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.

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 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.

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.

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.

A novel technique to evaluate nail softening effects of different urea formulations.

Urea has been incorporated into several topical ungual formulations to hydrate and soften the nail plate. In this study, we employed various characterization techniques (visual observation, scanning electron microscopy, measurement of thickness, transonychial water loss, nail electrical resistance, and mechanical study) to investigate the effect of urea concentration on the hydration of bovine hoof membranes - an in vitro model of infected human nails. We obtained inconsistent results in the thickness, transonychial water loss, nail electrical resistance, and scanning electron microscopy studies. In the mechanical study using a modified Texture Analyzer method, we reported an inverse and linear correlation between urea concentrations in the formulations and the force required to puncture the treated membrane (R2 = 0.9582, n ≥ 8). As the urea concentration decreased from 4x to 2x, 1x, and 0x % w/w, the puncture force increased significantly from 0.47 ± 0.07 to 0.77 ± 0.07, 0.91 ± 0.09, and 1.33 ± 0.26 N, respectively (p < 0.05). Thus, urea provided a positive softening effect on the membranes and the puncture force could indicate the urea level in topical formulations. In this study, we provided a novel, efficient, and reliable tool to evaluate the hydration level and physical properties of bovine hoof membranes.

Impact of Different Mixing Methods on the Performance of Suspension-Based Transdermal Delivery Systems.

Suspension-based matrix transdermal delivery systems (TDSs) are specialized systems that maintain a continuous driving force for drug delivery over prolonged wear. The pressure-sensitive adhesive (PSA) is the most critical constituent of such systems. Our study aimed to determine the effect of different mixing methods on the performance of silicone PSA-based suspension TDSs. Lidocaine suspension TDSs were prepared using conventional slow rotary mixing, high-speed homogenization, bead-mill homogenization, vortex shaking, and by an unguator. Resultant TDSs were tested for tack, shear, and peel properties and correlated to coat weight, content uniformity, microstructure, and in vitro permeation across dermatomed human skin. Every mixing method tested caused a significant reduction in peel. However, bead-mill homogenization resulted in significant loss of all adhesive properties tested, while unguator-mixed TDSs retained most properties. Good linear correlation (R2 = 1.000) between the shear properties of the TDSs with the average cumulative amount of lidocaine permeated after 24 h was observed, with no significant difference between percutaneous delivery from slow rotary-mixed systems (1334 ± 59.21 µg/cm2) and unguator-mixed systems (1147 ± 108.3 µg/cm2). However, significantly lower delivery from bead-mill homogenized systems (821.1 ± 28.00 µg/cm2) was noted. While many factors affect TDS performance, careful consideration must also be given to the processing parameters during development as they have been shown to affect the resultant system's therapeutic efficacy. Extensive mixing with bead-mill homogenization demonstrated crystallization of drug, loss in adhesive properties, coat weight, and film thickness, with reduced transdermal delivery of lidocaine from the prepared system.

Topical delivery of nordihydroguaretic acid for attenuating cutaneous damage caused by arsenicals.

This study evaluated the topical delivery of nordihydroguaretic acid (NDGA), a molecule that can potentially alleviate cutaneous damage caused by exposure to arsenic warfare chemicals. N-acetylcysteine (NAC 0.2% w/v) was added as an antioxidant, preventing the oxidation of NDGA to toxic quinones. A 24 h study was performed to arrive at a minimum concentration of NDGA needed to deliver maximum drug. A solution of 3% w/v delivered the maximum amount of drug at the end of 24 h (37.45 ± 4.32 µg). Short duration studies were carried out to determine the time needed to saturate skin with NDGA. There was no significant difference in the skin concentrations for 24 h and 8 h (14.89 ± 2.36 µg), due to skin saturation. However, there was significant difference in the amount of drug delivered to the epidermis (12.29 ± 1.87 µg) and dermis (2.54 ± 0.56 µg) at the end of 8 h. Solution of NDGA was applied on UV treated skin to assess changes in drug delivery. In vivo studies revealed that 3% NDGA was non-toxic for topical administration.

Transdermal Delivery of the Free Base of 3-Fluoroamphetamine: In Vitro Skin Permeation and Irritation Potential.

This work aimed to continue our effort in establishing the feasibility of 3-fluoroamphetamine (also known as PAL-353) to be a transdermal drug candidate by studying the delivery of the base form through the human cadaver skin in lieu of the previously investigated salt form, and for the first time using an EPIDERM™-reconstructed human epidermal model to predict the skin irritation potential of PAL-353, in support of development for a matrix-type transdermal delivery system. Passive and enhanced (with chemical permeation enhancers) transdermal delivery were investigated via in vitro permeation studies that were performed on Franz diffusion cells with dermatomed human cadaver skin. After 24 h, PAL-353 free base revealed high passive permeation of 417.49 ± 30.12, 1577.68 ± 165.41, and 4295.16 ± 264.36 µg/cm2, with applied formulation concentrations of 5.5 (F1), 20 (F2), and 40 (F3) mg/mL, respectively. Oleyl alcohol produced an approximately threefold steady-state flux enhancement at 5% or 10% w/w but may not be needed as the free base alone provided therapeutically relevant permeation. Further, it was predicted that therapeutically relevant delivery would be unlikely to cause skin irritation using the EPIDERM™-reconstructed human epidermal model. In conclusion, the present study further supported the development of PAL-353 transdermal delivery systems.

Fabrication and characterization of hyaluronic acid microneedles to enhance delivery of magnesium ascorbyl phosphate into skin.

This study investigated the in vitro transdermal delivery of magnesium ascorbyl phosphate (MAP) through porcine ear skin treated with hyaluronic acid (HA) microneedles (MNs). In this study, the micro-molding method was used to fabricate HA MNs. HA solution (10% w/v) containing 3% of MAP was placed onto a poly(dimethyl siloxane) mold to fill the microchannels under vacuum followed by drying in a desiccator. Scanning electron microscopy was performed to record the dimensions of the MNs. Skin microporation was demonstrated by dye binding. Histological skin sections revealed the shape of microchannels under hematoxylin-eosin staining. The actual depth of the microchannels and drug distribution pathways were studied by confocal microscopy. In vitro permeation on Franz diffusion cells were performed to determine the rate and extent of drug delivery into and across the skin. SEM captured individual MNs from the array, and the length of each MN was found to be ~400 µm. The 10 × 10 MN array prepared, resulted in the formation of 95 to 100 microchannels after 2 mins of treatment. In addition, the histological evaluations showed the formation of microchannels in the skin, complementary in shape to the MNs. The depths of the formed microchannels amounted to ~125 µm as determined by confocal microscopy. The application of the current MN technology enhanced the delivery of MAP into skin (96.8 ± 3.9 µg/cm2) compared to the passive delivery strategy of MAP (44.9 ± 16.3 µg/cm2). HA MNs markedly enhanced the in vitro transdermal delivery of MAP into and across skin.

Delivery of Methotrexate and Characterization of Skin Treated by Fabricated PLGA Microneedles and Fractional Ablative Laser.

PURPOSE: This study investigated in vitro transdermal delivery of methotrexate through dermatomed porcine ear and cadaver human skin treated with poly (D,L-lactide-co-glycolide) acid microneedles or fractional ablative laser. METHODS: PLGA microneedles were fabricated and characterized using scanning electron microscopy and mechanical assessment techniques. The integrity of treated skin was evaluated by rheometer, transepidermal water loss, and skin electrical resistance measurements. Successful skin microporation was demonstrated by dye binding, histology, pore uniformity, confocal laser microscopy, and DermaScan studies. In vitro permeation experiment was performed on Franz diffusion cells to determine drug delivery into and across the skin. RESULTS: Both physical treatments resulted in a considerable decrease in skin resistance and an increase in transepidermal water loss value. The laser-created microchannels were significantly larger than those formed by microneedles (p < 0.05). An effective force of 41.04 ± 18.33 N was required to achieve 100% penetration efficiency of the microneedles. For both porcine ear and human skin, laser ablation provided a significantly higher methotrexate permeability into the receptor chamber and skin layers compared to microneedle poration and untreated skin (p < 0.05). CONCLUSIONS: Both fractional ablative laser and polymeric microneedles markedly enhanced in vitro transdermal delivery of methotrexate into and across skin. Graphical Abstract ᅟ.

Evaluation of an activated carbon-based deactivation system for the disposal of highly abused opioid medications.

CONTEXT: The improper disposal of unused prescription opioids has a potential for abuse as well as environmental contamination. Consequently, there is an imperative need for an environmentally safe, convenient, and effective drug disposal system. OBJECTIVE: The objective of this study is to analyze the deactivation efficiency of the disposal system employing four model opioid drugs of high abuse potential. METHODS: The deactivation system used in this investigation is an activated granular carbon based disposal system in the form of a pouch, which can be used to safely and effectively deactivate unused or expired medications. HPLC method validation for each drug was performed prior to analyzing drug content in the deactivation study. Opioid drugs in different dosage forms were added to individual pouches in the presence of warm water. Pouches were shaken and sealed, then stored at room temperature. The deactivation efficiency of the system was tested by collecting samples at different time points up to 28 d. RESULTS: An average of 98.72% of medications were adsorbed by activated carbon within 8 h and continued to do so over time. At the end of the 28-d study, more than 99.99% of all drugs were deactivated. In the desorption study, almost no drug leached out from the activated carbon in larger volume of water and less than 1.3% leached out on extraction with ethanol. CONCLUSION: This unique drug disposal system successfully adsorbed and deactivated the model opioid medications by the end of 28 d, offering a safe and convenient route of disposal of unused or residual opioid drugs.

Enhancement in the Transdermal and Localized Delivery of Honokiol Through Breast Tissue.

Honokiol is a natural phenolic anti-cancer compound isolated from an extract of seed cones from Magnolia grandiflora. This study investigated the transdermal delivery of honokiol using various enhancement methods and to explore the potential of honokiol to treat breast cancer directly via delivery through mammary papilla. Poration of dermatomed human skin with microneedles significantly increased the delivery of honokiol by nearly 3-fold (97.81 ± 18.96 µg/cm2) compared with passive delivery (32.56 ± 5.67 µg/cm2). Oleic acid was found to be the best chemical penetration enhancer, increasing the delivery almost 27-fold (868.06 ± 100.91 µg/cm2). Addition of oleic acid also resulted in better retention of drug in the porcine mammary papilla (965.41 ± 80.26 µg/cm2) compared with breast skin (294.16 ± 8.49 µg/cm2). Anti-cancer effect of honokiol was demonstrated with the decrease in the release of cytokine IL-6 and further suppression of Ki-67 proliferative protein. In addition, the topical honokiol formulation investigated was found to be safe and non-irritant. In summary, both microneedles and chemical enhancers can improve the absorption of honokiol through skin. Directly applying honokiol on mammary papilla is a potential administration route which can increase localized delivery into breast tissue.

Development of Disposal Systems for Deactivation of Unused/Residual/Expired Medications.

PURPOSE: The objective of this work was to identify deactivation agents and develop a disposal system for unused/ residual/ expired medications. METHODS: Deactivation agents screened included oxidizing agent-sodium percarbonate, hydrolysis agent- sodium carbonate and adsorbants- zeolite and activated carbon. Deactivation studies using these agents were performed on four active pharmaceutical agents (APIs) including ketoprofen, dexamethasone sodium phosphate, metformin hydrochloride and amoxicillin trihydrate. Disposal systems were also designed for deactivation studies on dexamethasone pills, amoxicillin trihydrate capsules and fentanyl transdermal patches (Duragesic®). Briefly, APIs/ dosage forms were allowed to be in close contact with deactivation agents for a specified period of time and percentage decrease in the amount of API from the initial amount was measured. RESULTS: Sodium percarbonate and sodium carbonate were only successful in deactivation of amoxicillin trihydrate API. Adsorption agents resulted in more universal deactivation with activated carbon resulting in efficient deactivation of most APIs and all dosage forms tested. Also adsorption of oral dosage medications on activated carbons was maintained even on dilution and shaking and no desorption was observed. CONCLUSIONS: Deactivation systems containing activated carbon are promising for efficient, safe and environment friendly disposal of unused/residual/expired medications.

Intradermal and follicular delivery of adapalene liposomes.

BACKGROUND: Adapalene is a widely used topical anti-acne drug; however, it has many side effects. Liposomal drug delivery can play a major role by targeting delivery to pilosebaceous units, reducing side effects and offering better patient compliance. OBJECTIVE: To prepare and evaluate adapalene-encapsulated liposomes for their physiochemical and skin permeation properties. METHODS: A liposomal formulation of adapalene was prepared by the film hydration method and characterized for shape, size, polydispersity index (PDI), encapsulation efficiency and thermal behavior by techniques such as Zetasizer®, differential scanning calorimetry and transmission electron microscopy. Stability of the liposomes was evaluated for three months at different storage conditions. In vitro skin permeation studies and confocal laser microscopy were performed to evaluate adapalene permeation in pig ear skin and hair follicles. RESULTS: The optimized process and formulation parameters resulted in homogeneous population of liposomes with a diameter of 86.66 ± 3.5 nm in diameter and encapsulation efficiency of 97.01 ± 1.84% w/w. In vitro permeation studies indicated liposomal formulation delivered more drug (6.72 ± 0.83 µg/cm(2)) in hair follicles than gel (3.33 ± 0.26 µg/cm(2)) and drug solution (1.62 ± 0.054 µg/cm(2)). Drug concentration delivered to the skin layers was also enhanced compared to other two formulations. Confocal microscopy images confirmed drug penetration in the hair follicles when delivered using the liposomal formulation. CONCLUSION: Adapalene was efficiently encapsulated in liposomes and led to enhanced delivery in hair follicles, the desired target site for acne.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm(2)), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm(2) of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm(2) CDB and 58.12 µg/cm(2) APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm2), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm2 CDB and 58.12 µg/cm2 APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

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-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.

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.