Plasma pharmacokinetics and gastrointestinal transit of a new Propionyl-l-Carnitine controlled release formulation

1. Propionyl-l-carnitine is a naturally occurring analogue of l-carnitine (LC) produced in the body. PLC administration has shown beneficial effects in cardiovascular pathologies. In ulcerative colitis (UC), oral PLC treatment increased clinical presentation and positively influenced colon histology. In the present study, the MMX Multi Matrix System^® (MMX?) was used as drug delivery strategy for targeted PLC colon delivery.

2. A pharmacoscintigraphic study (n?=?6 healthy volunteers) described release characteristics of two MMX-PLC-HCl controlled release 500?mg tablets. A pharmacokinetic (PK) parallel group study (n?=?24) determined safety, plasma PLC concentrations and PK parameters after single and multiple doses.

3. Gastrointestinal transit was slow and variable. The colon was the main site of PLC release and absorption. After single 500 or 1000?mg PLC doses plasma PLC and LC increased up to 2.6 and 1.2–1.3-fold compared to baseline. Multiple doses of 500 and 1000?mg twice a day over 7 days did not significantly increase maximum plasma concentrations of PLC or LC with respect to concentrations achieved after single dose administration.

4. The colon is the main site of PLC release and absorption from MMX-PLC tablets. A daily dose of 500?mg to 1000?mg PLC twice a day was well tolerated, justifying further studies in patients with pathologies of the distal gastrointestinal tract to evaluate the efficacy of the MMX-PLC formulation.

     

The gastrointestinal transit of a controlled release formulation of indomethacin

The gastrointestinal transit of a controlled release indomethacin tablet has been evaluated in vivo in a group of six fasted and fed subjects using the technique of gamma-scintigraphy. The product was similar in its gastrointestinal transit behaviour to other pharmaceutical dosage forms; emptying of the tablet from the stomach was slowed by the presence of food but transit through the small intestine was not affected by feeding conditions. In vivo the tablet underwent a process of gradual dissolution and diffusion followed by complete dispersion. The bioavailability of indomethacin from this preparation was not affected by the presence of food.     

Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation

AIMS: The aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability. METHODS: Two phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of (153)Sm-labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco-scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls. RESULTS: (153)Sm-labelled tablets reached the ascending colon after a mean +/- SD 9.8 +/- 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety-six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased C(max) values from 1429 +/- 1014 to 1040 +/- 601 pg mL(-1) (P = 0.028) and AUC values from 14 814 +/- 11 254 to 13 486 +/- 9369 pg h(-1) mL(-1) (P = 0.008). Mean residence time and t(max) increased by 12-29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide. CONCLUSIONS: MMX-budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.     

Gastrointestinal transit of a controlled release naproxen tablet formulation

The gastrointestinal transit of a controlled release naproxen tablet formulation has been measured in healthy young and old subjects using the technique of gamma scintigraphy. Gastric emptying of the tablet was affected by food (mean emptying times for fasted subjects were 0.64 h (young) and 0.86 h (old) increased to 3.0 h (young) and 3.3 h (old) following a light breakfast). The small intestinal transit times for both fed and fasted states was about 3.2 h. There were no significant differences that could be attributed to subject age for gastric emptying and small intestinal transit.     

5-aminosalicylic acid release from a new controlled-release mesalazine formulation during gastrointestinal transit in healthy volunteers

BACKGROUND: Mesalazine (5-aminosalicylic acid, 5-ASA) containing formulations represent a cornerstone in the treatment of inflammatory bowel diseases. A novel formulation with an Eudragit L/S mixture coating has been developed to provide selective release of 5-ASA to the ileo-caecal region and the colon. AIM: To determine the release of 5-ASA during the gastrointestinal transit. METHODS: A single oral dose of mesalazine EC 500 mg gastroresistant tablets (Asamax) was administered to eight healthy male volunteers. Gastrointestinal transit and tablet disintegration were monitored by scintigraphy. 5-ASA release was verified by assessing plasma pharmacokinetics. RESULTS: Initial tablet disintegration was observed 5.65 +/- 0.86 h after dosing, corresponding to the detection of 5-ASA in plasma. This occurred in the ileo-caecal region in three subjects and the ascending colon in the remaining five. The relative percentage of 5-ASA absorption was more pronounced in the ascending colon (41 +/- 27.4%) than the ileo-caecal region (6.6 +/- 9.2%). CONCLUSION: This mesalazine EC gastroresistant tablets release locally active 5-ASA specifically in the ileo-caecal region and the ascending colon.     

Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation

BACKGROUND: Mesalazine (5-aminosalicylic acid, 5-ASA)-containing formulations represent a cornerstone in the treatment of inflammatory bowel diseases. Recently, a new formulation has been developed to provide selective and more homogeneous release of 5-ASA compared to traditional systems. METHODS: In a first study, gastrointestinal transit was followed by gamma-scintigraphy after single-dose application of tablets containing 1200 mg mesalazine to 12 healthy male volunteers. 5-ASA release was verified by the assessment of plasma pharmacokinetics. In a second, 7-day, multiple-dose study, the steady state plasma pharmacokinetics, urinary excretion and safety profile were characterized after twice-daily tablet administration to 12 healthy volunteers. RESULTS: Tablet erosion started after 6.9 +/- 1.1 h in the ascending or transverse colon. Radioactivity spread homogeneously throughout the colon, indicating the sustained release of active 5-ASA. Plasma kinetics indicated an earlier initial absorption of 5-ASA, i.e. during transit of the small intestine and ileum. Mean Cmax values (350.6 +/- 322.6 ng/mL) were observed during location in the ileo-caecal region. The mean relative absorption of 5-ASA was 19.9 +/- 18.2% in the small intestine and ileum and 80.1 +/- 18.2% in the colon. CONCLUSIONS: The administration of the new mesalazine formulation was well tolerated, and 5-ASA was continuously released along the whole colon, a favourable prerequisite for the therapy of distally located inflammatory bowel disease.     

Gamma-scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices

A xanthan gum matrix controlled release tablet formulation containing diclofenac sodium was evaluated in vitro and was found to release the drug at a uniform rate. The gastrointestinal transit behaviour of the formulation as determined by gamma scintigraphy, using healthy male volunteers under fasted and fed conditions, indicated that gastric emptying was delayed with food intake. In contrast, the small intestinal transit remained practically unchanged under both food statuses. Therefore, the delay in caecal arrival observed in the fed state can be attributed to the delay in gastric emptying. Rate of diclofenac sodium absorption was generally higher in the fed state compared to the fasted state, however the total amount absorbed under both food statuses remained practically the same. The rate of in vivo dissolution of the drug in the fed state was faster compared to that in the fasted state. Thus, at the time of caecal arrival, in vivo dissolution was complete in the fed state, unlike in the fasted state, where almost 60% of the drug was delivered to the colon.     

Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine

OBJECTIVE: To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers. DESIGN: Nonblind, randomised, 2-way crossover trial. PARTICIPANTS: 19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping. METHODS: Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined. RESULTS: 17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated. CONCLUSIONS: The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower rate of dry mouth subsequently observed in patients with overactive bladder.     

Effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained release theophylline preparation.

A scintigraphic and pharmacokinetic study of the behaviour of (Bronchoretard forte, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. Volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the prestudy day and the mean pH was significantly reduced compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p less than 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.d.) to achieve steady-state. On the study day the volunteers swallowed two theophylline sustained release capsules radiolabelled by inclusion of indium-111 micronised Amberlite resin and the gastrointestinal transit followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline when presented in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group when treated with ranitidine or placebo. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.     

A comparative study of the gastrointestinal transit of a pellet and tablet formulation

The gastrointestinal transit of a pellet and tablet formulation have been evaluated in a group of 6 subjects using the technique of gamma-scintigraphy. Each formulation was labelled with a different radionuclide and the preparations administered concurrently. The transits of the formulations were found to be highly dependent on food intake and there was a good correlation between transit times (gastric emptying, arrival at colon) and the calorific value of the meal taken shortly before dosing. In some cases the pellet system emptied rapidly from the stomach and showed little spreading in the small intestines.     

Alginate-pectin-poly-L-lysine particulate as a potential controlled release formulation

Drug delivery particulates were prepared using alginate, polylysine and pectin. Theophylline, chlorothiazide and indomethacin were used as the model drugs for in-vitro assessments, and mannitol was the model for assessing paracellular drug absorption across Caco-2 cell monolayers. Alginate and pectin served as the core polymers and polylysine helped to strengthen the particulates. Use of pectin specially helped in forming a more robust particulate that was more resistant in acidic pH and modulated the release profiles of the encapsulated model drugs in the alkaline pH. Alginate and pectin were also found to enhance the paracellular absorption of mannitol across Caco-2 cell monolayers by about three times. The release rate could be described as a first-order or square-root time process depending on the drug load. Use of alginate-polylysine-pectin particulates is expected to combine the advantages of bioadhesion, absorption enhancement, and sustained release. This particulate system may have potential use as a carrier for drugs that are poorly absorbed after oral administration.     

Design of a controlled release liquid formulation of lamotrigine

BACKGROUND AND THE PURPOSE OF THE STUDY: Lamotrigine is a broad spectrum anticonvulsant drug widely used as mono- or adjunct- therapy in adults and children. The aim of this study was to develop controlled release liquid formulation of lamotrigine to improve bioavailability and compliance of pediatric and geriatric epileptic patients. METHODS: Multiple (w/o/w) emulsion was prepared using one step emulsification technique. It was evaluated for entrapment efficiency (EE), morphology, zeta potential (ZP), polydispersity index (PI), rheology, thermal property, in vitro drug release behavior and stability. In vivo studies in albino mice were carried out using maximal electroshock seizure (MES) test and strychnine induced seizure (SIS) pattern test and results were compared with marketed formulation. RESULTS: The EE of the formulations varied from 84.37% to 98.11%. The ZP and PI values of the prepared batches were in the range of +23.46 to +28.07 and 0.256 and 0.365, respectively. Microscopic observation clearly indicated the stability of the emulsions during the storage period. All batches exhibited controlled in vitro drug release up to 12 hrs. Batch C11 exhibited significantly longer duration of protection of seizure in mice against MES and exhibited comparable efficacy in SIS as compared to the marketed formulation. MAJOR CONCLUSION: Multiple emulsion of lamotrigine compared to the marketed tablet showed plasma drug concentration within therapeutic range for longer time and comparable efficacy.     

Clinical pharmacokinetics and gastrointestinal tolerability of a novel extended-release microsphere formulation of azithromycin

BACKGROUND AND OBJECTIVE: A novel oral, extended-release, microsphere formulation of azithromycin (AZSR) was developed to improve the gastrointestinal tolerability profile while allowing administration of an entire treatment course of azithromycin in a single dose. Several phase I clinical pharmacology studies were conducted to (i) identify a well-tolerated single-dose formulation that met a predefined exposure target; and (ii) evaluate the effect of food and antacid on the absorption of this formulation. Of these, five pivotal studies are described here. METHODS: The pharmacokinetic profile of AZSR was compared with that of the commercially available immediate-release azithromycin formulation (AZM) in an open-label, crossover, single-dose study (Study A), and their gastrointestinal tolerability profiles were compared in an observer-blind, parallel group, single-dose study (Study B). The effects of food (a high-fat meal and a standard meal) and antacid (a single 20 mL dose of Maalox Regular Strength, containing magnesium hydroxide, aluminium hydroxide and simethicone) on the absorption of azithromycin from AZSR were evaluated in three separate open-label, crossover, single-dose studies (Studies C, D and E). Healthy adult subjects were enrolled in all five studies, and all subjects were evaluable for tolerability. The dose used for all azithromycin formulations was 2.0 g. Serum azithromycin concentrations were determined using a validated high-performance liquid chromatography/electrochemical detection method, and pharmacokinetic parameters were analysed using noncompartmental methods. RESULTS: 377 subjects received a single 2.0 g dose of azithromycin as AZSR and/or AZM in the five studies. Compared with AZM, AZSR had a slower absorption rate (57% decrease in the mean peak concentration [C(max)] and an approximate 2.5-hour delay in the time to reach C(max) [t(max)]), with a mean relative bioavailability of 82.8%, which met the predefined exposure target (at least 80% bioavailability relative to AZM). Compared with AZM, AZSR was associated with significantly lower rates of nausea and vomiting. A high-fat meal increased the mean area under the serum concentration-time curve [AUC] from time zero to 72 hours post-dose (AUC(72 h)) by 23% and increased the C(max) of azithromycin by 115%. A standard meal increased the mean C(max) by 119% but had no clinically significant effect on the AUC(72 h). AZSR appeared to be better tolerated in the fasted state than in the fed state. The AUC(72 h) and C(max) of AZSR were not significantly affected by co-administration with a single dose of antacid. CONCLUSIONS: The extended-release microsphere formulation of azithromycin, AZSR, allows administration of an entire therapeutic course of azithromycin as a well-tolerated single 2.0 g dose. This formulation should be administered on an empty stomach and can be co-administered with antacids.     

Clinical bioavailability evaluation of a controlled release formulation of diazepam

A controlled release formulation of diazepam was compared to equal daily dose of the trade tablet under single day and steady-state conditions. Virtually no differences were found in the mean steady-state concentrations of diazepam or its metabolites, N-desmethyldiazepam, when the subjects received the 5 mg trade table three times daily or the 15 mg controlled release formulation once daily. Similarly, there was no difference in mean diazepam or N-desmethyldiazepam plasma concentrations when single doses of the controlled release formulation were give to fed or fasted volunteers. These data indicate that the controlled release formulation produces plasma concentrations of diazepam and N-desmethyldiazepam comparable to those achieved with the same daily dose of the trade product given three times daily, suggesting that these regimens can be used interchangeably.     

Clinical bioavailability evaluation of a controlled release formulation of diazepam

A controlled release formulation of diazepam was compared to equal daily doses of the trade tablet under single day and steadystate conditions. Virtually no differences were found in the mean steadystate concentrations of diazepam or its metabolite, N-desmethyldiazepam, when the subjects received the 5 mg trade tablet three times daily or the 15 mg controlled release formulation once daily. Similarly, there was no difference in mean diazepam or N-desmethyldiazepam plasma concentrations when single doses of the controlled release formulation were given to fed or fasted volunteers. These data indicate that the controlled release formulation produces plasma concentrations of diazepam and N-desmethyldiazepam comparable to those achieved with the same daily dose of the trade product given three times daily, suggesting that these regimens can be used interchangeably.Diazepam/Roche is marketed under the trade name Valium^®.     

Development of a controlled release formulation based on a starch matrix system

Controlled release formulation (CRF) of the insecticide acetamiprid was made using tapioca starch, urea and sodium borate. The data show the recovery of this CRF process is > 95.43%, there is no obvious difference with increase of sodium borate added, however, with the increase of urea in the mixture, the formulation has a decrease recovery. In stability test, the decomposition rate of acetamiprid CRF was less one tenth than that of the acetamiprid emulsifiable concentrate (EC) under UV radiation. The release kinetics of acetamiprid from granules with variation content of urea, sodium borate and granule sizes were evaluated in water under laboratory condition. The release data were fitted to the generalized model Mt/Mz = kt(n), where Mt/Mz is the percentage of insecticide released at time t, k and n are constants, and n is constant that indicates the mechanism of release. The results indicated that the release of acetamiprid was diffusion-controlled. The time taken for 50% of the active ingredient to be released into water, T50, was also calculated for the comparison of formulations. The results showed that the formulation with the increasing urea in formulation had the higher value of T50, which means a slower release of the active ingredient, while that the formulation with the increasing sodium borate in formulation had the lower value of T50, which means a faster release of the active ingredient. It was also found that as the size of this formulation decreased, the release of the active ingredient was faster.     

Plasma and saliva concentrations for a new formulation of erythromycin stearate

Summary

Erythromycin saliva and plasma concentrations were determined in 10 subjects after the first and fourth doses of a new formulation of erythromycin stearate (‘Erythrocin’), 500?mg 8-hourly, taken immediately before food. Consistent absorption occurred and the steady state plasma levels compared favourably with the minimal inhibitory concentrations of erythromycin for common respiratory pathogens. There was a significant positive correlation between steady state saliva and plasma levels.     

Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation

AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment. METHODS: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females. CONCLUSIONS: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects.     

A new formulation of controlled release amitriptyline pellets and its in vivo/in vitro assessments

Controlled-release amitriptyline pellets (ATP) were formulated and its oral bioavailability was assessed in human volunteers after oral administration under fasting conditions. Core pellets were prepared using a CF granulator by two different methods (powder layering and solvent spraying) and coated with Eudragit RS or RL 100. Physical characteristics and dissolution rates of core pellets and coated pellets were evaluated to optimize the formulation. Powder layering method resulted in a better surface morphology than solvent spraying method. However, physical properties of the products were poorer when prepared by powder layering method with respect to hardness, friability and density. The dissolution profile of amitriptyline coated with Eudragit RS 100 was comparable to that of commercially available amitriptyline enteric-coated pellets (Saroten retard). After the oral administration of both products at the dose of 50 mg, the mean maximum concentrations (Cmax) were 36.4 and 29.7 ng/mL, and the mean areas under the concentration-time curve (AUC(0-96)) were 1180.2 and 1010.7 ng.h/mL for ATP and Saroten retard, respectively. The time to reach the maximum concentrations (Tmax) was 6 h for both formulations. Statistical evaluation suggested that ATP was bioequivalent to Saroten retard.     

Assessment of a controlled release hydrophilic matrix formulation for metoclopramide HCl.

Metoclopramide HCl showed controlled release behavior when embedded in a hydrophilic matrix of chitosan and sodium alginate. The in vitro release data was found to be first order according to the Higuchi mechanism. An in vivo evaluation of the metoclopramide controlled release matrix on six male volunteers was carried out. The plasma samples were analyzed using a high-performance liquid chromatography (HPLC) method using a mobile phase of acetonitrile:acetic acid (30:70), with the pH adjusted to 4.7, a reverse phase Hypersil BDS Phenyl column (4 microm, 250 x 4 mm) and the detection was performed at 305 nm. The controlled release formula was found to be effective in delaying absorption (t(max) 4.5h as compared to 1.2h), reducing the peak plasma concentrations (C(max) 63.4 ng/ml as compared to 95.9 ng/ml) and maintaining higher concentrations during the elimination phase when compared to the immediate release formula. This proves the suitability of the suggested system for further studies.