RESUMO
OBJECTIVE: To assess the variability of repeated measurements of serum etonogestrel concentration among contraceptive implant users. STUDY DESIGN: We measured 3 consecutive serum etonogestrel concentrations, drawn weekly, in women using etonogestrel implants for 12 to 36 months. We used a repeated measures test to evaluate differences. RESULTS: Among 20 participants, repeat serum etonogestrel concentrations did not differ from initial measurements (Friedman's test, p = 0.95). Mean serum etonogestrel concentrations had similar 95% confidence intervals at each time point: (134.09, 201.46), (135.08, 237.46), and (132.66, 192.45). CONCLUSION: We confirm that single-time measurements of serum etonogestrel concentration are acceptable pharmacokinetic outcomes for etonogestrel implant studies. IMPLICATIONS: Pharmacokinetic studies of the etonogestrel contraceptive implant assume single-time measurements are stable steady-state estimates based on small studies using older analysis methods. Our repeated measures study using modern liquid-chromatography mass-spectrometry analysis methods provides updated support for single-time pharmacokinetic measurements among etonogestrel implant users.
Assuntos
Anticoncepcionais Femininos , Anticoncepcionais Femininos/farmacocinética , Desogestrel , Implantes de Medicamento/farmacocinética , Feminino , HumanosRESUMO
Imaging-based characterization of polymeric drug-eluting implants can be challenging due to the microstructural complexity and scale of dispersed drug domains and polymer matrix. The typical evaluation via real-time (and accelerated in vitro experiments not only can be very labor intensive since implants are designed to last for 3 months or longer, but also fails to elucidate the impact of the internal microstructure on the implant release rate. A novel characterization technique, combining multi-scale high resolution three-dimensional imaging, was developed for a mechanistic understanding of the impact of formulation and manufacturing process on the implant microstructure. Artificial intelligence-based image segmentation and imaging analytics convert "visualized" structural properties into numerical models, which can be used to calculate key parameters governing drug transport in the polymer matrix, such as effective permeability. Simulations of drug transport in structures constructed on the basis of image analytics can be used to predict the release rates for the drug-eluting implant without running lengthy experiments. Multi-scale imaging approach and image-based characterization generate a large amount of quantitative structural information that are difficult to obtain experimentally. The direct-imaging based analytics and simulation is a powerful tool and has potential to advance fundamental understanding of drug release mechanism and the development of robust drug-eluting implants.
Assuntos
Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Composição de Medicamentos/métodos , Imageamento Tridimensional , Microscopia Eletrônica de Varredura , Polímeros , Tomografia Computadorizada por Raios XAssuntos
Implantes de Medicamento/administração & dosagem , Fluocinolona Acetonida/análogos & derivados , Uveíte/tratamento farmacológico , Ensaios Clínicos como Assunto/métodos , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Fluocinolona Acetonida/administração & dosagem , Fluocinolona Acetonida/química , Fluocinolona Acetonida/farmacocinética , Humanos , Injeções Intravítreas , Polímeros/administração & dosagem , Polímeros/farmacocinética , Uveíte/metabolismoRESUMO
As a result of the low oral bioavailability of several drugs, there is a renewed interest for parenteral administration to target their absorption directly into the blood bypassing the long gastrointestinal route and hepatic metabolism. In order to address the potential side effects of frequent injections, sustained release systems are the most popular approaches for achieving controlled long-acting drug delivery. Injectable in-situ forming implants (ISFIs) have gained greater popularity in comparison to other sustained systems. Their significant positive aspects are attributed to easier production, acceptable administration route, reduced dosing frequency and patient compliance achievement. ISFI systems, comprising biodegradable polymers such as poly (lactide-co-glycolide) (PLGA) based on solvent exchange mechanisms, are emerged as liquid formulations that develop solid or semisolid depots after injection and deliver drugs over extended periods. The drug release from ISFI systems is generally characterized by an initial burst during the matrix solidification, followed by diffusion processes and finally polymeric degradation and erosion. The choice of suitable solvent with satisfactory viscosity, miscibility and biocompatibility along with considerable PLGA hydrophobicity and molecular weights is fundamental for optimizing the drug release. This overview gives a particular emphasis on evaluations and the wide ranges of requirements needed to achieve reasonable physicochemical characteristics of ISFIs.
Assuntos
Composição de Medicamentos , Implantes de Medicamento/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Composição de Medicamentos/métodos , Humanos , Injeções IntramuscularesRESUMO
Poly (lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer, is one of the most commonly used vehicles for controlled-release (CR) implantable dosage forms. Drug molecules formulated in such CR vehicles are released slowly over an extended period of time - often months to years - posing challenges for batch release and quality control testing. Thus, reliable and reproducible accelerated testing methods are required to bridge this gap during early formulation development. This work describes the development of an accelerated in vitro release testing method to predict the real-time in vitro release of a synthetic peptide from a 6-month CR PLGA implant formulation. While accelerated methods have been previously reported for PLGA-based formulations, this work describes a unique case of an aggregation-prone peptide, which required careful attention to the impact of different conditions on both release kinetics and peptide stability. This method describes a suitable combination of release conditions that could help in understanding the release profiles of such peptides prone to aggregation. Parameters including pH, buffer species, temperature, and addition of organic co-solvents and surfactants were evaluated separately and in combination for their ability to achieve complete peptide release within 2 weeks while accurately recapitulating release rate, profile and peptide stability. The accelerated release method that gave the best agreement with real-time release was a mixed media of co-solvent (5% tetrahydrofuran), surfactant (5% TritonX-100) and elevated temperature (50 °C) in a neutral buffer (PBS pH 7.4). This optimized accelerated release method achieved complete release of the peptide load within 14-21 days compared to 3- to 6-months of real-time release and could discriminate critical differences in release behavior between different CR formulations to guide formulation and process development.
Assuntos
Química Farmacêutica/métodos , Implantes de Medicamento/farmacocinética , Excipientes/química , Peptídeos/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Microesferas , Peptídeos/administração & dosagem , Peptídeos/química , Reprodutibilidade dos TestesRESUMO
PURPOSE: To investigate the effects of solvents on the formation of self-assembled nanonization of albumin-oleic acid conjugates (AOCs) using a solvent exchange mechanism for the construction of in situ forming implants (ISFI). METHODS: A poorly water-soluble drug, paliperidone palmitate (PPP), was chosen as the model drug. AOC was synthesized with the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reaction. Dichloromethane, tetrahydrofuran, ethanol, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and deionized water were selected to investigate the formation of self-assembled AOC nanoparticles (AONs). The volume ratios of organic solvents against water could determine the miscibility, injectability, and in situ nanonizing capability without aggregation. RESULTS: As the polarity of the organic solvents increased, the AONs exhibited a spherical shape, and the larger the volume of the solvent, the smaller the size of the AONs. To use AOC in ISFI for controlled release of PPP, poly(d,l-lactide-co-glycolide) (PLGA) was combined with the AOC in 2 mL of N-methyl-2-pyrrolidone and water solution (1.8/0.2 ratio). The release rates of all formulations exhibited similar curve patterns overall but were more controlled in decreasing order as follows: AOC, PLGA, and AOC/PLGA for 14 days. CONCLUSION: A combined formulation of AOC and PLGA was found to effectively control the initial burst release of the drug.
Assuntos
Nanopartículas/química , Palmitato de Paliperidona/farmacocinética , Solventes/química , Albuminas/química , Preparações de Ação Retardada , Dimetil Sulfóxido/química , Implantes de Medicamento/farmacocinética , Etanol/química , Ácido Oleico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Pirrolidinonas , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , ÁguaRESUMO
The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (µMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single µMESH application, carrying 0.75 mg kg-1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the µMESH increases the median overall survival (â¼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The µMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions.
Assuntos
Implantes Absorvíveis , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Diclofenaco/farmacocinética , Diclofenaco/farmacologia , Docetaxel/farmacocinética , Docetaxel/farmacologia , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The interest in the development and the therapeutic use of long-acting injectable (LAI) products for chronic or long-term treatments has grown exponentially. The complexity and the multiphase drug release process represent serious issues for an effective modeling of the PK properties of LAI products. The objective of this article is to show how convolution-based models with piecewise-linear approximation of the nonlinear drug release function can provide an enhanced modeling tool for (1) characterizing the complex PK profiles of LAI formulations with completely different drug release properties, and (2) addressing key questions supporting the optimal development of LAI products by simulating the PK time course resulting from different dosing strategies. Convolution-based modeling and simulation were implemented in NONMEM, and 3 case studies were presented to assess the performances of this new modeling approach using PK data of LAI products developed using different technologies and administered using different routes: microsphere technology and aqueous nanosuspension intramuscularly administered and biodegradable polymer subcutaneously administered. The performance of the convolution-based modeling approach was compared with the performance of conventional parametric models using a reference data set on theophylline. The results of the comparison indicated that the nonparametric input function provided a more accurate description of the data either in terms of global measure of goodness of fit (ie, Akaike information criterion and Bayesian information criterion) or in terms of performance of the fitted model (ie, the percent prediction error on Cmax and AUC0-t ).
Assuntos
Implantes de Medicamento/farmacocinética , Modelos Biológicos , Teorema de Bayes , Simulação por Computador , Liberação Controlada de Fármacos , HumanosRESUMO
In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements.
Assuntos
Preparações de Ação Retardada/administração & dosagem , Implantes de Medicamento/administração & dosagem , Stents Farmacológicos/história , Preparações de Ação Retardada/farmacocinética , Aprovação de Drogas/história , Composição de Medicamentos/métodos , Composição de Medicamentos/tendências , Implantes de Medicamento/história , Implantes de Medicamento/farmacocinética , História do Século XX , História do Século XXI , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
The initial drug release from in situ forming implants is affected by factors such as the physicochemical properties of the active pharmaceutical ingredient, the type of the excipients utilized, and the surrounding environment. The feasibility of UV-vis imaging for characterization of the initial behavior of poly(d,l-lactide-co-glycolide) (PLGA)/1-methyl-2-pyrrolidinone (NMP) in situ forming implants was investigated. The in vitro release of leuprolide acetate (LA) and implant formation in real time were monitored using dual-wavelength imaging at 280 and 525 nm, respectively, in matrices based on agarose gel and hyaluronic acid (HA) solution emulating the subcutaneous matrix. Three hours upon injection of the pre-formulation, approximately 15% of the total amount of LA administered was found in the agarose gel, while 5% was released from the implant into the HA solution. Concurrently, more extensive swelling of the implants in the HA solution as compared to implants in the agarose gel was observed. Transport of both LA and the solvent NMP was investigated using UV-vis imaging in a small-scale cell where the geometry of the formulation was controlled, showing a linear correlation between drug release and solvent escape. Light microscopy showed that the microstructures of the resulting implants in agarose gel and HA solution were different, which may be attributed to the different solvent exchange rates. UV imaging was also used to examine the interaction of LA with the release medium by characterizing the diffusion of LA in agarose gel, HA solution, and phosphate buffered saline. The reduced LA diffusivity in HA solution as compared to agarose gel and the LA distribution coefficient in the agarose gel-HA system indicated the presence of interactions between LA and HA. Our findings show that the external environment affects the solvent exchange kinetics for in situ forming implants in vitro, resulting in different types of initial release behavior. UV-vis imaging in combination with biorelevant matrices may offer an interesting approach in the development of in situ forming implant delivery systems.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Implantes de Medicamento/farmacocinética , Excipientes/química , Leuprolida/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Leuprolida/administração & dosagem , Leuprolida/química , Microscopia Ultravioleta , Imagem Molecular/métodos , SolubilidadeRESUMO
OBJECTIVE: To compare plasma etonogestrel concentrations sampled from the contralateral- versus ipsilateral-to-implant arm. STUDY DESIGN: Sub-analysis of a cross-sectional study in Botswana in 33 participants who provided contralateral and ipsilateral blood samples. RESULTS: Plasma etonogestrel concentrations in contralateral and ipsilateral specimens were highly correlated (correlation coefficient = 0.99; p < 0.0001). Bland-Altman analysis of agreement showed that etonogestrel levels were on average 5.9 pg/mL higher (2.1%) in ipsilateral compared to contralateral specimens (95% confidence interval: -4.1, 15.9 pg/mL). CONCLUSIONS: We found no meaningful differences in plasma etonogestrel concentrations between samples taken from the contralateral- versus ipsilateral-to-implant arm. IMPLICATIONS: Our data suggest that etonogestrel plasma concentrations are unlikely to be meaningfully different between samples drawn from the ipsilateral- versus the contralateral-to-implant arms in etonogestrel contraceptive implant users.
Assuntos
Anticoncepcionais Femininos/sangue , Desogestrel/sangue , Implantes de Medicamento/administração & dosagem , Braço , Botsuana , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Estudos Transversais , Desogestrel/administração & dosagem , Desogestrel/farmacocinética , Implantes de Medicamento/farmacocinética , Feminino , HumanosRESUMO
Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release. In this study, we developed a system capable of releasing functional drug-carrying particles over a prolonged time. First, we evaluated the feasibility of our approach by encapsulating silica particles of different sizes (500 nm and 1 µm) and surface properties (OH or NH2 groups) into in situ-forming PLGA implants. In this way, we achieved sustained release of particles over periods ranging from 30 to 70 days. OH-carrying particles were released much more quickly when compared to NH2-modified particles. We demonstrated that the underlying release mechanisms involve size-dependent diffusion and polymer-particle interactions. Second, particles that carried covalently-attached ovalbumin (OVA) on their surfaces were incorporated into the implant. We demonstrated that OVA was released in association with the particles as functional entities over a period of 30 days. The released particle-drug conjugates maintained their colloidal stability and were efficiently taken up by antigen presenting cells. This system consisting of particles incorporated into PLGA-based in situ-forming implants offers the dual advantage of sustained and particulate release of drugs as a functional unit and has potential for future use in many applications, particularly in single-dose vaccines.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Dióxido de Silício/farmacocinética , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/síntese química , Liberação Controlada de Fármacos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem , Ovalbumina/síntese química , Ovalbumina/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Dióxido de Silício/administração & dosagem , Dióxido de Silício/síntese químicaRESUMO
Deferasirox (DFX) is an oral iron-chelating agent and classified into class II of the Biopharmaceutics Classification System. Low bioavailability of the drug due to insufficient solubility in physiological fluids is the main drawback of DFX. The idea of the current study was to explore the potential of solid dispersion (SD) as an effective method to improve the dissolution rate of DFX in pellets. The SDs were made by the solvent evaporation technique using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K25 with different drug-to-carrier ratios. Then, the dispersion was milled and mixed with other components and the mixture layered on sugar-based cores by pan coating technique. The pellets were evaluated in terms of size distribution, morphology (SEM), and dissolution behaviour. Drug-polymer interactions were studied using differential scanning calorimetry (DSC), X-ray diffraction study (XRD), and Fourier transformation infrared (FTIR) spectroscopy. The pellets coated with SD showed a remarkable rise in the solubility of DFX than that of free drug-loaded pellets. The dispersion with PVP K25 showed a faster dissolution rate as compared to other mixtures. The DSC and XRD analysis indicated that the drug was in the amorphous state when dispersed in the polymer. The FTIR studies demonstrated any ruled out interaction between drug and polymer. The SEM showed smoothness on the surface of the pellets. It is resolved that the SD method considerably enriched the dissolution rate of DFX in pellets, which can also be utilized for other poorly water-soluble drugs.
Assuntos
Deferasirox , Varredura Diferencial de Calorimetria , Química Farmacêutica , Deferasirox/química , Deferasirox/farmacocinética , Composição de Medicamentos , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Solubilidade , Difração de Raios XRESUMO
The aim of this study was to formulate and evaluate SR matrix pellets containing losartan potassium (LP) solid dispersion using extrusion-spheronization technique to minimize the fluctuation of its plasma concentration. LP solid dispersions were prepared by using different hydrophobic polymers at different weight ratios (0.5, 1, 2, and 5%). LP-Eudragit RS solid dispersion at 1:5 ratio resulted in slower drug release (only 20% of LP was released in about 8 h). Different concentrations of hydrophilic polymer, PEG 6000, were mixed with Avicel® PH 101 to prepare the LP SR matrix pellets containing solid dispersion using 32 full factorial design to evaluate the effects of formulation parameters on the pellets attributes. The magnitude of torque for the pellet wet masses and binder ratio were decreased significantly with increasing PEG 6000 concentration. LP sustained release pellet formula composed of 9.24% PEG 6000 and 8 × 10-9% PVP K30 solution was chosen as optimized formula. Pharmacokinetic studies revealed that calculated t max was 9.72 ± 2.22 h from the optimized sustained release pellets compared to 2.11 ± 0.49 h in case of Cozaar® immediate release tablet, indicating a slower release of the LP from pellets.
Assuntos
Preparações de Ação Retardada/química , Implantes de Medicamento/química , Losartan/química , Resinas Acrílicas/química , Animais , Celulose/química , Química Farmacêutica/métodos , Preparações de Ação Retardada/farmacocinética , Implantes de Medicamento/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , Losartan/farmacocinética , Masculino , Peso Molecular , Polietilenoglicóis/química , Polímeros/química , Coelhos , Solubilidade/efeitos dos fármacos , Comprimidos/química , Comprimidos/farmacocinéticaRESUMO
PURPOSE: Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) coupled with gas-phase ion mobility spectrometry was used to characterize the drug distribution in polymeric implants before and after exposure to accelerated in vitro release (IVR) media. DESI-MSI provides definitive chemical identification and localization of formulation components, including 2D chemical mapping of individual components with essentially no sample preparation. METHODS: Polymeric implants containing 40% (w/w) entecavir and poly(D,L-lactide) (PLA) were prepared and then exposed to either acidified PBS (pH 2.5) or MeOH:H2O (50:50, v/v) medias during a 7-day IVR test using continuous flow-through (CFT) cell dissolution. The amount of drug released from the polymer matrix during the 7-day IVR test was monitored by online-ultraviolet spectroscopy (UV) and HPLC-UV. After that period, intact implants and radial sections of implants were analyzed by DESI-MSI with ion mobility spectrometry. The active ingredient along with impurities and contaminants were used to generate chemical maps before and after exposure to the release medias. RESULTS: Bi-phasic release profiles were observed for implants during IVR release using both medias. During the second phase of release, implants exposed to PBS, pH 2.5, released the entecavir faster than the implants exposed to MeOH:H2O (50:50, v/v). Radial images of the polymer interior show that entecavir is localized along the central core of the implant after exposure to MeOH:H2O (50:50, v/v) and that the drug is more uniformly distributed throughout the implant after exposure to acidified PBS (pH 2.5). CONCLUSIONS: DESI-MSI coupled with ion mobility analysis produced chemical images of the drug distribution on the exterior and interior of cylindrical polymeric implants before and after exposure to various release medias. These results demonstrated the utility of this technique for rapid characterization of drug and impurity/degradant distribution within polymeric implants with direct implications for formulation development as well as analytical method development activities for various solid parenteral and oral dosage forms. These results are especially meaningful since samples were analyzed with essentially no preparative procedures.
Assuntos
Química Farmacêutica/métodos , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Polímeros/química , Espectrometria de Massas por Ionização por Electrospray , Implantes de Medicamento/farmacocinéticaRESUMO
Mounting evidence showing that local nitric oxide (NO) delivery may significantly improve the wound healing process has stimulated the development of wound dressings capable of releasing NO topically. Herein, we describe the preparation of a self-expandable NO-releasing hydrolyzed collagen sponge (CS), charged with the endogenously found NO donor, S-nitrosoglutathione (GSNO). We show that cold pressed and GSNO-charged CS (CS/GSNO) undergo self-expansion to its original 3D shape upon water absorption to a swelling degree of 2,300 wt%, triggering the release of free NO. Topical application of compressed CS/GSNO on wounds in an animal model showed that exudate absorption by CS/GSNO leads to the release of higher NO doses during the inflammatory phase and progressively lower NO doses at later stages of the healing process. Moreover, treated animals showed significant increase in the mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1), murine macrophage marker (F4/80), transforming growth factor beta (TGF-ß), stromal cell-derived factor 1 (SDF-1), insulin-like growth factor-1 (IGF-1), nitric oxide synthase(iNOS), and matrix metalloproteinase(MMP-9). Cluster differentiation 31 (CD31), vascular endothelial growth factor (VEGF), and F4/80 were measured on Days 7 and 12 by immunohistochemistry in the cicatricial tissue. These results indicate that the topical delivery of NO enhances the migration and infiltration of leucocytes, macrophages, and keratinocytes to the wounded tissue, as well as the neovascularization and collagen deposition, which are correlated with an accelerated wound closure. Thus, self-expandable CS/GSNO may represent a novel biocompatible and active wound dress for the topical delivery of NO on wounds.
Assuntos
Colágeno , Óxido Nítrico , S-Nitrosoglutationa , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Animais , Colágeno/química , Colágeno/farmacologia , Modelos Animais de Doenças , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Masculino , Camundongos , Óxido Nítrico/química , Óxido Nítrico/farmacocinética , Óxido Nítrico/farmacologia , S-Nitrosoglutationa/química , S-Nitrosoglutationa/farmacocinética , S-Nitrosoglutationa/farmacologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologiaRESUMO
Purpose: Reliable drug therapy with injectable intravitreal implants requires implants of consistent quality. The purpose of this study was to prepare dexamethasone-poly(d,l-lactide-co-glycolide) (PLGA) biodegradable implants and assess implant quality within and between batches for different polymer compositions. Methods: Implants containing 20% w/w dexamethasone with 3 theoretical rates of release (fast, intermediate, and slow) were manufactured with decreasing proportion of acid-terminated PLGA (50:50) and increasing proportion of ester-terminated PLGA (50:50) in a batch process using hot-melt extrusion. The implants were manufactured without and with in-process modification of extrusion/conveyor speed in the late phase of each batch. Implant samples collected at early, middle, and late phases of each batch were analyzed for diameter, drug loading, mechanical properties (strength and toughness), and drug release. Results: With a fixed process, unlike a modified process with an increase in extrusion speed and reduction of conveyor speed in the late phase, all implant formulations tended to decrease in diameter and mechanical properties in the late phase. Drug release profiles for the intermediate and slow release compositions were similar with or without process modification, unlike the fast release composition. Addition of ester-terminated PLGA resulted in a slower drug release. When all formulations are grouped together, the implant diameter exhibited a moderate correlation with mechanical properties, but no correlation was observed with drug release. Conclusions: Within a hot-melt extrusion batch process, the dexamethasone-PLGA implant diameter and hence toughness and strength tend to decline in the latter phase. In-process adjustment of extrusion and conveyor speeds can improve batch consistency and, potentially, implant integrity or performance during or after injection. Process changes did not affect drug release for 2 of the 3 implant compositions.
Assuntos
Dexametasona/farmacocinética , Tecnologia de Extrusão por Fusão a Quente/métodos , Bombas de Infusão Implantáveis/estatística & dados numéricos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Implantes Absorvíveis/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/farmacocinética , Preparações de Ação Retardada/química , Dexametasona/administração & dosagem , Composição de Medicamentos/métodos , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Oftalmopatias/patologia , Humanos , Inflamação/tratamento farmacológico , Bombas de Infusão Implantáveis/efeitos adversos , Injeções Intravítreas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Reprodutibilidade dos TestesRESUMO
We propose an elastic net made of a biocompatible polymer to wrap silicone implants of various sizes, which also allows for the sustained release of an anti-inflammatory drug, triamcinolone, to prevent fibrosis. For this, we first prepared a strand composed of a mixture of polyurethane and triamcinolone via electrospinning, which was then assembled to prepare the elastic drug-delivery net (DDN). The DDN was prepared to just fit for wrapping the small silicone implant sample herein, but was also able to wrap a sample 7 times as large at 72% strain due to the elastic property of polyurethane. The DDN exhibited sustained drug release for 4 weeks, the profile of which was not very different between the intact and strained DDNs. When implanted in a subcutaneous pocket in living rats, the DDN-wrapped silicone implant samples showed an obvious antifibrotic effect due to the sustained release of triamcinolone. Importantly, this effect was similar for the small and large silicone samples, both wrapped with the same DDN. Therefore, we conclude that this drug-loaded net made of an elastic, biocompatible polymer has high potential for sustained drug delivery around silicone implants manufactured in various sizes.
Assuntos
Poliuretanos , Silicones , Triancinolona , Animais , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Masculino , Poliuretanos/química , Poliuretanos/farmacologia , Ratos , Ratos Sprague-Dawley , Silicones/química , Silicones/farmacologia , Triancinolona/química , Triancinolona/farmacocinética , Triancinolona/farmacologiaRESUMO
Finding an ideal anesthetic agent for postoperative pain control, with long action and low side effects, is still a challenge. Local anesthetics have potential for such application if their time of action is improved. This work introduces a new hybrid formulation formed by the association of a nanostructured lipid carrier with a biopolymeric system to encapsulate bupivacaine (BVC). The hybrid formulation was physicochemical and structurally characterized by DLS, TEM, DSC, XRD and FTIR-ATR, and it remained stable for 12 months at room temperature. In vivo analgesia and imaging tests showed that the hybrid system was able to modulate the release, and to increase the concentration of BVC at the site of action, by forming a nanogel in situ. Such nanogel improved over 5 times (>24 h) the anesthesia duration, when compared to free BVC at clinical (0.5%) doses. Therefore, this novel in situ-forming nanogel shows great potential to be used in postsurgical pain control, improving the action of BVC, without losing its versatility of (infiltrative) application.
Assuntos
Anestésicos Locais , Bupivacaína , Nanoestruturas , Alginatos/química , Alginatos/farmacologia , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Anestésicos Locais/farmacologia , Animais , Bupivacaína/química , Bupivacaína/farmacocinética , Bupivacaína/farmacologia , Implantes de Medicamento/química , Implantes de Medicamento/farmacocinética , Implantes de Medicamento/farmacologia , Géis , Masculino , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Ratos , Ratos WistarRESUMO
The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.