Ex-vivo Permeation Studies Research Articles

Delivery of free amino acids into and through the stratum corneum of the skin using micro emulsions and microemulsion-based hydrogels: Formulation, characterization, and ex-vivo permeation studies.

Free amino acids constitute the largest portion (40%) of the natural moisturizing factor. Their level might decline and cause dry skin condition. The treatment strategy involves the replenishment of these components to the skin, and, to our knowledge, there are no reports that involve dermal delivery of free amino acids. The purpose of the current study was therefore to prepare and characterize different micro-emulsions, micro-emulsion-based hydrogels, and hydrophilic creams loaded with free amino acids for dermal delivery. Oil-in-water microemulsions were prepared using carefully selected formulation components. Poloxamer® 407 and carbopol® 934 were used to prepare the hydrogels. All the formulations were characterized for physico-chemical, permeation and cytotoxicity properties. The results showed that the prepared microemulsions had desired droplet size, size distribution, zeta potential, refractive index, and pH. In the gel preparations, the elastic properties prevailed over the viscous behavior. The hydrogels had non-Newtonian shear-thinning behavior with some thixotropic properties. The free amino acids permeated into the deeper layers of the stratum corneum from the microemulsions, and microemulsion-based hydrogels as compared to conventional hydrophilic cream. The hydrogels were more effective than the microemulsions to deliver the FAAs to the desired site of the skin in a sustained manner. Poloxamer-based hydrogel permeated into deeper skin layers than Carbopol-based hydrogel. Formulations prepared using standard free amino acids and those extracted and purified from oyster mushroom had similar characteristics. All the formulations were stable and safe to be applied topically. In conclusion, microemulsions and microemulsion-based hydrogels can be considered as safe carrier systems for dermal delivery of free amino acids.

Preparation of Idebenone as a Thermosetting Nasal Gel for Better Bioavailability and Histopathological Effect

Background Idebenone is an extensively metabolized drug with poor water solubility that is used to treat Leiber’s hereditary optical neuropathy. Objective This study aims to prepare idebenone nanoemulsion as a poloxamer-based nasal gel to overcome the extensive rate of hepatic metabolism for better bioavailability and lower histopathological effect on the nasal mucosa. Methods The formulation strategy was based on eliciting mutual concentration reduction between the nanoemulsion and the carrier gel by setting their gelation temperature between 30-32°C to overcome the mucociliary dose washout. The o/w nanoemulsions rely on cremophor EL and transcutol as an emulsifying system to stabilize idebenone-loaded lemongrass oil. The spontaneous emulsification method was used to prepare nanoemulsions that were characterized by zeta sizer while the thermosensitive hydrogels were prepared using the cold method. In-vitro dissolution test and ex-vivo permeation study through excised sheep nasal mucosa were performed to evaluate the enhanced permeation ratio, rate of permeation, and permeation coefficient. The histopathological effect of direct application on sheep nasal mucosa was studied using optical microscopy to evaluate cellular toxicity. Results The formula prepared from NE1 with poloxamer 407: poloxamer188 in concentrations 10:3% w/w respectively showed almost complete drug release in 120 minutes due to complete polymers blend erosion. Furthermore, thermosensitive nano-emulgel at a temperature of gelation 31.8°C was obtained at much lower concentrations of poloxamer 407 (10%) compared to previous studies. Nanoemulsions retained their globular size below 100nm due to further gel entrapment stabilization. Conclusions Drug permeation through excised sheep nasal mucosa elicited an increase in enhanced permeation ratio to 20.3 times and other flux kinetics parameters compared to those of IDB oil dispersion. Direct cellular toxicity showed a minor inflammatory response characterized by serous infiltration of inflammatory cells and edema. In contrast, most of the epithelial cells retained their histological characteristics compared to control slides. Received: Mar. 2023 Accepted: Aug 2023 Published: Oct.2023

Loratadine oral bioavailability enhancement via solid dispersion loaded oro-dispersible films: Formulation, characterization and pharmacokinetics.

Loratadine (LRD) belongs to second-generation tricyclic H1 antihistamine class, known for its non-sedating properties in allergic reactions. H1 antihistamines avoid and block the responses to allergens or histamine in nose and conjunctivae, thereby abolishing itching, congestion and sneezing. LRD is a Biopharmaceutical Class System (BCS) class II drug with dissolution or solubility limited absorption which limited the oral bioavailability and therapeutic efficacy of LRD. To improve the oral bioavailability of LRD for allergic disease (urticaria) treatment, LRD solid dispersions (LRD-SDs) were integrating into oro-dispersible films (ODFs). LRD-SDs were prepared through hot-melt extrusion method (HME) using d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS-1000), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SP). Subsequently, LRD-SDs were incorporated in ODFs by solvent casting method. The physicochemical and mechanical properties of LRD solid dispersions-loaded oro-dispersible films (LRD-SDs-ODFs), were evaluated. The in-vitro dissolution, ex-vivo permeation, oral bioavailability, and pharmacodynamics studies were conducted to evaluate LRD-SDs-ODFs efficiency. LRD-SDs-ODFs showed superior solubility and in-vitro dissolution results compared to that of pure LRD (p<0.05). The solubility of the LRD-SD coded as LTS-4 was 190 times higher than the pure drug in aqueous media. The average hydrodynamic particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of SD particles were 76±2.1nm, 0.20±0.08 and -19.16±1.4mV, respectively. Moreover, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results confirmed the amorphousness of LRD in LRD-SDs-ODFs. The permeability flux of LRD was 44.6±3.1μg/cm2/h from DPF-5 formulation. Likewise, in vivo oral bioavailability of DPF-5 in Sprague-Dawley rats was significantly increased (p<0.05) compared to free LRD. Further, wheal area was reduced 20 % higher than LRD in 8h (p<0.05). Overall, LRD-SDs-ODFs considerably enhanced LRD solubility, dissolution rate, bioavailability, and antihistaminic efficacy. Our findings show that SDs-ODFs is an effective carrier system for delivering poorly soluble LRD.

Pharmaceutical Considerations of Translabial Formulations for Treatment of Parkinson's Disease: A Concept of Drug Delivery for Unconscious Patients.

The goal of the present research was to isolate a biopolymer from Phaseolus vulgaris (P. vulgaris) and Zea mays (Z. mays) plants and used it to construct Resveratrol (RES)-loaded translabial films. Biopolymers were extracted from P. vulgaris and Z. mays seeds using a simple process. Separated biopolymers, sodium carboxymethylcellulose (SCMC) and tragacanth were subjected to formulation development by incorporating RES-loaded translabial films. The Fourier-transform infrared spectroscopy (FTIR), physical appearance, weight, thickness, folding endurance, swelling index, surface pH, percent moisture absorption, percent moisture loss, vapor transfer rate, and content uniformity of the translabial films were examined. The mucoadhesive, ex-vivo permeation, in vivo and stability studies, were performed. The results showed that RES-loaded translabial films produced from P. vulgaris and Z. mays biopolymers exhibited exceptional mucoadhesive, stability, and permeation properties. Results revealed that the best formulations were prepared from a combination of biopolymer (P. vulgaris C or Z. mays C) with tragacanth. Formulations with tragacanth revealed good swelling and thus permeation profiles. In vivo release of TL 11 was found to be 24.05 ng/ml in 10 hours and it was stable enough at 45°C. This research suggested that RES-loaded translabial formulations can be potentially used for the treatment of Parkinson's disease with good patient compliance to geriatric and unconscious patients.

FORMULATION AND EVALUATION OF A TOPICAL GEL CONTAINING MINOXIDIL AND TOFACITINIB CITRATE FOR ALOPECIA AREATA

Objective: The objective of the present study is to formulate and evaluate a topical gel containing Minoxidil and Tofacitinib citrate for alopecia areata. Methods: Six gels were formulated using the direct-dispersion method by using polymers in the ratio of Carbopol 934: HPMC and Carbopol 934: HPC in three different concentrations each. All the prepared gels were then characterized for its drug content, pH, Rheological measurement, Spreadibility, skin adhesion study, In vitro drug release, Ex-vivo skin permeation study and stability studies. Results: All the six formulations were evaluated for various parameters such as pH, viscosity, spreadibility, and drug content and in vitro drug release. The pH of all the formulations was in the range of 6.3-6.8 which was optimum for the skin. As the concentration of the polymer increased the viscosity also increased, F6 had the highest viscosity among all of 1082 cps. F5 had the highest spreadibility of 4.3±0.15 cm and the drug content of all ranged between 88-96% of Minoxidil and 86-97% for Tofacitinib citrate with F5 giving the best result drug release across a cellulose membrane for a period 8 h of 94.22±0.19% for Minoxidil and 93.62±0.49% for Tofacitinib citrate. Formulation F2 and F5 were subjected to skin adhesion studies by the use of wistar rat skin with F5 giving the highest bioadhesion of 108 g/cm2. Formulation F5 was selected as an optimized formulation among the six as it gave the best results for all the parameters. Then the optimized formulation was subjected to an ex-vivo permeation study for a period of 8 h and by using wistar rat skin as a permeation barrier and the drug release for Minoxidil and Tofacitinib citrate was found to be 71.94±0.78% and 69.49±0.47%. The stability study was carried out for two months at accelerated condition i.e., 40 °C±2 °C/75±5% RH proved that the formulated gel was Stable. Conclusion: The formulated topical gel containing Minoxidil and Tofacitinib citrate were found to be a promising approach for the treatment of alopecia areata.

Quality by design engineered, enhanced anticancer activity of temozolomide and resveratrol coloaded NLC and brain targeting via lactoferrin conjugation in treatment of glioblastoma

The most dangerous type of high-grade astrocytoma is glioblastoma multiforme. The objective of the work was to engineer lactoferrin conjugated temozolomide and resveratrol co-loaded NLC for the treatment of glioblastoma using intranasal delivery for brain targeting. Synergistic activity of temozolomide and resveratrol was determined using combination index method and 1:1 ratio was selected. QbD approach was used to formulate and optimize NLC, with minimum particle size, maximum transmittance and entrapment efficiency using Central Composite Rotable Design (CCRD) method. The optimized LTR-NLC had desired average particle size (209.3 nm), narrow PDI along, high percentage transmittance (>95%) and better entrapment efficiency (95.26% of TEM and 87.59% of RES). From ex-vivo permeation studies it was found that the permeation at 24 h was 77.43 %, and 88.55 % from LTR-NLC and 25.76 % and 31.10% from suspension for resveratrol and temozolomide respectively. In comparison to drug suspension, NLC had nearly 3-fold increase in drug penetration. IC50 value was also significantly better in the groups treated with LTR-NLC. Hence it can be concluded that LTR-NLC may be an effective formulation for the treatment of glioblastoma, according to the findings of this investigation.

Formulation development and characterization of Lecarnidipine hydrochloride niosomal transdermal patches

The bioavailability of Lercanidipine Hydrochloride (LCP) is about 44% and half-life of the drug is about 4.6 hours. LCP due to its low therapeutic dose range of 2.5 to 20mg and substantial biotransformation in liver becomes it ideal molecule in development of transdermal therapeutic system. The primary objective of the present research work was to develop Niosomal transdermal patch (NP) of Lecarnidipine. The LCP nanoparticles were prepared by solvent evaporation method and the optimized Nanoparticles formulation has shown 225nm particle size with a polydispersity index (PDI) of 0.120. LCP patches were prepared by incorporating nanoparticles dispersion, using varying concentrations of polymers HPMC E5, HPMC 5cps, HPMC 15cps, Carbopol 734 and Sodium alginate using solvent casting techniques and further optimized by central composite design(CCD) the effect of polymer on the various physico-chemical characteristics and in-vitro drug release studies, ex-vivo skin permeation studies is studied. On the basis of in-vitro drug release and ex-vivo skin permeation studies, the formulation containing (HPMC 15cps and HPMC 5cps) has shown sustained and extended drug release over a period of 24 hrs.&#x0D; Keywords: Lecarnidipine; Niosomes; Transdermal patch; Central composite Design, Controlled release; Bioavailability etc.

Development and characterisation of MMT-reinforced polyacrylonitrile-pullulan nanofibers for controlled permeation of isotretinoin

Drug nanofibers play a crucial role in ameliorating therapeutic effects, reducing toxicity, and increasing the bioavailability of drugs. This study was aimed at the fabrication of isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin. In this study, montmorillonite (MMT)-reinforced cross-linked polyacrylonitrile and pullulan nanofibers combined with varying amounts of isotretinoin were fabricated through an electrospinning approach and investigated for their drug permeation potential. PAN-PU nanofibers were successfully integrated with the isotretinoin. The incorporation of isotretinoin into the nanofibrous structure was confirmed by FTIR and XRD. TGA study indicated the stability of the fabricated nanoparticles. The SEM results showed the beaded and smooth morphology of nanofibers. Formulation with a higher drug concentration had a non-significantly (p > 0.05) higher swelling ratio. Drug-loaded polymeric nanofiber erodes at a slower rate as compared to drug-free nanofibers. The ex-vivo permeation study of nanofibers revealed that the drug was not released all at once, but rather gradually and consistently over the period of 24 h, indicating a controlled release of the drug. In addition, the drug concentration in the nanofibers affected the permeation of the drug. According to the findings, isotretinoin-loaded MMT-reinforced bi-polymeric (PAN/PU) nanofibers with varying concentrations of isotretinoin were successfully fabricated. The fabricated nanofibers (PAN/PU) showed a promising potential for controlled permeation of drugs through rabbit skin.

A Study of Microemulsion Systems for Transdermal Delivery of Risperidone Using Penetration Enhancers

The aim of this study was to develop and characterize microemulsion formulations using penetration enhancers as potential transdermal delivery systems for risperidone. Initially, a simple formulation of risperidone in Propylene Glycol (PG) was prepared as a control formulation, together with formulations incorporating various penetration enhancers, alone and/or in combination, and also microemulsion formulations with various chemical penetration enhancers, were prepared and all were evaluated for risperidone transdermal delivery. An ex-vivo permeation study was carried out using human cadaver skin and vertical glass Franz diffusion cells to compare all the microemulsion formulations. The microemulsion prepared from oleic acid as the oil (15%), Tween 80 (15%) as the surfactant and isopropyl alcohol (20%) as the co-surfactant, and water (50%) showed higher permeation with a flux value of 32.50±3.60 ug/hr/sq.cm, a globule size of 2.96±0.01 nm, a polydispersity index of 0.33±0.02 and pH of 4.95. This novel in vitro research disclosed that an optimized microemulsion formulated using penetration enhancers was able to increase permeation of risperidone by 14-fold compared to the control formulation. The data suggested that microemulsions may be useful in the delivery of risperidone via the transdermal route.

Ferulic acid-loaded aspasomes: A new approach to enhance the skin permeation, anti-aging and antioxidant effects

In this study, an innovative approach to enhance the skin permeation, anti-aging and antioxidant effects of ferulic acid (FA)-loaded aspasomal formulations were developed and evaluated in vitro and ex vivo. The chemical interactions between FA and excipients in the formulation were characterized by Differential scanning calorimetry (DSC) and Fourier-transformed infrared (FTIR). Aspasomes (ASPs) were produced using the film hydration method with different components and were evaluated according to in vitro characterization parameters (particle size (PS), polydispersity index (PDI), zeta potential (ZP), scanning electron microscopy (SEM), drug entrapment efficiency (EE%) and drug release profile), and the optimized formulation was determined. The 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to test the cytotoxicity of the ASPs and different FA solutions on the L929 cell line. In the stability studies, changes in characterization parameters and FA content of optimum ASPs stored in both suspended and lyophilized dry powder form in two different conditions over 3 months were monitored. Ex-vivo skin permeation study was done using mouse abdominal skin and the amount of penetrated FA was measured. Also, skin depth and density of blank and FA-loaded ASPs were evaluated by fluorescence microscopy. At the end of the permeation study, the antioxidant capacity of FA reaching the dermis layer and its inhibitory effect on collagenase and elastase enzymes were assessed. FTIR spectra and DSC thermograms assured chemical and physical compatibility. The selected optimum formulation (F2 coded) showed PS of 384 ± 1.52 nm, PDI of 0.015 ± 0.011, ZP of −39.2 ± 3.45 mV, EE of 58 ± 2.01% and drug release of 77.3 ± 0.554% and was used for permeation study. The lyophilized ASPs were physically stable, and the FA content of ASPs did not decrease significantly during 3 months of storage at 4 °C. The skin permeation experimental results indicated positive results that successfully developed FA-loaded ASPs have an effective FA permeability rate and better antioxidant and anti-aging effects than the free drug and are useful and effective for improving skin permeation and slowing skin aging with topical applications.

ACECLOFENAC LOADED SOLID LIPID NANOPARTICLES: OPTIMIZATION, IN VITRO AND EX-VIVO EVALUATION

Objective: Rheumatoid arthritis is treated with aceclofenac as the first line of treatment. Aceclofenac is a BCS-II drug, when taken orally, causes first-pass metabolism and is partially water-insoluble causing some gastrointestinal (GI) issues. Objective of the work was preparation and evaluation of solid lipid nanoparticle for rheumatoid arthritis and increases the drug permeability and further possibility to decreasing the irritation. Methods: Different formulations batches were prepared by soya lecithin, tween 20, bees wax and cetyl alcohol lipid using lipid extrusion method. Further, the selected batch proceeded for Particle size, zeta potential, entrapment efficiency, in vitro release, Fourier transformed infrared (FTIR), X-ray diffraction studies (XRD), and ex-vivo study in goat skin. Results: As a result, selected batch have nanometric in size, 72.44% entrapment efficiency, and sustained drug released (71.33%) in 6 h. The Fourier transformed-infrared studies (FT-IR) and X-ray diffraction (XRD) study confirm the compatibility of the drug with excipients. Ex-vivo permeation study showed 74.85% in drug permeate in 6 h through goat skin. Conclusion: Research demonstrates that particle size and entrapment effectiveness are significantly influenced by the level of lipid and lecithin present. Additionally, it is suitable for the treatment of arthritis.

Transferosomal gel for transdermal delivery of insulin: Formulation development and ex vivo permeation study

The study was to develop a transdermal formulation of insulin, determine its pharmaceutical characteristics, and finally test its efficacy. In the current study - Transfersomes were selected as the carrier system for insulin. The transfersomes were produced by the hand-shaking method using soy lecithin phospholipid and sodium deoxycholate as the objective of the surfactant. The prepared transfersomes were subjected to characterization with optical microscopy and scanning electron microscope to estimate the shape and size of transfersomes respectively. In addition, the physical and drug-excipient interaction studies were carried out and the transfersomes were also studied for the insulin entrapment efficiency.Results of the study showed the shape of the transfersomes was well defined and spherical. The mean size of transfersomes was estimated to be 130 ​nm The transfersomes were found to be stable over a period of four weeks. The insulin entrapment efficiency of the transfersomes was estimated to be 87.3%. The ex-vivo skin permeation study employing goat ear skin with the transfersomes hydrogel revealed that there was a slow and sustained release of insulin till 180 ​min. From the above study, it may be concluded that transfersomes are suitable carriers of insulin across biological membranes.

Usefulness of Lipidic Nanoparticles of Curcumin and Tetrahydrocurcumin for Skin Inflammation: A Comparative Study

Background: Yellow curcumin, the “Indian Gold” is known since ancient times to modulate the activities of a wide variety of targets. The voluminous literature and several patents are a proof of the therapeutic value of curcumin. Tetrahydrocurcumin (THC), however, has remained as an unexplored molecule although its cosmeceutical properties have been documented. Their compromised bioavailability, poor aqueous solubility (curcumin 11 ng/mL, THC 56ng/mL), high log P (Cur: 3.28; THC: 2.98) are hurdles for developing as potential drugs. Objective: This article discusses the usefulness of lipidic nanoparticles of curcumin and THC for skin inflammation. Method: Nanocouturing to produce lipidic nanoparticles (LNs) of curcumin and THC was done via an optimized microemulsification technique. LNs were characterized by FTIR, TEM, pharmacokinetics, and pharmacodynamic study. Results: FTIR reflected the suitable incorporation of drugs into LNs. TEM examination revealed a spherical to ellipsoidal shape with a particle size of &lt;200 nm. In vitro release study indicates the release of both drugs is between 70-80% within 24 h. Ex-vivo permeation studies confirmed the ability of LNs to cross the stratum corneum. Stability studies (Q1AR2) indicated that both were stable, safe, and nonirritating (OECD 404). Xylene induced ear edema model of inflammation showed both molecules to possess equivalent abilities to treat inflammation. Conclusion: Curcumin being yellow in color is unstable at physiological pH and plasma and possesses poor bioavailability, while THC is a colorless stable molecule, making it a molecule of choice to be developed as an effective topical product.

Design, formulation, in-vitro and in-vivo pharmacokinetic evaluation of Nicardipine- nanostructured lipid carrier for transdermal drug delivery system

Nicardipine hydrochloride (NCP), a calcium channel blocker, may be useful for treating chronic stable angina and hypertension through a therapeutic transdermal system because it has a low dose, short half-life, and high first-pass metabolism. This study used a hydrogel incorporating nanostructured lipid carriers (NLCs) to enhance NCP retention and skin permeability. The NLCs formula was fine-tuned using a Central composite design with three factors and three levels. The effects of sonication time, lipid concentration, and surfactant concentration on particle size, Entrapment Efficiency (EE), and polydispersity index (PDI) were also studied. There were two main components to the strategy that allowed it to succeed. Mean particle size in the optimized formulation was 107.78 nm, and the entrapment efficiency was 70.52%. Drug loading was 6.59%. A pharmaceutical release research discovered that NCP has a half-life of 10 h in vitro. The selected formulation was then placed into a Carbopol gel, and ex-vivo permeation studies showed that the gel with NLCs provided more penetration (66.45%) and longer sustained release (up to 11 h) than the free drug-based gel. The gel used in NLCs is especially notable for limiting systemic access and minimizing the risk of side effects from free drug. The in-vivo absorption study shown that NCP bioavailability was greatly improved in wistar rats. Using an experimental methodology, we found that NCP-NLCs could efficiently transport NCP across the skin by transdermal injection, and that there was a quadratic relationship between the variables of interest.

Characterisation and Evaluation of prepared Fluconazole Nanogel for Treating Seborrheic Dermatitis

Objective: This study aims to demonstrate antifungal activity and in-vitroanalysis of fluconazole nanogel with different polymer concentration for seborrheic dermatitis. Methods: The class of antifungal drug- Fluconazole was used to formulate the nanogel with different concentrations of polymers. The prepared batches of nanogel were analyzed for its antifungal activity, ex-vivo skin permeation study, and skin thickness study. The animals are used in four groups for the in vivo antifungal activity of nanogel as control, disease, standard, and test. The prepared fluconazole (FLZ) nanogel was compared with marketed fluconazole gel. Results: The prepared formulation having hydroxymethyl cellulose (HPMC=1.5mg) as the polymer showed up with best properties among eight different batches. It was effective with a 38 mm inhibition zone in culture media of yeast Malassezia strain. The skin permeation study ensured 95% cumulative drug release in 18 hr. The ex-vivo studies also give the best result for F5 batch (HPMC=1.5mg) with a minimum skin thickness of 1.4 micrometer. Conclusion: In-vivo and ex-vivo studies on the different batches of fluconazole, when compared with marketed gel, showed evidence that nanogel of FLZ (1mg with HPMC=1.5mg) can treat seborrheic dermatitis.

Investigation of a biopolymer-based pH-responsive and sustained release raft-gel-forming tablet of famotidine: In-vitro, ex-vivo, bioavailability and anti-ulcer evaluation in New Zealand albino rabbit

Famotidine (FAM), a histamine H2 receptor antagonist, routinely used for gastric ulcers. However, the poor permeability, short biological half-life and degradation in acidic gastric environment, limits its bioavailability and reduces the expression of potential bioactivity. The present study investigated sodium alginate as a pH responsive and raft-gel-forming biopolymer along with slowly releasing ingredients to achieve stomach site-specific, stable and sustained release FAM tablet (FAMRFT) for the management of gastric ulcer. The Box Behnken design was adopted to optimize raft strength and sustained release profile. The optimized FAMRFT was evaluated in terms of in-vitro, ex-vivo and in-vivo in suitable animal models. In-vitro release study showed that FAMRFT can effectively and continuously sustained-release with diffusion mechanism. Ex-vivo permeation study in porcine gastric mucosa showed two-fold increase in permeation parameters. In-vivo studies in New Zealand albino rabbits, the X-ray scintigraphy confirmed the formation of raft-gel in gastric and buoyancy, improved 3-fold bioavailability as compared to pure FAM and commercial tablet, respectively. Further, the improved gastro protective effects were reflected in gastric volume, total acid output, pH, ulcer score, ulcer index, ulcer protection and biomarkers level such as malondialdehyde (MDA), total glutathione (GSH) and nitric oxide (NO) in aspirin-induced gastric ulcers in albino rabbit. Moreover, histopathological study revealed the absence of epithelial erosion, submucosal edema and leucocytes infiltration in gastric mucosa. The results indicate that sodium alginate-based pH responsive raft-gel may be a new formulation for the application of FAM for the treatment of gastric ulcer.

BOX-BEHNKEN DESIGN OPTIMIZATION OF SALICYLIC ACID LOADED LIPOSOMAL GEL FORMULATION FOR TREATMENT OF FOOT CORN

Objective: The present research is aimed to design and optimize a liposomal gel formulation of salicylic acid (SA) for enhanced drug permeation, higher skin drug retention, sustained release drug delivery and reduced side effects in the effective treatment of foot corn. Methods: Formulation designing and optimization of SA-loaded liposomes was done by box-Behnken experimental design using the three-factor, three-level approach. Phospholipid content, cholesterol content and drug content were selected as independent variables; while the critical quality attributes (CQAs) of liposomal formulation like particle size, PDI, zeta potential, entrapment efficiency and cumulative % drug release were considered as response variables. The SA-loaded liposomes were prepared by ethanol injection method and were characterized for desired CQAs. Finally, topical gel formulation of SA-loaded liposomes was developed and evaluated for drug content, homogeneity, spreadability, in vitro drug release, drug release kinetics, ex-vivo drug permeation and skin retention properties. Results: The particle size, PDI, zeta potential, entrapment efficiency and cumulative % drug release of SA-loaded liposomes was found to be 261.2 nm, 0.28, 0.7 mV, 57.53% and 99.57%, respectively. Developed topical gel formulation of SA-loaded liposomes exhibited a sustained drug release profile (64.48% cumulative release over 360 min) following Higuchi model kinetics. The developed formulation showed almost 2-fold enhanced drug permeation (i.e., 26.50%) and more than 2-fold higher drug retention (i.e., 10.90%) on porcine ear skin as compared to the plain salicylic acid gel. Conclusion: The SA-loaded liposomes and developed topical gel formulation possessed all desired CQAs. The in vitro drug release kinetics, ex-vivo drug permeation and skin retention studies confirmed the suitability of the developed formulation for topical application in the effective treatment of foot corn.

Boosting hair growth through follicular delivery of Melatonin through lecithin-enhanced Pickering emulsion stabilized by chitosan-dextran nanoparticles in testosterone induced androgenic alopecia rat model

The strategy in this work was loading Melatonin (MEL), the powerful antioxidant photosensitive molecule, in novel Pickering emulsions (PEs) stabilized by chitosan-dextran sulphate nanoparticles (CS-DS NPs) and enhanced by lecithin, for treatment of androgenic alopecia (AGA). Biodegradable CS-DS NPs dispersion was prepared by polyelectrolyte complexation and optimized for PEs stabilization. PEs were characterized for droplet size, zeta potential, morphology, photostability and antioxidant activity. Ex-vivo permeation study through rat full thickness skin was conducted with optimized formula. Differential tape stripping trailed by cyanoacrylate skin surface biopsy was executed, for quantifying MEL in skin compartments and hair follicles. In-vivo evaluation of MEL PE hair growth activity was performed on testosterone induced AGA rat model. Visual inspection followed by anagen to telogen phase ratio (A/T) and histopathological examinations were conducted and compared with marketed 5% minoxidil spray “Rogaine ®”. Data showed that PE improved MEL antioxidant activity and photostability. Ex-vivo results displayed MEL PE high follicular deposition. In-vivo study demonstrated that MEL PE treated testosterone induced AGA rat group, restored hair loss and produced maximum hair regeneration along with prolonged anagen phase amongst tested groups. The histopathological examination revealed that MEL PE prolonged anagen stage, increased follicular density and A/T ratio by 1.5-fold. The results suggested that lecithin-enhanced PE stabilized by CS-DS NPs was found to be an effective approach to enhance photostability, antioxidant activity and follicular delivery of MEL. Thus, MEL-loaded PE could be a promising competitor to commercially marketed Minoxidil for treatment of AGA.

Formulation, and optimization of transdermal Atorvastatin Calcium-Loaded Ultra-flexible vesicles; ameliorates poloxamer 407-caused dyslipidemia

Atorvastatin calcium (AC), a cholesterol-lowering medication, has limited oral bioavailability (14 %) and adverse impacts on the gastrointestinal tract (GIT), liver, and muscle. So, in an effort to improve the poor availability and overcome the hepatotoxicity complications attendant to peroral AC administration, transdermal transfersomal gel (AC-TFG) was developed as a convenient alternative delivery technique. The impact of utilizing an edge activator (EA) and varying the phosphatidylcholine (PC): EA molar ratio on the physico-chemical characteristics of the vesicles was optimized through a Quality by Design (QbD) strategy. The optimal transdermal AC-TFG was tested in an ex-vivo permeation study employing full-thickness rat skin, Franz cell experiments, an in-vivo pharmacokinetics and pharmacodynamics (PK/PD) evaluation, and a comparison to oral AC using poloxamer-induced dyslipidemic Wister rats. The optimized AC-loaded TF nanovesicles predicted by the 23-factorial design strategy had a good correlation with the measured vesicle diameter of 71.72 ± 1.159 nm, encapsulation efficiency of 89.13 ± 0.125 %, and cumulative drug release of 88.92 ± 3.78 % over 24 h. Ex-vivo data revealed that AC-TF outperformed a free drug in terms of permeation. The pharmacokinetic parameters of optimized AC-TFG demonstrated 2.5- and 13.3-fold significant improvements in bioavailability in comparison to oral AC suspension (AC-OS) and traditional gel (AC-TG), respectively. The transdermal vesicular technique preserved the antihyperlipidemic activity of AC-OS without increasing hepatic markers. Such enhancement was proven histologically by preventing the hepatocellular harm inflicted by statins. The results showed that the transdermal vesicular system is a safe alternative way to treat dyslipidemia with AC, especially when given over a long period of time.

Loteprednol loaded nanoformulations for corneal delivery: Ex-vivo permeation study, ocular safety assessment and stability studies

Loteprednol etabonate (LE) is a topical corticosteroid that is used in inflammatory and allergic conditions of the eye. Nanoformulations including solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and nanoemulsion (NE) of LE were prepared for increasing its ocular bioavailability and minimizing the risk of side effects. Nanoformulations were prepared using hot emulsification and ultrasonication technique. The stabilities of the SLN, NLC, and NE were studied at different thermal conditions for 180 days. In this context, alterations in particle size (PS), zeta potential (ZP), viscosity, pH, %EE, and thermal behavior of the formulations were determined. Ex vivo corneal permeation study was performed, subsequently, the tape stripping approach was conducted for defining the LE amount that was blocked by the tear film layer. In addition, to determine the LE amount in epithelial tissue, a homogenization test was performed. the PS of the formulations was between 82.23 and 126.9 nm, and ZPs were between −20.8 mV and −24.6 mV. Furthermore, SLN, NLC, and NE formulations were found to be 2.05, 1.86, and 1.39 times higher LE retained in the cornea against the marketed product, respectively. SLN, NLC, and NE might be alternative delivery systems by reducing the amount of LE for each dose and being used safely based on the results both of MTT and histopathological examinations as well.