依非韦伦两种剂型在健康人体的药动学和相对生物利用度

目的:研究依非韦伦片剂和胶囊剂的健康人体药动学和相对生物利用度。方法:采用高效液相色谱法测定20名健康志愿者单剂量、自身交叉口服依非韦伦胶囊剂和片剂各600 mg后血浆中依非韦伦浓度。用DAS药动学软件进行药动学参数计算及生物等效性评价。结果:胶囊剂和片剂依非韦伦主要药动学参数如下:Cmax分别为(2.5±0.3)mg.L-1和(2.6±0.5)mg.L-1;tmax分别为(3.05±0.08)h和(3.0±0.7)h;T1/2分别为(38.5±3.3)h和(39.8±6.5)h;AUC0-t分别为(163.3±21.1)mg.h.L-1和(157.6±24.2)mg.h.L-1;AUC0-∞分别为(165.5±23.9)mg.h.L-1和(162.6±23.4)mg.h.L-1。与胶囊剂相比,片剂的相对生物利用度F0-t为(95.3±10.9)%,F0-∞为(96.3±11.3)%。经方差分析和双向单侧t检验,两剂型间的主要药动学参数无明显差异(P>0.05)。结论:建立的方法适用于依非韦伦药动学研究,依非韦伦两种剂型具有生物等效性。     

Pharmacokinetics of buflomedil after various dosage forms

The pharmacokinetic disposition of buflomedil was compared in humans after oral administration of solution, tablets and film tablets. Six healthy male volunteers received a single oral dose of the three different dosage formulations. Blood and urine samples were taken before dosing and at selected times over 24 h and 72 h, resp., after dosing. The concentration of the drug in samples was measured by gas-chromatography with nitrogen detector. The absorption of buflomedil was faster after solution administration, while other plasma parameters did not show any major differences. Also the amount of drug excreted in urines was higher with solution dosing.     

Pharmacokinetics of probucol dosage forms in clinical tests

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 29, No. 4, pp. 21–23, April, 1995.     

Pharmacokinetics and laxative effect of bisacodyl following administration of various dosage forms

Since its introduction into the market in 1952, bisacodyl has been successfully used worldwide as a laxative. In discussions on the kinetics and the laxative effect, it is often neglected that results obtained after the administration of the pure compound bisacodyl cannot be transferred to distinctive bisacodyl formulations. The aim of the present investigation is therefore to study the absorption and the plasma level profile and to correlate plasma level profile and laxative effect after the administration of various dosage forms. 12 healthy volunteers were administered with 10 mg bisacodyl as an experimental solution, with an acid resistant, commercially available Dulcolax Dragees (2 x 5 mg) and with a 10 mg Dulcolax suppository. Following glucuronidase cleavage, mean maximum plasma levels of 236.5 +/- 59.2 ng/ml of bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) were reached after the administration of the solution 1.7 h post administration (p.a.), however, the laxative effect did not occur until 5.7 h +/- 0.7 h p.a. The dominant biological half-life of deconjugated BHPM, the diphenol of bisacodyl which circulated as BHPM-glucuronide, was about 16.5 +/- 4.2 h. The dragee yielded the desired low plasma levels which were between 7 and 47 ng/ml at 4-10 h p.a. In comparison to the solution only 16% were absorbed after the administration of the dragee. The laxative effect started 7.7 h +/- 1.7 h p.a. with no apparent relationship between effect and plasma level. The administration of the suppository resulted 20 +/- 10 min p.a. in a prompt laxative effect, although in 6 out 12 subjects, the plasma levels were below the detection limit.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of papaverine hydrochloride and the biopharmaceutics of its oral dosage forms

The pharmacokinetics of completely metabolized papaverine hydrochloride were characterized by a linear sum of three exponentials on intravenous administration with respective 1.5, 19 and 107 min apparent half lives. There was a time-dependent partition from plasma water into red blood cells with an apparent half life of 1.5--3 min. The partition coefficient normally ranged between 8 and 15 at therapeutic levels but approached unity at high plasma concentrations to indicate a saturable partition. Apparent compartmental volumes of distribution referenced to total concentrations in the plasma were 4.3--4.8, 11--13 and 20--25 liters. Protein binding was 91--95%. The hepatic clearance of blood was 960 ml/min, corresponding to a hepatic efficiency of 69%, and indicated that the clearance of protein-bound drug was consistent with the observed first pass metabolism of 70% for oral solutions. No dose dependency was observed on intravenous administration or on oral administration of solutions and tablets. Tablets with release lag times of 10--15 min showed relative bioavailabilities of 52%. Two different lots of sustained release capsules showed 68 and 89% relative bioavailabilities. Release lag times among capsules ranged between 0 and 170 min. Loo-Riegelman calculations and analog computer fittings were consistent with a half life of absorption from oral solutions of 19 min and zero order release rates from tablets and sustained release capsules. Chronic studies of tablets q.i.d. and capsules b.i.d. confirmed lack of accumulation. An appropriately designed 300 mg sustained release capsule, b.i.d., for an arbitrary plasma level of 0.200 microgram/ml should have one tenth the release rate of the studied capsules.     

Pharmacokinetics and dissolution of two crystalline forms of carbamazepine

The dissolution, crystal growth in aqueous milieu and pharmacokinetics of carbamazepine, as the dihydrate and anhydrate, have been studied. The only difference in pharmacokinetics between the two forms was a somewhat higher absorption rate for the dihydrate. The slower absorption of the thermodynamically more active anhydrous form was attributed to rapid transformation, in aqueous milieu, of this form to the dihydrate, resulting in a fast growth in particle size.     

Papaverine hydrochloride: the evaluation of two new dosage forms.

The bioavailability of papaverine, administered as sustained release capsules, an elixir, and soft gelatin capsules, was studied with volunteers. Blood samples were assayed for papaverine, using a gas chromatographic method, following the administration of single 150 mg doses of papaverine HC1. The elixir and the soft gelatin capsule resulted in nearly identical papaverine blood levels, while peak levels, area under the blood level-time curve, and plasma levels 0.5, 1.0, 1.5, and 2.0 hours after dosing with the sustained release capsule were significantly (p less than 0.01) lower.     

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray C_max was higher (39.0 ng·ml^-1) and t_max was shorter (3.9 min) than after the sublingual (22.8 ng·ml^-1 and 13.8 min) and peroral (16.9 ng·ml^-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml^-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e_max=130%) and the time to e_max (t_emax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.     

Steady-state bioavailability of two clorazepate dipotassium dosage forms.

A specially designed tablet dosage form of the benzodiazepine clorazepate dipotassium (Tranxene) was developed for once-a-day administration. The drug was administered at a dose of 22.5 mg as (1) the tablet, (2) three 7.5 mg capsules, or (3) one 7.5-mg capsule given every 6 hours. Peak serum levels from the tablet were intermediate between those of the single- and divided-dose capsule regimens. The desired decrease in magnitude of peak levels was obtained without affecting the extent of absorption. Pharmacokinetic analysis of the data according to a two-compartment open model with first-order absorption indicated that the serum half-life (t0.5beta) of nordiazepam, the major biotransformation product present in serum, was about 48 hours and served as a basis for the design of a multiple-dose steady-state study. Multiple-dose administration of the tablet and divided-capsule regimen to two groups of subjects for ten days indicated each dosage form yielded similar minimum steady-state serum levels of about 0.6 micrograms/ml which plateaued following seven days of drug administration. The dosage forms were crossed over between the groups on day 11 and administered for an additional four days. The minimum serum levels obtained with the tablet and capsule were not statistically different. Additionally, the peak serum level and area under the curve (pi=24 hours) at steady state were equivalent between the dosage forms. Good agreement was obtained between model-predicted and observed serum levels during multiple-dose administration for both the tablet and capsule regimens. The serum half-life of nordiazepam following 14 days of clorazepate dipotassium administration was similar to that found after a single dose. These results indicate that a single daily dose of drug as the tablet produced serum levels equivalent to a divided-capsule regimen.     

Pharmacokinetics of two cyclosporine formulations using FPIA and HPLC assay in volunteers

The analytical methods for the analysis of cycloporine (CsA), a fluorescence polarization immunoassay (FPIA) and HPLC method, were compared in a pharmacokinetic study of two CsA soft capsule formulations (Sandimmun^®; Sandoz, Implanta^®; Hanmi). Sixteen healthy volunteers completed the study and each subject ingested single doses (4×100 mg) of the test and the reference formulations in a two-way crossover design with a one-week drug-free interval between doses. Following each administration, whole blood concentrations of CsA were monitored over a period of 24 hour by both FPIA and HPLC methods. Blood concentrations and pharmacokinetic parameters determined by either analytical method showed large intersubject variation, with the FPIA data showing relatively higher magnitude of intersubject variation than the HPLC data. The blood concentrations determined by FPIA were 1.1–1.3 times higher than those determined by HPLC. There were strong and significant correlations between the two methods (r>0.83: p<0.0001). Intersubject variation for the AUC_inf. and AUC_24hr of the test formulation was slightly reduced without statistical significance (paired-t test: p>0.05. tmax was earlier and C_max was slightly lower for the test formulation. AUC_24h, C_max, t_max and MRT determined separately from the data obtained by the two methods for the two formulations were examined by analyses of variance (ANOVA) for the bioequivalency evaluation. Results of ANOVA and confidence limits of test/reference ratios of AUC_24h, C_max, t_max and MRT, and statistical tests indicated the bioequivalence of the two formulations (i.e., test/reference ratio was within 100×20%) except for C_max and t_max. The mean of C_max showed only 7.9% and 11.6% differences but the detection limit were 26.6% and 21.4% as determined by FPIA and HPLC respectively which is slightly over the 20% criteria. The mean of tmax also showed 11.1% and 9.3% differences but the detection limit were 29.2% and 29.6% as determined by FPIA and HPLC respectively. This experiments suggest that the data yielded for the two formulations demonstrated that they were bioequivalent.     

Retention and distribution of two 99mTc-DTPA labelled vaginal dosage forms

To objectively evaluate the performance of new vaginal dosage forms, it is important to determine their time of residence and their distribution. This paper describes the in vivo characteristics of a reference and test product in this situation. METHOD: A randomised cross-over study was performed in the same phase of the menstrual cycle in eight pre-menopausal women. The retention and distribution of a commercially available vaginal clotrimazole cream and a test gel product, each "labelled" with 99mTc-DTPA was assessed by gamma scintigraphy for 24 h after administration of the products. Mass balance analysis was attempted by collecting and counting sanitary napkins worn for the study time. RESULTS: Within individuals there was little variation in the clearance of the formulations, but wide variation between individuals with a range between 81 and 1% of the administered doses retained by 24 h. The losses appeared to occur mainly at times of urination with 12 +/- 8% (cream) and 20 +/- 23% (gel) collected on the sanitary napkins, but 46 +/- 34% (cream) and 38 +/- 22% gel activity not accounted for by 24 h. The intravaginal distribution of activity was similar for each product. CONCLUSIONS: Radioactive tracer methods are useful in assessing and comparing vaginal dosage forms.     

Comparative bioavailability of S-carboxymethylcysteine from two dosage forms: Hard gelatin capsule and syrup

Measurement of plasma concentrations after the oral administration of S-carboxymethylcysteine in two different dosage forms, as a hard gelatin capsule and as a syrup, shows its relative bioavailability from the two formulations to be similar. With the exception of the time required to reach peak concentration, which shows a slight variation attributable to the time taken for the drug to be released from the capsule and to dissolve, parameters such as peak concentration, biological half-life and area under the serum-concentration curve whether from t=0 to t = 8h or from t = 0 to t=∞, are not statistically different. The areas under the plasma-concentration curves between t = 0 and t = 8 h and between t = 0 and t = ∞ shows that for a confidence limit of 95 per cent, the mean for the capsular form does not differ by more than 3.3–10.3 per cent from the mean for the syrup.     

Aluminum hydroxide: evaluation of two dosage forms and two dosing schedules in reducing intestinal phosphate absorption

A crossover, randomized, eight-week trial using eight adult volunteers was undertaken to (1) determine the efficacy of aluminum hydroxide in decreasing gastrointestinal phosphate absorption, (2) compare the effectiveness of "with meal" and "between meal" dosing schedules, and (3) compare the effectiveness of the capsule and liquid dosage forms. Four treatments, each with a daily dose of approximately 6 g, were taken on a three-times-a-day regimen. The effectiveness of the treatment regimens was measured by using two variables: the decrease in total urinary phosphorus excretion, and the increase in the percent tubular reabsorption of phosphorus (TRP). Aluminum hydroxide treatment produced a significant change in urinary phosphorus excretion (p less than 0.0005) and in percent TRP (p less than 0.0005). For the study population, total urinary phosphorus excretion was the determining factor in changing the percent TRP. The increase in TRP and the decrease in total urinary phosphorus excretion was of the same degree regardless of dosage form or dosage schedule. Aluminum hydroxide was effective in decreasing phosphorus absorption as measured in this study. It appears that aluminum hydroxide capsules could be used with equal efficacy as the liquid dosage form in controlling hyperphosphatemia in patients with chronic renal failure who will not comply with a treatment program using the liquid.     

Liquisolid technique: a promising alternative to conventional coating for improvement of drug photostability in solid dosage forms

Objective: The objective of this study was to investigate the photoprotective effect of liquisolid technique on amlodipine, a calcium channel blocker antihypertensive drug, representing a photosensitive drug model.

Method: Several liquisolid formulations were prepared using propylene glycol as a water-miscible nonvolatile vehicle at drug/solvent ratio (1:1), Avicel PH 102 as a carrier, nanometer-sized amorphous silicon and titanium dioxide either alone or in combination as coating materials. The carrier/coat ratio (R) was varied from 5 to 50. The prepared liquisolids, coated, noncoated tablets and drug substance were irradiated with a light dose of 0.5 W/m²/h visible light, 55.1 W/m²/h UVA, and 0.247 W/m²/h UVB for 8 h. The effect of coating material type and (R) value on the drug dissolution rate and photostability was studied. Results were statistically analyzed by post hoc two-way ANOVA at a probability level (α = 0.05).

Results: The results indicated that liquisolid technique not only improved the dissolution rate, but also significantly inhibited the photodegradative effect of different light energies in all prepared liquisolid formulations. The residual drug percentage reached 97.37% in comparison to 73.8% for the drug substance after 8 h of irradiation. The residual drug percentage was affected by the (R) value. Statistically; the detected difference was significant at the selected probability level (α = 0.05).

Conclusion: It can thus be concluded that this liquisolid technique is a promising alternative to conventional coating procedures in formulations containing photosensitive drugs.     

Drug release from semisolid dosage forms: a comparison of two testing methods

Abstract

The aim of the present work was to extend our previous in-vitro drug release studies using semisolid dermatological bases with non-impregnated cellulose acetate membranes. A comparison of the performances of two apparatuses, the more commonly used Franz cell and the new modified USP (mini paddle with ointment holding cell) systems were applied to this work. Five different semisolid as well as two marketed preparations containing 1% diclofenac sodium were used. Complex, slightly non-linear release curves indicating sink conditions were found. This was explained by the co-diffusion of excipients modifying the characteristics of the membrane and the receiving medium dynamically. Although our test model is, as a rule, not suitable to establish an in-vivo–in-vitro correlation, good qualitative as well as quantitative correlations were found within some types of dermatological bases. The correlation between the results of the two in-vitro methods also depends on the type of semisolids studied. The release curve characteristics and the amount of diclofenac sodium released at 6?h were measured. Their repeatability and reproducibility were calculated. The slopes and Q-values were correlated with in-vivo data. In general, the modified USP method provided more precise results than the Franz cell method.     

Selection of drug candidates for gastroretentive dosage forms: Pharmacokinetics following continuous intragastric mode of administration in a rat model

The purpose of the study was to evaluate the pharmacokinetic effects obtained by gastroretentive dosage form (GRDF) for drugs absorbed by passive paracellular diffusion (atenolol, acyclovir) or active transport (valacyclovir). Model drugs were delivered as gastric infusion (GInf) through an implanted catheter (resembling GRDF), intravenous, oral (PO), and colonic administration to rats. For atenolol (highly soluble drug), GInf resulted in a prolonged T_max and reduced C_max in comparison to PO, whereas bioavailability was similar. Bioavailability after colonic bolus was significantly lower. Results were also simulated by a pharmacokinetic model. For acyclovir, GInf and PO demonstrated almost the same pharmacokinetic profile with low bioavailability, most probably due to the solubility-limited absorption. Valacyclovir demonstrated the significant change in the shape of pharmacokinetic profile as a function of the rate of gastric delivery, without variation in bioavailability. Valacyclovir was not absorbed from colon. Experimental and theoretical methodologies to assess the pharmacokinetic influences of GRDF mode of administration were developed, avoiding the need to compound the drug in a dosage form. GRDF provides a mean for controlled release of compounds that are absorbed by active transport in the upper intestine. It also enables controlled delivery for paracellularly absorbed drugs without a decrease in bioavailability.     

Pharmacokinetics of targeting with liposomes

The optimization of drug disposition in the body leads to an increase in its therapeutic effect and to a decrease in adverse effects. Liposomes can serve as a potential drug carrier for achieving this. However, the behavior of a drug carrier system under in vivo conditions is complex. Therefore, a more complete understanding of the pharmacokinetics of liposomes themselves, as well as that of the encapsulated drug, is required. The optimization of the pharmacokinetics of liposomes can be performed by linking a pharmacodynamic model of the free drugs that are encapsulated into liposomes. Sensitivity analysis was applied to optimize the delivery system to maximize the antitumor effect of liposomal doxorubicin (DOX). Advanced technology for ligand-mediated selective targeting and intracellular targeting is also introduced for antitumor agents and for gene delivery systems.     

Evaluation of two nitroglycerin dosage forms: a metered spray and a soft gelatin capsule

Two studies were performed to evaluate two nitroglycerin dosage forms. The dosage forms of main interest were a metered 0.4 mg nitroglycerin spray and a soft gelatin capsule containing 0.8 mg nitroglycerin solution. Each of these two dosage forms was evaluated in a separate study, versus both a placebo and an equivalent sublingual nitroglycerin tablet dose. The studies employed the digital plethysmographic methodology for evaluation of organic nitrate antianginal dosage forms. The results indicated that all the nitroglycerin dose treatments generated significantly greater digital plethysmographic activity versus the placebo. Also, the metered spray and soft gelatin capsule treatments were as effective, or more effective, than the respective sublingual tablet treatment in generating a digital plethysmographic response. Several implications and applications of these results are discussed.     

Pharmacokinetics of antimalarials and proposals for dosage regimens.

Blood level data for the antimalarials amodiaquine, chloroguanide, chloroquine, pyrimethamine, quinine and sulphadoxine have been retrieved from the literature and pharmacokinetically analyzed. Minimum, average and maximum blood level concentrations at steady state in suppressive treatment and peak concentrations in therapeutic treatment were predicted and blood level-time curves simulated. Based on the computer-predicted data, changes in dosage regimens are proposed to reduce the fluctuations between maximum and minimum levels in suppressive treatment, and for obtaining maximum peak levels in therapeutic treatment already with the loading dose.