Variable Bioavailability Research Articles

Dosing Variability and Clinical Outcomes of Oxybutynin: A Pediatric Cohort of Patients With Neurogenic Bladder.

Despite the therapeutic advancements of the last several decades, neurogenic bladder remains a significant source of morbidity for patients with a spinal pathology. Oxybutynin is a mainstay of treatment in pediatric populations despite significant side effects and highly variable bioavailability. To characterize the use of oxybutynin in a cohort of pediatric patients with neurogenic bladder. Retrospective data were collected of dosing, drug interactions, and urodynamics parameters in the 100 consecutive patients in a spinal differences clinic who had an appointment between October 7, 2015, and December 30, 2015. In addition to descriptive statistics, a linear regression model of oxybutynin dose versus age and sex was developed to examine the impact of age on dosing variability. One hundred patients (52% female) with a median age of 6.8 years were included. The median daily dose of oxybutynin was 0.36 mg/kg (interquartile range, 0.28-0.54 mg/kg). Of the 48 patients with a recent urodynamics study, 13 had a detrusor leak point pressure (DLPP) greater than the typical cutoff of 40 cm H2O, indicating a need for management escalation. However, of these 13 patients, 38% were already on or exceeding oxybutynin's maximum recommended dose. The wide dosing variability and high DLPPs despite maximal dosing indicate a need for further investigation of oxybutynin's bioavailability in this population compared to its side effects and clinical outcomes. If variability in response to the medication is due to differences in bioavailability, then a precision-dosing model based on patient genomics could be developed for oxybutynin.

Levothyroxine sodium loaded dissolving microneedle arrays for transdermal delivery.

Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm2) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm2) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm2) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.

A SYSTEMATIC REVIEW ON SUPERSATURABLE SELF-NANO EMULSIFYING DRUG DELIVERY SYSTEM: A POTENTIAL STRATEGY FOR DRUGS WITH POOR ORAL BIOAVAILABILITY

The most fundamental important extensive constitutive of drug molecules to be available for systemic absorption is aqueous solubility; subsequently, that is the nature of GIT fluid. When the drug molecules become solubilized, it has to reach the systemic circulation via the biological membrane. The solubility problem of many effective pharmaceutical molecules is still one of the major challenges in the formulation of this molecule. Drug molecules that belong to class II have a problem in bioavailability mainly due to low aqueous solubility and the rate-limiting step is the dissolution process and so electing of suitable drug delivery and proper additives are decisive to overcome this major obstruction and promote the fraction that will reach the systemic circulation. Among the different lipid-based systems, the su-SNEDDSs have gained attention because the inclusion of precipitation inhibitors within su-SNEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This enhances the bioavailability of drugs and minimizes the variability of exposure. Nowadays, supersaturable self-nano emulsifying and nano lipid-based drug delivery systems have constrained a substantial concern from pharmaceutical scientists for managing the oral delivery of poorly water-soluble compounds. By following oral administration, self-nano emulsifying drug delivery systems show complex aqueous dispersion and digestion in the GIT and enduring intestinal lymphatic transport, exorbitant pre-absorptive metabolism by gut membrane-bound cytochrome enzymes and preventing P-gp mediated drug efflux. Mostly these processes result in drug supersaturation, which leads to increased absorption or the high drug concentrations may cause precipitation with capricious and variable oral bioavailability. This procession review briefly summarized drug supersaturation obtained from self-nano emulsifying and other lipid-based formulations and this review also delineate the effects of numerous physiological factors and the probable interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SNEDDS and focuses on reviewing the application of su-SNEDDS in enhancing the solubility and bioavailability of anti-cancer drugs in cancer therapy.

Poor and variable oral bioavailability of dimethandrolone (DMA), an investigational male hormonal contraceptive, is likely associated with UGT2B17 mediated first‐pass metabolism

Dimethandrolone (DMA), an active metabolite of dimethandrolone undecanoate (DMAU) is a novel derivative of 19‐nortestosterone that is undergoing clinical investigation as an experimental male hormonal contraceptive.1 However, poor and variable oral bioavailability of DMAU including dramatic food‐effect2 may decrease its potential use by oral route. Moreover, DMA to DMAU serum concentration ratios revealed that food significantly alters the first‐pass metabolism of DMAU or DMA (Fig. 1A). Thus, the objective of this study was to investigate intestinal and hepatic metabolism of the active metabolite, DMA, to understand its poor bioavailability. We first detected and elucidated the structures of DMA metabolites formed in human hepatocyte incubations and in serum samples after oral administration in men using nano‐liquid chromatography high‐resolution mass spectrometry. The accurate mass and the mass fragmentation data confirmed DMA (m/z 303.2318) analogues of androstenedione (m/z 301.2162) and glucuronide (m/z 479.2639) in the human hepatocyte incubation, however, only DMA‐glucuronide was detected in the serum samples following an oral dose of 400 mg DMAU. DMA‐glucuronide serum concentration was >100‐fold higher than DMA levels, revealing glucuronidation as the major elimination mechanism for DMA. The targeted metabolomics of DMA revealed that unlike testosterone, DMA is not metabolized by other androgen metabolizing enzymes such as aromatase and 5‐α‐ and 5‐β‐ reductases, likely due to the absence of the C19‐methyl group.3,4 Next, to identify UGT isoforms involved in DMA metabolism, thirteen clinically‐relevant UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B15, and 2B17) were screened for their capacity to metabolize DMA. Only UGT2B17 and UGT1A9 were able to metabolize DMA to DMA‐glucuronide. Finally, since UGT2B17 is a highly variable enzyme (>3000‐fold variability) with highly prevalent gene deletion, an enzyme kinetic experiment was performed in human intestinal microsomes (HIM) samples with known UGT2B17 expression. The kinetics data revealed >200‐fold higher maximum reaction velocity (Vmax) in the high UGT2B17‐expressing HIM samples as compared to the null expressors (Fig. 1B). Proteomics‐informed modeling estimated the intestinal fractional contributions (fm) of UGT2B17 in DMA glucuronidation to be 0.996, 0.994, and 0.0 in the high, average, and null expressors of UGT2B17, respectively. These data suggest that genetic variations in UGT2B17 and its high‐intestinal abundance are the potential reasons for the variable first‐pass metabolism and oral pharmacokinetics of DMA, whereas UGT1A9, which is expressed in the liver and kidney, likely decreases fm, UGT2B17 in DMA metabolism after intramuscular dosing.Refs.1. Attardi B J (2010).2. Ayoub R (2017).3. Attardi B J (2008).4. Han Y (2021).

MP35-14 PATIENT SATISFACTION AFTER SWITCHING TO ORAL TESTOSTERONE UNDECANOATE IN MEN CURRENTLY RECEIVING TESTOSTERONE THERAPY: AN OPEN-LABEL SINGLE-CENTER PHASE IV CLINICAL TRIAL

You have accessJournal of UrologyCME1 May 2022MP35-14 PATIENT SATISFACTION AFTER SWITCHING TO ORAL TESTOSTERONE UNDECANOATE IN MEN CURRENTLY RECEIVING TESTOSTERONE THERAPY: AN OPEN-LABEL SINGLE-CENTER PHASE IV CLINICAL TRIAL Rohit Reddy, Mehul Patel, and Ranjith Ramasamy Rohit ReddyRohit Reddy More articles by this author , Mehul PatelMehul Patel More articles by this author , and Ranjith RamasamyRanjith Ramasamy More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002589.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testosterone deficiency (TD) is defined by an insufficient production of testosterone (T) combined with symptoms such as decreased libido. Multiple delivery systems such as gels and injections are currently available; however, oral formulations have been unavailable in the United States due to hepatoxicity and variable bioavailability. Oral formulations of T are convenient, easy to use, and avoid the problems of other forms of testosterone therapy (TT) such as painful injections and transference. Jatenzo® is a novel US FDA approved formulation of oral T undecanoate that provides a uniform response. In this study, we evaluated patient satisfaction of Jatenzo® as compared to other forms of T. We hypothesize Jatenzo® will have similar patient satisfaction compared to other forms. METHODS: Qualifying patients between ages 18 and 65 with TD symptoms and two T levels <300 ng/dL were recruited into this 26-week single-center open-label non-randomized phase IV clinical trial. Patients were required to previously have received TT, completed an adequate washout period, and then were started on Jatenzo®. The primary outcome was Treatment Satisfaction Questionnaire for Medication (TSQM-9), a validated questionnaire for medication satisfaction, as well as changes in TD symptoms as measured by the quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire at the 3 and 6 month intervals compared to baseline. Serum T, PSA, hematocrit, and estradiol were also evaluated at each time point. RESULTS: Of the patients recruited, 53% were previously on subdermal pellets, 27% on intramuscular injections, 13% on dermal gels, and 7% on nasal gels. T levels increased from a baseline mean of 201 ng/dL to 686 ng/dL at 1 month and 527 ng/dL at 3 months. Patient satisfaction as measured by TSQM-9 remained similar on oral T undecanoate at 38.3 compared to 39.3 on the prior TT. TD symptoms as measured by qADAM were also similar at 34 compared to 33.5 on prior TT. No significant difference was noted in side effects such as polycythemia or changes in estradiol and PSA. CONCLUSIONS: Oral T undecanoate appears to provide similar patient satisfaction and similar improvement in TD symptoms as other forms of TT. In addition, it increases serum total T to the normal range (300–1000 ng/dL) in >90% of men without a difference in side effect profile. Source of Funding: Investigator-initiated grant provided by Clarus Therapeutics to RR. Trial registration: NCT04983940. Registered 30 July 2021. https://clinicaltrials.gov/ct2/show/NCT04983940 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e592 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rohit Reddy More articles by this author Mehul Patel More articles by this author Ranjith Ramasamy More articles by this author Expand All Advertisement PDF DownloadLoading ...

Proteomics‐informed physiologically‐based pharmacokinetic (PBPK) modeling revealed differential effects of UGT2B17 variability on the pharmacokinetics of diclofenac following intravenous and oral administration

Uridine 5′‐diphospho‐glucuronosyltransferase 2B17 (UGT2B17) demonstrates dramatic inter‐individual variability (&gt;3000‐fold) in the activity and expression in humans, which is associated with age, sex, genotype, and ethnicity.1We recently found that diclofenac is a UGT2B17 substrate, however, the quantitative contribution of UGT2B17 in the metabolism and pharmacokinetics (PK) of diclofenac is not well studied. Moreover, we hypothesized that the higher intestinal abundance of UGT2B17 could further amplify the magnitude and variability in its in vivo PK. We first investigated diclofenac glucuronide (DG) formation kinetics in human liver microsomes (HLM) and human intestinal microsomes (HIM) that were isolated from human donors containing the deletion genotype and the highest‐expressor of UGT2B17 in our tissue bank. Diclofenac showed 4‐ and 16‐fold difference in maximum DG formation rate (Vmax) in UGT2B17 highest‐expressor versus deletion in HLM and HIM, respectively (Fig. 1). Proteomics‐informed PBPK modeling2 estimated the quantitative contribution (fm) of UGT2B17 in the intestinal and hepatic glucuronidation of diclofenac, which revealed fm of 0.77, 0.24, and 0.0 in the highest, average, and null UGT2B17 expressors, respectively. Interestingly, intestinal fm of UGT2B17 was 0.94, 0.90, and 0.0 in the highest, average, and null expressors, respectively. The organ‐specific changes in the fm were also substantiated by the predicted fraction gut escaped (fg), which was primarily associated with UGT2B17 abundance in the enterocytes. A PBPK model was first developed and validated in the UGT2B17 average expressor and then extended to other populations utilizing UGT2B17 abundance data. Predicted plasma levels (AUC) of diclofenac were 20 % and 100 % higher following an IV dose (50 mg) in UGT2B17 deletion versus the average and the highest expressor subjects, respectively. Similalry, after 50 mg oral dose, ~2‐fold and 8.5‐fold higher AUC was observed in UGT2B17 deletion as compared to that in the average and the highest UGT2B17 expressors, respectively. Sex differences in UGT2B17 abundance explained ~2‐fold higher diclofenac AUC in females after oral administration. In summary, the unique intestinal abundance and the highly prevalent gene deletion of UGT2B17 could likely contribute to the variable bioavailability of its substrate drugs. Similarly, poor metabolism of diclofenac in children and in UGT2B17 deletion subjects could predispose these patients to high GI discomfort.References Bhatt et al., Drug Metab. Dispos. (2018). Parvez Md M et al., Drug Metab. Dispos.(2021).

Effect of Naringin Co-administration on Oral Bioavailability of Efavirenz in Rabbit

Efavirenz is a first line anti-retroviral drug belonging to category of non-nucleoside reverse transcriptase inhibitor (NNRTIs), However, it has variable bioavailability due to its limited aqueous solubility. Naringin is a bioavailability enhancer which has been used to increase bioavailability of several drugs. Therefore, the purpose of this study was to investigate the possibility of improving the bioavailability of Efavirenz using Naringin in experimental rabbits. The experimental rabbits were divided into four groups. Group I received Efavirenz 9.33 mg/kg, p.o (which corresponded to 200mg of human dose), Group II received Efavirenz 9.33mg/kg, + Naringin 20.8mg/kg, p.o; Group III received Efavirenz 28mg/kg, p.o (which corresponded to 600mg of human dose); Group IV received Efavirenz 28mg/kg + Naringin 20.8mg/kg, p.o. Afterwards, plasma from each group of rabbits was extracted and at fixed time interval drug plasma concentration was estimated using HPLC. Pharmacokinetic parameters of were determined for each group. Efavirenz (9.33mg/kg and 28mg/kg) - Naringin (20.8mg/kg) co-administration significantly increased absorption rate constant (Ka) and elimination rate constant (Kel), Cmax, T1/2, Tmax significantly. Efavirenz 9.33mg/kg - Naringin (20.8mg/kg) co-administration increased area under the curve significantly. The relative bioavailability of Efavirenz 9.33 mg/kg - Naringin (20.8mg/kg) co-administration and Efavirenz 28mg/kg - Naringin (20.8mg/kg) co-administration was found to be 113.77% and 106.75% respectively. Based on the results it can be concluded that Naringin co-administration increased the oral exposure of Efavirenz to some extent. Bioavailability of Efavirenz with Naringin was found to be higher than Efavirenz control.

In vitro and in vivo characterization of Entacapone-loaded nanostructured lipid carriers developed by quality-by-design approach

Entacapone, a reversible catechol-o-methyl transferase inhibitor, is used to enhance the action of dopamine agonists by reducing their metabolism and the ‘Wearing-off’ effects associated with long-term use in the treatment of Parkinson's disease. It is used as an adjunct to levodopa/Carbidopa therapy. Due to limited dissolution and first-pass clearance, it suffers low and variable bioavailability issues. To overcome this problem, the present study aims to explore the potential of nanostructured lipid carriers (NLCs) for the delivery of Entacapone. The Quality by Design (QbD) approach was used for the systematic development of NLCs. The 23 full factorial designs were investigated using Design-Expert®11 software. The three independent variables namely content of total lipid (X1), surfactant (X2), and sonication time (X3) were optimized against two responses namely particle size and entrapment efficiency. The optimized NLCs were characterized for their size, surface morphology, entrapment efficiency, drug release, thermal and crystallographic studies. In-vivo pharmacokinetic studies in Entacapone-loaded NLCs showed an increase in t 1/2, AUC0–∞, MRT compared to free drug. The reduction in elimination (Kel) depicts the prolonged action of Entacapone by loading in NLCs. The results displayed Entacapone-loaded NLCs have promising potential for oral delivery and enhanced therapeutic effect which otherwise was a major issue.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Enhanced Intramuscular Bioavailability of Cannabidiol Using Nanocrystals: Formulation, In Vitro Appraisal, and Pharmacokinetics.

Cannabidiol (CBD) has poor water solubility and is subjected to extensive first-pass metabolism. These absorption obstacles are responsible for low and variable oral bioavailability of CBD. This study endeavored to improve CBD bioavailability by intramuscular (IM) injection of CBD nanocrystals (CBD-NC). The nanocrystals were prepared by antisolvent precipitation method and were characterized in terms of the particle size, polydispersity index (PDI), zeta potential, morphology, and crystalline status. CBD-NC displayed a particle size of 141.7±1.5 nm, a PDI of 0.18±0.01, and a zeta potential of -25.73 mV. CBD-NC freeze-dried powder using bovine serum albumin (BSA) as cryoprotectant had good redispersibility, and the average particle size was 139.1±1.4 nm after reconstitution. Moreover, these freeze-dried powders were characterized for drug loading and pH and were evaluated for in vitro dissolution and in vivo studies in a rat model. The in vivo results showed that AUC0-24 h and Cmax of CBD by IM injection of CBD nanocrystals increased significantly compared with that of oral (P.O) administration of CBD nanocrystals and CBD oil solution. This underlines the nano-sized CBD could be suggested as a practical and simple nanosystem for IM delivery with improved bioavailability. More importantly, these results pave the way for future development of CBD-NC retentive dosage forms. Graphical abstract.

Oral Bioavailability Enhancement of Efavirenz using Piperine coadministration in Experimental Rabbits

Background: Efavirenz, a first line anti-retroviral drug has variable bioavailability owing to its limited aqueous solubility. Piperine, a bioavailability enhancer has been often used to enhance the bioavailability of many drugs. Objective: The present study was aimed to investigate the possibility of improving the bioavailability of efavirenz using piperine. Methods: Two doses of efavirenz 9.33 mg/kg and 28 mg/kg which corresponded to 200 and 600 mg/kg of human dose were selected. Single oral dose of efavirenz and piperine co administration was given to rabbit and at fixed time interval drug blood concentration was estimated by HPLC. Pharmacokinetic parameters of efavirenz and piperine co administration were determined. Results: Efavirenz 9.33 mg/kg co administration with piperine 20.8 mg/kg increased area under the curve significantly at p&lt;0.01 and Cmax at p&lt;0.05 compared to efavirenz control (9.33 mg/kg). The relative bioavailability of efavirenz and piperine co-administration was found to be 149.08%, i.e., higher than efavirenz control. T1/2 of piperine co-administration was also increased significantly at p&lt;0.05 compared to efavirenz control. Tmax of piperine co-administration was found to be 0.5 h, followed by efavirenz control i.e., 1 h. Co-administration of efavirenz (28 mg/kg) with piperine (20.8 mg.kg) significantly increased AUC and Cmax at p&lt;0.001 compared to efavirenz control (28 mg/kg). The relative bioavailability of Piperine co-administration was found to be 158.92%, higher than efavirenz control. There was significant increase in T1/2 of piperine co-administration at p&lt;0.01 compared to efavirenz control. Tmax of piperine co-administration and efavirenz were found to be same i.e., 1 h. Conclusion: Based on the results it can be concluded that piperine co-administration significantly increases the oral exposure of efavirenz. Bioavailability of efavirenz with piperine was found to be higher than efavirenz control.

REVIEW STUDY ON ANALYSIS OF THE SOLUBILITY OF BIOPHARMACEUTICAL CLASSIFICATION SYSTEM CLASS II DRUGS IN A SELF-EMULSIFYING DRUG DELIVERY SYSTEM

By dissolving drug molecules in these solutions, a unit dosage form for oral administration can be generated for oral administration. Self-emulsifying drug delivery system (SEDDS) is utilized to address the inadequate bioavailability of poorly soluble and highly permeable drugs, according to the literature. These methods can disseminate and deliver hydrophobic medications as a unit dose form for oral administration in this fashion. SEDDS formulations self-emulsify (micro/nano) after being discharged into the intestinal lumen and coming into contact with the gastrointestinal (GI) fluid. Several factors must be considered to make the oral drug administration difficult, including poor water solubility and limited permeability. Self-emulsifying drug delivery can increase the solubility of biopharmaceutical classification system (BCS) II medicines. The SEDDS is a drug delivery system that enhances the solubility of lipophilic medications. It has risen in popularity over time. Under moderate agitation and subsequent dilution, GI fluids are categorized as hydrophilic liquid mixes that are isotropic. This research looks at a variety of uses as well as recent advancements in SEDDS composition, evaluation, dosage forms, and novel techniques to convert liquid SEDDS to solids. Final Thoughts Determining whether or not it is feasible to construct a BCS Category 2 medication formulation based on SEDDS represents a significant contribution of this effort. Medicines with solubility issues and low and variable bioavailability will benefit from the connected technologies.

Tablet Formulation Studies on Recrystallized Active Pharmaceutical Ingredients of Valsartan and Olmesartan Medoxomil

Both the Valsartan (VAL) and Olmesartan medoxomil (OLM) are widely prescribed anti-hypertensive agents with angiotensin II type I receptor antagonistic activity. Both VAL and OLM are type of BCS class II drugs and having a low and variable oral bioavailability. Recrystallization of VAL and OLM from different organic solvents improved its aqueous solubility and thereby in vitro dissolution properties. In the present investigation, tablets containing Valsartan (VAL), Olmesartan medoxomil (OLM and) recrystallized products were prepared by direct compression method and evaluated for drug content, uniformity of weight, hardness, friability, disintegration time and dissolution properties. All the tablets fulfilled the compendial requirements with regarding to weight variation, friability and disintegration time etc for immediate release tablets. The DP15 (drug percent dissolved at 15 min) values for V-1 (tablets of VAL), V-4 (tablets of methanol recrystallized product with crospovidone as disintegrant) and DIOVAN™ 40mg tablet formulations are 45.97, 98.95 and 82.65 respectively and V-4 formulation showed higher dissolution rate when compared to other formulations. The DP15 values of O-1(tablets of OLM), O-4 (tablets of acetonitrile recrystallized product with crospovidone as disintegrant and OLMY™ (20mg) tablet formulations are 29.25, 99.93 and 84.82 respectively. O-4 tablet formulations showed higher dissolution rate when compared to other tablet formulations.&#x0D; Keywords: Valsartan, Olmesartan medoxomil, Recrystallization, Aqueous solubility

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&gt;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.&#x0D; Keywords: Bioanalytical method, Bioavailability, Male Wistar rats, Valsartan, Recrystallization

Identification and characterization of a novel glutaminase inhibitor.

In humans, there are two forms of glutaminase (GLS), designated GLS1 and GLS2. These enzymes catalyse the conversion of glutamine to glutamate. GLS1 exists as two isozymes: kidney glutaminase (KGA) and glutaminase C (GAC). Several GLS inhibitors have been identified, of which DON (6‐diazo‐5‐oxonorleucine), BPTES (bis‐2‐(5‐phenylacetamido‐1, 3, 4‐thiadiazol‐2‐yl) ethyl sulphide), 968 (5‐(3‐Bromo‐4‐(dimethylamino)phenyl)‐2,2‐dimethyl‐2,3,5,6‐tetrahydrobenzo[a]phenanthridin‐4(1H)‐one) and CB839 (Telaglenastat) are the most widely used. However, these inhibitors have variable efficacy, specificity and bioavailability in research and clinical settings, implying the need for novel and improved GLS inhibitors. Based on this need, a diverse library of 28,000 compounds from Enamine was screened for inhibition of recombinant, purified GAC. From this library, one inhibitor designated compound 19 (C19) was identified with kinetic features revealing allosteric inhibition of GAC in the µm range. Moreover, C19 inhibits anti‐CD3/CD28‐induced CD4+ T‐cell proliferation and cytokine production with similar or greater potency as compared to BPTES. Taken together, our data suggest that C19 has the potential to modulate GLS1 activity and alter metabolic activity of T cells.

Cefdinir Inclusion in Mesoporous Silica as Effective Dissolution Enhancer with Improved Physical Stability

Objective: The objective of this research was to enhance the physical stability and the dissolution rate of cefdinir, a BCS class IV drug, characterized by low and variable bioavailability due to both its low solubility and low permeability. Methods: Cefdinir was loaded into the mesoporous silica (SBA-15), by using the solvent immersion method starting from different organic solvents. And then formula (F3), which exhibited the highest loading percentage, was selected to study its drug release in media with different pH (1.2, 4.5, and 6.8), and has been fully characterized by using: Fourier Transform Infrared Spectroscopy (FT-IR) Spectroscopy, Differential Scanning Calorimetry, Powder X-ray Diffraction, and has been subjected to accelerated stability tests using different temperatures and relative humidity. Drug release kinetics were studied by using the following models: Probit, Gompertz, Weibull, and Logistic. Results: The results showed a remarkable dissolution improvement of cefdinir from the loaded silica in comparison to the crystalline drug at the different studied media. Drug release behaviors were well simulated by the Weibull model for F3 in all studied media and for pure Cefdinir in phosphate buffer only, and by the Gompertz function for pure Cefdinir in HCl buffer and Acetate buffer. FTIR results showed hydrogen bonds formed between the drug and silica, DSC and PXRD results revealed the transformation of cefdinir into an amorphous form upon adsorption. Stability studies under different conditions revealed the ability of mesoporous silica to maintain the amorphous state of the drug, which has been formed upon adsorption, and to prevent re-organization in the crystal nucleus of the drug molecules. Conclusion: Thus, loading cefdinir onto mesoporous silica can be used as a promising method to enhance drug dissolution, and maintain the physical stability of its amorphous form.

Preparation and Evaluation of a Novel Oral Microemulsion Drug Delivery System for Enhancing the Bioavailability of Diltiazem

Diltiazem, a calcium ion cellular influx inhibitor is known for its limited and variable bioavailability. This study is intended to explore the benefits of microemulsion formulation as an oral drug delivery system for immediate release to improve the bioavailability and efficacy of Diltiazem. Methods: Oil in water microemulsion was prepared using the simple water titration method. The optimized formulation was evaluated for physicochemical parameters like viscosity, pH, conductivity, and accelerated stability studies. In vitro release, diltiazem microemulsion was investigated.

Molecular Coordination, Structure, and Stability of Metal-Polyphosphate Complexes Resolved by Molecular Modeling and X-ray Scattering: Structural Insights on the Biological Fate of Polyphosphate.

Polyphosphate-accumulating organisms (PAOs), which can store high levels of phosphate (Pi) in the form of polyphosphate (polyP), are employed to engineer enhanced biological P removal (EBPR) from wastewaters. Co-localization of Mg and K in polyP granules of PAOs has been reported, and higher abundance of Mg-polyP granules relative to other metal complexes was correlated positively with EBPR performance stability. However, the underlying mechanism remains unknown. Here, we obtained molecular structural information of hydrated polyP complexes with four physiologically relevant metal cations (Na+, K+, Ca2+, and Mg2+) using computational and experimental techniques. Molecular dynamics simulations revealed that Mg-polyP and K-polyP complexes were the most and least stable of the complexes, respectively, suggesting that the co-occurrence of these complexes facilitates variable polyP bioavailability. The relative thermodynamic stability reflected the strength of metal chelation whereby the coordination distance between the polyP ligand O and the metal was 1.71-2.01 Å for Mg2+ but this distance was 2.64-2.70 Å for K+. Pair distribution function analysis of X-ray scattering data obtained with a Mg-polyP solution corroborated the theoretical Mg-polyP coordination geometry. These findings implied a possible mechanistic role of metal complexation in the P cycling traits of PAOs in engineered and natural systems.

Therapeutic Drug Monitoring Strategies for Envarsus in De Novo Kidney Transplant Patients Using Population Modelling and Simulations.

Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients. The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles. The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day4 and significantly reduce the proportion of overexposed patients at risk of toxicity. A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.

Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax

Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.