Pharmacokinetics of nortilidine and naloxone after administration of tilidine/naloxone solution or tilidine/naloxone sustained release tablets

Valoron N is a compound which consists of the prodrug tilidine (CAS 20380-58-9), from which the active metabolite nortilidine is formed by demethylation in the liver, and the opiate antagonist naloxone (CAS 465-65-6), which prevents the abuse of the analgesic by opiate dependents. The pharmacokinetics of nortilidine and naloxone were studied in 18 male healthy subjects after oral application of tilidine/naloxone solution or tilidine/naloxone retard tablets, respectively. The following report gives the results on investigations of a) dose linearity after application of 25 mg, 50 mg and 100 mg Valoron N solution, b) dose equivalence of Valoron N solution (4 x 50 mg tilidine) and Valoron N retard tablets (2 x 100 mg tilidine) under steady state conditions, and c) the equivalence of different dose strengths of Valoron N retard tablets (50 mg, 100 mg, 200 mg tilidine/tablet). The results obtained in these studies demonstrate a dose linear kinetic for nortilidine after the application of 25 mg to 100 mg tilidine. Furthermore, there is dose equivalence between the tilidine/naloxone solution and tilidine/naloxone retard tablets, which permits the replacing of the solution with the retard tablets. Because of the equivalence of different dose strengths of Valoron N tablets, patients are able to exchange low dosed Valoron N retard tablets for higher-dosed ones (50 mg, 100 mg and 200 mg tilidine/tablet), if necessary. With their constant release of tilidine and the possibility for individual dosage, the retard tablets are efficient analgesics that improve pain therapy considerably for patients with chronic pain.     

Bioavailability of a new ketoprofen formulation for once-daily oral administration

A new sustained-release formulation (sustained release Ibifen) that gradually releases ketoprofen within 24 h and ensures therapeutic plasma concentration for the entire period has been developed. It consists of tableted pH-dependent barrier film-coated ketoprofen granules and was administered at a single dose of 200 mg to 12 volunteers. Ketoprofen plasma profiles were compared with: (1) administration of Orudis retard 200 capsule (200 mg); (2) two 12-h doses of prompt release Ibifen capsules (100 mg). In vitro dissolution kinetics and ketoprofen plasma levels were measured by HPLC. Sustained release Ibifen dissolution rate was constant for 10 h, whereas Orudis retard 200 dissolution profile presented one higher slope (0-6 h) and a lower one (6-12 h). Both formulations showed a delayed kinetics with respect to prompt release Ibifen. After sustained release Ibifen administration, ketoprofen plasma peak, reached within 2 h, remained practically constant for at least 12 h (average 4 microg/ml), which is higher than therapeutic levels. Differently, Orudis retard 200 produced a delayed, higher C(max) (5.91+/-0.66 vs. 4.51+/-0.65 microg/ml; P<0.01) and disappeared more quickly. In conclusion, sustained release Ibifen can ensure therapeutic ketoprofen plasma levels for the entire 24 h period, avoiding plasma concentration spikes, with bioavailability similar to other ketoprofen preparations.     

Bioavailability of a new controlled-release oral naproxen formulation given with and without food.

The influence of concomitant food intake on the plasma concentration of naproxen given as a new controlled-release (CR) formulation (750-mg tablet) was investigated in a crossover study design. Twelve healthy volunteers received a single tablet of naproxen on two occasions separated by a 3-week washout period:- after an overnight fast and immediately after a standard meal. Plasma naproxen levels were measured through HPLC at intervals suitable for obtaining concentration-time curves of both regimens in the range 1--48 hours. It was found that average plasma AUC values were 1978.7 mcg.hr/ml in fasting participants and 1778.6 mcg.hr/ml in postprandial participants. The confidence interval computed by Westlake's method indicated equivalence of values. Food decreased the peak plasma concentration of CR naproxen by about 14%, but the confidence interval (+/- 22%) barely exceeded equivalence limits. There were no significant differences between fasting versus postprandial values for the mean absorption time, or plasma absorption and disposition half-lifes. It is concluded that the bioavailability of CR naproxen is not substantially altered by the ingestion of food.     

Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex

As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced.     

Bioavailability of griseofulvin from a novel capsule formulation.

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.     

Bioavailability assessment of a new liquid controlled-release pseudoephedrine product

Development of a liquid controlled-release pseudoephedrine product is described. Two bioequivalence studies were conducted. In a single-dose study involving 20 subjects, the bioavailabilities of five controlled-release suspensions with a broad range of drug-release rates were compared with an immediate-release form of pseudoephedrine hydrochloride in a four-way crossover, incomplete block, sequence-randomized study. Serial blood sampling up to 36 hours after drug ingestion provided area-under-the-curve (AUC), maximum plasma concentration (Cmax), and time to peak (tmax). In the multiple-dose study, involving 18 subjects, the bioavailability of the optimal formulation determined from the single-dose study was compared with a reference pseudoephedrine hydrochloride syrup. Serial blood sampling up to 12 hours after drug ingestion was performed to determine AUC, Cmax, and tmax. The single-dose investigation showed that all formulations were bioequivalent except the product with the slowest release rate, which had lower AUC and Cmax values. The results of the multiple-dose study confirmed these findings with the reference syrup. The use of a series of drug formulations with a wide range of release rates permitted selection of an optimal product in addition to providing the information needed to ensure continuous production of bioequivalent products.     

Bioavailability study of a freeze-dried sodium phenytoin-milk formulation.

The problematic bioavailability of phenytoin's (5,5-diphenylhydantoin) oral formulations serves as a stimulus for examining new formulations and/or administration conditions that may provide more predictable absorption. Attempts to achieve more consistent peroral phenytoin bioavailability from conventional solid dosage forms include changes of binder and crystal size, use of salt form, and inclusion of the drug in cyclodextrins. In addition, various factors which may affect the environment and/or the physiology of the upper gastrointestinal tract can profoundly affect the absorption of phenytoin. Among other approaches, the use of drug-milk freeze-dried formulations has been proposed to overcome problems associated with dissolution-limited bioavailability. The effect has been attributed to the formation of an amorphous precipitate during the drying process which facilitates the re-dissolution of the drug during the regeneration of the milk solution. In this work, we report comparative bioavailability studies utilizing a freeze-dried sodium phenytoin-milk formulation and a capsule formulation administered with either water or milk. In addition, the interaction of the drug with milk components was evaluated in vitro through binding and solubility studies.     

Bioavailability of phenylbutazone from a new enteric-coated formulation with superior dissolution characteristics

The bioavailability of an improved formulation of enteric-coated phenylbutazone with faster dissolution, more consistent in vitro rate of drug release and improved stability was compared in 8 normal subjects at doses of 100 and 200 mg with commercially available Butacote®. Phenylbutazone was more rapidly absorbed from the new formulation and higher plasma concentrations were achieved at shorter intervals after dosing. Drug elimination rate was unaffected by reformulation and despite faster absorption the total amounts of drug reaching the circulation from the new and commercial products were similar. It was concluded that replacing Butacote® by the new formulation would provide the same therapeutic benefit.     

Bioavailability of divalproex extended-release formulation relative to the divalproex delayed-release formulation

Divalproex sodium extended-release tablet (divalproex-ER) is a novel formulation of the conventional divalproex sodium delayed-release tablet (divalproex). In five multiple-dose studies in healthy subjects (n=82) and epilepsy patients (n=86) the estimates of divalproex-ER/divalproex ratios for steady-state 24 h valproic acid area under the curve (AUC) central values, maximum concentration (C(max)) central values and minimum concentration (C(min)) means had ranges of 0.77-0.97, 0.71-0.87 and 0.78-1.03, respectively. These studies used different divalproex regimens (two, three or four times daily) and meal conditions (fasting, low, medium and high calorie meals). Divalproex-ER was administered once daily. A meta-analysis of divalproex-ER/divalproex relative bioavailability across five studies under different meal conditions and divalproex dosing frequencies was performed. This meta-estimate of relative bioavailability was used to provide dosing recommendations for conversion of patients from divalproex to divalproex-ER. The estimated AUC, C(max) and C(min) divalproex-ER/divalproex ratios (95% confidence interval) were 0.89 (0.85-0.94), 0.79 (0.74-0.84) and 0.96 (0.90-1.02), respectively. The food and divalproex regimen had no effect on the relative bioavailability. While switching from divalproex to divalproex-ER, the divalproex-ER daily dose may have to be increased by an average of 12% (calculated as 1.0/0.89) to achieve comparable plasma exposure. Since the divalproex-ER dosage strengths (250 and 500 mg) are not 12% higher than the divalproex dosage strengths (125, 250 and 500 mg), an 8% to 20% higher divalproex-ER daily dose should be considered for conversion from divalproex to divalproex-ER.     

Comparison of tilidine/naloxone, tramadol and bromfenac in experimental pain: a double-blind randomized crossover study in healthy human volunteers.

AIM: The analgesic efficacy and safety of single oral doses of two centrally acting compounds, the combination of 50 mg tilidine and 4 mg naloxone (Valoron N) and 50 mg tramadol (Tramal), were compared to 25, 50 and 75 mg of the non-steroidal antiinflammatory bromfenac in experimental pain. SUBJECTS AND METHODS: It was a placebo-controlled double-blind 6-way crossover study design with 12 human volunteers. Acute pain was generated by electrical tooth pulp stimulation. Treatment effects were determined by recording somatosensory-evoked potentials and by subjective pain rating. RESULTS: The tilidine/naloxone combination clearly was the most potent medication in this study, followed by bromfenac 75 mg, which produced an early pain relief. Tramadol produced poor analgesia, as did bromfenac 25 and 50 mg. There was no dose-response relationship for bromfenac. Control of plasma levels revealed pronounced interindividual differences in peak plasma concentrations for bromfenac, but not for tramadol. Tilidine/naloxone exerted adverse effects in 9, tramadol in 3 volunteers. Under medication with 25 and 50 mg bromfenac, respectively, only one subject reported adverse effects. No adverse effects were experienced with 75 mg bromfenac or placebo. CONCLUSION: The results support previous conclusions about the analgesic efficacy of tilidine/naloxone and tramadol in experimental pain. Moreover, the findings suggest that 75 mg bromfenac might be suitable for fast but short relief of pain of non-inflammatory genesis.     

Comparative bioavailability of a new commercial tablet formulation and two lots of a reference formulation of haloperidol

The bioavailability of a new tablet formulation (5 mg) of haloperidol was estimated relative to two lots of a reference product. Twenty-eight healthy male volunteers completed all three phases in that they received the test (T) and the two reference formulations (R1 and R2) in a balanced three-way crossover design. Using a sensitive HPLC method, plasma concentrations of haloperidol and reduced haloperidol were monitored over a period of 96 h following administration of each formulation. Haloperidol was measurable in the plasma of all the volunteers, whereas reduced haloperidol was measurable in only 6 out of 28 volunteers following each administration. Therefore, the assessment of bioequivalence in this study is based on haloperidol data only. The maximum plasma concentration (Cmax), time to Cmax (tmax), and area under the curve up to the last measurable concentration (AUCot) or infinity (AUCo infinity) were compared by analyses of variance and found not to be significantly different across the formulations. The relative bioavailability based on T:R1 or T:R2 ratios of AUCo infinity, AUCot, and Cmax was, in each case, within the acceptable range of 100 +/- 20%. Also, the relative bioavailability of R1 compared with R2 was within 100 +/- 20% in terms of the above bioavailability parameters. Except for tmax, all other pharmacokinetic parameters showed wide intersubject variation.     

Bioavailability of griseofulvin from a novel capsule formulation

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.     

Bioavailability of riboflavin from a gastric retention formulation

A gastric retention formulation (GRF) made of naturally occurring carbohydrate polymers and containing riboflavin was tested in vitro for swelling and dissolution characteristics as well as in fasting dogs for gastric retention. The bioavailability of riboflavin, a drug with a limited absorption site in the upper small intestine, from the GRF was studied in fasted healthy humans and compared to an immediate release formulation. It was found that when the GRF is dried and immersed in gastric juice it swells rapidly and releases its drug content in a zero-order fashion for a period of 24 h. In vivo studies in dogs showed that a rectangular shaped GRF stayed in the stomach of fasted dogs for more than 9 h, then disintegrated and reached the colon in 24 h. Endoscopic studies in dogs showed that the GRF hydrates and swells back to about 75% of its original size in 30 min. These in vivo results correlated with in vitro results. Pharmacokinetic parameters determined from urinary excretion data from six human subjects under fasting conditions showed that bioavailability depended on the size of the GRF. The biostudy indicated that bioavailability of riboflavin from a large size GRF was more than triple that measured after administration of an immediate release formulation. Deconvolved input functions from biostudy data suggest that the large size GRF stayed in the stomach for about 15 h.     

Bioavailability and selected pharmacokinetic parameters of clindamycin hydrochloride after administration of a new 600 mg tablet formulation.

The study was conducted to investigate the pharmacokinetics and relative bioavailability of clindamycin after administration of two oral clindamycin HCl formulations. A new tablet preparation containing 600 mg clindamycin (Clinda-saar 600, test) was compared to a marketed capsule containing 300 mg clindamycin (Sobelin 300, reference). Both preparations revealed comparable in vitro dissolution profiles with high batch conformity and homogeneity. Twenty healthy male volunteers received single doses of 600 mg clindamycin (test: 1 tablet, reference: 2 capsules) in an open, randomized, two-period crossover design. Blood samples were drawn up to 14 h p.a. and clindamycin plasma concentrations were measured using a sensitive and specific HPLC-UV method. Pharmacokinetic characteristics were similar for both preparations, arithmetic mean values (standard deviation) were computed as: AUC(0-infinity) 12.2 (4.2) and 13.1 (4.6) microg x h/ml, Cmax 3.1 (0.8) and 3.4 (0.8) microg/ml, t(max) 0.83 (0.24) and 0.85 (0.34) h, t(1/2) 2.3 (0.4) and 2.3 (0.6) h for test and reference, respectively. Mean relative bioavailability (point estimate) was 93% for AUC and 91% for Cmax. 90% confidence intervals for AUC and Cmax were within the predefined bioequivalence acceptance limits. Bioequivalence of test and reference preparations could be demonstrated. Single doses of 600 mg clindamycin orally were well tolerated without relevant differences between both preparations.     

Bioavailability of bemetizide and triamterene from a combination formulation

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (P < 0.01) from that from a tablet containing 25mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3ngml^?1) was lower than that after administration of bemetizide alone (87.9 ngml^?1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml^?1) was higher than and significantly different (p< 0.001) from that after administration of triamterene alone (15.7 ng ml^?1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.     

Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution

The bioavailability of quinidine sulfate after oral administration of a commercial sustained-release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross-over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level-time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml^?1, comparable to that of the solution, 9145.9 ng × h ml^?1.     

Bioavailability evaluation of a controlled-release dextromethorphan liquid

A randomized, two-way, steady-state crossover study was performed in 24 healthy male volunteers to evaluate the bioavailability of a controlled-release (CR) dextromethorphan (DM) suspension. Only slow and intermediate DM metabolizers were allowed to participate in the study; determination of metabolizer status was performed before study enrollment. Each volunteer was administered 30 mg of an immediate-release (IR) DM solution qid or 60 mg DM as a CR suspension bid for two weeks, for a total daily dose of 120 mg. After a two-week washout period, the subjects were administered the alternate treatment. Blood samples were collected over a 12-hour dosing period on the last day of each treatment and analyzed for DM and its active metabolite, dextrorphan (DP). In addition, urine was collected over the 12-hour steady-state dosing interval and measured for DM and two metabolites. Pharmacokinetic determinations were made from plasma DM and DP data, and total urinary excretion was determined. All comparisons made between the two formulations indicated that the CR DM suspension was bioequivalent to the IR DM solution at steady state, while producing a prolonged release of the drug over time.     

Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach

Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing.     

Bioavailability in man of atenolol and chlorthalidone from a combination formulation

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drugs as a fixed combination ('Tenoret 50'), as a free combination, and individually, at doses of 50 mg atenolol and 12.5 mg chlorthalidone. There were no statistically or clinically significant differences between the three treatments of atenolol in terms of individual blood levels, areas under the curve, and urinary excretion. The mean half-lives were between 5 and 7 h, in agreement with other published data. The variation in peak systemic levels is less than that observed for a number of other beta-blocking drugs and is of the same order as seen in other investigations involving atenolol. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet. The mean peak blood concentrations of chlorthalidone were 0.94, 1.00, and 0.99 micrograms ml-1 for the fixed and free combinations and the chlorthalidone tablet, respectively. The mean areas under the curve were also similar as were the mean half-lives and urinary recovery. There were no statistically or clinically significant differences between the three treatments. Thus the bioavailability of chlorthalidone from the fixed combination is equivalent to that from the free combination and from the chlorthalidone tablet. It is concluded that combining chlorthalidone and atenolol in a single tablet does not affect the systemic bioavailability of either component.