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Extracellular vesicles (EVs) are a population of small vesicles secreted by essentially all cell types, containing a wide variety of biological macromolecules. Due to their intrinsic capabilities for efficient intercellular communication, they are involved in various aspects of cellular functioning. In the past decade, EVs derived from stem cells attracted interest in the field of regenerative medicine. Owing to their regenerative properties, they have great potential for use in tissue repair, in particular for tissues with limited regenerative capabilities such as cartilage. The maintenance of articular cartilage is dependent on a precarious balance of many different components that can be disrupted by the onset of prevalent rheumatic diseases. However, while cartilage is a tissue with strong mechanical properties that can withstand movement and heavy loads for years, it is virtually incapable of repairing itself after damage has occurred. Stem cell-derived EVs (SC-EVs) transport regenerative components such as proteins and nucleic acids from their parental cells to recipient cells, thereby promoting cartilage healing. Many possible pathways through which SC-EVs execute their regenerative function have been reported, but likely there are still numerous other pathways that are still unknown. This review discusses various preclinical studies investigating intra-articular injections of free SC-EVs, which, while often promoting chondrogenesis and cartilage repair in vivo, showed a recurring limitation of the need for multiple administrations to achieve sufficient tissue regeneration. Potentially, this drawback can be overcome by making use of an EV delivery platform that is capable of sustainably releasing EVs over time. With their remarkable versatility and favourable chemical, biological and mechanical properties, hydrogels can facilitate this release profile by encapsulating EVs in their porous structure. Ideally, the optimal delivery platform can be formed in-situ, by means of an injectable hydrogel that can be administered directly into the affected joint. Relevant research fulfilling these criteria is discussed in detail, including the steps that still need to be taken before injectable hydrogels for sustained delivery of EVs can be applied in the context of cartilage regeneration in the clinic.

Background The current relevance of functional foods in human health and well-being has led to an increased interest in developing new types of oral administration systems for probiotics and nutraceuticals. Encapsulation may provide protection and sustained delivery in food formulations. Scope and approach The recent discussions about probiotics encapsulation for application in both nutraceutical and food sectors are addressed. The topics approached include encapsulation systems, nutraceuticals and probiotics concepts and current market situation, microbial microencapsulation, and food applications for beyond their use in the pharmaceutical industry. Studies analyzing the viability and stability of encapsulated probiotics applied in food matrices are presented and discussed as well. Key findings and conclusions This review sought to present the most recent discussions regarding the nano/microencapsulation of nutraceuticals and probiotics process for application in food products. Although many protocols found in the scientific literature are not viable for commercial applications, some formulations can be employed in food systems. In addition, in vivo human studies are extremely necessary to prove the effectiveness of such formulations.

Most of the people in the world are affected by glaucoma, which leads to irreversible blindness. Several patient friendly treatments are available, nevertheless medications lack an easy and efficient way of sustained delivery. To make the delivery with enhanced bioavailability, biodegradable and non-biodegradable polymers-based drug carriers are explored. However, ocular drug delivery issues have not been resolved yet due to less adhesiveness, poor penetration ability, pH, and temperature dependent burst releases. Chitosan is found to be effective for ocular drug delivery due to excellent physio-chemical properties in terms of overcoming the existing issues. In this review, we aim to highlight why it has been chosen and the holy grail for ocular drug delivery. Besides, we have comprehensively reviewed recent patents on chitosan as a platform for ocular drug delivery and future perspectives on factors, lacunae and challenges that need to be addressed for better ocular delivery methods for glaucoma management.

Exopolysaccharides (EPS) are important bioproducts produced by some genera of lactic acid bacteria. EPS are famous for their shelf-life improving properties, techno-functional enhancing abilities in food and dairy industries, besides their beneficial health effects. Furthermore, exopolysaccharides have many prospective and well-established contributions in the field of drugs and diagnostic industry. In this review, classification of EPS produced by LAB was presented. Moreover, current and potential applications of EPS in food, dairy, baking industries, cereal-based, and functional products were described. Also, some clinical and pharmaceutical applications of EPS such as intelligent drug delivery systems (microsystems and nanosystems for sustained delivery), interpenetrating polymer networks (IPNs), anticancer drug-targeting, recombinant macromolecular biopharmaceuticals, gene delivery, tissue engineering, and role of EPS in diagnostics were highlighted. Finally, future prospects concerning enhancing EPS production, minimizing costs of their production, and exploring their contribution in further applications were discussed.

Pulmonary route of drug delivery has drawn significant attention due to the limitations associated with conventional routes and available treatment options. Drugs administered through pulmonary route has been an important research area that focuses on to developing effective therapeutic interventions for asthma, chronic obstructive pulmonary disease, tuberculosis, lung cancer etc. The intravenous route has been a natural route of delivery of proteins and peptides but associated with several issues including high cost, needle-phobia, pain, sterility issues etc. These issues might be addressed by the pulmonary administration of macromolecules to achieving an effective delivery and efficacious therapeutic impact. Efforts have been made to develop novel drug delivery systems (NDDS) such as nanoparticles, microparticles, liposomes and their engineered versions, polymerosomes, micelles etc to achieving targeted and sustained delivery of drug(s) through pulmonary route. Further, novel approaches such as polymer-drug conjugates, mucoadhesive particles and mucus penetrating particles have attracted significant attention due to their unique features for an effective delivery of drugs. Also, use of semi flourinated alkanes is in use for improvising the pulmonary delivery of lipophilic drugs. Present review focuses on to unravel the mechanism of pulmonary absorption of drugs for major pulmonary diseases. It summarizes the development of interventional approaches using various particulate and vesicular drug delivery systems. In essence, the orchestrated attempt presents an inflammatory narrative on the advancements in the field of pulmonary drug delivery.

Implantable drug-eluting devices that provide therapeutic cover over an extended period of time following a single administration have potential to improve the treatment of chronic conditions. These devices eliminate the requirement for regular and frequent drug administration, thus reducing the pill burden experienced by patients. Furthermore, the use of modern technologies, such as 3D printing, during implant development and manufacture renders this approach well-suited for the production of highly tuneable devices that can deliver treatment regimens which are personalised for the individual. The objective of this work was to formulate subcutaneous implants loaded with a model hydrophobic compound, olanzapine (OLZ) using robocasting - a 3D-printing technique. The formulated cylindrical implants were prepared from blends composed of OLZ mixed with either poly(caprolactone) (PCL) or a combination of PCL and poly(ethylene)glycol (PEG). Implants were characterised using scanning electron microscopy (SEM), thermal analysis, infrared spectroscopy, and X-ray diffraction and the crystallinity of OLZ in the formulated devices was confirmed. In vitro release studies demonstrated that all the formulations were capable of maintaining sustained drug release over a period of 200 days, with the maximum percentage drug release observed to be c.a. 60% in the same period.

Polymeric vehicles are versatile tools for therapeutic gene delivery. Many polymers—when assembled with nucleic acids into nanoparticles or polyplexes—can protect the cargo from degradation and clearance in vivo, and facilitate its transport into intracellular compartments. Design options in polymer synthesis yield a comprehensive range of molecules and resulting vehicle formulations. These properties can be manipulated to achieve stronger association with nucleic acid cargo and cells, improved endosomal escape, or sustained delivery depending on the application. Here, we describe current approaches for polymer use and related strategies for gene delivery in preclinical and clinical applications. Polymer vehicles delivering genetic material have already achieved significant therapeutic endpoints in vitro and in animal models. From our perspective, with preclincal assays that better mimic the in vivo environment, improved strategies for target specificity, and scalable techniques for polymer synthesis, the impact of this therapeutic approach will continue to expand.

Cell microencapsulation within biocompatible polymers is an established technology for immobilizing living cells that secrete therapeutic products. These can be transplanted into a desired site in the body for the controlled and continuous delivery of the therapeutic molecules. One of the most important properties of the material that makes up the microcapsule is its oxygen penetrability, which is critical for the cells’ survival. Oxygen reaches the cells inside the microcapsules via a diffusion process. The diffusion coefficient for the microcapsules’ gel material is commonly measured using bulk techniques, where the gel in a chamber is first flushed with nitrogen and the subsequent rate of oxygen diffusion back into it is measured by an oxygen electrode placed in the chamber. This technique does not address possible heterogeneities between microcapsules, and also cannot reveal O2 heterogeneity inside the microcapsule resulting from the living cells’ activity. Here we develop and demonstrate a proof of principle for a new approach to measuring and imaging the partial pressure of oxygen (pO2) inside a single microcapsule by means of high-resolution and high-sensitivity electron spin resonance (ESR). The proposed methodology makes use of biocompatible paramagnetic microparticulates intercalated inside the microcapsule during its preparation. The new ESR approach was used to measure the O2 diffusion properties of two types of gel materials (alginate and extracellular matrix – ECM), as well as to map a 3D image of the oxygen inside single microcapsules with living cells. Statement of Significance The technology of cell microencapsulation offers major advantages in the sustained delivery of therapeutic agents used for the treatment of various diseases ranging from diabetes to cancer. Despite the great advances made in this field, it still faces substantial challenges, preventing it from reaching the clinical practice. One of the primary challenges in developing cell microencapsulation systems is providing the cells with adequate supply of oxygen in the long term. Nevertheless, there is still no methodology good enough for measuring O2 distribution inside the microcapsule with sufficient accuracy and spatial resolution without affecting the microcapsule and/or the cells’ activity in it. In the present work, we introduce a novel magnetic resonance technique to address O2 availability within cell-entrapping microcapsules. For the first time O2 distribution can be accurately measured and imaged within a single microcapsule. This new technique may be an efficient tool in the development of more optimal microencapsulation systems in the future, thus bringing this promising field closer to clinical application.

We describe surgical sutures enabled with the local, sustained delivery of a TGF-β inhibitory drug, tranilast. To fabricate drug-delivery sutures, we separately prepared a tranilast-loaded strand using poly(lactic-co-glycolic acid), which was then physically braided with a surgical suture already in clinical use. By this method, the drug-delivery sutures maintained the mechanical strength and allowed the modulation of drug release profiles by simply altering the tranilast-loaded strand. The drug-delivery sutures herein released tranilast for up to 14 days. When applied to animal models, scarring was indeed reduced with diminished TGF-β expression and fibroblast numbers during the entire 21 day testing period.

The study aimed at investigating the potential of spray drying method for encapsulation of protein drugs into solid lipid microparticles (MP) and evaluating effects of excipients on encapsulation and release of protein from MP. After transformation of model protein insulin to insulin-phospholipid complex, it was dissolved together with lipid excipients in organic solvent, which was spray-dried to form solid lipid MP. Polymeric MP with D, L-lactic-co-glycolic acid (PLGA) were prepared similarly. Around 90% of insulin was encapsulated in glycerol monostearate MP and glycerol distearate MP, whereas the encapsulation efficiency was 60% and 35% for tristearate (TG18) MP and tribehenate (TG22) MP, respectively. The secondary structure of insulin in the spray-dried MP was substantially similar to that of the insulin control solution, suggesting that only minor alterations occurred during the spray drying process. Sustained release of insulin was observed from both TG18 MP and TG22 MP. The burst release of insulin from TG18 MP and TG22 MP was around 30% and 10%, respectively, which was significantly lower than that from PLGA MP (40%). In conclusion, spray drying a solution containing both lipids and protein-phospholipid complex is a promising method for encapsulating protein into solid lipid MP, which can be used for sustained delivery of protein drugs.

The study design is that lipophilic drug was encapsulated within dissolving microneedles (DMNs) for sustained-release delivery over 1 week. Etonogestrel (ENG), the progestogen used in hormonal contraceptives, was loaded in 2-layered DMNs in the form of microcrystal particles (MPs). In vitro release study indicated that ENG in the MP form could sustain drug release compared to noncrystal form. Hydroxypropyl methylcellulose and polyvinyl alcohol were used to prepare the fast dissolving needle tips and flexible back layer, respectively. The mechanical strength of microneedles was not affected even with the drug-loading efficiency of 50.0% in needle tips. The penetration depth of DMNs in skin, observed using a confocal laser scanning microscope, was approximately 280 μm. The tips of DMNs could be dissolved in rat skin within 1 h with a drug delivery efficiency of 63.8 ± 2.0%. The pharmacokinetic study of DMN treatment in rats showed that the plasma levels of ENG were a dose-dependent profile and were much steadier than intradermal (ID) injections. There was no statistical difference between bioavailability of ENG treated with DMNs or ID injections ( p >0.05). Therefore, the novel DMNs loaded with drug MP provided a potential minimally invasive route for ID sustained delivery of lipophilic drug.

Conventional eyedrops commonly used to deliver ophthalmologic treatments do not provide a sustained delivery of the drug, since a large portion of the intended dose is lost through eye drainage immediately following application. Micrometric sized crosslink gel based on copolymers incorporating thermal-sensitive copolymers were proposed for use in ophthalmic drug delivery. Eyedrops based on a thermoresponsive polymer were developed by mixing poly(acrylic acid- graft - N -isopropylacrylamide) (PAAc- graft -PNIPAAm) with PAAc- co -PNIPAAm gel and incorporating [ 3 H]-epinephrine for in vitro evaluation of ophthalmic drug release. Polymeric eyedrops are clear solutions at room temperature but undergo partial solidification to a soft thin film on coming into contact with the corneal surface. On evaluation of the in vitro release kinetics of the embedded [ 3 H]-epinephrine, PAAc- graft -PNIPAAm was found to exhibit faster drug release, while the mixture of PAAc- graft -PNIPAAm and PAAc- co -PNIPAAm gel showed a more sustained release profile and identifying the anomalous transport mechanism as a key factor. Intraocular pressure (IOP) was monitored by administration of epinephrine in polymeric eyedrops effectively reduced IOP for 36 h, which is a considerable prolongation of the effect compared to the 8-h IOP decrease observed following administration via traditional eyedrops. Overall, our results indicate that the kinetics of drug release from the polymeric eyedrops are determined by crosslinking density, which affects the formation of capillary networks in the polymer matrix and thereby regulates drug diffusion into the polymeric network, hence considered as feasible approach to controlled drug release in ophthalmic drug delivery.

The influence of macromolecules in major eye disorders including retinal neovascularization, retinopathy, age-related macular degeneration, choroidal neovascularization, etc. offers substantial advantages in the development of formulations, designing of new delivery approaches, and setting of new effective therapies. The transportation of proteins and peptides like recombinant proteins, aptamers, monoclonal antibodies face major challenges due to their high molecular weight (MW > 100 kDa), rapid degradation, low solubility and instability for long-term and alleviated condition. To overcome such limitations, the ocular route offers major advantages like prevention of first-pass metabolism, high retention time, less degradation, ease of access for injectables as well as accurate dosing of dosage form. This review article focuses on newer and advanced approaches like dendrimers, nanoparticles/spheres, microparticles/spheres, minimally-invasive microneedles, stimuli-responsive polymeric systems, in-situ gel formulations, delivery using cell-penetrating peptide, use of penetration enhancers and prodrug approach, chemical chaperones, use of anti-VEGF agents, TNF-α agents, use of living cells, etc. for effective and strategic transportation of macromolecules across the eye for controlled and sustained delivery systems without significant adverse events. For advancement in diagnostic and treatment, ophthalmic route is integrated with 3D printing, electronic chip-embedded drug delivery, artificial intelligence, teleophthalmology and quantum dots. These approaches propose efficient delivery of actives with lower toxicity and higher stability for serving the purpose of modernised delivery systems in near future.

There is a clear and urgent clinical need to develop soft tissue fillers that outperform the materials currently used for adipose tissue reconstruction. Recently, extensive research has been performed within this field of adipose tissue engineering as the commercially available products and the currently existing techniques are concomitant with several disadvantages. Commercial products are highly expensive and associated with an imposing need for repeated injections. Lipofilling or free fat transfer has an unpredictable outcome with respect to cell survival and potential resorption of the fat grafts. Therefore, researchers are predominantly investigating two challenging adipose tissue engineering strategies: in situ injectable materials and porous 3D printed scaffolds. The present work provides an overview of current research encompassing synthetic, biopolymer-based and extracellular matrix-derived materials with a clear focus on emerging fabrication technologies and developments realized throughout the last decade. Moreover, clinical relevance of the most promising materials will be discussed, together with potential concerns associated with their application in the clinic.

Tendon injuries are more common, and due to the lack of adequate growth factors, the healing capacity of the injured tendon is limited. The objective of this study is to evaluate the effectiveness of Nanoparticle-coated sutures carrying growth factors on accelerating tendon repair. We found that nanoparticles can adhere uniformly to the surface of the suture modified with polydopamine. After stitching, the nanoparticles remain on the surface of the suture, and its loaded proteins can spread in the tendon tissues. After treatment, in the chicken flexor tendon healing model and the rat Achilles healing model, the ultimate strengths of repaired tendons treated with bFGF and VEGFA-releasing sutures was significantly greater than the tendons repaired with control sutures at multiple time-points. At 6 weeks, adhesion scores in the bFGF and VEGFA-releasing suture group were significantly smaller than those of the control suture group. Tendon gliding excursions were significantly greater in the bFGF and VEGFA-releasing suture group than in the unmodified control sutures. Work of digital flexion was significantly decreased in the bFGF and VEGFA-releasing suture group than in the control group. In a word, we developed a novel platform for local and sustained delivery of growth factors based on the Nanoparticle-coated sutures, which can effectively deliver growth factors to tissues and control the release of growth factors. Dual growth factors loaded Nanoparticle-coated sutures can significantly promote tendon healing. This growth factors delivery system is an attractive therapeutic tool to repair injured tendons.

Over the years, extensive studies on erythrocytes, also known as red blood cells (RBCs), as a mechanism for drug delivery, have been explored mainly because the cell itself is the most abundant and has astonishing properties such as a long life span of 100-120 days, low immunogenicity, good biocompatibility, and flexibility. There are various types of RBC-based systems for drug delivery, including those that are genetically engineered, non-genetically engineered RBCs, as well as employing erythrocyte as nanocarriers for drug loading. Although promising, these systems are still in an early development stage. In this review, we aimed to highlight the development of biomimicking RBC-based drug and vaccine delivery systems, as well as the loading methods with illustrative examples. Drug-erythrocyte associations will also be discussed and highlighted in this review. We have highlighted the possibility of exploiting erythrocytes for the sustained delivery of drugs and vaccines, encapsulation of these biological agents within the erythrocyte or coupling to the surface of carrier erythrocytes, and provided insights on genetically- and non-genetically engineered erythrocytes-based strategies. Erythrocytes have been known as effective cellular carriers for therapeutic moieties for several years. Herein, we outline various loading methods that can be used to reap the benefits of these natural carriers. It has been shown that drugs and vaccines can be delivered via erythrocytes but it is important to select appropriate methods for increasing the drug encapsulated or conjugated on the surface of the erythrocyte membrane. The outlined examples will guide the selection of the most effective method as well as the impact of using erythrocytes as delivery systems for drugs and vaccines.

Enabling angiogenesis is critical for the success of tissue repair therapies and the fate of tissue-engineered constructs. Although many biochemical signaling molecules have been used, their biological functions in vivo are known to be limited, mainly due to their short lifetime and poor activity. Matrices (or engineered biomaterials), beyond the biochemical signals, play pivotal roles in stimulating angiogenic processes. Here we discuss the proangiogenic effort taken to repair and regenerate various tissues including skin, bone, muscle and nerve, focusing on the roles of engineered matrices. This includes the design of pore structure and physico-chemical properties (nanotopology, stiffness, chemistry and degradability), the tailoring of matrices for proper presentation of growth factors and their crosstalks with adhesion ligands, the controlled and sustained delivery of angiogenic molecules and metallic ions, and the engineering of cells and construction of prevascularized tissues. Collectively, the materials-driven strategies are envisaged to tune the cell and tissue microenvironments where angiogenic events can be significantly favored through the matrix cues and properly presented or delivered signaling molecules and cells.

Background Sarcoma accounts for 20% of solid tumors in children. Surgery has significant morbidity. We hypothesized that delivering chemotherapy directly into tumors through sustained release silk systems could slow tumor growth. Methods Human Ewing sarcoma cells A673 were cultured with vincristine and doxorubicin to determine half maximal inhibitory concentration (IC 50 ). Cells were injected into mouse hind leg to create orthotopic tumors. Tumor volumes were measured using ultrasound. When volume reached >250mm 3, interventions included: implantation of drug-free silk foam (Control-F), doxorubicin 400μg foam (Dox400-F), vincristine 50μg foam (Vin50-F), drug-free silk gel (Control-G), vincristine 50μg gel (Vin50-G), or single dose intravenous vincristine 50μg (Vin50-IV). End-point was volume>1000mm 3 . Kaplan Meier and ANOVA were used. Results IC 50 for vincristine and doxorubicin was 0.5ng/mL and 200ng/mL, respectively. There was no difference between Dox400-F [6±1days to end point (DTEP)] and Control-F (5±1.3 DTEP). Vin50-F (12.4±3.5 DTEP) had slower growth compared to Control-F (p Conclusion Sustained delivery of vincristine inside the sarcoma tumor with silk gel decreased tumor growth. Applying this intratumoral treatment strategy may potentially decrease the extent of surgical excision.

1. PURPOSE: To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys. We also compared the IOP reduction to that achieved with daily 0.005% latanoprost ophthalmic solution. 2. DESIGN: Preclinical efficacy study of three treatment arms in a crossover design. 3. SUBJECTS: Female cynomolgus monkeys with glaucoma-induced in one eye by repeated argon laser trabeculoplasty. 4. METHODS: Low dose (CL(LO)) and high dose (CL(HI)) latanoprost eluting contact lenses were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. In this crossover study, we assessed the IOP lowering effect of CL(LO), CL(HI), or daily latanoprost ophthalmic solution in a single eye in the same four female monkeys. Each monkey consecutively received 1 week of continuous wear CL(LO), 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous wear CL(HI). On two consecutive days prior to initiation of each study arm, the IOP of anesthetized monkeys was measured using a calibrated pneumatonometer every hour over 7 consecutive hours from 9:30 AM to 3:30 PM to establish the baseline IOP at the predetermined time points and to account for any diurnal variations that may have occurred over the time period studied. Two-tailed Student t-tests and repeated measures ANOVA were used for statistical analysis with two-tailed values of p < 0.05 considered statistically significant. 5. Main Outcome Measure: Intraocular pressure. 6. RESULTS: Latanoprost ophthalmic solution resulted in IOP reduction of 5.4 ± 1.0 mmHg on days 3 and peak IOP reduction of 6.6 ± 1.3 mmHg on day 5. CL(LO) reduced IOP by 6.3 ± 1.0, 6.7 ± 0.3, and 6.7 ± 0.3 mmHg on days 3, 5, and 8 respectively. CL(HI) lowered IOP by 10.5 ± 1.4, 11.1 ± 4.0, and 10.0 ± 2.5 mmHg on days 3, 5, and 8 respectively. For the CL(LO) and CL(HI) treatment groups, the IOP was statistically significantly reduced compared to the untreated baseline at most time points measured. CL(HI) demonstrated significantly greater IOP reduction than latanoprost ophthalmic solution on Day 3 (p = 0.001) and Day 5 (p = 0.015), and at several time points on Day 8 (p < 0.05). There was no statistically significant difference in IOPs when comparing CL(HI) and CL(LO). 7. CONCLUSIONS: Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery.

Biocompatible 2-dimensional layered compounds such as clays and layered double hydroxides (anionic clays) have been explored and utilized in drug delivery system for therapeutic application because they can safely encapsulate drug molecules via intercalation reaction. Therefore, various kinds of drug molecules and bio-functional molecules with cationic or anionic charge have been incorporated into clay delivery carriers, giving rise to the heterostructured layered nanohybrids with chemo-therapeutic and gene-therapeutic functions. Recently, such inorganic delivery systems have received growing attention because their inertness and low toxicity gives rise to safety and stability in bio-systems. Furthermore, the hybridization of drug with clays offers the fascinating features such as controlled and sustained release, improved water-solubility, and even protective and targeted delivery. Unique release behaviors of drugs from the drug clay nanohybrids are originated from molecular level incorporation, and strong interaction between drug and inorganic layers including electrostatic and hydrogen bonding interactions. In the present review, various drug clay nanohybrids will be introduced, and their recent development will be highlighted in the viewpoint of oral administration drugs with controlled and sustained release. This work was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korea Government (MSIP) ( 2005-0049412 and 2013R1A1A2062239 ). Scopus

Hyaluronic acid (HA) hydrogel has been used as a carrier of recombinant human bone morphogenetic protein (rhBMP)-2 for sustained delivery. To enhance peri-implant osteogenesis, a dried coating of rhBMP-2 HA hydrogel (BMP-HAH) on dental implants was designed; this approach provides the advantage of omitting in situ preparation of wet HA hydrogel. Sustained release of rhBMP-2 was more efficient for dried hydrogel over wet hydrogel. For both types, the released rhBMP-2 consistently led to enhanced alkaline phosphatase activity and osterix expression in human mesenchymal stromal cells. Histomorphometric analysis 4 weeks after placement of a dental implant in canine mandibles showed that the dried coating of BMP-HAH (10 μg/ml, n = 6) resulted in a significantly greater bone area (BA) than the wet BMP-HAH (10 μg/ml, n = 6) (p = 0.006) and implants without any coating (n = 6) (p = 0.022), while simple dip coating with rhBMP-2 (10 μg/ml, n = 6) resulted in significantly greater BA than the other three groups (p < 0.0005). Bone-to-implant contact (BIC) was significantly different only between the dried and wet coating of BMP-HAH (p = 0.014). Our results suggest that a simple dip coating of rhBMP-2 is more effective for increased peri-implant osteogenesis compared to a coating of BMP-HAH with sustained release.

We prepared a bone plate enabled with the local, sustained release of alendronate, which is a drug known to inhibit osteoclast-mediated bone resorption and also expedite the bone-remodeling activity of osteoblasts. For this, we coated a bone plate already in clinical use (PLT-1031, Inion, Finland) with a blend of alendronate and a biocompatible polymer, azidobenzoic acid-modified chitosan (i.e., Az-CH) photo-crosslinked by UV irradiation. As we performed the in vitro drug release study, the drug was released from the coating at an average rate of 4.03μg/day for 63days in a sustained manner. To examine the effect on bone regeneration, the plate was fixed on an 8mm cranial critical size defect in living rats and the newly formed bone volume was quantitatively evaluated by micro-computed tomography (micro-CT) at scheduled times over 8weeks. At week 8, the group implanted with the plate enabled with sustained delivery of alendronate showed a significantly higher volume of newly formed bone (52.78±6.84%) than the groups implanted with the plates without drug (23.6±3.81%) (p

Recent clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) may prevent HIV infection in a significant number of HIV-1 negative individuals in venerable populations; however, trial efficacy has been highly variable, with notable successes and failures. Poor adherence to PrEP regimens has been implicated as a primary factor in determining efficacy of these trials. With the exception of CAPRISA 004 where use of a pericoital tenofovir gel led to a 39% reduction in HIV infection, all successful PrEP regimens to date have used the fumarate salt of the tenofovir disoproxil ester prodrug of tenofovir (TDF) alone or in combination with emtricitabine (FTC). A sustained-release, intravaginal ring (IVR) formulation of TDF holds promise for improving adherence and, thus, increasing the effectiveness of PrEP. Here, a novel IVR delivering TDF with sustained zero-order release characteristics that may be controlled over nearly two orders of magnitude is described. Pod-IVRs containing 1-10 pods delivering TDF at 0.01-10 mg d(-1) were fabricated and their release characteristics evaluated in vitro. The pod-IVRs stabilized TDF against hydrolytic degradation both in storage and during in vitro release experiments. Successful translation of the TDF pod-IVR from laboratory evaluation to large-scale clinical trials requires the ability to manufacture the devices at low cost and in high quantity. Methods for manufacturing and scale-up were developed and applied to pilot-scale production of TDF pod-IVRs that maintained the IVR's release characteristics while significantly decreasing the variability in release rate observed between pod-IVRs. This pod-IVR enables for the first time the dose-ranging clinical studies that are required to optimize topical TDF PrEP in terms of efficacy and safety.

The intention behind the present work was to develop a microsponge based novel dosage form for sustained delivery of domperidone. Quasi-emulsion solvent diffusion method was employed using Eudragit RS-100 with various drug–polymer ratios for the preparation of microsponges. For optimization purposes, several factors which affect microparticles' physical properties were investigated. Characterization techniques followed for the formed microsponges were DSC, FTIR, SEM, XRD and particle size analysis, along with morphology, drug loading and in vitro drug release. It was found that there were no chemical interactions between drugs and polymers used as per DSC and FTIR results. The drug–polymer ratio showed remarkable impact on drug content, encapsulation efficiency and particle size. SEM micrographs revealed that microsponges were spherical in shape with porous surface, and had 104 ± 0.22 µm mean particle size. The microsponges were then loaded in capsules followed by in vitro drug release study; which depicted that microsponges with drug–polymer ratio of 1:2 were more proficient to give extended drug release of 76.38% at the end of 8 h, superior in contrast to conventional marketed formulation Domstal ® , which got exhausted incredibly earlier by releasing 82.57% drug at the end of ½ h only. Hence, the developed microsponge based formulation of domperidone would be an expectant, promising substitute to conventional therapy of gastroparesis, emesis and alike gastric ailments.

Characterization of the physicochemical and physicomechanical properties as well as biopharmaceutical suitability of a drug delivery system is needful in optimization of the formulation and manufacturing processes in order to achieve the desired responses. Interpolymeric blend (IPB) nano-enabled gastroretentive levodopa-loaded drug delivery systems were formulated, optimized and characterized using techniques such as spectroscopy, calorimetry, density, textural analysis, morphological analysis, porosity analysis and magnetic resonance imaging. The in vitro drug release of the delivery systems was compared to those of the conventional dosage forms and in vivo absorption was predicted. The average densities were 1.41 mg/mm(3) and 1.56 mg/mm(3) for the two formulations; rigidities were 75.05 N/mm and 84.93 N/mm; and 92% of the pores of the IPB drug delivery system were mesoporous. MR imaging displayed the swollen front at pH 1.5 and the eroded front at pH 4.5. In comparisons to the conventional dosage forms, the IPB nano-enabled gastroretentive levodopa-loaded drug delivery systems exhibited drug release over a prolonged period of time and levodopa-loaded IPB matrices were the best fit for zero-order release. Indeed the analyses of IPB nano-enabled gastroretentive levodopa-loaded drug delivery systems indicate that they hold promise as sustained delivery system for management of Parkinson's disease.

Delivery of therapeutic agents to posterior segment of the eyes is challenging due to the anatomy and physiology of ocular barriers and thus long-acting implantable formulations are much desired. In this study, a thermogelling system composed of two poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was developed as an injectable matrix for intravitreal drug delivery. The thermogel was prepared by mixing a sol and a precipitate of PLGA-PEG-PLGA triblock copolymers with different block ratios, among which a hydrophobic glucocorticoid, dexamethasone (DEX), was incorporated. The DEX-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. The in vitro release rate of DEX from the thermogel could be conveniently modulated by varying the mixing ratio of the two copolymers. The long-lasting intraocular residence of the thermogel was demonstrated by intravitreal injection of a fluorescence-labeled thermogel to rabbits. Compared with a DEX suspension, the intravitreal retention time of DEX increased from a dozen hours to over 1week when being loaded in the thermogel. Additionally, intravitreal administration of the thermogel did not impair the morphology of retina and cornea. This study reveals that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for sustained delivery of bioactive agents into the eyes, and provides an alternative approach for treatment of posterior segment diseases.

Sustainability of the Body Project, a dissonance-based selective eating disorder prevention program supported by efficacy and effectiveness trials, has not previously been examined. This mixed-methods study collected qualitative and quantitative data on training, supervision, and the intervention from 27 mental health clinicians from eight US universities who participated in an effectiveness trial and quantitative data on 2-year sustainability of program delivery. Clinicians, who were primarily masters-level mental health providers, had limited experience delivering manualized interventions. They rated the training and manual favorably, noting that they particularly liked the role-plays of session activities and intervention rationale, but requested more discussion of processes and group management issues. Clinicians were satisfied receiving emailed supervision based on videotape review. They reported enjoying delivering the Body Project but reported some challenges with the manualized format and time constraints. Most clinicians anticipated running more groups after the study ended but only four universities (50%) reported providing additional Body Project groups at the 1-year follow-up assessment and sustained delivery of the groups decreased substantially two years after study completion, with only one university (12%) continuing to deliver groups. The most commonly reported barriers for conducting additional groups were limited time and high staff turnover.

In the past decade, mesoporous silica nanoparticles (MSNs) with a large surface area and pore volume have attracted considerable attention for their application in drug delivery and biomedicine. In this review, we highlight the recent advances in silica-assisted drug delivery systems, including (1) MSN-based immediate/sustained drug delivery systems and (2) MSN-based controlled/targeted drug delivery systems. In addition, we summarize the biomedical applications of MSNs, including (1) MSN-based biotherapeutic agent delivery; (2) MSN-assisted bioimaging applications; and (3) MSNs as bioactive materials for tissue regeneration. From the Clinical Editor This comprehensive review presents recent advances in mesoporous silica nanoparticles assisted drug delivery systems, including both immediate and sustained delivery systems as well as controlled release and targeted drug delivery systems. In addition to achieving therapeutic agent delivery, imaging applications and potential use of silica NPs in tissue regeneration are also discussed.

Simulations of delivery of IgG1 Fab, an anti-vascular epithelial growth factor (VEGF) macromolecular drug for the treatment of age-related macular degeneration (AMD), from an episcleral thermally responsive-poly(N-isopolyacrylamide) (NIPAM)-gel implant, are made to evaluate the effectiveness of sustained delivery. The model of the human eye used in the above simulations is validated as far as its anatomical and physiological features by the agreement observed in comparing results of simulations of intravitreal fluorescein delivery with relevant experimental data. Simulations of IgG1 Fab delivery from an episcleral NIPAM-gel implant to the posterior eye, with the previously validated anatomically and physiologically correct model of the human eye, show that drug therapeutic levels in the posterior eye are sustained for 8 weeks similarly to those associated with intravitreal injection of IgG1 Fab. Thus, delivery of the macromolecular anti-VEGF drug IgG1 Fab from an episcleral NIPAM-gel implant seems to be a viable alternative to more invasive, risk-related delivery by intravitreal injection, as effective and sustainable as the latter.

A method for the sustained delivery of exenatide was proposed using nanoparticles (NPs) with a core/shell structure. The interactions between lipid bilayers and Pluronics were utilized to form various NPs using a layer-by-layer approach. Transmittance electron microscopy and dynamic light scattering were used to examine the morphology of the NPs. The in vitro release pattern was observed as a function of changes in the structure of the NPs, and the structural integrity of exenatide released was examined by SDS–PAGE analysis. Pharmacokinetics and antidiabetic effects were also observed with the structural change of NPs using in vivo animal models. In vitro–in vivo correlation was discussed in relation to manipulation of the NP structures.

The availability of stabilization and sustained delivery systems for antibody therapeutics remains a major clinical challenge, despite the growing development of antibodies for a wide range of therapeutic applications due to their specificity and efficacy. A mechanistic understanding of protein-matrix interactions is critical for the development of such systems and is currently lacking as a mode to guide the field. We report mechanistic insight to address this need by using well-defined matrices based on silk gels, in combination with a monoclonal antibody. Variables including antibody loading, matrix density, charge interactions, hydrophobicity and water access were assessed to clarify mechanisms involved in the release of antibody from the biomaterial matrix. The results indicate that antibody release is primarily governed by hydrophobic interactions and hydration resistance, which are controlled by silk matrix chemistry, peptide domain distribution and protein density. Secondary ionic repulsions are also critical in antibody stabilization and release. Matrix modification by free methionine incorporation was found to be an effective strategy for mitigating encapsulation induced antibody oxidation. Additionally, these studies highlight a characterization approach to improve the understanding and development of other protein sustained delivery systems, with broad applicability to the rapidly developing monoclonal antibody field.

Aim The aim of the present study was to prepare sustained release pellets of aceclofenac using pelletization technique. Methods The sustained release was ensured by coating the pellets with ethyl cellulose N50 and hydroxy propyl methyl cellulose E5. The influence of rate retarding polymer, ethyl cellulose in combination with film forming agent, HPMC in different weight ratios on drug release kinetics was studied. Results The in vitro dissolution studies of aceclofenac from the sustained release pellets were carried out in pH 6.8 phosphate buffer using USP type I apparatus. Statistically significant differences were found among the drug release profile from different formulations. Conclusion The kinetic study revealed that the release of drug from the optimized formulation was appeared to follow first order kinetics. The dissolution profile and in vitro release kinetics showed that aceclofenac pellets were promising for sustained delivery of the drug.

In vitro testing and quantitative analysis of a matrix, hydrophilic polyether urethane (HPEU) intravaginal ring (IVR) for sustained delivery of the anti-HIV agent tenofovir (TFV) are described. To aid in device design, we employed a pseudo-steady-state diffusion model to describe drug release, as well as an elastic mechanical model for ring compression to predict mechanical properties. TFV-HPEU IVRs of varying sizes and drug loadings were fabricated by hot-melt extrusion and injection molding. In vitro release rates of TFV were measured at 37 °C and pH 4.2 for 30 or 90 days, during which times IVR mechanical properties and swelling kinetics were monitored. Experimental data for drug release and mechanical properties were compared to model predictions. IVRs loaded with 21% TFV (w/w) released greater than 2mg TFV per day for 90 days. The diffusion model predicted 90 day release data by extrapolating forward from the first 7 days of data. Mechanical properties of IVRs were similar to NuvaRing, although the matrix elastic modulus decreased up to three-fold following hydration. This is the first vaginal dosage form to provide sustained delivery of milligram quantities of TFV for 90 days. Drug release and mechanical properties were approximated by analytical models, which may prove useful for the continuing development of IVRs for HIV prevention or other women's health indications.

Smart polymers have revolutionized the field of polymeric drug delivery to achieve sustained and/or targeted delivery of protein therapeutics. These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties. The stimulus is categorized as physical, chemical or biochemical and could be internal, external, single or a combination of two or more. A broad classification of smart polymers, their fabrication and refinement of release characteristics, advantages, limitations and applications have been highlighted in this review. Special emphasis has been placed on temperature and phase-sensitive polymers to deliver protein therapeutics.

The release kinetics for human immunoglobulin (IgG) through the permeable structure of nanofiber scaffold hydrogels consisting of the ac-(RADA)(4)-CONH(2) and ac-(KLDL)(3)-CONH(2) self-assembling peptides were studied during a period of 3 months. Self assembling peptides are a class of stimuli-responsive materials which undergo sol-gel transition in the presence of an electrolyte solution such as biological fluids and salts. IgG diffusivities decreased with increasing hydrogel nanofiber density providing a means to control the release kinetics. Two-layered hydrogel structures were created consisting of concentric spheres of ac-(RADA)(4)-CONH(2) core and ac-(KLDL)(3)-CONH(2) shell and the antibody diffusion profile was determined through the 'onion-like' architecture. Secondary and tertiary structure analyses as well as biological assays using single molecule analyses and quartz crystal microbalance of the released IgG showed that encapsulation and release did not affect the conformation of the antibody and the biological activity even after 3 months inside the hydrogel. The functionality of polyclonal human IgG to the phosphocholine antigen was determined and showed that IgG encapsulation and release did not affect the antibody binding efficacy to the antigen. Our experimental protocol allows for 100% IgG loading efficiency inside the hydrogel while the maximum amount of antibody loading depends solely on the solubility of the antibody in water because the peptide hydrogel consists of water up to 99.5%. Our results show that this fully biocompatible and injectable peptide hydrogel system may be used for controlled release applications as a carrier for therapeutic antibodies.

The purpose of this study was to prepare a poly(lactide-co-glycolide) (PLGA) encapsulated hydroxyapatite microspheres (HAP-MSs) as injectable depot for sustained delivery of Doxycycline (Doxy). Doxy loaded HAP-MSs (Doxy-HAP-MSs) were encapsulated with PLGA by solid-in-oil-in-water (S/O/W) emulsion-solvent evaporation technique, the effects of the PLGA used (various intrinsic viscosity and LA/GA ratio) and ratio of PLGA/HAP-MSs on the formation of Doxy-HAP-MSs and in vitro release of Doxy were studied. The results showed that sustained drug release without obvious burst was obtained by using PLGA encapsulated HAP-MSs as the carrier, also the drug release rate could be tailored by changing the ratio of PLGA/HAP-MSs, or PLGA of various intrinsic viscosities or LA/GA ratio. Lower ratio of PLGA/HAP-MSs corresponded faster Doxy release, e.g. for the microspheres of PLGA/HAP-MSs ratio of 8 and 0.25, the in vitro Doxy release percents at the end of 7days were about 23% and 76%, respectively. Higher hydrophilicity (higher ratio of GA to LA) and lower molecular weight of PLGA corresponded to higher Doxy release rates. For in vivo release study, PLGA encapsulated HAP-MSs were subcutaneously injected to the back of mice, and the results showed good correlation between the in vivo and in vitro drug release. Meanwhile, the plasma Doxy levels after subcutaneous administration of PLGA encapsulated Doxy-HAP-MSs were relatively lower and steady compared to that of the un-encapsulated microspheres. In conclusion, PLGA encapsulated HAP-MSs may be a potential vehicle for the sustained delivery of Doxy.

Heparin-conjugated hyaluronan (HA-Hp) microgels with different heparin content, i.e., 1%, 5% and 10% (w/w), were synthesized by an inverse emulsion polymerization technique for the controlled release of bone morphogenetic protein-2 (BMP-2). A heparin conjugation percentage of about 90% was obtained by elemental analysis. Hyaluronan microgels showed a smooth surface and dense network, whereas HA-Hp microgels exhibited a rougher surface with holes and concaves, and a looser internal structure with increasing the heparin content instead. However, the major microgel size of about 3 μm was independent of the heparin amount. Among the samples, HA-Hp-10% microgels existed the highest equilibrium swelling ratio of 11.8 due to its least cross-linking network. A higher BMP-2 loading efficiency and a slower release profile with increasing the heparin content indicated the conjugated heparin in HA-Hp microgels was in favor of BMP-2 binding and the sustained delivery maybe attributed to the electrostatic interaction between heparin and BMP-2.

Therapeutic modalities for posterior-eye diseases involve mostly interventions through the anterior eye, which are difficult for physicians and patients alike. Currently, sustained drug delivery to the posterior eye is gaining importance. A study for sustained delivery of an anti-VEGF agent to the posterior eye from an implant, made of poly(N-isopropylacrylamide) (NIPAM) and placed episclerally, is presented. The thermally sensitive gel is modelled as a poroelastic material with a phase transition characterized by a lower critical solution temperature (LCST). The study utilizes compartments for various eye tissues, with individual compartments considered to be completely mixed and drug transport between compartments occurring by one-dimensional diffusion.

The aim of this work is to explore the possibilities of using hydroxyapatite microspheres (HAP-MS) and polymer coated HAP-MS as the vehicles for the sustained release of small molecular drugs. The adsorption/desorption behaviors of model drug, doxycycline hydrochloride (Dox·HCl), on HAP-MS were systemically studied. Drug loaded HAP-MS was encapsulated by biodegradable PLGA using S/O/W emulsion–solvent evaporation method, and the in vitro drug release was tested. The adsorption kinetics of Dox·HCl onto HAP-MS fitted well to Freundlich model at lower drug concentrations, but when the HAP-MS was incubated in concentrated drug solutions higher than a critical concentration, precipitation of drug from solutions occurred. Rapid desorption or release of Dox·HCl from HAP-MS was observed. While, the release profile of Dox·HCl from PLGA coated microspheres showed steady slow drug release lasted for at least 7 days without obvious burst release. PLGA coated HAP-MS may provide a novel, injectable carrier for loading and long-period sustained release of small molecular, water-soluble drugs.

Biocompatible polymer solutions that can crosslink in situ following injection to form stable hydrogels are of interest as depots for sustained delivery of therapeutic factors or cells, and as scaffolds for regenerative medicine. Here, injectable self-gelling alginate formulations obtained by mixing alginate microspheres (as calcium reservoirs) with soluble alginate solutions were characterized for potential use in immunotherapy. Rapid redistribution of calcium ions from microspheres into the surrounding alginate solution led to crosslinking and formation of stable hydrogels. The mechanical properties of the resulting gels correlated with the concentration of calcium-reservoir microspheres added to the solution. Soluble factors such as the cytokine interleukin-2 were readily incorporated into self-gelling alginate matrices by simply mixing them with the formulation prior to gelation. Using alginate microspheres as modular components, strategies for binding immunostimulatory CpG oligonucleotides onto the surface of microspheres were also demonstrated. When injected subcutaneously in the flanks of mice, self-gelling alginate formed soft macroporous gels supporting cellular infiltration and allowing ready access to microspheres carrying therapeutic factors embedded in the matrix. This in situ gelling formulation may thus be useful for stimulating immune cells at desired locales, such as solid tumors or infection sites, as well as for other soft tissue regeneration applications., United States. Defense Advanced Research Projects Agency (Contract W81XWH-04-C-0139), National Institutes of Health (U.S.) (EB007280-02), National Science Foundation (U.S.) (Award 0348259)

The pharmacokinetic properties of a drug can be significantly improved by the delivery process. Scientists have understood that developing suitable drug delivery systems that release the therapeutically active molecule at the level and dose it is needed and during the optimal time represents a major advance in the field. Cell microencapsulation is an alternative approach for the sustained delivery of therapeutic agents. This technology is based on the immobilization of different types of cells within a polymeric matrix surrounded by a semipermeable membrane for the long-term release of therapeutics. As a result, encapsulated cells are isolated from the host immune system while allowing exchange of nutrients and waste and release of the therapeutic agents. The versatility of this approach has stimulated its use in the treatment of numerous medical diseases including diabetes, cancer, central nervous system diseases and endocrinological disorders among others. The aim of this review article is to give an overview on the current state of the art of the use of cell encapsulation technology as a controlled drug delivery system. The most important advantages of this type of "living" drug release strategy are highlighted, but also its limitations pointed out, and the major challenges to be addressed in the forthcoming years are described.

Experimental protocols used for chronic infusion of neuroactive agents within regions of the brain often utilize a mini-osmotic pump system. Agents are commonly delivered via a stainless steel cannula with a diameter of 0.30 mm or greater. Systems utilizing a cannula of this caliber may impose trauma to the area of interest resulting in architectural damage, thereby compromising structural integrity and normal functioning. As neuroscience inquiry becomes more sophisticated, investigation of brain structures and circuitry requires improved levels of accuracy and higher resolution. We have developed a method for the preparation and implantation of a chronic infusion system within the brain utilizing a borosilicate microcannula with a tip diameter of 50 microm. This technique reduces damage to the local environment and diminishes reactive gliosis at the site of infusion. The configuration of the microinfusion system is also able to conform to the surface of the animal's skull, precluding the need for large cranial pedestals, and thus facilitating closure of the scalp incision and reducing the risk of infection. We demonstrate reliable sustained delivery of a dye having a representative molecular weight using an in vitro model and in vivo studies in rats.

Therapeutic angiogenesis of coronary and peripheral disease has gone through a period of great hype but has now entered a rational phase. Initial clinical trials with fibroblast growth factor-2 and vascular endothelial growth factor-A have been disappointing, probably owing to suboptimal delivery and incorrect targeting. It is now understood that sustained delivery will be required and that enhancement of collateral formation, rather than angiogenesis, should be targeted. The timing of growth factor therapy might be important as most of these agents protect against ischemic and reperfusion injury, and some may favorably affect post-infarct cardiac remodeling. Preclinical testing of novel delivery strategies, combination therapy as well as novel growth factors and transcription factors pave the way for duly designed and timed clinical trials.

International audience; Equilibrium data of the solubility of carbon dioxide in Precirol(R) ATO5, Compritol(R) 888 ATO and Gelucire(R) 43-01, three solid lipid carriers suitable for controlled/sustained delivery, were measured by a static analytical method for three different temperatures each, in a pressure range from 10 to 20 MPa. The influence of the presence of carbon dioxide in the melting point of the lipid matrices was also studied by a visual method for pressures up to 30 MPa. All the compounds studied presented a similar behaviour in the presence of carbon dioxide, showing a decrease in the melting points between 5 and 13 degrees C, whereas the solubility of carbon dioxide varies from 0.3 to 0.5 g/g of lipid compound. These results are of utmost importance to design supercritical fluid processes for particle formation at lower operating costs.

Caffeine is utilized as a stimulant to impart a desired level of alertness during certain working hours. Usually, a single dose of caffeine induces 2–3 h of alertness coupled with side effects whereas a longer effect of 8–12 h is very useful for both daily life and military action. Thus, there is a need to deliver the stimulant continuously to an individual at one time to impart an increased level of alertness for the period stated after administration. This study aimed to design a polymeric microparticle system for sustained delivery of caffeine using a polymeric matrix. Poly(ethylene oxide) (PEO) was used as the erodible matrix material and the caffeine polymeric tablets were fabricated by compression using a Graseby Specac hydraulic press. In vitro release profiles as well as the pharmacokinetics studies data were obtained. Caffeine tablets fabricated using various polymers showed a high initial burst release type profile as compared to the caffeine-PEO-tablet. The PK studies showed sustained delivery of caffeine resulted in two expected phenomena: a reduction in the initial high rate of caffeine release (burst release) as well as a reduction in the change in caffeine concentration in the systemic circulation. A simple two-component system for sustained-release caffeine formulation therefore has been achieved.

Combined angiogenic therapies may be superior to single angiogenic therapy for treatment of limb ischemia. First, we investigated whether the angiogenic efficacy of basic fibroblast growth factor (bFGF) administration and bone marrow-derived mononuclear cell (BMMNC) transplantation can be enhanced by sustained delivery (SD) of bFGF and BMMNC transplantation using a matrix, respectively, in mouse ischemic limbs. Next, we investigated whether the angiogenic efficacy of combination of two angiogenic strategies is superior to either strategy alone. One day after surgical induction of mouse hindlimb ischemia, mice were randomized to receive either no treatment, daily injection (DI) of bFGF, SD of bFGF, BMMNC transplantation using culture medium, BMMNC transplantation using fibrin matrix (FM), or combination of SD of bFGF with BMMNC transplantation using FM. The SD of bFGF significantly increased the microvessel density, compared with DI of bFGF (659±48/mm2 versus 522±39/mm2, p 0.05 ). BMMNC transplantation using FM significantly increased the microvessel density, compared with BMMNC transplantation using culture medium (523±103/mm2 versus 415±75/mm2, p 0.05 ). Importantly, combination of bFGF sustained release with BMMNC transplantation using FM further increased the densities of microvessels and arterioles, compared to either strategy alone ( p 0.05 ). The SD method of angiogenic protein and cell transplantation using matrix potentiate the angiogenic efficacy of bFGF and BMMNC transplantation, respectively, for limb ischemia. In addition, the combined therapy of SD of bFGF and BMMNC transplantation synergistically enhances angiogenesis in mouse ischemic limb, compared to each separate therapy.

The purpose of this study was to evaluate the potential for the oral sustained delivery of paracetamol of two formulations with in situ gelling properties. Oral administration of aqueous solutions of either gellan gum (1.0%, w/v) or sodium alginate (1.5%, w/v) containing calcium ions in complexed form resulted in the formation of gel depots in rabbit and rat stomachs as a consequence of the release of the calcium ions in the acidic environment. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6h. The bioavailability of paracetamol from the gels formed in situ in the stomachs of rabbits following oral administration of the liquid formulations was similar to that of a commercially available suspension containing an identical dose of paracetamol.