The purpose of this study was to determine the feasibility of applying accelerated in vitro release testing to correlate or predict long-term in vitro release of leuprolide poly(lactideco-glycolide) microspheres. Peptide release was studied using a dialysis technique at 37°C and at elevated temperatures (50°C-60°C) in 0.1M phosphate buffered saline (PBS) pH 7.4 and 0.1M acetate buffer pH 4.0. The data were analyzed using a modification of the Weibull equation. Peptide release was temperature dependent and complete within 30 days at 37°C and 3 to 5 days at the elevated temperatures. In vitro release profiles at the elevated temperatures correlated well with release at 37°C. The shapes of the release profiles at all temperatures were similar. Using the modified Weibull equation, an increase in temperature was characterized by an increase in the model parameter, α, a scaling factor for the apparent rate constant. Complete release at 37°C was shortened from 30 days to 5 days at 50°C, 3.5 days at 55°C, 2.25 days at 60°C in PBS pH 7.4, and 3 days at 50°C in acetate buffer pH 4.0. Values for the model parameter β indicated that the shape of the release profiles at 55°C in PBS pH 7.4 (2.740) and 50°C in 0.1M acetate buffer pH 4.0 (2.711) were similar to that at 37°C (2.677). The E a for hydration and erosion were determined to be 42.3 and 19.4 kcal/mol, respectively. Polymer degradation was also temperature dependent and had an E a of 31.6 kcal/mol. Short-term in vitro release studies offer the possibility of correlation with long-term release, thereby reducing the time and expense associated with longterm studies. Accelerated release methodology could be useful in the prediction of long-term release from extended release microsphere dosage forms and may serve as a quality control tool for the release of clinical or commercial batches.

This study suggests that KSL-W could be used as an antiplaque agent in a chewing gum formulation.

No abstract

The objective of this study was to characterize the stability of KSL-W, an antimicrobial decapeptide shown to inhibit the growth of oral bacterial strains associated with caries development and plaque formation, and its potential as an antiplaque agent in a chewing gum formulation. KSL-W formulations with or without the commercial antibacterial agent cetylpyridinium chloride (CPC) were prepared. The release of KSL-W from the gums was assessed in vitro using a chewing gum apparatus and in vivo by a chew-out method. A reverse-phase high-performance liquid chromatography method was developed for assaying KSL-W. Raw material stability and temperature and pH effects on the stability of KSL-W solutions and interactions of KSL-W with tooth-like material, hydroxyapatite discs, were investigated. KSL-W was most stable in acidic aqueous solutions and underwent rapid hydrolysis in base. It was stable to enzymatic degradation in human saliva for 1 hour but was degraded by pancreatic serine proteases. KSL-W readily adsorbed to hydroxyapatite, suggesting that it will also adsorb to the teeth when delivered to the oral cavity. The inclusion of CPC caused a large increase in the rate and extent of KSL-W released from the gums. The gum formulations displayed promising in vitro/in vivo release profiles, wherein as much as 90% of the KSL-W was released in a sustained manner within 30 minutes in vivo. These results suggest that KSL-W possesses the stability, adsorption, and release characteristics necessary for local delivery to the oral cavity in a chewing gum formulation, thereby serving as a novel antiplaque agent.

In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the in vitro profile lagged slightly behind in vivo release, but the results were not statistically significant (P < 0.0001). Using the four formulations that exhibited different release rates, a Level A IVIVC was established using the deconvolution and fractional AUC approaches. A nearly 1 : 1 correlation (R 2 > 0.96) between in vitro release and in vivo measurements confirmed the excellent relationship between in vitro drug release and the amount of drug absorbed in vivo. The results of this study suggest that proper selection of an in vitro method will greatly aid in establishing a Level A IVIVC for long acting injectables.

The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug.

No abstract

The objective of this study was to compare the in vitro behavior of four long-acting subcutaneous risperidone formulations with in vivo performance, with the intent of establishing an IVIVC. Two copolymers of PLGA (50:50 and 75:25) were used to prepare four microsphere formulations of risperidone, an atypical antipsychotic. In vitro behavior was assessed at the physiological temperature (37 °C) using the ‘modified dialysis’ technique. The in vitro release profile demonstrated rank order behavior with Formulations A and B, prepared using the 50:50 copolymer, exhibiting rapid drug release, while Formulations C and D, prepared using 75:25 PLGA, released drug in a slower manner. In vivo profiles were obtained by two approaches, i.e., deconvolution using the Nelson–Wagner equation (the FDA recommended approach) and using fractional AUC. With both in vivo approaches, the 50:50 PLGA preparations released drug faster than the 75:25 PLGA microspheres, exhibiting the same rank order observed in vitro. Additionally, profiles for the four formulations obtained using the deconvolution approach were nearly superimposable with fractional AUC, implying that the latter procedure could be used as a substitute for the Nelson–Wagner method. A comparison of drug release profiles for the four formulations revealed that in three of the four formulations, in vivo release was slightly faster than that in vitro, but the results were not statistically significant (P > 0.0001). An excellent linear correlation (R2 values between 0.97 and 0.99) was obtained when % in vitro release for each formulation was compared with its corresponding in vivo release profile, obtained by using fraction absorbed (Nelson–Wagner method) or fractional AUC. In summary, using the four formulations that exhibited different release rates, a Level A IVIVC was established using the FDA-recommended deconvolution method and fractional AUC approach. The excellent relationship between in vitro drug release and the amount of drug absorbed in vivo in this study was corroborated by the nearly 1:1 correlation (R2 greater than 0.97) between in vitro release and in vivo performance. Thus, the results of the current study suggest that proper selection of an in vitro method to assess drug release from long-acting injectables will aid in obtaining a Level A IVIVC.