RESUMEN
To understand effects of formulation variables on the critical quality attributes (CQA) of acyclovir topical cream, this study investigated effects of propylene glycol (PG), poloxamer, and sodium lauryl sulfate (SLS) concentrations, acyclovir particle size, and formulation pH of the acyclovir cream. Fifteen formulations were prepared and characterized for rheological properties, particle size distribution, drug release and in vitro skin permeation. Drug distribution between various phases of the cream was determined. The concentration of soluble acyclovir in the aqueous phase was determined as a surrogate of the equilibrium with other acyclovir species in the cream. The interaction among effects of the formulation variables on the amount of acyclovir retained by skin was also evaluated. The results showed that PG significantly (p < 0.05) increased the yield stress, viscosity, drug concentration in the aqueous phase, and drug release. The PG and SLS significantly (p < 0.05) increased acyclovir retention by skin samples. Particle size of acyclovir inversely affected the drug release. This study revealed that the employed concentrations of PG and SLS and particle size of the dispersed acyclovir are critical formulation variables that should be carefully controlled when developing acyclovir topical creams with desired performance characteristics.
Asunto(s)
Aciclovir , Antivirales , Aciclovir/metabolismo , Antivirales/metabolismo , Liberación de Fármacos , Piel/metabolismo , Absorción CutáneaRESUMEN
To evaluate the bioavailability and pharmacokinetic profiles of two novel galantamine formulations as medical countermeasure products, an ultra-performance liquid chromatography-single quadrupole mass spectrometry (UPLC-MS) method was developed and validated for quantifying galantamine in guinea pig plasma using solid-phase extraction with a mixed mode strong cation exchange reversed-phase cartridge. Chromatographic separation was achieved on a Waters Acquity UPLC BEH C18 column maintained at 40°C. The mobile phases were solution A, acetonitrile-water, 5:95 (v/v) and solution B, acetonitrile-water 90:10 (v/v), both containing 2 mM ammonium formate and 0.2% formic acid. The mobile phase was delivered utilizing a 3 min gradient program start with 95%A-5%B at a flow rate of 0.6 mL/min. The analyte and internal standard, galantamine-d3, were detected by selected ion monitoring mode on a Waters 3100 single quadrupole mass spectrometer with positive electrospray ionization. The method was validated according to the US Food and Drug Administration bioanalytical guidance. The method was selective and was linear over the analytical range of 2-2000 ng/mL. Accuracy and precision were acceptable with intra- and inter-day accuracies between 96.8 and 101% and precisions (RSD) <4.88%. The method was successfully implemented to measure galantamine plasma levels in a series of pre-clinical bioavailability studies for the evaluation of novel galantamine formulations.
RESUMEN
Commonly used characterization techniques such as cryogenic-transmission electron microscopy (cryo-TEM) and batch-mode dynamic light scattering (DLS) are either time consuming or unable to offer high resolution to discern the poly-dispersity of complex drug products like cyclosporine ophthalmic emulsions. Here, a size-based separation and characterization method for globule size distribution using an asymmetric flow field flow fractionation (AF4) is reported for comparative assessment of cyclosporine ophthalmic emulsion drug products (model formulation) with a wide size span and poly-dispersity. Cyclosporine emulsion formulations that are qualitatively (Q1) and quantitatively (Q2) the same as Restasis® were prepared in house with varying manufacturing processes and analyzed using the optimized AF4 method. Based on our results, the commercially available cyclosporine ophthalmic emulsion has a globule size span from 30â¯nm to a few hundred nanometers with majority smaller than 100â¯nm. The results with in-house formulations demonstrated the sensitivity of AF4 in determining the differences in the globule size distribution caused by the changes to the manufacturing process. It is concluded that the optimized AF4 is a potential analytical technique for comprehensive understanding of the microstructure and assessment of complex emulsion drug products with high poly-dispersity.
Asunto(s)
Ciclosporina/administración & dosificación , Fraccionamiento de Campo-Flujo/métodos , Inmunosupresores/administración & dosificación , Tecnología Farmacéutica/métodos , Administración Oftálmica , Química Farmacéutica/métodos , Ciclosporina/química , Composición de Medicamentos/métodos , Emulsiones , Inmunosupresores/química , Tamaño de la PartículaRESUMEN
The present investigation was carried out to understand the impact of formulation and process variables on the quality of oral disintegrating films (ODF) using Quality by Design (QbD) approach. Lamotrigine (LMT) was used as a model drug. Formulation variable was plasticizer to film former ratio and process variables were drying temperature, air flow rate in the drying chamber, drying time and wet coat thickness of the film. A Definitive Screening Design of Experiments (DoE) was used to identify and classify the critical formulation and process variables impacting critical quality attributes (CQA). A total of 14 laboratory-scale DoE formulations were prepared and evaluated for mechanical properties (%elongation at break, yield stress, Young's modulus, folding endurance) and other CQA (dry thickness, disintegration time, dissolution rate, moisture content, moisture uptake, drug assay and drug content uniformity). The main factors affecting mechanical properties were plasticizer to film former ratio and drying temperature. Dissolution rate was found to be sensitive to air flow rate during drying and plasticizer to film former ratio. Data were analyzed for elucidating interactions between different variables, rank ordering the critical materials attributes (CMA) and critical process parameters (CPP), and for providing a predictive model for the process. Results suggested that plasticizer to film former ratio and process controls on drying are critical to manufacture LMT ODF with the desired CQA.
Asunto(s)
Química Farmacéutica , Desecación , Composición de Medicamentos , Plastificantes , Temperatura , Administración Oral , Diseño de FármacosRESUMEN
Hyperspectral imaging using near infrared spectroscopy (NIRS) integrates spectroscopy and conventional imaging to obtain both spectral and spatial information of materials. The non-invasive and rapid nature of hyperspectral imaging using NIRS makes it a valuable process analytical technology (PAT) tool for in-process monitoring and control of the manufacturing process for transdermal drug delivery systems (TDS). The focus of this investigation was to develop and validate the use of Near Infra-red (NIR) hyperspectral imaging to monitor coat thickness uniformity, a critical quality attribute (CQA) for TDS. Chemometric analysis was used to process the hyperspectral image and a partial least square (PLS) model was developed to predict the coat thickness of the TDS. The goodness of model fit and prediction were 0.9933 and 0.9933, respectively, indicating an excellent fit to the training data and also good predictability. The % Prediction Error (%PE) for internal and external validation samples was less than 5% confirming the accuracy of the PLS model developed in the present study. The feasibility of the hyperspectral imaging as a real-time process analytical tool for continuous processing was also investigated. When the PLS model was applied to detect deliberate variation in coating thickness, it was able to predict both the small and large variations as well as identify coating defects such as non-uniform regions and presence of air bubbles.
Asunto(s)
Sistemas de Liberación de Medicamentos , Administración Cutánea , Análisis de los Mínimos Cuadrados , Análisis de Componente Principal , Control de Calidad , Espectroscopía Infrarroja CortaRESUMEN
Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.
Asunto(s)
Estradiol , Administración Cutánea , Sistemas de Liberación de Medicamentos/métodos , Epidermis/fisiología , Estradiol/administración & dosificación , Estradiol/farmacología , Estrógenos/administración & dosificación , Estrógenos/farmacología , Geles/administración & dosificación , Humanos , Absorción CutáneaRESUMEN
The availability of in vitro performance tests such as in vitro drug release testing (IVRT) and in vitro permeation testing (IVPT) are critical to comprehensively assure consistent delivery of the active component(s) from semisolid ophthalmic drug products. The objective was to study the impact of drug loading and type of ointment base on the in vitro performance (IVRT and IVPT) of ophthalmic ointments using acyclovir as a model drug candidate. The in vitro drug release for the ointments was evaluated using a modified USP apparatus 2 with Enhancer cells. The transcorneal permeation was carried out using rabbit cornea on modified vertical Franz cells. The drug retention in cornea (DRC) was also determined at the end of transcorneal drug permeation study. The in vitro drug release, transcorneal drug permeation as well as DRC exhibited a proportional increase with increasing drug loading in the ointment. On comparing the in vitro drug release profile with transcorneal permeation profile, it appears that drug release from the ointment is controlling acyclovir transport through the cornea. Furthermore, enhanced in vitro transcorneal permeation relative to the in vitro drug release underscores the importance of the interplay between the physiology of the ocular tissue and ointment formulation. The results indicated that IVRT and IVPT could be used to discriminate the impact of changes in drug load and formulation composition of ophthalmic ointments.
Asunto(s)
Aciclovir/administración & dosificación , Antivirales/administración & dosificación , Córnea/metabolismo , Sistemas de Liberación de Medicamentos , Aciclovir/farmacocinética , Administración Oftálmica , Animales , Antivirales/farmacocinética , Química Farmacéutica/métodos , Liberación de Fármacos , Masculino , Pomadas , Permeabilidad , ConejosRESUMEN
Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance.
Asunto(s)
Aciclovir/química , Antivirales/química , Aciclovir/administración & dosificación , Administración Oftálmica , Animales , Antivirales/administración & dosificación , Química Farmacéutica , Córnea/metabolismo , Composición de Medicamentos , Liberación de Fármacos , Masculino , Pomadas , Tamaño de la Partícula , Permeabilidad , Control de Calidad , Conejos , Reología , ViscosidadRESUMEN
In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time.
Asunto(s)
Liberación de Fármacos , Pomadas/química , Preparaciones Farmacéuticas/química , Aciclovir/química , Química Farmacéutica/métodos , Excipientes , Concentración de Iones de Hidrógeno , Cinética , Bases Oleosas/química , Física , Solubilidad , TemperaturaRESUMEN
The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100µg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X-0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100µg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100µg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100µg/day.
Asunto(s)
Sistemas de Liberación de Medicamentos , Estradiol/administración & dosificación , Estradiol/farmacocinética , Estrógenos/administración & dosificación , Estrógenos/farmacocinética , Modelos Biológicos , Administración Cutánea , Adulto , Disponibilidad Biológica , Estudios Cruzados , Estradiol/sangre , Estrógenos/sangre , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Reproducibilidad de los Resultados , Piel/metabolismo , Absorción Cutánea , Adulto JovenRESUMEN
The objective was to quantify drug loss due to cold flow (CF) in marketed estradiol transdermal drug delivery systems (TDDS), and study its influence on the in vitro flux and drug transfer across contacting skin. TDDS samples (products-A and B) were induced with CF at 25 and 32°C/60% RH by applying 1-kg force for 72h. CF was measured as percent dimensional change and amount of drug loss/migration in CF region. In vitro drug permeation studies were conducted across human epidermis from TDDS excluding CF region, and CF region alone against control (without CF). In both products, significantly higher percentage of CF (dimensional change and drug migration) was observed at 32°C compared to 25°C. In vitro flux from both products excluding CF region either at 25 or 32°C was the same, but significantly lower compared to control. Drug transferred from CF region of product-A after 8h was the same at 25 and 32°C, but significantly higher in product-B. Flux from both products together with CF region at 32°C was significantly lower than that observed at 25°C. Results showed that excessive CF at storage (25°C) and clinical usage (32°C) conditions may have implications on product performance and safety of estradiol TDDS.
Asunto(s)
Sistemas de Liberación de Medicamentos , Epidermis/metabolismo , Estradiol/administración & dosificación , Absorción Cutánea , Administración Cutánea , Adulto , Frío , Almacenaje de Medicamentos , Estradiol/farmacocinética , Femenino , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Adulto JovenRESUMEN
The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3.
Asunto(s)
Aciclovir/metabolismo , Antivirales/metabolismo , Aprobación de Drogas/métodos , Medicamentos Genéricos/metabolismo , Epidermis/metabolismo , Crema para la Piel/metabolismo , Aciclovir/análisis , Aciclovir/química , Antivirales/análisis , Antivirales/química , Cadáver , Fenómenos Químicos , Composición de Medicamentos , Medicamentos Genéricos/análisis , Medicamentos Genéricos/química , Emulsiones , Epidermis/química , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Tamaño de la Partícula , Permeabilidad , Crema para la Piel/química , Solubilidad , Temperatura de Transición , Estados Unidos , United States Food and Drug Administration , ViscosidadRESUMEN
Cold flow is a phenomenon occurring in drug-in-adhesive type of transdermal drug delivery systems (DIA-TDDS) because of the migration of DIA coat beyond the edge. Excessive cold flow can affect their therapeutic effectiveness, make removal of DIA-TDDS difficult from the pouch, and potentially decrease available dose if any drug remains adhered to pouch. There are no compendial or noncompendial methods available for quantification of this critical quality attribute. The objective was to develop a method for quantification of cold flow using stereomicroscopic imaging technique. Cold flow was induced by applying 1 kg force on punched-out samples of marketed estradiol DIA-TDDS (model product) stored at 25°C, 32°C, and 40°C/60% relative humidity (RH) for 1, 2, or 3 days. At the end of testing period, dimensional change in the area of DIA-TDDS samples was measured using image analysis software, and expressed as percent of cold flow. The percent of cold flow significantly decreased (p < 0.001) with increase in size of punched-out DIA-TDDS samples and increased (p < 0.001) with increase in cold flow induction temperature and time. This first ever report suggests that dimensional change in the area of punched-out samples stored at 32°C/60%RH for 2 days applied with 1 kg force could be used for quantification of cold flow in DIA-TDDS.
Asunto(s)
Adhesivos/química , Sistemas de Liberación de Medicamentos/métodos , Microscopía/métodos , Administración Cutánea , Frío , Piel/efectos de los fármacosRESUMEN
Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products.
Asunto(s)
Ciclosporina/química , Sistemas de Liberación de Medicamentos , Emulsiones , Inmunosupresores/química , Soluciones Oftálmicas/química , Control de Calidad , Tecnología Farmacéutica/normas , Química Farmacéutica , Estabilidad de Medicamentos , Humanos , Tamaño de la Partícula , Equivalencia TerapéuticaRESUMEN
CONTEXT: Colesevelam hydrochloride is used as an adjunct to diet and exercise to reduce elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia as well as to improve glycemic control in patients with type 2 diabetes. This is likely to result in submission of abbreviated new drug applications (ANDA). OBJECTIVE: This study was conducted to compare the efficacy of two tablet products of colesevelam hydrochloride based on the in vitro binding of bile acid sodium salts of glycocholic acid (GC), glycochenodeoxycholic acid (GCDA) and taurodeoxycholic acid (TDCA). METHODS: Kinetic binding study was carried out with constant initial bile salt concentrations as a function of time. Equilibrium binding studies were conducted under conditions of constant incubation time and varying initial concentrations of bile acid sodium salts. The unbound concentration of bile salts was determined in the samples of these studies. Langmuir equation was utilized to calculate the binding constants k1 and k2. RESULTS: The amount of the three bile salts bound to both the products reached equilibrium at 3 h. The similarity factor (f2) was 99.5 based on the binding profile of total bile salts to the test and reference colesevelam tablets as a function of time. The 90% confidence interval for the test to reference ratio of k2 values were 96.06-112.07 which is within the acceptance criteria of 80-120%. CONCLUSION: It is concluded from the results that the test and reference tablets of colesevelam hydrochloride showed a similar in vitro binding profile and capacity to bile salts.
Asunto(s)
Alilamina/análogos & derivados , Comprimidos/química , Alilamina/química , Ácidos y Sales Biliares/química , Clorhidrato de Colesevelam , Ácido Glicoquenodesoxicólico/química , Ácido Glicocólico/química , Cinética , Ácido Taurodesoxicólico/químicaRESUMEN
Colorectal cancer (CRC) is the third most common cause of cancer-related death in both men and women. Often, surgical intervention remains the choice in treating CRC. Traditional dosage forms used for treating CRC deliver drug to wanted as well as unwanted sites of drug action resulting in several adverse side effects. Targeted oral drug delivery systems are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific delivery of a drug to colon increases its concentration at the target site, and thus requires a lower dose with reduced incidence of side effects. The major obstacle to be overcome for successful targeting of drug to colon through oral route is that drug absorption/degradation must be avoided in stomach and small intestine before the dosage form reaches colon. The review includes discussion of physiological factors that must be considered when targeting drugs directly to colorectal region, an outline on drugs used for treatment and prevention of CRC, and a brief description of various types of colon-targeted oral drug delivery systems. The focus is on the assessment of various formulation approaches being investigated for oral colon-specific delivery of drugs used in the treatment and prevention of CRC.
Asunto(s)
Antineoplásicos/administración & dosificación , Colon/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/prevención & control , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/metabolismo , HumanosRESUMEN
The objective was to investigate the difference in penetration enhancing effect of R-carvone, S-carvone and RS-carvone on the in vitro transdermal drug permeation. In vitro permeation studies were carried out across neonatal rat epidermis from 2%w/v HPMC (hydroxypropyl methylcellulose) gel containing 4%w/v of nicorandil (a model drug) and a selected concentration (12%w/v) of either R-carvone, S-carvone or RS-carvone against a control. The stratum corneum (SC) of rats was treated with vehicle (70%v/v ethanol-water) or ethanolic solutions of 12%w/v R-carvone, S-carvone or RS-carvone. The enhancement ratio (ER) of R-carvone, S-carvone and RS-carvone when compared to control was about 37.1, 31.2 and 29.9, respectively indicating enantioselective penetration enhancing effect of carvone enantiomers. Furthermore, there was a significant decrease in the lag time required to produce a steady-state flux of nicorandil with S-carvone when compared to R-carvone and RS-carvone. DSC and FT-IR studies indicate that the investigated enantiomers of carvone exhibit a difference in their ability to affect the cellular organization of SC lipids and proteins thereby showing enantioselective transdermal drug permeation. It was concluded that R-carvone exhibited a higher penetration enhancing activity on transdermal permeation of nicorandil when compared to its S-isomer or racemic mixture.
Asunto(s)
Monoterpenos/farmacología , Nicorandil/administración & dosificación , Nicorandil/farmacocinética , Absorción Cutánea/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacocinética , Administración Cutánea , Animales , Monoterpenos Ciclohexánicos , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Isomerismo , Masculino , Monoterpenos/química , Vehículos Farmacéuticos/metabolismo , RatasRESUMEN
OBJECTIVE: To investigate the ability of α-tocopherol acetate (TA) and α-tocopherol (T), widely used ingredients in cosmetics, to cross the epidermal barrier using the neonatal rat as a model. MATERIALS AND METHODS: The content of T and TA in four marketed products (A-D) and two experimental formulations (F1, F2) was investigated by HPLC. An in vitro permeation study was performed in neonatal rat epidermis using diffusion cells. In vivo permeation was studied in neonatal rats after repeated application of the products and analysis of T and TA in the stratum corneum/deeper skin layers. RESULTS: Variable contents of TA were found in the marketed products (0.12-0.53%). No vitamin permeation was detected through the stratum corneum as in vitro biological barrier after 4 h. No detectable T and TA were seen in the in vivo permeation study in the epidermis. Variable degrees of drug penetration (4.3-12.6%) of the applied dose into the deeper skin layers were observed, depending on the formulation. In vivo application of TA-containing preparations did not result in any transformation of TA into T under the described experimental conditions. CONCLUSION: TA and T exhibited variable skin penetration and TA did not transform into T under the experimental conditions. The data underscored the need for further studies to optimize such formulations to improve vitamin E transdermal permeation and eventually achieve the expected cosmetic/therapeutic outcome.
Asunto(s)
Cosméticos/química , Epidermis/efectos de los fármacos , Absorción Cutánea/efectos de los fármacos , Vitamina E/química , Administración Cutánea , Animales , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Cosméticos/farmacología , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Kuwait , Ratas , Vitamina E/farmacologíaRESUMEN
A specific HPLC method, with an RP-C-18 column and a UV detector, for simultaneous determination of vitamin E (tochopherol, T)/T acetate (TA) in four commercial and two experimental cosmetic products is described. Three solvent systems for extraction of T/TA were assessed: isopropyl alcohol; 10:90 v/v hexane-methanol mixture (method 1); and methanol alone (method 2). The procedure was accurate, as indicated by high recovery (97.8-101.8% and 100.1-102.5% for T and TA, respectively) and precise (RSD was only 0.9-3.26% and 0.73-3.35% for T and TA, respectively). The limits of detection for T and TA were 200 and 300 ng/ml, respectively, while the limits of quantitation were 250 and 400 ng/ml, respectively. The range of reliable quantification was 5-50 µg/ml. Isopropanol as solvent resulted in a turbid extract. Method 1 and method 2 of extraction showed high recovery (98.5-99.9% and 97.2-97.9% for T and TA, respectively). After a few weeks of analysis, method 1 resulted in retention time drift, peak broadening, non-reproducible results, and progressive loss of HPLC-column integrity. Methanol alone (method 2) was equally as efficient as that of the mixture of methanol with 10% hexane (method 1) for extraction. The described analytical procedure proved to be accurate, precise, and suitable for simultaneous determination of T and TA in real commercial cosmetic products.