布洛芬片剂生物利用度的研究

临床反映各种布洛芬片剂疗效并不一致。为了提高布洛芬片剂的相对生物利用度,我们和药厂协作,进行片剂新处方的研制,测定了国产品之一的片剂(A)、新处方片剂(B)和英国布茨公司的片剂(E)的体外溶出度,用 GC 法研究了 A、B 两片剂相对于 E     

贝诺酯片剂的研制及生物利用度研究

通过减小药物粒径,提高贝诺酯片剂的生物利用度。在市售片以A(500mg)基础上研制了新处方片剂B(400mg)。建立贝诺酯片剂体外溶出度试验方法,即以表面活性剂溶液作溶出介质,以浆法进行溶出度测定。用HPLC法测定贝诺酯在体内的水解产物水杨酸和扑热息痛的血药浓度。结果表明药物研磨粉碎前后体外溶出速度常数分别为0.0152min-1及0.0337min^-1(P<0.001)。A及B体外平均溶出时间分别为42.25min及15.77min(P<0.001)。体内研究表明A及B水杨酸的C_max,T_p,AUC之间均无显著性差异(P>0.1)(A,B的服用量分别为4.5g及3.6g),B的相对生物利用度为125.59%。     

增效联磺片的体外溶出度和体内生物利用度

建立了测定体外溶出介质中磺胺嘧啶(SD)、磺胺甲噁唑(SMZ)和甲氧苄啶(TMP)及血浆中SD,SMZ,TMP和两个代谢产物N⁴-acetyl-SD和N⁴-acetyl-SMZ的反相高效液相色谱法,并对市售两种增效联磺片(片剂A和B)进行了体外溶出度和人体内生物利用度的研究。体外溶出度实验表明:两种片剂相同主药的T⁵⁰差异非常显著(P<0.001),片剂A主药的溶出比B快。生物利用度试验表明:片剂B相对于A的口服吸收分数为0.73(SD),0.78(SMZ)和0.83(TMP),口服片剂后各主药的体内过程符合表观一级吸收和一级消除的单室模型。     

安体舒通的晶型

安体舒通是一种有效的利尿药,由于其溶解性差,因此溶出度及口服生物利用度与粒度有很大关系。本文研究不同晶型与溶出度和生物利用度的关系,采用4种结晶方法,并对结晶进行粒度、溶出度、溶解度以及红外光谱:电镜扫描、差热分析和X线衍射等测定,证明有3种多晶型(Ⅰ、Ⅱ、Ⅲ)和5种溶剂化晶型(A、B、C、D、E)。它们在水中的起始溶解速度不同,可相差12倍。其中晶D和     

海风藤中新木脂素类PAF拮抗活性成分的研究

自中药海风藤[Piper kadsura (Choisy)Ohwi]的藤茎中又分离得到四个macrophyllin型双环[3,2,1]辛烷类新木脂素,经光谱分析及衍生物的制备,确定化合物Ⅰ和Ⅲ为新结构,命名为风藤素K(kadsurenin K)和风藤素L(kadsurenin L),其化学结构分别为7R,8R,3′R,5′R-△^8′-3,5′-二甲氧基-4-羟基-2′,3′,4′,5′-四氢-2′,4′-氧-7.3′,8.5′-新木脂素(Ⅰ)和7R,8R,3′S,4′R,5′R-△^8′-3,4,5′-三甲氧基-4′-乙酰氧基-2′,3′,4′,5′-四氢-2′-氧-7.3′,8.5′-新木脂素(Ⅲ)。化合物Ⅱ和Ⅳ分别为已报道过的风藤素C和风藤素B。化合物Ⅰ～Ⅳ均有明显的PAF受体拮抗活性。     

罗红霉素片剂生物利用度的比较研究

为比较不同剂型罗红霉素的生物利用度,用微生物管碟检定法(藤黄微球菌CMCC(B)28001)测定了10名男性健康受试者口服罗红霉素分散片(制剂A)和罗红霉素片(制剂B)后不同时间血浆中活性药物的浓度,绘制了血药浓度—时间曲线。结果表明,受试者交叉口服含罗红霉素150mg的制剂A和制剂B后,血浆T_max分别为1.7±0.9和3.7±1.6h,C_max分别为4.97±1.17和2.04±1.26μg·ml^-1,AUC_0→∞分别为62.2±11.9和35.0±16.9μg·h·ml^-1。以制剂A为参比,制剂B中罗红霉素的相对生物利用度仅为59.8%±32.6%,两种制剂的药物吸收程度有显著差异(P<0.01)。初步分析提示,罗红霉素在胃中的迅速溶出是保证其片剂生物利用度的关键之一。     

仪器分析在新药研究中的应用及前景

仪器分析保障了新药临床安全有效,评价新药好坏的唯一标准就是“安全、有效、稳定、可控”八个字,仪器分析是不可缺少的重要手段。以药物的晶型为例：如无味氯霉素有A、B、C3种晶型,其中A为稳定型（无疗效）;B为亚稳定型（有疗效）;C为不稳定型,形成瞬间即转变为晶型A,而我国1975年以前生产的无味氯霉素原料、片剂及胶囊剂均为无疗效的晶型A。     

厄贝沙坦多晶型X-射线粉末衍射定量分析

目的 建立厄贝沙坦晶型原料药的晶型含量分析方法，为药品晶型质量控制提供技术支撑。方法 采用X-射线粉末衍射法表征厄贝沙坦晶型A和晶型B。分别选取晶型A的特征衍射峰2θ=4.65°和晶型B的特征衍射峰2θ=7.99°的峰面积比值为定量参数，建立标准曲线检测晶型B的含量。结果 晶型B在晶型A和晶型B混合物中含量为2%~50%（质量分数）内线性关系良好（r=0.999 5），方法仪器精密度为4.7%，检测限浓度为1.12%（S/N=4.4）。结论 本研究建立的方法准确方便，可用于厄贝沙坦原料晶型A和晶型B混合物中晶型B的定量分析。     

消炎痛缓释胶囊的生物利用度研究

消炎痛普通制剂口服吸收迅速,可出现不必要的高血药浓度,导致不良反应。为此我们对三种消炎痛缓释胶囊(A,B,C)和一种常用片剂(D)作了体外溶出试验和体内生物利用度比较。胶囊制剂由丙烯酸类树脂材料E₃₀D包衣的药物小丸制成,其体外溶出行为显示缓慢释放图象。在8名成年男性交叉实验中,不同胶囊制剂和普通片剂之间的Tmax,Cmax和AUC_0～12h经方差分析无统计学差异,但是在给药后4至12小时的血清浓度—时间曲线,均比普通片剂高而平滑。在第12小时,三种胶囊产生的血清浓度显著高于普通片剂(P<0.1)。根据体外溶出行为和体内生物利用度发现T₅₀或Tmax和包衣厚度呈良好线性关系。     

复方新诺明片的生物利用度研究

本文设计了速释片剂新处方 C,并建立了测定溶出介质和血浆中磺胺甲(口恶)唑(SMZ)和甲氧苄啶(TMP)含量的反相高效液相色谱法。体外溶出度和人体内生物利用度的研究,表明 C 的主药吸收快、血浆峰浓度高,但血浓-时间曲线下面积与另二片剂 A 和 B 无显著差异。在人工胃液中,三种片剂 TMP 溶出均迅速,但 SMZ 的平均溶出时间有显著差异。     

Evaluation of the absorption from three ibuprofen formulations

The pharmacokinetic differences between two sustained-release 300 mg (A) and 400 mg (B) formulations and a rapid-release 400 mg ibuprofen conventional sugar-coated formulation (C) were compared after a single dose. Mean peak levels of 25.1 micrograms/ml for preparation A (2 X 300 mg), 31.3 micrograms/ml for preparation B (2 X 400 mg) and 68.5 micrograms/ml for preparation C (2 X 400 mg) were reached at 5.3, 3 and 2 hours respectively, after ingestion of the drugs. The individual plasma-level time-profiles for the majority of doses suggested prolonged absorption of product A and B. The absorption from formulations A and B was significantly slower (p less than 0.001 and p less than 0.05 respectively) than that from the conventional tablets. The bioavailability of ibuprofen from sustained-release capsules, was not found to differ significantly from that of ibuprofen from conventional tablets. The relative bioavailability was very close to 100% in almost all subjects (coefficient of variation 14% and 17%). Projections of plasma concentrations upon multiple dosing were made from single dose data. The dosage interval concentration ratio which reflects both the frequency and the entry of the drug into and from the body was much lower for sustained-release formulations (A: 3.0; B: 3.7; C: 12.9).     

尼群地平片剂生物利用度的研究

为提高国产尼群地平片剂的生物利用度,采用球磨混合粉碎法工艺进行处方设计,试制出新处方片剂,与西德Bayer公司片剂进行了体外溶出、体内生物利用度的比较。体内血浆药浓用GC-MS法测定,体内数据按零级溶出、一级吸收口服单室模型,经计算机用Gauss-Newton-Damping法处理求得药动学参数。本文研制的尼群地平新处方片剂生物利用度已超过西德Bayer公司片剂。     

Gastroretentive mucoadhesive tablet of lafutidine for controlled release and enhanced bioavailability

Abstract

Lafutidine a newly developed histamine H2-receptor antagonist having biological half-life of 1.92?±?0.94?h due to its selective absorption from upper part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was developed using the natural polymer, sodium alginate, xanthan gum and karaya gum. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. The prepared tablets of various formulations were evaluated for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release transport was confirmed as the drug release mechanism from the optimized formulation by Korsmeyer–Peppas. The optimized formulation (B3) showed a mucoadhesive strength >35?g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10?h in rabbit’s stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40?°C temperature 75?±?5% relative humidity for 3 months.     

Effect of antacids on aspirin dissolution and bioavailability

The in vitrodissolution profile, in vitroand in vivobuffering characteristics, and single-dose bioavailability of various buffered aspirin tablet formulations were studied. Buffering agents,such as magnesium and aluminum hydroxides (formulations B and C) or magnesium carbonate and aluminum glycinate (formulation D), significantly increased the rate of aspirin dissolution from solid dosage forms as compared to an unbuffered tablet (formulation A). The extent of aspirin absorption was equivalent with all formulations;however, the faster rate of dissolution (t₅₀ and t₉₀)with buffered formulations resulted in earlier and higher peak concentration of salicylate compared to that with unbuffered formulation, following a two-tablet dose in the fasting state. A comparison of the in vivobuffer capacity of a four-tablet dose of formulations B and D was performed in the postcibal state at the time of maximal meal-induced acid secretion, using a radiotelemetry procedure for determination of pH. Formulation B prolonged the interval of elevation of intragastric pH > 3 for 32 min as compared to 12 min for D.     

Relative bioavailability and bioequivalence study of theophylline sustained release formulations

The objective of this study was to determine the bioequivalence of two theophylline (CAS 58-55-9) sustained release formulations containing 400 mg (Theophyllin 400 retard Heumann, formulation A) and 375 mg (formulation C) theophylline, respectively. In addition, the relative bioavailability of the sustained release formulations in comparison to an oral solution (formulation B) was investigated. Twenty-four healthy male volunteers participated in the open randomized three-way crossover study. Multiple doses of the formulations were administered during three study periods of four days each (A: 400 mg once daily; B: 133 mg t.i.d.; C: 375 mg once daily). The absorption kinetics and the bioavailability of theophylline were investigated by model-independent and deconvolution methods. The relative bioavailability of formulation A as compared to the solution was 72%. The oral sustained release capsules did not exhibit any differences with respect to AUCss, tau and Css, max whereas differences were detected regarding tss, max and peak trough fluctuation indicating minor deviations of the plasma profiles of both formulations. However, 90% confidence intervals of the ratios of AUCss, tau and Css, max were within the respective acceptance limits. Thus, both formulations are bioequivalent considering rate and extent of absorption.     

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

Bioequivalence evaluation of three different oral formulations of ciprofloxacin in healthy volunteers.

Two bioequivalence studies were performed in twenty four healthy male volunteers with the objective of comparing the bioavailability of three different oral formulations of ciprofloxacin as immediate release tablets 250, 500 and 750 mg (test formulations) with a reference formulation at 500 and 750 mg strengths forms. In study 1, the subjects were enrolled in a single-dose, open-label, 3-period, crossover randomised study, designed to compare the bioavailability of two test formulations of ciprofloxacin (A and B) as 250 and 500 mg tablets, compared to the reference formulation (C), as 500 mg tablets. In study 2, the same 24-subjects were included in a single-dose, open-label, 2-period, crossover randomised study, designed to compare the bioavailability of one test formulation of ciprofloxacin (A) as compared to the reference formulation (B), both products as 750 mg tablets. In both studies multiple blood samples were collected over 24 hours post-dosing. One washout period of six days was observed between the periods. Plasma was harvested and assayed for ciprofloxacin using a selective and sensitive high-performance liquid chromatography (HPLC) method with UV detection. The pharmacokinetic parameter values of Cmax and tmax were obtained directly from plasma data, ke was estimated by log-linear regression, and AUC was calculated by trapezoidal rule. Different statistical tests were performed on the basis of untransformed and log-transformed data and the overall residual variance from ANOVA. Assuming the accepted tolerance intervals, a beta-error of 20% and 90% confidence intervals (alpha = 0.10) of all the generally accepted tests (Westlake, Schuirmann test and Wilcoxon-Tukey nonparametric tests) showed that the formulations can be considered as bioequivalent with respect to the extent of absorption, given by the AUC0-infinity and with respect to rate of absorption as assessed by Cmax and tmax.     

Relative bioavailability of diclofenac after a single administration of a new multiple-unit formulation of enteric-coated pellets

The relative bioavailability of diclofenac (CAS 15307-86-5) was investigated after a single administration of a multiple-unit formulation containing 75 mg diclofenac sodium in enteric-coated pellets (A) in comparison to an enteric-coated tablet with 50 mg diclofenac sodium (B), a capsule containing 140 mg diclofenac resinate (C) and a dispersible tablet containing 46.5 mg diclofenac acid (D). The study was carried out in a four-way crossover design in 16 healthy male volunteers. Serum concentrations of diclofenac were determined with a validated and specific HPLC-method. After dose normalisation, a mean relative bioavailability of 99% (B), 142% (C) and 116% (D) was determined for the pellet formulation. According to the corresponding 90%-confidence interval, bioequivalence for the extent of bioavailability of the test formulation can be concluded compared to the enteric-coated tablet. In comparison to the formulations C and D, the test formulation showed an increased extent of bioavailability. Further differences in pharmacokinetics were observed for the rate-dependent parameters. For the test formulation, the highest mean maximum serum concentration (1595 ng/ml) was measured with a corresponding tmax of 0.8 h. For the reference formulations, mean peak serum concentrations of 1285 ng/ml after 2.0 h (B), 370 ng/ml after 1.8 h (C) and 735 ng/ml after 1.9 h (D) were observed. Despite the enteric-coating of the pellets, a short lagtime of 0.4 h was determined for the test formulation. For the other rapid-release formulation (D), the lagtime was of a similar magnitude (0.3 h), while drug release and absorption from the enteric-coated tablet and the diclofenac resinate capsule were delayed (1.8 and 0.7 h, respectively). Due to the rapid and high bioavailability of diclofenac, the multiple-unit formulation fulfills the prerequisites for the oral treatment of acute painful conditions when prompt analgesic and anti-inflammatory efficacy is desired.     

A study in normal human volunteers to compare the rate and extent of levothyroxine absorption from Synthroid and Levoxine.

Numerous branded and generic formulations of levothyroxine (LT4) sodium tablets are currently available. Results from previous studies attempting to examine the comparative bioavailability of these formulations are difficult to interpret because of subject heterogeneity, single time-point blood sampling, varying degrees of hypothyroidism, and other factors. This study was devised to compare the rate and extent of absorption of LT4 from different LT4 sodium tablet formulations, in a simple model using a single-dose two-way single-blind, randomized cross-over design in 30 normal, healthy, nonpregnant, female subjects. This design controlled for many factors that limited previous LT4 bioavailability studies. Subjects were given a single 600 micrograms dose of LT4 as either Synthroid (Boots Pharmaceuticals, Inc., Lincolnshire, IL) tablets (formulation A) or Levoxine tablets (Daniels Pharmaceuticals, St. Petersburg, FL; formulation B). Measurements of baseline-corrected total T4 serum concentrations determined at multiple time points demonstrated statistically significant differences between the two formulations at the 1.00, 3.00, 5.00, and 18.00 hour sampling times. Statistically significant differences for area under the curve (AUC) (0 to 48 hours) (formulation A, 159.9 +/- 9.4 micrograms-hour/dL; formulation B, 193.4 +/- 10.1 micrograms-hour/dL) and maximum peak plasma concentration (Cmax) (formulation A, 5.91 +/- .34; formulation B, 7.12 +/- .32) also were demonstrated. Furthermore, the ratio of the baseline-corrected total T4 concentrations (B/A x 100) were 120.9% for AUC and 120.5% for Cmax. These data demonstrate that the administration of Synthroid and Levoxine result in a significantly different rate and extent of absorption of LT4, and therefore these two formulations cannot be considered bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Activity and pharmacokinetics of a new oral dosage form of soluble ibuprofen.

The pharmacokinetics and the relative bioavailability of a soluble granular form (sachets) of a pharmaceutical formulation containing ibuprofen (CAS 15687-27-1) and 1-arginine were investigated in healthy volunteers. Two granular dosage forms were evaluated, 200 and 400 mg, in comparison with the commercial equivalents (tablets). After the oral administration of both granular dosage forms, a quicker absorption and a significantly higher plasma bioavailability of ibuprofen in the first hour following the treatment than after tablets administration were observed. The mean values of peak plasma concentration (microgram/ml) were 26.1 and 56.4 after treatment with 200 and 400 mg sachets respectively vs. 16.3 and 43.0 after treatment with 200 and 400 mg tablets. The mean values of peak time were 16.9 and 24.4 min after treatment with 200 and 400 mg sachets respectively vs. 90.0 and 63.7 min after treatment with 200 and 400 mg tablets. The shortening in the absorption time and the increase in the plasma concentrations did not involve a quicker drug elimination nor cause any changes in the bioavailability (mean values of the relative bioavailability indexes of 0.98 for 200 mg dosage form and 1.02 for the 400 mg one). The analgesic activity of soluble ibuprofen 400 mg was compared with that of ibuprofen 400 mg tablets in patients with osteo-articular pain, according to a single dose, double-blind cross-over balanced design. The results showed that the soluble granular form is able to determine an analgesic effect significantly quicker and higher than that of tablets.