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Hydrogels are of great significance in the field of bioactive delivery. This study designed the self-assembly of gallic acid-loaded nano cellulose crystals/chitosan (NC/CS) hydrogels via Nano bubbles (NBs). NC/CS NBs 4:2 hydrogels improved the mechanical properties compared to those without NBs. The hardness of NC/CS (4:2) NBs hydrogels was greatly enhanced by 1.15 ± 0.05. The water-holding and swelling behavior can be tuned at different ratios. NC/CS NBs (4:2) showed the electrostatic interaction analyzed by FTIR, XRD, and XPS. SEM results displayed smoother and smaller pores along dense networks promoted by NBs. The antioxidant activity of hydrogels was increased by adding NBs (P < 0.05). In vitro and vivo release activity of gallic acid was higher in simulated intestinal fluid (SIF) at 4:2, depicting the controlled release mechanism. Thus, current work revealed that NBs and low concentrations of NC can be self-assembled with chitosan chains, producing a highly compact hydrogel structure.

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Berberine hydrochloride (BH) has long been known for its therapeutic efficacy. In the present study, we aimed to treat mice with colitis using dung beetle chitosan (DCS) -transported BH. To achieve this, BH-loaded DCS/sodium alginate microspheres (SA-DCS-BH) were prepared. The SA-DCS-BH was characterized using SEM, DLS, FT-IR, and XRD, then was used for administration and anti-inflammatory examination in mice. SEM and DLS confirmed the surface morphology of the microspheres, and the particle size was relatively uniform. FT-IR and XRD results confirmed that BH was successfully loaded. In vitro and in vivo studies showed that SA-DCS-BH had slow-release ability. After treatment with SA-DCS-BH, DAI was significantly reduced, colon weight and length increased, spleen length and weight reduced, concentrations of pro-inflammatory cytokines in colonic tissues were reduced, and gut microbiota species abundance was modulated. In addition, this study found a correlation between specific microbes and colitis indicators, Muribaculaceae showed sequential growth after receiving BH, SA-CS-BH, and SA-DCS-BH treatments, respectively. It was concluded that SA-DCS-BH effectively delivered the BH to the intestine with slow-release ability and exhibited anti-inflammatory effects by immune response. Compared to commercial chitosan, DCS has potential for modulating intestinal microorganisms and more suitable carrier for intestinal drug delivery systems.

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pH-responsive hydrogels have become effective and attractive materials for the controlled release of drugs at pre-determined destinations. In the present study, a novel hydrogel system based on Prunus armeniaca gum (PAG) and acrylic acid (AA) was prepared by a free radical mechanism using N, N-methylene bisacrylamide (MBA) as cross-linker and potassium persulfate (KPS) as initiator. A series of hydrogels varying PAG, AA, and MBA concentration was developed to determine the impact of these components. Formulated hydrogels were characterized for pH-responsive swelling, drug release, gel content, and porosity. Structural analysis was performed by FTIR, XRD, and SEM analysis. TGA study was applied to assess thermal stability. Oral acute toxicity and in vivo drug release were performed in rabbits. Hydrogels exhibited pH-dependent swelling and drug release. Swelling, drug loading and release, and porosity increased by increasing PAG and AA concentration while decreased by increasing MBA. The gel content of formulations was increased by increasing all three components. FTIR studies confirmed the development of copolymeric networks and the loading of drug. XRD studies revealed that hydrogels were amorphous, and the crystalline drug was changed into an amorphous form during loading. TGA results indicated that hydrogels were stable up to 600 °C. Acute oral toxicity results confirm that hydrogels were nontoxic up to a dose of 2 g/kg body weight in rabbits. The pharmacokinetic evaluation revealed that hydrogels prolonged the availability of the drug and the peak plasma concentration of the drug was obtained in 6 h as compared to the oral solution of the drug. Tramadol hydrochloride (THC) was used as a model drug. Hence, pH-responsive swelling and release, nontoxic nature and improved pharmacokinetics support that PAG-based hydrogels may be considered as potential controlled-release polymeric carriers.

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BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.

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The siRNA-loaded lipid nanoparticles have attracted much attention due to its significant gene silencing effect and successful marketization. However, the in vivo distribution and release of siRNA still cannot be effectively monitored. In this study, based on the fluorescence resonance energy transfer (FRET) principle, a fluorescence dye Cy5-modified survivin siRNA was conjugated to nanogolds (Au-DR-siRNA), which were then wrapped with lipid nanoparticles (LNPs) for monitoring the release behaviour of siRNA in vivo. The results showed that once Au-DR-siRNA was released from the LNPs and cleaved by the Dicer enzyme to produce free siRNA in cells, the fluorescence of Cy5 would change from quenched state to activated state, showing the location and time of siRNA release. Besides, the LNPs showed a significant antitumor effect by silencing the survivin gene and a CT imaging function superior to iohexol by nanogolds. Therefore, this work provided not only an effective method for monitoring the pharmacokinetic behaviour of LNP-based siRNA, but also a siRNA delivery system for treating and diagnosing tumors.

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This study aimed to prepare alcohol-free curcumin-loaded zein-propylene glycol alginate (zein-PGA-Cur) nanoparticles using the pH-driven method to enhance the bioavailability and physicochemical stability of curcumin. The prepared zein-PGA-Cur nanoparticles exhibited a small size (360 nm) and negative zeta-potential (-5.8 mV), as well as excellent physical stability, under storage conditions of pH 4.0 and temperature at 4 °C for 30 days. In addition, the Fourier transform infrared spectroscopy results demonstrated that the main interactions of pH-driven for the formation of zein-PGA-Cur nanoparticles were hydrogen bonding, hydrophobic, and electrostatic interactions. Fluorescence spectroscopy revealed that the curcumin-induced fluorescence quenching of zein was static. Circular Dichroism spectroscopy demonstrated that the pH-driven method mainly decreased the ß-sheet structure of zein from 3.9 % to 1.4 %. Furthermore, the HT-29 colorectal adenocarcinoma cells viability experiments revealed that the prepared zein-PGA-Cur nanoparticles exhibited excellent biocompatibility. In vivo rat experiments also demonstrated that the prepared nanoparticles resulted in a higher plasma concentration of curcumin, representing a 7.2-fold enhancement in bioavailability compared with pure curcumin crystals. The findings of this study will provide a green and energy-saving method for the development of insoluble drug self-assembly systems and promote their wider applications in drug delivery.

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As insoluble polymer materials, ion-exchange resins (IERs) can exchange their own ions with desirable charged ions in the solution. According to the affinity of active moieties for soluble counterions, IERs could be categorized into the following four types: strongly acidic cation, weakly acidic cation, strongly basic anion, and weakly basic anion exchange resins. Due to their relative safety and high drug-loading capacity, IERs have garnered extensive attention in the pharmaceutical field since the 1950s. As numerous investigations combine drugs with IERs, this article summarizes the technologies employed in these studies from four aspects: IER screening principles, combining technologies, characterization methods, and in vitro and in vivo release of drug-resinate complexes. In addition, the advantages and disadvantages of various technologies and their scope are expounded. The article provides new insights on the preparation of ion-exchange resin complexes.

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Contact lenses (CLs) offer a wide variety of advantages as ocular drug-releasing platforms, but the feasibility of medicated CL development is constrained by numerous scientific, technological, and regulatory challenges. One main difficulty is the setting of release rate specifications for each drug, since at present there are no standardized in vitro release models that can appropriately predict the performance of drug-eluting CLs once placed onto the eye. CL-adapted release tests may provide knowledge on how the drug release pattern should perform in vivo to trigger and maintain the therapeutic effects for both anterior and posterior ocular tissues. Moreover, in vitro release tests are valuable tools for quality assessment during production and to investigate the effect of a change in composition or process variables. This review aims to shed light on biorelevant ways of evaluating in vitro drug release from CLs and the feasibility of establishing in vitro-in vivo correlations (IVIVC) to predict in vivo performance. First, general guidelines and Pharmacopeia release tests for topical ophthalmic formulations as well as in vitro release tests implemented for drug-CLs in the last two decades are analyzed. Then, development of an appropriate method to investigate IVIVC is attempted from the few papers simultaneously reporting in vitro release profiles and either in vivo release or therapeutic response. Finally, key points to be considered for in vitro testing drug release from a medicated CL are suggested to pave the way to the clinical arena.

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BACKGROUND: Astaxanthin (ASTA) is a kind of food-derived active ingredient (FDAI) with antioxidant and antidiabetic functions. It is nontoxic but its poor solubility and low bioavailability hinder its application in the food industry. In this study, a novel carrier, polyethylene glycol-grafted chitosan (PEG-g-CS) was applied to enhance the bioavailability of astaxanthin. It encapsulated astaxanthin completely by solvent evaporation to manufacture astaxanthin using poly (ethylene glycol)-graft-chitosan nanoparticles (ASTA-PEG-g-CS) nanoparticles to improve absorption. RESULTS: The ASTA-PEG-g-CS nanoparticles were spherical, with a particle size below 200 nm and a ζ potential of about -26 mV. Polyethylene glycol-grafted chitosan can encapsulate astaxanthin well, and the encapsulated astaxanthin was released rapidly - in 15 min in an in vitro release study. In a rat single-pass intestinal perfusion study, a low concentration of ASTA-PEG-g-CS nanoparticle (0.2 µg mL-1 ) was better absorbed in the intestine. In particular, the jejunum could absorb most astaxanthin without a change in the concentration. An in vivo release study also demonstrated that ASTA-PEG-g-CS nanoparticles enhanced oral bioavailability significantly. CONCLUSION: This novel carrier, PEG-g-CS, provided a simple way to encapsulate food, which improved the bioavailability of hydrophobic ingredients. © 2021 Society of Chemical Industry.

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This study aimed to systematically evaluate the effect of a commercial grape seed tannin extract (GSE) fully characterized (53% monomers, 47% procyanidins) on wine ester release and perception using a global approach. The behavior of two esters (ethyl hexanoate, ethyl decanoate) was studied in a control wine or in the same wine supplemented with the GSE in preconsumption (in vitro headspace-stir bar sorptive extraction-gas chromatography mass spectrometry (HS-SBSE-GC/MS) and orthonasal perception) and consumption (intraoral-HS-SBSE-GC/MS and dynamic retronasal perception) conditions. For the compound ethyl hexanoate, no significant differences (p > 0.05) among wines were observed in the in vitro analyses while they were observed in the three in vivo experiments (p < 0.05). Thus, the wine supplemented with the GSE showed lower (35%) in vivo release and ortho (36%) and retronasal (16%) perception scores than the control wine. Overall, this suggests that components of the GSE could interact with this compound, directly and/or through complexes with oral components, affecting its release and conditioning its perception. However, perceptual interactions and effects of polyphenols on oral esterases cannot be discarded. On the contrary, the compound ethyl decanoate was not significantly affected by the addition of GSE. In conclusion, the addition of tannin extracts to wines can modulate aroma perception in a compound-dependent manner.

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As a depot drug delivery system, injectable polylactide-polyglycolide (PLGA) sustained-release microspheres have been successfully used to treat many diseases since the first microsphere product Lupron depot was approved for marketing in the United States in 1989. It has the ability of long-term release in the body for several days to several months, which can not only reduce the times of administration, but also reduce the drug blood concentration fluctuations, significantly improve the safety and patient compliance. In vitro-in vivo correlation (IVIVC) makes the development of microspheres more possible. It can describe the dynamic information of drug release in vivo through the in vitro release behavior of microspheres, and can reduce the workload of each stage and shorten the time span while characterizing the performance of microspheres. IVIVC can provide guidance or support for drug development, production changes, supervision and management. This article summarizes the release mechanism of injectable PLGA sustained-release microspheres, common measurement methods and theories of in vitro and in vivo release. And we also focus on the establishment and application of IVIVC, especially A level IVIVC in the field of microsphere preparations, to provide a reference for further study on in vitro-in vivo correlation of microspheres.

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Essential oils (EO) are defined as plant-derived natural bioactive compounds, which can have positive effects on animal growth and health due to their antimicrobial and antioxidative properties. However, EO are volatile, can evaporate quickly, and be rapidly absorbed in the upper gastrointestinal tract. Also, due to their labile nature, the stability of EO during feed processing is often questionable, leading to variations in the final concentration in feed. Encapsulation has become one of the most popular methods of stabilizing EO during feed processing, storage, and delivery into the lower gut. The objectives of the present study were to 1) evaluate the stability of thymol microencapsulated in combination with organic acids in commercially available lipid matrix microparticles during the feed pelleting process and storage; 2) validate and demonstrate the slow release of thymol from the lipid matrix microparticles in a simulated pig gastric fluid (SGF) and a simulated pig intestinal fluid (SIF); and 3) evaluate in vivo release of thymol from the lipid matrix microparticles along the pig gut. The results showed that thymol concentration was not significantly different in the mash and pelleted feeds (P > 0.05). In the in vitro study, 26.04% thymol was released in SGF, and the rest of the thymol was progressively released in SIF until completion, which was achieved by 24 h. The in vivo study showed that 15.5% of thymol was released in the stomach, and 41.85% of thymol was delivered in the mid-jejunum section. Only 2.21% of thymol was recovered in feces. In conclusion, the lipid matrix microparticles were able to maintain the stability of thymol during a feed pelleting process and storage and allow a slow and progressive intestinal release of thymol in weaned pigs.

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The purpose of this study was to develop solid dispersions of fenretinide(4HPR), incorporate them into poly(lactic-co-glycolic)(PLGA) millicylindrical implants, and evaluate the resulting implants in vitro and in vivo for future applications in oral cancer chemoprevention. Due to the extreme hydrophobicity of 4HPR, 4HPR-polyvinylpyrrolidone (PVP) amorphous solid dispersions(ASDs) were prepared for solubility enhancement. The optimal PVP-4HPR ratio of 9/1(w/w) provided a 50-fold solubility enhancement in aqueous media, which was sustained over 1 week. PVP-4HPR ASD particles were loaded into PLGA millicylinders and drug release was evaluated in vitro in PBST and in vivo by recovery from subcutaneous injection in rats. While initial formulations of PLGA PVP-4HPR millicylinders only released 10% 4HPR in vitro after 28 days, addition of the plasticizer triethyl-o-acetyl-citrate(TEAC) into PVP-4HPR ASDs resulted in a 5.6-fold total increase in drug release. Remarkably, the TEAC-PVP-4HPR PLGA implants demonstrated slow, continuous, and nearly complete release over 1 month in vivo compared to a 25% release for our previously reported formulation incorporating solubilizers and pore-forming agents. Hence, a combination of PLGA plasticizer and ASD formation provides an avenue for long-term controlled release in vivo for the exceptionally difficult drug to formulate, 4HPR, and a suitable formulation for future evaluation in rodent models of oral cancer.

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Sustained release of active interferon-α (IFN-α) has been achieved from core-shell nanoparticles (NPs) prepared by aqueous precipitation of IFN-α-enriched human serum albumin (HSA-IFN-α) and layer-by-layer (L-b-L) by coating of the IFN-α NPs with poly(sodium-4-styrene) sulphonate (PSS) and chitosan (Chit). The concentration and the pH of HSA solution were optimized during the development of this method. Dynamic light scattering (DLS), zeta-potential, thermal analysis (differential scanning calorimetry (DSC) and termogravimetry (TG)), X-ray diffraction (XRD), IFN-α activity and morphology (transmission electron microscope (TEM)) studies were used to control the preparation and analyse the products. The dissolution kinetics of NPs was measured in vitro over 7 days in Hanson dissolution tester with Millex membrane. In vivo studies in Pannon white rabbit detected steady IFN-α plasma level for 10 days after subcutaneous injection administration of the HSA-IFN-α NPs. The IFN-α plasma concentration was detected by using the enzyme-linked immunosorbent assay (ELISA) method. In the present paper we discuss the preparation method, the optimization steps and the results of in vitro and in vivo release studies. It was established that 76.13% HSA-IFN-α are encapsulated in the core-shell NPs.

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Organogels are excellent drug carrier for controlled release. Organogels based on amino acid derivatives has been widely used in the area of drug delivery. In this study, a series of the organogel system based on amino acid derivatives gelators was designed and prepared to investigate the structure-property correlation in organogels. To investigate the factors that influence the property of drug release, we varied the formulation in the organogels: gelator structure, gelator concentration, volume of antigelation solvent, and drug loading. Through the Box-Behnken tests, the optimum organogel formulation in vitro was obtained. The self-healing properties of the organogel have been utilised for injection of a model lipophilic risperidone in situ, and sustained release of the drug has been studied over about one week in vivo. In conclusion, the gelation ability of gelators could be adjusted by the gelator structure. Gel property is related with the whole composition of the formulation. As drug carrier, the drug release property of organogels is affected by multiple factors. Our investigation of the gel release property will play a theoretical guiding role in the application in the in situ drug delivery system.

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Due to its very low water solubility and complex pharmacokinetics, a reliable point-to-point correlation of its in vitro release with its pharmacokinetics has not been achieved so far with amiodarone. The correlation of the in vitro dissolution of a drug with the pharmacokinetics of one of its metabolites was recently proposed by the authors of the article as an additional or alternative analysis to the usual in vitro correlations in vivo, mainly in the case of fast-absorbing drugs that have metabolites with a significant therapeutic effect. The model proposed by the authors considers that amiodarone has a slow dissolution, rapid absorption, and rapid metabolism, and before returning to the blood from other compartments, its pharmacokinetics is determined mainly by the kinetics of release in the intestine from the pharmaceutical formulation. Under these conditions, the rate of apparition of desethylamiodarone in the blood is a metric of the release of amiodarone in the intestinal fluid. Furthermore, it has been shown that such an estimated in vivo dissolution is similar, after time scaling, to the dissolution measured experimentally in vitro. Dissolution data of amiodarone and the pharmacokinetic data of its active metabolite desethylamiodarone were obtained in a bioequivalence study of 24 healthy volunteers. The elimination constant of the metabolite from plasma was estimated as the slope of the linear regression of logarithmically transformed data on the tail of plasma levels. Because the elimination of desethylamiodarone was shown to follow a monoexponential model, a Nelson-Wagner-type mass equilibrium model could be applied to calculate the time course of the "plasma metabolite fraction." After Levi-type time scaling for imposing the in vitro-in vivo correlation, the problem became that of the correlation between in vitro dissolution time and in vivo dissolution time, which was proven to follow a square root model. To validate the model, evaluations were performed for the reference drug and test drug separately. In both cases, the scaled time for in vivo dissolution, t*, depended approximately linearly on the square root of the in vitro dissolution time t, with the two regression lines being practically parallel.

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Currently, bacterial conjunctivitis is treated by frequent administration of antibiotic eye drop solutions, which is tedious and patient noncompliant. Contact lenses could be ideal medical devices to sustain the release of ophthalmic drugs, but the incorporation of the latter can alter the optical and physical properties of the lenses. In addition, many contact lens users have reported the pink eye syndrome, making them unsuitable as ocular medical devices. In the present study, we have designed a novel type of lenses containing semi-circular rings loaded with moxifloxacin HCl (a broad spectrum antibiotic) and hyaluronic acid (a comfort agent), respectively, in order to treat bacterial conjunctivitis without altering the critical lens properties. The drug loaded rings were implanted separately within the periphery of the contact lenses using the modified cast moulding technology. The atomic force microscopy report showed an average roughness of 22.27 nm for the implant lens, which was significantly lower in comparison to the marketed Freshlook® (116.27 nm) contact lens. The major amount of moxifloxacin HCl was leached (68.16-74.55%) during the monomer extraction and wet sterilization (autoclave) steps; hence the lenses were terminally sterilized by radiation and packaged under dry condition (dehydrated). The in vitro release data showed release for moxifloxacin HCl and hyaluronic acid up to 96 h. The in vivo drug release studies showed significant improvement [>MIC for Staphylococcus aureus] in the drug residence time in comparison to the eye drop therapy. The in vivo efficacy study in the staphylococcus aureus induced conjunctivitis showed equivalent healing effect with the single implant contact lens in comparison to the frequent high dose eye drop therapy. The study demonstrated the successful application of the implantation technology to co-deliver moxifloxacin HCl and hyaluronic acid from the contact lenses for the extended period of time to treat conjunctivitis.

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Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits' eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future.

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Local, long-acting release fenretinide (4HPR) millicylindrical implants were prepared and evaluated for their release kinetics in vivo and their ability to suppress oral cancer tumor explant growth. Poly(lactic-co-glycolic acid)(PLGA) implants were prepared as a function of drug loading and the presence of various excipients (pore-formers, solubilizers, crystallization inhibitors) to enhance release of the insoluble 4HPR. Release kinetics and bioerosion of PLGA were monitored both in vitro in a PBS/Tween 80 buffer and in vivo by recovery of the drug remaining at the injection site. 4HPR was released from PLGA implants much slower in vivo than in the drug solubilizing media in vitro, with a 3-week lag phase and continuous release of >2 months, but showed some release enhancement by addition of solubilizers. Water-soluble PVA/sucrose implants for release of 4HPR served to determine if drug dissolution provided suitable controlled release without the PLGA, and this formulation showed continuous drug release over 6 weeks in vivo. Placement of PLGA-4HPR implants adjacent to oral cancer tumor murine xenografts showed inhibition of tumor growth relative to sham implants, indicating the potential for the local 4HPR delivery approach to be useful for oral cancer chemoprevention.

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The aim of this study was to develop a formulation with a sustained intra-articular release of the anti-inflammatory drug tacrolimus. Drug release kinetics from the prepared tacrolimus loaded monodisperse biodegradable microspheres based on poly(d-l-lactide-PEG)-b-poly(l-lactide) multiblock copolymers were tunable by changing polymer composition, particularly hydrophobic-hydrophilic block ratio. The monospheres were 30 µm and released the drug, depending on the formulation, in 7 to >42 days. The formulation exhibiting sustained release for 1 month was selected for further in vivo evaluation. Rat knees were injected with three different doses of tacrolimus (10 wt %) loaded monospheres (2.5, 5.0, and 10 mg), contralateral control knees with saline. Micro-CT and histology showed no negative changes on cartilage, indicating good biocompatibility. Minor osteophyte formation was seen in a dose dependent fashion, suggesting local drug release and therapeutic action thereof. To investigate in vivo drug release, tacrolimus monospheres were injected into horse joints, after which multiple blood and synovial fluid samples were taken. Sustained intra-articular release was seen during the entire four-week follow-up, with negligible systemic drug concentrations (<1 ng/mL), confirming the feasibility of local intra-articular drug delivery without provoking systemic effects. Intra-articular injection of unloaded monospheres led to a transient inflammatory reaction, measured by total synovial leucocyte count (72 h). This reaction was significantly lower in joints injected with tacrolimus loaded monospheres, showing not only the successful local tacrolimus delivery but also local anti-inflammatory action. This local anti-inflammatory potential without systemic side-effects can be beneficial in the treatment of inflammatory joint diseases, among which is osteoarthritis.