Fraction of theophylline in sustained-release formulation which is absorbed from the large bowel

Summary In a cross-over study of six healthy male volunteers, 500 mg theophylline was administered either as plain tablets or in a sustained release preparation. On each occasion 2 g of non-enteric coated sulphasalazine was administered simultaneously as the time of appearance of sulphapyridine, the product of hydrolysis, in the blood provides an approximation of the oral — caecal transit time. The mean fraction absorbed — time profile was calculated from serial serum concentration measurements of theophylline by a modification of the Wagner-Nelson equation. The mean cumulative fraction of the dose absorbed following administration of the plain tablets was maximal at 3 h i.e. approximately 3 h ahead of the mean oral-caecal transit time, which was 5.9 h. Thus complete absorption occurred in the small intestine.With the sustained — release formulation, approximately only half of the dose was absorbed at the time the medication reached the large bowel i.e. at about 5.4 h. Absorption continued and at least 38% of the administered dose was additionally absorbed over the next 25 h.A reliable lengthened dosage interval is therefore possible with this particular sustained — release formulation.     

混合设计优化格列喹酮缓释片处方

目的：优化格列喹酮缓释片的处方，得到最佳的缓释曲线。方法：使用混合设计对处方进行优化。结果：使用混合设计预测的处方的验证值和目标值比较，其相似因子f2能够达到70，而且其体外累积释放曲线也符合Higuchi方程和Ritger—Peppas方程。结论：混合设计是一种较方便的实验设计方法，能够有效地优化药物处方，并预测药物释放。     

Comparative study of the dissolution profiles of a commercial theophylline product after storage

The purpose of this work was to study the effect of storage time and temperature on the in vitro release kinetics of a commercial sustained-release dosage form of theophylline, at different pHs of the dissolution medium. The formulation was stored at 35 degrees C for 16 months and at 45 degrees C for 8 months, with a relative humidity of 60%. The in vitro release tests were performed at pHs 2, 4, 6 and 7.4. The mean values of the transport coefficient n, were close to 0.5 in all the conditions tested, which indicates that the transport system is not modified after storage of the formulation at 35 degrees C and 45 degrees C. The mean values of the dissolution rate constant ranged from 0.036 to 0.043 min(-n), under all the conditions tested. Significant differences (alpha = 0.05) were found between pHs 2, 4 and 6, 7.4 for all the model-independent parameters studied. When the formulation was kept at 35 degrees C for 16 months, the mean percentage of drug dissolved at 8 hours was 25.61% (pHs 2, 4) and, 36.12% (pHs 6, 7.4), representing a 26% and 24% reduction, respectively. Similar results were obtained after storing the formulation at 45 degrees C for 8 months, corresponding to 33.3% (pHs 2, 4) and, 22.5% (pHs 6, 7.4) diminution, respectively.The values of the similarity factor, f2, obtained were lower than 50, which indicates the lack of similarity among the dissolution profiles, after storing the formulation under the experimental conditions tested.     

Development of a multidose formulation for a humanized monoclonal antibody using experimental design techniques

The purpose of this study was to identify optimal preservatives for a multidose formulation of a humanized monoclonal antibody using experimental design techniques. The effect of antimicrobial parenteral preservatives (benzyl alcohol, chlorobutanol, methyl paraben, propylparaben, phenol, and m-cresol) on protein stability was assessed using size-exclusion chromatography, differential scanning calorimetry, right-angle light scattering, UV spectroscopy, and potency testing using a cell-based fluorescence-activated cell sorting method. A quick, cost-effective preservative screening test was designed. Combinations of preservatives were examined using an I-optimal experimental design. The protein was most stable in the presence of methylparaben and propylparaben, and was compatible with benzyl alcohol and chlorobutanol at low concentrations. Phenol and m-cresol were not compatible with the protein. The I-optimal experimental design indicated that as an individual preservative, benzyl alcohol was promising. The model also indicated several effective combinations of preservatives that satisfied the antimicrobial efficacy and physical stability constraints. The preservative screening test and the experimental design approach were effective in identifying optimal concentrations of antimicrobial preservatives for a multidose protein formulation; (1) benzyl alcohol, and (2) the combination of methylparaben and chlorobutanol were screened as potential candidates to satisfy the regulatory requirements of various preservative efficacy tests.     

Formulation optimization of transdermal meloxicam potassium-loaded mesomorphic phases containing ethanol,oleic acid and mixture surfactant using the statistical experimental design methodology

Response surface methodology (RSM) was used to develop and optimize the mesomorphic phase formulation for a meloxicam transdermal dosage form. A mixture design was applied to prepare formulations which consisted of three independent variables including oleic acid (X₁), distilled water (X₂) and ethanol (X₃). The flux and lag time (LT) were selected as dependent variables. The result showed that using mesomorphic phases as vehicles can significantly increase flux and shorten LT of drug. The analysis of variance showed that the permeation parameters of meloxicam from formulations were significantly influenced by the independent variables and their interactions. The X₃ (ethanol) had the greatest potential influence on the flux and LT, followed by X₁ and X₂. A new formulation was prepared according to the independent levels provided by RSM. The observed responses were in close agreement with the predicted values, demonstrating that RSM could be successfully used to optimize mesomorphic phase formulations.     

The effects of omeprazole-induced hypochlorhydria on absorption of theophylline from a sustained-release formulation

Summary The present study was designed to investigate the effects of raised intragastric pH on the absorption of theophylline from a sustained-release formulation. Six healthy male volunteers participated in the cross-over randomised study and on one of two occasions were pretreated with 240 mg omeprazole, administered in three divided doses over the 22 h preceding the test. The sulphasalazine/sulphapyridine method of assessing oral-caecal transit time was implemented in order to assess upper bowel and colonic absorption. The mean fraction absorbed — time profile was calculated from serial serum theophylline concentration measurements by a modification of the Wagner-Nelson equation.During hypochlorhydria the mean oral-caecal transit time was 4.6 h, mean time to 90% absorption 6.8 h, and the percentage theophylline presumably to be absorbed from the colon 32.3. The corresponding values with normochlorhydria were, respectively, 3.8 h, 8.5 h, and 57.5%. The shorter oral-caecal transit time and lesser upper bowel absorption during normochlorhydria is postulated to result from motilin release due to duodenal acidification.Gastric hypoacidity resulted in significantly increased cumulative fractions of theophylline absorbed during a 3.5 h period, starting 0.5 h after breakfast. Possibly hypochlorhydria amplifies the increased motility which follows the intake of a meal, resulting in increased peristalsis and antiperistalsis, with more rapid drug absorption.     

均匀设计法筛选跌打止痛巴布剂的基质处方

目的筛选跌打万花巴布剂的基质处方。方法采用均匀设计方法,以黏着力、持黏力和透皮速率为评价指标,各基质及其用量为因素和水平进行U17(1711)的实验,得出最优配比组成。结果巴布剂最佳配比为明胶∶CMC-Na∶PANA∶高岭土∶PEG400∶甘油∶山梨醇∶卡波姆940=3∶5∶1.5∶6∶4∶20∶10∶1。结论该基质具有一定的黏度、良好的延展性和保湿性。     

正交实验法优选巴布剂基质配方的研究

目的研究巴布剂基质的最佳配方。方法采用正交设计法,以黏着力为指标,对巴布剂基质配比进行实验研究。结果优化的基质配方为胶液∶甘油∶聚乙烯醇=5∶4∶0.2。结论优化处方具有良好的涂展性、保湿性,且黏着力适中。     

正交实验法优选巴布剂基质配方的研究

目的研究巴布剂基质的最佳配方。方法采用正交设计法,以黏着力为指标,对巴布剂基质配比进行实验研究。结果优化的基质配方为胶液∶甘油∶聚乙烯醇=5∶4∶0.2。结论优化处方具有良好的涂展性、保湿性,且黏着力适中。     

甲苯磺酸索拉非尼片的制备以及体外溶出行为考察

目的：制备甲苯磺酸索拉非尼片并考察其体外溶出行为。方法：以交联羧甲基纤维素钠为崩解剂,微晶纤维素为填充剂,十二烷基硫酸钠为增溶剂,制备本片。以f2值为考察指标,采用正交设计法筛选最优处方。结果：在不同溶出介质中,自制制剂的溶出曲线和进口制剂的体外溶出特征相似。结论：按优化的处方工艺制备的本片符合规定,可操作性强;溶出动力学特征符合一级方程。     

Pharmacokinetic and pharmacodynamic comparison of a new controlled-release formulation of metoprolol with a traditional slow-release formulation

The plasma concentration-time profile and haemodynamic effects of metoprolol after the administration of metoprolol CR¹ (a new multiple-unit controlled-release formulation) and metoprolol SR² (a traditional slow-release formulation) once daily, were investigated in 12 healthy men. Data were collected over one 24-h dose interval at steady state after five days of treament.The study was a randomized, three-way, crossover comparison of metoprolol CR, 100 mg, metoprolol SR, 100 mg, and placebo. The reduction in exercise heart rate in relation to placebo treatment was used as a measure of ₁-blockade.     

Box-Behnken效应面法优化长春西汀长循环脂质体处方

目的通过优化手段筛选最佳处方,制备长春西汀长循环脂质体。方法采用薄膜分散法制备长循环脂质体,分别以磷脂质量浓度(1ρ)、Tween80质量浓度(ρ2)、磷脂-药质量比(ms∶md)为考察对象,以包封率(Y1)、载药量(Y2)和粒径(d)为评价指标,利用三因素三水平Box-Behnken效应面设计法筛选长循环脂质体的最佳处方;透射电子显微镜考察其形态与粒径。结果长循环脂质体的包封率为85.9%;载药量18.5 mg.g-1;粒径为213.4 nm,与理论值偏差均小于10%。结论长春西汀长循环脂质体采用Box-Behnken实验设计法优化是可行的。     

Box-Behnken实验设计法优化胸腺五肽脂质体的处方工艺

目的优化胸腺五肽脂质体的处方工艺。方法采用三因素三水平的Box-Behnken实验设计,利用响应面法对影响胸腺五肽脂质体包封率的主要因素进行考察,以包封率为响应值,建立相应的二项式数学模型优化处方。结果最优处方是脂质体膜材料中磷脂与胆固醇的质量比为17∶5,磷脂与药物的质量比为17∶2,有机相与水相的体积比为3∶1。包封率的预测值与理论值偏差较小。结论 Box-Behnken实验设计法可用于胸腺五肽脂质体处方的优化,经优化的处方工艺稳定可行。     

Integrated computer-aided formulation design: A case study of andrographolide/ cyclodextrin ternary formulation

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists, which is time-consuming, high cost and waste materials. This research aims to integrate various computational tools, including machine learning, molecular dynamic simulation and physiologically based absorption modeling (PBAM), to enhance andrographolide (AG) /cyclodextrins (CDs) formulation design. The lightGBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy. AG/γ-CD inclusion complexes showed the strongest binding affinity, which was experimentally validated by the phase solubility study. The molecular dynamic simulation was used to investigate the inclusion mechanism between AG and γ-CD, which was experimentally characterized by DSC, FTIR and NMR techniques. PBAM was applied to simulate the in vivo behavior of the formulations, which were validated by cell and animal experiments. Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate (TPGS) significantly increased the intracellular uptake of AG in MDCK-MDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers. The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills, respectively. In conclusion, this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility, dissolution rate and bioavailability. The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.     

Absolute bioavailability of theophylline from a sustained-release formulation using different intravenous reference infusions

Summary The effect of different intravenous infusions on the absolute bioavailability of theophylline from a sustained-release formulation has been investigated. Oral administration of 750 mg theophylline (2 capsules Euphylong 375) was referenced to intravenous aminophylline infusions corresponding to 506 mg theophylline over 8 h (63 mg·h^–1) in Study 1, and to 749 mg theophylline over 14 h in Study 2. A reduction in the infusion rate from 69 to 33 mg·h^–1 was made in Study 2 after 8 h in order to mimic the concentration/time profile of the oral formulation as closely as possible. The absolute bioavailability was 100 (89, 115) % in Study 1 and 88 (73, 105) % in Study 2.The lower clearance values and, as a consequence, the lower bioavailability ratios observed with the higher intravenous dose, although not significant, indicate that the absolute bioavailability of theophylline might appear to depend on the choice of the intravenous reference standard.     

PBL与LBL在"药物制剂的设计"教学中的应用比较

目的 探讨以问题为基础的教学法(PBL)在药剂学理论教学中的应用价值。 方法 以湖北医药学院药学专业四年制本科06级学生为研究对象,实施 PBL 教学和讲授为基础(LBL)教学两种教学方法,采用问卷调查和理论考核形式,评价PBL教学法在药物制剂的设计中应用效果和可行性。 结果 参加问卷调查的学生中有 88.6%以上的乐意接受PBL教学法,理论考试结果显示,在知识性考核方面两组成绩比较无显著性差异(P>0.05),而在综合能力考核方面PBL教学组成绩优于对照组(P<0.0     

The effect of experimental design on the modeling of a tablet coating formulation using artificial neural networks

The aim of this study was to investigate the effect of experimental design strategy on the modeling of a film coating formulation by artificial neural networks (ANNs). Box-Behnken, central composite and pseudo-random designs of 102, 90 and 100 simulated records, respectively were used to train a multilayer perceptron (MLP) ANN comprising six input and two output nodes separated by a single hidden layer of five nodes. Network over-training was limited by using a test set of 40 pseudo-randomly distributed records. The models were validated using a set of 60 pseudo-randomly distributed records. Crack velocity was highly curved with respect to pigment particle size and size distribution. Similarly, film opacity was highly curved in response to pigment concentration and film thickness. The Box-Behnken and central composite designs generated models that were unable to predict crack velocity and showed extensive bias in prediction of film opacity. The pseudo-random design was unable to predict crack velocity of the test data set but yielded acceptable predictions for the validation set. Film opacity was well predicted by the pseudo-random design model. The poor predictive ability of the Box-Behnken and central composite models was attributed to poor interpolation of the high curvature of the response surfaces. In contrast, the pseudo-random design mapped the interior of the design space allowing improved interpolation and predictive ability. It is concluded that Box-Behnken and central composite experimental designs are inappropriate for ANN modeling of highly curved responses and that extensive internal mapping of the design space is essential to generate predictive ANN models.     

Comparison of the in vitro dissolution properties and in vivo steady-state pharmacokinetics of two sustained-release theophylline preparations

The sustained-release properties and relative bioavailability of Theolin^® Retard and Pharphylline^® Retard were studied in eight healthy adults after treatment for five days with twice daily 450 mg, respectively 425 mg. During the day-time dosing interval on the fourth and fifth day theophylline plasma concentrations were assayed by HPLC. After intake of Theolin^® Retard, minimum theophylline plasma concentrations were significantly higher, fluctuations in theophylline plasma concentrations were significantly smaller andt ₇₅ (the period within a dosing interval during which the plasma concentration exceeds 75% of the maximal concentration) was significantly longer than after Pharphylline^® Retard. Maximal concentrations and AUC values were not significantly different. For both products the plasma concentration time-curves on day 5 were significantly lower than on day 4.In vitro dissolution tests confirmed the more sustained release of theophylline from Theolin^® Retard. These results indicate an equal extent of absorption from the two products but better sustained-release properties for Theolin^® Retard.     

Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design

In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1–2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X₁), spray flow (X₂), sodium caseinate amount (X₃) and lecithin amount (X₄). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2⁴-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved.