Pure Drug Research Articles

In vivo pharmacokinetic study and PBPK modeling: Comparison between 3D-printed nanocrystals and solid dispersions.

The solubility of drugs remains one of the most challenging aspects of formulation development. Several technologies exist to enhance the properties of poorly soluble drugs, with nanocrystal (NC) and solid dispersion (SD) technologies being among the most important. This work compared NCs and SDs under identical conditions using albendazole as a model drug and 3D printing technology as the delivery method. SDs were initially prepared and characterized, and then compared to the NCs system. Techniques such as TGA, DSC, XRD, FTIR, SEM, and Raman spectroscopy were employed to assess the solid-state properties and formulation homogeneity. Solubility and dissolution profiles were evaluated under simulated gastric and intestinal conditions. An in vivo pharmacokinetic study in dogs compared 3D-printed formulations (NC-3D and SD-3D) with a control group treated with the pure drug (ABZ-C) was carry out. A PBPK model was developed also in dogs to further analyse the results. While no statistically significant differences were observed in the in vitro dissolution profiles in 0.1 N HCl, differences emerged in precipitation time and solubility at intestinal pH (6.8). The pharmacokinetic study revealed improvements in the pharmacokinetic profile of both systems compared to the control, as expected. Between the NCs and the SD, the NC system demonstrated significantly superior pharmacokinetic parameters of interest. The PBPK model helped explain the differences observed in the in vivo study. The results suggest that nanocrystal technology is more effective at enhancing the in vivo performance of Class II drugs, at least when using albendazole as the model drug.

ENHANCING FLUCONAZOLE SOLUBILITY AND BIOAVAILABILITY THROUGH SOLID DISPERSION TECHNIQUES: EVALUATION OF POLYETHYLENE GLYCOL 6000 AND SODIUM CARBOXYMETHYLCELLULOSE SYSTEMS USING FIBER OPTICS

Objective: The triazole antifungal fluconazole is widely used for treating mycotic infections, but its efficacy is limited by its poor aqueous solubility and low dissolution rate, leading to reduced oral bioavailability. This study aimed to enhance the solubility and dissolution rate of fluconazole using solid dispersion techniques with Polyethylene Glycol 6000 (PEG 6000) and Sodium Carboxymethylcellulose (SCMC) as carriers. Methods: Solid dispersions were prepared using the fusion method, and their physicochemical properties were evaluated against physical mixtures and pure drug samples. Results: The solid dispersion showed a significant increase in the dissolution rate, achieving 89.01% drug release in 180 min compared to 40.3% for the pure drug (p<0.0032) and 84.1% for the physical mixture (p<0.0453). The encapsulation efficiency of the solid dispersion was 39.24%, with a drug loading capacity of 19.62%. Fourier Transform Infrared (FTIR) spectroscopy confirmed the stability of the drug within the dispersion, while Scanning Electron Microscopy (SEM) revealed amorphous particles, indicating enhanced solubility. Conclusion: These results demonstrate that the solid dispersion of fluconazole with PEG 6000 and SCMC significantly improves its dissolution rate and flow properties, providing a promising strategy for enhancing the oral bioavailability of poorly water-soluble drugs.

Sustained release of nano-encapsulated glimepiride drug with chitosan nanoparticles: A novel approach to control type 2 diabetes in streptozotocin-induced Wistar albino rats.

The objective of the present study was to encapsulate the effective antidiabetic glimepiride (GLM) drug with biodegradable chitosan nanoparticles (CS NPs) in order to reduce the risk of side effects, regulate and improve alternatives to therapy for people with type 2 Diabetes mellitus. The characterizations of the encapsulated EGLM-CS NPs were published in a previous paper. In continuation of the past study, here we report the in vitro and in vivo activities of EGLM-CS NPs in streptozotocin-induced diabetes Wistar albino rats orally treated for 28 days. Based on our results, the in vitro 3 T3-L1 cell lines observed that the highest concentration of 500 μg/mL exhibited 91.48 % cell viability after 24 h of treatment. The in vivo results of the EGLM-CS NPs treated rats group showed gradual control of the blood glucose level at 90 and 120 min compared to other groups because the drug showed a sustained release mechanism. A significant difference was observed in serum lipid profiles between diabetic treated and control rats. It is believed that the CS NPs served as a carrier system for the GLM drug, protected it from degradation, and enhanced its solubility as well as bioavailability. After 28 days of treatment, all the animal groups organs (pancreas, liver, and kidney) were dissected for histopathological analysis. The EGLM-CS NPs treated group displayed regeneration cells of the islets of Langerhans in the pancreas and normal cellular size with hyperplasia. The therapeutic potential was observed by the liver and kidney from rats reveals few tubule necrosis, improved bioavailability as compared to pure GLM drug treated rats. Hence, our formulated NPs are safe, no toxic effect on the vital organs, which will be helpful to improve the lives of diabetic patients and contribute to the overall health of the individuals.

Engineering sodium alginate microparticles with different crystallinities for niclosamide repositioning and solubilization to improve solubility and oral bioavailability in rats

Niclosamide is a commonly used anthelmintic; however, its poor aqueous solubility limits its oral bioavailability. Enhancing its solubility and oral bioavailability is crucial for its repositioning as an anticancer agent. Here, we aimed to develop new sodium alginate–poloxamer microparticles with different crystallinities to increase drug solubility and oral bioavailability. Sodium alginate and poloxamer were used as the polymer and surfactant, respectively, to prepare niclosamide-loaded microparticles via spray drying. The optimized amorphous and crystalline microparticles were prepared with niclosamide/sodium alginate/poloxamer weight ratios of 1:2.5:3 and 1:1.125:0.375, respectively. Their solubilities, dissolution rates, physicochemical properties, and oral bioavailabilities were compared with those of drug powder in rats. Physicochemical characterization of the developed particles revealed changed structure from crystalline to amorphous, with no irregular crystalline characteristics but decreased particle size. Compared to the pure drug powder, crystalline microparticles retained their crystalline nature with no significant changes in particle size. Both microparticles showed significantly higher aqueous solubilities, dissolution rates, and oral bioavailabilities than niclosamide powder in rats. Amorphous microparticles showed higher solubility (approximately 1775-fold) and oral bioavailability (approximately 5.6-fold) than niclosamide powder due to the crystalline-to-amorphous change and decreased particle size. The developed amorphous microparticles can be used to improve niclosamide solubility and oral bioavailability.

Breaking barriers: enhancing solubility and dissolution of efonidipine using co-amorphous formulations.

The study aims to enhance the solubility and dissolution characteristics of efonidipine hydrochloride ethanolate (EFD), an antihypertensive drug, through the co-amorphous approach. Hypertension is a prevalent chronic condition characterized by consistently elevated blood pressure. Efonidipine, a BCS class II drug, has high permeability but low solubility, limiting its therapeutic effectiveness. Amorphization, which disrupts the crystal lattice of crystalline medications, can significantly enhance drug solubility and dissolution rates. Co-amorphous systems of EFD were prepared using solvent evaporation, ball milling, and liquid-assisted grinding methods. The drug and co-former were used in a different ratio, a stoichiometric proportion known for forming stable amorphous phases. The in vitro dissolution of the co-amorphous form was evaluated and compared with the pure crystalline form of EFD. The co-amorphous system of EFD with benzoic acid demonstrated significantly higher dissolution rates in vitro compared to the pure drug. PXRD analysis confirmed the transformation from a crystalline to an amorphous state, indicated by the disappearance of sharp peaks characteristic of the crystalline form. The resultant co-amorphous system exhibited dissolution properties. The co-amorphous approach effectively improved the solubility and dissolution of efonidipine hydrochloride ethanolate. Benzoic acid, as a co-former, facilitated the formation of a stable amorphous phase, thereby enhancing the drug's dissolution rate. The developed a co-amorphous system of EFD with benzoic acid, significantly enhancing its dissolution characteristics. PXRD analysis confirmed the amorphous nature and improved stability of the co-amorphous form, indicating its potential for better therapeutic efficacy in hypertension management.

L-Cystine-Based Polyurethane as a Drug-Delivery Vehicle in Targeted Cancer Therapy and Biomedical Applications.

Controlled and sustained drug release is a critical aspect of drug-delivery systems (DDSs) that can be used in chemotherapy while ensuring therapy effectiveness and biosafety. Hence, polyurethane (PU) is modified using a biomolecule Cystine (CYS) for protracted drug release, aiming to enhance cancer treatment efficacy while minimizing adverse side effects in tumor patients. To confirm the formation of a polymer structure, characterization techniques such as NMR and FTIR are used, and the morphology is determined using SEM. Biocompatibility of the synthesized polymers is evaluated through cellular assessments, including MTT assay, cell adhesion, and antibacterial assay along with drug release using an anticancer drug, Paclitaxel (PTX). Notably, the incorporation of PTX in the polymer matrix results in minimal mortality (85% viable cells) rates in healthy cells (3T3), in contrast to a 56% mortality rate observed with the pure drug. While PTX shows a burst release and kills cancer cells only for the first 24 h, PU loaded with the drug shows sustained release and kills the cancer cells for 3 days. This vehicle selectively kills 59% of SiHA cells after a consecutive study of 3 days, which highlights the potential of this newly designed vehicle for effective drug delivery, particularly in anticancer treatments. Moreover, cystine's antibacterial property adds up with PU; hence, PU shows antibacterial activity against Staphylococcus aureus (MIC, 20 μg/mL) and also acts as a reductive oxygen species scavenger. Therefore, modifying PU with CYS has shown sustained release of PTX along with a selective effect on cells, underscoring its significance as a superior delivery agent and supported by a shred of convincing evidence.

Multifunctional approach with LHRH-mediated PLGA nanoconjugate for site-specific codelivery of curcumin and BCL2 siRNA in mice lung cancer

BackgroundLung cancer remains a leading cancer type, but current chemotherapy is limited by issues including poor drug delivery, toxicity, and resistance. To address these challenges, we developed a novel PLGA-PEG-LHRH (PPL) nanoconjugate system for improved drug delivery. Curcumin, known for its anticancer and P-gp inhibition properties, was co-loaded with bcl2siRNA (bclsR) to inhibit the bcl2 protein, thus overcoming both resistance mechanisms.ResultsThe PPL conjugate was successfully synthesized and characterized using FTIR, 1H NMR, XRD, XPS and BCA assay. Curcumin and bclsR-loaded PLGA nanoemulsions were prepared by double emulsion solvent evaporation method and characterized. The optimized nanoconjugate had size of 179 ± 16 nm, favorable zeta potential, high drug entrapment, and was confirmed via TEM. Controlled release studies indicated 83% drug release within 24 h. In vitro studies revealed significant cytotoxicity against A549 lung cancer cells, with the nanoconjugate showing IC50 of 8.24 µg/mL compared to 21.26 µg/mL for plain curcumin. Enhanced cellular uptake and effective targeting of A549 cells were observed. Molecular analyses demonstrated significant downregulation of MDR1 and Bcl2 RNA and protein expression, highlighting the nanoconjugates' ability to suppress resistance mechanisms. Pharmacokinetic studies in Wistar rats showed superior plasma drug concentrations, half-life, and AUC for the nanoconjugate versus pure drug suspension. Biodistribution studies showed increased drug accumulation in the lungs. In vivo efficacy studies in Balb/c mice demonstrated higher tumor inhibition ratios for CUR-siRNA PPL NPs (66.89%) and CUR-PPL NPs (59.84%) which was further confirmed with TNFα and p53 levels in blood. Histopathological studies showed good healing in the CUR-siRNA PPL NP- and CUR-PPL NP-treated mice compared to suspension.ConclusionFrom the study, it may be concluded that the PPL nanoconjugate system, loaded with curcumin and bcsR, can be potentially effective, multifunctional targeted approach for lung cancer therapy.Graphical

Experimental and computational studies on possibility of using glucose diazacrown cryptand as a carrier for anticancer drugs busulfan and lomustine

Drug carriers play a very important role in pharmacy, especially in cancer therapy. Most drugs used in the treatment of cancer are characterized by poor solubility in water and lack of selectivity in their toxic effects on normal and cancer cells. Administration of the drug in the form of a complex with an appropriately selected carrier can significantly improve its therapeutic effect and reduce side effects. In this study, the possibility of using the cryptand L1, containing two diazacrown ethers and two saccharide groups, as a potential drug carrier is investigated. In order to determine whether it can form complexes with drugs, the cryptand L1 and its complexes with two anticancer drugs, busulfan (BSF) and lomustine (CCNU), were synthesized. Their selected structural and energetic properties were investigated using both experimental and computational methods. Additionally, water solubility and cytotoxicity tests were performed for all compounds. The measured 1H NMR spectra confirm that L1 forms complexes L1:BSF and L1:CCNU, the solubility of which in water appears to be much higher than that of the pure drugs. The results of DFT calculations made in water described with the implicit solvent model confirm high stability of L1:BSF and L1:CCNU and indicate that L1 forms with the drugs mainly non-inclusion complexes. However, additional tests with 20 H2O molecules explicitly included in the model suggest that both inclusion and non-inclusion forms can occur in a real solution. Cytotoxicity studies show that the macrocycle L1 is non-toxic towards both normal and cancer cells, and its complexes with drugs show greater selectivity towards cancer cells. Interestingly, while the cytotoxicity of the L1:BSF complex is stronger than that of pure BSF, the relationship is opposite in the case of L1:CCNU and CCNU. Therefore, L1 can be considered as a potential drug carrier, especially for those drugs that have weak activity on cancer cells.

Antitumoral action of carvedilol–a repositioning study of the drug incorporated into mesoporous silica MCM-41

We have studied repositioning of carvedilol (an antihypertensive drug) incorporated into MCM-41 mesoporous silica. The repositioning proposes a reduction in the slow pace of discovery of new drugs, as well as toxicological safety and a significant reduction in high research costs, making it an attractive strategy for researchers and large pharmaceutical companies. We obtained MCM-41 bytemplatesynthesis and functionalized it by post-synthesis grafting with aminopropyltriethoxysilane (APTES) only or with folic acid (FA), which gave MCM-41-APTES and MCM-41-APTES-FA, respectively. We characterized the materials by scanning and transmission electron microscopy, zeta potential (ZP) measurements, Fourier transform infrared absorption spectroscopy, x-ray diffractometry, nitrogen gas adsorption, and CHNS elemental analysis. We quantified the percentage of drug that was incorporated into the MCM-41 materials by thermogravimetric analysis and evaluated their cytotoxic activity in non-tumor human lung fibroblasts and the tumor human melanoma and human cervical adenocarcinoma cell lines by XTT salt reduction (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-arboxanilide). The x-ray diffractograms of the MCM-41 materials displayed low-angle peaks in the 2θrange between 2° and 3°, and the materials presented type IV nitrogen adsorption isotherms and H2 hysteresis typical of the MCM-41hexagonal network. The infrared spectra, the charge changes revealed by ZP measurements, and the CHN ratios obtained from elemental analysis showed that MCM-41 was amino-functionalized, and that carvedilol was incorporated into it. MCM-41-APTES incorporated 23.80% carvedilol, whereas MCM-41 and MCM-41-APTES-FA incorporated 18.69% and 12.71% carvedilol, respectively. Incorporated carvedilol was less cytotoxic to tumor and non-tumor cells than the pure drug. Carvedilol repositioning proved favorable and encourages further studies aimed at reducing its cytotoxicity to non-tumor cells. Such studies may allow for larger carvedilol incorporation into drug carriers or motivate the search for a new drug nanocarrier to optimize the carvedilol antitumoral activity.

Paliperidone-loaded nose to brain targeted NLCS: optimisation, evaluation, histopathology and pharmacokinetic estimation for schizophernia

Study was to develop a nanostructured-lipid-careers (NLCs) of paliperidone (PLP) for nose-to-brain targeting. NLCs was prepared by sonication, high-shear homogenisation method, and characterised their mean diameter, PDI, zeta-potential, morphology (by SEM, TEM and AFM), entrapment efficiency, drug loading, in vitro release, interaction study (by FTIR), and stability. Further, ex vivo permeation and ciliotoxicity performed in sheep nasal mucosa, and in vivo biodistribution/pharmacokinetic was performed in rats for schizophernia. Developed NLCs showed spherical and clearly 3-dimentinal structure with 129 ± 2.7 nm mean diameter, 0.304 ± 0.003 PDI, −7.61 ± 0.56 mV zeta-potential, 58.16 ± 0.17% entrapment efficiency, 65.8 ± 2% drug loading and 74.32 ± 0.003% release in 12 h, followed by Higuchi model. Ex vivo study showed NLCs have three times higher permeation, compare to pure drug (around 71.50.32% in 6 h) and 3.98 g/cm2/h steady sate flux. The blood/brain ratio given by intranasally have higher compare to IV route, and 94.53 ± 21.45% drug targeting efficiency in brain. In conclusion, NLCs have easily crossed BBB, higher drug delivery and effective for schizophrenia in given by intranasal.

Formulation and Assessment of Tolnaftate Microsponges for Topical Medication Deliverance

Objective: This study aimed to develop and evaluate the sustained delivery of Tolnaftate using topical polymeric microsponges. Materials and Methods: Tolnaftate-loaded microsponges made of ethyl cellulose were prepared via quasi-emulsion solvent diffusion. The effects of the drug-to-polymer ratio on active drug content, particle size, and entrapment efficiency were examined. The optimized formulation was incorporated into a Carbopol gel and evaluated for drug content, pH, viscosity, and in vitro drug release. The study considered internal phase volume, stirring rate, and emulsifier concentration as variables and analyzed their impact on entrapment efficiency and particle size. Results: Increasing stirring speed reduced particle size and improved entrapment efficiency, while a higher volume of dichloromethane decreased particle size. Scanning electron microscopy revealed porous and spherical microsponges. The 1.5:1 drug-to-polymer ratio yielded the highest active drug content, optimal entrapment efficiency, and smallest particle size, making it the preferred ratio for further studies. Conclusions: The drug release from the microsponge gel was more sustained compared to both the marketed product and pure drug gel. An ex vivo drug deposition study using rat abdominal skin showed satisfactory drug deposition. These polymeric microsponges show potential as a topical drug delivery system for antifungal therapy.

Development of erythromycin loaded PLGA nanoparticles for improved drug efficacy and sustained release against bacterial infections and biofilm formation

Bacterial infections are a common cause of sepsis, often leading to high patient mortality. Such infections are challenging to treat due to bacterial resistance to many existing drugs. Erythromycin (Ery) is a macrolide antibiotic used against bacterial infections with reported resistance. Recently, synthetic poly-lactide co-glycolic acid (PLGA) polymer nanoparticles (NPs) have displayed improved drug delivery characteristics and biocompatibility. In this study, PLGA-Ery NPs were synthesized by the o/w emulsion diffusion method, having a particle size of 159 ± 23 nm and displayed 71.89 % of encapsulation efficiency. The PLGA-Ery NPs showed 1.5, 2.1 and 1.5-fold improved MIC and antibacterial efficacy against E. coli, S. aureus, and P. aeruginosa, respectively than the pure drug. As illustrated by scanning electron microscopy, PLGA-Ery NPs caused damage to the bacterial cell walls. Furthermore, a surface coating with PLGA-Ery NPs on a glass surface showed efficient inhibition (>90 %) of the biofilm formation by P. aeruginosa, as determined by fluorescence microscopy and MTT assay. This study demonstrates that PLGA-Ery NPs can increase the efficiency of erythromycin and can suppress the growth and biofilm formation of P. aeruginosa. Such polymeric nanoparticles drug nanoformulations have potential as an antimicrobial and as a surface coating for medical devices.

Determining the anticancer effect of Gefitinib-loaded NLCs through investigating the inflammatory cytokine (JAK-STAT) pathway

This research aims to investigate the feasibility of using nanostructured lipid carriers (NLC) loaded with Gefitinib to treat colorectal cancer by focusing on the inflammatory cytokine pathway, particularly on the JAK-STAT pathway. As part of the study, Gefitinib-loaded NLC (Nano-GEF) was prepared by homogenization method. Colorectal cancer cells HCT116 were subjected to a series of tests to determine cytotoxicity, including morphological assessment, MTT assay, DNA fragmentation analysis, evaluation of interleukin cytokines, and JAK-STAT pathway expression. According to the study's results, Nano-GEF has far stronger anti-cancer effects than the pure drug (GEF) against cells of colorectal cancer. Morphological studies and cytotoxicity assays confirm the selective action of Nano-GEF on cancer cells. Furthermore, the expression of pathways mediated by JAK-STAT provides further evidence of Nano-GEF's effectiveness as a potential anti-cancer therapy. By focusing on the inflammatory cytokine pathway (JAK-STAT), this research shows that gefitinib-loaded NLC might be a good technique to treat colorectal cancer. Based on the results, Nano-GEF has the potential to be an effective anti-cancer method that is more selective than the pure drug. These findings open the door to the creation of innovative pharmaceutical products as well as the possibility of applications in the assessment and treatment of cancer.

Recent Updates in Nanocrystal Technology: A Reference to Oral Drug Delivery System

Increasing the oral bioavailability of drugs that dissolve slowly may be possible with the use of nanocrystal technology. It is being employed for drug engineering and research after making rapid advancements in recent years. The manufacturing process for pharmaceuticals is significantly hampered by the low solubility and quick rate of dissolution of poorly soluble medications. When taken orally, medications that are poorly soluble often have low and inconsistent bioavailability, which could lead to therapeutic failure. Pure drug nanocrystals prepared via "bottom-up" or "topdown" procedu are able to significantly improve the way poorly soluble medications dissolve thanks to their enormous surface area, which in turn enhances oral absorption. Nanocrystal medications allow for the creation of various dosage formulations. The use of nanocrystal technology in pharmaceutical research, particularly for oral drug delivery systems, is the main focus of this review. First, a quick discussion on the characteristics of pharmaceutical nanocrystals and several nanocrystal technology preparation techniques is provided. The application of nanocrystal technology in pharmaceutical science is covered after a discussion of the creation of prolonged-release formulations. Next follows a brief overview of the scaling-up procedure, commercial nanocrystal drug products, and regulatory aspects of nanodrugs. This paper offers a thorough explanation of preparation techniques, their characterisation, and how they are used in oral drug delivery systems.

Atorvastatin loaded glycerosomal patch as an effective transdermal drug delivery: optimization and evaluation.

Aim: The study explores glycerosomes as effective vesicular systems for transdermal delivery of atorvastatin (ATO) to overcome drawbacks related to its oral administration.Methodology: The objectives of this study were to formulate, by thin-film hydration method, optimize using definitive screening design and evaluate ATO-loaded glycerosomes (ATOG) which were then incorporated into patch followed by the evaluation of glycerosomes containing different concentration of glycerol.Results & discussion: Vesicle size, Polydispersity index (PDI), zeta potential, entrapment efficiency and loading capacity of spherical ATOG (0-30%w/w) showed 137.3-192d.nm, 0.292-0.403, -3.81 to-6.76mV, 80.03-92.77% and 5.80-6.40%, respectively. In-vitro release study showed sustained release, increased skin permeability and better cell viability than pure drug. ATOG patches showed greater skin permeability than pure drug and ATO-liposomal patches.Conclusion: The study concludes that ATOGs are promising for effective transdermal delivery.

Development of a selective COX-2 inhibitor: from synthesis to enhanced efficacy via nano-formulation.

Non-steroidal anti-inflammatory drugs NSAIDs are widely used for managing various conditions including pain, inflammation, arthritis and many musculoskeletal disorders. NSAIDs exert their biological effects by inhibiting the cyclooxygenase (COX) enzyme, which has two main isoforms COX-1 and COX-2. The COX-2 isoform is believed to be directly related to inflammation. Based on structure-activity relationship (SAR) studies of known selective COX-2 inhibitors, our aim is to design and synthesize a novel series of 2-benzamido-N-(4-substituted phenyl)thiophene-3-carboxamide derivatives. These derivatives are intended to be selective COX-2 inhibitors through structural modification of diclofenac and celecoxib. The compound 2-benzamido-5-ethyl-N-(4-fluorophenyl)thiophene-3-carboxamide VIIa demonstrated selective COX-2 inhibition with an IC50 value of 0.29 μM and a selectivity index 67.24. This is compared to celecoxib, which has an IC50 value of 0.42 μM and a selectivity index 33.8. Molecular docking studies for compound VIIa displayed high binding affinity toward COX-2. Additionally, the suppression of protein denaturation with respect to albumin was performed as an indicative measure of the potential anti-inflammatory efficacy of the novel compounds. Compound VIIa showed potent anti-inflammatory activity with 93% inhibition and an IC50 value 0.54 μM. In comparison, celecoxib achieved 94% inhibition with an IC50 value 0.89 μM. Although molecule VIIa demonstrated significant in vitro anti-inflammatory activity, adhered to Lipinski's "five rules" (RO5) and exhibited promising drug-like properties, it showed indications of poor in vivo activity. This limitation is likely due to poor aqueous solubility, which impacts its bioavailability. This issue could be addressed by incorporating the drug in niosomal nanocarrier. Niosomes were prepared using the thin-film hydration technique. These niosomes exhibited a particle size of less than 200 nm, high entrapment efficiency, and an appropriate drug loading percentage. Transmission electron microscopy (TEM) and differential scanning calorimetry (DSC) studies revealed that the niosomes were spherical and demonstrated compatibility of all of its components. The drug release study indicated that the pure drug had limited practicality for in vivo use. However, incorporating the drug into niosomes significantly improved its release profile, making it more suitable for practical use.

Optimization of dolutegravir and Epigallocatechin gallate loaded nanoemulsion for enhanced oral delivery in NeuroAIDS management

The present study aimed to develop a nanoemulsion loaded with dolutegravir (DTG) and Epigallocatechin Gallate (EGCG) to achieve a combined and synergistic effect for improved oral delivery, facilitating more effective management of NeuroAIDS. Thyme oil was chosen as the oil, tween 80 as the surfactant, and transcutol®HP as the co-surfactant following extensive screening of experiments. The nanoemulsion was fabricated using the ultrasonication technique and optimization was performed using a Central Composite Rotatable Design (CCRD) to attain the best formulation following parameters like droplet size, polydispersity index (PDI), zeta potential, % transmittance, pH, refractive index, viscosity and conductivity of the optimized nanoemulsion, which were found to be 45.36 nm, 0.2462, −6.226 mV, 96.30 ± 0.20 %, 6.84 ± 0.32, 1.70 ± 0.12, 31.17 ± 0.21 mPas, and 0.217 ± 0.002 mS/cm, respectively. The developed formulation was thoroughly characterized and investigated through various in vitro studies, demonstrating enhanced drug release. The nanoemulsion showcased a spherical and globular nature of the droplets, resulting in improved drug bioavailability compared to the pure drug. In conclusion, the DTG and EGCG-loaded nanoemulsion formulation offers a promising approach for achieving a combined anti-HIV effect, with potential for effective NeuroAIDS management. Future investigations will focus on validating the anti-HIV-1 properties of this nanoemulsion formulation, employing in-depth mechanistic analysis through in vitro preclinical studies, to further elucidate their synergistic effects and optimize therapeutic potential against HIV-1 infection.

In vitro and in vivo performance of amorphous solid dispersions of ursolic acid as a function of polymer type and excipient addition.

The objective of this research was to enhance the bioavailability of ursolic acid (UA) by preparing multielement amorphous solid dispersion (ASD) systems comprising excipients. The ASDs were prepared via the solvent evaporation method, characterized by a range of techniques, and investigated with respect to permeability of human colorectal adenocarcinoma cell line (Caco-2) cells monolayers and pharmacokinetics, with comparisons made to the physical mixture and the pure drug. The (UA-choline)-Polyethylcaprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer (Soluplus)-Vitamin E polyethylene glycol succinate (TPGS) ASD demonstrated superior dissolution properties compared to the corresponding binary solid dispersions and ternary solid dispersions (P<.05). The permeability studies of Caco-2 cell monolayers revealed that the ASD exhibited moderate permeability, with an efflux rate that was significantly lower than that of the UA raw material (P<.05). Pharmacokinetic studies in rats demonstrated that the oral bioavailability of the ASD was 19.0 times higher than that of UA (P<.01). The research indicated that the multielement ASD could be employed as an efficacious drug delivery system for UA. Furthermore, the Soluplus/TPGS/choline combination represents a promising candidate for the fabrication of ASDs that can load weakly acidic and poorly soluble drugs.

B-268 Detection of xylazine in fentanyl-positive urine drug screen specimens using a quantitative LCMS/MS method

Abstract Background Fentanyl, a synthetic opioid used clinically for severe pain management, sedation, and as a perioperative analgesic, has been at the forefront of fatal drug-involved overdoses for almost a decade. Xylazine, an α-2 adrenergic receptor agonist, is an increasingly common adulterant in illicitly manufactured fentanyl products and analogs. Given its class, xylazine is non-responsive to naloxone, an opioid receptor antagonist used to reverse opioid overdose. Importantly, the U.S. Drug Enforcement Administration reported xylazine in 23% of seized fentanyl powders and 7% of fentanyl pills; additionally, a recent study by Kariisa et. al. identified an increase of xylazine presence in fatal fentanyl-involved overdoses (2.9% in January 2019 to 10.9% in June 2022) across twenty states.1 Collectively, these trends indicate a need for increased surveillance of xylazine in overdose-presenting patients to inform appropriate clinical responses. In this study, we developed a sensitive LC-MS/MS method for xylazine quantitation and used it to determine xylazine presence in our fentanyl positive patients. Methods An LC-MS/MS method for quantitation of xylazine from urine samples was developed using a Waters Xevo TQ-XS and reversed-phase CORTECS C8 2.7 µm column. MRMs and optimal MS tuning parameters were generated for xylazine and xylazine-d6 via IntelliStart, with transition ions of 221.18→90.04 (Quan) and 221.18→136.31 (Qual) selected for xylazine quantitation against a 227.23→89.98 xylazine-d6 transition as an internal standard. An LC method was developed using water (2 mM Ammonium Acetate; 0.1% Formic Acid v/v) and methanol (2 mM Ammonium Acetate; 0.1% Formic Acid v/v) gradient for a 4-minute runtime. Calibrators were prepared by addition of the pure drug to water, while QCs were prepared using healthy volunteer urine that was confirmed negative in a routine urine drug screen (UDS). Calibrators were value-assigned using a reference laboratory. A simple processing method consisting of the addition of 200 µL methanol containing 25 ng/mL xylazine-d6 to 50 µL of standards, QCs, or urine was used for sample preparation. Remnant fentanyl-positive patient samples (determined by ARK Fentanyl II Immunoassay - Abbott Architect C16000 analyzer) submitted for routine UDS evaluation were collected for xylazine analysis. Results Using custom xylazine standards, the method yielded a linear range from 2 ng/mL to 500 ng/mL with an average R2 of 0.9995 across runs (n = 12). The LLoQ for this assay was 2 ng/mL with a CV of 18.1%. The intra-assay CVs were &amp;lt; 5.0% and inter-assay CVs were &amp;lt; 15.0%. Of preliminary patient samples tested (n = 25), xylazine was detected in 32% of fentanyl-positive samples, ranging in concentration from 2.8 ng/mL to 192.8 ng/mL with an average of 64.8 ng/mL. Conclusions Here we report a simple LC-MS/MS method for quantitation of xylazine in remnant fentanyl-positive UDS specimens by LC-MS/MS. Preliminary testing revealed a xylazine positivity rate of 32% in fentanyl-positive patients. Uncomplicated sample work-up makes this method applicable to xylazine surveillance in all UDS-positive patient samples in high-throughput clinical laboratories. Reference: 1. Kariisa M, et. al. “Illicitly Manufactured Fentanyl-Involved Overdose Deaths with Detected Xylazine.” MMWR Morb Mortal Wkly Rep 2023;72:721-727.

Enhanced drug release through nitrendipine/hydroxypropyl methylcellulose solid dispersion via supercritical antisolvent technique

The poor water solubility of nitrendipine (NT) results in low oral bioavailability, which hinders its practical application. Hydroxypropyl methylcellulose (HPMC) is a prominent drug carrier that has been applied in the biomedical field due to its significant characteristics, such as large surface area, biocompatibility and biodegradability. In this study, an efficient drug delivery system based on the preparation of NT/HPMC solid dispersion using supercritical antisolvent (SAS) technology was proposed. The effect of different operating parameters such as solvent, host guest ratio, concentration, temperature, and pressure on NT/HPMC was optimized to obtain dispersed particles with maximum solubility. The formed solid dispersion presents non-static spherical particles with a high surface area and small particle size. Importantly, in vitro drug release studies have demonstrated that the dissolution and solubility of NT in solid dispersion are significantly enhanced compared to pure drug. In vitro bioactivity experiments showed that the NT/HPMC solid dispersion has good biocompatibility and antibacterial performance. Thus, this study indicates that solid dispersion prepared using SAS technology are considered a promising drug delivery system.