RESUMEN
Preclinical profiling for a New Chemical Entity (NCE), if carried out carefully, can be a good predictor of human clinical outcome. Along with the pre-clinical study design a thorough understanding of the physico-chemical properties of the drug candidate and a careful selection of the formulation development strategy are of high importance. The study scientist can experience various challenges in executing a pre-clinical study. This review article provides an overview of the significance of pre-formulation study parameters and their relevance to preclinical studies. Various physico-chemical properties such as solubility, partition co-efficient, and permeability are attributes critical to the performance of the drug substance. This article presents unique formulation development strategies for the successful completion of pre-clinical studies. Formulation development approach for a pre-clinical study involves taking into consideration various important factors such as duration of the study, Biopharmaceutics Classification System (BCS) of the drug, intended duration of action and the desired route of administration. These parameters play key role in the selection of solubilizers, surfactants, co-solvents and optimum pH for the formulation. Two most common routes of administration in the early screening of pharmaceuticals viz., oral and intravenous are emphasized. The article also describes recent advances in preclinical formulation development including selected examples of in vivo preclinical models for anti-cancer, anti-viral, anti-diabetic and anti-hypertensive drugs. Adherence to the regulatory requirement is also the key to successful completion of the preclinical development. An overview of preclinical formulation development along with basic concepts and the recent studies conducted in the past decade are presented in this review.
Asunto(s)
Química Farmacéutica/métodos , Evaluación Preclínica de Medicamentos/métodos , Preparaciones Farmacéuticas/química , Animales , Vías de Administración de Medicamentos , Humanos , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
A novel multilamellar vesicular delivery system was developed for the controlled release application. Multilamellar vesicles were prepared by thin film hydration and converted into proliposomes by freeze-drying. A model drug metoclopramide, a highly hydrophilic drug, was successfully encapsulated into proliposomes. The proliposomes produced were non-sticky, free-flowing powders. The proliposomes were formulated into a unit dosage form by combining with various excipients. The effect of different compositions such as type and concentration of phospholipid or hydrophilic polymer was investigared to optimize the formulation. The formation of multilamellar vesicles was confirmed by observing the process of hydration of proliposomes under an optical microscope. The spherical shape of vesicles was confirmed by transmission electron microscopy (TEM) and mean particle sizes were in the range of 1.3-2.5 microm, as measured by dynamic light scattering technique. Differential scanning calorimetry (DSC) study of formulations was conducted to understand the crystalline nature of drug in the vesicles. The results indicated a molecular level dispersion of drug into proliposomes with encapsulation efficiency up to 43%. Critical formulation parameters were identified to obtain a near zero order in vitro release pattern. Proliposomal formulations produced were suitable as multiparticulate drug delivery systems for the controlled release of a highly hydrophilic molecule.
Asunto(s)
Administración Cutánea , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Membranas Artificiales , Termogravimetría/métodos , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica , Composición de Medicamentos , Estabilidad de Medicamentos , Excipientes/administración & dosificación , Excipientes/farmacocinética , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Fosfolípidos/química , Polímeros/química , Alcohol Polivinílico/química , Solubilidad/efectos de los fármacos , Propiedades de SuperficieRESUMEN
Timolol maleate-loaded chitosan (CS) nanoparticles were prepared by desolvation method. Experimental variables such as molecular weight of CS and amount of crosslinking agent were varied to study their effect on drug entrapment efficiency, size and release rates of nanoparticles. Chemical stability of timolol maleate (TM) and crosslinking of CS were confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetric studies were performed on drug-loaded nanoparticles to investigate crystalline nature of the drug after entrapment. Results indicated amorphous dispersion of drug in the polymer matrix. Scanning electron microscopy revealed irregularly shaped particles. Mean particle size of nanoparticles ranged between 118 and 203 nm, while zeta potential ranged between +17 and +22 mV. Entrapment efficiency of nanoparticles ranged between 47.6 and 63.0%. In-vitro release studies were performed in phosphate buffer saline of pH 7.4. A slow release of TM up to 24 h was observed. A 3(2) full factorial design was employed and second-order regression models were used to study the response (% drug release at 4 h). Release data as analyzed by an empirical relationship suggested that drug release deviated from the Fickian trend.
Asunto(s)
Quitosano/administración & dosificación , Nanopartículas/administración & dosificación , Timolol/administración & dosificación , Rastreo Diferencial de Calorimetría , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Timolol/químicaRESUMEN
The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, beta-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30-40% drug release during the initial 4-5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18-24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.
Asunto(s)
Antiprotozoarios/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Metronidazol/administración & dosificación , Polisacáridos/química , Amebiasis/tratamiento farmacológico , Animales , Antiprotozoarios/farmacocinética , Antiprotozoarios/uso terapéutico , Colon/metabolismo , Masculino , Metronidazol/farmacocinética , Metronidazol/uso terapéutico , Ratas , Ratas Wistar , Comprimidos RecubiertosRESUMEN
This study reports on the development of novel biodegradable microspheres prepared by water-in-oil-water (W/O/W) double emulsion technique using the blends of poly(d,l-lactide-co-glycolide) (PLGA) and poly(epsilon-caprolactone) (PCL) in different ratios for the controlled delivery of doxycycline (DXY). Doxycycline encapsulation of up to 24% was achieved within the polymeric microspheres. Blend placebo microspheres, drug-loaded microspheres and pristine DXY were analyzed by Fourier transform infrared spectroscopy (FT-IR), which indicated no interaction between drug and polymers. Differential scanning calorimetry (DSC) on drug-loaded microspheres confirmed the polymorphism of DXY and indicated a molecular level dispersion of DXY in the microspheres. Scanning electron microscopy (SEM) confirmed the spherical nature and smooth surfaces of the microspheres produced. Mean particle size of the microspheres as measured by dynamic laser light scattering method ranged between 90 and 200 mum. In vitro release studies performed in 7.4 pH media indicated the release of DXY from 7 to 11 days, depending upon the blend ratio of the matrix. Up to 11 days, DXY concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of DXY against most of the periodontal pathogens. One of the developed formulations was subjected to in vivo efficacy studies in thirty sites of human periodontal pockets. Significant results were obtained with respect to both microbiological and clinical parameters up to 3 months even as compared to commercial DXY gel. Statistical analyses of the release data and in vivo results were performed using the analysis of variance (ANOVA) method.
Asunto(s)
Doxiciclina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Ácido Láctico/administración & dosificación , Microesferas , Bolsa Periodontal/tratamiento farmacológico , Poliésteres/administración & dosificación , Ácido Poliglicólico/administración & dosificación , Polímeros/administración & dosificación , Doxiciclina/farmacocinética , Evaluación Preclínica de Medicamentos , Humanos , Ácido Láctico/farmacocinética , Bolsa Periodontal/metabolismo , Bolsa Periodontal/patología , Poliésteres/farmacocinética , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Polímeros/farmacocinética , Distribución AleatoriaRESUMEN
The present study was performed to evaluate the possibility of using modified xanthan films as a matrix system for transdermal delivery of atenolol (ATL), which is an antihypertensive drug. Acrylamide was grafted onto xanthan gum (XG) by free radical polymerization using ceric ion as an initiator. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated the formation of the graft copolymer. The obtained graft copolymer was loaded with ATL and films were fabricated by solution casting method for transdermal application. Various formulations were prepared by varying the grafting ratio, drug loading, and different penetration enhancers. The formulations prepared were characterized for weight, thickness uniformity, water vapor transmission rate, and uniformity in drug content of the matrix. All the thin films were slightly opaque, smooth, flexible, and permeable to water vapor, indicating their permeability characteristics suitable for transdermal studies. Fourier transform infrared spectroscopy and differential scanning calorimetry studies indicated no significant interactions between drug and polymer. Drug is distributed uniformly in the matrix but showed a slight amorphous nature. Drug-loaded films were analyzed by X-ray diffraction to understand the drug polymorphism inside the films. Scanning electron microscopic studies of the placebo and drug-loaded films demonstrated a remarkable change in their surface morphology. The skin irritation tests were performed in mice and these results suggested that both placebo and drug-loaded films produced negligible erythema and edema compared to formalin (0.8% v/v) as the standard irritant. The in vitro drug release studies were performed in phosphate buffer saline using a Keshary-Chien diffusion cell. Different formulations were prepared and variations in drug release profiles were observed. Release data were analyzed by using the Ritger and Peppas equation to understand the mechanism of drug release as well as the estimation of n values, which ranged between 0.41 and 0.53, suggesting a Fickian diffusion trend.
Asunto(s)
Atenolol/administración & dosificación , Polisacáridos Bacterianos/administración & dosificación , Resinas Acrílicas/administración & dosificación , Administración Cutánea , Animales , Atenolol/química , Preparaciones de Acción Retardada , Ratones , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
This paper describes the synthesis of capecitabine-loaded semi-interpenetrating network hydrogel microspheres of chitosan-poly(ethylene oxide-g-acrylamide) by emulsion crosslinking using glutaraldehyde. Poly(ethylene oxide) was grafted with polyacrylamide by free radical polymerization using ceric ammonium nitrate as a redox initiator. Capecitabine, an anticancer drug, was successfully loaded into microspheres by changing experimental variables such as grafting ratio of the graft copolymer, ratio of the graft copolymer to chitosan, amount of crosslinking agent and percentage of drug loading in order to optimize process variables on drug encapsulation efficiency, release rates, size and morphology of the microspheres. A 2(4) full factorial design was employed to evaluate the combined effect of selected independent variables on percentage of drug release at 5h (response). Regression models were used for the response and data were compared statistically using the analysis of variance (ANOVA). Grafting, interpenetrating network formation and chemical stability of the capecitabine after encapsulation into microspheres was confirmed by Fourier infrared spectra (FTIR). Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) studies were made on drug-loaded microspheres to investigate the crystalline nature of drug after encapsulation. Results indicated amorphous dispersion of capecitabine in the polymer matrix. Scanning electron microscope (SEM) confirmed spherical shapes and smooth surface morphology of the microspheres. Mean particle size of the microspheres as measured by the laser light scattering technique ranged between 82 and 168microm. Capecitabine was successfully encapsulated into semi-IPN microspheres and percentage of encapsulation efficiency varied from 79 to 87. In vitro release studies were performed in simulated gastric fluid (pH 1.2) for the initial 2h, followed by simulated intestinal fluid (pH 7.4) until complete dissolution. The release of capecitabine was continued up to 10h. Release data were fitted to an empirical relationship to estimate the transport parameters. Dynamic swelling studies were performed in the simulated intestinal fluid and diffusion coefficients were calculated by considering the spherical geometry of the matrices.
Asunto(s)
Quitosano/administración & dosificación , Desoxicitidina/análogos & derivados , Microesferas , Resinas Acrílicas , Rastreo Diferencial de Calorimetría , Capecitabina , Preparaciones de Acción Retardada , Desoxicitidina/administración & dosificación , Desoxicitidina/química , Difusión , Fluorouracilo/análogos & derivados , Hidrogel de Polietilenoglicol-Dimetacrilato , Polietilenglicoles , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Gellan gum beads containing cephalexin were prepared by extruding the dispersion of cephalexin and gellan gum into a solution containing a mixture of calcium and zinc ions (counterions). Beads were prepared by changing experimental variables such as pH of the counterion solution and amount of cephalexin loading in order to optimize process variables on the final % drug entrapment efficiency, release rates, size, and morphology of the beads. Absence of chemical interactions between drug, anionic polymer, and counterions after production of beads was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry was used to understand the crystalline nature of the drug after its successful entrapment. These data indicated the amorphous dispersion of cephalexin in the polymer matrix. Beads were spherical in shape, with the average bead size ranging from 925 to 1183 microm as measured by the laser light scattering technique. Cephalexin entrapment of up to 69.24% was achieved. In vitro release studies were performed in 0.1 N HCl or pH 7.4 phosphate buffer and the release of cephalexin was achieved up to 6 h. Dynamic swelling studies were performed in 0.1 N HCl or pH 7.4 phosphate buffer. Diffusion coefficients were calculated for spherical geometry. The release data have been fitted to an empirical relation to estimate the transport parameters. Mathematical modeling studies were performed for spherical geometry by solving Fick's equation to compute concentration profiles. These results were correlated with the release profiles.
Asunto(s)
Cefalexina/administración & dosificación , Polisacáridos Bacterianos/administración & dosificación , Cefalexina/química , Química Farmacéutica , Preparaciones de Acción Retardada , Difusión , Concentración de Iones de Hidrógeno , Modelos Teóricos , SolubilidadRESUMEN
Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 microm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.
Asunto(s)
Carbazoles/farmacocinética , Preparaciones de Acción Retardada/farmacocinética , Microesferas , Polisacáridos Bacterianos/química , Alcohol Polivinílico/química , Propanolaminas/farmacocinética , Algoritmos , Antihipertensivos/química , Antihipertensivos/farmacocinética , Rastreo Diferencial de Calorimetría/métodos , Carbazoles/química , Carvedilol , Preparaciones de Acción Retardada/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Propanolaminas/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Tecnología Farmacéutica/métodos , Resistencia a la Tracción , Difracción de Rayos X/métodosRESUMEN
Considerable research efforts have been directed towards developing safe and efficient chitosan-based particulate drug delivery systems. The present review outlines the major new findings on the pharmaceutical applications of chitosan-based micro/nanoparticulate drug delivery systems published over the past decade. Methods of their preparation, drug loading, release characteristics, and applications are covered. Chemically modified chitosan or its derivatives used in drug delivery research are discussed critically to evaluate the usefulness of these systems in delivering the bioactive molecules. From a literature survey, it is realized that research activities on chitosan micro/nanoparticulate systems containing various drugs for different therapeutic applications have increased at the rapid rate. Hence, the present review is timely.
Asunto(s)
Quitosano/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanoestructuras , Precipitación Química , Emulsiones , Terapia Genética , Micelas , Neoplasias/terapiaRESUMEN
A simple and commercially viable method of preparation of chitosan microparticles (MPs) was adopted for the entrapment of clozapine, which can be easily scaled-up to controlled drug delivery dosage form. This method is devoid of tedious processes like emulsification in oil phase, spray-drying, etc. MPs have been prepared by changing the experimental variables such as extent of crosslinking and amount of clozapine loading in order to optimize the process variables on the final percent drug entrapment efficiency, size of MPs and release rates. Absence of chemical interactions between drug, polymer and crosslinking agent after the production of MPs was confirmed by Fourier transform infrared spectroscopy (FTIR). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) spectra were obtained for clozapine-loaded chitosan MPs to understand the crystalline nature of the drug after entrapment. The results indicated a molecular level dispersion of clozapine in the polymer matrix. Effect of crosslinking and drug loading on thermal decomposition of chitosan was studied by thermogravimetry (TGA) and these data indicated that pure chitosan is stable when compared to clozapine-loaded chitosan. MPs produced were irregular in shape, with average particle sizes in the range of 543-698 microm as measured by the laser light scattering technique. Clozapine entrapment up to 98.97% was obtained as determined by high performance liquid chromatography. In vitro release studies were performed in phosphate buffer pH 7.4 solution and the release of clozapine was achieved up to 12 h. Swelling studies were conducted in water and diffusion coefficients (D) and diffusional exponents (n) for water transport were determined using the empirical equation. In vivo absorption kinetics of clozapine and clozapine-loaded MPs were investigated in albino rats. These results indicated that absorption of clozapine from MPs was delayed since the area under the curve was higher when compared to neat clozapine.