[Self-assembly and in vitro and in vivo evaluation of spherical crystallized interferon for sustained delivery].

It is a challenging and important project to prolong the in vivo half life of protein and peptide drugs by physicochemical methods without new molecular entities generation. Protein crystallization provides a new strategy for improving the stability and in vivo delivery of these drugs. We show here that recombinant human interferon-alpha (rhIFN) can form spherical crystals. The physical and chemical features of the crystals were characterized, and drug dissolution was determined in vitro. The pharmacokinetics of crystallized interferon after sc injection in rabbit at 1.5 x 10(7) U x kg(-1) was compared to that of soluble form. The crystals were characterized as mono-dispersed spheres, with yield of > 80%, mean diameter size of about 16 microm and crystallinity of 23.2%. The in vitro dissolution behavior of crystallized rhIFN was featured as low initial burst release (21% within the first 2 h) and prolonged cumulative dissolution time up to 72 h without biological potency lost. After sc administration of soluble and crystallized interferon in rabbits, the peak time (T(max)) and half life (t1/2) were prolonged from (1.80 +/- 0.45) h and (1.35 +/- 0.35) h to (13.20 +/- 2.68) h and (10.68 +/- 1.97) h, respectively. The corresponding peak concentration decreased from (1 411.10 +/- 575.28) U x mL(-1) to (721.37 +/- 206.55) U x mL(-1). PK/PD analysis indicated that (96.87 +/- 20.30) % of relative bioavailability was obtained. The research results of this work will provide important academic value and application prospect for improving clinical therapeutic effect and development of biomacromolecules delivery system for protein and peptide drugs.

An investigation on intestinal absorption of a new anticancer drug, 2-methoxyestradiol.

In this paper, the intestinal absorptive property of a new anticancer drug, 2-methoxyestradiol (2ME2) was investigated by in situ rat intestinal recirculation perfusion experimental techniques. The results indicated that the concentrations of 2ME2 had no influence on absorption rate constant (ka) of 2ME2 and the small intestinal absorption of 2ME2 was a first-order process with passive diffusion mechanism within the concentration tested. 2ME2 was well absorbed at each intestinal segment except duodenum and the best site of intestinal absorption of 2ME2 was the ileum. In addition, the PH of drug perfusate and the concentration of SDS had significant effects on absorption kinetics. Faintly basic environment profitted small intestinal absorption of 2ME2. Tween 80 and SDS could not enhance the intestinal absorption of 2ME2. The above study provided a theoretical foundation for developing effective oral preparations with higher bioavailability to treat cancers. In addition, the improved ligation way for studying the best site of intestinal absorption of 2ME2, should be used extensively in related studies because of decreasing number of experimental rats and saving time.

[Progress in the development of crystallized proteins as drug delivery system].

Crystallization has been widely applied in pharmaceutical formulations as an effective approach to improve the stability and efficacy of small agents. However protein crystals are suffered from limitation in the drug delivery system due to their complex crystallization behaviors. With development of crystallization technologies and their industrial application, protein crystals are receiving more and more attentions as a novel delivery system for biomacromolecules. Crystals with thermodynamic stable structure can improve the physical and chemical stability of protein drugs and present a sustained release behavior. On the basis of pertinent literatures, this review introduces the recent research situation and development process of protein crystals as drug delivery system. Moreover, the crystallization process of proteins, as well as the preparation and potential application are discussed systematically.

Studies on PEG-modified SLNs loading vinorelbine bitartrate (I): preparation and evaluation in vitro.

In this study, the conjugate of PEG2000-stearic acid (PEG2000-SA) was used to prepare PEGylated solid lipid nanoparticles loading vinorelbine bitartrate (VB-pSLNs) by cold homogenization technique. The particle size and zeta potential of resulted VB-pSLNs ranged 180-250nm and 0-10mV, which were determined using a Zetasizer, respectively. Although the drug entrapment efficiency (EE) slightly decreased after the PEG modification of VB-SLNs, above 60 % EE could be reached. The drug release tests in vitro indicated the faster drug release from VB-pSLNs than that from VB-SLNs without PEG modification. To investigate the cellular uptake of VB-pSLNs, the chemical conjugate of octadecylamine-fluorescein isothiocynate (FITC-ODA) was synthesized, and was used as a fluorescence marker to incorporate into nanoparticles. The results from cellular uptake indicated that the phagocytosis of VB-pSLNs by RAW264.7 cells was inhibited effectively by the PEG modification of SLNs, while the uptake by cancer cells (MCF-7 and A549) could be improved significantly. The assay of anticancer activity in vitro demonstrated that the anticancer activity of VB was significantly enhanced by the encapsulation of SLNs and pSLNs due to the increased cellular internalization of drug. The results suggested that SLNs and pSLNs could be excellent carrier candidates to entrap VB for tumor chemotherapeutics.

Preparation of insulin loaded PLGA-Hp55 nanoparticles for oral delivery.

The aim of the present work was to investigate the preparation of PLGA nanoparticles (PNP) and PLGA-Hp55 nanoparticles (PHNP) as potential drug carriers for oral insulin delivery. The nanoparticles were prepared by a modified emulsion solvent diffusion method in water, and their physicochemical characteristics, drug release in vitro and hypoglycemic effects in diabetic rats were evaluated. The particle sizes of the PNP and PHNP were 150+/-17 and 169+/-16 nm, respectively, and the drug recoveries of the nanoparticles were 50.30+/-3.1 and 65.41+/-2.3%, respectively. The initial release of insulin from the nanoparticles in simulated gastric fluid over 1 h was 50.46+/-6.31 and 19.77+/-3.15%, respectively. The relative bioavailability of PNP and PHNP compared with subcutaneous (s.c.) injection (1 IU/kg) in diabetic rats was 3.68+/-0.29 and 6.27+/-0.42%, respectively. The results show that the use of insulin-loaded PHNP is an effective method of reducing serum glucose levels.

Enhanced immune responses induced by vaccine using Sendai virosomes as carrier.

Sendai virosomes can deliver encapsulated contents into the cytoplasm directly in a virus fusion-dependent manner. In this paper, Sendai virosomes-formulated melanoma vaccine was constructed and its anti-tumor effects were investigated. The melanoma vaccine was prepared by encapsulating mixture antigen into the Sendai virosomes. The antigen, mixture proteins were extracted from B(16) melanoma cells. The cytotoxic T lymphocyte (CTL) response level was evaluated by (51)Cr release method, and the change of CD4(+) and CD8(+) expression as well as the concentration of IgG in serum of immunized mice was measured. The results showed that Sendai virosomes-formulated melanoma vaccine can effectively elicit not only systemic immune response but also strong CTL response. Sendai virosomes can be used as an effective vector for use in anti-tumor vaccine therapy.

Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation.

An improved PEGylated liposomal formulation of paclitaxel has been developed with the purpose of improving the solubility of paclitaxel as well as the physicochemical stability of liposome in comparison to the current Taxol formulation. The use of 3% (v/v) Tween 80 in the hydration media was able to increase the solubility of drug. The addition of sucrose as a lyoprotectant in the freeze-drying process increased the stability of the liposome particles. There was no significant difference in the entrapment efficiency of paclitaxel between the conventional non-PEGylated liposomes and our PEGylated liposomes. Cytotoxicity in human breast cancer cell lines (MDA-MB-231 and SK-BR-3) of our paclitaxel formulation was less potent compared to Taxol after 24h incubation, but was equipotent after 72 h due to the slower release of drug from the liposome. Our PEGylated liposomes increased the biological half-life of paclitaxel from 5.05 (+/-1.52)h to 17.8 (+/-2.35)h compared to the conventional liposomes in rats. Biodistribution studies in breast cancer xenografted nude mouse model showed that our liposomes significantly decreased the uptake in reticuloendothelial system (RES)-containing organs (liver, spleen and lung) while increasing the uptake in tumor tissues after injection compared to Taxol or the conventional liposomal formulation. Moreover, the PEGylated liposome showed greater tumor growth inhibition effect in in vivo studies. Therefore, our PEGylated liposomal formulation of paclitaxel could serve as a better alternative for the passive targeting of human breast tumors.

Liposome formulation of paclitaxel with enhanced solubility and stability.

Despite its strong antitumor activity, paclitaxel (Taxol) has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by Cremophor EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol, a paclitaxel incorporated liposome has been constructed to improve solubility and physicochemical stability. The effect of various components of the liposome, including cholesterol and lipid, on the solubility and entrapment efficiency (EE) of paclitaxel was systematically investigated. The results showed that 5% (v/v) of polyethylene glycol 400 in the hydration medium of liposome significantly increased the solubility (up to 3.39 mg/mL) as well as the EE and the paclitaxel content in the liposome formulation composed of 10% (w/v) of S(100)PC with cholesterol (cholesterol-to-lipid molar ratio = 10:90). When sucrose (sugar-to-lipid molar ratio = 2.3) was added as a lyoprotectant during the freeze-drying of the liposome, physicochemical stability of liposome was significantly improved. Moreover, the cytotoxicity of the final liposome formulation against MDA-MB-231 human breast cancer cell line was not significantly different from that of Taxol. The enhanced aqueous solubility as well as the physicochemical stability of paclitaxel in the liposome formulation developed in this study could be a safer and effective alternative to the Cremophor EL and ethanol formulation.

Pharmacodynamic comparison of prostaglandin E1 administered by different routes to rats.

The pharmacodynamics of prostaglandin E1 (PGE1) administered by different routes to rats was investigated in this paper. The hypotensive effect of PGE, was used as an index of drug efficacy, pharmacodynamic parameters such as time to reach peak effect (Tmax), maximal percentage of blood pressure decrease (Emax, %), duration of effect (Td), and the area under the blood pressure decrease percent-time curves (AUC, % x min) were determined after PGE1 given to rats intranasally, sublingually, intraperitoneally (ip), and intramuscularly (im), separately, and compared with those obtained from intravenous (iv) administration. Similar to iv route, the pharmacodynamic parameters of PGE1 from the other administration routes, Emax, Td and in particular AUC values were all increased with increasing doses, showing dose-efficacy relationship. Tmax was found to be approximately 3-4 min for nasal route, 3-8 min for im, 6-8 min for ip and 12-30 min for sublingual route, separately. Thus, the order of magnitude of absorption rate of the drug was as follows: nasal approximately = im > ip > sublingual. If the pharmacological bioavailability (PF) for each administration route was used as a tentative measure of drug absorption extent, the order of magnitude of absolute bioavailability appeared as follows: nasal > im approximately = ip > sublingual. Furthermore, the interindividual difference was found to be larger for im and ip route than that for nasal and sublingual route. These results indicate nasal and sublingual routes are two promising routes for the systemic delivery of PGE1 in clinical applications.

Preparation of roxithromycin-polymeric microspheres by the emulsion solvent diffusion method for taste masking.

Microspheres of roxithromycin with Eudragit S100 and silica were prepared by the emulsion solvent diffusion method to mask the bitter taste of the antibiotic. The effect of different polymers and drug-polymer ratios on the taste masking and the characteristics of the microspheres were investigated. It was found that Eudragit S100 was the best for masking the unpleasant taste of roxithromycin among the six kinds of polymers investigated. The results of DSC, X-ray diffraction and IR showed that there were several combinations of roxithromycin and Eudragit S100. The influence of other formulation factors, i.e. dichloromethane-acetone ratios and silica-polymer ratios on the properties of the microspheres were also examined. In conclusion, the results of the present study will be helpful for the preparation of oral forms of roxithromycin with an acceptable taste.

Study of the preparation of sustained-release microspheres containing zedoary turmeric oil by the emulsion-solvent-diffusion method and evaluation of the self-emulsification and bioavailability of the oil.

The purpose of this study was to design a sustained-release formulation of an oily drug. The sustained-release microspheres with self-emulsifying capability containing zedoary turmeric oil (ZTO) were prepared by the quasi-emulsion-solvent-diffusion method. The micromeritic properties, the efficiency of emulsification and the drug-release behavior of the resultant microspheres were investigated. The bioavailability of the microspheres was compared with conventional ZTO self-emulsifying formulations for oral administration using 12 healthy rabbits. An HPLC method was employed to determine the concentration of germacrone in plasma, which was used as an index of ZTO. Spherical and compacted microspheres with average diameters of 100-600 microm have been prepared, and their release behavior in distilled water containing 1.2% (w/v) of polysorbate-80 can be controlled by the ratio of polymer/Areosil200 in the microspheres. The resultant emulsions with mean droplet sizes of 200-500 nm are produced when the microspheres are immersed in phosphate buffer (pH 6.8) under gentle agitation. The stability and the droplet size of the resultant emulsions are also affected by the polymer/Areosil200 ratio in the formulation, while the amount of talc has a marked effect on the self-emulsifying rate. The plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the microspheres with a bioavailability of 135.6% with respect to the conventional self-emulsifying formulation (a good strategy for improving the bioavailability of an oily drug). In conclusion, the sustained-release microspheres with self-emulsifying capability containing ZTO have an improved oral bioavailability. Our study offers an alternative method for designing sustained-release preparations of oily drugs.

[Pharmacokinetic study of ketoprofen in rat by blood microdialysis technique].

AIM: To investigate the in vitro recovery and influencing factors of ketoprofen in microdialysis probe, and study the pharmacokinetic of unbound ketoprofen in rat after iv administration. METHODS: The recovery of ketoprofen was detected by a concentration difference method. After microdialysis probe was inserted into the jugular vein of male Wistar rats, the probe was infused with various concentrations perfusate. The in vivo recovery and the pharmacokinetics of unbound ketoprofen in rat were investigated. Dialysate samples were determined by HPLC. RESULTS: The recovery detected by gain was as the same as that by loss; the recovery was independent of the drug concentration surrounding the probe. The in vitro recovery was 28.75% by concentration difference method and the in vivo recovery was (40.3 +/- 2.7) % by retrodialysis method. After i.v. administration of ketoprofen in rat, T 1/2, AUC and CL of unbound ketoprofen were (181 +/- 16) min, (112 +/- 27) microg x min x mL(-1) and (0.22 +/- 0.05) L x min(-1), respectively. CONCLUSION: Microdialysis sampling can be used for the pharmacokinetic study of unbound ketoprofen in rat.

A HPLC method for the analysis of germacrone in rabbit plasma and its application to a pharmacokinetic study of germacrone after administration of zedoary turmeric oil.

A validated new, simple and highly sensitive reversed-phase HPLC method is developed for studying the pharmacokinetics of germacrone after intravenous administration of zedoary turmeric oil (ZTO) oil-in-water microemulsion. The method did not require a complex and expensive equipment. A high extraction recovery (>80%) of germacrone was obtained. Linear calibration curves obtained with the peak-area ratio (y) of germacrone to internal standard (tanshinoneIIA) versus drug concentration (x) were found to be linear between 8.08 and 808 ng/ml. The limit of quantitation was 8.08 ng/ml. The monitored compounds were completely separated from others in ZTO and from endogenous species in plasma by HPLC. Pharmacokinetic investigations were performed on 18 male rabbits after intravenous administration of ZTO microemulsion via the ear vein at germacrone doses of 3.2, 6.4 and 9.6 mg/kg. The plasma concentration-time data fit to a two-compartment intravenous model with a weight of 1/C(2) (C: germacrone concentration in plasma). Germacrone exhibited linear pharmacokinetics after intravenous administration of ZTO microemulsion to rabbits over the germacrone dose range 3.2-9.6 mg/ml.

Colon-specific drug delivery systems based on cyclodextrin prodrugs: in vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates.

AIM: To investigate the release of cyclodextrin-5-aminosalicylic acid (CyD-5-ASA) in cecum and colon. METHODS: An anti-inflammatory drug 5-ASA was conjugated onto the hydroxyl groups of alpha-, beta- and gamma-cyclodextrins (CyDs) through an ester linkage, and the in vivo drug release behavior of these prodrugs in rat's gastrointestinal tract after the oral administration was investigated. RESULTS: The 5-ASA concentration in the rat's stomach and small intestine after the oral administration of CyD-5-ASA conjugate was much lower than that after the oral administration of 5-ASA alone. The lower concentration was attributable to the passage of the conjugate through the stomach and small intestine without significant degradation or absorption, followed by the degradation of the conjugate site-specific in the cecum and colon. The oral administration of CyD-5-ASA resulted in lower plasma and urine concentration of 5-ASA than that of 5-ASA alone. CONCLUSION: CyD-5-ASA conjugates may be used as prodrugs for colon-specific drug delivery system.

Preparation of prostaglandin E1-hydroxypropyl-beta-cyclodextrin complex and its nasal delivery in rats.

The potential use of hydroxypropyl-beta-cyclodextrin (HP-betaCD) in the solubilization and stabilization of prostaglandin E(1) (PGE(1)) was investigated. The solubility and chemical stability of PGE(1) were significantly improved upon complexation with HP-betaCD. The nasal delivery of PGE(1) from the complex formulation was also studied in Wistar rats and compared with intravenous administration. PGE(1) complex after nasal administration caused a rapid decrease of blood pressure and exhibited an obvious dose-efficacy relationship, showing results nearly similar to those obtained for intravenous route. The time to reach the peak effect (T(max)) was approximately 3-4 min. Except T(max), other pharmacodynamic parameter values such as the maximal percent of blood pressure decrease (E(max), %), the lasting time of effect (T(d)), and the area under the curve (AUC, blood pressure decrease % min) were increased with increasing the administered doses. The E(max), T(d), and in particular AUC values between doses were significantly different (P < 0.01), but T(max) between doses were not significantly different (P < 0.05). The AUC values per unit dose of PGE(1) for nasal administration, however, were smaller than those for intravenous route, probably due to the incomplete absorption of nasally administered PGE(1). Besides, the in vitro effect of the PGE(1) complex on nasal mucociliary movement was also investigated with a toad palate model. The PGE(1) complex formulation exerted only minor effect on nasal mucociliary movement. These results indicate that the PGE(1)-HP-betaCD complex formulation for nasal delivery is a very promising preparation with advantages such as rapid and effective absorption, good chemical stability, ease of administration, and minor nasal ciliotoxicity.

A novel formulation design about water-insoluble oily drug: preparation of zedoary turmeric oil microspheres with self-emulsifying ability and evaluation in rabbits.

To enhance in vivo absorption of zedoary turmeric oil (ZTO) and develop new formulations of a water-insoluble oily drug, novel ZTO microspheres with self-emulsifying ability, called self-emulsifying microspheres here, were prepared in a liquid system by the quasi-emulsion solvent diffusion method. The microspheres containing hydroxypropyl methylcellulose acetate succinate (HPMCAS-LG), Talc and Aerosil 200 formed the stable surfactant-free emulsion when exposed to the pH 6.8 phosphate buffer, and were significantly different from the conventional self-emulsifying systems (SES), defined as isotropic mixtures of oil, surfactant and drug. Micromeritic properties, the efficiency of emulsification and the drug-release rate of the resultant microspheres were investigated. The bioavailability of the microspheres to the conventional self-emulsifying formulation for oral administration was evaluated in 12 healthy rabbits. A HPLC method was employed to determine the plasma concentration of Germacrone, an indexical component found in ZTO. The release rates of ZTO and Germacrone from the microspheres were enhanced significantly with increasing amounts of dispersing agents, and the efficiency of self-emulsification greatly depended on the HPMCAS-LG/Aerosil 200 ratio. The emulsion droplets released from the microspheres were much smaller than that of the conventional SES. The microsphere bioavailability (F) to the conventional SES for oral administration was 157.7%. Our method greatly improved the bioavailability of the water-insoluble oily drug from the self-emulsifying microspheres over the conventional SES and it is useful for the oily drug to form solid preparations.

[Preparation of solid lipid nanoparticles loaded with all-trans retinoic acid and their evaluation in vitro and in vivo].

AIM: To prepare solid lipid nanoparticles (SLN) loaded with all trans retinoic acid using an ultrasonic technique with Compritol 888 ATO as matrix material, and investigate properties of nanoparticles in vitro and in vivo. METHODS: Ultrasonic technique was adopted to prepare solid lipid nanoparticles in an aqueous system using all-trans retinoic acid (ATRA) as a model drug. Physicochemical proterties of SLN were investigated in detail. Drug release from two sorts of ATRA-SLN was investigated using a dialysis bag method. Compared with ATRA solution, the in vivo pharmacokinetics of two sorts of ATRA-SLN after intravenous injection to rats were studied. RESULTS: Solid lipid nanoparticles loaded with all-trans retinoic acid was readily and quickly prepared by ultrasonic technique. The morphological investigation by Transmission Electron Microscopy (TEM) showed that the particles had round and uniform shapes. The mean diameters of them were (158 +/- 9) nm and (89 +/- 11) nm separately. The SLN dispersion was stable at 4 degrees C for more than one year. Drug loading was 3.3%, drug entrapment efficiency was more than 95%, the in vitro release was well in accordance with Weibull distribution. Compared with ATRA control solution, SLN could stay in the blood circulation for a longer time after intravenous injection. CONCLUSION: The ultrasonic technique was appropriate for the preparation of solid lipid nanoparticles.

Preparation of enteric microsphere of oleanolic acid dihemiphthalate sodium by salting-out action using spherical crystallization technique.

AIM: Enteric microspheres were prepared to prevent the interaction of drug with gastric acid and to improve its bioavailability. METHODS: The enteric microspheres with a matrix structure were successfully produced using a spherical crystallization technique. Hydroxypropyl methylcellulose phthalate (HP-55), an enteric material, was coprecipitated with the drug by salting-out effect during the preparation process. A mixture of water and ethanol was chosen as a good solvent and dichloromethane was used as a bridging agent while 0.1 mol x L(-1) sodium chloride solution was selected as a poor solvent. RESULTS: It is the first time to prepare microspheres by making the water-soluble drug and water-insoluble excipient coprecipitated. In vivo test demonstrated that the drug absorption from the enteric oleanolic acid dihemiphthalate sodium (OADHPS) microspheres was significantly prolonged compared to that with OADHPS powder after a lag-time. Furthermore, the drug bioavailability was 181.6% greater than that with the OADHPS powder. CONCLUSION: The microspheres of water soluble drug could be prepared by using water phase replacing organic phase as poor solvent which decrease the quantity of organic solvent and benefit the environment prevention.

Bioadhesive polysaccharide in protein delivery system: chitosan nanoparticles improve the intestinal absorption of insulin in vivo.

There are many ongoing investigations to improve the oral bioavailability of peptide and protein formulations. Bioadhesive polysaccharide chitosan nanoparticles (CS-NPs) would seem to further enhance intestinal absorption of them. In this study, Insulin-loaded CS-NPs were prepared by ionotropic gelation of CS with tripolyphosphate anions. Its particle size distribution and zeta potential were determined by photon correction spectroscopy and laser Dopper anemometry. The ability of CS-NPs to enhance intestinal absorption of insulin and increase the relative pharmacological bioavailability of insulin was investigated by monitoring the plasma glucose level of alloxan-induced diabetic rats after oral administration of various doses of insulin-loaded CS-NPs. CS-NPs had a particle size in the range of 250-400 nm and its polydispersity index was smaller than 0.1, positively charged, stable. Insulin association was found up to 80% and its in vitro release showed a great initial burst with a pH-sensitivity property. CS-NPs enhanced the intestinal absorption of insulin to a greater extent than the aqueous solution of CS in vivo. Above all, after administration of 21 I.U./kg insulin in the CS-NPs, the hypoglycemia was prolonged over 15 h and the average pharmacological bioavailability relative to SC injection of insulin solution was up to 14.9%.

Preparation of sustained-release nitrendipine microspheres with Eudragit RS and Aerosil using quasi-emulsion solvent diffusion method.

Sustained-release nitrendipine microspheres were prepared in liquid system by quasi-emulsion solvent diffusion method, in which the Aerosil was employed as an inert dispersing carrier to improve the dissolution rate of nitrendipine, and Eudragit RS as a retarding agent to control the release rate. The resultant microspheres were evaluated for the recovery, bulk density, average particle size, drug loading, and incorporation efficiency. And the factors affecting the formation of microspheres and the drug-release rate were investigated. It was observed by a scanning electron microscope (SEM) that the microspheres were finely spherical and uniform, and no entire nitrendipine crystals were observed visually. The results of X-ray diffraction indicated that nitrendipine in microspheres was disordered, suggesting that nitrendipine was highly dispersed in microspheres. The drug loading of microspheres was enhanced with increasing the ratio of drug to excipients, and the incorporation efficiency was always >90%. The formation of microspheres was mainly influenced by the amount of bridging liquid and sodium dodecyl sulfate (SDS) in poor solvent. The dissolution profiles could be modulated with adjusting the amount of retarding agent and dispersing carrier formulated.