Drug Suspension Research Articles

Enhancing oral bioavailability of dasatinib via supersaturable SNEDDS: Investigation of precipitation inhibition and IVIVC through in-vitro lipolysis-permeation model

Dasatinib (DASA), a potent second-generation multitarget kinase inhibitor marketed as Sprycel® (Tablet), is limited by poor oral bioavailability (14–24 %) and dose-related gastrointestinal side effects. A supersaturable self-nanoemulsifying drug delivery system (su-SNEDDS) designed to enhance DASA’s solubility, sustain supersaturation, and improve oral bioavailability. The su-SNEDDS formulation comprises DASA, an oil, surfactant, co-surfactant, and polyvinylpyrrolidone (PVP) K30 as a precipitation inhibitor (PI). This innovative system demonstrated exceptional stability in gastrointestinal fluids and robustness against dilution, maintaining significantly elevated drug concentrations in the aqueous milieu. su-SNEDDS achieved ∼ 13.5-fold and 2-fold higher aqueous drug concentrations than DASA suspension and SNEDDS without PI, respectively, after 60 min of digestion. This improvement is attributed to the inhibition of crystal growth by PVP K30. In-vitro lipolysis-permeation and Caco-2 cell assays revealed significantly enhanced drug permeation with su-SNEDDS compared to DASA suspension and SNEDDS without PI. In-vivo pharmacokinetic studies further demonstrated ∼ 1.9-fold and 2.7-fold higher AUC compared to SNEDDS without PI and drug suspension, respectively. A linear correlation (R2 = 0.9042) was established between the AUC data obtained from in to vitro vs in-vivo study. These findings underscore the potential of su-SNEDDS to significantly enhance DASA’s solubility, permeation and oral bioavailability, presenting a substantial advancement in pharmaceutical drug delivery systems. Moreover, in-vitro lipolysis-permeation could be promising tool to predict the in-vivo fate of the oral SNEDDS formulations.

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

Tailoring cilnidipine nanostructured lipid carriers loaded transdermal patch for the treatment of hypertension: optimization, ex vivo and in vivo studies

The current investigation aimed to develop nanostructured lipid carriers (NLCs) as a potential transdermal drug delivery system for the improvement of cilnidipine (CIL) bioavailability. The high-pressure homogenization (HPH) method was utilized for the formulation of NLCs. Box-Behnken Design (BBD) was utilized to optimize CIL NLCs for entrapment efficiency, particle size and zeta potential. The resultant NLCs had a mean particle size of 98.2 ± 05.08 nm, a zeta potential of −16.1 ± 2.05 mV and an entrapment efficiency of 92.51 ± 4.18%. Transmission electron microscopy (TEM) revealed spherical or elongated particles for CIL-NLCs. The optimized NLCs were embedded in the transdermal patch and were formulated utilizing the solvent casting method and investigated for CIL content, physical characteristics, skin permeation and in vivo pharmacokinetics study. In vivo pharmacokinetics experiments with an NLCs-embedded transdermal patch show, an increase in C max and T max , 1305.66 ± 7.96 ng/mL and 4 h, respectively, when compared to the oral CIL dose. The flux values for ex vivo permeation studies for the CIL NLCs patch were determined to be 82.54 ± 4.80 µg/cm2/h. The bioavailability of CIL-loaded NLCs transdermal patch was found to be 2.9-fold greater than that of oral drug suspension, thus confirming the improvement of bioavailability of CIL by NLCs loaded transdermal patch.

A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles.

BTZ043 is an 8-nitro-1,3-benzothiazin-4-one with potency against multidrug-resistant Mycobacterium tuberculosis. Low solubility and hepatic metabolism are linked to poor oral bioavailability. Amorphous drug nanoparticles (ADN) were formulated to improve the bioavailability. Comparative pharmacokinetics of BTZ043 ADN following intranasal (2.5 mg kg-1) and oral administration (25 mg kg-1) in Balb/c mice was investigated using oral BTZ043 drug suspensions (neat; 25 mg kg-1) as a standard-of-care reference. Plasma exposure following oral ADN administration was 8-fold higher than for oral neat BTZ043. Intranasal ADN increased plasma exposure 18-fold compared to oral neat BTZ043 after dose normalization. BTZ043 was detectable in lung lining fluid following ADN administration, but not after oral neat BTZ043 dosing. BTZ043 was cleared faster from the lung and plasma following intranasal administration with a shorter time above the minimum inhibitory concentration (MIC) compared to oral ADN. Since time > MIC is reported to drive activity, oral ADN may represent a promising delivery strategy for BTZ043.

IMPACT OF LIGAND CONJUGATION OF PHYSICOCHEMICAL ATTRIBUTES OF POLYMERIC NANOPARTICLES OF ATYPICAL ANTIPSYCHOTIC DRUG FOR NOSE-TO-BRAIN DELIVERY

Objective: To formulate and characterize the ligand-conjugated chitosan nanoparticles of Ziprasidone Hydrochloride (ZH) and compare with its plain chitosan nanoparticles. Methods: Transferrin (Tf) conjugated Chitosan Nanoparticles (CH-NP) containing ZH were prepared by ionotropic gelation method by using modified chitosan and Tf. Physicochemical attributes of nanoparticles which can potentially impact the nose-to-brain delivery were evaluated. Results: The Tf-CH-NP has demonstrated 207.1 nm mean particle size, 87.6% entrapment efficiency with a release of 89.34% at 24 h and has shown about 2.22 times more release than drug suspension and about 4.5% more than plain CH-NP. The similar trend was observed in Ex vivo nasal permeation study. Its acceptability was shown in histomorphology study, where a minimal inflammation seen, that might be due to the pH of the formulation. There is deeper penetration with Tf-CH-NP, which is more promising for penetration into brain. Conclusion: The formulated Tf-CH-NP has a greater potential due to ligand conjugation to reach the brain and, facilitate targeted delivery and enables better treatment of schizophrenia at minimal doses.

Drug-induced acute kidney injury: a cohort study on incidence, identification of pathophysiological mechanisms, and prognostic factors.

Acute Kidney Injury (AKI) is a common clinical syndrome characterized by an abrupt decline in the glomerular filtration rate (GFR), which can cause severe alterations in blood volume and acid-base balance. Drug-Induced Acute Kidney Injury (DI-AKI) is associated with exposure to nephrotoxic medications, particularly among hospitalized patients. Adverse drug reactions comprises type A and type B reactions. Type A reactions are predictable based on the pharmacology of the substance, dose-dependent, and manifest as Acute Tubular Necrosis (ATN). Type B reactions are unpredictable, idiosyncratic, not dose-dependent, and manifest as Acute Interstitial Nephritis (AIN), Crystal-Induced Nephropathy, among others. To evaluate DI-AKI incidence, identify the main associated drugs and the pathophysiological mechanism of the observed injury, analyze prognostic factors associated with unfavorable outcomes, and compare the outcomes of death and the need for Acute Kidney Support Therapy (AKST) between patients with DI-AKI vs. AKI due to other etiologies. A retrospective cohort study conducted at the Hospital das Clínicas of the Faculty of Medicine of Botucatu - UNESP (HC-FMB), using data from patients hospitalized between January 2016 and April 2022 and followed, via consultation, by the AKI-Nephrology team. Inclusion criteria: diagnosis of AKI and Chronic Kidney Disease (CKD) with superimposed AKI. Exclusion criteria: patients under 18 years old or on chronic Renal Replacement Therapy. AKI was diagnosed based on creatinine increase as established by KDIGO 2012. Data were presented as mean and standard deviation or median with interquartile range and frequency. Statistical significance was set at 5% (p < 0.05). Comparative analyses were performed using the Chi-Square test for categorical variables and the T-test for continuous variables. Subsequently, logistic regression was performed to identify factors associated with the need for AKST and death. A total of 1,398 patients were analyzed, most of them males (61.4%), with a mean age of 64 years ±14.4 years. The most prevalent etiology of AKI was Mixed Ischemic + Septic AKI (28%). DI-AKI was a significant cause of AKI (19.3%). Of these, 25.2% were isolated DI-AKI and 74.8% were Mixed DI-AKI + Ischemia and/or Sepsis. Among patients with DI-AKI, the mean age was 61.15 ± 15.26, males were the most frequent, the majority were not subjected to AKST and survived. Most of these patients were hospitalized in the ward, did not need vasoactive drugs, nor did they use mechanical ventilation. DI-AKI showed lower severity and mortality compared to other AKI etiologies but had a similar need for AKST (26.3% vs. 35.4%, p < 0.05 and 31.8% vs. 36.8%, p > 0.05). Most nephrotoxic drugs caused type A reactions, with Vancomycin being the primary nephrotoxin. Among drugs associated with DI-AKI, Vancomycin was associated with a higher need for AKST and death, while Amphotericin B was associated with a lower risk of AKST and death. Although the mortality rate is lower among DI-AKIs compared to other AKI etiologies, the need for AKST was similar. Therefore, it is recommended that DI-AKI be recognized early to enable dose reduction or even drug suspension, depending on the type of reaction, to reduce healthcare costs and improve clinical outcomes for patients.

Self-microemulsifying drug delivery system (SMEDDS) for oral delivery of zafirlukast: Design, formulation, and pharmacokinetic evaluation

The current research aimed to develop a self-microemulsifying drug delivery system (SMEDDS) of zafirlukast to enhance its oral bioavailability by increasing its solubility and overcoming the negative food effect. For the formulation of SMEDDS, the solubility of zafirlukast was determined in different oils, surfactants, and cosurfactants. Based on this study's results, pseudo-ternary phase diagrams were plotted to select the efficient self-emulsification region. Eudragit EPO was employed as a precipitation inhibitor to avoid the supersaturation of zafirlukast in the SMEDDS system. The formulated system was evaluated for transparency, cloud point, optical birefringence, and globule size analysis using techniques like DLS, SANS and TEM. The SMEDDS preconcentrate was solidified by adsorbing it on Neusilin US2 and further formulated as a tablet. It was then evaluated for in vitro drug release against the marketed tablet. The optimized composition of zafirlukast SMEDDS and suspension of the plain drug were evaluated for a pharmacokinetic profile in rats for both fed and fasted conditions. The SMEDDS yielded microemulsion found transparent and homogeneous with globule size less than 50 nm by DLS, SANS and TEM techniques. On dilution with water, the microemulsion was found robust without any phase separation even after 24 h of storage. The tablet form of SMEDDS was stable and passed all the IPQC tests for a tablet. The optimized SMEDDS tablet form exhibited a superior in vitro dissolution profile than a marketed tablet. The pharmacokinetic study of optimized SMEDDS showed improved value for Cmax and AUC in both fed and fasted conditions compared to the plain drug.

Formulation and Evaluation of Nano Suspension Based Oro Disoersible Film of Aripiprazole

The present study was aimed to enhance the solubility and dissolution of BCS class 4 drug aripiprazole, by nano formulation approach. Acid-base neutralization method had been used to produced nanosuspension. The nanosuspensions remained stable without any aggregations with particle size 209.6nm and PDI 0.247. Zeta potential was found to be 3.5mV. Drug content, Entrapment and solubility of nanosuspension formulations were determined. In vitro drug release of the selected formulation has shown a drug release of 95.63% by the end of 1 hr, whereas plain drug suspension has shown only 12.3% release. XRD and DSC studies revealed that the solid form of aripiprazole altered from the crystalline state to the amorphous state after incorporation into nanosuspensions. Hence, from the results, it can be concluded that Aripiprazole, when formulated by acid-base neutralization method as a nanosuspension, leads to enhanced solubility, dissolution, and stability

8679 Case: The Sexual, Physical and Psychological Effects of Post-Finasteride Syndrome

Abstract Disclosure: E.M. Lonergan: None. S.M. Maher: None. I. Yaseen: None. D.B. O'Shea: None. Post-finasteride syndrome (PFS) is an increasingly recognised disorder with a myriad of physical and neuropsychiatric symptoms persisting for greater than three months in a small proportion of patients treated with Finasteride. We present the case of a 45-year-old male who was taking oral Finasteride for hair loss. He first presented to endocrinology services having stopped Finasteride after twenty years reporting new onset reduced libido, penile shrinkage, fatigue, new food intolerances and agitated depression which was the predominant symptom in this case. He described the emergence of gynaecomastia, which was evident on examination, as well as muscle atrophy. Biochemistry was unremarkable including testosterone 24.6 nmol/L (8.6-29.0), oestradiol 100 pmol/L (50 – 159), LH 7.1 IU/L (1.7-8.6), FSH 16.8 IU/L (1.5-12.4), urinary free cortisol 177 nmol/24h (12-486) and urinary steroid profile. The patient was offered a trial of IM testosterone for 3 months followed by a course of hCG which he declined after discussing with patients online via a PFS patient forum citing anecdotal pseudo immune downregulation in this cohort. GLP-1 receptor agonist therapy was considered as a second-line treatment option. The patient expressed a preference for hydrocortisone treatment after conducting online research which has not been commenced due to a lack of evidence. The inhibition of 5-alpha-reductase in Finasteride-treated patients has been documented to cause reversible sexual dysfunction. However, with increasing case reports of PFS, it was included in the list of Rare and Genetic Diseases of the NIH in 2015. The syndrome encompasses symptoms and signs seen in our case, as well as erectile dysfunction, decreased ejaculatory volume, infertility, Peyronie’s disease, testicular pain, dry skin, memory problems and insomnia. Suicidal ideation was included in the product label as per FDA mandate in 2022. The literature is largely inconclusive regarding the underlying aetiology, duration, and severity of the disorder. A large retrospective study revealed 0.8% of patients developed sexual dysfunction with persistence in 33% of these cases after drug suspension, the main independent risk factor being drug treatment for longer than 7 months. Neuropsychiatric symptoms are likely related to the presence of 5-alpha-reductase isoforms in the brain with resulting alterations in CSF and plasma neuroactive steroid levels and metabolites. Evidence-based treatment options for PFS are limited. PFS is a rare but debilitating syndrome to which a subset of patients appears to be predisposed, but of which the pathophysiology is poorly understood. Further studies in this regard, as well as an exploration of effective treatment options are required. Presentation: 6/1/2024

Self-assembled mixed nanomicelles based hydrogel for enhanced transdermal bioavailability of allopurinol in gout therapy: In vitro and In vivo evaluation

Allopurinol (ALP), a preferred first line medication for the treatment of gout and hyperuricemia, exhibits poor solubility, a short half-life, and undergoes the hepatic first-pass effect, thus resulting in low oral bioavailability. Additionally, ALP is associated with several adverse effects, including hypersensitivity reactions, gastrointestinal issues, and hepatotoxicity. Here, we developed methoxy poly (ethylene glycol)- poly(lactide) (mPEG-PLA)/D-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed nanomicelles (MNs)-based hydrogel for transdermal delivery of ALP to enhance its bioavailability, In vivo safety, and efficacy for gout treatment. To this end, mPEG-PLA diblock copolymer was synthesized via ring-opening copolymerization and characterized using Fourier transform infrared spectroscopy (FTIR), SEM micrograph, proton nuclear magnetic resonance (1H NMR) and Differential scanning calorimetric thermograms (DSC) analysis. Self-assembled mixed nanomicelles were formulated by thin film dispersed technique. The optimized mixed nanomicelles were analyzed for their physicochemical properties and subjected to in vitro, ex vivo and in vivo investigations. The final formulation (ALP-loaded MNs) exhibited a size of 59.12 nm, an encapsulation efficiency (EE) of 87 %, a PDI of 0.053, and a zeta potential of −22.3 mV. In Vitro release kinetics of the ALP-loaded MNs exhibited a sustained and site-specific release profile (p < 0.001). As compared with the ALP based hydrogel, 32-fold higher permeation flux was noticed from ALP-MNs loaded hydrogel with argan oil (ALP-MNs-AO-HG). The in vivo skin irritation study showed that the ALP-MNs-HG was well-tolerated with minimal signs of edema or erythema. ALP-MNs-AO-HG notably enhanced ALP bioavailability with a 7.67 ± 0.01 fold higher AUC0−t, 4.8 ± 0.03 fold longer mean residence time, and a 6 ± 0.04 fold extension in half-life as compared to the oral drug suspension. These results indicate that ALP-MNs based transdermal hydrogels exhibit the potential to enhance therapeutic outcomes by increasing bioavailability and abating the adverse effects associated with oral administration.

Co-delivery of novel valsartan and hydrochlorothiazide pH-responsive electrospun polymeric nanofibers for improved oral delivery

Valsartan (VAL) and Hydrochlorothiazide (HCTZ) as a fixed-dose combination are widely used for the management of hypertension. To enhance the dissolution and oral delivery of VAL (BCS class II drug) and HCTZ (BCS class IV drug), nanofibers containing both drugs were prepared using an electrospinning technique. VAL/HCTZ-loaded NFs were prepared using Eudragit L100-55 (EUD L100-55) and Poly (ethyne oxide) (PEO) polymer mixture and the formulation process was optimized through three process variables of polymer composition, polymer concentration, and spinning voltage. VAL/HCTZ-loaded NFs were characterized for their size, surface morphology, entrapment efficiency (%EE), drug-polymer interaction, in vitro drug release, ex-vivo permeation, and in vivo studies. Smooth, beadles and uniform drug-loaded NFs were successfully fabricated using optimum polymer composition (EUD L100-55/PEO 3:1), concentration (12 % w/v), and applied voltage (30 KV). The optimum formula (F9) showed a low average nanosize of 300 nm and a high drug loading of > 90 % was achieved. In vitro, release results showed a pH-dependent drug release, with minimum drug released at pH lower than 4.5, but a significant and complete release of both drugs was achieved at pH 6.5. The EUD L100-55/PEO improved the dissolution of VAL and HCTZ compared to free drugs at the intestinal site of absorption. Differential Scanning calorimetry and Fourier Transform Infra-Red studies showed both drugs’ amorphization and compatibility between drugs and polymers. Permeability behavior for the VAL/HCTZ-loaded NFs was found to be significantly higher than free drug suspensions of both drugs which indicated the improvement of VAL and HCTZ permeability through the intestinal membrane. The in vivo study proved the enhanced oral anti-hypertensive action of drugs-loaded NFs compared to free drug suspensions. The superior in vitro release, ex-vivo permeation, and in vivo anti-hypertensive effect indicate that drug-loaded nanofibers have the potential to improve the biological activity and hence oral delivery of the fixed-drug combination.

Bioavailability enhancement of atazanavir sulphate using mixed micelles: in vitro characterization and in vivo pharmacokinetic study.

This study aims to enhance the oral bioavailability of atazanavir sulphate, a human immunodeficiency virus-1 protease inhibitor known for its poor oral absorption, by formulating mixed micelles using Soluplus® and Kolliphor HS 15. Mixed micelles were prepared through the thin film hydration technique. The micelles were characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, and confirmed for atazanavir sulphate encapsulation via FTIR studies. In vitro release studies were conducted, and the morphology of the micelles was examined using TEM. Atazanavir sulphate mixed micelles exhibited a particle size of 62.92nm, PDI of 0.221, zeta potential of - 17.8mV, high entrapment efficiency (99.76 ± 1.06), and drug loading (14 ± 0.82). In vitro release studies demonstrated sustained release up to 12h, with maximum solubility observed at 2h under pH 1.2 conditions. TEM analysis revealed spherical micelle morphology. Oral administration of atazanavir sulphate mixed micelles showed a 1.23-fold increase in relative bioavailability compared to pure drug suspension. The formulation of mixed micelles using Soluplus® and Kolliphor HS 15 offers a promising strategy to improve the oral bioavailability of atazanavir sulphate. These findings suggest the potential utility of mixed micelles as an effective delivery system for atazanavir sulphate, offering enhanced therapeutic outcomes for patients.

Pain catastrophizing negatively impacts drug retention rate in patients with Psoriatic Arthritis and axial Spondyloarthritis: results from a 2-years perspective multicenter GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica) study

BackgroundChronic pain and inflammation are common features of rheumatic conditions such as Psoriatic Arthritis (PsA) and Axial Spondyloarthritis (axSpA), often needing prolonged medication treatment for effective management. Maintaining drug retention is essential for both achieving disease control and improving patients' quality of life. This study investigates the influence of pain catastrophizing, a psychological response to pain, on the drug retention rates of PsA and axSpA patients.MethodsA two-year prospective multicenter observational study involved 135 PsA and 71 axSpA patients. Pain Catastrophizing Scale (PCS) was employed to assess pain catastrophizing. Univariable and multivariable regression analyses were utilized to identify factors associated with drug retention.ResultsIn the PsA group, patients early discontinuing therapy showed higher baseline disease activity as well as higher incidence of comorbid fibromyalgia. Notably, pain catastrophizing, specifically the domains of Helplessness, Magnification, and Rumination, were significantly elevated in PsA patients who interrupted the treatment. Multivariable analysis confirmed pain catastrophizing as an independent predictor of drug suspension within two years.In axSpA, drug discontinuation was associated with female gender, shorter disease duration, higher baseline disease activity as well as elevated levels of pain catastrophizing. Univariable analysis supported the role of pain catastrophizing, including its domains, as predictors of treatment interruption. However, limited events in axSpA patients precluded a multivariate analysis.ConclusionThis prospective study emphasizes the impact of pain catastrophizing on drug retention in patients with PsA and axSpA.

Anthelmintic efficacy of Fenbendazole and Niclosamide suspensions obtained by liquid phase mechano-chemical treatment

The purpose of the research is to study the anthelmintic efficacy of suspensions based on a combined solid dispersion of Fenbendazole and Niclosamide.Materials and methods. Mechanochemistry methods were used to prepare suspensions of Fenbendazole (FBZ) and Niclosamide (NSM) substances, in particular, liquid phase grinding of substances with additives (licorice extract, polyvinylpyrrolidone (PVP)) in water or in aqueous sodium carboxymethylcellulose (NaCMC) solution. The grinding was conducted in LE-101 roller mill at energy intensity of 1 g for 1 hour at a roll rotation speed of 60–70 rpm. The resulting suspension samples of combined FBZ and NSM dispersions were studied for cestodocidal activity on a laboratory model of hymenolepiosis of white mice that were infected at a dose of 200 infective Hymenolepis nana eggs per animal.Results and discussion. The 100% efficacy of a combined NaCMC-based drug suspension containing FBZ 13 mg and NSM 130 mg in 1 g of suspension was achieved at a dose of 20 mg/kg of NSM and 2 mg/kg of FBZ. The suspension based on licorice extract, NaCMC, and dioctyl sulfosuccinate sodium salt containing FBZ 18.6 mg and NSM 186 mg in 1 g of suspension at the same dose, i.e. 20 mg/kg of NSM and 2 mg/kg of FBZ showed 71.43% efficacy against H. nana. The suspension based on licorice extract and NaCMC containing FBZ 24.6 mg and NSM 246 mg in 1 g of suspension at the same dose showed a 62.0% effect against H. nana. The activity of the basic drug, the FBZ and NSM suspension was 28.58% at this dose without using mechano-chemical treatment.

Development of biocompatible lipid-polymer hybrid nanoparticles for enhanced oral absorption of posaconazole: A mechanistic in vitro and in silico assessment

The current research focuses on the development of lipid-polymer hybrid nanoparticles (LPHNs) designed to enhance the solubility and bioavailability of posaconazole (PCZ). PCZ, an antifungal drug, faces challenges due to its poor water solubility, resulting in inconsistent absorption and limited bioavailability. LPHNs composed of stearic acid and poly-δ-decalactone (PDL) were successfully fabricated and characterized. The optimized formulation (P-LPHN4) exhibited a particle size of 104.0 nm, negative zeta potential (−38.9 mV), high drug loading (19.5 %), and efficient encapsulation (82.6 %). In vitro release studies demonstrated sustained drug release over 18 h, with P-LPHN4 displaying the highest drug release (92 %). Stability studies revealed good physical stability over 45 days with no significant changes in particle size, zeta potential, and PDI. In silico simulations using GastroPlus® predicted significantly improved intestinal absorption and systemic exposure for P-LPHN4 compared to the pure drug suspension in a simulated rat model. The model predicted a higher peak plasma concentration (Cmax) for P-LPHN4 (∼0.012 μg/mL) compared to the PCZ suspension (∼0.0058 μg/mL). The model identified the duodenum and jejunum as primary absorption sites for both formulations, with P-LPHNs showing significantly higher overall absorption (84.5 %) compared to the suspension (47.5 %). Simulation results revealed a dose-dependent increase in both Cmax and AUC with increasing oral P-LPHN4 dose, while Tmax remained unaffected. In conclusion, the developed posaconazole-loaded lipid-polymer hybrid nanoparticles (P-LPHN4) showed promising results in terms of enhanced drug release, stability, and bioavailability.

Novel dissolution methods for drug release testing of Long-Acting injectables

Long-acting parenteral drug products are a popular choice for therapeutic areas requiring long term treatment. These products range from dispersed systems such as drug suspensions and polymeric microspheres to in situ forming polymeric implants. The lack of reliable drug release testing methods for these drug products not only impedes the development of new drug products but also affects generic drug development. Current release methods suffer from a range of problems such as high variability, poor reproducibility, poor discriminatory ability, lack of depot-like structure formation (that could mimic the in vivo situation). Moreover, shorter duration (less than a week) of release renders them unsuitable for in vitro-in vivo correlations (IVIVCs). To overcome these issues, novel adapters were developed for both USP-type-II & IV apparatus. These adapters were validated and assessed using the long-acting injectable (LAI) suspension drug product Depo Provera 150® as well as its Q1/Q2 equivalents. For USP-type-IV apparatus, two open adapter designs (conical and ellipsoidal shaped cavity with volume capacities of 50 µl and 1 ml, respectively) were developed. A closed conical adapter design with a volume capacity of 0.05 ml was developed for USP apparatus type-II. All three novel adapter designs effectively retained the suspensions, achieved release durations of 3–6 weeks with good reproducibility, minimal variability (RSD≤5%) and had good discriminatory ability. Based on this, the adapter-based dissolution methods were deemed suitable for IVIVC development of long-acting injectables. A successful Level A IVIVC was developed for Depo SubQ Provera 104® and its Q1Q2 equivalents using USP apparatus type IV with a conical adapter design. The closed adapter design for apparatus type-II was also investigated for suitability with risperidone in situ forming implants. The adapter was able to securely retain and maintain the shape of the in situ forming implants and resulted in release profiles of up to one month with good discriminatory ability and low standard error (RSD≤5%). These novel adapters hold promise of wide use for in vitro release testing of different long-acting parenteral drug products.

Post-Kidney Transplant Cancer: A Real-World Retrospective Analysis From a Single Italian Center.

We describe the epidemiology of cancer after kidney transplantation (KTx), investigating its risk factors and impact on therapeutic management and survival in KTx recipients (KTRs). The association between modification of immunosuppressive (IS) therapy after cancer and survival outcomes was analyzed. We collected data from 930 KTRs followed for 7 [1-19]years. The majority of KTRs received KTx from a deceased donor (84%). In total, 74% of patients received induction therapy with basiliximab and 26% with ATG. Maintenance therapy included steroids, calcineurin inhibitors, and mycophenolate. Patients with at least one cancer (CA+) amounted to 19%. NMSC was the most common tumor (55%). CA+ were older and had a higher BMI. Vasculitis and ADPKD were more prevalent in CA+. ATG was independently associated with CA+ and was related to earlier cancer development in survival and competing risk analyses (p = 0.01 and <0.0001; basiliximab 89 ± 4 vs. ATG 40 ± 4months). After cancer diagnosis, a significant prognostic impact was derived from the shift to mTOR inhibitors compared to a definitive IS drug suspension (p = 0.004). Our data confirm the relevance of cancer as a complication in KTRs with ATG as an independent risk factor. An individualized choice of IS to be proposed at the time of KTx is crucial in the prevention of neoplastic risk. Finally, switching to mTORi could represent an important strategy to improve patient survival.

Oral in vivo biodistribution of fluorescent labelled nano lipid carrier system of erlotinib using real time optical imaging technique

This study investigates the biodistribution of a nano lipid carrier system (NLCs) containing the hydrophobic drug erlotinib (ERL-NLCs). The system was labelled with the fluorescent dye IR-780 for real-time dynamic imaging. ERL-NLCs were initially developed using the ultrasonication method with oleic acid and stearic acid. In vitro and ex vivo studies were performed to confirm the formation and penetration of NLCs within the intestine. Subsequently, the biological distribution of ERL-NLCs was monitored using a fluorescent dye through the IVIS® fluorescent optical imaging technique in whole live animals. Mice were orally administered blank IR 780 dye solution, ERL suspension, and IR 780 labelled NLCs. Fluorescence images were acquired at different time intervals up to 24 h and then total radiant efficiency was calculated through the region of interest (ROI) of the whole animal at each interval of time for all three groups. To validate the results obtained from in vivo imaging, various organs including lungs, heart, liver, both kidneys, stomach, and intestine were subsequently extracted and examined after 24 h. The ROI was found to be higher in the blank IR 780 dye solution, followed by the drug suspension and IR 780 labelled NLCs. These results confirm that the plain ERL suspension distributes across the body, and its encapsulation in NLCs facilitates passage through the lymphatic intestinal pathway, effectively avoiding first-pass metabolism. The remarkable results indicated that the NLCs formulation effectively circumvents first-pass metabolism by adopting the intestinal lymphatic pathway, thereby enhancing the oral bioavailability of the drug. This observed behaviour underscores the potential of NLCs in optimizing drug delivery and minimizing adverse effects associated with gastrointestinal and metabolic processes.

Efficacy and safety of alfaxalone compared to propofol in canine refractory status epilepticus: a pilot study.

Refractory status epilepticus (RSE) is defined as seizure activity that is minimally responsive to first- or second-line antiseizure medications. Constant rate infusion (CRI) intravenous propofol (PPF) is commonly used to treat RSE in dogs and cats. The antiseizure activity of alfaxalone (ALF) in RSE has been demonstrated in various experimental studies. This study compared the clinical efficacy and safety of intramuscular administration followed by CRI infusion of ALF with intravenous administration followed by CRI infusion of PPF to treat canine RSE. This was a multicenter, prospective, randomized clinical trial of client-owned dogs referred for status epilepticus that did not respond to first- and second-line drugs. Animals with suspected or confirmed idiopathic or structural epilepsy were included. The dogs were randomly assigned to either the PPF or ALF treatment groups and each group received drug CRI infusions for 6 h. Drug dosages were progressively reduced by 25% every hour from the third hour until suspension after 6 h. Patients were classified as responders or non-responders based on the relapse of epileptic seizures during the 24 h therapy infusion or within 24 h of drug suspension. Univariate statistical analyses were performed. Twenty dogs were enrolled in the study. Ten (10/20) dogs were randomly allocated to the PPF group and 10 (10/20) to the ALF group. Successful outcomes were obtained in six (6/10) patients in the PPF group and five (5/10) patients in the ALF group. Adverse effects were recorded in six (6/10) and three (3/10) animals in the PPF and ALF groups, respectively. No statistically significant differences in outcomes or the presence of adverse effects were observed between the groups. The results of this preliminary study suggest that ALF can be considered a valid and safe alternative to PPF for the treatment of RSE in dogs, with the additional advantage of intramuscular administration. However, caution should be exercised when using these drugs to provide airway and hemodynamic support.

Ketoconazole Nanocrystals Fortified Gel for Improved Transdermal Applications

Ketoconazole (KTZ) is a commonly prescribed antifungal drug used to treat several tropical and systemic fungus infections. The topical bioavailability of KTZ is limited due to extremely low water solubility and high molecular weight. The present investigation aimed to develop a ketoconazole nanocrystals formulation to improve the biomimetic attributes. The ketoconazole nanocrystals were prepared using a top-down media milling technique with a size of less than 800 nm and a narrow polydispersity index (PDI) of 0.434. The simplex lattice design was used to further investigate the effect of change in the proportion of different stabilizers on critical product attributes such as particle size and PDI. The result of the in vitro drug release and anti-fungal study proved the superiority of the optimized KTZ nanocrystal in inhibiting fungal infection and suspension of pure drug. The optimized nanocrystals entrapped within Carbopol-934P gel had higher permeability through cellulose membrane compared, to the marketed product (2 % ketoconazole % w/w Ketodoc Cream®) with sustained release for 24 h. Moreover, the release profile indicated diffusion-controlled release from gel following Korsmeyer-Peppas. The present investigation successfully demonstrated the application of simplex lattice design and desirability function in optimizing ketoconazole nanocrystals to improve its transdermal application.