双氯芬酸缓释片的人体生物利用度试验(英文)

目的进行两种双氯芬酸缓释片的单次给药的生物利用度比较研究和多次给药的峰谷浓度波动研究。方法12位健康男性受试者按交叉试验单剂量服用试验片和对照片,采用HPLC方法测定人血清中的药物浓度 ,并比较其生物利用度。结果两种片剂的Cmax 和AUC无显著差异(P>0.05),但试验片给药后的达峰时间(Tpeak)显著小于对照片 ,与对照片相比有非常显著差异(P<0.01)。试验片相对于对照片的相对生物利用度为98 11 %,经统计学检验证明这两种制剂具有生物等效性。12位受试者连续服用试验片和对照片的交叉试验表明 ,两种缓释片在稳态时的峰浓度(Cmax)、谷浓度(Cmax)、平均浓度(Cavg)、峰谷比(r)和峰谷波动度(DF)均无显著差异(P>0.05) ,最小有效浓度持续时间(Tmec50)也基本一致 ,说明两种缓释片在稳态时的峰谷浓度波动程度相当 ,具有较好的缓释特征。在多次给药时 ,试验片的达峰时间同样显著小于对照片(P<0.01)。结论试验结果表明两种缓释片具有生物等效性 ,都具有峰谷浓度差异小 ,波动幅度小的特点 ,与对照片相比 ,无论单次给药还是多次给药 ,试验片的达峰时间都显著缩短。     

Bioavailability of diclofenac potassium at low doses

AIM: Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K. METHODS: A randomized, three-way, cross-over study was performed in 10 subjects. Each received diclofenac-K, 22.5 mg via short-term i.v. infusion and orally at single doses of 12.5 mg and 25 mg. RESULTS: Mean (+/- SD) times to maximal plasma concentration (t(max)) of diclofenac were 0.48 +/- 0.28 h (12.5 mg) and 0.93 +/- 0.96 h (25 mg). The absolute bioavailability of diclofenac-K after oral administration did not differ significantly in the 12.5-mg and 25-mg dose group (63.1 +/- 12.6%vs. 65.1 +/- 19.4%, respectively). The 90% confidence intervals for the AUC(infinity) and AUC(t) ratios for the two oral regimes were 82.6, 103.4% (point estimate 92.4%) and 86.2, 112.9% (point estimate 98.6%), respectively. These values were within the acceptance criteria for bioequivalence (80-125%). CONCLUSIONS: Our data indicate that diclofenac-K is rapidly and well absorbed at low dose, and are consistent with a rapid onset of action of the drug. Abbreviations AUC, area under plasma concentration-time curve; C(max), peak plasma concentration; CI, confidence interval; COX, cyclooxygenase; D, dose; F, absolute bioavailability; t(max), time to reach C(max).     

环孢素A-Eudragit S100纳米粒冻干粉制剂在犬体内的药动学

目的:研究环孢素A-Eudragit S100纳米粒冻干粉制剂(freeze-dried cyclosporine A-Eudragit S100 nanoparticles,CyA-S100-NP)在家犬体内药动学及相对生物利用度。方法:以双周期交叉随机试验设计法,高效液相色谱法测定6只家犬口服给予环孢素A-Eudragit S100纳米粒冻干粉硬胶囊和新山地明微乳软胶囊(Neoral)后环孢素A的血药浓度,采用3P97软件计算药动学参数。结果:经3P97软件拟合,环孢素A的药动学过程符合二室模型。与Neoral相比,CyA-S100-NP的AUC显著增大(P<0.05),CL显著降低(P<0.05),相对生物利用度为135.9%。结论:CyA-S100-NP可促进药物口服吸收,显著提高环孢素A的生物利用度,有望开发成为一种新型口服环孢素A纳米粒固体制剂。     

Pharmacokinetics and bioavailability of diclofenac in the rat

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.The present work is part of a research project developed with a grant for the Plan Nacional de I + D (FAR 90-0092) of the Ministry of Industry and Energy of Spain.     

双氯芬酸钠脉冲控释微丸的研究

目的制备双氯芬酸钠脉冲控释微丸（DS-PRP）并考察体内外释药特性。方法采用水溶胀性材料为内包衣溶胀层，乙基纤维素水分散体为外包衣控释层制备DS-PRP，考察影响其体外释药的因素，并进行体内药代动力学研究。结果溶胀层材料类型、溶胀层和控释层包衣厚度、释放介质中十二烷基硫酸钠（SDS）的加入对DS-PRP的释药时滞和释药速率有显著影响，在0.1％ SDS溶液中释药时滞t_0.1为3.1 h，体内释药时滞tlag为2.8　h，与DS丸芯的相对生物利用度为（91±1２）%。结论DS-PRP在体内外均具有脉冲释药特性。     

双氯芬酸钠胶浆剂家兔直肠给药的药动学特征

目的 研究双氯芬酸钠胶浆剂直肠给药在家兔体内的药动学.方法 24只家兔随机分为2组,每组12只(♀♂各半),分别直肠给予双氯芬酸钠胶浆剂和栓剂(3 mg·ks-1),按试验方案采血,采用HPLC法测定血药浓度.结果 双氯芬酸钠胶浆剂组tmax为12.60 min,ρmax为8.39 mg·L-1(P＜0.001);双氯芬酸钠栓剂组tmax为94.46 min,ρmax为5.62 mg·L-1(P＜0.001).结论 双氯芬酸钠胶浆剂直肠给药后血药峰浓度高,且达峰时间短,优于双氯芬酸钠栓剂直肠给药.     

双氯芬酸钠缓释微丸在兔体内的药动学

目的：测定双氯芬酸钠缓释微丸（DS－SRMP）在家兔体内药动学及相对生物利用度。方法：用紫外分光光度法测定家兔体内的血药浓度，研究DS－SRMP的吸收动力学及生物利用度。结果：DS－SRMP在体内0－8h的吸收速度符合表观零级动力学过程，其Ka^0＝12．14％/h。结论：体内药动学研究表明，DS－SRMP缓释效果明显，给药后血药浓度较为平缓，持续作用时间长，可减少给药次数。该缓释制剂相对于其普通片剂具有释药稳定，生物利用度高，安全有效等制剂学意义。     

Comparative bioavailability of diclofenac hydroxyethylpyrrolidine vs diclofenac sodium in man

Summary A pharmacokinetic study in man has been made of a new dosage form of diclofenac hydroxyethylpyrrolidine (DIEP); soluble salt packed in sachets was compared with diclofenac sodium as enteric coated tablets.Oral DIEP 2×50 mg showed a significant difference in absorption kinetics (ka, lag time and t_max) as compared to oral diclofenac sodium 2×50 mg. A relevant plasma concentration of diclofenac was detected just 15 min after DIEP, while diclofenac sodium produced a measurable plasma concentration only 0.5–1 h after the treatment. C_max and t_1/2 after DIEP and diclofenac sodium were comparable. Comparison of the two AUC values showed that DIEP was bioequivalent to diclofenac sodium (Q=100%).     

萘普生钠注射液的药物动力学研究

以萘普生钠水溶液作对照,研究了萘普生钠注射液在家兔体内药物动力学。结果表明萘普生钠注射液的T_(max)(1.32±0.25h)较萘普生钠水溶液(4.7±1.4h)短;C_(max)(327±27μg/ml)较水溶液(168±28μg/ml)高;而Ka和Ke(0.55±0.18h~(-1),0.107±0.025h~(-1))较水溶液(0.40±0.20h~(-1),0.050±0.014h~(-1))大。以萘普生钠水溶液作“标准”制剂,计算注射液的相对生物利用度为102.96%。说明萘普生钠注射液肌注给药比口服水溶液吸收快,排泄也快,吸收程度高。     

Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in normal and dehydrated rabbits

Two different salts of diclofenac, diclofenac sodium and diclofenac potassium, in tablet dosage form were tested for their bioavailability and disposition kinetics in a group of eighteen rabbits in normal and experimentally induced dehydrated conditions with a wash out period of 7 days between both stages of study.  Biochemical and physiological parameters were also measured in both normal and dehydrated states.  Diclofenac levels in plasma were determined using a validated reversed phase HPLC method.  Primary kinetic parameters i.e.  AUC_0－¥, C_max, T_max and other disposition kinetics were obtained with non-compartmental procedure.  Biochemical parameters i.e. packed cell volume, plasma glucose and total lipid concentration in dehydrated rabbits increased significantly.  Plasma concentration of diclofenac sodium and diclofenac potassium decreased significantly in water deprived rabbits.  In comparison, diclofenac potassium in normal and dehydrated state of the same group of rabbits showed a significantly increased plasma concentration when compared with diclofenac sodium.     

Lack of effect of a single-dose of sulglicotide on the bioavailability of diclofenac

Summary The bioavailability of diclofenac (D) was assessed in 12 healthy volunteers treated orally with single doses of 100 mg (retard formulation) and subsequently retreated with the same dose of (D) plus sulglicotide (S) 200 mg.(D) blood levels were measured by GLC in samples collected after 1, 2, 4, 6, 8, 12, 24 h. No relevant difference was seen in (D) bioavailability after (S) administration; after 8 h plasma levels of (D) were slightly higher after (S) (p<0.05), but this difference can be considered incidental only. Thus, sulglicotide does not interfere with the bioavailability of diclofenac, and can be administered concurrently with the latter to prevent possible gastric injury by the antiinflammatory drug.     

A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects

AIMS

To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C).

METHODS

This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren® Emulgel® gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4.

RESULTS

All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren® Emulgel® and were approximately 30–40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren® Emulgel® (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation.

CONCLUSION

DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development.     

Pharmacokinetic profile and bioavailability of a new galenic formulation of ticlopidine

The bioavailability of a new film-coated tablet of ticlopidine hydrochloride was compared in 12 healthy male subjects to that of the older sugar-coated tablet. Plasma levels of ticlopidine were measured by gas-liquid chromatography up to 120 h after a single 500 mg dose of each preparation. Drug intake was separated by a four-week interval. No statistically significant differences could be found between the pharmacokinetic parameters for these two preparations. Bioequivalence was confirmed when applying the test of Westlake to the area under the curves (calculated difference: 8.3%; upper limit: 20%). No unwanted effect was reported during the study.     

复方双氯芬酸钠注射液的研制

目的：研制复方双氯芬酸钠注射液。方法：以提高澄明度和稳定性为指标筛选处方及制备工艺。结果：注射液采用40％的PEG400和1，2-丙二醇(3：1)为混合溶剂，加入抗氧剂提高溶液的澄明度和稳定性，调节pH值在7．4～8．5，在配制过程中宜控制水温在6012左右，充N2灌封。结论：复方双氯芬酸钠注射液经稳定性考察，其质量标准符合药典规定的注射剂质量标准。     

新型双氯芬酸钠缓释片的人体相对生物利用度研究

８名健康男性志愿者单剂量交叉口服１００ｍｇ受试双氯芬酸钠缓释片、扶他林或ＶｏｌｔａｒｅｎＳＲ１００后,Ｔｍａｘ分别为２．４±１．０、２．１±０．５和４．４±１．８ｈ;Ｃｍａｘ分别为６０２．６±９２．８、３３３７．６±１０８８．２　７６１．０±３４２．０ｎｇ／ｍｌ;ＭＲＴ分别为１３．２±４．８、２．９±０．８和７．９±１．９ｈ;ＡＵＣ０分别为４８６６．２±６４４．６、５３１４．３±５３４．３和４８２９．１±５８２．８ｎｇ／（ｍｌ－１·ｈ）;双氯芬酸钠缓释片和ＶｏｌｔａｒｅｎＳＲ１００相对于扶他林的生物利用度分别为８８．３±１３．２％和８６．３±１２．６％。另８名志愿者交叉口服受试双氯芬酸钠缓释片（１００ｍｇ,ｐｄ）和扶他林（５０ｍｇ,ｂｉｄ〕,连服５天。Ｃｍａｘ分别为５９３．９±１３４．１、１２４７．８±５２７．５ｎｇ／ｍｌ,峰谷波动率（ＰＴＦ）分别为３．３±１．２、５．３±２．１。本研究将为新型双氯芬酸钠缓释片的临床应用提供依据。     

双氯灭痛缓释片的人体相对生物利用度

目的：对两种双氯灭痛缓释片进行相对生物利用度的测定。方法：１８名健康者交叉服用两种双氯灭痛缓释片后，用高效液相色谱法测定不同时间的血药浓度，检测波长２８０ｎｍ，测定方法的线性范围为３￣２０００ｎｇ／ｍｌ（ｒ＝０．９９９８）。高中低３个浓度的回收率为９７．４０％￣９５．０２％。结果：由测定结果可以看出两种缓释片的ＡＵＣ、ＦＩ、ＭＲＴ均无统计学差异，平均相对生物利用度为９６．７５％。结论：试验片与对照     

Pharmacokinetic profile and bioavailability of a new pharmaceutical formulation of isosorbide-5-mononitrate sustained-release formulation

The pharmacokinetic profile and the bioavailability of a new galenic formulation of isosorbide-5-mononitrate sustained released capsules (Olicard 40 retard) was tested under standardized conditions. 12 healthy, male volunteers (mean age 24.9 +/- 3.0 years) in a randomized, intraindividual crossover design (wash-out phase: 6 days) received the isosorbide-5-mononitrate sustained-release capsules (testformulation) and a standard-release formulation of the same active substance as single dose (40 mg each). Venous blood sampling for analysing the plasma concentration of isosorbide-5-mononitrate was done before and at 21 fixed times after medication. The AUC0----36h of the concentration/time curve was calculated using the linear trapezoidal rule and the AUC0----infinity extrapolated after computing the half-life of the terminal elimination phase. The leading variable was the AUC0----infinity. For the sustained-release preparation an AUC0----36h of 5764.5 +/- 909 ng/ml.h was measured, an AUC0----infinity of 5863.9 +/- 981.9 ng/ml.h was calculated, with a peak maximum (Cmax) of 472.5 +/- 29.7 ng/ml after 2.9 +/- 0.5 h (tmax). For the standard-release formulation an AUC0----36h of 5679.8 +/- 690.3 ng/ml.h was measured, an AUC0----infinity of 5688.7 +/- 695.7 ng/ml.h was calculated, with a peak maximum (Cmax) of 842.4 +/- 100.2 ng/ml after 1.2 +/- 0.2 h (tmax). The bioavailability of the standard-release formulation was postulated to be 100%. The non-parametric calculation of the bioavailability-ratio (geometric Walsh-averages) was 101.47% (95% confidence limits 85.24% to 121.09%). There was no statistically significant difference between the both galenical formulations, the sustained-release preparation has no influence on the total amount of resorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Short-term sucralfate administration alters potassium diclofenac absorption in healthy male volunteers

Aims Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokmetics of diclofenac.
Methods Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5-day pre-treatment with sucralfate (2000 mg twice daily). Blood samples were collected at intervals post-dose and serum concentrations of diclofenac were determined by reverse-phase h.p.1.c. Results Pre-treatment with sucralfate significantly decreased both the AUC(0,8 h) [2265 ng h Ml⁻¹ (geometric mean) (range 1815–2827)vs 1821 ng h ml⁻'(1295–2562)] and the C_max [1135 ng ml⁻¹ (geometric mean) (range 898–1436) vs 701 ng ml⁻¹ (501–981)] with no significant delay in absorption [t_max 1.0 h (median) (range 0.5–2.0) vs 1.0 h (0.5-4.0)l.
Conclusions The short-tern treatment of healthy male volunteers with sucralfate decreases potassium diclofenac bioavailability. These findings suggest that either an appropriate increase in the diclofenac intake or the use of another gastric mucosa protector must be adopted.