Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation,optimization using central composite design and in vivo bioavailability study

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08?nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension.     

我国健康受试者体内帕洛诺司琼的药物动力学研究

目的建立帕洛诺司琼血浆中药物浓度的液-质联用检测方法,研究其在人体的药物动力学。方法9名健康男性受试者随机自身交叉给药,分别注射高、中、低3个不同剂量帕洛诺司琼,样品经MTBE萃取,用HypersilBDS C18柱分离,以格拉司琼为内标,采用HPLC-MS/MS检测血浆中药物浓度。结果帕洛诺司琼在0.23~14.20ng.mL-1呈线性关系,日内、日间变异均<15%,1.5、0.75、0.25 mg不同剂量组帕洛诺司琼药物动力学参数分别是Cmax:(7.46±1.03)、(3.27±0.76)、(1.06±0.23)ng.mL-1。AUC0~∞:(235.68±32.06)、(108.84±35.77)、(32.44±12.69)ng.mL-1.h,t1/2:(41.87±5.36)、(41.88±4.68)、(39.88±3.54)h,达峰时间均为0.083 h。结论本方法准确、灵敏,运用本法研究了9名健康受试者静脉注射不同剂量帕洛诺司琼后药物动力学,为临床确定给药方案提供了很好的理论基础。     

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

Summary Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method.Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours.We found a linear relationship (r=0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.     

A comparative study of the pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers

OBJECTIVE: Ibuprofen arginate is a salt formulation of ibuprofen designed to reach target concentrations rapidly. The primary objective of this study was to compare the 12-h pharmacokinetic profile of S(+)-ibuprofen following administration of single doses of ibuprofen arginate (600 mg) and dexibuprofen (400 mg) in healthy volunteers. METHODS: Twenty-four volunteers were recruited into an open-label, randomised, two-period, single-centre study with crossover design. RESULTS: Both treatments were well tolerated. Ibuprofen arginate and dexibuprofen showed similar bioavailability for S(+)-ibuprofen. Compared with dexibuprofen, ibuprofen arginate demonstrated a 45% higher maximum concentration (C(max)), and a time to peak concentration (T(max)) 2 h sooner. CONCLUSION: Ibuprofen arginate approaches maximum concentrations of S(+)-ibuprofen faster and higher than dexibuprofen.     

Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers

Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min⁻¹·1.73 m⁻². Peak plasma concentrations of 10–20 ng·ml⁻¹ were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.     

姜黄素聚合物胶束的制备及体外评价

目的:制备姜黄素的Soluplus聚合物胶束,并对其进行体外评价。方法:采用薄膜分散法制备姜黄素聚合物胶束;采用粒径测定仪、透射电镜、X-射线衍射(XRD)对其进行表征;采用紫外分光光度法测定胶束的包封率和载药量;采用动态膜透析法考察载药胶束的体外释药特性。结果:薄膜分散法制备的胶束呈球形或类球形,平均粒径为(65.54±2.57)nm,平均包封率为(87.73±2.94)%,平均载药量(7.96±2.13)%;XRD结果表明姜黄素以无定型状态或分子状态包载在聚合物胶束中;体外释放结果表明姜黄素的soluplus聚合物胶束具有缓释作用。结论:该胶束制备工艺简单,其粒径、包封率、载药量可控,具有缓释作用。     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t_1/2β) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and C_max, as well as a slightly shorter T_max, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters C_max, T_max, and AUC, suggesting that the Coltramyl^® tablets have an adequate in vivo dissolution profile.     

Novel oral delivery system of indomethacin by solidified mPEG-PDLLA micelles: in vivo study

To administer indomethacin (IND) orally using polymeric micelles, IND loaded solidified polymeric micelles (IND-SPM) were prepared and evaluated for their in vitro and in vivo characteristics. IND and methoxy-poly(ethylene glycol) poly(d, l-lactide) copolymer (mPEG-PDLLA) were dissolved in acetone followed by the addition of an equivalent amount of polyplasdone XL-10 and stirred to obtain a suspension. Afterwards, acetone was completely evaporated. It was found that IND-SPM generates small polymeric micelles of 18.1 nm. Moreover, the solubility of IND at pH 6.8 increased 4.6-folds, and more than 90% of IND in 20 mg of IND-SPM was dissolved in 250 mL SIF pH 6.8 within 30 min. Pharmacokinetic parameters in fasted rats showed that IND-SPM 1:3 resulted in 3-folds increase of AUC and C_max compared to commercial IND. mPEG-PDLLA micelles were found to be efficient carriers for oral administration of IND as solid dosage forms by adsorption on polyplasdone XL-10.     

中国健康男性志愿者单次口服甲磺酸酚妥拉明片耐受性研究

目的：在中国男性健康志愿中评价单次口服Ⅳ＋Ⅴ类新药甲磺酸酚妥拉明片的安全性、耐受性。方法：根据新药临床试验指导原则设计试验方案，按照赫尔辛基宣言和GCP指导原则，选择18－50岁健康成人，用区组随机化设计方法，按随机表将36名受试随机分配至10、20、30、40、50和60mg剂量组，每组6名受试。观察指标为临床症状、生命体征、心电图、血常规、尿常规、肝功能、肾功能、电解质等。结果：单次口服10-60mg甲磺酸酚妥拉明片，志愿体温、脉搏、呼吸频率、卧立位血压、心电图、血常规、肝功能、肾功能、电解质等各项指标测定值均在正常范围内，仅见面部潮红、鼻塞、头晕头痛或脉率增快（20例）等与药物可能有关的一过性轻微不良反应。9例志愿在给药后20-30min后发生阴茎勃起现象，约持续5min左右。结论：36名中国男性健康受试单次口服甲磺酸酚妥拉明片最大剂量至60mg比较安全、耐受性较好。     

Fabrication of novel elastosomes for boosting the transdermal delivery of diacerein: statistical optimization,ex-vivo permeation,in-vivo skin deposition and pharmacokinetic assessment compared to oral formulation

Diacerein (DCN) is a hydrophobic osteoarthritis (OA) drug with short half-life and low oral bioavailability. Furthermore, DCN oral administration is associated with diarrhea which represents obstacle against its oral use. Hence, this article aimed at developing elastosomes (edge activator (EA)-based vesicular nanocarriers) as a novel transdermal system for delivering DCN efficiently and avoiding its oral problems. For achieving this goal, elastosomes were prepared according to 4¹.2¹ full factorial design using different EAs in varying amounts. The prepared formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and deformability index (DI). Desirability function was employed using Design-Expert^® software to select the optimal elastosomes (E1) which showed EE% of 96.25?±?2.19%, PS of 506.35?±?44.61?nm, PDI of 0.46?±?0.09, ZP of ?38.65?±?0.91?mV, and DI of 12.74?±?2.63?g. In addition, E1 was compared to DCN-loaded bilosomes and both vesicles exhibited superior skin permeation potential and retention capacity compared to drug suspension. In-vivo histopathological study was performed which ensured the safety of E1 for topical application. Furthermore, the pharmacokinetic study conducted in albino rabbits demonstrated that there was no significant difference in the rate and extent of DCN absorption from topically applied E1 compared to oral suspension. Multiple level C in-vitro in-vivo correlation showed good correlation between in-vitro release and in-vivo drug performance for E1 and DCN oral suspension. Overall, results confirmed the admirable potential of E1 to be utilized as novel carrier for transdermal delivery of DCN and bypassing its oral side effects.     

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers

Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.     

药理试验中动物间和动物与人体间的等效剂量换算

不同动物的剂量换算，在基础药理和Ⅰ期临床研究中具有现实指导意义，本文将动物体型系数及其标准体重引入公式，通过查表，可方便地估算出不同动物间和动物与人体间的等效剂量。     

Subcutaneously injected ivermectin-loaded mixed micelles: formulation,pharmacokinetics and local irritation study

Clinical application of ivermectin (IVM) is limited by several unfavorable properties, induced by its insolubility in water. Slight differences in formulation may change the plasma pharmacokinetics and efficacy. In this study, an IVM-loaded Soy phosphatidylcholine-sodium deoxycholate mixed micelles (IVM-SPC-SDC-MMs) were developed to improve its aqueous solubility, aiming to make it more applicable for clinical use. First, IVM-SPC-SDC-MMs were prepared using the co-precipitation method. After formulation optimization, the particle size was 9.46?±?0.16?nm according to dynamic light scattering. The water solubility of IVM in SPC-SDC-MMs (4.79?±?0.02?mg/mL) was improved by 1200-fold, comparing with free IVM (0.004?mg/mL). After subcutaneous administration, the pharmacokinetic study showed that IVM-SPC-SDC-MMs and commercially available IVM injection were bioequivalent. Also, the local irritation study confirmed that IVM-SPC-SDC-MMs reduced side reactions of the commercially available IVM injection. These results indicated that IVM-SPC-SDC-MMs represented a promising new drug formulation suitable for subcutaneous delivery of IVM.     

Lack of a pharmacokinetic interaction between oral famciclovir and allopurinol in healthy volunteers

Famciclovir has been shown to have potent and selective activity against herpesviruses. The possibility of a pharmacokinetic interaction between the anti-viral agent, famciclovir and allopurinol has been investigated in twelve healthy male volunteers following a single oral dose of famciclovir (500 mg) in the presence and absence of steady-state levels of allopurinol (300 mg). Similarly, the pharmacokinetic profiles of allopurinol and oxypurinol prior to and following a single dose of famciclovir were compared.Mean values of C_max, AUC and terminal-phase half-life for penciclovir following administration of famciclovir alone at 3.3 g·ml^-1, 8.8 ·h·ml^-1 and 2.1 h, respectively were unchanged by co-administration of allopurinol. Similarly, mean urinary recovery and renal clearance values of penciclovir following famciclovir alone were 56.8% and 271·h^-1, and when given with allopurinol 59.7% and 27.51·h^-1, respectively. No evidence of accumulation of the inactive precursor to penciclovir, BRL 42359, was noted as a result of co-administration of the two drugs.Mean steady-state C_max, AUC and terminal-phase half-life values for allopurinol after co-administration of allopurinol with famciclovir also appeared unchanged from values obtained after dosing of allopurinol alone, at 2.12 g·ml^-1, 5.73 g·h·ml^-1 and 1.38h, respectively. Mean C_max and AUC values of the active metabolite of allopurinol, oxypurinol were 11.2 g·ml^-1 and 96.0 g·h·ml^-1, respectively, and these were also unaltered by co-administration of famciclovir with allopurinol, with values of 10.6 g/ml and 89.8 g·h/ml, respectively.In summary, no evidence of a pharmacokinetic interaction between allopurinol and famciclovir was observed when the two drugs were given concomitantly to healthy volunteers.     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 g·kg^–1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing.All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 g·kg^–1).Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (<20%) systemic clearances and larger values of C_max and AUC.Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 g·kg^–1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 g·kg^–1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 g·kg^–1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.     

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers

Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg^–1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg^–1 i.v. of dlsotalol.There was no significant difference in the disposition of the d-enantiomer and the racemate.The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h^–1·kg^–1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).     

A pharmaceutical study on chlorzoxazone orodispersible tablets: formulation,in-vitro and in-vivo evaluation

Context: Muscle spasm needs prompt relief of symptoms. Chlorzoxazone is a centrally muscle relaxant.

Objectives: The aim of this study was to prepare chlorzoxazone orodispersible tablets (ODTs) allowing the drug to directly enter the systemic circulation and bypassing the first-pass metabolism for both enhancing its bioavailability and exerting a rapid relief of muscular spasm.

Materials and methods: ODTs were prepared by direct compression method using Pharmaburst®500, Starlac®, Pearlitol flash®, Prosolv® odt and F-melt® as co-processed excipients. Three ratios of the drug to the other excipients were used (0.5:1, 1:1 and 2:1).

Results and Discussion: All ODTs were within the pharmacopeial limits for weight and content. ODTs containing Pharmaburst®500 showed the shortest wetting time (～45.33?s), disintegration time (DT) (～43.33?s) and dissolution (Q_15min 100.63%). By increasing the ratio of CLZ: Pharmaburst®500 from 0.5:1 to 1:1 and 2:1, the DT increased from 26.43 to 28.0 and 43.33?s, respectively. By using Prosolv® odt, ODTs failed to disintegrate in an acceptable time?>180?s. DT of ODTs using different co-processed excipients can be arranged as follows: Pharmaburst® 500?<?F-melt®?<Pearlitol flash®?<Starlac®?<Prosolv® odt. Pharmacokinetic study of the optimum formula F1 (50?mg CLZ) in rabbits using HPLC-UV detector revealed a shorter T_max (0.333?h) compared with Myofen® capsules (250?mg CLZ) (1.083?h) which is considered a promising treatment, especially for the rapid relief of muscle spasm.

Conclusion: It could be concluded that orodispersible tablets are a promising carrier for CLZ designed for management of muscle spasm due to the enhanced dissolution and rapid absorption of the drug through the oral mucosa.     

聚合物胶束用于口服给药的研究进展

聚合物胶束是由两亲性聚合物自发形成的热力学稳定体系,它对难溶性药物具有良好的增溶效果。许多具有良好活性的药物由于溶解性差,其口服给药受到限制。将聚合物胶束作为口服给药的载体可以显著改善药物的溶解性,增加透过生物膜的药量,进而提高药效。此外,聚合物组成和性质具有多样性,利用聚合物的这一特性可以制备出对pH值、温度敏感或者具有黏膜黏附性的胶束。在提高药物溶解度的同时,通过改变药物在胃肠道中的释放过程,进一步提高其生物利用度。本文主要介绍聚合物胶束在口服给药方面的研究进展,分析并总结其作为口服给药载体应用的特点和前景。     

Zero-order absorption and linear disposition of oral colchicine in healthy volunteers

Summary The pharmacokinetics of colchicine has been studied in nine healthy male volunteers after oral doses of 0.5, 1, and 1.5 mg as tablets. Plasma and urine samples were collected over 48 h and analysed for colchicine by radioimmunoassay.Individual colchicine concentration profiles in plasma and urine were well described by a two-compartment open model with zero-order input. Considering the absorption variables as specific to each experiment, the lag time (0–0.35 h) and duration (0.39–2.38 h) of absorption were found to be independent of dose, while the zero-order rate constant of absorption (k₀) increased linearly with dose.Disposition variables were taken as common to the three experiments, except in six subjects in whom renal excretion varied significantly across experiments in a dose-independent manner. For seven subjects the terminal half-life was 19.4 h, the oral apparent volume of distribution at steady-state (V_ss/f) was 691 l, and the oral systemic clearance (CL/f) was 33.1 l·h^–1. In the two other subjects, the values were unreliable, but the estimated terminal half-life was greater than 48 h, V_ss/f ranged from 1690 to 3480 l, and CL/f was in the range of the other subjects in 1 subject, and it was about 15l·h^–1 in the other. In the latter subject, these estimates, together with the observation that plasma concentration reached a plateau at 2 to 5 h after ingestion, suggest enterohepatic cycling of colchicine.Overall, the disposition of colchicine was linear in the dose range 0.5–1.5 mg, with a long terminal half-life, and absorption obeyed zero-order kinetics, with k₀ proportional to dose.