Evaluation of The Food Effect On a Drospirenone Only Contraceptive Containing 4 mg Administered With and Without High-Fat Breakfast

Background:The objective of the present trial was to assess the difference in pharmacokinetics of an oral test preparation containing 4 mg drospirenone. under fasting conditions compared to food intake after single dose administration.Methods:Open label, single centre, two-treatment, two-sequence, crossover study in 24 healthy female volunteers, with duration of 1 day per sequence and with a real wash-out period of 14 days to investigate the relative bioavailability of DRSP with both forms of administration. The 90% confidence intervals were calculated for the intra-individual ratio (test with food vs. without food) of the pharmacokinetic endpoints AUC(0-72h) and Cmax of drospirenone. Results:The 90% CI calculated by means of ANOVA-log for the endpoint, intra-individual ratio (Test ‘A’ = with food intake) vs. Test ‘B’ = without food intake) of AUC(0-72h) of drospirenone was between 104.72% and 111.36%. The 90% CI calculated by means of ANOVA- log for the endpoint intra-individual ratio (Test ‘A’ vs. Test ‘B’) of Cmax of drospirenone was between 118.58% and 141.10%.The mean relative bioavailability of the Test with food ‘A’ compared to the Test without food ‘B’ after single dose administration based on the endpoints AUC(0-72h) was 107.99%; for the endpoint Cmax it was 129.35%.Conclusions:The rate of absorption, based on the endpoint Cmax of drospirenone was increased by about 30% under fed conditions which differs to a COC containing 0,02 mg EE and 3 mg drospirenone in a 24/4 regimen where the rate of absorption was reduced by about 40% for both components. Implications: Our results suggest that the food intake has no impact on the absorption of 4 mg drospirenone in the management for contraception.This raises up the contraceptive efficacy as no interference with food is expected in real life use when consuming the oral formulation

A comparative pharmacokinetics study of Ashwagandha (Withania somnifera) Root Extract sustained-release capsules: an open-label, randomized, two treatment, two-sequence, two period, single-dose crossover clinical study

Background: In this open-label, randomized, balanced, two-treatment, two-sequence, two-period, crossover, single-dose oral comparative pharmacokinetics study, the pharmacokinetics, safety, and tolerability of test product ‘ashwagandha (Withania somnifera)’ root extract sustained release capsule 300 mg (Prolanza™), each containing 15 mg withanolides (administered dose: 2×15 mg) was compared with that of a reference product (organic KSM-66 ashwagandha extract [vegan] capsule, each containing 15 mg withanolides [administered dose: 2×15 mg]).Methods: Total 14 healthy men were randomized to receive either the test or the reference product as a single dose of 2 capsules in sequence, administered under fasting conditions. Plasma concentrations of total withanolides, withanolide A and 12-deoxywithastramonolide were measured using validated liquid chromatography–mass spectroscopy/mass spectroscopy.Results: The test product had higher relative absorption, better relative bioavailability, and longer elimination half-life indicating a sustained-release profile compared to reference. Specifically, the relative bioavailability of the test formulation was 12, 44, and 11 times higher for total withanolides, withanolide A and 12-deoxywithastramonolide, respectively. No adverse events were reported during the study.Conclusions: The sustained-release profile of the test product, compared to reference product, will provide more long-lasting therapeutic effects from a single daily dose (Retrospectively applied on Clinical Trials Registry - India [CTRI]. Application reference number: REF/2020/03/032408). The study reports the unique sustained release formulation of Withania somnifera (Ashwagandha) root extract. The pharmacokinetic study also reports for first time, the successful plasma estimation of withanolide A and 12-deoxywithastraamonolide, the major phytoactives of ashwagandha.

Preparation, Characterization, and Bioavailability of Host-Guest Inclusion Complex of Ginsenoside Re with Gamma-Cyclodextrin

This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M−1 (α-CD), 612 M−1 (β-CD), and 14,410 M−1 (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC0–∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions

Objectives To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. Methods The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. Results The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. Conclusions The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Effect of Recrystallization Technique on Oral Bioavailability of Valsartan

Valsartan (VAL) is a widely prescribed anti-hypertensive agent with angiotensin II type I receptor antagonistic activity. VAL belongs to BCS class II having a low and variable oral bioavailability (10-35%) and its absorption is dissolution rate limited. Recrystallization of VAL from different organic solvents improved VAL aqueous solubility and thereby in vitro dissolution properties. In this investigation in vivo oral bioavailability (BA) of VAL and its recrystallized products with methanol and ethanol (VMET and VETH respectively) solvents was evaluated in male Wistar rats. Also, a rapid, economical and reliable RP-HPLC-PDA method was developed for the estimation of VAL in rat plasma samples and validated according to ICH guidelines. Chromatographic separation was achieved on an Agilent eclipse C18 column (150×4.6mm, 5µ) with a mobile phase composition of 10mM ammonium acetate: acetonitrile (75:25%v/v) at a flow rate of 1.2 mL/min. The retention time of VAL was found to be 2.9 min and showed good linearity (R2>0.996) in the selected concentration range of 0.5-25µg/mL. A 2.9, 2.8 folds increase in Cmax and a relative bioavailability of 320, 305% was observed with VMET and VETH respectively, when compared to that of untreated VAL. Thus it can be inferred that recrystallization is easy and economical technique for enhancing the pharmaceutical properties like solubility, dissolution properties and oral BA of poorly water soluble drugs like VAL. Keywords: Bioanalytical method, Bioavailability, Male Wistar rats, Valsartan, Recrystallization

Systematic Review on the Effectiveness of Strategies for Increasing Insulin Bioavailability in Oral Route Delivery Systems Based on Manufacturing Techniques and Materials Used

Diabetes is a metabolic disease characterized by hyperglycemia due to impaired insulin secretion, insulin action, or both. All patients with type 1 diabetes and many type 2 diabetes require insulin therapy to achieve reasonable glycemic control. During this time, insulin is given through the subcutaneous injection route because it can be destroyed by gastric acid when given orally. Until now, many studies have developed oral insulin therapy using various delivery system strategies. This systematic literature review aims to answer several questions about the effect of technique and material on increasing oral insulin bioavailability and the best technique and type of material that can produce the best oral insulin bioavailability. We searched for published articles regarding the development of oral route insulin. Bioavailability parameters were assessed based on plasma insulin levels for relative bioavailability values and/or plasma glucose levels for pharmacological bioavailability values. Conclusion: The manufacturing technique in the delivery system affects insulin stability in maintaining its conformation to provide a therapeutic effect. The type of substance affects insulin bioavailability through its properties in paving the way for insulin across various barriers in the digestive tract. To date, the best results in the development of oral insulin have obtained oral insulin bioavailability of 73.10% achieved by mesoporous silica nanoparticles (MSN) delivery system with layer-by-layer technique coated with [poly (methacrylic acid-co-vinyl triethoxylsilane)] (PMV)]. Keywords: bioavailability, diabetes, insulin, nanoparticles, oral delivery system.