RESUMEN
Clotrimazole (CT) is a poorly soluble antifungal drug that is most commonly employed as a topical treatment in the management of vaginal candidiasis. The present work focuses on a formulation approach to enhance the solubility of CT using cyclodextrin (CD) complexation. A CT-CD complex was prepared by a co-precipitation method. Various characterization techniques such as differential scanning calorimetry, infrared (IR) and X-ray spectroscopy, scanning electron microscopy and nuclear magnetic resonance (NMR) spectroscopy were performed to evaluate the complex formation and to understand the interactions between CT and CD. Computational molecular modeling was performed using the Schrödinger suite and Gaussian 09 program to understand structural conformations of the complex. The phase solubility curve followed an AL-type curve, indicating formation of a 1:1 complex. Molecular docking studies supported the data obtained through NMR and IR studies. Enthalpy changes confirmed that complexation was an exothermic and enthalpically favorable phenomenon. The CT-CD complexes were formulated in a gel and evaluated for release and antifungal activity. The in vitro release studies performed using gels demonstrated a sustained release of CT from the CT-CD complex with the complex exhibiting improved release relative to the un-complexed CT. Complexed CT-CD exhibited better fungistatic activity toward different Candida species than un-complexed CT.
Asunto(s)
Antifúngicos/química , Candidiasis , Clotrimazol/química , Ciclodextrinas/química , Manejo de la Enfermedad , Antifúngicos/administración & dosificación , Antifúngicos/metabolismo , Sitios de Unión/fisiología , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Química Farmacéutica , Clotrimazol/administración & dosificación , Clotrimazol/metabolismo , Ciclodextrinas/administración & dosificación , Ciclodextrinas/metabolismo , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Resultado del Tratamiento , Difracción de Rayos XRESUMEN
This study investigated the processing parameters and formulation factors on the bioadhesive properties, temperature stability properties, and drug release properties of miconazole in PolyOx® and Klucel® matrix systems produced by Hot-melt Extrusion (HME) technology. Miconazole incorporated into these matrix systems were found to be stable for 8 months by X-ray diffraction (XRD). The addition of miconazole increased area under the curve (AUC) at contact time intervals of 30 and 60 sec, while the bioadhesion decreased with an increase in processing temperatures. The release profiles suggest that a sustained release of miconazole was observed from all of the tested HME film formulations for approximately 10 h. The release from the optimal HME film extruded at 205°C was found to be significantly different than that extruded at 190°C. Therefore, this matrix system may address the present shortcomings of currently available therapy for oral and pharyngeal candidiasis.
Asunto(s)
Antifúngicos/química , Calor , Miconazol/química , Polímeros/química , Tecnología Farmacéutica/métodos , Adhesividad , Área Bajo la Curva , Celulosa/análogos & derivados , Celulosa/química , Química Farmacéutica , Cristalografía por Rayos X , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Estudios de Factibilidad , Cinética , Polietilenglicoles/química , Solubilidad , TermogravimetríaRESUMEN
The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH.
Asunto(s)
Celulosa/análogos & derivados , Composición de Medicamentos/métodos , Fenofibrato/química , Hipolipemiantes/química , Polímeros/química , Celulosa/química , Estabilidad de Medicamentos , Calor , Peso Molecular , SolubilidadRESUMEN
The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.
Asunto(s)
Celulosa/análogos & derivados , Portadores de Fármacos/química , Cetoprofeno/administración & dosificación , Cetoprofeno/química , Polímeros/química , Comprimidos/química , Tecnología Farmacéutica/métodos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Cápsulas/química , Celulosa/química , Química Farmacéutica , Composición de Medicamentos/métodos , Implantes de Medicamentos/química , Estabilidad de Medicamentos , Excipientes/química , Pruebas de Dureza , Interacciones Hidrofóbicas e Hidrofílicas , Manitol/química , Tamaño de la Partícula , Porosidad , SolubilidadRESUMEN
INTRODUCTION: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. AREAS COVERED: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems. EXPERT OPINION: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.