Self-assembly and in vitro and in vivo evaluation of spherical crystallized interferon for sustained delivery / 药学学报

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.

Progress in the development of crystallized proteins as drug delivery system / 药学学报

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.

Pharmacodynamic comparison of prostaglandin E1 administered by different routes to rats / 药学学报

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.

Pharmacokinetic study of ketoprofen in rat by blood microdialysis technique / 药学学报

<p><b>AIM</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>Microdialysis sampling can be used for the pharmacokinetic study of unbound ketoprofen in rat.</p>

Preparation of enteric microsphere of oleanolic acid dihemiphthalate sodium by salting-out action using spherical crystallization technique / 药学学报

<p><b>AIM</b>Enteric microspheres were prepared to prevent the interaction of drug with gastric acid and to improve its bioavailability.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>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.</p>

Preparation of solid lipid nanoparticles loaded with all-trans retinoic acid and their evaluation in vitro and in vivo / 药学学报

<p><b>AIM</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>The ultrasonic technique was appropriate for the preparation of solid lipid nanoparticles.</p>

Evaluation of in vitro/in vivo correlation for three kinds of self-designed sustained-release nitrendipine formulations using deconvolution method / 药学学报

<p><b>AIM</b>To evaluate the in vitro/in vivo correlation for three kinds of self-designed sustained-release nitrendipine formulations using deconvolution method.</p><p><b>METHODS</b>The characteristics of in vivo release were calculated by deconvolution method using the data of plasma concentration of three kinds of self-designed sustained-release nitrendipine formulations in healthy dogs, in which the in vivo results of nitrendipine solution after oral administrated to dogs were used as weight function. It was the compared with characteristics of in vitro release to assess the in vitro/in vivo correlations.</p><p><b>RESULTS</b>The good correlations of in vitro/in vivo were shown in three kinds of self-designed sustained-release nitrendipine formulations using deconvolution method.</p><p><b>CONCLUSION</b>The deconvolution method exhibited advantage in evaluation of in vitro/in vivo correlation for self-designed sustained-release nitrendipine formulations.</p>

The complexation of prostaglandin E1 with hydroxylpropyl-beta-cyclodextrin in aqueous solution / 药学学报

<p><b>AIM</b>To investigate the complexation of prostaglandin E1 (PGE1) with hydroxylpropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solutions, inclusion molar ratio of the host and guest molecules and change of thermodynamic parameters during the complexation process.</p><p><b>METHODS</b>The measurements of the complexation mechanism, inclusion molar ratio of the host and guest molecules and change of thermodynamic parameters were carried out by the following methods separately: phase solubility method, UV absorption spectroscopy, circular dichroism spectroscopy, equimolar series method and thermodynamic method, respectively.</p><p><b>RESULTS</b>That all the phase solubility diagrams showed a typical AL-type in various pH buffered solutions, suggested the formation of a soluble complex of 1:1 molar ratio. Both UV absorption spectroscopy and circular dichroism spectroscopy confirmed that the significant interaction between the host and guest molecules was probably due to the inclusion of chromophore moiety of PGE1 molecule into the hydrophobic cavity of HP-beta-CD molecule. The change in the thermodynamic parameters suggested that the complexation could proceed spontaneously along with the release of heat and the decrease of entropy.</p><p><b>CONCLUSION</b>An 1:1 molar ratio inclusion complex of PGE1 with HP-beta-CD could be formed spontaneously and, hence, the solubility of PGE1 in aqueous solution increased. Appropriate temperature and suitable media pH probably favor the progress of complexation procedure.</p>

Absorption of zedoary oil in rat intestine using in situ single pass perfusion model / 药学学报

<p><b>AIM</b>To study the absorption of zedoary oil in intestine of rat.</p><p><b>METHODS</b>In situ single pass perfusion model was used and the concentrations of three components in perfusate were determined by HPLC in combination with diode array detection.</p><p><b>RESULTS</b>The P(app) s of curcumol, curdione and germacrone were all low and had no significant difference (P > 0.05) at zedoary oil concentration of 0.4, 0.8 and 1.2 mg x mL(-1) in transmucosal fluid or in four different regions of intestine of rat [duodenum, jejunum, ileum, colon]. The absorption rates of germacrone and curdione were faster than curcumol's in this study.</p><p><b>CONCLUSION</b>The zedoary oil concentration in transmucosal fluid had no significant effect on the P(app) s within the scope of 0.4-1.2 mg x mL(-1). The absorption of curcumol, curdione and germacrone showed the passive diffusion process, and didn't contain a special absorption window.</p>

Preparation of sustained-release nitrendipine microspheres with a solid dispersed structure in liquid system / 药学学报

<p><b>AIM</b>To prepare the sustained-release nitrendipine microspheres with a solid dispersed structure in liquid system.</p><p><b>METHODS</b>The sustained-release nitrendipine microspheres with a solid dispersed structure was prepared in liquid system by combining spherical crystallization technique and solvent deposition method in one step. The resultant microspheres were evaluated for the recovery, micromeritc properties, incorporation efficiency. The factors of effect on the formation and the release rate of microspheres were also investigated.</p><p><b>RESULTS</b>The recovery of microspheres (280-900 microns) was more than 70% and the bulk density was around 0.7 kg.L-1. The incorporation efficiency always exceeded 95%. The formation of microspheres was mainly affected by the amount of bridging liquid and the emulsifying agents in poor solvent. The release rate of nitrendipine from the microspheres could be controlled as desired by adjusting the ratio of talc to Eudragit RS PO in the formulation.</p><p><b>CONCLUSION</b>The presented method was suitable for preparing sustained-release microspheres of a water insoluble drug.</p>