In vitro drug release and antibacterial activity evaluation of silk fibroin coated vancomycin hydrochloride loaded poly (lactic-co-glycolic acid) (PLGA) sustained release microspheres

Currently, the treatment of osteomyelitis poses a great challenge to clinical orthopedics. The use of biodegradable materials combined with antibiotics provides a completely new option for the treatment of osteomyelitis. In this study, vancomycin hydrochloride (VANCO) loaded poly (lactic-co-glycolic acid) (PLGA) microspheres were prepared by a double emulsion solvent evaporation method, and the in vitro drug release behaviors of the drug loaded microspheres were explored after coating with different concentrations of silk fibroin (SF). Drug loading, encapsulation efficiency, Scanning electron microscopy, particle size analysis, Fourier transform infrared spectroscopy, hydrophilicity, in vitro drug release, and in vitro antibacterial activity were evaluated. The results showed that the drug loading of vancomycin loaded PLGA microspheres was (24.11 ±1.72)%, and the encapsulation efficiency was (48.21 ±3.44)%. The in vitro drug release indicated that the drug loaded microspheres showed an obvious initial burst release, and the drug loaded microspheres coated with SF could alleviate the initial burst release in varying degrees. It also can reduce the amount of cumulative drug release, and the effect of microspheres coated with 0.1% concentration of SF is the best. The time of in vitro drug release in different groups of drug loaded microspheres can be up to 28 days. The microspheres coated with (0.1%SF) or without (0%SF) SF showed a cumulative release of (82.50±3.51)% and (67.70±3.81)%,respectively. Therefore, the surface coating with SF of vancomycin loaded microspheres can alleviate the initial burst release, reduce the cumulative drug release, potentially prolong the drug action time, and improve the anti-infection effect.

The impacts of PLGA/PEG triblock copolymers with variable molecular weights on sustained release of buprenorphine

Introduction: Current in-situ injectable implants of buprenorphine (BP) such as Sublocade® consist of N-methyl-2-pyrrolidone (NMP)-dissolved PLGA. To control the initial burst release of Sublocade® during the first 24 hours after injection, we used a BP in-situ forming composite (ISFC) to employ different molecular weights of PLGA-PEG-PLGA triblock. Methods: The triblock was synthesized by ring-opening polymerization (ROP) using PEG molecules with weights of 1500, 3000, and 4000 Da via the melting method. The specifications of the triblock were evaluated by 1H-NMR, FTIR, GPC, and DSC. The sol-gel, gel-precipitate temperatures, in-vitro release, and composites’ morphology, degradation, and toxicity were assessed for determining the features of ISFC 1500, ISFC 3000, and ISFC 4000 formulations. ROP was performed successfully via the melting method. The yields of all polymerization reactions were greater than 83.4 %. Results: The PEG 1500 triblock showed both sol-gel and gel-precipitate temperatures, but PEG 3000 and 4000 only showed a sol-precipitate temperature. The values of initial burst release of BP from ISFC 1500, ISFC 3000, and ISFC 4000 were 6.52 ± 0.22 %, 12.39 ± 0.61 %, and 15.80 ± 0.98 %, respectively. BP release from the ISFCs was completed over three weeks for ISFC 1500 and 10 days for ISFC 3000 and ISFC 4000. The composites containing PEG 3000 and PEG 4000 were more spongy and porous than PEG 1500. The ISFC 1500 delivered a higher cell viability (95.17 ± 1.15 %) compared with ISFC 3000 (86.37 ± 2.25%) and ISFC 4000 (79.70 ± 3.77%). Conclusion: These results indicated that ISFC 1500 were biocompatible and delivered suitable early initial burst reactions compared with ISFC 3000 and 4000 and might be a good candidate for preparing sustained-release formulation of BP.

Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin

The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer’s disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 ± 12.8 µm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G′), loss modulus (G″), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the Cmax value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUClast value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer’s disease.

Polylactide/Polyvinylalcohol-Based Porous Bioscaffold Loaded with Gentamicin for Wound Dressing Applications

: This study explores the feasibility of modifying the surface liquid spraying method to prepare porous bioscaffolds intended for wound dressing applications. For this purpose, gentamicin sulfate was loaded into polylactide-polyvinyl alcohol bioscaffolds as a highly soluble (hygroscopic) model drug for in vitro release study. Moreover, the influence of inorganic salts including NaCl (10 g/L) and KMnO4 (0.4 mg/L), and post-thermal treatment (T) (80 °C for 2 min) on the properties of the bioscaffolds were studied. The bioscaffolds were characterized by scanning electron microscopy, Fourier Transform infrared spectroscopy, and differential scanning calorimetry. In addition, other properties including porosity, swelling degree, water vapor transmission rate, entrapment efficiency, and the release of gentamicin sulfate were investigated. Results showed that high concentrations of NaCl (10 g/L) in the aqueous phase led to an increase of around 68% in the initial burst release due to the increase in porosity. In fact, porosity increased from 68.1 ± 1.2 to 94.1 ± 1.5. Moreover, the thermal treatment of the Polylactide-polyvinyl alcohol/NaCl (PLA-PVA/NaCl) bioscaffolds above glass transition temperature (Tg) reduced the initial burst release by approximately 11% and prolonged the release of the drug. These results suggest that thermal treatment of polymer above Tg can be an efficient approach for a sustained release.

Biodegradable Nanoparticles-Loaded PLGA Microcapsule for the Enhanced Encapsulation Efficiency and Controlled Release of Hydrophilic Drug

Recently, nano- and micro-particulate systems have been widely utilized to deliver pharmaceutical compounds to achieve enhanced therapeutic effects and reduced side effects. Poly (DL-lactide-co-glycolide) (PLGA), as one of the biodegradable polyesters, has been widely used to fabricate particulate systems because of advantages including controlled and sustained release, biodegradability, and biocompatibility. However, PLGA is known for low encapsulation efficiency (%) and insufficient controlled release of water-soluble drugs. It would result in fluctuation in the plasma levels and unexpected side effects of drugs. Therefore, the purpose of this work was to develop microcapsules loaded with alginate-coated chitosan that can increase the encapsulation efficiency of the hydrophilic drug while exhibiting a controlled and sustained release profile with reduced initial burst release. The encapsulation of nanoparticles in PLGA microcapsules was done by the emulsion solvent evaporation method. The encapsulation of nanoparticles in PLGA microcapsules was confirmed by scanning electron microscopy and confocal microscopy. The release profile of hydrophilic drugs can further be altered by the chitosan coating. The chitosan coating onto alginate exhibited a less initial burst release and sustained release of the hydrophilic drug. In addition, the encapsulation of alginate nanoparticles and alginate nanoparticles coated with chitosan in PLGA microcapsules was shown to enhance the encapsulation efficiency of a hydrophilic drug. Based on the results, this delivery system could be a promising platform for the high encapsulation efficiency and sustained release with reduced initial burst release of the hydrophilic drug.

PLGA Microspheres of hGH of Preserved Native State Prepared Using a Self-Regulated Process

The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke osmotic pressure inside the microspheres, and the contact of the protein with the interface between water and organic solution of the polymer must be minimized. To meet these criteria, rhGH was pre-formulated into polysaccharide particles via an aqueous–aqueous emulsion in the present study, followed by encapsulating the particles into microspheres through a self-regulated process to minimize the contact of the protein with the water–oil interface. Polysaccharides as the protein stabilizer did not evoke osmotic pressure as small sugar stabilizers, the cause of severe initial burst release. Reduced initial burst enabled reduced protein loading to 9% (from 22% of the once commercialized Nutropin depot), which in turn reduced the dosage form index from 80 to 8.7 and eased the initial burst. A series of physical chemical characterizations as well as biologic and pharmacokinetic assays confirmed that the present method is practically feasible for preparing microspheres of proteins.

PLGA Microspheres with Alginate-Coated Large Pores for the Formulation of an Injectable Depot of Donepezil Hydrochloride

As the main symptom of Alzheimer’s disease-related dementia is memory loss, patient compliance for donepezil hydrochloride (donepezil), administered as once-daily oral formulations, is poor. Thus, we aimed to design poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) with alginate-coated large pores as an injectable depot of donepezil exhibiting sustained release over 2–3 weeks. The PLGA MS with large pores could provide large space for loading drugs with high loading capacity, and thereby sufficient amounts of drugs were considered to be delivered with minimal use of PLGA MS being injected. However, initial burst release of donepezil from the porous PLGA MS was observed. To reduce this initial burst release, the surface pores were closed with calcium alginate coating using a spray-ionotropic gelation method. The final pore-closed PLGA MS showed in vitro sustained release for approximately 3 weeks, and the initial burst release was remarkably decreased by the calcium alginate coating. In the prediction of plasma drug concentration profiles using convolution method, the mean residence time of the pore-closed PLGA MS was 2.7-fold longer than that of the porous PLGA MS. Therefore, our results reveal that our pore-closed PLGA MS formulation is a promising candidate for the treatment of dementia with high patient compliance.

Effect of Process Parameters on the Initial Burst Release of Protein-Loaded Alginate Nanospheres

The controlled release or delivery of proteins encapsulated in micro/nanospheres is an emerging strategy in regenerative medicine. For this, micro/nanospheres made from alginate have drawn considerable attention for the use as a protein delivery device because of their mild fabrication process, inert nature, non-toxicity and biocompatibility. Though promising, one key issue associated with using alginate micro/nanospheres is the burst release of encapsulated protein at the beginning of the release, which may be responsible for exerting toxic side effects and poor efficiency of the delivery device. To address this issue, this study aimed to investigate the effect of process parameters of fabricating protein-loaded alginate nanospheres on the initial burst release. The alginate nanospheres were prepared via a combination of water-in-oil emulsification and the external gelation method and loaded with bovine serum albumin (BSA) as a model protein. The examined process parameters included alginate concentration, ionic cross-linking time and drying time. Once fabricated, the nanospheres were then subjected to the examination of BSA release, as well as the characterization of their morphology, size, and encapsulation efficiency. Our results revealed that by properly adjusting the process parameters, the initial burst release can be reduced by 13%. Taken together, our study demonstrates that regulating process parameters of fabricating alginate nanospheres is a possible means to reduce the initial burst release.