QbD Assisted Systematic Review for Optimizing the Selection of PVP as a Ternary Substance in Enhancing the Complexation Efficiency of Cyclodextrins: a Pilot Study.

Inclusion complexes require higher concentration of Beta cyclodextrins (ßCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (Ks) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a ßCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and ß-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research.

Transethosome: An ultra-deformable ethanolic vesicle for enhanced transdermal drug delivery.

Drug delivery through the skin improves solubility, bioavailability, and unwanted systemic side effects of the drug. The selection of a suitable carrier is a challenging process. The conventional lipid vesicles have some limitations. They deliver the drug in the stratum corneum and have poor colloidal stability. Here comes the need for ultra-deformable lipid vesicles to provide the drug beyond the stratum corneum. Transethosomes are novel ultra-deformable vesicles that can deliver drugs into deeper tissues. The composition of transethosomes includes phospholipid, ethanol and surfactants. Each ingredient has a pivotal role in the properties of the carrier. This review covers the design, preparation method, characterisation, and characteristics of the novel vesicle. Also, we cover the impact of surfactants on vesicular properties and the skin permeation behaviour of novel vesicles.

Optimised neem oil-bilayer tablets: A safe, effective and stable tool for the prevention of vector-borne disease outbreaks by Aedes albopictus.

The control of mosquito breeding is an essential step towards the reduction of vector-borne disease outbreaks. Synthetic larvicidal agents produce resistance in vectors and cause safety concerns in humans, animals and aquatic species. The drawback of synthetic larvicides opened a new avenue for natural larvicidal agents, but poor dosage accuracy, need for frequent applications, low stability and sustainability are the major challenges with them. Hence, this investigation aimed to overcome those drawbacks by developing bilayer tablets loaded with neem oil to prevent mosquito breeding in stagnant water. The optimised batch of neem oil-bilayer tablets (ONBT) had 65%w/w hydroxypropyl methylcellulose K100M and 80%w/w ethylcellulose in its composition. After the completion of 4th week, 91.98 ± 0.871% azadirachtin was released from the ONBT, which was followed by a subsequent drop in the in vitro release. ONBT reported long-term larvicidal efficacy (>75%) and a good deterrent effect which was better than neem oil-based marketed products. The acute toxicity study on a non-target fish model (Poecilia reticulata), OECD Test No.203 confirmed the safety of the ONBT on non-target aquatic species. The accelerated stability studies predicted a good stability profile for the ONBT. The neem oil-based bilayer tablets can be used as an effective tool for the control of vector-borne diseases in society. The product may be a safe, effective and eco-friendly replacement for the existing synthetic as well as natural products in the market.

Orally Administered Amphotericin B Nanoformulations: Physical Properties of Nanoparticle Carriers on Bioavailability and Clinical Relevance.

Amphotericin B is an effective polyene antifungal considered as a "gold standard" in the management of fungal infections. Currently, it is administered mainly by IV due to poor aqueous solubility, which precludes its delivery orally. Paradoxically, IV administration is akin to side effects that have not been fully eliminated even with more recent IV formulations. Thus, the need for alternative formulations/route of administration for amphotericin B remains crucial. The oral route offers the possibility of delivering amphotericin B systemically and with diminished side effects; however, enterocyte permeation remains a constraint. Cellular phagocytosis of submicron particles can be used to courier encapsulated drugs. In this regard, nanoparticulate delivery systems have received much attention in the past decade. This review examines the trajectory of orally delivered amphotericin B and discusses key physical factors of nanoformulations that impact bioavailability. The review also explores obstacles that remain and gives a window into the possibility of realizing an oral nanoformulation of amphotericin B in the near future.

Revisiting the concept of incretin and enteroendocrine L-cells as type 2 diabetes mellitus treatment.

The significant growth in type 2 diabetes mellitus (T2DM) prevalence strikes a common threat to the healthcare and economic systems globally. Despite the availability of several anti-hyperglycaemic agents in the market, none can offer T2DM remission. These agents include the prominent incretin-based therapy such as glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors that are designed primarily to promote GLP-1R activation. Recent interest in various therapeutically useful gastrointestinal hormones in T2DM and obesity has surged with the realisation that enteroendocrine L-cells modulate the different incretins secretion and glucose homeostasis, reflecting the original incretin definition. Targeting L-cells offers promising opportunities to mimic the benefits of bariatric surgery on glucose homeostasis, bodyweight management, and T2DM remission. Revising the fundamental incretin theory is an essential step for therapeutic development in this area. Therefore, the present review explores enteroendocrine L-cell hormone expression, the associated nutrient-sensing mechanisms, and other physiological characteristics. Subsequently, enteroendocrine L-cell line models and the latest L-cell targeted therapies are reviewed critically in this paper. Bariatric surgery, pharmacotherapy and new paradigm of L-cell targeted pharmaceutical formulation are discussed here, offering both clinician and scientist communities a new common interest to push the scientific boundary in T2DM therapy.

Characterization and ex vivo evaluation of curcumin nanoethosomes for melanoma treatment.

This study aimed at developing curcumin nanoethosomes (Cur-Ets) with superior skin permeation intended for melanoma treatment. Although curcumin is active against many types of skin cancers, a suitable topical formulation is still lacking due to its hydrophobicity and poor skin permeation. The formulation was characterized using Scanning Transmission Electron Microscopy (STEM), atomic force microscopy (AFM), ATR-FTIR, DSC and XRD. In vitro skin permeation was carried out using human skin, and the cytotoxicity of the formulation was evaluated on human melanoma cells (SK-MEL28). The vesicle size and zeta potential of the Cur-Ets were determined as 67 ± 1.6 nm and -87.3 ± 3.3 mV, respectively. STEM and AFM analysis further support the size and morphology of the formulation. Curcumin's compatibility with formulation additives was confirmed by ATR-FTIR analysis. In addition, DSC and XRD analyses showed successful drug encapsulation in nanoethosomes. The drug encapsulation efficiency was determined as 87 ± 0.9%. The skin permeation of curcumin from Cur-Ets showed a superior flux (0.14 ± 0.03 µg cm-2 h-1) compared to the control (p < 0.05). Cytotoxicity of the formulation demonstrated a time-dependent and concentration-dependent antiproliferative activity against melanoma cells. The developed Cur-Ets is suggested as a promising topical formulation for melanoma treatment.

An evaluation of tocotrienol ethosomes for transdermal delivery using Strat-M® membrane and excised human skin.

Tocotrienol (TRF) ethosomes were developed and evaluated in vitro for potential transdermal delivery against melanoma. The optimised TRF ethosomal size ranged between 64.9 ± 2.2 nm to 79.6 ± 3.9 nm and zeta potential (ZP) between -53.3 mV to -62.0 ± 2.6 mV. Characterisation of the ethosomes by ATR-FTIR indicated the successful formation of TRF-ethosomes. Scanning electron microscopy (SEM) images demonstrated the spherical shape of ethosomes, and the entrapment efficiencies of all the formulations were above 66%. In vitro permeation studies using full-thickness human skin showed that the permeation of gamma-T3 from the TRF ethosomal formulations was significantly higher (p < 0.05) than from the control. The cumulative amount of gamma-T3 permeated from TRF ethosome after 48 hours was 1.03 ± 0.24 µg cm-2 with a flux of 0.03 ± 0.01 µg cm-2 h-1. Furthermore, the flux of gamma-T3 across the Strat-M ® and the epidermal membrane was significantly higher than that across full-thickness human skin (p < 0.05). In vitro cytotoxicity studies on HaCat cells showed significantly higher cell viability than the pure drug solution (p < 0.05). The enhanced skin permeation and high cell viability associated with this formulation suggest a promising carrier for transdermal delivery.

An Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles for Transdermal Delivery.

Curcumin-loaded chitosan nanoparticles were synthesised and evaluated in vitro for enhanced transdermal delivery. Zetasizer® characterisation of three different formulations of curcumin nanoparticles (Cu-NPs) showed the size ranged from 167.3 ± 3.8 nm to 251.5 ± 5.8 nm, the polydispersity index (PDI) values were between 0.26 and 0.46 and the zeta potential values were positive (+ 18.1 to + 20.2 mV). Scanning electron microscopy (SEM) images supported this size data and confirmed the spherical shape of the nanoparticles. All the formulations showed excellent entrapment efficiency above 80%. FTIR results demonstrate the interaction between chitosan and sodium tripolyphosphate (TPP) and confirm the presence of curcumin in the nanoparticle. Differential scanning calorimetry (DSC) studies of Cu-NPs indicate the presence of curcumin in a disordered crystalline or amorphous state, suggesting the interaction between the drug and the polymer. Drug release studies showed an improved drug release at pH 5.0 than in pH 7.4 and followed a zero order kinetics. The in vitro permeation studies through Strat-M® membrane demonstrated an enhanced permeation of Cu-NPs compared to aqueous curcumin solution (p ˂ 0.05) having a flux of 0.54 ± 0.03 µg cm-2 h-1 and 0.44 ± 0.03 µg cm-2 h-1 corresponding to formulations 5:1 and 3:1, respectively. The cytotoxicity assay on human keratinocyte (HaCat) cells showed enhanced percentage cell viability of Cu-NPs compared to curcumin solution. Cu-NPs developed in this study exhibit superior drug release and enhanced transdermal permeation of curcumin and superior percentage cell viability. Further ex vivo and in vivo evaluations will be conducted to support these findings.

An evaluation of crude palm oil (CPO) and tocotrienol rich fraction (TRF) of palm oil as percutaneous permeation enhancers using full-thickness human skin.

The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.

Permeation Studies of Captopril Transdermal Films Through Human Cadaver Skin.

Mortality rate due to heart diseases increases dramatically with age. Captopril is an angiotensin converting enzyme inhibitor (ACE) used effectively for the management of hypertension. Due to short elimination half-life of captopril the oral dose is very high. Captopril is prone to oxidation and it has been reported that the oxidation rate of captopril in skin tissues is considerably low when compared to intestinal tissues. All these factors make captopril an ideal drug candidate for transdermal delivery. In this research work an effort was made to formulate transdermal films of captopril by utilizing polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) as film formers and polyethylene glycol 400 (PEG400) as a plasticizer. Dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) were used as permeation enhancers. Physicochemical parameters of the films such as appearance, thickness, weight variation and drug content were evaluated. The invitro permeation studies were carried out through excised human cadaver skin using Franz diffusion cells. The in-vitro permeation studies demonstrated that the film (P4) having the polymer ratio (PVP:PVA = 80:20) with DMSO (10%) resulted a promising drug release of 79.58% at 24 hours with a flux of 70.0 µg/cm(2)/hr. No signs of erythema or oedema were observed on the rabbit skin as a result of skin irritation study by Draize test. Based on the stability report it was confirmed that the films were physically and chemically stable, hence the prepared films are very well suited for transdermal application.

Involvement of opioidergic and serotonergic systems in the analgesic activity of Cissus quadrangularis L. stem extract in mice.

BACKGROUND: Cissus quadrangularis L. (Vitaceae) is used as a bonesetter and as an analgesic. However, the bioactive fractions and the pharmacological mechanism of analgesic activity are not clearly known. Hence, this study aimed to characterize the analgesic activity profile of successively extracted fractions of C. quadrangularis and the pharmacological mechanism of analgesic activity in mice. METHODS: Dried C. quadrangularis stem was extracted successively with chloroform and methanol. The dried extracts were separately administered to mice intraperitoneally at the doses of 75, 150 and 300 mg/kg. The mice were tested separately in hot plate and tail flick tests. The mechanism of analgesic activity of chloroform extract was explored in the hot plate test at the dose of 300 mg/kg after pretreatment with naloxone, p-chlorophenylalanine methyl ester (pCPA) and phentolamine. The data were analyzed by one-way analysis of variance followed by Dunnett's test. RESULTS: Chloroform extract showed significant (p<0.05) analgesic effect at the doses of 75, 150 and 300 mg/kg in hot plate and tail flick tests. Methanol extract showed significant (p<0.05) analgesic effect at the dose of 300 mg/kg in hot plate and tail flick tests. Analgesic activity was not blocked (p<0.05) in the group pretreated with phentolamine but blocked in the groups pretreated with naloxone and pCPA. CONCLUSIONS: The chloroform extract was found to be more potent than methanol extract in inducing analgesic effect in mice, and the analgesic activity may be mediated through opioidergic and serotonergic pathways.