An evaluation of the pharmacokinetics of tiotropium following a single-dose inhalation in healthy subjects using an ultra-sensitive bioanalytical method

Abstract

Objective and significance: The systemic bioavailability of tiotropium following administration via inhalation is known to be very low. A validated ultra-sensitive bioanalytical method with the lowest lower limit of quantitation (LLOQ) was developed and used to evaluate the complete pharmacokinetic profile of tiotropium.

Methods: This was a pharmacokinetic study performed in 18 healthy subjects. Each subject was administered a dose of 18?mcg of tiotropium from a dry powder inhaler (DPI). The subjects’ plasma tiotropium concentrations were assayed with LLOQ of 0.1?pg/mL.

Results: The results showed a mean C_max of 4.98 ± 3.55?pg/mL, and a median (t_max) of 3.6?minutes (range: 1.8–12?minutes). The means for area under the concentration–time curve (AUC) from time zero hours to infinity (AUC_inf) and AUC from time zero hours to the time of the last measurable tiotropium concentration (AUC_t) were 51.11 ± 27.4?pg*h/mL and 37.37 ± 23.38?pg*h/mL, respectively. The mean apparent elimination half-life (t_1/2) was 68.02 ± 24.55?hours. This calculated half-life is longer than what others have reported where a less sensitive LLOQ was used.

Conclusion: The lower LLOQ enabled further insight into the pharmacokinetics of tiotropium that was not possible with other analytical methods. With this method, we were able to quantify tiotropium concentrations as early as one minute following drug administration and up to 144?hours after dosing. The application of this method will allow for studies to be designed properly and enable further investigations into the pharmacokinetics of tiotropium.     

Three-ways crossover bioequivalence study of cephalexin in healthy Malay volunteers

Context: Although the general pharmacokinetics of cephalexin is quite established up-to-date, however, no population-based study on Cephalexin pharmacokinetics profile in Malay population has been reported yet in the literature.

Objective: The objective of this study was to investigate the pharmacokinetics and to compare the bioavailability of three cephalexin products, Ospexin® versus MPI Cephalexin® tablet and MPI Cephalexin® capsule, in healthy Malay ethnic male volunteers in Malaysia.

Material and method: A single dose, randomized, fasting, three-period, three-treatment, three-sequence crossover, open label bioequivalence study was conducted in 24 healthy Malay adult male volunteers, with 1 week washout period. The drug concentration in the sample was analyzed using high performance liquid chromatography.

Result: The mean (SD) pharmacokinetic parameter results of Ospexin® were C_max, 17.39 (4.15) μg/mL; AUC_0–6, 28.90 (5.70) µg/mL?*?h; AUC_0–∞, 30.07 (5.94) µg/mL?*?h; while, those of MPI Cephalexin® tablet were C_max, 18.29 (3.01) μg/mL; AUC_0–6, 30.02 (4.80) µg/mL?*?h; AUC0_0–∞, 31.33 (5.18) µg/mL?*?h and MPI Cephalexin® capsule were C_max, 18.25 (3.92) μg/mL; AUC_0–6, 30.04 (5.13) µg/mL?*?h; AUC_0–∞, 31.22 (5.29) µg/mL?*?h.

Conclusion: The 90% confidence intervals for the logarithmic transformed C_max, AUC_0–6 and AUC_0–∞, of Ospexin® versus MPI Cephalexin® tablet and Ospexin® versus MPI Cephalexin® capsule were between 0.80 and 1.25. Both C_max and AUC met the predetermined criteria for assuming bioequivalence. The pharmacokinetic profile of cephalexin in Malay population does not vary much from other world population.     

Pharmacokinetics and pharmacodynamics of FSK0808 and Gran after single intravenous drip administration or single subcutaneous administration: comparative study in healthy Japanese adult male subjects

FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200?µg/m²) and single subcutaneous dose (400?µg/m²) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration – time curve by 48 hours after administration (AUC_0–48) in a single intravenous drip (IVD) study, and AUC_0–48 and maximum blood concentration (C_max) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34⁺ cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC_0–48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for C_max and AUC_0–48 were within the range of log(0.8)–log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)–log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.     

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers

Candesartan is a long-acting and selective nonpeptide AT₁ subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16?mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16?mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36?h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC_last, AUC_inf and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC_last in the reference and the test drug were 1530.1?±?434.6 and 1315.7?±?368.6 ng·h/mL. The mean for AUC_inf in the reference and the test drug were 1670.0?±?454.5 and 1441.2?±?397.8 ng·h/mL. The mean value for C_max in the reference and the test drug was 142.6?±?41.0 and 134.9?±?41.4?ng/mL. The 90% confidence intervals for the AUC_last, AUC_inf and C_max were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16?mg of candesartan cilexetil hydrochloride.     

Preparation,characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA–SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA–PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA–PEG6000 (1:3) SD and NA–suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA–PEG6000 (1:3) SD (C_max?=?0.645?±?0.262?µg/ml, AUC_0–t?=?0.471?±?0.084?µg/ml?h) were higher than that of NA–suspension (C_max?=?0.328?±?0.183?µg/ml, AUC_0–t =?0.361?±?0.093?µg/ml?h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.     

Average Bioequivalence of Clarithromycin Immediate Released Tablet Formulations in Healthy Male Volunteers

Abstract

The objective of this study was to assess average bioequivalence of two immediate released tablet formulations of 500-mg clarithromycin tablets in 24 healthy Thai male volunteers. In a randomized, single dose, fasting state, two-period, crossover study design with a 1-week washout period, each subject received a 500-mg clarithromycin tablet. Plasma samples were collected over a 24-hour period after oral administration and were analyzed by using a validated method using high performance liquid chromatography with electrochemical detection. Pharmacokinetic parameters were determined by using noncompartmental analysis. The time to reach the maximal concentration (t_max, h), the peak concentration (C_max, ng/mL), and the area under the curve (AUC_{0 ? ∞}, ng.h/mL) of the Reference and Test formulations were 2.0 ± 0.8 vs. 2.2 ± 0.9, 2793 ± 1338 vs. 2642 ± 1344, and 17912 ± 7360 vs. 17660 ± 7992, respectively. Relative bioavailability was 0.99. The 90% confidence interval of C_max and AUC_{0 ? ∞} were 82.6–112.1% and 84.7–112.0%. Bioequivalence between the Test and Reference formulation can be concluded.     

Bioequivalence Evaluation of Two Formulations of Doxazosin Tablet in Healthy Thai Male Volunteers

ABSTRACT

The bioequivalence of two doxazosin 2 mg tablets was determined in 24 healthy Thai male volunteers after one single dose in a randomized cross-over study with a one week washout period. The study was conducted at Faculty of Pharmaceutical Sciences and Health Sciences Research Institute, Naresuan University, Phitsanulok, Thailand. Reference (Cardura®, Heinrich Mack Nachf. GmbH & Co. GK, Illertissen, Germany) and test (Dozozin-2®, Umeda Co., Ltd., Bangkok Thailand) were administered to volunteers after overnight fasting. Blood samples were collected at specified time intervals and plasma was separated. The validated HPLC method with fluorescence detection was used for quantification of doxazosin in plasma samples. The pharmacokinetic parameters, T_max, C_max, AUC_t, AUC_∞, T_1/2, λ_z, Cl and V_d, were determined from plasma concentration time profile of both formulations by using non-compartment analysis. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) using log-transformed C_max, AUC_t, and AUC_∞ did not show any significant difference between two formulations. The point estimates and 90% confidence intervals for C_max, AUC_t and AUC_∞ were within the acceptance range (0.80–1.25), satisfying the bioequivalence criteria of the Thailand Food and Drug Administration Guidelines. These results indicate that Dozozin-2® is bioequivalent to Cardura® and, thus, may be prescribed interchangeably.     

Preparation of fenofibrate immediate-release tablets involving wet grinding for improved bioavailability

Objective: The purpose of this study was to investigate the dissolution and oral bioavailability of an immediate-release tablet involving wet grinding of a poorly water-soluble drug, fenofibrate. Methods: The milled suspension was prepared using a Basket Dispersing Mill in the presence of a hydrophilic polymer solution and then granulated with common excipients, and compressed into an immediate-release tablet with blank microcrystalline cellulose granules. Results: Compared with unmilled tablets (56% within 30 minutes), the dissolution of wet-milled tablets (about 98% in 30 minutes) was markedly enhanced. No significant decrease in the dissolution rate (96% in 30 minutes) of the wet-milled tablet was observed after 3 months under 40°C and 75% relative humidity storage. In addition, the oral bioavailability of the wet-milled tablets (test) and Lipanthyl® supra-bioavailability tablets (reference) was determined in beagle dogs after a single dose (160 mg fenofibrate) in a randomized crossover, own-control study. The results suggested that both the area under the plasma concentration–time curve (AUC_(0?t) = 46.83 ± 11.09 μg/mL h) and the mean peak concentration of the test (C_max = 4.63 ± 1.71 μg/mL) were higher than the reference (AUC_(0?t) = 35.12 ± 10.97 μg/mL h, C_max = 2.11 ± 0.08 μg/mL). The relative bioavailability of the wet-milled tablet was approximately 1.3-fold higher. Furthermore, the apparent rate of absorption of fenofibrate from the wet-milled tablet (T_max = 2.63 hours) was faster than that from Lipanthyl® (T_max = 3.75 hours). Conclusion: These results indicated that the dissolution and the bioavailability of fenofibrate were significantly enhanced by wet-grinding process. So, this shows that wet grinding is a powerful technique to improve the bioavailability for poorly water-soluble drugs, especially for Biopharmaceutics Classification System Class II compounds.     

Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs

REQUIP XL, prolonged release formulation of ropinirole hydrochloride (RH) in market, could release ropinirole constantly and showed satisfactory therapeutic effect and good compliance. REQUIP XL was composed of more than 10 kinds of excipients and prepared by Geomatrix technology, which was complex and laborious. The purpose of this study was to obtain a dosage form of RH with similar in vitro release profile and bioequivalence in vivo compared to REQUIP XL. Osmotic pump tablet combined with fast release phase was selected as the delivery system of RH and similar release curves were obtained in different media. The tablets were also administered to beagle dogs and the pharmacokinetic parameters were calculated using a non-compartmental model. C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 24?h (AUC_0–24) were 3.97?±?0.53?ng/mL, 3.58?±?0.49?h, 8.29?±?0.93?h, and 35.20?±?8.11?ng/mL???h for ropinirole osmotic pump tablets (ROPT) and 4.15?±?1.07?ng/mL, 2.92?±?0.49?h, 7.84?±?1.09?h, and 34.34?±?10.06?ng/mL???h for REQUIP XL. The log-transformed mean C_max and AUC_0–24 of ROPT were about 92.15% and 102.49% relative to that of REQUIP XL, respectively. The 90% confidence intervals of C_max and AUC_0–24 for ROPT were 75.69–115.31% and 88.89–122.30%, respectively. So it could be concluded that ROPT was uniform with REQUIP XL both in vitro and in beagles and the release profiles of Geomatrix technology may be obtained by osmotic pump combined with fast release technology.     

Bioavailability Assessment of Oral Coenzyme Q10 Formulations in Dogs

ABSTRACT

The purpose of this investigation was to compare the bioavailability of three coenzyme Q10 (CoQ10) formulations in dogs using an open, randomized, multiple-dose crossover design. The formulations included a powder-filled capsule (A, control) and two soft gelatin formulations (Q-Gel ® as the water-miscible form of CoQ10, B and Q-Nol?as the water-miscible form of ubiquinol, the reduced form of CoQ10, C). Formulations were evaluated in pairs, allowing a washout period of 14 days prior to crossing over. Blood samples were collected from each animal prior to dosing to determine the endogenous plasma CoQ10 concentrations. Serial blood samples were collected for 72 hr and plasma CoQ10 concentrations were determined by high-performance liquid chromatography. Plasma concentration–time profiles were corrected for endogenous CoQ10 concentrations. Results showed that the relative bioavailabilities of formulations B and C were approximately 3.6 and 6.2-fold higher than that of control formulation A. The AUC(µg. hr/mL)±SD, C_max(µg/mL)±SD, and T_max(hr)± SD for formulations A, B, and C were 1.695±0.06, 6.097±0.08, and 10.510±0.10; 0.096±0.035, 0.169±0.038, and 0.402±0.102; and 4.2±1.48, 4.1±1.57, and 4.5±0.58, respectively. While no significant differences were observed between T_max values of the three formulations, the AUC and C_max values for formulations B and C were significantly higher than those of the control (p<0.05). The present investigation demonstrates that soft gelatin capsules containing water-miscible CoQ10 formulations B (Q-Gel®) and C (Q-Nol?) are superior to powder-filled formulations with regard to their biopharmaceutical characteristics.     

Pharmacokinetic properties and bioequivalence of orally inhaled salbutamol in healthy Chinese volunteers

Context: Salbutamol is a short-acting β₂-adrenergic receptor agonist that has been used for many years for relief of bronchospasm. However, studies on the pharmacokinetic profile of orally inhaled salbutamol doses used in clinical practice have not yet been reported in Chinese subjects.

Objective: The aim of this study was to compare the pharmacokinetics and evaluate the bioequivalence of two orally inhaled salbutamol formulations.

Materials and methods: A single-dose randomized fasting two-period, two-treatment and two-sequence crossover open-label bioequivalence study was conducted in 24 healthy Chinese adult male volunteers, with a 1-week washout period between treatments. Plasma concentrations of salbutamol were determined using liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic parameters, including AUC_0–0.33?h, AUC_0–24?h and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data.

Results: The mean (SD) pharmacokinetic parameters of the reference drug were AUC_0–0.33?h, 227.2 (89.9) pg·h/ml; AUC_0–24?h, 2551.9 (1008.0) pg·h/ml; C_max, 801.3 (307.3) pg/ml and t_1/2, 5.14(1.36) h. Those of the test drug were AUC_0–0.33?h, 244.0 (104.4) pg·h/ml; AUC_0–24?h, 2664.4 (1081.8) pg·h/ml; C_max, 873.7 (374.4) pg/ml, t_1/2, 5.29 (1.23) h. The median value for T_max was 0.25?h for both formulations. The 90% confidence intervals for the AUC_0–0.33?h, AUC_0–24?h and C_max were in the range of 0.892–1.208, 0.876–1.195 and 0.911–1.203, respectively.

Conclusion: This single-dose study found that the test and reference products met the regulatory criteria for bioequivalence of China in healthy Chinese volunteers.     

Pharmacokinetic Investigation on a Novel Antitumour Platinum Compound in Rabbit Plasma by Inductively Coupled Plasma Mass Spectrometry After Intravenous Administration

The purpose of this study was to investigate a novel platinum anticancer compound named as SM54111 [cis-3, 5-diisopropylsalylic cyclohexanodiaminoplatinum (II)], which is under development as a new drug candidate, on its pharmacokinetics in plasma after intravenous administration to rabbits at concentration of 2.5, 5.0, and 9.0 mg/kg. The concentration of SM54111 in plasma expressed as Pt was determined utilizing ICP-MS method, and the method was thoroughly validated. The data were analyzed with 3P97 pharmacokinetic software to find the parameters. The results showed that the linear range lay at the 1 ～1000 ng/mL level, and the LOD and LOQ were 0.4 ng/mL and 1 ng/mL, respectively. It proved that this new drug candidate underwent disposition in rabbit plasma by a two-compartment open model at the three doses above, and the main pharmacokinetic parameters were obtained as the initial concentrations of three doses (C₀) were 8.68 ± 0.80, 20.04 ± 1.92, and 28.88 ± 2.32 mg/L, respectively; the areas under concentration-time profile from time 0 to 72 h (AUC_0～t) were 90.0 ± 13.0, 251.3 ± 45.3, and 396.9 ± 61.1 mg*h/L, respectively; the terminal elimination half-life times (t_1/2β) 29.1 ± 4.8, 35.2 ± 7.5, and 29.4 ± 2.8 h, respectively; and the total clearances (CL_tot) were 0.026 ± 0.004, 0.019 ± 0.002, and 0.022 ± 0.004 L/h, respectively. First order rate pharmacokinetics were observed for SM54111 with the doses used, and it showed a long retention and slow elimination in vivo, There showed no prolongation of the t_1/2β with larger dose, and the CLs of the three doses were proximate. It is reasonable to surmise that SM54111 follows first order rate pharmacokinetics, and no saturation was detected at concentrations from 2.5 to 9.0 mg/kg. This result suggested that SM54111 experienced an amiable procedure in vivo and was worthy of the further development.     

Evaluation of Bioequivalence of Two Formulations Containing 100 Milligrams of Aceclofenac

ABSTRACT

The bioequivalence of two oral formulations containing aceclofenac 100 mg was determined in 24 healthy Indian male volunteers. The study was designed as a single dose, fasting, two-period two-sequence crossover study with a washout period of 1 week. The content of aceclofenac in plasma was determined by a validated HPLC method with UV detection. The preparations were compared using the parameters area under the plasma concentration–time curve (AUC_0–t), area under the plasma concentration–time curve from zero to infinity (AUC_0–∞), peak plasma concentration (C_max), and time to reach peak plasma concentration (t_max). No statistically significant difference was observed between the logarithmic transformed AUC_0–∞ and C_max values of the two preparations. The 90% confidence interval for the ratio of the logarithmic transformed AUC_0–t, AUC_0–∞, and C_max were within the bioequivalence limit of 0.80–1.25.     

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10?mg/kg, p.o. and naringenin (25, 50 and 100?mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the C_max and increased the AUC_total of felodipine in dose-dependent manner. The C_max of felodipine was increased from 173.25?±?14.65 to 275.61?±?44.62 and 223.26?±?26.35 to 561.32?±?62.53?ng/mL in SDS and MDS, respectively, at the dose of naringenin 100?mg/kg. The AUC_total of felodipine was significantly (p?max and AUC of felodipine is due to P-gp and CYP3A4 inhibition.     

Comparative Bioavailability Study of a Generic Naltrexone Tablet Preparation

The bioavailability of a generic preparation of naltrexone (Narpan) was compared with the innovator product, Trexan. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration–time curve AUC_0–∞, peak plasma concentration C_max, and time to reach peak plasma concentration T_max. No statistically significant difference was observed between the logarithmic transformed AUC_0–∞ and the logarithmically transformed C_max values of the two preparations. Also, no statistically significant difference was observed between the untransformed T_max values. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC_0–∞ values of Narpan over those of Trexan was found to lie between 0.87 and 1.01, while that of the logarithmic transformed C_max values was between 0.94 and 1.23, both being within the bioequivalence limit of 0.80–1.25. The numerical values of the elimination half-life (t_1/2) obtained with the two preparations were also not significantly different and were comparable to those reported in the literature.     

Bioavailability of oral methylnaltrexone increases with a phosphatidylcholine-based formulation

Objective: Methylnaltrexone (MNTX), a peripherally restricted opioid antagonist with mu-opioid receptor selectivity, can reduce opioid activity in the gastrointestinal tract while sparing the pain relief afforded by opioids. Since the bioavailability of oral MNTX is low, it is necessary to explore the oral formulations of MNTX that increase its bioavailability.

Materials and methods: An MNTX-phosphatidylcholine complex (MNTX-PC) formulation was prepared. The physicochemical properties of MNTX-PC were analyzed, and its bioavailability was evaluated in rats. After 250?mg/kg of oral MNTX-PC, plasma samples were collected up to 9?h. The concentrations of the compound in rat plasma were quantified using LC/MS/MS.

Results: Two MNTX plasma concentration peaks were observed at 120 and 180?min for the MNTX-PC group and control (MNTX in a water solution). T_max was 180?min, C_max was 1083.7?±?293.9?ng/mL, and T_1/2 was 496?min for the MNTX-PC group. For control, T_max was 180?min, C_max was 448.4?±?126.0?ng/mL, and T_1/2 was 259?min. The AUC_{0–540 min} for the MNTX-PC group was 5758.2?±?1474.2?ngh/mL; for control, 1405.9?±?447.8?ngh/mL. Thus, the relative bioavailability after the oral administration of MNTX-PC was 410% compared to that of control.

Conclusion: MNTX-PC formulation significantly enhanced the oral bioavailability of MNTX.     

Removal of vancomycin administered during dialysis by a high‐flux dialyzer

Introduction: Hemodialysis patients frequently receive vancomycin for treatment of gram‐positive bacterial infections. This drug is most conveniently administered in outpatient dialysis units during the hemodialysis treatment. However, there is a paucity of data on the removal of vancomycin by high‐flux polyamide dialyzers. Methods: This is a prospective crossover study in which seven uninfected chronic hemodialysis patients at three dialysis units received vancomycin 1 gram intravenously over one hour immediately after the dialysis treatment (Phase 1), and vancomycin 1.5 grams during the last hour of dialysis treatment using a polyarylethersulfone, polyvinylpyrrolidone, polyamide high‐flux (Polyflux 24R) dialyzer (Phase 2). There was a three‐week washout period between phases. Serial serum vancomycin concentrations were used to determine the removal of vancomycin when administered during dialysis. Findings: Dialysis removed 35 ± 15% (range 18‐56%) of the vancomycin dose when administered during the last hour of dialysis. The calculated area under the curve (AUC) of vancomycin levels for 0‐44.5 hours from the start of infusion were similar between the two phases (AUC_{Phase 1} 884 ± 124 mg‐hr/L, mean ± SD; AUC_{Phase 2} 856 ± 208 mg‐hr/L; P=0.72). Serum vancomycin concentrations immediately prior to the next dialysis treatment following vancomycin administration were also similar between the two phases (13.1 ± 2.7 mg/L in Phase 1 and 12.3 ± 3.3 mg/L in Phase 2; P=0.55). Discussion: When using a polyarylethersulfone, polyvinylpyrrolidone, and polyamide high‐flux HD membrane with a 24R Polyflux dialyzer, vancomycin can be administered during the last hour of dialysis if the dose that is prescribed for intra‐dialysis dosing is empirically increased to account for intra‐dialytic drug removal.     

Evaluation of systemic exposure of nanoparticle suspensions subcutaneously administered to mice regarding stabilization,volume, location,concentration and size

Different routes of administration are likely to result in very different outcomes due to different availability or plasma profile. The objective of the present study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administration of nanoparticle suspensions of a lipophilic compound to mice. Pharmacokinetics of the selected test compound and the effect of drug concentration, particle size, location of administration, volume given and particle stabilizers were studied. Adding PEGylated lipids or pluronic F-127 to the negatively charged surface of the nanoparticles increased the stability of the particles and the bioavailability. The in vivo studies demonstrated linear absorption kinetics for the selected model compound up to at least 500?µmol/kg. Absorption from upper-neck resulted in different systemic exposure compared to administration in the hip. The former was preferred if a prolonged C_max was desired while the latter ensured a flat profile for approximately 24 hours. Administering the double volume (but the same dose) had no effect on the pharmacokinetics, whereas smaller particle size significantly increased the exposure.     

Preparation and IVIVC evaluation of salvianolic acid B micro-porous osmotic pump pellets

Purpose: Salvianolic acid B micro-porous osmotic pump controlled release pellets (SalB-CRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed.

Method: Extrusion-spheronization was used to prepare the starter cores containing SalB/MCC/Kollidon®CL-SF/Flowlac®100 of 30:40:15:15 [w/w, The formulation composition of SalB immediate-release pellets (SalB-IRPs)] and complexed with lactose. The pellets were subsequently coated with Surelease aqueous dispersion to achieve controlled-release properties. Furthermore, a single-dose pharmacokinetics study was carried out in New Zealand White (NZW) rabbits.

Results: In the starter cores, the lactose content was 25% based on the SalB-IRPs constituent. The optimal coating polymer ratio of Surelease aqueous dispersion and polyvinyl alcohol–polyethylene glycol (PVA–PEG) graft copolymer (EC/PVA–PEG) was found to be 70:30 (w/w, %) with a coating weight of 5%. The prepared SalB-CRPs had similar in vitro release under three different pH release mediums. A good IVIVC was characterized by a high coefficient of determination (r?=?0.9801). The in vivo study indicated that the maximum plasma concentration (C_max) of SalB-CRPs was decreased, peak concentration time (T_max) and mean residence time (MRT) were all prolonged, as that of SalB-IRPs. In addition, the area under concentration–time curve from 0 to 24?h (AUC_0–24?h) and 0 to infinity (AUC_0–∞) were significantly higher, compared with those of SalB-IRPs.

Conclusion: Collectively, these results manifested that SalB-CRPs were likely to be a more suitable formulation in treating cardiovascular disease with improved in vivo retention, decreased plasma drug concentration fluctuation.