Controlled Release Dosage Forms Research Articles

EVALUATION OF STABILITY OF ROPINIROLE HYDROCHLORIDE AND PRAMIPEXOLE DIHYDROCHLORIDE MICROSPHERES AT ACCELERATED CONDITION

Objective: The objective of the present work was to conduct accelerated stability study as per international council for harmonisation (ICH) guidelines and to establish shelf life of controlled release dosage form of ropinirole hydrochloride and pramipexole dihydrochloride microspheres for a period of 6 mo.Methods: Most optimized batch of ropinirole hydrochloride and pramipexole dihydrochloride (F12 and M12 respectively) were selected and subjected to exhaustive stability testing by keeping the sample in stability oven for a period of 3 and 6 mo. Various parameters like surface morphology, particle size, drug content, in vitro drug release and shelf life were evaluated at 3 and 6 mo period. The surface morphology of the formulated microspheres was determined by scanning electron microscopy (SEM). The particle size of the microspheres was estimated by optical microscopy method. The drug content was assayed by the help of ultra-violet spectrophotometer (UV). The in vitro drug release was performed by using Paddle II type dissolution apparatus and the filtrate was analyzed by UV spectrophotometer. The shelf life of the optimized microspheres was calculated by using the rate constant value of the zero-order reaction.Results: A minor change was recorded in average particle size of F12 and M12 microspheres after storage for 6 mo. For F12 and M12, initially the particle size was 130.00 µm and 128.92 µm respectively and after 6 mo it was found to be 130.92 µm and 128.99 µm respectively. There was no change in surface morphology of F12 and M12 microspheres after 6 mo of storage. The shape of microspheres remained spherical and smooth after 6 mo. An insignificant difference of drug content was recorded after 6 mo compared to the freshly prepared formulation. For F12 and M12, 94.50% and 93.77% of the drug was present initially and after 6 mo 94.45% and 93.72% of the drug was recorded. In vitro drug release was recorded after 6 mo for F12 and M12. Initially, 97.99% and 97.69% of the drug was released till 14th hour respectively for F12 and M12. After 6 mo, 98.23% and 97.99% of the drug was released respectively. The percentage residual drug content revealed that the degradation of microspheres was low. Considering the initial percentage residual drug content as 100%, 99.94% of the drug was recorded for both F12 and M12. The shelf life for F12 and M12 was found to be 10 y 52 d and 10 y 70 d respectively which were determined by the zero-order kinetic equation.Conclusion: A more or less similar surface morphology, particle size, drug content and percent of drug release before and after stability study confirmed the stability of F12 and M12 microspheres after storage for 6 mo and prove the efficacy of the microspheres in the site-specific delivery of drugs in Parkinson’s disease.

Development and In Vitro – In Vivo Evaluation of Gastro-retentive Floating Tablets Containing Repaglinide

The present investigation concerns the development of the repaglinide floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. FTIR studies revealed that there is no interaction between the drug and polymers used for the formulation. Among all the formulations F21 containing HPMC K1500 PH PRM, Polyox WSR-303 and Sodium bicarbonate, as gas generating agent was selected as optimized formulation based on physico chemical properties, floating lag time (36 sec) and total floating time (>24 h). From in vitro dissolution studies, the optimized formulation F21 showed drug release of 98.92±5.19% within 24h whereas 95.09±5.01% of the drug was released from the marketed product within 1h. The major mechanism of drug release follows zero order kinetics and non-Fickian transport by coupled diffusion and erosion. In vivo experiments supported the expectations in prolonging the gastric residence time in the fasted state in beagle dogs. The mean gastric residence time for the tested tablets was 270 min±60. This result is encouraging, because a longer gastric residence time is an important condition for higher bioavailability of the drugs included in the prolonged or controlled release dosage forms.

Controlled-release domperidone pellets compressed into fast disintegrating tablets forming a multiple-unit pellet system (MUPS)

Controlled release dosage forms are essential when the drug release rate impacts the effectiveness of therapy. In the present study, a modified-release dosage form of domperidone was developed in the form of pellets, which were subsequently compressed into a tablet to disintegrate and be swallowed by patients, without changing the release profile. Sustained-release pellets of domperidone prepared by the extrusion-spheronization and layering technique using Celphere® 102 (microcrystalline cellulose spheres) and Suglet® (sugar spheres) as core seed, subsequently coated with Kollicoat® SR 30 D (polyvinyl acetate dispersion) as rate controlling polymer, were developed using the multiple unit pellet system (MUPS) as a plateform technology. Then, 2ˆ3 full factorial design (two level and three parameters) was applied to assess the impact of the different variables on the properties of the resulting pellets prepared by extrusion-spheronization. Different types of tableting excipients were combined for better pellet compressibility. The combination of Ceolus® granules (granules prepared using a fibrous grade of microcrystalline cellulose) and Ludipess® (lactose based co-processed excipient) was found as a suitable tableting excipient for MUPS preparation. The MUPS based sustained-release domperidone formulation prepared using Celphere® 102 was found to possess rapid disintegration properties, hardness, and unaltered release profile even after compression.

THE ROLE OF MATRIX TABLET IN DRUG DELIVERY SYSTEM

Matrix tablet is an important tool for controlled and sustained release dosage forms. The oral route remains the most common route for the administration of drugs. Tablets offer the lowest cost approach to sustained and controlled release dosage forms. The hydrophilic polymer matrix is widely used in this dosage form. The use of different polymers in controlling the release of drugs has become the most important tool in the formulation of matrix tablets. The drug releases by both dissolution-controlled as well as diffusion-controlled mechanisms from the matrix. The development of oral controlled release systems has been a challenge to formulation scientists due to their inability to restrain and localize the system at targeted areas of the gastrointestinal tract. There are several advantages of matrix devices including improved patient compliance due to less frequent drug administration, reduction of fluctuation in steady-state drug levels, maximum utilization of the drug, increased safety margin of a potent drug. This review aims on the discussion of different materials used to prepare matrix tablets, different types of matrix tablets and the drug release mechanism from the matrices.

Formulation and evaluation of Self-Poring osmotic tablet of diltiazem HCl for the treatment of hypertension

With emergence of new technology and concept, self-poring osmotic tablets were developed in order to reduce the complications and problems associated with micro drilling and laser drilling in osmotic tablet. This research describes a very simple and cheap method of developing self-poring osmotic tablet that deliver Diltiazem HCl in a controlled rate for prolonged duration. For this purpose 5 formulations of osmotictablets were prepared through wet granulation technique in which different concentration of sodium lauryl sulphate (SLS) were used as pore forming agent in coating solution. In tablet core also varied concentration of sorbitol as osmogens, guar gum and HPMC were encorporated, which forms gel like matrix through which drug releases at zero order. Through optimization out of 5 formulations, F3 (C2) formulation was selected as best. From result of invitro drug release study it was clear that more concentration of pore former and osmogens releases drug in short time while less concentration takes more time for drug release. Therefore, it is necessary to use SLS, polymer and osmogens in balance concentration for getting optimum control release at zero order upto 24 hrs. Self-poring Osmotic tablets hold promising potential for increasing drug efficacy and reducing dosing frequency with minimal side effects also provides an economic means of developing controlled release dosage forms.

Formulation of unidirectional buccal tablet of Mirtazapine: An in vitro and ex vivo evaluation

The objective of this study was to develop buccoadhesive controlled release dosage form of Mirtazapine. The unidirectional buccal tablets of Mirtazapine were prepared by direct compression method using Carbopol 934P and HPMC K4M as a buccoadhesive controlled release agents. FTIR studies showed that the drug and excipients were compatible. A 32 full factorial design was applied to systematically optimize the formulation. The formulations were evaluated for pre and post compression parameters, swelling studies, ex vivo buccoadhesive strength and in vitro drug release studies. The results indicated that the concentration of Carbopol 934P (X1) and concentration of HPMC K4M (X2) significantly affected the cumulative drug release in 1 h and 6 h (%) (R1, R2), Swelling Index (%) at 6 h (R3) and buccoadhesive strength (R4). The results of ex vivo permeability through sheep buccal mucosa suggested good permeability of drug from optimized formulation. The formulation remained stable during stability study. The prepared unidirectional buccal tablets provided low drug release in initial time point (1 h) and complete drug release in 6 h, optimum swelling and good bioadhesive strength which indicates a potential alternative drug delivery system of Mirtazapine.

Araucaria Gum: Novel Natural Polymer for Controlled Drug Delivery. Development, In Vitro and In Vivo Evaluation of Araucaria Gum Based Matrix Tablets for Controlled Release.

Assessment of natural polymers in oral controlled drug delivery. The objective of the present investigation was to assess of Araucaria gum (AHG) obtained from bark exudates of the Araucaria heterophylla (family: Araucariaceae) for the design of oral controlled release forms, in particular tablet dosage forms by using matrix systems. Diclofenac sodium was used as model drug and compared with the marketed formulation. Matrix tablets were prepared by wet granulation technique and 5% w/v of AHG dispersion water was used as granulating agent for preparation of AHG matrix tablets. AHD2 (3:20) was found to be the optimized formulation based on in vitro drug dissolution studies. FTIR and DSC studies performed on the optimized formulations indicated no drug-polymer interaction. AHD2 (3:20) was found to be stable after accelerated stability testing for 6 months as per ICH guidelines. Pharmacokinetic studies of the optimized formulation were performed in healthy Albino Wister rabbits in comparison with that of the pure drug by estimating pharmacokinetic parameters and mean residence time (MRT). It was found that there is a significant increase in the bioavailability of diclofenac sodium from AHD2 formulation which was evident from the high AUC and MRT values compared with the pure drug. The above results clearly indicated that AHG gum can be used for the development of oral controlled release dosage forms by using matrix systems.

IONOTROPIC TRAPPING LECITHIN BASED CILOSTAZOL NANOCOCHLEATES FOR DRUG DELIVERY APPLICATIONS

The nanocochleate drug delivery is based on encapsulating drugs in multilayered lipid crystal matrix (a cochleate) to potentially deliver the drug safely and effectively through the lipoidal membrane. Cilostazol is approved for the treatment of intermittent claudication and used as fibrinolytic agent, platelet aggregation inhibitor, bronchodilator agent, phosphodiesterase III Inhibitor and vasodilator agent. therefore, this drug delivery is suitable to deliver drug molecules into blood vessels. Formulations with lecithin showed good in vitro drug release, drug entrapment study results and the drug in formulations was found to be intact and compatible with lipids used. Two optimized formulations containing cilostazol lecithin-cholesterol showed Korsemayer peppas model perfect zero order release and showed better sustained and controlled drug release. Lecithin-cholesterol nanocochleates prepared by external ionotropic trapping method was found to be better ionic cross linking of drug-lipids particles. Therefore, ionotropic cross-linked particles are promising carriers for oral controlled release dosage forms.

RETRACTED: Evaluation of the surface chemistry and drug-polymer interaction of semi-crystalline micro-particles for the development of controlled release formulations

This research work explores the surface chemistry and drug-polymer interaction in the manufactured controlled release micro-particles. Isoniazid (INH) was used as a model anti-tubercular drug while Eudragit® S100 (S100), Eudragit® L100-55 based co-processed Acryl EZE (EZE) and Ethylcellulose ECN10 (ECN10) were used as polymeric carriers. INH containing micro-particles were prepared using a mini spray dryer B-290 (Buchi, Switzerland). The drug polymer ratios were optimized at 1:1 and 1:3 to evaluate the effect of polymers on the release of the drug from the micro-particles. Solid state characterization via SEM and particle size analysis of the manufactured micro-particles showed densely aggregated spherical particles with a mean diameter <10μm. The advanced surface analysis via EDS revealed a homogenous drug distribution on the spray dried micro-particles. The physico-chemical characterization carried out by using DSC and XRPD showed an increase in the amorphicity of the drug during the spray drying process while the chemical elemental analysis via XPS revealed a strong intermolecular interaction between the amine group of the drug and the carboxyl group of the polymers. As expected, the in vitro dissolution study showed a slow release pattern for the highly water soluble drug INH in acidic media (pH1.2) for the first 2h followed by a burst release upon changing the pH to 6.8. It was concluded that emerging spray drying processing can be used as a valuable tool to encapsulate drug for controlled release dosage forms by means of facilitating a possible drug/polymer interaction as outlined by novel XPS analysis.

Controlling the Release of Indomethacin from Glass Solutions Layered with a Rate Controlling Membrane Using Fluid-Bed Processing. Part 1: Surface and Cross-Sectional Chemical Analysis.

Fluid bed coating has been shown to be a suitable manufacturing technique to formulate poorly soluble drugs in glass solutions. Layering inert carriers with a drug-polymer mixture enables these beads to be immediately filled into capsules, thus avoiding additional, potentially destabilizing, downstream processing. In this study, fluid bed coating is proposed for the production of controlled release dosage forms of glass solutions by applying a second, rate controlling membrane on top of the glass solution. Adding a second coating layer adds to the physical and chemical complexity of the drug delivery system, so a thorough understanding of the physical structure and phase behavior of the different coating layers is needed. This study aimed to investigate the surface and cross-sectional characteristics (employing scanning electron microscopy (SEM) and time of flight secondary ion mass spectrometry (ToF-SIMS)) of an indomethacin-polyvinylpyrrolidone (PVP) glass solution, top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) were also considered. In addition, polymer miscibility and the phase analysis of the underlying glass solution were investigated. Significant differences in surface and cross-sectional topography of the different rate controlling membranes or the way they are applied (solution vs dispersion) were observed. These observations can be linked to the polymer miscibility differences. The presence of PVP was observed in all rate controlling membranes, even if it is not part of the coating solution. This could be attributed to residual powder presence in the coating chamber. The distribution of PVP among the sample surfaces depends on the concentration and the rate controlling polymer used. Differences can again be linked to polymer miscibility. Finally, it was shown that the underlying glass solution layer remains amorphous after coating of the rate controlling membrane, whether formed from an ethanol solution or an aqueous dispersion.

Development and Evaluation of Diclofenac sodium Controlled Release Dosage Forms Using Natural, Hydrophilic and Hydrophobic Polymers and its Comparative Studies

Abstract: The aim of the present study is to develop the controlled release dosage form of diclofenac using hydrophilic polymers (xanthan gum from natural origin, hydroxy propyl methyl cellulose K 100M from semisynthetic origin) and hydrophobic polymer (compritol 888 ATO from synthetic origin). Diclofenac sodium matrix tablets were prepared by xanthan gum and hydroxy propyl methyl cellulose by wet granulation method. Hot melt granulation method was used for compritol as it was insoluble polymer. Fourier transform infrared spectroscopy (FTIR) analysis, differential scanning calorimetry (DSC) and X-Ray diffraction (XRD) studies indicated that there was no interaction between drug and polymers. Matrix tablets were formulated according to formulae and evaluated the suitability for controlled release systems for 24 h. Tablets prepared with xanthan gum, hydroxy propyl methyl cellulose and compritol matrix tablets showed zero order drug release. The hardness for all the formulations found to be in the range of 4-5 kg/cm2. The friability values of all formulations were found to be less than 1 %. The drug content of each individual preparation was found to be within the specified limits of the stated amount of diclofenac sodium. XGD4, HPD4 and CD2 formulations were considered as optimum formulations for oral controlled release of diclofenac sodium. Key words: Diclofenac sodium, Hydroxy propyl methyl cellulose K 100M, Xanthan gum, controlled release dosage forms, Compritol 888 ATO.

Citric Acid cross linked cellulose based Hydrogel for Drug Delivery

The main objective of this investigation was to formulate controlled release dosage form by using citric acid cross linked cellulose based hydrogel. Hydrogels were prepared by cross liking the polymer HPMC-K4M by using suitable cross linking agent, citric acid. Due to cross linking reaction hydrogel gave good swelling as well as controlled release property to metoprolol succinate hydrogels. In this study 3 2 full factorial design, which was augmented for 2 central points was used by using Design-Expert 8.0.7.1. It gave 11 runs. In this design the concentration of citric acid (X1) and reaction time (X2) were selected as independent variables, while as drug content, swelling index and t 75 of % cumulative drug release were selected as dependent variables. From the results it can be concluded that the effect of citric acid concentration on drug content and t 75 of % CDR was nonsignificant. But the effect of citric acid concentration on swelling index was much significant, means as citric acid concentration increased; there was decrease in swelling index of hydrogel. Again effect of reaction time on drug content as well as on t 75 of % CDR was much significant, means as reaction time increased; there was increase in drug content as well as t 75 of %CDR of hydrogel. But the effect of reaction time on swelling index was nonsignificant. On the basis of all responses obtained, drug content, swelling index and t 75 of % CDR of run R1 are best. Drug content, swelling index and t 75 of % CDR of this run are 99.5%, 276.64% and 207.6 min. respectively. So optimized formulation was run R1, which gave the best in vitro release up to 94.24% in 360 min (6hrs).IR and DSC study shows no evidence on interaction between drug, polymers and other excipient. The in vitro data were fitted to different kinetic models.

Cellulosic on Transdermal Drug Delivery System: A Review

Transdermal patch is a medicated adhesive patch that is placed on the skin to deliver the drug through the skin in order to achieve systemic absorption of drug at a predetermined rate over a prolonged period of time. The amalgamation of polymer and pharmaceutical sciences led to the introduction of polymer in the design and development of drug delivery systems. Polymeric delivery systems are mainly intended to achieve controlled or sustained drug delivery. Polysaccharides fabricated into hydrophilic matrices remain popular biomaterials for controlled-release dosage forms and the most abundant naturally occurring biopolymer is cellulose; thus, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose (MCC) and ethyl cellulose (EC) can be used for production of controlled transdermal drug delivery systems (TDDS). This paper assembles the current knowledge on the structure and chemistry of cellulose, and in the development of innovative cellulose esters and ethers for controlled release TDDS. In addition, bacterial cellulose applications through chemical modification as a new TDDS will be discussed. Key words: Cellulosic, Transdermal Drug Delivery System, Bacterial Cellulose, Adhesive Patch

Optimization of preparation method for ketoprofen-loaded microspheres consisting polymeric blends using simplex lattice mixture design

In the present investigation, simplex lattice mixture design was applied for formulation development and optimization of a controlled release dosage form of ketoprofen microspheres consisting polymers like ethylcellulose and Eudragit®RL 100; when those were formed by oil-in-oil emulsion solvent evaporation method. The investigation was carried out to observe the effects of polymer amount, stirring speed and emulsifier concentration (% w/w) on percentage yield, average particle size, drug entrapment efficiency and in vitro drug release in 8h from the microspheres. Analysis of variance (ANOVA) was used to estimate the significance of the models. Based on the desirability function approach numerical optimization was carried out. Optimized formulation (KTF-O) showed close match between actual and predicted responses with desirability factor 0.811. No adverse reaction between drug and polymers were observed on the basis of Fourier transform infrared (FTIR) spectroscopy and Differential scanning calorimetric (DSC) analysis. Scanning electron microscopy (SEM) was carried out to show discreteness of microspheres (149.2±1.25μm) and their surface conditions during pre and post dissolution operations. The drug release pattern from KTF-O was best explained by Korsmeyer-Peppas and Higuchi models. The batch of optimized microspheres were found with maximum entrapment (~90%), minimum loss (~10%) and prolonged drug release for 8h (91.25%) which may be considered as favourable criteria of controlled release dosage form.

AN OVERVIEW OF NOVEL AND CONTROLLED DRUG DELIVERY SYSTEMS

The therapeutic effectiveness of any drug can be achieved by delivering the drug to the body in a suitable form through a proper route. Minimal drug degradation and improved bioavailability are the key factors considered in drug delivery. The drugs associated with the problems related to the low half-life would require frequent administration of the drug and hence controlled release dosage forms are beneficial. Targeted delivery systems release the drug at a specific site, avoid the availability of drug at unwanted sites and hence minimize the adverse reactions. The controlled and targeted drug delivery systems extend the product life cycle and also possess good market potential. The present article reviews the work done by our research group on some of the novel drug delivery systems.

Factorial Design and a Practical Approach for Gastro-Retentive Drug Delivery System

Over the years, different formulation technologies intended for gastro retentive dosage delivery were investigated and patented. Oral drug administration has been the predominant route for drug delivery. During the past two decades, numerous oral delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a defined period of time at a predetermined and controlled rate. From a pharmacokinetic point of view, the ideal sustained and controlled release dosage form should be comparable with an intravenous infusion, which supplies continuously the amount of drug needed to maintain constant plasma levels once the steady state is reached. Although some important applications, including oral administration of peptide and protein drugs, can be used to prepare colonic drug delivery systems, targeting drugs to the colon by the oral route. This review article clearly explains the advantages, limitations and need of gastro-retentive drug delivery system. It also covers the various criteria for drugs suitable and not suitable for such delivery. Also, the different types of gastro retentive delivery systems are described with suitable examples.

An Overview on Sustain Release Matrix Drug Delivery System

The oral route is the most frequently used route for the administration of drugs. Many of the pharmaceutical dosage form are formulated as sustained release dosage form to retard the release of a therapeutic agent such that its appearance in the systemic circulation is prolonged and its plasma profile is sustained in duration. Tablets offer the lowest cost approach to sustained and controlled release dosage forms. Matrix tablets serves as an important tool for oral extended-release dosage forms. Hence, problems like patient compliance, drug targeting, local side effects, frequent administration and fluctuations in blood concentration levels. Conventional drug delivery systems are known to provide a prompt release of drug or immediate release drug product. Such immediate release products result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. Hence, change in the operation is a suitable and optimized way to make the some drug more effective by slight alteration in the drug delivery. Pharmaceutical industries and academic laboratories have been focused on development of novel drug delivery system or modified release dosage form rather investigation and development of new drug. Advance in technology have resulted in novel modified release dosage form. In contrast to conventional form, modified release products provide either delayed release or extended release of drug.

Development of controlled release systems over the past 50 years in the area of contraception

The field of controlled release has contributed significantly to female reproductive health and in particular the prevention of unintended pregnancy. For at least 50years, there have been significant advances in controlled release dosage forms used for contraception. These advances have been driven by the need to provide women a wide array of products that address adherence problems noted with oral contraceptives. The first long-acting injectable product (Depo-Provera®) was approved in the US in 1959. Since then, there has been an emphasis on development of long-acting reversible contraceptives. These products include implants, intrauterine systems, and vaginal rings. A shorter acting contraceptive option is the transdermal patch. Despite these advances there are still a large number of unplanned pregnancies around the world. New controlled release technologies will be needed to continue providing women safe and easy to use contraceptive products.

Formulation Approach to Improve the Gastric Residence Time of Bisoprolol Fumarate by Gastro-Retentive Tablets

Purpose: Gastric retentive drug delivery devices can be used for controlled drug delivery systems containing drugs, which are degraded in the colon. The main objective of the present study is to design and formulate gastric retentive controlled release dosage form of bisoprolol fumarate in order to improve the gastric residence time, which in turn increases its bioavailability. Approach: Floating dosage form of bisoprolol fumarate was prepared by direct compression method using different concentration and grades of hydroxypropyl methylcellulose and sodium bicarbonate. Prepared powder mixtures and tablets were subjected to various pre-compression and post-compression evaluations respectively. Findings: Powder mixture showed good flow properties for uniform die filling. The SEM analysis showed minimum number of pores and erosion on the surface of the tablet. The optimized formulation F8 gave floating lag time less than 3 min with a floating time of 12 h, and an in vitro release profile very near to the desired release. The prepared dosage form reported to follow the zero order release and non-Fickian mechanism. Best formulations were subjected to accelerated stability studies. The assay results showed that the drug was stable for 3 months without any change in the drug content. Conclusion: Finally it can be concluded that the gastric retentive time of bisoprolol can be increased by formulating it in a floating dosage form.

Development of timely controlled-release systems for chronotherapy of propranolol with minimization of the pH effect in the simulated gastrointestinal medium

A timely controlled release dosage form with minimization of transit time and pH effects of gastrointestinal tract for chronotherapy of propranolol was developed. Ethylcellulose (EC) and Eudragit RS selected as the controlling membrane for drug-layering non-pareil seeds (NP) or extrusion-spheronized pellets incorporated with matrix materials or osmogents were characterized in the simulated gastric fluid (SGF) and pH change medium. Results demonstrated that when propranolol was layered on NP, Eudragit RS plasticized with 30% triethylcitrate (TEC) coated at 15% level could adjust a lag time close to the reference but with a slower release rate after then, while EC plasticized with HPMC could not delay drug release at a lag time close to the reference. Furthermore, EC incorporated with lactose coated on the extrusion-spheronized pellets could adjust the lag time, but a release rate correspondingly decreased with increasing lag time. Nevertheless, coating Eudragit RS on matrix pellets as controlling membrane at different levels could adjust a desired lag time with a pulsatile release pattern. However, the lag time adjusted was only within a 5 h range. Finally, coating Eudragit RS at different level on matrix pellets containing various ratio of osmogent, NaCl or lactose, could effectively adjust a desired lag time as long as 15 h with a pulsatile release pattern to accomplish the timely controlled release with minimization of the pH effects of gastrointestinal tract that could meet the clinical need for chronotherapy of propranolol.