Solid lipid nanoparticles of irbesartan: preparation, characterization, optimization and pharmacokinetic studies

Irbesartan is an antihypertensive with limited bioavailability and solid lipid nanoparticles (SLN) is one of the approaches to improve bioavailability. Solid lipid nanoparticles were prepared using glyceryl monostearate by solvent emulsification method followed by probe sonication. Irbesartan loaded SLNs were characterized and optimized by parameters like particle size, zeta potential, surface morphology entrapment efficiency and in vitro release. The optimized formulation was then further evaluated for the pharmacokinetic studies in Wistar rats. Irbesartan-loaded SLN of particle size 523.7 nm and 73.8% entrapment efficiency showed good bioavailability in Wistar rats and also showed optimum stability in the studies. The SLN prepared using glyceryl monostearate by solvent emulsification method leads to improve bioavailability of the drug

Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritised using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj]=4×10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj=3.2x10−3), had lower EF (27.3% vs. 29.8%; padj=5.8x10−3), and less likely to have ischaemic aetiology (37.3% vs 67.4%; padj=4×10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association to DCM were identified in ~5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower EF and were less likely to have had an ischaemic aetiology

Preparation and Characterization of Nanosuspension of Aprepitant by H96 Process

Purpose: Nanosuspension in drug delivery is known to improve solubility, dissolution and eventually bioavailability of the drugs. The purpose of the study was to compare particle size of nanosuspensions prepared by the first generation approach and H96 approach and to evaluate the effectiveness of H96 approach. Methods: The nanosuspension of aprepitant was prepared by HPH and H96 approach. The prepared nanosuspensions were characterized for their particle size and zeta potential. The optimized nanosuspension was further evaluated for DSC, FT-IR, solubility and dissolution. Results: The optimized nanosuspension (NCLH5) prepared using combination of tween 80 and poloxamer 188 as stabilizer, showed particle size of 35.82 nm and improved solubility and dissolution profile over pure drug. NCLH5 was chosen optimized formulation and further evaluated for other parameters after lyophilization. Lyophilization resulted in increase in particle size. The solubility and dissolution studies showed favorable increase in the performance. The FT-IR and DSC analysis showed change in the crystallinity after nanosizing. Conclusion: The observations indicated that lyophilization prior to high pressure homogenization resulted in efficient particle size reduction yielding smaller particles than first generation preparation technique. H96 is a good and easy alternative to achieve efficient particle size reduction of drug in lesser time and increase its solubility and dissolution

Subacute Toxicity Profile of Lacidipine Nanoformulation in Wistar Rats

The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats