Category Archives: Microparticles/insert drug delivery

Category for injectable microparticles (1um-100um) and solid emplacable inserts for drug delivery

Two types of PLGA from PolySciTech used in development of directional Resolvin delivery-system for improved cardiac care

PolySciTech Division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers for several applications. One of these is PLGA type polymers including a wide array of molecular weights and lactide:glycolide ratios. For this type of polymer, the degradation time increases as the lactide content increases. This allows different types of PLGA to be combined in specific orientations so as to encourage degradation or drug release to preferentially occur on one side. Recently, two PLGA polymers from PolySciTech with different lactide contents (AP061 (LA:GA 75:25 (Mn 35-45 kDa)) and AP021 (85:15 (Mn 35-45 kDa))) were utilized by researchers at UCSF to design a system which delivers Resolvin D1, a mediator which promotes injury recovery, in a directional manner from a thin film with 98% of the resolvin released through the low-lactide side over the course of 56 days. Such a system holds promise for use in cardiac therapy to prevent restenosis of arteries following stenting or other procedures. Read more: Lance, Kevin D., Anuran Chatterjee, Bian Wu, Giorgio Mottola, Harald Nuhn, Phin Peng Lee, Brian E. Sansbury, Matthew Spite, Tejal A. Desai, and Michael S. Conte. “Unidirectional and Sustained Delivery of the Pro‐Resolving Lipid Mediator Resolvin D1 from a Biodegradable Thin Film Device.” Journal of Biomedical Materials Research Part A (2016). http://onlinelibrary.wiley.com/doi/10.1002/jbm.a.35861/full

“Abstract: Resolvin D1 (RvD1) belongs to a family of endogenously derived pro-resolving lipid mediators that have been shown to attenuate inflammation, activate pro-resolution signaling and promote homeostasis and recovery from tissue injury. In this study we present a poly(lactic-co-glycolic acid) (PLGA) based thin-film device composed of layers of varying ratios of lactic and glycolic acid that elutes RvD1 unidirectionally to target tissues. The device demonstrated sustained release in vitro for 56 days with an initial burst of release over 14 days. The asymmetric design of the device released 98% of RvD1 through the layer with the lowest molar ratio of lactic acid to glycolic acid, and the remainder through the opposite side. We validated structural integrity of RvD1 released from the device by mass spectrometry and investigated its bioactivity on human vascular endothelial (EC) and smooth muscle cells (VSMC). RvD1 released from the device attenuated VSMC migration, proliferation and TNF-α induced NF-κB activation, without evidence of cytotoxicity. Delivery of RvD1 to blood vessels was demonstrated ex vivo in a flow chamber system using perfused rabbit aortas and in vivo in a rat carotid artery model, with the devices applied as an adventitial wrap. Our results demonstrate a novel approach for sustained, local delivery of Resolvin D1 to vascular tissue at therapeutically relevant levels. Keywords: PLGA; resolvin; inflammation; vascular delivery; wrap”

Fluorescently labeled PLGA from PolySciTech used as part of self-assembled PLGA microparticle system research

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable polymers for research usage. This includes fluorescently conjugated polymers such as PLGA conjugated to flamma-fluor dyes. Recently, researchers used Fluorescent PolyVivo AV008 (PLGA-FPR648, reference named in paper as related material PLGA-CY5) for development of a self-assembled microparticle system. Read more: Yeredla, Nitish, Taisuke Kojima, Yi Yang, Shuichi Takayama, and Mathumai Kanapathipillai. “Aqueous Two Phase System Assisted Self-Assembled PLGA Microparticles.” Scientific Reports 6 (2016): 27736. http://www.nature.com/articles/srep27736

“Abstract: Here, we produce poly(lactide-co-glycolide) (PLGA) based microparticles with varying morphologies, and temperature responsive properties utilizing a Pluronic F127/dextran aqueous two-phase system (ATPS) assisted self-assembly. The PLGA polymer, when emulsified in Pluronic F127/dextran ATPS, forms unique microparticle structures due to ATPS guided-self assembly. Depending on the PLGA concentration, the particles either formed a core-shell or a composite microparticle structure. The microparticles facilitate the simultaneous incorporation of both hydrophobic and hydrophilic molecules, due to their amphiphilic macromolecule composition. Further, due to the lower critical solution temperature (LCST) properties of Pluronic F127, the particles exhibit temperature responsiveness. The ATPS based microparticle formation demonstrated in this study, serves as a novel platform for PLGA/polymer based tunable micro/nano particle and polymersome development. The unique properties may be useful in applications such as theranostics, synthesis of complex structure particles, bioreaction/mineralization at the two-phase interface, and bioseparations.”

PLGA microparticle drug delivery elucidated by in-depth mechanistic study

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polyesters including poly(lactide-co-glycolide) PLGA and related polymers. One of the common usages for this polymer is to use it for encapsulating a medicinal molecule inside and generating a micron sized spheres of PLGA (microspheres or microparticles) which can be directly injected into a patient via typical syringe and needle either intra-muscular or subcutaneous. Over time, the PLGA microparticles slowly releases the medicine into the patient’s blood-stream ideally maintaining the medicinal concentration within the therapeutic window (above the effective dose but below the toxic dose) over an extended course of time (weeks to months). Afterwards, the PLGA degrades into its nontoxic components lactic and glycolic acid and is naturally metabolized by the body. This delivery system is currently used for a variety of clinical formulations (Risperdal Consta®, Trelstar ®, and several others) so that there is no need for the patient to receive daily injections to maintain a therapeutic dose. The release mechanism is known to be a combination of diffusion of the drug through the PLGA matrix out into the blood-stream as well as the degradation of the polymer which contributes to drug release from PLGA microparticles. However, not all of these complex and overlapping processes are fully understood in a mechanistic sense. Without this understanding, development to drug delivery microparticles still require a great deal of trial-and-error. Recently, one of the most in-depth mechanistic studies to date regarding the PLGA controlled delivery of medicines has been reported by researchers at the University of Connecticut. Here they trapped the PLGA microspheres in a PVA hydrogel and imaged them in sequence during drug release and degradation. They correlated these results to polymer physicochemical properties to elucidate parameters which affect release in a micro-environment setting. They managed to track several complex and overlapping interactions including pore-formation and closure, microclimate acidification, water uptake, and microdialysis. You can learn more about these fascinating processes that affect PLGA microparticle performance here: Gu, Bing, Xuanhao Sun, Fotios Papadimitrakopoulos, and Diane J. Burgess. “Seeing is believing, PLGA microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites.” Journal of Controlled Release (2016). http://www.sciencedirect.com/science/article/pii/S0168365916301353

“Abstract: The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7 kDa) to achieve different drug release profiles, with a 9-day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25 kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7 kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25 kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS. Keywords: swelling; release mechanism; heterogeneous degradation; outside-in pore formation; cryo-SEM; glucose diffusion”

Article highlights use of PEG-PLGA for antibiotic delivery to bone as osteomyelitis treatment

PolySciTech division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable block copolymers including PEG-PLGA type polymers. These have the benefit of being easily formulated into microparticles by simple emulsion techniques (effectively rapidly stirring the organic solvent dissolved polymer into a water bath). One useful aspect of these polymers is that the hydrophilic PEG-chain of the block copolymer naturally turns to the exterior of the microparticle upon emulsion. PEG has a very useful feature in that, due to its hydrodynamic structure, it is highly bio-inert and prevents protein absorption. This allows pegylated particles to resist immune system responses such as attack by macrophages and other forms of particle clearance that affect non-pegylated microparticles. In a recent study, a group for the University of Pavia in Italy generated a series of pegylated microparticles and investigated their application for delivery of gentamicin to bone structures to prevent postoperative orthopedic infections such as osteomyelitis. Read more: Dorati, Rossella, Antonella DeTrizio, Ida Genta, Pietro Grisoli, Alessia Merelli, Corrado Tomasi, and Bice Conti. “An experimental design approach to the preparation of pegylated polylactide-co-glicolide gentamicin loaded microparticles for local antibiotic delivery.” Materials Science and Engineering: C 58 (2016): 909-917. http://www.sciencedirect.com/science/article/pii/S0928493115303799

“Abstract: The present paper takes into account the DOE application to the preparation process of biodegradable microspheres for osteomyelitis local therapy. With this goal gentamicin loaded polylactide-co-glycolide-co-polyethyleneglycol (PLGA-PEG) microspheres were prepared and investigated. Two preparation protocols (o/w and w/o/w) with different process conditions, and three PLGA-PEG block copolymers with different compositions of lactic and glycolic acids and PEG, were tested. A Design Of Experiment (DOE) screening design was applied as an approach to scale up manufacturing step. The results of DOE screening design confirmed that w/o/w technique, the presence of salt and the 15%w/v polymer concentration positively affected the EE% (72.1–97.5%), and span values of particle size distribution (1.03–1.23), while salt addition alone negatively affected the yield process. Process scale up resulted in a decrease of gentamicin EE% that can be attributed to the high volume of water used to remove PVA and NaCl residues. The results of in vitro gentamicin release study show prolonged gentamicin release up to three months from the microspheres prepared with salt addition in the dispersing phase; the behavior being consistent with their highly compact structure highlighted by scanning electron microscopy analysis. The prolonged release of gentamicin is maintained even after embedding the biodegradable microspheres into a thermosetting composite gel made of chitosan and acellular bovine bone matrix (Orthoss® granules), and the microbiologic evaluation demonstrated the efficacy of the gentamicin loaded microspheres on Escherichia coli. The collected results confirm the feasibility of the scale up of microsphere manufacturing process and the high potential of the microparticulate drug delivery system to be used for the local antibiotic delivery to bone. Keywords: DOE; Gentamicin; Osteomyelitis; Microspheres; Polylactide-co-glycolide; Polyethyleneglycol; Bone delivery. Highlights: To get a more effective therapy for the prevention and treatment of osteomyelitis. To exploit the local delivery of gentamicin to bone by a biodegradable microparticulate drug delivery system. Polylactide-co-glycolide-co-polyethyleneglycol (PLGA-PEG) microsphere as biodegradable drug delivery system. Process variables affecting microspheres properties are investigated. Design Of Experiment (DOE) screening design as approach to scale up manufacturing step.”

PLGA and PEG-PLGA investigated for release of neuregulin as part of heart-attack treatment

PolySciTech Division of Akina, Inc (www.polyscitech.com) provides a wide array of biodegradable polymers including PLGA and block PEG-PLGA copolymers. Recently, these polymers have been used for development of microparticles which deliver the neuregulin growth factor into damaged heart tissue. It was found that the MPs were able to reside in the cardiac tissue and release active neuregulin for up to three months and that PEGylated PLGA resisted phagocytosis. Read more: Pascual-Gil, S., T. Simón-Yarza, E. Garbayo, F. Prosper, and M. J. Blanco-Prieto. “Tracking the In vivo release of bioactive NRG from PLGA and PEG-PLGA microparticles in infarcted hearts.” Journal of Controlled Release (2015). http://www.sciencedirect.com/science/article/pii/S0168365915302236

 

“Abstract: The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG–PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG–PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term (12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG–PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials. Keywords: Myocardial infarction; Microparticles; Protein therapy; Phagocytosis; Bioactivity; Biotinylation”

Image: http://4.bp.blogspot.com/-SHNzltHYoz0/VlM8WUcwLkI/AAAAAAAAB8Q/mlEXRNakaCY/s1600/Pascual-Gil%252C%2B2015%2BPLGA%2Bneuregulin%2Bheart-attack%2Btreatment.png

PolySciTech PLGA used for anti-HIV drug delivery by electrospun scaffold

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable polymer products including PLGA. Recently, researchers at the University of Washington have focused their efforts on generating an electrospun scaffold for the delivery of anti-HIV medicines using PolySciTech PLGA (PolyVivo AP060). These meshes can be used for a variety of applications including vaginal anti-HIV medicinal delivery for treatment and prevention. By varying the blend of PLGA with another biodegradable polyester, PCL, the research group was able to control the release rate of the medicines. Read more: Carson, Daniel, Yonghou Jiang, and Kim A. Woodrow. “Tunable Release of Multiclass Anti-HIV Drugs that are Water-Soluble and Loaded at High Drug Content in Polyester Blended Electrospun Fibers.” Pharmaceutical Research (2015): 1-12. http://link.springer.com/article/10.1007/s11095-015-1769-0

“Abstract: Objectives: Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters. Methods: Drug-loaded fibers were fabricated by electrospinning ratios of PCL and PLGA. Fiber morphology was imaged by SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay. Results: We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 h or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro. Conclusions: These data suggest that we were able to overcome current limitations associated with sustained release of small molecule hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications.”

PolySciTech (www.polyscitech.com) provides a wide variety of PLGA and related biodegradable polymers. One of the uses for this type of polymer is to generate biodegradable microparticles which contain medicine that slowly leaches out of the particles over the course of time (typically 1 to 6 months depending on formulation) so that this can be administered as long-acting injections. Recently a research article has been published in which the various parameters for generating protein loaded PLGA microparticles were optimized. This research has promise for the development of long-acting protein drug based injections which can be applied to many diseases. For example, proteins such as insulin is used to treat diabetes, infliximab is used to treat Crohns disease/arthritis, rituximab is used to treat lymphoma/leukemia and cetuximab is used to colorectal cancer. Use of PLGA-protein microparticles could one day provide for long-acting versions of these injected medicines. Read more: Martín-Sabroso, C., A. I. Fraguas-Sánchez, J. Aparicio-Blanco, M. F. Cano-Abad, and A. I. Torres-Suárez. “Critical attributes of formulation and of elaboration process of PLGA-protein microparticles.” International journal of pharmaceutics 480, no. 1 (2015): 27-36. http://www.sciencedirect.com/science/article/pii/S0378517315000101

“Abstract: Low drug loading, burst effect during release and drug inactivation account for the main drawbacks of protein microencapsulation in poly(d,l-lactic-co-glycolic) acid (PLGA) matrix by the water-in oil-in water (W/O/W) solvent evaporation method. Thus, the current study was set to invest the critical attributes of formulation and of elaboration process which determine protein loading into microparticles as well as its further release, using albumin as protein model. NaCl concentration in the external aqueous phase, poly(vinyl alcohol) (PVA) concentration and mostly viscosity of both the internal aqueous phase and the organic phase were critical attributes for improving drug loading, with polymer molecular weight and hydrophobicity likewise directly related to albumin loading. In such a way, when using 0.5% PVA as internal aqueous phase the highest albumin loading was achieved. Optimized microparticles exhibited a sustained in vitro release of albumin over 130 days. The influence of the microencapsulation process on albumin stability and biological activity was evaluated by carrying out cell proliferation assays on PC12 cells with albumin released from microparticles. Such assay demonstrated that the microencapsulation procedure optimized in this study did not affect the biological stability of the microencapsulated protein. Abbreviations: ALB, albumin; BCA, bicinchoninic acid; BSA, bovine serum albumin; DCM, dichloromethane; DMEM, Dulbecco’s modified Eagle’s medium; DMSO, dimethylsulfoxide; MP, microparticles; OD, optical density; PAO, phenylarsine oxide; PBS, phosphate buffered saline; PEG, poly(ethylene glycol); PLGA, poly(d,l-lactic-co-glycolic) acid; PVA, poly(vinyl alcohol); SEM, scanning electron microscopy; SPARC, secreted protein acidic and rich in cysteine; W/O/W, water-in oil-in water Keywords: Protein microencapsulation; Albumin; Microparticles; Quality by design; Critical attributes; Poly(lactic-co-glycolic) acid”

PLGA-PEG-PLGA/montmorillonite system used for delivery of aspirin

PolySciTech (www.polyscitech.com) provides a wide array of PLGA-PEG-PLGA block copolymers. Recently these types of polymers were used to generate a system of microparticles and this was used for asparin delivery. Read more: Liu, Hsin-Jiant, Hawn-Chung Chu, Li-Huei Lin, and Shu-Yuan Hsu. “Preparation and Drug Release of Aspirin-Loaded PLGA-PEG-PLGA/Montmorillonite Microparticles.” International Journal of Polymeric Materials and Polymeric Biomaterials 64, no. 1 (2015): 7-14. http://www.tandfonline.com/doi/abs/10.1080/00914037.2014.886238

“Abstract: A polymerization method was used to synthesize biodegradable poly(lactide-co-glycolide)/poly(ethyleneglycol)/poly(lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers. These copolymers were then used to prepare microparticles for encapsulating drug (aspirin). The results of X-ray diffraction (XRD) analysis showed that the montmorillonite (MMT) can be converted into organic montmorillonite (o-MMT). Subsequently, the emulsion solvent evaporation method was used to separately prepare aspirin-loaded PLGA-PEG-PLGA and aspirin-loaded PLGA-PEG-PLGA/o-MMT microparticles. The results of scanning electron microscopy (SEM) showed that microparticle formation was related to the polyvinyl alcohol (PVA) concentration and the proportion of o-MMT. In addition, the ultraviolet-visible (UV-Vis) spectroscopy was conducted to determine the release rate of these microparticles.”

PolySciTech PLGA used for development of episcleral drug delivery

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable polymers. Recently, a PLGA 85:15 (cat# AP087) was utilized by University of Cincinnati as part of their research for development of an adhesive ocular drug release system. Read more: Wen, He, and S. Kevin Li. “Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery.” Drug Development and Industrial Pharmacy 0 (2015): 1-9. http://informahealthcare.com/doi/abs/10.3109/03639045.2015.1035280

“Abstract: The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5 mm and a thickness of 0.8 mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route. Keywords: Controlled release, episcleral implant, macromolecules, silicone adhesive, transscleral delivery”

PEG-PLA used to create hydrogel-microparticle polymersome

PolySciTech (www.polyscitech.com) provides a wide array of biodegradable block copolymers including PEG-PLA. Recently this kind of polymer was utilized to generate cell-like hydrogel/microparticle structures. Read more: Martino, Chiara, Tae Yong Lee, and Shin-Hyun Kim. “Microfluidic generation of PEG-b-PLA polymersomes containing alginate-based core hydrogel.” Biomicrofluidics 9, no. 2 (2015): 024101. http://scitation.aip.org/content/aip/journal/bmf/9/2/10.1063/1.4914112

“Abstract: Herein, we demonstrate a novel method for the generation of monodisperse cell-like structures containing a biocompatible hydrogel matrix surrounded by a membrane responsive to chemical cues. Specifically, we employ droplet-based microfluidics to generate PEG-PLA polymersomes encapsulating alginate in liquid form. We investigate alginate core gelation by creating an osmotic pressure gradient across the polymeric membrane that, through expansion, allows the passage of calcium ions. The effects of calcium concentration on the core gelation are explored.”