ABSTRACT
This study evaluated the specific interactions between drug and polymers in amorphous spray dried dispersions (SDDs). Four Biopharmaceutics Classification System (BCS) II class drugs were evaluated. Binary and ternary SDDs were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between drug and polymer were determined using theoretical calculations and DSC data. Analytical methods were used to evaluate solid and solution state interactions. Maximum amorphous content for each formulation was calculated using DSC. Flory-Huggins Specific Interaction Parameters were calculated. Negative specific parameters were associated with solid-state interactions and improved capacity of drug in the amorphous state. Ternary SDDs containing drug, polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary SDDs. Solution-state interactions observed in binary systems may be used in tertiary systems to improve the amorphous drug capacity and improved dissolution compared to the binary. The resultant tertiary systems are an improvement over binary drug polymer systems.
Este estudio evaluó las interacciones específicas entre el fármaco y los polímeros en dispersiones amorfas secadas por pulverización (SDD). Se evaluaron cuatro fármacos de clase II del Sistema de Clasificación Biofarmacéutica (BCS). Los SDD binarios y ternarios se fabricaron con polímeros convencionales y arabinogalactano. Los parámetros de interacción específicos entre el fármaco y el polímero se determinaron utilizando cálculos teóricos y datos de DSC. Se utilizaron métodos analíticos para evaluar las interacciones del estado sólido y de la solución. El contenido amorfo máximo para cada formulación se calculó usando DSC. Se calcularon los parámetros de interacción específicos de Flory-Huggins. Los parámetros específicos negativos se asociaron con interacciones en estado sólido y una capacidad mejorada del fármaco en el estado amorfo. Los SDD ternarios que contienen fármaco, polímero y arabinogalactano mostraron enlaces de hidrógeno similares a los observados con los SDD binarios. Las interacciones de estado de solución observadas en sistemas binarios pueden usarse en sistemas terciarios para mejorar la capacidad del fármaco amorfo y mejorar la disolución en comparación con el binario. Los sistemas terciarios resultantes son una mejora con respecto a los sistemas de polímeros de fármacos binarios.
Subject(s)
Polymers/chemistry , Solubility , Pharmaceutical Preparations/chemistry , Biological Availability , Temperature , X-Ray Diffraction , Microscopy, Electron, Scanning , Spectroscopy, Fourier Transform Infrared , Proton Magnetic Resonance SpectroscopyABSTRACT
There is a need for new topical antipruritics that are effective on many types of itch. This study examined the antipruritic efficacy of a new formulation of topical acetaminophen. In vitro skin permeability studies showed that 2.5% and 5% formulations are able to rapidly deliver an adequate amount of the drug into the skin. In a double-blind, vehicle-controlled, randomized study in 17 healthy volunteers, 1%, 2.5% and 5% acetaminophen gels and a vehicle gel were applied to the skin prior to histaminergic and non-histaminergic itch induction and assessment of thermal pain thresholds. The 2.5% and 5% gel formulations significantly reduced the itch intensity time course and the area under the curve for both histamine and cowhage itch. No effect was noted on heat pain thresholds and no adverse effects were observed. These results suggest that topical acetaminophen would be a safe and effective over-the-counter medication for itch.
Subject(s)
Acetaminophen , Antipruritics , Acetaminophen/adverse effects , Antipruritics/adverse effects , Gels , Histamine/adverse effects , Humans , Pilot Projects , Pruritus/chemically induced , Pruritus/diagnosis , Pruritus/drug therapyABSTRACT
Taste-masking of drugs, particularly to produce formulations for pediatric patients, can be challenging and require complex manufacturing approaches. The objective of this study was to produce taste-masked ibuprofen granules using a novel process, twin-screw melt granulation (TSMG). TSMG is an emerging, high-productivity, continuous process. Granules of ibuprofen embedded in a lipid matrix were produced across a range of process conditions, resulting in a range of output granule particle sizes. The ibuprofen appeared to be miscible with the lipid binder though it recrystallized after processing. The ibuprofen melt granules were tested in simulated saliva using a novel, small-volume dissolution technique with continuous acquisition of the ibuprofen concentration. The ibuprofen release from the granules was slower than the neat API and physical blend, beyond the expected residence time of the granules in the mouth. The ibuprofen release was inversely related to the granule size. A Noyes-Whitney dissolution model was used and the resulting dissolution rate constants correlated well with the granule size.
ABSTRACT
Many chronic diseases require repetitive injections as maintenance treatment. It is therefore important to investigate a possible alternative. A simulated subcutaneous implant prototype was fabricated as a polymer matrix covered by cylinder-shape tubing having a porous membrane. Sucrose, bovine serum albumin, and gelatin were selected as matrix excipients. Eight APIs with different physiochemical properties were used to investigate the releasing mechanism. Drug release was tested through an in vitrodissolution apparatus. Drug release of eight APIs followed zero-order kinetics with a minimum 12-hour duration. Release rates also showed linear correlations with the APIs' solubilities under physiological pH. For releasing mechanism studies, different combinations of matrix and membrane were investigated in detail. A 144-hour continuous zero-order release of caffeine was achieved as the best controlled simulated prototype. The results showed that drug release of our simulated prototype was primarily achieved by drug diffusion rather than dissolution.
Muchas enfermedades crónicas requieren inyecciones repetitivas como tratamiento de mantenimiento. Por lo tanto, es importante investigar una posible alternativa. Se fabricó un prototipo de implante subcutáneo simulado a partir de una matriz de polímero cubierta por un tubo en forma de cilindro que tiene una membrana porosa. La sacarosa, la albúmina de suero bovino y la gelatina se seleccionaron como excipientes matriciales. Se utilizaron ocho APIs con diferentes propiedades fisicoquímicas para investigar el mecanismo de liberación. La liberación del fármaco se probó a través de un aparato de disolución in vitro. La liberación del fármaco de las ocho APIs siguió una cinética de orden cero con una duración mínima de 12 horas. Las tasas de liberación también mostraron correlaciones lineales con las solubilidades de las APIs a pH fisiológico. Para los estudios de mecanismos de liberación, se investigaron en detalle diferentes combinaciones de matriz y membrana. El prototipo simulado con mejor control logró una liberación continua de cafeína de orden cero durante 144 horas. Los resultados mostraron que la liberación del fármaco del prototipo simulado ocurrió principalmente mediante la difusión del fármaco en lugar de la disolución.
Subject(s)
Pharmaceutical Preparations/administration & dosage , Drug Implants/metabolism , In Vitro Techniques , Pilot Projects , Chromatography, High Pressure Liquid , Subcutaneous Tissue , Delayed-Action Preparations , Drug Evaluation, Preclinical , Drug Liberation , Freeze DryingABSTRACT
Solid lipid nanoparticles (SLN) have demonstrated good potential for oral peptide delivery. However, their hydrophobic nature generally accounts for low peptide entrapment efficiency (EE%). In this study, a new strategy was adopted to improve peptide EE% by incorporating a hydrophilic viscosity-enhancing agent (VA) within SLN cores to develop viscosity enhanced nanocarriers (VEN). Three agents namely, propylene glycol (PG), polyethylene glycol (PEG) 400 and PEG 600, were tested with human insulin serving as a model peptide drug. The effects of VA were both concentration- and type-dependent. 70% w/w PG had achieved the highest EE% (54.5%), versus the two PEGs, compared to only 20.4% in unmodified SLN. PG based VEN had demonstrated good dispersion stability at gastrointestinal (GI) pHs and preferential uptake by intestinal Caco2 cells while showing low cytotoxicity. Additionally, they preserved the integrity of insulin and significantly protected it against GI enzymatic degradation. Freeze dried VEN had shown good stability upon storage at -20°C. Orally administered insulin-VEN had achieved good hypoglycemic effect in fasted rats with relative bioavailability of 5.1%. To conclude, an easily implementable technique to improve peptide entrapment within SLN has been validated, and the resulting VEN had proved promising efficacy for oral peptide delivery.
Subject(s)
Drug Carriers/administration & dosage , Drug Delivery Systems/methods , Drug Discovery/methods , Insulin/administration & dosage , Nanoparticles/administration & dosage , Administration, Oral , Animals , Caco-2 Cells , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Drug Carriers/chemistry , Drug Evaluation, Preclinical/methods , Humans , Insulin/chemistry , Male , Nanoparticles/chemistry , Random Allocation , Rats , Rats, Sprague-Dawley , ViscosityABSTRACT
The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm × 5 mm (25 mm(2)), 7 mm × 7 mm (49 mm(2)), and 9 mm × 9 mm (81 mm(2)) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.
Subject(s)
Antifungal Agents/metabolism , Nails/metabolism , Pyridones/metabolism , Administration, Topical , Antifungal Agents/administration & dosage , Azo Compounds/administration & dosage , Azo Compounds/metabolism , Cadaver , Chromatography, High Pressure Liquid , Ciclopirox , Diffusion , Humans , Permeability , Pyridones/administration & dosage , Spectrophotometry, UltravioletABSTRACT
Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.
