Comparative pharmacokinetic analysis of a novel sustained release dosage form of valproic acid in dogs

A new sustained release dosage form of valproic acid (VPA) was developed. The new sustained release dosage form was administered (twice, with and without food) to five dogs in comparison to a standard tablet (Depakine, Labaz) and an i.v. preparation of the drug. Drug level monitoring in the plasma was performed by a GLC assay. Results indicate that the sustained release formulation exhibited a more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.84 (95 per cent C.I. = 0.72, 0.96) relative to an equivalent dose of a conventional tablet.     

A new subcutaneously-implantable reservoir for sustained release of nicotine in the rat

A subcutaneously-implantable reservoir for the sustained release of nicotine is described. The device, dubbed INR for Implantable Nicotine Reservoir, is a small glass cup sealed with Silastic^® polymer. It releases 3.4 mg of nicotine per 24 hours. When implanted into moderately-sized female Sprague-Dawley rats it produces blood nicotine levels of 400–500 ng/ml which remain relatively stable over at least 18 days. INRs are nontoxic, reproducible, inexpensive, and adaptable for pharmacological and toxicological studies in rats and other small animals.     

Attitude and perception of patients and health care practitioners toward oral sustained release dosage forms in Palestine

Aim

To evaluate the knowledge of health professionals in Palestine regarding the advantages of sustained release dosage forms (SRDFs) over conventional therapy.

Methods

Data were gathered from a questionnaire that was handed out to community pharmacists, physicians and patients. Pharmaceutical industry decision makers were enrolled in this study. Data were analyzed using the SPSS.

Results

Pharmacists (92.9%) and 89.2% of physicians thought that SRDFs improve patient compliance. 81.5% of pharmacists and 77% of physicians were in agreement regarding the capacity of SRDFs to maintain therapeutic activity during night. In this study, 81.5% of pharmacists and 81% of physicians believed that SRDFs provide further advantage with psychiatric patients who forget to take their medications. Pharmacists (63.1%) and only 63.5% of physicians believed that SRDFs yield a time saving for nurses who use SRDFs in hospital. Only 45.3% of physicians and 43.4% of pharmacists thought that SRDFs result in cost saving due to better disease management. Pharmacists (95.2%) and 95.9% of physicians agreed that SRDFs could be the right choice for faith patient’s who must take their medication during the month of Ramadan. Pharmacists (66.7%) and 50.7% of physicians recognize that SRDFs may be unsafe if they are improperly formulated. Bad swallowing was also recognized as inconveniences of SRDFs by 67.9% of pharmacists and 57.3% of physicians. Given the above advantages, 75% of patients showed economical problems regarding the cost of the single course therapy of SRDFs and 100% of interviewed patients were enthusiastic about the advantage of SRDFs during Ramadan.

Conclusion

The advantages of SRDFs are not completely understood by Palestinian health professionals. Pharmaceutical industries should pay more attention to the development and advertising of SRDFs due to the valuable advantages of these dosage forms.     

Polymeric microneedle‐mediated sustained release systems: Design strategies and promising applications for drug delivery

Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.     

Sustained release of hydrophobic and hydrophilic drugs from a floating dosage form

Floating dosage forms enable the sustained delivery of drugs in the gastro-intestinal tract. In this study, a type of multi-unit floating gel bead was synthesized with calcium alginate, sunflower oil, and a drug of interest through an emulsification/gelation process. The alginate beads with oil addition were able to continuously float over the medium for 24h under constant agitation while the non-oily beads could not. Three kinds of drugs with different hydrophilicities, ibuprofen, niacinamide and metoclopramide HCl, were tested in the study. The hydrophobic drug ibuprofen was released in a sustained manner for 24h, due to the oil partitioning. With suitable modification, the beads were able to also release the hydrophilic drugs, niacinamide and metoclopramide HCl, for a similar duration. Therefore a floating dosage form that is able to sustain release both hydrophobic and hydrophilic drugs within its extended gastric retention time has been developed.     

Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study

Fifteen 18- to 25-year-old male smokers were tested in a within-subjects design to determine the influence of a transdermal patch of 21 mg nicotine on vigilance. Subjects were tested on the RVIP test (Rapid Visual Information Processing test) 1.30, 3.00 and 6.30 h after patch application, to verify the involvement of the dose of nicotine on the performance. This study confirms and extends the increasing effects of nicotine on vigilance previously found with orally and transdermally given nicotine. Moreover, it showed that such performance was independent of the time of nicotine absorption (1.30, 3.00 and 6.30 h after patch application), which suggests that a relatively low dose of nicotine suffices to activate vigilance processing. Regarding motor performance, no convincing effect of nicotine was observed on reaction time. Received: 20 October 1997/Final version: 2 September 1998     

Absence of effect of food on alprazolam absorption from sustained release tablets

This study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavailabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7.2 h while fasting and 7.0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.     

缓释控释制剂的释放度测定方法的研究进展

目的　介绍缓、控释制剂的体外释放度测定方法 ,使其能更好地模拟体内状态。方法　综述最近的中外文献中有关缓释、控释制剂的体外释放度测定实验方法 ,实验条件的选择及影响因素。结果　体外释放度实验条件如释放介质的 pH值、离子强度、增溶剂、表面活性剂和释放仪器等可影响缓、控释制剂的体外释放度。结论　根据不同药物选择尽可能接近体内状态的方法     

对乙酰氨基酚非pH依赖性缓释片的处方优化

目的:设计及优化非pH依赖性缓释片处方.方法:以对乙酰氨基酚为模型药物,设计不同配比的海藻酸钠和壳聚糖为混合骨架的缓释片处方,测定各处方在 0.1 mol·L-1盐酸和pH 6.8磷酸盐缓冲液中的释放度,采用多指标同步优化筛选处方.结果:优化的乙酰氨基酚缓释片处方含壳聚糖 85 mg、海藻酸钠 135 mg 时,呈现良好的体外非pH依赖性释放特征.结论:采用海藻酸钠和壳聚糖混合骨架易制得非pH依赖性缓释片,且方法简单、成本低,具有较高的实用价值.     

盐酸四环素缓释微球的制备

目的制备盐酸四环素聚乳酸-聚羟基乙酸共聚物(PLGA)微球并优化其工艺。方法采用复乳-溶剂蒸发法制备盐酸四环素PLGA微球,以微球包封率为检测指标,通过单因素试验和正交试验优选最佳制备工艺。结果在优化条件下制备的微球形态规则,粒径为16.72±0.33μm,载药量为0.52%±0.01%,包封率为78.56%±1.05%,微球的体外释药规律符合Higuichi方程(r=0.9986)。结论该制备工艺合理,为制备盐酸四环素PLGA微球提供了理论基础。     

In vitro–in vivo correlation of modified release dosage form of lamotrigine

The plasma concentration profile of lamotrigine was predicted from the dissolution test data of the modified release 100 mg lamotrigine tablet by applying the in vitro–in vivo correlation (IVIVC). Three different release formulations (L‐1, L‐2 and L‐3) and its profiles of in vitro data were generated in different dissolution media. Pharmacokinetics evaluation of these formulations was carried out in 12 healthy volunteers. In vitro–in vivo correlation was established from the generated dissolution and bioavailability data. A good correlation between the percentages dissolved vs absorbed (r²>0.989) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of percent prediction error, which was found to be below 15%. Copyright © 2009 John Wiley & Sons, Ltd.     

HPLC测定利巴韦林缓释片的含量

目的　建立利巴韦林缓释片的含量测定方法。方法　采用HPLC ,C1 8色谱柱 ,进口填料 (5 μm ,1 5 0mm× 4 6mm) ,检测波长 2 0 7nm ,流动相为水。结果　进样量在 0 2～ 0 8μg范围内线性关系良好 (r =0 9999) ,回收率平均值为 99 1 % ,RSD =1 1 1 % (n =9)。结论　所用方法简便 ,准确 ,重复性好。     

Effects of changing dosage and urinary pH in rats self-administering nicotine on a food delivery schedule

The effects of different available dosage and of acidic and alkaline urinary pH have been investigated on the rates of self-administration of nicotine by rats on an FT60 food delivery schedule. Different groups of rats initially received one of 3 doses of nicotine (0.05, 0.1 and 0.25 mg/kg/infusion) contingent upon bar-pressing. The self-administration rates during an initial 6-day period of the 3 groups of rats were significantly different from each other, 26.1 ± 3.2 SEM), 15.4 ± 1.5 and 9.5 ± 0.9 at doses of 0.05, 0.1 and 0.25 mg/kg/infusion, respectively. However, once the rates of responding were established during the initial period, no significant changes occured when the doses were changed in all 3 groups after each subsequent 6-day period. These rates of self-administration decreased when saline replaced the available nicotine solution after Day 18. The urinary pH of groups of rats was maintained alkaline (pH9.0), acidic (pH 5.9) or normal (pH 6.7) by allowing them to drink sodium bicarbonate solution, ammonium chloride solution or water, respectively. The self-administration rates during the initial periods of these 3 groups of rats were also significantly different from each other 4.7 ± 0.66, 17.0 ± 0.76 and 9.4 ± 1.11, respectively). In contrast, however, when the rates of responding were established at normal urinary pH during the initial period when water was available, no significant changes occurred when urinary pH was subsequently changed in either an acidic or alkaline direction. The results suggest that the bar-pressing rates are dependent on the amount of nicotine available or present in plasma during the acquisition phase. Nevertheless, once the rate of bar-pressing is established on a food delivery schedule, it seems that the schedule exerts too powerful an effect on behavior for subsequent changes in nicotine levels to modify responding over the period of these experiments.     

Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum

The aim of this study was to investigate the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets containing chitosan and xanthan gum prepared by a hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthan gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers. All directly compressed (DC) tablets prepared in this study also exhibited pH and buffer species dependent release. In contrast, the HME tablets containing both chitosan and xanthan gum exhibited pH and buffer species independent sustained release. When placed in 0.1N HCl, the HME tablets formed a hydrogel that functioned to retard drug release in subsequent pH 6.8 and 7.4 phosphate buffers even when media contained high ionic strength, whereas tablets without chitosan did not form a hydrogel to retard drug release in 0.1N HCl. The HME tablets containing both chitosan and xanthan gum showed no significant change in drug release rate when stored at 40 °C for 1 month, 40 °C and 75% relative humidity (40 °C/75% RH) for 1 month, and 60 °C for 15 days.     

An investigation into effects of <Emphasis Type="Italic">In Vitro</Emphasis> Test condition on the release properties of theophylline from HPMC matrices using factorial design

The purpose of this study was to investigate the effect of various in vitro test conditions, on the release properties of theophylline (TP) from aminophylline (AP) matrices based on different hydroxypropylmethylcellulose (HPMC) ratio and viscosity grades. The General full factorial experimental design 3 × 3 × 3 was used, based on three independent variables: applied in vitro test (X1), HPMC/drug ratio (X2) and polymer viscosity grade (X3). The drug release percent at 2h (Y_2h), 4h (Y_4h) and 8 h (Y_8h) and time for 50% of TP release from matrices (Y_T50%) were response variables. Three in vitro tests were used: Test 1 and Test 4 (Theophylline Extended-release Capsules, USP 30) and Half-change method. According to factorial design analyses, in vitro test was the most significant factor influencing mechanism and amount of drug release. For Half Change method erosion was the predominant mechanism indicating Case — II transport, while for Test 1 the release mechanism were followed by both diffusion and erosion. The lowest release exponent n values, obtained from Ritger-Pepass equation, for Test 4 indicate diffusion process inclining from Fickian diffusion to Anomalous transport. Therefore, it is in the stage of development, useful to consider the influence of various in vitro test conditions on the formulation, in order to choose an optimal test for the purpose of future drug release examination.     

Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation

Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X₁ (Capryol^®), Smix X₂ (a mixture of Labrasol^®/Transcutol^®, 1:2 w/w) and water X₃ were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X₁, X₂, and X₃) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector^® gel, the optimized ME showed the highest cumulative amount of DE permeated after 8 h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12 h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug.     

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.     

缓释型氟尿嘧啶局部植入治疗口腔癌的初步研究

目的探讨口腔癌局部植入缓释型氟尿嘧啶间质化疗加手术及全身化疗的疗效及安全性。方法间质化疗组:22例患者实施口腔鳞癌根治手术及全身静脉化疗,术前在癌灶内及癌灶周边植入缓释型氟尿嘧啶间质化疗药物,平均用药剂量为300mg;对照组18例为手术结合全身静脉化疗患者。两组均随访36个月,比较其术后复发率以及各种化疗毒副反应。SPSS统计软件进行统计分析。结果随访观察的患者中,间质化疗组术后24、36个月的复发率低于静脉化疗组(P<0.05),且其毒副反应与对照组无显著性差异(P>0.05)。结论手术切除+全身化疗结合局部癌灶植入缓释氟尿嘧啶间质化疗药物,可以提高肿瘤局部化疗药物的浓度,延长作用时间,在不增加毒副反应的同时提高疗效及生存质量。     

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and t_d of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and t_d between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t_1/2 (7.12 h), while apparent t_1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for C_max and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.     

Optimization of ibuprofen gel formulations using experimental design technique for enhanced transdermal penetration

The aims of this study were to develop a transdermal gel formulation for ibuprofen using experimental design techniques and to evaluate its pharmacokinetic properties. The three factors chosen for factorial design were the concentrations of drug, polyoxyethylene(5)cetyl/oleyl ether and ethanol and the levels of each factor were low, medium and high. Skin permeation rates and lag times of ibuprofen were evaluated using the Franz-type diffusion cell in order to optimize the gel formulation. The permeation rate of ibuprofen significantly increased in proportion to the drug concentration, but significantly decreased in proportion to POE(5)cetyl/oleyl ether concentration. Ethanol concentration was inversely proportional to the lag time. The pharmacokinetic properties of the optimized formulation were compared with those of two marketed products in rats. The relative bioavailability of ibuprofen gel compared to the two marketed products was 228.8% and 181.0%. In conclusion, a transdermal ibuprofen gel was formulated successfully using the technique of experimental design and these results helped in finding the optimum formulation for transdermal drug release.