Pharmacokinetics In Beagle Dogs Research Articles

Core-shell tablets designed for modified and sequential release of ibuprofen and rabeprazole

In this study, core–shell tablets comprising an ibuprofen (IBU) enteric-coated core for modified release and a rabeprazole (RAB) shell for immediate release were developed using wet granulation method. The primary aim was to produce a sequential release of RAB and IBU with pharmacokinetic profiles comparable to those of the respective single tablets, thereby reducing the potential for IBU-associated gastrointestinal (GI) side effects. The composition of the IBU/RAB core–shell tablets was finalized on a comparative basis by evaluating various trial formulations. IBU/RAB core–shell tablets (400/20 mg) were assessed for physicochemical attributes, storage stability, and in vivo pharmacokinetics in beagle dogs. IBU/RAB core–shell tablets showed immediate RAB release (99.5 % in 1 h at pH 1.2) and delayed IBU release (3.4 % and 88 % in the acid and buffer stages, respectively). IBU/RAB core–shell tablets produced either comparable or improved plasma concentrations in dogs (Cmax; 1163.3 vs. 1160.0 ng/mL for RAB and 27,370 vs. 24170 ng/mL for IBU) compared to those of the respective single tablets. The IBU/RAB core–shell tablets also demonstrated long-term and accelerated storage stability. In conclusion, the core–shell design could be a promising strategy for the co-administration and sequential release of IBU and RAB to relieve inflammatory conditions and reduce GI complications.

Novel Fimasartan Fluidized Solid Dispersion and Its Tablet: Preparation, Crystallinity, Solubility, Dissolution, and Pharmacokinetics in Beagle Dogs.

Fimasartan, an angiotensin II receptor antagonist, exhibits low bioavailability due to its poor solubility; consequently, using solubilization technologies is essential to improve its bioavailability. In this study, novel fimasartan fluidized solid dispersion (FFSD) was developed using a fluid bed granulator to enhance the drug solubility andoral bioavailability. An appropriate FFSD was prepared in 50% ethanol using a fluid bed granulator, and its drug dissolution, morphology, and crystallinity were evaluated in comparison to the powdered drug. Moreover, the dissolution in various pH conditions and pharmacokinetics of the FFSD tablet in beagle dogs were investigated compared to the commercial fimasartan tablet. Among the hydrophilic polymers tested, hydroxypropyl methylcellulose (HPMC)showed the highest solubility. The FFSD, composed of fimasartan, HPMC, and microcrystalline cellulose at the weight ratio of 20:10:25, gave a granular aggregation of several particles with a smooth surface. The drug in this FFSD existed as an amorphous state, leading to a greatly increased drug dissolution. The FFSD tablet was prepared by compressing a mixture of FFSD, mannitol, croscarmellose sodium, and magnesium stearate at the weight ratio of 55:40:5:1. The FFSD tablet gave significantly higher drug dissolution, plasma concentrations, maximum plasma concentration (Cmax) andarea under the whole blood concentration-time curve (AUC) values than did the commercial fimasartan tablet. In the beagle dogs, the FFSD tablet (140.39±27.40ng·h/ml) had about a 1.7-fold higher AUC than the commercial fimasartan tablet (80.58±22.18 ng·h/ml), indicating an enhancement in thebioavailability. This novel FFSD tablet could be a potential oral pharmaceutical product with the improved oral bioavailability of fimasartan.

Validated UPLC-MS/MS Method for Determination of Futibatinib and Its Pharmacokinetics in Beagle Dogs

Futibatinib, a highly selective, irreversible potent fibroblast growth factor receptor (FGFR) inhibitor, has been proved to be effective in clinical trials of intrahepatic cholangiocarcinoma (ICCA) patients. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determine the concentration of futibatinib in beagle dog plasma was developed and validated for the study of pharmacokinetics. After the plasma protein was removed by acetonitrile precipitation, futibatinib was detected and derazantinib was used as the internal standard (IS). Futibatinib and IS were separated in an UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with acetonitrile and 0.1% formic acid as the mobile phase, and the flow rate was 0.3 mL/min. Under the positive ion condition of an electrospray spray ion (ESI+) source, multireaction detection was used, and the ion pairs for futibatinib and IS were m/z 418.99 ⟶ 295.97 and 468.96 ⟶ 382.00, respectively. Futibatinib had a good linear relationship in the linear range of 0.5∼100 ng/mL; the lower limit of quantification (LLOQ) was 0.5 ng/mL. The RSDs of the intraday and interday precision were all less than 10.70%, and the RE value of accuracy was between −3.87% and 3.28%. The extraction recovery of futibatinib was more than 80%, and the matrix effect was around 100%, and futibatinib was found to be stable under four experimental conditions. The new optimized and validated UPLC-MS/MS method was an effective tool to determine the concentration of futibatinib in plasma and has been successfully applied to the pharmacokinetics of futibatinib in beagle dogs. This method would also be used to study drug-drug interaction (DDI).

Comparative Study of Preparation, Evaluation, and Pharmacokinetics in Beagle Dogs of Curcumin β-Cyclodextrin Inclusion Complex, Curcumin Solid Dispersion, and Curcumin Phospholipid Complex.

Curcumin is a natural acidic polyphenol extracted from turmeric with a wide range of biological and pharmacological effects. However, the application of curcumin for animal production and human life is limited by a low oral bioavailability. In this study, natural curcumin was prepared for the curcumin β-cyclodextrin inclusion complex (CUR-β-CD), curcumin solid dispersion (CUR-PEG-6000), and curcumin phospholipid complex (CUR-HSPC) using co-precipitation, melting, and solvent methods, respectively. Curcumin complex formations were monitored using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) techniques via the shifts in the microscopic structure, molecular structure, and crystalline state. Subsequently, twenty-four female beagle dogs were randomly divided into four groups to receive unmodified curcumin and three other curcumin preparations. The validated UPLC–MS assay was successfully applied to pharmacokinetic and bioavailability studies of curcumin in beagle dog plasma, which were collected after dosing at 0 min (predose), 5 min, 15 min, 30 min, 40 min, 50 min, 1.5 h, 3 h, 4.5 h, 5.5 h, 6 h, 6.5 h, 9 h, and 24 h. The relative bioavailabilities of CUR-β-CD, CUR-PEG-6000, and CUR-HSPC were 231.94%, 272.37%, and 196.42%, respectively. This confirmed that CUR-β-CD, CUR-HSPC, and especially CUR-PEG-6000 could effectively improve the bioavailability of curcumin.

Simultaneous determination of novel β-lactamase inhibitor WCK 4234 and Meropenem in dog plasma by LC-MS/MS and its application to preclinical pharmacokinetic study.

A precise and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) bioanalytical method has been developed and validated for the simultaneous quantification of WCK 4234 and meropenem (MEM) in dog plasma. Protein precipitation using acetonitrile was employed as a sample preparation approach. Cefepime was used as an internal standard. The developed method was selective, sensitive (limit of quantification, 0.075 μg/ml for both drugs), accurate (recovery > 90%), precise (CV <10%) and linear (r2 ≥0.99, concentration range 0.075-120 μg/ml for both analytes). The developed method was successfully applied for the determination of both drugs in plasma to assess the pharmacokinetics in beagle dogs. WCK 4234 + MEM in a 1:1 ratio at 15 + 15 and 30 + 30 mg/kg doses were administered by the intravenous route. The mean plasma concentration and area under the concentration-time curve of WCK 4234 ranged from 38.3 to 77.4μg/ml and from 47.8 to 77.1μg h/ml, respectively, and the values for MEM ranged from 52.2 to 115.3μg/ml and 70.5 to 133.6μg h/ml respectively. The elimination half-life of WCK 4234 and MEM was around 0.8h.

Novel dapagliflozin di-L-proline cocrystal-loaded tablet: preparation, physicochemical characterization, and pharmacokinetics in beagle dogs and mini-pigs

Dapagliflozin base and a commercial dapagliflozin propanediol hydrate cocrystal (DPF-PDHC) were highly hygroscopic and thermally unstable. In this study, to address this limitation, we prepared a novel dapagliflozin di-L-proline cocrystal (DPF-LPC) and evaluated its physicochemical characterization compared with DPF-PDHC. After the preparation of the DPF-LPC-loaded tablet, its dissolution, stability and bioequivalence in beagle dogs and mini-pigs were assessed. DPF-LPC was well prepared with a dapagliflozin base and L-proline in a molar ratio of 1:2. Similar to DPF-PDHC, DPF-LPC was highly lipophilic and crystalline in nature. However, these two cocrystals exhibited different melting points and crystalline structures, indicating their different cocrystal forms. Moreover, DPF-LPC exhibited less hygroscopicity and lower water content than DPF-PDHC. The DPF-LPC-loaded tablet composed of DPF-LPC, Comprecel M102, lactose monohydrate, crospovidone, magnesium stearate, and Opadry (coating) at a weight ratio of 15.6:104.4:100.0:8.0:2.0:7.0, was dissolution-equivalent to the commercial tablet. Moreover, it provided lower impurities than the commercial tablet, indicating its better stability. In the two animals, there were no significant differences in the plasma concentrations, AUC, C max, and T max values, suggesting that they were bioequivalent. Therefore, the novel DPF-LPC-loaded tablet with excellent stability and bioequivalence may be used as a potential alternative to the commercial DPF-PDHC-loaded tablet.

Preparation, evaluation, and pharmacokinetics in beagle dogs of a taste-masked flunixin meglumine orally disintegrating tablet prepared using hot-melt extrusion technology and D-optimal mixture design

Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135℃; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.

Simultaneous Determination of Celecoxib, Dezocine and Dexmedetomidine in Beagle Plasma Using UPLC-MS/MS Method and the Application in Pharmacokinetics.

BackgroundAn efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established.MethodsThe beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10→282.10 for CEL, m/z 246.20→147.00 for DEZ, m/z 201.10→94.90 for DEX, and m/z 326.10→291.10 for IS.ResultsThis UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31–7.66% and 0.11–9.63%, respectively; the RE values were from −6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA.ConclusionThis UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.

Influence of general anaesthesia on the intravenous acetaminophen pharmacokinetics in Beagle dogs

ObjectiveTo determine if general anaesthesia influences the intravenous (IV) pharmacokinetics (PK) of acetaminophen in dogs. Study designProspective, crossover, randomized experimental study. AnimalsA group of nine healthy Beagle dogs. MethodsAcetaminophen PK were determined in conscious and anaesthetized dogs on two separate occasions. Blood samples were collected before, and at 5, 10, 15, 30, 45, 60 and 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after 20 mg kg–1 IV acetaminophen administration. Haematocrit, total proteins, albumin, alanine aminotransferase, aspartate aminotransferase, urea and creatinine were determined at baseline and 24 hours after acetaminophen. The anaesthetized group underwent general anaesthesia (90 minutes) for dental cleaning. After the administration of dexmedetomidine (3 μg kg–1) intramuscularly, anaesthesia was induced with propofol (2–3 mg kg–1) IV, followed by acetaminophen administration. Anaesthesia was maintained with isoflurane in 50% oxygen (Fe′Iso 1.3–1.5%). Dogs were mechanically ventilated. Plasma concentrations were analysed with high-performance liquid chromatography. PK analysis was undertaken using compartmental modelling. A Wilcoxon test was used to compare PK data between groups, and clinical laboratory values between groups, and before versus 24 hours after acetaminophen administration. Data are presented as median and range (p < 0.05). ResultsA two-compartmental model best described time–concentration profiles of acetaminophen. No significant differences were found for volume of distribution values 1.41 (0.94–3.65) and 1.72 (0.89–2.60) L kg–1, clearance values 1.52 (0.71–2.30) and 1.60 (0.91–1.78) L kg–1 hour–1 or terminal elimination half-life values 2.45 (1.45–8.71) and 3.57 (1.96–6.35) hours between conscious and anaesthetized dogs, respectively. Clinical laboratory variables were within normal range. No adverse effects were recorded. Conclusions and clinical relevanceIV acetaminophen PK in healthy Beagle dogs were unaffected by general anaesthesia under the study conditions. Further studies are necessary to evaluate the PK in different clinical contexts.

Acetaminophen and tramadol hydrochloride-loaded soft gelatin capsule: preparation, dissolution and pharmacokinetics in beagle dogs

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC.

c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung cancer (NSCLC) patient-derived xenograft (PDX) model. ABN401 was found to be a weak basic compound, with pKa and log P values of 7.49 and 2.46, respectively. It is poorly water-soluble but soluble at acidic pH. The accelerated storage stability is dependent on temperature, but the purity remains at over 97% after 6 months. The bioavailability is approximately 30% in dogs and it is highly efficient in the PDX model, achieving around 90% tumor growth inhibition in combination with erlotinib. These observations indicate that the compound is acceptable for the next phase of trials.

Studies of pharmacokinetics in beagle dogs and drug-drug interaction potential of a novel selective ZAK inhibitor 3h for hypertrophic cardiomyopathy treatment

Overexpression of leucine-zipper and sterile-α motif kinase (ZAK) in heart has been closely associated with the development of hypertrophic cardiomyopathy (HCM). N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl) benzene-sulfonamides, novel highly selective ZAK inhibitors, had exhibited reasonable orally therapeutic effects on HCM in spontaneous hypertensive rat models. In the present study, a rapid and sensitive HPLC-MS/MS method for determining ZAK inhibitor 3h in beagle dog plasma was developed and validated. Meanwhile, the pharmacokinetics in beagle dog and drug-drug interaction potential of 3h had been conducted. The pharmacokinetic results showed that the absolute oral bioavailability for 3h in beagle dogs was determined to be 61.9%, which was significantly higher than that in the previous determination in Spragur-Dawley rats (F = 20%). The Cytochrome P450 enzymes and P-glycoprotein mediated drug-drug interactions by 3h were also investigated using dog and human liver microsomes and Caco-2 cells. The results demonstrated that only CYP2C9 was obviously inhibited (IC50 = 1.66 μM). Besides, 3h could significantly decrease digoxin efflux ratio in Caco-2 experiments in a dose-dependent manner (IC50 = 13.3 μM). Considering 3h strongly suppressed the ZAK kinase activity with an IC50 of 3.3 nM, there are significantly differences between this IC50 value for ZAK inhibition and the present determinations of IC50 values. In general, the clinical drug-drug interaction potential for 3h could be well monitored during the treatment of HCM.

Sustained Release Bilayer Tablet of Ibuprofen and Phenylephrine Hydrochloride: Preparation and Pharmacokinetics in Beagle Dogs.

Cold is a global common infectious disease accompanied by symptoms such as headache and stuffy nose. Ibuprofen (IBU) and phenylephrine hydrochloride (PE) were commonly used for common cold due to their different effects in relieving fever and the main symptoms such as nasal congestion and high sinus pressure. However, the commercial tablets of IBU and PE have to be administered 2 to 3 times per day due to their short half-life, with inconvenience for patient and fluctuations of plasma concentration. Bilayer tablet technology was utilized to design the IBU-PE sustained release tablets because of the significantly different solubility of IBU and PE in release media. The formulations of IBU layer and PE layer contain different viscosity grades of hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, hydrophilic diluent, and traditional glidant and lubricant. The sustained release bilayer tablet exhibited satisfying sustained release performance with the mechanisms of diffusion and matrix erosion. Compared with the conventional tablets, the IBU-PE sustained release bilayer tablet expressed significantly sustained-release behavior with decreased Cmax and prolonged Tmax in fasted conditions for IBU and PE. Though IBU of IBU-PE sustained release bilayer tablet was bioequivalent to the commercial IBU tablet, the relative bioavailability of PE from the bilayer tablets was 87.49 ± 20.00% (90% confidence interval was 72.3 to 102.5%), indicating bioinequivalence probably due to the "first pass" effect.

A New Model to Describe the Single-dose Pharmacokinetics of Bevacizumab and Predict Its Multiple-Dose Pharmacokinetics in Beagle Dogs.

Complex pharmacokinetic (PK) properties including nonlinear elimination were encountered by some monoclonal antibodies (mAbs), and classic compartment models sometimes failed to appropriately describe those properties. In this work, a new model was built on a comprehensive analysis of the complex elimination of mAbs. This new model was firstly utilized to fit with the single-dose plasma concentration data of bevacizumab in beagle dogs receiving an intravenous administration of 2.5 mg/kg bevacizumab. Then, the optimal PK parameters from fitting with the single-dose PK data were employed into the multiple-dose mathematical expressions to predict bevacizumab’s multiple-dose PK profiles. One-compartment model recommended as the optimal classic model by DAS 2.0 software was set as a control. As a result, new model fitted better with the single-dose PK profiles of bevacizumab with smaller weighted residual sum of squares and higher fitting degree compared with the classic model. Importantly, new model also accurately predicted the multiple-dose PK profiles of bevacizumab and performed well at the single-to-multiple transition. In conclusion, the new model reasonably explained the complex elimination of bevacizumab, and it might play a big role in the PK studies of bevacizumab and other mAbs.

In vitro/vivo assessment of praziquantel nanocrystals: Formulation, characterization, and pharmacokinetics in beagle dogs

To investigate the impact of particle size on in vitro/vivo performance of praziquantel (PZQ), nanocrystals (NCs) and microcrystals (MCs) of PZQ were prepared using the methods of wet milling and jet milling, respectively. PZQ NCs and MCs were characterized with dynamic light scattering, laser particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray powder diffraction and fourier transform infrared spectroscopy. The average diameters of PZQ NCs and MCs were 364.4 nm and 3.7 µm, respectively. No change in crystalline form was observed. Dissolution tests were performed in two different media, where the cumulative dissolution and dissolution rate of NCs were significantly improved in comparison with those of MCs and KANGQING® in non-sink condition. Similarly, oral bioavailability of PZQ NCs in beagle dogs was 1.68 (P < 0.05) and 1.83 fold (P < 0.01) higher than that of MCs and KANGQING®. Considering the advantages of in vitro/vivo performance and facile preparation, PZQ NCs may have a great application in the treatment of schistosomiasis.

Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration.

Berberine (BBR) is considered a multi-target drug that has significant advantages. In contrast to its significant pharmacological effects in clinic, the plasma level of BBR is very low. Our previous work revealed that dihydroberberine (dhBBR) could be an absorbable form of BBR in the intestine, and butyrate is an active metabolite that is generated by gut bacteria in rats. In this study, for the first time we describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR by single (50 mg/kg) or multiple doses (50 mg/kg/d) for 7 days. GC-MS, GC, LC-MS/MS, and LC/MSn-IT-TOF were used to detect dhBBR, butyrate and BBR as well as its Phase I and II metabolites, respectively. The results showed that dhBBR was not detected in dog plasma but was excreted in small amounts in the feces of dogs examined on days 3 and 7. Butyrate was generated by gut bacteria and increased by 1.3- and 1.2-fold in plasma or feces, respectively, after 7 days of BBR treatment compared to the levels before treatment. Changes of intestinal bacterial composition were analyzed by 16S rRNA genes analysis. The results presented that dogs treated with BBR for 7 days increased both the abundance of the butyrate- and the nitroreductases- producing bacteria. We also identified chemical structures of the Phase I and II metabolites and analyzed their contents in beagle dogs. Eleven metabolites were detected in plasma and feces after BBR oral administration (50 mg/kg) to dogs, including 8 metabolites of Phase I and III metabolites of Phase II. The pharmacokinetic profile indicated that the concentration of BBR in plasma was low, with a Cmax value of 36.88 ± 23.45 ng/mL. The relative content of glucuronic acid conjugates (M11) was higher than those of other metabolites (M1, M2, M12, and M14) in plasma. BBR was detected in feces, with high excreted amounts on day 3 (2625.04 ± 1726.94 μg/g) and day 7 (2793.43 ± 488.10 μg/g). In summary, this is the first study to describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR, which is beneficial for discovery of drugs with poor absorption but good therapeutic efficacy.

Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability

Felodipine (FD) has been widely used in anti-hypertensive treatment. However, it has extremely low aqueous solubility and poor bioavailability. To address these problems, FD hollow microspheres as multiple-unit dosage forms were synthesized by a solvent diffusion evaporation method. Particle size of the hollow microspheres, types of ethylcellulose (EC), amounts of EC, polyvinyl pyrrolidone (PVP) and FD were investigated based on an orthogonal experiment of three factors and three levels. In addition, the release kinetics in vitro and pharmacokinetics in beagle dogs of the optimized FD hollow microspheres was investigated and compared with Plendil (commercial FD sustained-release tablets) as a single-unit dosage form. Results showed that the optimal formulation was composed of EC10 cp:PVP:FD (0.9:0.16:0.36, w/w). The FD hollow microspheres were globular with a hollow structure and have high drug loading (17.69±0.44%) and floating rate (93.82±4.05%) in simulated human gastric fluid after 24h. Pharmacokinetic data showed that FD hollow microspheres exhibited sustained-release behavior and significantly improved relative bioavailability of FD compared with the control. Pharmacodynamic study showed that the FD hollow microspheres could effectively lower blood pressure. Therefore, these findings demonstrated that the hollow microspheres were an effective sustained-release delivery system for FD.

Forecasting gastrointestinal precipitation and oral pharmacokinetics of dantrolene in dogs using an in vitro precipitation testing coupled with in silico modeling and simulation.

The aim of the current research was to determine the precipitation kinetics of dantrolene sodium using canine biorelevant in vitro testing and to model the precipitation kinetics by appropriately coupling the data with an in silico tool adapted for dogs. The precipitation profiles of dantrolene sodium solutions were obtained with the in vitro paddle apparatus at a revolution rate of 50rpm. The in silico prediction tool was designed using STELLA software and the predicted plasma concentration profiles of dantrolene using the in vitro precipitation data were compared with the observed in vivo pharmacokinetics in beagle dogs. The plasma profiles of dantrolene, which served as a model weakly acidic drug which precipitates in the upper gastrointestinal tract, was successfully predicted using the in vitro precipitation testing coupled with the in silico modeling and simulation approach. The approach was subsequently used to forecast the effect of pharmaceutical excipients (HPMC/PG) on the ability of the drug to supersaturate in the gut and the resulting pharmacokinetics. The agreement of the simulated pharmacokinetics with the observed values confirms the ability of canine biorelevant media to predict oral performance of enhanced dosage forms in dogs.

Preclinical Pharmacokinetics and Toxic Kinetics Study of 2, 4-Dinitrophenol (DNP)

1.1. Purpose: To research the pharmacokinetics and tissue distribution of 2,4-dinitrophenol (DNP) in tumor-bearing mice and the pharmacokinetics and toxicokinetics in beagle dogs. 1.2. Methods: a. Pharmacokinetics in tumor-bearing mice: DNP was administrated intra tumorally to the mice with three different dosages, the drug concentration and tissue distribution were determined by the HPLC at different time, then analyze the pharmacokinetic parameters. b. Pharmacokinetics in beagle dogs: DNP was intravenously administrated in forelimb with three different dosages and drug concentrations were determined in dog’s plasma before and after each injection to calculate pharmacokinetic parameters. c. Toxicokinetics: the beagle dogs received intramuscular injection for two weeks and the plasma on the first day and the 13th day after the treatment were collected for the toxicity evaluation. 1.3. Results: i. DNP showed the characteristics of linear dynamic when administrated intra temporally in mice from the dosage of 8mg/kg to 32mg/kg. DNP was widely distributed with the relative targets including liver, kidney and lung. ii. Pharmacokinetics in beagle dogs: both of the elimination half time (T1/2) and the area under curve (AUC) of DNP increased with the increasing dose of DNP, showed the characteristics of non-linear dynamics. The systemic toxicity increased with the increasing dose of DNP, showed the characteristics of linear dynamics after multiple injections. No drug accumulation or sex differences happened in beagle dogs. 1.4. Conclusion: DNP is a relatively safe agent, showing the characteristics of linear dynamics after intratumor and intramuscular injection. Thus, the study provides reference for the clinical application.

Development of novel prasugrel base microsphere-loaded tablet with enhanced stability: Physicochemical characterization and in vivo evaluation in beagle dogs

The objective of this study was to develop a novel prasugrel base microsphere-loaded tablet (PBMST) with enhanced stability as a bioequivalent to the commercial prasugrel hydrochloride-loaded tablet. Numerous prasugrel base-loaded microspheres were prepared with hydroxypropylmethyl cellulose (HPMC), colloidal silica and various acidifying agents using a spray-drying process, and the physicochemical properties, solubility and stability were investigated. The PBMSTs were prepared and their dissolution, pharmacokinetics in beagle dogs and stability were evaluated compared to commercial prasugrel hydrochloride-loaded tablets. Among the acidifying agents tested, phosphoric acid provided the greatest increase in drug solubility, by as much as 110-fold. The prasugrel base-loaded microspheres composed of prasugrel base, HPMC, colloidal silica and phosphoric acid at a weight ratio of 10/10/5/2.5 provided an amorphous drug and reduced particle size of about 11.3μm. Moreover, it exhibited excellent solubility and improved stability compared to prasugrel base and hydrochloride. Moreover, PBMST drug dissolution was improved in comparison to the prasugrel base-loaded tablet (PBT), with similar dissolution to the commercial prasugrel hydrochloride-loaded tablet at pH 1.2 and 4.0. PBMST provided significantly higher plasma concentrations of AUC and Cmax in beagle dogs compared to PBT. In particular, the AUC of PBMST was approximately four times greater than PBT, leading to improved oral bioavailability. There were no significant differences observed for all pharmacokinetic parameters between PBMST and the commercial prasugrel hydrochloride-loaded tablet, suggesting their bioequivalence in beagle dogs. Furthermore, the prepared PBMSTs were stable for at least six months. Therefore, this novel prasugrel base microsphere-loaded tablet could be a potential alternative for enhancing the stability and bioavailability of prasugrel.