Nanocrystals as an emerging nanocarrier for the management of dermatological diseases.

Skin conditions are amongst the most prevalent health issues in the world and come with a heavy economic, social, and psychological burden. Incurable and chronic skin conditions like eczema, psoriasis, fungal infections are linked to major morbidity in the manner of physical pain and a reduction in quality life of patients. Several drugs have difficulties for penetrating the skin due to the barrier mechanism of the skin layers and the incompatible physicochemical characteristics of the drugs. This has led to the introduction of innovative drug delivery methods. Currently, formulations depend on nanocrystals have indeed been researched for topical administration of drugs and have resulted in enhanced skin penetration. This review focuses on skin penetration barriers, modern methods to enhance topical distribution, and the use of nanocrystals to overcome these barriers. By means of mechanisms such as adherence to skin, creation of diffusional corona, targeting of hair follicles, and the generation of a greater concentration gradient throughout the skin, nanocrystals could enhance transport across the skin. Scientists working on product formulations incorporating chemicals that are "challenging-to-deliver" topically may find the most current findings to be of relevance.

Role of phytoconstituents in the management of COVID-19.

BACKGROUND: COVID-19, a severe global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as one of the most threatening transmissible disease. As a great threat to global public health, the development of treatment options has become vital, and a rush to find a cure has mobilized researchers globally from all areas. SCOPE AND APPROACH: This review focuses on deciphering the potential of different secondary metabolites from medicinal plants as therapeutic options either as inhibitors of therapeutic targets of SARS-CoV-2 or as blockers of viral particles entry through host cell receptors. The use of medicinal plants containing specific phytomoieties could be seen in providing a safer and long-term solution for the population with lesser side effects. Key Findings and Conclusions: Considering the high cost and time-consuming drug discovery process, therapeutic repositioning of existing drugs was explored as treatment option in COVID-19, however several molecules have been retracted as therapeutics either due to no positive outcomes or the severe side effects. These effects call for exploring the alternate treatment options which are therapeutically effective as well as safe. Keeping this in mind, phytopharmaceuticals derived from medicinal plants could be explored as important resources in the development of COVID-19 treatment, as their role in the past for treatment of viral diseases like HIV, MERS-CoV, and influenza has been well reported. Considering this fact, different phytoconstituents such as flavonoids, alkaloids, tannins and glycosides etc. Possessing antiviral properties against coronaviruses and possessing potential against SARS-CoV-2 have been reviewed in the present work.

Antimicrobial activity of a novel polyherbal combination for the treatment of vaginal infection.

The present study evaluated the antimicrobial activity of Azadirachta indica (AI), Cichorium intybus (CI), and Trigonella foenum-graecum (TFG) against bacterial and fungal pathogens responsible for the vaginal infections. The AI, CI, and TFG were selected to include antimicrobial and antifungal action against wide range of microbes. The different extracts of the herbs were evaluated for antibacterial and antifungal activity by well diffusion assays. Based on the results, the combination was selected and evaluated, "polyherbal antimicrobial (PHA)." The developed PHA extract demonstrated synergistic broad-spectrum antimicrobial activities including antibacterial and antifungal activity (minimum inhibition concentration: 5-7 mg/ml).

Lungs deposition and pharmacokinetic study of submicron budesonide particles in Wistar rats intended for immediate effect in asthma.

The purpose of the present investigation was to study the aerosolization, lungs deposition and pharmacokinetic study of inhalable submicron particles of budesonide in male Wistar rats. Submicron particles were prepared by antisolvent nanoprecipitation method and freeze-dried to obtain free flowing powder. The freeze-drying process yielded dry powder with desirable aerodynamic properties for inhalation therapy. An in-house model inhaler was designed to deliver medicine to lungs, optimized at dose level of 10 mg for 30 sec of fluidization. The in vitro aerosolization study demonstrates that submicron particles dissolve faster with improved aerosolization effect as compared to micronized budesonide. Both submicron and micron particles were compared for in vivo lungs deposition. The results showed that relatively high quantity of submicron particles reaches deep into the lungs as compared to micron particles. Most pronounced effect observed with submicron particles from pharmacokinetic parameters was the enhancement in peak plasma concentration (Cmax) by 28.85 %, and increase in area under concentration curve (AUC0-8h) by 30.33 % compared to micron sized particles. The results suggested that developed submicronized formulation of budesonide can be used for pulmonary drug delivery for high deposition to deep lungs tissues.

Modulation of liver and kidney toxicity by herb Withania somnifera for silver nanoparticles: a novel approach for harmonizing between safety and use of nanoparticles.

In the present study, toxicity of nanoparticles is evaluated for assessing their effect on liver and kidney. We have synthesized highly mono-disperse spherical and rod-shaped silver nanoparticles using reverse microemulsion and aqueous phase methods. These were characterized by UV-vis spectrophotometer, dynamic light scattering, and transmission electron microscope confirming the formation of different sizes of spherical-shaped and rod-shaped silver nanoparticles (Ag NPs). Acute toxicity of different shapes and sizes of Ag NPs and their modulations by using Withania somnifera were evaluated through biochemical and histopathological changes in liver and kidney tissues of Wistar rats. We also evaluated cytotoxicity in specific murin macrophages through confocal microscopy. Cytotoxicity analysis indicates that median lethal dose (LD50) for 20, 50, and 100-nm size spherical and 100-nm rod-shaped Ag NPs was 0.25, 0.35, 0.35, and 0.35 mg/ml, respectively. We also calculated clinically important protein concentration to illustrate the efficacy of Ag nanomaterials. These studies indicated that 20, 50, and 100-nm spherical Ag NPs (35 mg/kg, 23 days) increased the biochemically important enzymes and substrate levels glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alkaline phosphatase (ALP), creatinine, and urea concentration in serum, showing liver and kidney tissue damage. After 23 days of treatment of Ag NPs (20, 50, and 100 nm spherical), along with W. somnifera, toxicity of Ag NPs significantly decreased and marginalized. However, no significant changes were observed for 100-nm rod-shaped Ag NPs on normal liver and kidney architecture. Given their low toxic effects and high uptake efficiency, these have a promising potential as to lower the toxicity of Ag NPs.

Dorzolamide-loaded PLGA/vitamin E TPGS nanoparticles for glaucoma therapy: Pharmacoscintigraphy study and evaluation of extended ocular hypotensive effect in rabbits.

Poor drug penetration and rapid clearance after topical instillation of a drug formulation into the eyes are the major causes for the lower ocular bioavailability from conventional eye drops. Along with this, poor encapsulation efficiency of hydrophilic drug in polymeric nanoparticles remains a major formulation challenge. Taking this perspective into consideration, dorzolamide (DZ)-loaded PLGA nanoparticles were developed employing two different emulsifiers (PVA and vitamin E TPGS) and the effects of various formulation and process variables on particle size and encapsulation efficiency were assessed. Nanoparticles emulsified with vitamin E TPGS (DZ-T-NPs) were found to possess enhanced drug encapsulation (59.8±6.1%) as compared to those developed with PVA as emulsifier (DZ-P-NPs). Transcorneal permeation study revealed a significant enhancement in permeation (1.8-2.5 fold) as compared to solution. In addition, ex vivo biodistribution study showed a higher concentration of drug in the aqueous humour (1.5-2.3 fold). Histological and IR-camera studies proved the non-irritant potential of the formulations. Pharmacoscintigraphic studies revealed the reduced corneal clearance, as well as naso-lachrymal drainage in comparison to drug solution. Furthermore, efficacy study revealed that DZ-P-NPs and DZ-T-NPs significantly reduced the intraocular pressure by 22.81% and 29.12%, respectively, after a single topical instillation into the eye.

Collagen loaded nano-sized surfactant based dispersion for topical application: formulation development, characterization and safety study.

Collagen, a high molecular weight, hydrophilic and highly abundant protein is known to have anti-ageing, anti-wrinkle, anti-acne, anti-scar and wound healing properties. High molecular weight and hydrophilic nature hinder its effective topical delivery. So, the objective of present study was to develop effective topical nano-surfactant dispersion (NSD) for collagen delivery. NSD was prepared from sorbitan monostearate (Span60) and cholesterol using ethanol injection method followed by probe sonication. NSD was characterized for entrapment efficiency (%EE), size and size distribution (Z-avg and polydispersity index (PDI)), shape, zeta-potential (ζ), in vitro drug release, skin hydration and skin irritation test and histopathological examination. Optimized NSD (NSD3) had %EE, z-avg, PDI and ζ-potential of 77.56% ± 1.09%, 158.1 ± 2.31 nm, 0.211 and -17.2 ± 0.64 mV, respectively. In in vivo skin hydration test, NSD treatment showed nearly 2.5-fold and 3-fold increase in the thickness of stratum corneum (SC) as compared to the collagen gel treated and untreated skin, respectively. The mean scores of skin irritation test in two animal species, rats and rabbits, were found to be 1.42 ± 1.01 and 1.71 ± 0.29, respectively, indicating the non-irritant nature of collagen loaded NSD. Histopathology of the skin after application of developed NSD showed non-significant changes in skin anatomy indicating its safe nature.

Self-nanoemulsifying lipid carrier system for enhancement of oral bioavailability of etoposide by P-glycoprotein modulation: in vitro cell line and in vivo pharmacokinetic investigation.

The purpose of this work is intended to investigate the potential of self-nanoemulsifying (SNE) drug delivery system for enhanced oral bioavailability of etoposide by P-glycoprotein (P-gp) modulation. The components of SNE formulation were optimized by their solubilization and emulsification efficiency. The ternary phase diagrams provided nanoemulsion existence ranges and the corresponding formulations were developed and evaluated via thermodynamic and dispersibility tests. The successful formulations were characterized for various parameters including time required for self-emulsification, percentage transmittance, droplet size, surface morphology, zeta potential and in vitro release. The etoposide loaded SNE9 formulation showed 2.6- and 11-fold higher permeability coefficient in apical to basolateral direction across Caco-2 monolayers as compared to the Etosid and plain drug solution, respectively. The etoposide loaded SNE9 formulation showed a higher cytotoxicity at the highest tested concentration compared to the blank SNE9 formulation and the free etoposide. Furthermore, an in vivo pharmacokinetic study of etoposide in SNE9 formulation showed 3.2- and 7.9-fold increase in relative oral bioavailability compared with that of etoposide in Etosid and drug suspension, respectively. Thus, the developed SNE drug delivery system could be a valuable tool for the effective oral delivery of etoposide.

Nanoparticles laden in situ gel for sustained ocular drug delivery.

Proper availability of drug on to corneal surface is a challenging task. However, due to ocular physiological barriers, conventional eye drops display poor ocular bioavailability of drugs (< 1%). To improve precorneal residence time and ocular penetration, earlier our group developed and evaluated in situ gel and nanoparticles for ocular delivery. In interest to evaluate the combined effect of in situ gel and nanoparticles on ocular retention, we combined them. We are the first to term this combination as "nanoparticle laden in situ gel", that is, poly lactic co glycolic acid nanoparticle incorporated in chitosan in situ gel for sparfloxacin ophthalmic delivery. The formulation was tested for various physicochemical properties. It showed gelation pH near pH 7.2. The observation of acquired gamma camera images showed good retention over the entire precorneal area for sparfloxacin nanoparticle laden in situ gel (SNG) as compared to marketed formulation. SNG formulation cleared at a very slow rate and remained at corneal surface for longer duration as no radioactivity was observed in systemic circulation. The developed formulation was found to be better in combination and can go up to the clinical evaluation and application.

Aerodynamics and deposition effects of inhaled submicron drug aerosol in airway diseases.

Particle engineering is the prime focus to improve pulmonary drug targeting with the splendor of nanomedicines. In recent years, submicron particles have emerged as prettyful candidate for improved fludisation and deposition. For effective deposition, the particle size must be in the range of 0.5-5 µm. Inhalers design for the purpose of efficient delivery of powders to lungs is again a crucial task for pulmonary scientists. A huge number of DPI devices exist in the market, a significant number are awaiting FDA approval, some are under development and a large number have been patented or applied for patent. Even with superior design, the delivery competence is still deprived, mostly due to fluidisation problems which cause poor aerosol generation and deposition. Because of the cohesive nature and poor flow characteristics, they are difficult to redisperse upon aerosolization with breath. These problems are illustrious in aerosol research, much of which is vastly pertinent to pulmonary therapeutics. A technical review is presented here of advances that have been utilized in production of submicron drug particles, their in vitro/in vivo evaluations, aerosol effects and pulmonary fate of inhaled submicron powders.

Role of CD44 in tumour progression and strategies for targeting.

CD44 or hyaluronan receptor is a transmembrane receptor associated with aggressive tumour growth, proliferation, and metastasis. In normal physiology, this receptor has a crucial role in cell adhesion, inflammation, and repair processes. However, many tumour cells over-express this receptor and abuse it to become progressive and perpetual units. The article comments from common functioning of the CD44 receptor, to its diabolic multi-dimensional effects in promotion of malignant cells. It also illuminates the relations of CD44 endorsed processes with other biomolecular events in cancer progression. In an end, the review focuses comprehensively at ongoing researches to exploit the CD44 over-expression as a probable target in treatment, management, and diagnosis of malignancy.

Stabilized terbutaline submicron drug aerosol for deep lungs deposition: drug assay, pulmonokinetics and biodistribution by UHPLC/ESI-q-TOF-MS method.

Terbutaline submicron particles (SµTBS) were prepared by nanoprecipitation technique followed by spray drying for deep lungs deposition. Inhalable SµTBS particles were 645.16 nm of diameter with 0.11µm of MMAD, suggested for better aerosol effects. Both submicron and micron-sized TBS particles were administered in rodents administered via major delivery routes, and their biological effects were compared by using UHPLC/ESI-q-TOF-MS method. TBS was found stable in all exposed conditions with 96.28-99.0% of recovery and <4.34% of accuracy (CV). An inhalation device was designed and validated to deliver medicines to lungs, which was found best at dose level of 25mg for 30 min of fluidization. Both submicron and micron particles were compared for in vivo lung deposition and a 1.67 fold increase in concentration was observed for SµTBS exposed by inhalation. Optimized DPI formulation contained lesser fraction of ultrafine particle (<500 nm) with the major fraction of submicron particles (>500 nm), advocated for better targeting to lungs. UHPLC/ESI-q-TOF-MS confirmed that designed submicron particles has been successfully delivered to the lungs. From tongue to lungs, the landing of pulmonary medicines can be improved by submicronization technology.

Development and validation of a stability-indicating method for determination of free sterols in the Asian medicinal leech Hirudo manillensis.

A rapid, simple, sensitive, selective, precise and robust thin-layer chromatography densitometric method for the determination of free sterols in leech was developed and validated on silica gel layer using carbon tetrachloride-methanol-formic acid (9.5:1.5:0.55, v/v/v). Spectrodensitometric scanning was carried using a Camag TLC scanner III at 366 nm after spraying 2% methanolic sulphuric acid, which gave compact spots for cholesterol (R(F) = 0.35 ± 0.02). The regression analysis data for calibration plot implied a good linear relationship (r(2) = 0.99958) between response and concentration over the range 100-600 ng per spot with respect to peak area. The limits of detection and quantification were found to be 13.8 ± 0.51 and 45.01 ± 1.29 ng per spot, respectively. Validation was in accordance to the International Conference on Harmonization guidelines. Cholesterol was subjected to forced stress conditions of oxidation, hydrolysis and heat. Degradation products resulting from the forced stress did not interfere with detection because the degradant peaks were well separated from the cholesterol peak. The densitometric method can be regarded as stability-indicating and can be used for quality control assay of cholesterol in leech extract.

Therapeutic stratagems for vascular degenerative disorders of the posterior eye.

In this review we discuss insights into therapeutic stratagems that can selectively target the choroid, retinal cells and vitreoretinal space for the treatment of vision-threatening vascular degenerative disorders of the posterior eye. Despite the relative success of these novel drugs, new problems related to its delivery remain. Systems carrying drugs to the target site, such as nanoparticles, liposomes, vectosomes, spanlastics, micelles, dendrimers and implants are also discussed. Further, we also consider drug penetration enhancement approaches along with cutting-edge strategies for regaining vision during vision-threatening vascular degenerative disorders of the eye. Finally, challenges, such as ocular or even systemic complications associated with use of prolonged therapies and future prospects, such as combination of approaches with multidisciplinary integration to optimize delivery to the posterior eye are also addressed.

Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes.

In the present work, concomitant use of self-microemulsifying drug delivery systems (SMEDDS) and a novel third-generation P-gp inhibitor, GF120918 (elacridar), for the effective transport of taxanes (paclitaxel and docetaxel) across an in vitro model of the intestinal epithelium and uptake into tumor cells were investigated. On the basis of solubility studies and ternary phase diagrams, different SMEDDS formulations of taxanes were prepared and characterized. In caco-2 cell permeation study, paclitaxel-loaded SMEDDS along with GF120918 showed a four-fold increase in apparent permeability, while docetaxel-loaded SMEDDS in combination with GF120918 showed a nine-fold increase in permeability, as compared to plain drug solution. Cell uptake studies on A549 cells were performed with microemulsions formed from both SMEDDS formulations loaded with rhodamine 123 dye and showed good uptake than plain dye solution. Confocal laser scanning microscopic images further confirmed the higher uptake of both SMEDDS formulations in the presence of GF120918.

Enhanced antimalarial activity of lumefantrine nanopowder prepared by wet-milling DYNO MILL technique.

Lumefantrine (LMF) is an antimalarial drug that exhibits poor oral bioavailability, owing to its poor aqueous solubility. To improve its antimalarial activity, nanopowder formulation using DYNO MILL was prepared. Combination of HPMC E3 (4%, w/v) and Tween 80 (2.5%, w/v) as dispersing agents, favored the production of smaller LMF particles with mean size of 0.251 µm. LMF nanopowder showed enhanced dissolution rate attributed to nanonization of LMF. The IC(50) value of nano-sized LMF was found to be 0.1 ng/mL, which was 175-times lower than the IC(50) value of unmilled LMF powder (17.5 ng/mL) and 42-times lower than the IC(50) value of chloroquine (4.2 ng/mL). The in vivo antimalarial activity demonstrated an enhanced antimalarial potential of LMF nanopowder against P. Yoelii nigeriensis compared to unmilled drug. Wet-milling using DYNO MILL offers a highly effective approach to produce stable drug nanopowders. Furthermore, LMF nanopowder makes the Coartem therapy more effective.

Development and evaluation of nanosized niosomal dispersion for oral delivery of Ganciclovir.

Encapsulation of Ganciclovir in lipophilic vesicular structure may be expected to enhance the oral absorption and prolong the existence of the drug in the systemic circulation. So the purpose of the present study was to improve the oral bioavailability of Ganciclovir by preparing nanosized niosomal dispersion. Niosomes were prepared from Span40, Span60, and Cholesterol in the molar ratio of 1:1, 2:1, 3:1, and 3:2 using reverse evaporation method. The developed niosomal dispersions were characterized for entrapment efficiency, size, shape, in vitro drug release, release kinetic study, and in vivo performance. Optimized formulation (NG8; Span60:Cholesterol 3:2 molar ratio) has shown a significantly high encapsulation of Ganciclovir (89±2.13%) with vesicle size of 144±3.47 nm (polydispersity index [PDI]=0.08). The in vitro release study signifies sustained release profile of niosomal dispersions. Release profile of prepared formulations have shown that more than 85.2±0.015% drug was released in 24 h with zero-order release kinetics. The results obtained also revealed that the types of surfactant and Cholesterol content ratio altered the entrapment efficiency, size, and drug release rate from niosomes. In vivo study on rats reveals five-time increment in bioavailability of Ganciclovir after oral administration of optimized formulation (NG8) as compared with tablet. The effective drug concentration (>0.69 µg/mL in plasma) was also maintained for at least 8 h on administration of the niosomal formulation. In conclusion, niosomes can be proposed as a potential oral delivery system for the effective delivery of Ganciclovir.

Oil based nanocarrier system for transdermal delivery of ropinirole: a mechanistic, pharmacokinetic and biochemical investigation.

Ropinirole, a recent introduction in the clinical treatment of Parkinson's disease, suffers with the problems of low oral bioavailability and frequent dosing. An effective transdermal nano-emulsion drug delivery system can however resolve these issues effectively with greater therapeutic benefits and clinical significance. Therefore, the present work focuses precisely on pharmacokinetic, biochemical and mechanistic assessment of transdermal nanoemulsion gel in rats induced with Parkinson lesioned brain by 6-OHDA. DSC and FT-IR studies showed that NEG affects the normal lipid packing of stratum corneum to enhance the drug permeation. Study of pharmacokinetic parameters (AUC, C(max), and T(max)) revealed a greater and more extended release of ropinirole from nanoemulsion gel compared to that from a conventional gel (RPG) and oral marketed tablet (Ropitor). The AUC(0→∞) for RPCNG and RPTNG was found to be 928.07 ± 206.5 and 1055.99 ± 251.7 ngh/mL, respectively in comparison to 137.25 ± 31.3 and 467.15 ± 106.1 ngh/mL for RPG and oral tablet, respectively. The relative bioavailability of ropinirole has been enhanced more than two fold by RPTNG. Furthermore, antiparkinson activity was evaluated in terms of estimating the level of thiobarbituric acid reactive substances, glutathione antioxidant enzymes and catalase in lesioned brain of rats. Formulations were also found to be non-toxic and non-irritant by histological investigations.

Enhanced bioavailability of nano-sized chitosan-atorvastatin conjugate after oral administration to rats.

A novel approach to improve the bioavailability and stability of atorvastatin (AT) was developed by constructing a nano-sized polymer-atorvastatin conjugate. Firstly, a novel chitosan-atorvastatin (CH-AT) conjugate was efficiently synthesized through amide coupling reaction. The formation of conjugate was confirmed by (1)H NMR and FT-IR spectrometry. Nano-sized conjugate with a mean size of 215.3±14.2 nm was prepared by the process of high pressure homogenization (HPH). Scanning electron microscopy (SEM) revealed that CH-AT nano-conjugate possess smooth surface whereas X-ray diffraction (XRD) spectra demonstrated amorphous nature of nano-conjugate. Further, CH-AT nano-conjugate showed solubility enhancement of nearly 4-fold and 100-fold compared to CH-AT conjugate and pure AT, respectively. In vitro drug release studies in simulated gastric fluid and simulated intestinal fluid suggested sustained release of AT from the conjugate. Additionally, the nano-conjugate significantly reduced the acidic degradation of AT. The plasma-concentration time profile of AT after oral administration of CH-AT nano-conjugate (2574±95.4 ng/mL) to rat exhibited nearly 5-fold increase in bioavailability compared with AT suspension (583±55.5 ng/mL). Finally, variable bioavailability, as observed for AT suspension was also reduced when AT was administered in form of CH-AT nano-conjugate. Taken together these data demonstrate that chitosan conjugate nano-prodrugs may be used as sustained polymeric prodrugs for enhancing bioavailability.

Antiepileptic intranasal Amiloride loaded mucoadhesive nanoemulsion: development and safety assessment.

Current investigation aimed to develop a novel Amiloride loaded mucoadhesive nanoemulsion formulation for nose-to-brain delivery. Furthermore, nasal irritation study and histopathological examination of the nasal mucosa were also carried out to assess nonirritant nature of the nanoemulsion. The optimized formulation, surface epithelium lining and the granular cellular structure of the nasal mucosa were totally intact, whereas KCl caused major changes in the ultrastructure of mucosa. Amiloride loaded mucoadhesive nanoemulsion formulations are non toxic on nasal mucosa and can be administered by intranasal route for effective treatment of epilepsy.