Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation

Bioadhesive buccal tablet formulations for delivery of nicotine into the oral cavity were developed. Carbomer (Carbopol)974P NF) (CP) and alginic acid sodium salt (NaAlg) were used as bioadhesive polymers in combination with hydroxypropyl methylcellulose (HPMC) at different ratios. Magnesium carbonate was incorporated into the formulations as a pH increasing agent. In vitro release and bioadhesion studies were performed on the developed tablets. In the formulations containing CP:HPMC, the NHT released increased with the increasing HPMC concentration whereas a decrease was observed with increasing HPMC concentration in formulations containing NaAlg:HPMC. The bioadhesive properties of the tablets containing NaAlg:HPMC was not affected by the concentration of the NaAlg (P>0.05) but increased significantly with the increasing CP concentration (P>0.05). A decrease in pH of the dissolution medium to acidic values was avoided by incorporation of magnesium hydroxide into the formulations. The developed formulations released NHT for 8h period, and remained intact except for the formulation containing CP:HPMC at 20:80 ratio.     

Caco-2 cell culture as a model for famotidine absorption

The aim of the study was to determine penetration properties of Famotidine fro the formulations through colon adenocarcinoma (Caco)-2 cell monolayers and to compare in vitro with in vivo test results. It also aimed to determine the effect of particle size on the penetration properties of Famotidine when microsphere formulations were used. Famotidine was chosen as a model drug and Caco-2 cell culture model was used. Biodegradable Famotidine microspheres of poly(lactide-co-glycolide)(PLGA) polymer (50:50) were prepared by using multiple emulsion technique. Microspheres were coded according to their particle size and polymer[LHIV:60 microm Famotidine-PLGA(high viscosity), SHIV:6 microm Famotidine PLGA(high viscosity), LLIV:60 microm Famotidine-PLGA (low viscosity), SLIV:6 microm Famotidine-PLGA (low viscosity)]. Famotidine solution(5 mg/ml) and microsphere formulations were administered orally to mice and blood drug levels were determined and compared with the Caco-2 cell experiments. Permeability values of Famotidine through Caco-2 cells from various formulations were determined (log k(solution) = 7,274 +/- 0,010,log kSHIV = -3,884 +/- 0,033,log kLHIV = -2,300 +/- 0,009,log kSLIV = -4,076 +/- 0,208,log kLLIV = 3,525 +/- 0,045). Our results showed that H2 receptor antagonists alter the barrier properties of the Caco-2 cell monolayer by causing an increment in the tightness of the tight junctions. Therefore, amount of the H2 receptor antagonist-like drug at the site of action was found to be important as well as polymer type and particle size of microspheres for drug permeation. Permeation of the drug was lower when higher amounts of Famotidine were present at the diffusion site. A controlled release dosage form of H2 receptor antagonist-like drugs may be beneficial for long-term treatments.     

Caco-2 Cell Culture as a Model for Famotidine Absorption

The aim of the study was to determine penetration properties of Famotidine fro the formulations through colon adenocarcinoma (Caco)-2 cell monolayers and to compare in vitro with in vivo test results. It also aimed to determine the effect of particle size on the penetration properties of Famotidine when microsphere formulations were used. Famotidine was chosen as a model drug and Caco-2 cell culture model was used. Biodegradable Famotidine microspheres of poly(lactide-co-glycolide)(PLGA) polymer (50:50) were prepared by using multiple emulsion technique. Microspheres were coded according to their particle size and polymer[LHIV:60 μm Famotidine-PLGA(high viscosity), SHIV:6 μm Famotidine PLGA(high viscosity), LLIV:60 μm Famotidine-PLGA (low viscosity), SLIV:6 μm Famotidine-PLGA (low viscosity)]. Famotidine solution(5 mg/ml) and microsphere formulations were administered orally to mice and blood drug levels were determined and compared with the Caco-2 cell experiments. Permeability values of Famotidine through Caco-2 cells from various formulations were determined (log k_solution = 7, 274 ± 0, 010, log k_SHIV = -3, 884 ± 0, 033, log k_LHIV = -2, 300 ± 0, 009, log k_SLIV = -4, 076 ± 0, 208, log k_LLIV = 3, 525 ± 0, 045). Our results showed that H₂ receptor antagonists alter the barrier properties of the Caco-2 cell monolayer by causing an increment in the tightness of the tight junctions. Therefore, amount of the H₂ receptor antagonist-like drug at the site of action was found to be important as well as polymer type and particle size of microspheres for drug permeation. Permeation of the drug was lower when higher amounts of Famotidine were present at the diffusion site. A controlled release dosage form of H₂ receptor antagonist-like drugs may be beneficial for long-term treatments.     

埃索美拉唑镁肠溶片的制备

目的：制备埃索美拉唑镁肠溶片并对自制片进行质量分析。方法：采用流化床包衣法制备埃索美拉唑镁肠溶微丸,然后选用适宜辅料采用直接压片法对微丸压片,并将自制片与市售片进行药物体外药物释放度、耐酸力及稳定性的比较。结果：自制的埃索美拉唑镁肠溶片的各项指标均符合质量标准的要求。结论：优选的埃索美拉唑镁肠溶片的处方工艺合理,重现性好,有效地解决了埃索美拉唑镁的稳定性问题。     

丙戊酸镁联合富马酸奎硫平治疗快速循环型双相情感障碍的效果观察

目的 探讨丙戊酸镁缓释片联合富马酸奎硫平治疗快速循环型双相情感障碍的效果.方法 42例随机分为治疗组和对照组,每组21例.治疗组给予丙戊酸镁缓释片联合富马酸奎硫平治疗,对照组给予单用丙戊酸镁缓释片治疗,均治疗2个月后评定临床疗效,随访2年,观察复发情况.结果 治疗组总有效率高于对照组,治疗后治疗组EI评分显著高于对照组,治疗组复发率明显低于对照组,差异有统计学意义(P<0.05,P<0.01).结论 丙戊酸镁缓释片联合富马酸奎硫平治疗快速循环型双相情感障碍效果明显,复发率低.     

吲达帕胺缓释片的研制及释药机理考察

目的：研制吲达帕胺缓释片，并考察其释药机理。方法：以HPMC为骨架材料，以微晶纤维素、乳糖和可压性淀粉调节释放度，对吲达帕胺缓释片的影响因素进行了考察，并采用正交试验设计筛选处方。结果：吲达帕胺缓释片的组成为：HPMC K4M 37．5mg，HPMC K15M7．5mg，乳糖45．0mg，可压性淀粉37．5mg，微晶纤维素21．0mg，硬脂酸镁1．5mg，药物的释放符合零级动力学方程，释放机制为骨架溶蚀机制；释药速率受介质pH值的影响，几乎不受压片压力的影响。结论：研制的吲达帕胺缓释片体外释放符合国外同类产品的释药特性。     

Predicting the physical properties of tablets from ATR-FTIR spectra using partial least squares regression

Context: The formulation of a new tablet is a time-consuming activity involving the preparation and testing of many different formulations with the aim of identifying one with the desired properties. In complex formulations it may not be clear which excipient is responsible for eliciting a particular property.

Objective: To investigate partial least squares (PLS) regression analysis of ATR-FTIR spectra of tablets as a predictive and investigative tool in the formulation of novel tablet formulations.

Materials: Magnesium stearate, lactose, acetylsalicylic acid and Ac-Di-Sol.

Results and discussion: ATR-FTIR spectra of a simple aspirin tablet formulation with varying amounts of the lubricant magnesium stearate were obtained. PLS models were built using the spectral data as the multivariate variable and various physical properties of the tablets as the univariate variables. PLS models that allowed good predications to be made for samples not included in the training set were obtained for tablet hardness and disintegration time. It was clear from PLS model regression coefficients that magnesium stearate was responsible for the variation in the tablets’ physical properties.

Conclusion: PLS regression in combination with ATR-FTIR spectroscopy has been shown to be a useful approach for the prediction of the physical properties of tablets.     

Studies on controlled release dimenhydrinate from matrix tablet formulations

In this study, controlled release dosage forms of dimenhydrinate were prepared with different polymers as MC, HEC, Carbopol 934, Eudragit RLPM and Eudragit NE 30 D at different concentrations (2.5-10%). Direct compression (DC) and wet granulation (WG) techniques were used to prepare the tablets. Magnesium stearate was the lubricant while starch gel was the binder. For the quality control of tablets prepared according to 11 different formulations, weight deviation, hardness, friability, diameter-height ratio, content uniformity of the active substance and in vitro dissolution techniques were performed. Dissolution rate of these tablets was controlled by USP XXII dissolution method and the profile of each tablet was plotted and only for F 5 was evaluated kinetically.     

法莫替丁分散片的研制

探讨了聚乙烯哟咯烷酮浓度,羧甲基淀粉钠用量对法莫替丁分散片崩解的影响及不同介质对其溶出的影响。     

Development and in vitro/in vivo evaluations of bioadhesive buccal tablets for nicotine replacement therapy

Buccal bioadhesive tablet formulations of nicotine hydrogen tartrate (NHT) for nicotine replacement therapy (NRT) were developed using chitosan and carbomer at different ratios. Magnesium hydroxide was incorporated into the formulations as pH increasing agent. In vitro release and bioadhesion properties of the tablets were investigated. Release of NHT from the tablets was increased with the increasing amount of chitosan in formulations whilst the bioadhesion of the tablet was decreased. In vivo studies were carried out in healthy, non-smoker volunteers in comparison to a commercially available transdermal patch. Plasma nicotine and cotinine levels were determined using gas chromatography-mass spectrophotometry. No significant difference was found between the maximum plasma nicotine concentrations (Cmax) obtained with the buccal tablet and the transdermal patch (p > 0.05). Time to reach the Cmax was 2.9 +/- 0.2 h and 11.5 +/- 1.3 h, and AUC0-24 values were 59.3 +/- 5.1 ng x h x mL(-1) (0-12 h) and 204.1 +/- 31.2 ng x h x mL(-1) for buccal tablet and transdermal patch, respectively.     

A study of powder adhesion to metal surfaces during compression of effervescent pharmaceutical tablets

Effervescent tablets were produced using four different formulations containing citric and/or tartaric acid and sodium bicarbonate with povidone and macrogol 6000. The same formulations were prepared with the addition of 1% sucrose ester powder. The adhesion of each formulation to the metal faces of tableting machine punch tips was determined using electron microscopy, surface roughness measurements and quantification of punch weight variations during tablet production. The basic formulations were inherently adhesive and produced tablets with a weak, porous structure which were qualitatively and quantitatively rougher than conventional, non-effervescent compressed tablets. Both formulations containing tartaric acid produced tablets with a lower surface roughness and with less tendency to stick to tablet punch faces than the two formulations containing citric acid alone. The addition of a water-soluble sucrose ester had a beneficial effect especially on the formulations with inherently high adhesive tendencies.     

丙戊酸镁缓释片治疗症状性癫痫97例临床分析

目的:了解传统药丙戊酸镁缓释片对症状性癫痫的疗效。方法:以患者用药前4周内癫痫发作次数为基线,之后单用丙戊酸镁缓释片治疗,随访6个月～3年。以用药后每4周的发作次数与用药前基线比较,临床发作减少49%及以下者为无效,减少50%～99%为有效,临床无发作为控制。结果:在对97例症状性癫痫的研究中发现,丙戊酸镁缓释片治疗由于头外伤引起癫痫的发作控制率为64.7%;脑血管病所致癫痫的发作控制率为73.3%;脑肿瘤所致癫痫的发作控制率为57.1%;脑囊虫所致癫痫的发作控制率为54.5%。总有效率82.5%。结论:丙戊酸镁缓释片对症状性癫痫具有较好的疗效,其中对脑血管病、头外伤、肿瘤、脑囊虫等所致的癫痫可能具有更大的优势。     

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system.     

法莫替丁缓释片的实验研究

用紫外分光光度法测定法莫替丁缓释片的体外释放。体外释放数据表明该缓释片在模拟人工胃液中缓慢释放药物,维持8小时以上。分别用单指数分布模型、威布尔分布模型和希古契方程进行拟合,得出t_0、t_(50)值及拟合方程的相关系数。结果表明3种模型都可以较好地反映该缓释片的释放过程,其中以单指数分布模型为最佳。     

硫糖铝联合法莫替丁治疗急性胃炎疗效观察

目的 观察硫糖铝联合法莫替丁治疗急性胃炎的临床疗效.方法 选择2007年3月～2012年1月于本院消化内科、内科就诊并被诊断为急性胃炎的患者217例,严格按照随机化的原则将所有入选患者按奇数、偶数分为对照组109例和治疗组108例,对照组采用法莫替丁40 mg静脉输注,治疗组在采用法莫替丁治疗的同时外加硫糖铝,治疗后两组进行疗效对比.结果 1个疗程后,治疗组的有效率为95.6%,对照组的有效率为86.2%,两组的疗效差异具有统计学意义（P 〈 0.05）.结论 硫糖铝联合法莫替丁治疗急性胃炎比单用法莫替丁能够取得更好的临床疗效,值得进一步推广使用.     

Single-step Coprocessing of Cohesive Powder via Mechanical Dry Coating for Direct Tablet Compression

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression.     

Use of natural gums and cellulose derivatives in production of sustained release metoprolol tablets

Metoprolol tartrate sustained-release tablets (100 mg) were prepared using xanthan/guar gums and also hydroxypropyl methyl cellulose (HPMC) carboxymethyl-Cellulose (CMC) polymers by direct compression method. Physical characteristics of the tablets and water uptake in addition to their dissolution profiles were compared with standard (Lopressor® SR) tablets. Dissolution test was performed in the phosphate buffer solution (pH 6.8) and the samples were analyzed spectrophotometerically in 275.7 nm. Dissolution studies showed that formulations containing 100 and 80% of HPMC, 100% of guar, and 20% of xanthan followed the Higuchi model, while those containing 60 and 40% HPMC and 100 and 80% xanthan followed a zero-order model. The tablets with 40% xanthen followed a Hixon-Crowell model. In cellulose derivatives the highest MDT and dissolution efficiency until 8 hr (DE₈%) belonged to tablets with 40% HPMC, increasing the amount of CMC decreased the drug release rate, and formulations containing 60 and 40% of HPMC had the USP dissolution standards. While, in the gum formulations, the highest mean dissolution time and the lowest DE₈% belonged to tablets with 100% xanthan, increasing the xanthan decreased the release rate of metoprolol, and formulations containing 80 and 100% xanthan had the USP dissolution standards. Results showed that natural gums are suitable for production of sustained-release tablets of metoprolol.     

法莫替丁颗粒剂在健康人体内药动学研究

对自制的法莫替丁颗粒剂在１０名健康人体内的药动学进行了研究，以ＨＰＬＣ法测定体内血药浓度，用＂ＰＫＢＰ－ＮＩ＂药动学程序处理数据。结果表明：本品的吸收半衰期为１．０４±０．４５ｈ，血药浓度峰值为１０５．２±３５．９μｇ·Ｌ－１，相对于片剂的生物利用度为１．００２±０．０６１，可认为颗粒剂与片剂基本等效。     

Final amended report on the safety assessment of Octyldodecyl Stearoyl Stearate

Octyldodecyl Stearoyl Stearate is an ester that functions as a skin-conditioning agent and viscosity-increasing agent. It is reported to be used in 105 cosmetic products at concentrations from 2% to 15%. In an isolated human skin permeation and penetration study, 0.005% of the applied dose permeated the skin, around 3% was found in the epidermis, around 1.5% was in tape stripped skin layers, and around 95% stayed in the material applied to the skin. A formulation having 20.6% Octyldodecyl Stearoyl Stearate was classified as minimally to mildly irritating in an in vitro ocular irritation assay. Several tests of products containing from 7.5% to 12.7% Octyldodecyl Stearoyl Stearate using rabbits produced minimal to mild ocular irritation. One test of 100% Octyldodecyl Stearoyl Stearate (a trade compound) and another of 10% Octyldodecyl Stearoyl Stearate in corn oil using rabbits produced no ocular irritation. Tests using rabbits demonstrated that Octyldodecyl Stearoyl Stearate at use concentrations was non- to mildly irritating to skin; only one study reported moderate irritation. Octyldodecyl Stearoyl Stearate was not mutagenic, with or without S-9 activation, in an Ames test and did not produce a significant increase in micronucleated cells in a mouse in vivo study. In clinical single-insult patch tests at use concentrations, Octyldodecyl Stearoyl Stearate was nonirritating to mildly irritating; in a cumulative irritation study, it caused mild irritation. Octyldodecyl Stearoyl Stearate was nonsensitizing in clinical tests. Because few toxicity data were available on Octyldodecyl Stearoyl Stearate, summaries of data from existing safety assessments of related ingredients (Octyl Dodecanol, Stearic Acid, and Octyl Stearate) were included. Undiluted Octyl Dodecanol was nontoxic during acute oral and dermal studies using rats and guinea pigs. Stearic Acid was nontoxic to rats during acute oral studies, but caused toxicity during subchronic studies. Rabbits treated topically with the acid were not affected adversely, and mild erythema and slight induration were observed when Stearic Acid was administered intradermally to guinea pigs and rabbits. Octyl Stearate had very low acute oral toxicity in rats and mice. Octyl Dodecanol produced only transient mild ocular irritation in rabbits when administered at concentrations up to 100%. Octyl Dodecanol (30% and 100%) was nonirritating to skin in one study using rabbits. In another study using multiple species, 100% Octyl Dodecanol (described as technical grade) caused severe skin irritation in rabbits, moderate irritation in guinea pigs and rats, and no irritation in swine. Stearic Acid was non- to moderately irritating in animal studies, and did not cause photosensitization. In studies using rabbits, undiluted Octyl Stearate caused slight, transient ocular irritation, and minimal skin irritation. Stearic Acid did not induce mitotic crossovers and aneuploidy in Saccharomyces cerevisiae, and was nonmutagenic in the Ames test. In a feeding study using mice, Stearic Acid was noncarcinogenic at doses up to 50 g/kg/day. Mice given subcutaneous injections of the acid had low incidences of carcinomas, sarcomas, and lymphomas. In clinical studies, concentrations of up to 100% Octyl Dodecanol were non- to mildly irritating, nonsensitizing, nonphototoxic, and nonphotosensitizing. Stearic Acid was nonirritating at concentrations up to 100%, and at concentrations up to 13% it was nonsensitizing and nonphotosensitizing. Octyl Stearate (7.6%) in formulation was nonirritating, nonsensitizing, and nonphotosensitizing. Based on skin permeation and penetration data, the Panel does not expect any significant amount of Octyldodecyl Stearoyl Stearate to be systemically available. There is no evidence of systemic toxicity associated with any of the related chemicals reviewed in previous safety assessments. None of the available toxicology or clinical data suggest a concern about adverse skin reactions to Octyldodecyl Stearoyl Stearate, or to any of the related chemicals. There is no evidence of ocular toxicity, except for a mild, transient ocular irritation associated with Octyldodecyl Stearoyl Stearate and the related chemicals. Overall, Octyldodecyl Stearoyl Stearate was considered safe as used in cosmetics.     

法莫替丁泡腾片的制备与质量考察

目的研制法莫替丁泡腾片并建立质量控制方法。方法单因素筛选处方,粉末直接压片制备法莫替丁泡腾片,并对其性状、重量差异、崩解时限、酸度、含量等进行检查。结果确定了泡腾片的处方,即酒石酸-碳酸氢钠=1∶1,崩解剂用量为60%,乳糖为填充剂,润滑剂为PEG6000 3%,硬脂酸镁0.3%,本品在5 min内可完全崩解。结论本品处方合理,制备工艺简单,可进行推广开发。