Search

The application of dexamethasone releasing poly (lactic-co-glycolic acid) (PLGA) microspheres embedded in a poly vinyl alcohol (PVA) hydrogel coatings have been successfully used in the suppression of the foreign body response (FBR) to implantable glucose sensors. In the current study, dexamethasone-loaded PLGA microspheres were prepared by blending two types of PLGA polymers (RG503H and DLG7E with MW of ca. 25 kDa and 113 kDa, respectively) to achieve long-term (6 months) inhibition of the FBR. The microsphere composition was optimized according to the in vitro drug release profiles. Microspheres with DLG7E/RG503H/dexamethasone = 70/13.3/16.7 wt% composition, when embedded in a PVA hydrogel, provided a continuous drug release for 6 months. By combining the aforementioned microspheres with microspheres composed solely of the DLG7E polymer within a similar PVA hydrogel realized an even longer (>7 months) in vitro drug release. A heat map was constructed to depict the daily in vitro drug released and elucidate possible lag phases that could affect the pharmacodynamic response. These drug-loaded implant coatings were investigated in vivo (rat model) and showed inhibition of the foreign body response for 6 months. These results suggest that the minimum effective daily dose to counter chronic inflammation is ca. 0.1 μg per mg of coating surrounding a 0.5 × 0.5 × 5 mm silicon implant (dummy sensor). Accordingly, these drug-eluting composite coatings can ensure long-term inflammation control for miniaturized implantable devices., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Evidence suggests that women who are naturally resistant to HIV infection exhibit low baseline immune activation at the female genital tract (FGT). This "immune quiescent" state is associated with lower expression of T-cell activation markers, reduced levels of gene transcription and pro-inflammatory cytokine or chemokine production involved in HIV infection while maintaining an intact immune response against pathogens. Therefore, if this unique immune quiescent state can be pharmacologically induced locally, it will provide an excellent women-oriented strategy against HIV infection To our knowledge, this is the first research article evaluating in vivo, an innovative trackable implant that can provide controlled delivery of hydroxychloroquine (HCQ) to successfully attenuate vaginal T lymphocyte activation and inflammation in a rabbit model as a potential strategy to induce an "immune quiescent" state within the FGT for the prevention of HIV infection. This biocompatible implant can deliver HCQ above therapeutic concentrations in a controlled manner, reduce submucosal immune cell recruitment, improve mucosal epithelium integrity, decrease protein and gene expression of T-cell activation markers, and attenuate the induction of key pro-inflammatory mediators. Our results suggest that microbicides designed to maintain a low level of immune activation at the FGT may offer a promising new strategy for reducing HIV infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The field of controlled release has contributed significantly to female reproductive health and in particular the prevention of unintended pregnancy. For at least 50years, there have been significant advances in controlled release dosage forms used for contraception. These advances have been driven by the need to provide women a wide array of products that address adherence problems noted with oral contraceptives. The first long-acting injectable product (Depo-Provera®) was approved in the US in 1959. Since then, there has been an emphasis on development of long-acting reversible contraceptives. These products include implants, intrauterine systems, and vaginal rings. A shorter acting contraceptive option is the transdermal patch. Despite these advances there are still a large number of unplanned pregnancies around the world. New controlled release technologies will be needed to continue providing women safe and easy to use contraceptive products., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Orthopaedic implants have been the subject of intense research in recent years, with academics, clinicians and industrialists seeking to broaden our understanding of their function and potential consequences within the human body. Current research is focussed on ways to improve the integration of an orthopaedic device within the body, whether it be to encourage better osseointegration, combat possible infection or stem the foreign body response. A key emerging strategy is the controlled delivery of therapeutics from the device, which may take the form of, for example, antibiotics, analgesics, anti-inflammatories or growth factors. However, the optimal device design that gives rise to the desired controlled release has yet to be defined. There are many examples in the literature of experimental approaches which attempt to tackle this issue. However, the necessity of having to conduct multiple experiments to test different scenarios is a major drawback of this approach. So enter stage left: mathematical modelling. Using a mathematical modelling approach can provide much more than experiments in isolation. For instance, a mathematical model can help identify key drug release mechanisms and uncover the rate limiting processes; allow for the estimation of values of the parameters controlling the system; quantify the effect of the interaction with the biological environment; and aid with the design of optimisation strategies for controlled drug release. In this paper we review current experimental approaches and some relevant mathematical models and suggest the future direction of such approaches in this field., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Delivery of anti-inflammatory steroids concurrently to both anterior and posterior segments of the eye is a challenge. The anterior ocular structures limit topical delivery. Injection can be disproportionately and repeatedly invasive and selective for only one ocular hemisphere. We developed a novel implant that can compensate for the limited conveyance of topical medicine and reduce the repetitive invasiveness of injection from the capsular bag allowing dexamethasone (DXM) delivery to both the anterior and posterior chambers. To establish proof of concept, microparticles were prepared with PLGA [poly(d,l-lactide-co-glycolide), 50:50, MW. 7000-17000], hydroxypropyl methyl cellulose (HPMC), and DXM by oil-in-water emulsion/solvent evaporation technique. Zeatsizer Nano and SEM (scanning electron microscopy) results showed microspheres in the range of 8±1µm. The target load of DXM in the microparticles was ~20.0% with a % recovery of 99.9% (w/w). Dose related pharmacokinetics with near zero order kinetics was observed for up to 6 weeks in rabbits with intracapsular bag implants. DXM flow was bidirectional from the endocapsular space and significant concentrations were found in the anterior and posterior chambers after up to 6 weeks. Whereas, with topical drops the exposure was minimal in all the ocular tissues with greater systemic exposure. Intraocular pressure was normal in all of the study groups; slit lamp biomicroscopy examinations revealed that no cells or fibrin formation in the anterior and posterior chamber with implants but flare, cells and fibrin was present in the topical drops group. Histological examination revealed normal tissues and no signs of inflammation in all the groups. The implant did not migrate to the center of the eye or obstruct the visual axis. We believe these findings demonstrate the feasibility of drug delivery from the capsular bag to the anterior and posterior segments effectively compared to topical alternatives., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In the area of parenteral controlled release formulations, in situ forming implants (ISFI) are attractive alternatives to preformed implants and microparticles. ISFI avoid the use of large needles or microsurgery and they can be manufactured in simple steps with a low requirement of equipment and processes. They are injected as low viscous solutions and transform in the body to a gel or solid depot. Different triggers can be used to stimulate this transformation: (1) in situ cross-linking, (2) in situ solidifying organogels, and (3) in situ phase separation. The review discusses the principles and the pros and cons of each strategy. It also gives examples of clinically used products or systems which are currently in clinical trials. Although the principle of ISFI is so attractive, key issues remain to be solved. They include (i) variability of the implant shape and structure, (ii) avoidance of burst release during implant formation, and (iii) toxicity issues. Unfortunately, until now our knowledge concerning the detailed processes of the implant formation is still very limited. This is due to the fact that the processes of implant formation and degradation, drug release and tissue response are complex, heterogeneous, interconnected and not easy to follow, especially in vivo. Despite this statement, many efforts are made in industry and academia to improve current approaches. New materials and approaches enter the preclinical and clinical phases and one can be sure, that ISFI will gain further clinical importance within the next years., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Electron paramagnetic resonance (EPR) spectroscopy was applied to monitor non-invasively the formation of in situ forming implants in vitro and in vivo after the administration of poly(lactide-co-glycolide) (PLGA)/N-methyl-pyrrolidone (NMP) solutions. The nitroxide spin probe 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TB) was incorporated in polymer solutions and samples were incubated in 0.1 M phosphate buffer (pH 7.4) at 37 degrees C or injected subcutaneously in the femoral of BALB/c mice. EPR permitted the direct and continuous determination of the NMP-water exchange during implant formation both in vitro and in living mice. The formation of the implant structure followed a two phase mechanism: over 75% of the polymer precipitated immediately after injection within the first 30 min and formed a solid shell. The subsequent moderate solidification of the implants was governed by diffusion and was completed after 24 h. The replacement of the organic solvent NMP by water was determined by polarity shifts within the implant and could be quantified. Both the kinetic of NMP-water exchange and polymer precipitation showed good in vitro-in vivo correlation.

The paper introduced an improved fabrication technique, by which the hydrophobic polymer monofilament fiber loading hydrophilic drug was obtained. The micronized 5-Fu (5-fluorouracil) powders were homogeneously dispersed in PLLA (poly(l-lactic acid))-chloroform solution to form the suspension, and then the suspension was solidified in the nonsolvent to prepare the fibers by wet-spinning method under mild condition. The diameter of drug-loaded fiber was in the range of 50-250 microm. The hydrophilic drug powders were successfully encapsulated into the monofilament fiber with good stability, high drug loading content and efficacy. The MTT cytotoxicity assay in vitro revealed the satisfactory anticancer activity of the drug-loaded fibers. The long-term release characteristics of these fibers were also achieved. Furthermore, the drug release rate of the fibers could be regulated by the formulation and fabricating parameters, such as drug loading content, polymer concentration in suspension, nonsolvent composition and flow rate in wet-spinning. The release mechanism of the fibers was investigated and described by Fickian diffusion equation.

In this study, the release characteristics of lidocaine conveyed in base (LB) and salt (LS) forms from an anionic hydrogel composed of carbopol and a cationic hydrogel composed of chitosans were examined for optimizing hydrogel formulation as a sponge filler to stop the bleeding and as a carrier for delivering lidocaine to relief pain after a tooth extraction. A Franz cell was used to simulate the in vivo environment and evaluate the drug release kinetics. It was confirmed that the release profiles of LB and LS from both the carbopol and chitosan hydrogels were best described by the Higuchi model, and values of the release rate constant (K) calculated from the slope of the linear portion of the plot were compared. Results demonstrated that the K value increased with increasing LB concentration at the same three carbopol levels of the hydrogels, whereas it increased with a decreasing level of carbopol for the same concentration of LB in the hydrogels. A minimum in the value of K was observed near neutral pH, which was attributed to two influencing factors of the viscosity and the complexing effect of carbopol gel. However, K values at the same concentration of lidocaine were larger for those formulations using the salt form compared to those using the base form. Results further revealed that the K value increased with an increasing amount of LB added to chitosan hydrogels with the same 0.5% concentration of C1000 (Chitosan, viscosity 1000 cps). K values increased with a decreasing MW of chitosan at the same level in the same concentration of an acetic acid solution with the same amount of LB added. K values for the release from chitosan hydrogels prepared at a lower level were lower than those of hydrogels prepared at a higher level. However, similarities in the release profiles between LB and LS were observed. In conclusion, the viscosity of the gel matrix and the ionic complexing effect between the anionic acid groups of hydrogels and basic groups with lidocaine were two main factors influencing regulation of the diffusion coefficient for controlling drug release.

To elucidate the antibiotic release mechanism from implants composed of calcium phosphates (hydroxyapatite [HAP] and tricalcium phosphate [TCP]), 30 kDa poly(DL-lactide) (PLA-30) and ciprofloxacin (CFX), nine formulations were prepared. In vitro results show that the release rate decreased as compression load and PLA/phosphates ratio increased. In contrast, a slower percent release rate was observed with higher drug loading. Swelling-erosion-disintegration of the implants was observed during the release assays, due to CFX swelling. Two CFX implant formulations were selected for implantation in the femur of rabbits, according to in vitro results. The implant drug loads tested were 10% and 40% of CFX. The in vivo results showed that the antibiotic concentrations achieved throughout the femur were higher for 4 weeks than the minimum inhibitory concentrations (MIC) against the most common of the pathogens that cause osteomyelitis. The CFX-10% implant was considered the best formulation as CFX was totally released within 6 weeks, and therapeutic bone levels were achieved, and the histological and radiographic analyses showed the osteoconductive properties of the materials. All these results showed that CFX release is limited by its solubility, and the erosion-disintegration and bone ingrowth into the implants enhanced the antibiotic release.

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630, <630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.

A gentamicin carrier system composed of calcium phosphates, poly(DL-lactide) (PLA) and gentamicin was developed and characterized in vitro and in vivo for use in the prevention and treatment of bone infection. Four formulations were prepared according to an experimental design based on the Hadamard matrix. The technological variables included in the design were: gentamicin loading with respect to the implant weight, weight average molecular weight (M(w)) of the PLA as a compound of the matrix and the presence or absence of a PLA coating of 200 kDa. The variable to be optimized in vitro was the gentamicin release level during the first week. According to this goal, the selected formulation was F-D which was composed of 80% phosphates (25% hydroxyapatite, HAP and 75% tricalcium phosphate, TCP), 20% PLA (M(w), 30 kDa) and 3.5% gentamicin sulfate (GS) and was coated with PLA (M(w), 200 kDa). To elucidate the in vitro release mechanism of this implant, another implant lot (F-X) uncoated, but with identical matrix composition, was prepared. Results showed that the PLA coating delay the gentamicin release, indicating that part of the antibiotic released from the matrix diffuses through the polymer coating film. The selected formulation was tested in the femur of rabbits and showed a faster release rate in vivo than in vitro. This is due to a greater degree of PLA degradation, changes in the phosphate blend, and bone tissue invading the implant. Gentamicin concentration in the areas of the bone closest to the implant was higher than the minimum inhibitory concentration (MIC) against Staphylococcus aureus.

Pharmaceutical formulations can be designed as Multiple Unit Systems, such as Roxiam CR, studied in this work. The dose is administrated as a capsule, which contains about 100 individual pellets, which in turn contain the active drug remoxipride. Experimental data for a large number of single pellets can be obtained by studying the release using microtitre plates. This makes it possible to study the release of the individual subunits making up the total dose. A mathematical model for simulating the release of remoxipride from single film-coated pellets is presented including internal and external mass transfer hindrance apart from the most important film resistance. The model can successfully simulate the release of remoxipride from single film-coated pellets if the lag phase of the experimental data is ignored. This was shown to have a minor influence on the release rate. The use of the present model is demonstrated by a parametric study showing that the release process is film-controlled, i.e. is limited by the mass transport through the polymer coating. The model was used to fit the film thickness and the drug loading to the experimental release data. The variation in the fitted values was similar to that obtained in the experiments.