Franz Diffusion Cells Research Articles

Towards the discovery of unrevealed flufenamic acid cocrystals via structural resemblance for enhanced topical drug delivery.

Cocrystallization has emerged as a promising formulation strategy for modulating transdermal drug absorption by enhancing solubility and permeability. However, challenges related to cocrystal dissociation in the semi-solid state need to be addressed to mitigate regulatory concerns before the widespread implementation of topical cocrystal products in clinical practice. This study aimed to develop oil-based topical formulations incorporating cocrystals with distinct thermodynamic stabilities, followed by investigating the roles of different structurally similar coformers and oily vehicles on their physicochemical properties. Three pharmaceutical cocrystals of poorly water-soluble flufenamic acid (FFA) were synthesized with isomeric pyridine carboxamides in a 1:1 stoichiometry via rapid solvent removal. These included the reported flufenamic acid-nicotinamide cocrystal (FFA-NIC), the long-elusive flufenamic acid-isonicotinamide cocrystal (FFA-IST) and flufenamic acid-picolinamide cocrystal (FFA-PIC). The resulting cocrystals, which exhibited different hydrogen bonding patterns, were characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and structural analysis through single crystal X-ray diffraction. The cocrystals were further formulated in a series of oleaginous and absorption bases, including liquid paraffin, Vaseline, lanolin, and theobroma oil, for topical delivery. The cocrystal dissociation, content uniformity, and in vitro membrane diffusion were assessed. Notably, although all FFA cocrystals exhibited thermodynamic instability in aqueous solution, a significantly reduced propensity for cocrystal dissociation was observed in the ointment bases. Integrated computational analyses of packing efficiency and interaction energy revealed that the thermodynamic stability of cocrystals followed a descending order of FFA-NIC > FFA-PIC > FFA-IST. Compared with raw FFA, FFA-IST and FFA-PIC, which had larger positive ΔVnon-H and ΔEcocryst, achieved superior cumulative diffusion of FFA from Vaseline, with a 4.3-fold (p = 0.0003) and 3.3-fold (p = 0.0029) increase at 6 h in a Franz diffusion cell model, respectively. The diffusion of all FFA cocrystals mainly followed the Higuchi kinetic model and was positively correlated with the intrinsic dissolution rate.

TRANSETHOSOMES FOR ENHANCED TRANSDERMAL DELIVERY OF METHOTREXATE AGAINST RHEUMATOID ARTHRITIS: FORMULATION, OPTIMISATION AND CHARACTERISATION

Objective: The study aimed to develop and optimise Methotrexate (MTX)-loaded Transethosomal Film-Forming Gel (TE FFG) for transdermal delivery to treat rheumatoid arthritis while alleviating the side associated with oral administration. Methods: The Transethosomes (TE) were prepared using the thin film hydration technique and incorporated into an FFG using chitosan. The Box-Behnken Design method was used to analyse the influence of independent variables such as the concentration of soya lecithin, surfactant, and ethanol on parameters including vesicle size, PDI (Polydispersity Index), zeta potential, and entrapment efficiency. The optimised transethosomal suspension was incorporated into the FFG using 3% chitosan and other excipients. In vitro drug release and ex vivo skin permeation of FFG were performed using Franz diffusion cells. Results: The vesicle size, PDI, zeta potential and entrapment efficiency of the optimised formulation of TE were 110.3 nm, 0.352,-14.4 mV and 49.36%, respectively. The Transmission Electron Microscopy (TEM) image showed that the vesicles were uniform and spherical. The in vitro drug release study was higher for Conventional (CL) FFG) than TE FFG and the drug release mechanism was fitted into the Higuchi model. The permeation was higher for TE FFG, with the steady-state flux being 1.55 times greater than the CL FFG. The skin irritation test on Wistar rats revealed no indication of irritation on the skin. The histopathology examination showed a significant reduction in the inflammatory cells in the treated group. Conclusion: Therefore, the results concluded that the formulated MTX-loaded TE FFG could be a potentially promising substitute for the oral delivery of methotrexate

Novel Synthesized Seleno-glycoconjugates as Cosmeceutical Ingredients: Antioxidant Activity and In Vitro Skin Permeation

Following recent successful results in the search for innovative semi-synthetic cosmeceutical Se-glycoconjugates, the work reported herein explores the development and evaluation of second-generation selenosugar-linked hydroxycinnamic acids as new potential cosmeceutical ingredients. Utilizing a Pummerer-like rearrangement for C1-acetylation, these novel compounds were synthesized and characterized using NMR spectroscopy and HRMS, confirming their structures and purity. The biological evaluation focused on their radical scavenging preliminary screening, and cytotoxic and antioxidant activities in human immortalized keratinocytes, revealing significant potential for use in skin care formulations aimed at counteracting oxidative stress and promoting skin health. Cellular uptake studies conducted on HaCaT keratinocytes using UHPLC-QqTOF-MS metabolomics demonstrated effective internalization of these compounds, which is crucial for their efficacy as topical agents. Furthermore, percutaneous absorption tests using the Franz diffusion cell method and subsequent HPLC-DAD analysis provided insights into the compound skin permeation capabilities, a critical factor for their practical application in cosmeceuticals.

Chitosan Nanoparticles Embedded in In Situ Gel for Nasal Delivery of Imipramine Hydrochloride: Short-Term Stage Development and Controlled Release Evaluation.

Imipramine hydrochloride (IMP), a tricyclic antidepressant used for major depression, enuresis, and neuropathic pain, is limited by gastrointestinal complications, low oral bioavailability (44%), and complex dosing requirements. This study aimed to explore a novel non-invasive nasal delivery system using chitosan nanoparticles (Cs NPs) embedded in an in situ gel to address the limitations of oral IMP administration. Cs NPs loaded with IMP were synthesized via ionic gelation and assessed for precision in drug concentration using a validated HPLC method. The particles were integrated into a thermoresponsive polymer, Pluronic F127, to form an in situ gel suitable for nasal administration. The formulation was characterized for gelation temperature, duration, viscosity, mucoadhesive strength, and overall gel robustness. Drug release kinetics and the controlled release mechanism were studied using ex vivo permeation tests with Franz diffusion cells and nasal sheep mucosa. The optimized nanoparticle formulation (F4-50) exhibited a consistent PS of 141.7 ± 2.2 nm, a zeta potential (ZP) of 16.79 ± 2.1 mV, and a high encapsulation efficiency of 67.71 ± 1.9%. The selected in situ gel formulation, F4-50-P1, demonstrated a gelation temperature of 33.6 ± 0.94 °C and a rapid gelation time of 48.1 ± 0.7 s. Transform-attenuated total reflectance infrared spectroscopy (ATR-IR) confirmed the compatibility and effective encapsulation of IMP within the formulation. The release profile of F4-50 included an initial burst release followed by a sustained release phase, with F4-50-P1 showing improved control over the burst release. The flux rates were 0.50 ± 0.01 mg/cm2/h for F4-50 and 0.33 ± 0.06 mg/cm2/h for F4-50-P1, indicating effective permeation. The developed chitosan nanoparticle-based in situ gel formulation provides a promising approach for the controlled release of IMP, enhancing therapeutic efficacy and patient compliance while mitigating the disadvantages associated with oral delivery.

Betulin-NLC-hydrogel for the Treatment of Psoriasis-like Skin Inflammation: Optimization, Characterisation, and In vitro and In vivo Evaluation.

Psoriasis is a chronic inflammatory skin disorder that poses significant challenges regarding effective and targeted drug delivery. Bioactive substances like betulin have shown tremendous utility in treating these conditions; however, they pose limited utility owing to their physicochemical characteristics. Here, we aimed to develop a novel topical dosage form for treating psoriasis, utilising betulin-loaded solid lipid nanoparticles (NLCs) incorporated into a hydrogel matrix. The optimization of the formulation was meticulously conducted using a design of experiments methodology, and its diverse physicochemical attributes were thoroughly examined. Evaluating betulin's in vitro release pattern from the NLC-hydrogel demonstrated consistent and regulated drug release properties. Additionally, the formulation demonstrated improved skin penetration abilities as determined by in vitro skin permeation experiments employing Franz diffusion cells- furthermore, the therapeutic effectiveness of the betulin-NLC-hydrogel was assessed by an in vivo experiment carried out using an imiquimod-induced psoriasis-like skin inflammation model in BALB/c female mice. The NLCs exhibited a pH of 5.67±0.86, particle size of 148.16±12.66 nm, and zeta potential of -22.84±2.37 mV, ensuring stability and suitability for topical use. The gel, with a pH of 6.05±0.43 and viscosity of 17550±120 cPs, showed enhanced skin hydration and lipid restoration. Drug release studies indicated a slower release from NLCs and gel, improving skin retention. Stability tests revealed that the formulations were stable at room temperature but not at elevated temperatures. The in vitro safety profile of the formulation revealed no significant adverse effects on HaCaT cell lines. The NLC gel demonstrated significant anti-psoriatic activity, reducing inflammation and cytokine levels. The betulin-NLC-hydrogel formulation exhibited promising characteristics for the topical treatment of psoriasis, showcasing optimised drug delivery, sustained release, and notable therapeutic efficacy. The findings from this study provide a foundation for the potential clinical translation of this innovative topical dosage form for improved psoriasis management.

Retinol semisolid preparations in cosmetics: transcutaneous permeation mechanism and behaviour

Retinol is widely used to treat skin ageing because of its effect on cell differentiation, proliferation and apoptosis. However, its potential benefits appear to be limited by its skin permeability. Herein, we investigated the transcutaneous behavior of retinol in semisolid cosmetics, in both in vitro and in vivo experiments. In vitro experiments used the modified Franz diffusion cell combined with Raman spectroscopy. In in vivo experiments, the content of retinol in rat skin and plasma was detected with HPLC. Retinol in semisolid cosmetics was mainly concentrated in the stratum corneum in the skin of the three animal models tested, and in any case did not cross the skin barrier after a 24 h dermatologic topical treatment in Franz diffusion cells tests. Similar results were obtained in live mice and rats, where retinol did not cross the skin barrier and did not enter the blood circulation. Raman spectroscopy was used to test the penetration depth of retinol in skin, which reached 16 μm out of 34 μm in pig skin, whereas the skin of mouse and rat showed too strong bakground interference. To explore epidermal transport mechanism and intradermal residence, skin transcriptomics was performed in rats, which identified 126 genes upregulated related to retinol transport and metabolism, relevant to the search terms “retinoid metabolic process” and “transporter activity”. The identity of these upregulated genes suggests that the mechanism of retinol action is linked to epidermis, skin, tissue and epithelium development.

Niosome as a drug delivery carrier for Sorafenib: Preparation, investigation of physicochemical properties, and in vitro effects on HepG2 cell line

Purpose: Sorafenib is known as one of the oral anti-cancer drugs used in liver cancer. However, its lipophilic nature can lead to side effects, variable pharmacokinetics, and poor absorption. The use of novel drug delivery systems, such as niosomes, may help address these issues and improve the effectiveness of sorafenib. Methods: Different niosomal formulations of sorafenib were prepared. The morphology, size analysis, and physical stability were investigated. The encapsulation efficiency percent of the selected formulations was measured using the dialysis method, and the release of sorafenib was checked for four hours using the Franz diffusion cell. The cytotoxicity and in vitro effect on the HepG2 cell line was investigated using the MTT assay and flow cytometry. Results: The mean volume diameter of Span 60/ Tween 60/ cholesterol (45/45/10 mole%) niosomal formulation was 6 µm with minimal size changes and good stability over six months of storage. The encapsulation efficiency percent of this formulation was 66.40±1.11, and 61.43±1.42 percent of the drug was released within four h. In vitro release followed Higuchi kinetics. Cytotoxicity tests showed an IC50 of 7.5 µg/mL for the niosomal formulation, compared to 15.96 µg/mL for the sorafenib solution. Conclusion: Niosomes containing Span 60/ Tween 60/ cholesterol (45/45/10 mole%) are promising for loading and sustained release of sorafenib. The use of niosome as a carrier can enhance the effectiveness of sorafenib on the HepG2 cell line. This niosomal formulation of sorafenib shows potential for future studies.

Percutaneous Absorption of Two Bisphenol A Analogues, BPAF and TGSA: Novel In Vitro Data from Human Skin

Bisphenol AF (BPAF) and TGSA are analogues of Bisphenol A (BPA). BPAF is used in polymer synthesis, while TGSA is applied in thermal papers. The EU classifies BPAF as toxic to reproduction and TGSA as a skin sensitizer. However, TGSA's other health effects remain unclear. BPAF contamination has been noted among electronic waste workers, and TGSA exposure is documented in various professions. Despite the significance of skin contact, data on skin permeation rates for BPAF and TGSA are limited. This study aimed to generate percutaneous absorption data for BPAF and TGSA following OECD guidelines.[14C]-labelled BPAF or TGSA was applied to human skin samples in vitro using Franz diffusion cells for 20 and 40 h, respectively. Key parameters such as steady-state flux, lag time, and skin permeability coefficient (Kp) were calculated. Furthermore, the distribution of the dose across different compartments, particularly within the skin, was evaluated at the conclusion of the experiment. Sequential strippings and epidermis-dermis separation were conducted for BPAF to predict the potential absorption of the remaining dose present within the skin.The permeability coefficients for BPAF and TGSA were found to be 1.9 E-03 and 1.6 E-03 cm/h, with 22% and 23% of the applied doses absorbed, respectively. Both chemicals are classified as "fast" penetrants based on their Kp values. These findings suggest that BPAF and TGSA are absorbed through the skin, highlighting potential occupational risks through dermal exposure. The new percutaneous absorption data will enhance the assessment of the occupational risks.

Ultrasound-compatible 3D-printed Franz diffusion system for sonophoresis with microbubbles

Sonophoresis is a topical drug delivery approach that utilises ultrasound as a physical stimulus to enhance permeation of active pharmaceutical ingredients through the skin. Only limited research has however been conducted to evaluate the potential of ultrasound-responsive drug carriers, such as gas microbubbles, in sonophoresis. Franz diffusion cells have been extensively used for measuring drug permeation in vitro; however, traditional systems lack compatibility with ultrasound and only limited characterisation of their acoustical behaviour has been carried out in previous research. To overcome this limitation, we designed and manufactured a novel Franz cell donor compartment coupled with a conventional glass receptor, and performed a functional characterisation of the assembly for application in sonophoresis with ultrasound-responsive agents (specifically imiquimod-loaded gas microbubbles). The donor was fabricated using a photoreactive resin via 3D printing and was designed to enable integration with a therapeutically relevant ultrasound source. The assembly was capable of effectively retaining liquids during prolonged incubation and the absorption of imiquimod onto the 3D-printed material was comparable to the one of glass. Moreover, a predictable ultrasound field could be generated at a target surface without any significant spatial distortion. Finally, we demonstrated applicability of the developed assembly in sonophoresis experiments with StratM®, wherein ultrasound stimulation in the presence of microbubbles resulted in significantly enhanced drug permeation through and partitioning within the membrane (2.96 ± 0.25 μg and 3.84 ± 0.39 μg) compared to passive diffusion alone (1.74 ± 0.29 μg and 2.29 ± 0.32 μg), over 24 h.

Development and Characterization of Oxiconazole Loaded Plga Nanogel.

The goal of the current study is to develop and improve polylactic co-glycolic acid (PLGA) loaded with oxiconazole nanogel for topical application. Oxiconazole Nanoprecipitation was used to create the nanoparticles method using PLGA and acetone. The point prediction method served as the foundation for the ideal oxiconazole nanoparticle composition using the Minitab®21 software, three levels two factors (32 ). The optimized composition of oxiconazole nanoparticle showed a particle size of 185 ± 0.5nm with an entrapment efficiency of 95.2 ± 0.09%. Using chitosan, a naturally occurring polymer, the ideal oxiconazole nanoparticle composition was further transformed into a gel formulation. The developed topical nano gel formulation underwent additional evaluations for antifungal, drug release, permeability, and nano gel characterization. The developed oxiconazole nanogel formulation had the ideal drug content, pH, viscosity, and spreadability. The results of the medication release and penetration investigation showed that Oxiconazole released slowly (74.06 ± 0.5%) with significantly enhanced permeation across Franz diffusion cell using membrane. The antifungal ex-vivo study and skin irritancy study of nanogel results would conclude higher activity of oxiconazole nano gel. According to the overall analysis of the data, oxiconazole nanogel is the best delivery method for treating fungal infections on the skin.

In vivo reduction of skin inflammation using ferulic acid-loaded lipid vesicles derived from Brewer’s spent grain

Breweŕs spent grain (BSG) is the main by-product of the brewing industry, and due to its rapid decomposition, it generates serious environmental problems such as malodors and greenhouse gases emissions. On the other hand, this lignocellulosic compound contains a large number of antioxidants, being ferulic acid (FA) the most abundant. FA is a powerful antioxidant molecule that has demonstrated significant protective effects on key components of the skin, including keratinocytes, fibroblasts, collagen, and elastin. FA inhibits melanogenesis, promotes angiogenesis and accelerates the wound healing although its use is limited by its rapid oxidation. In this study, different hydrolysis treatments (chemical, enzymatic and hydrothermal) were performed on BSG to obtain FA. Herein FA-loaded ultradeformable liposomes (ULs) were designed to improve their stability and in vivo performance. These nanosystems allow FA permeability through human skin, as proven by an ex vivo skin permeability assay using Franz diffusion cells. The toxicity and anti-inflammatory activity of the formulation has been investigated. The free form and 100 nm FA_ULs were evaluated. Cell viability was dose-dependent and provided optimal results for the treatment of inflammatory skin conditions in an in vivo Oxazolone-induced Delayed Type Hypersensitivity model using Swiss CD1 mice, demonstrated by the reduction of the inflammatory cytokines expression, ear thickness, bioluminescence and histological evaluation. These results pave the way for FA-based treatments of skin and inflammatory conditions.

Characterization of naproxen salts with amino acid esters and their application in topical skin preparations

In the study, the modification of naproxen (NAP) with esters of four amino acids (AAs): glycine (GlyOiPr), L-proline (ProOiPr), L-leucine (LeuOiPr), and L-serine (SerOiPr) isopropyl ester was performed to improve water solubility and enhance the permeation of the drug through the skin in comparison to the parent NAP. The NAP derivatives were prepared using the equimolar ratio of the components. In-depth NMR and FTIR analysis revealed that the salts formed with the proton transfer from the carboxylic group of NAP to the amine group of the appropriate AA ester. The NAP salts exhibited improved solubility in water and PBS solution (pH 7.4) when compared to parent NAP. The values of the partition coefficient (log PO/W) for prepared salts were lower than for NAP, however, the salts maintained hydrophobic character determined by the positive values of log P. The In vitro permeation through the pig skin performed in Franz diffusion cells showed that all NAP salts exhibited a higher cumulative mass of permeated NAP (Q24h) than the parent acid. The highest permeation value was noted for [ProOiPr][NAP], with a pseudo-steady state flux (Jss) 32.5 µg NAP cm−2h−1, and Q24h = 246.4 µg NAP cm−2, it was 2.5 % of the applied dose. Moreover, topical preparations with [ProOiPr][NAP] and NAP were prepared based on two vehicles − Celugel® and Pentravan®- approved in pharmacy recipes. The permeation experiments through the Strat-M® showed, that both the Jss and Q24h of permeated drug from preparations containing [ProOiPr][NAP], were statistically several times greater than from the respective preparations with the unmodified acid. Additionally, preparations with [ProOiPr][NAP] provided significantly improved permeation of NAP than two commercial preparations, one of which contained naproxen as the acid and the other – as the sodium salt.

Assessment of Enzymatically Derived Blackcurrant Extract as Cosmetic Ingredient-Antioxidant Properties Determination and In Vitro Diffusion Study.

Blackcurrant is an anthocyanin-rich berry with proven antioxidant and photoprotective activity and emerging prebiotic potential, widely applied in cosmetic products. Hereby, highly efficient enzyme-assisted extraction of blackcurrant polyphenols was performed, giving extract with very high antioxidant activity. Obtained extract was characterized in terms of anthocyanin composition, incorporated into three different cosmetic formulations and subjected to Franz cell diffusion study. Experimental values obtained using cellulose acetate membrane for all four dominant anthocyanins (delphinidin 3-glucoside, delphinidin 3-rutinoside, cyanidin 3-glucoside and cyanidin 3-rutinoside) were successfully fitted with the Korsmeyer-Peppas diffusion model. Calculated effective diffusion coefficients were higher for hydrogel compared to oil-in-water cream gel and oil-in-water emulsion, whereas the highest value was determined for cyanidin 3-rutinoside. On the other hand, after a 72 h long experiment with transdermal skin diffusion model (Strat-M® membrane), no anthocyanins were detected in the receptor fluid, and only 0.5% of the initial quantity from the donor compartment was extracted from the membrane itself after experiment with hydrogel. Present study revealed that hydrogel is a suitable carrier system for the topical delivery of blackcurrant anthocyanins, while dermal and transdermal delivery of these molecules is very limited, which implies its applicability for treatments targeting skin surface (i.e., prebiotic, photoprotective).

Microneedle System Coated with Hydrogels Containing Protoporphyrin IX for Potential Application in Pharmaceutical Technology.

The article aims to outline the potential of treating malignant skin cancer with microneedles covered with polymer layers containing a photosensitizer-protoporphyrin IX disodium salt (PPIX). The usefulness of stereolithography (SLA), which is a form of 3D-printing technology, for the preparation of a microneedle system with protoporphyrin IX was demonstrated. The SLA method allowed for pyramid-shaped microneedles to be printed that were covered with three different 0.1% PPIX hydrogels based on sodium alginate, xanthan, and poloxamer. Rheological tests and microscopic analysis of the hydrogels were performed. Microneedles coated with two layers of poloxamer-based hydrogel containing 0.1% PPIX were subjected to release tests in Franz diffusion cells. The release profile of PPIX initially increased and then remained relatively constant. The amount of substance released after a four-hour test in three Franz cells was 0.2569 ± 0.0683 mg/cm2. Moreover, the acute toxicity of this type of microneedle was assessed using the Microtox system. The obtained results show the usefulness of further development studies on microneedles as carriers of photosensitizing agents.

In vitro assessment of skin permeation properties of enzymatically derived oil-based fatty acid esters of vitamin C.

Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat-M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium-chain coconut oil-derived FAAEs exhibited faster diffusion rates compared to sunflower oil-based FAAEs with long-side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a lag phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long-chain esters, the lag phase was prolonged, and the calculated effective diffusion coefficients (Deff) were lower compared to medium-chain FAAEs. Accordingly, the highest Deff value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil-derived FAAEs for efficiently delivering vitamin C into the skin.

Novel therapeutic deep eutectic system for the enhancement of ketoconazole antifungal activity and transdermal permeability

In this study, we reported the investigation of a novel therapeutic deep eutectic system (THEDES) formed between capric acid (CA) and ketoconazole (KCZ) to enhance the permeability and efficacy of the antifungal drug KCZ. A THEDES was formulated by combining KCZ and CA at different molar ratios, with a 1:5 ratio (K5) representing the most stable and lowest melting point. Characterization of the interactions between CA and KCZ using NMR and FT-IR spectroscopy revealed a hydrogen bonding interaction between the amine group of KCZ’s imidazole ring and the carboxylic acid moiety of CA. This interaction resulted in converting the solid materials into liquid at room temperature, leading to a significant decrease in the melting points of the components, as confirmed by DSC. Next, the effectiveness of K5 as an antifungal agent against Candida albicans was evaluated. The results indicated a 2-fold reduction in the minimum inhibitory concentration (MIC). In addition, permeability studies conducted using a Franz diffusion cell revealed a significant enhancement in permeability with a 6.19-fold increase in flux compared to commercially available KCZ cream. The findings suggest that fatty acid-based deep eutectic systems, such as the KCZ THEDES, can serve as effective and green drug delivery systems, offering significant enhancements in drug permeability and therapeutic performance. This approach improves the efficacy of drugs and promotes the development of eco-friendly pharmaceutical formulations.

Fabrication of Poly Lactic-co-Glycolic Acid Microneedles for Sustained Delivery of Lipophilic Peptide-Carfilzomib.

Transdermal drug delivery (TDD) is an attractive route of administration, providing several advantages, especially over oral and parenteral routes. However, TDD is significantly restricted due to the barrier imposed by the uppermost layer of the skin, the stratum corneum (SC). Microneedles is a physical enhancement technique that efficiently pierces the SC and facilitates the delivery of both lipophilic and hydrophilic molecules. Dissolving microneedles is a commonly used type that is fabricated utilizing various biodegradable and biocompatible polymers, such as polylactic acid, polyglycolic acid, or poly(lactide-co-glycolide) (PLGA). Such polymers also promote the prolonged release of the drug due to the slow degradation of the polymer matrix following its insertion. We selected carfilzomib, a small therapeutic peptide (MW: 719.924 g/mol, log P 4.19), as a model drug to fabricate a microneedle-based sustained delivery system. This study is a proof-of-concept investigation in which we fabricated PLGA microneedles using four types of PLGA (50-2A, 50-5A, 75-5A, and 50-7P) to evaluate the feasibility of long-acting transdermal delivery of carfilzomib. Micromolding technique was used to fabricate the PLGA microneedles and characterization tests, including Fourier transform infrared spectroscopy, insertion capability using the skin simulant Parafilm model, histological evaluation, scanning electron microscopy, and confocal microscopy were conducted. In vitro release and permeation testing were conducted in vertical Franz diffusion cells. N-methyl pyrrolidone was utilized as the organic solvent and microneedles were solidified in controlled conditions, which led to good mechanical strength. Both in vitro release and permeation testing showed sustained profiles of carfilzomib over 7 days. The release and permeation were significantly influenced by the molecular weight of PLGA and the lipophilic properties of carfilzomib.

Enhancement of therapeutic efficacy of Brinzolamide for Glaucoma by nanocrystallization and tyloxapol addition

BackgroundBrinzolamide (BRI) suspensions are used for the treatment of glaucoma; however, sufficient drug delivery to the target tissue after eye drop administration is hampered by poor solubility. To address this issue, we focused on nanocrystal technology, which is expected to improve the bioavailability of poor-solubility drugs, and investigated the effect of BRI nanocrystal formulations on corneal permeability and intraocular pressure (IOP)-reducing effect.MethodsBRI nanocrystal formulations were prepared by the wet-milling method with beads and additives. The particle size was measured by NANOSIGHT LM10, and the morphology was determined using a scanning probe microscope (SPM-9700) and a scanning electron microscope (SEM). Corneal permeability was evaluated in vitro using a Franz diffusion cell with rat corneas and in vivo using rabbits, and the IOP-reducing effect was investigated using a rabbit hypertensive model.ResultsThe particle size range for prepared BRI nanocrystal formulation was from 50 to 300 nm and the mean particle size was 135 ± 4 nm. The morphology was crystalline, and the nanoparticles were uniformly dispersed. In the corneal permeability study, BRI nanocrystallization exhibited higher corneal permeability than non-milled formulations. This result may be attributed to the increased solubility of BRI by nanocrystallization and the induction of energy-dependent endocytosis by the attachment of BRI nanoparticles to the cell membrane. Furthermore, the addition of tyloxapol to BRI nanocrystal formulation further improved the intraocular penetration of BRI and showed a stronger IOP-reducing effect than the commercial product.ConclusionsThe combination of BRI nanocrystallization and tyloxapol is expected to be highly effective in glaucoma treatment and a useful tool for new ophthalmic drug delivery.

Quality by design (QbD) based approach for development of itraconazole loaded transferosomes for skin cancer: In vitro, ex vivo and cell line studies

Objective Itraconazole (ITZ), a widely used systemic antifungal drug, has been ingeniously repurposed for its antitumor effects. In the present work, we have prepared and optimized the ITZ-loaded transferosomes by Quality by Design (QbD) approach and repurposed them for skin cancer. Methods The transferosomal formulation was optimized by employing a QbD approach with the design of experiment. A combination of screening and optimization design was used for formulation optimization. The optimized formulation was characterized by particle size, PDI, zeta potential, FTIR, XRD, and surface morphology using TEM. In vitro and ex vivo studies were performed using Franz diffusion cells. An in vitro cell line study was performed on the human melanoma A375 cell line. Results The optimized formulation has a particle size of 192.37 ± 13.19 nm, PDI of 0.41 ± 0.03, zeta potential -47.80 ± 3.66, and an entrapment efficiency of 64.11 ± 3.75%. In vitro release studies showed that ITZ encapsulated transferosomes offer higher and sustained release than pure drugs. Ex vivo drug penetration and retention studies show that the penetration and retention of transferosomes are more visible in the skin than in the drug. The cell viability study confirms that ITZ encapsulated transferosomes have almost 2-fold more potency against the A375 cell line than pure drug. Conclusion ITZ encapsulated transferosomes were successfully prepared and optimized using a combination of screening and optimization designs. Based on ex vivo and cell line studies, we conclude that ITZ-loaded transferosomes could aid melanoma management alongside standard therapies.

Formulation and Characterization of Emulgel Lornoxicam Containing Lemon Grass Oil as Penetration Enhancer.

Emulgel dosage form is an advanced form of transdermal drug de-livery. It is a combination of emulsion and gel in a definite ratio. Emulsions are incorporated into the gel with proper mixing. The emulsion present in emulgel can be either oil/water or water/oil, which is thickened by mixing it with a gelling agent. On the basis of the solubility of lornoxicam in various oils, a surfac-tant and a co-surfactant were selected for further research. For the preparation of emulgel, the emulsion was prepared with Smix (surfactant and co-surfactant) in a ratio of 1:2. The prepared emulsion was incorporated into different concentrations of carbapol 934 in a 1:1 ratio to make a homogenous emulgel. The emulgel was inspected visually to see if it had any phase behaviour, spreadabil-ity, or grittiness by applying it to a slide. All formulations were evaluated for pH, physical properties, drug content, spreadability, extrudability, swelling index, viscosity, and centrifu-gation. Franz diffusion cell was used to perform in-vitro release of formulation with the help of egg membrane. Among all formulations, F3 showed 83% release after 6 hours and showed acceptable physical properties like homogeneity, colour, consistency, pH value, spreadability, extrudability, and drug content. Thus, emulgel can be regarded as a more feasible drug delivery system for hy-drophobic drugs (lornoxicam) than the currently marketed formulation. Optimized emulgel formulation consists of a microemulsion of lornoxicam, 1 % of carbopol 934, propylene gly-col, sodium benzoate, lemon grass oil, glycerin, and distilled water. In the in-vitro release studies, pH 7.4 phosphate buffer emulgel formulation (F3) showed 83% after 6 hours. Emulgel was found to be stable under stable conditions. The emulgel of the poorly water-soluble drug (lornoxicam) was formulated. The components and their optimum ratio for the formulation of microemulsion were obtained by solubility studies and droplet size analysis. Thus, microemulsion can be regarded as a more feasible dose delivery system for lornoxicam than the currently marketed tablet, capsule, and injection formulations. Optimized microemulsion of lornoxicam was incorporated into the gel base. Therefore, it may be concluded that emulgel of lornoxicam can be used as a controlled-release dosage form of the drug for local application in rheumatoid arthritis.