HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus-Based In Vivo Prediction in Humans: Part I.

Tolterodine tartrate (TOTA) is associated with adverse effect, high hepatic access, varied bioavailability, slight aqueous solubility, and short half-life after oral delivery. Hansen solubility parameters (HSP, HSPiP program), experimental solubility (T = 298.2 to 318.2 K and p = 0.1 MPa), computational (van't Hoff and Apelblat models), and thermodynamic models were used to the select solvent(s). HSPiP predicted PEG400 as the most suitable co-solvent based on HSP values (δd = 17.88, δp = 4.0, and δh = 8.8 of PEG400) and comparable to the drug (δd = 17.6, δp = 2.4, and δh = 4.6 of TOTA). The experimental mole fraction solubility of TOTA was maximum (xe = 0.0852) in PEG400 confirming the best fit of the prediction. The observed highest solubility was attributed to the δp and δh interacting forces. The activity coefficient (ϒi) was found to be increased with temperature. The higher values of r2 (linear regression coefficient) and low RMSD (root mean square deviation) indicated a good correlation between the generated "xe" data for crystalline TOTA and the explored models (modified Apelblat and van't Hoff models). TOTA solubility in "PEG400 + water mixture" was endothermic and entropy-driven. IR (immediate release product) formulation can be tailored using 60% PEG400 in buffer solution for 2 mg of TOTA in 0.25 mL (dosing volume). The isotonic binary solution was associated with a pH of 7.2 suitable for sub-Q delivery. The approach would be a promising alternative with ease of delivery to children and aged patients.

It Is All about Probiotics to Control Cervical Cancer.

Cervical cancer (CC) is the fourth most common malignancy in female patients. "Human papillomavirus" (HPV) contamination is a leading cause of all forms of cervical cancer, accounting for an expected 570,000 reported incidents in 2018. Two HPV strains (16 and 18) are responsible for 70% of CC and pre-cancerous cervical abnormalities. CC is one of the foremost reasons for the malignancy death rate in India among women ranging from 30 to 69 years of age in India, responsible for 17% of all cancer deaths. Currently approved cervical cancer treatments are associated with adverse reactions that might harm the lives of women affected by this disease. Consequently, probiotics can play a vital role in the treatment of CC. It is reflected from various studies regarding the role of probiotics in the diagnosis, prevention or treatment of cancer. In this review article, we have discussed the rationale of probiotics for treatment of CC, the role of probiotics as effective adjuvants in anti-cancer therapy and the combined effect of the anti-cancer drug along with probiotics to minimize the side effects due to chemotherapy.

Spray Drying as an Effective Method in the Development of Solid Self- Emulsifying Drug Delivery Systems.

Most of the new drug candidates and present ones are lipophilic, which leads to low bioavailability. Self-emulsifying drug delivery systems (SEDDS) have emerged as promising formulation system for poorly water-soluble drug candidates. Over the last two decades, various such drug compounds were used by researchers for the development of SEDDS. At present, many SEDDS formulations are also available in the market. Though SEDDS offer many advantages but drawbacks like low drug loading, few dosage form choices, difficulty in handling and storage led to the solidification of this system by various methods. Solidification by spray drying technique offers a lot of advantages like scalability and stability. This particular method is the focus of this review. Adsorbent carriers have the most significant role in the fate of this formulation and its compatibility with the drug candidate. This review addresses the advantages, method of development, spray drying specifications, and characterization of S-SEDDS in detail. Furthermore, the prospect of turning spray-dried SEDDS into tablets by punching which offers potential advantages of increased bioavailability and stability has also been discussed.

Computational Design of Molecularly Imprinted Polymers in Drug Delivery Systems: A Comprehensive Review.

BACKGROUND: Nowadays, biomedical research has been focusing on the design and development of new drug delivery systems that provide efficient drug targeting. The molecularly imprinted polymers (MIPs) have attracted wide interest and play an indispensable role as a drug carrier. Drug delivery systems based on MIPs have been frequently cited in the literature. They are cross-linked polymers that contain binding sites according to the complementary structure of the template molecules. They possess distinctive features of structure predictability and site recognition specificity. Versatile applications of MIPs include purification, biosensing, bioseparation, artificial antibodies, and drug delivery. An ideal MIPs should include features such as biocompatibility, biodegradability, and stability. OBJECTIVE: In this article, we elaborate on the historic growth, synthesis, and preparation of different MIPs and present an updated summary of recent advances in the development of new drug delivery systems which are based on this technique. Their potential to deliver drugs in a controlled and targeted manner will also be discussed. CONCLUSION: MIPs possess unique advantages, such as lower toxicity, fewer side effects, and good therapeutic potential. They offer administration of drugs by different routes, i.e., oral, ocular or transdermal. Despite several advantages, biomedical companies are hesitant to invest in MIPs based drug delivery systems due to the limited availability of chemical compounds.

The Role of 4-Thiazolidinone Scaffold in Targeting Variable Biomarkers and Pathways Involving Cancer.

BACKGROUND: Cancer can be considered as a genetic as well as a metabolic disorder. The current cancer treatment scenario looks like aggravating tumor cell metabolism, causing the disease to progress even with greater intensity. The cancer therapy is restricted to the limitations of poor patient compliance due to toxicities to normal tissues and multi-drug resistance development. There is an emerging need for cancer therapy to be more focused towards better understanding of genetic, epigenetic and transcriptional changes resulting in cancer progression and their relationship with treatment sensitivity. OBJECTIVE: The 4-thiazolidinone nucleus possesses marked anticancer potential towards different biotargets, thus targeting different cancer types like breast, prostate, lung, colorectal and colon cancers, renal cell adenocarcinomas and gliomas. Therefore, conjugating the 4-thiazolidinone scaffold with other promising moieties or directing the therapy towards targeted drug delivery systems like the use of nanocarrier systems, can provide the gateway for optimizing the anticancer efficiency and minimizing the adverse effects and drug resistance development, thus providing stimulus for personalized pharmacotherapy. METHODS: An exhaustive literature survey has been done to give an insight into the anticancer potential of the 4- thiazolidinone nucleus either alone or in conjugation with other active moieties, with the mechanisms involved in preventing proliferation and metastasis of cancer covering a vast range of publications of repute. CONCLUSION: This review aims to summarise the work reported on anticancer activity of 4-thiazolidinone derivatives covering various cancer biomarkers and pathways involved, citing the data from the year 2005 till now, which may be beneficial to the researchers for future development of more efficient 4-thiazolidinone derivatives.

Pluronic-Coated Biogenic Gold Nanoparticles for Colon Delivery of 5-Fluorouracil: In vitro and Ex vivo Studies.

The aim of the study was to prepare 5-fluorouracil (5-FU)-loaded biogenic gold nanoparticles with pluronic-based coating (PFGNPs), their optimization (full factorial predicted OBPN-1) and in vitro-ex vivo evaluation. Several formulations were prepared, selected for optimization using Design Expert®, and compared for morphology, 5-FU release kinetics, compatibility, cell line toxicity, in vitro hemocompatibility, and ex vivo intestinal permeation across the rat duodenum, jejunum, and ileum. The pluronic-coated 5-FU-carrying GNPs were spherical, 29.11-178.21 nm in diameter, with a polydispersity index (PDI) range of 0.191-292, and a zeta potential (ZP) range of 11.19-29.21 (-mV). The optimized OBPN-1 (desirability = 0.95) demonstrated optimum size (175.1 nm), %DL as 73.8%, ZP as 21.7 mV, % drug release (DR) as 75.7%, and greater cytotoxicity (viability ~ 8.9%) against the colon cancer cell lines than 5-FU solution (~ 24.91%), and less hemocompatibility. Moreover, OBPN-1 exhibited 4.5-fold permeation across the rat jejunum compared with 5-FU solution. Thus, the PFGNPs exhibit high DL capacity, sustained delivery, hemocompatibility, improved efficacy, and enhanced permeation profiles compared with 5-FU solution and several other NPs preparations suggesting it is a promising formulation for effective colon cancer control with reduced side effects.

Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic.

Coronaviruses have led to severe emergencies in the world since the outbreak of SARS CoV in 2002, followed by MERS CoV in 2012. SARS CoV-2, the novel pandemic caused by coronaviruses that began in December 2019 in China has led to a total of 24,066,076 confirmed cases and a death toll of 823,572 as reported by World Health Organisation on 26 August 2020, spreading to 213 countries and territories. However, there are still no vaccines or medications available till date against SARS coronaviruses which is an urgent requirement to control the current pandemic like situations. Since many decades, heterocyclic scaffolds have been explored exhaustively for their anticancer, antimalarial, anti-inflammatory, antitubercular, antimicrobial, antidiabetic, antiviral and many more treatment capabilities. Therefore, through this review, we have tried to emphasize on the anticipated role of heterocyclic scaffolds in the design and discovery of the much-awaited anti-SARS CoV-2 therapy, by exploring the research articles depicting different heterocyclic moieties as targeting SARS, MERS and SARS CoV-2 coronaviruses. The heterocyclic motifs mentioned in the review can serve as crucial resources for the development of SARS coronaviruses treatment strategies.

Solidified SNEDDS for the oral delivery of rifampicin: Evaluation, proof of concept, in vivo kinetics, and in silico GastroPlusTM simulation.

The present investigation was performed to develop a rifampicin (RIF)-loaded solidified self-nanoemulsifying drug delivery system (SNEDDS) (solidified RIF-OF1) for in vitro and in vivo evaluations. Optimized formulations were tested for their powder flow characteristics, loading efficiency, and in vitro dissolution (at pH-1.2, 6.8 and 7.4). Compatibility studies were also performed. The formulations were also tested for hemocompatibility, intestinal permeation, histopathological effects, and in vivo pharmacokinetics. Additionally, an in silico simulation study using GastroPlus was performed. At different varied pH values, we observed immediate release (T85% within 15 min) based on the dissolution profile. This could be due to labrasol-assisted RIF solubilization. In vitro hemolysis study of the reconstituted RIF-OF1 revealed normal architecture of erythrocytes compared to the positive control (lysed and fragmented). Through in vivo permeation and biopsy studies, a rationale for facilitated intestinal permeation of RIF with components deemed physiological safe (normal anatomy of mucosal membrane evidenced from biopsy study) could be established. The in vitro-in vivo correlation (IVIVC) plus module of GastroPlusTM simulation showed a good IVIVC between in vitro release and in vivo absorption with a predicted systemic absorption of ∼96.5%. Solidified SNEDDS showed improved pharmacokinetic profiles compared to RIF suspension. Solid RIF-SNEDDS was demonstrated to be a suitable carrier for enhanced intestinal permeation and oral bioavailability. Hence, it may serve as a suitable alternative to conventional delivery systems for tuberculosis treatment.

Laponite-based Nanomaterials for Biomedical Applications: A Review.

Laponite based nanomaterials (LBNMs) are highly diverse regarding their mechanical, chemical, and structural properties, coupled with shape, size, mass, biodegradability and biocompatibility. These ubiquitous properties of LBNMs make them appropriate materials for extensive applications. These have enormous potential for effective and targeted drug delivery comprised of numerous biodegradable materials which results in enhanced bioavailability. Moreover, the clay material has been explored in tissue engineering and bioimaging for the diagnosis and treatment of various diseases. The material has been profoundly explored for minimized toxicity of nanomedicines. The present review compiled relevant and informative data to focus on the interactions of laponite nanoparticles and application in drug delivery, tissue engineering, imaging, cell adhesion and proliferation, and in biosensors. Eventually, concise conclusions are drawn concerning biomedical applications and identification of new promising research directions.

Elastic liposomes as novel carriers: recent advances in drug delivery.

Elastic liposomes (EL) are some of the most versatile deformable vesicular carriers that comprise physiologically biocompatible lipids and surfactants for the delivery of numerous challenging molecules and have marked advantages over other colloidal systems. They have been investigated for a wide range of applications in pharmaceutical technology through topical, transdermal, nasal, and oral routes for efficient and effective drug delivery. Increased drug encapsulation efficiency, enhanced drug permeation and penetration into or across the skin, and ultradeformability have led to widespread interest in ELs to modulate drug release, permeation, and drug action more efficiently than conventional drug-release vehicles. This review provides insights into the versatile role that ELs play in the delivery of numerous drugs and biomolecules by improving drug release, permeation, and penetration across the skin as well as stability. Furthermore, it provides future directions that should ensure the widespread use of ELs across all medical fields.

Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade.

Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1-S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent.

Enhanced stability and permeation potential of nanoemulsion containing sefsol-218 oil for topical delivery of amphotericin B.

AIM: To characterize the enhanced stability and permeation potential of amphotericin B nanoemulsion comprising sefsol-218 oil at varying pH and temperature of aqueous continuous phase. METHODOLOGY: Several batches of amphotericin B loaded nanoemulsion were prepared and evaluated for their physical and chemical stability at different pH and temperature. Also, a comparative study of ex vivo drug permeation across the albino rat skin was investigated with commercial Fungisome® and drug solution at 37 °C for 24 h. The extent of drug penetrated through the rat skin was thereby evaluated using the confocal laser scanning microscopy (CLSM). RESULTS AND CONCLUSIONS: The optimized nanoemulsion demonstrated the highest flux rate 17.85 ± 0.5 µg/cm(2)/h than drug solution (5.37 ± 0.01 µg/cm(2)/h) and Fungisome® (7.97 ± 0.01 µg/cm(2)/h). Ex vivo drug penetration mechanism from the developed formulations at pH 6.8 and pH 7.4 of aqueous phase pH using the CLSM revealed enhanced penetration. Ex vivo drug penetration studies of developed formulation comprising of CLSM revealed enhanced penetration in aqueous phase at pH 6.8 and 7.4. The aggregation behavior of nanoemulsion at both the pH was found to be minimum and non-nephrotoxic. The stability of amphotericin B was obtained in terms of pH, optical density, globular size, polydispersity index and zeta potential value at different temperature for 90 days. The slowest drug degradation was observed in aqueous phase at pH 7.4 with shelf life 20.03-folds higher when stored at 4 °C (3.8 years) and 5-fold higher at 25 °C (0.951 years) than at 40 °C. The combined results suggested that nanoemulsion may hold an alternative for enhanced and sustained topical delivery system for amphotericin B.