ABSTRACT
A thermo-reversible in situ forming implant, based on the combination of Pluronic® F-127 and Pluronic® F-68 with nanostructured lipid carriers (NLC), was formulated with the aim of achieving the sustained release of estradiol valerate (EV). EV-loaded NLC, prepared by the hot high-pressure homogenization technique, presented an entrapment efficiency of 90 ± 2.9 %, a particle size (PS) of 122 ± 11.2 nm, a polydispersity index (PDI) of 0.344 ± 0.07, and a zeta potential (ZP) of - 10.5 ± 1.3 mV. Once obtained, NLC were then included in a thermo-reversible gel (EV-loaded NLC gel), which was characterized by its rheological behavior, gelation temperature, and injectability. The in vitro release tests showed that the EV-loaded NLC gel delayed the release significantly, in comparison with a solution of the drug and with the EV-loaded NLC. The EV-loaded NLC gel and a commercially available suspension containing estradiol were administered parenterally to rabbits. A 16.8-fold greater AUC and a 40-fold higher Cmax were obtained with the EV-loaded NLC gel, compared to the commercial suspension. A rapid initial release of EV in vivo, from the EV-loaded NLC gel, suggests that it is necessary to adjust the ratio of the copolymers or to include in the gel an additive that improves gelation time and gel strength, in order to achieve a sustained release. An interesting observation was that the in vitro profile, which has a three-phase behavior, coincides with what was observed in the in vivo study. Graphical abstract.
Subject(s)
Drug Carriers , Estradiol/administration & dosage , Lipids , Nanostructures , Animals , Particle Size , RabbitsABSTRACT
A drug that contains a recombinant protein as an active principle is called a biotechnological drug or biopharmaceutical.There are currently over 300 biopharmaceuticals worldwide. Many of these contains a similar active principle (biosimilar drug) as other previously registered (innovator drug). It has suggested that due to the complex implications in a formulation containing a protein, the manufacturing process is a key factor for efficacy and safety requirements. In fact, certain variability has been detected of the protein properties in different lots (or batches) of the same manufacturer, which produce changes at a clinical level. For this reason, the evaluation of biosimilar drugs has acquired great relevance, being the preclinical level of one of the more important stages of the development due to its lower cost (with respect to the clinical level) and its high capacity to detect formulation-manufacture problems. However, the demonstration of comparability at physicochemical, preclinical, and clinical levels is required in order to achieve market registration. In this review the in vitro and in vivo models used for the assessment of proposed biosimilars will be discussed.
Subject(s)
Biosimilar Pharmaceuticals/pharmacology , Models, Biological , Animals , Drug Evaluation, Preclinical , Humans , In Vitro TechniquesABSTRACT
The aim of the present study was to determinate the factors affecting carbamazepine (CBZ) clearance (CL) in adults with epilepsy using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 104 adults receiving CBZ. A total of 161 CBZ steady state serum concentration samples were analyzed. Population CL was calculated by using NONMEM with a one compartment model with first-order absorption and elimination. The following covariates were tested for their influence on clearance (CL): total body weight, age, dose/day, sex, surface area (SA) and comedication with primidone (PRIM), ualproic acid or phenytoin (DFH). The final regression model for carbamazepine clearance found best to describe the data was: CL = (0.614 SA + 0.0016 dose/day)(1 + 0.278 DFH)(1 + 0.326 PRIM).
Subject(s)
Carbamazepine/pharmacokinetics , Epilepsy/metabolism , Adolescent , Adult , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
The aim of the present study was to determinate the factors affecting carbamazepine (CBZ) clearance (CL) in adults with epilepsy using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 104 adults receiving CBZ. A total of 161 CBZ steady state serum concentration samples were analyzed. Population CL was calculated by using NONMEM with a one compartment model with first-order absorption and elimination. The following covariates were tested for their influence on clearance (CL): total body weight, age, dose/day, sex, surface area (SA) and comedication with primidone (PRIM), valproic acid or phenytoin (DFH). The final regression model for carbamazepine clearance found best to describe the data was: CL = (0.614 SA + 0.0016 dose/day)(1 + 0.278 DFH)(1 + 0.326 PRIM).
El objetivo de este trabajo es determinar los factores que influyen en el aclaramiento (CL) de carbamacepina (CBZ) en pacientes epilépticos adultos usando un modelo de efectos mixtos y datos de concentraciones séricas de CBZ generados del cuidado rutinario de los pacientes. El número de pacientes incluidos en el estudio fue de 104. Se analizaron un total de 161 concentraciones séricas de CBZ en el estado estacionario. El aclaramiento poblacional se determinó con el programa NONMEM aplicando un modelo monocompartimental con absorción y eliminación de primer orden. Se analizó la influencia de las siguientes covariables sobre el CL: peso corporal total, edad, dosis/día, sexo, superficie corporal (SC) y la comedicación con primidona (PRIM), ácido valproico o difenilhidantoína (DFH). El modelo final de regresión obtenido es el siguiente: CL = (0.614 SC + 0.0016 dosis/día)( 1+ 0.278 DFH)(1 + 0.326 PRIM).