Bioavailability of a controlled-release cyclobenzaprine tablet and influence of a high fat meal on bioavailability.

OBJECTIVE: To evaluate the systemic bioavailability of a new controlled release cyclobenzaprine tablet, and the influence of a high fat meal on its bioavailability. SUBJECTS, MATERIALS AND METHODS: 24 and 12 healthy male subjects were recruited for the bioavailability and influence of diet studies, respectively. Experimental design for both studies was an open randomized, 2-period, single dose, crossover study. In the bioavailability study, each subject received in different occasions, a single oral dose of cyclobenzaprine of immediate (10 mg) or controlled release (20 mg) tablet, followed by a 2-week washout period. In the influence of diet study, the volunteers received the controlled-release tablet concomitantly with a high fat meal or in a state of fasting. RESULTS: In the bioavailability study, plasma cyclobenzaprine profiles were in agreement with a controlled release system. This formulation presented a 92.8% of relative bioavailability (IC 85.5 - 105%) and a significant reduction in Cmax (IC 58 - 65.5%), when compared with equal dose of the immediate release tablet. The presence of food increased AUC (11.6%) and Cmax (48%). For both parameters the calculated 90% confidence interval was not in the bioequivalence interval, 97.4 - 125.8% for AUC and 111.7 - 184.2% for Cmax. CONCLUSIONS: The controlled release tablet showed a relative bioavailability comparable with equal dose of the immediate release product and produced a significantly lower Cmax, as expected in a controlled release formulation. The concomitant administration of the tablet with a high fat meal produced an increase on its bioavailability, mainly in Cmax, with no evidence of dose-dumping.

Study of the release mechanism of diltiazem hydrochloride from matrices based on chitosan-alginate and chitosan-carrageenan mixtures.

The aim of this work was to establish the diltiazem hydrochloride release mechanism from the chitosan-alginate matrix tablet (MCB/AS) and chitosan-carrageenan matrix tablet (MCS/CSI). The weight loss for MCS/CSI is mainly due to the weight loss of the matrix while for MCB/AS it is mainly due to the diltiazem hydrochloride released from the tablet. Using the Peppa's model the release order for MCS/CSI was n = 1.07 +/- 0.13 and for MCB/AS was n = 0.76 +/- 0.02. Thus, MCS/CSI has a transport mechanism, and for MCB/AS the drug release mechanism is a combined process of diffusion and relaxation. MCB/AS has an elastic modulus (G' = 10(5) Pa) one order of magnitude higher than MCS/CSI (G' = 10(4) Pa). MCB/AS is able to uptake solvent without disrupting the microstructure due to its high elastic modulus. Instead MCS/CSI showed a quick erosion process, which conducted to the tablet disintegration due to a fast solvent uptake process.

Pharmacokinetics of prednisolone in man during acute and chronic exposure to high altitude.

INTRODUCTION: The exposure to high altitude (H) produces several physiologic alterations which may induce changes in the pharmacokinetics of drugs. This hypothesis has been confirmed in previous studies which suggest that drugs which are highly bound to plasma proteins are most likely to exhibit altered pharmacokinetics. OBJECTIVES: To further elucidate the influence of H on pharmacokinetics, prednisolone was selected, since it is highly bound to plasma proteins, renally excreted and poorly bound to red blood cells. SUBJECTS, MATERIALS AND METHODS: Prednisolone (80 mg) was given orally to three groups of young healthy volunteers. One group was residing at sea level (L): the same volunteers were studied again after 15 hours of exposure to high altitude (3600 m, HA group), and volunteers living at H for at least six months (group HC). RESULTS: There were no statistically significant differences in the pharmacokinetic parameters calculated from plasma data in the three situations studied. When calculated from whole blood data, however, AUC and Cmax were increased and both volume of distribution and clearance diminished after exposure to H, either acute or chronically. Binding to proteins increased significantly after H exposure from 57% in group L to 75% and 94% in group H and HC, respectively. Binding to erythrocytes also increased with H exposure from 43.7% in group L to 50.6% and 61.6% in group HA and HC, respectively. The prednisolone/prednisone ratio in urine was 11.1 in group L, 7.3 in group HA and 45.6 in group HC. CONCLUSION: Since prednisone has very little intrinsic glucocorticoid activity and has to be converted to prednisolone for therapeutic effect, the alteration of the prednisolone/prednisone ratio, as a result of high altitude exposure could be clinically relevant. Additional experiments are desirable to further evaluate this observation.

Validated HPLC method for the determination of ranitidine in plasma.

A validated HPLC method for the determination of ranitidine in human plasma is presented. Sulfanilamide as internal standard (IS) was used. Plasma samples were purified by solid phase extraction (SPE) using a copolymeric [poly(divinyl-benzene-co-N-vinylpyrrolidone)] column ("Oasis Waters"). Mobile phase consisting of dibasic potasium phosphate 0.08 M/acetonitrile/methanol/triethylamine 0.05% (89.5:3:7:0.05) pH5 was used at a flow rate of 0.9 ml/min on a C18 column (Nova-Pack, 3,9 x 300 mm, Waters). The eluate was monitored using an UVNis detector set at 300 nm. Ratio of peak area of ranitidine to sulfanilamide was used for the quantitation of plasma samples. FDA criteria for bioanalytical validation was used to validate the method. Linearity was assessed between 100-1600 ng/ml, the limit of quantitation was 100 ng/ml and recovery was greater than 94%. Accuracy, precision and selectivity met the current recommendations for bioanalytical method validation. The method was successfully used in a bioavailability study of a ranitidine tablet in healthy volunteers.

Effect of three different diets on the bioavailability of a sustained release lithium carbonate matrix tablet.

BACKGROUND: Food-induced changes on the bioavailability of a sustained release lithium carbonate matrix tablet, which uses an acrylic matrix of Eudragit RSPM as sustaining agent, have been studied in healthy male volunteers. The tablet was developed in our laboratory using conventional technology. SUBJECTS, MATERIALS AND METHODS: The study design was a 4 x 4 Latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standardized normal, high fat or high fat/high protein meal. RESULTS: The results showed no differences in half-lifebeta, renal clearance, Vdbeta, AUC, tmax, Xinfinite(u), fraction absorbed and MRT. Higher Cmax (mg/l) were obtained when the tablet was administered with any kind of meal: 2.09 +/- 0.47 (fast), 2.95 +/- 1.04 (normal diet), 2.64 +/- 0.54 (high fat diet) and 2.87 +/- 0.67 (high fat/high protein diet). The analysis of the ratio Cmax/AUC indicated that changes in Cmax were more probably due to changes in the rate of absorption. To evaluate if the magnitude of the change could be clinically relevant, Cmax and C at 12 hours (dosing interval) were treated by the superposition method in order to establish maximum and minimum concentrations at steady-state. For all the experimental conditions both concentrations would remain in the therapeutic range (4.2 10 mg/l or 0.6 - 1.4 mEq/l). CONCLUSION: The behavior of the formulation is appropriate for a sustained release tablet and fasting or non-fasting state seems not to be a major consideration for bioavailability when deciding on the regimen administration.

In vitro conditions for the study of the in vivo performance of sustained-release theophylline matrix tablets administered in fasted conditions and with a high-fat diet.

Dissolution profiles of theophylline (TP) from three types of sustained-release (SR) matrix tablets (plastic [PL], lipid [LP], and hydrophilic [HP]) in different dissolution media, with and without enzymes, were established. Also investigated was the influence of a treatment of the tablets with peanut oil prior to the dissolution test. The in vivo behavior of the tablets under the fasted state and with the concomitant administration with a high-fat diet was previously evaluated; the diet produced changes in the absorption profiles for the three matrix tablets in comparison with fasted administration. Level A correlations were obtained between cumulative percentage dissolved (CPD) and cumulative percentage absorbed (CPA). For the fasted condition, better correlations were obtained with water as the dissolution medium for the HP and LP matrix; for PL matrix, the best correlation was obtained with a medium with gradual change of pH. The pretreatment with peanut oil showed better correlations for the fed state.

Dissolution kinetics evaluation of controlled-release tablets containing propranolol hydrochloride.

In the present research, controlled-release propranolol hydrochloride tablets were prepared for twice-daily administration, allowing more uniform plasmatic levels of the drug. Pharmaceutical formulations were prepared with hydrophobic Eudragit RSPO. The physical properties of the tablets were determined. Dissolution tests were performed in capsules containing the raw material using the following dissolution media: (A) distilled water, (B) simulated gastric juice without enzymes, and (C) simulated enteric juice without enzymes. A dissolution test was also performed for simulated samples (tablets) using distilled water as the dissolution medium.

Evaluation of the in vitro and in vivo performance of two sustained-release lithium carbonate matrix tablets. Effect of different diets on the bioavailability.

Two sustained-release (SR) lithium carbonate (Li) matrix tablets, which use a hydrophilic (HP) matrix of hydroxypropylmethylcellulose (Methocel 4K MP) and a lipid (L) matrix of hydrogenated castor oil (Cutina HR) as sustaining agents, have been studied. In vitro performance through dissolution tests in different media was established. The L and HP formulations were affected by the composition of the dissolution media, and liberation was complete in 8 hr using a variable-pH medium that simulates the gastrointestinal (Gl) pH. Liberation was better described by the diffusional model of the square root of time for the L matrix and by zero-order kinetics for the HP matrix. Absolute bioavailability (BA) and food-induced changes on BA of both formulations were studied. The in vivo study design was a 4 x 4 Latin square involving 12 subjects who received two tablets of a 300-mg dose of SR formulations while fasting or with a standardized normal, high-fat, or high-fat/high-protein meal. The results for both formulations showed no differences in the disposition parameters and mean residence time when the tablets were administered with any type of diet. Changes in rate of absorption were found when both types of tablets were administered with any class of diet. The analysis of the ratio Cmax/AUC (area under the curve) evidenced that changes in Cmax were attributable to a higher rate of absorption for the HP matrix and to a higher amount absorbed for the L matrix. In the last, high-fat and high-fat/high-protein diets produced higher AUCs than under fasting condition. The SR Li tablets formulated with hydrogenated castor oil were affected more by high-fat food, probably because of the increase of pancreatic and biliary secretions promoted by the meal, which would affect the matrix itself. The HP matrix was also affected, but to a lesser extent. The magnitude of the change in Cmax observed with this matrix probably is not important from a clinical point of view. Absolute BA was very low for the lipid matrix; in addition, since it is more seriously affected by food, probably it is not a good choice for a drug such as lithium. The in vivo behavior of the HP matrix makes it advisable to invest in efforts to achieve increased BA. Comparing in vitro and in vivo results, the focus should be achieving sustained, but complete, in vitro liberation in not more than 3 hr, with simulation of the transit time through the stomach and small bowel since lithium ion is only absorbed to this point.

Evaluation of the effect of 3 different diets on the bioavailability of 2 sustained release theophylline matrix tablets.

Food-induced changes on bioavailability of 2 sustained release theophylline matrix tablets, which uses an hydrophilic matrix of Carbopol 974P and lipid matrix of hydrogenated castor oil (Cutina HR) as sustaining agents, have been studied in 2 different groups of 12 healthy male volunteers. The study design was a 4 x 4 Latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standarized normal, high fat or high fat/high protein meal. The results for both formulations showed no differences in t1/2 and MRT when the tablets were administered with any type of diet. No differences in tmax and AUC were found when the Carbopol matrix tablet was administered with any class of diet. Higher Cmax were obtained when the tablet was administered with any class of meal. The analysis of the ratio Cmax/AUC evidenced that changes in Cmax for normal and high fat diet were attributable to higher rate of absorption, probably due to a delay in gastric emptying, thus avoiding the rapid formation of the gel structure which controls the liberation of theophylline. Three subjects showed a probable bioadhesive behavior of the formulation in the fasted condition. The lipid matrix tablet showed a statistical significant delay in tmax comparing the fasted condition with the different diets. AUC, Cmax, and the ratio Cmax/AUC did not change when the tablet was administered with the normal diet. High fat and high fat/high protein diets produced higher AUC (31% and 40%, respectively) and Cmax (40% and 56%, respectively) than under fasting condition. The analysis of the ratio Cmax/AUC indicated that changes in Cmax were more probably due to changes in the amount absorbed. In conclusion, a sustained-release theophylline tablet formulated as a lipid matrix is affected by any meal with a high fat content, probably because of the increase of pancreatic and biliary secretions promoted by the meal that would affect the matrix itself. Normal diet showed this behavior but only as a nonsignificant trend. It seems appropiate to recommend to dose both formulations at least 2 hours before meal, or under consistent conditions of fasting or nonfasting state to assure reproducible absorption or clinical response.

Chronopharmacokinetics of theophylline administered as a controlled-release tablet.

The result obtained from different studies of the chronopharmacokinetics of some controlled-release tablets of theophylline are variable, since some authors report differences while others do not. At our laboratory we have developed a formulation of a controlled-release theophylline tablet using acrylic resins and we studied the chronopharmacokinetics of theophylline from this dosage form. Seven Caucasian healthy male volunteers participated in the study approved by the Institutional Review Board (IRB). Each volunteer received a controlled release tablet of 300 mg theophylline and an i.v. dose equivalent to 131.46 mg theophylline once at 8.00 a.m. and once at 8.00 p.m. Theophylline plasma concentrations were determined by HPLC. The following pharmacokinetic parameters were calculated: maximum concentration, time to reach maximum concentration, mean residence time, absorption constant, area under the curve of plasma concentration versus time, distribution volume (Vd beta), and total clearance. No statistically significant differences were found between diurnal and nocturnal data. This implied that, with this formulation, there is a lower risk of toxic plasma concentrations or concentrations under the therapeutic level than with formulations that exhibit circadian rhythm.

Evaluation of the effect of different kinds of foods on the bioavailability of a sustained-release theophylline tablet.

Food-induced changes on the bioavailability of a sustained-release theophylline tablet, which uses acrylic resins Eudragit as sustaining agent, were studied in 12 healthy male volunteers. The tablet was developed in our laboratory using conventional technology. It presented a good bioavailability pattern and maintained plasmatic concentrations within the therapeutic range for 12 hours under conditions of steady-state. The study design was a 4 x 4 latin square involving 12 subjects who received a single dose of the tablet while fasting or with a standardized normal, high fat or high fat/high protein meal. The results showed no differences in AUC, K, tmax, ka and MRT. Statistical differences were found in Cmax comparing the fasting condition with high fat/high protein diet. A delay was also observed in the detection of the drug in plasma when the tablet was administered with high fat and high fat/high protein food, but clinically the changes seem to be irrelevant.

Influence of alcohol consumption on erythromycin ethylsuccinate kinetics.

The effect of ethyl alcohol ingestion on erythromycin kinetics was studied. Nine healthy volunteers, four males and five females, participated in the study. They received, in two separate occasions, 500 mg of erythromycin ethylsuccinate ester given with water or with an alcoholic beverage. The antibiotic was assayed in plasma, using a microbiological method. Absorption and disposition parameters were calculated according to classical pharmacokinetic techniques. A longer lag time and a decrease in AUC were observed when the antibiotic was given with alcohol. The differences were statistically significant. It is likely that the effect of alcohol on gastric emptying could be responsible for the delayed absorption of the antibiotic.

Effect of mixing on the bioavailability of nitrofurantoin capsules.

The effect of blending time on the "in vivo" absorption of powder mixtures of similar composition, containing nitrofurantoin (NF), both in crystalline (10-50 u diameter) and macrocrystalline (70-80 u diameter) forms, was studied. The blending operations were performed using a Twin-Shell Blender (V-Type). The ingredients were blended long enough to obtain homogeneity, and this point was considered as "zero time". The mixing was continued and a intensifier bar was placed inside the blender. Samples were collected at 0; 30 and 45 minutes of blending and hard gelatin capsules were filled with these samples. A bioavailability study was performed in six healthy male volunteers. The experiments were conducted in a crossover fashion and each volunteer took one capsule of each time of blending of both microcrystalline and macrocrystalline nitrofurantoin. Urine samples were collected after the administration of the drug, and assayed by a spectro-fluorometric method. The total nitrofurantoin (NF) amount excreted in urine showed statistically significant differences at different times of blending only when capsules containing microcrystalline drug were administered.

Design and evaluation of a controlled-release theophylline tablet. Preliminary communication.

A 300 mg controlled-release theophylline formulation was developed as a tablet prepared by wet granulation using the acrylic resins Eudragit S 100R and Eudragit RSPMR. The tablet was compared with a marketed controlled-release capsule using in vivo and in vitro tests. The in vitro dissolution of theophylline from the tablets followed an apparent zero order kinetics. The in vivo comparison was performed in a cross over fashion in four healthy volunteers who received one tablet or capsule every 12 hours during seven days. The results showed no statistically significant differences in AUC, tmax and in plasma theophylline concentrations at the different times. Nevertheless, concentrations were lower after the administration of the tablets than when the volunteers received the capsules. On the other hand, the apparent elimination half lives obtained after the tablets were longer than with the capsules. An excessive retardation in the release of theophylline from the tablet could be responsible for this fact.