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Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients' adherence. [ABSTRACT FROM AUTHOR]

Miconazole nitrate (MCNR) is a BCS class II antifungal drug with poor water solubility. Although numerous attempts have been made to increase its solubility, formulation researchers struggle with this significant issue. Transethosomes are promising novel nanocarriers for improving the solubility and penetration of drugs that are inadequately soluble and permeable. Thus, the objective of this study was to develop MCNR-loaded transethosomal gel in order to enhance skin permeation and antifungal activity. MCNR-loaded transethosomes (MCNR-TEs) were generated using the thin film hydration method and evaluated for their zeta potential, particle size, polydispersity index, and entrapment efficiency (EE%). SEM, FTIR, and DSC analyses were also done to characterize the optimized formulation of MCNR-TEs (MT-8). The optimized formulation of MCNR-TEs was incorporated into a carbopol 934 gel base to form transethosomal gel (MNTG) that was subjected to ex vivo permeation and drug release studies. In vitro antifungal activity was carried out against Candida albicans through the cup plate technique. An in vivo skin irritation test was also performed on Wistar albino rats. MT-8 displayed smooth spherical transethosomal nanoparticles with the highest EE% (89.93 ± 1.32%), lowest particle size (139.3 ± 1.14 nm), polydispersity index (0.188 ± 0.05), and zeta potential (−18.1 ± 0.10 mV). The release profile of MT-8 displayed an initial burst followed by sustained release, and the release data were best fitted with the Korsmeyer-Peppas model. MCNR-loaded transethosomal gel was stable and showed a non-Newtonian flow. It was found that ex vivo drug permeation of MNTG was 48.76%, which was significantly higher than that of MNPG (plain gel) (p ≤ 0.05) following a 24-h permeation study. The prepared MCNR transethosomal gel exhibited increased antifungal activity, and its safety was proven by the results of an in vivo skin irritation test. Therefore, the developed transethosomal gel can be a proficient drug delivery system via a topical route with enhanced antifungal activity and skin permeability. [ABSTRACT FROM AUTHOR]

The rheological and viscoelastic properties of hybrid formulations composed of vehicles designed for cutaneous topical application and loaded with ultradeformable liposomes (UDL) were assessed. UDL were selected for their established ability to transport both lipophilic and hydrophilic compounds through the skin, and are applicable in pharmaceuticals and cosmetics. Formulations underwent flow analysis and were fitted to the Herschel–Bulkley model due to their prevalent non-Newtonian behavior in most cases. Linear viscoelastic regions (LVR) were identified, and G′ and G″ moduli were determined via frequency sweep steps, considering the impact of temperature and aging. The formulations exhibited non-Newtonian behavior with pseudoplastic traits in most cases, with UDL incorporation inducing rheological changes. LVR and frequency sweep tests indicated predominantly elastic solid behavior, with G′ higher than G″, at different temperatures and post-production times. Tan δ values also illustrated a predominant solid-like behavior over liquid. This study provides pivotal insights into the rheological and viscoelastic features of topical formulations, emphasizing the crucial role of meticulous vehicle and formulation selection when incorporating UDL or analogous liposomal drug delivery systems. [ABSTRACT FROM AUTHOR]

This work is aimed at developing a kappa-carrageenan (kCR) gel with increased methotrexate (MTX) content. β-Cyclodextrin (βCD), which is able to inclusion complex formation with MTX, has been used to increase the drug concentration in the hydrogel. The rheological behavior of the designed gels was investigated and the influence of MTX and βCD on the viscoelastic properties of kCR gel was studied in detail. The effect of βCD and its concentration on the MTX-releasing rate from the kCR gels was examined. The properties of kappa- and iota-carrageenans loaded with MTX were compared and the differences observed were explained in terms of different binding affinities of MTX to these polymers. The obtained gels provided desirable viscoelastic properties useful for topical application. [ABSTRACT FROM AUTHOR]

This study aimed to develop and evaluate nicotine--stearic acid conjugate-loaded solid lipid nanoparticles (NSA-SLNs) for transdermal delivery in nicotine replacement therapy (NRT). Nicotine conjugation to stearic acid prior to SLN formulation greatly increased drug loading. SLNs loaded with a nicotine–stearic acid conjugate were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and morphology. Pilot in vivo testing was carried out in New Zealand Albino rabbits. The size, PDI, and ZP of nicotine–stearic acid conjugate-loaded SLNs were 113.5 ± 0.91 nm, 0.211 ± 0.01, and −48.1 ± 5.75 mV, respectively. The entrapment efficiency of nicotine–stearic acid conjugate in SLNs was 46.45 ± 1.53%. TEM images revealed that optimized nicotine–stearic acid conjugate-loaded SLNs were uniform and roughly spherical in shape. Nicotine–stearic acid conjugate-loaded SLNs showed enhanced and sustained drug levels for up to 96 h in rabbits when compared with the control nicotine formulation in 2% HPMC gel. To conclude, the reported NSA-SLNs could be further explored as an alternative for treating smoking cessation. [ABSTRACT FROM AUTHOR]

Wounds are alterations in skin integrity resulting from any type of trauma. The healing process is complex, involving inflammation and reactive oxygen species formation. Therapeutic approaches for the wound healing process are diverse, associating dressings and topical pharmacological agents with antiseptics, anti-inflammatory, and antibacterial actions. Effective treatment must maintain occlusion and moisture in the wound site, suitable capacity for the absorption of exudates, gas exchange, and the release of bioactives, thus stimulating healing. However, conventional treatments have some limitations regarding the technological properties of formulations, such as sensory characteristics, ease of application, residence time, and low active penetration in the skin. Particularly, the available treatments may have low efficacy, unsatisfactory hemostatic performance, prolonged duration, and adverse effects. In this sense, there is significant growth in research focusing on improving the treatment of wounds. Thus, soft nanoparticles-based hydrogels emerge as promising alternatives to accelerate the healing process due to their improved rheological characteristics, increased occlusion and bioadhesiveness, greater skin permeation, controlled drug release, and a more pleasant sensory aspect in comparison to conventional forms. Soft nanoparticles are based on organic material from a natural or synthetic source and include liposomes, micelles, nanoemulsions, and polymeric nanoparticles. This scoping review describes and discusses the main advantages of soft nanoparticle-based hydrogels in the wound healing process. Herein, a state-of-the-art is presented by addressing general aspects of the healing process, current status and limitations of non-encapsulated drug-based hydrogels, and hydrogels formed by different polymers containing soft nanostructures for wound healing. Collectively, the presence of soft nanoparticles improved the performance of natural and synthetic bioactive compounds in hydrogels employed for wound healing, demonstrating the scientific advances obtained so far. [ABSTRACT FROM AUTHOR]

Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded bilosomes (BSs) for the improvement of therapeutic efficacy. MZBSs were prepared by using the thin-film hydration method and further optimized by using the Box–Behnken statistical design (BBD). The optimized miconazole bilosome (MZBSo) showed nano-sized vesicles, a low polydispersity index, a high entrapment efficiency, and zeta potential. Further, MZBSo was incorporated into the gel using carbopol 934P and chitosan polymers. The selected miconazole bilosome gel (MZBSoG2) demonstrated an acceptable pH (6.4 ± 0.1), viscosity (1856 ± 21 cP), and spreadability (6.6 ± 0.2 cm2). Compared to MZBSo (86.76 ± 3.7%), MZBSoG2 showed a significantly (p < 0.05) slower drug release (58.54 ± 4.1%). MZBSoG2 was found to be a non-irritant because it achieved a score of zero (standard score) in the HET-CAM test. It also exhibited significant antifungal activity compared to pure MZ against Candida albicans and Aspergillus niger. The stability study results showed no significant changes after stability testing under accelerated conditions. MZ-loaded gels could serve as effective alternative carriers for improving therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients’ adherence.

PLGA-based in situ forming implants (ISFI) often require a high amount of potentially toxic solvents such as N methyl-Pyrrolidone (NMP). The aim of the present study was to develop lipid in-situ-forming oleogels (ISFOs) as alternative delivery systems. 12-Hydroxystearic acid (12-HSA) was selected as the oleogelling agent and three different oleoformulations were investigated: (a) 12-HSA, peanut oil (PO), NMP; (b) 12-HSA, medium-chain triglycerides (MCT), ethanol; (c) 12-HSA, isopropyl myristate (IPM), ethanol. The effects of the 12-HSA concentration, preparation method, and composition on the mechanical stability were examined using a texture analysis and oscillating rheology. The texture analysis was used to obtain information on the compression strength. The amplitude sweeps were analyzed to provide information on the gel strength and the risk of brittle fractures. The frequency sweeps allowed insights into the long-term stability and risk of syneresis. The syringeability of the ISFOs was tested, along with their acute and long-term cytotoxicity in vitro. The developed ISFOs have the following advantages: (1) the avoidance of highly acidic degradation products; (2) low amounts of organic solvents required; (3) low toxicity; (4) low injection forces, even with small needle sizes. Therefore, ISFOs are promising alternatives to the existing polymer/NMP-based ISFIs. [ABSTRACT FROM AUTHOR]

Miconazole nitrate (MCNR) is a BCS class II antifungal drug with poor water solubility. Although numerous attempts have been made to increase its solubility, formulation researchers struggle with this significant issue. Transethosomes are promising novel nanocarriers for improving the solubility and penetration of drugs that are inadequately soluble and permeable. Thus, the objective of this study was to develop MCNR-loaded transethosomal gel in order to enhance skin permeation and antifungal activity. MCNR-loaded transethosomes (MCNR-TEs) were generated using the thin film hydration method and evaluated for their zeta potential, particle size, polydispersity index, and entrapment efficiency (EE%). SEM, FTIR, and DSC analyses were also done to characterize the optimized formulation of MCNR-TEs (MT-8). The optimized formulation of MCNR-TEs was incorporated into a carbopol 934 gel base to form transethosomal gel (MNTG) that was subjected to ex vivo permeation and drug release studies. In vitro antifungal activity was carried out against Candida albicans through the cup plate technique. An in vivo skin irritation test was also performed on Wistar albino rats. MT-8 displayed smooth spherical transethosomal nanoparticles with the highest EE% (89.93 ± 1.32%), lowest particle size (139.3 ± 1.14 nm), polydispersity index (0.188 ± 0.05), and zeta potential (−18.1 ± 0.10 mV). The release profile of MT-8 displayed an initial burst followed by sustained release, and the release data were best fitted with the Korsmeyer-Peppas model. MCNR-loaded transethosomal gel was stable and showed a non-Newtonian flow. It was found that ex vivo drug permeation of MNTG was 48.76%, which was significantly higher than that of MNPG (plain gel) (p ≤ 0.05) following a 24-h permeation study. The prepared MCNR transethosomal gel exhibited increased antifungal activity, and its safety was proven by the results of an in vivo skin irritation test. Therefore, the developed transethosomal gel can be a proficient drug delivery system via a topical route with enhanced antifungal activity and skin permeability.

The rheological and viscoelastic properties of hybrid formulations composed of vehicles designed for cutaneous topical application and loaded with ultradeformable liposomes (UDL) were assessed. UDL were selected for their established ability to transport both lipophilic and hydrophilic compounds through the skin, and are applicable in pharmaceuticals and cosmetics. Formulations underwent flow analysis and were fitted to the Herschel–Bulkley model due to their prevalent non-Newtonian behavior in most cases. Linear viscoelastic regions (LVR) were identified, and G′ and G″ moduli were determined via frequency sweep steps, considering the impact of temperature and aging. The formulations exhibited non-Newtonian behavior with pseudoplastic traits in most cases, with UDL incorporation inducing rheological changes. LVR and frequency sweep tests indicated predominantly elastic solid behavior, with G′ higher than G″, at different temperatures and post-production times. Tan δ values also illustrated a predominant solid-like behavior over liquid. This study provides pivotal insights into the rheological and viscoelastic features of topical formulations, emphasizing the crucial role of meticulous vehicle and formulation selection when incorporating UDL or analogous liposomal drug delivery systems.

This work is aimed at developing a kappa-carrageenan (kCR) gel with increased methotrexate (MTX) content. β-Cyclodextrin (βCD), which is able to inclusion complex formation with MTX, has been used to increase the drug concentration in the hydrogel. The rheological behavior of the designed gels was investigated and the influence of MTX and βCD on the viscoelastic properties of kCR gel was studied in detail. The effect of βCD and its concentration on the MTX-releasing rate from the kCR gels was examined. The properties of kappa- and iota-carrageenans loaded with MTX were compared and the differences observed were explained in terms of different binding affinities of MTX to these polymers. The obtained gels provided desirable viscoelastic properties useful for topical application.

This study aimed to develop and evaluate nicotine--stearic acid conjugate-loaded solid lipid nanoparticles (NSA-SLNs) for transdermal delivery in nicotine replacement therapy (NRT). Nicotine conjugation to stearic acid prior to SLN formulation greatly increased drug loading. SLNs loaded with a nicotine–stearic acid conjugate were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and morphology. Pilot in vivo testing was carried out in New Zealand Albino rabbits. The size, PDI, and ZP of nicotine–stearic acid conjugate-loaded SLNs were 113.5 ± 0.91 nm, 0.211 ± 0.01, and −48.1 ± 5.75 mV, respectively. The entrapment efficiency of nicotine–stearic acid conjugate in SLNs was 46.45 ± 1.53%. TEM images revealed that optimized nicotine–stearic acid conjugate-loaded SLNs were uniform and roughly spherical in shape. Nicotine–stearic acid conjugate-loaded SLNs showed enhanced and sustained drug levels for up to 96 h in rabbits when compared with the control nicotine formulation in 2% HPMC gel. To conclude, the reported NSA-SLNs could be further explored as an alternative for treating smoking cessation.

Wounds are alterations in skin integrity resulting from any type of trauma. The healing process is complex, involving inflammation and reactive oxygen species formation. Therapeutic approaches for the wound healing process are diverse, associating dressings and topical pharmacological agents with antiseptics, anti-inflammatory, and antibacterial actions. Effective treatment must maintain occlusion and moisture in the wound site, suitable capacity for the absorption of exudates, gas exchange, and the release of bioactives, thus stimulating healing. However, conventional treatments have some limitations regarding the technological properties of formulations, such as sensory characteristics, ease of application, residence time, and low active penetration in the skin. Particularly, the available treatments may have low efficacy, unsatisfactory hemostatic performance, prolonged duration, and adverse effects. In this sense, there is significant growth in research focusing on improving the treatment of wounds. Thus, soft nanoparticles-based hydrogels emerge as promising alternatives to accelerate the healing process due to their improved rheological characteristics, increased occlusion and bioadhesiveness, greater skin permeation, controlled drug release, and a more pleasant sensory aspect in comparison to conventional forms. Soft nanoparticles are based on organic material from a natural or synthetic source and include liposomes, micelles, nanoemulsions, and polymeric nanoparticles. This scoping review describes and discusses the main advantages of soft nanoparticle-based hydrogels in the wound healing process. Herein, a state-of-the-art is presented by addressing general aspects of the healing process, current status and limitations of non-encapsulated drug-based hydrogels, and hydrogels formed by different polymers containing soft nanostructures for wound healing. Collectively, the presence of soft nanoparticles improved the performance of natural and synthetic bioactive compounds in hydrogels employed for wound healing, demonstrating the scientific advances obtained so far.

Miconazole nitrate (MN) is a poorly water-soluble and antifungal drug used for fungal infections. The present research work was designed to develop topical MN-loaded bilosomes (BSs) for the improvement of therapeutic efficacy. MZBSs were prepared by using the thin-film hydration method and further optimized by using the Box–Behnken statistical design (BBD). The optimized miconazole bilosome (MZBSo) showed nano-sized vesicles, a low polydispersity index, a high entrapment efficiency, and zeta potential. Further, MZBSo was incorporated into the gel using carbopol 934P and chitosan polymers. The selected miconazole bilosome gel (MZBSoG2) demonstrated an acceptable pH (6.4 ± 0.1), viscosity (1856 ± 21 cP), and spreadability (6.6 ± 0.2 cm2). Compared to MZBSo (86.76 ± 3.7%), MZBSoG2 showed a significantly (p < 0.05) slower drug release (58.54 ± 4.1%). MZBSoG2 was found to be a non-irritant because it achieved a score of zero (standard score) in the HET-CAM test. It also exhibited significant antifungal activity compared to pure MZ against Candida albicans and Aspergillus niger. The stability study results showed no significant changes after stability testing under accelerated conditions. MZ-loaded gels could serve as effective alternative carriers for improving therapeutic efficacy.

PLGA-based in situ forming implants (ISFI) often require a high amount of potentially toxic solvents such as N methyl-Pyrrolidone (NMP). The aim of the present study was to develop lipid in-situ-forming oleogels (ISFOs) as alternative delivery systems. 12-Hydroxystearic acid (12-HSA) was selected as the oleogelling agent and three different oleoformulations were investigated: (a) 12-HSA, peanut oil (PO), NMP; (b) 12-HSA, medium-chain triglycerides (MCT), ethanol; (c) 12-HSA, isopropyl myristate (IPM), ethanol. The effects of the 12-HSA concentration, preparation method, and composition on the mechanical stability were examined using a texture analysis and oscillating rheology. The texture analysis was used to obtain information on the compression strength. The amplitude sweeps were analyzed to provide information on the gel strength and the risk of brittle fractures. The frequency sweeps allowed insights into the long-term stability and risk of syneresis. The syringeability of the ISFOs was tested, along with their acute and long-term cytotoxicity in vitro. The developed ISFOs have the following advantages: (1) the avoidance of highly acidic degradation products; (2) low amounts of organic solvents required; (3) low toxicity; (4) low injection forces, even with small needle sizes. Therefore, ISFOs are promising alternatives to the existing polymer/NMP-based ISFIs.

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined.

Chewable gel tablets are an underdeveloped subject, even though there are many simple chewable tablets and gummy candies in the food and pharmaceutical industries. Chewable gel tablets are not as sweet, they can have an active substance, pharmacological effect, and a value of nutrition. The aim of this study was to prepare gelatin-based chewable tablets with Myristica fragrans as a preservative and to determine the shelf-life variability depending on storage conditions, and to evaluate texture changes. Firmness and springiness of gel tablets were measured by a texture analyzer and compared between different storage conditions and the shelf-life of tablets was established by mold growing time. Chewable gel tablets were prepared by using silicone form. Mold was most likely to grow on tablets that have been packaged in squeezable bags (after 14 days 60% of all formulations had a mold, p < 0.05). The most stable tablets (over 180 days) were in sealed boxes and contained nutmeg essential oil or its solution, or ethanolic nutmeg extract. The gel tablets’ firmness increased about 4 times when they were stored in opened plastic boxes and their springiness decreased about 1.65 times after 28 days in the mentioned conditions, p < 0.05. Nutmeg hydrolat had the highest influence on texture variation (p < 0.05).

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 23. Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy.

Papain is a therapeutic enzyme with restricted applications due to associated allergenic reactions. Papain nanoparticles have shown to be safe for biomedical use, although a method for proper drug loading and release remains to be developed. Thus, the objective of this work was to develop and assess the stability of papain nanoparticles in a prototype semi-solid formulation suitable for dermatological or topical administrations. Papain nanoparticles of 7.0 ± 0.1 nm were synthesized and loaded into carboxymethylcellulose- and poly(vinyl alcohol)-based gels. The formulations were then assayed for preliminary stability, enzyme activity, cytotoxicity studies, and characterized according to their microstructures and protein distribution. The formulations were suitable for papain nanoparticle loading and provided a stable environment for the nanoparticles. The enzyme distribution along the gel matrix was homogeneous for all the formulations, and the proteolytic activity was preserved after the gel preparation. Both gels presented a slow release of the papain nanoparticles for four days. Cell viability assays revealed no potential cytotoxicity, and the presence of the nanoparticles did not alter the microstructure of the gel. The developed systems presented a potential for biomedical applications, either as drug delivery systems for papain nanoparticles and/or its complexes.

Skin is an attractive site for drug administration partly because of its easy accessibility and favorable properties (e.g., less invasiveness and high patient compliance) over some other common routes of administration. Despite this, the efficiency in transdermal drug delivery has been largely limited by poor skin permeation. To address this problem, this study reports the generation of oleic acid-containing vesicles, which can enhance the drug delivery efficiency while showing good stability and limited skin disruption. Upon being loaded into a complex gel, along with the incorporation of the polymer blending technique, a delivery system exhibiting tunable transdermal flux of 2,3,5,4′-tetrahydroxystilbene 2-O-β-D-glucoside is reported. Taking the good biocompatibility and tunable delivery performance into account, our system warrants further development and optimization for future applications in the treatment of skin diseases.

Novel polyethylene oxide (PEO) hydrogel films were synthesized via UV crosslinking with varying concentrations of pentaerythritol tetra-acrylate (PETRA) as crosslinking agent. The aim was to study the effects of the crosslinking agent on the material properties of hydrogel films intended for dermatological applications. Fabricated film samples were characterized using swelling studies, scanning electron microscopy, tensile testing and rheometry. Films showed rapid swelling and high elasticity. The increase of PETRA concentration resulted in significant increase in the gel fraction and crosslinking density (ρc), while causing a significant decrease in the equilibrium water content (EWC), average molecular weight between crosslinks (\({\overline{M}}_{c}\)), and mesh size (ζ) of films. From the scanning electron microscopy, cross-linked PEO hydrogel network appeared as cross-linked mesh-like structure with interconnected micropores. Rheological studies showed PEO films required a minimum of 2.5% w/w PETRA to form stable viscoelastic solid gels. Preliminary studies concluded that a minimum of 2.5% w/w PETRA is required to yield films with desirable properties for skin application.

Chitosan is biopolymer with promising properties in wound healing. Chronic wounds represent a significant burden to both the patient and the medical system. Among chronic wounds, pressure ulcers are one of the most common types of complex wound. The efficacy and the tolerability of chitosan gel formulation, prepared into the hospital pharmacy, in the treatment of pressure ulcers of moderate severity were evaluated. The endpoint of this phase II study was the reduction of the area of the lesion by at least 20% after four weeks of treatment. Thus, 20 adult volunteers with pressure ulcers within predetermined parameters were involved in a 30 days study. Dressing change was performed twice a week at outpatient clinic upon chronic wounds management. In the 90% of patients involved in the study, the treatment was effective, with a reduction of the area of the lesion and wound healing progress. The study demonstrated the efficacy of the gel formulation for treatment of pressure ulcers, also providing a strong reduction of patient management costs. [ABSTRACT FROM AUTHOR]

This study aimed to develop a carbamazepine (CBZ) sustained release formulation suitable for pediatric use with a lower risk of precipitation. The CBZ was first prepared as sustained release microparticles, and then the microparticles were embedded in alginate beads, and finally, the beads were suspended in a gel vehicle. The microparticles were prepared by a solvent evaporation method utilizing ethyl cellulose as a sustained release polymer and were evaluated for particle size, encapsulation efficiency, and release profile. The beads were fabricated by the dropwise addition of sodium alginate in calcium chloride solution and characterized for size, shape, and release properties. The gel was prepared using iota carrageenan as the gelling agent and evaluated for appearance, syneresis, drug content uniformity, rheology, release profile, and stability. The microparticles exhibited a particle size of 135.01 ± 0.61 µm with a monodisperse distribution and an encapsulation efficiency of 83.89 ± 3.98%. The beads were monodispersed with an average size of 1.4 ± 0.05 mm and a sphericity factor of less than 0.05. The gel was prepared using a 1:1 ratio (gel vehicle to beads) and exhibited no syneresis, good homogeneity, and good shear-thinning properties. The release profile from the beads and from the gel was not significantly affected, maintaining similarity to the tablet form. The gel properties were maintained for one month real time stability, but the accelerated stability showed reduced viscosity and pH with time. In conclusion, CBZ in a gel sustained release dosage form combines the advantages of the suspension form in terms of dosing flexibility, and the advantages of the tablet form in regards to the sustained release profile. This dosage form should be further investigated in vivo in animal models before being considered in clinical trials.

The co-administration of absorption enhancing agents with macromolecular drugs (e.g., protein and peptide drugs) has been identified as a means to improve the oral bioavailability of these drugs. Absorption-enhancing agents of natural origins have received a great deal of attention due to their sustainable production, in support of green chemistry. In previous studies, certain parts of the Aloe vera leaf (e.g., gel and whole leaf extract) have shown a potential to enhance drug permeation across the intestinal epithelial barrier. The mechanism of the drug-absorption-enhancement action and the capacity for absorption-enhancement of the A. vera gel and whole leaf, were investigated in this study. A clear decrease in transepithelial electrical resistance (TEER) of Caco-2 cell monolayers exposed to A. vera gel and wholeleaf extract, in various concentrations, indicated the opening of tight junctions between the epithelial cells. The transport of Fluorescein isothiocyanate (FITC)-dextran, with a molecular weight of 4 kDa (FD-4), could be enhanced across the Caco-2 cell monolayers, by the A. vera gel and whole-leaf extract, but not the FITC-dextran with larger molecular weights (i.e., 10, 20, and 40 kDa), which indicated a limited drug absorption enhancement capacity, in terms of the molecular size. Accumulation of FD-4 between the Caco-2 cells (and not within the cells), after treatment with the A. vera gel and whole-leaf extract was shown with a confocal laser scanning microscopy (CLSM) imaging, indicating that the paracellular transport of FD-4 occurred after the interaction of the A. vera gel and whole-leaf extract, with the epithelial cell monolayers. Furthermore, changes in the F-actin distribution in the cytoskeleton of the Caco-2 cell monolayers was observed by means of a fluorescence staining, which confirmed tight junction modulation as the mechanism of action for the absorption enhancement effect of the A. vera gel and whole-leaf extract.

N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ.

Chitosan is biopolymer with promising properties in wound healing. Chronic wounds represent a significant burden to both the patient and the medical system. Among chronic wounds, pressure ulcers are one of the most common types of complex wound. The efficacy and the tolerability of chitosan gel formulation, prepared into the hospital pharmacy, in the treatment of pressure ulcers of moderate severity were evaluated. The endpoint of this phase II study was the reduction of the area of the lesion by at least 20% after four weeks of treatment. Thus, 20 adult volunteers with pressure ulcers within predetermined parameters were involved in a 30 days study. Dressing change was performed twice a week at outpatient clinic upon chronic wounds management. In the 90% of patients involved in the study, the treatment was effective, with a reduction of the area of the lesion and wound healing progress. The study demonstrated the efficacy of the gel formulation for treatment of pressure ulcers, also providing a strong reduction of patient management costs.

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined.

Chewable gel tablets are an underdeveloped subject, even though there are many simple chewable tablets and gummy candies in the food and pharmaceutical industries. Chewable gel tablets are not as sweet, they can have an active substance, pharmacological effect, and a value of nutrition. The aim of this study was to prepare gelatin-based chewable tablets with Myristica fragrans as a preservative and to determine the shelf-life variability depending on storage conditions, and to evaluate texture changes. Firmness and springiness of gel tablets were measured by a texture analyzer and compared between different storage conditions and the shelf-life of tablets was established by mold growing time. Chewable gel tablets were prepared by using silicone form. Mold was most likely to grow on tablets that have been packaged in squeezable bags (after 14 days 60% of all formulations had a mold, p < 0.05). The most stable tablets (over 180 days) were in sealed boxes and contained nutmeg essential oil or its solution, or ethanolic nutmeg extract. The gel tablets' firmness increased about 4 times when they were stored in opened plastic boxes and their springiness decreased about 1.65 times after 28 days in the mentioned conditions, p < 0.05. Nutmeg hydrolat had the highest influence on texture variation (p < 0.05). [ABSTRACT FROM AUTHOR]

Acetazolamide (ACZ) is a diuretic used in glaucoma treatment; it has many side effects. Carvedilol (CAR) is a non-cardioselective beta-blocker used in the treatment of elevated intraocular pressure; it is subjected to the first-pass metabolism and causes fluids accumulation leading to edema. This study focuses on overcoming previous side effects by using a topical formula of a combination of the two previous drugs. Sixty formulations of niosomes containing Span 20, Span 60, Tween 20, and Tween 60 with two different ratios were prepared and characterized. Formulation with the lowest particle size (416.30 ± 0.23), the highest zeta potential (72.04 ± 0.43 mv), and the highest apparent coefficient of corneal permeability (0.02 ± 0.29 cm/h) were selected. The selected formula was incorporated into the gel using factorial design 23. Niosomes (acetazolamide/carvedilol) consisting of Span 60 and cholesterol in the molar ratio (7:6), HMPC, and carbopol with two different ratios were used. The selected formula was subjected to an in vivo study of intraocular pressure in ocular hypertensive rabbits for 60 h. The sustained gel formula of the combination decreased (IOP) to normal after 1 h and sustained efficacy for 4 days. Histological analysis of rabbit eyeballs treated with the selected formula showed improvement in glaucomatous eye retinal atrophy. [ABSTRACT FROM AUTHOR]

Papain is a therapeutic enzyme with restricted applications due to associated allergenic reactions. Papain nanoparticles have shown to be safe for biomedical use, although a method for proper drug loading and release remains to be developed. Thus, the objective of this work was to develop and assess the stability of papain nanoparticles in a prototype semi-solid formulation suitable for dermatological or topical administrations. Papain nanoparticles of 7.0 ± 0.1 nm were synthesized and loaded into carboxymethylcellulose- and poly(vinyl alcohol)-based gels. The formulations were then assayed for preliminary stability, enzyme activity, cytotoxicity studies, and characterized according to their microstructures and protein distribution. The formulations were suitable for papain nanoparticle loading and provided a stable environment for the nanoparticles. The enzyme distribution along the gel matrix was homogeneous for all the formulations, and the proteolytic activity was preserved after the gel preparation. Both gels presented a slow release of the papain nanoparticles for four days. Cell viability assays revealed no potential cytotoxicity, and the presence of the nanoparticles did not alter the microstructure of the gel. The developed systems presented a potential for biomedical applications, either as drug delivery systems for papain nanoparticles and/or its complexes. [ABSTRACT FROM AUTHOR]

Skin is an attractive site for drug administration partly because of its easy accessibility and favorable properties (e.g., less invasiveness and high patient compliance) over some other common routes of administration. Despite this, the efficiency in transdermal drug delivery has been largely limited by poor skin permeation. To address this problem, this study reports the generation of oleic acid-containing vesicles, which can enhance the drug delivery efficiency while showing good stability and limited skin disruption. Upon being loaded into a complex gel, along with the incorporation of the polymer blending technique, a delivery system exhibiting tunable transdermal flux of 2,3,5,4′-tetrahydroxystilbene 2-O-β-D-glucoside is reported. Taking the good biocompatibility and tunable delivery performance into account, our system warrants further development and optimization for future applications in the treatment of skin diseases. [ABSTRACT FROM AUTHOR]

This study aimed to develop a carbamazepine (CBZ) sustained release formulation suitable for pediatric use with a lower risk of precipitation. The CBZ was first prepared as sustained release microparticles, and then the microparticles were embedded in alginate beads, and finally, the beads were suspended in a gel vehicle. The microparticles were prepared by a solvent evaporation method utilizing ethyl cellulose as a sustained release polymer and were evaluated for particle size, encapsulation efficiency, and release profile. The beads were fabricated by the dropwise addition of sodium alginate in calcium chloride solution and characterized for size, shape, and release properties. The gel was prepared using iota carrageenan as the gelling agent and evaluated for appearance, syneresis, drug content uniformity, rheology, release profile, and stability. The microparticles exhibited a particle size of 135.01 ± 0.61 µm with a monodisperse distribution and an encapsulation efficiency of 83.89 ± 3.98%. The beads were monodispersed with an average size of 1.4 ± 0.05 mm and a sphericity factor of less than 0.05. The gel was prepared using a 1:1 ratio (gel vehicle to beads) and exhibited no syneresis, good homogeneity, and good shear-thinning properties. The release profile from the beads and from the gel was not significantly affected, maintaining similarity to the tablet form. The gel properties were maintained for one month real time stability, but the accelerated stability showed reduced viscosity and pH with time. In conclusion, CBZ in a gel sustained release dosage form combines the advantages of the suspension form in terms of dosing flexibility, and the advantages of the tablet form in regards to the sustained release profile. This dosage form should be further investigated in vivo in animal models before being considered in clinical trials. [ABSTRACT FROM AUTHOR]

The co-administration of absorption enhancing agents with macromolecular drugs (e.g., protein and peptide drugs) has been identified as a means to improve the oral bioavailability of these drugs. Absorption-enhancing agents of natural origins have received a great deal of attention due to their sustainable production, in support of green chemistry. In previous studies, certain parts of the Aloe vera leaf (e.g., gel and whole leaf extract) have shown a potential to enhance drug permeation across the intestinal epithelial barrier. The mechanism of the drug-absorption-enhancement action and the capacity for absorption-enhancement of the A. vera gel and whole leaf, were investigated in this study. A clear decrease in transepithelial electrical resistance (TEER) of Caco-2 cell monolayers exposed to A. vera gel and wholeleaf extract, in various concentrations, indicated the opening of tight junctions between the epithelial cells. The transport of Fluorescein isothiocyanate (FITC)-dextran, with a molecular weight of 4 kDa (FD-4), could be enhanced across the Caco-2 cell monolayers, by the A. vera gel and whole-leaf extract, but not the FITC-dextran with larger molecular weights (i.e., 10, 20, and 40 kDa), which indicated a limited drug absorption enhancement capacity, in terms of the molecular size. Accumulation of FD-4 between the Caco-2 cells (and not within the cells), after treatment with the A. vera gel and whole-leaf extract was shown with a confocal laser scanning microscopy (CLSM) imaging, indicating that the paracellular transport of FD-4 occurred after the interaction of the A. vera gel and whole-leaf extract, with the epithelial cell monolayers. Furthermore, changes in the F-actin distribution in the cytoskeleton of the Caco-2 cell monolayers was observed by means of a fluorescence staining, which confirmed tight junction modulation as the mechanism of action for the absorption enhancement effect of the A. vera gel and whole-leaf extract. [ABSTRACT FROM AUTHOR]

N -Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5 MTZ ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5 PG-MTZ and F5 IPM-MTZ further increased the skin permeation of MTZ when compared to F5 MTZ. Interestingly, F5 PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ.

Novel polyethylene oxide (PEO) hydrogel films were synthesized via UV crosslinking with varying concentrations of pentaerythritol tetra-acrylate (PETRA) as crosslinking agent. The aim was to study the effects of the crosslinking agent on the material properties of hydrogel films intended for dermatological applications. Fabricated film samples were characterized using swelling studies, scanning electron microscopy, tensile testing and rheometry. Films showed rapid swelling and high elasticity. The increase of PETRA concentration resulted in significant increase in the gel fraction and crosslinking density (ρc), while causing a significant decrease in the equilibrium water content (EWC), average molecular weight between crosslinks (\({\overline{M}}&#95;{c}\)), and mesh size (ζ) of films. From the scanning electron microscopy, cross-linked PEO hydrogel network appeared as cross-linked mesh-like structure with interconnected micropores. Rheological studies showed PEO films required a minimum of 2.5% w/w PETRA to form stable viscoelastic solid gels. Preliminary studies concluded that a minimum of 2.5% w/w PETRA is required to yield films with desirable properties for skin application.