Comparative health risk assessment of realgar and NiuHuangJieDu tablets based on tissue arsenic levels after multiple oral administration to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar (As2S2), a mineral traditional Chinese medicine (TCM), is proved to have great therapeutic effects in clinic and has been widely used in China for hundreds of years. As one of the most popular realgar-containing TCMs, NiuHuangJieDu Tablets (NHJDT) is used as OTC (over-the-counter) drug in daily life for fever relieving, detoxicating, as well as cure of sore throat and gingival swelling. However, the safety of realgar and its-containing TCMs still remains unclear. AIM OF THE STUDY: This study was to investigate the accumulation of arsenic in rat body and evaluate the safety of realgar-containing TCMs in vivo. MATERIALS AND METHODS: The health risk of arsenic was evaluated in rats by tissue distribution and histopathology, as well as arsenic speciation in plasma after multiple oral gavage of low and high doses of realgar and NiuHuangJieDu Tablets (NHJDT), respectively. Total arsenic and arsenic speciation were determined by hydride generation-atomic fluorescence spectrometry (HG-AFS) and high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS), respectively. RESULTS: Arsenic accumulated in rat tissues especially in heart, liver, spleen, lung, kidney, uterus and ovary. Dimethylarsenic acid (DMA) was detected as the predominant species in rat plasma after dosing. In comparison of realgar, NHJDT with co-existing components significantly alleviated tissues injury, and reduced arsenic concentration in rat tissues and plasma. CONCLUSIONS: NHJDT with co-existing components combination was relatively safer than realgar, but the accumulation of arsenic was still significant after long-term medication. Therefore, great attentions should be paid to realgar-containing TCMs to avoid toxicity from arsenic accumulation. Moreover, the dose regimen of realgar-containing TCMs should be designed rationally for clinical application. These results may provide useful references for the application of realgar-containing TCMs and might be helpful for the understanding of TCM compound compatibility.

Simultaneous Evaluation of Dissolution and Permeation of Oral Drug Solid Formulations for Predicting Absorption Rate-Limiting Factors and In Vitro-In Vivo Correlations: Case Study Using a Poorly Soluble Weakly Basic Drug.

Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIFmod of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.

Development of multi-layered gastric floating tablets based on konjac glucomannan: a modified calcium supplement with enhanced bioavailability.

This study developed a gastric-floating delivery system of calcium based on konjac glucomannan (KGM). The developed calcium tablets, consisting of one core layer coated with two barrier layers, were fabricated with a facile method. The role of KGM within the tablets was evaluated from characteristics including swelling behavior, hydrated gel properties, floating ability and release profiles of calcium (Ca). The results indicated that upregulating the KGM fraction accelerated the formation of a more compact gel network in gastric conditions, which prolonged both the floating lag time and floating duration, which resulted in a more sustained swelling behavior and a slower release of calcium. Among all the formulations, a core tablet containing 20% KGM (K20) was selected as the optimized one as it could quickly float up in 7.21 s, exhibited an almost linear release and obtained a release amount of 87.73% within 12 h. Finally, a comparison of in vivo calcium bioavailability between a KGM-based calcium tablet and a commercial calcium tablet (Caltrate®) was carried out by monitoring the serum calcium concentration after administration in rabbits. The results suggested that, after having the KGM-based calcium tablet, the changes of serum calcium levels were gentler due to a sustained-release property. The difference integral value between profile K20 and the baseline was 1.4358, larger than that of Caltrate® (1.1808), suggesting the higher absorption efficiency of KGM-based calcium tablets.

Established UPLC-MS/MS procedure for multicomponent quantitative analysis in rat plasma: A contrastive pharmacokinetics study of Qiangshen tablet in normal and kidney yang deficiency syndrome models.

Qiangshen tablet, an important prescription consisting of 14 kinds of Chinese herbal medicines, has been used for decades to treat kidney yang deficiency syndrome (KYDS) in China. Qiangshen tablet has been recorded in ChP (2015 edition) and possesses the effect of strengthening yang, invigorating qi and tonifying kidneys. In this research, a simple, reliable and specific method was established for simultaneous determination of stachydrine, psoralen, isopsoralen, morroniside, paeoniflorin and loganin in normal and KYDS rat plasma after intragastric administration of a Qiangshen tablet suspension by UPLC-MS/MS. Protein precipitation (PP) by acetonitrile and liquid-liquid extraction (LLE) by ethyl acetate - n-butanol (1: 1, v/v) were used for pretreatment of plasma samples. Chromatographic separation of two IS (Internal Standard) and six analytes was achieved using an ACQUITY UPLC® BEH C18 column (2.1 × 100 mm, 1.7 µm). The mobile phase consisted of 0.1% formic acid aqueous solution (solvent A) and acetonitrile (solvent B) with a gradient scheme. Multiple reaction monitoring (MRM) mode with positive and negative ion source switching was applied to perform the mass spectrometric analyses. This method has been validated with good linearity (r ≥ 0.9942) and acceptable precision and accuracy (RSD ≤ 11%, RE from -4.8% to 7.7%). The mean recovery values of the analytes and IS were all ≥68.28%, and the matrix effects ranged from 94.4% to 101.7%. The stability of the IS and analytes was measured throughout the experiment. The results showed significant differences between the pharmacokinetic traits of the analytes in the normal and KYDS groups, suggesting that pharmacokinetic procedures involving these analytes could be modified in cases of KYDS.

Poly-pharmacokinetic strategy-delineated metabolic fate of bioactive compounds in a traditional Chinese medicine formula, Yuanhu Zhitong tablets, using parallel reaction monitoring mode.

OBJECTIVE: To evaluate the pharmacokinetics of eight constituents in Yuanhu Zhitong tablets, which may provide a method for the poly-pharmacokinetic study of traditional Chinese medicine. METHODS: A robust platform using Thermo Scientific™ Dionex™ UltiMate™ 3000 rapid separation LC, integrated with Thermo Scientific™ Q Exactive™ MS, was developed and validated to acquire, in a high-resolution full-scan mode, a global profile of all ionized components in rat plasma after oral administration of a suspension of Yuanhu Zhitong tablets. RESULTS: This robust UPLC-HRMS method was successfully applied for pharmacokinetic evaluation after oral administration of Yuanhu Zhitong tablets. The MS response showed a good linear relationship, with a coefficient of determination (r2) of >0.99. The levels of detection were in the range of 0.088-0.414 ng·ml-g for the different constituents. The recoveries ranged from 92.23% to 104.47%, and the matrix effect ranged from 85.24% to 101.02%. The intra- and inter-day accuracy was in the range of 0.00-12.54%, while the intra- and inter-day precision ranged from 0.44% to 7.63%. Short-term stability, long-term stability, freeze-thaw stability, and post-preparative stability ranged from -recision rangedThe time to reach peak plasma concentration (tmax) values for the analytes was less than 10 h, except that for tetrahydropalmatine, which was quickly absorbed into the bloodstream. The large area under the concentration-time curve (AUC) values (≥105 ng·h·l-g) for the eight compounds indicated good absorption and utility in rat plasma. The mean residence time was more than 6 h, indicating slow elimination. CONCLUSION: UPLC-HRMS was shown to be a very promising and powerful tool for the kinetic screening and characterization of compounds in medicinal herbs and traditional Chinese medicine formulas. Pharmacokinetic profiling of multiple compounds enables the clarification of metabolic processes and fates of the selected medicinal herbs or traditional Chinese medicine formula. This allows us to better understand the actions and associated therapeutic mechanisms of the traditional Chinese medicine.

Moringa oleifera leaf powder alters the pharmacokinetics of amodiaquine in healthy human volunteers.

WHAT IS KNOWN AND OBJECTIVE: Moringa oleifera (MO) Lam (Moringaceae) is commonly used as food supplement and as medicine in most African countries where malaria is also endemic. Therefore, co-administration of MO with antimalarials is a possibility. This study investigated the effects of MO leaves powder on the pharmacokinetics of amodiaquine (AQ) in human subjects. METHODS: Twenty healthy volunteers were recruited for the 3-period study. In the first period, a single dose of AQ tablet (10 mg/kg) was administered orally after an overnight fast. After a 7-day washout period, AQ was co-administered with MO. For the third period, each subject took 3 g MO once daily for 7 days and on the 8th day, MO was co-administered with AQ. The plasma concentrations of amodiaquine and desethylamodiaquine (DEAQ) were simultaneously determined using a validated HPLC method. RESULTS AND DISCUSSION: The results showed a significant decrease (P = .037) in the Cmax of AQ after concurrent administration (CA) with MO, whereas after pretreatment (PT), there was a 32% decrease in the Cmax of AQ. For the metabolite, DEAQ, Cmax increased significantly (P = .006) by 79.36%, and Cmax in PT was significantly higher than (P = .001) that of the CA arm of the study. AUC of DEAQ increased significantly by 40.4% (P = .006) and by 188% (P = .001) after CA and PT, respectively. WHAT IS NEW AND CONCLUSION: The study established pharmacokinetic interaction between AQ and MO when given together or following a long period of ingestion of MO. This may have clinical implications for malaria therapy.

Health risk assessment of arsenic in Realgar and NiuHuangJieDu Tablets based on pharmacokinetic study.

NiuHuangJieDu Tablets (NHJDT), a popular realgar (As4S4) containing patented traditional Chinese medicine (TCM), is widely used in the treatment of acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. However, arsenic is considered as one of the most toxic elements, leading to growing concerns about the quality and safety of realgar-containing TCMs recently. In this study, health risk assessment of arsenic in realgar and NHJDT was conducted through oral administration of both substances to rats with single and multiple doses, respectively. The total blood arsenic concentration was used as the health risk indicator and determined by hydride generation-atomic fluorescence spectrometry after modified Kjeldahl digestion, and then applied to the pharmacokinetic study. For single oral dose study in rats, the low, medium, and high doses of realgar and NHJDT were set equivalent to 1, 5 and 20 times the human therapeutic dose (1.3 mg realgar/kg), respectively. Multiple doses were given at low and high dose levels every 12 h for seven consecutive days, respectively. Significant differences in the total blood arsenic pharmacokinetic profiles were observed between the corresponding realgar and NHJDT groups. These results indicated that NHJDT significantly reduced the total blood arsenic exposure present in realgar, and the detoxification mechanism might be attributed to herb-herb interactions in NHJDT. However, the accumulation of blood total arsenic was significant due to the long elimination half-life and high accumulation index in both realgar and NHJDT groups. Therefore, the potential health risk of arsenic caused by the administration of realgar-containing TCMs should be taken into account for excessive or long-term medication. Precautions should be taken for the clinical application of realgar-containing TCMs.

Identify super quality markers from prototype-based pharmacokinetic markers of Tangzhiqing tablet (TZQ) based on in vitro dissolution/ permeation and in vivo absorption correlations.

BACKGROUND: A quality marker (Q-marker) is defined as an inherent chemical compound that is used for the quality control of a drug. Its biological activities are closely related to safety and therapeutic effects. Generally, a multiple-component herbal medicine may have many Q-markers. We therefore proposed a concept of "super Q-marker" satisfying both the criterion of Q-markers and PK-markers to be used in more effective quality control of herbal medicine. PURPOSE: The first aim was to find suitable prototype-based PK-markers from Tangzhiqing tablets (TZQ), a Chinese patent medicine. Then super Q-markers were expected to be identified from the prototype-based PK-markers based on an in vitro-in vivo correlation study. METHODS: Potentially eligible prototype-based PK-markers were identified in a single- and multiple-dose pharmacokinetic study on TZQ in 30 healthy volunteers. The in vitro dissolution and permeation profiles of the prototype-based PK-markers of TZQ were evaluated by the physiologically-based drug dissolution/absorption simulating system (DDASS). An in vitro-in vivo correlation analysis was conducted between the dissolution/permeation behaviors in DDASS and the actual absorption profiles in human to test the transferability and traceability of the promising super Q-markers for TZQ. RESULTS: In human, plasma paeoniflorin and nuciferine as prototype-based PK-markers exhibited the appropriate pharmacokinetic properties, including dose-dependent systemic exposure (AUC, Cmax) and a proper elimination half-life (1∼3h). In DDASS, it was predicted that paeoniflorin and nuciferine are highly permeable but the absorption rates are primarily limited by the dissolution rates. Moreover, the established in vitro-in vivo correlations of paeoniflorin and nuciferine were in support of the super Q-markers features. CONCLUSION: Paeoniflorin and nuciferine are identified as the super Q-markers from the prototype-based PK-markers of TZQ based on findings from a combination of in vitro, in vivo, and in vitro-in vivo correlation studies. This method is practical for optimal identification of qualified Q-markers, thus helping improve the quality control of herbal medicines.

Pharmacokinetics of Panax notoginseng Saponins in Adhesive and Normal Preparation of Fufang Danshen.

BACKGROUND AND OBJECTIVE: Fufang Danshen formula, a famous Chinese patent medicine containing Salvia miltiorrhiza, Panax notoginseng and borneol, has been widely used in the treatment of coronary heart disease. The application is restricted by low bioavailability partly due to Panax notoginseng saponins (PNS) instability and low in vivo absorption. Thus, adhesive pellets were developed to improve bioavailability. The objectives of the present study were to evaluate the adhesive preparation by describing PNS's plasma pharmacokinetics in vivo and compare adhesive micro pills with normal preparation. METHOD: LC-MS/MS method was established to analyze five ingredients, notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), ginsenoside Re (Re), and ginsenoside Rd (Rd), in rats' plasma to describe the pharmacokinetic parameters of PNS. RESULTS: The pharmacokinetic parameters were significantly different after oral administration three formulations. The results show adhesive formulations are superior to Fufang Danshen tablet (FDT); there are differences between the two adhesive, but not obvious. CONCLUSIONS: It was found that the modification with adhesive materials improved PNS bioavailability in Fufang Danshen formula. These findings provide a way for further in vivo evaluation of different formulations.

Desenvolvimento e caracterização de filmes e comprimidos bucais a base de pectina e goma gelana para liberação tópica de triancinolona / Development and characterization of films and buccal tablets based on pectin and gellan gum for the topical release of triamcinolone

O tratamento farmacológico de patologias bucais é conduzido, geralmente, por via de administração local. No entanto, devido ao pouco tempo de permanência do fármaco no local de ação, esse tratamento pode ser bastante comprometido. Assim, este trabalho teve por objetivo o desenvolvimento de formas farmacêuticas que proporcionem a liberação local de triancinolona na cavidade oral. Foram produzidos filmes e comprimidos mucoadesivos a partir de polímeros naturais como gelana e pectina. Os filmes bucais foram preparados por meio de evaporação do solvente (solvent casting) utilizando diferentes quantidades de polímeros. As matérias-primas e os filmes foram caracterizados fisico quimicamente utilizando espectroscopia vibracional (in-infravermelho com transformada de Fourier e Raman) e difração de raios X. As propriedades físicas e mecânicas dos filmes também foram avaliadas. Além disso, realizou-se os ensaios de mucoadesividade e de dissolução do fármaco. Os comprimidos foram preparados por com-pressão direta usando como base os polímeros naturais. Diferentes parâmetros em relação as misturas e as formulações foram avaliados tais como as propriedades de fluxo dos pós constituintes, peso médio, dureza, friabilidade e desintegração. Em relação aos filmes bucais, estes foram obtidos com sucesso através de um método simples, sem a utilização de agentes reticulantes, ácidos ou solventes orgânicos. Todos apresentaram bons resultados nas propriedades avaliadas, no entanto as formulações com quantidades intermediarias de polímeros foram as melhores. Dentre as formulações de comprimidos preparadas, apenas 4 apresentaram boas características, no entanto, os resultados dos ensaios de dissolução mostraram que estas formulações têm capacidade de agir como sistema de liberação controlada de fármacos

Pharmacological treatment of oral pathologies is usually conducted by local administration. However, due to the short time the drug stays in the site of action, this treatment can be quite compromised. Thus, the objective of this work was to develop pharmaceutical forms that pro-vide the local release of triamcinolone in the oral cavity. Mucoadhesive films and tablets were made from natural polymers such as gellan and pectin. The buccal films were prepared by sol-vent casting using different amounts of polymers. The raw materials and films were characte-rized physically chemically using vibrational spectroscopy (FTIR and Raman) and X-ray diffraction. The physical and mechanical properties of the films were also evaluated. In addi-tion, the mucoadhesive and drug dissolution tests were performed. The tablets were prepared by direct pressing with the natural polymers. Different parameters in relation to mixtures and formulations were evaluated such as the flow properties of the constituent powders, average weight, hardness, friability and disintegration. In relation to oral films, these were successfully obtained by a simple method, without the use of crosslinking agents, acids or organic solvents. All presented good results in the evaluated properties, however the formulations with interme-diate amounts of polymers were the best. Among the tablet formulations prepared, only 4 sho-wed good characteristics, however, the dissolution test results showed that these formulations have the ability to act as a controlled drug delivery system

Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.

Bioavailability assessment of hydroxymethylglutaryl coenzyme A reductase inhibitor utilizing pulsatile drug delivery system: a pilot study.

Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC0-∞, Cmax, Tmax, t1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10 h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.

Gastroretentive Matrix Tablets of Boswellia Oleogum Resin: Preparation, Optimization, In Vitro Evaluation, and Cytoprotective Effect on Indomethacin-Induced Gastric Ulcer in Rabbits.

Currently available anti-ulcer drugs suffer from serious side effects which limited their uses and prompted the need to search for a safe and efficient new anti-ulcer agent. Boswellia gum resin (BR) emerged as a safe, efficient, natural, and economic potential cytoprotective agent. Thus, it is of medical importance to develop gastroretentive (GR) formulations of BR to enhance its bioavailability and anti-ulcer efficacy. Early attempts involved the use of organic solvents and non-applicability to large-scale production. In this study, different tablet formulations were prepared by simple direct compression combining floating and bioadhesion mechanisms employing hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), pectin (PC), and/or carbopol (CP) as bioadhesive polymers and sodium bicarbonate (SB) as a gas former. The prepared tablets were subjected for assessment of swelling, floating, bioadhesion, and drug release in 0.1 N HCl. The optimized GR formulation was examined for its protective effect on the gastric ulcer induced by indomethacin in albino rabbits compared with lactose tablets. The obtained results disclosed that swelling, floating, bioadhesion, and drug release of the GR tablets of BR depend mainly on the nature of the matrix and the ratio of polymer combinations. Moreover, a combination of SCMC-CP in a ratio of 2:1 (SCP21) exhibited desirable floating, bioadhesion, swelling, and extended drug release. Also, a 6-h pretreatment with SCP21 tablets decreased the severity of inflammation and number of bleeding spots among ulcer-induced rabbits in comparison to those treated with lactose tablets.

[Pharmacokinetics study on costunolide and dehydrocostuslactone after administration of traditional Chinese medicine Weichang'an pills].

A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 µg x L(-1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 µg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one-compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills.

Formulation and in vitro, in vivo evaluation of effervescent floating sustained-release imatinib mesylate tablet.

INTRODUCTION: Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. METHODOLOGY: Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. RESULTS AND DISCUSSION: Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours. CONCLUSION: In conclusion, in order to suggest a better drug delivery system with constant favorable release, resulting in optimized absorption and less side effects, formulated CP-HPMC-SA based imatinib mesylate floating sustained-release tablets can be a promising candidate for cancer chemotherapy.

Stability of Tilo ® tablets formulation obtained from dry extract of Justice pectoralis Jacq

Justicia pectoralis Jacq., Acanthaceae, is a herb known popularly in Cuba as Tilo and used traditionally as sedative. The development in a solid pharmaceutical (Tablets 100 mg) using dry extract of Justicia pectolaris aqueous extract is of interest for the development of phytomedicines, which uses this active raw material. The aim of the present study was to carry out chemical and biological stability studies to the formulation. A method of coumarin determination by High Performance Liquid Chromatography (HPLC) was used and validated. The stability studies during different periods of time (24 months) showed a stability of the product stored at 32 ± 2 °C, and protected of the light.

Justicia pectoralis Jacq., Acanthaceae é uma erva conhecida popularmente em Cuba como Tilo e utilizada tradicionalmente como sedativo. O desenvolvimento de formas farmacêuticas sólidas (comprimido 100 mg) usando extrato aquoso seco de J. pectoralis é de interesse no desenvolvimento de fitoterápicos que empreguem esse princípio ativo. O objetivo do presente estudo foi realizar estudos de estabilidade químicos e biológicos da formulação. Um método de determinação de cumarinas por Cromatografia Líquida de Alta Eficiência (CLAE) foi usado e devidamente validado. Os estudos de estabilidade durante diferentes períodos de tempo (24 meses) mostraram a estabilidade do produto preservado a 32 ± 2 °C e protegido da luz.

Safety, tolerability, and pharmacokinetics of a single ascending dose of baicalein chewable tablets in healthy subjects.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Scutellaria baicalensis Georgi has been used extensively in traditional Chinese medicine for the treatment of inflammation, fever, cough, dysentery, and hypertension. Baicalein is a flavonoid isolated from the root of Scutellaria baicalensis Georgi and is a novel neuroprotective agent under development for the treatment of Parkinson׳s disease. We aimed to investigate the pharmacokinetic (PK) properties of baicalein and its main metabolite, bacalin, after single-dose administration in healthy Chinese subjects. The safety and tolerability of baicalein were also assessed. MATERIALS AND METHODS: This was a Phase I, randomized, double-blind, single-dose trial of baicalein (100-2800 mg) in 72 healthy adults. Samples of blood, urine and feces were collected at regular intervals up to 48 h after administration of the study drug. Baicalein and baicalin were then analyzed using liquid chromatography-tandem mass spectrometry (LC/MS/MS). The maximum concentration that the drug achieved after dosing (Cmax), time to Cmax (Tmax), terminal half-life (t1/2), area under the curve from time zero to time of last quantifiable concentration (AUC(0, t)), area under the curve from time zero to infinity (AUC(0, ∞)), apparent total plasma clearance (CL/F), and apparent total volume of distribution (V/F) were determined using non-compartmental models. Dose proportion was tested using a method combining the equivalence criterion and power model. Physical examinations, vital signs, ECG findings, hematology, and urinalysis were monitored before and at regular intervals after administration of the study drug. RESULTS: The PK profile of baicelein and baicelin was characterized by a median Tmax of 0.75-3.5 h and 0.5-3 h, respectively, followed by a multiphasic profile with a t1/2 of 1.90-15.01 h and 4.22-10.80 h, respectively. The estimates of the proportionality coefficient (90% CI) for Cmax, AUC0-t and AUC0-∞ were 0.83 (0.70-0.96), 0.91 (0.81-1.00) and 0.92 (0.82-1.02), respectively. All values overlapped within the pre-specified range of (0.89-1.11), (0.93-1.07), and (0.93-1.07), respectively. Dose proportionality was inconclusive for a baicalein dose range of 100-2800 mg. The total urinary clearance of baicalein and baicalin was <1%. Approximately 27% of baicalein was eliminated as unchanged drug in feces. Baicalein was well tolerated. Eleven treatment-related adverse events were observed, and all were rated as "mild" and resolved without further treatment. No serious adverse events occurred. CONCLUSIONS: Single oral doses of 100-2800 mg of baicalein were safe and well tolerated by healthy subjects. Clinical laboratory assessments showed no signs of toxicity in the liver or kidney. The favorable safety profile and PK properties warrant further clinical studies for baicalein.

[Study on rational daily administration frequency of Fufang Biejia Ruangan tablet based on integrated serum pharmacologic and pharmacokinetic model].

To observe in vitro the effect of rat drug serum on the proliferation of HSC-T6 hepatic stellate cells in the pharmacokinetic model for determining peoniflorin in Fufang Biejia Ruangan tablet, in order to discover the rational daily administration frequency of Fufang Biejia Ruangan tablet. Fufang Biejia Ruangan tablet was orally administered to rats with different daily administration frequency. Their blood was collected from veins behind eye sockets at different time points before the administration and after the first administration, in order to determine the concentration of peoniflorin in blood plasma and the effect of rat drug serums on the proliferation of HSC-T6. A comprehensive analysis was made on the relationship between pharmacodynamics and pharmacokinetics to determine the rational daily administration frequency of Fufang Biejia Ruangan tablet. The results showed a good correlation between the inhibitory effect of Fufang Biejia Ruangan tablet-contained serum on HSC-T6 and the concentration of peoniflorin in blood. The two-time administration group showed higher pharmacologic and pharmacokinetic AUCs than one-time administration and three-time administration groups. In conclusion, Fufang Biejia Ruangan table is recommended to be taken twice a day for treating liver fibrosis in chronic hepatitis.

Development of a novel niosomal system for oral delivery of Ginkgo biloba extract.

BACKGROUND: The aim of this study was to develop an optimal niosomal system to deliver Ginkgo biloba extract (GbE) with improved oral bioavailability and to replace the conventional GbE tablets. METHODS: In this study, the film dispersion-homogenization method was used to prepare GbE niosomes. The resulting GbE niosome suspension was freeze-dried or spray-dried to improve the stability of the niosomes. GbE-loaded niosomes were formulated and characterized in terms of their morphology, particle size, zeta potential, entrapment efficiency, and angle of repose, and differential scanning calorimetry analysis was performed. In vitro release and in vivo distribution studies were also carried out. RESULTS: The particle size of the optimal delivery system prepared with Tween 80, Span 80, and cholesterol was about 141 nm. There was a significant difference (P < 0.05) in drug entrapment efficiency between the spray-drying method (about 77.5%) and the freeze-drying method (about 50.1%). The stability study revealed no significant change in drug entrapment efficiency for the GbE niosomes at 4°C and 25°C after 3 months. The in vitro release study suggested that GbE niosomes can prolong the release of flavonoid glycosides in phosphate-buffered solution (pH 6.8) for up to 48 hours. The in vivo distribution study showed that the flavonoid glycoside content in the heart, lung, kidney, brain, and blood of rats treated with the GbE niosome carrier system was greater than in the rats treated with the oral GbE tablet (P < 0.01). No flavonoid glycosides were detected in the brain tissue of rats given the oral GbE tablets, but they were detected in the brain tissue of rats given the GbE niosomes. CONCLUSION: Niosomes are a promising oral system for delivery of GbE to the brain.

Improvement of the bioavailability and glycaemic metabolism of cinnamon oil in rats by liquid loadable tablets.

The purpose of this study is to investigate the bioavailability and glycaemic metabolism of cinnamon oil (CIO) carried by liquid-loadable tablets (CIO-LLTs), the carrier of a CIO self-emulsifying formulation (CIO-LS). The results of tests performed to evaluate the physical properties of the CIO-LLT complied with Chinese Pharmacopeia (2010). The release profile suggested that the CIO-LLT preserved the enhancement of in vitro dissolution of cio. After orally administration, the plasma concentration-time profile and pharmacokinetic parameters suggested that a significant increase (P < 0.0001) in the C(max), AUC and F were observed in the CIO-LLT. The blood glucose and the HbA1c were significantly decreased in alloxan-induced hyperglycemic rats (P < 0.05, P < 0.01, resp.), while the level of insulin secretion was markedly elevated in alloxan-induced hyperglycemic rats (P < 0.05). The alloxan-damaged pancreatic ß-cells of the rats were partly recovered gradually after the rats were administered with CIO-LLT 45 days later. CIO-LLT could improve the bioavailability and glycaemic metabolism of CIO.