Novel oral amphotericin B formulation (iCo-010) remains highly effective against murine systemic candidiasis following exposure to tropical temperature

Purpose: To evaluate the antifungal activity of amphotericin B (AmB) in a mouse model of systemic candidiasis following administration of a novel oral AmB formulation (iCo-010) that has been pre-exposed to tropical temperatures.

Methods: Amphotericin B (AmB) was prepared as a 5?mg/mL dispersion in a mixture of Peceol, Gelucire 44/14 and VitE-TPGS 2,3 (iCo-010). The formulation was protected from light and incubated in a sealed container at 43?°C for 60 days. Mice infected with Candida albicans were treated with either iCo-010 formulation pre-incubated at 43?°C for 60 days or freshly prepared iCo-010 formulation at doses of 5, 10 and 20?mg/kg once daily for five consecutive days. Single intravenous 5?mg/kg dose of AmBisome® was used as a positive control group. Seven days following the last dose, the kidney, liver, spleen, lung, heart and brain were removed and the number of colony forming units (CFUs) was determined as a measure of tissue fungal load. In addition, the concentration of AmB within each tissue was determined using high performance liquid chromatography (HPLC).

Results: There were no significant differences in the reduction of CFUs and the concentration of AmB recovered in all organs at all iCo-010 doses tested between the freshly prepared iCo-010 formulation compared to the formulation that was incubated at 43?°C for 60 days.

Conclusions: A novel oral AmB formulation, iCo-010, incubated at 43?°C for 60 days to simulate the exposure of the formulation to tropical temperatures remained highly effective against murine systemic candidiasis.     

The Use of Lipid-Based Formulations to Increase the Oral Bioavailability of Panax Notoginseng Saponins Following a Single Oral Gavage to Rats

Purpose: This article was intended to improve the absorption of ginsenoside Rg1 and Rb1 of Panax notoginseng saponins (PNS). Methods: PNS-Phospholipid complex and a lipid-based formulation by dissolving the complex in the medium chain fattyglycerides were prepared, and their oral relative bioavailability was determined in rats and compared with an aqueous solution of PNS for each component. Results: The study gave evidence that the phospholipids could combine with the two active constitutes of PNS and form a PNS-phospholipid complex. The complex efficiently increased the solubility of hydrophilic ginsenoside Rg1 and Rb1 in some selected hydrophobic esters, such as fatty glycerides, and constructed the lipid-based formulations of PNS. The experimental result in rats in vivo showed that the oral relative bioavailability was enhanced remarkably by these lipid-based formulations composed of the PNS-Phospholipid complex and various esters. The absorption enhancement of the medium-chain glyceride (Labrafac cc and Capmul MCM (3:1)) was somewhat greater than that of other fatty glyceride. The area under the plasma concentration-time curve (AUC) of ginsenoside Rg1 and Rb1 of the PNS-complex in the medium-chain glyceride were 27.38 μg.mL-1.h and 600.08 μg.mL-1.h, compared with 2.52 μg.mL-1.h and 92.29 μg.mL-1.h of the PNS aqueous solution, respectively. Conclusions: The oral relative bioavailability of ginsenoside Rg1 and Rb1 of PNS was enhanced remarkably by the lipid-based formulations. These findings reveal a new strategy to increase oral bioavailability by lipophilicity enhancement for some highly water-soluble but poorly absorbed drugs.     

The use of lipid-based formulations to increase the oral bioavailability of Panax notoginseng saponins following a single oral gavage to rats

Purpose: This article was intended to improve the absorption of ginsenoside Rg1 and Rb1 of Panax notoginseng saponins (PNS). Methods: PNS-Phospholipid complex and a lipid-based formulation by dissolving the complex in the medium chain fattyglycerides were prepared, and their oral relative bioavailability was determined in rats and compared with an aqueous solution of PNS for each component. Results: The study gave evidence that the phospholipids could combine with the two active constitutes of PNS and form a PNS-phospholipid complex. The complex efficiently increased the solubility of hydrophilic ginsenoside Rg1 and Rb1 in some selected hydrophobic esters, such as fatty glycerides, and constructed the lipid-based formulations of PNS. The experimental result in rats in vivo showed that the oral relative bioavailability was enhanced remarkably by these lipid-based formulations composed of the PNS-Phospholipid complex and various esters. The absorption enhancement of the medium-chain glyceride (Labrafac cc and Capmul MCM (3:1)) was somewhat greater than that of other fatty glyceride. The area under the plasma concentration-time curve (AUC) of ginsenoside Rg1 and Rb1 of the PNS-complex in the medium-chain glyceride were 27.38 μg.mL-1.h and 600.08 μg.mL-1.h, compared with 2.52 μg.mL-1.h and 92.29 μg.mL-1.h of the PNS aqueous solution, respectively. Conclusions: The oral relative bioavailability of ginsenoside Rg1 and Rb1 of PNS was enhanced remarkably by the lipid-based formulations. These findings reveal a new strategy to increase oral bioavailability by lipophilicity enhancement for some highly water-soluble but poorly absorbed drugs.     

Subcutaneous administration of nano- and microsuspensions of poorly soluble compounds to rats

The aim of the present study was to evaluate and interpret the pharmacokinetic profiles of two compounds after subcutaneous (s.c.) administration. The compounds have similar physicochemical properties, but are a base (BA99) and an acid (AC88), respectively. The compounds were administered as nano- (5 and 500?µmol/kg) and microsuspensions (5?µmol/kg) s.c. to Sprague–Dawley rats. At the low dose, the exposure was higher for both compounds administered as nanocrystals compared to microparticles. The high dose of the compounds resulted in even higher exposure, but not in a dose-linear manner. The differences in exposure between nano- and microparticles were mainly ascribed to higher dissolution rate and improved solubility for smaller particles. In addition to differences in exposure, there were also differences in the elimination pattern. After s.c. injection of 5?µmol/kg of BA99 as nano- and microsuspensions, the elimination profile was similar as observed earlier after oral administration. However, after injection of the higher dose of BA99 and all formulations of AC88, an extended elimination profile was observed, forming a maintained plateau under the investigated time-period. Essentially, constant plasma levels were caused by a balanced equilibrium between total body clearance of the drug and supply rate of drug from the formulations.     

Does P-glycoprotein contribute to amphotericin B epithelial transport in Caco-2 cells?

Introduction: Amphotericin B (AmB) is a highly efficacious therapeutic for invasive fungal infections and protozoal diseases. Increasing prevalence of these conditions warrants the development of an oral AmB formulation. Efflux transporters, such as the ABCB1 gene product P-glycoprotein, affect the oral bioavailability and disposition of a range of clinically relevant compounds. At present, it remains to be determined whether AmB is a substrate of P-glycoprotein mediated efflux. The objective of this study was to determine whether P-glycoprotein contributes to the epithelial transport of AmB in a Caco-2 cell model.

Methods: Stimulation of P-glycoprotein ATPase activity was assessed using membranes containing human recombinant P-glycoprotein. An ABCB1 knockdown Caco-2 cell model was employed to determine non-toxic concentrations of AmB. AmB cellular association, following a 180?min incubation, was determined using an high performance liquid chromatography-ultraviolet (HPLC-UV) assay.

Results: At the concentrations investigated, AmB did not stimulate P-glycoprotein ATPase activity. Non-toxic concentrations of AmB were 1?μg/mL–5?μg/mL; these were used in subsequent experiments. No significant difference in AmB cellular association was observed for ABCB1 small interfering ribonucleic acid transfected and non-transfected Caco-2 cells, following a 180?min incubation with 1?μg/mL and 2.5?μg/mL AmB. However, significantly greater AmB was associated with transfected cells as compared to non-transfected cells, when cells were incubated with 5?μg/mL AmB.

Conclusions: These results suggest that AmB is not a substrate of P-glycoprotein mediated efflux in this Caco-2 cell model. P-glycoprotein is not expected to be a major barrier to the oral absorption and disposition of AmB.     

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20?min. Finally, the PK profile of SDG-T and a reference formulation Oraxol? (oral solution formulation used in Phase I clinical study) at a dose of 60?mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10?mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol? solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol? solution was 132.25% at a dose of 60?mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10–150?ng/mL for a period of 24?h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.     

Assessing the antifungal activity of a new oral lipid-based amphotericin B formulation following administration to rats infected with Aspergillus fumigatus

The purpose of this study was to assess the antifungal activity of a new oral amphotericin B (AmpB) lipid-based formulation following administration to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (2.1-2.5 × 10⁷ colony forming units [CFU]) were injected via the jugular vein; 48h later male albino Sprague-Dawley rats (350-400 g) were administered either a single oral dose of AmpB incorporated into Peceol (50 mg AmpB/kg), physiologic saline (nontreated controls) or Peceol alone (vehicle control) once daily for 4 days. To assess antifungal activity Brain, Lung, Heart, Liver, Spleen and Kidney sections were homogenized with normal saline (1 mL/g of tissue) and a 0.1-mL aliquot was spread plated onto a Sabourand dextrose agar plate. The plates were incubated for 48 hr at 37°C, at which time the number of fungal CFU were determined and corrected for tissue weight. In addition, plasma galactomannan antigen concentrations were determined. Data was reported as mean ± standard error of the mean. The AmpB-Peceol oral formulation significantly decreased total fungal CFU concentrations recovered in all the organs added together, brain CFU concentrations, spleen CFU concentrations and plasma galactomannan antigen concentrations compared to baseline. No significant differences in lung, heart, liver and kidney CFU concentrations between treatment and control groups were observed. Peceol vehicle control did not exhibit any antifungal activity. These findings suggest that a new oral lipid-based formulation of AmpB incorporated into Peceol can significantly decrease brain and spleen CFU concentrations and plasma galactomannan antigen concentrations compared to non-treated controls.     

Pharmacokinetics of Khellin in Rabbits: Oral,Intravenous, and Intramuscular Administrations

Abstract

This study was undertaken to investigate the pharmacokinetics of khellin in rabbits following oral, intravenous, and intramuscular administrations. Analysis of khellin in the plasma samples was performed according to a previously developed HPLC method. The data obtained from the rapid intravenous administration experiments fitted the two-compartment open model with β, α, total body clearance (TBC), and volume of central compartment (V_c) of 0.0306 hr^?1, 1.93 hr^?1, 573 ml. hr^?1.kg^?1, and 2.1 liter. kg^?1, respectively. The concentration-time profiles acquired following the administration of sugar-coated tablets of khellin were typical of sustained release formulations with time to peak concentration (t_max) and dose-normalized peak plasma concentration (C_max) of 21 hr and 23 ng. ml^?1.mg^?1.kg, respectively. With the exception of one animal, rapid absorption was obtained following the intramuscular or oral suspension administration with (t_max) ranging from 0.083 to 4 hr. A complete absorption was obtained with intramuscular injection, whereas, the fraction of dose absorbed following oral suspension administration was 38%.     

Assessing the Antifungal Activity of a New Oral Lipid-Based Amphotericin B Formulation Following Administration to Rats Infected with Aspergillus Fumigatus

ABSTRACT

The purpose of this study was to assess the antifungal activity of a new oral amphotericin B (AmpB) lipid-based formulation following administration to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (2.1–2.5 × 10⁷ colony forming units [CFU]) were injected via the jugular vein; 48h later male albino Sprague-Dawley rats (350–400 g) were administered either a single oral dose of AmpB incorporated into Peceol (50 mg AmpB/kg), physiologic saline (nontreated controls) or Peceol alone (vehicle control) once daily for 4 days. To assess antifungal activity Brain, Lung, Heart, Liver, Spleen and Kidney sections were homogenized with normal saline (1 mL/g of tissue) and a 0.1-mL aliquot was spread plated onto a Sabourand dextrose agar plate. The plates were incubated for 48 hr at 37°C, at which time the number of fungal CFU were determined and corrected for tissue weight. In addition, plasma galactomannan antigen concentrations were determined. Data was reported as mean ± standard error of the mean. The AmpB-Peceol oral formulation significantly decreased total fungal CFU concentrations recovered in all the organs added together, brain CFU concentrations, spleen CFU concentrations and plasma galactomannan antigen concentrations compared to baseline. No significant differences in lung, heart, liver and kidney CFU concentrations between treatment and control groups were observed. Peceol vehicle control did not exhibit any antifungal activity. These findings suggest that a new oral lipid-based formulation of AmpB incorporated into Peceol can significantly decrease brain and spleen CFU concentrations and plasma galactomannan antigen concentrations compared to non-treated controls.     

Pharmacokinetic,Tissue Distribution,and Excretion of Puerarin and Puerarin-Phospholipid Complex in Rats

ABSTRACT

Puerarin is a potential therapeutic agent for cardiovascular diseases. But its poor oral bioavailability restricts its clinical application. In present study, as an evaluation of a formulation to improve the bioavailability of the drug, puerarin and its phospholipid complex were given to rats by intragastrically (i.g.) administration to compare pharmacokinetic, tissue distribution, and excretion. Serum samples were obtained at designated times after a single oral dose of 400 mg/kg puerarin or its complex. Tissue samples (heart, liver, spleen, kidney, lung, and brain), urine, and feces were collected and analyzed by a sensitive and specific high performance liquid chromatography (HPLC) method after i.g. administration of puerarin or its phospholipid complex. Compartmental and non-compartmental analyses were applied to the serum concentration versus time data. Pharmacokinetic parameters were calculated using the 3P97 pharmacokinetic software package. An open two-compartment, first-order model was selected for pharmacokinetic modeling. The results showed that after i.g. administration of 400 mg/kg puerarin and its phospholipid complex (equivalent to 400 mg/kg of puerarin), the pharmacokinetic parameters of the two formulations were different. The serum concentrations reached peaks at 0.894 ± 0.521 h and 0.435 ± 0.261 h, respectively, indicating the complex was more readily absorbed in serum than puerarin. The maximum concentrations for puerarin and its complex were 1.367 ± 0.586 mg·L^?1 and 2.202 ± 1.28 mg·L^?1 and AUC were 5.779 ± 1.662 mg·h. L^?1 and 8.456 ± 0.44 mg·h L^?1, respectively, indicating a higher bioavailability for the complex. The widely distribution characteristics of puerarin and its complex in tissues post-i.g. administration was identical and in a descending order as follows: lung, kidney, liver, heart, spleen, and brain. However, the amount was different. Puerarin distribution was higher in heart, lung, and brain after administering the complex. The cumulative 72 h urinary excretion of puerarin after i.g. administration of puerarin and its complex accounted for 1.05%, 1.11% of the administered dose, respectively. The cumulative feces excretion of puerarin was 32.3% and 25.5%. To sum up, oral administration of puerarin phospholipid complex modified the pharmacokinetics and tissue distribution of puerarin and it could be an effective oral formulation for puerarin.     

A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men

The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70?mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10?±?14.32?ng/mL was attained after 1.00?±?0.16?h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28?±?654.57?μg and 314.68?±?395.43?μg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68?±?0.95?h^–1. The elimination rate constants K_urine and K_non-ur were 0.005?±?0.004?h^?1 and 0.42?±?0.08?h^?1, respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.     

Pharmacokinetics,tissue distribution,bioavailability, and excretion of nuciferine,an alkaloid from lotus,in rats by LC/MS/MS

Objective: In order to characterize the pharmacokinetics, tissue distribution, bioavailability, and excretion of nuciferine, a reliable gradient LC/MS/MS-based method was developed and validated.

Methods: Sprague-Dawley rats were intravenously injected with a bolus of nuciferine (0.2?mg/kg) and orally given a single dose of nuciferine (10.0?mg/kg). Blood samples were withdrawn via the ocular vein at specific times. Organs, including the liver, kidney, brain, lung, heart, and spleen, were collected at specific times after oral administration of 10.0?mg/kg nuciferine. The plasma and tissue samples were assayed by LC/MS/MS.

Results: The results indicated that nuciferine had rapid distribution and poor absorption into systemic circulation. The value of absolute bioavailability was only 1.9?±?0.8% after administration of 10.0?mg/kg nuciferine by oral and administration of 0.2?mg/kg nuciferine intravenously (IV) to rats. The AUC_0→4?h values in tissues were in the order of kidney?>?lung?>?spleen?>?liver?>?brain?>?heart. The majority of excretion of nuciferine (50.7%) was excreted through kidneys with parent drug after oral administration without liver metabolism.

Conclusion: This study may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines.     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.     

Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

Context: Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery.

Objective: To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability.

Methods: Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4?mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2?mg).

Results: Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively.

Conclusions: A sublingual tablet formulation with an improved acceptability has been successfully developed.     

Pharmacokinetic, tissue distribution, and excretion of puerarin and puerarin-phospholipid complex in rats

Puerarin is a potential therapeutic agent for cardiovascular diseases. But its poor oral bioavailability restricts its clinical application. In present study, as an evaluation of a formulation to improve the bioavailability of the drug, puerarin and its phospholipid complex were given to rats by intragastrically (i.g.) administration to compare pharmacokinetic, tissue distribution, and excretion. Serum samples were obtained at designated times after a single oral dose of 400 mg/kg puerarin or its complex. Tissue samples (heart, liver, spleen, kidney, lung, and brain), urine, and feces were collected and analyzed by a sensitive and specific high performance liquid chromatography (HPLC) method after i.g. administration of puerarin or its phospholipid complex. Compartmental and non-compartmental analyses were applied to the serum concentration versus time data. Pharmacokinetic parameters were calculated using the 3P97 pharmacokinetic software package. An open two-compartment, first-order model was selected for pharmacokinetic modeling. The results showed that after i.g. administration of 400 mg/kg puerarin and its phospholipid complex (equivalent to 400 mg/kg of puerarin), the pharmacokinetic parameters of the two formulations were different. The serum concentrations reached peaks at 0.894 ± 0.521 h and 0.435 ± 0.261 h, respectively, indicating the complex was more readily absorbed in serum than puerarin. The maximum concentrations for puerarin and its complex were 1.367 ± 0.586 mg·L^-1 and 2.202 ± 1.28 mg·L^-1 and AUC were 5.779 ± 1.662 mg·h. L^-1 and 8.456 ± 0.44 mg·h L^-1, respectively, indicating a higher bioavailability for the complex. The widely distribution characteristics of puerarin and its complex in tissues post-i.g. administration was identical and in a descending order as follows: lung, kidney, liver, heart, spleen, and brain. However, the amount was different. Puerarin distribution was higher in heart, lung, and brain after administering the complex. The cumulative 72 h urinary excretion of puerarin after i.g. administration of puerarin and its complex accounted for 1.05%, 1.11% of the administered dose, respectively. The cumulative feces excretion of puerarin was 32.3% and 25.5%. To sum up, oral administration of puerarin phospholipid complex modified the pharmacokinetics and tissue distribution of puerarin and it could be an effective oral formulation for puerarin.     

Characterization of amphotericin B liposome formulations

Liposomes composed of hydrogenated soya phosphatidylcholine (Emulmetik 950®)/cholesterol/charged lipids [dicetyl phosphate (-) or stearylamine (+)] were developed. The hydrogenated soya phosphatidylcholine/cholesterol/charged lipid liposomes at molar ratios of 1:1:0, 7:2:0, 7:2:1 (-), and 7:2:1 (+), with and without the entrapped amphotericin B (0.05 mg AmB/mg lipid), were prepared by a chloroform-film method with sonication. The charges of liposomes were characterized by a Zeta-Meter. The negative liposomes with and without the entrapped AmB showed higher surface charge density than other formulations. The size distribution of liposomes determined by standard error of the mean (SEM) was in the range of 0.115 to 0.364 µm. The smallest size was observed in the negative liposomes with the entrapped drug [7:2:1 (-) AmB]. The lamellarity of more than 15 layers was observed by transmission electron microscope (TEM) in the neutral liposomes with the entrapped drug [7:2 AmB]. The transition temperature and enthalpy of transition (ΔH) were determined by differential scanning calorimetry (DSC). Positive liposomes with the entrapped and unentrapped AmB demonstrated higher ΔH of the first peak than other formulations, indicating higher rigidity of liposomal membrane. The AmB contents in liposomes were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection at 382 nm. The percentages of entrapment of AmB in all formulations were above 85%. The positive liposome [7:2:1 (+) AmB] formulation, which gave the highest thermal stability, was selected for further skin absorption evaluation.     

Aerosol-based efficient delivery of telithromycin,a ketolide antimicrobial agent,to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections

Purpose: The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration. Method: The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer®. Results and discussion: The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values. Conclusion: This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.     

Benchtop MRI for pharmacokinetic evaluation of two aqueous-based nano-scaled formulations of oleic acid stabilized magnetite nanocrystals

Background: The interplay between numerous factors, including the size, shape, coating, surface charge and composition of particles is known to affect the pharmacokinetics and biodistribution of superparamagnetic iron oxides (SPIOs). This makes understanding the role of each factor independently quite challenging.

Methods: In the present study, the in vivo magnetic resonance imaging (MRI), biodistribution and hepatic clearance evaluations of two SPIOs Formulations A and B developed from ～13.5?nm hydrophobic oleic acid stabilized monodisperse magnetite nanocrystals core and lipid-based amphiphilic stabilizers were performed using a prototype benchtop MR imager (22?MHz) and pulsed nuclear magnetic resonance (NMR) system (20?MHz), respectively. Formulation A was composed of mPEG-2000-DSPE and Formulation B was composed of Phospholipon-100H, sucrose ester M-1695 and Cremophor RH-40.

Results: The in vivo MRI investigations showed that both formulations were safe and effective as potential liver MR contrast agents with sustained liver contrast for at least seven days. In addition, ex vivo relaxometric investigations revealed that the formulations predominantly distribute to the liver and spleen following I.V. injection. The hepatic clearance kinetics determined based on the relaxometric quantification method indicated that both formulations exhibited a biphasic clearance process with a slow terminal clearance half-life of 11.5 and 12.7 days, respectively, for Formulations A and B.

Conclusions: The results of this study showed the potential biomedical applications of the investigated magnetopharmaceutical formulations as MRI contrast agents.     

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers

Candesartan is a long-acting and selective nonpeptide AT₁ subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16?mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16?mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36?h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC_last, AUC_inf and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC_last in the reference and the test drug were 1530.1?±?434.6 and 1315.7?±?368.6 ng·h/mL. The mean for AUC_inf in the reference and the test drug were 1670.0?±?454.5 and 1441.2?±?397.8 ng·h/mL. The mean value for C_max in the reference and the test drug was 142.6?±?41.0 and 134.9?±?41.4?ng/mL. The 90% confidence intervals for the AUC_last, AUC_inf and C_max were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16?mg of candesartan cilexetil hydrochloride.