-surfactants, has been evidenced to have a phenomenal role in a number of applications. Oils play an important role in the formation of ME and increase the drug absorption at the site of action. Oils employed in microemulsion formulation solubilize lipophilic drug. As the concept of natural therapies is recently gaining importance amongst researchers all over the world, scientists are employing essential oil as an organic component in this system. The active components of essential oils include flavonoids, phenylpropanoids, monoterpenes and polyunsaturated mega-6-fatty acids. These oils are enriched with characteristic intrinsic properties such as anti-oxidant, anti-bacterial, anti-viral, etc., bestowing enhanced supremacy to the whole microemulsion system. This mini-review is the first to document various types of essential oils employed in microemulsion systems and highlight their therapeutic potential and applications as drug delivery vehicles. Key inferences from this study suggest: 1) Clove oil is the most explored oil for incorporation into a microemulsion based system, followed by peppermint and Tea Tree Oil (TTO). 2) Penetration enhancing effects of these oils are due to the presence of terpenic constituents. 3) Essential oil based microemulsions protect volatility of ethereal oils and protect them from degradation in the presence of light, air, temperature. 4) These systems may also be explored for their applications in different industries like aromatherapy, food, drink, fragrance, flavour, cosmeceutical, soap, petroleum and pharmaceutical industry

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

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

Investigating the Effect of Salcaprozate Sodium on Skin Permeation of Cromolyn Sodium

Drug delivery via skin is a non-invasive, patient compliant, and effective method for circulatory or skin-targeted therapeutic treatment. Based on its mechanism of action, a topical system employing cromolyn sodium (CS) poses as a cheaper, safer alternative to current treatments for atopic dermatitis, an allergic skin disease. Clinical studies have successfully treated atopic dermatitis with CS emulsions; however, semisolid CS gels have not been investigated and no commercial formula is available to date. Additionally, clinical doses of CS do not passively permeate skin, although different chemical enhancers can be incorporated into formulation to enhance cutaneous drug absorption. This study aimed to investigate salcaprozate sodium (SNAC) as a chemical enhancer for optimized drug delivery to the dermis for potential remedial effects of CS gels. Gels were prepared weight-to-weight by combining 4% CS, 1% hydroxypropyl cellulose as gelling agent, and respective amounts of propylene glycol as base. For SNAC gels, contents included 2.5%, 4.5%, and 9% SNAC, and amount of propylene glycol was adjusted accordingly. CS gel (4%) containing no SNAC was used as a control. After overnight shaking, gels were sonicated for 30 min to use in in vitro permeation studies. Porcine ear skin was mounted on Franz diffusion cells maintained at 37°C, and permeation studies were performed over 24 h for each formulated gel to determine their effect on CS permeation across skin. Donor compartment contained 100 μL gel while the receptor held phosphate buffered saline (PBS). At predetermined timepoints, 300 μL of receptor solution was sampled, replaced with fresh PBS, and analyzed using HPLC with CS detection at 236 nm. Following 24 h, remaining gel was removed, and skin surface was cleaned. Skin layers were manually separated, minced, and left to shake for 4 h to extract permeated drug using methanol. These samples were vacuum dried overnight and reconstituted with PBS to be analyzed using HPLC. Efficiency of skin extraction methods was evaluated by assessing amount of drug recovered from skin compared to amount of drug absorbed where results were plotted, and subsequent equations were used to correct skin data. Student’s T test with Welch’s correction was applied to confirm statistical significance between gels. Passive delivery of the 4% CS control gel to the dermis was 0 μg/cm2. The SNAC containing gels demonstrated significantly improved drug delivery to the dermis when compared to control for 2.5% (36.26 ± 13.05, p=0.05), 4.5% (11.64 ± 1.45, p=0.001), and 9% (35.87 ± 2.23, p=0.004) SNAC groups. No significant differences were observed between any SNAC gel group and the control gel regarding drug delivered to the epidermis or receptor over 24 h. This study observed the greatest delivery of CS to the dermis with the 2.5% SNAC gel, posing as a promising option for a commercially available topical CS gel for the skin-targeted treatment of atopic dermatitis

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 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 (