RESUMEN
BACKGROUND AND OBJECTIVE: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. METHODS: MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). RESULTS: Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. CONCLUSIONS: The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.
Asunto(s)
Área Bajo la Curva , Disponibilidad Biológica , Preparaciones de Acción Retardada , Modelos Biológicos , Equivalencia Terapéutica , Ácido Valproico , Ácido Valproico/farmacocinética , Ácido Valproico/administración & dosificación , Humanos , Preparaciones de Acción Retardada/farmacocinética , Masculino , Adulto , Adulto Joven , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administración & dosificación , Femenino , Voluntarios Sanos , Estudios CruzadosRESUMEN
Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways.
Asunto(s)
Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos , Citrato de Sildenafil , Preparaciones de Acción Retardada/farmacocinética , Disponibilidad Biológica , Solubilidad , Comprimidos/farmacocinéticaRESUMEN
The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion in vitro as the water content increased and released 30% of fenretinide in vitro after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC50 values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in â¼30% smaller structures. The depot formed in vivo prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.
Asunto(s)
Anticarcinógenos/administración & dosificación , Neoplasias de la Mama/prevención & control , Fenretinida/administración & dosificación , Neoplasias Mamarias Experimentales/prevención & control , Animales , Anticarcinógenos/farmacocinética , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Emulsiones , Femenino , Fenretinida/farmacocinética , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea/administración & dosificación , Metilnitrosourea/toxicidad , Ratones , RatasRESUMEN
Innate and adaptive immune responses lead to wound healing by regulating a complex series of events promoting cellular cross-talk. An inflammatory response is presented with its characteristic clinical symptoms: heat, pain, redness, and swelling. Some smart thermo-responsive polymers like chitosan, polyvinylpyrrolidone, alginate, and poly(ε-caprolactone) can be used to create biocompatible and biodegradable scaffolds. These processed thermo-responsive biomaterials possess 3D architectures similar to human structures, providing physical support for cell growth and tissue regeneration. Furthermore, these structures are used as novel drug delivery systems. Locally heated tumors above the polymer lower the critical solution temperature and can induce its conversion into a hydrophobic form by an entropy-driven process, enhancing drug release. When the thermal stimulus is gone, drug release is reduced due to the swelling of the material. As a result, these systems can contribute to the wound healing process in accelerating tissue healing, avoiding large scar tissue, regulating the inflammatory response, and protecting from bacterial infections. This paper integrates the relevant reported contributions of bioengineered scaffolds composed of smart thermo-responsive polymers for drug delivery applications in wound healing. Therefore, we present a comprehensive review that aims to demonstrate these systems' capacity to provide spatially and temporally controlled release strategies for one or more drugs used in wound healing. In this sense, the novel manufacturing techniques of 3D printing and electrospinning are explored for the tuning of their physicochemical properties to adjust therapies according to patient convenience and reduce drug toxicity and side effects.
Asunto(s)
Materiales Biocompatibles/química , Preparaciones de Acción Retardada/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Polímeros/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Ingeniería Biomédica/métodos , Bioimpresión/métodos , Preparaciones de Acción Retardada/farmacocinética , Modelos Animales de Enfermedad , Liberación de Fármacos , Calor , Humanos , Hidrogeles/química , Interacciones Hidrofóbicas e Hidrofílicas , Impresión TridimensionalRESUMEN
BACKGROUND: Leishmaniasis is a neglected disease, and the current therapeutic arsenal for its treatment is seriously limited by high cost and toxicity. Nanostructured lipid carriers (NLCs) represent a promising approach due to high drug loading capacity, controlled drug release profiles and superior stability. Here, we explore the efficacy of a unique pH-sensitive amphotericin B-loaded NLC (AmB-NLC) in Leishmania braziliensis infection in vitro and in vivo. METHODS AND RESULTS: AmB-NLC was assessed by dynamic light scattering and atomic force microscopy assays. The carrier showed a spherical shape with a nanometric size of 242.0 ± 18.3 nm. Zeta potential was suggestive of high carrier stability (-42.5 ± 1.5 mV), and the NLC showed ~99% drug encapsulation efficiency (EE%). In biological assays, AmB-NLC presented a similar IC50 as free AmB and conventional AmB deoxycholate (AmB-D) (11.7 ± 1.73; 5.3 ± 0.55 and 13 ± 0.57 ng/mL, respectively), while also presenting higher selectivity index and lower toxicity to host cells, with no observed production of nitric oxide or TNF-α by in vitro assay. Confocal microscopy revealed the rapid uptake of AmB-NLC by infected macrophages after 1h, which, in association with more rapid disruption of AmB-NLC at acidic pH levels, may directly affect intracellular parasites. Leishmanicidal effects were evaluated in vivo in BALB/c mice infected in the ear dermis with L. braziliensis and treated with a pentavalent antimonial (Sb5+), liposomal AmB (AmB-L) or AmB-NLC. After 6 weeks of infection, AmB-NLC treatment resulted in smaller ear lesion size in all treated mice, indicating the efficacy of the novel formulation. CONCLUSION: Here, we preliminarily demonstrate the effectiveness of an innovative and cost-effective AmB-NLC formulation in promoting the killing of intracellular L. braziliensis. This novel carrier system could be a promising alternative for the future treatment of cutaneous leishmaniasis.
Asunto(s)
Anfotericina B/administración & dosificación , Leishmaniasis Cutánea/tratamiento farmacológico , Nanoestructuras/administración & dosificación , Anfotericina B/farmacocinética , Anfotericina B/farmacología , Animales , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Femenino , Concentración de Iones de Hidrógeno , Leishmania braziliensis/efectos de los fármacos , Leishmania braziliensis/patogenicidad , Lípidos/química , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Masculino , Ratones Endogámicos BALB C , Nanoestructuras/químicaRESUMEN
In this study, the ability of different beta-cyclodextrins to facilitate homogeneous dispersion of triamcinolone acetonide (TA) into chitosan membranes is assessed. Drug loading was assessed through atomic force microscopy (AFM), scanning electron microscopy (MEV-FEG), and X-ray diffraction analyses. Drug interactions with the co-polymer were investigated with Fourier transform infrared spectroscopy, thermal analyses. Swelling assay, and in vitro drug release experiment were used to assess TA release behavior. Undispersed particles of drug were observed to remain in the simple chitosan membranes. Hydroxypropyl-ß-cyclodextrin enabled the dispersion of TA into chitosan membranes and subsequent sustained drug release. In addition, the membrane performance as a drug delivery device is improved by adding specified amounts of the co-solvent triethanolamine. The experimental data presented in this study confirm the utility of our novel and alternative approach for obtaining a promising device for slow and controlled release of glucocorticoids, such as triamcinolone acetonide, for topical ulcerations.
Asunto(s)
Corticoesteroides/administración & dosificación , Quitosano/química , Preparaciones de Acción Retardada/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , beta-Ciclodextrinas/química , Corticoesteroides/química , Corticoesteroides/farmacocinética , Química Farmacéutica/métodos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Glucocorticoides/administración & dosificación , Glucocorticoides/química , Glucocorticoides/farmacocinética , Membranas Artificiales , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Polímeros/química , Solubilidad , Solventes/química , Espectroscopía Infrarroja por Transformada de Fourier , Triamcinolona/administración & dosificación , Triamcinolona/química , Triamcinolona/farmacocinética , Difracción de Rayos XRESUMEN
Transdermal patches for analgesic purposes are widely used, however, their occlusive characteristics can often cause allergic reactions, irritating contact dermatitis, and allergic contact dermatitis upon extended use. Chitosan is a natural positively charged bioadhesive polysaccharide with several biological properties, being promising templates for sustained and controlled topical or transdermal drug delivery. Methyl salicylate (MS) is a non-steroidal topical anti-inflammatory drug (NSAID). MS is a lipophilic oily drug commonly found in transdermal patches, being difficult to incorporate into hydrophilic formulations such as Chitosan-based films. Thus, MS is a good candidate to be encapsulated into nanoemulsions (NE). This work reports the formulation development, physical-chemical characterization, and in vitro drug release of NE-loaded Chitosan films formulated with MS, as a novel substitute for transdermal analgesic patches. MS was encapsulated into NE, which were prepared by ultrasonication and presented 29.3 nm ± 0.1 and PdI 0.167 ± 0.005. The incorporation of MS into NE prevented phase separation and provided a homogeneous physical blending formulation, as confirmed by FTIR, TGA. NE-loaded films provided high drug incorporation in the films 94.08% ± 6.63%), and a smaller crystallinity degree in comparison with physical mixture films, suggesting a plasticizing effect of nano-sized droplets. Besides, mean weight, thickness, and moisture content were increased in NE-loaded films in comparison with chitosan-based control films. In vitro drug release from NE-loaded films was significantly higher than for physical mixture films, following Weibull and Korsmeyer-Peppas release kinetics models. The results suggest that NE-loaded chitosan film can increase the drug loading capacity of oil drugs and successfully control in vitro release, constituting a novel approach for transdermal drug delivery of NSAIDs.
Asunto(s)
Quitosano/química , Membranas Artificiales , Salicilatos , Parche Transdérmico , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Emulsiones , Humanos , Salicilatos/química , Salicilatos/farmacocinéticaRESUMEN
BACKGROUND: The encapsulation of anti-cancer drugs in stimulus-sensitive release systems may provide advantages such as enhanced drug toxicity in tumour tissue cells due to increased intracellular drug release. Encapsulation may also improve release in targeted tissue due to the response to a stimulus such as pH, which is lower in the tumour tissue microenvironment. Here, we evaluated the in vitro toxicity of the Drug Doxorubicin (DOX) loaded into a release system based on poly(ß-amino ester)- modified MCM-41 silica nanoparticles. METHODS: The MCM-41-DOX-PbAE release system was obtained by loading DOX into MCM-41 nanoparticles amino-functionalized with 3-aminopropyltriethoxysilane (APTES) and then coated with a pH-responsive poly(ß-amino ester) (PbAE). The physicochemical characteristics of the release system were evaluated through TEM, FTIR and TGA. Cytotoxicity assays were performed on the MCM-41- DOX-PbAE system to determine their effects on the inhibition of human MCF-7 breast cancer cell proliferation after 48 h of exposure through crystal violet assay; the investigated systems included MCF-7 cells with MCM-41, PbAE, and MCM-41-PbAE alone. Additionally, the release of DOX and the change in pH in vitro were determined. RESULTS: The physicochemical characteristics of the synthesized MCM-41-PbAE system were confirmed, including the nanoparticle size, spherical morphology, mesoporous ordered structure, and presence of PbAE on the surface of the MCM-41 nanoparticles. Likewise, we demonstrated that the release of DOX from the MCM-41-DOX-PbAE system promoted an important reduction in MCF-7 cell viability (~ 70%) compared to the values obtained with MCM-41, PbAE, and MCM-41-PbAE, as well as a reduction in the viability under treatment with just DOX (~ 50%). CONCLUSION: The results suggest that all the components of the release system are biocompatible and that the encapsulation of DOX in MCM-41-PbAE could allow better intracellular release, which would probably increase the availability and toxic effect of DOX.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Dióxido de Silicio/química , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Doxorrubicina/administración & dosificación , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Nanopartículas/química , Polímeros/químicaRESUMEN
The objective of this study was to develop a dissolution test in order to establish an in vitro-in vivo correlation (IVIVC) model for desvenlafaxine succinate monohydrate (DVSM) extended release (ER) tablets. The in vitro release characteristics of the drug were determined using USP apparatus 1 at 75 rpm, with volume of HCl pH 1.2, acetate buffer solution (ABS) pH 4.5, or phosphate buffer solution (PBS) pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in healthy volunteers were obtained from a bioequivalence study. The similarity factors f1 and f2 were used to compare the dissolution data. The IVIVC model was developed using fraction dissolved and fraction absorbed of the reference product. For predictability, the results showed that the percentage prediction error (%PE) value of Cmax was 7.63%. The observed low prediction error for Cmax demonstrated that the IVIVC model was valid for this parameter.
Asunto(s)
Succinato de Desvenlafaxina/administración & dosificación , Inhibidores de Captación de Serotonina y Norepinefrina/administración & dosificación , Comprimidos , Adulto , Área Bajo la Curva , Preparaciones de Acción Retardada/farmacocinética , Succinato de Desvenlafaxina/farmacocinética , Semivida , Humanos , Técnicas In Vitro , Masculino , Inhibidores de Captación de Serotonina y Norepinefrina/farmacocinética , Solubilidad , Adulto JovenRESUMEN
The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60â¯Å and SiO2-90â¯Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21⯱â¯0.85%) antinociceptive effect than the ibuprofen (46⯱â¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90⯱â¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73⯱â¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.
Asunto(s)
Analgésicos , Ibuprofeno , Dolor/tratamiento farmacológico , Dióxido de Silicio , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Evaluación Preclínica de Medicamentos , Ibuprofeno/análogos & derivados , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacología , Masculino , Ratones , Dolor/metabolismo , Dolor/fisiopatología , Porosidad , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Dióxido de Silicio/farmacologíaRESUMEN
BACKGROUND: Malaria is still a dangerous disease that impacts specifically Africa, Asia, and Latin America. The development of therapies to overcome the parasite infection is an important challenge nowadays. The medicine primaquine (PQ) is used in the treatment, although several side effects and low oral bioavailability are reported. OBJECTIVE: This work focused on the preparation and characterization of a complex between PQ and 2- hydroxypropyl-ß-cyclodextrin (HPCD), besides performing release tests of this formulation. METHODS: PQ:HPCD complexes were prepared at 1:1 and 1:2 molar ratios, by the lyophilization method. The association between PQ and HPCD was tested using UV-vis, infrared (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy and NMR techniques (chemical shift, Job Plot, DOSY, and ROESY). Tests were also conducted to evaluate drug release before and after complexation with HPCD. RESULTS: Results showed that there was a weak interaction of PQ with HPCD, forming non-inclusion complexes. These results were supported by FTIR results and spatial correlations between hydrogens from PQ with the external HPCD hydrogens. A 1:2 PQ:HPCD preferred molar ratio was determined by DSC and Job Plot experiments and the time to release 96% of the drug was 21.2 h slower after complexation. CONCLUSION: Conclusion indicate that PQ interacts poorly with HPCD, probably due to its hydrophilic character, as well as to its interaction with the external rim of HPCD. Our results demonstrate that there was a significant improvement in the release time after the complexation process, which could lead to an increase in the activity of the drug.
Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Antimaláricos/farmacocinética , Composición de Medicamentos/métodos , Excipientes/química , Primaquina/farmacocinética , Administración Oral , Antimaláricos/química , Antimaláricos/uso terapéutico , Disponibilidad Biológica , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , Liberación de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Malaria/tratamiento farmacológico , Primaquina/química , Primaquina/uso terapéutico , SolubilidadRESUMEN
The subdivision of sustained release tablets is a controversial issue, especially concerning its impact on dissolution profiles. The purpose of this study was to elucidate the behavior upon subdivision of this class of tablets. For this, three common sustained release matrices containing different technologies were selected, e.g., a tablet comprised of a multiple-unit particulate system (MUPS), a lipid matrix tablet, and a polymeric inert matrix tablet. These tablets were studied concerning their physicochemical performance, dissolution rate, and kinetic profile before and after their subdivision. When subdivision occurred in the scoreline, mass variation and mass loss were below the mean values described in the literature. The dissolution of tablets with inert matrices and some lipid tablets that had their matrices preserved along the dissolution was influenced directly by tablet surface area, which increased after the subdivision. Such a result implies possible clinical consequences, especially in the case of drugs with a narrow therapeutic window, such as clomipramine. Conversely, the subdivision of MUPS tablets did not interfere in the dissolution profile since the drug was released from the granules that resulted from tablet disintegration. Hence, MUPS technology is the most recommended to produce sustained release matrix tablets intended for dose adjustment upon subdivision.
Asunto(s)
Preparaciones de Acción Retardada/química , Comprimidos/química , Tecnología Farmacéutica/métodos , Preparaciones de Acción Retardada/farmacocinética , Polímeros/química , Polímeros/farmacocinética , Solubilidad , Comprimidos/farmacocinéticaRESUMEN
Solid inclusion complexes with cyclodextrins (CD) may be used to overcome volatility and solubility problems of essential oils of pharmacological interest. However, they lack the many dermatological advantages of lipid nanoparticles. This study intends to evaluate the ability of nanostructured lipid carriers (NLC) to encapsulate hydroxypropyl-ß-cyclodextrin inclusion complexes of Lippia origanoides essential oil (EO) and to maintain the desirable aspects of lipid colloids interaction with the skin, specifically follicular accumulation and controlled delivery. CD and NLC were also evaluated separately. Thymol (TML) was used as the essential oil marker and to produce control formulations. As expected, CD alone, though effective in overcoming volatility and low aqueous solubility of TML, were ineffective in controlling marker release (Ë50% of EO released after 3â¯h, Hixson-Crowell kinetics). Even though NLC controlled drug release (Ë20% EO released after 12â¯h, zero-order kinetics) enabling TML penetration into the skin (> 40⯵g/cm2after 12â¯h), NLC alone were not efficient in preventing TML volatility, especially at higher temperatures (calculated shelf-life of 2 days at 35⯰C). The combined approach resulted in a synergistic effect (Ë20% EO released after 12â¯h; shelf life of 6 days). The lack of statistical difference of TML skin penetration from NLC and NLC-CD suggests the developed system maintained all skin interaction aspects of lipid colloids, including follicular accumulation forming a depot for controlled delivery. In conclusion, lipid nanoparticles demonstrated to be promising carriers for inclusion complexes of this particular volatile essential oil.
Asunto(s)
Ciclodextrinas/administración & dosificación , Portadores de Fármacos/química , Lípidos/química , Nanopartículas/química , Aceites Volátiles/administración & dosificación , Administración Cutánea , Animales , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Nanopartículas/ultraestructura , Aceites Volátiles/química , Aceites Volátiles/farmacocinética , Piel/metabolismo , Solubilidad , Porcinos , Temperatura , Timol/administración & dosificación , Timol/química , Timol/farmacocinética , VolatilizaciónRESUMEN
Florfenicol (FLO) is a broad-spectrum fluorinated antibiotic used for the treatment of bacterial diseases such as bovine respiratory disease (BRD) in cattle. FLO is a poorly soluble drug in aqueous solution, and its encapsulation in various nanovehicles has been reported to be less than 30%. In this context, the use of bovine serum albumin (BSA) as a nanocarrier for FLO is an interesting approach. BSA is a biocompatible, biodegradable, nontoxic, and nonimmunogenic natural protein, allowing the vehiculization of hydrophilic and hydrophobic drugs with a well-tolerated administration. The present work focuses on the fabrication and characterization of florfenicol-loaded BSA (FLO-BSA NPs), incorporation efficiency, and in vitro release pattern. FLO-BSA NPs nanoparticles were successfully obtained by a simple, low-cost and in a few steps method. The physicochemical properties of the obtained nanoparticles such as size (~ 120 nm), polydispersity index (0.04), and zeta potential (approximately - 40 mV) suggest a high colloidal stability and suitable characteristics for drug delivery. The drug loading reveals a high incorporation of florfenicol in the nanoparticles, in which 33.6 molecules of FLO are encapsulated per each molecule of BSA. The in vitro release profile exhibits an initial stage characterized by the burst effect and then a prolonged release of FLO from the albumin matrix, which is compatible with the Higuchi model and which follows a Fickian diffusion. The results together suggest a suitable tool for future investigations in drug delivery field in order to use this nanomaterial in food, pharmaceutical, and veterinary industry.
Asunto(s)
Antibacterianos/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/metabolismo , Albúmina Sérica Bovina/farmacocinética , Tianfenicol/análogos & derivados , Animales , Antibacterianos/administración & dosificación , Antibacterianos/síntesis química , Bovinos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/tendencias , Interacciones Hidrofóbicas e Hidrofílicas , Nanopartículas/administración & dosificación , Nanopartículas/química , Tamaño de la Partícula , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/síntesis química , Tianfenicol/administración & dosificación , Tianfenicol/síntesis química , Tianfenicol/farmacocinéticaRESUMEN
Topical nitric oxide (NO) delivery has been shown to accelerate wound healing. However, delivering NO to wounds at appropriate rates and doses requires new biomaterial-based strategies. Here, we describe the development of supramolecular interpolymer complex hydrogels comprising PEO-PPO-PEO (F127) micelles embedded in a poly(acrylic acid) (PAA) matrix, with S-nitrosoglutathione (GSNO) molecules dissolved in the hydrophilic domain. We show that PAA:F127/GSNO hydrogels start releasing NO upon hydration at rates controlled by their rates of water absorption. SAXS measurements indicate that the supramolecular structure of the hydrogels retains long-range order domains of F127 micelles. The PAA/F1227 hydrogels displayed dense morphologies and reduced rates of hydration. The NO release rates remain constant over the first 200â¯min, are directly correlated with the hydration rates of the PAA:F127/GSNO hydrogels, and can be modulated in the range of 40â¯nmol/gâ¯h to 1.5⯵mol/gâ¯h by changing the PAA:F127 mass ratio. Long-term NO-release profiles over 5â¯days are governed by the first-order exponential decay of GSNO, with half-lives in the range of 0.5-3.4â¯days. A preliminary in vivo study on full-thickness excisional wounds in mice showed that topical NO release from the PAA:F127/GSNO hydrogels is triggered by exudate absorption and leads to increased angiogenesis and collagen fiber organization, as well as TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue. In summary, these results suggest that hydration-controlled NO release from topical PAA:F127/GSNO hydrogels is a potential strategy for enhancing wound healing. STATEMENT OF SIGNIFICANCE: The topical delivery of nitric oxide (NO) to wounds may provide significant beneficial results and represent a promising strategy to treat chronic wounds. However, wound dressings capable of releasing NO after application and allowing the modulation of NO release rates, demand new platforms. Here, we describe a novel strategy to overcome these challenges, based on the use of supramolecular poly(acrylic acid) (PAA):F127 hydrogels charged with the NO donor S-nitrosoglutathione (GSNO) from whereby the NO release can be triggered by exudate absorption and delivered to the wound at rates controlled by the PAA:F127 mass ratio. Preliminary in vivo results offer a proof of concept for this strategy by demonstrating increased angiogenesis; collagen fibers organization; and TGF-ß, IGF-1, SDF-1, and IL-10 gene expressions in the cicatricial tissue after topical treatment with a PAA:F127/GSNO hydrogel.
Asunto(s)
Resinas Acrílicas , Hidrogeles , Óxido Nítrico , Polietilenos , Polipropilenos , Cicatrización de Heridas/efectos de los fármacos , Heridas y Lesiones , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacología , Animales , Citocinas/biosíntesis , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacocinética , Hidrogeles/farmacología , Ratones , Micelas , Óxido Nítrico/química , Óxido Nítrico/farmacocinética , Óxido Nítrico/farmacología , Polietilenos/química , Polietilenos/farmacocinética , Polietilenos/farmacología , Polipropilenos/química , Polipropilenos/farmacocinética , Polipropilenos/farmacología , S-Nitrosoglutatión/química , S-Nitrosoglutatión/farmacocinética , S-Nitrosoglutatión/farmacología , Heridas y Lesiones/tratamiento farmacológico , Heridas y Lesiones/metabolismo , Heridas y Lesiones/patologíaRESUMEN
In this work, we prepared a novel composite based on hybrid gelatin carriers and montmorillonite clay (MMT) to analyze its viability as controlled drug delivery system. The objective of this research involves the characterization of composites formed by structured lipid-gelatin micro-particles (MP) and MMT clay. This analysis included the evaluation of the composite according to its rheological properties, morphology (SEM), particle size, XRD, FT-IR, and in vitro drug release. The effect of pH in the properties of the composite is evaluated. A novel raspberry-like or armor MP/MMT clay composite is reported, in which the pH has an important effect on the final structure of the composite for ad-hoc drug delivery systems. For pH values below the isoelectric point, we obtained defined morphologies with entrapment efficiencies up to 67%. The pH level controls the MP/MMT composite release mechanism, restringing drug release in the stomach-like environment. Intended for oral administration, these results evidence that the MP/MMT composite represents an attractive alternative for intestinal-colonic controlled drug delivery systems.
Asunto(s)
Atorvastatina/química , Bentonita/química , Preparaciones de Acción Retardada/química , Nanocompuestos/química , Atorvastatina/administración & dosificación , Atorvastatina/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Concentración de Iones de Hidrógeno , Microscopía Electrónica de Rastreo , Nanocompuestos/ultraestructura , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
PURPOSE: 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. METHODS: Microparticles were prepared by spray drying. The effect of formulation parameters and experimental conditions on particle features and delivery was studied. A mathematical model to predict progesterone plasma concentration in animals was developed and validated with experimental data. RESULTS: Microparticle size was not affected by formulation parameters but sphericity enhances as Tween 80 content increases and it impairs as TPP content rises. Z potential decreases as phosphate content rises. Particles remain stable in acidic solution but the addition of surfactant is required to stabilize dispersions in neutral medium. Encapsulation efficiencies was 69-75%. In vitro delivery studies showed burst and diffusion-controlled phases, being progesterone released faster at low pH. In addition, delivery extend in cows was affected mainly by particle size and hormone initial content, while the amount injected altered plasma concentration. Theoretical predictions with excellent accuracy were obtained. CONCLUSION: The mathematical model developed can help to find proper particle features to reach specific delivery rates in the animals. This not only save time, money and effort but also minimized experimentation with animals which is desired from an ethical point of view.
Asunto(s)
Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Sincronización del Estro/efectos de los fármacos , Progesterona/administración & dosificación , Animales , Bovinos , Quitosano/química , Reactivos de Enlaces Cruzados/química , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Femenino , Modelos Biológicos , Tamaño de la Partícula , Polifosfatos/química , Progesterona/farmacocinéticaRESUMEN
Several authors have studied the release profile of drugs incorporated in different devices. However, to the best of our knowledge, although many studies have been done on the release of tetracycline, in these release devices, no study has investigated if the released compound is actually the tetracycline, or, instead, a degraded product. This approach is exploited here. In this work, we analyse the influence of two drying methods on the tetracycline delivery behaviour of synthesised glasses using the sol-gel process. We compare the drying methods results using both theoretical models and practical essays, and analyse the chemical characteristic of the released product in order to verify if it remains tetracycline. Samples were freeze-dried or dried in an oven at 37°C and characterised by several methods such as Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TG), differential thermogravimetric analysis (DTG), differential thermal analyses (DTA) and gas adsorption analysis (BET). The released concentration of tetracycline hydrochloride was studied as a function of time, and it was measured by ultraviolet spectrophotometry in the tetracycline wavelength. The drug delivery profiles were reasonably consistent with a diffusion model analysis. In addition, we observed higher release rates for the freeze-dried compared to those dried in an oven at 37°C. This higher release can be attributed to larger pore size for the freeze-dried sample systems with tetracycline, which promoted more water penetration, improving the drug diffusion. The analysis of the solution obtained in the release tests using high-performance liquid chromatography- mass spectrometry (HPLC-MS) confirmed that tetracycline was being released.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Tetraciclinas/síntesis química , Antibacterianos/administración & dosificación , Antibacterianos/síntesis química , Antibacterianos/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Difusión , Composición de Medicamentos/métodos , Liofilización/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Tetraciclinas/administración & dosificación , Tetraciclinas/farmacocinéticaRESUMEN
Oral insulin administration is limited due to its degradation by proteases. The hormone was encapsulated in spheres made of either pure calcium alginate (ALG) or its association with whey protein isolate (WPI-ALG) in order to minimise loss in the stomach region while allowing liberation in the maximum absorption area, located in the intestine. Diffusion coefficients for both matrix compositions were determined in vitro for gastric pH (5.88 and 10.26 × 10-12 m2 s-1) and intestinal pH (21.11 and 79.29 × 10-12 m2 s-1). Higher initial insulin concentrations and lower diameters accelerated its release, confirming Fickian behaviour. The analytic model exhibited a good fit in most cases. Computer simulations revealed that ALG spheres are more convenient for oral administration because they release more insulin in the intestine than the WPI-ALG ones, thus supporting its therapeutic viability for the purpose of reducing stress in those who depend on insulin.
Asunto(s)
Alginatos , Diabetes Mellitus/tratamiento farmacológico , Insulina , Microesferas , Proteína de Suero de Leche , Administración Oral , Alginatos/química , Alginatos/farmacocinética , Alginatos/farmacología , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Ácido Glucurónico/química , Ácido Glucurónico/farmacocinética , Ácido Glucurónico/farmacología , Ácidos Hexurónicos/química , Ácidos Hexurónicos/farmacocinética , Ácidos Hexurónicos/farmacología , Humanos , Concentración de Iones de Hidrógeno , Insulina/química , Insulina/farmacocinética , Insulina/farmacología , Proteína de Suero de Leche/química , Proteína de Suero de Leche/farmacocinética , Proteína de Suero de Leche/farmacologíaRESUMEN
This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR® bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, tmax, area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications.