RESUMEN
The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.
Asunto(s)
Disponibilidad Biológica , Indoles , Solubilidad , Indoles/farmacocinética , Indoles/química , Indoles/administración & dosificación , Administración Oral , Animales , Química Farmacéutica/métodos , Rastreo Diferencial de Calorimetría/métodos , Difracción de Rayos X/métodos , Masculino , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Composición de Medicamentos/métodos , Conejos , Polímeros/química , Tecnología de Extrusión de Fusión en Caliente/métodos , Liberación de FármacosRESUMEN
This study aimed to develop a 3D-printed fixed-dose combination tablet featuring differential release of two drugs using double-melt extrusion (DME). The hot-melt extrusion (HME) process was divided into two steps to manufacture a single filament containing the two drugs. In Step I, a sustained-release matrix of acetaminophen (AAP) was obtained through HME at 190 °C using Eudragit® S100, a pH-dependent polymer with a high glass transition temperature. In Step II, a filament containing both sustained-release AAP from Step I and solubilized ibuprofen (IBF) was fabricated via HME at 110 °C using a mixture of hydroxy propyl cellulose (HPC-LF) and Eudragit® EPO, whose glass transition temperatures make them suitable for use in a 3D printer. A filament manufactured using DME was used to produce a cylindrical 3D-printed fixed-dose combination tablet with a diameter and height of 9 mm. To evaluate the release characteristics of the manufactured filament and 3D-printed tablet, dissolution tests were conducted for 10 h under simulated gastrointestinal tract conditions using the pH jump method with the United States Pharmacopeia apparatus II paddle method at 37 ± 0.5 °C and 50 rpm. Dissolution tests confirmed that both the sustained-release and solubilized forms of AAP and IBF within the filament and 3D-printed tablet exhibited distinct drug-release behaviors. The physicochemical properties of the filament and 3D-printed tablet were confirmed by thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy. HME transforms crystalline drugs into amorphous forms, demonstrating their physicochemical stability. Scanning electron microscopy and confocal laser scanning microscopy indicated the presence of sustained AAP granules within the filament, confirming that the drugs were independently separated within the filament and 3D-printed tablets. Finally, sustained-release AAP and solubilized IBF were independently incorporated into the filaments using DME technology. Therefore, a dual-release 3D-printed fixed-dose combination was prepared using the proposed filament.
Asunto(s)
Acetaminofén , Celulosa , Preparaciones de Acción Retardada , Liberación de Fármacos , Ibuprofeno , Impresión Tridimensional , Solubilidad , Comprimidos , Ibuprofeno/química , Ibuprofeno/administración & dosificación , Preparaciones de Acción Retardada/química , Acetaminofén/química , Acetaminofén/administración & dosificación , Celulosa/química , Celulosa/análogos & derivados , Combinación de Medicamentos , Ácidos Polimetacrílicos/química , Tecnología de Extrusión de Fusión en Caliente/métodos , Composición de Medicamentos/métodos , Concentración de Iones de HidrógenoRESUMEN
We applied computing-as-a-service to the unattended system-agnostic miscibility prediction of the pharmaceutical surfactants, Vitamin E TPGS and Tween 80, with Copovidone VA64 polymer at temperature relevant for the pharmaceutical hot melt extrusion process. The computations were performed in lieu of running exhaustive hot melt extrusion experiments to identify surfactant-polymer miscibility limits. The computing scheme involved a massively parallelized architecture for molecular dynamics and free energy perturbation from which binodal, spinodal, and mechanical mixture critical points were detected on molar Gibbs free energy profiles at 180 °C. We established tight agreement between the computed stability (miscibility) limits of 9.0 and 10.0 wt% vs. the experimental 7 and 9 wt% for the Vitamin E TPGS and Tween 80 systems, respectively, and identified different destabilizing mechanisms applicable to each system. This paradigm supports that computational stability prediction may serve as a physically meaningful, resource-efficient, and operationally sensible digital twin to experimental screening tests of pharmaceutical systems. This approach is also relevant to amorphous solid dispersion drug delivery systems, as it can identify critical stability points of active pharmaceutical ingredient/excipient mixtures.
Asunto(s)
Excipientes , Polisorbatos , Excipientes/química , Polisorbatos/química , Vitamina E/química , Tensoactivos/química , Pirrolidinas/química , Simulación de Dinámica Molecular , Termodinámica , Tecnología de Extrusión de Fusión en Caliente/métodos , Compuestos de ViniloRESUMEN
Purpose: Curcumin nanocrystals (Cur-NCs) were prepared by hot melt extrusion (HME) technology to improve the dissolution and bioavailability of curcumin (Cur). Methods: Cur-NCs with different drug-carrier ratios were prepared by one-step extrusion process with Eudragit® EPO (EEP) as the carrier. The dispersed size and solid state of Cur in extruded samples were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The thermal stability of Cur was analyzed by thermogravimetric analysis (TGA) and high performance liquid chromatography (HPLC). Dissolution and pharmacokinetics were studied to evaluate the improvement of dissolution and absorption of Cur by nano-preparation. Results: Cur-NCs with particle sizes in the range of 50~150 nm were successfully prepared by using drug-carrier ratios of 1:1, 2:1 and 4:1, and the crystal form of Cur was Form 1 both before and after HME. The extrudate powders showed very efficient dissolution with the cumulative dissolution percentage of 80% in less than 2 min, and the intrinsic dissolution rates of them were 13.68 ± 1.20 mg/min/cm2, 11.78 ± 0.57 mg/min/cm2 and 4.35 ± 0.20 mg/min/cm2, respectively, whereas that of pure Cur was only 0.04 ± 0.00 mg/min/cm2. The TGA data demonstrated that the degradation temperature of Cur was about 250 °C, while the HPLC results showed Cur was degraded when extruded at the temperature over 150 °C. Pharmacokinetic experiment showed a significant improvement in the absorption of Cur. The Cmax of Cur in the Cur-NC group was 1.68 times that of pure Cur group, and the Cmax and area under the curve (AUC0-∞) of metabolites were 2.79 and 4.07 times compared with pure Cur group. Conclusion: Cur-NCs can be prepared by HME technology in one step, which significantly improves the dissolution and bioavailability of Cur. Such a novel method for preparing insoluble drug nanocrystals has broad application prospects.
Asunto(s)
Disponibilidad Biológica , Curcumina , Tecnología de Extrusión de Fusión en Caliente , Nanopartículas , Tamaño de la Partícula , Solubilidad , Curcumina/farmacocinética , Curcumina/química , Curcumina/administración & dosificación , Nanopartículas/química , Animales , Tecnología de Extrusión de Fusión en Caliente/métodos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Masculino , Rastreo Diferencial de Calorimetría , Estabilidad de Medicamentos , Liberación de Fármacos , Difracción de Rayos X , Ácidos PolimetacrílicosRESUMEN
Cannabidiol (CBD) is a highly lipophilic compound with poor oral bioavailability, due to poor aqueous solubility and extensive pre-systemic metabolism. The aim of this study was to explore the potential of employing Hot Melt Extrusion (HME) technology for the continuous production of Self Emulsifying Drug Delivery Systems (SEDDS) to improve the solubility and in vitro dissolution performance of CBD. Accordingly, different placebos were processed through HME in order to obtain a lead CBD loaded solid SEDDS. Two SEDDS were prepared with sesame oil, Poloxamer 188, Gelucire®59/14, PEO N80 and Soluplus®. Moreover, Vitamin E was added as an antioxidant. The SEDDS formulations demonstrated emulsification times of 9.19 and 9.30 min for F1 and F2 respectively. The formed emulsions showed smaller droplet size ranging from 150-400 nm that could improve lymphatic uptake of CBD and reduce first pass metabolism. Both formulations showed significantly faster in vitro dissolution rate (90% for F1 and 83% for F2) compared to 14% for the pure CBD within the first hour, giving an enhanced release profile. The formulations were tested for stability over a 60-day time period at 4°C, 25°C, and 40°C. Formulation F1 was stable over the 60-day time-period at 4°C. Therefore, the continuous HME technology could replace conventional methods for processing SEDDS and improve the oral delivery of CBD for better therapeutic outcomes.
Asunto(s)
Cannabidiol , Química Farmacéutica , Sistemas de Liberación de Medicamentos , Emulsiones , Solubilidad , Cannabidiol/química , Cannabidiol/administración & dosificación , Emulsiones/química , Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Química Farmacéutica/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Liberación de Fármacos , Tamaño de la Partícula , Disponibilidad Biológica , Composición de Medicamentos/métodos , Polietilenglicoles/química , Estabilidad de Medicamentos , Aceite de Sésamo/química , PolivinilosRESUMEN
The study endeavors the fabrication of extended-release adipic acid (APA) buccal films employing a quality by design (QbD) approach. The films intended for the treatment of xerostomia were developed utilizing hot-melt extrusion technology. The patient-centered quality target product profile was created, and the critical quality attributes were identified accordingly. Three early-stage formulation development trials, complemented by risk assessment aligned the formulation and process parameters with the product quality standards. Employing a D-optimal mixture design, the formulations were systematically optimized by evaluating three formulation variables: amount of the release-controlling polymer Eudragit® (E RSPO), bioadhesive agent Carbopol® (CBP 971P), and pore forming agent polyethylene glycol (PEG 1500) as independent variables, and % APA release in 1, 4 and 8 h as responses. Using design of experiment software (Design-Expert®), a total of 16 experimental runs were computed and extruded using a Thermofisher ScientificTM twin screw extruder. All films exhibited acceptable content uniformity and extended-release profiles with the potential for releasing APA for at least 8 h. Films containing 30% E RSPO, 10% CBP 971P, and 20% PEG 1500 released 88.6% APA in 8 h. Increasing the CBP concentration enhanced adhesiveness and swelling capacities while decreasing E RSPO concentration yielded films with higher mechanical strength. The release kinetics fitted well into Higuchi and Krosmeyer-Peppas models indicating a Fickian diffusion release mechanism.
Asunto(s)
Preparaciones de Acción Retardada , Liberación de Fármacos , Xerostomía , Xerostomía/tratamiento farmacológico , Tecnología de Extrusión de Fusión en Caliente/métodos , Polietilenglicoles/química , Humanos , Administración Bucal , Química Farmacéutica/métodos , Adipatos/química , Acrilatos/química , Ácidos Polimetacrílicos/química , Polímeros/química , Composición de Medicamentos/métodosRESUMEN
PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.
Asunto(s)
Preparaciones de Acción Retardada , Composición de Medicamentos , Liberación de Fármacos , Ibuprofeno , Polímeros , Preparaciones de Acción Retardada/química , Ibuprofeno/química , Ibuprofeno/administración & dosificación , Polímeros/química , Composición de Medicamentos/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Solubilidad , Tecnología de Extrusión de Fusión en Caliente/métodos , Compuestos de Vinilo/química , Pirrolidinas/química , Química Farmacéutica/métodos , Povidona/químicaRESUMEN
This study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics.
Asunto(s)
Liberación de Fármacos , Felodipino , Derivados de la Hipromelosa , Impresión Tridimensional , Solubilidad , Comprimidos , Felodipino/química , Felodipino/administración & dosificación , Derivados de la Hipromelosa/química , Composición de Medicamentos/métodos , Simulación de Dinámica Molecular , Portadores de Fármacos/química , Preparaciones de Acción Retardada/química , Química Farmacéutica/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Tecnología Farmacéutica/métodosRESUMEN
This study aimed to develop a tablet that shows a drug release profile similar to the tofacitinib sustained-release tablet (Xeljanz XR®; OROS™) using hot melt extrusion technology. Tofacitinib citrate was selected as the drug. HPMCAS, HPMCP, and Kollidon VA64 were used as thermoplastic polymers to prepare a hot-melt extrudate. The extrudate was obtained from a twin screw extruder and pelletizer. The granules were compressed using a single punch press machine and then coated. TGA, DSC, XRD, FT-IR, and SEM were performed on the hot melt extrudate to understand its physicochemical properties. Dissolution tests were performed using the paddle method (USP Apparatus II). The results showed that the crystallinity state of tofacitinib changed to amorphous after the hot melt extrusion process; however, no chemical change was observed. The drug release profile was similar to that of Xeljanz XR®, which has an initial lag time owing to its OROS™ formulation; a coating process was performed to obtain a similar drug release profile. The lag time was controlled by adjusting the thickness of the coating layer. Moreover, the extrudate size and compression force during tableting did not significantly affect drug release. In conclusion, the new tofacitinib sustained-release tablet prepared using hot melt extrusion showed a drug release behavior similar to that of Xeljanz XR®.
Asunto(s)
Tecnología de Extrusión de Fusión en Caliente , Calor , Piperidinas , Pirimidinas , Tecnología de Extrusión de Fusión en Caliente/métodos , Preparaciones de Acción Retardada/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Comprimidos/química , Liberación de Fármacos , Composición de Medicamentos/métodosRESUMEN
The primary focus of the research is to study the role of cocrystal and amorphous solid dispersion approaches for enhancing solubility and preserving the stability of a poorly soluble drug, i.e., ibuprofen (IBP). First, the solvent-assisted grinding approach determined the optimum molar ratio of the drug and the coformer (nicotinamide (NIC)). Later, the polymeric filaments of cocrystals and amorphous solid dispersions were developed using the hot melt extrusion (HME) process, and the printlets were fabricated using the fused deposition modeling (FDM) additive manufacturing process. In addition, the obtained filaments were also milled and compressed into tablets as reference samples. The formation of cocrystals and amorphous solid dispersions was evaluated and confirmed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffraction (PXRD) analysis. The drug release profiles of 3D printlets with 50% infill were found to be faster and are in line with the release profiles of compressed tablets. In addition, the 3D-printed cocrystal formulation was stable for 6 months at accelerated conditions. However, the 3D printlets of amorphous solid dispersions and compressed tablets failed to retain stability attributed to the recrystallization of the drug and loss in tablet mechanical properties. This shows the suitability of a cocrystal platform as a novel approach for developing stable formulations of poorly soluble drug substances over amorphous solid dispersions.
Asunto(s)
Tecnología de Extrusión de Fusión en Caliente , Ibuprofeno , Solubilidad , Tecnología de Extrusión de Fusión en Caliente/métodos , Liberación de Fármacos , Polímeros/química , Composición de Medicamentos/métodos , ComprimidosRESUMEN
Hot-melt extrusion (HME) is a technology increasingly common for the commercial production of pharmaceutical amorphous solid dispersions (ASDs), especially for poorly water-soluble active pharmaceutical ingredients (APIs). However, recrystallization of the APIs during dissolution must be prevented to maintain the supersaturation state enabled by ASD. Unfortunately, the amorphous formulation may be contaminated by seed crystals during the HME manufacturing process, which could lead to undesirable crystal growth during the dissolution process. In this study, the dissolution behavior of ritonavir ASD tablets prepared using both Form I and Form II polymorphs was examined, and the effects of different seed crystals on crystal growth rates were investigated. The aim was to understand how the presence of seed crystals can impact the dissolution of ritonavir, and to determine the optimal polymorph and seeding conditions for the production of ASDs. The results showed that both Form I and Form II ritonavir tablets had similar dissolution profiles, which were also similar to the reference listed drug (RLD). However, it was observed that the presence of seed crystals, particularly the metastable Form I seed, led to more precipitation compared to the stable Form II seed in all formulations. The Form I crystals that precipitated from the supersaturated solution were easily dispersed in the solution and could serve as seeds to facilitate crystal growth. On the other hand, Form II crystals tended to grow more slowly and presented as aggregates. The addition of both Form I and Form II seeds could affect their precipitation behaviors, and the amount and form of the seeds had significant effects on the precipitation process of the RLD tablets, as are the tablets prepared with different polymorphs. In conclusion, the study highlights the importance of minimizing the contamination risk of seed crystals during the manufacturing process and selecting the appropriate polymorph for the production of ASDs.
Asunto(s)
Tecnología de Extrusión de Fusión en Caliente , Ritonavir , Ritonavir/química , Composición de Medicamentos/métodos , Solubilidad , Tecnología de Extrusión de Fusión en Caliente/métodos , Comprimidos/químicaRESUMEN
Amorphous solid dispersions (ASD) are one of the most adopted technologies for improving the solubility of novel molecules. Formulation of ASDs using solvent free methods such as hot melt extrusion (HME) has been in the spotlight off-lately. However, early-stage formulation development is tricky and a difficult bridge to pass due to limited drug availability. Material-sparing techniques (theoretical & practical) have been used for selecting suitable polymeric carriers for formulating ASDs. However, these techniques have limitations in predicting the effect of process parameters. The objective of this study is to use both theoretical and practical material-sparing techniques to optimize a polymer for the developing Triclabendazole (TBZ) ASDs. Initial screening by theoretical approaches suggested that TBZ is highly miscible with Kollidon®VA64 (VA64) and poorly miscible with Parteck®MXP (PVA). However, results from ASDs prepared using SCFe were opposite to these predictions. ASDs prepared using either technique and both VA64 and PVA showed >200x increase in solubility. Each formulation released >85% of drug in less than 15 mins. Although the thermodynamic phase diagram suggested that VA64 was the ideal polymer for TBZ-ASDs, it has certain limitations in factoring the different elements during melt-processing and hence, practical approaches like SCFe could help in predicting the drug-polymer miscibility for HME processing.
Asunto(s)
Química Farmacéutica , Tecnología de Extrusión de Fusión en Caliente , Composición de Medicamentos/métodos , Química Farmacéutica/métodos , Triclabendazol , Tecnología de Extrusión de Fusión en Caliente/métodos , Polímeros , Solubilidad , CalorRESUMEN
High-temperature exposure during hot melt extrusion processing of amorphous solid dispersions may result in thermal degradation of the drug. Polymer type may influence the extent of degradation, although the underlying mechanisms are poorly understood. In this study, the model compound, ritonavir (Tm = 126 °C), undergoes thermal degradation upon high-temperature exposure. The extent of degradation of ritonavir in amorphous solid dispersions (ASDs) formulated with poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone) vinyl acetate copolymer (PVP/VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose (HPMC) following isothermal heating and hot melt extrusion was evaluated, and mechanisms related to molecular mobility and intermolecular interactions were assessed. Liquid chromatography-mass spectrometry (LC-MS/MS) studies were used to determine the degradation products and pathways and ultimately the drug-polymer compatibility. The dominant degradation product of ritonavir was the result of a dehydration reaction, which then catalyzed a series of hydrolysis reactions to generate additional degradation products, some newly reported. This reaction series led to accelerated degradation rates with protic polymers, HPMCAS and HPMC, while ASDs with aprotic polymers, PVP and PVP/VA, had reduced degradation rates. This work has implications for understanding mechanisms of thermal degradation and drug-polymer compatibility with respect to the thermal stability of amorphous solid dispersions.
Asunto(s)
Composición de Medicamentos/métodos , Polímeros , Ritonavir/química , Cromatografía Líquida de Alta Presión , Liberación de Fármacos , Tecnología de Extrusión de Fusión en Caliente/métodos , Ritonavir/administración & dosificación , Espectrofotometría Infrarroja , TermogravimetríaRESUMEN
Oral drug therapy requiring large quantities of active pharmaceutical ingredients (APIs) can cause a substantial pill burden, which can increase nonadherence and worsen healthcare outcomes. Maximizing the drug loading of APIs in oral dosage forms is essential to reduce pill burden. This can be challenging for poorly water-soluble APIs without compromising performance. We show a promising strategy for maximizing the drug loading of pH-dependent APIs in amorphous solid dispersions (ASDs) produced by hot-melt extrusion (HME) without compromising their dissolution performance. We examine potential increases in the drug loading (w/w) of telmisartan in ASDs by incorporating bases to modify pH during HME. Telmisartan is a weakly acidic, poorly water-soluble API with pH-dependent solubility. It is practically insoluble at physiological pH, but its solubility increases exponentially at pH values above 10. Telmisartan was extruded with the polymer Soluplus and various bases. With no base, the maximum drug loading achieved by extrusion was only 5% before crystalline telmisartan was detected. Including a strong, water-soluble base (NaOH or KOH) increased the maximum amorphous drug loading to 50%. These results indicate that telmisartan has pH-dependent solubility in a molten polymer, similar to that in an aqueous solution. We also examine the stability of Soluplus when extruded with a strong base, using solid-state nuclear magnetic resonance (ssNMR) to determine that NaOH (but not KOH) causes degradation by hydrolysis. Supersaturation was maintained for at least 20 h during dissolution testing of a 50% telmisartan ASD in biorelevant media.
Asunto(s)
Composición de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Telmisartán/química , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Telmisartán/administración & dosificaciónRESUMEN
Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.
Asunto(s)
Química Farmacéutica/métodos , Portadores de Fármacos/síntesis química , Desarrollo de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Disponibilidad Biológica , Composición de Medicamentos/métodos , Composición de Medicamentos/tendencias , Tecnología de Extrusión de Fusión en Caliente/tendencias , Calor , Solubilidad , Tecnología Farmacéutica/métodos , Tecnología Farmacéutica/tendencias , TermodinámicaRESUMEN
In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug-polymer system. Melt viscosity as a function of temperature was determined for the drug-polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.
Asunto(s)
Tecnología de Extrusión de Fusión en Caliente/métodos , Excipientes Farmacéuticos/síntesis química , Povidona/síntesis química , Pirrolidinas/síntesis química , Fumarato de Quetiapina/síntesis química , Compuestos de Vinilo/síntesis química , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Calor , Oxidación-Reducción , Excipientes Farmacéuticos/farmacocinética , Povidona/farmacocinética , Pirrolidinas/farmacocinética , Fumarato de Quetiapina/farmacocinética , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Compuestos de Vinilo/farmacocinéticaRESUMEN
Interest in 3D printing for pharmaceutical applications has increased in recent years. Compared to other 3D printing techniques, hot melt extrusion (HME)-based fused deposition modeling (FDM) 3D printing has been the most extensively investigated for patient-focused dosage. HME technology can be coupled with FDM 3D printing as a continuous manufacturing process. However, the crucial pharmaceutical polymers, formulation and process parameters must be investigated to establish HME-coupled FDM 3D printing. These advancements will lead the way towards developing continuous drug delivery systems for personalized therapy. This brief overview classifies pharmaceutical additive manufacturing, Hot Melt Extrusion, and Fused Deposition Modeling 3D printing techniques with a focus on coupling HME and FDM 3D printing processes. It also provides insights on the critical material properties, process and equipment parameters and limitations of successful HME-coupled FDM systems.
Asunto(s)
Sistemas de Liberación de Medicamentos , Tecnología de Extrusión de Fusión en Caliente/métodos , Tecnología Farmacéutica/métodos , Diseño de Equipo , Excipientes/química , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Polímeros/química , Impresión TridimensionalRESUMEN
Main purpose was to evaluate the applicability of a 3D-printer equipped with a hot-melt pneumatic dispenser as a single-step process to prepare tablet dosage forms. Dutasteride, a poorly water-soluble drug, was selected as a model drug. Soluplus®, Kollidon® VA 64, Eudragit® E PO, and hydroxypropyl cellulose (HPC) were premixed as bulking agents prior to printing. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA) were utilized to evaluate the physicochemical properties of the 3D-printed tablets. Moreover, different geometries were designed to correlate the surface area/volume (SA/V) of the tablets with respect to their release profiles. As a result, printed dutasteride was confirmed to be in an amorphous state and not recrystallized even after the accelerated storage stability. Out of the four bulking agents, Kollidon® VA 64, enhanced the dissolution of the printed dutasteride, reaching above 80% within 15 min. These results suggest that the hot-melt pneumatic dispenser was efficient in converting the solid state into an amorphous state, which significantly enhanced the dissolution. On the other hand, the tube-shaped 3D-printed tablet exhibited the fastest drug dissolution profile, which had the highest SA/V ratio in comparison to the cube, hemisphere, and pyramid shapes. These results confirm the dependency of the drug dissolution rate not only on its crystallinity but also on the surface area of the 3D-printed tablet. Therefore, a 3D-printer equipped with a hot-melt pneumatic dispenser possesses useful applicability in enhancing drug dissolution, especially for poorly water-soluble drugs, in a single-step process.
Asunto(s)
Composición de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Comprimidos/química , Rastreo Diferencial de Calorimetría , Liberación de Fármacos , Dutasterida/química , Excipientes/química , Polietilenglicoles/química , Polímeros/química , Impresión Tridimensional , Solubilidad , Termogravimetría , Difracción de Rayos XRESUMEN
The use of hot-melt extrusion (HME) technique in the preparation of semi-solid products offers several advantages over conventional processes. However, the optimization of the technique for preparation of semi-solid pharmaceuticals is challenging due to involvement of ingredients with different physical properties. Hence, a simple tool to optimize the mixing of ingredients that results in a target ratio and drug content uniformity is utmost important. In this study, a handheld colorimeter has been explored to optimize the process variables of twin screw processor for preparation of hydrophilic PEG-based ointment. The process parameters which were optimized with use of handheld colorimeter have been used for preparation of polyethylene glycol-based metronidazole ointment. The metronidazole ointment prepared by twin screw processor was compared with commercially available metronidazole gel for in vitro release testing and ex vivo permeation. The flux, ex vivo bioavailability, and Tmax of polyethylene glycol-based metronidazole ointment was found to be similar to that of marketed metronidazole gel.
Asunto(s)
Antibacterianos/química , Composición de Medicamentos/métodos , Tecnología de Extrusión de Fusión en Caliente/métodos , Metronidazol/química , Pomadas , Disponibilidad Biológica , Congelación , Tecnología Farmacéutica/métodosRESUMEN
Biopharmaceuticals are usually administered intravenously with frequent dosing regimens which may decrease patient compliance. Controlled-release formulations allow to reduce the frequency of injections while providing a constant dosing of the biopharmaceutical over extended periods. These formulations are typically produced by emulsions, requiring high amounts of organic solvents and have limited productivity. Hot-melt extrusion (HME) is an alternative technology to produce controlled drug delivery systems. It is a continuous solvent-free process, leading to a small ecological footprint and higher productivity. However, it may induce thermolabile compounds' degradation. In this work, the impact of the formulation and extrusion temperature on lysozyme's bioactivity and release profile of poly(lactic-co-glycolic acid) (PLGA)-based extended release formulations were evaluated using a design-of-experiments (DoE) approach. The lysozyme-loaded PLGA microparticles were produced by HME followed by milling. It was observed that the in vitro release (IVR) profile was mainly affected by the drug load; higher drug load led to higher burst and total lysozyme release after 14 days. HME temperature seemed to decrease lysozyme's activity although this correlation was not statistically significant (p value = 0.0490). Adding polyethylene glycol 400 (PEG 400) as a plasticizer to the formulation had no significant impact on the lysozyme release profile. The burst release was effectively mitigated with the inclusion of a washing step. Washing the microparticles with water reduced the burst release by 80% whereas washing them with a poly(vinyl alcohol) (PVA) aqueous solution eliminated it. In conclusion, HME is demonstrated to be suitable in producing controlled-release microparticles of small biopharmaceuticals. Graphical abstract.