Development of An Oral Sustained-Release Antibiotic Matrix Tablet Using In-Vitro/In-Vivo Correlations

A sustained release (SR) cephalexin tablet formulation containing xanthan gum and sodium alginate as matrix formers was evaluated in human volunteers. The formulation was optimized based on response surface analysis and computer simulation of cephalexin plasma levels versus time curves. The optimized formulation was tested in-vivo in human volunteers along with a fast release (FR) capsule formulation. The SR matrix formulation prolonged the cephalexin blood levels up to 8 hours in humans. The matrix formulation reduced variations in cephalexin plasma levels in individual subjects without any dose dumping as compared to the FR formulation. The plasma levels predicted by the computer program using in-vitro release data and the drug's pharmacokinetic parameters showed excellent correlation with in-vivo data. Using the Wagner-Nelson method, there was good correlation between in-vitro dissolution and in-vivo absorption in individual subjects. The relative bioavailability of cephalexin was reduced by about thirty percent. Very little absorption was seen after six to eight hours. The SR matrix formulation is an alternative delivery method to produce prolonged concentrations.     

Dissolution Profiling of Six Modified-Release Oral Solid Dosage Forms

Dissolution testing was conducted for six non-combination, single entity, modified-release oral solid dosage forms. Dissolution medium was water and 0.1 N hydrochloric acid. USP Apparatus 1 and Apparatus 2 were used arid were rotated at either 50 or 100 rpm. A complete dissolution profile was obtained for all six dosage forms based on their stated dosing interval, D. The three strengths of Theo-dur tablets, Norpace CR 150 mg capsules, and the two strengths of Chlor-trimeton tablets passed the Compendial Case One requirements (USP XXI, 2S, 1906). Thorazine spansules and Quinidex tablets were unable to meet the specifications with water as the dissolution medium; the latter showed improved dissolution character in 0.1 N hydrochloric acid. Tenuate Dospan 75 mg tablets showed good release characteristics in water when the authentic (dosing interval (D = 24 hours) was changed to a modified dosing interval of D* = 12 hours. All dissolution aliquots were assayed by UV absorbance measurements at the absorbance maximum for each drug and were also checked for excipient interference. Newer drugs appearing on the market will be more likely candidates for meeting compendial specifications; modified-release pharmaceuticals that appeared before the new specifications may have to be allocated specifically expanded window percentages.     

Polymeric Pseudolatices Dispersion Bearing Isosorbide Dinitrate for Transdermal Application

A pseudolatex based system for transdermal delivery (PL-ISDN-D) of isosorbide dinitrate (ISDN) was developed for its prolonged and controlled systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL-100 and polyvinylpyrrolidone were used in the preparation of pseudolatices polymeric dispersions. These preparations were evaluated for in-vitro release and permeation of the drug across human cadavar skin. The designed systems exhibited linear relationship between drug release (Q) Vs 0.80 function of time (t^0.80).

The product exhibiting required skin permeation (500 mcg/h/ 100 mg) calculated to achieve an effective plasma concentration was selected for the in-vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of conventional oral dose of isosorbide dinitrate.

The study revealed that designed pseudolatex transdermal drug delivery system of isosorbide dinitrate could be used successfully with improved performance.     

Suppository Dissolution Testing: Apparatus Design and Release of Aspirin

Present methods of in vitro dissolution testing for suppositories were found to be lacking in universal acceptance, reproducibility, and difficult to perform. Initially a USP basket for tablet dissolution with one-hundred milliliters of phosphate buffer of pH 8 to approximate rectal pH was used. A slow constant stirring speed was maintained by means of a Hanson dissolution drive control and hollow spindle-stirrer apparatus as well as a constant temperature of 37.5±0.1° Aspirin in polyethylene glycol bases gave plausible, reproducible results with this apparatus. However, oil bases (i.e. cocoa butter) gave unacceptable, irreproducible results since the base blocked the openings of the basket mesh. This report describes a modified basket method where the basket is polyurethane of the same size and configuration as the USP basket. The basket described has twelve linear vertical slots of 0.25 mm width allowing for a porosity of 52%. Results of aspirin release from four PEG bases prepared in this laboratory are presented and discussed. The results were reproducible. Five commercially available suppositories were also tested in the above described manner.

Dissolution, or drug release has been extensively studied and reported for only a few selected tablets and other oral solid dosage forms. Dissolution has been shown to be the best in vitro parameter to correlate release of drug to bioavailability. Dissolution of drug from non-oral dose forms however, has not been extensively investigated. Past research into drug release from suppository bases has taken a number of approaches, some of which are not very scientifically sound or reproducible. Gibaldi and Gundhofer in 1975 studied bioavailability of aspirin from commercially available suppositories (1). These researchers reported “the rate of absorption of aspirin was sufficiently slow to raise considerable doubt as to whether efficaceous body levels of aspirin or salicylate are obtained after a single dose” (1). Other reports also question the absorption of aspirin from suppositories (2, 3).

Because present methods of in vitro dissolution testing appeared lacking in universal acceptance and reproducibility or were difficult to perform, this study was undertaken to develop an apparatus for suppository dissolution. To test the reproducibility of the devised method, four PEG base blends were used as vehicle for aspirin. Several commercially available products were also tested to determine their release patterns.     

Preparation and evaluation of a sustained-release formulation of nifedipine HPMC tablets

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.     

Preparation and Evaluation of a Sustained-Release Formulation of Nifedipine HPMC Tablets

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.     

Controlled Transdermal Occlusive Delivery Device of Primaquine

Primaquine an antimalarial drug was studied for its permeation behavior across the human cadaver skin. Ethylene vinyl acetate copolymer (E.V.A. cop) was used for the preparation of drug reservoir. To optimize the drug delivery from the drug reservoir E.V.A. cop of different vinyl acetate mole content (40%, 25%, 18%) was used. To achieve an enhanced skin permeation an occlusive face adhesive type delivery system was fabricated. The prepared systems were characterized for in-vitro studies. The system that delivered the drug in accordance with the theortically calculated required delivery rate was selected for in-vivo performance evaluation. The prepared system functions over an predicted definite time period in an uniform and defined fashion. The drug transdermal application has therapeutic potential.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

Bioavailability in Man of Nalidixic Acid Tablets

An invivo absorption study was carried out in volunteers to compare the bioavailability of two brands of nalidixic acid tablets against a marketed paediatric suspension serving as a reference standard. Absorption was assessed by a urinary excretion method in which drug and major metabolite were assayed fluorimetrically. The excretion data were statistically treated. Results of the analysis of variance indicated a significant difference in rate, but not in extent of absorption, among the preparations tested. Poor disintegration quality of one of the tablet brands was found responsible for its delayed dissolution and, consequently, slow absorption.     

Development of Fast-Dissolving Tablets of Flurbiprofen-Cyclodextrin Complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0-t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Effect of Aging on the Bioavailability of Nitrdfurantoin Tablets Containing Carbopol 934

This article reports a study of two nitrofurantoin tablet formulations differing in the percentage of Carbopol 934 used as binder. The tablets of both formulations each contained 50 mg of nitrofurantoin. Those of formulation A contained 0.625 mg of Carbopol 934, and those of formulation B 1.25 mg. When freshly prepared, tablets of both formulations were bioequivalent to capsules containing 50 mg of nitrofurantoin, but a year's storage at 40°C and 60% relative humidity caused a significant decrease in the bioavailability of nitrofurantoin from formulation B, whereas formulation A was still bioequivalent to capsules. USP XXI Ed. Method II successfully reflected the observed variations in bioavailability, but not Method I.     

Release of a Low Dose Water Soluble Medicinal Agent from Inert Wax Matrix Tablets

Directly compressible wax matrix tablets have been developed for a low dose medicinal agent (Chloropheniramine maleate). A mixture of castor wax NF and Hydrogenated Vegetable Oil NF, was optimized in the ratio of 50:50 as matrix based on their bulk density and particle size distribution and compression properties The compression properties indicated that the increase in compression forces resulted in a tablet of higher hardness up to 8 Kp. However further increase in compression forces resulted in the decrease in hardness and capping was apparent.

The result of dissolution studies indicated no significant effect of hardness and tablet shape (Round and rectangular shaped) on the dissolution properties of wax matrix tablets. A plot of percent drug released various square root of time exhibited a linear relationship. The release rates of CPM from wax matrix tablets were found to be independent of the rotational speed of paddles between 50-75 RPM. From these results, the release mechanism of CPM from wax matrix tablets appears to be primarily diffusion controlled rather than matrix erosion.     

Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

Preparation and Evaluation of Sustained Release Ibuprofen Beads

Sustained release beads of ibuprofen were prepared by a capillary method using cellulose acetate phthalate, surfactants (Tween 80 and Span 80), and polymers (K 100 M Methocel and K 100 LV Methocel). These beads were formulated into capsule and tablet dosage forms. The beads did not disintegrate in simulated gastric fluid; however, they disintegrated in simulated intestinal fluid. The dissolution profiles of ibuprofen beads and dosage forms of beads (tablets and capsules) were conducted in phosphate buffer (pH 7.2) at 37°C. The beads containing Span 80 and K 100 M Methocel resulted in prolonged drug release. The preparation containing Span 80 and equal quantities of both the polymers (K 100 M Methocel and K 100 LV Methocel), also showed good sustained release properties. The formulations prepared with Tween 80 and K 100 LV Methocel released over 90% of the drug in 2 hours indicating no sustained release properties. The beads in tablet dosage form yielded slower dissolution profiles compared to the beads in capsule form which, in turn, had slower release profiles compared to the beads alone. Release of ibuprofen was much slower from tablets after one year of storage compared to tablets immediately after their manufacture.     

Ketorolac Tromethamine Bioavailability Via Tablet, Capsule, and Oral Solution Dosage Forms

The single-dose mean pharmacokinetic characteristics and relative bioavailability of 10-mg ketorolac tromethamine tablet, capsule, and oral solution dosage forms were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The tablet and the capsule formulations used were shown to have similar in vitro dissolution profiles. Ketorolac tromethamine was rapidly absorbed from all three dosage forms. The tablet and capsule were not significantly different with respect to any of the mean pharmacokinetic parameters: time to maximum plasma concentration (T_max) (35 and 42 min for the tablet and capsule, respectively), peak plasma concentration (C_max) (0.865 and 0.809 μg/ml for the tablet and capsule, respectively), area under the curve (AUC) (3.50 and 3.43 μg/ml × hr for the tablet and capsule, respectively), and half-life (t1/2) (5.2 and 4.8 hr for the tablet and capsule, respectively). Ninety-five percent fiducial (confidence) limits supported the equivalence of all of the tablet and capsule pharmacokinetic characteristics except for T^max, because of the higher variability of this parameter. The solution was absorbed significantly faster than the tablet (the time to maximum plasma concentration was 23 min for the solution versus 35 min for the tablet), but was not significantly different from the tablet in any other pharmacokinetic aspect. The fiducial intervals supported these tablet versus solution findings. Therefore, when functional or anatomical abnormality make tablet administration inadvisable, the solution or capsule formulations employed in this study may be used as alternatives to the commercially marketed tablet without adversely impacting the absorption profile of the drug substance.     

Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Physicochemical Characterization and Evaluation of Buccal Adhesive Tablets Containing Omeprazole

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium enhanced the release of omeprazole from the tablets; however, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet composed of omeprazole/sodium alginate/HPMC/magnesium oxide/croscarmellose sodium (20/24/6/50/10 mg) could be attached on the human cheek without disintegration, and it enhanced the stability of omeprazole in human saliva for at least 4 h and gave fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to a maximum of 370 ng/ml at 45 min after buccal administration and continuously maintained a high level of 146–366 ng/ml until 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7% ± 3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful for delivery of an omeprazole that degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.     

Physicochemical Characterization and Evaluation of Buccal Adhesive Tablets Containing Omeprazole

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium enhanced the release of omeprazole from the tablets; however, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet composed of omeprazole/sodium alginate/HPMC/magnesium oxide/croscarmellose sodium (20/24/6/50/10 mg) could be attached on the human cheek without disintegration, and it enhanced the stability of omeprazole in human saliva for at least 4 h and gave fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to a maximum of 370 ng/ml at 45 min after buccal administration and continuously maintained a high level of 146-366 ng/ml until 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7% ± 3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful for delivery of an omeprazole that degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.     

Development of sustained-release tablets containing sodium valproate: in vitro and in vivo correlation

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.