Extended Release Dosage Research Articles

Carbon Nanotube: A Novel Carrier for Sustained Release Formulation

The present work describes the physicochemical interaction of multi-walled carbon nanotubes (MWCNTs) with drugs differing in physicochemical properties and shows the potential of MWCNTs in extended release dosage form design. The drug-nanotube adsorbate of candesartan cilexetil (CC), diclofenac sodium (DS) and diltiazem hydrochloride (DH) was prepared by nanoprecipitation technique. Adsorbates were evaluated for drug content, drug release mechanism and physicochemical interaction using scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and dissolution study. The effect of carbon nanotube on the drug release profile was investigated. The prepared adsorbates exhibited satisfactory physico-chemical characteristics. The spectral studies shows only physical interaction between all drug molecules and MWCNTs. Hydrophobic drug shows stronger interaction with MWCNTs. Both the nanoscale diameter of MWCNTs and hydrophobicity of the drug affected the rate of release. The most hydrophobic drug candesartan cilexetil shows extended drug release of only 20% in 15 hours; highly water soluble drug diltiazem hydrochloride shows 90% release in 15 hours. MWCNTs thus promise considerable utility in the development of extended release drug delivery systems.

Enabling clinical development of an HIV attachment inhibitor through innovative pharmaceutical development: novel extended‐release delivery of prodrug

BackgroundHIV‐1 attachment inhibitors are a new class of viral entry inhibitors which target viral gp120 preventing attachment of virus to its host cell receptor CD4. This class presents major challenges for development based upon low solubility and short half‐lives. For progression into clinical studies, requirements include reliable and reproducible absorption from a tolerable and convenient oral dosing regimen.MethodsA series of highly soluble prodrugs were designed to overcome the poor absorption caused by the low solubility of the active compounds. A regional absorption study was conducted to assess the uptake of active throughout the gastro‐intestinal tract following oral prodrug delivery. An extended‐release (ER) strategy was subsequently devised to optimise tolerability, decrease peak to trough ratios and reduce frequency of dosing. In silico absorption modelling was used to verify feasibility and drive in vitro testing leading to dosage form development and selection. The performance of the ER dosage form was verified in vivo prior to use in clinical studies.ResultsPhosphonooxymethyl prodrugs with aqueous solubilities in excess of 250 mg/mL were synthesised and shown to be readily converted to parent compound via alkaline phosphatase in vitro. Results of regional absorption studies for the selected compound, BMS‐663068, confirmed the rapid absorption but short half‐life of active following oral administration of prodrug. Delivery to specific regions throughout the GI tract showed absorption of active to be subject to regional variation with an extent of colonic absorption of approximately 40% of intestinal absorption. Incorporation of this data into an in silico model guided development of an ER tablet which releases prodrug over 24 hours and achieves the required exposure, pharmacokinetics and reproducibility in vivo.ConclusionsThe novel approach of combining prodrug synthesis and ER formulation has enabled clinical evaluation of a promising new class of therapeutic entity into Phase 2b studies.

Formulation and Characterization of Novel Solid Dispersions of Hydrochlorothiazide bySolvent Evaporation Technique

The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. In addition to bioavailability enhancement, much recent research on solid dispersion systems was directed towards the development of extended-release dosage forms. Knowledge about behavior of solid dispersions during preparation, storage and dissolution can help to tackle these problems. A thorough understanding of processes that occurs place on the molecular level is a prerequisite for rational and more efficient design of solid dispersions. However, development of solid dispersions has often been a trial-and-error approach. Solid dispersion prepared by solvent evaporation method were subjected to x ray diffraction study, dissolution study, In the present study, a 32 full factorial design was employed containing 2 factors evaluated at 3 levels and experimental trials were performed at all 9 possible combinations. Two independent variables selected were HPMC E5 and PVP K30. The objective achieved and these findings suggested that the above-mentioned technique can be employed successfully for improvement of solubility profile and stability of Solid dispersions of poorly water soluble drugs.

Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations

Metrics are discussed which are used for the evaluation of bioequivalence of modified-release formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and C (max). For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative.

Pharmacokinetics of Levodopa/Carbidopa Delivered From Gastric‐Retentive Extended‐Release Formulations in Patients With Parkinson's Disease

The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric-retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6-hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease.

Pharmacokinetics of abuse deterrent, extended release once-a-day dosage forms of levorphanol: a single-dose, 5-way crossover study

Extended release (ER) opioid analgesics are widely utilized for the treatment of chronic pain unresponsive to non-opioid analgesics. Levorphanol is an analgesic with opioid agonism, monoaminergic reuptake inhibition and NMDA antagonism. The pharmacokinetics of levorphanol are poorly characterized. This study evaluated the pharmacokinetics of four novel abuse deterrent ER dosage forms of levorphanol versus immediate release (IR) levorphanol. Fifteen healthy subjects participated in this single-center, randomized, analytically masked, fasted five-way crossover study in the USA under naltrexone block.

Microencapsulation approach for orally extended delivery of glipizide: In vitro and in vivo evaluation

Glipizide is an effective antidiabetic agent, however, it suffers from relatively short biological half-life. To solve this encumbrance, it is a prospective candidate for fabricating glipizide extended release microcapsules. Microencapsulation of glipizde with a coat of alginate alone or in combination with chitosan or carbomer 934P was prepared employing ionotropic gelation process. The prepared microcapsules were evaluated in vitro by microscopical examination, determination of the particle size, yield and microencapsulation efficiency. The filled capsules were assessed for content uniformity and drug release characteristics. Stability study of the optimised formulas was carried out at three different temperatures over 12 weeks. In vivo bioavailability study and hypoglycemic activity of C9 microcapsules were done on albino rabbits. All formulas achieved high yield, microencapsulation efficiency and extended t1/2. C9 and C19 microcapsules attained the most optimised results in all tests and complied with the dissolution requirements for extended release dosage forms. These two formulas were selected for stability studies. C9 exhibited longer shelf-life and hence was chosen for in vivo studies. C9 microcapsules showed an improvement in the drug bioavailability and significant hypoglycemic activity compared to immediate release tablets (Minidiab® 5 mg). The optimised microcapsule formulation developed was found to produce extended antidiabetic activity.

Optimization of metoprolol tartrate modified- release matrix tablet formulation using Eudragit NE as binder for metoprolol fluid bed granulation

The aim of this experimental work was to investigate the possibility of obtaining hydroxypropyl methylcellulose (HPMC) hydrophilic matrix extended-release dosage forms with metoprolol by using aqueous dispersions of Eudragit NE, as binders in fluid bed granulation. To evaluate the influence of formulation variables (levels of HPMC—Methocel K100 M and Surelease E7 19010) on drug release during a period of time of 12 hours, and on the kinetic release, a full factorial experimental design with two factors and three levels was used. The formulation factors were the granulation polymer concentration and the matrix-forming polymer concentration. The obtained results have shown that the percentage of the drug released during the 12 hours is influenced both by the Methocel ratio and the Eudragit NE ratio; increasing the ratios of Eudragit and Methocel leads to the decrease of the percentage of the released drug.The influence of Eudragit NE percentage is maximum at four and six hours, but the influence of Methocel K100 M concentration is almost the same at all sampling times; all studied formulations showed a kinetic release that fitted best with the Peppas model.

Increased bioavailability of primaquine using poly(ethylene oxide) matrix extended-release tablets administered to beagle dogs

Primaquine (PQ) is used for the radical cure of Plasmodium vivax malaria and can cause serious side effects in some individuals. The development of an extended-release dosage with poly(ethylene oxide) as a hydrophilic polymer has been investigated to improve drug efficacy and tolerability. The aim of this study was to evaluate in vivo a new extended-release formulation of PQ (60 mg). The formulation was administered to beagle dogs and plasma PQ concentrations were compared to a conventional immediate-release formulation of PQ (60 mg). The evaluation was carried out using a validated high-performance liquid chromatography method using solid-phase extraction. Total PQ exposure in beagle dogs was 2.2 times higher (area under curve of 12 193 versus 5678 ng h/ml) and the elimination half-life of PQ was a 19-fold greater (12.95 hours versus 0.68 hours) with the extended-release tablets compared with the immediate-release tablets. These findings suggest that the extended-release formulation of PQ merits further evaluation for the treatment of P. vivax malaria and/or chemoprophylaxis.

Recent advances in materials for extended-release antibiotic delivery system

To maintain antimicrobial activity, frequent administration of conventional formulations of many antibiotics with short half-life is necessary. Otherwise, concentration under MIC occurs frequently in the course of anti-infective treatment, which induces antibiotic resistance. By maintaining a constant plasma drug concentration over MIC for a prolonged period, extended-release dosage forms maximize the therapeutic effect of antibiotics while minimizing antibiotic resistance. Another undoubted advantage of extended-release formulation is improved patient compliance. For better release properties, many materials have been introduced into the matrix and coating extended-release system in the past few years. Materials that have been widely used in industry are hydrophilic matrix materials such as hydroxypropylmethylcellulose. The excellent biocompatibility and extensive laboratory studies provide biodegradable polymers great potential for industrial applications. In addition, it seems like the researches on tailored materials that are obtained by chemical modification of the existing materials or combination of different carriers in physical mixtures have a long way to go. Meanwhile, with the development of polymers and inorganic porous nanocarriers, nanotechnology is applied increasingly for the extended delivery of antibiotics. This review highlights the development of materials used in extended-release formulation and nanoparticles for antibiotic delivery. We also provide an overview of the antibiotic extended-release products that have provided clinical benefit or are undergoing the clinical trial.

Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor ( t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets.

Intermittent drug dosing intervals guided by the operational multiple dosing half lives for predictable plasma accumulation and fluctuation

Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives.

“Forgiving” a Missed Daily Dose

Editor: adherence is an essential component of a successful drug regimen.1 Simplification of a therapeutic regimen with once-daily treatment options is an important strategy to improve or sustain adherence to treatment. An extended release 400 mg tablet formulation of the nonnucleoside reverse transcriptase inhibitor nevirapine has been developed2 to offer the potential benefit of once-daily highly active antiretroviral therapy (HAART) to HIV-1-positive patients. The double-blind 48-week VERxVE trial with a total of over 1000 patients confirmed the noninferior virologic efficacy of the nevirapine 400 mg extended release once-daily regimen as compared to the standard immediate release 200 mg twice-daily regimen of nevirapine. The extended release formulation also demonstrated minimal peak-to-trough fluctuations in plasma nevirapine levels.3 As a result of metabolic enzyme autoinduction following a month of oral therapy, the half-life of nevirapine (200 mg twice daily) stabilizes at approximately 24 h. Simplification to a once-daily regimen was the objective in developing an extended release formulation. This was achieved by delaying the release of the total nevirapine dose at a slower rate over a 24-h period. Systemic absorption is prolonged for an additional day, thereby minimizing the fluctuations in the peak-to-trough concentrations of the active drug. As long as there is drug in the intestinal tract,4 this smoothing of the circulating drug concentrations leads to a longer timeframe at which the drug is at therapeutic concentrations, thereby minimizing the impact of a single missed dose of extended release nevirapine. Minimizing the impact of a single missed dose is important for a nonnucleoside reverse transcriptase inhibitor (NNRTI) such as nevirapine, as adherence rates of less than 95% have been associated with inadequate long-term treatment outcome.5 In the 2NN study,6 one treatment arm consisting of 208 patients on immediate release nevirapine 400 mg once daily had a median Cmax concentration of 7.88 μg/ml and a trough concentration of 3.26 μg/ml, resulting in a peak-to-trough ratio slightly greater than 2, consistent with dosing based on the half-life of the drug. In the VERxVE trial,3 with 418 patients on nevirapine extended release 400 mg once daily, the trough concentration of 3.50 μg/ml was maintained. However, the estimate of Cmax in a subset of patients was only 3.77 μg/ml, resulting in a peak-to-trough ratio approaching 1, consistent with extended first-order release and absorption matching the elimination rate of the drug. To illustrate the relative impact of a single missed daily dose of nevirapine, data from 2NN (two immediate release tablets for a total of 400 mg) and data from VERxVE (a single 400 mg extended release tablet) were modeled at steady state (4 weeks after treatment initiation), along with a simulation of expected nevirapine concentrations if the next dose was missed (Fig. 1). As illustrated in Fig. 1, trough nevirapine concentrations 48 h after the last dose are 2.1 μg/ml (88 × EC50 of 90 nM) for the extended release dosage form, but only 1.3 μg/ml (54 × EC50) for an immediate release 400 mg (2 × 200 mg tablets) dose taken once daily in an off-label manner. The extended release formulation maintains a 60% greater plasma concentration of nevirapine, a “forgiveness” difference that may be clinically significant for some patients on HAART therapy. Medication adherence to the entire HAART regimen must still be emphasized to the patient in order to avoid functional monotherapy and because consistent missed doses (more than once in 2 weeks) will lower overall systemic nevirapine levels irrespective of “forgiveness.” Consecutively missing more than one day of therapy may require reinitiation of a HAART loading regimen to obtain proper therapeutic levels of each drug and to prevent selection of resistance. FIG. 1. Modeled nevirapine concentration time curves for 2NN and VERxVE trials over a 24-h steady-state interval (troughs of 3.4 μg/ml at 0 and 24 h, respectively) and simulated curves for a missed dose at 24 h (troughs of 2.1 ...

A New Definition of Pharmaceutical Quality: Assembly of a Risk Simulation Platform to Investigate the Impact of Manufacturing/ Product Variabcpility on Clinical Performance

The absence of a unanimous, industry-specific definition of quality is, to a certain degree, impeding the progress of ongoing efforts to "modernize" the pharmaceutical industry. This work was predicated on requests by Dr. Woodcock (FDA) to re-define pharmaceutical quality in terms of risk by linking production characteristics to clinical attributes. A risk simulation platform that integrates population statistics, drug delivery system characteristics, dosing guidelines, patient compliance estimates, production metrics, and pharmacokinetic, pharmacodynamic, and in vitro-in vivo correlation models to investigate the impact of manufacturing variability on clinical performance of a model extended-release theophylline solid oral dosage system was developed. Manufacturing was characterized by inter- and intra-batch content uniformity and dissolution variability metrics, while clinical performance was described by a probabilistic pharmacodynamic model that expressed the probability of inefficacy and toxicity as a function of plasma concentrations. Least-squares regression revealed that both patient compliance variables, percent of doses taken and dosing time variability, significantly impacted efficacy and toxicity. Additionally, intra-batch content uniformity variability elicited a significant change in risk scores for the two adverse events and, therefore, was identified as a critical quality attribute. The proposed methodology demonstrates that pharmaceutical quality can be recast to explicitly reflect clinical performance.

Osmotically Controlled Drug Delivery System with Associated Drugs

Conventional drug delivery systems have slight control over their drug release and almost no control over the effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the controlled or modified release drug delivery systems. They include dosage forms for oral and transdermal administration as well as injectable and implantable systems. For most of drugs, oral route remains as the most acceptable route of administration. Certain molecules may have low oral bioavailability because of solubility or permeability limitations. Development of an extended release dosage form also requires reasonable absorption throughout the gastro-intestinal tract (GIT). Among the available techniques to improve the bioavailability of these drugs fabrication of osmotic drug delivery system is the most appropriate one. Osmotic drug delivery systems release the drug with the zero order kinetics which does not depend on the initial concentration and the physiological factors of GIT. This review brings out new technologies, fabrication and recent clinical research in osmotic drug delivery.

Design, Evaluation and Statistical Optimization of Diazepam Loaded Controlled Release Micropellets

This work aims at designing and evaluating a Extended release dosage form of Diazepam using Alginate- Eudragit RS 30D as the matrix-forming polymer employing the Ionotropic Gelation technique of micropellletization. The product was characterized by physicochemical parameters such as yield, drug entrapment efficiency, particle size, surface topography, granulometric study, loose surface crystal study, drug-excipient compatibility and in vitro release. The controlled release profile was optimized using a factorial design for achieving the correct blend of microparticles that closely matches the target release profile. The study illustrates the utility and advantage of designed experimentation in controlled drug delivery research.

Colonoscopic method for estimating the colonic absorption of extended-release dosage forms in dogs

The purpose of this study was to develop a new method using beagle dogs in order to evaluate the colonic absorption properties of oral extended-release (ER) solid dosage forms. The established method is not only noninvasive and inexpensive but full-sized ER dosage forms are also directly administered to the colons of conscious dogs through the anus with an endoscope and modified bioptome. In the method, it was possible to administer the ER dosage forms into the ascending colon of dogs within 30 s–1 min. The colonic absorption of Voltaren-XR (Diclofenac sodium), Glucophage-XR (metformin), Pacif (morphine hydrochloride), Herbesser-R (diltiazem hydrochloride) and Plendil (felodipine), which are currently on the market, were investigated by this method. The relative bioavailabilities of these ER dosage forms to oral drug solution were 100.3%, 42.5%, 60.6%, 46.3% and 29.8%, respectively. Some of these results reflected the human colonic absorption profiles reported in the literature. This newly developed method could provide researchers with an alternative way to predict the human colon absorption performance of oral ER delivery systems.

A Randomized, Placebo-Controlled, Multicenter Study of Divalproex Sodium Extended-Release in the Acute Treatment of Mania

Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here. A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States. There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL. The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing. clinicaltrials.gov Identifier: NCT00060905.

The Relationship between the Drug Concentration Profiles in Plasma and the Drug Doses in the Colon

After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.

Dosage form design and in vitro/ in vivo evaluation of cevimeline extended-release tablet formulations

The objective of the present work is to develop an extended-release dosage form of cevimeline. Two types of extended-release tablets (simple matrix tablets and press-coated tablets) were prepared and their potential as extended-release dosage forms were assessed. Simple matrix tablets have a large amount of hydroxypropylcellulose as a rate-controlling polymer and the matrix is homogeneous throughout the tablet. The press-coated tablets consisted of a matrix core tablet, which was completely surrounded by an outer shell containing a large amount of hydroxypropylcellulose. The simple matrix tablets could not sustain the release of cevimeline effectively. In contrast, the press-coated tablets showed a slower dissolution rate compared with simple matrix tablets and the release curve was nearly linear. The dissolution of cevimeline from the press-coated tablets was not markedly affected by the pH of the dissolution medium or by a paddle rotating speed over the range of 50–200 rpm. Furthermore, cevimeline was constantly released from the press-coated tablets in the gastrointestinal tract and the steady-state plasma drug levels were maintained in beagle dogs. These results suggested that the designed PC tablets have a potential for extended-release dosage forms.