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Glycyrrhizic acid (GA) exhibited potential anti-cancer efficacy and was used for the treatment of skin cancer. Transethosomes were developed to improve the solubility, bioavailability, and permeability of GA since it shows high solubility in ethanol. The topical route offers the benefits of higher patient compliance, easy administration, and withdrawal in case of any side effects. The GA loaded transethosome (GA-TE) was optimized by using the Box-Behnken design. The optimized GA-TE formulation was characterized for vesicle size, and zeta potential, which were 127.6 ± 0.8 nm and −24.41 ± 0.7 mV respectively. The % entrapment efficiency and % drug loading of the optimized GA-TE formulation were found to be 85.22 ± 0.94 % and 6.22 ± 0.43 % respectively. The prepared GA-TE formulation was converted to topical gel by incorporating 1 % Carbopol 934 as a gelling agent. The texture analysis of GA-TE gel showed that the values of cohesiveness, work of cohesion, consistency, and firmness were suitable for the topical delivery system for skin cancer as compared to the conventional gel. The results of ex-vivoand in-vitropermeation of GA-TE gel showed better and enhanced permeation than conventional gel. The confocal laser scanning microscopy results showed better permeation, retention, deposition, and distribution of rhodamine B-loaded GA-TE gel formulation into the skin as compared to conventional gel. The produced GA-TE formulation was proven to be beneficial in treating skin cancer based on the in-vivoresults.

Advancement in nanotechnology and its intervention into the medical field has led to significant development in the field of oral health. Also, the combination of nanomaterial science and biotechnology in dental nanorobotics has enthralled us by adding momentum to contemporary dental practices. The progressive nature of dental afflictions often requires an umbrella approach for their prevention, diagnosis, and complete treatment. Furthermore, the complex nature of dental diseases entails customized treatment modalities, which provides the development of various nanotechnology armamentariums. Furthermore, with the objective of controlled drug delivery, researchers have done a plethora of work to apply nanomaterials such as nanospheres, nanotubes, and nanocomposites for dental infections. However, the fundamental concern with nanotechnology is cost involvement and scaleup hurdles which limits its commercialization. Nevertheless, we hope that optimal utilization of the available nanotechnological interventions for modern dental practice will shortly improve oral health. Hence, this review primarily focuses on the types of nanotechnological interventions explored for various dental afflictions. Also, the authors have attempted to enlighten the readers about the practical aspects of nanotherapeutics for dental disease, that is, a journey from laboratory to product commercialization.

Background: The present work aimed to develop an ethosomal gel of naproxen sodium for the amelioration of rheumatoid arthritis. Objective: In the present work, we have explored the potential of ethosomes to deliver naproxen into deeper skin strata. Further, the anti-inflammatory efficacy of naproxen ethosomal formulation was assessed using the carrageenan-induced rat paw edema model. Methods: Naproxen sodium nanoethosomes were prepared using different proportions of lipoid S100 (50mg-200mg), ethanol (20-50%) and water, and were further characterized on the basis of vesicle morphology, entrapment efficiency, zeta potential, in-vitro drug release and ex-vivo permeation studies. Results: The optimized ethosomal formulation was found to have 129 ± 0.01 nm particle size, 0.295 Polydispersity Index (PDI), -3.29 mV zeta potential, 88% entrapment efficiency and 96.573% drug release in 24 hours. TEM and SEM analysis of the optimized formulation showed slightly smooth spherical structures. The Confocal laser scanning microscopy showed that ethosomes could easily infiltrate into deeper dermal layers (upto 104.9μm) whereas the hydroalcoholic solution of the drug could penetrate up to 74.9μm. Further, the optimized ethosomal formulation was incorporated into 1% carbopol 934 gel base and optimized wherein the transdermal flux was found to be approximately 10 times more than the hydroethanolic solution. Also, the in-vivo pharmacodynamic study of the optimized ethosomal gel exhibited a higher percentage inhibition of swelling paw edema than marketed diclofenac gel. Conclusion: The ethosomal gel was successfully developed and has shown the potential to be a good option for the replacement of conventional therapies of rheumatoid arthritis.

Gatifloxacin eye drops are frequently used in eye infections. However such formulations have a major drawback i.e. short duration of action and usually require 4–6 times installations daily. A chitosan coated niosomal formulation of gatifloxain was purposed to show a longer retention time on eyes and subsequent reduction in dosing frequency. Vesicles were prepared by solvent injection method using cholesterol and Span-60. An extensive optimization of formulation was done using different ratios of cholesterol, Span-60 and drug, revealed NS60-5 (cholesterol: span-60 50: 50 and drug content of 20 mg) to be the optimized niosome formulation. NS60-5 had shown a highest entrapment efficiency of 64.9 ± 0.66% with particle size 213.2 ± 1.5 nm and zeta potential −34.7 ± 2.2 mV. Optimized niosomes were also coated with different concentrations of chitosan and evaluated. Permeation studies had revealed that optimized niosomes (86.77 ± 1.31%) had increased the transcorneal permeation of Gatifloxacin more than two fold than simple drug solution (37.19 ± 1.1%). Longer retention potential of the coated niosomes was further verified by fluorescence microscopy. Study revealed that simple dye solution got easily washed out with in 6 h. The uncoated niosomes (NS60-5) showed a longer retention (more than 6 h), which was further enhanced in case of coated niosomes i.e. CNS60-1 (more than 12 h). Antimicrobial studies had shown the better efficacy of CNS60-1 (zone of inhibition) when compared to marketed formulation. The final chitosan formulation was found to have shown better ocular tolerability as demonstrated by corneal hydration test histopathology investigations.

The present investigation was carried out with the aim of optimization of raloxifene hydrochloride-entrapped, limonene containing transfersomes for transdermal delivery. Several formulations were prepared by varying independent variables such as Phospholipid, sodium cholate and limonene while vesicles size, entrapment efficiency and polydispersity index were the dependent variables for Box-Behnken Design. Further, bioavailability assessment of raloxifene in Wistar rats was evaluated after transdermal application and compared with its oral formulation. It was observed that the optimized raloxifene loaded transfersomes formulation showed vesicle size of 107.8 nm, polydispersity index of 0.252 and entrapment efficiency of 90.2% which is close to the predicted values of 114.45 nm, 0.251 and 82.82% respectively generated by the Design Expert software. The TEM image shows the outline and the core of the well identified sealed spherical structure. Confocal laser microscopy study demonstrated that the prepared transfersomes formulation was capable to increase the permeation of probe dye into deeper layer of rat's skin in comparison to the control dye solution. The transdermal flux presented by the transfersomes gel formulation was found to be 13.20 μg/cm2/h whereas the control gel showed the transdermal flux of 2.35 μg/cm2/h across rat skin. Further the in vivo pharmacokinetic study revealed that the relative bioavailability following application of transfersomes gel in Wistar rats was found be increased by 2.71 times as compared to the oral suspension of raloxifene. It was concluded that the prepared transfersomes formulation was found to be a potentially useful drug carrier for the enhancement of raloxifene bioavailability in rats.

Background: Vaginal drug delivery approach represents one of the imperative strategies for local and systemic delivery of drugs. The peculiar dense vascular networks, mucus permeability, and range of physiological characteristics of the vaginal cavity have been exploited for therapeutic benefit. Furthermore, the vaginal drug delivery has been curtailed due to the influence of different physiological factors like acidic pH, constant cervical secretion, microflora, cyclic changes during periods along with turnover of mucus of varying thickness. Objective: This review highlights advancement of nanomedicine and its prospective progress towards the clinic. Methods: Relevant literature reports and patents related to topics are retrieved and used. Result: The extensive literature search and patent revealed that nanocarriers are efficacious over conventional treatment approaches. Conclusion: Recently, nanotechnology based drug delivery approach has promised better therapeutic outcomes by providing enhanced permeation and sustained drug release activity. Different nanoplatforms based on drugs, peptides, proteins, antigens, hormones, nucleic material, and microbicides are gaining momentum for vaginal therapeutics.

The aim of the current study was to develop a dual-loaded core shell nanoparticles encapsulating paclitaxel (PTX) and ellagic acid (EA) by membrane dialysis method. Based on particle size, polydispersity index (PDI), and entrapment efficiency, the dual drug-loaded nanoparticles (F2) was optimized. The optimized nanoparticles (F2) showed a particle size of 140±2 nm and a PDI of 0.23±3. The size and the morphology were confirmed by transmission electron microscopy (TEM) and found agreement with the results of dynamic light scattering. The entrapment efficiencies of total drug (PTX and EA), PTX, and EA in the nanoparticles (F2) were measured as 80%, 62.3%, and 37.7%, respectively. The in vitrorelease profile showed a controlled release pattern for 48 h. A higher cytotoxicity was observed with nanoparticles (F2) in comparison to free PTX. The results revealed that co-delivery of PTX and EA could be used for its oral delivery for the effective treatment of breast cancer.

Background: Nanotechnology-based drug delivery approach has emerged as a promising field, where different kinds of formulations are developed for therapeutic applications. Inflowing of nanomedicine developed through various biomaterials appears to be a game changer in the domain of pharmaceutical and biotechnological industries. Nanomedicines propose to overcome the major constraints of conventional medicine of low solubility and stability, non-adequate pharmacokinetic profiles and side effects. Objectives: Mesoporous Silica Nanoparticles (MSNs) have garnered significant attention in biomedical applications for its multifunctionality. The porous structure of MSNs provides the opportunity for heavy drug loading, controlled release and ligand functionality. From last decades, a lot of interest has been generated owing to the better drug delivery attributes of MSNs to introduce unique biological effects for its suitable therapeutic application. Methods: The review article gives an insight into the current advancement of usage of MSNs in drug delivery for cancer, non-cancer and biosensors based biomedical applications along with technology that is protected by patents. Conclusion: The future success of MSNs is widened because of their valuable characteristic that easily combines with various functionalities which would display enormous potential translational possibilities.

Background: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. Objective: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. Methods: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. Results: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. Conclusion: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.

The objective of the present study was to develop solid self-nanoemulsifying drug delivery system (SNEDDS) of poorly absorbed drug sertraline (SRT) and evaluation of its pharmacokinetic parameters in rats. The composition of optimized liquid SNEDDS was (25.42 % v/v) Labrafil M 2125 CS and Maisine 35-1 (1:1), (49.72 % v/v) Tween 80 and (24.86 % v/v) Lauroglycol 90 containing 25 mg SRT. Solid SNEDDS was prepared by spray-drying the liquid SNEDDS using dextran 40 as solid carrier. There was no significant difference (p > 0.05) in the droplet size of reconstituted nanoemulsion between both liquid and solid SNEDDS. The surface characterization of spray-dried powder showed a satisfactory regular spherical shape of particles. The internal physical state of SRT was verified by X-ray diffraction analysis indicated the transformation of crystalline structure of SRT to amorphous and molecularly dispersed state. In vitro release of SRT from solid SNEDDS was highly significant (p < 0.01) as compared to unformulated SRT. After oral administration of solid SNEDDS to adult Sprague–Dawley (SD) rats, the area under the curve (AUC) were 2.8- and 6.8-folds and the maximum plasma concentration (Cmax) were 3.5 -and 13-folds higher, respectively compared to those of conventional capsule and unformulated drug suspension. These results reveal that solid SNEDDS results in a significantly increased absorption of SRT compared with that from the marketed conventional capsule and aqueous suspension of SRT. Thus, this solid SNEDDS may provide a useful solid dosage form for oral delivery of poorly-water soluble lipophilic compounds.

In the present study, Ketoconazole loaded transfersomal formulation was developed using 3-factor, 3-level Box-Behnken design to find out the best formulation. Optimized transfersomal formulation was prepared by solvent evaporation method and evaluated in vitrofor vesicle size (126.9 ± 5.45 nm) and entrapment efficiency (82.6%). Transfersomal gel were developed by incorporation of optimized transfersomal formulation into 1% carbopol gel base and characterized by physical evaluation and rheological studies. The cumulative release of drug were shown at 72 h approximately 74% and 97% of ketoconazole from suspension and transfersomal gels respectively. The flux for transfersomal gel was found to be about 3 times that of drug suspension gel. Results of the histopathological studies of gel treated skin indicated negligible sign of toxicity and irritation. The prepared transfersomal gel showed antimicrobial activity against Candida albicans with MIC 4.57–4.6 μg/mL and better zone of inhibition as compared to reference standard. The developed gel showed promising antimicrobial activity. These overall findings suggested that transfersomal gel holds an excellent potential for ketoconazole delivery.

Background: In order to establish safety and efficacy, generic medicines are required to prove bioequivalence with the innovator product while in case of Biosimilars (copy version innovator biologicals) requirements are product specific (case by case basis) and there is no common data requirement to establish the safety and efficacy. The challenge is to determine the nature of clinical and non-clinical studies required. Methods: The major causes of variability are its large size, complicated structure, stability issues, microheterogeneity involved and manufacturing process, etc. It is also difficult to draw a common regulatory pathway which covers all possible complex products. So, in this article we discuss the technicalities involved with this complex therapeutics (emphasizing on biosimilars) and look into regulatory frameworks for market authorization, keeping USFDA, EMA and ICH guidelines as standards. Results: Regulatory authorities have identified three main characteristics of a protein that must be considered during development i.e., 3D structures, post translational modifications (PTMs) and protein aggregation. Agencies generally consider the totality of the evidence to support a demonstration of biosimilarity, and recommend that sponsors should use a stepwise approach in the development of biosimilar products which may include a comparison of the proposed product and RBP with respect to Structure, Function, Animal Toxicity, Human Pharmacokinetics (PK) and Pharmacodynamics (PD), Clinical Immunogenicity, and Clinical Safety and effectiveness. Conclusion: There is also ambivalence about its future market considering the complicated development process involved. Its market growth has been alluring for pharmaceutical companies so far. An in-depth understanding of science involved and technologies available to explore may lead us to an affable regulatory pathway. In this review we put an effort to touch upon these aspects of biopharmaceuticals.

Background: The last few decades have witnessed enormous advancements in the field of Pharmaceutical drug, design and delivery. One of the recent developments is the advent of 3DP technology. It has earlier been successfully employed in fields like aerospace, architecture, tissue engineering, biomedical research, medical device and others, has recently forayed into the pharmaceutical industry.Commonly understood as an additive manufacturing technology, 3DP aims at delivering customized drug products and is the most acceptable form of“personalized medicine”. Methods: Data bases and search engines of regulatory agencies like USFDA and EMA have been searched thoroughly for relevant guidelines and approved products. Other portals like PubMed and Google Scholar were also ferreted for any relevant repository of publications are referred to wherever required. Results: So far only one pharmaceutical product has been approved in this category by USFDA and stringent regulatory agencies are working over the drafting of guidelines and technical issues. Major research of this category belongs to the academic domain. Conclusion: It is also implicit to such new technologies that there would be numerous challenges and doubts before these are accepted as safe and efficacious. The situation demands concerted and cautious efforts to bring in foolproof regulatory guidelines which would ultimately lead to the success of this revolutionary technology.

Topotecan being highly water-soluble drug with a property of getting converted from biologically active lactone form to biologically inactive carboxylate form, thus making it a candidate with very less bioavailability; so, our approach was to develop a stable Topotecan lactone (active) form nanoparticles (TNPs). TNPs were developed and optimized successfully with size of 130.0 ± 3.9 nm, 0.102 ± 0.009 PDI and zeta potential of −18.0 ± 2.1 mV. The percent entrapment efficiency of active lactone form of Topotecan (TOP) in optimized formulation of TNPs was 65.72 ± 1.9%, that was enhanced by approximately 15% from 65.72 ± 1.9% to 73.27 ± 2.1% by using Zn2+ions as a complexing agent between PLGA polymer and Topotecan drug. Lyophilized TNPs under DSC study showed the entrapment of TOP in amorphous or solution form, which was further confirmed by XRD studies. In vitrorelease study depicts that the drug TOP in TNPs showed initial burst release followed by sustained release for up to 72 h in PBS (pH 7.4). Ex-vivogut permeation study revealed that TNPs enhanced the permeation of TOP through the gut. Further, in vivopharmacokinetic data showed that the oral bioavailability of TOP was increased by four folds from TNPs. TNPs in comparison to TOP drug also showed a significant reduction in IC50in cell line studies on MCF-7/Adr resistant cells.

The pivotal idea toward the development of chronotherapeutics is synchronizing the in vivo drug bioavailability with the rhythms of the disease to optimize therapeutic outcomes and minimize side effects, which is contrary to the homeostatic theory of drug delivery. The advent of formulation technologies, marketing exclusivities of innovative products, and provisions/amendments in regulatory frameworks have led to the development of commercial chronotherapeutic products, but their numbers are few and are confined mainly to diseases of the cardiovascular system. A major bottleneck for its development would be the understanding of rhythmic variations of disease, but following regulatory pathways for commercial development has always been challenging. In this article, a few commercial products have been investigated in view of their developmental strategies in order to find out the minimum preclinical and clinical studies needed for the development of chronotherapeutics.

The pivotal idea toward the development of chronotherapeutics is synchronizing the in vivo drug bioavailability with the rhythms of the disease to optimize therapeutic outcomes and minimize side effects, which is contrary to the homeostatic theory of drug delivery. The advent of formulation technologies, marketing exclusivities of innovative products, and provisions/amendments in regulatory frameworks have led to the development of commercial chronotherapeutic products, but their numbers are few and are confined mainly to diseases of the cardiovascular system. A major bottleneck for its development would be the understanding of rhythmic variations of disease, but following regulatory pathways for commercial development has always been challenging. In this article, a few commercial products have been investigated in view of their developmental strategies in order to find out the minimum preclinical and clinical studies needed for the development of chronotherapeutics.

Typically, chemotherapy has been dominated by intravenous administration. Though, inclination towards oral ingestion of chemotherapeutics is increasing since it offers ample of fascinating opportunities including better quality of life, treatment advantages and low healthcare cost. However, low or moderate bioavailability along with significant inter-patient variability and narrow therapeutic window challenges their oral administration. Thus, optimization of oral route with maximized efficacy and miniminal adverse events is a challenging area. To surmount the challenges, a number of strategies like P-glycoprotein (P-gp) modulation, colloidal carrier etc. have been under investigation and scientists are exploring the utility of solid dispersions, prodrugs, biconjugates, complexes, microparticulate, and nanoparticulate systems (liposome, SLN, dendrimers, SEDDS, nanoparticles). Among these, nanoparticulate systems have shown promising results due to their targeting potential and ability to alter absorption pathways. Functional excipients with P-gp modulating activity are also being explored for more effective oral delivery of chemotherapeutics. This article explores the encouraging reports, recent patents and inventions on the feasibility and applicability of oral administration of chemotherapeutics.

Lutein has low oral bioavailability and penetration through the skin. Therefore, the major objective is the development of ethosomal gel loaded with lutein to enhance dermal deposition of lutein. Lutein-loaded formulation (Lut-eth) was developed and optimized using QbD software. The characterization of Lut-eth formulation was performed using zeta sizing (131.3 ± 1.10 nm) and zeta potential (−21.9 mV) which was later validated by electron microscopy. The lut-eth gel was prepared and values for content uniformity, spreadability, consistency, firmness, and toughness were found to be 97.89 ± 1.05%, 7.29 ± 0.015 gcm/s, 2.495 ± 0.24 g s, 0.210 ± 0.01g, and 0.37 ± 0.01 respectively. Rheological investigation reveals viscosity was 2.56.2 mPa s (millipascal second) and shows high elasticity and stability. whereas, consistency, firmness, toughness, the force of adhesion, and work of adhesion was found to be 2.495 ± 0.24 g s, 0.210 ± 0.01g, 0.37 ± 0.01, −0.23 ± 0.05 N, and −55.61 ± 0.11 N s respectively. The lut-eth gel had a maximum plasma concentration of 9.428 ± 3.5 ng/mL in 4 h with AUC0-1279. 679 ± 9.87 ng h mL−1. The drug release study shows sustain release behavior of prepared formulation and a similar sustain release pattern was observed in and Ex-vivo release studies. Confocal laser microscopy, In-vitro,antioxidant study shows better deposition and improved antioxidant effect of formulation which was further validated by Ex-vivoantioxidant assay. Therefore, bearing in mind all these findings, it can be said that Lut-eth gel could be a novel formulation to improve lutein deposition on skin.

A simple, sensitive, precise, rapid, and reliable high-performance thin-layer chromatographic (HPTLC) method for the simultaneous estimation of sparfloxacin (SPF) and flurbiprofen (FLB) in bulk drug as well as in dual drug loaded poly-(lactic-co-glycolic acid) (PLGA) nanoparticles was developed. In this method, aluminumbacked silica gel 60 F254plates (20 × 10 cm: 200 µm thickness) were used as stationary phase and chloroform-methanol-formic acid (7.5:1:1, v/v) as an optimized mobile phase. Developed chromatogram was scanned at 258 nm, the wavelength of maximum absorption SPF and FLB. Regression analysis of the calibration data showed an excellent linear relationship between peak area versus drug concentration. Linearity was found to be in the range of 100–600 ng spot−1and 40–800 ng spot−1for SPF and FLB, respectively. The suitability of the developed HPTLC method for simultaneous estimation of SPF and FLB was established by validating it as per the ICH guidelines. The limits of detection (LOD) and quantification (LOQ) for SPF were found to be ≈13 and ≈40 ng spot−1, respectively, and those for FLB ≈27 ng spot−1and ≈82 ng spot−1, respectively. The developed method was found to be linear (r2= 0.999), precise (% RSD < 1.5% repeatability and <2.55% for intermediate precision), accurate (mean recovery of within the range of 98–102%), specific, and robust. Stress-induced degradation studies revealed the suitability of method for the quantitative determination of drugs in the presence of degradants. The developed method has been successfully applied for the determination of entrapment efficiency, drug loading, in vitrodrug release profile and stability assessment of dual drug loaded PLGA nanoparticles (NPs).

Indian Propolis, a resin-like substance obtained from plants and modified by bees is a blend of various naturalcomponents and a potential candidate for topical application for chemoprevention of skin cancer. In the present study, thepotential role of propolis loaded ethosomal transgel for the chemoprevention of skin cancer was investigated. Ethosomalvesicular systems were optimized by varying the proportions of lecithin and ethanol taking vesicle size, polydispersity index(PDI) and entrapment efficiency as dependent variables. The vesicles were found to be unilamellar spherical shapedentities with size varying from 100 nm to 300 nm and entrapment efficiency in a range of 48% to 84%. The permeationand extent of penetration of the optimized formulation were evaluated by Franz diffusion cell and Confocal scanning lasermicroscopy (CSLM) respectively. It showed a sustained mode of release and remarkable penetration capacity of vesicles(133µm) as compared to hydroethanolic solution of the drug. Histopathological evaluation of the formulation treated skinrevealed the interaction of vesicles with the skin which was further supported by FTIR analysis reflecting the mechanismof vesicle permeation via skin. Propolis loaded ethosomal vesicles were then incorporated into carbopol gel and characterizedusing a texture profile analyzer. The optimized gel so obtained was then finally evaluated for its chemo preventiveactivity by exposing Swiss albino mice to UVB radiation. The study indicated the possible use of propolis for the preventionof skin cancer through a deep-rooted delivery via ethosomal system eventually circumventing the problem of poorpenetrability of topical preparations.

The oil of black seed (Nigella sativa) has been used as a folk medicine to treat a number of physiological disorders such as epilepsy, gastric problems, allergic conditions and various hepato-biliary ailments. Despite being unaware of the underlying phenomena for the cure of these diseases, people especially in the Mediterranean region have been using this ancient herb since ages. Researches in the 20th century conducted with the aim of tracking molecular pathways of anti-oxidant and anti-inflammatory mechanisms disclosed a great deal of information pertaining to the structural-activity relationships. Rigorous studies revealed that the major active constituent of Nigella sativa oil (NSO) is Thymoquinone (THQ) which exerts the majority of pharmacological actions observed by the essential oil. Since then, a large number of investigator groups have identified numerous molecular pathways of almost all major diseases which can be cured by THQ. Being a phytochemical, THQ has a high lipophilicity which makes it a poorly soluble agent in aqueous fluids restricting its systemic bioavailability. Also, THQ is highly light and heat-sensitive which further complicates its successful formulation for drug delivery. This review thus offers an insight to adequately comprehend the large number of pharmacological actions along with general mechanisms and major molecular targets pertaining to THQ. Additionally, a section dealing with the application of nanotechnological approaches to appropriately deliver the drug to its intended site of action has been elaborated.

The purpose of this study was to develop a solid nanoemulsion preconcentrate (NanOsorb) for poorly watersoluble drug sertraline (SRT). The liquid SNEDDS consisted of LabrafilM 2125 CS and Maisine 35-1 in 1:1 ratio as oil phase, Tween 80 as surfactant, Lauroglycol 90 as co-surfactant and active constituent sertraline free base. SRT free base, rather than commercially available hydrochloride salts (SRT.HCl) was used due to its much higher solubility in lipidic solvents. The NanOsorb formulation was prepared by adsorbing the liquid SNEDDS on different solid adsorbents. Reconstitution properties of both liquid and solid formulation demonstrate insignificant difference (p 0.05) in the globule size. External morphology and physical state of sertraline in NanOsorb formulation were examined by TEM, DSC, and X-ray powder diffraction. In vitro release profile of NanOsorb was found to be significant (p < 0.001) in comparison to the plane SRT in pH 1.2, 4.5 and 6.8 buffers. Formulation was subjected to stability studies as per International Conference on Harmonization (ICH) guidelines and was found to be stable. No significant variations were observed in the formulation over a period of 3 months at accelerated conditions. Results deduced that NanOsorb formulation may provide an improvement in dissolution profile of poorly water-soluble drugs in the form of solid dosage form.

Sertraline is a selective serotonin reuptake inhibitors used as major therapeutic advances in psychiatry and is drug of choice for treatment of major depressive disorders. The drug (free base) encounters problem of poor aqueous solubility and vulnerability to enzymatic degradation in liver. The hydrochloride salts of free base revert back to its original form in gastrointestinal tract leading to slow/poor absorption. In the current study, sertraline loaded self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent the problems associated with poor aqueous solubility, vulnerability to enzymatic degradation in liver and to sort out the problems associated with salt formation. Preliminary screening was carried out to select proper ingredient combinations. Ternary phase diagrams were then constructed and an optimum system was designated. Formulations selected were then compared for optimization. The systems were assessed for robustness, globule size, cloud point, percentage transmittance, surface morphology and drug release. An optimum system composed of oil (25.42 %), surfactant (49.72 %), and co-surfactant (24.86 %). It possessed a mean globule size, cloud point and percentage transmittance of 63.5 nm, 90 °C and 82.43 %, respectively. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension as well. Optimized formulation was subjected to stability studies at different temperature and relative humidity and was found to be stable. No significant variations were observed in the formulation over a period of 3 months at accelerated conditions.Sertraline is a selective serotonin reuptake inhibitors used as major therapeutic advances in psychiatry and is drug of choice for treatment of major depressive disorders. The drug (free base) encounters problem of poor aqueous solubility and vulnerability to enzymatic degradation in liver. The hydrochloride salts of free base revert back to its original form in gastrointestinal tract leading to slow/poor absorption. In the current study, sertraline loaded self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent the problems associated with poor aqueous solubility, vulnerability to enzymatic degradation in liver and to sort out the problems associated with salt formation. Preliminary screening was carried out to select proper ingredient combinations. Ternary phase diagrams were then constructed and an optimum system was designated. Formulations selected were then compared for optimization. The systems were assessed for robustness, globule size, cloud point, percentage transmittance, surface morphology and drug release. An optimum system composed of oil (25.42 %), surfactant (49.72 %), and co-surfactant (24.86 %). It possessed a mean globule size, cloud point and percentage transmittance of 63.5 nm, 90 °C and 82.43 %, respectively. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension as well. Optimized formulation was subjected to stability studies at different temperature and relative humidity and was found to be stable. No significant variations were observed in the formulation over a period of 3 months at accelerated conditions.

An ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometric method (UHPLC/ESI-Q-TOF-MS) for the analysis of terbutaline (TB) in Wistar rat plasma has been developed and validated. The chromatographic separation was achieved on a Waters ACQUITY UPLCTM BEH C18 (100.0 mmx2.1 mm; 1.7 μm) column using isocratic mobile phase, consisting of 2 mM ammonium acetate and acetonitrile (90: 10; v/v), at a flow rate of 0.25 mL min-1. The transitions occurred at m/z 226.19→152.12 for TB, and m/z 260.34→183.11 for the internal standard. The recovery of the analytes from Wistar rat plasma was optimized using liquid- liquid extraction technique (LLE) in ethyl acetate. The total run time was 3.0 min and the elution of TB occurred at 1.85±0.05 min. The linear dynamic range was established over the concentration range 1–1000 ng mL-1 (r2; 0.9938±0.0005) for TB. The intra-assay and inter-assay accuracy in terms of CV was in between 1.8–3.5. The lower limit of quantitation (LLOQ) for TB was 1.0 ng mL-1. Analytes were stable under various conditions (in autosampler, during freeze–thaw, at room temperature, and under deepfreeze conditions). The developed method was successfully applied for pharmacokinetic profiling in rodents.

Introduction:The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability.Areas covered:This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery.Expert opinion:Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.

A stability-indicating high-performance thin-layer chromatographic (HPTLC) method has been developed for the determination of terbutaline sulfate (TBS) as a bulk drug and in pharmaceutical formulations (submicronized dry powder inhalers). The separation was achieved on TLC aluminum plates precoated with silica gel 60F-254 using chloroform-methanol (9.0:1.0 v/v) as mobile phase. The densitometric analysis was carried out at 366 nm wavelength. Compact spots appeared at Rf= 0.34 ± 0.02. For the proposed procedure, linearity (r2= 0.9956 ± 0.0015), limit of quantification (28.35 ng spot−1), limit of detection (9.41 ng spot−1), recovery (97.06 - 99.56%), and precision (≤1.86) were found to be satisfactory. TBS was subjected to acid and alkali hydrolyses, oxidation and photodegradation treatments. The degraded products were well separated from the pure drug. Statistical analysis reveals that the developed method has potential for routine analysis and stability testing of terbutaline sulfate in pharmaceutical drug delivery systems.

In the recent years, there has been a growing interest in the development of nanoparticles based targeting agents for the tumor diagnostics and therapeutics. This is because of their potential to detect the tumor and treat the diseased tissue at the cellular and molecular level. In this respect nanoscale magnetic materials have shown a very promising therapeutic concept and offer a new perspective for the diagnostic and target drug delivery approach. The magnetic nanocarriers have the ability to accumulate at any desired pharmacological site just by the guidance of external magnetic field. But, the interactions of these magnetic nanocarriers with the biological environment are rare and depend largely upon their surface chemistry and size. To increase the interactions and achieve the desired pharmaceutically acceptable delivery system, the surface of magnetic nanocarriers is modified in various ways by coating with organic polymers and inorganic metals or oxides. On the basis of surface characteristics, a number of effective magnetically driven therapies have been proposed by many researchers and protected through patents time to time.

Proper selection of oils, surfactants and cosurfactants along with their optimum concentration is crucial to obtain stable, mild and clinically acceptable nanoemulsions. The focus of the present study was, therefore, to provide an efficient screening approach for the excipients selection for the optimum nanoemulsion formulation development. The oils studied included Lauroglycol 90, Capryol 90, olive oil, jojoba oil, oleic acid and Labrafil M1944. The drug solubility in the oil was taken as the criterion for oil selection. Labrasol, Cremophor EL, Tween 60 and Tween 80 were the surfactants evaluated for determining the solubilizing capacity for the oil. Among them Cremophor EL was found to be an efficient emulsifier for the oil phase. The effect of different cosurfactants such as ethanol, isopropyl alcohol, butanol, propylene glycol, PEG 400 and Carbitol on the phase behaviour of the pseudoternary system Capryol 90/Cremophor EL/cosurfactant/water was investigated. Nanoemulsion region obtained was used as an assessment criterion to evaluate the cosurfactants. The effect of Cremophor EL/carbitol mass ratio on the nanoemulsion formation was also studied by varying the ratio from 3:1 to 1:3 for the further optimization of the system. The highest nanoemulsion region was obtained at Cremophor EL: Carbitol in the mass ratio of 1:1. Formulations were selected from the phase diagram at this mass ratio at a fixed concentration of surfactant mixture (i.e. 45 wt/wt) with increasing concentration of oil (5, 10, 15, 20 wt/wt) and subjected to thermodynamic stability tests. The optimized formulations were characterized for particle size, viscosity, pH and refractive index measurements. The droplet size of all the selected formulations was found to be less than 100 nm. The formulations were thermodynamically stable and can be effectively used for the drug delivery applications.

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.

A rapid, sensitive and specific high-performance thin-layer chromatographic (HPTLC) method was developed and validated for determination of minocycline in human plasma, saliva, and gingival fluid samples. Densitometric analysis of minocycline was carried out at 345 nm after single step extraction with methanol. The method uses TLC aluminium plates pre-coated with silica gel 60F-254 as a stationary phase and methanol–acetonitrile–isopropyl alcohol–water (5:4:0.5:0.5, v/v/v/v) as mobile phase. In all the three matrices, the calibration curve was linear (r2≥ 0.9958) in the tested range of 100 – 1200 ng spot−1with a limit of quantification of 15.4 ng spot–1. Drug recovery from plasma, saliva and gingival fluid averaged 97.7%. Intra- and inter-day accuracies, determined at three different concentrations, were 95.08 to 100.6% and the corresponding precision (% CV) values were < 4.61%. In all the three matrices, rapid degradation of drug occurred and the half-life of drug ranged from 9.9 to 16.1 h at 4˚C and from 6.3 to 11.5 h at 20˚C. Frozen at −20˚C, this drug was stable for at least 2 months and can tolerate two freeze-thaw cycles without losses higher than 10%. The method’s ability to quantify minocycline with precision, accuracy and sensitivity makes it useful in pharmacokinetic studies.

Peroral administration of drugs, although most preferred by both clinicians and patients has several disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosae are considered as potential sites for administration of these drugs. Among the various transmucosal routes studied the buccal mucosa offers several advantages for controlled drug delivery for extended period of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract is avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form, design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is thus a promising area for continued research with the aim of systemic and local delivery of orally inefficient drugs as well as feasible and attractive alternative for non-invasive delivery of potent protein and peptide drug molecules. Extensive review pertaining specifically to the patents relating to buccal drug delivery is currently available. However, many patents e.g. US patents 6, 585,997; US20030059376A1 etc. have been mentioned in few articles. It is the objective of this article to extensively review buccal drug delivery by discussing the recent patents available. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.

The recognition of periodontal diseases as amenable to local antibiotherapy has resulted in a paradigmatic shift in treatment modalities of dental afflictions. Moreover the presence of antimicrobial resistance, surfacing of untoward reactions owing to systemic consumption of antibiotics has further advocated the use of local delivery of physiologically active substances into the periodontal pocket. While antimicrobials polymerized into acrylic strips, incorporated into biodegradable collagen and hollow permeable cellulose acetate fibers, multiparticulate systems, bio-absorbable dental materials, biodegradable gels/ointments, injectables, mucoadhesive microcapsules and nanospheres will be more amenable for direct placement into the periodontal pockets the lozenges, buccoadhesive tablets, discs or gels could be effectively used to mitigate the overall gingival inflammation. Whilst effecting controlled local delivery of a few milligram of an antibacterial agent within the gingival crevicular fluid for a longer period of time, maintaining therapeutic concentrations such delivery devices will circumvent all adverse effects to non- oral sites. Since the pioneering efforts of Goodson and Lindhe in 1989, delivery at gingival and subgingival sites has witnessed a considerable progress. The interest in locally active systems is evident from the patents being filed and granted. The present article shall dwell in reviewing the recent approaches being proffered in the field. Patents as by Shefer, et al. US patent, 6589562 dealing with multicomponent biodegradable bioadhesive controlled release system for oral care products, Lee, et al. 2001, US patent 6193994, encompassing a locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof and method of treating periodontal disease as suggested by Basara in 2004via US patent 6830757, shall be the types of intellectual property reviewed and presented in the current manuscript.

Pharmaceutical technologists have been working extensively on various mucoadhesive polymeric systems to create an intimate and prolonged contact at the site of administration. Chitosan is one of the most promising polymers because of its non-toxic, polycationic biocompatible, biodegradable nature, and particularly due to its mucoadhesive and permeation enhancing properties. Due to its potential importance in controlled drug delivery applications, pharmaceutical scientists have exploited this mucoadhesive polymer. However, chitosan suffers from limited solubility at physiological pH and causes presystemic metabolism of drugs in intestinal and gastric fluids in the presence of proteolytic enzymes. These inherent drawbacks of chitosan have been overcome by forming derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan, thus providing a platform for sustained release formulations at a controlled rate, prolonged residence time, improved patient compliance by reducing dosing frequency, enhanced bioavailability and a significant improvement in therapeutic efficacy. We have explored the potential benefits of these improved chitosan derivatives in modern drug delivery.

Pharmaceutical technologists have been working extensively on various mucoadhesive polymeric systems to create an intimate and prolonged contact at the site of administration. Chitosan is one of the most promising polymers because of its non‐toxic, polycationic biocompatible, biodegradable nature, and particularly due to its mucoadhesive and permeation enhancing properties. Due to its potential importance in controlled drug delivery applications, pharmaceutical scientists have exploited this mucoadhesive polymer. However, chitosan suffers from limited solubility at physiological pH and causes presystemic metabolism of drugs in intestinal and gastric fluids in the presence of proteolytic enzymes. These inherent drawbacks of chitosan have been overcome by forming derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan, thus providing a platform for sustained release formulations at a controlled rate, prolonged residence time, improved patient compliance by reducing dosing frequency, enhanced bioavailability and a significant improvement in therapeutic efficacy. We have explored the potential benefits of these improved chitosan derivatives in modern drug delivery.

The objective of the present study was to prepare valencene (sesquiterpene) containing invasomes for itraconazole (ITZ) transungual delivery using central composite design. The phospholipid (X1) and valencene (X2) were selected as an independent variables, while vesicles size (Y1), entrapment efficiency (Y2) and in vitro drug release (Y3) were chosen as dependent variables. The antifungal activity of optimized formulation was screened against Trichophyton rubrum, a common causative onychomycosis pathogen, by cup plate method. The optimized ITZ-loaded invasomes formulation presented vesicles size of 176.8 ± 6.03 nm, entrapment efficiency of 83.21 ± 4.11% and in vitro drug release of 75.22 ± 5.03%. The ITZ-loaded invasomes gel formulation showed good homogeneity, pH 6.5 ± 0.23, viscosity 7.33± 0.67 Pa s and drug content 94.13 ± 1.13%. The spreadability and extrudability of developed ITZ-loaded invasomes gel were found to be 7.85 ± 0.24 gcm/s and 162 ± 2.74 g, respectively. The ITZ-loaded invasomes gel presented 71.11 ± 3.65% cumulative permeation of drug via goat hooves. The in vitro antifungal activity depicted that the ITZ-loaded invasomes gel and marketed preparation were presented zone of inhibition of 21.42 mm and 10.64 mm against T. rubrumrespectively. Hence the prepared ITZ-loaded invasomes formulation could therefore be a promising topical dosage to mitigate the indications and hasten the cure for onychomycosis than conventional available therapies.

Poor aqueous solubility and bioavailability of the drugs is the major impediment in the field of drug development. Amongst the various solubility enhancing techniques, complexation of the ketoconazole with the peat sourced fulvic acid was adopted in the current study. Phase solubility study revealed that at 4%w/v of fulvic acid, maximum amount of drug gets entrapped. Further   the complex of fulvic acid with ketoconazole was prepared in a molar ratio of 1:1 (w/w) by freeze drying method and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier Transforms Infra-Red Spectroscopy (FT-IR). All these studies confirm the formation of an amorphous inclusion complex. Phase solubility study with fulvic acid indicates that maximum percentage increase in solubility of the KTZ was found to be 621 ± 2.3%, whereas with the Shilajit derived HA it was reported as 645.2%. In 60 min, 45% release was obtained with the pure drug, 82% with the peat sourced fulvic acid complexed drug and 81% with the shilajit derived humic acid complex. It was found that 68% of the pure drug and 95% of the complexed drug gets permeated across the intestinal gut sac whereas it is reported that with shilajit derived humic acid 3.7 times drug gets permeated. With the pure drug Cmax, tmax and AUC was found to be as 2.64 µg/ml, 0.5 h and 7.39 µg/ml*h, whereas with the complexed drug Cmax, tmax and AUC was found to be as 5.1 µg/ml, 1.0 h and 15.51 µg/ml*h.Antifungal study conducted on Candida albicansand Tricophytonrubrumindicates that the fulvic acid alone does not have promising anti-fungal activity but when complexed with KTZ, it enhances the antifungal activity of the pure drug. Hence it can be concluded that peat sourced derived fulvic acid can be used as a promising complexing agent for enhancing the solubility and bioavailability of the ketoconazole.