RESUMEN
The main purposes of this work were to prepare, characterize and optimize a self-emulsified drug delivery system of probucol (PBSEDDS) with enhanced dissolution and better chance for oral absorption. The methods included determination of the solubility of probucol in different oils, surfactants and co-surfactants using saturation solubility method and HPLC for drug analysis. The ingredients showing high drug solubility were used to prepare PBSEDDS after being tested for physical and chemical compatibility with the drug using DSC and FTIR. The prepared formulations were evaluated for droplet size, turbidity, spontaneity of emulsification and dissolution in water. Optimization was performed using a three-factor, three-level Box-Behnken experimental design. The results showed high drug solubility and compatibility with soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (cosurfactant). Oil to surfactant/co-surfactant ratio showed large influence on the characteristics of PBSEDDS. Several fold improvement of drug dissolution was observed compared to drug solution in soybean oil alone. Optimization study showed that observed and predicted values of cumulative percent drug dissolution after 60 min were in reasonable agreement. The experimental design applied helped in understanding the effects and the interaction effects between the independent factors. The prepared PBSEDDS may have the potential to enhance the therapeutic bioavailability of probucol.
Asunto(s)
Anticolesterolemiantes/farmacocinética , Probucol/farmacocinética , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/química , Rastreo Diferencial de Calorimetría , Fenómenos Químicos , Química Farmacéutica , Química Física , Cromatografía Líquida de Alta Presión , Sistemas de Liberación de Medicamentos , Emulsiones , Excipientes , Indicadores y Reactivos , Modelos Estadísticos , Nefelometría y Turbidimetría , Aceites/química , Tamaño de la Partícula , Probucol/administración & dosificación , Probucol/química , Solubilidad , Soluciones , Espectroscopía Infrarroja por Transformada de Fourier , Tensoactivos , Agua/químicaRESUMEN
The aim of the present study was to use factorial design to enhance the dissolution rate of nimesulide using solid binary systems with the hydrophilic carriers D-mannitol and polyethylene glycol (PEG 4000). Two-factor full factorial design was employed to investigate the effects of the drug/carrier ratio (X(1), 10 and 20%) and the method ofãpreparation (X(2), physical or co-melted mixture) onãthe percent drug release after 60 min (Y(1)). Drugcarrier co-melted mixtures were prepared by melting the carriers D-mannitol or PEG with the drug. For physical mixtures, the drug and carrier were mixed thoroughly in a mortar until a homogeneous mixture was obtained. Drug-carrier interactions were investigated by differential scanning calorimetry (DSC). All prepared mixtures were filled in hard gelatin capsules, size 0, and then their dissolution rate was tested. The results showed an increase in the solubility of the drug with increasing polymer concentrations. Thermal analysis revealed no notable differences regarding thermal events of nimesulide, D-mannitol, PEG 4000, and their physical or comelted mixtures. The percent drug released after 60 min was 29.5% for nimesulide alone, 37.14 and 32.0% for a PEG/Physical mixture with a 10 or 20% drug/polymer ratio, and 69.7 and 53.1% for a PEG/Co-melted mixture with the same ratios. For nimesulide/D-mannitol, this percent drug released was 33.57 and 29.6% for a physical mixture and 63.13 and 48.04% for a co-melted mixture. Formulations with PEG showed an increase in solubility as well as dissolution in comparison to those prepared with D-mannitol. Factorial design was successfully used to optimize the dissolution rate of nimesulide. The chosen polymers caused a notable increase in drug solubility and co-melted formulations generally showed a higher dissolution than those prepared with physical mixtures.
RESUMEN
The aim of the study was to investigate the effect of terpene enhancers (nerodilol, carvone or anethole) on the in vitro transdermal delivery of selegiline hydrochloride with a broad objective of developing a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation studies were carried across the rat epidermis from hydroxypropyl methylcellulose (HPMC) gel drug reservoir containing selected concentrations of nerodilol, carvone or anethole and selegiline hydrochloride. The amount of selegiline hydrochloride permeated during the 24 h of the study (Q24) from HPMC gel drug reservoir without terpene enhancer was 2169 +/- 50 microg/cm2 and the corresponding flux of the drug was 92 +/- 1 microg/cm2 x h. The amount of drug permeated and its flux increased with an increase in terpne concentration in HPMC gel drug reservoir. Nerodilol provided an approximately 3.2-fold increase in the flux of selegiline hydrochloride followed by carvone with a 2.8-fold increase, and anethole with a 2.6-fold increase. It is concluded that the terpene nerodilol, carvone and anethole produced a marked penetration enhancing effect on the in vitro transdermal delivery of selegiline hydrochloride that could possibly be used in the formulation of membrane-moderated TTS.
Asunto(s)
Anisoles/farmacología , Monoterpenos/farmacología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacocinética , Selegilina/administración & dosificación , Selegilina/farmacocinética , Absorción Cutánea/efectos de los fármacos , Terpenos/farmacología , Administración Cutánea , Derivados de Alilbenceno , Animales , Monoterpenos Ciclohexánicos , Masculino , Ratas , Ratas Wistar , SolventesRESUMEN
The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm(2)) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for approximately 24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.
Asunto(s)
Antihipertensivos/administración & dosificación , Monoterpenos/química , Nicorandil/administración & dosificación , Adhesivos , Administración Cutánea , Animales , Antihipertensivos/farmacocinética , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Monoterpenos Ciclohexánicos , Preparaciones de Acción Retardada , Cámaras de Difusión de Cultivos , Sistemas de Liberación de Medicamentos , Excipientes , Humanos , Lactosa/análogos & derivados , Masculino , Membranas Artificiales , Metilcelulosa/análogos & derivados , Nicorandil/farmacocinética , Oxazinas , Ratas , Absorción Cutánea , Espectrofotometría Ultravioleta , Compuestos de ViniloRESUMEN
The present study was carried out to develop and evaluate guar gum-based matrix tablets of rofecoxib for their intended use in the chemoprevention of colorectal cancer. Matrix tablets containing 40% (RXL-40), 50% (RXL-50), 60% (RXL-60) or 70% (RXL-70) of guar gum were prepared by wet granulation technique, and were subjected to in vitro drug release studies. Guar gum matrix tablets released only 5 to 12% of rofecoxib in the physiological environment of stomach and small intestine. The matrix tablets RXL-40 disintegrated completely within 10 h in a dissolution medium without rat caecal contents (control study), and hence not studied further. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets RXL-50 were acted upon by colonic bacterial enzymes releasing the entire quantity of drug wherein there was no appreciable difference when compared to that released in control study. The matrix tablets RXL-60 released another 88% of rofecoxib whereas matrix tablets RXL-70 released only 57% of rofecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The guar gum matrix tablets RXL-70 were subjected to in vivo evaluation in human volunteers to find their ability of targeting rofecoxib to colon. The delayed Tmax, prolonged absorption time (ta), decreased Cmax and decreased ka indicated that rofecoxib was not released significantly in stomach and small intestine, but was delivered to colon resulting in a slow absorption of the drug and making it available for local action in human colon.
Asunto(s)
Colon/metabolismo , Sistemas de Liberación de Medicamentos , Galactanos/administración & dosificación , Lactonas/administración & dosificación , Mananos/administración & dosificación , Sulfonas/administración & dosificación , Adolescente , Adulto , Neoplasias Colorrectales/prevención & control , Humanos , Gomas de Plantas , Solubilidad , ComprimidosRESUMEN
Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nicorandil/administración & dosificación , Absorción Cutánea , Vasodilatadores/administración & dosificación , Administración Cutánea , Administración Oral , Adulto , Animales , Área Bajo la Curva , Estudios Cruzados , Ciclohexenos , Antebrazo , Geles , Humanos , Derivados de la Hipromelosa , Limoneno , Masculino , Metilcelulosa/análogos & derivados , Nicorandil/sangre , Nicorandil/farmacocinética , Permeabilidad , Ratas , Piel/metabolismo , Solventes , Terpenos , Adhesivos Tisulares , Vasodilatadores/sangre , Vasodilatadores/farmacocinéticaRESUMEN
The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.
Asunto(s)
Portadores de Fármacos/química , Metilcelulosa/análogos & derivados , Nicorandil/administración & dosificación , Nicorandil/farmacocinética , Sesquiterpenos , Administración Cutánea , Adulto , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/sangre , Antiarrítmicos/farmacocinética , Disponibilidad Biológica , Estudios Cruzados , Geles , Humanos , Derivados de la Hipromelosa , Técnicas In Vitro , Masculino , Nicorandil/sangre , Polímeros/química , Ratas , Absorción Cutánea , Vasodilatadores/administración & dosificación , Vasodilatadores/sangre , Vasodilatadores/farmacocinética , Compuestos de Vinilo/químicaRESUMEN
The objective of this study was to prepare saturated solutions of ibuprofen, of different concentrations, and to investigate their effect on permeation of ibuprofen across rat epidermis. Ibuprofen saturated solutions were prepared using 0.1, 0.2, 0.3 and 0.4 M disodium hydrogen phosphate solution (DHP). The solubility of ibuprofen in DHP increased as the molarity of DHP increased. Thus the four saturated solutions of ibuprofen (0.1M-DHP-IBU, 0.2M-DHP-IBU, 0.3M-DHP-IBU and 0.4M-DHP-IBU) have different concentrations of the same drug, and showed same pH (pH 7.0+/-1). The permeability study was also carried out using human epidermis and silastic membrane. Permeation rate of ibuprofen across rat epidermis and human epidermis from 0.4M-DHP-IBU was much greater than from 0.1M-DHP-IBU. The magnitudes of increase in the drug flux were 46.4-fold with rat epidermis and 9.4-fold with human epidermis. Such a great increase in drug flux was not observed with silastic membrane, only 1.4-fold. This suggests that the increased drug flux is likely due to drug-skin interaction and not the increased concentration of ibuprofen per se. Surface tension (ST) measurements of DHP versus ibuprofen concentration showed ST reduction of DHP, from 72 to 27.9 dyn/cm. This is an indication that ibuprofen acted as ionic surfactant and the observed skin permeability enhancement is attributed to disruption of stratum corneum barrier. Results of DSC study supported this assumption. DSC of untreated rat stratum corneum samples showed lipid transitions at 41.9+/-0.0 degrees C (T1), 55.1+/-1.6 degrees C (T(x)), 70.2+/-0.1 degrees C (T2) and 77.5+/-0.1 degrees C (T3), while those pretreated with 0.4M-DHP-IBU did not show the first three lipid transitions. Also, pretreatment of rat epidermis with 0.4M-DHP-IBU enhanced permeation of diclofenac sodium greater than 1250-fold. This corroborates that ibuprofen not only enhances its own permeation but also that of other drugs, such as diclofenac sodium.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacocinética , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Animales Recién Nacidos , Rastreo Diferencial de Calorimetría , Cromatografía Líquida de Alta Presión , Diclofenaco/administración & dosificación , Diclofenaco/farmacocinética , Epidermis/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Membranas Artificiales , Soluciones Farmacéuticas , Ratas , Ratas Sprague-Dawley , Solubilidad , Tensión Superficial , Tensoactivos , TermodinámicaRESUMEN
The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.
Asunto(s)
Antihipertensivos/metabolismo , Metilcelulosa/análogos & derivados , Nicorandil/metabolismo , Absorción Cutánea/efectos de los fármacos , Terpenos/farmacología , Administración Cutánea , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/análisis , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Ciclohexenos , Derivados de la Hipromelosa , Limoneno , Masculino , Nicorandil/administración & dosificación , Nicorandil/análisis , Permeabilidad/efectos de los fármacos , Ratas , Solventes , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The objective of the present study is to carry out pharmacokinetic evaluation of oral controlled release formulation (guar gum-based three-layer matrix tablets) containing highly soluble metoprolol tartrate as a model drug. Six healthy volunteers participated in the study, and a two-way crossover design was followed. The plasma concentration of metoprolol tartrate was estimated by reverse-phase HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of metoprolol tartrate versus time data. The delayed T(max) lower C(max) decreased K(a) unaltered bioavailability and prolonged t(1/2) indicated a slow and prolonged release of metoprolol tartrate from guar gum three-layer matrix tablets in comparison with the immediate release tablet dosage form. The results of the study indicated that guar gum three-layer matrix tablets were able to provide oral controlled delivery of highly water-soluble drug such as metoprolol tartrate in humans.
Asunto(s)
Galactanos/administración & dosificación , Galactanos/farmacocinética , Mananos/administración & dosificación , Mananos/farmacocinética , Metoprolol/administración & dosificación , Metoprolol/farmacocinética , Modelos Químicos , Administración Oral , Adulto , Análisis de Varianza , Química Farmacéutica , Estudios Cruzados , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Evaluación de Medicamentos/métodos , Humanos , Masculino , Gomas de Plantas , Solubilidad/efectos de los fármacos , Comprimidos RecubiertosRESUMEN
The purpose of this investigation was to evaluate the bioavailability of three salbutamol sulfate suppository formulations. The formulations were; 2 mg salbutamol sulfate in Suppocire NA base containing 6% Eudispert gel (F1), 2mg salbutamol sulfate in Witepsol H15 base containing 3% methyl cellulose gel (F2), and 2 mg salbutamol sulfate in Witepsol W25 base containing 3% methyl cellulose gel (F3). The formulations were administered via rectal route in six healthy male adult volunteers. The bioavailability of the three suppository formulations was compared with the oral bioavailability of salbutamol sulfate 2mg tablets (F4). Six volunteers participated in a four-way crossover study, where each study was separated from the other by an interval of 1 weak. Venous blood samples of 5 ml were taken immediately before dosing and after predetermined time intervals of 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6 and 8 h. The result showed that Cmax +/- S.D. observed were 12.96 +/- 2.11, 14.78 +/- 2.33, 10.02 +/- 1.42 and 11.51 +/- 1.22 ng ml(-1) for F1, F2, F3 and F4, respectively. The Tmax +/- S.D. were found to be 1.91 +/- 0.20, 1.83 +/- 0.26, 2.50 +/- 0.00 and 2.67 +/- 0.24 h for F1, F2, F3 and F4, respectively. AUC +/- S.D. values were 40.25 +/- 1.88, 42.16 +/- 1.55, 28.62 +/- 1.98 and 37.63 +/- 1.44 ng h per ml for F1, F2, F3 and F4, respectively. The relative bioavailabilities of the investigated formulations were 112.04, 106.96 and 76.06 for formula F2, F1 and F3, respectively, when compared with the oral preparation (F4). The finding indicates that the bioavailability of salbutamol sulfate can be enhanced by delivering it rectally with Suppocire NA base containing 6% Eudispert gel or with Witepsol W25 base containing 3% methyl cellulose to match that of oral tablets. Salbutamol sulfate can be rectally administered in patients who are less compliant with the oral administration.
Asunto(s)
Albuterol/administración & dosificación , Albuterol/farmacocinética , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Masculino , Persona de Mediana Edad , Vehículos Farmacéuticos , Supositorios , ComprimidosRESUMEN
The effect of dimethylsulfoxide (DMSO) concentration on the permeability of neonatal rat stratum corneum to 14C labeled propan-1-ol and hexan-1-ol was studied in vitro. The permeability coefficients were determined from a range of DMSO-water systems. After soaking in water overnight, the same stratum corneum was used with water as both delivery and recipient phases for the alkanols. Concentrations below 70% DMSO reduced the penetration rate as a result of the solvent effect of DMSO and the formation of a DMSO-alkanol complex. Above 70% DMSO permeability increased, with a permeability coefficient greater than that from water being achieved at concentrations in excess of 80% DMSO. The second run, with water as delivery phase, showed that the effect was reversible below 70% DMSO, but that at higher concentrations DMSO had produced an irreversible change in the permeability of stratum corneum. We hypothesize a hydrogen bond-mediated mechanism for the increased permeability.
Asunto(s)
1-Propanol/metabolismo , Dimetilsulfóxido/farmacología , Epidermis/efectos de los fármacos , Hexanoles/metabolismo , Animales , Animales Recién Nacidos , Difusión , Enlace de Hidrógeno , Técnicas In Vitro , Permeabilidad , Ratas , AguaRESUMEN
We heated flat sheets of neonatal rat stratum corneum for various times at temperatures between 40 and 90 degrees C before determining the permeability coefficient (Kp) of propanol and/or hexanol from water. Below 70 degrees C, Kp remained constant; at 75 degrees C, Kp increased linearly with exposure time; at 80 degrees C and above, there was a large increase in under 2 h, with no further increase on longer heating. There was a 15-fold increase in 6-h Kp between 70 degrees C and 80 degrees C, values being constant above 80 degrees C but at a figure less than for lipid-extracted stratum corneum. Thermal analysis showed that the increase in Kp corresponds to changes in the 80 degrees C lipid endotherm, suggesting that the increased Kp is due to a disordering of the lipid structures. The effect of treating preheated stratum corneum with dimethylsulfoxide (DMSO) vapor for 16 h was also studied. Below 70 degrees C, Kp was increased five-fold, but between 70 and 80 degrees C this difference was eliminated, so that above 80 degrees C the Kp was the same as with heat treatment alone. We concluded that both heat and DMSO affect the lipid structures of stratum corneum. DMSO produced a small, reversible structural change, while the effect of heat is irreversible and produces a greater degree of disorder in the lipid structures, but the lipid still contributed to the barrier effect of stratum corneum.