Ceftiofur is a third-generation cephalosporin approved to treat numerous infections in production animals. Its commercial formulations are administered daily due to the mean life time, leading to several inconveniences, like operative challenges and non-uniform plasma levels. The objective of this work was to microencapsulate ceftiofur in chitosan particles using spray drying technology to extend the delivery and consequently reduce the dosage frequency. The effect of formulation factors on particle features was studied using a multilevel factorial design. In addition, ceftiofur thermal stability was assayed by differential scanning calorimetry and microbiological assays. Finally, a pharmacokinetic model was developed to predict theoretical plasma concentration in goats. Results showed that ceftiofur thermal stability increased after microencapsulation, indicating a protective effect of chitosan particles. Besides, MIC, IC50 and inhibition halos against E. coli and S. aureus were similar than those of the commercial product. In addition, suitable plasma levels can be theoretically maintained in goats during 48 h with a single injection. These findings suggest that chitosan microparticles could be a good vehicle for ceftiofur administration.

Drug controlled release technologies (DCRTs) represent an opportunity for designing new therapies. Main objectives are dose number optimization and secondary effects reduction to improve the level of patient/client acceptance. The present work studies DCRTs based in blended polymeric implants for single dose and long-term therapies of florfenicol (FF), a broad spectrum antibiotic. Polymers used were PLGA and Eudragit E100/S100 types. Eudragit/PLGA and FF/PLGA ratios were the main studied factors in terms of encapsulation efficiencies (EEs) and drug release profiles. In addition, morphological and physicochemical characterization were carried out. EEs were of 50–100% depending on formulation composition, and the FF releasing rate was increased or diminished when E100 or S100 were added, respectively. PLGA hydrolytic cleavage products possibly affect Eudragit solubility and matrix stability. Different mathematical models were used for better understanding and simulating release processes. Implants maintained the antimicrobial activity against Pseudomonas aeruginosa up to 12 days on agar plates. The developed DCRTs represents a suitable alternative for florfenicol long-term therapies.

In bovine estrus synchronization, intravaginal devices made of silicone are used to administer exogenous progesterone with the aim of maintain plasmatic levels above 2 ng ml−1 during the treatment. After their use, devices must be discarded. There is an important concern on the environmental impact of the disposal of these used products due mainly to the non-degradability of the silicone and to the residual content of the hormone. Different alternatives are being studied, and the use of ecological materials appears as the more important. The objective of the present contribution was to design and evaluate a recyclable intravaginal prototype using ethylene vinyl acetate copolymer (EVA). Devices were fabricated by an injection-molding technique and characterized in terms of dimensions, loading efficiency, release rate, and wing tension. An analysis was first conducted to compare three different matrices and two supports. Secondly, the best candidate prototype was assayed in both beef and dairy cattle. Finally, used matrices were recycled measuring the progesterone content in the resulting devices and testing them in vitro. According to release tests, no differences were observed between the three matrices both in vitro and in vivo. On the contrary, a better performance was achieved when a support with a more flexible Y shape was used in comparison with a rigid T geometry. Successful results were observed in non-lactating cows, with plasma concentrations above the threshold value defined for the synchronization therapy. However, lower progesterone levels resulted when devices were tested in animals with large milk production. By last, recycled matrices presented a similar initial content and in vitro release rate than original matrices. These findings could open the possibility to use recyclable EVA devices as an alternative to the non-degradable silicone intravaginal inserts. Future research must be carried out to optimize the performance of the recycled matrices in dairy cattle. Modifications of the release surface and/or the initial loading can give a solution to the lower values observed in these animals.

Planned reproduction in cattle involves regulation of estrous cycle and the use of artificial insemination. Cycle control includes the administration of exogenous progesterone during 5–8 days in a controlled manner allowing females to synchronize their ovulation. Several progesterone delivery systems are commercially available but they have several drawbacks. The aim of the present contribution was to evaluate chitosan microparticles entrapping progesterone as an alternative system.

Advances in miniaturization and material sciences as well as the boom in micro and nanotechnology have led to the improvement of manufacturing process and precision control expanding the possibilities of design and the application fields.In this context, three major micro fluidic systems can be distinguished, chip-based, capillary-based, and paper-based systems.A brief description of each one is presented below as well as their most important applications. Chip-based systemsThe main type of micro fluidic device is the chip-based system.This comprises a chip having micro channels by which

Fil: Helbling, Ignacio Marcelo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Santa Fe. Instituto de Desarrollo Tecnologico para la Industria Quimica. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnologico para la Industria Quimica; Argentina

ABSTRACTA new mathematical model for the prediction of the heterogeneous hydrolytic degradation of poly(D,L‐lactide‐co‐glycolide) (PLGA)‐based microspheres was developed. The model takes into account the autocatalytic effect of carboxylic groups and polymer composition on the degradation rate. It is based on mass balances for the different species, considering the kinetic and mass transport phenomena involved. The model estimates the evolution of average molecular weight, mass loss, and morphological change of the particles during degradation, and it was validated with novel experimental data. Theoretical predictions are in agreement with the hydrolysis data of PLGA microspheres (error values less than 5%). The model is able to predict the effect of particle size and molecular weight on the degradation of PLGA‐based microspheres and estimates the morphological changes of the particles due to the autocatalytic effect. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45464.

Poly(lactic-co-glycolic acid) (PLGA) microparticles containing progesterone were prepared by the solvent extraction/evaporation and microfluidic techniques. Microparticles were characterized by their size distribution, encapsulation efficiency, morphology and thermal properties. The effect of particle size, polydispersity and polymer degradation on the in vitro release of the hormone was studied. A triphasic release profile was observed for larger microparticles, while smaller microspheres showed a biphasic release profile. This behavior is related to the fact that complete drug release was achieved in a few days for smaller microparticles, during which polymer degradation effects are still negligible. A mathematical model was developed that predicts the progesterone release profiles from different-sized PLGA microspheres. The model takes into account both the dissolution and diffusion of the drug in the polymeric matrix as well as the autocatalytic effect of polymer degradation. The model was adjusted and validated with novel experimental data. Simulation results are in very good agreement with experimental results.

Burst release was observed when ethylene vinyl acetate copolymer (EVA) intravaginal rings were tested for progesterone release in our previous work (Helbling et al. Pharm Res. 31(3):795–808, 2014 ). Burst release is undesirable in controlled delivery devices because release is uncontrollable and higher levels of active pharmaceutical ingredient could lead to the occurrence of adverse effect. The present contribution is about the use of membranes to coat EVA rings to eliminate burst release. Physicochemical state of progesterone in uncoated rings and the solubility and diffusion coefficient in membrane were studied. Hormone delivery from several rings of different sizes was compared. A mathematical model was used to analyze the effects of membrane properties on delivery rate. No chemical interactions were detected between hormone and polymer. Hormone was mainly forming amorphous aggregates inside rings, and migration to membrane was not observed during storage. Diffusion coefficient was smaller in membrane (∼10 −8 cm 2 s −1 ) than in matrix (∼10 −7 cm 2 s −1 ). Zero-order release kinetics were obtained for coated rings, and release rate decreases as the thickness of the coat increases. Cellulose membrane successfully eliminates burst release and controls the delivery from EVA rings. The equations developed can be used to determine the appropriate coat thickness to produce specific release rate.

Response surface methodology was successfully used to study effect of formulation parameters on progesterone release from rings made of ethylene-vinyl acetate copolymers. Significant effects were estimated by an analyses of variance (ANOVA) and statistical model was constructed. Model predictions showed good agreement with experimental data. Results showed that mass of progesterone released can be enhanced by several strategies. In addition, model behavior was compared with previously validated model reported in the literature obtaining satisfactory results. The statistical model was also employed to optimize formulation parameters with the aim to reach release rate of about 3.545 0.020 mg cm(-2) days(-1/2). Optimized prototype was tested in vitro. Results showed that optimized IVR has similar profiles than the commercial silicone device used as reference. Optimized ring would have several advantages over commercial one like lower initial and residual content of progesterone and the possibility of recycling rings after their usage avoiding incineration of used device (as in the case of silicone commercial device). Pharmacokinetics studies must be done to corroborate in vivo performance of optimized IVRs made of EVA. (C) 2015 Elsevier B.V. All rights reserved.

Bovine estrus synchronization is an important field for the veterinary pharmaceutical industry. A description of the natural bovine cycle and methods to cycle control are presented. In addition, commercially available silicone devices for bovine estrus synchronization are listed. The mathematical modeling of progestagens release from such devices is a crucial tool in the development of novel and/or optimized delivery systems. For this purpose, several in vitro models, approaches to explain the ADME processes and overall models are described. This type of mathematical modeling could help in the future to customize drug delivery systems to specific animals and/or situations.

Fil: Helbling, Ignacio Marcelo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Santa Fe. Instituto de Desarrollo Tecnologico para la Industria Quimica. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnologico para la Industria Quimica; Argentina

A mechanistic mathematical model applicable to the controlled dispersed‐drug release from cylindrical device such as implantable drug delivery system was derived. Analytical solutions based on the pseudosteady state approximation are derived taken account an exact external medium volume. The model prediction is accurate when the initial drug load is higher than the drug solubility in the polymer. The results obtained are compared with the analytical solutions available in the literature. The equations are corroborated by comparison with experimental profiles reported in the literature for sink conditions and non sink conditions. The evolution of concentration distribution profiles is compared for different volume of external medium. A reduction in the volume of the external solution leads to an increase in the concentration on the surface of the device, which determines decreases in the release of drug. One criterion for determining whether the volume of external solution should be considered for the prediction of drug release from cylindrical devices is established. This criterion is based on establishing a maximum percentage error allowed in the values of amount of drug released. The usefulness of the model is focused in the design of implant for controlled release of drug into a small volume of external medium of release. Copyright © 2014 John Wiley & Sons, Ltd.

Progering® is the only intravaginal ring intended for contraception therapies during lactation. It is made of silicone and releases progesterone through the vaginal walls. However, some drawbacks have been reported in the use of silicone. Therefore, ethylene vinyl acetate copolymer (EVA) was tested in order to replace it.

Chitosan is a versatile carrier for biologically active agent from a small molecule such as an antibiotic to macromolecules such as proteins and nucleic acids. In addition, drug delivery devices based on chitosan can be available in a variety of morphologies including films, fibers, nanoparticles and microspheres. Otherwise the inherent advantages of this polymer such as biocompatibility, tissue adhesions and hydrophilic nature, chitosan can be modified to accomplish a specific purpose, for example improves release kinetics. In this review, recent patents of chitosan-based film systems for drug delivery are presented and discussed. This review include matrix type systems, membrane coated systems and film forming solution. For each one of these systems, several examples of manufacture processes, bioactive agents to be delivered and specifics applications are considered. This work highlights the use of chitosan in the film technology for drug delivery, presenting examples of chitosan used in an unmodified state and examples of modifications of the polymer backbone.

Analytical solutions for the case of dispersed–drug controlled release from non–erodible planar matrices, based on Refined Integral Method, are presented. A new adjusting equation is used for the dissolved drug concentration profile in the depletion zone of the matrix. In order to illustrate the validity and usefulness of the model, comparisons with experimental profiles reported in the literature are presented. A close match between the model predictions and the experimental data is observed. In addition, a comparison with a model reported previously by others authors is also presented. The results show that our model has a better performance than the previously reported equations in the prediction of the experimental release profiles. As conclusion, the obtained results show that the model can be employed in a broad range of drug delivery systems.

A mathematical modeling of controlled release of drug from one-layer and two-layer torus-shaped devices with external mass transfer resistance is presented.Analytical solutions based on the pseudosteady state approximation are derived.The validity of the equations is established in two stages.In the first stage, the validity of the models derived for more complex systems is determined by comparison with profiles predicted by the simplest model, in asymptotic cases.In the second stage, the reliability and usefulness of the models are ascertained by comparison of the simulation results with vaginal rings experimental release data reported in the literature.In order to measures quantitatively the fit of the theoretical models to the experimental data, the pair-wise procedure is used.A good agreement between the prediction of the models and the experimental data is observed.The models are applicable only to torusshaped systems in where the initial load of drug is higher than its solubility in the polymer.

A mathematical modeling of controlled release of drug from torus-shaped single-layer devices is presented. Analytical solutions based on the pseudo-steady state approximation are derived. The reliability and usefulness of the model are ascertained by comparison of the simulation results with matrix-type vaginal ring experimental release data reported in the literature. A good agreement between the model prediction and the experimental data is observed. An analysis of the effect of the variation in torus design parameters on the solute release is also presented. The model is applicable only to torus-shaped single-layer systems wherein the initial load of drug is higher than its solubility in the polymer.

Analytical solutions for the case of controlled dispersed-drug release from planar non-erodible polymeric matrices, based on Refined Integral Method, are presented. A new adjusting equation is used for the dissolved drug concentration profile in the depletion zone. The set of equations match the available exact solution. In order to illustrate the usefulness of this model, comparisons with experimental profiles reported in the literature are presented. The obtained results show that the model can be employed in a broad range of applicability.

Analytical solutions based on the pseudo-steady state approximation (PSSA) were derived for the case of controlled dispersed-drug release from erodible and non-erodible planar matrices, through a membrane, and taking into account the existence of a diffusion boundary layer and a finite release medium. The solutions can be applied to a broad range of situations from drug release into finite or infinite medium, from erodible or non-erodible matrices, in the presence or absence of a membrane, and in the presence or absence of a stagnant liquid layer. The prediction is accurate for the cases in which the initial drug load is higher than the drug solubility in the polymer (e.g. A/Cs≥3) till the entire dispersed drug is dissolved. The dependence on the release kinetics with different parameters was simulated and provides a theoretical platform for the design of dispersed-drug release devices.