Design,in vitro release characterization and pharmacokinetics of novel controlled release pellets containing levodropropizine

Abstract

This study was performed to investigate the in vitro release characteristics of levodropropizine (LDP) from novel dual-coated sustained release (SR) pellets, and evaluate the pharmacokinetics of a novel controlled release (CR) preparation composed of the dual-coated SR pellets and immediate release (IR) LDP pellets. The dual-coated SR pellets composed of a drug-loaded nonpareil core, a sub-coating layer (HPMC 6cps) and an SR-coating layer (Aquacoat® ECD, Eudragit® RS 30D or Kollicoat® SR 30D) were prepared by a bottom-spray fluidized bed-coating method. The drug release from the dual-coated SR pellets coated with Aquacoat® ECD followed a zero-order profile in water, and the drug release was not affected by the coating level of the sub-coating layer and stable under the accelerated storage condition (40?°C, 75% RH) for 6 months. The CR preparation showed significantly decreased values of maximum drug concentration (C_max) and elimination rate (K) than the reference product (LEVOTUS® SYR) but the similar bioavailability (F?=?95.43%). The novel CR preparation presents promising delivery of LDP with an immediate and sustained release manner, with similar clinical effect as the commercial IR product.     

Preparation and evaluation of 1-deoxynojirimycin sustained-release pellets vs conventional immediate-release tablets

1-Deoxynojirimycin sustained-release pellets, which exhibit known release and absorption profiles, are used for the treatment of diabetes mellitus. In this study, a fluidised bed coater was employed to prepare new, drug-loaded pellets. In the dissolution test, it was found that 1-DNJ pellets exhibited a sustained release effect after being coated with hydroxypropyl methyl cellulose phthalate-55?S. For sustained-release pellets and immediate-release pellets, there was significant difference in the mean cumulative drug concentration profile in different media evaluation. In the bioavailability study, the ratio of mean relative bioavailability of the SR pellets to the IR tablets was calculated by the DAS from the AUC_0-24?h of 1-DNJ and was found to be 117.3%. This suggested that the behaviour in vivo of the 1-DNJ SR pellets was superior to the IR tablets, which indicated the designed preparation method of the 1-DNJ SR pellets was acceptable for achieving sustained release of 1-DNJ with enhanced bioavailability.     

Relaxant effects of mefloquine on vascular smooth muscle in vitro

Summary Antacids can modify the pharmacokinetic parameters of sustained-release preparations of theophylline by changing the gastric pH. Though this has been studied with various theophylline/antacid combinations, the specific preparations investigated here have not previously been tested. The objective of the study was to assess any change in the availability of theophylline from a sustained-release preparation (SR), induced by the coadministration with an antacid.The study was designed as a double-blind randomized crossover trial in the Pneumology Departments of three general hospitals.Fifteen patients were studied. They all had stable asthma treated with theophylline and no major organ failure or gastro-intestinal lesions requiring the use of antacids. The antacide (aluminium hydroxide 800 mg and magnesium hydroxide 800 mg), or placebo, tid, was added to a stable regimen of theophylline SR bid, for 4 days, in crossover fashion.Plasma theophylline concentrations were measured before and 1,2,3,4,6,8,10,12,16 and 24 h after the morning dose of Armophylline on the fourth day of each treatment period; the maximum plasma concentration (C_max), and time to C_max (t_max) were noted, and the area under the 24-h time-concentration curve (AUC_0–24) and mean plasma concentration (C_mean) were computed. Peak expiratory flows on the same day, before and 3, 6 and 12 h after the morning dose of Armophylline were also measured.There was no change in any of the parameters studied.The addition of the antacide to theophylline, each given according to standard clinical practice, did not modify the pharmacokinetics of the latter. This result probably can not be generalized to all pairs of sustained-release theophylline-antacid preparations.     

注射用酒石酸长春瑞滨胶束及注射用长春瑞滨在比格犬体内的毒动学比较

目的 测定连续给予注射用酒石酸长春瑞滨胶束的毒动学参数，并与注射用酒石酸长春瑞滨进行比较。方法 选取16只比格犬随机分为4组，雌雄各半，分别连续iv给予注射用酒石酸长春瑞滨胶束低、中、高剂量（0.29、0.58、1.174 mg/kg）与注射用酒石酸长春瑞滨1.174 mg/kg，建立测定比格犬血浆中酒石酸长春瑞滨浓度的液相色谱-串联质谱（LC-MS/MS）法，测定血药浓度，采用DAS3.1.4药动学软件计算动力学参数。结果 比格犬iv给予注射用酒石酸长春瑞滨胶束低、中、高3个剂量，血药浓度、AUC_（0-t）、C_max随给药剂量的增加而增大；连续iv给药，低、中、高剂量组动物血药浓度、AUC_（0-t）、C_max在给药第1、29、71天时均变化不大，无明显蓄积倾向。而注射用长春瑞滨胶连续iv给药后随给药时间延长，动物血药浓度、AUC_（0-t）、C_max有上升趋势，AUC_（0-t）蓄积因子分别为2.08、1.80，C_max蓄积因子分别为2.58、2.32，均有蓄积倾向。结论 注射用酒石酸长春瑞滨胶束与普通注射用酒石酸长春瑞滨毒动学参数比较，无明显的蓄积倾向，可降低长期服药的毒性风险。     

Zero-Order Release Formulation of Oxprenolol Hydrochloride with Swelling and Erosion Control

Zero-order release of oxprenolol hydrochloride was obtained by controlling the swelling and erosion of the matrix. This formulation involves only mixing of drug, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (Na CMC) at the ratio of 1:0.4:1.6, respectively, and compressing the mixture directly into tablets. The in vitro release pattern from this optimized matrix tablet was reproducible. Accelerated stability studies revealed that the optimized formulation remains stable for an approximately 2-year shelf life. This sustained-release (SR) tablet was evaluated in dogs, and for comparison a conventional (CV) formulation was also given at the same dose level. Plasma oxprenolol levels were monitored by a sensitive and specific high-performance liquid chromatographic (HPLC) method. Significant differences in the pharmacokinetic parameters, i.e., lower C _max, higher values of t _max, MRT, AUC, and plasma concentration at 24 hr, and nearly constant plasma levels over 12 hr, indicated that the SR matrix tablet is superior to the CV rapid-releasing formulation. The in vitro release parameters and in vivo pharmacokinetics correlated well.     

单剂量口服茶碱缓释胶囊的人体生物等效性评价

目的选择12名男性健康志愿者,进行单剂量口服茶碱缓释胶囊的人体生物等效性评价。方法采用反相高效液相色谱法,以紫外273nm为检测波长,测定了单剂量口服200mg国产茶碱缓释胶囊受试药品在健康人体内的茶碱浓度,并与进口茶碱缓释胶囊参比药品进行对照。结果茶碱缓释胶囊的体内动态过程呈一级吸收的一房室开放模型,国产受试药品和进口参比药品的Cmax分别为(5.12±0.74)mg/L和(5.14±0.63)mg/L,tmax分别为(5.4±1.0)h和(5.3±1.1)h,MRT分别为(17.79±1.48)h和(17.61±1.78)h,t1/2分别为(10.55±0.75)h和(10.59±1.10)h,AUC0-36分别为(85.33±10.56)mg*h/L和(86.26±8.80)mg*h/L。结论以体内茶碱AUC0-36数值表征的国产茶碱缓释胶囊的相对生物利用度为(98.9±6.4)%;选择Cmax、AUC0-36和AUC0-∞进行三因素方差分析与双单侧t检验,结果表明国产茶碱缓释胶囊和进口茶碱缓释胶囊两种制剂具有生物等效性。     

Generic sustained release tablets of trimetazidine hydrochloride: Preparation and in vitro–in vivo correlation studies

The aim of the current work was to develop generic sustained-release tablets containing 35 mg trimetazidine dihydrochloride and to establish an in vitro–in vivo correlation that could predict the bioavailability. The marketed sustained release tablet (Vastarel MR) used as reference, a sustained-release matrix tablet was prepared using hydroxypropyl methylcellulose (HPMC) as matrix by wet granulation and the in vitro dissolution profiles of the self-made tablets were determined in four different dissolution media (0.1 M HCl, pH 4.5 PBS, pH 6.8 PBS and water). A higher similarity between prepared tablets and Vastarel MR was established, with similarity factor (f₂) ranging from 60 to 75 in the four media. The in vivo pharmacokinetics was studied in six healthy beagles. Compared with Vastarel MR, the C_max of self-made tablets was slightly decreased, while the T_max and MRT_0–t were slightly prolonged, but with no significant difference (P > 0.05). The average of relative bioavailability (F) was 102.52% based on AUC_0–t. For log-transformed AUC_0–t and C_max, the upper confidence limit on the appropriate criterion is <0, indicating these two formulations were population bioequivalent. The in vivo–in vitro correlation coefficient obtained from point-to-point analysis of self-made tablets was 0.9720. In conclusion, the prepared tablets were bioequivalent to the marketed tablets, according to both the in vitro release rate and extent of absorption, and a good in vivo–in vitro correlation was established for the self-made tablets that indicated in vitro dissolution tests could be used as a surrogate for bioavailability studies.     

<Emphasis Type="Italic">In vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluations of ketoprofen extended release pellets prepared using powder layering technique in a rotary centrifugal granulator

In the present study, an extended release pellet dosage form of ketoprofen was prepared using powder layering technique. A combination of ethyl cellulose (45 cps) and shellac polymers was used as a binder (12% w/w polymer) during drug layering and an extended release coating (1:3 ratio at 2%, 4% and 7% w/w polymer) within the same apparatus. The coated pellets were characterized for sphericity, Hardness-Friability Index, and drug content, and also underwent scanning electron microscopy. In vitro dissolution was performed in 900 mL of phosphate buffer (pH 6.8) using paddle apparatus at 100 rpm. Ethyl cellulose and shellac when used as binders during drug loading did not extend ketoprofen release beyond 3 h. However, coating of the drug loaded pellets using ethyl cellulose and shellac resulted in an extended release profile of about 10 h. Using Higuchi’s model and the Korsmeyer equation, the drug release mechanism from the pellets was found to be an anomalous type involving diffusion and erosion. Scanning electron microscopy was used to visualize the pellet morphology and drug release mechanism during dissolution testing. In vivo evaluations of the extended release pellets in rats indicated a significant increase in the time to reach maximum concentration (t_max) and extent of absorption (AUC_0-∞) compared to the ketoprofen immediate release tablet blend dispersed and dosed. In conclusion, extended release pellets of ketoprofen could perform therapeutically better than conventional dosage forms, leading to improved efficacy for a prolonged period.     

Stability and bioavailability of diltiazem/polyethylene oxide matrix tablets

Abstract

The aim of this study was to prepare and evaluate in vitro and in vivo; Diltiazem-Hydrochloride (DTZ) in sustained-release matrix tablets. Stability of DTZ tablets prepared with polyethylene oxide (MWs 900?000, 4?000?000, and 8?000?000) with or without addition of electrolytes was carried-out for 1-month, under short-term storage at 40?°C/75% RH. Stability was evaluated by DTZ content, DSC and drug release using the Flow-Through Cell (USP # IV). The majority of stored tablets were stable for 1-month under short-term storage with respect to DTZ content and drug release. DSC curves of stored samples showed appearance of new exothermic peak after 1-month storage at 40?°C/75% RH, which was not observed after 5?years storage at room temperature. A selected formula was tested in vivo against reference product on eight healthy human volunteers. DTZ-plasma profiles were different between the two formulae. However, no statistically significant differences were detected between C_max, AUC_0–48 and AUC_0–∞. The two products were therapeutically in-equivalent, as 90% confidence intervals “T/R” were 88.82–205.76, 91.40–139.94, and 93.73–134.97 for C_max, AUC_0–48 and AUC_0–∞, respectively. This study highlighted possible differences observed between the two regimes frequently applied for stability testing.     

Development of gastroretentive drug delivery system for cefuroxime axetil: In vitro and in vivo evaluation in human volunteers

The objective of this investigation was to develop the cefuroxime axetil sustained-release floating tablets to prolong the gastric residence time and compare their pharmacokinetic behavior with marketed conventional tablets (Zocef). The floating tablets were developed using polymers like HPMC K4M and HPMC K100M alone, and polymer combination of HPMC K4M and Polyox WSR 303 by effervescent technique. Tablets were prepared by slugging method and evaluated for their physical characteristics, in vitro drug release, and buoyancy lag time. The best formulation (F10) was selected based on in vitro characteristics and used in vivo radiographic and bioavailability studies in healthy human volunteers. All the formulations could sustain drug release for 12 h. The dissolution profiles were subjected to various kinetic release models and it was found that the mechanism of drug release followed Peppas model. The in vivo radiographic studies revealed that the tablets remained in stomach for 225±30 min. Based on in vivo performance, the developed floating tablets showed superior bioavailability than Zocef tablet. Based on in vivo performance significant difference was observed between C_max, t_max, t_1/2, AUC_0–∞, and mean residence time of test and reference (p<0.05). The increase in relative bioavailability of test was 1.61 fold when compared to reference.     

Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice

Objectives The pharmacokinetic interaction between metronidazole, an antibiotic–antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P‐glycoprotein substrate kinase inhibitor anticancer drug, was evaluated. Methods Male imprinting control region mice were given 50 mg/kg imatinib PO (control group) or 50 mg/kg imatinib PO, 15 min after 40 mg/kg PO metronidazole (study group). Imatinib plasma, brain, kidney and liver concentrations were measured by HPLC and non‐compartmental pharmacokinetic parameters estimated. Key findings Metronidazole coadministration resulted in a double‐peak imatinib disposition profile. The maximum concentration (C_max) decreased by 38%, the area under the curve (AUC_0–∞) decreased by 14% and the time to C_max (T_max) was earlier (50%) in plasma. Apparent volume of distribution (V_SS/F) and oral clearance (Cl/F) increased by 21% and 17%, respectively. Imatinib tissue penetration was higher after metronidazole coadministration, with 1.7 and 2.1‐fold AUC_0–∞ increases in liver and kidney, respectively. Metronidazole increased imatinib's tissue‐to‐plasma AUC_0–∞ ratio in liver from 2.29 to 4.53 and in kidney from 3.04 to 7.57, suggesting higher uptake efficiency. Brain C_max was 3.9‐fold higher than control and AUC_{0–t last} was 2.3‐fold greater than plasma (3.5% in control group). No tissue‐plasma concentration correlation was found. Conclusions Metronidazole slightly decreased imatinib systemic exposure but enhanced liver, kidney and brain penetration, probably due to metronidazole‐mediated inhibition of P‐glycoprotein and other efflux transporters. The high brain exposure opens possibilities for treatment of glioma and glioblastoma. Renal and hepatic functions may need to be monitored due to potential renal and hepatic toxicity.     

A 1‐step Bayesian predictive approach for evaluating in vitro in vivo correlation (IVIVC)

IVIVC (in vitro in vivo correlation) methods may support approving a change in formulation of a drug using only in vitro dissolution data without additional bioequivalence trials in human subjects. Most current IVIVC methods express the in vivo plasma concentration of a drug formulation as a function of the cumulative in vivo absorption. The absorption is not directly observable, so is estimated by the cumulative dissolution of the drug formulation in in vitro dissolution trials. The calculations conventionally entail the complex and potentially unstable mathematical operations of convolution and deconvolution, or approximations aimed at omitting their need. This paper describes, and illustrates with data on a controlled‐release formulation, a Bayesian approach to evaluating IVIVC that does not require convolution, deconvolution or approximation. This approach incorporates between‐ and within‐subject (or replicate) variability without assuming asymptotic normality. The plasma concentration curve is expressed in terms of the in vitro dissolution percentage instead of time, recognizing that this correspondence may be noisy because of the various sources of error. All conventional functions of the concentration curve such as AUC, C_max and T_max can be expressed in terms of dissolution percentage, with uncertainties arising from variability in measuring absorption and dissolution accounted for explicitly. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs

1.?Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.

2.?The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.

3.?Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC_0–t) and maximum plasma concentration (C_max) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC_0–t and C_max and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC_0–t and E_max of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.

4.?Coadministration of warfarin had no markedly effects on the AUC_0–t and C_max of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC_0–t and E_max of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.

5.?Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.     

Development and validation of an in vitro–in vivo correlation (IVIVC) model for propranolol hydrochloride extended-release matrix formulations

The objective of this study was to develop an in vitro–in vivo correlation (IVIVC) model for hydrophilic matrix extended-release (ER) propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8). In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR) commercial products. The similarity factor f₂ was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE) values of C_max and AUC_0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for C_max and AUC_0–∞ demonstrated that the propranolol IVIVC model was valid.     

盐酸强力霉素缓释微丸的制备及药物动力学研究

本文采用膜控法制备盐酸强力霉素缓释微丸。实验表明,本品的体外溶出符合零级动力学过程(K_r⁰=20.5 mg/h);贮存期为两年,胃刺激性明显低于普通片剂(p<0.001),体内动力学过程符合表观零级吸收与一级消除的单室模型。体内数据经NONLIN计算机程序处理,求得各项参数如下:K_a=58.08 mg/h,K=0.032 h^-1,V_d=82.211,t_max=3.94 h,c_max=2.30μg/ml。按强力霉素的常规用药方案给药,本品与市售普通片生物等效。本品的体内外数据具有显著的相关性(p<0.001)。     

A pharmacokinetic drug interaction study of ceftazidime with clavulanic acid in healthy male Indian subjects

Ceftazidime is a third generation cephalosporin with a broad range of activity. Clavulanic acid is a β-lactamase inhibitor. A fixed dose combination, with the wide spectrum of action of ceftazidime and clavulanic acid’s high stability to β-lactamases has been developed by Ranbaxy Laboratories Limited (India). The present study was planned to predict any interaction between ceftazidime and clavulanic acid which could affect the safety and efficacy of the fixed dose combination. The study was an open label, balanced, randomized two-treatment, two-period, two-sequence, crossover, single-dose comparative pharmacokinetic study under fed conditions. A single intravenous injection of the test product containing a fixed dose combination of ceftazidime 2000?mg and potassium clavulanate 200?mg and the reference product containing ceftazidime 2000?mg only, was administered during each period. Serial blood samples were collected until 12?h post-dose in each period. Ceftazidime and clavulanic acid concentration in plasma were determined using two separate LC-MS/MS methods and then pharmacokinetic parameters were evaluated. No significant difference was seen in the mean T_max, C_max, AUC_0–t, and AUC_0–∞ when the drug was administered as ceftazidime alone and in combination with clavulanic acid. The Confidence Intervals for the log transformed parameters C_max, AUC_0–t and AUC_0–∞ were within limits of 80–125% of ceftazidime for the test and reference products. The lack of significant difference between the pharmacokinetic parameters for ceftazidime alone and in the presence of clavulanic acid ruled out any significant interaction between ceftazidime and clavulanic acid.     

Buccal films of prednisolone with enhanced bioavailability

Abstract

The conventional formulation of prednisolone is considered to be low in efficacy, primarily on account of their failure in providing and maintaining effective therapeutic drug levels. This study aims to focus on development of a mucoadhesive buccal delivery system with a twofold objective of offering a rapid as well as a prolonged delivery of prednisolone coupled with enhanced therapeutic efficacy. Buccoadhesive films of prednisolone were prepared by solvent-casting method using hydroxyl propyl methyl cellulose (K100), Carbopol 940 and/or Eudragit® NE 40?D. Placebo films possessing the most desirable physicomechanical properties were selected for drug loading. The effect of polymer and its content on film properties, i.e. mucoadhesive strength, swelling and hydration, in vitro drug release was studied. Based on these studies, film F7D was selected for ex vivo permeation across porcine cheek mucosa. The steady state flux of prednisolone across the buccal mucosa was found to be 105.33?±?32.07?µg/cm²/h. A comparative pharmacokinetic study of prepared film (F7D) and oral suspension of prednisolone was conducted. In vivo data of buccal film show greater bioavailability (AUC_0–α: 24.26?±?4.06?µg.h/ml versus 10.65?±?2.15?µg.h/ml) and higher C_max (2.70?±?0.38?µg/ml versus 2.29?±?0.32?µg/ml) value when compared to oral suspension. The data observed from this study highlight the feasibility of the buccal route as a viable option for delivery of prednisolone.     

Bioavailability assessment of hydroxymethylglutaryl coenzyme A reductase inhibitor utilizing pulsatile drug delivery system: a pilot study

Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC_0–∞, C_max, T_max, t_1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10?h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.     

In Vivo/in Vitro Correlation of Experimental Sustained-Release Theophylline Formulations

A novel multiparticulate sustained-release theophylline formulation, which consisted of spherical drug pellets coated with a rate-controlling membrane, was evaluated in vivo. Two preparations that differ solely in the coat thickness, and hence rate of in vitro drug release, were studied in comparison with a solution of the drug. Both preparations produced serum concentration profiles that are reflective of a slow and sustained rate of absorption. The in vivo release versus time profiles calculated using a deconvolution procedure showed that the two preparations differed in the rate but not the extent of drug release. Satisfactory correlation was also obtained between the in vivo and the in vitro results. When the two preparations were further compared using the parameters, time to reach peak concentration (T _p), peak concentration (C _p), and total area under the serum concentration versus time curves (AUC), a statistically significant difference was observed in the T _p and C _p values but not the AUC values, suggesting that the preparations differed in the rate but not the extent of absorption. In addition, the extent of absorption from both preparations was comparable to that obtained with the drug solution.     

Evaluation of pharmacokinetics and pharmacodynamics relationships for Salvianolic Acid B micro-porous osmotic pump pellets in angina pectoris rabbit

The work aims to investigate the in vitro release, pharmacokinetics (PK), pharmacodynamics (PD) and PK–PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets (SalB-MPOPs) in angina pectoris New Zealand White (NZW) rabbits, compared with those of SalB immediate-release pellets (SalB-IRPs). The SalB plasma concentrations and Superoxide dismutase levels (PD index) were recorded continuously at predetermined time interval after administration, and the related parameters were calculated by using WinNonlin software. The release profile of MPOPs was more sustained than that of IRPs. PK results indicated that the mean C_max was significantly lower, the SalB plasma concentrations were steadier, both area under concentration-time curve from 0 to 24 h (AUC_0–24 h) and from 0 to infinity (AUC_0–∞) were presented larger, and both the peak concentration time (T_max) and mean residence time (MRT) were prolonged for MPOPs, as compared with those of IRPs. PD results suggested that peak drug effect (E_max) was lower and the equilibration rate constant (k_e0) between the central compartment and the effect compartment was higher of MPOPs vs. those of IRPs. PK–PD relationships demonstrated that the effect-concentration-time (ECT) course of MPOPs was clockwise hysteresis loop, and that of IRPs was counter-clockwise hysteresis loop. Collectively, those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.