Formulation development of tazarotene-loaded PLGA nanoparticles for follicular delivery in the treatment of inflammatory skin diseases.

Tazarotene is a widely prescribed topical retinoid for acne vulgaris and plaque psoriasis and is associated with skin irritation, dryness, flaking, and photosensitivity. In vitro permeation of tazarotene was studied across the dermatomed human and full-thickness porcine skin. The conversion of tazarotene to the active form tazarotenic acid was studied in various skin models. Tazarotene-loaded PLGA nanoparticles were prepared using the nanoprecipitation technique to target skin and hair follicles effectively. The effect of formulation and processing variables on nanoparticle properties, such as particle size and drug loading, was investigated. The optimized nanoparticle batches with particle size <500 µm were characterized further for FT-IR analysis, which indicated no interactions between tazarotene and PLGA. Scanning electron microscopy analysis showed uniform, spherical, and non-agglomerated nanoparticles. In vitro release study using a dialysis membrane indicated a sustained release of 40-70 % for different batches over 36 h, following a diffusion-based release mechanism based on the Higuchi model. In vitro permeation testing (IVPT) in full-thickness porcine skin showed significantly enhanced follicular and skin delivery from nanoparticles compared to solution. The presence of tazarotenic acid in the skin from tazarotene nanoparticles indicated the effectiveness of nanoparticle formulations in retaining bioconversion ability and targeting follicular delivery.

Development of 4-phenylbutyric acid microsponge gel formulations for the treatment of lewisite-mediated skin injury.

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1ß, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.

Long-acting transdermal drug delivery formulations: Current developments and innovative pharmaceutical approaches.

Transdermal administration remains an active research and development area as an alternative route for long-acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. This review focuses on the current state of long-acting transdermal drug delivery, including adhesive patches, microneedles, and molecularly imprinted polymeric systems. Each subsection describes an approach including key considerations in formulation development, design, and process parameters with schematics. An overview of commercially available conventional (adhesive) patches for long-acting drug delivery (longer than 24 h), the reservoir- and matrix-type systems under preclinical evaluation, as well as the advanced transdermal formulations, such as the core-shell, nanoformulations-incorporated and stimuli-responsive microneedles, and 3D-printed and molecularly imprinted polymers that are in development, is also provided. Finally, we elaborated on translational aspects, challenges in patch formulation development, and future directions for the clinical advancement of new long-acting transdermal products.

Microneedle-Assisted Transdermal Delivery of Lurasidone Nanoparticles.

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide therapeutic effects for three days. Passive diffusion was found to be insufficient for lurasidone delivery. The addition of chemical enhancers increased permeation, but it was still insufficient to reach the designed target dose from a patch, so a microneedle patch array was fabricated by using biodegradable polymers. For prolonged and effective delivery, the drug was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles which were made using the solvent evaporation method and incorporated in microneedles. Effervescent technology was also employed in the preparation of the microneedle patch to facilitate the separation of the needle tip from the patch. Once separated, only the needle tip remains embedded in the skin, thus preventing premature removal by the patient. The microneedles demonstrated robust preformation in a characterization test evaluating their insertion capacity, mechanical strength, and the uniformity of microneedle arrays, and were able to deliver a dose equivalent to 20 mg oral administration. Therefore, the potential of a transdermal delivery system for lurasidone using microneedles with nanoparticles was demonstrated.

Comparative evaluation of physical and chemical enhancement techniques for transdermal delivery of linagliptin.

Linagliptin is a dipeptidyl peptidase-4 inhibitor used for the management of type-2 diabetes. US FDA-approved products are available exclusively as oral tablets. The inherent drawbacks of the oral administration route necessitate exploring delivery strategies via other routes. In this study, we investigated the feasibility of transdermal administration of linagliptin through various approaches. We compared chemical penetration enhancers (oleic acid, oleyl alcohol, and isopropyl myristate) and physical enhancement techniques (iontophoresis, sonophoresis, microneedles, laser, and microdermabrasion) to understand their potential to improve transdermal delivery of linagliptin. To our knowledge, this is the first reported comparison of chemical and physical enhancement techniques for the transdermal delivery of a moderately lipophilic molecule. All physical enhancement techniques caused a significant reduction in the transepithelial electrical resistance of the skin samples. Disruption of the skin's structure post-treatment with physical enhancement techniques was further confirmed using characterization techniques such as dye binding, histology, and confocal microscopy. In vitro permeation testing (IVPT) demonstrated that the passive delivery of linagliptin across the skin was < 5 µg/sq.cm. Two penetration enhancers - oleic acid (93.39 ± 8.34 µg/sq.cm.) and oleyl alcohol (424.73 ± 42.86 µg/sq.cm.), and three physical techniques - iontophoresis (53.05 ± 0.79 µg/sq.cm.), sonophoresis (141.13 ± 34.22 µg/sq.cm.), and laser (555.11 ± 78.97 µg/sq.cm.) exceeded the desired target delivery for therapeutic effect. This study established that linagliptin is an excellent candidate for transdermal delivery and thoroughly compared chemical penetration and physical transdermal delivery strategies.

Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.

Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.

Transdermal delivery of naloxone hydrochloride using minimally invasive physical ablation techniques.

NAL's hydrophilicity and the inherent lipophilic properties of the stratum corneum hinders its capacity for immediate delivery through skin in opioid rescue cases. In this study, we had sought to investigate the feasibility of using minimally invasive physical ablative techniques including sonophoresis, laser, dermaplaning, microneedles, and microdermabrasion for systemically delivering NAL via the skin. These techniques reduced lag time to NAL delivery to about 3-12 min from 71.22 ± 9.62 min seen for passive delivery. Also, they all significantly enhanced the amount of NAL delivered in 1 h and over 24 h period of evaluation as compared to the passive group (p < 0.05). Sonophoresis and laser showed the greatest delivery in 1 h, followed by dermaplaning. The cumulative amount of drug delivered by these approaches in 1 h were 1277.95 ± 387.06, 83.33 ± 11.11, 30.66 ± 5.67 µg/cm2, respectively. Though the most remarkable, inconsistencies in in vitro permeation profile of NAL were observed with the 1 MHz ultrasound frequency used. With proper optimization of the conditions of use and design, the different approaches explored in this study can be potentially applied for the systemic delivery of naloxone in opioid overdose emergencies and opioid disaccustoming purposes.

Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite.

Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm2 for 4 h followed by passive diffusion till 24 h significantly enhanced the delivery of NAC with a total delivery of 65.16 ± 1.95 µg/cm2 and 87.23 ± 7.02 µg/cm2, respectively. Amongst chemical enhancers, screened oleic acid, oleyl alcohol, sodium lauryl ether sulfate, and dimethyl sulfoxide (DMSO) showed significantly enhanced delivery of NAC with DMSO showing highest delivery of 28,370.2 ± 2355.4 µg/cm2 in 24 h. Furthermore, 4-PBA permeated passively from PG with total delivery of 1745.8 ± 443.5 µg/cm2 in 24 h. Amongst the chemical enhancers screened for 4-PBA, oleic acid, oleyl alcohol, and isopropyl myristate showed significantly enhanced delivery with isopropyl myristate showing highest total delivery of 17,788.7 ± 790.2 µg/cm2. These studies demonstrate feasibility of delivering these antidotes via skin and will aid in selection of excipients for the development of topical/transdermal delivery systems of these agents.

Microneedle Mediated Iontophoretic Delivery of Tofacitinib Citrate.

PURPOSE: To investigate in vitro transdermal delivery of tofacitinib citrate across human skin using microporation by microneedles and iontophoresis alone and in combination. METHODS: In vitro permeation studies were conducted using vertical Franz diffusion cells. Microneedles composed of polyvinyl alcohol and carboxymethyl cellulose were fabricated and successfully characterized using scanning electron microscopy. The microchannels created were further characterized using histology, dye binding study, scanning electron microscopy, and confocal microscopy studies. The effect of microporation on delivery of tofacitinib citrate was evaluated alone and in combination with iontophoresis. In addition, the effect of current density on iontophoretic delivery was also investigated. RESULTS: Total delivery of tofacitinib citrate via passive permeation was found out to be 11.04 ± 1 µg/sq.cm. Microporation with microneedles resulted in significant enhancement where a 28-fold increase in delivery of tofacitinib citrate was observed with a total delivery of 314.7±33.32 µg/sq.cm. The characterization studies confirmed the formation of microchannels in the skin where successful disruption of stratum corneum was observed after applying microneedles. Anodal iontophoresis at 0.1 and 0.5 mA/sq.cm showed a total delivery of 18.56 µg/sq.cm and 62.07 µg/sq.cm, respectively. A combination of microneedle and iontophoresis at 0.5 mA/sq.cm showed the highest total delivery of 566.59 µg/sq.cm demonstrating a synergistic effect. A sharp increase in transdermal flux was observed for a combination of microneedles and iontophoresis. CONCLUSION: This study demonstrates the use of microneedles and iontophoresis to deliver a therapeutic dose of tofacitinib citrate via transdermal route.

Development and evaluation of transdermal delivery system of tranylcypromine for the treatment of depression.

Tranylcypromine (logP = 1.34, MW = 133.19 g/mol) is a monoamine oxidase inhibitor used in treating major depressive disorder and is available only as oral tablets. Transdermal delivery of tranylcypromine minimizes hepatic and gastrointestinal side effects associated with oral dosing and prevents systemic side effects improving patient compliance. A two-day suspension-based transdermal delivery method was developed in this study, and the delivery of tranylcypromine across dermatomed porcine ear skin was evaluated. Different penetration enhancers were screened, namely, isopropyl myristate, oleyl alcohol, oleic acid, and a combination of oleic acid and oleyl alcohol. Isopropyl myristate was chosen as the penetration enhancer, and suspension-based transdermal patches were formulated with acrylate and polyisobutylene pressure-sensitive adhesives by the solvent evaporation method. The release liner and backing membrane were chosen, and the drying time for each patch was optimized. The optimized patches were characterized for their adhesive properties, drying time, peel test, shear strength, and uniformity in drug content. In vitro permeation studies were performed on dermatomed porcine ear skin using vertical static Franz diffusion cells, and the receptor samples were collected at predetermined time points for 48 h. The samples were analyzed in a validated UPLC method. Acrylate-based suspension patch delivered a significantly higher amount of drug (712 ± 21.46 µg/cm2) as compared to passive delivery from drug dissolved in propylene glycol (461.49 ± 75.55 µg/cm2), reaching the two-day therapeutic target. However, the PIB-based suspension patch delivered 559.25 ± 12.37 µg/cm2 of tranylcypromine across the skin but did not reach the required target.

Development and evaluation of a drug-in-adhesive transdermal delivery system for delivery of olanzapine.

OBJECTIVES: Olanzapine (OZP) is a safe and effective atypical antipsychotic drug used in treating schizophrenia and bipolar disorders. The dosage forms currently on the market for OZP are administered via oral or intramuscular routes. However, there are many problems associated with oral and intramuscular routes of drug administration. Thus, our aim was to develop a drug-in-adhesive transdermal delivery system (TDS) that can deliver OZP for 3 days. METHODS: We determined passive permeation, effect of oleic acid as chemical enhancer, and delivery of OZP across different skin types. Based on preliminary studies and saturation solubility of OZP in different pressure-sensitive adhesives (PSAs), we formulated and characterized solution-based TDS in acrylate PSA and suspension-based TDS in silicone and PIB PSA, with oleic acid as chemical enhancer. RESULTS: Acrylate solution-based TDS, silicone, and PIB suspension-based TDS delivered 58.97 ± 6.59 µg/sq.cm, 129.34 ± 16.59 µg/sq.cm, and 245.00 ± 2.51 µg/sq.cm, respectively, using in vitro permeation testing. PIB PSA suspension-based TDS met the 3 days desired target delivery. Skin irritation testing using In vitro EpiDermTM skin irritation test (EPI-200-SIT) kit found PIB TDS to be nonirritant. CONCLUSION: The PIB PSA suspension-based TDS could serve as a potentially effective transdermal delivery system for olanzapine.

Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis.

Application of drugs on skin with compromised barrier can significantly alter permeation of drugs with the possibility of increased adverse side effects or even toxicity. In this study, we tested in vitro delivery of diclofenac sodium from marketed brand and generic formulations across normal and compromised skin using microneedles and iontophoresis, alone and in combination. Ten tape strips on dermatomed human skin were used to create a compromised skin model, as demonstrated by changes in skin resistance and transepidermal water loss. Histology studies further confirmed creation of a compromised skin barrier. There was no significant difference between brand and generic formulations for delivery of diclofenac sodium into and across normal and compromised skin. Compromised skin showed higher total delivery (µg/sq.cm) of diclofenac sodium for all groups - microneedles (brand: 79.45 ± 8.81, generic: 92.15 ± 8.63), iontophoresis (brand: 233.13 ± 8.32, generic: 242.07 ± 11.17), combination (brand: 186.88 ± 6.76, generic: 193.8 ± 5.69) as compared to intact normal skin for same groups, microneedles (brand: 21.83 ± 1.96, generic: 20.38 ± 0.91), iontophoresis (brand: 149.78 ± 18.43, generic: 145.53 ± 12.61), and combination (brand: 80.97 ± 9.86, generic: 70.76 ± 6.56). These results indicate the effect of barrier integrity on delivery of diclofenac sodium which suggests increased absorption and systemic exposure of the drug across skin with compromised skin barrier.

Fabrication of Polymeric Microneedles using Novel Vacuum Compression Molding Technique for Transdermal Drug Delivery.

PURPOSE: To demonstrate the feasibility of vacuum compression molding as a novel technique for fabricating polymeric poly (D, L-lactic-co-glycolic acid) microneedles. METHODS: First, polydimethylsiloxane molds were prepared using metal microneedle templates and fixed in the MeltPrep® Vacuum Compression Molding tool. Poly (D, L-lactic-co-glycolic acid) (EXPANSORB® DLG 50-5A) was added, enclosed, and heated at 130°C for 15 min under a vacuum of -15 psi, cooled with compressed air for 15 min, followed by freezing at -20°C for 30 min, and stored in a desiccator. The microneedles and microchannels were characterized by a variety of imaging techniques. In vitro permeation of model drug lidocaine as base and hydrochloride salt was demonstrated across intact and microporated dermatomed human skin. RESULTS: Fabricated PLGA microneedles were pyramid-shaped, sharp, uniform, and mechanically robust. Scanning electron microscopy, skin integrity, dye-binding, histology, and confocal laser microscopy studies confirmed the microchannel formation. The receptor delivery of lidocaine salt increased significantly in microporated (270.57 ± 3.73 µg/cm2) skin as compared to intact skin (142.19 ± 13.70 µg/cm2) at 24 h. The receptor delivery of lidocaine base from microporated skin was significantly higher (312.37 ± 10.57 µg/cm2) than intact skin (169.68 ± 24.09 µg/cm2) up to 8 h. Lag time decreased significantly for the base (2.24 ± 0.17 h to 0.64 ± 0.05 h) and salt (4.76 ± 0.31 h to 1.47 ± 0.21 h) after microporation. CONCLUSION: Vacuum compression molding was demonstrated as a novel technique to fabricate uniform, solvent-free, strong polymer microneedles in a short time.

Development and Evaluation of a Topical Foam Formulation for Decontamination of Warfare Agents.

Lewisite is a highly toxic and potent chemical warfare vesicating agent capable of causing pain, inflammation, and blistering. Therapeutic strategies that safely and effectively attenuate this damage are important. Early and thorough decontamination of these agents from skin is required to prevent their percutaneous absorption. In our studies, we used phenylarsine oxide (PAO), a surrogate for arsenicals, to simulate lewisite exposure. Various parameters such as determination of extraction solvents, skin extraction efficiency, donor volume, and donor concentration were optimized for decontamination of PAO. We aimed to develop a novel, easy to apply foam formulation that can decontaminate arsenicals. We screened various foaming agents, vehicles, and chemical enhancers for the development of foam. Lead formulation foam F30 was further characterized for foam density, foam expansion, foam liquid stability, foam volume stability, and foam gas fraction. The amount of PAO delivered into human skin in 30 min of exposure was 228.57 ± 28.44 µg/sq·cm. The amount of PAO remaining in human skin after decontamination with blank foam F30 was 50.09 ± 9.71, demonstrating an overall percentage decontamination efficiency of over 75%. Furthermore, the decontamination efficacy of F30 was also tested in the porcine skin model and results indicated an even higher decontamination efficacy. These studies demonstrated that the developed foam formulation can be used for effective decontamination of chemical warfare agents.

Formulation and Evaluation of the In Vitro Performance of Topical Dermatological Products Containing Diclofenac Sodium.

The selection of an appropriate vehicle in a semi-solid topical product is of utmost importance since the vehicle composition and microstructure can potentially cause changes in drug-vehicle or vehicle-skin interactions and affect drug release and subsequent permeation into and across skin. Hence, the aim of this study was to evaluate different semi-solid formulations containing diclofenac sodium for the physicochemical and structural performance of excipients used and various physiological factors governing permeation of drugs applied to skin. The formulations (emulsion, emulgel, gel, and ointment) were prepared using conventional excipients and were found to be homogenous and stable. Rheological analysis demonstrated characteristic shear-thinning and viscoelastic behavior of formulations. The mean release rate of the gel formulation (380.42 ± 3.05 µg/cm2/h0.5) was statistically higher compared to all other formulations. In vitro permeation using human skin showed a significantly greater extent of drug permeation and retention for the emulgel formulation (23.61 ± 1.03 µg/cm2 and 47.95 ± 2.47 µg/cm2, respectively). The results demonstrated that the different formulations influenced product performance due to their inherent properties. The findings of this study demonstrated that a comprehensive physicochemical and structural evaluation is required to optimize the in vitro performance for dermatological formulations depending on the intended therapeutic effect.

Microneedle and iontophoresis mediated delivery of methotrexate into and across healthy and psoriatic skin.

Psoriasis is a condition of the skin which involves scales, dry patches, and inflammation. Methotrexate (logP: -1.8, MW:454.44 g/mol) is administered orally or intravenously to treat psoriasis. The first-pass metabolism and systemic toxicity can be avoided by administration via skin. Topical and transdermal delivery of methotrexate using iontophoresis and microneedles, alone and in combination was investigated using full-thickness healthy human skin. It is also equally relevant to evaluate the delivery into and across damaged/diseased skin. Hence, this study investigated the delivery of methotrexate using ex vivo healthy and psoriatic human skin to understand the effect of skin disease condition on delivery of methotrexate via skin. A lower resistance and a higher TEWL for psoriatic skin indicated damaged barrier function, while histology studies indicated epithelial hyperproliferation and elongated rete ridges. Using the optimized iontophoretic parameters, there was no significant difference in receptor delivery for psoriatic skin (39.51 ± 4.45 µg/sq.cm) as compared to healthy skin (43.15 ± 0.83 µg/sq.cm). However, methotrexate delivery into psoriatic skin (126.23 ± 24.65 µg/sq.cm) was significantly higher as compared to healthy skin (12.02 ± 4.89 µg/sq.cm). Thus, significantly higher total delivery was observed from psoriatic skin than healthy skin.

Formulation Development for Transdermal Delivery of Raloxifene, a Chemoprophylactic Agent against Breast Cancer.

Raloxifene (RLX) is a second-generation selective estrogen receptor modulator approved for the prevention of invasive breast cancer in women. Oral therapy of RLX requires daily intake and is associated with side effects that may lead to low adherence. We developed a weekly transdermal delivery system (TDS) for the sustained delivery of RLX to enhance the therapeutic effectiveness, increase adherence, and reduce side effects. We evaluated the weekly transdermal administration of RLX using passive permeation, chemical enhancers, physical enhancement techniques, and matrix- and reservoir-type systems, including polymeric gels. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin or human epidermis. Oleic acid was selected as a chemical enhancer based on yielding the highest drug delivery amongst the various enhancers screened and was incorporated in the formulation of TDSs and polymeric gels. Based on in vitro results, both Eudragit- and colloidal silicon dioxide-based transdermal gels of RLX exceeded the target flux of 24 µg/cm2/day for 7 days. An infinite dose of these gels delivered 326.23 ± 107.58 µg/ cm2 and 498.81 ± 14.26 µg/ cm2 of RLX in 7 days, respectively, successfully exceeding the required target flux. These in vitro results confirm the potential of reservoir-based polymeric gels as a TDS for the weekly administration of RLX.

Transdermal Delivery of Baclofen Using Iontophoresis and Microneedles.

Baclofen, a GABAb agonist, is used in the treatment of multiple sclerosis, a neurodegenerative disease. Currently available dosage forms to deliver baclofen are through the oral and the intrathecal routes. The disadvantage of oral baclofen is that it requires administering the drug multiple times a day, owing to baclofen's short half-life. On the other hand, intrathecal baclofen pumps are invasive and cannot be an alternative to oral baclofen. Hence, there is a need to develop a dosage form that can deliver baclofen non-invasively and for an extended period at a steady rate, increasing the dosing interval. A transdermal baclofen delivery system might be the solution to this problem. Hence, this research focuses on evaluating microneedles, iontophoresis, and a combination of microneedles-iontophoresis as transdermal delivery enhancement strategies for baclofen. In vitro permeation studies were conducted on dermatomed porcine ear skin using vertical Franz diffusion cells to evaluate transdermal baclofen delivery. Anodal iontophoresis was applied at a current density of 0.5 mA/cm2, and transdermal delivery was assessed from pH 4.5 (45.51±0.76 µg/cm2) and pH 7.4 (68.84±10.13 µg/cm2) baclofen solutions. Iontophoresis enhanced baclofen delivery but failed to reach target delivery. Maltose microneedles were used to create hydrophilic microchannels on the skin, and this technique enhanced baclofen delivery by 89-fold. Both microneedles (447.88±68.06 µg/cm2) and combination of microneedles - iontophoresis (428.56±84.33 µg/cm2) reached the target delivery range (222-1184 µg/cm2) for baclofen. The findings of this research suggest that skin could be a viable route for delivery of baclofen. Graphical Abstract.

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/cm2) and 10% (232.79 ± 20.82 cm2) cannabidiol solutions. However, 1% delivered (23.02 ± 4.74 µg/cm2) 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/cm2) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98 ± 3.40 µg/cm2) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.

Topical and transdermal delivery with diseased human skin: passive and iontophoretic delivery of hydrocortisone into psoriatic and eczematous skin.

Psoriasis and atopic dermatitis (eczema) are both common immune-mediated inflammatory skin diseases associated with changes in skin's stratum corneum lipid structure and barrier functionality. The present study aimed to investigate healthy, eczematous, and psoriatic excised human tissue for the effect of non-infectious skin diseases on skin characteristics (surface color, pH, transepidermal water loss, electrical resistance, and histology), as well as on permeation and retention profile of hydrocortisone. Further, differences in percutaneous absorption on application of iontophoresis on healthy and diseased skin were also investigated. Measurements of transepidermal water loss and electrical resistance showed a significant difference in psoriasis skin samples indicating a damaged barrier function. In vitro permeation studies on full-thickness human skin using vertical diffusion cells further confirmed these results as the drug amount retained in the psoriatic tissue was significantly higher when compared with the other groups. Despite no significant difference, the presence of the drug in the receptor chamber in both diseased groups can be concerning as it suggests the increased possibility of systemic absorption and adverse reactions associated with it in the use of topical corticosteroids. Application of anodal iontophoresis resulted in greater distribution of hydrocortisone into deeper layers of skin and the receptor chamber, in comparison to passive permeation. However, no significant differences were observed due to the healthy or diseased condition of skin.