Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products.

Breast cancer is the prominent cause of cancer-related death in women globally in terms of incidence and mortality. Despite, recent advances in the management of breast cancer, there are still a lot of cases of resistance to medicines, which is currently one of the biggest problems faced by researchers across the globe. Out of several mechanisms, breast cancer resistance protein (BCRP) arbitrated drug resistance is a major concern. Hormonal, cytotoxic and immunotherapeutic drugs are used in the systemic therapy of breast cancer. It is vital to choose drugs based on the clinical and molecular attributes of the tumor to provide better treatment with greater efficacy and minimal harm. Given the aforementioned necessity, the use of marine flora in treating breast cancer cannot be neglected. The scientists also stressed the value of marine-derived goods in avoiding breast cancer resistance. Future research into the identification of anticancer drugs will heavily draw upon the marine environment's ample supply of marine-derived natural products (MNPs), which have a wide range of biological functions. Cell cycle arrest, induction of apoptosis and anti-angiogenic, anti-proliferative and anti-metastasis actions are all part of their processes. The overview of breast cancer, the mechanisms underlying its resistance, recent clinical trials based on marine-derived products in breast cancer and the use of marine products in the treatment of breast cancer are highlighted in this paper. Moreover, the authors also emphasised the importance of marine-derived products in preventing breast cancer resistance.

New Insights into the Applications of 3D-Printed Biomaterial in Wound Healing and Prosthesis.

Recently three-dimensional bioprinting (3D-bioP) has emerged as a revolutionary technique for numerous biomedical applications. 3D-bioP has facilitated the printing of advanced and complex human organs resulting in satisfactory therapeutic practice. One of the important biomedical applications of 3D-bioP is in tissue engineering, wound healing, and prosthetics. 3D-bioP is basically aimed to restore the natural extracellular matrix of human's damage due to wounds. The relevant search was explored using various scientific database, viz., PubMed, Web of Science, Scopus, and ScienceDirect. The objective of this review is to emphasize interpretations from the pre-executed studies and to assess the worth of employing 3D-bioP in wound healing as well as prosthetics in terms of patient compliance, clinical outcomes, and economic viability. Furthermore, the benefits of applying 3D-bioP in wound healing over traditional methods have been covered along with the biocompatible biomaterials employed as bioinks has been discussion. Additionally, the review expands about the clinical trials in 3D-bioP field, showing promise of biomedical applicability of this technique with growing advancement in recent years.

Biotin anchored nanostructured lipid carriers for targeted delivery of doxorubicin in management of mammary gland carcinoma through regulation of apoptotic modulator.

Mammary gland tumour has the highest incidence rate and mortality in women, worldwide. The present study envisaged a molecularly targeted nanostructured lipid carrier (NLCs) for doxorubicin (Dox) delivery capable of inducing cellular apoptosis in mammary gland tumour. NLCs were prepared utilizing Perilla frutescens oil (54-69% ω3-fatty acid) as liquid lipid to enhance entrapment of Dox through molecular ion pairing. Biotin decorated NLCs (b-Dox-NLCs) were evaluated in vitro and in vivo. The b-Dox-NLCs showed particle size of 105.2 ± 3.5 nm, zeta potential -35 ± 2 mV, entrapment 99.15 ± 1.71%, drug content 19.67 ± 2.6 mg.g-1, biotin content 5.85 ± 0.64 µg.g-1 and drug release 98.67 ± 2.43% (facilitated by acidic microenvironment) respectively. MTT assay and Flow cytometric analysis revealed higher anti-proliferative capability of b-Dox-NLCs to force apoptosis in MCF-7 cell line vis-à-vis marketed Dox, evidenced by reactive oxygen species level and mitochondrial membrane potential mediated apoptosis. Enhanced antitumor targeting, therapeutic safety and efficacy was exhibited by b-Dox-NLCs, as investigated through tumour volume, animal survival, weight variation, cardiotoxicity and biodistribution studies in 7,12-Dimethylbenz[a]anthracene induced mammary gland tumour. Immunoblotting assay demonstrated b-Dox-NLCs downregulated anti-apoptotic proteins, i.e. bcl-2, MMP-9 while upregulated pro-apoptotic proteins, i.e. caspase-9, p16 and BAX. The experimental results suggest that biotinylated ω3-fatty acid augmented NLCs loaded with Dox are capable of inducing programmed cell death in mammary tumour and can be utilized as safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

ω-3 Fatty Acid Synergized Novel Nanoemulsifying System for Rosuvastatin Delivery: In Vitro and In Vivo Evaluation.

The present study was undertaken to improve rosuvastatin (RSV) bioavailability and pharmacological response through formation of SNES using Perilla frutescens oil as lipid carrier. The composition of oil was estimated by fatty acid methyl ester (FAME) analysis using gas chromatography. Solubility of RSV in Perilla frutescens oil and Cremophor EL was 25.0 ± 3.0 and 60.0 ± 5.0 mg/mL, respectively. Later, nanophasic maps and a central composite design were employed to determine the maximum nanoemulsion region and further optimize SNES in this study. Finally, the optimized formulation was evaluated in vitro and in vivo. FAME analysis revealed that PUFA content was 70.3% of total fatty acid. Optimized SNES formulation demonstrated particle size of 17.90 nm, dissolution 98.80%, cloud point 45°C, emulsification time 2 min, and viscosity 241.41 ± 5.52 cP. The hypolipidemic property of SNES was further explored using Triton X-100-induced hyperlipidemic rat model, and there were reductions of serum cholesterol, triglyceride, and LDL and VLDL levels in the SNES-treated group as compared to the toxic control. Pharmacokinetic study of SNES revealed significantly higher C max (60.13 ± 25.43 ng/mL) and AUC0-∞ (6195 ± 42.38 ng h/mL) vis-à-vis marketed tablet (284.80 ± 13.44 ng/mL, 3131.72 ± 51.93 ng h/mL, respectively). RSV was successfully incorporated into ω-3 fatty acid-based SNES with improved pharmacokinetic parameters (~ 2-fold improved bioavailability) and better hypolipidemic properties, owing to the synergistic effects of hepatic lipid regulation itself. The results clearly explicated that ω-3 fatty acid-based SNES effectively enhanced bioavailability and pharmacological responses of RSV, suggesting that these formulations may be useful as alternative for hyperlipidemia treatment in future drug design perspective.

Oral delivery of allopurinol niosomes in treatment of gout in animal model.

CONTEXT: Gout is a painful disorder which does not have an efficient delivery system for its treatment. OBJECTIVE: Development and in vitro, in vivo evaluation of allopurinol-loaded nonionic surfactant-based niosomes was envisaged. MATERIALS AND METHODS: Niosomes were prepared with Span 20 and Tween 20 (1:1 molar ratio) using ether injection method. The formulations were screened for entrapment efficiency, particle size analysis, zeta potential, release kinetics, in vivo activity, and stability studies. RESULT: Stable, spherical vesicles of average particle size 304 nm with zeta-potential and entrapment efficiency of 22.2 mV and 79.44 ± 0.02%, respectively, were produced. In vitro release study revealed 82.16 ± 0.04% release of allopurinol within 24 h. The niosomal formulation was further evaluated for its antigout potential in monosodium urate (MSU) crystal induced gout animal model. The formulation demonstrated significant uric acid level reduction and enhanced antigout activity when compared with the pure allopurinol. DISCUSSION: The better antigout activity displayed by niosomal formulation could be attributed to sustained release of drug, higher drug solubility within biological fluids, better membrane interaction, smaller size, and presence of cholesterol and surfactant. CONCLUSIONS: This study reveals that niosomes can be an efficient delivery system for the treatment of gout.

A comprehensive review of the application of 3D-bioprinting in chronic wound management.

INTRODUCTION: Chronic wounds require more sophisticated care than standard wound care because they are becoming more severe as a result of diseases like diabetes. By resolving shortcomings in existing methods, 3D-bioprinting offers a viable path toward personalized, mechanically strong, and cell-stimulating wound dressings. AREAS COVERED: This review highlights the drawbacks of traditional approaches while navigating the difficulties of managing chronic wounds. The conversation revolves around employing natural biomaterials for customized dressings, with a particular emphasis on 3D-bioprinting. A thorough understanding of the uses of 3D-printed dressings in a range of chronic wound scenarios is provided by insights into recent research and patents. EXPERT OPINION: The expert view recognizes wounds as a historical human ailment and emphasizes the growing difficulties and expenses related to wound treatment. The expert acknowledges that 3D printing is revolutionary, but also points out that it is still in its infancy and has the potential to enhance mass production rather than replace it. The review highlights the benefits of 3D printing for wound dressings by providing instances of smart materials that improve treatment results by stimulating angiogenesis, reducing pain, and targeting particular enzymes. The expert advises taking action to convert the technology's prospective advantages into real benefits for patients, even in the face of resistance to change in the healthcare industry. It is believed that the increasing evidence from in-vivo studies is promising and represents a positive change in the treatment of chronic wounds toward sophisticated 3D-printed dressings.

Progress in Polymeric Micelles as Viable Wagons for Brain Targeting.

Polymeric micelles have opened up new horizons for improving drug delivery to brain particularly due to their small size, long circulation time, good stability and targetability. They are used to treat a variety of brain conditions, including glioblastoma, migraine, Alzheimer's, Parkinson's, and other conditions linked to the brain. Micelles are currently underutilised in brain targeting despite having several benefits and spanning a wide variety of brain illnesses. Since most medications are unable to cross the blood brain barrier, scientists are continuously working to discover efficient solutions to the problems. The most pressing issue was thought to be the viability and difficulties of translating micelles into the therapeutic setting. This review describes the role of micellar delivery system in brain diseases treatment along with their route of administration and outcomes. The review also discusses the current state of patents and clinical trials in the relevant fields and their potential future applications.

Role of Brain-Gut-Microbiota Axis in Depression: Emerging Therapeutic Avenues.

The human gut microbiota plays a significant role in the pathophysiology of central nervous system-related diseases. Recent studies suggest correlations between the altered gut microbiota and major depressive disorder (MDD). It is proposed that normalization of the gut microbiota alleviates MDD. The imbalance of brain-gut-microbiota axis also results in dysregulation of the hypothalamicpituitary- adrenal (HPA) axis. This imbalance has a crucial role in the pathogenesis of depression. Treatment strategies with certain antibiotics lead to the depletion of useful microbes and thereby induce depression like effects in subjects. Microbiota is also involved in the synthesis of various neurotransmitters (NTs) like 5-hydroxy tryptamine (5-HT; serotonin), norepinephrine (NE) and dopamine (DA). In addition to NTs, the gut microbiota also has an influence on brain derived neurotrophic factor (BDNF) levels. Recent research findings have exhibited that transfer of stress prone microbiota in mice is also responsible for depression and anxiety-like behaviour in animals. The use of probiotics, prebiotics, synbiotics and proper diet have shown beneficial effects in the regulation of depression pathogenesis. Moreover, transplantation of fecal microbiota from depressed individuals to normal subjects also induces depression-like symptoms. With the precedence of limited therapeutic benefits from monoamine targeting drugs, the regulation of brain-gut microbiota is emerging as a new treatment modality for MDDs. In this review, we elaborate on the significance of brain-gut-microbiota axis in the progression of MDD, particularly focusing on the modulation of the gut microbiota as a mode of treating MDD.

Advances and Challenges in Intranasal Delivery of Antipsychotic Agents Targeting the Central Nervous System.

Treatment of central nervous system (CNS) disorders is challenging using conventional delivery strategies and routes of administration because of the presence of the blood-brain barrier (BBB). This BBB restricts the permeation of most of the therapeutics targeting the brain because of its impervious characteristics. Thus, the challenges of delivering the therapeutic agents across the BBB to the brain overcoming the issue of insufficient entry of neurotherapeutics require immediate attention for recovering from the issues by the use of modern platforms of drug delivery and novel routes of administration. Therefore, the advancement of drug delivery tools and delivering these tools using the intranasal route of drug administration have shown the potential of circumventing the BBB, thereby delivering the therapeutics to the brain at a significant concentration with minimal exposure to systemic circulation. These novel strategies could lead to improved efficacy of antipsychotic agents using several advanced drug delivery tools while delivered via the intranasal route. This review emphasized the present challenges of delivering the neurotherapeutics to the brain using conventional routes of administration and overcoming the issues by exploring the intranasal route of drug administration to deliver the therapeutics circumventing the biological barrier of the brain. An overview of different problems with corresponding solutions in administering therapeutics via the intranasal route with special emphasis on advanced drug delivery systems targeting to deliver CNS therapeutics has been focused. Furthermore, preclinical and clinical advancements on the delivery of antipsychotics using this intranasal route have also been emphasized.

Appraisal of anti-gout potential of colchicine-loaded chitosan nanoparticle gel in uric acid-induced gout animal model.

Present study is aimed at transdermal delivery of colchicine-loaded chitosan nanoparticles. The nanoformulations were prepared utilising spontaneous emulsification method and optimised through 23 factorial designs. The optimised formulation (CHNP-OPT) displayed an average particle size of 294 ± 3.75 nm, entrapment efficiency 92.89 ± 1.1% and drug content 83.45 ± 2.5%, respectively. In vitro release study demonstrated 89.34 ± 2.90% release over a period of 24 h. Further, CHNP-OPT incorporated into HPMC-E4M (hydroxypropyl methylcellulose) to form transdermal gel. CHNPgel displayed 74.65 ± 1.90% permeation and stability over a period of 90 days. The anti-gout potential of CHNPgel formulation was evaluated in vivo against monosodium urate (MSU) crystal-induced gout in animal model. There was significant reduction in uric acid level, during MSU administration, when compared with the conventional gel of colchicine. The enhanced therapeutic potential was witnessed through X-ray. The study revealed that colchicine-loaded CHNPgel proved their supremacy over plain colchicine and can be an efficient delivery system for gout treatment.

Exosomes: A Novel Therapeutic Paradigm for the Treatment of Depression.

Extracellular vesicles (EVs) of endocytic origin are known as exosomes. These vesicles are released by cells and are found in biofluids, such as saliva, urine, and plasma. These vesicles are made up of small RNA, DNA, proteins, and play a vital role in many physiological processes. In the central nervous system (CNS), they participate in various physiological processes such as stress of nerve cells, communication between the cells, synaptic plasticity, and neurogenesis. The role of exosomes in depression needs to be explored further. It is known that exosomes can cross the blood brain barrier (BBB), which is made up of glial cells astrocytes. One of the advantages of these vesicles is that they are able to transfer macromolecules like DNA, protein, mRNAs, and miRNAs to recipient cells. This review focuses on the potential role of exosomes in depression and their utilization as a treatment option or diagnostic tool of depression.

Sericin: A Versatile Protein Biopolymer with Therapeutic Significance.

Sericin is a unique proteinaceous biopolymer obtained from cocoons of Bombyx Mori. It has become very popular since it is bestowed with numerous health benefits. Sericin is composed of 18 types of amino acids, out of which 8 amino acids play a significant role in human metabolic pathways. Sericin is easily amenable to make into novel dosage forms and also has been conferred with numerous therapeutic activities such as wound healing, antihypertensive, neuro-protective, antitumor, anti-diabetic, anti-wrinkle, anti-ageing and antioxidant amongst various others. This review summarizes the current status of sericin, as a therapeutic moiety with a focus on active constituents as well as their proposed mechanism in the treatment of various chronic diseases. It also summarizes previous and current in-vitro, in-vivo, cell lines studies and clinical trials based pieces of evidence corroborating the therapeutic activities of sericin.

Correction to: a facile approach for fabricating CD44-targeted delivery of hyaluronic acid-functionalized PCL nanoparticles in urethane-induced lung cancer: Bcl-2, MMP-9, caspase-9, and BAX as potential markers.

In the original article the blots for BAX were inadvertently flipped in Fig. 11a. The inadvertent error in the case of BAX does not change any of the results.

A synergistic approach for management of lung carcinoma through folic acid functionalized co-therapy of capsaicin and gefitinib nanoparticles: Enhanced apoptosis and metalloproteinase-9 down-regulation.

BACKGROUND: Lung cancer is one of the most lethal cancers and lacks effective treatment strategy. Therapeutic efficacy can be improved through active targeting approach utilizing surface engineered nanoparticles (NPs) for cancer therapy. PURPOSE: The present study envisioned development of Folic acid (FA) functionalized NPs for co-administration of gefitinib (Gnb) and capsaicin (Cap) respectively to enhance the therapeutic outcome by disabling the barriers related to tumors extracellular matrix. RESEARCH METHODS AND PROCEDURE: The FA conjugated Gnb/Cap polymeric (PLGA-PEG) NPs were prepared using oil in water emulsion technique and methodically developed using Quality by Design (QbD) concept employing central composite design. The developed formulations were subjected to various in vitro (A549 cell lines) and in vivo evaluations in urethane-induced lung cancer. RESULTS: The modified NPs displayed particle sizes of 217.0 ±â€¯3.2 nm and 213.0 ±â€¯5.2 nm and drug release of 85.65 ±â€¯3.21% and 81.43 ±â€¯4.32% for Gnb and Cap respectively. Higher cellular uptake and lower cell viability in A549 cell line was displayed by functionalized NPs compared to free drug. Co administration of Gnb and Cap NPs displayed significant targeting potential, reduction in tumor volume while restoring the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels when compared with toxic group. Significant down regulation was observed for anti-apoptotic proteins (MMP-9) and up regulation of pro-apoptotic proteins (caspase-3, caspase-9 and MMP-9) with co-therapy of Gnb and Cap NPs, when compared with individual therapy through Gnb/Cap. CONCLUSION: Potentiation of the action of Gnb when co administered with Cap NPs can be a promising breakthrough for developing safe, effective and targeted delivery for lung carcinoma therapy.

A facile approach for fabricating CD44-targeted delivery of hyaluronic acid-functionalized PCL nanoparticles in urethane-induced lung cancer: Bcl-2, MMP-9, caspase-9, and BAX as potential markers.

Lung carcinoma ranks highest in cancer-related death (about 20% of total cancer deaths) due to poor prognosis and lack of efficient management therapy. Owing to the lack of effective therapeutic approaches, survival rate of less than 5 years persists over the years among non-small cell lung cancer (NSCLC) patients. Capsaicin (CAP) is well reported for its antiproliferative and antioxidant properties in various literature but lacks an appropriate delivery carrier. The present study was aimed to develop CAP-loaded hyaluronic acid (HA) nanoparticles (NPs) utilizing layer by layer technique to achieve enhanced and precise delivery as well as target specificity. The NPs were evaluated for in vitro release, particle size, zeta potential, and cytotoxicity on A549 cells. The optimized NPs exhibited a particle size of 194 ± 2.90 nm, - 27.87 ± 3.21 mV zeta potential, and 80.70 ± 4.29% release, respectively, over a period of 48 h. Flow cytometric analysis revealed superior performance of HA-PCL-CAP in terms of suppressed cell viability in A549 cell lines when compared with CAP and PCL-CAP. Further, HA-anchored NPs were evaluated in vivo for their therapeutic efficacy in urethane-induced lung carcinoma in rat model. The superlative therapeutic potential of HA-PCL-CAP was advocated from the results of reactive oxygen species and mitochondrial membrane-mediated apoptosis. HA-PCL-CAP-administered groups presented greater therapeutic efficacy as revealed through reduced tumor volume and improved animal survival rate. A greater drug accumulation in tumor tissue as revealed from biodistribution studies evidences targeting potential of HA-PCL-CAP in urethane-induced lung carcinoma. Graphical abstract ᅟ.

Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets.

Phytic acid (PA) has momentous chemotherapeutic potential. Due to the chelate formation and rapid elimination, it is not popular in cancer treatment. The present work was inquested to develop a surface-modified nanoformulation of PA which prevents its speedy elimination and maximizes chemotherapeutic action. Chloroauric acid was reduced with pectin to produce pectin-gold nanoparticles (PGNPs). PGNPs were incubated with PA and jacalin for drug loading and surface modifications, respectively, to form PA-loaded jacalin-pectin-gold nanoparticles (PA-J-PGNPs). Formulation(s) were assessed for various pharmaceutical/pharmacological parameters. To validate the efficacy against colon carcinogenesis, formulation(s) were assessed in 1,2-dimethylhydrazine (DMH)-treated Wistar rats. DMH treatment distorted colonic architecture, oxidative, and hemodynamic parameters, which were favorably restored by PA-J-PGNP administration. To further confirm our deliberations, formulation(s) were also examined against DMH-altered metabolic changes and expression of markers pertaining to cellular proliferation, which was reinstated by PA-J-PGNPs. Our findings establish PA formulation(s) as a promising approach for suppression of colon carcinogenesis.

QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation.

Breast cancer is the most common cancer of occurrence in women and has the highest mortality incidence rate therein. The present study envisaged to develop doxorubicin (Dox) loaded folate functionalized nanoemulsion (NE) for profound therapeutic activity against mammary gland cancer. NE was prepared using pseudo-ternary phase diagrams utilizing α-linolenic acid (ALA) as lipid phase, to further enhance the anticancer potential of Dox. Box-Behnken design was employed to systematically develop the NE. Optimized NE (f-Dox-NE) was evaluated for in vitro and in vivo performance. f-Dox-NE, with globule size 55.2 ± 3.3 nm, zeta potential - 31 ± 2 mV, entrapment 92.51 ± 3.62%, drug loading 0.42 ± 0.08% and percent drug release 94.86 ± 1.87% in 72 h, was capable of reducing cell viability in MCF-7 cell lines vis-à-vis pure and marketed drug. Further, mechanistic studies in MCF-7 cell lines demonstrated that f-Dox-NE induces cellular apoptosis by reactive oxygen species generated and mitochondrial membrane mediated apoptosis. The antitumor effect was evaluated in 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland tumor in female Albino Wistar rats. f-Dox-NE exhibited enhanced antitumor targeting potential, therapeutic safety and efficacy vis-à-vis pure and marketed drug, as revealed by tumor volume, animal survival, weight variation, cardiotoxicity and biodistribution studies. f-Dox-NE restored the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels in comparison to DMBA induced animal group. f-Dox-NE displayed downregulation of anti-apoptotic (Bcl-2 and MMP-9) proteins and upregulation of pro-apoptotic proteins (caspase-9 and BAX). The experimental results suggest that ALA augmented folate functionalized NE are able to overcome the challenges of developing safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

Assessment of improved buccal permeation and bioavailability of felodipine microemulsion-based cross-linked polycarbophil gel.

The oral bioavailability of felodipine (FEL) is very low, i.e., about 15%. This could be due to low water solubility and hepatic first-pass effect. The objective of the present study was to develop FEL microemulsion-based gel, to bypass the first pass effect, for buccal delivery. The optimized FEL microemulsion (OPT-MEF) was used to prepare buccoadhesive gels, with varying concentrations of hydroxypropyl methylcellulose (HPMC) E4M and polycarbophil (PCP), and evaluated. The cross-linking of the PCP gelling agent was done by adjusting the pH with a neutralizing agent, triethanolamine (TEA). The formulations, namely drug suspension, OPT-MEF, microemulsion-based buccal gel containing 1% w/v (MEF-E4M1), 2% w/v (MEF-E4M2), and 3% w/v (MEF-E4M3) of HPMC K4M and 1% w/v (MEF-PCP1), 2% w/v (MEF-PCP2), and 3% w/v (MEF-PCP3) of PCP were prepared and optimized on the basis of ex vivo permeation study, mucoadhesion force, and viscosity. The optimized buccal gel (MEF-PCP1) showed significantly higher (p < 0.01) permeation flux (J = 0.44 ± 0.16 mg/cm2/h), when compared with the drug suspension (J = 0.17 ± 0.14 mg/cm2/h). The permeation enhancement ratio of MEF-PCP1 was found to be 2.59 times higher than that of the aqueous suspension of the drug. The texture profile analysis of MEF-PCP1 was performed which showed spreadability (3.2 mJ), extrudability (151.8 mJ), hardness (13.8 g), and adhesiveness (41.0 g), and results indicated good spreadability and adhesiveness. The rheological study revealed the pseudoplastic flow behavior of MEF-PCP1 buccal gel. The Cmax value 9.21 ± 2.88 µg/ml of MEF-PCP1 gel was found to be significantly higher (P < 0.01) compared to the same dose administered by oral route (Cmax value 3.51 ± 1.74 µg/ml). The relative bioavailability (Fr) of the optimized MEF-PCP1 buccal gel was about 397.39% higher than that of oral route. In conclusion, consistent and effective buccal gel containing optimized FEL-loaded microemulsion, with improved buccal permeation and pharmacokinetic parameters was developed successfully to improve the bioavailability of FEL.

Augmented bioavailability of felodipine through an α-linolenic acid-based microemulsion.

The oral bioavailability of felodipine, a dihydropyridine calcium channel antagonist, is about 15%. This may be due to poor water solubility, and a lower intestinal permeability than a BCS class I drug, and hepatic first-pass metabolism of the drug. Many drugs are unpopular due to solubility issues. The goal of this study was to develop and optimize a felodipine-containing microemulsion to improve the intestinal permeability and bioavailability of the drug. The felodipine microemulsions were developed with the selected components, i.e., α-linolenic acid as the oil phase, Tween 80 as a surfactant, and isopropyl alcohol as co-surfactant using Box-Behnken design and characterized for in vitro release and particle size. The optimized felodipine-loaded microemulsion was investigated for physicochemical interaction, surface morphology, intestinal permeability, rheology, cytotoxicity, cellular uptake, pharmacodynamic (electrocardiogram and heart rate variability), and pharmacokinetic studies to explore its suitability as a promising oral drug delivery system for the treatment of hypertension. The optimized felodipine-loaded microemulsion showed significantly higher (P < 0.05) apparent permeability coefficients (Papp) at 7.918 × 10-5 cm/s after 1 h, when compared with conventional formulations that are marketed tablet, drug oily solution, and drug emulsion, which showed a maximum Papp of 3.013, 4.428, and 5.335 × 10-5 cm/s, respectively. The optimized felodipine-loaded microemulsion showed biocompatibility and no cytotoxicity. Cellular uptake studies confirmed payload delivery to a cellular site on the J774.A1 cell line. The rheology study of the optimized felodipine-loaded microemulsion revealed Newtonian-type flow behavior and discontinuous microemulsion formation. In pharmacodynamic studies, significant differences in parameters were observed between the optimized felodipine-loaded microemulsion and marketed formulation. The optimized felodipine-loaded microemulsion showed significantly higher (p < 0.01) C max (7.12 ± 1.04 µg/ml) than marketed tablets (2.44 ± 1.03 µg/ml). It was found that AUClast obtained from the optimized felodipine-loaded microemulsion (84.53 ± 10.73 µg h/ml) was significantly higher (p < 0.01) than the marketed tablet (27.41 ± 5.54 µg h/ml). The relative bioavailability (Fr) of the optimized felodipine-loaded microemulsion was about 308.3% higher than that of the marketed formulation. The results demonstrate that the prepared microemulsion is an advanced and efficient oral delivery system of felodipine for the management of hypertension.