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The fluid dynamics in the flow-through cell (USP apparatus 4) has been predicted using the mathematical modeling approach of computational fluid dynamics (CFD). The degree to which flow structures in this apparatus can be qualified as 'ideal' both spatially and temporally has been assessed. The simulations predict the development of the velocity field in this apparatus for configurations with and without beads during the discharge stroke of the pump. When the cell is operated only with the red ruby bead ('open column' mode), highly non-uniform flow is predicted just downstream of the bead in the latter stages of the pump's pulse. In contrast, a strong degree of profile uniformity and symmetry is predicted throughout the entire pulse in the region of the tablet holder for both standard configurations involving beads. However, noticeable differences in the tablet shear stress distribution are predicted at times when the same instantaneous inlet flow rates are being pumped through the apparatus. This effect is caused by flow separation in the velocity boundary layer formed around the tablet under the influence of an adverse pressure gradient, an effect not predicted with constant (non-pulsating) flow. While the degree of tablet erosion correlates with the average flow rate, during a particular pulse both the free-stream velocity and the boundary layer thickness are also influential.

Despite more than 30 years of clinical use, only few studies have been published reporting on the release mechanism underlying the drug delivery from push-pull osmotic pumps (PPOP). The aim of this study is to understand which factors have an effect on the drug delivery for modelling the drug release and to develop a mathematical model predictive of the drug release kinetics. The influence of the drug property was tested on two model drugs, isradipine (ISR) and chlorpheniramine (CPA) which are respectively practically insoluble and freely soluble. Results show that, regardless of the drug properties which do not significantly affect the drug delivery, the release kinetics is mainly controlled by four factors, (i) the PEG proportion in the membrane, (ii) the tablet surface area, (iii) the osmotic agent proportion and (iv) the drug layer polymer grade. The influence of each key formulation factors on the release mechanism was investigated defining their applicability range. A mathematical approach was developed to predict the drug delivery kinetics varying the PPOP controlling factors and helps to more efficiently design PPOP.

Objective: To study the release mechanism of Huperzine-A swelling sustained-release tablets (HA-ST) and the factors influencing the release rate., Method: The HA-ST were prepared by using Polyoxyethylene (PEO) as the matrix material, polyvinyl alcohol (PVA) as the expandable reagent and microcrystalline cellulose (MCC) as the filling reagent. The effect of the amount of PEO, PVA and MCC on the drug release from the tablets was evaluated using the release index n value of the Ritger-Peppas equation., Result: The addition of PEO and PVA speeded up the rate of drug release from the tablets, while MCC did not affect the release rate. The release profiles of HA-ST conformed to the Higuchi model and the release mechanism was non-Fick release that coupled diffusion and erosion., Conclusion: The release of HA-ST is influenced by the amount of PEO and PVA but not the MCC. The release process can be depicted by the Ritger-Peppas equation and release mechanism was is non-Fick release.

Background: Generic drugs are lower-cost versions of patent-expired brand-name medications. Bioequivalence is decreed when the 90% confidence intervals for the ratios of the generic to the reference compound for the area under the curve and maximum plasma concentration (C(max)) fall within a 0.80 to 1.25 range. The aim of the present pilot study was to compare the pharmacokinetic profiles of brand-name and generic formulations of citalopram and extended-release venlafaxine., Method: Effexor XR/Novo-venlafaxine XR 75 mg and Celexa/Gen-citalopram 40 mg were studied in a randomized crossover design. Healthy male volunteers took either Effexor XR or Novo-venlafaxine XR for 4 days, a 4-day washout was allowed, and then participants took the other venlafaxine formulation for 4 days. This was followed by a washout of at least 7 days. The participants then took Celexa or Gen-citalopram for 8 days, a 14-day washout was allowed, and then participants took the other citalopram formulation for 8 days. In each of the study phases, the sequence of treatment (brand-name x generic) was randomly assigned. Plasma levels of drugs were measured at fixed intervals after participants took the drugs and at steady state. The study was conducted from November 2007 through July 2008., Results: Twelve participants completed the venlafaxine study. Nine of the participants, plus 3 new participants, were then enrolled in the citalopram study, to maintain a total of 12. The plasma levels of citalopram were similar after ingestion of the brand-name and generic drugs. After ingestion of venlafaxine, the C(max) values were 36 +/- 6 ng/mL and 52 +/- 8 ng/mL in the brand-name and generic groups, respectively. The ratio of the log-transformed values of C(max) was 150% and, therefore, not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-desmethyl-venlafaxine [ODV]) was also significantly increased in the generic group (+43% higher in the generic group at 3 h; +48% higher at 5 h; p < .05). No differences were seen at steady state for either ODV or venlafaxine. Participants taking Novo-venlafaxine reported 3 times more side effects than those taking Effexor XR. Pill contents were identical in the 2 groups, but extraction of venlafaxine occurred more readily with the generic formulation than with the brand-name formulation, which required an additional sonication., Conclusion: Gen-citalopram appeared to be bioequivalent to Celexa, whereas Novo-venlafaxine XR was not bioequivalent to Effexor XR. Consequently, the Novo-venlafaxine formulation released its active ingredient more rapidly and outside the acceptable norm., Trial Registration: clinicaltrials.gov Identifier: NCT00676039., (©Copyright 2009 Physicians Postgraduate Press, Inc.)

Herbal medicines have been widely used all over the world since ancient times and have been recognized by physicians and patients for their better therapeutic value as they have fewer adverse effects as compared with modern medicines. However, phytotherapeutics needs a scientific approach to deliver the components in a sustained manner to increase patient compliance and avoid repeated administration. This can be achieved by designing novel drug delivery systems for herbal constituents. Novel drug delivery systems not only reduce the repeated administration to overcome non-compliance, but also help to increase the therapeutic value by reducing toxicity and increasing the bioavailability, and so on. Recently, pharmaceutical scientists have shifted their focus to designing a drug delivery system for herbal medicines using a scientific approach. For a long time herbal medicines were not considered for development as novel formulations owing to lack of scientific justification and processing difficulties, such as standardization, extraction and identification of individual drug components in complex polyherbal systems. However, modern phytopharmaceutical research solves the scientific needs for herbal medicines as in modern medicine, which gives way for developing novel formulations such as nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, solid lipid nanoparticles, and so on. This article summarizes various drug delivery technologies for herbal actives, which are gaining more attention for better therapeutic response.

The usefulness of a dissolution/permeation (D/P) system to predict the in vivo performance of solid dosage forms containing the poorly soluble drug, fenofibrate, was studied. Biorelevant dissolution media simulating the fasted and fed state conditions of the human gastrointestinal tract were used in order to simulate the effect of food on the absorption of fenofibrate. Moreover, the results obtained from the D/P system were correlated with pharmacokinetic parameters obtained following in vivo studies in rats. The in vitro parameter (amount permeated in the D/P system) reflected well the in vivo performance in rats in terms of AUC and C(max) of fenofibric acid. This study thus demonstrates the potential of the D/P system as valuable tool for absorption screening of dosage forms for poorly soluble drugs., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To compare the relative bioavailability of levetiracetam extended-release tablets (XR) with immediate release tablets (IR) following single and multiple dosing; to assess the food effect and the dose-proportionality of XR from 1000 to 3000mg., Methods: Two panels of 24 healthy subjects were enrolled. Study N01160 was a three-way crossover between IR fasted (single and repeated 500mg b.i.d.), XR fasted (single and repeated 1000mg o.d.) and XR with food (1000mg single dose). Study N01260 was a three-way crossover single dose-proportionality between XR 1000, 2000 and 3000mg., Results: After single dose, levetiracetam XR and IR were bioequivalent with respect to AUC((0-t)), AUC(infinity) and C(max). The median t(max) was delayed from 0.9 to 4h. For the fed/fasted comparison, the confidence intervals around the C(max) and AUC ratios were within the 80-125% limits. At steady-state, the AUC(24h) were also bioequivalent. In the dose-proportionality trial, the AUC and C(max) increased linearly with the dose. Levetiracetam XR was well tolerated., Conclusions: Levetiracetam XR 1000mg o.d. is bioequivalent to levetiracetam IR 500mg b.i.d. There is no food effect, and the absorption of XR is dose-proportional from 1000 to 3000mg.

The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner-Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur, and a level A "in vitro-in vivo correlation" was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.

The in vivo evaluation of colon-targeting tablets was conducted in six healthy male volunteers. A pectin-hydroxypropyl methylcellulose coating was compressed onto core tablets labelled with 4MBq (99m)Tc-DTPA. The tablets released in the colon in all subjects; three in the ascending colon (AC) and three in the transverse colon (TC). Tablets that released in the TC had reached the AC before or just after food (Group A). The other three tablets released immediately upon AC entry at least 1.5h post-meal (Group B). Release onset for Group B was earlier than Group A (343min vs 448min). Group B tablets exhibited a clear residence period at the ileocaecal junction (ICJ) which was not observed in Group A. Prolonged residence at the ICJ is assumed to have increased hydration of the hydrogel layer surrounding the core tablet. Forces applied as the tablets progressed through the ICJ may have disrupted the hydrogel layer sufficiently to initiate radiolabel release. Conversely, Group A tablets moved rapidly through the AC to the TC, possibly minimising contact times with water pockets. Inadequate prior hydration of the hydrogel layer preventing access of pectinolytic enzymes and reduced fluid availability in the TC may have retarded tablet disintegration and radiolabel diffusion.

The mechanism of drug release from push-pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push-pull osmotic systems, which enable a more efficient optimization of such formulations.

Purpose: Find a novel delivery system for oral administration of drugs that have absorption window in the upper part of gastrointestinal (GI) track., Methods: Dipyridamole was chosen as the model drug. A novel system, which combined the osmotic pump controlled release system and the floating system, was designed; matrix tablets (MT) were prepared for compares. The effects of pH, temperature and hydrodynamic conditions on drug release and the floating behavior of floating osmotic pump system (FOP) were investigated. In vivo evaluation was performed by a three-crossover study in six Beagle dogs relative to the conventional tablet (CT). Cumulative percent input in vivo was compared with that of in vitro release profiles., Results: Floating behavior of FOP, drug releases from FOP and MT were sensitive to pH of dissolution media but not sensitive to temperature; the release of dipyridamole from MT was influenced by stirring rate while drug release from FOP was not. AUC of FOP was larger than MT and CT. The linear correlations between fraction absorbed in vivo and fraction dissolved in vitro was established for FOP-a true zero-order release formula, whereas only a nonlinear correlation was obtained for MT., Conclusions: FOP could be a novel way for the oral administration for drugs like dipyridamole.

Background: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation., Methods: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups., Results: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients., Conclusions: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries.

Direct tableting is simpler and more cost-effective from the point of view of good manufacturing practice (GMP) than wet granulation or dry compacting. Moreover, the use of dry plant extracts in the process of direct tableting, omitting granulation, decreases the possibility of biological activity loss of active substances. Thus, pharmaceutical industry uses this particular process more and more frequently. Only few therapeutic substances form under compression tablets meeting current requirements. Very often addition of auxiliary substances appears to be indispensable. The aim of this study was to obtain uncoated tablets by the method of direct tableting with the use of selected auxiliary substances. Dry extract from Solidago virgaurea L. was the study material. Shrimp chitosan, silicified microcrystalline cellulose (Prosolv), polyvinylpyrrolidone, calcium carbonate and sodium stearyl fumarate were used as auxiliary substances. Eleven tablet batches were manufactured in a reciprocating instrumented tableting machine (Ewreka). The produced tablets were subjected to morphological tests comprising the tablet size, determination of batching accuracy (determination of mass uniformity of individual tablets), test of mechanical resistance (crushing strength), determination of disintegration time. The statistical hardness of the manufactured tablets was also estimated. Pharmaceutical availability tests were performed of the biologically active substances released from tablets to the acceptor fluid. The study was based on general and detailed regulations of Polish Pharmacopoeia VII (PP VII). The obtained results allow to conclude that the applied auxiliary substances appeared to be useful in adequate proportions in manufacturing tablets containing dry extract from Solidago virgaurea L. The properties of the obtained batches of tablets were in majority consistent with the current requirements. The applied method provides technological reproducibility and high durability of the drug. These tablets as compared to available herbal mixtures and aqueous extracts can be a more comfortable form of a drug.

A sensitive LC-MS method was developed and validated for the determination of niflumic acid (NFA), the active metabolite of the talniflumate formulation, in human plasma. The analyses were performed on C(18) column using acetonitrile-ammonium acetate buffer (pH 5.7, 40:60) as a mobile phase with quadrupole MS detection of NFA at m/z 281 in a negative ion-monitoring mode. Calibration curve was linear in the concentration range of 1-1000ng/mL in human plasma. The higher sensitivity of LC-MS allowed low concentrations of NFA to be determined at initial drug absorption and terminal elimination phases following oral administration of talniflumate tablet.

Background: Meclofenoxate hydrochloride is a psychostimulant in the nootropic agent group available in capsule and tablet formulations approved for traumatic cataphora, alcoholic poisoning, anoxia neonatorum, and children's enuresis in China. Although these 2 generic formulations are marketed in China, information regarding their pharmacokinetics and bioequivalence in humans has not been published., Objective: The aim of this study was to compare the pharmacokinetic properties and bioequivalence of the capsule (test) and tablet (reference) formulations of meclofenoxate hydrochloride 200 mg in healthy Chinese volunteers., Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 200-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. As a prodrug, meclofenoxate is hydrolyzed into 4-chlorophenoxyacetic acid and is not detected in plasma. The active metabolite of meclofenoxate, chlorophenoxyacetic acid, was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity, blood samples were obtained at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 14, and 24 hours after administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Subjects were interviewed concerning the occurrence of adverse events including excitement, insomnia, lassitude, and headache. Tolerability was assessed at baseline (before administration) and at 1, 2, 6, and 12 hours after administration by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis)., Results: Twenty-four Chinese male subjects (mean [range]age,23.5[22-30]years;weight,63.3[56-68]kg; height, 171 [165-184] cm) were enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of chlorophenoxyacetic acid Cmax, AUC0-24, and AUC0-infinity were 95.7 to 122.9, 97.6 to 111.9, and 97.8 to 111.7, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No adverse events were reported or observed during this single-dose study., Conclusions: In this small study in healthy Chinese adult male volunteers, a single 200-mg dose of the capsule formulation was found to be bioequivalent to a single 200-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Objective: The study examined relative bioavailability of a novel valproic acid (VPA) delayed-release (DR) soft gelatin capsule formulation to divalproex sodium DR tablet under fasting conditions and the effect of food on the bioavailability of the VPA DR soft gelatin capsule., Method: This open-label, randomized three-way crossover study enrolled 36 healthy non-smoking adult volunteers. Treatments included a single 500 mg divalproex sodium DR tablet, fasting; a single 500 mg VPA DR soft gelatin capsule, fasting; and, a single 500 mg VPA DR soft gelatin capsule 500 mg, non-fasting. Analysis of variance was performed on the pharmacokinetic parameters. The ratio of geometric means and corresponding 90% confidence intervals (CI) were calculated on ln-transformed data for the area under the serum concentration-time curve (mug-hr/mL) from time zero to the time of the last quantifiable concentration (t) (AUC(0-t)), AUC(0-infinity) and maximum plasma concentration (C(max)). Bioequivalence was shown when 90% CIs were within the 80-125% range., Results: All subjects completed the study. The 90% CIs of VPA DR soft gelatin capsules compared to divalproex sodium DR tablets were within the 80-125% limits for AUC(0-t), AUC(0-infinity), and C(max). The time of maximum or peak concentration (T(max)) of VPA DR soft gelatin capsules was 2.3 hours versus 3.7 hours with divalproex sodium DR tablets. AUC(0-t) and AUC(0-infinity) of VPA soft gelatin capsules were not affected in the non-fasting condition, but T(max) occurred at 6.1 hours compared to 2.3 hours fasting. Eight subjects experienced a total of 10 adverse events; none were serious., Conclusion: The VPA DR soft gelatin capsule formulation was shown to be bioequivalent to divalproex sodium DR tablet and no serious adverse events occurred. Because this was not a multiple-dose study, however, direct comparisons in chronic dosing were not possible. Administration with food affected rate but not extent of absorption of the VPA DR soft gelatin capsules, but comparisons with the reference product were not conducted under non-fasting conditions.

Objective: Efficacy and tolerability of risperidone oral solution (RIS-OS) and olanzapine orally disintegrating tablet (OLZ-ODT) were compared for the treatment of acute psychotic agitation., Method: During a 2-month period, patients scoring > or =15 on the Excited Component for Positive and Negative Syndrome Scale (PANSS-EC) were assigned to treatment with OLZ-ODT (n=34) or RIS-OS (n=53) on psychiatric emergency situations, and assessed every 15 min., Results: Two (OLZ-ODT and RIS-OS) by five (0-, 15-, 30-, 45- and 60-min time points) repeated-measures analysis of variance revealed only a significant main effect of time course on PANSS-EC (F=82.2, P<.0001). No differences in the number of patients receiving additional injection due to worsening were found (OLZ-ODT, 11.8%; RIS-OS, 9.4%). No differences in rate of extrapyramidal symptoms and patient satisfaction with assigned treatment were found. However, patients in the OLZ-ODT group recovered significantly more from tachycardia than those in the RIS-OS group (t=2.17, P=.03)., Conclusion: OLZ-ODT and RIS-OS treatments yielded similar improvements in acutely agitated patients who accepted oral medication. However, on one physiological parameter (i.e., tachycardia) OLZ-ODT might be superior to RIS-OS. Physiological indicators may also be useful for measuring levels of agitation.

Objective: To develop an HPLC method to determine vitexin-rhamnoside in plasma of Beagle dogs and study the pharmacokinetics and bioavailability of Yixintong sustained release tablets in Beagle dogs., Method: A newly-developed HPLC method using C18 column and methanol-acetonitrile-tetrahydrogenfuran-0.5% acetic acid (1:1:19.4:78.6) as mobile phase was validated, and then was employed to determine vitexin-rhamnoside in plasma of Beagle dogs after oral administration of Yixintong sustained release tablets and general tablets. The main pharmacokinetic parameters were estimated by pharmacokinetic program 3p87. The non-compartmental pharmacokinetic parameters were also calculated on basis of the statistic moment theory., Result: The pharmacokinetic profiles of Yixintong sustained release tablets and the general tablets were fitted to a one-and two-compartment open model, respectively. The T1/2, Tmax, AUC0-infinity and MRT for Yixintong sustained release tablets were 5.22 h, 4.0 h, 6,792.75 ng x h x mL(-1) and 8.4 h, respectively, compared with 8.94 h, 1.0 h, 5,880.4 ng x h x mL(-1) and 6.1 h for the general tablets. The relative bioavailability of the Yixintong sustained release tablets was 115.5% in Beagle dogs., Conclusion: The sustained-release characteristic of Yixintong sustained release tablets were confirmed by pharmacokinetic study.

Background: A new combined oral contraceptive formulation has been developed consisting of a beta-cyclodextrin (betadex) clathrate formulation of ethinyl estradiol in combination with drospirenone (EE-betadex clathrate/drsp). In this novel EE-betadex clathrate/drsp preparation, betadex serves as an inert complexing agent to enhance stability and shelf-life. The study was conducted to investigate the relative bioavailability and pharmacokinetic parameters of EE and drsp after oral administration of EE-betadex clathrate/drsp., Methods: This was an open-label, randomized, single-dose, three-period, three-treatment, crossover study conducted in 18 healthy postmenopausal women aged 45-75 years. The women received single oral doses of 40 mcg EE/6 mg drsp formulated as EE-betadex clathrate/drsp or EE/drsp (EE as a free steroid) tablets, or as a microcrystalline suspension on three separate occasions. Serum samples were collected for pharmacokinetic analyses., Results: The relative bioavailability of EE and drsp after EE-betadex clathrate/drsp tablet administration was comparable with that achieved with the EE/drsp tablet (107% and 101%, respectively). In addition, the inclusion of EE in a betadex clathrate does not affect the pharmacokinetics of either EE or drsp. There were no safety concerns with any of the medications., Conclusion: The betadex clathrate formulation of EE, when combined with DRSP, does not affect the pharmacokinetics and relative bioavailability of either EE or drsp.

Background & Objectives: The availability of numerous brands of artesunate in our drug market today places clinicians and pharmacists in a difficult situation of choice of a suitable brand or the possibility of alternative use. The aim of the present study was to predict the bioequivalence of nine brands of artesunate tablets marketed in Nigeria using in vitro tests., Methods: The in vitro dissolution study was carried out on the nine brands of artesunate tablets using the basket method according to US Pharmacopoeia (USP) guidelines. Other general quality assessment tests like hardness and disintegration time were also determined., Results: All the brands tested passed the British Pharmacopoeia (BP) standard for disintegration time. Only AT2, AT4, AT6 and AT9 passed the standard for hardness. There were significant differences in the dissolution profiles of the nine brands. All the brands except AT1, however, released >70% of artesunate within 30 min. Four of the brands AT5, AT6, AT7 and AT8 exhibited >90% dissolution in <10 min. The other brands AT1, AT2, AT3, AT4 and AT9 (innovator brand) have calculated similarity factors of 23.8, 59.8, 50, 54.8 and 100., Interpretation & Conclusion: Based on the in vitro tests, AT5, AT6, AT7 and AT8 are considered bioequivalent and interchangeable, while AT2, AT3 and AT4 are considered bioequivalent and interchangeable with the innovator brand (AT9). AT1 has very low dissolution rate, which will likely result in poor bioavailability. The results show the need for constant monitoring of new brands of artesunate introduced into the drug market to ascertain bioequivalence and conformity with pharmacopoeia standards.

The aim of this study was to optimize and formulate fast disintegrating tablets (FDTs) for nausea and vomiting using aminoacetic acid, carmellose and sodium alginate with enough mechanical strength. Ondansetron HCl (water soluble) or domperidone (water insoluble) drug were added to FDTs and their disintegration behaviour was evaluated. Plackett Burman Screening Design was used to screen the independent active process variables [concentration of aminoacetic acid (X (1)), concentration of carmellose (X (2)) and tablet crushing strength (X (3))] which were found to actively influence the dependent variables [disintegration time in the mouth (DT), wetting time (WT), and water absorption ratio (WAR)] for both the drugs. Also, the coefficients of active variables (DT, WT and WAR) of FDTs containing domperidone was found to be significantly different (P < 0.05) from the coefficients of active factors (X (1), X (2) and X (3)) containing ondansetron HCl FDTs. Further, FDTs containing domperidone was prepared according to central composite design for estimating the effect of active factors (X (1), X (2), X (3)) in extended spherical domain. The regression analysis of quadratic fit revealed that DT, WT and WAR were 98% correlated with active factors (X (1), X (2) or X (3)). The optimized domperidone FDTs were further compared with superdisintegrants (croscarmellose sodium or crospovidone). The data revealed that optimized domperidone FDTs were better than domperidone FDTs containing croscarmellose or crospovidone. Hence, this novel excipients combination can be used for delivery of water insoluble drugs in place of superdisintegrants.

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone-XL, Primojel and ion-exchanger Tulsion339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 +/- 2 degrees C/60 +/- 5% RH, and 40 +/- 2 degrees C/75 +/- 5%RH for 3 months showed no significant changes in the tablets quality at 30 +/- 2 degrees C/60 +/- 5% RH. However, at 40 +/- 2 degrees C/75 +/- 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.

Objective: Efavirenz (EFV; 600 mg), emtricitabine (FTC; 200 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) are preferred agents for treatment of HIV-1 infection in adults. This study evaluated the pharmacokinetics (PK) and bioequivalence of an investigational coformulation of EFV/FTC/TDF (test) single-tablet regimen compared with the commercially available individual dosage forms (EFV+FTC+TDF; reference treatment) in healthy subjects., Methods: Subjects were randomized to 1 of 2 treatment sequences (test-->reference or reference-->test) in an open-label crossover study design. Study drug was administered under fasted conditions, and serial blood samples were obtained over 504 hours after oral administration of each treatment. Formulation bioequivalence was assessed in accordance with the US Food and Drug Administration bioequivalence criteria., Results: Forty-eight subjects were enrolled, and 45 completed the study, with all study treatments being generally well tolerated. For EFV (n = 44), the geometric mean ratios (90% confidence interval [CI]) for maximum concentration (C(max)), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC(0-last)), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC(inf)) were 99.9 (93.4 to 107), 95.7 (90.5 to 101), and 95.2 (88.9 to 102), respectively. For FTC (n = 45), the geometric mean ratios (90% CI) for C(max), AUC(0-last), and AUC(inf) were 88.8 (84.0 to 93.9), 98.0 (94.9 to 101), and 98.0 (94.9 to 101), respectively. For tenofovir (n = 45), the geometric mean ratios (90% CI) for C(max), AUC(0-last), and AUC(inf) were 91.5 (84.6 to 98.8), 99.3 (91.0 to 108), and 100 (93.2 to 108), respectively., Conclusions: The coformulation of EFV/FTC/TDF is bioequivalent to administration of its individual components.

The aim of this study was to investigate liquid penetration into both cylindrical and convex hydrophobic matrix tablets and to relate the changes in tablet structure to drug release. Starch acetate with degree of substitution of 2.7 was used as a hydrophobic matrix former and anhydrous caffeine as a freely soluble model drug. Phenolred was used as a colouring agent to enhance the visual detection of the liquid boundary movements, which were examined in axial and radial directions for both types of tablets. The tablets started to expand during the dissolution, resulting in cracking as the liquid boundary penetrated into tablet. The cracking influences drug release by shortening the diffusion path and decreasing the tortuosity. The liquid boundaries proceed differently in cylindrical and convex tablets, this being attributable to differences in pore structure and density distribution. Cylindrical tablets are quite homogeneous in terms of density, but convex tablets have more porous areas at the domes of the tablet.

A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The formulation of atenolol osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f2). The optimal formulation was evaluated in various release media and agitation rates. Indentation size of core tablet hardly affected drug release in the range of (1.00-1.14) mm. The optimal osmotic tablet was found to be able to deliver atenolol at an approximately constant rate up to 24h, independent of both release media and agitation rate. The method that is simplified by coating the indented core tablet with the elimination of laser drilling may be promising in the field of the preparation of osmotic pump tablet.

The objective of this study was to evaluate the effect of some processing parameters on the release of lipid formulation from a tablet dosage form. A 17-run, face-centered cubic design was employed to evaluate the effect of colloidal silicates (X(1)), magnesium stearate mixing time (X(2)), and compression force (X(3)) on flow, hardness, and dissolution of Coenzyme Q(10) (CoQ(10)) lipid formulation from a tablet dosage form. The optimized formulation was subsequently subjected to a short-term accelerated stability study. All preparations had a flowability index values ranging from 77 to 90. The cumulative percent of CoQ(10) released within 8h (Y(5)) ranged from 40.6% to 90% and was expressed by the following polynomial equation: Y(5)=49.78-16.36X(1)+2.90X(2)-3.11X(3)-0.37X(1)X(2)+1.06X(1)X(3)-1.02X(2)X(3)+11.98X(1)(2)+10.63X(2)(2)-7.10X(3)(2). When stored at 4 degrees C, dissolution rates were retained for up to 3 months. Storage at higher temperatures, however, accelerated lipid release and caused leakage, and loss of hardness. Processing parameters have a profound effect on the release of lipid formulations from their solid carriers. While optimized controlled release formulations could be attained, further considerations should be made to prepare "liquisolids" that are physically stable at higher storage temperatures.

Transdermal bioadhesive tablets were formulated by the direct compression method and evaluated. Carboxyfluorescein (CF) was used as a model permeant. The compression parameters were kept consistent and the composition of the formulation was varied to alter the release rate of the drug from the formulations. The dosage form was evaluated for physicochemical, adherence, and in vitro diffusion parameters. The transdermal flux of the drug decreased with the increasing ratio of Ethyl cellulose (EC)/hydroxypropyl cellulose (HPC). The test formulations were subjected to pharmacokinetic studies in mice. The formulations were able to maintain a steady state plasma concentration up to 12 hours. They were found to be safe for transdermal use as interpreted from skin irritation studies carried out on rabbits.

The aim of this work was to investigate the dissolution rate from both the curved and planar surfaces of cylindrical compacts of benzoic acid, which were placed centrally and non-centrally at the base of the vessel of the paddle dissolution apparatus. The effect of fixing the compacts to a particular position on the variability of dissolution results was also examined. In addition, computational fluid dynamics (CFD) was used to simulate fluid flow around compacts in the different positions in the vessel, and the relationship between the local hydrodynamics in the region of the compacts and the dissolution rate determined. The dissolution rate was found to increase from the centre position to the off-centre positions for each surface examined. There was a corresponding increase in maximum fluid velocities calculated from the CFD fluid flow simulations at a fixed distance from the compact. There was less variability in dissolution from compacts fixed to any of the positions compared with those that were not fixed. Fluid flow around compacts in different positions could be successfully modelled, and hydrodynamic variability examined, using CFD. The effect of asymmetric fluid flow was evident visually from the change in shape of the eroded compacts.

Conventionally, pharmaceutical substances are administered orally because the gastrointestinal tract possesses the appropriate features for drug absorption. Nevertheless, the gastrointestinal tract physiology is complex and influenced by many factors. These factors must be completely understood for the optimization of oral drug delivery systems. Although in vitro tests provide information about release and drug absorption profiles, in vivo studies are essential, due to the biological variability. Several techniques have been employed in an attempt to conveniently characterize the behavior of solid dosage forms in vivo. The noninvasive biomagnetic technique of alternate current biosusceptometry (ACB) has been used in studies focusing on gastrointestinal motility and, more recently, to evaluate the performance of magnetic dosage forms. This article will discuss the main characteristics of AC biosusceptometry and its applicability for determination of the relationship between the human gastrointestinal tract and orally administered pharmaceutical dosage forms.

Magnetic Marker Monitoring offers an alternative to investigate the behavior of solid dosage forms in the organs of the gastrointestinal tract without the need to apply radiation. For Magnetic Marker Monitoring, the dosage form is marked as a permanent magnetic dipole by the incorporation of small amounts of ferromagnetic material, as for example the colorant black iron oxide, and subsequent magnetization. Thereby, the dosage form is labeled as the source of a well defined magnetic field, which can be measured using a measurement technique that is established for biomagnetic investigations. Using the established concepts for magnetic source localization, the three dimensional localization and orientation as well as the strength of the magnetic source can be reconstructed from these magnetic measurement data as a function of time. Furthermore, it is possible to gain quantitative information on the disintegration of dosage forms in vivo. Examples are given for results obtained concerning the esophageal transit, the gastric and the intestinal behavior of capsules and tablets.

Khaya and albizia gums were evaluated as compression coatings for target drug delivery to the colon using indometacin (a water insoluble drug) and paracetamol (a water soluble drug) as model drugs. The core tablets were compression-coated with 300 and 400 mg of 100% khaya gum, 100% albizia gum and a mixture of khaya and albizia gum (1:1). Drug release studies were carried out in 0.1(M) HCl (pH 1.2) for 2 h, Sorensen's buffer (pH 7.4) for 3 h and then in phosphate-buffered saline (pH 6.8) or in simulated colonic fluid for the rest of the experiment to mimic the physiological conditions from the mouth to colon. The results indicated that khaya and albizia gums were capable of protecting the core tablet in the physiological environment of the stomach and small intestine, with albizia gum showing greater ability than khaya gum. The release from tablets coated with the mixture of khaya and albizia gums was midway between the two individual gums, indicating that there was no interaction between the gums. Studies carried out using rat caecal matter in phosphate-buffered saline at pH 6.8 (simulated colonic fluid) showed that the gums were susceptible to degradation by the colonic bacterial enzymes, leading to release of the drug. The results demonstrate that khaya gum and albizia gum have potential for drug targeting to the colon.

The aim of the work was the characterization of a new polysaccharidic physical hydrogel, obtained from Scleroglucan (Sclg) and borax, following water uptake and dimension variations during the swelling process. Furthermore, the release of molecules of different size (Theophylline (TPH), Vitamin B12 (Vit. B12) and Myoglobin (MGB)) from the gel and from the dried system used as a matrix for tablets was studied. The increase of weight of the tablets with and without the loaded drugs was followed together with the relative variation of the dimensions. The dry matrix, in the form of tablets was capable, during the swelling process, to incorporate a relevant amount of solvent (ca. 20 g water/g dried matrix), without dissolving in the medium, leading to a surprisingly noticeable anisotropic swelling that can be correlated with a peculiar supramolecular structure of the system induced by compression. Obtained results indicate that the new hydrogel can be suitable for sustained drug release formulations. The delivery from the matrix is deeply dependent on the size of the tested model drugs. The experimental release data obtained from the gel were satisfactorily fitted by an appropriate theoretical approach and the relative drug diffusion coefficients in the hydrogel were estimated. The release profiles of TPH, Vit. B12 and MGB from the tablets have been analyzed in terms of a new mathematical approach that allows calculating of permeability values of the loaded drugs.

Purpose: Conventional lithium carbonate (LC) tablets not only produce rapid and relatively high peak blood levels resulting in adverse effects but also should be administered 3 to 4 times daily. These drawbacks can be overcome by designing a suitable sustained-release LC preparation., Methods: Sustained-release matrix tablets containing 450 mg LC were developed using different types and ratios of polymers including carbopol (CP), Na carboxymethylcellulose (Na CMC) and hydroxypropylmethylcellulose (HPMC). The tablets were prepared by either direct compression or wet granulation. In vitro and in vivo, newly formulated sustained-release LC tablets were compared with sustained-release commercial tablet (Eskalith CR). In vivo studies were conducted in nine healthy subjects in a cross over design, with a 3 3 Latin square sequence. Pharmacokinetic parameters were estimated using classical methods., Results: The matrix tablets containing 15% CP exhibited suitable release kinetics and uniform absorption characteristics comparable to that of Eskalith CR. In vivo, this formulation produced a smooth and extended absorption phase very much similar to that of Eskalith CR with the identical elimination half-life and extent of absorption., Conclusion: In vitro release studies demonstrated that the releases of LC from all formulated sustained matrix tablets were generally sustained. Na CMC, CP, and HPMC can, therefore, be used to modify release rates of LC in hydrophilic matrix tablets. The sustained release behavior of tablets containing 15% CP prevents high peak blood levels in man and could be given twice daily to promote patient compliance during maintenance therapy.

MK-0869 (aprepitant), a potent substance P antagonist, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Early clinical tablet formulations of MK-0869 showed significant food effects on absorption, suggesting that formulation could have a significant role in improving bioavailability. A Beagle dog model was developed in an effort to guide novel formulation development. Using the suspension of the micronized bulk drug used for the tablet formulations, the food effect on absorption was confirmed in the dog at a similar magnitude to that observed in humans. Further dog studies demonstrated a clear correlation between particle size and in vivo exposures, with the nanoparticle (NanoCrystal) colloidal dispersion formulation providing the highest exposure, suggesting dissolution-limited absorption. The NanoCrystal dispersion also eliminated the food effect on oral absorption in the dog at a dose of 2mg/kg. Regional absorption studies using triport dogs indicated that the absorption of MK-0869 was limited to the upper gastrointestinal tract. These results provided strong evidence that the large increase in surface areas of the drug nanoparticles could overcome the narrow absorption window and lead to rapid in vivo dissolution, fast absorption, and increased bioavailability. In addition, the dog model was used for optimizing formulation processes in which the nanoparticles were incorporated into solid dosage forms, and for selecting excipients to effectively re-disperse the nanoparticles from the dosage units. The human pharmacokinetic data using the nanoparticle formulation showed excellent correlations with those generated in the dog., (copyright 2004 Elsevier B.V.)

The sustained release of amoxicillin is desired to be confined to the upper gastrointestinal tract to treat certain kind of infections. In vitro dissolution, at pH 1.2, of amoxicillin sustained release tablets has been studied varying the proportion of Carbopol 971P NF and sodium alginate as well as the ethanol/water proportion in the granulation fluid. M(t), the amount of drug released at time (t) and defined in terms of the total drug released over a long time period (M(inf), was described by M(t)/M(inf) = kt(n). Matrices with increasing proportions of sodium alginate showed increasing values of the exponent indicative of the release mechanism (n) and increasing release constant values (k). This is attributed to a drop in the coherence of the polymeric matrix with increasing alginate proportions that produces an increasing polymer relaxation and erosion. Decreasing Carbopol 971P NF proportions reduce the amount of dissolved polymer during granulation, producing a lesser obstruction of amoxicillin dissolution. Alginate proportions of 80% produce near zero order release profiles. Granules obtained with increasing ethanol proportions showed increasing release constant values and a minor change in the exponent (n) values. This is considered a result of lower polymer dissolution during granulation that allows a lesser matrix coherence and a greater amoxicillin dissolution. Alginate matrices granulated with different ethanol/water proportions showed no significant changes in the amoxicillin release profile. There is a trend toward increasing floating times with increasing Carbopol 971P NF proportions.

Previous single-dose studies have shown clear blood pressure-lowering effects of a potential sustained release (SR) profile of rilmenidine, with concentration-dependent effects on the central nervous system. The aim of this study was to evaluate potential changes in concentration-effect-relationships for these central nervous system effects during a 4-week treatment period with an experimental SR formulation of rilmenidine 3 mg once daily in 15 mild-to-moderate hypertensive patients. The central nervous system effects of the treatment were evaluated using saccadic eye movements for sedative effects and visual analogue scales for subjective effects on alertness, mood and calmness. Measurements for pharmacokinetic and pharmacodynamic evaluations were performed on the first day of the treatment period and repeated after 1 week and 4 weeks of treatment. Drug concentrations increased during the study, whereas treatment related reductions in saccadic peak velocity (SPV) remained similar on all three study days. The slopes of the concentration-effect-curves for SPV remained unchanged throughout the study, while the intercepts tended to increase as a result of increased pre-dose values. Similar effects were observed for visual analogue scales for alertness: pre-dose values increased significantly during the study, while the size of the treatment responses (slopes) remained unaltered. The reasons for these adaptations cannot be determined but may include drug tolerance and habituations to study procedures. Blood pressure control remained stable and adequate throughout the study.

The formulation of Garcinia kola seeds into tablet dosage form and evaluation of some physical properties of the tablets are presented. A chemical assay was conducted on the dry, powdered seeds as well as the crude aqueous extract of the seeds. The dry powdered seeds contain 0.003% of flavonoids while the crude extract contained 0.007% of flavonoids based on rutin used as the standard. The powdered material (50 mg) and crude extract (10 mg) were formulated into tablets using the wet granulation method. Named binders were evaluated in these formulations. The various tablet parameters were evaluated, namely: weight variation, thickness and diameter, hardness, friability, disintegration time, dissolution profile and content uniformity. The results indicated that the tablets had good disintegration time, dissolution and hardness/friability profiles. Tablets formulated with starch had the best disintegration properties but were consequently very friable. Tablets formulated from 10 mg of the crude extract needed a larger proportion of diluents, which affected the tablet properties.

The aims of the present study was to investigate if food components, as represented by a multi-component nutritional drink for tube feeding, could affect tablet disintegration of standard tablets in vitro as well as in vivo and propose a mechanism for potential food effects on tablet disintegration. The tablet disintegration was delayed between 5 min and more than 1h in the simulated gastric fed medium compared to a simple buffer. This effect was dependent on the tablet composition. A similar delay in tablet disintegration was also found in vivo after administration of the nutritional drink to three Labradors as observed by removing the tablet from the stomach at different times through a gastric fistula. The delay in tablet disintegration appeared to be caused by precipitation of a film, mainly consisting of protein, on the tablet surface as indicated by disintegration studies with pure nutrients, identification by IR spectroscopy of contents of precipitates obtained in a model study were the nutrients were incubated with different tablet excipients and visual observations of tablets exposed to the simulated fed medium. The drug dissolution of a soluble compound, metoprolol tartrate, from a standard tablet was also strongly delayed in the simulated fed medium. In conclusion, food, could significantly delay tablet disintegration and drug dissolution in the stomach by formation of a film around the tablets. This effect could be monitored by a simple in vitro disintegration test using a test medium based on a nutritional drink. More studies are needed to investigate the significance of the slow tablet disintegrations on bioavailability and for which types of food the present effect occurs.

Mucoadhesive tablets using different mixture of cellulose and polyacrylic derivatives were prepared in order to obtain new formulations containing metronidazole for periodontal disease treatment. All tablets were characterized by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion force, in vitro and in vivo release. The best mucoadhesive performance and the best in vitro drug release profile were achieved by using hydroxyethyl cellulose (HEC) and carbomer 940 2:2 ratio. The chosen tablet, containing 20 mg of metronidazole, performed 12 h drug sustained release with buccal concentrations always higher than its MIC.

It was the aim of this study to develop a delivery system providing an improved efficacy of orally administered insulin utilizing a thiolated polymer. 2-Iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate exhibited 453.5+/-64.1 micromol thiol groups per gram polymer. 3.1% of these thiol groups were oxidised. Additionally, the enzyme inhibitors BBI (Bowman-Birk-Inhibitor) and elastatinal were covalently linked to chitosan representing 3.5+/-0.1% and 0.5+/-0.03% of the total weight of the resulting polymer conjugate, respectively. Chitosan-TBA conjugate (5 mg), insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg) and the two inhibitor conjugates (in each case 0.75 mg) were compressed to so-called chitosan-TBA-insulin tablets. Control tablets consisted of unmodified chitosan (7.25 mg) and insulin (2.75 mg). Chitosan-TBA-insulin tablets showed a controlled release of insulin over 8 h. In vitro mucoadhesion studies showed that the mucoadhesive/cohesive properties of chitosan were at least 60-fold improved by the immobilisation of thiol groups on the polymer. After oral administration of chitosan-TBA-insulin tablets to non-diabetic conscious rats, the blood glucose level decreased significantly for 24 h corresponding to a pharmacological efficacy of 1.69+/-0.42% (means+/-S.D.; n=6) versus s.c. injection. In contrast, neither control tablets nor insulin given in solution showed a comparable effect. According to these results the combination of chitosan-TBA, chitosan-enzyme-inhibitor conjugates and reduced glutathione seems to represent a promising strategy for the oral application of insulin.

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.

The aim of this work was to evaluate the possibility of using mixtures and/or polyelectrolyte complexes from both chitosan-alginate and chitosan-carrageenan as prolonged drug release systems. Different dissolution profiles were obtained by changing the polymer matrix system (chitosan-alginate or chitosan-carrageenan) and the method used to include these polymers into the formulation (physical mixture or polyelectrolyte complex). Drug dissolution profiles from the matrices have been discussed by considering the swelling behavior of the polymers used. The swelling behavior of the chitosan-carrageenan and chitosan-alginate systems was analyzed by using the Hopfenberg model which permits to separate the diffusional contribution, kf, from the relaxational contribution, kr, involved in solvent penetration/sorption in glassy polymers. The chitosan-alginate system is better than the chitosan-carrageenan system as prolonged drug release matrix because the drug release is controlled at low percentage of the polymers in the formulation, the mean dissolution time is high, and different dissolution profiles could be obtained by changing the mode of inclusion of the polymers. Good agreement between td and kf/kr values for the system chitosan-alginate was found, which means that the swelling behavior of the polymers controlled the drug release from the matrix. In the case of the system chitosan-carrageenan, the high capacity of carrageenan promotes the entry of water into the tablet and therefore the main mechanism of drug release would be the disintegration instead of the swelling of the matrix.

In this study, minitablet and granule formulations were developed as solid oral dosage forms for the delivery of peptide drugs with the absorption enhancer N-trimethyl chitosan chloride (TMC). Minitablets were deemed suitable as a dosage form due to their ability, as components of multiple unit dosage forms (MUDFs), to disperse from each other, before disintegration, effectively increasing the area in which the polymer can assert its absorption-enhancing effect. The polymer should be released from the dosage forms prior to the release of the peptide, which was, together with achieving maximum release of both ingredients, the main focus of this study. Desmopressin (1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (DDAVP) was used as model peptide drug. The optimized minitablet formulation consisted of two types of granules, namely DDAVP and TMC granules. DDAVP granules, containing tetraglycerol pentastearate (TGPS), were specifically aimed at delaying the release of the peptide from the dosage form. Burst release of TMC was attempted with TMC granules. Both these granule types were included in the granule formulation. Release profiles for both the optimized minitablet formulation as well as the granule formulation showed that the release of DDAVP was effectively delayed from the formulation compared to the formulation where no attempt at delaying the release was made. In comparison, more TMC was released, and at a faster rate, from the granule formulation than the optimized minitablet formulations. Both the optimized minitablet formulation and the granule formulation show suitable release profiles for the delivery of peptide drugs with TMC as absorption enhancer in solid oral dosage forms.

Optimized bumetanide extended (ER) and immediate release (IR) formulations were developed using fluid bed layering and coating techniques. We postulated that the ER bumetanide formulation would have more effective and sustained diuretic and saluretic effects than IR. The diuretic/saluretic effects of both formulations were measured in rabbits (n=8) for two days after dosing with 1mg/kg bumetanide. During the first day, both formulations produced 2-3 times more urine volume and sodium excretion than baseline. In the first 24h, despite less bumetanide excretion from the ER formulation (101+/-13.9microg/kg compared to 146+/-14.6microg/kg for the IR formulation; P<0.04); the ER formulation produced diuresis and natriuresis that was equivalent to that of the IR formulation. In contrast, urine production in the IR formulation group fell below that of placebo controls on day 2. During the second day, the ER formulation was noted to produce persistent bumetanide excretion; the diuretic and natriuretic effects were not statistically significant from baseline control. We speculate that the decrease in response to bumetanide observed especially for the IR formulation during the second day may be due to the activation of compensatory counter-regulatory homeostatic mechanism(s). We conclude that the ER formulation had similar diuretic/saluretic effects but better drug excretion to urine production efficiencies than the IR formulation in the healthy rabbit model. The ER formulation, while providing comparable diuretic/saluretic effect to the IR formulation, offers the advantage of avoiding the initial, rapid and robust diuretic effect experienced with the IR formulations. Taken together, the data provide sufficient basis to warrant further investigation and refinement of our ER bumetanide formulation in humans.

Oral administration is the most convenient route for drug therapy. The knowledge of the gastrointestinal transit and specific site for drug delivery is a prerequisite for development of dosage forms. The aim of this work was to demonstrate that is possible to monitor the disintegration process of film-coated magnetic tablets by multi-sensor alternate current Biosusceptometry (ACB) in vivo and in vitro. This method is based on the recording of signals produced by the magnetic tablet using a seven sensors array and signal-processing techniques. The disintegration was confirmed by signals analysis in healthy human volunteers' measurements and in vitro experiments. Results showed that ACB is efficient to characterize the disintegration of dosage forms in the stomach, being a research tool for the development of new pharmaceutical dosage forms.

Background: Modern medical imaging modalities can trace labelled oral drug dosage forms in the gastrointestinal tract, and thus represent important tools for the evaluation of their in vivo performance. The application of gastric-retentive drug delivery systems to improve bioavailability and to avoid unwanted plasma peak concentrations of orally administered drugs is of special interest in clinical and pharmaceutical research., Aim: To determine the influence of meal composition and timing of tablet administration on the intragastric performance of a gastric-retentive floating tablet using magnetic resonance imaging in the sitting position., Methods: A tablet formulation was labelled with iron oxide particles as negative magnetic resonance contrast marker to allow the monitoring of the tablet position in the food-filled human stomach. Labelled tablet was administered, together with three different solid meals, to volunteers seated in a 0.5-T open-configuration magnetic resonance system. Volunteers were followed over a 4-h period., Results: Labelled tablet was detectable in all subjects throughout the entire study. The tablet showed persistent good intragastric floating performance independent of meal composition. Unfavourable timing of tablet administration had a minor effect on the intragastric tablet residence time and floating performance., Conclusion: Magnetic resonance imaging can reliably monitor and analyse the in vivo performance of labelled gastric-retentive tablets in the human stomach.

A randomized, two-way, crossover, bioequivalence study was conducted in 24 fasting, healthy, male volunteers to compare two brands of furosemide 40 mg tablets, Salurin (Julphar, UAE) as test and Lasix (Hoechst AG, Germany) as reference product. The study was performed at the International Pharmaceutical Research Centre (IPRC), in a joint venture with Al-Mowasah Hospital, Amman, Jordan. One tablet of either formulation was administered with 240 ml of water after a 10 h overnight fast. After dosing, serial blood samples were collected for a period of 12 h. Plasma harvested from blood was analysed for furosemide by a validated HPLC method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2), and elimination rate constant were determined from plasma concentrations of both formulations. Statistical modules (ANOVA and 90% confidence intervals) were applied to AUC(0-t), AUC(0-infinity), and C(max) to assess the bioequivalence of the two brands which revealed no significant difference between them, and 90% CI fell within the US FDA accepted bioequivalence range of 80%-125%. Based on these statistical inferences, Salurin was found to be bioequivalent to Lasix., (Copyright 2003 John Wiley & Sons, Ltd.)