Formulation and in vivo human bioavailability of dissolving tablets containing a self-nanoemulsifying itraconazole solid dispersion without precipitation in simulated gastrointestinal fluid.

To investigate the performance of a solid-state self-nanoemulsifying system with no precipitation in gastric and intestinal fluid, itraconazole (ITZ) was selected as a model drug because of its practically insoluble nature in intestinal fluid. A self-nanoemulsifying ITZ solid dispersion (SNESD) system was prepared as follows: (1) establishment of self-nanoemulsifying composition via the hot melting method, (2) solidification with fumed silicon dioxide (Aerosil 300) via adsorption to prepare SNESD and (3) preparation of a directly compressible tablet containing SNESD. This SNESD was easily formulated in the form of a dissolving tablet and provided a favourable nanoemulsifying microenvironment with no precipitation in the testing media. The SNESD and SNESD-loaded tablet displayed highly enhanced dissolution via nanomisation (266.8 nm and 258.3 nm at 60 min and 120 min, respectively), whereas the drug alone or a reference ITZ Sporanox® capsule displayed very low dissolution and precipitated immediately in intestinal fluid. Drug precipitation in intestinal fluid may affect the in vivo performance of poorly soluble weakly basic drugs and was estimated according to the crystal growth theory. The superdisintegrant and surfactant in the formulation of the tablet were very crucial to the dissolution of the SNESD-loaded tablet. The drug contents and dissolution rates of the SNESD-loaded tablets were also stable during storage in terms of dissolution and drug content. The SNESD-loaded tablet displayed significantly increased oral bioavailability in healthy human volunteers compared with the reference Sporanox® capsule. The current solid-state SNESD-loaded tablet could provide an alternative to liquid-based emulsifying preparations for various poorly water-soluble drugs without precipitation in testing media.

Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing self-emulsifying solid dispersion.

Poorly water-soluble drug with a short half-life such as isradipine (IDP) offer challenges in the controlled release formulation because of low dissolution rate and poor bioavailability. Self-emulsifying solid dispersions (SESD) of IDP consisted of surfactant and fatty acid in poloxamer 407 (POX 407) as a carrier and were manufactured by the melting method. Then, controlled release HPMC matrix tablet containing SESD were prepared via direct compression. The dissolution behaviors and in vivo bioavailability of controlled release matrix tablet in healthy human volunteers were investigated. The physical properties of solid dispersion were also examined using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). It was shown that structure of IDP was amorphous in the solid dispersion. The dissolution rate of IDP from SESD was markedly enhanced because of increased solubility and wetting effect. Controlled release HPMC matrix tablets containing SESD released drug in a controlled manner and were stable during storage over 3 months at 40 °C/75% RH. Furthermore, the tablet containing 5mg IDP SESD showed significantly increased oral bioavailability and extended plasma concentration compared with the marketed 5 mg Dynacirc(®) capsule. A combined method of solid dispersion and controlled release technology could provide versatile dosage formulations containing IDP with poor water solubility and short half-life.

Enhanced bioavailability and retinal accumulation of lutein from self-emulsifying phospholipid suspension (SEPS).

Ability of any formulation to keep the drug in solubilized form in vivo is essential for bioavailability (BA) enhancement rather than the solubility of drug in the formulation vehicle/matrix itself. Besides, utilization of an excess amount of surfactants/co-surfactants to solubilize the drug in the lipid formulation poses potential pharmaceutical as well as health problems. To address this problem, self-emulsifying phospholipid suspension (SEPS) consisting of high amount of phospholipid (an endogenous lipid with efficient in vivo emulsification capability) and relatively low amount of surfactant/co-surfactant has been proposed to enhance the bioavailability (BA) of lutein. In this study, the ability of SEPS formulation to enhance the BA of lutein was assessed from three SEPS formulations with various amounts of phospholipid (SEPS-0, SEPS-I, and SEPS-II with 0mg, 250 mg, and 500 mg of Phosal 53 MCT, respectively) in beagle dogs following a single oral administration of lutein equivalent to 100mg, and were compared with commercial formulation (CF). In addition, the retinal accumulation of lutein in Sprague Dawley (SD) rats' eyes from SEPS-II formulation (lutein dose of 100mg/kg/day) was investigated following single daily oral administration for a period of 14 days. CF and placebo (vegetable oil without lutein) were also administered for the same period of time and were compared with the SEPS-II formulation. In the relative BA study in beagle dogs, no significant differences were observed between the pharmacokinetic (PK) parameters of formulation SEPS-O and CF. However, the C(max) in comparison to CF was 3.70 folds and 11.76 folds higher for SEPS-I and SEPS-II, respectively. Relative BA compared to CF was 178.88% and 473.13% for SEPS-I and SEPS-II, respectively. The retinal lutein accumulation was 0.91 ± 0.31 ng/g, 3.45 ± 1.63 ng/g, and 14.72 ± 2.02 ng/g for placebo, CF, and SEPS-II, respectively. This enhancement was about 16.1 folds and 4.27 folds compared to placebo and CF, respectively. The relative BA study in dogs and retinal accumulation study in rats demonstrated the excellent ability of SEPS to enhance the BA of lutein. For this reason, SEPS containing lutein could be a promising lipid based delivery system for the prevention of ocular diseases.

Comparison of release-controlling efficiency of polymeric coating materials using matrix-type casted films and diffusion-controlled coated tablet.

Polymeric coating materials have been widely used to modify release rate of drug. We compared physical properties and release-controlling efficiency of polymeric coating materials using matrix-type casted film and diffusion-controlled coated tablet. Hydroxypropylmethyl cellulose (HPMC) with low or high viscosity grade, ethylcellulose (EC) and Eudragit(R) RS100 as pH-independent polymers and Eudragit S100 for enteric coatings were chosen to prepare the casted film and coated tablet. Tensile strength and contact angle of matrix-type casted film were invariably in the decreasing order: EC> Eudragit S100> HPMC 100000> Eudragit RS100>HPMC 4000. There was a strong linear correlation between tensile strength and contact angle of the casted films. In contrast, weight loss (film solubility) of the matrix-type casted films in three release media (gastric, intestinal fluid and water) was invariably in the increasing order: EC < HPMC 100000 < Eudragit RS100 < HPMC 4000 with an exception of Eudragit S100. The order of release rate of matrix-type casted films was EC > HPMC 100000 > Eudragit RS100 > HPMC 4000 > Eudragit S100. Interestingly, diffusion-controlled coated tablet also followed this rank order except Eudragit S100 although release profiles and lag time were highly dependent on the coating levels and type of polymeric coating materials. EC and Eudragit RS100 produced sustained release while HPMC and Eudragit S100 produced pulsed release. No molecular interactions occurred between drug and coating materials using (1)H-NMR analysis. The current information on release-controlling power of five different coating materials as matrix carrier or diffusion-controlled film could be applicable in designing oral sustained drug delivery.

Improved analytical validation and pharmacokinetics of valsartan using HPLC with UV detection.

The primary objective of the study was to validate a simple and sensitive method of determining valsartan concentration in human plasma samples using high performance liquid chromatography (HPLC) combined with ultraviolet (UV) detection. Methanol appeared to be the best with a high recovery efficiency compared to other solvents such as acetonitrile, ethylacetate and methyl-tert-butyl ether. After a simple protein precipitation using methanol, the analytes were separated on a Phenomenex Luna C(18) column using 42% acetonitrile with 15 mM potassium dihydrogenphosphate in water (pH 2.0; adjusted with phosphoric acid) as the mobile phase at a flow rate of 1.2 mL/min. The standard calibration curve constructed in the concentration range of 50-2000 ng/mL showed good linearity (r(2)>0.9997). Spironolactone was used as an internal standard (IS). Valsartan and IS eluted at 10.25 and 12.17 min, respectively. The intra-day and inter-day precision and accuracy were satisfactory with relative standard deviations of less than 15%. No interference peaks or matrix effects were observed in human plasma. Valsartan concentration in human plasma was well established following a single 80 mg oral dose (Diovan capsule) to eight healthy volunteers. The current determination of valsartan concentration by protein precipitation using methanol followed by analysis using HPLC with UV detection was rapid and sensitive, and provide an alternative to the analysis of valsartan by studying its clinical applications.

Colonic release and reduced intestinal tissue damage of coated tablets containing naproxen inclusion complex.

A colonic-release delivery system containing naproxen inclusion complex with 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) was originally proposed. The core tablets consisting of the naproxen inclusion complex and disintegrants (Ac-Di-Sol), Primojel), Avicel) or Polyplasdone) were formed by direct compression, and then coated with the polymers, either pH-dependent Eudragit S100 and/or pH-independent Eudragit RS100 with plasticizers like dibutyl sebacate (DBS) and aluminum tristearate (AT). The in vitro release characteristics were evaluated in simulated gastric fluid for 2h and then subsequently in simulated intestinal fluid for 12h. The potential histological changes were also evaluated after direct dosing of suspensions of naproxen alone and powdered mixtures of inclusion complex-loaded tablet into rat intestinal segments. No distinct colonic release was observed when disintegrants were excluded in the single-layered coated tablets regardless of coated structures, giving a zero-order fashion over 12h. The coated tablet with double-layered structures of Eudragit S100 and Eudragit RS100 was not also applicable. In contrast, colonic release was achieved when the core tablet containing inclusion complex and disintegrant was coated with only Eudragit S100 in a single-layered structure. The colonic-release tablet was resistant in gastric fluid for 2h and for 2-4h in intestinal fluid, followed by rapid release of the drug after a total of 4-6h of lag time depending on the type of disintegrants. The lag time was advanced in case of DBS while delayed in case of AT. On histological examination, the inclusion complex-loaded suspension caused less intestinal tissue damage than naproxen alone. Based on these findings, the colonic-release tablet with enteric coatings which contains inclusion complex and disintegrants could be useful to deliver drugs like naproxen to the lower small intestine and upper colon with increased dissolution and reduced intestinal tissue damage.

Effect of solubilizing and microemulsifying excipients in polyethylene glycol 6000 solid dispersion on enhanced dissolution and bioavailability of ketoconazole.

Polyethylene glycol (PEG) 6000-based solid dispersions (SDs), by incorporating various pharmaceutical excipients or microemulsion systems, were prepared using a fusion method, to compare the dissolution rates and bioavailabilities in rats. The amorphous structure of the drug in SDs was also characterized by powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC). The ketoconazole (KT), as an antifungal agent, was selected as a model drug. The dissolution rate of KT increased when solubilizing excipients were incorporated into the PEG-based SDs. When hydrophilic and lipophilic excipients were combined and incorporated into PEG-based SDs, a remarkable enhancement of the dissolution rate was observed. The PEG-based SDs, incorporating a self microemulsifying drug delivery system (SMEDDS) or microemulsion (ME), were also useful at improving the dissolution rate by forming a microemulsion or dispersible particles within the aqueous medium. However, due to the limited solubilization capacity, these PEG-based SDs showed dissolution rates, below 50% in this study, under sink conditions. The PEG-based SD, with no pharmaceutical excipients incorporated, increased the maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC(0-6h)) two-fold compared to the drug only. The bioavailability was more pronounced in the cases of solubilizing and microemulsifying PEG-based SDs. The thermograms of the PEG-based SDs showed the characteristic peak of the carrier matrix around 60 degrees C, without a drug peak, indicating that the drug had changed into an amorphous structure. The diffraction pattern of the pure drug showed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of the numerous distinctive peaks of the drug in the PEG-based SDs demonstrated that a high concentration of the drug molecules was dissolved in the solid-state carrier matrix of the amorphous structure. The utilization of oils, fatty acid and surfactant, or their mixtures, in PEG-based SD could be a useful tool to enhance the dissolution and bioavailability of poorly water-soluble drugs by forming solubilizing and microemulsifying systems when exposed to gastrointestinal fluid.