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1.
Drug Dev Ind Pharm ; 40(2): 172-7, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23600652

ABSTRACT

OBJECTIVE: A novel flurbiprofen-loaded nanoemulsion which gave uniform emulsion droplets with a narrow size distribution was previously reported to be prepared using membrane emulsification method. The purpose of this study is to develop a novel flurbiprofen-loaded nanoparticle with a narrow size distribution and improved bioavailability. METHOD: The nanoparticle was prepared by solidifying nanoemulsion using sucrose as a carrier via spray drying method. Its physicochemical properties were investigated using SEM, DSC and PXRD. Furthermore, dissolution and bioavailability in rats were evaluated compared to a flurbiprofen-loaded commercial product. RESULTS: The flurbiprofen-loaded nanoparticles with flurbiprofen/sucrose/surfactant mixture (1/20/2, weight ratio) gave good solidification and no stickiness. They associated with about 70,000-fold improved drug solubility and had a mean size of about 300 nm with a narrow size distribution. Flurbiprofen was present in a changed amorphous state in these nanoparticles. Moreover, the nanoparticles gave significantly shorter Tmax, and higher AUC and Cmax of the drug compared to the commercial product (p < 0.05). In particular, they showed about nine-fold higher AUC of the drug than did the commercial product. CONCLUSION: These flurbiprofen-loaded nanoparticles prepared with sucrose by the membrane emulsification and spray drying method would be a potential candidate for orally delivering poorly water-soluble flurbiprofen with enhanced bioavailability.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Drug Carriers/chemistry , Flurbiprofen/chemistry , Nanoparticles/chemistry , Sucrose/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Drug Carriers/administration & dosage , Flurbiprofen/administration & dosage , Male , Nanoparticles/administration & dosage , Particle Size , Rats , Rats, Sprague-Dawley , Sucrose/administration & dosage
2.
J Pharm Sci ; 101(12): 4584-96, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23023800

ABSTRACT

The aim of our study was to characterize and optimize a self-nanoemulsifying drug delivery system (SNEDDS) formulation by a three-factor, three-level Box-Behnken design (BBD) combined with a desirability function. The independent factors were the amounts of Capryol PGMC (X(1)), Tween 20 (X(2)), and Transcutol HP (X(3)). The dependent variables were droplet size (Y(1)), equilibrium solubility (Y(2)), and cumulative percentage of drug released in 15 min (Y(3)) from the SNEDDS formulation. The responses were fitted to a second-order quadratic model and statistical validation of the fitted models was carried out by analysis of variance. Various response surface graphs and contour plots were constructed to understand the effects of different factor level combinations on the responses. The optimized SNEDDS formulation consisting of Capryol PGMC-Tween 20-Transcutol HP at proportions of 5:58.4:40 (w/w) was prepared and a comparison of the predicted values and experimental values was found to be in close agreement. Furthermore, an in vivo pharmacokinetic study of the optimized SNEDDS formulation showed a 2.2-fold increase in relative oral bioavailability compared with that of the suspension. In conclusion, the BBD demonstrated its effectiveness in optimizing the SNEDDS formulation and in understanding the effects of formulation variables on the performance of SNEDDS.


Subject(s)
Analgesics/administration & dosage , Drug Delivery Systems/methods , Emulsions/chemistry , Flurbiprofen/administration & dosage , Ethylene Glycols/chemistry , Glycerides/chemistry , Models, Chemical , Particle Size , Polysorbates/chemistry , Solubility
3.
Arch Pharm Res ; 35(6): 1037-43, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22870813

ABSTRACT

In this study, we developed an optimized formulation of a breviscapine lipid emulsion (BLE) and evaluated the physicochemical properties and in vivo pharmacokinetics of BLE in rats. For the preparation of the lipid emulsion, soybean oil and oleic acid were used as the oil phase, lecithin and poloxamer 188 as surfactants and glycerol as co-surfactant. An optimized formulation consisting of soybean oil (10.0%), oleic acid (0.9%), lecithin (1.5%), poloxamer 188 (0.4%), and glycerol (2.25%) was selected. The results showed that the average particle size, polydispersity index, and zeta potential of the optimized formulation were 183.5 ± 5.5 nm, 0.098 ± 0.046, and -35.0 ± 2.5 mV, respectively. The BLE was stable for at least three month at room temperature. After a single intravenous dose of 4 mg/kg to rats, the AUC of scutellarin from the lipid emulsion was about 1.5-fold higher than that of the commercial product (breviscapine injection). In conclusion, the optimized formulation of BLE showed positive results over the commercial product in terms of the physicochemical properties and pharmacokinetics of BLE in rats.


Subject(s)
Drug Carriers , Drugs, Chinese Herbal/chemistry , Flavonoids/chemistry , Lipids/chemistry , Animals , Area Under Curve , Chemistry, Pharmaceutical , Drug Stability , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacokinetics , Emulsions , Flavonoids/administration & dosage , Flavonoids/pharmacokinetics , Glycerol/chemistry , Injections, Intravenous , Lecithins/chemistry , Male , Nanoparticles , Oleic Acid/chemistry , Particle Size , Poloxamer/chemistry , Rats , Rats, Sprague-Dawley , Soybean Oil/chemistry , Surface-Active Agents/chemistry , Technology, Pharmaceutical/methods
4.
Int J Pharm ; 422(1-2): 202-10, 2012 Jan 17.
Article in English | MEDLINE | ID: mdl-22085435

ABSTRACT

With the aim of developing a novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes, various valsartan-loaded solid dispersions were prepared with water, hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulphate (SLS). Effects of the weight ratios of SLS/HPMC and carrier/drug on both the aqueous solubility of valsartan and the drug-release profiles of solid dispersions were investigated. The physicochemical properties of solid dispersions were characterized using scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of the solid dispersions in rats was evaluated compared to valsartan powder and a commercial product (Diovan). Unlike the conventional solid dispersion system, the valsartan-loaded solid dispersion had a relatively rough surface and did not change the crystalline form of the drug. It was suggested that the solid dispersions were formed by attaching hydrophilic carriers to the surface of the drug, thus changing from a hydrophobic to a hydrophilic form without changing the crystalline form. The drug-loaded solid dispersion composed of valsartan/HPMC/SLS at a weight ratio of 3/1.5/0.75 improved the drug solubility by about 43-fold. It gave a higher AUC, C(max) and shorter T(max) compared to valsartan powder and the commercial product. The solid dispersion improved the bioavailability of the drug in rats by about 2.2 and 1.7-fold in comparison with valsartan powder and the commercial product, respectively. Thus, the valsartan-loaded solid dispersion would be useful for delivering poorly water-soluble valsartan with enhanced bioavailability and no crystalline changes.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Tetrazoles/pharmacokinetics , Valine/analogs & derivatives , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin II Type 1 Receptor Blockers/chemistry , Animals , Biological Availability , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical , Crystallization , Crystallography, X-Ray , Drug Carriers , Drug Compounding , Hydrophobic and Hydrophilic Interactions , Hypromellose Derivatives , Male , Methylcellulose/analogs & derivatives , Methylcellulose/chemistry , Microscopy, Electron, Scanning , Powders , Rats , Rats, Sprague-Dawley , Sodium Dodecyl Sulfate/chemistry , Solubility , Surface Properties , Technology, Pharmaceutical/methods , Tetrazoles/administration & dosage , Tetrazoles/chemistry , Valine/administration & dosage , Valine/chemistry , Valine/pharmacokinetics , Valsartan , Water/chemistry
5.
Eur J Drug Metab Pharmacokinet ; 37(3): 217-24, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22201019

ABSTRACT

The present study investigated the effects of a curcumin self-emulsifying drug delivery systems (SEDDS) on the pharmacokinetics of orally administered docetaxel in rats. A single dose of docetaxel was orally administered (30 mg/kg) alone or after oral curcumin SEDDS (25, 50, 100 and 150 mg/kg) administration with time intervals of 0, 15 and 30 min, respectively. After oral administration, the C (max) and the area under the plasma concentration-time curve (AUC) of docetaxel were significantly increased (0 min, p < 0.05; 15 and 30 min, p < 0.01) by 2.2, 4.7 and 4.6 times and 2.0, 3.8 and 4.1 times compared to that of control group, respectively, after treatment with curcumin SEDDS (100 mg/kg) for each interval. Moreover, The C (max) of docetaxel was increased by 2.6 and 4.4 times in response to 25 and 50 mg/kg curcumin SEDDS treatment, respectively, the corresponding AUC was increased by about 2.4 and 3.1 times, and consequently the absolute bioavailabilities of docetaxel in these two treatment groups were 7.9 and 10.4%, respectively, which showed a significant increase of about 2.4- and 3.2-fold in comparison to the control value (3.3%). However, no further increase in either AUC or C (max) values of docetaxel was observed as the curcumin SEDDS dose was increased from 50 to 150 mg/kg. It is worth noting that the presence of curcumin SEDDS did not significantly decrease the systemic clearance, which was shown by the almost unchanged terminal half-life (t (1/2)) of docetaxel in all treatment groups. Thus, the enhanced bioavailability of oral docetaxel by curcumin SEDDS seemed to be likely due to an inhibition function of cytochrome P450 (CYP) 3A and P-glycoprotein (Pgp) in the intestines of the rats. However, further in vivo studies are needed to verify these hypotheses.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Curcumin/administration & dosage , Drug Delivery Systems , Taxoids/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Biological Availability , Docetaxel , Emulsions , Male , Rats , Rats, Sprague-Dawley , Taxoids/administration & dosage
6.
Int J Pharm ; 419(1-2): 154-60, 2011 Oct 31.
Article in English | MEDLINE | ID: mdl-21839822

ABSTRACT

Various amide prodrugs of salicylic acid were synthesised, and their physicochemical properties including lipophilicity, chemical stability and enzymatic hydrolysis were investigated. In vivo skin permeation and accumulation profiles were also evaluated using a combination of common permeation enhancing techniques such as the use of a supersaturated solution of permeants in an enhancer vehicle, a lipophilic receptor solution, removal of the stratum corneum and delipidisation of skin. Their capacity factor values were proportional to the degree of carbon-carbon saturation in the side chain. All these amides were highly stable in acetonitrile and glycerine. Amide prodrugs were converted to salicylic acid both in hairless mouse liver and skin homogenates. N-dodecyl salicylamide (C12SM) showed the lowest permeation of salicylic acid in skin compared to the other prodrugs, probably due to its low aqueous solubility. It had a high affinity for the stratum corneum and its accumulation was restricted to only the uppermost layer of skin. Thus, this amide prodrug could be a safer topical sunscreen agent with minimum potential for systemic absorption.


Subject(s)
Salicylates/pharmacokinetics , Skin Absorption , Sunscreening Agents/pharmacokinetics , Administration, Cutaneous , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacokinetics , Animals , Drug Stability , In Vitro Techniques , Liver/metabolism , Mice , Mice, Hairless , Permeability , Prodrugs , Salicylates/chemical synthesis , Salicylates/chemistry , Skin/metabolism , Solubility , Sunscreening Agents/chemical synthesis , Sunscreening Agents/chemistry
7.
Biol Pharm Bull ; 34(8): 1179-86, 2011.
Article in English | MEDLINE | ID: mdl-21804203

ABSTRACT

In this study, a novel liquid self-emulsifying drug delivery system (SEDDS) containing curcumin was formulated and further developed into a solid form by a spray drying method using Aerosil 200 as the solid carrier. The optimum liquid SEDDS consisted of Lauroglycol Fcc, Labrasol and Transcutol HP as the oil phase, the surfactant and the co-surfactant at a weight ratio of 15.0 : 70.8 : 14.2 (w/w/w), respectively. There was no difference in droplet size between the emulsions obtained from the liquid and solid forms of SEDDS. Solid state characterization of the solid SEDDS was performed by scanning electron micrograph (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The drug formulated in the solid SEDDS was quickly and completely dissolved within 5 min, both in 0.1 N HCl and phosphate buffer pH 6.8 dissolution media, whereas crude curcumin powder was significantly less dissoluble. The solid SEDDS formulation was stable for at least 3 months at 40°C with 75% relative humidity. After oral administration to rats, curcumin in the solid SEDDS resulted in significant improvement in in vivo absorption compared with that of curcumin powder. As the dose of curcumin formulated in solid SEDDS increased from 25 to 100 mg/kg, the C(max) and area under the drug concentration time curve (AUC) of curcumin were increased by 4.6 and 7.6 times, respectively. However, the over-proportional increase in the AUC in the higher dose group might be due to underestimation of AUC in the lower dose group. In conclusion, this solid SEDDS is a promising solid dosage form for poorly water-soluble curcumin.


Subject(s)
Curcuma/chemistry , Curcumin/pharmacokinetics , Desiccation/methods , Drug Delivery Systems , Lipids , Plant Extracts/pharmacokinetics , Animals , Area Under Curve , Biological Availability , Curcumin/administration & dosage , Dosage Forms , Emulsions , Male , Plant Extracts/administration & dosage , Rats , Rats, Sprague-Dawley
8.
J Pharm Pharmacol ; 63(4): 491-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21401600

ABSTRACT

OBJECTIVES: To avoid the major adverse effects induced by Cremophor EL formulated in the commercial paclitaxel products of Taxol. METHODS: An injectable paclitaxel solid dispersion free of Cremophor was prepared by a supercritical antisolvent process and then was fully characterized and investigated with regard to its short-term and long-term stability. Pharmacokinetics in rats was also evaluated compared with the commercial product. KEY FINDINGS: The solid dispersion system at a 1/20/40 weight ratio of paclitaxel/HP-ß-CD/HCO-40 had a paclitaxel solubility of about 10 mg/ml, an almost 10 000-fold increase over its aqueous solubility. This system was physically stable for at least six months or four weeks in accelerated conditions (40 ± 2°C; RH: 75 ± 5%) and stress conditions (60°C), respectively. The precipitation time of paclitaxel solid dispersion in 0.9% sodium chloride injection at a concentration of 1000 µg/ml was above 70 h at room temperature. Intravenous administration of paclitaxel solid dispersion at a dose of 6 mg/kg revealed no significant differences when compared with the commercial product. However, our results obtained at a dose of 12 mg/kg showed a striking non-linear increase in the plasma Cmax and AUCall with increased dose. In addition, the concentrations of paclitaxel in various organs in the solid dispersion group were found to be higher than those of Taxol at 6 mg/kg, and the paclitaxel levels in these organs increased proportionately with increasing dose. CONCLUSIONS: Nano-scale paclitaxel solid dispersion without Cremophor EL provided advantageous results over Taxol with respect to the physicochemical properties, safety, clinic convenience and pharmacokinetic behaviour in rats.


Subject(s)
Chemistry, Pharmaceutical/methods , Paclitaxel/chemistry , Paclitaxel/pharmacokinetics , Animals , Drug Stability , Glycerol/adverse effects , Glycerol/analogs & derivatives , Injections, Intravenous , Male , Nanotechnology/methods , Paclitaxel/administration & dosage , Rats , Rats, Sprague-Dawley , Solubility , Tissue Distribution
9.
Drug Deliv ; 18(5): 305-11, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21226548

ABSTRACT

To develop a thermo-sensitive injectable hydrogel that is easy to administer, gels quickly in the body, and allows sustained release of the drug, various poloxamer-based hydrogels containing doxorubicin were prepared with poloxamer and hydrochloric acid under light protection using the cold method. Their rheological characterization, dissolution, and pharmacokinetics after intramuscular administration to rats were evaluated. Hydrochloric acid decreased the viscosity and retarded the gelation time of the injectable gel. The drug was dissolved from the hydrogels by Fickian diffusion through the extramicellar aqueous channels of the gel matrix. P 188 and hydrochloric acid barely affected the dissolution mechanism. However, P 188 increased and hydrochloric acid decreased the dissolution rate of the drug from the injectable gels. The thermo-sensitive injectable gel composed of 0.6% doxorubicin, 15% P 407, 6% P 188, and 0.1% hydrochloric acid was easy to administer intramuscularly and gelled quickly in the body. Moreover, it maintained the plasma concentrations of drug for 60 h and gave an ~ 5-fold higher AUC compared to doxorubicin solution. Thus, it would be useful for delivering doxorubicin in a pattern that allows sustained release for a long time, leading to better bioavailability.


Subject(s)
Antibiotics, Antineoplastic/pharmacokinetics , Doxorubicin/pharmacokinetics , Excipients/chemistry , Poloxamer/chemistry , Animals , Antibiotics, Antineoplastic/administration & dosage , Area Under Curve , Biological Availability , Delayed-Action Preparations , Doxorubicin/administration & dosage , Hydrochloric Acid/chemistry , Hydrogels , Injections, Intramuscular , Male , Rats , Rats, Sprague-Dawley , Rheology , Solubility , Temperature , Time Factors , Viscosity
10.
Mol Pharm ; 7(6): 2132-40, 2010 Dec 06.
Article in English | MEDLINE | ID: mdl-20849146

ABSTRACT

EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human. In vivo absorption was investigated following regional intestinal dosing in rats, and the pharmacokinetics was determined using rats after a single oral administration. EXP3174-pivoxil exhibited predictable stability in the aqueous solution within a pH range of 1.2-9.0 as well as in the solid form of powder. An in vitro metabolism study revealed that EXP3174-pivoxil was rapidly and efficiently converted into EXP3174 by enzymatic hydrolysis. The dose administered into the duodenum and jejunum resulted in higher values for the AUC(0-24h) and C(max) than those following ileum dosing (p < 0.05). Furthermore, the AUC(0-24h) and C(max) values for EXP3174 increased in a dose-dependent manner as dose increased from 0.5 to 5 mg/kg. A comparable AUC(0-24h), shortened T(max) and a significant increase in the plasma C(max) of EXP3174 were observed following oral administration of EXP3174-pivoxil (as EXP3174, 1 mg/kg) compared with those of losartan (as EXP3174, 5 mg/kg) in rats, suggesting faster absorption and a 5-fold enhancement in the bioavailability of EXP3174. These results suggest that EXP3174-pivoxil may serve as a more effective drug even at lower clinical doses by exhibiting increased bioavailability and faster therapeutic response, compared with losartan.


Subject(s)
Esters/chemistry , Esters/pharmacokinetics , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Tetrazoles/chemistry , Tetrazoles/pharmacokinetics , Animals , Chemistry, Physical , Dogs , Dose-Response Relationship, Drug , Esters/metabolism , Humans , Hydrogen-Ion Concentration , Imidazoles/metabolism , Intestinal Mucosa/metabolism , Intestines/chemistry , Liver/chemistry , Liver/metabolism , Losartan/chemistry , Losartan/metabolism , Losartan/pharmacokinetics , Male , Molecular Structure , Prodrugs/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism , Tetrazoles/metabolism , Tissue Distribution
11.
Biol Pharm Bull ; 33(8): 1364-70, 2010.
Article in English | MEDLINE | ID: mdl-20686233

ABSTRACT

The purpose of this research was to prepare and evaluate a non-bitter donepezil hydrochloride (DH) orally disintegrating tablet (ODT) for enhanced patient compliance. Taste masking was done by preparing microspheres with different ratios of drug and Eudragit EPO using spray drying method. The entrapment of the drug into microspheres was confirmed by scanning electron microscope (SEM) and X-ray powder diffraction. It was found that microspheres with a drug-polymer ratio of 1 : 2 could mask the taste obviously by inhibiting the release of DH in simulated salivary fluid. Microspheres-loaded tablets containing Polyplasdone NF and Low substituted Hydroxypropyl Cellulose (L-HPC) both at a 10% level showed rapid disintegration, in vitro (15.5 s) and in vivo (19.8 s), which were faster than that of marketed tablets (36.7, 41.3 s, respectively). Results from taste evaluation in human volunteers revealed that the ODTs with taste-masked microspheres had significantly enhanced palatability. Dissolution in vitro and pharmacokinetics in rats were evaluated for the tested ODTs compared to the donepezil hydrochloride commercial product (ARICEPT). Both tablets showed comparable dissolution patterns in vitro and similar area under curve from 0 to 24 h (AUC(0-24)), C(max) and T(max) of DH in vivo to each other, suggesting that the tested ODTs might give the similar drug efficacy in rats compared to that of ARICEPT. Thus, it was concluded that DH ODTs with masked taste were obtained by Eudragit EPO-based microspheres, drug loaded microspheres neither decreased the bioavailability nor delayed the release of DH.


Subject(s)
Drug Compounding/methods , Indans/administration & dosage , Indans/chemistry , Piperidines/administration & dosage , Piperidines/chemistry , Taste , Administration, Oral , Animals , Biological Availability , Donepezil , Drug Carriers/chemistry , Humans , Indans/pharmacokinetics , Male , Microscopy, Electron, Scanning , Microspheres , Particle Size , Piperidines/pharmacokinetics , Polymethacrylic Acids/chemistry , Rats , Rats, Sprague-Dawley , Saliva/chemistry , Solubility , Surface Properties , Tablets , Taste Threshold , X-Ray Diffraction
12.
Int J Pharm ; 399(1-2): 116-20, 2010 Oct 31.
Article in English | MEDLINE | ID: mdl-20727390

ABSTRACT

As with many other anti-cancer agents, docetaxel is a substrate for ATP-binding cassette transporters such as P-glycoprotein and its metabolism is mainly catalysed by CYP3A. In order to improve the oral bioavailability of docetaxel, a component of turmeric, curcumin, which can down-regulate the intestinal P-glycoprotein and CYP3A protein levels, was used for the pre-treatment of rats before the oral administration of docetaxel. Curcumin (100 mg/kg) did not significantly modify the pharmacokinetics of docetaxel when given orally 30 min before the administration of docetaxel. However, the C(max) of docetaxel in rats pre-treated with curcumin for four consecutive days was significantly increased (p<0.01) by about 10 times compared to that of the docetaxel control, and the area under the plasma concentration-time curve (AUC) was about eight times higher than that of the control. Consequently, the absolute bioavailability of docetaxel in the treatment group (four days of curcumin at 100 mg/kg) was about 40%, which was a significant increase of about eightfold in comparison to the control value. Thus, the oral bioavailability of docetaxel was enhanced by the co-administration of regular curcumin. It could be possible to administer docetaxel orally, besides the established i.v. route.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Curcumin/therapeutic use , Cytochrome P-450 CYP3A Inhibitors , Enzyme Inhibitors/therapeutic use , Taxoids/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacology , Biological Availability , Chromatography, High Pressure Liquid , Curcumin/pharmacology , Docetaxel , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Injections, Intravenous , Male , Rats , Rats, Sprague-Dawley , Substrate Specificity , Taxoids/blood , Taxoids/pharmacology
13.
Drug Deliv ; 17(5): 322-9, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20367177

ABSTRACT

To develop a valsartan-loaded gelatin microcapsule using hydroxypropylmethylcellulose (HPMC) as a stabilizer, which could improve the physical stability and bioavailability of valsartan, the gelatin microcapsules were prepared with various ratios of gelatin and HPMC using a spray-drying technique. Their solubility, dissolution, thermal characteristics, crystallinity, and physical stability were investigated. The bioavailability of drug in valsartan-loaded microcapsule was then evaluated compared to drug powder and commercial product in rats. The microcapsule with gelatin and/or HPMC enhanced the solubility and dissolution of drug compared to valsartan powder. Among the formulations tested, the valsartan-loaded gelatin microcapsule at the weight ratio of valsartan/gelatin/HPMC of 1/2/1 gave excellent drug solubility of approximately 2 microg/ml and dissolution of 70% at 1 h. The crystal state of valsartan in this microcapsule was changed from crystalline to amorphous form during the spray-drying process and maintained as an amorphous form at 40 degrees C for at least 3 months, indicating that it was physically stable. HPMC in this microcapsule could inhibit the recrystallization, resulting in stabilizing the amorphous form of valsartan. Furthermore, it improved the oral bioavailability of valsartan compared to valsartan powder and gave the similar AUC, C(max), and T(max) values to commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, the gelatin microcapsule with HPMC would be a more effective and stable oral delivery system of poorly water-soluble valsartan.


Subject(s)
Antihypertensive Agents/administration & dosage , Excipients/chemistry , Methylcellulose/analogs & derivatives , Tetrazoles/administration & dosage , Valine/analogs & derivatives , Administration, Oral , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacokinetics , Area Under Curve , Biological Availability , Capsules , Crystallization , Drug Delivery Systems , Drug Stability , Drug Storage , Gelatin/chemistry , Hypromellose Derivatives , Male , Methylcellulose/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Temperature , Tetrazoles/chemistry , Tetrazoles/pharmacokinetics , Valine/administration & dosage , Valine/chemistry , Valine/pharmacokinetics , Valsartan
14.
Arch Pharm Res ; 33(1): 95-101, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20191350

ABSTRACT

The main purpose of this study was to evaluate the effect of a mixed drug solution containing a surfactant and beta-cyclodextrin (beta-CD) on the solubility and bioavailability of a poorly water soluble drug, flurbiprofen. Solubility, dissolution and in vivo pharmacokinetics of flurbiprofen in the presence of surfactant, beta-CD or mixture of surfactant and beta-CD were investigated. Among the surfactants tested, Tween 80 produced the highest improvement in the aqueous solubility of flurbiprofen. The solubility of flurbiprofen increased linearly as a function of beta-CD, resulting in B8 type that suggested a formation of inclusion complex in a molar ratio of 1:1. The solubility of flurbiprofen increased further when Tween 80 was included in addition to beta-CD, suggesting that a micelle formation in the presence of Tween 80 was the likely reason for additional increase. Furthermore, the data suggested that Tween 80 did not interfere with the inclusion interaction between flurbiprofen and beta-CD. The solubility of flurbiprofen was the highest in the mixed system containing 1.3 mM beta-CD and 0.3% w/v Tween 80, and the maximum solubility of 160 microg/mL was achieved. Consistent with the enhanced solubility, the plasma exposure (both AUC and Cmax) of flurbiprofen when dosed as the mixed system was significantly higher (as much as 2 to 3-fold) than that without surfactant or beta-CD, with surfactant alone, or with beta-CD alone. Therefore, the mixed system consists of surfactant and beta-CD could be used as an effective oral dosage form to improve bioavailability of poorly water soluble drugs such as flurbiprofen.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Flurbiprofen/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Biological Availability , Drug Carriers , Flurbiprofen/administration & dosage , Kinetics , Male , Micelles , Polysorbates , Powders , Rats , Rats, Sprague-Dawley , Solubility , Solutions , Surface-Active Agents/chemistry , beta-Cyclodextrins/chemistry
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