Development of a gastroretentive pulsatile drug delivery platform

Objectives To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. Methods A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag‐time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag‐time controlling layer. The lag‐time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. Key findings By varying the composition of the lag‐time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. Conclusions This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered.     

磷酸川芎嗪脉冲塞胶囊的制备与体外释放

目的　制备一种由溶蚀塞控制时滞的新型脉冲给药系统并对其体外释药行为进行评价。方法　用灌注法制备非渗透性胶囊体 ,用湿法制粒压片法制备含药片和溶蚀塞 ,将填充剂和含药片用溶蚀塞密封在非渗透性胶囊体中制备磷酸川芎嗪 (TMPP)脉冲塞胶囊 ,用释放度测定法研究溶蚀塞的制剂学特征及溶出条件对释药时滞的影响。结果　溶蚀塞的处方组成和重量能显著影响磷酸川芎嗪脉冲塞胶囊的释药时滞 ,释药时滞随溶蚀塞中凝胶形成赋形剂羟丙甲基纤维素 (HPMC)含量和溶蚀塞重量的增加而增加 ,而溶蚀塞的硬度对时滞无显著影响。此外 ,释药时滞还随搅拌桨转速的增加而缩短。溶出介质的pH则对时滞无显著影响。结论　通过调节溶蚀塞的处方组成和重量可获得具有适当时滞的脉冲给药系统 ,满足时辰治疗的要求     

Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD

The objective of this study was to develop and evaluate a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter, when 10% (w/w) theophylline was layered on sugar cores compared with cores consisting of 100% theophylline. Regarding swelling layer, the release after lag time was fast and complete, when cross-linked carboxymethyl cellulose (AcDiSol) was used as a swelling agent. In contrast, a sustained release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab) were used as swelling agents. The optimal level of AcDiSol to achieve a fast and complete release after the lag time was 26% (w/w) (based on the weight of the coated pellets) for poorly soluble theophylline and 48% (w/w) for highly soluble propranolol HCl. The lag time can be controlled by the coating level of an outer membrane and increased with increasing coating level of the outer membrane. Outer membrane, formed using aqueous dispersion Aquacoat ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous because of (i) reduced sensitivity of lag time on variations in the coating level and (ii) fast and complete drug release. Drug release starts only after rupturing of outer membrane, which was illustrated by microscopical observation of pellet during release.     

Investigational drug information through a hospitalwide computer system.

A hospitalwide computer system that combines protocol-specific information on investigational drugs with order entry is described. A large university teaching hospital had in place a computerized clinical information system. Among other uses, physicians used the system for direct entry of total parenteral nutrient solution orders and associated laboratory tests; labels are produced automatically. Personnel from the pharmacy and information services departments met to discuss how to apply the computer system to investigational drug information. The application they designed has three components: protocol information, order entry, and patient monitoring. Protocol information, including all the standard drug data plus regulatory and investigator information, is displayed as a report on the user's terminal. The order-entry pathway allows the research pharmacist to predesign medication labels that are specific to each study and include all required information. This saves time, ensures accurate labeling, and provides a means for generating patient charges. The patient-monitoring component provides information to the research pharmacist in a daily report to assist in locating subject patients and to monitor compliance with protocols. The system has improved the access of health-care professionals to investigational drug information and decreased the time pharmacists spend dispensing these agents. The system has been well received, although up to three weeks is needed to bring the information online. A hospitalwide information system is effective in disseminating information on investigational drugs and facilitating order entry.     

Design and evaluation of a dry coated drug delivery system with an impermeable cup, swellable top layer and pulsatile release

In this investigation a novel oral pulsatile drug delivery system based on a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and circumference wall with inactive material, is proposed. The system consists of three different parts, a core tablet, containing the active ingredient, an impermeable outer shell and a top cover layer-barrier of a soluble polymer. The core contained either diclofenac sodium or ketoprofen as model drugs. The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic swellable materials, such as polyethylene oxide, sodium alginate or sodium carboxymethyl cellulose. The effect of the core, the polymer characteristics and quantity at the top cover layer, on the lag time and drug release was investigated. The results show that the system release of the drug after a certain lag time generally due to the erosion of the top cover layer. The quantity of the material, its characteristics (viscosity, swelling, gel layer thickness) and the drug solubility was found to modify lag time and drug release. The lag time increased when the quantity of top layer increased, whereas drug release decreased. The use of sodium carboxymethyl cellulose resulted in the greatest swelling, gel thickness and lag time, but the lowest drug release from the system. Polyethylene oxide showed an intermediate behaviour while, the sodium alginate exhibited the smallest swelling, gel thickness and the shortest lag time, but the fastest release. These findings suggest that drug delivery can be controlled by manipulation of these formulations.     

低成本二维码扫描在医院药库管理中的应用

目的：通过使用二维码技术,零成本提高医院药库药品的验收效率,降低医院管理成本。方法：对现有人工验收、一维码扫描验收与建立二维码扫描验收进行对照研究,对比三者在时间、出现差错次数、工作强度、数据处理时间的差异,实验数据用SPSS13.0进行统计学分析。结果：与人工验收相比,使用扫描二维码验收的方式,验收时间缩短了82.4%、差错降低了84.2%、工作强度减轻了36.1%、数据录入速度提高了93.9%;与一维码验收相比,以上指标分别是68.4%,60.0%,11.5%,75.8%。结论：二维码扫描流程准确率高、数据处理时间短、扫描效率高,极大节约了人力资源,并且方法建立简单,花费成本极低,为医院节省了巨大的管理成本。     

Time-release compression-coated core tablet containing nifedipine for chronopharmacotherapy

Compression-coated time-release tablets (CC tablets) containing nifedipine, dihydropyridine Ca channel blocker, in the core tablet were prepared by dry coating with different polyethylene oxide-polyethylene glycol mixtures. Each formulation showed a clear lag period before nifedipine release initiation, followed by sustained drug release lasting up to 24 h. The lag time of nifedipine release increased as the amount of polyethylene oxide in the outer layer increased. To investigate the applicability of such CC-tablets for chronopharmacotherapy, the pharmacokinetics of CC-1 and CC-2 tablets, with different in vitro lag times before drug release, were compared with the pharmacokinetics of a sustained-release (SR) tablet in dogs. The times of first nifedipine appearance (TFA) in plasma were 0.7 ± 0.3 h for SR, 2.5 ± 1.2 h for CC-1, and 5.3 ± 1.0 h for CC-2. These data show a significant difference in in vivo lag time (P < 0.01) among the three formulations that correlates with the in vitro lag times. Thus, the in vivo lag time could be predicted from the in vitro lag time. Additionally, higher plasma nifedipine concentrations were observed at 8 h after administration of the CC-2 than that observed for the SR-tablet. These results indicate that a CC-tablet with a lag time before drug release is a potentially useful formulation for chronopharmacotherapy that can control the time and duration of plasma drug concentration better than existing SR technologies.     

Design and evaluation of a dry coated drug delivery system with floating-pulsatile release

The objective of this work was to develop and evaluate a floating-pulsatile drug delivery system intended for chronopharmacotherapy. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel K4M, Carbopol 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time.     

A novel system for three-pulse drug release based on "tablets in capsule" device

The objective of the present study was to obtain programmed drug delivery from a novel system, which contains a water-soluble cap, impermeable capsule body, and two multi-layered tablets. Types of materials for the modulating barrier and its weight can significantly affect the lag time (defined as the time when drug released 8% of the single pulse dosage). We chose sodium alginate and hydroxy-propyl methyl cellulose (HPMC E5) as the candidate modulating barrier material. Through adjusting ratio of sodium alginate and lactose, lag time was controllable between the first two pulsatile release. Linear relationship was observed between the ratio and the lag time. Through adjusting the ratio of HPMC E5/lactose, lag time between the second and the third pulse can be successfully modulated. In further studies, drug release rate of the second pulsatile dose can be improved by adding a separating layer between the third and the modulating barrier layer in the three-layered tablet. To evaluate contribution of bulking agent to drug release rate, lactose, sodium chloride, and effervescent blend were investigated. No superiority was found using sodium chloride and effervescent blend. However, lactose favored it. The results reveal that programmed drug delivery to achieve pulsatile drug release for three times daily can be obtained from these tablets in capsule system by systemic formulation approach.     

Salting-out taste-masking system generates lag time with subsequent immediate release

Salting-out effects were utilized for developing a multiparticulate system balancing numbness masking and high bioavailability. A "salting-out taste-masking system" consisting of a drug core containing acetaminophen as a model drug, a salting-out layer containing sodium carbonate (Na(2)CO(3)) and hydroxypropylmethylcellulose (HPMC), and a water-penetration-control layer consisting of cetanol was designed and prepared. The system successfully generated a long lag time while achieving immediate drug release. In the system, the Na(2)CO(3) release rate was slower and the lag time was longer than when the water-penetration-control layer was not present. During the release of Na(2)CO(3) from the system, the release of HPMC and drug was suppressed. These results indicated that the water-penetration-control layer maintained a high concentration of Na(2)CO(3), prevented HPMC's dissolution, and generated a long lag time of drug release. The system generated longer lag time and released drug more immediately than formulation containing the water-penetration-control layer of same thickness without the salting-out layers. These results indicated the salting-out layers were necessary for obtain a long lag time and subsequent immediate drug release. This novel taste-masking system has the potential to be a useful multiparticulate dosage form for effective, safe, and user-friendly drug therapy.     

How Modeling and Simulation Have Enhanced Decision Making in New Drug Development

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer’s disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the “Learn-Confirm” paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products” made this scientific approach to the drug approval process possible.     

Application of Radiotelemetric Technique in Evaluating Diclofenac Sodium Absorption After Oral Administration of Various Dosage Forms in Healthy Volunteers

A radiotelemetric technique with the Heidelberg capsule (HC) was used to improve the quality of data generated in a bioavailability study involving an enteric-coated (EC) formulation. Further, changes in plasma levels of the drug from other dosage forms were related to changes in the pH environment as determined by the HC. Eight healthy male subjects received the following treatments, 15 min after a light breakfast, according to a randomized, four-way crossover design: (A) HC and 75 mg of a diclofenac sodium aqueous buffered solution; (B) HC and one 75-mg Voltaren EC tablet; (C) HC and one 100-mg Voltaren slow-release (SR) tablet; and (D) HC alone. Each treatment was separated by a 1-week washout period. Two additional subjects subsequently received Treatment B only. Multiple peaks were observed in the drug plasma level–time profiles for the buffered aqueous solution which, in all cases, occurred before gastric emptying of the HC. The multiple peaks were not observed for the Voltaren SR tablet, but a variable absorption lag time occurred which coincided with the gastric residence time of the SR tablet. For the EC tablet the variability of individual plasma level–time profiles was drastically reduced when the time after dosing was adjusted to coincide with gastric emptying of the HC. Finally, the lag time between gastric emptying of the EC tablet and the onset of drug absorption was consistently at 1 hr for all subjects. This lag time was longer than the in vitro disintegration or dissolution times measured under USP conditions.     

On the impact of error cross‐sectional dependence in short dynamic panel estimation

Summary This paper explores the impact of error cross‐sectional dependence (modelled as a factor structure) on a number of widely used IV and generalized method of moments (GMM) estimators in the context of a linear dynamic panel data model. It is shown that, under such circumstances, the standard moment conditions used by these estimators are invalid – a result that holds for any lag length of the instruments used. Transforming the data in terms of deviations from time‐specific averages helps to reduce the asymptotic bias of the estimators, unless the factor loadings have mean zero. The finite sample behaviour of IV and GMM estimators is investigated by means of Monte Carlo experiments. The results suggest that the bias of these estimators can be severe to the extent that the standard fixed effects estimator is not generally inferior anymore in terms of root median square error. Time‐specific demeaning alleviates the problem, although the effectiveness of this transformation decreases when the variance of the factor loadings is large.     

Statistical evaluation of drug efficacy for bridging study in companion diagnostic test trials

ABSTRACT

Personalized medicine is an area of growing attention in medical research and practice. A market-ready companion diagnostic test (CDx) is used in personalized medicine for identifying the best treatment for an individual patient. Unfortunately, development of CDx may lag behind the development of the drug, and consequently we use a clinical trial assay (CTA) to enroll patients into the drug pivotal clinical trial instead. Thus, when CDx becomes available, a bridging study will be required to assess the drug efficacy in the CDx intended use (CDx IU) population. Due to missingness of the CDx results that could be associated with randomization, one challenge we face in a bridging study is covariate imbalance between treatment arms for the subpopulation with both positive CDx and CTA. In this paper, we evaluate the performance of two methods in bridging studies under a causal inference framework. Particularly, we aim to use the propensity score method with doubly robust estimation and optimal matching to address the challenge. We extend under a current framework on drug efficacy estimation in the CDx IU population, using data from both the bridging study and the CTA drug pivotal clinical trial. Both approaches are discussed in the context of a randomized bridging study, and a targeted design clinical trial with simulations, followed by analyzing simulated data that mimic a real ongoing clinic trial.     

Vaccines against drugs of abuse: a viable treatment option?

Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a means of eliminating illicit drug use as well as drug overdose and neurotoxicity. Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and nicotine are now in clinical trials because they can offer long-term protection with minimal treatment compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are currently under development. An underlying theme in this research is the need for high concentrations of circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is repeatedly available, especially in high doses. Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks that need to be considered. These include: a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of choice;a lack of an effect on drug craving that predisposes an addict to relapse; and tremendous individual variability in antibody formation. Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal and ethical concerns. All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.     

The Impact of Lag Time on the Estimation of Pharmacokinetic Parameters. I. One-Compartment Open Model

Lag time in pharmacokinetics corresponds to the finite time taken for a drug to appear in systemic circulation following extravascular administration. Lag time is a reflection of the processes associated with the absorption phase such as drug dissolution and/or release from the delivery system and drug migration to the absorbing surface. Failure to specify the lag time can lead to inappropriate or erroneous estimates of pharmacokinetic parameters. This has been demonstrated in the case of a one-compartment open model by the pharmacokinetic analysis of bioequivalence data from a study involving the administration of propoxyphene napsylate to human volunteers. Subsequently, pharmacokinetic and statistical analyses of data obtained from a series of 49 simulations involving a wide range of absorption and elimination rate constants (0.05 to 5.00 and 0.01 to 0.95 hr^–1, respectively) showed that lag time has a substantial effect on several primary and secondary pharmacokinetic parameters.     

pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat ECD.

The objective of this study was to develop a rupturable, capsule-based pulsatile drug delivery system with pH-independent properties prepared using aqueous coating. The drug release is induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating. Croscarmellose sodium (AcDiSol) is a preferable superdisintegrant compared to low substituted hydroxypropylcellulose (L-HPC) and sodium starch glycolate (Explotab), because of controlled lag time, followed by a quick and complete drug release. However, due to its anionic character, AcDiSol showed pH-dependent swelling characteristics (pH 7.4 > 0.1N HCl) resulting in a pH-dependent lag time. The pH dependency could be eliminated by the addition of fumaric acid to the swelling layer, which allowed to keep an acidic micro-environment. Formation of the rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose (Aquacoat) ECD), whereby sufficient drying during the coating was needed to avoid swelling of the AcDiSol layer. A higher coating level was required, when aqueous dispersion was used, compared to organic coatings. However, an advantageous aspect of the aqueous coating was the lower sensitivity of the lag time to a deviation in the coating level.     

Preparation and evaluation of pectin-based colon-specific pulsatile capsule in vitro and in vivo

The purpose of this study was to develop and evaluate a colon-specific, pulsatile drug delivery system, which consists of an impermeable capsule body filled with a 5-aminosalicylic acid rapid-disintegrating tablet and a pectin-based erodible plug placed in the opening of the capsule body. To obtain an appropriate gel-forming ability and suitable lag time for the colon-specific drug delivery, high-methoxy pectin (HM-pectin) was formulated with lactose and lowmethoxy pectin (LM-pectin) with HPMC to prepare the plug tablet. In order to evaluate the lag time, prior to the rapid drug release, both the formulation of the plug tablet and in vitro release medium were studied. The lag time prior to the rapid drug release was mainly determined by the HM-pectin/lactose or LM-pectin/HPMC ratio. The addition of pectinase or rat cecal content into the release medium shortened the lag time significantly, which predicted the probable enzyme sensitivity of pectin plug tablet. In vivo studies showed that the plasma concentration of drug can only be detected 6h after oral administration of the pulsatile capsule, which indirectly proved the colon-specific characteristics. These results show that the pulsatile capsule may have the therapeutic action for colon-specific drug delivery.     

Optimizing Metrics for the Assessment of Bioequivalence Between Topical Drug Products

PURPOSE: Stratum corneum tape stripping post-application of a drug product followed by analysis of the active agent in this tissue layer is an approach being seriously considered for the comparative assessment of topical bioavailability. Key issues revolve around how best to perform this experiment and interpret the data. METHODS: Using previously published results from a comparative study of three 0.025% tretinoin gel products, alternative data analysis approaches are presented that may render the technique more accessible to the evaluation of new and generic topical dosage forms. RESULTS: For the tretinoin gel study, the conclusions for bioequivalence from measurements of drug levels at only one uptake and one clearance time were the same as those from the original study, which required measurements at eight different treatment times. Furthermore, comparisons of drug levels at one uptake and one clearance time discriminated differences in bioequivalence for clearance and uptake, which had previously been missed. Half-life estimates, derived from time course data of drug clearance, can be related to lag time for drug penetration through the SC. CONCLUSIONS: This new data analysis demonstrates that comparative bioequivalence might be assessed more easily.     

Characterization of 5-fluorouracil release from hydroxypropylmethylcellulose compression-coated tablets

Hydrogel compression-coated tablets are able to release the core drug after a period of lag time and have potential for colon-specific drug delivery based on gastrointestinal transit time concept. This study investigated the factors influencing in vitro release characteristics of a model drug 5-fluorouracil from hydroxypropylmethycellulose (HPMC) compression-coated tablets. The core tablet, prepared by a wet granulation compression method, was designed to disintegrate and dissolute quickly. To prepare the compression-coated tablets, 50% of the HPMC/lactose coat powder was precompressed first, followed by centering the core tablet and compressing with the other 50% of the coat powder. Release characteristics were evaluated in distilled water by using a Chinese Pharmacopoeia rotatable basket method. Effect of HPMC viscosity, lactose content in outer shell, and overall coating weight of outer shell on release lag time (T(lag)), and zero-order release rate (k) were studied. Release of drug from compression-coated tablets began after a time delay as a result of hydrogel swelling/retarding effect, followed by zero-order release for most of the formulations studied. HPMC of higher viscosity (K4M and K15M) provided better protection of the drug-containing core, showing increased release lag time and slower release rate. Incorporating lactose in outer shell led to decrease of T(lag) and increase of k. T(lag) and k are exponentially and linearly correlated to lactose content, expressed as weight percentage of the outer shell. Larger coating weight (W) of outer shell produced larger coating thickness (D) around core tablet, which resulted in increase in T(lag) and decrease in k. There was good fitting of a linear model for each of the four variables W, D, T(lag), and k. Hardness of the compression-coated tablets and pHs of the release media had little effect on drug release profile. It is concluded that the release lag time and release rate are able to be tailored through adjusting the formulation variables to achieve colon-specific drug delivery of 5-fluorouracil.