In vitro profiling and molecular dynamics simulation studies of berberine loaded MCM-41 mesoporous silica nanoparticles to prevent neuronal apoptosis.

Neuronal loss in Alzheimer's disease has been reported to display features of apoptosis, pyroptosis (programmed necrosis), or necroptosis. This study thoroughly examines the production and characterization of MCM-41 based berberine (BBR)-loaded porous silica nanoparticles (MSNs) by a modified Stöber method, focusing on their possible role in inhibiting the apoptotic process. Particle size, polydispersity index, morphology, drug loading, zeta potential, entrapment efficiency, and drug release were examined. The formulation was analyzed using various spectroscopic techniques. The surface area was computed by the Brunauer-Emmett-Teller plot. Computational models were developed for molecular dynamics simulation studies. A small PDI value indicated an even distribution of particles at nanoscale sizes (80-100 nm). Results from XRD and SEAD experiments confirmed the amorphous nature of BBR in nanoparticles. Nanoparticles had high entrapment (75.21 ± 1.55%) and drug loading (28.16 ± 2.5%) efficiencies. A negative zeta potential value (-36.861.1 mV) indicates the presence of silanol groups on the surface of silica. AFM findings reveal bumps due to the surface drug that contributed to the improved roughness of the MSNs-BBR surface. Thermal gravimetric analysis confirmed the presence of BBR in MSNs. Drug release was controlled by simple diffusion or quasi-diffusion. Molecular dynamics simulations confirmed the existence of diffused drug molecules. Cellular studies using SH-SY-5Y cells revealed dose-dependent growth inhibition. Fragmented cell nuclei and nuclear apoptotic bodies in DAPI-stained cells exposed to nanoparticles showed an increase in apoptotic cells. Flow cytometry analysis demonstrated a lower red-to-green ratio in SH-SY-5Y cells treated with nanoparticles. This suggests improved mitochondrial health, cellular viability restoration, and prevention of the apoptotic process. This study provides essential data on the synthesis and potential of MSNs loaded with BBR, which may serve as a viable therapeutic intervention for conditions associated with apoptosis.

Design, development and evaluation of Resveratrol transdermal patches for breast cancer therapy.

Resveratrol (RVT) is a polyphenolic phytoestrogen which has shown antiproliferative activity in breast cancer. However, its low bioavailability and short half-life have restricted its use. The current study aimed to develop transdermal patches of RVT and evaluate its site-specific delivery for breast cancer therapy. Different penetration enhancers were screened using a computational tool, quantitative structure propery relationship (QSPR). The best permeation of RVT was observed in a patch comprising hydroxypropyl methylcellulose (HPMC) E15LV: HPMC-K4M: polyvinyl pyrrolidone (PVP) K30 in the ratio of 3:1:2 as release controlling polymers with Glycerol:Capryol 90 (4:1) as penetration enhancer and plasticizer. To assess the localized delivery of RVT, the patch was applied to the breast of female rats. Higher breast tissue disposition with lower systemic concentration was observed compared to oral administration, demonstrated by increased AUC and MRT. Further, the optimized RVT patches were tested in 7,12-Dimethylbenz[a]anthracene (DMBA) induced rat mammary cancer. Compared to oral RVT, the application of RVT tansdermal patches significantly reduced the tumor volume and serum CA 15-3, a cancer biomarker. Thus, the RVT transdermal patch may be a viable approach for ensuring high local concentration of drug for site-specific delivery in breast cancer therapy.

Transpapillary iontophoretic delivery of resveratrol loaded transfersomes for localized delivery to breast cancer.

Localized drug delivery to the breast tissues is an area of interest as a potential route to ensure site-specific drug delivery. Transpapillary delivery via the mammary papilla has advantages as most breast tumors arise from the milk ducts. The present study explored the plausibility of transpapillary delivery of a phytochemical, resveratrol (RVT), for breast cancer treatment. RVT was encapsulated within the transfersomes (RVT-TRF) to enable a sustained release of the drug using the biomaterial soya phosphatidylcholine (SPC). Iontophoresis was applied to further accelerate the penetration of the RVT-TRF across the mammary papilla to the breast tissue. The RVT-TRF development was optimized by the Design of Experiments (DoE) approach. The in vitro transpapillary iontophoresis study on porcine mammary papilla showed an enhanced penetration of RVT-TRF when compared to passive diffusion. The transpapillary delivery was further confirmed from the in vitro fluorescent microscopy study using FITC conjugated RVT-TRF. The optimized RVT-TRF delivered via transpapillary route showed a higher Cmax and AUC when compared to pure RVT given orally. A significant reduction in the tumor volume and the serum biomarker CA 15-3, when evaluated in a chemically induced breast cancer rat model, provided evidence of the effectiveness of the developed formulation when delivered locally via transpapillary route compared to the oral route. Thus the developed RVT-TRF administered via transpapillary iontophoresis technique is a promising strategy enabling a localized delivery for effective breast cancer therapy.

Understanding the Effect of Functionalization on Loading Capacity and Release of Drug from Mesoporous Silica Nanoparticles: A Computationally Driven Study.

MCM-41, a type of mesoporous silica nanoparticle, has garnered widespread interests as a useful carrier for drug delivery wherein the drug gets adsorbed into the pores of the carrier. To understand the adsorption mechanism and release of the drug at the molecular level, in the current study, it was attempted to generate a computational model for the loading of 5-fluorouracil (5-FU), a chemotherapeutic agent into surface-modified MCM-41. The molecular surface models of the mesoporous silica (MCM-41) nanoparticle with different surface substitutions were created. In the first stage, molecular mechanics (MM) simulations were carried out to obtain the optimized surface structures. Subsequently, a 5-FU drug molecule in its different forms was docked on top of different MCM-41 surfaces to understand the adsorption orientation and energetics. To further validate the results, more accurate quantum mechanical (QM) calculations were also carried out, and the energetics between the QM and MM calculations are found to be similar. All the substitutions (-NH2, -CN, -COOH) except the methyl substitution exhibited favorable interactions compared to the unsubstituted MCM-41 surface which was in accordance with the experimental observations. The release rate of 5-FU from MCM-41 and aminopropyl-substituted MCM-41 (MCM-NH2) was studied using molecular dynamics simulations which revealed that the release rate of 5-FU from the MCM-NH2 surface was slower compared to that of plain MCM-41. The detailed surface characteristics and the adsorption energies from the molecular simulations correlating the loading capacity and release are reported in here.

Development and preclinical evaluation of microneedle-assisted resveratrol loaded nanostructured lipid carriers for localized delivery to breast cancer therapy.

Resveratrol (RVT) is one of the potent anticancer phytochemicals which has shown promising potential for breast cancer therapy. However, its short half-life and low bioavailability is a major hurdle in its effective use. In this study, we have developed nanostructured lipid carriers (NLCs) of RVT to enable localized delivery of the drug to the breast tissues using microneedle arrays to improve effectiveness. The NLCs were optimized using the Design of Experiments approach and characterized for their particle size, polydispersity index, zeta potential and entrapment efficiency. The RVT-NLCs delivered using microneedle array 1200 showed a higher permeation of RVT across the skin with lower skin retention compared to pure RVT. Further, RVT-NLCs showed higher anticancer activity on MDA-MB-231 breast cancer cell lines and enhanced internalization compared to pure RVT. Moreover, the RVT-NLCs were found to inhibit the migration of MDA-MB-231 breast cancer cell lines. Preclinical studies in rats showed that RVT-NLCs delivered via microneedles demonstrated a remarkable increase in the Cmax, Tmax and AUC0-inf, and a higher localization in breast tissue compared to pure RVT administered orally. These results suggests that the RVT-NLCs administered by microneedle array system is an effective strategy for the local delivery of RVT for breast cancer therapy.

Chitosan-glucuronic acid conjugate coated mesoporous silica nanoparticles: A smart pH-responsive and receptor-targeted system for colorectal cancer therapy.

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ± 0.43 nm, pore volume of 0.73 ± 0.21 cm3/g, and particle size of 245.24 ± 5.75 nm. A high loading of 180.51 ± 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosan-glucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer.

Recent advances in the development of asenapine formulations.

INTRODUCTION: Asenapine maleate (AM) is an atypical antipsychotic agent, that has been widely prescribed for the management of schizoaffective disorders. However, the bioavailability of AM is extremely poor due to the extensive first-pass metabolism. With the advancement in pharmaceutical technologies, significant strides have been made to create novel formulations to address the bioavailability problem of AM. AREAS COVERED: This review article provides an insight into all the formulation approaches undertaken by researchers to increase the bioavailability of AM encompassing the works utilizing ultrasound mediated transdermal delivery, nose to brain delivery, intestinal lymphatic system targeting, in situ implants, etc. All the patents associated with AM formulation have also been discussed and summarized. EXPERT OPINION: Numerous studies have been carried out on AM formulations over the recent years, many of these studies have shown significant improvement in bioavailability. We have also mentioned the unexplored domains which can be exploited for further enhancing the bioavailability of AM. Nonetheless, most of these studies are still limited to the research laboratory level and face multiple hurdles before making into the market. Attaining controllability and reproducibility for the production of novel formulations is needed to enable its transition from bench to bedside.

Nanoemulgel: A Promising Phase in Drug Delivery.

Recently, the delivery of hydrophobic/ poorly water-soluble drugs has been a challenging task. Various strategies have been developed to counter the former along with other prime issues, such as stability, bioavailability etc. However, only few formulations have been successful in addressing the problems and nanoemulgel is a standout among them. Nanoemulgels are appropriate candidates for drug delivery because of their dual character i.e. the presence of an emulsion in the nano scale and a gel base, both combined as a single formulation. The nanoemulsion component of the nanoemulgel conforms protection to the active moiety by preventing the enzymatic degradation and certain reactions like hydrolysis. The gel base attributes thermodynamic stability to the emulsion by increasing the viscosity of the aqueous phase by decreasing the interfacial and surface tension. Nanoemulgels possess rheological characteristics which are suited especially for topical delivery and other forms such as dental delivery with the aid of better patient acceptance. As the globule size is present in the nano form alongside the employment of certain penetration enhancers can increase the effectiveness of the formulation by enhancing the permeability and diffusibility. Reports suggest that certain commercially available topical dosage forms have a low spreading coefficient in comparison with the nanoemulgel thereby focusing on the application of nanoemulgels in the field of dermatology, although paving way for various other fields have not been thoroughly exploited. This comprehensive review highlights the benefits of nanoemulgel as a potential carrier for drug delivery with an overview of few illustrations supporting the cause.

Anti-aging and Sunscreens: Paradigm Shift in Cosmetics.

Skin, being one of the vital organs and a protective barrier needs to be pampered and taken care of from early childhood. It is the most visible and the widest exposed organ and by far reflects the general health condition and the aging process in humans. Both intrinsic and extrinsic factors contribute to this complex biological process of skin aging. In recent times, skin health and its beauty is perceived as an indicator of one's health which has resulted in an increasing demand for anti-aging products. Exposure to UV radiation is considered to be one of the factors responsible for aging termed as photoaging. In this review, we have discussed the various factors which may accelerate the process of skin aging. Various approaches and strategies to delay the process of skin aging have been emphasized upon. The patents filed in the area of anti-aging and sunscreen products have also been reviewed to gain an insight into the new formulations which have been developed as an anti-aging product. There has been a tremendous rise in the cosmetic and cosmeceuticals market with products having a dual activity of anti-aging and sun protection. Research is constantly on the rise to ensure the safety of these products. Alternatives to the current topical application of sunscreen are being considered to overcome the drawback of reapplication of the sunscreen often which can be a boon to the cosmeceutical market.

2,5-Dimethyl-4-hydroxy-3(2H)-furanone as an Anti-biofilm Agent Against Non-Candida albicans Candida Species.

BACKGROUND: The predominance of non-Candida albicans Candida (NCAC) species causing healthcare-associated infections has increased over the last decade pertaining to their ability to form biofilms on medical devices. These biofilm-associated infections are challenging to treat as they are resistant to antifungal agents and evade host-immune response resulting in a high risk of device failure or biomaterial removal. Thus, to minimize the risk of biofilm-associated infections, preventing biofilm formation is the best approach which is mediated by the quorum quenching process. METHODS: The present study investigated the modulatory effect of 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) on NCAC biofilm formation and also assessed the effect of the DMHF-coated catheters on biofilm formation of NCAC. The NCAC isolates studied were Candida tropicalis, Candida glabrata and Candida krusei isolated from catheter tip, urine and blood, respectively. RESULTS: DMHF at a concentration of 30 µg/mL showed an inhibitory effect against NCAC biofilms at various stages and was statistically significant (p ≤ 0.05) against the various concentrations (50-5 µg/mL) tested and also among the three phases of experiment. The furanone content on coated catheters ranged from 170 to 750 µg and release of furanone from the coated catheter was about 15 µg for 30 days. The effect of DMHF-coated catheters on NCAC biofilm formation was observed by the scanning electron microscopy which revealed the absence of NCAC adherence on DMHF-coated catheters. DISCUSSION: This study provides a design to develop furanone-coated biomaterials which could be implemented in healthcare settings to reduce medical device-associated infections. The excellent biological performance, combined with their antimicrobial properties, suggests that 2,5-dimethyl-4-hydroxy-3(2H)-furanone could be an effective anti-infective coating for implantable devices.

Computational modeling for formulation design.

Formulation design is an important phase in the drug development process. However, this process at an experimental level requires exhaustive experimental work. Excipient selection, prediction of solubility, encapsulation efficiency, release patterns, drug absorption, stability, and mechanism of nanoparticle formation are some of the essential steps in formulation design. The use of various computational tools, including quantitative structure-activity relationships (QSARs), molecular modeling, molecular mechanics, discrete element modeling, finite element method, computational fluid dynamics, and physiologically based pharmacokinetics (PBPK) modeling, help in the identification of drug product inadequacies and to recommend avenues for understanding complex formulation design in less time with lower investment. Here, we focus on computational modeling tools used in formulation design and its applications.

Mesoporous Silica Nanoparticles: A Comprehensive Review on Synthesis and Recent Advances.

Recent advancements in drug delivery technologies utilizing a variety of carriers have resulted in a path-breaking revolution in the approach towards diagnosis and therapy alike in the current times. Need for materials with high thermal, chemical and mechanical properties have led to the development of mesoporous silica nanoparticles (MSNs). These ordered porous materials have garnered immense attention as drug carriers owing to their distinctive features over the others. They can be synthesized using a relatively simple process, thus making it cost effective. Moreover, by controlling the parameters during the synthesis; the morphology, pore size and volume and particle size can be transformed accordingly. Over the last few years, a rapid increase in research on MSNs as drug carriers for the treatment of various diseases has been observed indicating its potential benefits in drug delivery. Their widespread application for the loading of small molecules as well as macromolecules such as proteins, siRNA and so forth, has made it a versatile carrier. In the recent times, researchers have sorted to several modifications in the framework of MSNs to explore its potential in drug resistant chemotherapy, antimicrobial therapy. In this review, we have discussed the synthesis of these multitalented nanoparticles and the factors influencing the size and morphology of this wonder carrier. The second part of this review emphasizes on the applications and the advances made in the MSNs to broaden the spectrum of its use especially in the field of biomedicine. We have also touched upon the lacunae in the thorough understanding of its interaction with a biological system which poses a major hurdle in the passage of this carrier to the clinical level. In the final part of this review, we have discussed some of the major patents filed in the field of MSNs for therapeutic purpose.

Localized In Situ Nanoemulgel Drug Delivery System of Quercetin for Periodontitis: Development and Computational Simulations.

This study was aimed at formulating a bioabsorbable, controlled-release, nanoemulgel of Quercetin, a potent antimicrobial and anti-inflammatory agent for the treatment of periodontitis that could improve its solubility and bioavailability. Screening of components was carried out based on the solubility studies. Nanoemulsion containing cinnamon oil as the oil phase, tween 80 and Carbitol® as the surfactant-cosurfactant mixture (Smix) and water as the aqueous phase containing 125 µg/200 µL of Quercetin was prepared by using spontaneous emulsification method. Nanoemulgel was prepared using 23% w/v poloxamer 407 as gel base. Comprehensive evaluation of the formulated nanoemulgel was carried out, and the optimized formulation was studied for drug release using Franz vertical diffusion cells. The formulated nanoemulgelexhibited a remarkable release of 92.4% of Quercetin at the end of 6 h, as compared to that of pure Quercetin-loaded gel (<3% release). The viscosity of the prepared nanoemulgel was found to be 30,647 ± 0.32 cPs at 37 °C. Also, molecular dynamics (MD) simulation was utilized to understand the gelation process and role of each component in the formulation. The present study revealed that the developed nanoemulgel of Quercetin could be a potential delivery system for clinical testing in periodontitis.

A top-down technique to improve the solubility and bioavailability of aceclofenac: in vitro and in vivo studies.

The aim of the present work was to tackle the solubility issue of a biopharmaceutics classification system (BCS)-II drug, aceclofenac. Although a number of attempts to increase the aqueous solubility have been made, none of the methods were taken up for scale-up. Hence size reduction technique by a top-down approach using wet milling process was utilized to improve the solubility and, consequently, the dissolution velocity of aceclofenac. The quality of the final product was ensured by Quality by Design approach wherein the effects of critical material attributes and critical process parameters were assessed on the critical quality attributes (CQAs) of nanocrystals. Box-Behnken design was applied to evaluate these effects on critical quality attributes. The optimized nanocrystals had a particle size of 484.7±54.12 nm with a polydispersity index (PDI) of 0.108±0.009. The solid state characterization of the formulation revealed that the crystalline nature of the drug was slightly reduced after the milling process. With the reduced particle size, the solubility of the nanocrystals was found to increase in both water and 0.1 N HCl when compared with that of unmilled pure aceclofenac. These results were further supported by in vitro release studies of nanocrystals where an appreciable dissolution velocity with 100.07%±2.38% release was observed for aceclofenac nanocrystals compared with 47.66%±4.53% release for pure unmilled aceclofenac at the end of 2 h. The in vivo pharmacokinetic data generated showed a statistically significant increase in the Cmax for aceclofenac nanocrystals of 3.75±0.28 µg/mL (for pure unmilled aceclofenac Cmax was 1.96±0.17 µg/mL). The results obtained indicated that the developed nanocrystals of aceclofenac were successful in improving the solubility, thus the absorption and bioavailability of the drug. Hence, it may be a viable and cost-effective alternative to the current therapy.

Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting.

AIMS: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. MATERIALS AND METHODS: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. KEY FINDINGS: The mean particle size was found to be in the range of 126.6 to 306.2nm with PDI of 0.340-1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of -18.1 to -20.2mv. Biotinylated proliposomes (LIP-5B) were in the size of 149.8±6.8nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP-5) and biotin proliposomes (LIP-5B) were executed. SIGNIFICANCE: The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site.

Development of risperidone liposomes for brain targeting through intranasal route.

The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.

Formulation and evaluation of buccal film of Ivabradine hydrochloride for the treatment of stable angina pectoris.

BACKGROUND: Ivabradine hydrochloride is an anti-anginal drug with a biological half-life of about 2 h, and repeated daily administration is needed to maintain effective plasma level. Present investigation of buccal films of Ivabradine hydrochloride is an attempt to avoid the repeated administration and release of drug in more controlled fashion, thereby, to improve the bioavailability. MATERIALS AND METHODS: Buccal patches were fabricated by solvent casting technique and were evaluated for its physical properties like physical appearance, weight uniformity, thickness, swelling index, surface pH, mucoadhesive time, and folding endurance, in vitro and ex vivo release studies. RESULTS: A combination of hydroxypropyl methyl cellulose (HPMC) K15M and K100M with carbopol 940, PEG 6000 gave promising results. Further, the drug content of all the formulations was determined and was found to be uniform. All the formulations were subjected to in vitro release study using phosphate buffer pH 6.6. Patches exhibited drug release in the range of 90.36% ± 0.854 to 98.37% ± 0.589 at the end of six hrs. The best formulations (F2 and F5) containing the composition of HPMC K15-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg and HPMC K100-37.50 mg, carbopol-0.42 mg, PEG6000-16.87 mg, Aspertane-0.28 mg, Tween-0.0023 mg respectively exhibited in vitro drug release of 97.61% ± 0.589 and 98.37% ± 0.114 respectively. The results of ex vivo diffusion using goat cheek pouch revealed that the drug release rate was retarded up to seven hrs. Films prepared with permeation enhancer (Tween 80) showed faster drug release. Finally, stability studies were carried out by using human saliva for the optimized formulation (F2-F5). CONCLUSION: The present study indicated enormous potential of mucoadhesive buccal patches containing Ivabradine for systemic delivery with an added advantage of circumventing hepatic first pass metabolism. Further work is recommended to support its efficacy claims by long term pharmacokinetic and pharmacodynamic studies in human beings.