Nose to brain delivery of naringin loaded transniosomes for epilepsy: formulation, characterisation, blood-brain distribution and invivo pharmacodynamic evaluation.

The current work limns the preparation of naringin-loaded transnioosomes (NRN-TN) to enhance NRN solubility, permeation and bioavailability via nasal mucosa for intranasal delivery. NRN-TN was created by the thin-film hydration technique, and with the BBD (Box-Behnken design), optimisation was carried out. NRN-TNopt was characterised for the vesicle size, PDI (Polydispersity index), zeta potential, entrapment efficiency (EE) and in vitro NRN release. For further assessment, nasal permeation study, study of Blood-brain distribution, TEM (Transmission Electron Microscopy), and CLSM (Confocal Scanning Laser Microscopy) were conducted withal. The NRN-TNopt exhibited spherical as well as sealed vesicles with a considerable small size of 151.3 nm, an EE of 75.23 percent, a PDI of 0.1257, and an in vitro release of 83.32 percent. CLSM investigation revealed that the new formulation allows for higher NRN permeation across nasal mucosa than the NRN solution. The blood-brain distribution investigation revealed that intranasally administered NRN-TN had a greater Cmax and AUC0-24 h than orally administered NRN-TN. Seizure activity and neuromuscular coordination as measured by the rotarod test, biochemical estimate of oxidative stress indicators, and histological investigations demonstrated that the NRN-TN has superior anti-epileptic potential in comparison to the standard diazepam. In addition, nasal toxicity studies demonstrate that the NRN-TN formulation is safer for intranasal administration. This study confirmed that the created TN vesicle formulation is a valuable carrier for the intranasal administration of NRN for the treatment of epilepsy.

Quality by design-based development and validation of an HPLC method for simultaneous estimation of pregabalin and piperine in dual drug-loaded liposomes.

The current research work describes the development of a rapid HPLC method for the concurrent detection of pregabalin and piperine in dual drug-loaded nanoformulations. The primary goal was to recognize the chromatographic conditions wherein propitious segregation of the integrants with quality peaks can be attained. An attempt to expound the target analytical profile was made to accomplish this goal, and critical method attributes (CMAs), viz. percentage acetonitrile content, injection volume and pH, which affect critical quality attributes (CQAs), were identified using systemic risk analysis. Box-Behnken design was employed to develop a relationship between CMAs and CQAs, which engenders an analytical design space. Efficient chromatographic separation for pregabalin and piperine was attained using an analytical C18 column and mobile phase comprising acetonitrile-water (pH 6.9; 70:30%, v/v) in an isocratic elution mode with a 1 ml/min flow rate. The elution was descried at an isosbestic wavelength of 221 nm using a photodiode array detector. The International Conference on Harmonization guidelines were adopted for the developed HPLC method. The validated HPLC method can be further utilized for the simultaneous quantification and detection of pregabalin and piperine in other lipid-based nanopharmaceuticals such as polymeric nanoparticles, nanocrystals, solid-lipid nanoparticles, metallic nanoparticles, etc., in in vitro and in vivo studies.

Application of QbD based approach in development and validation of RP-HPLC method for simultaneous estimation of methotrexate and baicalin in dual-drug-loaded liposomes.

The present study delineates the development of a novel, rugged and sensitive stability-indicating risk-based HPLC method for the concurrent estimation of methotrexate (MTX) and baicalin (BCL) in dual-drug-loaded-nanopharmaceuticals based on an analytical quality-by-design approach. Preliminary screening trials along with systemic risk analysis were performed, endeavouring to explicate the critical method attributes, namely pH, percentage of orthophosphoric acid and percentage of acetonitrile, that influence the critical quality attributes. Box-Behnken design was utilized for the optimization of the tailing factor as the response for MTX and BCL in a short run time. The chromatographic conditions were optimized by performing 17 experimental runs using design expert software. The chromatographic conditions were selected after the analysis of the optimized zone within the confines of the design space: water:acetonitrile adjusted to a pH of 3.0 with 0.05% orthophosphoric acid (60:40, %v/v) was the mobile phase, the flow rate was 1.0 ml/min and an analytical C18 column was used at an isobestic wavelength of 282 nm. Furthermore, the optimized method was validated in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and was found to be within the prescribed limits. Therefore, the developed reversed-phase-high-performance liquid chromatography method has a high degree of practical utility for synchronous detection of MTX and BCL in pharmaceutical nano-dosage forms such as protein-based nanoparticles, nanocrystals, polymeric nanoparticles and metallic nanoparticles in in vivo and in vitro studies.

Application of a Quality by Design-based approach in development and validation of an RP-HPLC method for simultaneous estimation of methotrexate and mangiferin in dual drug-loaded liposomes.

The present study delineates the development of a novel rugged and sensitive stability-indicating risk-based HPLC method for the concurrent estimation of methotrexate and mangiferin in dual drug-loaded nanopharmaceuticals based on an analytical QbD approach. Preliminary screening trials along with systemic risk analysis were performed, endeavouring to explicate the critical method attributes, namely pH, percentage orthophosphoric acid content and percentage methanol content, that influence critical quality attributes. Box-Behnken design was utilized for the optimization of the tailing factor as response for methotrexate and mangiferin in short run time. The chromatographic conditions were optimized by performing 17 experimental runs acquired from Design-Expert software. The chromatographic conditions after the analysis of an optimized zone within the confines of the design space were chosen as mobile phase water-methanol adjusted to pH 3.0 with 0.05% orthophosphoric acid (65:35, v/v) and flow rate 1.0 ml/min using a C18 analytical column at an isosbestic wavelength of 265 nm. Furthermore, the validation of the optimized method was done in accordance with International Conference on Harmonization guidelines and were reckoned to be in the prescribed limits. The developed RP-HPLC method has a high degree of practical utility for synchronous detection of methotrexate and mangiferin in pharmaceutical nano-dosage forms such as protein-based-nanoparticles, nanocrystals, polymeric nanoparticles and metallic nanoparticles in in vivo and in vitro studies.

Application of QbD-based approach to the development and validation of an RP-HPLC method for simultaneous estimation of pregabalin and naringin in dual-drug loaded liposomes.

The current work delineates the development of a novel, rugged and sensitive stability-indicating risk-based HPLC method based on an analytical quality-by-design (QbD) approach for the concurrent estimation of naringin and pregabalin in dual-drug-loaded nanopharmaceuticals. Preliminary screening trials were conducted, along with systemic risk analysis, in order to identify the critical method attributes, namely injection volume, pH and acetonitrile content, that influence critical quality attributes. The Box-Behnken design was used to optimize the tailing factor as a response to pregabalin and naringin in a short run time. The chromatographic conditions were improved by running 17 experimental runs generated by design expert software. After analysing the optimized zone within the confines of the design space, the following chromatographic conditions were chosen: mobile phase water-acetonitrile adjusted to pH 6.9 with phosphate buffer (80:20, %v/v), at flow rate of 1.0 ml/min using a C18 analytical column at an isobestic wavelength of 212 nm. Furthermore, the optimized method was validated in accordance with International Conference on Harmonization guidelines and was found to be within the prescribed limits. The developed RP-HPLC method has a high degree of practical utility in in vivo and in vitro studies for the synchronous detection of pregabalin and naringin in pharmaceutical nanodosage forms such as protein-based nanoparticles, nanocrystals, polymeric nanoparticles and metallic nanoparticles.

Spanlastics a Novel Nanovesicular Carrier: Its Potential Application and Emerging Trends in Therapeutic Delivery.

Nanotechnology-based drug delivery system has played a very crucial role in overpowering the tasks allied with the conventional dosage form. Spanlastics, an elastic nanovesicle with an ability to carry wide range of drug molecules, make it a potential drug delivery carrier. Spanlastics have extended rising curiosity for diverse sort of route of administration. They can squeeze themselves through the skin pore due to elastic and deformable nature which makes them favorable for transdermal delivery. Spanlastics consist of non-ionic surfactant or blend of surfactants. Many researchers proved that spanlastics have been significantly augment therapeutic efficacy, enhanced drug bioavailability, and reduced drug toxicity. This review summarizes various vesicular systems, composition and structure of spanlastics, advantages of spanlastics over other drug delivery systems, and mechanism of drug penetration through skin. It also gives a brief on different types of drug encapsulated in spanlastics vesicles for the treatment of various diseases.

Development and validation of stability indicating reversed-phase liquid chromatographic method for simultaneous quantification of methotrexate and teriflunomide in nanoparticles and marketed formulation.

Methotrexate (MTX) and teriflunomide (TEF) are the two most effective disease-modifying antirheumatic drugs used as combination therapy for rheumatoid arthritis and no robust high-performance liquid chromatography (HPLC) method is available for their simultaneous estimation to date. Therefore, we have developed and validated an isocratic reversed-phase HPLC method for simultaneous analysis of MTX and TEF spiked in the form of active pharmaceutical ingredients, tablets and nanoformulations. The best separation was achieved on a BDS, C18 , 4.6 × 250 mm, 5 µm analytical column (Thermo Hypersil) with methanol-ethylammonium formate-potassium dihydrogen phosphate buffer (55 mm, pH 3.5; 65:5:30, v/v) as mobile phase at a flow rate of 0.8 mL/min. All the samples were subjected to force degradation studies. Responses of MTX and TEF were found to be a linear function of concentration over the range 1-50 µg/mL (r2 = 0.9976 and 0.9982). The limits of detection and limit of quantification were 7.74 and 25.82 ng/mL and 10.74 and 35.80 ng/mL, respectively. Degradation products produced under the stress studies did not interfere with the detection of MTX and TEF and therefore the developed method can be regarded as stability indicating.

Nonionic surfactant based thymoquinone loaded nanoproniosomal formulation: in vitro physicochemical evaluation and in vivo hepatoprotective efficacy.

CONTEXT: The present study was carried out to formulate thymoquinone proniosomal formulation (TQP) and evaluate their efficacy in methotrexate (Mtx) induced hepatotoxicity in rats. OBJECTIVE: The objective of the study was to explore a new therapeutic approach focusing on hepatoprotective activity using thymoquinone proniosomal formulation. MATERIAL AND METHODS: TQP was formulated using span60, cholesterol and phospholipid by film hydration technique. The animals were divided into six groups with five animals each receiving different treatments for 7 days. On the 8th day, rats were anesthetized with ether, blood samples were withdrawn, livers were dissected out for biochemical tests and histopathological examinations. RESULTS AND DISCUSSION: The size of vesicle was found to be in the nanometric range with higher entrapment efficiency. The high entrapment efficiency is probably due to the lipophilic character of TQ. The morphological structure showed the outline and core of the well-identified spherical vesicle, and also displaying the retention of sealed vesicular structure. The release of TQ from developed formulation was found to be significantly higher compared to control. Mtx treated rats showed significant elevation in ALT, AST, ALP and TBARs, whereas, TQP treated group showed significant reduction. CONCLUSION: The developed formulation (TQP) significantly inhibited the elevated levels of serum marker enzymes and showed improved histopathological deformities.

The application of anethole, menthone, and eugenol in transdermal penetration of valsartan: Enhancement and mechanistic investigation.

CONTEXT: The main barrier for transdermal delivery is the obstacle property of the stratum corneum. Many types of chemical penetration enhancers have been used to breach the skin barrier; among the penetration enhancers, terpenes are found as the most highly advanced, safe, and proven category. OBJECTIVE: In the present investigation, the terpenes anethole, menthone, and eugenol were used to enhance the permeation of valsartan through rat skin in vitro and their enhancement mechanism was investigated. MATERIALS AND METHODS: Skin permeation studies of valsartan across rat skin in the absence and the presence of terpenes at 1% w/v, 3% w/v, and 5% w/v in vehicle were carried out using the transdermal diffusion cell sampling system across rat skin and samples were withdrawn from the receptor compartment at 1, 2, 3, 4, 6, 8, 10, 12, and 24 h and analysed for drug content by the HPLC method. The mechanism of skin permeation enhancement of valsartan by terpenes treatment was evaluated by Fourier transform infrared spectroscopy (FTIR) analysis and differential scanning calorimetry (DSC). RESULTS: All the investigated terpenes provided a significant (p < 0.01) enhancement in the valsartan flux at a concentration of 1%, and less so at 3% and 5%. The effectiveness of terpenes at 1% concentration was in the following order: anethole > menthone > eugenol with 4.4-, 4.0-, and 3.0-fold enhancement ratio over control, respectively. DSC study showed that the treatment of stratum corneum with anethole shifted endotherm down to lower melting point while FTIR studies revealed that anethole produced maximum decrease in peak height and area than other two terpenes. CONCLUSION: The investigated terpenes can be successfully used as potential enhancers for the enhancement of skin permeation of lipophilic drug.

Systemic delivery of ß-blockers via transdermal route for hypertension.

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including ß-blockers, an important antihypertensive class. ß-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with ß-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different ß-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.

Synergistically engineered nanotransethosomes for co-delivery of methotrexate and baicalin for enhanced transdermal delivery against rheumatoid arthritis: formulation, characterisation and in vivo pharmacodynamic evaluation.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease that significantly impacts the quality of life of those affected. Owing to the complex pathophysiology of RA, it is not possible for any singular treatment to entirely impede the progression of the disease. Hence, the current study aimed to adopt a holistic and synergistic approach towards the management of RA by means of a co-delivery strategy involving methotrexate (MTH), a conventional slow-acting anti-rheumatic drug, and baicalin (BCN), a bioactive phytochemical using a transethosomal (TRS) gel formulation.Purpose: The present study aims to evaluate the potential benefits of administering MTH and BCN in nanoparticulate form, which may lead to improved stability and solubility, as well as enhanced penetration into the arthritic tissues of interest.Methods and results: The MTH-BCN-TRS that were synthesised exhibited small particle size of 151.3 nm and polydispersity index of 0.125, as well as a favourable zeta potential of -32.22 mV. Additional assessments were conducted, including a pharmacokinetic analysis, TEM, skin permeation analysis and confocal microscopy. According to the Confocal laser scanning microscopy (CLSM) study, the formulated MTH-BCN-TRS gel exhibited superior MTH and BCN permeation through the skin layers when compared to the MTH-BCN suspension gel. The MTT experiment on Raw 264.7 and SW982 cell lines revealed a considerable reduction (p < .05) in the IC50 value of the MTH-BCN-TRS formulation (9.2 mM and 43.2 mM, respectively) in comparison to the drug suspension. According to the findings of the in vivo study, it was found that the MTH-BCN-TRS gel exhibits significantly promising anti-arthritic properties when compared to the conventional diclofenac gel. This was demonstrated through histopathological studies and radiographic analysis. Furthermore, skin irritation investigation on Wistar albino rats confirmed that the formulated MTH-BCN-TRS is a safe option for topical treatment on the skin. The present study has confirmed that the formulated TRS vesicles are a valuable carrier for the transdermal delivery of MTH and BCN, which may be used for the management of rheumatoid arthritis.

Exploring the therapeutic potential of silymarin-based herbal remedy (prebiotic) and probiotic blend in a mouse model of NAFLD: Insights into gut microbiota modulation and liver health.

Non-alcoholic fatty liver disease (NAFLD) is a significant consequence of metabolic dysfunction, often associated with changes in the intestinal microbiota. Prebiotics and probiotics have shown promise in NAFLD management. This study evaluated a silymarin-based herbal remedy with piperine and fulvic acid, alongside a probiotic blend of Bifidobacterium adolescentis, Bifidobacterium bifidum, Lactobacillus casei, and Lactobacillus rhamnosus. Using a NAFLD mouse model induced by a high-fat and high-fructose diet, we assessed biochemical parameters, liver function, glucose levels, and conducted histological analysis. Stool samples underwent 16S rRNA metagenomic analysis to explore changes in microbiota composition. Mice on the high-fat diet exhibited elevated lipids, liver enzymes, and glucose, with reduced high-density lipoprotein levels (with p value < 0.001). Treatment, particularly with F3 (silymarin-piperine-fulvic acid herbal remedy and probiotic blend), significantly reduced hepatic fat accumulation and improved gut microbiota composition. This study highlights the potential of silymarin-based therapy combined with probiotics in attenuating NAFLD progression.

An overview of phospholipid enriched-edge activator-based vesicle nanocarriers: New paradigms to treat skin cancer.

Skin cancer poses a significant global health concern necessitating innovative treatment approaches. This review explores the potential of vesicle nanoformulation incorporating EA (edge activators) to overcome barriers in skin cancer management. The skin's inherent protective mechanisms, specifically the outermost layer called the stratum corneum and the network of blood arteries, impede the permeation of drugs. Phospholipid-enriched EA based nanoformulation offer a promising solution by enhancing drug penetration through skin barriers. EAs like Span 80, Span 20, Tween 20, and sodium cholate etc., enhance vesicles deformability, influencing drug permeation. This review discusses topical application of drugs treat skin cancer, highlighting challenges connected with the conventional liposome and the significance of using EA-based nanoformulation in overcoming these challenges. Furthermore, it provides insights into various EA characteristics, critical insights, clinical trials, and patents. The review also offers a concise overview of composition, preparation techniques, and the application of EA-based nanoformulation such as transfersomes, transliposomes, transethosomes, and transniosomes for delivering drugs to treat skin cancer. Overall, this review intends to accelerate the development of formulations that incorporate EA, which would further improve topical drug delivery and enhance therapeutic outcomes in skin cancer treatment.

Medicinal potential of embelin and its nanoformulations: An update on the molecular mechanism and various applications.

Natural herbs have garnered significant research recently as their components target multiple disease signaling pathways, making them highly potential for various disease prevention and treatment. Embelin, a naturally occurring benzoquinone isolated from Embelia ribes, has shown promising biological activities such as antitumor, antidiabetic, anti-oxidant, and antimicrobial. Various mechanisms have been reported, including monitoring genes that synchronize the cell cycle, up-regulating multiple anti-oxidant enzymes, suppressing genes that prevent cell death, influencing transcription factors, and preventing inflammatory biomarkers. However, the hydrophobic nature of embelin leads to poor absorption and limits its therapeutic potential. This review highlights a wide range of nanocarriers used as delivery systems for embelin, including polymeric nanoparticles, liposomes, nanostructured lipid carriers, micelles, nanoemulsion, and metallic nanoparticles. These embelin nanomedicine formulations have been developed in preclinical studies as a possible treatment for many disorders and characterized using various in vitro, ex vivo, and in vivo models.

Development and Validation of a Robust RP-HPLC Method for the Simultaneous Analysis of Exemestane and Thymoquinone and Its Application to Lipid-Based Nanoformulations.

The present study describes the development and validation of a simple and rapid HPLC method for the simultaneous quantification of exemestane and thymoquinone. The separation of both compounds was performed on a 5 µ C-18 column utilizing phase A as water/methanol (45:5 v/v) and phase B as acetonitrile (50 v/v) (total ratio of A/B = 40:60 v/v) in isocratic elution mode as the mobile phase at a flow rate of 0.8 mL/min. Further, the Box-Behnken design was used for optimizing the analytical method. The proposed method was validated for various parameters, and all parameters were found to be within an acceptable range. The simultaneous detection of both drugs was monitored at 243 nm with a retention time of 5.73 and 6.93 min, respectively. Moreover, the forced degradation studies were conducted under various stress conditions, and the relevance of the validated RP-HPLC method was further explored for the estimation of drugs from lipid-based nanoformulation. Taken together, the study construed the development of an efficient and robust method that could be used for the quantification of these agents in various in vitro as well as in vivo models.

Lipid-based nanoparticle-mediated combination therapy for breast cancer management: a comprehensive review.

Breast cancer due to the unpredictable and complex etiopathology combined with the non-availability of any effective drug treatment has become the major root of concern for oncologists globally. The number of women affected by the said disease state is increasing at an alarming rate attributed to environmental and lifestyle changes indicating at the exploration of a novel treatment strategy that can eradicate this aggressive disease. So far, it is treated by promising nanomedicine monotherapy; however, according to the numerous studies conducted, the inadequacy of these nano monotherapies in terms of elevated toxicity and resistance has been reported. This review, therefore, puts forth a new multimodal strategic approach to lipid-based nanoparticle-mediated combination drug delivery in breast cancer, emphasizing the recent advancements. A basic overview about the combination therapy and its index is firstly given. Then, the various nano-based combinations of chemotherapeutics involving the combination delivery of synthetic and herbal agents are discussed along with their examples. Further, the recent exploration of chemotherapeutics co-delivery with small interfering RNA (siRNA) agents has also been explained herein. Finally, a section providing a brief description of the delivery of chemotherapeutic agents with monoclonal antibodies (mAbs) has been presented. From this review, we aim to provide the researchers with deep insight into the novel and much more effective combinational lipid-based nanoparticle-mediated nanomedicines tailored specifically for breast cancer treatment resulting in synergism, enhanced antitumor efficacy, and low toxic effects, subsequently overcoming the hurdles associated with conventional chemotherapy.

Linalool-Incorporated Synergistically Engineered Modified Liposomal Nanocarriers for Enhanced Transungual Delivery of Terbinafine against Onychomycosis.

This work investigates the synthesis of linalool-containing invasomes for terbinafine (TBF-IN) in order to increase the solubility, bioavailability, and nail permeability of terbinafine (TBF) for transungual administration. TBF-IN was created utilising the thin-film hydration technique, and with the Box-Behnken design (BBD), optimisation was carried out. TBF-INopt were investigated for vesicle size, zeta potential, PDI (Polydispersity index), entrapment efficiency (EE) and in vitro TBF release. In addition, nail permeation analysis, TEM (transmission electron microscopy), and CLSM (confocal scanning laser microscopy) were performed for further evaluation. The TBF-INopt exhibited spherical as well as sealed vesicles with a considerably small size of 146.3 nm, an EE of 74.23 per cent, a PDI of 0.1612, and an in vitro release of 85.32 per cent. The CLSM investigation revealed that the new formulation had better TBF nail penetration than the TBF suspension gel. The antifungal investigation demonstrated that the TBF-IN gel has superior antifungal activity against Trichophyton rubrum and Candida albicans compared to the commercially available terbinafine gel. In addition, an investigation of skin irritation using Wistar albino rats indicates that the TBF-IN formulation is safe for topical treatment. This study confirmed that the invasomal vesicle formulation is an effective vehicle for the transungual delivery of TBF for the treatment of onychomycosis.

Insights into Pharmacological Potential of Apigenin through Various Pathways on a Nanoplatform in Multitude of Diseases.

Apigenin is a natural polyphenolic compound widely distributed as a glycoside in fruits and vegetables. Apigenin belongs to BCS class II with low solubility, which leads to poor absorption and bioavailability. It is mostly absorbed from the small intestine and extensively metabolized through glucuronidation and sulfation processes. Apigenin is known for its antioxidant and anti-inflammatory properties. It is also used as a chemopreventive drug in the management of various cancers. Pharmacological effects of apigenin have a wide range, from neuroprotective to treating renal disorders. Apigenin is non-toxic in nature and acts through various pathways (JAK/STAT, Wnt/ß-catenin, MAPK/ERK, PI3K/Akt, and NF-κB) to exert its therapeutic efficacy. Numerous formulations have been researched to enhance the bioavailability and pharmacological effects of apigenin. Combinatorial therapies are also researched to minimize the side-effects of chemotherapeutic drugs. The review presents pharmacokinetic and pharmacodynamic aspects of apigenin. Apigenin is safe for the treatment and management of numerous diseases. It can be easily incorporated into nanoformulation alone or in combination with other active ingredients to widen the therapeutic window. This review intends to help in drug optimization and therapeutic efficacy maximization for future studies.

Omega-3 fatty acid-based self-microemulsifying drug delivery system (SMEDDS) of pioglitazone: Optimization, in vitro and in vivo studies.

Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose, improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of -20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0-24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.

Nanotransethosomes for enhanced transdermal delivery of mangiferin against rheumatoid arthritis: formulation, characterization, invivo pharmacokinetic and pharmacodynamic evaluation.

The present research study limns the preparation of MNF loaded transethosomes (MNF-TE) to improve MNF solubility, bioavailability and permeation through skin layers for transdermal delivery. MNF-TE was formulated using thin-film hydration method and optimization was done using Box-Behnken design (BBD). MNF-TEopt was characterized for Polydispersity index (PDI), vesicle size, entrapment efficiency, zeta potential and in vitro MNF release. For further evaluation, Pharmacokinetic study, Transmission electron microscopy (TEM), Skin permeation study and Confocal scanning laser microscopy (CLSM) were performed withal. The MNF-TEopt presented spherical and sealed shape vesicles with small vesicle size of 148.6 nm, entrapment efficiency of 74.23%, PDI of 0.1139 and in vitro release of 65.32%. The CLSM study unveiled that the developed formulation has greater permeation of MNF across the skin layers in comparison with the MNF suspension gel. The pharmacokinetic study demonstrated Cmax and AUC0-24 h of 6.94 ± 0.51 µg/ml and 43.92 ± 7.90 µg.h/ml via transdermal route in comparison to Cmax and AUC0-24 h of 3.74 ± 1.91 µg/ml and 22.96 ± 9.76 µg.h/ml presented by MNF-TE oral administration. The in vivo study revealed that the MNF-TE gel has good anti-arthritic potential in comparison with the standard diclofenac gel which was evinced by radiographic analysis and histopathological studies. Further, skin irritation study on Wistar albino rats confirm that the developed MNF-TE formulation is safer for skin application. The current investigation corroborated that the prepared TE vesicle formulation is a treasured carrier for the MNF transdermal delivery for the management of rheumatoid arthritis.