An in vitro study of the design and development of a novel doughnut-shaped minitablet for intraocular implantation

PurposeTo characterize a biodegradable microsphere-hydrogel drug delivery system (DDS) for controlled and extended release of ranibizumab.MethodsThe degradable microsphere-hydrogel DDSs were fabricated by suspending ranibizumab-loaded or blank poly(lactic-co-glycolic acid) microspheres within a poly(ethylene glycol)-co-(L-lactic-acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) hydrogel. The thermal responsive behavior of various DDS formulations was characterized in terms of volume phase transition temperature (VPTT) and swelling ratios changes from 22°C to 42°C. The mechanical properties were characterized using rheological methods. Degradability of hydrogels were also examined via wet weight loss. Finally, Iodine-125 was used to radiolabel ranibizumab for characterization of encapsulation efficiency and in vitro release.ResultsAll DDS formulations investigated were injectable through a 28-gauge needle at room temperature. The VPTT increased with increase of cross-linker concentration. The swelling ratios decreased as temperature increased and were not influenced by presence of microspheres. Rheology data confirmed that increase of cross-linker concentration and microsphere loading made DDS stiffer. Increase of degradable cross-linker concentration facilitated hydrogel in vitro degradation. Controlled release of ranibizumab were achieved for investigated DDS formulations for 6 months; and increased degradable cross-linker concentration produced faster and more complete release.ConclusionsThe biodegradable DDSs are suitable for sustained release of ranibizumab. Considering ease of injection, degradability and release of ranibizumab, DDS with 3 mM cross-linker concentration and less than 20 mg/mL microsphere loadings is more favorable for future application.Translational RelevanceThe investigated DDS is promising for controlled and extended release of anti-VEGF therapeutics to achieve better treatment regimen in ocular neovascularizations.

The use of biodegradable polymeric materials as drug carriers is a relatively new dimension in polymeric drug delivery systems. A number of biodegradable or bioerodible polymers, such as poly (lactic/glycolic acid) copolymer, poly(α-amino acid), polyanhydride, and poly (ortho ester) are currently being investigated for this purpose. These polymers are useful for matrix and reservoir-type delivery devices. In addition, when chemical functional groups are introduced to the biodegradable polymer backbone, such as poly (N-(2-hydroxypropy) methacrylamide), the therapeutic agent can be covalently bound directly orvia spacer to the backbone polymer. These polymer/drug conjugates represent another new dimension in biodegradable polymeric drug delivery systems. In this paper, major emphasis is placed on clinical applications of biodegradable polymeric delivery systems. In addition, examples of biodegradable polymeric durg delivery systems currently being investigated will be discussed for the purpose of demonstrating the potential importance of this new field.

Brown and beige adipocytes are potent therapeutic agents to increase energy expenditure and reduce risks of obesity and its affiliated metabolic symptoms. One strategy to increase beige adipocyte content is through inhibition of the evolutionarily conserved Notch signaling pathway. However, systemic delivery of Notch inhibitors is associated with off-target effects and multiple dosages of application further faces technical and translational challenges. Here, we report the development of a biodegradable polymeric microsphere-based drug delivery system for sustained, local release of a Notch inhibitor, DBZ. The microsphere-based delivery system was fabricated and optimized using an emulsion/solvent evaporation technique to encapsulate DBZ into poly(lactide-co-glycolide) (PLGA), a commonly used biodegradable polymer for controlled drug release. Release studies revealed the ability of PLGA microspheres to release DBZ in a sustained manner. Co-culture of white adipocytes with and without DBZ-loaded PLGA microspheres demonstrated that the released DBZ retained its bioactivity, and effectively inhibited Notch and promoted browning of white adipocytes. Injection of these DBZ-loaded PLGA microspheres into mouse inguinal white adipose tissue depots resulted in browning in vivo. Our results provide the encouraging proof-of-principle evidence for the application of biodegradable polymers as a controlled release platform for delivery of browning factors, and pave the way for development of new translational therapeutic strategies for treatment of obesity.

PurposeTo evaluate the in vivo treatment efficacy and biocompatibility of a biodegradable aflibercept-loaded microsphere-hydrogel drug delivery system (DDS) in a laser-induced choroidal neovascularization (CNV) rat model.MethodsTwo weeks after CNV induction, animals were randomly assigned into four experimental groups: (1) no treatment, (2) single intravitreal (IVT) injection of blank DDS, (3) bimonthly bolus IVT aflibercept injections, and (4) single IVT injection of aflibercept-DDS. CNV lesion sizes were monitored longitudinally using fluorescence angiography and multi-Otsu thresholding for 6 months. For safety and biocompatibility assessment, an additional three non-CNV animals received a blank DDS injection. Electroretinogram, intraocular pressure, and clinical ophthalmoscopic examinations were performed.ResultsThe average lesion areas at week 0 (treatment intervention) were (1) 8693 ± 628 µm2 for no treatment, (2) 8261 ± 709 µm2 for blank DDS, (3) 10,368 ± 885 µm2 for bolus, and (4) 10,306 ± 1212 µm2 for aflibercept-DDS. For the nontreated groups, CNV lesion size increased by week 2 and remained increased throughout the study. The treated groups exhibited CNV size reduction after week 2 and remained for 6 months. At week 22, the average percent changes in CNV lesion area were +38.87% ± 7.08%, +34.19% ± 9.93%, –25.95% ± 3.51%, and –32.69% ± 5.40% for the above corresponding groups. No signs of chronic inflammation and other ocular abnormalities were found.ConclusionsThe aflibercept-DDS was effective in treating CNV lesions for 6 months and is safe, well tolerated, and biocompatible.Translational RelevanceThe proposed DDS is a promising system to reduce IVT injection frequency for anti–vascular endothelial growth factor treatment.

The present study aimed to formulate 5-fluorouracil loaded cross linked chitosan nanoparticles based on chemical cross-linking of low molecular weight chitosan with glutaraldehyde by reverse micelles technique as 5-FU is less hydrophobic, relatively potent, has a shorter half-life, is rapidly metabolized, less tolerated, and has low oral bioavailability; therefore, we aimed to formulate potential nanocarriers of 5-FU for efficient drug delivery to specific targeted areas of action, reduce oral toxicity, improve tolerability and therapeutic outcomes of 5-FU, in a restricted fashion to enhance the bioavailability of 5-FU. Nanoparticles were formulated by the reverse micelle method based on the chemical cross-linking of glutaraldehyde (25% aqueous solution) into a w/o emulsion in different ratios. LMWCH-NPs were characterized for post-formulation parameters by mean particle size, zeta potential, %age yield, loading/entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), DSC/TGA, TEM, PXRD, drug release at pH 1.2, and pH 7.4. 5-FU loaded NPs showed a size range (198 nm-200 nm) and zeta potential (−39mV to −41mV), which ensured mechanical stability and increased retention time in blood vessels by the sustained release properties of biodegradable nanocarrier drug delivery systems. % age yield showed the range 92% to 96% while % LC ranged 2.0% to 3.4% and %EE ranged 40% to 43%. The TEM images showed spherical nanoparticles. FTIR revealed the compatibility between the drug and the cross-linked polymer. DSC/TGA ensured the thermal stability of the drug, while the solid-state stability of the drug-loaded cross-linked chitosan nanoparticles was evaluated by powder X-ray diffraction (PXRD) analysis. Drug release studies were performed using the dialysis bag technique at both pH (1.2 and 7.4) to mimic the gastrointestinal tract. Highly stable NPs displayed targeted release in phosphate buffer pH 7.4 at 37°C. Fickian diffusion was the predominant release with an R2 value of 0.9975-0.9973—and an N value 0.45-0.53. Prepared nanoparticles are inert, biodegradable, and biocompatible drug delivery systems for sustained release of 5-FU with maximum therapeutic efficacy and bioavailability.

Sustained drug release at specific sites is clinically favorable for the treatment of many diseases. The discovery of new polymeric materials suitable for prolonging drug release, improving therapeutic efficiency, and decreasing systemic toxicity is always of great interest in local sustained-release drug delivery systems (LSRDDSs). In this study, a new cross-linked cyanoacrylate (CA)-based LSRDDS is developed, in which the drug depot consists of a formulation of methoxyethyl cyanoacrylate (MOE-CA) with the cross-linking agent CA-PEG-CA. The MOE-CA endowed the CA polymer with good degradability. The drug-release profile could be affected by the structure and composition ratio of the MOE-CA/CA-PEG-CA monomer. The liquid CA monomer could dissolve the drug without using other solvents, and could polymerize into a solid glue just in a few seconds after injection. An optimal formulation loaded with 5-fluorouracil (J-Fu-1.25) showed excellent anticancer activity both in vitro and in vivo, with 50% survival of the mice and no significant systemic toxicity detected during the experiment. The CA depot might affect the blood flow in microvessels of tumors, thus contributing to the synergetic anticancer effect of 5-fluorouracil. We believe that this work provides a practical, biodegradable, and biocompatible LSRDDS for chemotherapeutic drug delivery that can also be applied universally with various drugs for certain therapeutic aims.

ABSTRACTIntroduction: Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy.Areas covered: This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered.Expert opinion: Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

Continuous drug delivery to the ocular surface remains difficult due to the rapid tear clearance of topically applied agents. The purpose of this study was to evaluate biodegradable and biocompatible drug delivery systems on the ocular surface using poly-lactic-co-glycolic acid (PLGA) based polymers. Fluorescein-labeled albumin and doxycycline were individually encapsulated into a PLGA-based matrix using a water-oil-water double emulsion method. The drug elution rates for various microspheres were evaluated spectrofluorometrically. Particle size was measured using image analysis software. Subconjunctival injections of PLGA microspheres were used to evaluate safety and inflammatory response to the polymer in the murine model. Efficacy of the drug delivery system was evaluated by a single subconjunctival injection of PLGA-doxycycline (a broad metalloproteinase inhibitor) prior to induction of desiccating stress (DS) model in C57BL/6 mice for 5 days. PLGA-based microspheres successfully elute encapsulated drugs of interest continuously over controlled periods of time. Mean PLGA-based microparticle diameter was 4.6 μm±1.54 μm. Drug elution rates and delivery times were easily modifiable by altering polymers and synthesis parameters. In vitro studies demonstrate successful continuous elution of encapsulated drugs for at least 2 weeks. In vivo testing of PLGA-doxycycline was efficacious in preventing DS-induced corneal barrier disruption with desiccating stress, similarly to topically applied doxycycline. PLGA-based drug delivery systems are safe and non-inflammatory. They can be successfully used to treat ocular surface and corneal diseases by continuously delivering biopharmaceuticals of interest.

The perpetuation of healthy vision is paramount in an individual. It has been observed that various drug delivery systems have been fabricated to develop vision quality in individuals. Systemic ocular drug therapies have limited efficacy due to poor bioavailability, systemic and toxic side effects and low patient compliance. Various drug systems which follow the ocular route of administration are manufactured to achieve optimized bioavailability along with better patient compliance. Ocular implant is one such example. It is divided into biodegradable and non-biodegradable drug delivery systems wherein the former is more beneficial. This review aims to demonstrate the current momentum in the formulation and optimization of various biodegradable ocular drug delivery systems and its characteristics.

The goal of this research was the development of cellulose-based biodegradable drug delivery systems solutions for cosmetic mask applications. Cellulose-based materials derived from natural renewable sources provide a sustainable alternative to nonwoven cosmetic masks derived from nondegradable fossil-based raw materials. An experimental design was executed to assemble the 3D cellulose fibres matrix and the water in oil emulsion comprising the active molecules from Mentha piperita L. Two types of biopolymeric additives were used, one derived from a nano/micro fibrillated cellulose pulp and another one including chitosan. A 3D computational simulation study was performed to enhance porosity and strength properties. The results indicated that the cosmetic face mask optimized prototypes, made from a biodegradable 3D matrix of cellulose fibres and active molecules, are suitable for dermic use.
 Keywords: biopolymers, dermic application, drug delivery systems (DDS), essential oil, Mentha piperita

Biodegradable drug delivery systems have advanced treatment of a wide spectrum of musculoskeletal problems. However, their lack of availability and cost can restrict use. To find an easily available and inexpensive biodegradable implant, we tested a widely used tissue adhesive, n-butyl-2-cyanoacrylate, as a drug-trapping material. We tested vancomycin with commercially available absorbable gelatin-sponge pieces as the scaffold. We evaluated the in vitro and in vivo drug release profiles and in vivo inflammatory response. A mouse muscle pouch model was used for in vivo evaluations. The released vancomycin level was measured by fluorescence polarization immunoassay technique, and a leukocyte count-based grading system was used to evaluate inflammatory response. Our findings suggest the proposed implant provides effective drug release for as much as 42 days in vitro and 14 days in vivo. The presence of n-butyl-2-cyanoacrylate led to a local inflammatory response which decreased after 3 weeks in the group with less adhesive. These results showed that n-butyl-2-cyanoacrylate could efficiently trap and slowly release a drug when used in the structure of a biodegradable local drug delivery device.

Phase II results of an intraocular steroid delivery system for cataract surgery

To assess the efficacy of a new intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in a high-risk corneal transplantation model. Lewis rats that received orthotopic corneal transplants (Balb/c mice donors) were divided into three groups (six rats in each); group 1 received no treatment and served as controls, group 2 was treated with 0.1% betamethasone eyedrops three times daily for 6 weeks, and group 3 received DEX DDS in the anterior chamber at the time of transplantation. All grafts in the untreated control group were rejected within 8 days. In the betamethasone eyedrop group, five eyes (83%) were rejected during the 8-week study period. None of the grafts in the DEX DDS group was rejected. The administration of DEX DDS significantly prolonged the survival rate of the corneal grafts (p < 0.001, log-rank test). DEX DDS is effective in suppressing graft rejection in high-risk corneal transplantation.

Camptothecin (CPT) has demonstrated antitumor activity in lung, ovarian, breast, pancreas, and stomach cancers. However, this drug, like many other potent anticancer agents, is extremely water-insoluble. Furthermore, pharmacology studies have revealed that prolonged schedules must be administered continuously. For these reasons, several of its water-soluble analogues, prodrugs, and macromolecular conjugates have been synthesized, and various formulation approaches have been investigated. Biodegradable polyesters have gained popularity in cancer treatment in recent years. A number of biodegradable polymeric drug delivery systems (DDSs), designed for localized and systemic administration of therapeutic agents, as well as tumor-targeting macromolecules, have entered clinical trials, demonstrating the importance of biodegradable polyesters in cancer therapy. Biodegradable polyester-based DDSs have the potential to deliver the payload to the target while also increasing drug availability at intended site. The systemic toxicity and serious side-effects associated with conventional cancer therapies can be significantly reduced with targeted polymeric systems. This review elaborates on the use of biodegradable polyesters in the delivery of CPT and its analogues. The design of various DDSs based on biodegradable polyesters has been described, with the drug either adsorbed on the polymer's surface or encapsulated within its macrostructure, as well as those in which a hydrolyzed chemical bond is formed between the active substance and the polymer chain. The data related to the type of DDSs, the kind of linkage, and the details of in vitro and in vivo studies are included.

The aim was to design sterile biodegradable microparticulate drug delivery systems based on poly(dl-lactide) (PLA) and poly(ɛ-caprolactone) (PCL) and containing ivermectin (IVM), an antiparasitic drug, for subcutaneous administration in dogs. The drug delivery system should: (i) ensure a full 12-month protection upon single dose administration; (ii) be safe with particular attention regarding IVM dosage and its release, in order to prevent over dosage side effects. This preliminary work involves: polymer selection, evaluation of the effects of γ-irradiation on the polymers and IVM, investigation and set up of suitable microparticle preparation process and parameters, IVM-loaded microparticles in vitro release evaluation.Results of gel permeation chromatography analysis on the irradiated polymers and IVM mixtures showed that combination of IVM with the antioxidant α-tocopherol (TCP) reduces the damage extent induced by irradiation treatment, independently on the polymer type.Solvent evaporation process was successfully used for the preparation of PLA microparticles and appropriately modified; it was recognized as suitable for the preparation of PCL microparticles. Good process yields were achieved ranging from 76.08% to 94.72%; encapsulation efficiency was between 85.76% and 91.25%, independently from the polymer used. The type of polymer and the consequent preparation process parameters affected microparticle size that was bigger for PCL microparticles (480–800 µm) and solvent residual that was >500 ppm for PLA microparticles. In vitro release test showed significantly faster IVM release rates from PCL microparticles, with respect to PLA microparticles, suggesting that a combination of the polymers could be used to obtain the suitable drug release rate.