Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: in-vitro–in-vivo evaluation

In order to target celecoxib which is a COX2 inhibitor, with potentials in the prevention and treatment of colitis and colon cancer, it was formulated as microparticles using the solvent/evaporation method and various pH-dependent Eudragit polymers. The in-vitro evaluation of the prepared microparticles showed spherical and smooth morphology. The encapsulation efficiency and yield were high, indicating that the method used is simple and efficient at this scale. The in-vitro release study showed no release in the acidic medium for 2?h followed by the release of the drug in pH 6.8 in case of Eudragit L100-55 and L100 and pH 7.4 in case of Eudragit S100. The pharmacokinetic parameters were calculated and method validation was performed to insure that it is suitable and reliable. Pharmacokinetic parameters were investigated by determining the C_max, T_max, AUC_0–t, K_el, and t_1/2 of the drug as a suspension and as microparticles. There was a significant difference (p?<?0.05) in T_max between the drug as a suspension and as microparticles. The effect of celecoxib on the degree of inflammation was examined on acetic acid induced colitis rat model and the drug was given as a suspension and as microparticles. The evaluation was done using macroscopical, microscopical and biochemical examination. There was a significant difference between the acetic acid control group and the treatment groups regarding all examination criteria in the order microparticles formulated using Eudragit S100 followed by Eudragit L100-55 while microparticles using Eudragit L100 and drug suspension showed almost the same results.     

In Vitro-In Vivo Evaluation of a Controlled Release Buccal Bioadhesive Device for Oral Drug Delivery

Purpose. To investigate the use of buccal bioadhesive device in targeting controlled drug delivery to the gastrointestinal tract. Methods. A three-leg crossover study was designed to evaluate the application of buccal bioadhesive device for providing controlled drug delivery to the gastrointestinal tract of a model drug cyanocobalamin in four healthy adult male beagle dogs. Results. In vitro dissolution studies using deionized water as the medium indicated that 100% of the drug was released within 15 min from a immediate release oral capsule formulation, whereas 90% of the drug was released within a period of 18 hrs from a buccal bioadhesive device formulation. Drug release from the buccal bioadhesive devices appeared to follow Higuchi's square root of time dependent model. The terminal half-life of the drug following I.V. administration in four dogs was found to be 16.4 ± 2.4 hrs. Following immediate release oral capsule administration of the drug C_max, t_max and bioavailability were 2333 ± 1469 ng/L, 2.5± 1.0 hrs and 14.1 ± 7.9%, respectively. Following buccal bioadhesive device administration of the drug C_max, t_max and bioavailability were 4154 ± 1096 ng/L, 11 ± 1.2 hrs and 35.8 ± 4.1%, respectively. Significantly higher bioavailability of the drug was observed with the buccal bioadhesive device administration when compared to the immediate release oral capsule. Conclusions. The buccal bioadhesive device appears to improve the oral bioavailability of cyanocobalamin by providing controlled delivery of the drug to the gastrointestinal tract.     

Novel Tanshinone II A ternary solid dispersion pellets prepared by a single-step technique: In vitro and in vivo evaluation

Novel Tanshinone II A (TA) ternary solid dispersion (tSD) pellets with the combination of polyvinylpyrrolidone and poloxamer 188 as dispersing carriers were prepared by a single-step technique. A formulation screening study showed that the addition of poloxamer 188 to binary TA-PVP system could remarkably promote the dissolution rate of TA from 60% to 100% after 60 min. Scanning electron microscopy study revealed a smooth surface and a tightly packed coating structure. Differential scanning calorimetry analysis confirmed the formation of solid dispersions. In vivo test showed that TA tSD pellets presented significantly larger AUC_0-t, which was 0.76 times more than that of binary solid dispersion (bSD) pellets, 2.87 times more than that of physical mixtures (PMs) and 5.40 times more than that of TA. C_max of TA tSD pellets also increased by 1.82-8.97-fold as that of bSD pellets, PMs and TA. TA tSD pellets generated obviously shortened T_max of (3.80 ± 0.398) h, compared to bSD pellets with (4.15 ± 0.456) h, PMs with (4.65 ± 0.226) h and TA with (5.52 ± 0.738) h. In conclusion, the addition of poloxamer 188 to pellets containing PVP-based solid dispersions could achieve complete dissolution, accelerated absorption rate and superior oral bioavailability. The fluid-bed technique becomes an alternative approach to obtain solid dispersion-coated pellets.     

Improved bioavailability of darunavir by use of κ-carrageenan versus microcrystalline cellulose as pelletisation aid

The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronisation with κ-carrageenan or microcrystalline cellulose (MCC) as pelletisation aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2 ± 3.5 h from MCC pellets (1301 ± 301 μm) and 6.1 ± 0.7 min from κ-carrageenan pellets (966 ± 136 μm). In contrast to κ-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300 mg dose were more than 60-fold higher when formulated with κ-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10 mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (F_rel) was 155% with κ-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in κ-carrageenan pellets, likely due to their better disintegration behavior.     

Preparation, characterization and in vivo assessment of the bioavailability of glycyrrhizic acid microparticles by supercritical anti-solvent process

In this study, glycyrrhizic acid (GA) microparticles were successfully prepared using a supercritical anti-solvent (SAS) process. Carbon dioxide and ethanol were used as the anti-solvent and solvent, respectively. The influences of several process parameters on the mean particle size (MPS), particle size distribution (PSD) and total yield were investigated. Processed particle sizes gradually decreased as temperature and solution flow rate increased. In addition, processed particle sizes increased from 119 to 205 nm as GA concentration increased. However, CO₂ flow rate did not significantly affect particle size. The optimized process conditions were applied, those included temperature (65 °C), pressure (250 bar), CO₂ and drug solution flow rate (15 and 8 mL min⁻¹), drug concentration in ethanol (20 mg mL⁻¹). Microparticles with a span of PSD ranging from 95 and 174 nm, MPS of 128 nm were obtained, and total yield was 63.5%. The X-ray diffraction patterns of glycyrrhizic acid microparticles show apparent amorphous nature. Fourier transform infrared (FT-IR) spectroscopy results show that no chemical structural changes occurred. The in vitro dissolution tests showed that the GA microparticles exhibited great enhancement of dissolution performance when compared to GA original drug. Furthermore, the in vivo studies revealed that the microparticles provided improved pharmacokinetic parameter after oral administration to rats as compared with original drug.     

Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy

We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40 °C and 75% in humidity for up to 24 weeks. The film was disintegrated within 15 s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5 min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4 mg dexamethasone suspension or topical application of the film preparation containing 4 mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which C_max (h), T_max (μg/mL), AUC (μg/mL/h) and half-life (h) were 12.7 ± 6.6 (mean ± SD, N = 10), 3.4 ± 1.4, 93.6 ± 37.8 and 1.66 ± 0.07, respectively, for oral suspension and 13.3 ± 4.0, 3.2 ± 1.0, 98.0 ± 22.3 and 1.65 ± 0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.     

Pharmacokinetic and tissue distribution of doxycycline in broiler chickens pretreated with either: Diclazuril or halofuginone

Following IV injection of doxycycline in a dose of 20 mg kg⁻¹ b.wt., its serum concentration was best fitted in two-compartment open model in chickens fed either on control or on anticoccidials-containing rations. Diclazuril and halofuginone resulted in a significant short distribution half-life (t_½α) (7.17 ± 0.39 and 11.88 ± 1.05 min, respectively) and increased total body clearance (Cl_tot) 0.37 ± 0.024 and 0.295 ± 0.034 L/kg/h, respectively. Following oral dosing the tested drug absorbed with t_½ab of 41.38 ± 1.6, 17.48 ± 0.86 and 41.83 ± 1.8 min, respectively and their C_max values (3.18 ± 0.18, 5.425 ± 0.48 and 0.986 ± 0.037 μg/ml) were attained at 2.07 ± 0.097, 1.403 ± 0.074 and 2.55 ± 0.106 h. For doxycycline alone and in presence of diclazuril and halofuginone, respectively. Systemic bioavailability was 22.64 ± 3.46, 86.74 ± 9.23 and 22.38 ± 3.09%, respectively. Following IM injection t_½ab were 9.096 ± 1.34 for doxycycline alone, 16.24 ± 2.21 and 15.6 ± 1.7 min in the presence of diclazuril and halofuginone, respectively. C_max was 3.10 ± 0.28, 4.63 ± 0.57 and 0.55 ± 0.07 μg/ml reached at 0.8 ± 0.083, 1.13 ± 0.126 and 1.21 ± 0.105 h. For the antibiotic alone, and in presence of either diclazuril and halofuginone, respectively. Systemic bioavailability was 22.41 ± 3.86, 88.97 ± 12.9 and 12.31 ± 0.99% in chickens fed on anticoccidial-free, diclazuril- and halofuginone-containing rations, respectively. Both the tested anticoccidials induced higher doxycycline tissue residues in all tested tissue samples.     

不同载体对缬沙坦纳米骨架载药系统溶出行为和生物利用度影响的研究

目的 通过调节纳米骨架载药系统（NDDS）中载体类型和比例实现对缬沙坦体外溶出和体内生物利用度的调控。方法 以缬沙坦作为模型药物,分别选取酸性敏感材料Eudragit E100（E100）、碱性敏感材料Eudragit L100-55（L100-55）作为载体材料,介孔二氧化硅Sylysia 350（S350）、Aerosil 200（A200）作为纳米骨架,通过调节载体和骨架材料的类型和比例筛选出具有pH 1.2、6.8敏感释放行为的纳米骨架载体处方,考察缬沙坦在pH 1.2、6.8环境中释放和在大鼠体内的药动学行为特征。结果 筛选的pH 1.2敏感释放缬沙坦NDDS处方缬沙坦、S350、E100比例为1∶3∶1,pH 6.8敏感释放缬沙坦NDDS处方为缬沙坦、A200、L100-55比例为1∶1∶3。pH 6.8敏感释放处方可调控缬沙坦在肠道pH 6.8条件下特异性溶出;pH 1.2敏感释放处方在保持缬沙坦在pH 6.8高溶出特性的同时可特异性地提高胃部酸性条件下的药物释放。pH 1.2、6.8敏感释放缬沙坦NDDS均一定程度上改善了缬沙坦的生物利用度,其中pH 6.8敏感释放缬沙坦NDDS提高生物利用度的幅度更高,血药浓度变化比较平缓。结论 NDDS可以调控缬沙坦的体外溶出和生物利用度,有望应用于pH值敏感性难溶药物的递送。     

Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): Tools to predict in vivo bioavailability from orally applied drug suspensions

Low solubility of drug candidates generated in research contributes to their elimination during subsequent development due to insufficient oral bioavailability (BA) of crystalline compound. Therefore, the purpose of the study was to identify critical in vitro solubility and dissolution parameter that would predict critical in vivo dissolution by means of in vitro-in vivo correlation. Thermodynamic solubility and apparent dissolution rate (ADR) were determined using the shake-flask method and mini-flow-through-cell, respectively. Oral BA studies in rats and humans were conducted from drug solution and suspension/tablets. Relative BA was calculated using F_rel [%] = AUC_suspension/AUC_solution * 100, representing a measure of in vivo dissolution. Roughly, F_rel rat >50% translates into F_rel human of >90%. Both, ADR and log volume to dissolve applied dose (VDAD), when plotted against F_rel rat, revealed certain threshold levels, (ADR, ∼150-200 μg of compound dissolved under respective assay conditions; VDAD, ∼100-500 ml/kg) which translate into F_rel in rats of >50%.Thus, assuming that F_rel > 50% in rats is indicative of sufficient in vivo dissolution in humans after oral application, drugs should exhibit a VDAD of ∼100-500 ml/kg or less in aqueous media to avoid insufficient or varying drug absorption.     

Inhibiting the Gastric Burst Release of Drugs from Enteric Microparticles: The Influence of Drug Molecular Mass and Solubility

Undesired drug release in acid medium from enteric microparticles has been widely reported. In this paper, we investigate the relative contribution of microparticle and drug properties, specifically microsphere size and drug’s molecular weight and acid solubility, on the extent of such undesired release. A series of nine drugs with different physicochemical properties were successfully encapsulated into Eudragit S and Eudragit L microparticles using a novel emulsion solvent evaporation process. The process yielded spherical microparticles with a narrow size distribution (27–60 and 36–56 mm for Eudragit L and Eudragit S microparticles, respectively). Upon incubation in acid medium (pH 1.2) for 2 h, the release of dipyridamole, cinnarizine, amprenavir, bendroflumethiazide, budesonide and prednisolone from both Eudragit microparticles was less than 10% of drug load and conformed with the USP specifications for enteric dosage forms. In contrast, more than 10% of the entrapped paracetamol, salicylic acid and ketoprofen were released. Multiple regression revealed that the drug’s molecular weight was the most important factor that determined its extent of release in the acid medium, while its acid solubility and microsphere’s size had minor influences.     

Development of udenafil-loaded microemulsions for intranasal delivery: in vitro and in vivo evaluations

To achieve rapid onset of action and improved bioavailability of udenafil, a microemulsion system was developed for its intranasal delivery. Phase behavior, particle size, transmission electron microscope (TEM) images, and the drug solubilization capacity of the microemulsion were investigated. A single isotropic region was found in pseudo-ternary phase diagrams developed at various ratios with CapMul MCM L8 as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol (1:0.25, v/v) as a cosurfactant. Optimized microemulsion formulations with a mean diameter of 120-154 nm achieved enhanced solubility of udenafil (>10 mg/ml) compared with its aqueous solubility (0.02 mg/ml). An in vitro permeation study was performed in human nasal epithelial (HNE) cell monolayers cultured by the air-liquid interface (ALI) method, and the permeated amounts of udenafil increased up to 3.41-fold versus that of pure udenafil. According to the results of an in vivo pharmacokinetic study in rats, intranasal administration of udenafil-loaded microemulsion had a shorter T_max value (1 min) compared with oral administration and improved bioavailability (85.71%) compared with oral and intranasal (solution) administration. The microemulsion system developed for intranasal administration may be a promising delivery system of udenafil, with a rapid onset of action and improved bioavailability.     

Generic sustained release tablets of trimetazidine hydrochloride: Preparation and in vitro–in vivo correlation studies

The aim of the current work was to develop generic sustained-release tablets containing 35 mg trimetazidine dihydrochloride and to establish an in vitro–in vivo correlation that could predict the bioavailability. The marketed sustained release tablet (Vastarel MR) used as reference, a sustained-release matrix tablet was prepared using hydroxypropyl methylcellulose (HPMC) as matrix by wet granulation and the in vitro dissolution profiles of the self-made tablets were determined in four different dissolution media (0.1 M HCl, pH 4.5 PBS, pH 6.8 PBS and water). A higher similarity between prepared tablets and Vastarel MR was established, with similarity factor (f₂) ranging from 60 to 75 in the four media. The in vivo pharmacokinetics was studied in six healthy beagles. Compared with Vastarel MR, the C_max of self-made tablets was slightly decreased, while the T_max and MRT_0–t were slightly prolonged, but with no significant difference (P > 0.05). The average of relative bioavailability (F) was 102.52% based on AUC_0–t. For log-transformed AUC_0–t and C_max, the upper confidence limit on the appropriate criterion is <0, indicating these two formulations were population bioequivalent. The in vivo–in vitro correlation coefficient obtained from point-to-point analysis of self-made tablets was 0.9720. In conclusion, the prepared tablets were bioequivalent to the marketed tablets, according to both the in vitro release rate and extent of absorption, and a good in vivo–in vitro correlation was established for the self-made tablets that indicated in vitro dissolution tests could be used as a surrogate for bioavailability studies.     

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with ^99mTc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h.Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC_0-360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate.The two formulations showed interesting pharmacokinetic profiles (T_max of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.     

Pharmacokinetic study of melamine in rhesus monkey after a single oral administration of a tolerable daily intake dose

To perform pharmacokinetic study of melamine in rhesus monkey, melamine was orally administered to three experimental monkeys at a single dose of 1.4 mg/kg body weight. Plasma and urine were collected for the determination of melamine and cyanuric acid with a liquid chromatography tandem mass spectrometry method. The mean ± SD area under the concentration–time curve from time zero to 48 h (AUC0–t) was 14,145 ± 2002 μg/L h. The maximum concentration of melamine in plasma (C_max) was 1767 ± 252 μg/L. The time to maximum concentration (T_max) was 2.67 ± 1.16 h and the half-life of melamine in plasma (t_1/2) was 4.41 ± 0.43 h. Following oral administration, melamine was rapidly excreted, mainly through urinary clearance. No significant correlation was found between melamine and cyanuric acid, suggesting that cyanuric acid may not be derived from melamine.     

Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers

This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC_0–24?h and C_max in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.     

Amorphous ternary cyclodextrin nanocomposites of telmisartan for oral drug delivery: Improved solubility and reduced pharmacokinetic variability

Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary β-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary β-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 ± 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively.     

Effect of Microenvironmental pH Modulation on the Dissolution Rate and Oral Absorption of the Salt of a Weak Acid – Case Study of GDC-0810

Purpose

The purpose of this work is to investigate the effect of microenvironmental pH modulation on the in vitro dissolution rate and oral absorption of GDC-0810, an oral anti-cancer drug, in human.

Methods

The pH-solubility profile of GDC-0810 free acid and pH_max of its N-Methyl-D-glucamine (NMG) salt were determined. Precipitation studies were conducted for GDC-0810 NMG salt at different pH values. GDC-0810 200-mg dose NMG salt tablet formulations containing different levels of sodium bicarbonate as the pH modifier were tested for dissolution under the dual pH-dilution scheme. Three tablet formulations were evaluated in human as a part of a relative bioavailability study. A 200-mg dose of GDC-0810 was administered QD with low fat food.

Results

Intrinsic solubility of GDC-0810 free acid was found to be extremely low. The pH_max of the NMG salt suggested a strong tendency for form conversion to the free acid under GI conditions. In vitro dissolution profiles showed that the dissolution rate and extent of GDC-0810 increased with increasing the level of sodium bicarbonate in the formulation. The human PK data showed a similar trend for the geometric mean of C_max and AUC_0-t for formulations containing 5%, 10%, and 15% sodium bicarbonate, but the difference is not statistically significant.

Conclusion

Incorporation of a basic pH modifier, sodium bicarbonate, in GDC-0810 NMG salt tablet formulations enhanced in vitro dissolution rate of GDC-0810 via microenvironmental pH modulation. The human PK data showed no statistically significant difference in drug exposure from tablets containing 5%, 10%, and 15% sodium bicarbonate.

     

Pharmacokinetic/pharmacodynamic modelling of the bactericidal activity of free lung concentrations of levofloxacin and gatifloxacin against Streptococcus pneumoniae

The aim of this work was to compare the pharmacological properties of levofloxacin and gatifloxacin against Streptococcus pneumoniae by pharmacokinetic/pharmacodynamic (PK/PD) modelling of the time-kill curves employing an E_max model. An in vitro infection model was used to simulate free pulmonary fluctuating concentrations expected after multiple dosing regimens of both drugs in humans or constant multiples of the minimum inhibitory concentration. PK/PD parameters and PK/PD indices of the simulated dosing regimens were compared. The levofloxacin EC₅₀ (concentration producing 50% of the maximum effect) (mean ± standard deviation 3.57 ± 2.16 mg/L) was higher than that for gatifloxacin (0.95 ± 0.56 mg/L) when simulating multiple dosing regimens as well as constant concentrations (EC_{50,levofloxacin} = 2.75 ± 0.45 mg/L; EC_{50,gatifloxacin} = 1.03 ± 0.52 mg/L). The maximum killing rate constant (k_max) was not statistically different for both drugs independent of fluctuating (k_{max,levofloxacin} = 0.40 ± 0.19 h⁻¹; k_{max,gatifloxacin} = 0.48 ± 0.15 h⁻¹) or constant concentrations (k_{max,levofloxacin} = 0.34 ± 0.06 h⁻¹; k_{max,gatifloxacin} = 0.39 ± 0.23 h⁻¹). The PK/PD model was able to describe the effect of levofloxacin and gatifloxacin against S. pneumoniae in vitro for all the simulations investigated. Gatifloxacin was more potent than levofloxacin, but both presented equivalent efficacy. The model can be used for simulating alternative regimens and optimising therapy to treat streptococcal infextions.     

Development of coated nifedipine dry elixir as a long acting oral delivery with bioavailability enhancement

To develop the long acting nifedipine oral delivery with bioavailability enhancement, a nifedipine dry elixir (NDE) containing nifedipine ethanol solution in dextrin shell was prepared using a spray-dryer, and then coated nifedipine dry elixir (CNDE) was prepared by coating NDE with Eudragit acrylic resin. The physical characteristics and bioavailability of NDE and CNDE were evaluated, and then compared to those of nifedipine powder. NDE and CNDE, which were spherical in shape, had about 6.64 and 8.68–8.75 μm of geometric mean diameters, respectively. The amount of nifedipine dissolved from NDE for 60 min increased about 7- and 40-fold compared to nifedipine powder in pH 1.2 simulated gastric fluid and pH 6.8 simulated intestinal fluid, respectively. Nifedipine released from CNDE was retarded in both dissolution media compared with that from NDE. After oral administration of NDE, the C_max and AUC_0→8h of nifedipine in rat increased about 13- and 7-fold, respectively, and the Tmax of nifedipine was reduced significantly compared with those after oral administration of nifedipine powder alone. The AUC_0→8h and T_max of nifedipine in CNDE increased markedly and the C_max of nifedipine in CNDE was significantly reduced compared to those in NDE. It is concluded that CNDE, which could lower the initial burst-out plasma concentration and maintain the plasma level of nifedipine over a longer period with bioavailability enhancement, might be one of potential alternatives to the marketed long acting oral delivery system for nifedipine.     

Andrographolide Liquisolid using Porous-Starch as the Adsorbent with Enhanced Oral Bioavailability in Rats

Andrographolide (AGL) is the major component of Andrographispaniculata. The poor water solubility and low dissolution strongly affect its oral absorption. Liquisolid technology has been used to improve its dissolution and oral bioavailability. Liquisolid powders of AGL (AGL-LS-PSG) were obtained by firstly dissolving AGL in the mixture of NMP, PEG 6000 and Soluplus®, and solidified by absorption of the blend in porous starch. Angle of repose, Carr index and Hauser ratio presented good powder fluidity and compressibility characteristics of AGL-LS-PSG. The results of optical microscopic observation, PXRD and DSC analysis indicated that AGL has been completely adsorbed in porous starch granules and existed in an amorphous or molecularly dispersing state. AGL-LS-PSG can obviously increase the drug dissolution rate compared to commercial guttate pills and raw drug. In vivo pharmacokinetic behavior of AGL-LS-PSG was investigated following a single oral administration to rats. The C_max (0.37 ± 0.06 μg mL^?1) and AUC_0?2h (13.55 ± 2.67 μg h mL^?1) of AGL-LS-PSG were evidently increased compared to commercial guttate pills (C_max = 0.30 ± 0.21 μg mL^?1, AUC_0–2h = 9.88 ± 3.57 μg h mL^?1). This study indicated great potential of liquisolid technology in effectively improving the dissolution and bioavailability of AGL.