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.

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.

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.

Characterization and Systemic Delivery of Dibenzoylmethane via the Intranasal Route.

Intranasal (IN) administration is known to be noninvasive with the potential to carry a drug or vaccine directly to the blood, bypassing first-pass metabolism in the liver and the harsh environment of the gastrointestinal system. Orally administered dibenzoylmethane (DBM) has been shown experimentally to be neuroprotective in animal models of tauopathy and prion disease and effective in the treatment of certain forms of cancers. The purpose of this study was to prepare, characterize, and test formulations of DBM designed for IN administration. DBM was formulated in brain homogenate (BH) and hypromellose and as nanoparticles (NPs). These formulations were detected using UPLC and characterized in solid and suspension states; NPs were also characterized by in vitro cell culture-based studies. Particle size for DBM NP was 163.8 ± 3.2 nm, and in vitro release studies showed 95.80% of DBM was released from the NPs within 8 days. In vitro cell, culture studies suggested no drug uptake until 6 h. A histological analysis of nasal cavity (NC) sections and blood detection studies were carried out 30 min after inhalation. DBM amounting to 40.77 ± 4.93 and 44.45 ± 5.36 ng/mL was detected in the blood of animals administered DBM in polymeric and NP formulation, respectively. Histological studies on NCs confirmed the presence of BH within lymphatic vessels in the lamina propria of each animal; BH was identified traversing the mucosa in 2 animals. Thus, formulations for DBM administered via IN route were successfully designed and characterized and able to cross the nasal mucosa following inhalation.

Development and evaluation of a heparin gel for transdermal delivery via laser-generated micropores.

Aim: Our study investigated the feasibility of transdermal delivery of heparin, an anticoagulant used against venous thromboembolism, as an alternative to intravenous administration. Materials & methods: Skin was pretreated using ablative laser (Precise Laser Epidermal System [P.L.E.A.S.E.®] technology) for enhanced delivery of heparin. In vitro permeation studies using static Franz diffusion cells provided a comparison between delivery from 0.3% w/v heparin-loaded poloxamer gel and solution across untreated and laser-treated dermatomed porcine ear skin. Results: No passive delivery of heparin was observed. Laser-assisted delivery from solution (26.07 ± 1.82 µg/cm2) was higher (p < 0.05) than delivery from heparin gel (11.28 ± 5.32 µg/cm2). However, gel is likely to sustain the delivery over prolonged periods like a maintenance dose via continuous intravenous infusion. Conclusion: Thus, ablative laser pretreatment successfully delivered heparin, establishing the feasibility of delivering hydrophilic macromolecules using the transdermal route.

Preparation, Characterization and Antioxidant Evaluation of Poorly Soluble Polyphenol-Loaded Nanoparticles for Cataract Treatment.

Cataract, one of the leading causes of blindness worldwide, is a condition in which complete or partial opacity develops in the lens of the eyes, thereby impairing vision. This study aimed to examine the potential therapeutic and protective effects of poorly soluble polyphenols like curcumin, resveratrol, and dibenzoylmethane, known to possess significant antioxidant activity. The polyphenols were loaded into novel lipid-cyclodextrin-based nanoparticles and characterized by particle size, polydispersity index, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, scanning electron microscopy (SEM), entrapment efficiency, and release studies. Ferric-reducing ability of plasma and 2,2-diphenyl-1-picrylhydrazyl chemical assays were used to evaluate their antioxidant properties based on their free radical quenching ability. Biochemical in vitro assays were used to examine these polyphenols on hydrogen peroxide-induced formation of cataracts in bovine lenses by estimating total glutathione content and superoxide dismutase activity. Nanoparticles were thermostable and amorphous. Particle size of curcumin, resveratrol, and dibenzoylmethane nanoparticles were 331.0 ± 17.9 nm, 329.9 ± 1.9 nm, and 163.8 ± 3.2 nm, respectively. SEM confirmed porous morphology and XRD confirmed physical stability. Entrapment efficiency for curcumin-, resveratrol-, and dibenzoylmethane-loaded nanoparticles was calculated to be 84.4 ± 2.4%, 72.2 ± 1.5%, and 86.4 ± 0.6%, respectively. In vitro release studies showed an initial burst release followed by a continuous release of polyphenols from nanoparticles. Chemical assays confirmed the polyphenols' antioxidant activity. Superoxide dismutase and glutathione levels were found to be significantly increased (p < 0.05) after treatment with polyphenol-loaded nanoparticles than pure polyphenols; thus, an improved antioxidant activity translational into potential anticataract activity of the polyphenols when loaded into nanoparticles was observed as compared to pure polyphenols.