Reducing burst release and enhancing sustained release in SAIB-based implants: The role of polyphenol-modification.

The purpose of this study was to develop an in situ forming SAIB (sucrose acetate isobutyrate)-PLGA (poly (d, lactide-co-glycolide)) mixture matrix depot for sustained release of risperidone. The factors affecting the risperidone release kinetics were investigated to obtain further insight into the drug release mechanisms. The burst release in vitro was significantly reduced (4.95%) by using DMSO as solvent. And, increasing the PLGA content from 2 to 10% w/w decreased the initial release from 6.95 to 1.05%. The initial release in vivo decreased with increasing PLGA content (2.0% w/w PLGA, C(max) = 1161.7 ± 550.2 ng ml(-1); 10% w/w PLGA, C(max) = 280.3 ± 98.5 ng ml(-1)). The persistence (AUC(4-20 days)) over 20 days increased from 76.8 ± 20.7 to 362.8 ± 75.0 ng d ml(-1) by inclusion of 10% PLGA compared with the PLGA-free depot. These results demonstrate that the SAIB-PLGA mixture matrix depot could be useful as a sustained delivery system for risperidone.

The focus of the present investigation was to develop amorphous glassy solutions (AGSs) of BCS Class II and IV drugs using sucrose acetate isobutyrate (SAIB). The drugs studied were rifaximin (RFX), dasatinib (DST), aripiprazole (APZ), dolutegravir (DLT), cyclosporine (CYS), itraconazole (ITZ), tacrolimus (TAC), sirolimus (SRL), aprepitant (APT), and carbamazepine (CBZ). AGSs were prepared by dissolving known quantity of the drug in the SAIB at 120 (TAC and APZ), 140 (CYS) or 150 oC (RFX, DST, DLT, ITZ, SRL, APT, and CBZ). They were characterized visually and by NIR, NIR hyperspectroscopy (NIR-H), and XRPD. Stability were determined by exposing open vials to 40 oC/75% RH for a week. AGSs behave like a glassy solid at room temperature and liquified above 60 oC. The solubility of APT, DLT, SRL, APZ, RFX, CBZ, TAC and CYS in SAIB was 0.4±0.0, 1.7±0.4, 1.9±0.0, 21.6±2.6, 36.4±0.9, 76.5±4.0, 115.1±2.3, and 239.0±12.6 mg/g, respectively. NIR, NIR-H, and XRPD data indicated the amorphous nature of the AGSs. Furthermore, AGSs were stable against devitrification on exposure to high temperature and humidity. In summary, SAIB can be employed to develop stable AGSs of poorly soluble drugs to increase dissolution, and oral bioavailability with the addition of hydrophilic excipients.

In prostate cancer, hormone therapy via leuprolide acetate drug (LUP) is used to lower the level of testosterone down to castration level to effectively control the development of prostate cancer. The objective of this study was to evaluate the effective parameters in degradation and controlled release of an injectable in situ formed polymeric implant, loaded with leuprolide acetate, in order to achieve an optimum formulation for sustained drug release for 90 days with minimum burst release. The main problem associating with such implants is their high burst release. Designing an injectable implant with sustained and minimum burst release has thus become an attractive challenge in drug delivery field. Effects of type of poly(lactic-co-glycolic acid) 75:25 copolymers (RG752, RG756) and addition of nano-hydroxyapatite (HA) particles on degradation rates of the implants and release profiles were examined in vitro and in vivo in a rabbit animal model. Results showed that implants containing polymers with higher molecular weights had significantly lower weight loss and molecular weight reduction. Adding nanoparticles of hydroxyapatite into poly(lactic-co-glycolic acid) implants caused further reduction in degradation rates, leading to a more sustained drug release in vivo, with reduced burst release. Different conventional kinetic models were applied to drug release and degradation data. The degradation data fit well to the first-order degradation model. Higuchi model was the best kinetic release model fitted to the experimental in vitro release data. This study led to an optimum formulation (RG756:RG752 3:1 + 5% HA) with sustained leuprolide release and testosterone suppression over a 90-day period with significant decrease of burst release phase (50%, p < 0.001) compared with the conventional Eligard formulation. The histopathology test showed that the formulated implant had no effects of toxicity or tissue necrosis in organs of the animal model. Copyright © 2017 John Wiley & Sons, Ltd.

A modified hydrophobic ion-pairing complex strategy for long-term peptide delivery with high drug encapsulation and reduced burst release from PLGA microspheres

Novel injectable progesterone-loaded nanoparticles embedded in SAIB-PLGA in situ depot system for sustained drug release

PLGA particles have been extensively used as a sustained drug-delivery system, but there are multiple drawbacks when delivering proteins. The focus of this work is to address the most significant disadvantages to the W/O/W double emulsion procedure and demonstrate that simple changes to this procedure can have significant changes to particle size and dispersity and considerable improvements to protein loading, activity and sustained active protein release. A systematic approach was taken to analyze the effects of the following variables: solvent miscibility (dichloromethane (DCM), ethyl acetate, acetone), homogenization speed (10 000–25 000 rpm), PLGA concentration (10–30 mg/ml) and additives in both the organic (sucrose acetate isobutyrate (SAIB)) and aqueous (bovine serum albumin (BSA)) phases. Increasing solvent miscibility decreased particle size, dispersity and protein denaturation, while maintaining adequate protein loading. Increasing solvent miscibility also lowered the impact of homogenization on particle size and dispersity and protein activity. Changes to PLGA concentration demonstrated a minimum impact on particle size and dispersity, but showed an inverse relationship between protein encapsulation efficiency and particle protein weight percent. Most particles tested provided sustained release of active protein over 60 days. Increasing solvent miscibility resulted in increases in the percent of active protein released. When subjected to synthesis conditions with DCM as the solvent, BSA as a stabilizer resulted in the maximum stabilization of protein at a concentration of 100 mg/ml. At this concentration, BSA allowed for increases in the total amount of active protein delivered for all three solvents. The benefit of SAIB was primarily increased protein loading.

The high initial burst release of a highly water-soluble drug from poly (D,L-lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) solvent extraction/evaporation method was reduced by coating with an additional polymeric PLGA layer. Coating with high encapsulation efficiency was performed by dispersing the core microparticles in peanut oil and subsequently in an organic polymer solution, followed by emulsification in the aqueous solution. Hardening of an additional polymeric layer occurred by oil/solvent extraction. Peanut oil was used to cover the surface of core microparticles and, therefore, reduced or prevented the rapid erosion of core microparticles surface. A low initial burst was obtained, accompanied by high encapsulation efficiency and continuous sustained release over several weeks. Reduction in burst release after coating was independent of the amount of oil. Either freshly prepared (wet) or dried (dry) core microparticles were used. A significant initial burst was reduced when ethyl acetate was used as a solvent instead of methylene chloride for polymer coating. Multiparticle encapsulation within the polymeric layer increased as the size of the core microparticles decreased (< 50 µm), resulting in lowest the initial burst. The initial burst could be controlled well by the coating level, which could be varied by varying the amount of polymer solution, used for coating.

Combined modeling and experimental approach for the development of dual-release polymer millirods

Hemodialysis graft coated with paclitaxel prevents stenosis; however, large initial burst release of paclitaxel causes many negative effects such as drug toxicity and inefficient drug loss. Therefore we developed and tested a novel coating method, double dipping, to provide controlled and sustained release of paclitaxel locally. Expanded polytetrafluoroethylene (ePTFE) grafts were dipped twice into a solution of several different paclitaxel concentrations. In vitro release tests of the double dipping method showed that early burst release could be somewhat retarded and followed by sustained release for a long time. We observed the effect of paclitaxel coating by double dipping in porcine model of arterio-venous (AV) grafts between the common carotid artery and the external jugular vein. 12 weeks after constructing AV grafts, cross sections of the graft venous anastomosis were obtained and analyzed. Paclitaxel coated ePTFE grafts by double dipping were observed to prevent neointimal hyperplasia and therefore reduced stenosis of the arteriovenous hemodialysis grafts, especially at the graft venous anastomosis sites. Our results demonstrate that second dipping of ePTFE graft, which was already coated once with paclitaxel, washes off the drug on a surface of the graft and affects the ratio of paclitaxel on the surface to that of the inner space, possibly by diffusion: thus the early burst of drug can be somewhat reduced.

Formulation of injectable In situ forming implant (ISI) systems of lornoxicam for dental and postoperative pain management to decrease dosing frequency and increase patient compliance. Polymeric in situ implant solutions were prepared using different concentrations and inherent viscosities of Poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG) using 22X4 factorial experimental design. Nonpolymeric systems were prepared using different concentrations of lipids like cetyl alcohol and stearyl alcohol and also sucrose acetate isobutyrate (SAIB) using 32 factorial experimental design. In vitro release study, rheological measurement, syringeability assessment and effect of γ-sterilization were used for evaluation of the prepared formulae. In vivo pharmacokinetic study of lornoxicam from the most optimum formula was conducted in a rabbit model using HPLC analysis of blood samples. Polymeric systems showed high burst release followed by very slow release rate over 72 hours. Formula I 24 (containing SAIB 80% (w/w)) showed relatively low burst release followed by diffusion controlled release pattern, low viscosity, Newtonian flow behavior and good syringeability. γ- sterilization had no significant effect on the in vitro release and the physical nature of the most optimum formula. In vivo study concluded that intramuscularly injected In situ implant formula I 24 showed prolonged release pattern compared to the marketed product which was indicated by the increased Tmax and the extended mean residence time. Lornoxicam ISI systems could be promising as convenient injectable sustained release delivery systems for dental and postoperative pain management.

In vivo evaluation of risperidone-SAIB in situ system as a sustained release delivery system in rats

Nanoelectrospray fabrication of pH-responsive double-layered drug-eluting contact lenses for ocular drug delivery.

In vitro and in vivo evaluation of ketotifen-gold nanoparticles laden contact lens for controlled drug delivery to manage conjunctivitis

Enhanced drug release control in coaxial electrospun fibers via heat pressing: Reducing burst release and achieving dual-phase delivery.

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