[Preparation and evaluation of risperidone-loaded microsphere/sucrose acetate isobutyrate in situ forming complex depot with double diffusion barriers].

In the present study, a risperidone loaded microsphere/sucrose acetate isobutyrate (SAIB) in situ forming complex depot was designed to reduce the burst release of SAIB in situ forming depot and to continuously release risperidone for a long-term period without lagime. The model drug risperidone (Ris) was first encapsulated into microspheres and then the Ris-microspheres were embedded into SAIB depot to reduce the amount of dissolved drug in the depot. The effects of different types of microsphere matrix, including chitosan and poly(lactide-coglycolide) (PLGA), matrix/Ris ratios in microspheres and morphology of microspheres on the drug release behavior of complex depot were investigated. In comparison with the Ris-loaded SAIB depot (Ris-SAIB), the complex depot containing chitosan microspheres (in which chitosan/Ris = 1 : 1, w/w) (Ris-Cm-SAIB) decreased the burst release from 12.16% to 5.80%. However, increased drug release rate after 4 days was observed in Ris-Cm-SAIB, which was caused by the high penetration of the medium to Ris-Cm-SAIB due to the hydrophilie of chitosan. By encapsulation of risperidone in PLGA microspheres, most drugs can be prevented from dissolving in the depot and meanwhile the hydrophobic PLGA can reduce the media penetration effect on the depot. The complex depot containing PLGA microspheres (in which PLGA/ drug=4 : 2, w/w) (Ris-Pm-SAIB) showed a significant effectiveness on reducing the burst release both in vitro and in vivo whereby only 0.64% drug was released on the first day in vitro and a low AUC0-4d value [(105.2± 24.4) ng.mL-1.d] was detected over the first 4 days in vivo. In addition, drug release from Ris-Pm-SAIB can be modified by varying the morphology of microspheres. The porous PLGA microspheres could be prepared by adding medium chain triglyceride (MCT) in the organic phase which served as pore agents during the preparation of PLGA microspheres. The complex depot containing porous PLGA microspheres (which were prepared by co-encapsulation of 20% MCT) (Ris-PPm-SAIB) exhibited a slightly increased AUC0-4d of (194.6±15.8) ng.mL-1d and high plasma concentration levels from 4 to 78 days [Cs(4-78d)=(7.8±1.2) ng.mL-1]. The plasma concentration on 78 day C78d was (9.0 2.5) ng.mL-1 which was higher than that of Ris-Pm-SAIB [C78d= (1.6 ± 0.6) ng.mL-1]. In comparison with Ris-Pm-SAIB, the AUC4-78d of Ris-PPm-SAIB increased from (379.0±114.3) ng.mL-1.d to (465.0 ±149.2) ng.mL-1.d, indicating sufficient drug release from the Ris-PPm-SAIB. These results demonstrate that the risperidone loaded porous PLGA microsphere/SAIB in situ forming complex depot could not only efficiently reduce the burst release of SAIB depot both in vitro and in vivo, but also release the drug sufficiently in vivo, and be capable to continuously release the drug for 78 days.

[Effect of local injection of rhTGF-α1 on osteoclasts during orthodontic tooth movement in rats].

PURPOSE: To investigate the effect of exogenous TGF-ß1 on improving periodontal tissues remodeling during orthodontic tooth movement in rats. METHODS: Eighty male SD rats were randomly divided into 2 groups. Rats in the experimental group were injected respectively with rhTGF-ß1 in dosages of 0.1 mL (5 ng/mL) in the buccal submucosal area of the molar every other day, while rats in the control group received equivalent volumes of PBS. Each group (n=40) was subdivided equally into 5 subgroups. An orthodontic appliance, consisting of a 5 mm nickel titanium closed coil spring, was ligated between the maxillary left incisor and first molar of each rat to deliver an initial force of 0.49N. Eight rats in each subgroup were sacrificed at one of the five time points (1, 4, 7, 10 and 14 days) after appliance placement. The distance of the tooth movement was measured by using stereomicroscope. Tissue sections around the first maxillary left molar were stained with tartrate-resistant acid phosphatase (TRAP) histochemistry to analyze the changes of the amount and distribution of osteoclasts on the compression side of tooth. Statistical analysis was performed using SPSS 17.0 software package. RESULTS: Molars treated with rhTGF-ß1 moved mesially more rapidly than the control group. The distance of tooth movement of the experimental group showed a significant increase compared with the control group at day 7 (P<0.05) and significant increase compared with the control group at day 10 and 14 (P<0.01). The number of TRAP positive cells appearing in the periodontal ligament space on the pressure side of the alveolar bone were increased markedly in experimental group. There were statistically significant differences in the amount of osteoclasts between experimental and control groups (P<0.01). CONCLUSIONS: Local injection of rhTGF-ß1 in the periodontal tissues can accelerate orthodontic tooth movement via enhancing the numbers of osteoclasts. At the histologic level, increased numbers of mononuclear osteoclasts are recruited and activated, resulting in greater amounts of alveolar bone resorption on the pressure side of the periodontal ligament.

Multivesicular liposome formulations for the sustained delivery of interferon alpha-2b.

AIM: To develop and optimize a sustained release multivesicular liposome (MVL) formulation of interferon (IFN) alpha-2b. METHODS: IFN alpha-2b MVL were prepared using a typical double-emulsion procedure. The sustained release effects of IFN alpha-2b MVL were investigated by monitoring the blood IFN alpha-2b concentration using an enzyme-linked immunosorbent assay test after subcutaneous administration to healthy mice. RESULTS: IFN alpha-2b was successfully encapsulated in MVL with high efficiency, and the integrity of encapsulated protein was maintained. After subcutaneous injection, the MVL slowly released IFN alpha-2b into systemic circulation in a sustained manner. The estimated serum half-life of IFN alpha-2b was approximately 30 h. In addition, varying the size of the MVL preparations could further modify the in vivo release profile. CONCLUSION: IFN alpha-2b MVL may be a useful sustained release formulation in the clinical treatment of viral diseases.

Conjugate of bovine hemoglobin and human serum albumin as a candidate for blood substitute: characteristics and effects on rats.

Conjugate of bovine hemoglobin (bHb) and human serum albumin (HSA) was prepared. The product was simply composed of 89.7% one-to-one Hb-HSA conjugate, 6.0% oligomer of Hb and HSA, 3.5% unconjugated HSA and 0.8% unconjugated Hb, with an average molecular weight of 157 kD. The physicochemical characteristics were determined. Effects of single replacement on blood pressure and long-term survival of rats with 30% and 60% acute blood loss were studied, in comparison with Ringer-lactate solution, stroma-free hemoglobin (SFHb), 5% HSA in Ringer-lactate, whole blood and no resuscitation fluid. Results showed that Hb-HSA conjugate maintained the mean arterial pressure of rats to initial level with no pressor effect. Long-term effects of the replacement fluids on 30% bleeding rats showed that, for the group infused with Hb-HSA conjugate, histology of five major organs, heart, kidney, liver, spleen and lung, were essentially normal, similar to that of whole blood, while obviously renal side-effects appeared in other groups. The efficacy of the conjugate was further demonstrated by the resuscitation of lethal hemorrhagic shock rats (60% acute blood loss) with 100% survival rate (followed for 14 days), the same result as whole blood. The Hb-HSA conjugate can thus be another candidate for blood substitute in emergency.