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.     

Once-a-day controlled-release dosage form of divalproex sodium I: formulation design and in vitro/in vivo investigations

Divalproex sodium is a narrow therapeutic index drug that is widely used for the treatment of epilepsy, the manic episodes associated with bipolar disorder, and prophylaxis of migraine headaches. The present investigation was undertaken to design an oral dosage form that would provide once-daily administration with improved therapy and to explore the relationships between in vitro drug release and in vivo absorption. Controlled release hydrophilic matrix formulations of divalproex sodium were designed and evaluated via in vitro and in vivo studies. The release rate of divalproex sodium was modulated by varying different rate-controlling hydrophilic polymers and measured in vitro using a USP apparatus II dissolution method. Formulations with differing release rates were studied in beagle dogs and in healthy subjects. A selected formulation given once-daily was further evaluated against the commercial enteric tablet dosed twice-daily in a multiple dose study, and shown to provide desired nearly constant therapeutic plasma concentrations over the entire 24-h dosing interval. Preliminary linear relationships between in vitro dissolution and in vivo absorption were observed in both the animal model and in humans. However, the relationships were formulation dependent, indicating a need for further studies.     

In vitro/in vivo studies on a buccal bioadhesive tablet formulation of carbamazepine

A buccoadhesive controlled-release system for delivery of carbamazepine (CBZ) was prepared by compression of hydroxypropyl methylcellulose (HPMC) and carbomer, incorporating a penetration enhancer, sodium glycodeoxycholate (GDC). The release behaviour of systems containing CBZ and various amounts of the two polymers with and without GDC was found to be non-Fickian. Formation of an interpolymer complex between HPMC and carbomer was confirmed in acidic medium by turbidity, viscosity and FT-IR measurements. Addition of the drug to the buccoadhesive formulation reduced the adhesion force significantly (p < 0.1). GDC did not have any effect on bioadhesion. Permeability of bovine buccal mucosa to CBZ was determined using Ussing diffusion chambers [1]. In vivo interaction between the tablet and tissue was examined histologically as well as by scoring mucosal irritation. Histological changes observed in the buccal epithelium after 4 h contact with the tablets containing GDC recovered completely within 24 h after removal. No measurable plasma level of CBZ was obtained either in the absence or presence of GDC.     

新型口服固体速释制剂———口腔速崩片

目的：介绍目前口腔速崩片崩解剂的特性、制备工艺、特点,为国内口崩片的设计和制备提供参考及思路。方法：概述了近十几年来,国外选用的崩解剂和改善口感的方法及其应用概况。结果：通过对口崩片崩解剂特性的了解,为口崩制剂的处方设计提供依据,开阔思路。结论：对口崩制剂的深入研究有助于开发有价值的老年人和其他特殊病人用药。     

Optimization of sustained-release propranolol dosage form using factorial design and response surface methodology

The purpose of this study was to develop propranolol extended release formulations containing hydroxypropylmethylcellulose (HPMC). The results indicate that the drug release from the tablet form containing a high amount of HPMC was incomplete, and avicel addition could increase the release percent at a later stage. In order to readily obtain an optimal formulation, response surface methodology and multiple response optimization utilizing a quadratic polynomial equation was used. The model formulations were prepared according to a factorial design. The effects of causal factors including the HPMC/drug ratio (X1) and avicel level (X2), on drug release were also measured. The drug release percentage at 1.5, 4, 8, 14 and 24 h were the target response and were restricted to not more than 25%, 35-50%, 55-70%, 75-90%, and 95-110%, respectively. The results showed that the optimized formulation provided a dissolution pattern equivalent to the predicted curve, which indicated that the optimal formulation could be obtained using response surface methodology. The mechanism of drug release from HMPC matrices tablets followed quasi-Fickian diffusion.     

Floating matrix dosage form for propranolol hydrochloride based on gas formation technique: development and in vitro evaluation

Gastroretentive tablets of propranolol hydrochloride were developed by direct compression method using citric acid and sodium bicarbonate as the effervescent base. Hydroxypropyl methylcellulose; HPMC K15M was used to prepare the floating tablets to retard the drug release for 12h in stomach. Na-carboxymethyl cellulose (NaCMC) or carbopol 934P was added to alter the drug release profile or the dimensional stability of the formulation. Dicalcium phosphate (DCP) was used as filler. Formulations were evaluated for floating lag time, duration of floating, dimensional stability, drug content and in vitro drug release profile. The formulations were found to have floating lag time less than 1min. It was found that the dimensional stability of the formulations increase with increasing concentration of the swelling agent. The release mechanism of propranolol hydrochloride from floating tablets was evaluated on the basis of Peppas and Higuchi model. The ana value of the formulations ranged from 0.5201 to 0.7367 (0.5相似文献   

A multi-mechanistic drug release approach in a bead dosage form and in vitro/in vivo correlations

An in vitro/in vivo relationship of a combined multi-mechanistic dosage form has now been established in the literature. In our previous study, we successfully prepared a combination of immediate release, enteric coated, and controlled-release (CR) beads and mathematically modeled in vitro and in vivo drug release characteristics of the combination based on the release profiles of individual beads. The objective of the present study is to develop in vitro/in vivo correlations (IVIVC) for three individual beads and the combination using theophylline as a model drug and the beagle dog as an animal model. In the study, an IVIVC correlation is estimated by two-stage procedures: deconvolution followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. The Wagner-Nelson mass balance method was used to deconvolute plasma drug concentration-time curves. In vitro, a two-stage medium (0.1 N HCl and pH 6.5 phosphate buffer) was used for the dissolution test; a 2h first stage (acidic) was selected based on the average gastric emptying time in a fasted dog. In vivo, t(lag) was used for the gastric emptying process for enteric coated beads and the combination, which contains enteric coated beads. A time-scaling technique was used to consider the rate difference between in vitro dissolution and in vivo absorption in the process of IVIVC. As shown in the results, a point-to-point correlation was established for each formulation. The linear regression analysis of the correlation was r2>0.99 for all three individual beads and 0.97 for the combined bead dosage form. The results suggest level A IVIVCs indicating an appropriateness for the in vitro and in vivo models used in this study.     

齐多夫定缓释片的制备及体外评价

目的利用亲水性的Eudragit系列高分子物质单用、与疏水性的乙基纤维素合用制备齐多夫定骨架型缓释片。方法确定5个不同的处方，采用湿法制粒法制备骨架片。结果单独使用Eudragit系列产品作辅料，缓释片只能维持6h的药物持续释放，而RLPO、RSPO与乙基纤维素合用后可以维持12h的持续释药。结论齐多夫定缓释片与常规片比较，缓释片可以雏持12h的药物持续释放，这样会产生更好的治疗效果，减轻药物的副作用，大大改善患者依存率。     

Controlled release of a self-emulsifying formulation from a tablet dosage form: stability assessment and optimization of some processing parameters

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

The in vitro development of extended-release solid oral dosage forms

A system is described for developing extended-release products, based upon predicting or simulating the entire plasma level-time curve to be expected from the administration of a controlled-release oral dosage form. Termed "biorelevant dissolution," it employs the product's in vitro dissolution behavior and the drug's pharmacokinetic parameters in conjunction with a classical pharmacokinetic model. The basic system is described along with some pertinent examples.     

Optimization and in vivo evaluation of an oral dual controlled-release tablet dosage form of insulin and duck ovomucoid

The objectives of the present study were to (1) optimize the release rate of insulin from compressed microparticulates and (2) compare the in vivo hypoglycemic effect of optimized insulin microparticulates with compressed enzyme inhibitor (duck ovomucoid) and without inhibitor. A 3-factor, 15-run Box Behnken design was used to construct polynomial models correlating the dependent and independent variables. Independent processing variables were rate of addition of the alcoholic Eudragit L100 dispersion, volume of the antisolvent, and compression pressure. Responses were cumulative percent of insulin released from 1-6 hours. Insulin and ovomucoid release was simultaneously analyzed by high-performance liquid chromatography. They demonstrated variable release rates, which were optimized to the Higuchi's square root of time model to release the insulin and the inhibitor over 6 hours. The relationship between dissolution profiles and process parameters were demonstrated by contour and response surface plots. In vivo hypoglycemic effect was evaluated in rabbits in a 3-way crossover design. Cocompressed microparticulates of insulin and duck ovomucoid displayed a 3.2-fold greater hypoglycemic effect when compared with a similar preparation without ovomucoid. This study demonstrated the potential benefits of dosage forms with dual controlled-release mechanisms for both the protein and enzyme inhibitor.     

Stability-indicative HPLC determination of donepezil hydrochloride in tablet dosage form

Asimple, selective, precise and stability-indicative high-performance liquid chromatography (HPLC) method of analysis of donepezil hydrochloride in tablet dosage form has been developed and validated. The drug undergoes degradation under acidic, basic, peroxide, photochemical and thermal conditions. The method has been statistically validated for linearity, accuracy, precision, limit of detection, limit of quantitation, solution stability, and selectivity according to ICH recommendations. Due to its simplicity and accuracy, the method can be used for routine drug quality control.     

Once-a-day extended-release dosage form of divalproex sodium III: development and validation of a Level A in vitro-in vivo correlation (IVIVC)

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of a once-daily extended-release (ER) tablet of divalproex sodium, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish an internally and externally validated Level A IVIVC, a total of five different ER formulations of divalproex sodium were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way crossover study (N = 16) was performed using fast-, medium-, and slow-releasing ER formulations and a 12-h IV infusion of valproic acid as reference. To validate the IVIVC externally, a second three-way crossover study (N = 36) was performed using slightly-fast-, medium-, and slightly-slow-releasing ER formulations. The in vivo absorption-time profile was inferred by deconvolution of the observed plasma concentration-time profiles against the unit disposition function (UDF). A linear IVIVC model was established in which the in vivo absorption was expressed as a function of in vitro drug release. Plasma profiles of ER formulations were estimated via convolution of in vitro release profiles with the UDF. Successful internal and external validations of the model were demonstrated by individual and average absolute percent prediction errors of 相似文献   

Pharmacokinetic evaluation of conventional and controlled release dosage form of propranolol

A comparative pharmacokinetic study of a new controlled release multiple unit propranolol formulation and a conventional propranolol tablet was carried out in twelve healthy human volunteers in a randomized balanced crossover design. Under a single dosage regimen, subjects were administered either a single capsule containing controlled release propranolol equivalent to 160 mg of the drug or 80 mg of conventional propranolol tablet, twelve hourly. Peak plasma propranolol concentrations were low which occurred later after controlled release administration than after the administration of the conventional tablet. Analysis of the area under the plasma concentration-time curve (AUC) for the two formulations indicate no significant difference of bioavailability despite a prolonged absorption time and maintenance of effective plasma concentration for the controlled release preparation.     

Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers

The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration-time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (+/-) values for the C(max) of lovastatin were 1.04+/-0.43, 2.03+/-0.65 and 4.03+/-3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC(0-48 h) of lovastatin were 14.6+/-7.8, 34.1 +/-13.7, and 53.9+/-35.6 ng h/ml. The same tendency was also found for C(max) and AUC(0-48 h) values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the C(max) and AUC(0-48 h) values of lovastatin as well as lovastatin acid appeared to increase linearly.     

Analysis of clonazepam in a tablet dosage form using smallbore HPLC

A stability indicating, reversed phase high-performance liquid chromatographic method utilizing a smallbore HPLC column has been developed for the determination of clonazepam in a commercial tablet dosage form. The use of a small bore column results in a substantial solvent savings, as well as a greater mass sensitivity, especially in the identification of degradation peaks in a chromatogram. The method involves ultraviolet detection at 254 nm and utilized a 150 x 3.0 mm i.d. column packed with 3 microm octyldecylsilane particles with a mobile phase of water methanol acetonitrile (40:30:30, v/v/v) at a flow rate of 400 microl min(-1) at ambient temperature, with and without the use of 1,2-dichlorobenzene as the internal standard. The current USP method for the analysis of clonazepam using a 300 x 3.9 mm i.d. conventional octyldecylsilane column was utilized as a comparison to the smallbore method. The retention times for clonazepam and the internal standard on the 3.0 mm i.d. column were 4.0 and 12.5 min, respectively. The intra- and interday RSDs on the 3.0 mm i.d. column were < 0.55% (n =4) using the internal standard, and < 0.19% (n = 4) without the internal standard at the lower limit of the standard curve, 50 microg ml(-1) and had a limit of detection of 24 ng ml(-1). The assay using the 3.0 mm i.d. column was shown to be suitable for measuring clonazepam in a tablet dosage form.