RESUMEN
Bioinspired peptide waveguides of mesoscopic length scales have established a new paradigm in photonics with possible applications in precision bioimaging, sensing, and diagnostics. Here, we improve the efficiency of coupling various constituent colors of a white light source into single self-assembled microtube-shaped passive peptide waveguides by employing chromatic aberration. Thus, we use a chromatically aberrated microscope objective lens to couple light into peptide waveguides. Using both numerical simulation and experiments, we show that the waveguide response displays higher quality factor, wavelength selectivity, and axial coupling range compared to a chromatically corrected standard plan-fluoritic objective lens. We also demonstrate absorption and refractive index-based sensing by studying the changes in the optical responses of the peptide tubes in the presence of a wide concentration range of the absorptive Congo red, and the nonabsorptive Coumarin dyes. The former understandably display a much higher response than the latter due to the low finesse of the waveguides. We obtain a detection limit of around 10 nM for Congo red, and 10 mM for Coumarin. Our study opens up possibilities for deploying such peptide microtubes for various biosensing applications utilizing spectral and waveguide characteristics.
Asunto(s)
Rojo Congo , Óptica y Fotónica , Colorantes , Cumarinas , PéptidosRESUMEN
INTRODUCTION: Interest in hot-melt extrusion (HME) technology for novel applications is growing day by day, which is evident from several hundred publications within the last 5 years. HME is a cost-effective, solvent free, 'green' technology utilized for various formulations with low investment costs compared to conventional technologies. HME has also earned the attention of the pharmaceutical industry by the transformation of this technology for application in continuous manufacturing. AREAS COVERED: Part II of the review focuses on various novel opportunities or innovations of HME such as multiple component systems (co-crystals, co-amorphous systems and salts), twin-screw granulation, semi-solids, co-extrusion, abuse deterrent formulations, solid self-emulsifying drug delivery systems, chronotherapeutic drug delivery systems, and miscellaneous applications. EXPERT OPINION: HME is being investigated as an alternative technology for preparation of multicomponent systems such as co-crystals and co-amorphous techniques. Twin-screw granulation has gained increased interest in preparation of granules via twin-screw melt granulation or twin-screw dry granulation. This novel application of the HME process provides a promising alternate approach in the formulation of granules and solid dosage forms. However, this technology may need to be further investigated for scalability aspects of these novel applications for industrial production.
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Composición de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente , Preparaciones Farmacéuticas/administración & dosificación , Industria Farmacéutica , Calor , Tecnología Farmacéutica/métodosRESUMEN
INTRODUCTION: Currently, hot melt extrusion (HME) is a promising technology in the pharmaceutical industry, as evidenced by its application to manufacture various FDA-approved commercial products in the market. HME is extensively researched for enhancing the solubility and bioavailability of poor water-soluble drugs, taste masking, and modifying release in drug delivery systems. Additionally, its other novel opportunities or pharmaceutical applications, and capability for continuous manufacturing are being investigated. This efficient, industrially scalable, solvent-free, continuous process can be easily automated and coupled with other novel platforms for continuous manufacturing of pharmaceutical products. AREAS COVERED: This review focuses on updates on solubility enhancement of poorly water-soluble drugs and process analytical tools such as UV/visible spectrophotometry; near-infrared spectroscopy; Raman spectroscopy; and rheometry for continuous manufacturing, with a special emphasis on fused deposition modeling 3D printing. EXPERT OPINION: The strengths, weakness, opportunities, threats (SWOT) and availability of commercial products confirmed wide HME applicability in pharmaceutical research. Increased interest in continuous manufacturing processes makes HME a promising strategy for this application. However, there is a need for extensive research using process analytical tools to establish HME as a dependable continuous manufacturing process.
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Sistemas de Liberación de Medicamentos , Tecnología de Extrusión de Fusión en Caliente , Tecnología Farmacéutica/métodos , Disponibilidad Biológica , Composición de Medicamentos , Industria Farmacéutica/métodos , Preparaciones Farmacéuticas/química , Solubilidad , Espectrometría RamanRESUMEN
Dry granulation is an indispensable process used to improve the flow property of moisture-sensitive materials. Considering the limitations of currently available dry granulation techniques, it is necessary to develop a novel technique. In this study, a twin-screw dry granulation (TSDG) technology was successfully applied to produce a sustained-release dry granule formulation, which was subsequently compressed into sustained-release tablets. Based on a preliminary study, theophylline was selected as model drug, Klucel™ EF, Ethocel™, and magnesium stearate were selected as excipients. A Resolution V Irregular Fraction Design was applied to determine the effect of different processing parameters (screw speed, feeding rate, barrel temperature, and screw configuration) on product properties (flow properties, particle size distribution, and dissolution time). A reliable model was achieved by combining the data obtained, and processing parameters were automatically optimized to attain the setting goal. In general, TSDG was demonstrated to be an alternative method for the preparation of dry granules. The continuous processing nature, simplicity of operation, and ease of optimization made TSDG competitive compared with other conventional dry granulation techniques.
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Desecación/métodos , Composición de Medicamentos/métodos , Excipientes/química , Teofilina/química , Química Farmacéutica/instrumentación , Química Farmacéutica/métodos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Desecación/instrumentación , Composición de Medicamentos/instrumentación , Liberación de Fármacos , Estudios de Factibilidad , Tamaño de la Partícula , Solubilidad , Comprimidos , Temperatura , Resistencia a la Tracción , Teofilina/farmacocinéticaRESUMEN
Dry granulation is the preferred technique for solvent-sensitive products, especially drugs with stability problems such as hydrolysis. Twin-screw granulation is a continuous granulation technique, offering a potential alternative to conventional dry granulation techniques such as roller compaction. The major advantage of twin-screw granulation is the ability to adjust process parameters of dry granulation without compromising the compression properties. This study was aimed to perform exploratory studies of heat-assisted continuous twin-screw dry granulation process to formulate sustained release tablets for APIs with different melting points: theophylline, acetaminophen and lidocaine hydrochloride hydrate. Granulation feasibility was studied with different binders (e.g. Klucel™ EF, Kollidon® VA64), sustained release agents (e.g. Klucel™ MF, Eudragit® RSPO) and diluents at various drug loads. The processing conditions were below the melting point or glass transition temperature of the formulation ingredients. After successful granulation, DSC and XRD studies revealed the crystalline nature of the granules and FTIR studies showed no interaction of the API with the excipients. The granules were compressed into sustained release tablets without any compressibility issues. The tablets were stable after testing for 6â¯months at 25⯰C/60% RH. This novel continuous dry granulation technique may offer an excellent alternative to conventional dry granulation techniques.
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Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Excipientes/química , Tecnología Farmacéutica/métodos , Acetaminofén/administración & dosificación , Acetaminofén/química , Rastreo Diferencial de Calorimetría , Cristalización , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Calor , Lidocaína/administración & dosificación , Lidocaína/química , Comprimidos , Teofilina/administración & dosificación , Teofilina/química , Temperatura de Transición , Difracción de Rayos XRESUMEN
The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14-16â¯KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24â¯h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10â¯h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24â¯h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45â¯days at accelerated conditions (40⯰C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets.
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Preparaciones de Acción Retardada/química , Comprimidos/química , Tecnología Farmacéutica/métodos , Liberación de Fármacos , Excipientes/química , Lípidos/química , Teofilina/químicaRESUMEN
The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6-11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration.
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Antialérgicos/administración & dosificación , Clorfeniramina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Calor , Tecnología Farmacéutica/métodos , Administración Oral , Adolescente , Adulto , Animales , Antialérgicos/síntesis química , Antialérgicos/metabolismo , Clorfeniramina/síntesis química , Clorfeniramina/metabolismo , Portadores de Fármacos/síntesis química , Portadores de Fármacos/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Solubilidad , Percepción del Gusto/efectos de los fármacos , Percepción del Gusto/fisiología , Difracción de Rayos X/métodos , Adulto JovenRESUMEN
This study aimed to investigate the combined effect of magnesium oxide (MgO) as an alkalizer and polyethylene glycol (PEG) as a plasticizer and wetting agent in the presence of Kollidon® 12 PF and 17 PF polymer carriers on the release profile of mefenamic acid (MA), which was prepared via hot-melt extrusion technique. Various drug loads of MA and various ratios of the polymers, PEG 3350 and MgO were blended using a V-shell blender and extruded using a twin-screw extruder (16-mm Prism EuroLab, ThermoFisher Scientific, Carlsbad, CA) at different screw speeds and temperatures to prepare a solid dispersion system. Differential scanning calorimetry and X-ray diffraction data of the extruded material confirmed that the drug existed in the amorphous form, as evidenced by the absence of corresponding peaks. MgO and PEG altered the micro-environmental pH to be more alkaline (pH 9) and increased the hydrophilicity and dispersibility of the extrudates to enhance MA solubility and release, respectively. The in vitro release study demonstrated an immediate release for 2 h with more than 80% drug release within 45 min in matrices containing MgO and PEG in combination with polyvinylpyrrolidone when compared to the binary mixture, physical mixture and pure drug.
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Composición de Medicamentos , Óxido de Magnesio , Ácido Mefenámico , Polietilenglicoles , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Portadores de Fármacos , Calor , SolubilidadRESUMEN
Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations.
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Cafeína/administración & dosificación , Cafeína/química , Citratos/administración & dosificación , Citratos/química , Gusto/fisiología , Administración Oral , Animales , Química Farmacéutica/métodos , Nariz Electrónica , Excipientes/química , Humanos , Masculino , Pediatría , Control de Calidad , Ratas , Ratas Sprague-Dawley , Soluciones/química , Tecnología Farmacéutica/métodosRESUMEN
The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon® 12 PF (K12) polymeric matrix. Lutrol® F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit® L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods.
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Lansoprazol/química , Comprimidos Recubiertos/química , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica/métodos , Estabilidad de Medicamentos , Excipientes/química , Plastificantes/química , Polietilenglicoles/química , Polímeros/química , Povidona/química , Solubilidad/efectos de los fármacos , Tecnología FarmacéuticaRESUMEN
The main objective of this work was to explore the potential of coupling fused deposition modeling in three-dimensional (3D) printing with hot-melt extrusion (HME) technology to facilitate additive manufacturing, in order to fabricate tablets with enhanced extended release properties. Acetaminophen was used as the model drug and different grades and ratios of polymers were used to formulate tablets. Three-point bending and hardness tests were performed to determine the mechanical properties of the filaments and tablets. 3D-printed tablets, directly compressed mill-extruded tablets, and tablets prepared from a physical mixture were evaluated for drug release rates using a USP-II dissolution apparatus. The surface and cross-sectional morphology of the 3D-printed tablets were assessed by scanning electron microscopy. Differential scanning calorimetry and thermogravimetric analysis were used to characterize the crystal states and thermal properties of materials, respectively. The 3D-printed tablets had smooth surfaces and tight structures; therefore, they showed better extended drug release rates than the directly compressed tablets did. Further, this study clearly demonstrated the feasibility of coupling HME with 3D printing technology, which allows for the formulation of drug delivery systems using different grades and ratios of pharmaceutical polymers. In addition, formulations can be made based on the personal needs of patients.
Asunto(s)
Preparaciones de Acción Retardada/química , Comprimidos/química , Acetaminofén/química , Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Polímeros/química , Impresión Tridimensional , Tecnología Farmacéutica/métodosRESUMEN
OBJECTIVE To evaluate pharmacokinetics and bioavailability after administration of ceftiofur hydrochloride and ceftiofur sodium to water buffalo (Bubalus bubalis). ANIMALS 5 healthy adult water buffalo (3 males and 2 nonlactating females). PROCEDURES All animals received a dose (2.2 mg/kg) of 3 ceftiofur products (2 commercially available suspensions of ceftiofur hydrochloride [CEF1 and CEF2, IM] and ceftiofur sodium [CEF3, IV]). Blood samples were collected for up to 196 hours. Concentrations of ceftiofur in plasma were determined by use of high-performance liquid chromatography, and pharmacokinetic parameters were calculated on the basis of noncompartmental methods. RESULTS Most of the pharmacokinetic parameters, except for bioavailability and the area under the concentration-time curve extrapolated to infinity, were significantly different between the 2 products administered IM. Mean ± SD bioavailability of CEF1 and CEF2 was 89.57 ± 32.84% and 86.28 ± 11.49%, respectively, which indicated good absorption of both products. In addition, there was a longer drug residence time for CEF1 than for CEF2. Data analysis for CEF1 revealed a flip-flop phenomenon. CONCLUSIONS AND CLINICAL RELEVANCE In this study, there was good absorption of CEF1, and CEF1 had a longer drug residence time in vivo than did CEF2. On the basis of pharmacokinetic parameters and the in vitro antimicrobial susceptibility, a dosage regimen of 2.2 mg/kg administered at 48- and 36-hour intervals for CEF1 and CEF2, respectively, could be an appropriate choice for the treatment of buffalo with infectious diseases.
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Antibacterianos/farmacocinética , Búfalos/sangre , Cefalosporinas/farmacocinética , Animales , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/química , Disponibilidad Biológica , Búfalos/metabolismo , Cefalosporinas/administración & dosificación , Cefalosporinas/sangre , Cefalosporinas/química , Cromatografía Líquida de Alta Presión , Femenino , Masculino , Plasma , SuspensionesRESUMEN
The aim of this study was to formulate face-cut, melt-extruded pellets, and to optimize hot melt process parameters to obtain maximized sphericity and hardness by utilizing Soluplus(®) as a polymeric carrier and carbamazepine (CBZ) as a model drug. Thermal gravimetric analysis (TGA) was used to detect thermal stability of CBZ. The Box-Behnken design for response surface methodology was developed using three factors, processing temperature ( °C), feeding rate (%), and screw speed (rpm), which resulted in 17 experimental runs. The influence of these factors on pellet sphericity and mechanical characteristics was assessed and evaluated for each experimental run. Pellets with optimal sphericity and mechanical properties were chosen for further characterization. This included differential scanning calorimetry, drug release, hardness friability index (HFI), flowability, bulk density, tapped density, Carr's index, and fourier transform infrared radiation (FTIR) spectroscopy. TGA data showed no drug degradation upon heating to 190 °C. Hot melt extrusion processing conditions were found to have a significant effect on the pellet shape and hardness profile. Pellets with maximum sphericity and hardness exhibited no crystalline peak after extrusion. The rate of drug release was affected mainly by pellet size, where smaller pellets released the drug faster. All optimized formulations were found to be of superior hardness and not friable. The flow properties of optimized pellets were excellent with high bulk and tapped density.
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Carbamazepina/química , Liberación de Fármacos/efectos de los fármacos , Polietilenglicoles/química , Polímeros/química , Estabilidad de Medicamentos , Calor , Tamaño de la Partícula , Polivinilos/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability.
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Nanoestructuras/química , Pirrolidinas/administración & dosificación , Triptaminas/administración & dosificación , Administración Intranasal , Animales , Geles/química , Microscopía Electrónica de Transmisión , Mucosa Nasal , Pirrolidinas/química , Ovinos , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Triptaminas/químicaRESUMEN
INTRODUCTION: Hot-melt extrusion (HME) technology is applied successfully in the plastic, rubber and food industry. HME has also emerged as an important technology for drug delivery applications in pharmaceutical research and manufacturing because of its process automation and low-cost scale-up properties, which reduce labor costs and capital investment. There are a number of commercial FDA-approved HME-derived products, signifying the commercial feasibility of this novel technique in drug delivery applications. HME is a highly efficient, solvent-free continuous processing technique for the development of solid dispersions; thus, research efforts to develop sustained, modified and targeted drug delivery systems to improve the solubility and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) are of interest. AREAS COVERED: This review focuses on both the innovations and applications of HME in the production of pharmaceutical formulations, and on the significant findings of the general principles regarding formulation and process development via HME as described in published articles. EXPERT OPINION: Challenges faced by pharmaceutical companies to produce efficient drug formulations may be partly overcome by HME's advantages - high drug-loading capacity, good content uniformity, cost-effectiveness, and ease of processing scale-up. Nevertheless, HME's high processing temperatures may be an obstacle if adequate knowledge about the product's formulation is lacking.
Asunto(s)
Sistemas de Liberación de Medicamentos , Preparaciones Farmacéuticas/administración & dosificación , Tecnología Farmacéutica/métodos , Disponibilidad Biológica , Química Farmacéutica/métodos , Calor , SolubilidadRESUMEN
Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.
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Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Nanopartículas/química , Alquinos , Benzoxazinas/química , Rastreo Diferencial de Calorimetría/métodos , Ciclopropanos , Portadores de Fármacos/química , Estabilidad de Medicamentos , Liofilización/métodos , Calor , Tamaño de la Partícula , Polietilenglicoles/química , Polivinilos/química , Povidona/química , Solubilidad , Suspensiones/química , Agua/químicaRESUMEN
Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.
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Química Farmacéutica/métodos , Preparaciones Farmacéuticas/química , Tecnología Farmacéutica/métodos , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos/métodos , Industria Farmacéutica/métodos , Diseño de Equipo/métodos , Calor , SolubilidadRESUMEN
BACKGROUND: Bitter tasting drugs represent a large portion of active pharmaceutical ingredients. Mini-tablets are specifically designed for patients with difficulty in swallowing particular in young children up to 10 years of age, geriatric patients and patients with esophagitis. OBJECTIVE: The present study was aimed to prepare, taste-masked mini-tablets, which are easily swallowed dosage forms, primarily to be used by pediatric and geriatric patients. METHODS: Ketoprofen (10%-50% w/w) and Eudragit® EPO were blended and extruded with a 5-mm strand die and cut into consistent mini-tablets by using an adapted downstream pelletizer. RESULTS: Differential scanning calorimetry and polarized light microscopy-hot stage microscopy studies confirmed that the binary mixtures were miscible under the employed extrusion temperatures. In-vitro release studies showed that drug release was less than 0.5% within the first 2 min in simulated salivary fluid (pH 6.8) and more than 90% in the first 20 min in gastric media (pH 1.0). The results of the electronic tongue analysis were well correlated with the drug release profile of the mini-tablets in the artificial saliva. Scanning electron microscopy revealed no cracks on the surface of the minitablets, confirming that the mini-tablets were compact solids. Chemical imaging confirmed the uniform distribution of ketoprofen inside the polymer matrices. CONCLUSION: Eudragit® EPO containing ketoprofen at various drug loads were successfully melt extruded into tastedmasked mini-tablets. The reduced drug release at salivary pH correlated well with Astree e-Tongue studies for taste masking efficiency.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Excipientes/química , Cetoprofeno/química , Ácidos Polimetacrílicos/química , Tecnología Farmacéutica/métodos , Administración Oral , Antiinflamatorios no Esteroideos/administración & dosificación , Técnicas Biosensibles/instrumentación , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Preparaciones de Acción Retardada , Composición de Medicamentos , Nariz Electrónica , Jugo Gástrico/química , Humanos , Concentración de Iones de Hidrógeno , Cetoprofeno/administración & dosificación , Cinética , Microscopía Electrónica de Rastreo , Microscopía de Polarización , Difracción de Polvo , Saliva/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de Superficie , Comprimidos , Gusto , Tecnología Farmacéutica/instrumentación , TemperaturaRESUMEN
OBJECTIVE: The aim of this study was to evaluate the effect of polymer carrier, hot melt extrusion and downstream processing parameters on the water uptake properties of amorphous solid dispersions. METHODS: Three polymers and a model drug were used to prepare amorphous solid dispersions utilizing the hot melt extrusion technology. The sorption-desorption isotherms of solid dispersions and their physical mixtures were measured by the dynamic vapour sorption system, and the effects of polymer hydrophobicity, hygroscopicity, molecular weight and the hot melt extrusion process were investigated. Fourier transform infrared (FTIR) imaging was performed to understand the phase separation driven by the moisture. KEY FINDINGS: Solid dispersions with polymeric carriers with lower hydrophilicity, hygroscopicity and higher molecular weight could sorb less moisture under the high relative humidity (RH) conditions. The water uptake ability of polymer-drug solid dispersion systems were decreased compared with the physical mixture after hot melt extrusion, which might be due to the decreased surface area and porosity. The FTIR imaging indicated that the homogeneity of the drug molecularly dispersed within the polymer matrix was changed after exposure to high RH. CONCLUSION: Understanding the effect of formulation and processing on the moisture sorption properties of solid dispersions is essential for the development of drug products with desired physical and chemical stability.
Asunto(s)
Fenofibrato/química , Calor , Polímeros/química , Tecnología Farmacéutica/métodos , Agua/química , Absorción Fisicoquímica , Celulosa/análogos & derivados , Celulosa/química , Composición de Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Peso Molecular , Polietilenglicoles/química , Espectroscopía Infrarroja por Transformada de Fourier , HumectabilidadRESUMEN
Floating dosage forms are an important formulation strategy for drugs with a narrow absorption window and low intestinal solubility, and for localized gastric treatment. Novel floating pellets were prepared using the hot-melt extrusion (HME) technology. Uniformly foamed strands were created by liquid injection pumping and screw configuration modification. The ammonio methacrylate copolymer (Eudragit® RSPO) foaming structure was formed by a liquid-vapor phase transition inside the strand upon die exiting resulting from the sudden decrease in external pressure, vaporizing the liquid ethanol and vacating the extruded material. This generated uniform vacuous regions in the extrudate. The pellets' internal structure was investigated using scanning electron microscopy (SEM). The formulation constituents' and processing parameters' effects on the drug release profiles, floating force, and the pellets' micromeritic properties were evaluated by design of experiments: all formulations showed zero lag time and excellent floating strength, indicating immediate-floating pellet formation. The pellets' drug release profiles were controlled by multiple independent variables at different time points (⩽ 24 h). Drug loading significantly affected drug release within the first hour, the hydroxypropyl methylcellulose (HPMC) content thereafter. Understanding the variables' effects on the formulations allows for the tailoring of this delivery system to obtain various drug release profiles.