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.

Preparation and in vitro evaluation of pH, time-based and enzyme-degradable pellets for colonic drug delivery.

The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3-4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.

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 PGE1 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 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≈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≈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 enteric microsphere of oleanolic acid dihemiphthalate sodium by salting-out action using spherical crystallization technique / 药学学报

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 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.

Simultaneous release of index components in Gegen Qinlian Pellets / 中草药

Objective To obtain the same release rate of four index components with significant difference of physicochemical characters,puerarin,baicalin berberine and glycyrrhizin in Gegen Qinlian Pellets.Methods Studies on improving the release rate of less soluble components in Gegen Qinlian Pellets were carried out and the parameters were optimized.The release profiles were analyzed by simulating factor(f_2).Results The f_2 values for baicalin,berberine and glycyrrhizin vs puerarin were 52.27,56.13,and 75.1,respectively.Conclusion The result shows that the same release rate of four index components in Gegen Qinlian Pellets is obtained.

Preparation of Gegen Qinlian Pellets by extrusion-spheronization method / 中草药

Objective To prepare Gegen Qinlian Pellets with higher yield of drug loading and being good for industrial production.Methods The Gegen Qinlian Pellets were prepared by extrusion-spheronization.The effects of four key parameters on spheronization process were the proportion of bond,extrusion speed,spheronisation speed,and spheronisation time,which were investigated to obtain optimal formulation.Results Gegen Qinlian Pellets presented perfect sphericity and narrow diameter distribution.Drug loading in the pellets could be up to 70% and yelid over 90%.Conclusion The Gegen Qinlian Pellets are successfully prepared by extrusion-spheronization.It presents a method for industria-lized production of Chinese materia medica.

Determination of Zedoary turmeric oil microsphere / 中成药

AIM: To study a method for the determination of Zedoary turmeric oil microsphere (ZTO-MS). METHODS: ZTO-MS was extracted supersonically by solvent and then colored by sulfuric acid-vanillin reagent. The absorbance was measured by visible-spectrophotometry at 508nm. At the same time, ZTO-MS also could be determined by HPLC. RESULTS: The content of Zedoary turmeric oil was above 60% and the contents of Curdione、Curcuma、Germacrone were 6.88%,0.95%,5.0%, respectively, in ZTO-MS. CONCLUSION: Two methods for the determination of ZTO-MS are accurate, reliable; the method of visible-spectrophotometry is convenient and appropriate for determination for content of oil in ZTO-MS, while the method of HPLC gains the advantage for qualitative and quantitative analysis of components in ZTO-MS.

Study on Preparation and Stability of the Solid Dispersion of Radix Arnebiae seu Lithospermi / 中成药

Objective: To enhance the dissolution rate in vitro and bioavailability in vivo of the active components of extraction of Radix Arnebiae seu Lithospermi. Methods: Solid dispersion of extract of Radix Arnebiae seu Lithospermi were prepared with solid dispersion technology, X ray diffraction and stability experiments were also carried out. Results: The dissolution rates in vitro of the active components of extraction of Radix Arnebiae seu Lithospermi solid dispersion were obviously raised and stable, and the solid dispersion was not easy to age. Conclusion: The dissolution rate in vitro of the active components in Radix Arnebiae seu Lithospermi can be inproved greatly by the solid dispersion using PVP and HPMC as a carrier.