Pharmacokinetic Appraisal of Carprofen Delivery from Intra-Articular Nanoparticles: A Population Modeling Approach in Rabbits

Osteoarthritis is frequently treated in veterinary settings with non-steroidal anti-inflammatory drugs (NSAID) such as carprofen (CP). Its action over the articular cartilage can be enhanced by increasing drug uptake into the cartilage, alongside its site of action, and anticipating its rapid distribution towards the bloodstream. A pharmacokinetic study to evaluate carprofen nanoparticles (NP) after intraarticular administration (IA) in rabbits was performed through a modeling allometric approach. The pharmacokinetic analysis of plasma profiles showed a rapid CP distribution outwards the synovial chamber but mainly remaining in plasma (Vc = 0.14 L/5 Kg), according to its high protein-binding. The absorption data modeling showed the occurrence of two different release–absorption rate processes after nanoparticle administration in the synovial space, i.e., a fast rate process causing a burst effect and involving the 59.5% of the total CP absorbed amount and a slow rate process, involving 40.5%. Interestingly, the CP burst effect inside the joint space enhances its diffusion towards cartilage resulting in CP accumulation in about three times higher concentrations than in plasma. In line with these results, the normalized-by-dose area under the concentration vs. time curve (AUC) values after IA were 80% lower than those observed after the intravenous. Moreover, the slower slope of the concentration–time terminal phase after IA administration vs. intravenous (IV) suggested a flip-flop phenomenon (0.35 h-1 vs. 0.19 h-1). Notably, CP clearances are predictive of the pharmacokinetic (PK) profile of CP in healthy humans (0.14 L/h/5 kg vs. 2.92 L/h/70 kg) although an over-estimation has been detected for cats or dogs (10 times and 4 times, respectively). This fact could probably be attributed to inter-species metabolic differences. In summary, despite the limited number of animals used, this study shows that the rabbit model could be suitable for a predictive evaluation of the release enhancement of CP-NP towards the biophase in arthritic diseases not due to sterical retention of the formulation

Carprofen Permeation Test through Porcine Ex Vivo Mucous Membranes and Ophthalmic Tissues for Tolerability Assessments: Validation and Histological Study

Carprofen (CP), a non-steroidal anti-inflammatory drug (NSAID), is profusely used in veterinary medicine for its analgesic and anti-inflammatory activity. Some undesirable effects are associated with its systemic administration. Alternative local routes are especially useful to facilitate its administration in animals. The main aim of this paper is to validate the suitability of ex vivo permeation experiments of CP with porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) intended to be representative of naïve in vivo conditions. Chromatographic analysis of CP in membrane-permeated samples and drug-retained have been validated following standard bioanalytical guidelines. Then, recovery levels of drugs in tissue samples were assessed with aqueous phosphate buffered saline (PBS) buffer to preserve the histological integrity. Finally, as a proof of concept, a series of CP permeation tests in vertical Franz diffusion cells has been performed to evaluate permeation flux and permeability constants in all tissues, followed by a histological study for critical evaluation. Furthermore, synthetic tissue retention-like samples were prepared to verify the value of this experimental study. Results show linear relationships with good determination coefficient (R2 > 0.998 and R2 > 0.999) in the range of 0.78 to 6.25 mg/mL and 3.125 mg/mL to 100 mg/mL, respectively. Low limits of quantification around 0.40 µg/mL were allowed to follow permeation levels until a minimum of 0.40% of the locally-applied dose. This method showed a good accuracy and precision with values lower than 2%. After the recovery technique, reproducible values below 30% were achieved in all tissues, suggesting it is a non-damaging method with low efficiency that requires the use of further solvents to enhance the extraction percentages. After permeation and histology tests, no relevant peak interferences were detected, and no cell or tissue damage was found in any tissue. In conclusion, results demonstrate the suitability of this test to quantify the distribution of CP with good histological tolerability

Influence of freeze-drying and γ-irradiation in preclinical studies of flurbiprofen polymeric nanoparticles for ocular delivery using d-(+)-trehalose and polyethylene glycol.

This study investigated the suspension of poly(ε-caprolactone) nanoparticles as an ocular delivery system for flurbiprofen (FB-PεCL-NPs) in order to overcome the associated problems, such as stability, sterility, tolerance, and efficacy, with two different FB-PεCL-NP formulations. The formulations were stabilized with poloxamer 188 (1.66% and 3.5%) and submitted individually for freeze-drying and γ-irradiation with polyethylene glycol 3350 (PEG3350) and d-(+)-trehalose (TRE). Both formulations satisfied criteria according to all physicochemical parameters required for ocular pharmaceuticals. The FB-PεCL-NP formulations showed non-Newtonian behavior and sustained drug release. Ex vivo permeation analysis using isolated ocular pig tissues suggested that the presence of PEG3350 results in a reduction of FB transcorneal permeation. Moreover, TRE improved the penetration of FB across the cornea, especially after γ-irradiation. In addition, both formulations did not show a significant affinity in increasing FB transscleral permeation. Both formulations were classified as nonirritating, safe products for ophthalmic administration according to hen's egg test-chorioallantoic membrane and Draize eye test. Furthermore, an in vivo anti-inflammatory efficacy test showed that irradiated FB-PεCL-NPs prepared with PEG3350 (IR-NPsPEG) have longer anti-inflammatory effects than those presented with irradiated FB-PεCL-NPs prepared with TRE (IR-NPsTRE). IR-NPsPEG showed a suitable physical stability after an aqueous reconstitution over .30 days. This study concludes that both formulations meet the Goldman's criteria and demonstrate how irradiated nanoparticles, with innovative permeation characteristics, could be used as a feasible alternative to a flurbiprofen solution for ocular application in clinical trials

Ex Vivo Permeation of Carprofen Vehiculated by PLGA Nanoparticles through Porcine Mucous Membranes and Ophthalmic Tissues

(1) Background: Carprofen (CP), 2-(6-chlorocarbazole) propionic acid, is used as an anti-inflammatory, analgesic and anti-pyretic agent and it belongs to the family of non-steroidal anti-inflammatory drugs (NSAIDs). CP has some adverse reactions in systemic administration; for this reason, topical administration with CP nanoparticles (CP-NPs) can be an optimal alternative. The main objective of this work is the investigation of ex vivo permeation of CP through different types of porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) to compare the influence of CP-NPs formulation over a CP solution (CP-Solution). (2) Methods: The ex vivo permeation profiles were evaluated using Franz diffusion cells. Furthermore, in vivo studies were performed to verify that the formulations did not affect the cell structure and to establish the amount retained (Qr) in the tissues. (3) Results: Permeation of CP-NPs is more effective in terms of drug retention in almost all tissues (with the exception of sclera and sublingual). In vivo studies show that neither of the two formulations affects tissue structure, so both formulations are safe. (4) Conclusions: It was concluded that CP-NPs may be a useful tool for the topical treatment of local inflammation in veterinary and human medicine

Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration

Two optimized pranoprofen-loaded poly-L-lactic-co glycolic acid (PLGA) nanoparticles (PF-F1NPs; PF- 39 F2NPs) have been developed and further dispersed into hydrogels for the production of semi-solid formu- 40 lations intended for ocular administration. The optimized PF-NP suspensions were dispersed in freshly 41 prepared carbomer hydrogels (HG_PF-F1NPs and HG_PF-F2NPs) or in hydrogels containing 1% azone 42 (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone) in order to improve the ocular biopharmaceutical profile 43 of the selected non-steroidal anti-inflammatory drug (NSAID), by prolonging the contact of the pranopro- 44 fen with the eye, increasing the drug retention in the organ and enhancing its anti-inflammatory and 45 analgesic efficiency. Carbomer 934 has been selected as gel-forming polymer. The hydrogel formulations 46 with or without azone showed a non-Newtonian behavior and adequate physicochemical properties for 47 ocular instillation. The release study of pranoprofen from the semi-solid formulations exhibited a sus- 48 tained release behavior. The results obtained from ex vivo corneal permeation and in vivo anti-inflamma- 49 tory efficacy studies suggest that the ocular application of the hydrogels containing azone was more 50 effective over the azone-free formulations in the treatment of edema on the ocular surface. No signs of 51 ocular irritancy have been detected for the produced hydrogels

Nano-engineering of ketorolac tromethamine platforms for ocular treatment of inflammatory disorders

Aim: The development and optimization of Ketorolac tromethamine-loaded polylactic-co-glycolic acid nanoparticles (KT-NPs) for the treatment of inflammatory processes of the eye. Materials & methods: KT-NPs were developed by factorial design and characterized by assessing their physicochemical properties. Biopharmaceutical behavior studies, ocular tolerance, anti-inflammatory efficacy and bioavailability tests were performed on pigs. Results: Optimized KT-NPs of 112 nm, narrow distribution with encapsulation efficiency near 100% were obtained. KT release followed the Weibull model and there was significantly greater retention in the cornea and sclera than in the commercial reference. KT-NPs showed no signs of ocular irritancy and similar anti-inflammatory efficacy to the commercial reference. Conclusion: KT-NPs were a suitable alternative for the treatment of inflammatory disorders of the anterior and posterior segments of the eye as an alternative to conventional topical formulations

La formación en competencia matemática aplicada a la farmacia galénica: Diagnóstico en primer año de Farmacia en la UB

Projecte 2015PID-UB/039Se analizan los resultados de tests y problemas numéricos de Farmacia Galénica realizados por los alumnos de primero del Grado en Farmacia para detectar posibles carencias en competencia matemática en este ámbito. Los errores más frecuentes conciernen la aplicación del concepto de porcentaje. Por otra parte, las acciones de mejora propuestas por el profesorado no se han visto respaldadas por el alumnado, lo que demuestra la necesidad de un nuevo enfoque en la estrategia docente.Proyecto 2015PID-UB/039 financiado por la Universidad de Barcelon

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Nanopartículas de carprofen para diferentes vías de administración

[spa] El carprofen (CP), es un antiinflamatorio no esteroideo, con actividad antiinflamatoria, analgésica y antipirética, se utiliza en medicina veterinaria para el tratamiento de patologías de origen agudo y crónico, como osteoarticulares, musculares, osteomusculares, respiratorias y también a nivel perioperatorio. Actualmente la nanotecnología es aplicada cada vez más en todos los campos de la investigación. Las nanopartículas (NPs) a nivel farmacéutico hacen parte de un gran componente para la encapsulación de fármacos, dentro de estas están las NPs poliméricas que presentan una gran versatilidad debido a que encapsulan y liberan una molécula de forma sostenida, son biodegradables y no tóxicas, además pueden ser utilizadas por diferentes vías de aplicación en función de sus características. El desarrollo y optimización de NPs, debe cumplir con un mínimo de condiciones como un tamaño medio de partícula (TM P), índice de polidispersidad (IP), carga superficial o potencial zeta (ZP) y eficacia de encapsulación (EE) adecuados. Las NPs poliméricas de CP (N Ps-CP) elaboradas presentan las siguientes características: un TM P de 189.5 ± 1.67 nm, un IP de 0.01 ± 0.01, ZP de -22.8 ± 0.66 mV y una EE de 74.70 ± 0.95%. El análisis fisicoquímico confirmó que el CP se encuentra disperso dentro de las NPs. En cuanto a la estabilidad, mediante la liofilización, utilizando un crioprotector y además de someterlas a esterilización permite mantener las NPs-CP I iofi I izadas (L-N Ps-CP) y almacenadas por más tiempo. En la diálisis realizada, el fármaco liberado sigue un modelo cinético de primer orden proporcionando una liberación sostenida de CP. El test in vitro de irritación ocular (Hen'is Egg Test Chorioallantoic Membrane -HET-CAM), permite determinar que las L-N Ps-CP no presenta signos de irritación ocular. El análisis de la permeación ex vivo a través de la córnea de conejo (Nueva Zelanda —NZ-), piel humana, de cerdo y de glándula mamaria de vaca, revela que una concentración suficiente de CP fue retenido en el tejido evitando una excesiva permeación y por tanto que potencialmente llegue a nivel sistémico; los estudios de permeación muestran unos valores de difusión similar entre la piel humana y la porcina y superior para la bovina. Las caracterísiticas de las L-N Ps-CP permiten que puedan ser utilizadas por distintas vías de administración. Para la aplicación de NPs a nivel ocular el tamaño debe ser inferior a 10 p m, siendo un factor importante para evitar molestias debidas al tamaño. A nivel de la piel el TM P cuanto más pequeño permite una mayor penetración folicular y difusión de la nanoestructura. Cuando son aplicadas por vía intraarticular (IA) el tamaño de partícula debe ser inferior a 200 nm para evitar la formación de trombos. El test de Draize de tolerancia ocular, confirma que no hay signos de irritación, similarmente para el test de irritación Draize en piel de conejos NZ. Las L-NPs-CP aplicadas tópicamente disminuyen significativamente la inflamación in vivo comparado con el fármaco referencia en el modelo de inducción del edema en oreja de ratón TPA. Con las L-NPs-CP, se confirma una óptima eficacia y su potencial aplicación en cirugía ocular. En relación a su uso externo, pueden ser útiles para el tratamiento de la inflamación dérmica local. Se determinó la farmacocinética del CP comercial a una dosis única administrada a nivel IV en conejos NZ, seguido de diez semividas del CP, se administraron las L-NPs-CP por vía IA en el conejo. Las L-NPs-CP demostraron ser adecuadas para la administración parenteral. La biodisponibilidad del CP fue del 58.31%. Se determinó la concentración total de CP retenido a nivel IA, obteniéndose 0.46 µg/mL después de las 9.25 h en el cartílago articular, el menisco y el líquido sinovial.[eng] The CP is a nonsteroidal antiinflammatory used for inflammatory processes and articular analgesics such as, respiratory diseases and during and after surgical procedures. Nanostructured encapsulation of drugs, such as nanoparticles (NPs) polymer systems have great versatility because they sustained release molecule and are biodegradable and non-toxic. The development and optimization of NPs must meet minimum conditions such as the average particle size (Z-ave), polydispersity index (IP), surface charge or zeta potential (ZP) and encapsulation efficiency (EE). The polymeric NPs of CP (NPs-CP) were prepared with the following characteristics: A 189.5 ± 1.67nm TMP, a PI of 0.01 ± 0.01 -22.8 ± 0.66mV ZP and 74.70 ± 0.95 EE%. The physico-chemical analysis confirmed that the CP dispersed within the NPs. The stability by lyophilization, using a cryoprotectant and when subjected to sterilization with gamma irradiation allows NPs to keep lyophilised CP (L-NPs-CP) stored longer. The drug released follows a first order kinetic model. Permeation analysis ex vivo in the rabbit cornea, human skin, pork and bovine udder reveals that a sufficient concentration of CP was retained in the tissue avoiding excessive permeation therefore potentially reaching systemic level. Permeation shows values similar diffusion between human skin and the porcine and bovine superior for. The tests in vitro and in vivo, to determine the L-NPs-CP showed no signs of eye and skin irritation. At the eye level, the NPs allow the drug to remain longer at the level of the cornea. The smaller the skin is, Z-ave is a major follicular penetration and drug diffusion. The L-NPs-CP applied topically significantly decrease inflammation in vivo compared to the reference drug induction model of edema in mouse ear TPA. With L-NPs-CP, optimal efficiency in a potential application for eye surgery and for the treatment of local skin inflammation is confirmed. The bioavailability of CP IA is 58.31%, after single dose administration IA knee of L-NPs-CP in rabbits NZ. The total concentration of CP obtained together in the three types of tissue are: synovial fluid and synovium cartilage 0.46 h 9.25 g/mL

Nanopartículas de carprofen para diferentes vías de administración

El carprofen (CP), es un antiinflamatorio no esteroideo, con actividad antiinflamatoria, analgésica y antipirética, se utiliza en medicina veterinaria para el tratamiento de patologías de origen agudo y crónico, como osteoarticulares, musculares, osteomusculares, respiratorias y también a nivel perioperatorio. Actualmente la nanotecnología es aplicada cada vez más en todos los campos de la investigación. Las nanopartículas (NPs) a nivel farmacéutico hacen parte de un gran componente para la encapsulación de fármacos, dentro de estas están las NPs poliméricas que presentan una gran versatilidad debido a que encapsulan y liberan una molécula de forma sostenida, son biodegradables y no tóxicas, además pueden ser utilizadas por diferentes vías de aplicación en función de sus características. El desarrollo y optimización de NPs, debe cumplir con un mínimo de condiciones como un tamaño medio de partícula (TM P), índice de polidispersidad (IP), carga superficial o potencial zeta (ZP) y eficacia de encapsulación (EE) adecuados. Las NPs poliméricas de CP (N Ps-CP) elaboradas presentan las siguientes características: un TM P de 189.5 ± 1.67 nm, un IP de 0.01 ± 0.01, ZP de -22.8 ± 0.66 mV y una EE de 74.70 ± 0.95%. El análisis fisicoquímico confirmó que el CP se encuentra disperso dentro de las NPs. En cuanto a la estabilidad, mediante la liofilización, utilizando un crioprotector y además de someterlas a esterilización permite mantener las NPs-CP I iofi I izadas (L-N Ps-CP) y almacenadas por más tiempo. En la diálisis realizada, el fármaco liberado sigue un modelo cinético de primer orden proporcionando una liberación sostenida de CP. El test in vitro de irritación ocular (Hen'is Egg Test Chorioallantoic Membrane -HET-CAM), permite determinar que las L-N Ps-CP no presenta signos de irritación ocular. El análisis de la permeación ex vivo a través de la córnea de conejo (Nueva Zelanda —NZ-), piel humana, de cerdo y de glándula mamaria de vaca, revela que una concentración suficiente de CP fue retenido en el tejido evitando una excesiva permeación y por tanto que potencialmente llegue a nivel sistémico; los estudios de permeación muestran unos valores de difusión similar entre la piel humana y la porcina y superior para la bovina. Las caracterísiticas de las L-N Ps-CP permiten que puedan ser utilizadas por distintas vías de administración. Para la aplicación de NPs a nivel ocular el tamaño debe ser inferior a 10 p m, siendo un factor importante para evitar molestias debidas al tamaño. A nivel de la piel el TM P cuanto más pequeño permite una mayor penetración folicular y difusión de la nanoestructura. Cuando son aplicadas por vía intraarticular (IA) el tamaño de partícula debe ser inferior a 200 nm para evitar la formación de trombos. El test de Draize de tolerancia ocular, confirma que no hay signos de irritación, similarmente para el test de irritación Draize en piel de conejos NZ. Las L-NPs-CP aplicadas tópicamente disminuyen significativamente la inflamación in vivo comparado con el fármaco referencia en el modelo de inducción del edema en oreja de ratón TPA. Con las L-NPs-CP, se confirma una óptima eficacia y su potencial aplicación en cirugía ocular. En relación a su uso externo, pueden ser útiles para el tratamiento de la inflamación dérmica local. Se determinó la farmacocinética del CP comercial a una dosis única administrada a nivel IV en conejos NZ, seguido de diez semividas del CP, se administraron las L-NPs-CP por vía IA en el conejo. Las L-NPs-CP demostraron ser adecuadas para la administración parenteral. La biodisponibilidad del CP fue del 58.31%. Se determinó la concentración total de CP retenido a nivel IA, obteniéndose 0.46 µg/mL después de las 9.25 h en el cartílago articular, el menisco y el líquido sinovial.The CP is a nonsteroidal antiinflammatory used for inflammatory processes and articular analgesics such as, respiratory diseases and during and after surgical procedures. Nanostructured encapsulation of drugs, such as nanoparticles (NPs) polymer systems have great versatility because they sustained release molecule and are biodegradable and non-toxic. The development and optimization of NPs must meet minimum conditions such as the average particle size (Z-ave), polydispersity index (IP), surface charge or zeta potential (ZP) and encapsulation efficiency (EE). The polymeric NPs of CP (NPs-CP) were prepared with the following characteristics: A 189.5 ± 1.67nm TMP, a PI of 0.01 ± 0.01 -22.8 ± 0.66mV ZP and 74.70 ± 0.95 EE%. The physico-chemical analysis confirmed that the CP dispersed within the NPs. The stability by lyophilization, using a cryoprotectant and when subjected to sterilization with gamma irradiation allows NPs to keep lyophilised CP (L-NPs-CP) stored longer. The drug released follows a first order kinetic model. Permeation analysis ex vivo in the rabbit cornea, human skin, pork and bovine udder reveals that a sufficient concentration of CP was retained in the tissue avoiding excessive permeation therefore potentially reaching systemic level. Permeation shows values similar diffusion between human skin and the porcine and bovine superior for. The tests in vitro and in vivo, to determine the L-NPs-CP showed no signs of eye and skin irritation. At the eye level, the NPs allow the drug to remain longer at the level of the cornea. The smaller the skin is, Z-ave is a major follicular penetration and drug diffusion. The L-NPs-CP applied topically significantly decrease inflammation in vivo compared to the reference drug induction model of edema in mouse ear TPA. With L-NPs-CP, optimal efficiency in a potential application for eye surgery and for the treatment of local skin inflammation is confirmed. The bioavailability of CP IA is 58.31%, after single dose administration IA knee of L-NPs-CP in rabbits NZ. The total concentration of CP obtained together in the three types of tissue are: synovial fluid and synovium cartilage 0.46 h 9.25 g/mL